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Wang J, He Y, Kim AR, Lee KH, Choi SW. Effects of different types of exercise on inflammatory markers in cancer patients: A systematic review and Bayesian network meta-analysis. J Sports Sci 2025:1-18. [PMID: 40197224 DOI: 10.1080/02640414.2025.2486886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 03/23/2025] [Indexed: 04/10/2025]
Abstract
This systematic review and network meta-analysis (NMA) was to investigate the effects of different exercise modalities on inflammatory markers in cancer patients. Using the standardized mean difference (SMD) as the effect size, a Bayesian random-effects network meta-analysis and regression analysis were conducted. Searches were performed across five databases for randomized controlled trials (RCTs) involving cancer patients, with exercise as the intervention, reported outcomes related to inflammatory markers, and interventions lasting more than four weeks, up to June 2024. A total of 57 RCTs (3106 patients) were included. The Cochrane risk of Bias Tool was utilized to assess the RCTs, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool was employed to evaluate the quality of evidence. NMA results indicate that regular exercise is effective in reducing inflammation in cancer patients, with combined high-intensity aerobic and resistance exercises proving to be the most beneficial. The type, intensity, and total volume of exercise are critical factors in achieving positive outcomes. It is recommended to design exercise programs for cancer patients that combine aerobic and resistance training, with a gradual increase in intensity to ensure safety.
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Affiliation(s)
- Jingyu Wang
- Department of Sport Leisure, Sungshin Women's University, Seoul, Republic of Korea
| | - Yuxuan He
- Department of Sport Leisure, Sungshin Women's University, Seoul, Republic of Korea
- College of Education, GongQing Institute of Science and Technology, Jiujiang, China
| | - A-Ram Kim
- Department of Sport Leisure, Sungshin Women's University, Seoul, Republic of Korea
| | - Kyung-Hee Lee
- Department of Exercise Therapy, Gachon University, Seoul, Republic of Korea
| | - Seung-Wook Choi
- Department of Sport Leisure, Sungshin Women's University, Seoul, Republic of Korea
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Hsieh ML, Nishizaki D, Adashek JJ, Kato S, Kurzrock R. Toll-like receptor 3: a double-edged sword. Biomark Res 2025; 13:32. [PMID: 39988665 PMCID: PMC11849352 DOI: 10.1186/s40364-025-00739-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 02/02/2025] [Indexed: 02/25/2025] Open
Abstract
The discovery of Toll-like receptors (TLRs) and their role in dendritic cells earned the Nobel Prize for 2011 because TLRs profoundly enhanced our understanding of the immune system. Specifically, TLR3 is located within the endosomal compartments of dendritic cells and plays a crucial role in the immune response by acting as a pattern recognition receptor that detects both exogenous (viral) and endogenous (mammalian) double-stranded RNA. However, TLR3 activation is a double-edged sword in various immune-mediated diseases. On one hand, it can enhance anti-viral defenses and promote pathogen clearance, contributing to host protection. On the other hand, excessive or dysregulated TLR3 signaling can lead to chronic inflammation and tissue damage, exacerbating conditions such as autoimmune diseases, chronic viral infections, and cancer. In cancer, TLR3 expression has been linked to both favorable and poor prognoses, though the underlying mechanisms remain unclear. Recent clinical and preclinical advances have explored the use of TLR3 agonists in cancer immunotherapy, attempting to capitalize on their potential to enhance anti-tumor responses. The dual role of TLR3 highlights its complexity as a therapeutic target, necessitating careful modulation to maximize its protective effects while minimizing potential pathological consequences. In this review, we explore the intricate roles of TLR3 in immune responses across different disease contexts, including cancer, infections, autoimmune disorders, and allergies, highlighting both its protective and detrimental effects in these disorders, as well as progress in developing TLR3 agonists as part of the immunotherapy landscape.
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Affiliation(s)
| | - Daisuke Nishizaki
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Jacob J Adashek
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, MD, USA
| | - Shumei Kato
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Razelle Kurzrock
- Medical College of Wisconsin, Milwaukee, WI, USA.
- MCW Cancer Center and Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, USA.
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Shi Y, Min X, Li Y, Guo L, Cai Z, Li D, Jiang X, Feng N, Li X, Yang X. Yinjia pills inhibits the malignant biological behavior of HeLa cells through PKM2-medicated inhibition of JAK/STAT3 pathway. Cytotechnology 2025; 77:5. [PMID: 39575323 PMCID: PMC11579276 DOI: 10.1007/s10616-024-00668-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 11/01/2024] [Indexed: 11/24/2024] Open
Abstract
Cervical cancer is one of the most common tumors in women and is a major problem in gynecological health. Studies have shown that Yinjia pills (YJP), a traditional Chinese medicine, can effectively slow the progression of cervical cancer. Therefore, this study mainly explored the molecular mechanism by which YJP delays the progression of cervical cancer. The expression level of PKM2 in cervical cancer was evaluated by the gene expression profiling interactive analysis (GEPIA) database, and the prognostic value of the PKM2 gene was evaluated by the Kaplan‒Meier plotter database. HeLa cervical cancer cells were treated with different concentrations of YJP (2.5, 5, 10, and 20 mg/mL). The levels of the inflammatory factors were detected by ELISA. Cell proliferation activity, migration and invasion were detected by CCK-8 assay, Transwell assays and cell scratch experiment. Apoptosis was detected by flow cytometry. Western blotting was used to detect the expression of proteins. In this study, PKM2 was upregulated in both cervical squamous cell carcinoma (CESC) and endometrial adenocarcinoma tissues, and a Kaplan‒Meier analysis showed that higher PKM2 expression was associated with lower patient survival. YJP inhibited the proliferation, migration and invasion of HeLa cells in a dose-dependent manner, promoted the apoptosis of HeLa cells, and inhibited the expression of inflammatory factors. In addition, YJP inhibited the activation of the JAK/STAT3 pathway and the occurrence of EMT. Knockdown of PKM2 also inhibited the malignant biological behavior of HeLa cells, but overexpression of PKM2 weakened the inhibitory effect of YJP on the malignant biological behavior of HeLa cells. Angoline, a JAK/STAT3 pathway inhibitor, attenuated the effect of PKM2 overexpression on the efficacy of YJP. In conclusion, YJP can inhibit the activation of the JAK/STAT3 pathway by regulating PKM2, thereby inhibiting the malignant biological behavior of HeLa cells.
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Affiliation(s)
- Ying Shi
- Oncology Department, The First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, 120 Guanghua Street, Kunming, 650200 Yunnan China
| | - Xiaoli Min
- Department of Cerebrovascular Disease, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan China
| | - Yi Li
- Oncology Department, The First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, 120 Guanghua Street, Kunming, 650200 Yunnan China
| | - Lihua Guo
- Oncology Department, The First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, 120 Guanghua Street, Kunming, 650200 Yunnan China
| | - Zheng Cai
- Oncology Department, The First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, 120 Guanghua Street, Kunming, 650200 Yunnan China
| | - Dongge Li
- Oncology Department, The First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, 120 Guanghua Street, Kunming, 650200 Yunnan China
| | - Xueying Jiang
- The First Clinical Medical College, Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan China
| | - Ni Feng
- Oncology Department, The First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, 120 Guanghua Street, Kunming, 650200 Yunnan China
| | - Xiaolin Li
- Oncology Department, The First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, 120 Guanghua Street, Kunming, 650200 Yunnan China
| | - Xiaoxia Yang
- Oncology Department, The First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, 120 Guanghua Street, Kunming, 650200 Yunnan China
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Cao R, Li Q, Wei P, Ding Y, Bin Y, Zheng C. IL-6-Inducing Peptide Prediction Based on 3D Structure and Graph Neural Network. Biomolecules 2025; 15:99. [PMID: 39858493 PMCID: PMC11764147 DOI: 10.3390/biom15010099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/27/2024] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
Interleukin-6 (IL-6) is a potent glycoprotein that plays a crucial role in regulating innate and adaptive immunity, as well as metabolism. The expression and release of IL-6 are closely correlated with the severity of various diseases. IL-6-inducing peptides are critical for the development of immunotherapy and diagnostic biomarkers for some diseases. Most existing methods for predicting IL-6-induced peptides use traditional machine learning methods, whose feature selection is based on prior knowledge. In addition, none of these methods take into account the three-dimensional (3D) structure of peptides, which is essential for their functional properties. In this study, we propose a novel IL-6-inducing peptide prediction method called DGIL-6, which integrates 3D structural information with graph neural networks. DGIL-6 represents a peptide sequence as a graph, where each amino acid is treated as a node, and the adjacency matrix, representing the relationships between nodes, is derived from the predicted residue contact graph of the peptide sequence. In addition to commonly used amino acid representations, such as one-hot encoding and position encoding, the pre-trained model ESM-1b is employed to extract amino acid features as node features. In order to simultaneously consider node weights and information updates, a dual-channel method combining Graph Attention Network (GAT) and Graph Convolutional Network (GCN) is adopted. Finally, the extracted features from both channels are merged for the classification of IL-6-inducing peptides. A series of experiments including cross-validation, independent testing, ablation studies, and visualizations demonstrate the effectiveness of the DGIL-6 method.
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Affiliation(s)
- Ruifen Cao
- Information Materials and Intelligent Sensing Laboratory of Anhui Province, School of Computer Science and Technology, Anhui University, Hefei 230601, China; (R.C.); (Q.L.)
| | - Qiangsheng Li
- Information Materials and Intelligent Sensing Laboratory of Anhui Province, School of Computer Science and Technology, Anhui University, Hefei 230601, China; (R.C.); (Q.L.)
| | - Pijing Wei
- Institutes of Physical Science and Information Technology, Anhui University, Hefei 230601, China;
| | - Yun Ding
- School of Artificial Intelligence, Anhui University, Hefei 230601, China;
| | - Yannan Bin
- Institutes of Physical Science and Information Technology, Anhui University, Hefei 230601, China;
| | - Chunhou Zheng
- School of Artificial Intelligence, Anhui University, Hefei 230601, China;
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Tran MN, Kim NS, Lee S. Biological network comparison identifies a novel synergistic mechanism of Ginseng Radix-Astragali Radix herb pair in cancer-related fatigue. JOURNAL OF ETHNOPHARMACOLOGY 2024; 333:118447. [PMID: 38885914 DOI: 10.1016/j.jep.2024.118447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 06/01/2024] [Accepted: 06/06/2024] [Indexed: 06/20/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ginseng Radix and Astragali Radix are commonly combined to tonify Qi and alleviate fatigue. Previous studies have employed biological networks to investigate the mechanisms of herb pairs in treating different diseases. However, these studies have only elucidated a single network for each herb pair, without emphasizing the superiority of the herb combination over individual herbs. AIM OF THE STUDY This study proposes an approach of comparing biological networks to highlight the synergistic effect of the pair in treating cancer-related fatigue (CRF). METHODS The compounds and targets of Ginseng Radix, Astragali Radix, and CRF diseases were collected and predicted using different databases. Subsequently, the overlapping targets between herbs and disease were imported into the STRING and DAVID tools to build protein-protein interaction (PPI) networks and analyze enriched KEGG pathways. The biological networks of Ginseng Radix and Astragali Radix were compared separately or together using the DyNet application. Molecular docking was used to verify the predicted results. Further, in vitro experiments were conducted to validate the synergistic pathways identified in in silico studies. RESULTS In the PPI network comparison, the combination created 89 new interactions and an increased average degree (11.260) when compared to single herbs (10.296 and 9.394). The new interactions concentrated on HRAS, STAT3, JUN, and IL6. The topological analysis identified 20 core targets of the combination, including three Ginseng Radix-specific targets, three Astragali Radix-specific targets, and 14 shared targets. In KEGG enrichment analysis, the combination regulated additional signaling pathways (152) more than Ginseng Radix (146) and Astragali Radix (134) alone. The targets of the herb pair synergistically regulated cancer pathways, specifically hypoxia-inducible factor 1 (HIF-1) signaling pathway. In vitro experiments including enzyme-linked immunosorbent assay and Western blot demonstrated that two herbs combination could up-regulate HIF-1α signaling pathway at different combined concentrations compared to either single herb alone. CONCLUSION The herb pair increased protein interactions and adjusted metabolic pathways more than single herbs. This study provides insights into the combination of Ginseng Radix and Astragali Radix in clinical practice.
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Affiliation(s)
- Minh Nhat Tran
- Korean Medicine Data Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea; Korean Convergence Medical Science, University of Science and Technology, Daejeon, Republic of Korea; Faculty of Traditional Medicine, Hue University of Medicine and Pharmacy, Hue University, Thua Thien Hue, Viet Nam.
| | - No Soo Kim
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea.
| | - Sanghun Lee
- Korean Medicine Data Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea; Korean Convergence Medical Science, University of Science and Technology, Daejeon, Republic of Korea.
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Wei Y, Wu R, Yang S, Cao Y, Li J, Ma H, Wu J, Duan J, Yang S. MiR-137 mediated high expression of TIGD1 promotes migration, invasion, and suppresses apoptosis of lung adenocarcinoma. Lung Cancer 2024; 195:107918. [PMID: 39173230 DOI: 10.1016/j.lungcan.2024.107918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 07/25/2024] [Accepted: 08/02/2024] [Indexed: 08/24/2024]
Abstract
OBJECTIVES Tigger transposable element-derived 1 (TIGD1) expression and its underlying functions and regulatory mechanisms in lung adenocarcinoma (LUAD) remain unknown. Therefore, we intended to explore the expression, potential functions, and regulatory mechanisms of TIGD1 in LUAD. MATERIALS AND METHODS TIGD1 expression in LUAD tissues was determined by immunohistochemistry analysis of a tissue microarray. Functional experiments were conducted to determine how TIGD1 affects LUAD tumorigenesis and metastasis. The molecular mechanisms by which TIGD1 induces LUAD progression were determined. RESULTS TIGD1 was upregulated in LUAD tissues and was related to lymph node metastases. TIGD1 knockdown suppressed LUAD cell proliferation, migration, and invasion, while promoted cell apoptosis. Furthermore, decreased metastatic nodules were observed in the TIGD1 knockdown mouse metastasis model. Moreover, microarray analysis was performed to determine the potential downstream genes of TIGD1 in LUAD. Hallmark pathway analysis revealed that the downstream genes of TIGD1 were involved in epithelial-mesenchymal transition (EMT). Western blotting confirmed that vimentin and TWIST was downregulated in TIGD1 knockdown cells, while E-cadherin was upregulated. Ingenuity pathway and hallmark pathway analyses revealed that TIGD1 regulated the interleukin-6 signaling pathway and related gene members. Western blotting, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay indicated that downregulation of TIGD1 decreased interleukin-6 and CXCL1 expression. TIGD1 expression was negatively correlated with immune infiltration in LUAD. The upstream microRNA of TIGD1 was predicted, and subsequent luciferase reporter gene experiments confirmed the interactions between miR-137 and TIGD1. The expression of miR-137 was significantly downregulated in LUAD tissues and miR-137 suppressed the proliferation, migration, and invasion of LUAD cells, partially through negatively regulating the expression of TIGD1. CONCLUSION Our findings suggest that TIGD1, which was regulated by miR-137, contributed to LUAD progression by promoting cell proliferation, migration, invasion, and EMT and suppressing cell apoptosis.
