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Ma W, Yan H, Ma H, Xu Z, Dai W, Wu Y, Zhang H, Li Y. Roles of leukemia inhibitory factor receptor in cancer. Int J Cancer 2025; 156:262-273. [PMID: 39279155 DOI: 10.1002/ijc.35157] [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: 04/14/2024] [Revised: 06/19/2024] [Accepted: 07/29/2024] [Indexed: 09/18/2024]
Abstract
Leukemia inhibitory factor receptor (LIFR), in complex with glycoprotein 130 (gp130) as the receptor for leukemia inhibitory factor (LIF), can bind to a variety of cytokines and subsequently activate a variety of signaling pathways, including Janus kinase/signal transducer and activator of transcription 3. LIF, the most multifunctional cytokines of the interleukin-6 family acts as both a growth factor and a growth inhibitor in different types of tumors. LIF/LIFR signaling regulates a broad array of tumor-related processes including proliferation, apoptosis, migration, invasion. However, due to the activation of different signaling pathways, opposite regulatory effects are observed in certain tumor cells. Therefore, the role of LIFR in human cancers varies across different tumor and tissue, despite their recognized value in tumor treatment and prognosis observation is affirmed. Given its aberrant expression in numerous tumor cells and crucial regulatory function in tumorigenesis and progression, LIFR is considered as a promising targeted therapeutic agent. This review provides an overview of LIFR's initiating signaling pathway function as a cytokine receptor and summarize the current literature on the role of LIFR in cancer and its possible use in therapy.
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Affiliation(s)
- Wei Ma
- School of Stomatology, China Medical University, Shenyang, China
| | - Haixu Yan
- Department of Clinical Medicine, China Medical University, Shenyang, China
| | - Haoyuan Ma
- Department of Clinical Medicine, China Medical University, Shenyang, China
| | - Zengyan Xu
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
| | - Wei Dai
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Yudan Wu
- School of Nursing, China Medical University, Shenyang, China
| | - Hongyan Zhang
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
| | - Yanshu Li
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
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2
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Yu CC, Yang CY, Chang TY, Lan KC, Liu SH. A negative regulatory role of β-cell-derived exosomes in the glucose-stimulated insulin secretion of recipient β-cells. Arch Toxicol 2024; 98:3885-3896. [PMID: 39127846 DOI: 10.1007/s00204-024-03838-8] [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: 06/21/2024] [Accepted: 08/07/2024] [Indexed: 08/12/2024]
Abstract
Exosomes are extracellular vesicles that play a role in intercellular communication through the transportation of their cargo including mRNAs, microRNAs, proteins, and nucleic acids. Exosomes can also regulate glucose homeostasis and insulin secretion under diabetic conditions. However, the role of exosomes in insulin secretion in islet β-cells under physiological conditions remains to be clarified. The aim of this study was to investigate whether exosomes derived from pancreatic islet β-cells could affect insulin secretion in naïve β-cells. We first confirmed that exosomes derived from the RIN-m5f β-cell line interfered with the glucose-stimulated insulin secretion (GSIS) of recipient β-cells without affecting cell viability. The exosomes significantly reduced the protein expression levels of phosphorylated Akt, phosphorylated GSK3α/β, CaMKII, and GLUT2 (insulin-related signaling molecules), and they increased the protein expression levels of phosphorylated NFκB-p65 and Cox-2 (inflammation-related signaling molecules), as determined by a Western blot analysis. A bioinformatics analysis of Next-Generation Sequencing data suggested that exosome-carried microRNAs, such as miR-1224, -122-5p, -133a-3p, -10b-5p, and -423-5p, may affect GSIS in recipient β-cells. Taken together, these findings suggest that β-cell-derived exosomes may upregulate exosomal microRNA-associated signals to dysregulate glucose-stimulated insulin secretion in naïve β-cells.
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Affiliation(s)
- Chia-Ching Yu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ching-Yao Yang
- Department of Surgery, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan
| | - Ting-Yu Chang
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Kuo-Cheng Lan
- Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
| | - Shing-Hwa Liu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
- Department of Pediatrics, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan.
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3
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Singh SB, Braun CA, Carroll-Portillo A, Coffman CN, Lin HC. Sulfate-Reducing Bacteria Induce Pro-Inflammatory TNF-α and iNOS via PI3K/Akt Pathway in a TLR 2-Dependent Manner. Microorganisms 2024; 12:1833. [PMID: 39338507 PMCID: PMC11434237 DOI: 10.3390/microorganisms12091833] [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: 08/09/2024] [Revised: 08/31/2024] [Accepted: 09/02/2024] [Indexed: 09/30/2024] Open
Abstract
Desulfovibrio, resident gut sulfate-reducing bacteria (SRB), are found to overgrow in diseases such as inflammatory bowel disease and Parkinson's disease. They activate a pro-inflammatory response, suggesting that Desulfovibrio may play a causal role in inflammation. Class I phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway regulates key events in the inflammatory response to infection. Dysfunctional PI3K/Akt signaling is linked to numerous diseases. Bacterial-induced PI3K/Akt pathway may be activated downstream of toll-like receptor (TLR) signaling. Here, we tested the hypothesis that Desulfovibrio vulgaris (DSV) may induce tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase (iNOS) expression via PI3K/Akt in a TLR 2-dependent manner. RAW 264.7 macrophages were infected with DSV, and protein expression of p-Akt, p-p70S6K, p-NF-κB, p-IkB, TNF-α, and iNOS was measured. We found that DSV induced these proteins in a time-dependent manner. Heat-killed and live DSV, but not bacterial culture supernatant or a probiotic Lactobacillus plantarum, significantly caused PI3K/AKT/TNF/iNOS activation. LY294002, a PI3K/Akt signaling inhibitor, and TL2-C29, a TLR 2 antagonist, inhibited DSV-induced PI3K/AKT pathway. Thus, DSV induces pro-inflammatory TNF-α and iNOS via PI3K/Akt pathway in a TLR 2-dependent manner. Taken together, our study identifies a novel mechanism by which SRB such as Desulfovibrio may trigger inflammation in diseases associated with SRB overgrowth.
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Affiliation(s)
- Sudha B Singh
- Biomedical Research Institute of New Mexico, New Mexico Veterans Affairs (VA) Health Care System, 1501 San Pedro Dr. SE, Albuquerque, NM 87108, USA
| | - Cody A Braun