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Affiliation(s)
- Yiqun Wei
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China; Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, China
| | - Runmiao Wu
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, China
| | - Shuanying Yang
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China.
| | - Yanfei Cao
- Department of Thoracic Surgery, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, China
| | - Jing Li
- Department of Traditional Chinese Medicine, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, China
| | - Huihui Ma
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, China
| | - Junfang Wu
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, China
| | - Jinjin Duan
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, China
| | - Shumei Yang
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, China
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Bayat M, Sadri Nahand J. Exosomal miRNAs: the tumor's trojan horse in selective metastasis. Mol Cancer 2024; 23:167. [PMID: 39164756 PMCID: PMC11334467 DOI: 10.1186/s12943-024-02081-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 08/12/2024] [Indexed: 08/22/2024] Open
Abstract
Organs of future metastasis are not passive receivers of circulating tumor cells, but are instead selectively and actively modified by the primary tumor before metastatic spread has even occurred. Tumors orchestrate a pre-metastatic program by conditioning distant organs to create microenvironments that foster the survival and proliferation of tumor cells before their arrival, thereby establishing pre-metastatic niches. Primary tumor-derived exosomes modulate these pre-metastatic niches, generating a permissive environment that facilitates the homing and expansion of tumor cells. Moreover, microRNAs have emerged as a key component of exosomal cargo, serving not only to induce the formation of pre-metastatic niches but also to prime these sites for the arrival and colonization of specific secondary tumor populations. Against this backdrop, this review endeavors to elucidate the impact of tumor-derived exosomal microRNAs on the genesis of their individualized pre-metastatic niches, with a view towards identifying novel means of specifying cancer metastasis and exploiting this phenomenon for cancer immunotherapy.
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Affiliation(s)
- Mobina Bayat
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, 15731, Iran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, 15731, Iran.
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Bozzuto G, Calcabrini A, Colone M, Condello M, Dupuis ML, Pellegrini E, Stringaro A. Phytocompounds and Nanoformulations for Anticancer Therapy: A Review. Molecules 2024; 29:3784. [PMID: 39202863 PMCID: PMC11357218 DOI: 10.3390/molecules29163784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 08/05/2024] [Accepted: 08/05/2024] [Indexed: 09/03/2024] Open
Abstract
Cancer is a complex disease that affects millions of people and remains a major public health problem worldwide. Conventional cancer treatments, including surgery, chemotherapy, immunotherapy, and radiotherapy, have limited achievements and multiple drawbacks, among which are healthy tissue damage and multidrug-resistant phenotype onset. Increasing evidence shows that many plants' natural products, as well as their bioactive compounds, have promising anticancer activity and exhibit minimal toxicity compared to conventional anticancer drugs. However, their widespread use in cancer therapy is severely restricted by limitations in terms of their water solubility, absorption, lack of stability, bioavailability, and selective targeting. The use of nanoformulations for plants' natural product transportation and delivery could be helpful in overcoming these limitations, thus enhancing their therapeutic efficacy and providing the basis for improved anticancer treatment strategies. The present review is aimed at providing an update on some phytocompounds (curcumin, resveratrol, quercetin, and cannabinoids, among others) and their main nanoformulations showing antitumor activities, both in vitro and in vivo, against such different human cancer types as breast and colorectal cancer, lymphomas, malignant melanoma, glioblastoma multiforme, and osteosarcoma. The intracellular pathways underlying phytocompound anticancer activity and the main advantages of nanoformulation employment are also examined. Finally, this review critically analyzes the research gaps and limitations causing the limited success of phytocompounds' and nanoformulations' clinical translation.
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Affiliation(s)
- Giuseppina Bozzuto
- National Center for Drug Research and Evaluation, Italian National Institute of Health, 00161 Rome, Italy; (G.B.); (M.C.); (M.C.); (M.L.D.); (A.S.)
| | - Annarica Calcabrini
- National Center for Drug Research and Evaluation, Italian National Institute of Health, 00161 Rome, Italy; (G.B.); (M.C.); (M.C.); (M.L.D.); (A.S.)
| | - Marisa Colone
- National Center for Drug Research and Evaluation, Italian National Institute of Health, 00161 Rome, Italy; (G.B.); (M.C.); (M.C.); (M.L.D.); (A.S.)
| | - Maria Condello
- National Center for Drug Research and Evaluation, Italian National Institute of Health, 00161 Rome, Italy; (G.B.); (M.C.); (M.C.); (M.L.D.); (A.S.)
| | - Maria Luisa Dupuis
- National Center for Drug Research and Evaluation, Italian National Institute of Health, 00161 Rome, Italy; (G.B.); (M.C.); (M.C.); (M.L.D.); (A.S.)
| | - Evelin Pellegrini
- Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy;
| | - Annarita Stringaro
- National Center for Drug Research and Evaluation, Italian National Institute of Health, 00161 Rome, Italy; (G.B.); (M.C.); (M.C.); (M.L.D.); (A.S.)
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Zhang Q, Tuerxun N, Tuerxun S. IL-6 is associated with poor seizure control in low-grade glioma patients undergoing primary resection. iScience 2024; 27:110267. [PMID: 39021786 PMCID: PMC11253519 DOI: 10.1016/j.isci.2024.110267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 04/10/2024] [Accepted: 06/11/2024] [Indexed: 07/20/2024] Open
Abstract
In this study, 198 patients with low-grade gliomas (LGGs) undergoing primary resection were evaluated for seizure status at 24 months after primary resection with the Engel classification of seizures, and 120 patients had good seizure control (class I) while 78 patients had poor seizure control (class II-IV). Multivariate analysis showed that cortex involvement, subtotal resection, serum IL-6 concentration, and neutrophil to lymphocyte ratio (NLR) were associated with poor seizure control. The area under curve (AUC) of serum IL-6 concentration, NLR and their combination applied in predicting poor seizure control was 0.756, 0.714, and 0.857, respectively. The AUC of combination prediction was significantly higher than those of individual prediction. Therefore, elevated serum IL-6 concentration was associated with poor seizure control in LLG patients undergoing primary resection and could be applied in predicting seizure control, and the predictive value could be elevated through adding other serum indices to IL-6.
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Affiliation(s)
- Qingyan Zhang
- Key Laboratory of Ultra-Weak Magnetic Field Measurement Technology, Ministry of Education, School of Instrumentation and Optoelectronic Engineering, Beihang University, Beijing 100191, China
- Zhejiang Provincial Key Laboratory of Ultra-Weak Magnetic-Field Space and Applied Technology, Hangzhou Innovation Institute of Beihang University, Hangzhou 310000, China
- Department of Neurology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China
| | - Nisagul Tuerxun
- Department of Health Care for Cadres, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830000, China
| | - Shabier Tuerxun
- Department of Neurology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China
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Ray CMP, Yang H, Spangler JB, Mac Gabhann F. Mechanistic computational modeling of monospecific and bispecific antibodies targeting interleukin-6/8 receptors. PLoS Comput Biol 2024; 20:e1012157. [PMID: 38848446 PMCID: PMC11189202 DOI: 10.1371/journal.pcbi.1012157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 06/20/2024] [Accepted: 05/10/2024] [Indexed: 06/09/2024] Open
Abstract
The spread of cancer from organ to organ (metastasis) is responsible for the vast majority of cancer deaths; however, most current anti-cancer drugs are designed to arrest or reverse tumor growth without directly addressing disease spread. It was recently discovered that tumor cell-secreted interleukin-6 (IL-6) and interleukin-8 (IL-8) synergize to enhance cancer metastasis in a cell-density dependent manner, and blockade of the IL-6 and IL-8 receptors (IL-6R and IL-8R) with a novel bispecific antibody, BS1, significantly reduced metastatic burden in multiple preclinical mouse models of cancer. Bispecific antibodies (BsAbs), which combine two different antigen-binding sites into one molecule, are a promising modality for drug development due to their enhanced avidity and dual targeting effects. However, while BsAbs have tremendous therapeutic potential, elucidating the mechanisms underlying their binding and inhibition will be critical for maximizing the efficacy of new BsAb treatments. Here, we describe a quantitative, computational model of the BS1 BsAb, exhibiting how modeling multivalent binding provides key insights into antibody affinity and avidity effects and can guide therapeutic design. We present detailed simulations of the monovalent and bivalent binding interactions between different antibody constructs and the IL-6 and IL-8 receptors to establish how antibody properties and system conditions impact the formation of binary (antibody-receptor) and ternary (receptor-antibody-receptor) complexes. Model results demonstrate how the balance of these complex types drives receptor inhibition, providing important and generalizable predictions for effective therapeutic design.
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Affiliation(s)
- Christina M. P. Ray
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Medical-Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Huilin Yang
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Jamie B. Spangler
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland, United States of America
- Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, United States of America
- Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - Feilim Mac Gabhann
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
- Institute for Nano Biotechnology (INBT), Johns Hopkins University, Baltimore, Maryland, United States of America
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Giunashvili N, Thomas JM, Schvarcz CA, Viana PHL, Aloss K, Bokhari SMZ, Koós Z, Bócsi D, Major E, Balogh A, Benyó Z, Hamar P. Enhancing therapeutic efficacy in triple-negative breast cancer and melanoma: synergistic effects of modulated electro-hyperthermia (mEHT) with NSAIDs especially COX-2 inhibition in in vivo models. Mol Oncol 2024; 18:1012-1030. [PMID: 38217262 PMCID: PMC10994232 DOI: 10.1002/1878-0261.13585] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 12/18/2023] [Accepted: 01/02/2024] [Indexed: 01/15/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is a leading cause of cancer mortality and lacks modern therapy options. Modulated electro-hyperthermia (mEHT) is an adjuvant therapy with demonstrated clinical efficacy for the treatment of various cancer types. In this study, we report that mEHT monotherapy stimulated interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) expression, and consequently cyclooxygenase 2 (COX-2), which may favor a cancer-promoting tumor microenvironment. Thus, we combined mEHT with nonsteroid anti-inflammatory drugs (NSAIDs): a nonselective aspirin, or the selective COX-2 inhibitor SC236, in vivo. We demonstrate that NSAIDs synergistically increased the effect of mEHT in the 4T1 TNBC model. Moreover, the strongest tumor destruction ratio was observed in the combination SC236 + mEHT groups. Tumor damage was accompanied by a significant increase in cleaved caspase-3, suggesting that apoptosis played an important role. IL-1β and COX-2 expression were significantly reduced by the combination therapies. In addition, a custom-made nanostring panel demonstrated significant upregulation of genes participating in the formation of the extracellular matrix. Similarly, in the B16F10 melanoma model, mEHT and aspirin synergistically reduced the number of melanoma nodules in the lungs. In conclusion, mEHT combined with a selective COX-2 inhibitor may offer a new therapeutic option in TNBC.
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Grants
- STIA-OTKA-2022 Semmelweis Science and Innovation Fund
- OTKA_ANN 110810 National Research, Development, and Innovation Office
- OTKA_SNN 114619 National Research, Development, and Innovation Office
- ÚNKP-23-3-II-SE-45 National Research, Development, and Innovation Office
- ÚNKP-23-4-I-SE-22 National Research, Development, and Innovation Office
- OTKA_K 145998 National Research, Development, and Innovation Office
- Tempus Foundation
- EFOP-3.6.3-VEKOP-16-2017-00009 Semmelweis Excellence 250+ Scholarship
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Affiliation(s)
- Nino Giunashvili
- Institute of Translational Medicine, Semmelweis UniversityBudapestHungary
| | | | - Csaba András Schvarcz
- Institute of Translational Medicine, Semmelweis UniversityBudapestHungary
- HUN‐REN‐SU Cerebrovascular and Neurocognitive Diseases Research GroupBudapestHungary
| | | | - Kenan Aloss
- Institute of Translational Medicine, Semmelweis UniversityBudapestHungary
| | | | - Zoltán Koós
- Institute of Translational Medicine, Semmelweis UniversityBudapestHungary
| | - Dániel Bócsi
- Institute of Translational Medicine, Semmelweis UniversityBudapestHungary
| | - Enikő Major
- Institute of Translational Medicine, Semmelweis UniversityBudapestHungary
- HUN‐REN‐SU Cerebrovascular and Neurocognitive Diseases Research GroupBudapestHungary
| | - Andrea Balogh
- Institute of Translational Medicine, Semmelweis UniversityBudapestHungary
| | - Zoltán Benyó
- Institute of Translational Medicine, Semmelweis UniversityBudapestHungary
- HUN‐REN‐SU Cerebrovascular and Neurocognitive Diseases Research GroupBudapestHungary
| | - Péter Hamar
- Institute of Translational Medicine, Semmelweis UniversityBudapestHungary
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12
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Wilburn WJ, Gabure S, Whalen MM. Interleukin 1β and interleukin 6 production in human immune cells is stimulated by the antibacterial compound Triclosan. Arch Toxicol 2024; 98:883-895. [PMID: 38055018 PMCID: PMC10922422 DOI: 10.1007/s00204-023-03654-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 11/29/2023] [Indexed: 12/07/2023]
Abstract
Triclosan (TCS) is an antimicrobial compound widely used in personal hygiene products such as mouthwash and toothpaste; and has been found in human blood, breast milk, and urine. Interleukin (IL)-6 and IL-1 beta (IL-1β) are pro-inflammatory cytokines regulating cell growth, tissue repair, and immune function; increased levels of each have been associated with many diseases, including cancer. Previous studies showed that TCS at concentrations between 0.05 and 5 µM consistently increased the secretion of IL-1β and IL-6 from human immune cells within 24 h of exposure. The current study demonstrates that this increase in secretion was not due simply to release of existing stores but was due to an increase in cellular production/levels (both secreted and intracellular levels) of each of these cytokines. Production of IL-1β and IL-6 was increased by exposure to one or more concentration of TCS at each length of exposure (10 min, 30 min, 6 h, and 24 h). TCS-induced stimulation of cytokine production was shown to be dependent on the mitogen-activated protein kinase (MAPK) p44/42 (ERK 1/2). It was also shown that these TCS-induced increases in IL-1β and IL6 production were accompanied by increased mRNA for IL-1β and IL-6. The ability of TCS to increase production indicates that rather than activating a self-limiting process of depleting cells of already existing stores of IL-1β or IL-6, TCS can stimulate a process that has the capacity to provide sustained production of these cytokines and thus may lead to chronic inflammation and its pathological consequences.
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Affiliation(s)
- Wendy J Wilburn
- Department of Biology, Tennessee State University, 3500 John A. Merritt Blvd., Nashville, TN, 37209, USA
| | - Sahra Gabure
- Department of Chemistry, Tennessee State University, 3500 John A. Merritt Blvd., Nashville, TN, 37209, USA
| | - Margaret M Whalen
- Department of Chemistry, Tennessee State University, 3500 John A. Merritt Blvd., Nashville, TN, 37209, USA.
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13
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Adachi T, Goda H, Shinriki S, Tokuzen N, Kuribayashi N, Hino S, Nakashiro KI, Uchida D. Prognostic Significance of Serum Interleukin-6 Levels in Oral Squamous Cell Carcinoma. Cureus 2024; 16:e54439. [PMID: 38510850 PMCID: PMC10951754 DOI: 10.7759/cureus.54439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/19/2024] [Indexed: 03/22/2024] Open
Abstract
Introduction The prognosis of oral squamous cell carcinoma (OSCC) is often poor despite standard treatments. Additionally, no useful prognostic markers are available. Therefore, we aimed to investigate the relationship between serum Interleukin-6 (IL-6) levels and prognosis and explore its local and systemic effects in patients with OSCC. Methods Ninety-five new cases of OSCC were included, and the prognosis was compared between high and low serum IL-6 groups. The localization of IL-6 in OSCC tissues was examined. Furthermore, a comprehensive gene expression analysis was performed in OSCC tissues and compared between the two groups. Results A significant difference in overall survival and disease-free survival was observed. Furthermore, a substantial expression of IL-6 was localized in the stroma. Comprehensive gene expression analysis of tumor localization showed increased expression of genes related to oxidoreductase and lipid metabolism in the primary tissues of the group with high serum IL-6 levels. Regarding the correlation between blood tests and serum IL-6 levels, a strong positive correlation was observed between inflammatory responses and nutritional factors. Conclusion These results suggest that serum IL-6 may be a prognostic factor for metabolic abnormalities in patients with OSCC and that aggressive nutritional interventions may contribute to prognosis.
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Affiliation(s)
- Tomoko Adachi
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime, JPN
| | - Hiroyuki Goda
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime, JPN
| | - Satoru Shinriki
- Department of Molecular Laboratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, JPN
| | - Norihiko Tokuzen
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime, JPN
| | - Nobuyuki Kuribayashi
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime, JPN
| | - Satoshi Hino
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime, JPN
| | - Koh-Ichi Nakashiro
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime, JPN
| | - Daisuke Uchida
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime, JPN
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14
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Alamri OA, Qusti S, Balgoon M, Ageeli AA, Al-Marhaby FA, Alosaimi AM, Jowhari MA, Saeed A. The role of MoS 2 QDs coated with DSPE-PEG-TPP in the protection of protein secondary structure of the brain tissues in an Alzheimer's disease model. Int J Biol Macromol 2024; 255:128522. [PMID: 38040141 DOI: 10.1016/j.ijbiomac.2023.128522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 11/12/2023] [Accepted: 11/28/2023] [Indexed: 12/03/2023]
Abstract
In this investigation, we have explored the protective capacity of MoS2 QDs coated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethyleneglycol) -2000] (DSPE-PEG) linked with (3-carboxypropyl) triphenylphosphonium-bromide (TPP), on the secondary structure of proteins in Alzheimer's disease (AD)-affected brain tissues. Using a cohort of fifteen male SWR/J mice, we establish three groups: a control group, a second group induced with AD through daily doses of AlCl3 and D-galactose for 49 consecutive days, and a third group receiving the same AD-inducing doses but treated with DSPE-PEG-TPP-MoS2 QDs. Brain tissues are meticulously separated from the skull, and their molecular structures are analyzed via FTIR spectroscopy. Employing the curve fitting method on the amide I peak, we delve into the nuances of protein secondary structure. The FTIR analysis reveals a marked increase in β-sheet structures and a concurrent decline in turn and α-helix structures in the AD group in comparison to the control group. Notably, no statistically significant differences emerge between the treated and control mice. Furthermore, multivariate analysis of the FTIR spectral region, encompassing protein amide molecular structures, underscores a remarkable similarity between the treated and normal mice. This study elucidates the potential of DSPE-PEG-TPP-MoS2 QDs in shielding brain tissue proteins against the pathogenic influences of AD.
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Affiliation(s)
- Ohoud Abdulaziz Alamri
- Department of Medical Laboratory, King Fahad Armed Forces Hospital, Jeddah 23311, Saudi Arabia; Department of Biochemistry Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Safaa Qusti
- Department of Biochemistry Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Maha Balgoon
- Department of Biochemistry Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Abeer A Ageeli
- Department of Chemistry, Faculty of Science, Jazan University, Jazan 45142, Saudi Arabia
| | - F A Al-Marhaby
- Department of Physics, Al-Qunfudhah University College, Umm Al-Qura University, Makkah 24230, Saudi Arabia
| | - Abeer M Alosaimi
- Department of Chemistry, College of Science, Taif University, Taif 21944, Saudi Arabia
| | - Mohammed A Jowhari
- Medical Physics Department, Jazan Specialized Hospital, Ministry of Health, Jazan Health Affairs, Jazan 45142, Saudi Arabia
| | - Abdu Saeed
- Department of Physics, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Department of Physics, Thamar University, Thamar 87246, Yemen.
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15
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Ray CMP, Yang H, Spangler JB, Mac Gabhann F. Mechanistic computational modeling of monospecific and bispecific antibodies targeting interleukin-6/8 receptors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.18.570445. [PMID: 38187701 PMCID: PMC10769311 DOI: 10.1101/2023.12.18.570445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
The spread of cancer from organ to organ (metastasis) is responsible for the vast majority of cancer deaths; however, most current anti-cancer drugs are designed to arrest or reverse tumor growth without directly addressing disease spread. It was recently discovered that tumor cell-secreted interleukin-6 (IL-6) and interleukin-8 (IL-8) synergize to enhance cancer metastasis in a cell-density dependent manner, and blockade of the IL-6 and IL-8 receptors (IL-6R and IL-8R) with a novel bispecific antibody, BS1, significantly reduced metastatic burden in multiple preclinical mouse models of cancer. Bispecific antibodies (BsAbs), which combine two different antigen-binding sites into one molecule, are a promising modality for drug development due to their enhanced avidity and dual targeting effects. However, while BsAbs have tremendous therapeutic potential, elucidating the mechanisms underlying their binding and inhibition will be critical for maximizing the efficacy of new BsAb treatments. Here, we describe a quantitative, computational model of the BS1 BsAb, exhibiting how modeling multivalent binding provides key insights into antibody affinity and avidity effects and can guide therapeutic design. We present detailed simulations of the monovalent and bivalent binding interactions between different antibody constructs and the IL-6 and IL-8 receptors to establish how antibody properties and system conditions impact the formation of binary (antibody-receptor) and ternary (receptor-antibody-receptor) complexes. Model results demonstrate how the balance of these complex types drives receptor inhibition, providing important and generalizable predictions for effective therapeutic design.
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Affiliation(s)
- Christina MP Ray
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Medical-Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Huilin Yang
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Jamie B Spangler
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland, United States of America
- Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, United States of America
- Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - Feilim Mac Gabhann
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
- Institute for Nano Biotechnology (INBT), Johns Hopkins University, Baltimore, Maryland, United States of America
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16
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Su R, Zhuang J, Liu S, Liu D, Feng K. EnILs: A General Ensemble Computational Approach for Predicting Inducing Peptides of Multiple Interleukins. J Comput Biol 2023; 30:1289-1304. [PMID: 38010531 DOI: 10.1089/cmb.2023.0002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2023] Open
Abstract
Interleukins (ILs) are a group of multifunctional cytokines, which play important roles in immune regulations and inflammatory responses. Recently, IL-6 has been found to affect the development of COVID-19, and significantly elevated levels of IL-6 cytokines have been reported in patients with severe COVID-19. IL-10 and IL-17 are anti-inflammatory and proinflammatory cytokines, respectively, which play multiple protective roles in host defense against pathogens. At present, a number of machine learning methods have been proposed to predict ILs inducing peptides, but their predictive performance needs to be further improved, and the inducing peptides of different ILs are predicted separately, rather than using a general approach. In our work, we combine the statistical features of peptide sequence with word embedding to design a general ensemble model named EnILs to predict inducing peptides of different ILs, in which the predictive probabilities of random forest, eXtreme Gradient Boosting and neural network are integrated in an average way. Compared with the state-of-the-art machine learning methods, EnILs shows considerable performance in the prediction of IL-6, IL-10, and IL-17 inducing peptides. In addition, we predict the most promising IL-6 inducing peptides in Severe Acute Respiratory Syndrome Coronavirus 2 spike protein in the case study for further experimental verification.
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Affiliation(s)
- Rui Su
- Department of Statistics, School of Science, Dalian Maritime University, Dalian, Liaoning, China
| | - Jujuan Zhuang
- Department of Statistics, School of Science, Dalian Maritime University, Dalian, Liaoning, China
| | - Shuhan Liu
- Department of Statistics, School of Science, Dalian Maritime University, Dalian, Liaoning, China
| | - Di Liu
- Department of Computer Science and Technology, Information Science and Technology College, Dalian Maritime University, Dalian, Liaoning, China
| | - Kexin Feng
- Department of Statistics, School of Science, Dalian Maritime University, Dalian, Liaoning, China
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17
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Tian T, Xie X, Yi W, Zhou Y, Xu Y, Wang Z, Zhang J, Lin M, Zhang R, Lv Z, Li X, Lv L, Xu Y. FBXO38 mediates FGL1 ubiquitination and degradation to enhance cancer immunity and suppress inflammation. Cell Rep 2023; 42:113362. [PMID: 37938970 DOI: 10.1016/j.celrep.2023.113362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 08/30/2023] [Accepted: 10/16/2023] [Indexed: 11/10/2023] Open
Abstract
Upregulation of FGL1 helps tumors escape from immune surveillance, and therapeutic antibodies targeting FGL1 have potential as another immune checkpoint inhibitor. However, the underlying mechanism of high FGL1 protein level in cancers is not well defined. Here, we report that FBXO38 interacts with and ubiquitylates FGL1 to negatively regulate its stability and to mediate cancer immune response. Depletion of FBXO38 markedly augments FGL1 abundance, not only suppressing CD8+ T cell infiltration and enhancing immune evasion of tumor but also increasing inflammation in mice. Importantly, we observe a negative correlation of FBXO38 with FGL1 and IL-6 in non-small cell lung cancer specimens. FGL1 and IL-6 levels positively correlate with TNM (tumor, lymph node, metastasis) stages, while FBXO38 and the infiltrating CD8+ T cells negatively correlate with TNM stages. Our study identifies a mechanism regulating FGL1 stability and a target to enhance the immunotherapy and suggests that the combination of anti-FGL1 and anti-IL-6 is a potential therapeutic strategy for cancer immunotherapy.
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Affiliation(s)
- Tongguan Tian
- Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200065, China
| | - Xiao Xie
- Department of Cardiothoracic Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Wanwan Yi
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China
| | - Yuefan Zhou
- Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200065, China
| | - Yixin Xu
- Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200065, China
| | - Zhenxiang Wang
- Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200065, China
| | - Junjing Zhang
- Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200065, China
| | - Mingen Lin
- MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Ruonan Zhang
- MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Zhongwei Lv
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China
| | - Xinxing Li
- Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200065, China
| | - Lei Lv
- MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Yanping Xu
- Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200065, China.
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18
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Jia G, Ramalingam TR, Heiden JV, Gao X, DePianto D, Morshead KB, Modrusan Z, Ramamoorthi N, Wolters P, Lin C, Khanna D, Arron JR. An interleukin 6 responsive plasma cell signature is associated with disease progression in systemic sclerosis interstitial lung disease. iScience 2023; 26:108133. [PMID: 37867940 PMCID: PMC10585397 DOI: 10.1016/j.isci.2023.108133] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 08/14/2023] [Accepted: 09/30/2023] [Indexed: 10/24/2023] Open
Abstract
Systemic sclerosis (SSc) interstitial lung disease (ILD) is among the leading causes of SSc-related morbidity and mortality. Tocilizumab (TCZ, anti-IL6RA) has demonstrated a reduced rate of pulmonary function decline in two phase 2/3 trials (faSScinate and focuSSced) in SSc-ILD patients. We performed transcriptome analysis of skin biopsy samples collected in the studies to decipher gene networks that were potentially associated with clinical responses to TCZ treatment. One module correlated with disease progression showed pharmacodynamic changes with TCZ treatment, and was characterized by plasma cell (PC) genes. PC signature gene expression levels were also significantly increased in both fibrotic SSc and IPF lungs compared to controls. scRNAseq analyses confirmed that PC signature genes were co-expressed in CD38 and CD138 expressing PC subsets in SSc lungs. These data provide insights into the potential role of PC in disease progression and mechanisms of action of TCZ in fibrotic interstitial lung diseases.
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Affiliation(s)
- Guiquan Jia
- Genentech Inc, South San Francisco, CA 94080, USA
| | | | | | - Xia Gao
- Genentech Inc, South San Francisco, CA 94080, USA
| | | | | | | | | | | | - Celia Lin
- Genentech Inc, South San Francisco, CA 94080, USA
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19
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Blander JM, Yee Mon KJ, Jha A, Roycroft D. The show and tell of cross-presentation. Adv Immunol 2023; 159:33-114. [PMID: 37996207 DOI: 10.1016/bs.ai.2023.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2023]
Abstract
Cross-presentation is the culmination of complex subcellular processes that allow the processing of exogenous proteins and the presentation of resultant peptides on major histocompatibility class I (MHC-I) molecules to CD8 T cells. Dendritic cells (DCs) are a cell type that uniquely specializes in cross-presentation, mainly in the context of viral or non-viral infection and cancer. DCs have an extensive network of endovesicular pathways that orchestrate the biogenesis of an ideal cross-presentation compartment where processed antigen, MHC-I molecules, and the MHC-I peptide loading machinery all meet. As a central conveyor of information to CD8 T cells, cross-presentation allows cross-priming of T cells which carry out robust adaptive immune responses for tumor and viral clearance. Cross-presentation can be canonical or noncanonical depending on the functional status of the transporter associated with antigen processing (TAP), which in turn influences the vesicular route of MHC-I delivery to internalized antigen and the cross-presented repertoire of peptides. Because TAP is a central node in MHC-I presentation, it is targeted by immune evasive viruses and cancers. Thus, understanding the differences between canonical and noncanonical cross-presentation may inform new therapeutic avenues against cancer and infectious disease. Defects in cross-presentation on a cellular and genetic level lead to immune-related disease progression, recurrent infection, and cancer progression. In this chapter, we review the process of cross-presentation beginning with the DC subsets that conduct cross-presentation, the signals that regulate cross-presentation, the vesicular trafficking pathways that orchestrate cross-presentation, the modes of cross-presentation, and ending with disease contexts where cross-presentation plays a role.
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Affiliation(s)
- J Magarian Blander
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, United States; Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, United States; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, United States; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, United States; Immunology and Microbial Pathogenesis Programs, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY, United States.
| | - Kristel Joy Yee Mon
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, United States; Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, United States
| | - Atimukta Jha
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, United States; Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, United States
| | - Dylan Roycroft
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, United States; Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, United States
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20
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Zhang S, Zhang W, Sun H, Xue R, Lv Q. Therapeutic potential of single-nucleotide polymorphism-mediated interleukin-6 receptor blockade in cancer treatment: A Mendelian randomization study. Heliyon 2023; 9:e20474. [PMID: 37810867 PMCID: PMC10556766 DOI: 10.1016/j.heliyon.2023.e20474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 09/20/2023] [Accepted: 09/26/2023] [Indexed: 10/10/2023] Open
Abstract
Background Interleukin-6 (IL-6) is a crucial member of the cytokine network and plays a pivotal role in the pathogenesis of various diseases, including cancer. IL-6 receptor (IL-6R) blockade is widely employed as a therapeutic strategy; however, its efficacy in anticancer therapy remains ambiguous. Methods An inverse variance-weighted Mendelian randomization (MR) analysis was conducted to assess the causal effects exerted by IL-6R blockade in remediating cancer. Drug-targeted single-nucleotide polymorphisms (SNPs) were introduced within 300 kb of the IL-6R gene. An instrumental variable comprising 26 SNPs represented IL-6 signaling downregulation and C-reactive protein level reduction. Datasets pertaining to the 33 types of cancer investigated in this study were acquired from the FinnGen genome-wide association study. Results The selected instrumental variable lowered fibrinogen levels, confirming its ability to mimic IL-6R blockade. IL-6R blockade exhibited therapeutic effects on five different cancer types documented in the FinnGen database (N = 334,364, including 76,781 cancer patients): bladder (odds ratios (OR) = 0.563), laryngeal (OR = 0.293), eye (OR = 0.098), gallbladder (OR = 0.059), and myeloid leukemia (OR = 0.442); however, it simultaneously elevated the risk of developing basal cell carcinoma (OR = 1.312) and melanoma (OR = 1.311). Sensitivity analyses did not alter the primary results. Conclusion Therefore, this study aimed to evaluate the potential and efficacy of SNP-based IL-6R blockade in treating cancer.
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Affiliation(s)
- Shuwan Zhang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
- Key Laboratory of Intelligent and Precision Pathology Diagnosis in Oncology, China Medical University, Shenyang 110004, Liaoning Province, China
| | - Wenchuan Zhang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
- Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hanxue Sun
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Rui Xue
- School of Medicine, Chongqing University, Chongqing 400044, China
| | - Qingjie Lv
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
- Key Laboratory of Intelligent and Precision Pathology Diagnosis in Oncology, China Medical University, Shenyang 110004, Liaoning Province, China
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21
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Cheah S, Bassett JK, Bruinsma FJ, Hopper J, Jayasekara H, Joshua D, MacInnis RJ, Prince HM, Southey MC, Vajdic CM, van Leeuwen MT, Wong Doo N, Harrison SJ, English DR, Giles GG, Milne RL. Modifiable lifestyle risk factors and survival after diagnosis with multiple myeloma. Expert Rev Hematol 2023; 16:773-783. [PMID: 37667498 DOI: 10.1080/17474086.2023.2255747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/21/2023] [Accepted: 09/01/2023] [Indexed: 09/06/2023]
Abstract
BACKGROUND While remaining incurable, median overall survival for MM now exceeds 5 years. Yet few studies have investigated how modifiable lifestyle factors influence survival. We investigate whether adiposity, diet, alcohol, or smoking are associated with MM-related fatality. RESEARCH DESIGN AND METHODS We recruited 760 incident cases of MM via cancer registries in two Australian states during 2010-2016. Participants returned questionnaires on health and lifestyle. Follow-up ended in 2020. Flexible parametric survival models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for lifestyle exposures and risk of all-cause and MM-specific fatality. RESULTS Higher pre-diagnosis Alternative Healthy Eating Index (AHEI) scores were associated with reduced MM-specific fatality (per 10-unit score, HR = 0.84, 95%CI = 0.70-0.99). Pre-diagnosis alcohol consumption was inversely associated with MM-specific fatality, compared with nondrinkers (0.1-20 g per day, HR = 0.59, 95%CI = 0.39-0.90; >20 g per day, HR = 0.67, 95%CI = 0.40-1.13). Tobacco smoking was associated with increased all-cause fatality compared with never smoking (former smokers: HR = 1.44, 95%CI = 1.10-1.88; current smokers: HR = 1.30, 95%CI = 0.80-2.10). There was no association between pre-enrollment body mass index (BMI) and MM-specific or all-cause fatality. CONCLUSIONS Our findings support established recommendations for healthy diets and against smoking. Higher quality diet, as measured by the AHEI, may improve survival post diagnosis with MM.
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Affiliation(s)
- Simon Cheah
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - Julie K Bassett
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia
| | - Fiona J Bruinsma
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - John Hopper
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - Harindra Jayasekara
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - Doug Joshua
- Royal Prince Alfred Hospital, Sydney Medical School, University of Sydney, Sydney, Australia
| | - Robert J MacInnis
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - H Miles Prince
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
- Epworth Healthcare, Melbourne, Australia
| | - Melissa C Southey
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Melbourne, Australia
- Department of Clinical Pathology, The University of Melbourne, Parkville, Australia
| | | | - Marina T van Leeuwen
- Centre for Big Data Research in Health, The University of New South Wales, Sydney, Australia
| | - Nicole Wong Doo
- Concord Clinical School, University of Sydney, Sydney, Australia
| | - Simon J Harrison
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
- Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Parkville, Australia
| | - Dallas R English
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - Graham G Giles
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Melbourne, Australia
| | - Roger L Milne
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Melbourne, Australia
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22
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Wu Z, Fang ZX, Hou YY, Wu BX, Deng Y, Wu HT, Liu J. Exosomes in metastasis of colorectal cancers: Friends or foes? World J Gastrointest Oncol 2023; 15:731-756. [PMID: 37275444 PMCID: PMC10237026 DOI: 10.4251/wjgo.v15.i5.731] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 03/07/2023] [Accepted: 04/04/2023] [Indexed: 05/12/2023] Open
Abstract
Colorectal cancer (CRC), the third most common type of cancer worldwide, threaten human health and quality of life. With multidisciplinary, including surgery, chemotherapy and/or radiotherapy, patients with an early diagnosis of CRC can have a good prognosis. However, metastasis in CRC patients is the main risk factor causing cancer-related death. To elucidate the underlying molecular mechanisms of CRC metastasis is the difficult and research focus on the investigation of the CRC mechanism. On the other hand, the tumor microenvironment (TME) has been confirmed as having an essential role in the tumorigenesis and metastasis of malignancies, including CRCs. Among the different factors in the TME, exosomes as extracellular vesicles, function as bridges in the communication between cancer cells and different components of the TME to promote the progression and metastasis of CRC. MicroRNAs packaged in exosomes can be derived from different sources and transported into the TME to perform oncogenic or tumor-suppressor roles accordingly. This article focuses on CRC exosomes and illustrates their role in regulating the metastasis of CRC, especially through the packaging of miRNAs, to evoke exosomes as novel biomarkers for their impact on the metastasis of CRC progression.
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Affiliation(s)
- Zheng Wu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Ze-Xuan Fang
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yan-Yu Hou
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Bing-Xuan Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu Deng
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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23
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Del Prete A, Salvi V, Soriani A, Laffranchi M, Sozio F, Bosisio D, Sozzani S. Dendritic cell subsets in cancer immunity and tumor antigen sensing. Cell Mol Immunol 2023; 20:432-447. [PMID: 36949244 PMCID: PMC10203372 DOI: 10.1038/s41423-023-00990-6] [Citation(s) in RCA: 205] [Impact Index Per Article: 102.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 02/14/2023] [Indexed: 03/24/2023] Open
Abstract
Dendritic cells (DCs) exhibit a specialized antigen-presenting function and play crucial roles in both innate and adaptive immune responses. Due to their ability to cross-present tumor cell-associated antigens to naïve T cells, DCs are instrumental in the generation of specific T-cell-mediated antitumor effector responses in the control of tumor growth and tumor cell dissemination. Within an immunosuppressive tumor microenvironment, DC antitumor functions can, however, be severely impaired. In this review, we focus on the mechanisms of DC capture and activation by tumor cell antigens and the role of the tumor microenvironment in shaping DC functions, taking advantage of recent studies showing the phenotype acquisition, transcriptional state and functional programs revealed by scRNA-seq analysis. The therapeutic potential of DC-mediated tumor antigen sensing in priming antitumor immunity is also discussed.
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Affiliation(s)
- Annalisa Del Prete
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
- Humanitas Clinical and Research Center-IRCCS Rozzano, Milano, Italy
| | - Valentina Salvi
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Alessandra Soriani
- Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Mattia Laffranchi
- Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Francesca Sozio
- Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Daniela Bosisio
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Silvano Sozzani
- Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
- IRCCS Neuromed, Pozzilli, IS, Italy.
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24
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Brandstoetter T, Schmoellerl J, Grausenburger R, Kollmann S, Doma E, Huuhtanen J, Klampfl T, Eder T, Grebien F, Hoermann G, Zuber J, Mustjoki S, Maurer B, Sexl V. SBNO2 is a critical mediator of STAT3-driven hematological malignancies. Blood 2023; 141:1831-1845. [PMID: 36630607 PMCID: PMC10646773 DOI: 10.1182/blood.2022018494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/12/2022] [Accepted: 01/07/2023] [Indexed: 01/13/2023] Open
Abstract
Gain-of-function mutations in the signal transducer and activator of transcription 3 (STAT3) gene are recurrently identified in patients with large granular lymphocytic leukemia (LGLL) and in some cases of natural killer (NK)/T-cell and adult T-cell leukemia/lymphoma. To understand the consequences and molecular mechanisms contributing to disease development and oncogenic transformation, we developed murine hematopoietic stem and progenitor cell models that express mutated STAT3Y640F. These cells show accelerated proliferation and enhanced self-renewal potential. We integrated gene expression analyses and chromatin occupancy profiling of STAT3Y640F-transformed cells with data from patients with T-LGLL. This approach uncovered a conserved set of direct transcriptional targets of STAT3Y640F. Among these, strawberry notch homolog 2 (SBNO2) represents an essential transcriptional target, which was identified by a comparative genome-wide CRISPR/Cas9-based loss-of-function screen. The STAT3-SBNO2 axis is also present in NK-cell leukemia, T-cell non-Hodgkin lymphoma, and NPM-ALK-rearranged T-cell anaplastic large cell lymphoma (T-ALCL), which are driven by STAT3-hyperactivation/mutation. In patients with NPM-ALK+ T-ALCL, high SBNO2 expression correlates with shorter relapse-free and overall survival. Our findings identify SBNO2 as a potential therapeutic intervention site for STAT3-driven hematopoietic malignancies.
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Affiliation(s)
- Tania Brandstoetter
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | | | - Reinhard Grausenburger
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Sebastian Kollmann
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Eszter Doma
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Jani Huuhtanen
- Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- Department of Computer Science, Aalto University, Espoo, Finland
| | - Thorsten Klampfl
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Thomas Eder
- Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Florian Grebien
- Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria
| | | | - Johannes Zuber
- Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria
| | - Satu Mustjoki
- Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- ICAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland
- Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland
| | - Barbara Maurer
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Veronika Sexl
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
- University of Innsbruck, Innsbruck, Austria
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25
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Nada H, Sivaraman A, Lu Q, Min K, Kim S, Goo JI, Choi Y, Lee K. Perspective for Discovery of Small Molecule IL-6 Inhibitors through Study of Structure–Activity Relationships and Molecular Docking. J Med Chem 2023; 66:4417-4433. [PMID: 36971365 DOI: 10.1021/acs.jmedchem.2c01957] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
Abstract
Interleukin-6 (IL-6) is a proinflammatory cytokine that plays a key role in the pathogenesis and physiology of inflammatory and autoimmune diseases, such as coronary heart disease, cancer, Alzheimer's disease, asthma, rheumatoid arthritis, and most recently COVID-19. IL-6 and its signaling pathway are promising targets in the treatment of inflammatory and autoimmune diseases. Although, anti-IL-6 monoclonal antibodies are currently being used in clinics, huge unmet medical needs remain because of the high cost, administration-related toxicity, lack of opportunity for oral dosing, and potential immunogenicity of monoclonal antibody therapy. Furthermore, nonresponse or loss of response to monoclonal antibody therapy has been reported, which increases the importance of optimizing drug therapy with small molecule drugs. This work aims to provide a perspective for the discovery of novel small molecule IL-6 inhibitors by the analysis of the structure-activity relationships and computational studies for protein-protein inhibitors targeting the IL-6/IL-6 receptor/gp130 complex.
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26
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Khalil R, Diab-Assaf M, Lemaitre JM. Emerging Therapeutic Approaches to Target the Dark Side of Senescent Cells: New Hopes to Treat Aging as a Disease and to Delay Age-Related Pathologies. Cells 2023; 12:915. [PMID: 36980256 PMCID: PMC10047596 DOI: 10.3390/cells12060915] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 03/05/2023] [Accepted: 03/07/2023] [Indexed: 03/19/2023] Open
Abstract
Life expectancy has drastically increased over the last few decades worldwide, with important social and medical burdens and costs. To stay healthy longer and to avoid chronic disease have become essential issues. Organismal aging is a complex process that involves progressive destruction of tissue functionality and loss of regenerative capacity. One of the most important aging hallmarks is cellular senescence, which is a stable state of cell cycle arrest that occurs in response to cumulated cell stresses and damages. Cellular senescence is a physiological mechanism that has both beneficial and detrimental consequences. Senescence limits tumorigenesis, lifelong tissue damage, and is involved in different biological processes, such as morphogenesis, regeneration, and wound healing. However, in the elderly, senescent cells increasingly accumulate in several organs and secrete a combination of senescence associated factors, contributing to the development of various age-related diseases, including cancer. Several studies have revealed major molecular pathways controlling the senescent phenotype, as well as the ones regulating its interactions with the immune system. Attenuating the senescence-associated secretory phenotype (SASP) or eliminating senescent cells have emerged as attractive strategies aiming to reverse or delay the onset of aging diseases. Here, we review current senotherapies designed to suppress the deleterious effect of SASP by senomorphics or to selectively kill senescent cells by "senolytics" or by immune system-based approaches. These recent investigations are promising as radical new controls of aging pathologies and associated multimorbidities.
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Affiliation(s)
- Roula Khalil
- IRMB, University Montpellier, INSERM, 34090 Montpellier, France;
| | - Mona Diab-Assaf
- Fanar Faculty of Sciences II, Lebanese University, Beirut P.O. Box 90656, Lebanon;
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27
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Dhall A, Patiyal S, Sharma N, Usmani SS, Raghava GPS. A Web-Based Method for the Identification of IL6-Based Immunotoxicity in Vaccine Candidates. Methods Mol Biol 2023; 2673:317-327. [PMID: 37258924 DOI: 10.1007/978-1-0716-3239-0_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Interleukin 6 (IL6) is a major pro-inflammatory cytokine that plays a pivotal role in both innate and adaptive immune responses. In the past, a number of studies reported that high level of IL6 promotes the proliferation of cancer, autoimmune disorders, and cytokine storm in COVID-19 patients. Thus, it is extremely important to identify and remove the antigenic regions from a therapeutic protein or vaccine candidate that may induce IL6-associated immunotoxicity. In order to overcome this challenge, our group has developed a computational tool, IL6pred, for discovering IL6-inducing peptides in a vaccine candidate. The aim of this chapter is to describe the potential applications and methodology of IL6pred. It sheds light on the prediction, designing, and scanning modules of IL6pred webserver and standalone package ( https://webs.iiitd.edu.in/raghava/il6pred/ ).
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Affiliation(s)
- Anjali Dhall
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
| | - Sumeet Patiyal
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
| | - Neelam Sharma
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
| | - Salman Sadullah Usmani
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
| | - Gajendra P S Raghava
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India.
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28
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Gulubova MV, Chonov DC, Ivanova KV, Hristova MK, Krasimirova-Ignatova MM, Vlaykova TI. Intratumoural expression of IL-6/STAT3, IL-17 and FOXP3 immune cells in the immunosuppressive tumour microenvironment of colorectal cancer Immune cells-positive for IL-6, STAT3, IL-17 and FOXP3 and colorectal cancer development. BIOTECHNOL BIOTEC EQ 2022. [DOI: 10.1080/13102818.2022.2072765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
| | - Dimitur Chavdarov Chonov
- Department of General and Operative Surgery, Trakia University, Medical Faculty, Stara Zagora Bulgaria
- Ward of Operative Surgery, University Hospital “Prof. D-r Stoyan Kirkovich”, Stara Zagora, Bulgaria
| | - Koni Vancho Ivanova
- Department of Pathology, Trakia University, Medical Faculty, Stara Zagora, Bulgaria
| | | | | | - Tatyana Ivanova Vlaykova
- Department of Chemistry and Biochemistry, Medical Faculty, Trakia University, Stara Zagora, Bulgaria
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29
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Role of NKT cells in cancer immunotherapy-from bench to bed. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 40:29. [PMID: 36460881 DOI: 10.1007/s12032-022-01888-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 11/08/2022] [Indexed: 12/04/2022]
Abstract
Natural killer T (NKT) cells are a specific T cell subset known to express the αβ-T cell receptor (TCR) for antigens identification and express typical NK cell specifications, such as surface expression of CD56 and CD16 markers as well as production of granzyme. Human NKT cells are divided into two subgroups based on their cytokine receptor and TCR repertoire. Both of them are CD1-restricted and recognize lipid antigens presented by CD1d molecules. Studies have demonstrated that these cells are essential in defense against malignancies. These cells secret proinflammatory and regulatory cytokines that stimulate or suppress immune system responses. In several murine tumor models, activation of type I NKT cells induces tumor rejection and inhibits metastasis's spread. However, type II NKT cells are associated with an inhibitory and regulatory function during tumor immune responses. Variant NKT cells may suppress tumor immunity via different mechanisms that require cross-talk with other immune-regulatory cells. NKT-like cells display high tumor-killing abilities against many tumor cells. In the recent decade, different studies have been performed based on the application of NKT-based immunotherapy for cancer therapy. Moreover, manipulation of NKT cells through administering autologous dendritic cell (DC) loaded with α-galactosylceramide (α-GalCer) and direct α-GalCer injection has also been tested. In this review, we described different subtypes of NKT cells, their function in the anti-tumor immune responses, and the application of NKT cells in cancer immunotherapy from bench to bed.
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30
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Garrison Z, Hornick N, Cheng J, Kulkarni RP. Circulating biomarkers of response to immunotherapy and immune-related adverse events. Expert Rev Mol Diagn 2022; 22:855-865. [PMID: 36193802 DOI: 10.1080/14737159.2022.2130688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
INTRODUCTION Immune checkpoint blockade has revolutionized cancer treatment. However, response rates vary, and these treatments have a high rate of immune-related side effects, which can be limiting. Thus, tests to predict who will respond and who may experience side effects are of critical importance toward realizing the ultimate goal of precision oncology. AREAS COVERED We review several of the most recent advances in circulating biomarkers that have been reported to be useful in predicting response and immune-related adverse events (irAE) to checkpoint blockade immunotherapies (CBI). We focus on high-quality studies published within the last few years. We highlight significant findings, identify areas for improvement, and provide recommendations on how these biomarkers may be translated into clinical utility. EXPERT OPINION As newer immunotherapies are developed, there is a pressing need to identify circulating biomarkers that can help predict responses and side effects. Current studies are mostly small-scale and retrospective; there is a need for larger-scale and prospective studies to help validate several of the biomarkers detailed here. As oncology focuses more on precision-based approaches, it is likely that a combination of biomarkers, including circulating ones as detailed here, will have critical utility in guiding clinical decisions.
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Affiliation(s)
- Zachary Garrison
- Department of Dermatology, Oregon Health & Science University, Portland, OR, USA
| | - Noah Hornick
- Department of Dermatology, Oregon Health & Science University, Portland, OR, USA
| | - Jeffrey Cheng
- Department of Dermatology, University of California, San Francisco, CA, USA
| | - Rajan P Kulkarni
- Department of Dermatology, Oregon Health & Science University, Portland, OR, USA.,Cancer Early Detection Advanced Research Center (CEDAR), Portland, OR, USA.,Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.,Operative Care Division, U.S. Department of Veterans Affairs Portland Health Care System, Portland, OR, USA
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31
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Khachornsakkul K, Dungchai W, Pamme N. Distance-Based All-In-One Immunodevice for Point-of-Care Monitoring of Cytokine Interleukin-6. ACS Sens 2022; 7:2410-2419. [PMID: 35972061 DOI: 10.1021/acssensors.2c01122] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
We report the development of a distance-based paper analytical device combined with a hydrophilic bridge valve (B-dPAD) as a quantitative immunoassay method to monitor human interleukin-6 (IL-6) in human samples. Our device design features (i) a circular sample inlet zone, (ii) a circular capture zone with immobilized anti-IL-6 (anti-Ab1), and (iii) a detection zone channel coated with methylene blue (MB). Two hydrophilic valves are positioned between these three zones. IL-6 levels were determined quantitatively by measuring the extent of degradation of MB to a colorless product along the length of the detection zone channel. Following method optimization, we obtained a linear range from 0.05 to 25.0 pg/mL (R2 = 0.9995) and a detection limit (LOD) of 0.05 pg/mL by the naked-eye readout. This is directly within the clinically relevant range. The system does not require any external instrumentation, and the bridge valves can be easily connected and disconnected by a minimally trained operator. The total analysis time is 35 min, significantly reduced from a typical ELISA assay, which takes around 1 h since the B-dPAD workflow circumvents washing steps. The device was tested for IL-6 quantification in human saliva and urine samples of volunteers, with no significant difference found between our method and the standard clinical laboratory method at 95% confidence levels. Recoveries ranged from 98 to 105% with the highest standard deviation at 3.9%. Our B-dPAD immunodevice is therefore a promising approach for rapid IL-6 monitoring in the context of point-of-care diagnostics and analysis in resource-limited settings.
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Affiliation(s)
- Kawin Khachornsakkul
- Department of Chemistry, Faculty of Science, King Mongkut's University of Technology, Prachautid Road, Thungkru, Thonburi, Bangkok 10140, Thailand.,Department/ of Chemistry and Biochemistry, University of Hull, Cottingham Road, Hull HU6 7RX, United Kingdom
| | - Wijitar Dungchai
- Department of Chemistry, Faculty of Science, King Mongkut's University of Technology, Prachautid Road, Thungkru, Thonburi, Bangkok 10140, Thailand
| | - Nicole Pamme
- Department/ of Chemistry and Biochemistry, University of Hull, Cottingham Road, Hull HU6 7RX, United Kingdom.,Department of Materials and Environmental Chemistry, Stockholm University, Svante Arrhenius väg 16C, Stockholm 106 91, Sweden
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32
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Adhoute X, De Matharel M, Mineur L, Pénaranda G, Ouizeman D, Toullec C, Tran A, Castellani P, Rollet A, Oules V, Perrier H, Si Ahmed SN, Bourliere M, Anty R. Second-line therapy for advanced hepatocellular carcinoma with regorafenib or cabozantinib: Multicenter French clinical experience in real-life after matching. World J Gastrointest Oncol 2022; 14:1510-1527. [PMID: 36160737 PMCID: PMC9412937 DOI: 10.4251/wjgo.v14.i8.1510] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/08/2022] [Accepted: 07/17/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Starting a second-line systemic treatment for hepatocellular carcinoma (HCC) is a common situation. The only therapeutic options in France are two broad-spectrum tyrosine kinase inhibitors (TKIs), regorafenib (REG) and cabozantinib (CBZ), but no comparative real-life studies are available.
AIM To evaluate the progression-free survival (PFS) of patients treated with REG or CBZ, we investigated the disease control rate (DCR), overall survival (OS), and safety of both drugs. To identify the variables associated with disease progression over time.
METHODS A retrospective multicenter study was performed on the clinical data of patients attending one of three referral centers (Avignon, Marseille, and Nice) between January 2017 and March 2021 using propensity score matching. PFS and OS were assessed using the Kaplan-Meier method. Multivariate analysis (MA) of progression risk factors over time was performed in matched-pair groups.
RESULTS Fifty-eight patients 68 (62-74) years old with HCC, Barcelona clinic liver cancer (BCLC) B/C (86%), Child-Pugh (CP)-A/B (24%) received REG for 3.4 (1.4-10.5) mo as second-line therapy. Twenty-eight patients 68 (60-73) years, BCLC B/C (75%), CP-A/B (25%) received CBZ for 3.7 (1.8-4.9) mo after first-line treatment with sorafenib [3 (2-4) (CBZ) vs 4 (2.9-11.8) mo (REG), P = 0.0226]. Twenty percent of patients received third-line therapy. After matching, PFS and DCR were not significantly different after a median follow-up of 6.2 (2.7-11.7) mo (REG) vs 5.2 (4-7.2) mo (CBZ), P = 0.6925. There was no difference in grade 3/4 toxicities, dose reductions, or interruptions. The OS of CP-A patients was 8.3 (5.2-24.8) vs 4.9 (1.6-11.7) mo (CP-B), P = 0.0468. The MA of risk factors for progression over time identified C-reactive protein (CRP) > 10 mg/L, neutrophil-to-lymphocyte ratio (NLR) > 3, and aspartate aminotransferase (AST) > 45 IU as predictive factors.
CONCLUSION This multicenter indirect comparative study found no significant difference in PFS between REG and CBZ as second-line therapy for advanced HCC. Elevated levels of inflammatory markers (CRP and NLR) and AST were associated with non-control of TKIs over time. A 2-mo online progression risk calculation is proposed.
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Affiliation(s)
- Xavier Adhoute
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille 13000, France
| | - Marie De Matharel
- Department of Gastroenterology and Hepatology, Hôpital Universitaire de l’Archet, Nice 06000, France
| | - Laurent Mineur
- Department of Oncology, Institut Sainte-Catherine, Avignon 84000, France
| | | | - Dann Ouizeman
- Department of Gastroenterology and Hepatology, Hôpital Universitaire de l’Archet, Nice 06000, France
| | - Clemence Toullec
- Department of Oncology, Institut Sainte-Catherine, Avignon 84000, France
| | - Albert Tran
- Department of Gastroenterology and Hepatology, Hôpital Universitaire de l’Archet, Nice 06000, France
| | - Paul Castellani
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille 13000, France
| | - Armelle Rollet
- Department of Oncology, Institut Sainte-Catherine, Avignon 84000, France
| | - Valérie Oules
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille 13000, France
| | - Hervé Perrier
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille 13000, France
| | - Si Nafa Si Ahmed
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille 13000, France
| | - Marc Bourliere
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille 13000, France
| | - Rodolphe Anty
- Department of Gastroenterology and Hepatology, Hôpital Universitaire de l’Archet, Nice 06000, France
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Liu X, Wu W, Fang L, Liu Y, Chen W. TNF-α Inhibitors and Other Biologic Agents for the Treatment of Immune Checkpoint Inhibitor-Induced Myocarditis. Front Immunol 2022; 13:922782. [PMID: 35844550 PMCID: PMC9283712 DOI: 10.3389/fimmu.2022.922782] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 06/08/2022] [Indexed: 01/11/2023] Open
Abstract
With anti-PD-1 antibodies serving as a representative drug, immune checkpoint inhibitors (ICIs) have become the main drugs used to treat many advanced malignant tumors. However, immune-related adverse events (irAEs), which might involve multiple organ disorders, should not be ignored. ICI-induced myocarditis is an uncommon but life-threatening irAE. Glucocorticoids are the first choice of treatment for patients with ICI-induced myocarditis, but high proportions of steroid-refractory and steroid-resistant cases persist. According to present guidelines, tumor necrosis factor alpha (TNF-α) inhibitors are recommended for patients who fail to respond to steroid therapy and suffer from severe cardiac toxicity, although evidence-based studies are lacking. On the other hand, TNF-α inhibitors are contraindicated in patients with moderate-to-severe heart failure. This review summarizes real-world data from TNF-α inhibitors and other biologic agents for ICI-induced myocarditis to provide more evidence of the efficacy and safety of TNF-α inhibitors and other biologic agents.
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Affiliation(s)
| | | | | | | | - Wei Chen
- *Correspondence: Yingxian Liu, ; Wei Chen,
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Geng J, Wang J, Zhang Y, Song W, Zhu J, Chen J, Wu Z. The Effect of a Combined Modified Pectoral and Stellate Ganglion Block on Stress and Inflammatory Response in Patients Undergoing Modified Radical Mastectomy. Int J Breast Cancer 2022; 2022:3359130. [PMID: 35707316 PMCID: PMC9192316 DOI: 10.1155/2022/3359130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 05/13/2022] [Accepted: 05/19/2022] [Indexed: 11/17/2022] Open
Abstract
Background and Aims Regional anaesthesia reports to attenuate stress and inflammatory responses associated with surgical resection; however, the effectiveness of combined nerve blocks is less often investigated. We evaluated whether a combination of a pectoral nerve block (PNB) and stellate ganglion block (SGB) is more effective than a PNB alone in reducing these responses in women undergoing modified radical mastectomy (MRM). Methods This is a prospective randomized controlled trial. Fifty patients with breast cancer were randomly allocated to receive an ultrasound-guided PNB (n = 25, PNB only group) or ultrasound-guided PNB combined with SGB (n = 25, combined blockade group). The primary outcome was perioperative plasma level of interleukin- (IL-) 6. Secondary outcomes included perioperative plasma levels of cortisol, glucose, IL-8, and tumour necrosis factor- (TNF-) α, pain scores, haemodynamic variables, sleep quality, and complications postsurgery. Results The combined blockade group exhibited significantly lower IL-6 and TNF-α levels 24 h postsurgery. Cortisol levels were significantly lower in the combined blockade group at the end of the surgery. Glucose levels at the time of incision were lower in the combined blockade group. Pain scores up to 12 h postsurgery were significantly lower in the combined blockade group, which also exhibited better perioperative haemodynamic stability. Patients in the combined blockade group reported better sleep quality on the night of surgery. Conclusion In patients undergoing MRM, PNB combined with SGB block effectively blunted perioperative inflammatory response than PNB alone. A combined block approach can also alleviate stress response and postoperative acute pain with stable perioperative haemodynamics and better postoperative sleep quality.
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Affiliation(s)
- Jun Geng
- Department of Anesthesiology, Jiangyin Hospital Affiliated to Southeast University Medical School, Wuxi, 214400 Jiangsu, China
| | - Jing Wang
- Department of Anesthesiology, Jiangyin Hospital Affiliated to Southeast University Medical School, Wuxi, 214400 Jiangsu, China
| | - Yaowen Zhang
- Department of Anesthesiology, Jiangyin Hospital Affiliated to Southeast University Medical School, Wuxi, 214400 Jiangsu, China
| | - Wenxiang Song
- Department of Anesthesiology, Jiangyin Hospital Affiliated to Southeast University Medical School, Wuxi, 214400 Jiangsu, China
| | - Junjia Zhu
- Department of General Surgery, Jiangyin Hospital Affiliated to Southeast University Medical School, Wuxi, 214400 Jiangsu, China
| | - Jianqing Chen
- Department of Anesthesiology, Jiangyin Hospital Affiliated to Southeast University Medical School, Wuxi, 214400 Jiangsu, China
| | - Zhen Wu
- Department of Anesthesiology, Jiangyin Hospital Affiliated to Southeast University Medical School, Wuxi, 214400 Jiangsu, China
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Cheah S, Bassett JK, Bruinsma FJ, Cozen W, Hopper JL, Jayasekara H, Joshua D, MacInnis RJ, Prince HM, Vajdic CM, van Leeuwen MT, Doo NW, Harrison SJ, English DR, Giles GG, Milne RL. Alcohol and tobacco use and risk of multiple myeloma: A case-control study. EJHAEM 2022; 3:109-120. [PMID: 35846225 PMCID: PMC9175849 DOI: 10.1002/jha2.337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 10/15/2021] [Accepted: 10/16/2021] [Indexed: 11/08/2022]
Abstract
Multiple myeloma (MM) is the second most common hematological cancer and causes significant mortality and morbidity. Knowledge regarding modifiable risk factors for MM remains limited. This analysis of an Australian population-based case-control family study investigates whether smoking or alcohol consumption is associated with risk of MM and related diseases. Incident cases (n = 789) of MM were recruited via cancer registries in Victoria and New South Wales. Controls (n = 1,113) were either family members of cases (n = 696) or controls recruited for a similarly designed study of renal cancers (n = 417). Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional multivariable logistic regression. Heavy intake (>20 g ethanol/day) of alcohol had a lower risk of MM compared with nondrinkers (OR = 0.68, 95% CI: 0.50-0.93), and there was an inverse dose-response relationship for average daily alcohol intake (OR per 10 g ethanol per day = 0.92, 95% CI: 0.86-0.99); there was no evidence of an interaction with sex. There was no evidence of an association with MM risk for smoking-related exposures (p > 0.18). The associations between smoking and alcohol with MM are similar to those with non-Hodgkin lymphoma. Further research into potential underlying mechanisms is warranted.
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Affiliation(s)
- Simon Cheah
- Cancer Epidemiology DivisionCancer Council VictoriaMelbourneAustralia
- Centre for Epidemiology and BiostatisticsMelbourne School of Population and Global HealthUniversity of MelbourneMelbourneAustralia
| | - Julie K. Bassett
- Cancer Epidemiology DivisionCancer Council VictoriaMelbourneAustralia
| | - Fiona J. Bruinsma
- Cancer Epidemiology DivisionCancer Council VictoriaMelbourneAustralia
- Centre for Epidemiology and BiostatisticsMelbourne School of Population and Global HealthUniversity of MelbourneMelbourneAustralia
| | - Wendy Cozen
- Department of Preventive MedicineUniversity of Southern CaliforniaLos AngelesCaliforniaUSA
| | - John L. Hopper
- Centre for Epidemiology and BiostatisticsMelbourne School of Population and Global HealthUniversity of MelbourneMelbourneAustralia
| | - Harindra Jayasekara
- Cancer Epidemiology DivisionCancer Council VictoriaMelbourneAustralia
- Centre for Epidemiology and BiostatisticsMelbourne School of Population and Global HealthUniversity of MelbourneMelbourneAustralia
| | - Douglas Joshua
- Royal Prince Alfred HospitalSydney Medical SchoolUniversity of SydneySydneyAustralia
| | - Robert J. MacInnis
- Cancer Epidemiology DivisionCancer Council VictoriaMelbourneAustralia
- Centre for Epidemiology and BiostatisticsMelbourne School of Population and Global HealthUniversity of MelbourneMelbourneAustralia
| | - H. Miles Prince
- Sir Peter MacCallum Department of OncologyUniversity of MelbourneMelbourneAustralia
- Epworth HealthcareMelbourneAustralia
| | - Claire M. Vajdic
- Centre for Big Data Research in HealthThe University of New South WalesSydneyAustralia
| | - Marina T. van Leeuwen
- Centre for Big Data Research in HealthThe University of New South WalesSydneyAustralia
| | | | - Simon J. Harrison
- Sir Peter MacCallum Department of OncologyUniversity of MelbourneMelbourneAustralia
- Clinical HaematologyPeter MacCallum Cancer Centre and Royal Melbourne HospitalParkvilleAustralia
| | - Dallas R. English
- Cancer Epidemiology DivisionCancer Council VictoriaMelbourneAustralia
- Centre for Epidemiology and BiostatisticsMelbourne School of Population and Global HealthUniversity of MelbourneMelbourneAustralia
| | - Graham G. Giles
- Cancer Epidemiology DivisionCancer Council VictoriaMelbourneAustralia
- Centre for Epidemiology and BiostatisticsMelbourne School of Population and Global HealthUniversity of MelbourneMelbourneAustralia
- School of Clinical Sciences at Monash HealthPrecision MedicineMonash UniversityClaytonMelbourneAustralia
| | - Roger L. Milne
- Cancer Epidemiology DivisionCancer Council VictoriaMelbourneAustralia
- Centre for Epidemiology and BiostatisticsMelbourne School of Population and Global HealthUniversity of MelbourneMelbourneAustralia
- School of Clinical Sciences at Monash HealthPrecision MedicineMonash UniversityClaytonMelbourneAustralia
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Ren Z, Peng L, Chen S, Pu Y, Lv H, Wei H, Wan C. Lactiplantibacillus plantarum 1201 Inhibits Intestinal Infection of Salmonella enterica subsp. enterica Serovar Typhimurium Strain ATCC 13311 in Mice with High-Fat Diet. Foods 2021; 11:85. [PMID: 35010211 PMCID: PMC8750823 DOI: 10.3390/foods11010085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/03/2021] [Accepted: 12/27/2021] [Indexed: 11/17/2022] Open
Abstract
Salmonella Typhimurium is widely distributed in food. It can colonise the gastrointestinal tract after ingestion, causing lamina propria edema, inflammatory cell infiltration, and mucosal epithelial decomposition. A high-fat diet (HFD) can induce an inflammatory response, but whether HFD can increase the infection level of S. Typhimurium is unknown. We established a model of Salmonella enterica subsp. enterica serovar Typhimurium strain ATCC 13311 ATCC 13311 infection in healthy adult mice with a maintenance diet (MD) or HFD to explore the effect of Lactiplantibacillus plantarum 1201 intervention on S. Typhimurium ATCC 13311 colonization and its protective effects on mice. HFD exacerbated the infection of S. Typhimurium ATCC 13311, while the intervention of L. plantarum 1201 effectively mitigated this process. L. plantarum 1201 can reduce the colonies of S. ATCC 13311 in the intestines and tissues; and reduce intestinal inflammation by down-regulating the level of TLR4/NF-κB pathway related proteins in serum and the expression of related inflammatory factors in the colon and jejunum. Since L. plantarum 1201 can inhibit the colonization of S. Typhimurium ATCC 13311 and relieve inflammation in HFD, current research may support the use of L. plantarum 1201 to prevent S. Typhimurium infection.
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Affiliation(s)
- Zhongyue Ren
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China; (Z.R.); (L.P.); (S.C.); (Y.P.); (H.L.); (H.W.)
- School of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Lingling Peng
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China; (Z.R.); (L.P.); (S.C.); (Y.P.); (H.L.); (H.W.)
- School of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Shufang Chen
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China; (Z.R.); (L.P.); (S.C.); (Y.P.); (H.L.); (H.W.)
- School of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Yi Pu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China; (Z.R.); (L.P.); (S.C.); (Y.P.); (H.L.); (H.W.)
- School of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Huihui Lv
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China; (Z.R.); (L.P.); (S.C.); (Y.P.); (H.L.); (H.W.)
- School of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Hua Wei
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China; (Z.R.); (L.P.); (S.C.); (Y.P.); (H.L.); (H.W.)
- School of Food Science and Technology, Nanchang University, Nanchang 330047, China
- Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, China
| | - Cuixiang Wan
- School of Food Science and Technology, Nanchang University, Nanchang 330047, China
- Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, China
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Wei LY, Lin HC, Tsai FC, Ko JY, Kok SH, Cheng SJ, Lee JJ, Chia JS. Effects of Interleukin-6 on STAT3-regulated signaling in oral cancer and as a prognosticator of patient survival. Oral Oncol 2021; 124:105665. [PMID: 34891076 DOI: 10.1016/j.oraloncology.2021.105665] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 11/19/2021] [Accepted: 12/01/2021] [Indexed: 12/27/2022]
Abstract
OBJECTIVES Human oral squamous cell carcinoma (OSCC) produces an inflammatory microenvironment enriched with cytokines including interleukin-6 (IL-6); however, the underlying molecular mechanisms of OSCC progression are unclear. We aimed to delineate the STAT3-mediated signaling pathways involved in tumor cell survival and growth. MATERIALS AND METHODS Immunohistochemistry was used to semi-quantitate IL-6 and STAT3 in 111 OSCC tissues. IL-6-induced STAT3 signaling pathways and effects on tumor cell survival and progression were investigated in vitro and in xenograft mouse models. Effects of blocking IL-6-induced activation of STAT3 in an OSCC cell line were determined in vitro. RESULTS A higher level of IL-6 or STAT3 in situ was associated with an unfavorable prognosis in OSCC patients with regard to both disease-free and overall survival rates. Overexpressed or exogenous IL-6 could induce SAS cell proliferationin vitroand significantly enhanced tumor growthin vivo. In addition, knockdown or inhibition of STAT3 expression in SAS cells significantly reduced tumor growth and abolished the responsiveness to IL-6 stimulation. Siltuximab or Tocilizumab could also significantly suppress IL-6-induced STAT3 phosphorylation and STAT3 nuclear translocation, resulting in a significant decrease of downstream anti-apoptotic proteins Bcl-2, Bcl-xL, and survivin. CONCLUSION The IL-6 level in the tumor microenvironment could serve as a stage-independent predictor of OSCC progression and survival. Further, IL-6 may play a role in this disease through STAT3-dependent upregulation of anti-apoptotic genes and subsequent proliferation of tumor cells.
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Affiliation(s)
- Ling-Ying Wei
- Department of Dentistry, National Taiwan University Hospital, Bei-hu Branch, Taipei, Taiwan; Department of Oral and Maxillofacial Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Hsuan-Chao Lin
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Feng-Chiao Tsai
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jenq-Yuh Ko
- Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan
| | - Sang-Heng Kok
- Department of Oral and Maxillofacial Surgery, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan
| | - Shih-Jung Cheng
- Department of Oral and Maxillofacial Surgery, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan
| | - Jang-Jaer Lee
- Department of Oral and Maxillofacial Surgery, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan
| | - Jean-San Chia
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.
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Sajjadi-Dokht M, Merza Mohamad TA, Rahman HS, Maashi MS, Danshina S, Shomali N, Solali S, Marofi F, Zeinalzadeh E, Akbari M, Adili A, Aslaminabad R, Hagh MF, Jarahian M. MicroRNAs and JAK/STAT3 signaling: A new promising therapeutic axis in blood cancers. Genes Dis 2021; 9:849-867. [PMID: 35685482 PMCID: PMC9170603 DOI: 10.1016/j.gendis.2021.10.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 09/16/2021] [Accepted: 10/22/2021] [Indexed: 11/27/2022] Open
Abstract
Blood disorders include a wide spectrum of blood-associated malignancies resulting from inherited or acquired defects. The ineffectiveness of existing therapies against blood disorders arises from different reasons, one of which is drug resistance, so different types of leukemia may show different responses to treatment. Leukemia occurs for a variety of genetic and acquired reasons, leading to uncontrolled proliferation in one or more cell lines. Regarding the genetic defects, oncogene signal transducer and activator of transcription (STAT) family transcription factor, especially STAT3, play an essential role in hematological disorders onset and progress upon mutations, dysfunction, or hyperactivity. Besides, microRNAs, as biological molecules, has been shown to play a dual role in either tumorigenesis and tumor suppression in various cancers. Besides, a strong association between STAT3 and miRNA has been reported. For example, miRNAs can regulate STAT3 via targeting its upstream mediators such as IL6, IL9, and JAKs or directly binding to the STAT3 gene. On the other hand, STAT3 can regulate miRNAs. In this review study, we aimed to determine the role of either microRNAs and STAT3 along with their effect on one another's activity and function in hematological malignancies.
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Current Perspective on the Natural Compounds and Drug Delivery Techniques in Glioblastoma Multiforme. Cancers (Basel) 2021; 13:cancers13112765. [PMID: 34199460 PMCID: PMC8199612 DOI: 10.3390/cancers13112765] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/30/2021] [Accepted: 05/31/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Glioblastoma multiforme (GBM) is one of the belligerent neoplasia that metastasize to other brain regions and invade nearby healthy tissues. However, the treatments available are associated with some limitations, such as high variations in solid tumors and deregulation of multiple cellular pathways. The heterogeneity of the GBM tumor and its aggressive infiltration into the nearby tissues makes it difficult to treat. Hence, the development of multimodality therapy that can be more effective, novel, with fewer side effects, improving the prognosis for GBM is highly desired. This review evaluated the use of natural phytoconstituents as an alternative for the development of a new therapeutic strategy. The key aspects of GBM and the potential of drug delivery techniques were also assessed, for tumor site delivery with limited side-effects. These efforts will help to provide better therapeutic options to combat GBM in future. Abstract Glioblastoma multiforme (GBM) is one of the debilitating brain tumors, being associated with extremely poor prognosis and short median patient survival. GBM is associated with complex pathogenesis with alterations in various cellular signaling events, that participate in cell proliferation and survival. The impairment in cellular redox pathways leads to tumorigenesis. The current standard pharmacological regimen available for glioblastomas, such as radiotherapy and surgical resection following treatment with chemotherapeutic drug temozolomide, remains fatal, due to drug resistance, metastasis and tumor recurrence. Thus, the demand for an effective therapeutic strategy for GBM remains elusive. Hopefully, novel products from natural compounds are suggested as possible solutions. They protect glial cells by reducing oxidative stress and neuroinflammation, inhibiting proliferation, inducing apoptosis, inhibiting pro-oncogene events and intensifying the potent anti-tumor therapies. Targeting aberrant cellular pathways in the amelioration of GBM could promote the development of new therapeutic options that improve patient quality of life and extend survival. Consequently, our review emphasizes several natural compounds in GBM treatment. We also assessed the potential of drug delivery techniques such as nanoparticles, Gliadel wafers and drug delivery using cellular carriers which could lead to a novel path for the obliteration of GBM.
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Dhall A, Patiyal S, Sharma N, Usmani SS, Raghava GPS. Computer-aided prediction and design of IL-6 inducing peptides: IL-6 plays a crucial role in COVID-19. Brief Bioinform 2021; 22:936-945. [PMID: 33034338 PMCID: PMC7665369 DOI: 10.1093/bib/bbaa259] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 08/28/2020] [Accepted: 09/13/2020] [Indexed: 12/16/2022] Open
Abstract
Interleukin 6 (IL-6) is a pro-inflammatory cytokine that stimulates acute phase responses, hematopoiesis and specific immune reactions. Recently, it was found that the IL-6 plays a vital role in the progression of COVID-19, which is responsible for the high mortality rate. In order to facilitate the scientific community to fight against COVID-19, we have developed a method for predicting IL-6 inducing peptides/epitopes. The models were trained and tested on experimentally validated 365 IL-6 inducing and 2991 non-inducing peptides extracted from the immune epitope database. Initially, 9149 features of each peptide were computed using Pfeature, which were reduced to 186 features using the SVC-L1 technique. These features were ranked based on their classification ability, and the top 10 features were used for developing prediction models. A wide range of machine learning techniques has been deployed to develop models. Random Forest-based model achieves a maximum AUROC of 0.84 and 0.83 on training and independent validation dataset, respectively. We have also identified IL-6 inducing peptides in different proteins of SARS-CoV-2, using our best models to design vaccine against COVID-19. A web server named as IL-6Pred and a standalone package has been developed for predicting, designing and screening of IL-6 inducing peptides (https://webs.iiitd.edu.in/raghava/il6pred/).
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Affiliation(s)
- Anjali Dhall
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
| | - Sumeet Patiyal
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
| | - Neelam Sharma
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
| | - Salman Sadullah Usmani
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
| | - Gajendra P S Raghava
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
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Liang C, Luan J, Wang Z, Jiang Q, Gupta R, Cao S, Liu KK, Morrissey JJ, Kharasch ED, Naik RR, Singamaneni S. Gold Nanorod Size-Dependent Fluorescence Enhancement for Ultrasensitive Fluoroimmunoassays. ACS APPLIED MATERIALS & INTERFACES 2021; 13:11414-11423. [PMID: 33620204 DOI: 10.1021/acsami.0c20303] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Plasmon-enhanced fluorescence (PEF) is a simple and highly effective approach for improving the signal-to-noise ratio and sensitivity of various fluorescence-based bioanalytical techniques. Here, we show that the fluorescence enhancement efficacy of gold nanorods (AuNRs), which are widely employed for PEF, is highly dependent on their absolute dimensions (i.e., length and diameter). Notably, an increase in the dimensions (length × diameter) of the AuNRs from 46 × 14 to 120 × 38 nm2 while holding the aspect ratio constant leads to nearly 300% improvement in fluorescence enhancement efficiency. Further increase in the AuNR size leads to a decrease of the fluorescence enhancement efficiency. Through finite-difference time-domain (FDTD) simulation, we reveal that the size-dependent fluorescence enhancement efficiency of AuNR stems from the size-dependent electromagnetic field around the plasmonic nanostructures. AuNRs with optimal dimensions resulted in a nearly 120-fold enhancement in the ensemble fluorescence emission from molecular fluorophores bound to the surface. These plasmonic nanostructures with optimal dimensions also resulted in a nearly 30-fold improvement in the limit of detection of human interleukin-6 (IL-6) compared to AuNRs with smaller size, which are routinely employed in PEF.
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Affiliation(s)
- Chao Liang
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Department of Mechanical Engineering and Materials Science, Institute of Materials Science and Engineering, Washington University in St. Louis, St Louis, Missouri 63130, United States
| | - Jingyi Luan
- Department of Mechanical Engineering and Materials Science, Institute of Materials Science and Engineering, Washington University in St. Louis, St Louis, Missouri 63130, United States
| | - Zheyu Wang
- Department of Mechanical Engineering and Materials Science, Institute of Materials Science and Engineering, Washington University in St. Louis, St Louis, Missouri 63130, United States
| | - Qisheng Jiang
- Auragent Bioscience LLC, St Louis, Missouri 63108, United States
| | - Rohit Gupta
- Department of Mechanical Engineering and Materials Science, Institute of Materials Science and Engineering, Washington University in St. Louis, St Louis, Missouri 63130, United States
| | - Sisi Cao
- Department of Mechanical Engineering and Materials Science, Institute of Materials Science and Engineering, Washington University in St. Louis, St Louis, Missouri 63130, United States
| | - Keng-Ku Liu
- Auragent Bioscience LLC, St Louis, Missouri 63108, United States
| | - Jeremiah J Morrissey
- Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri 63110, United States
- Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri 63110, United States
| | - Evan D Kharasch
- Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina 27710, United States
| | - Rajesh R Naik
- 711th Human Performance Wing, Air Force Research Laboratory, Wright-Patterson Air Force Base, Dayton, Ohio 45433, United States
| | - Srikanth Singamaneni
- Department of Mechanical Engineering and Materials Science, Institute of Materials Science and Engineering, Washington University in St. Louis, St Louis, Missouri 63130, United States
- Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri 63110, United States
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Mumtaz SM, Bhardwaj G, Goswami S, Tonk RK, Goyal RK, Abu-Izneid T, Pottoo FH. Management of Glioblastoma Multiforme by Phytochemicals: Applications of Nanoparticle-Based Targeted Drug Delivery System. Curr Drug Targets 2021; 22:429-442. [PMID: 32718288 DOI: 10.2174/1389450121666200727115454] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 05/11/2020] [Accepted: 05/18/2020] [Indexed: 11/22/2022]
Abstract
The Glioblastoma Multiforme (GBM; grade IV astrocytoma) exhorts tumors of star-shaped glial cells in the brain. It is a fast-growing tumor that spreads to nearby brain regions specifically to cerebral hemispheres in frontal and temporal lobes. The etiology of GBM is unknown, but major risk factors are genetic disorders like neurofibromatosis and schwannomatosis, which develop the tumor in the nervous system. The management of GBM with chemo-radiotherapy leads to resistance, and current drug regimen like Temozolomide (TMZ) is less efficacious. The reasons behind the failure of drugs are due to DNA alkylation in the cell cycle by enzyme DNA guanidase and mitochondrial dysfunction. Naturally occurring bioactive compounds from plants referred as phytochemicals, serve as vital sources for anti-cancer drugs. Some prototypical examples include taxol analogs, vinca alkaloids (vincristine, vinblastine), podophyllotoxin analogs, camptothecin, curcumin, aloe-emodin, quercetin, berberine etc. These phytochemicals often regulate diverse molecular pathways, which are implicated in the growth and progression of cancers. However, the challenges posed by the presence of BBB/BBTB to restrict the passage of these phytochemicals, culminates in their low bioavailability and relative toxicity. In this review, we integrated nanotech as a novel drug delivery system to deliver phytochemicals from traditional medicine to the specific site within the brain for the management of GBM.
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Affiliation(s)
- Sayed M Mumtaz
- Department of Pharmacology and Toxicology, Delhi Pharmaceutical Sciences and Research University, PusphVihar Sector-3, M.B Road, New Delhi, India
| | - Gautam Bhardwaj
- Department of Pharmaceutical Chemistry, Delhi Pharmaceutical Sciences and Research University, PusphVihar Sector-3, M.B Road, New Delhi, India
| | - Shikha Goswami
- Department of Pharmacology and Toxicology, Delhi Pharmaceutical Sciences and Research University, PusphVihar Sector-3, M.B Road, New Delhi, India
| | - Rajiv Kumar Tonk
- Department of Pharmaceutical Chemistry, Delhi Pharmaceutical Sciences and Research University, PusphVihar Sector-3, M.B Road, New Delhi, India
| | - Ramesh K Goyal
- Department of Pharmacology and Toxicology, Delhi Pharmaceutical Sciences and Research University, PusphVihar Sector-3, M.B Road, New Delhi, India
| | - Tareq Abu-Izneid
- Pharmaceutical Sciences, College of Pharmacy, Al Ain University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Faheem Hyder Pottoo
- Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. BOX 1982, Dammam 31441, Saudi Arabia
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Abstract
IL-6 is involved both in immune responses and in inflammation, hematopoiesis, bone metabolism and embryonic development. IL-6 plays roles in chronic inflammation (closely related to chronic inflammatory diseases, autoimmune diseases and cancer) and even in the cytokine storm of corona virus disease 2019 (COVID-19). Acute inflammation during the immune response and wound healing is a well-controlled response, whereas chronic inflammation and the cytokine storm are uncontrolled inflammatory responses. Non-immune and immune cells, cytokines such as IL-1β, IL-6 and tumor necrosis factor alpha (TNFα) and transcription factors nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play central roles in inflammation. Synergistic interactions between NF-κB and STAT3 induce the hyper-activation of NF-κB followed by the production of various inflammatory cytokines. Because IL-6 is an NF-κB target, simultaneous activation of NF-κB and STAT3 in non-immune cells triggers a positive feedback loop of NF-κB activation by the IL-6-STAT3 axis. This positive feedback loop is called the IL-6 amplifier (IL-6 Amp) and is a key player in the local initiation model, which states that local initiators, such as senescence, obesity, stressors, infection, injury and smoking, trigger diseases by promoting interactions between non-immune cells and immune cells. This model counters dogma that holds that autoimmunity and oncogenesis are triggered by the breakdown of tissue-specific immune tolerance and oncogenic mutations, respectively. The IL-6 Amp is activated by a variety of local initiators, demonstrating that the IL-6-STAT3 axis is a critical target for treating diseases.
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Affiliation(s)
- Toshio Hirano
- National Institutes for Quantum and Radiological Science and Technology, Anagawa, Inage-ku, Chiba, Japan
- Division of Molecular Psychoimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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Chen HY, Hu Y, Lu NH, Zhu Y. Caudal type homeoboxes as a driving force in Helicobacter pylori infection-induced gastric intestinal metaplasia. Gut Microbes 2020; 12:1-12. [PMID: 33031021 PMCID: PMC7553748 DOI: 10.1080/19490976.2020.1809331] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
(H. pylori), a common pathogenic bacterium in the stomach, has been demonstrated to be a major cause of gastric cancer (GC). The typical pathological evolution of H. pylori infection-induced GC involves development from gastric atrophy, via intestinal metaplasia (IM) and dysplasia, to intestinal-type GC. During this process, IM is considered to be an "irreversible point" that significantly increases the risk for GC. Therefore, the elucidation of the mechanism underlying IM is of great significance for the prevention and treatment of gastric mucosal carcinogenesis associated with H. pylori infection. Caudal type homeoboxes (CDXs) are transcription factors involved in intestinal differentiation establishment and the maintenance of normal intestinal mucosa and IM. H. pylori infection increases the expression of CDXs through epigenetic regulation, the nuclear factor-kappaB signaling pathway and its downstream proinflammatory factors, and the transforming growth factor-beta signaling pathway, leading to the progression from normal gastric mucosa to IM. However, the precise mechanisms of gastric intestinal metaplasia have not yet been fully elucidated. In this review, we focus on research progress revealing the functions of CDXs in H. pylori infection-induced IM, as well as the regulators modulating this process.
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Affiliation(s)
- Hong-Yan Chen
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yi Hu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Nong-Hua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yin Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China,CONTACT Yin Zhu Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang330006, Jiangxi Province, China
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Lim JS, Lee DY, Kim HS, Park SC, Park JT, Kim HS, Oh WK, Cho KA. Identification of a novel senomorphic agent, avenanthramide C, via the suppression of the senescence-associated secretory phenotype. Mech Ageing Dev 2020; 192:111355. [PMID: 32941937 DOI: 10.1016/j.mad.2020.111355] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 07/14/2020] [Accepted: 09/07/2020] [Indexed: 01/07/2023]
Abstract
Senescent cells are deeply involved in the induction of tissue damage and aging-related diseases. The identification of factors that eliminate senescent cells or inhibit the senescence-associated secretory phenotype (SASP) in these cells is necessary. Here, we report an avenanthramice C (Avn C) extracted from oat as a new SASP modulator. Treatment with Avn C led to a significant reduction in the levels of markers of senescent cells, with no toxicity observed. The SASP was also inhibited by Avn C treatment, similar to non-senescent cells, and the suppression of cell division by autocrine signals associated with SASP was restored. To investigate the mechanism underlying SASP inhibition by Avn C, we analyzed the effect of Avn C in lipopolysaccharide (LPS)-induced inflammation in non-senescent cells. Avn C inhibited nuclear factor κB (NF-κB) activity and the secretion of inflammatory cytokines before or after LPS treatment. Although the activity of MAP kinases, which are NF-κB upstream signals, was inhibited by Avn C in LPS-induced inflammation, only p38 activity was specifically inhibited in senescent cells. Interestingly, the inhibition of p38 in senescent cells was observed through Avn C-induced 5'-adenosine monophosphate-activated protein kinase (AMPK) activity. Avn C-induced inhibition of the SASP is triggered by senescence-related stress.
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Affiliation(s)
- Jae Sung Lim
- Department of Biochemistry, Chonanm National University Medical School, 264 Seoyang-ro, Hwasun-gun, Jeonnam-do, 58128, Republic of Korea; Combinatorial Tumor Immunotherapy Medical Research Center, Chonnam National University Medical School, 264 Seoyang-ro, Hwasun-gun, Jeonnam-do, 58128, Republic of Korea
| | - Da Young Lee
- Department of Biochemistry, Chonanm National University Medical School, 264 Seoyang-ro, Hwasun-gun, Jeonnam-do, 58128, Republic of Korea; Center for Creative Biomedical Scientists, Chonnam National University Medical School, 264 Seoyang-ro, Hwasun-gun, Jeonnam-do, 58128, Republic of Korea
| | - Hyung Seok Kim
- Center for Creative Biomedical Scientists, Chonnam National University Medical School, 264 Seoyang-ro, Hwasun-gun, Jeonnam-do, 58128, Republic of Korea; Department of Forensic Science, Chonnam National University Medical School, 264 Seoyang-ro, Hwasun-gun, Jeonnam-do, 58128, Republic of Korea
| | - Sang Chul Park
- Future Life and Society Research Center, Chonnam National University Medical School, 264 Seoyang-ro, Hwasun-gun, Jeonnam-do, 58128, Republic of Korea
| | - Joon Tae Park
- Department of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, 22012, Republic of Korea
| | - Hyeon Sik Kim
- Medical Photonic Research Center, Korea Photonics Technology Institute, Gwangju, 61007, Republic of Korea
| | - Won Keun Oh
- Korea Bioactive Natural Material Bank, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Kyung A Cho
- Department of Biochemistry, Chonanm National University Medical School, 264 Seoyang-ro, Hwasun-gun, Jeonnam-do, 58128, Republic of Korea; Center for Creative Biomedical Scientists, Chonnam National University Medical School, 264 Seoyang-ro, Hwasun-gun, Jeonnam-do, 58128, Republic of Korea; Future Life and Society Research Center, Chonnam National University Medical School, 264 Seoyang-ro, Hwasun-gun, Jeonnam-do, 58128, Republic of Korea.
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Turky A, Bayoumi AH, Sherbiny FF, El-Adl K, Abulkhair HS. Unravelling the anticancer potency of 1,2,4-triazole-N-arylamide hybrids through inhibition of STAT3: synthesis and in silico mechanistic studies. Mol Divers 2020; 25:403-420. [PMID: 32830299 DOI: 10.1007/s11030-020-10131-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 08/06/2020] [Indexed: 12/26/2022]
Abstract
The discovery of potent STAT3 inhibitors has gained noteworthy impetus in the last decade. In line with this trend, considering the proven biological importance of 1,2,4-triazoles, herein, we are reporting the design, synthesis, pharmacokinetic profiles, and in vitro anticancer activity of novel C3-linked 1,2,4-triazole-N-arylamide hybrids and their in silico proposed mechanism of action via inhibition of STAT3. The 1,2,4-triazole scaffold was selected as a privilege ring system that is embedded in core structures of a variety of anticancer drugs which are either in clinical use or still under clinical trials. The designed 1,2,4-triazole derivatives were synthesized by linking the triazole-thione moiety through amide hydrophilic linkers with diverse lipophilic fragments. In silico study to predict cytotoxicity of the new hybrids against different kinds of human cancer cell lines as well as the non-tumor cells was conducted. The multidrug-resistant human breast adenocarcinoma cells (MDA-MB-231) was found most susceptible to the cytotoxic effect of synthesized compounds and hence were selected to evaluate the in vitro anticancer activity. Four of the designed derivatives showed promising cytotoxicity effects against selected cancer cells, among which compound 12 showed the highest potency (IC50 = 3.61 µM), followed by 21 which displayed IC50 value of 3.93 µM. Also, compounds 14 and 23 revealed equipotent activity with the reference cytotoxic agent doxorubicin. To reinforce these observations, the obtained data of in vitro cytotoxicity have been validated in terms of ligand-protein interaction and new compounds were analyzed for ADMET properties to evaluate their potential to build up as good drug candidates. This study led us to identify two novel C3-linked 1,2,4-triazole-N-arylamide hybrids of interesting antiproliferative potentials as probable lead inhibitors of STAT3 with promising pharmacokinetic profiles.
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Affiliation(s)
- Abdallah Turky
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, 11884, Egypt
| | - Ashraf H Bayoumi
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, 11884, Egypt
| | - Farag F Sherbiny
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, 11884, Egypt
- Pharmaceutical Organic Chemistry Department, College of Pharmacy, Misr University for Science and Technology (MUST), 6th October City, Egypt
| | - Khaled El-Adl
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt
| | - Hamada S Abulkhair
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, 11884, Egypt.
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Horus University - Egypt, International Costal Road, New Damietta, Egypt.
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Chen X, Tian J, Su GH, Lin J. Blocking IL-6/GP130 Signaling Inhibits Cell Viability/Proliferation, Glycolysis, and Colony Forming Activity in Human Pancreatic Cancer Cells. Curr Cancer Drug Targets 2020; 19:417-427. [PMID: 29714141 DOI: 10.2174/1568009618666180430123939] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 02/12/2018] [Accepted: 02/14/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Elevated production of the pro-inflammatory cytokine interleukin-6 (IL-6) and dysfunction of IL-6 signaling promotes tumorigenesis and are associated with poor survival outcomes in multiple cancer types. Recent studies showed that the IL-6/GP130/STAT3 signaling pathway plays a pivotal role in pancreatic cancer development and maintenance. OBJECTIVE We aim to develop effective treatments through inhibition of IL-6/GP130 signaling in pancreatic cancer. METHODS The effects on cell viability and cell proliferation were measured by MTT and BrdU assays, respectively. The effects on glycolysis was determined by cell-based assays to measure lactate levels. Protein expression changes were evaluated by western blotting and immunoprecipitation. siRNA transfection was used to knock down estrogen receptor α gene expression. Colony forming ability was determined by colony forming cell assay. RESULTS We demonstrated that IL-6 can induce pancreatic cancer cell viability/proliferation and glycolysis. We also showed that a repurposing FDA-approved drug bazedoxifene could inhibit the IL-6/IL-6R/GP130 complexes. Bazedoxifene also inhibited JAK1 binding to IL-6/IL-6R/GP130 complexes and STAT3 phosphorylation. In addition, bazedoxifene impeded IL-6 mediated cell viability/ proliferation and glycolysis in pancreatic cancer cells. Consistently, other IL-6/GP130 inhibitors SC144 and evista showed similar inhibition of IL-6 stimulated cell viability, cell proliferation and glycolysis. Furthermore, all three IL-6/GP130 inhibitors reduced the colony forming ability in pancreatic cancer cells. CONCLUSION Our findings demonstrated that IL-6 stimulates pancreatic cancer cell proliferation, survival and glycolysis, and supported persistent IL-6 signaling is a viable therapeutic target for pancreatic cancer using IL-6/GP130 inhibitors.
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Affiliation(s)
- Xiang Chen
- Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, United States
| | - Jilai Tian
- Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, United States.,State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu 210096, China.,Collaborative Innovation Center of Suzhou Nano-Science and Technology, Suzhou Key Laboratory of Biomaterials and Technologies, Suzhou, Jiangsu 215123, China
| | - Gloria H Su
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, United States
| | - Jiayuh Lin
- Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, United States
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Li LC, Pan ZH, Ning DS, Fu YX. Anti-Inflammatory Effect of Simonsinol on Lipopolysaccharide Stimulated RAW264.7 Cells through Inactivation of NF-κB Signaling Pathway. Molecules 2020; 25:molecules25163573. [PMID: 32781605 PMCID: PMC7463804 DOI: 10.3390/molecules25163573] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 08/04/2020] [Accepted: 08/04/2020] [Indexed: 11/16/2022] Open
Abstract
Simonsinol is a natural sesqui-neolignan firstly isolated from the bark of Illicium simonsii. In this study, the anti-inflammatory activity of simonsinol was investigated with a lipopolysaccharide (LPS)-stimulated murine macrophages RAW264.7 cells model. The results demonstrated that simonsinol could antagonize the effect of LPS on morphological changes of RAW264.7 cells, and decrease the production of nitric oxide (NO), tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) in LPS-stimulated RAW264.7 cells, as determined by Griess assay and enzyme-linked immunosorbent assay (ELISA). Furthermore, simonsinol could downregulate transcription of inducible nitric oxide synthase (iNOS), TNF-α, and IL-6 as measured by reverse transcription polymerase chain reaction (RT-PCR), and inhibit phosphorylation of the alpha inhibitor of NF-κB (IκBα) as assayed by Western blot. In conclusion, these data demonstrate that simonsinol could inhibit inflammation response in LPS-stimulated RAW264.7 cells through the inactivation of the nuclear transcription factor kappa-B (NF-κB) signaling pathway.
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49
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Sushak L, Gabure S, Maise J, Arnett J, Whalen MM. Dibutyltin alters immune cell production of the pro-inflammatory cytokines interleukin (IL) 1β and IL-6: role of mitogen-activated protein kinases and changes in mRNA. J Appl Toxicol 2020; 40:1047-1059. [PMID: 32141102 PMCID: PMC7354221 DOI: 10.1002/jat.3964] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 02/06/2020] [Accepted: 02/20/2020] [Indexed: 12/12/2022]
Abstract
Dibutyltin (DBT) is used to stabilize plastics and as a deworming agent in some poultry. It is found in human blood (levels as high as 0.3 μM). Interleukin (IL) 1β (IL-1β) and IL-6 are pro-inflammatory cytokines produced by lymphocytes, monocytes, and other cells. Elevated levels of IL-1β and IL-6 have been associated with pathologies including rheumatoid arthritis and cancers. DBT was shown to decrease IL-1β and IL-6 secretion from immune cells at higher concentrations while causing increases at lower concentrations. However, it was not clear if these changes were due to DBT's alteration of the secretory process or due its ability to change cellular synthesis/production of these proteins. This study addresses this question, as well as mechanisms for any observed changes in synthesis/production. Monocyte-depleted peripheral blood mononuclear cells (MD-PBMCs) were exposed to DBT at concentrations of 5, 2.5, 1, 0.5, 0.25, 0.1, and 0.05 μM for 1, 6, and 24 h and the production (combination of secreted and intracellular levels from the same cells) of both IL-1β and IL-6 were measured. Effects of selected DBT exposures on cytokine production were also examined in PBMCs and DBT's effects were similar when monocytes were present. The 24-h exposures to DBT decreased production of both IL-1β and IL-6 at the two highest concentrations but increased production at lower concentrations. Both decreases and increases in cytokine production appear to be explained by DBT-induced changes in mRNA levels. DBT-induced increases in cellular production of the cytokines appear to require p38 and ERK1/2 MAPK pathways.
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Affiliation(s)
- Linda Sushak
- Department of Chemistry, Tennessee State University, Nashville, TN, USA
| | - Sahra Gabure
- Department of Chemistry, Tennessee State University, Nashville, TN, USA
| | - JaQuel Maise
- Department of Chemistry, Tennessee State University, Nashville, TN, USA
| | - Jessica Arnett
- Department of Chemistry, Tennessee State University, Nashville, TN, USA
| | - Margaret M Whalen
- Department of Chemistry, Tennessee State University, Nashville, TN, USA
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50
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Strapcova S, Takacova M, Csaderova L, Martinelli P, Lukacikova L, Gal V, Kopacek J, Svastova E. Clinical and Pre-Clinical Evidence of Carbonic Anhydrase IX in Pancreatic Cancer and Its High Expression in Pre-Cancerous Lesions. Cancers (Basel) 2020; 12:E2005. [PMID: 32707920 PMCID: PMC7464147 DOI: 10.3390/cancers12082005] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 07/14/2020] [Accepted: 07/16/2020] [Indexed: 12/11/2022] Open
Abstract
Hypoxia is a common phenomenon that occurs in most solid tumors. Regardless of tumor origin, the evolution of a hypoxia-adapted phenotype is critical for invasive cancer development. Pancreatic ductal adenocarcinoma is also characterized by hypoxia, desmoplasia, and the presence of necrosis, predicting poor outcome. Carbonic anhydrase IX (CAIX) is one of the most strict hypoxia regulated genes which plays a key role in the adaptation of cancer cells to hypoxia and acidosis. Here, we summarize clinical data showing that CAIX expression is associated with tumor necrosis, vascularization, expression of Frizzled-1, mucins, or proteins involved in glycolysis, and inevitably, poor prognosis of pancreatic cancer patients. We also describe the transcriptional regulation of CAIX in relation to signaling pathways activated in pancreatic cancers. A large part deals with the preclinical evidence supporting the relevance of CAIX in processes leading to the aggressive behavior of pancreatic tumors. Furthermore, we focus on CAIX occurrence in pre-cancerous lesions, and for the first time, we describe CAIX expression within intraductal papillary mucinous neoplasia. Our review concludes with a detailed account of clinical trials implicating that treatment consisting of conventionally used therapies combined with CAIX targeting could result in an improved anti-cancer response in pancreatic cancer patients.
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Affiliation(s)
- Sabina Strapcova
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 84505 Bratislava, Slovakia; (S.S.); (M.T.); (L.C.); (L.L.); (J.K.)
| | - Martina Takacova
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 84505 Bratislava, Slovakia; (S.S.); (M.T.); (L.C.); (L.L.); (J.K.)
| | - Lucia Csaderova
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 84505 Bratislava, Slovakia; (S.S.); (M.T.); (L.C.); (L.L.); (J.K.)
| | - Paola Martinelli
- Institute of Cancer Research, Clinic of Internal Medicine I, Medical University of Vienna, 1090 Vienna, Austria;
- Cancer Cell Signaling, Boehringer-Ingelheim RCV Vienna, A-1121 Vienna, Austria
| | - Lubomira Lukacikova
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 84505 Bratislava, Slovakia; (S.S.); (M.T.); (L.C.); (L.L.); (J.K.)
| | - Viliam Gal
- Alpha Medical Pathology, Ruzinovska 6, 82606 Bratislava, Slovakia;
| | - Juraj Kopacek
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 84505 Bratislava, Slovakia; (S.S.); (M.T.); (L.C.); (L.L.); (J.K.)
| | - Eliska Svastova
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 84505 Bratislava, Slovakia; (S.S.); (M.T.); (L.C.); (L.L.); (J.K.)
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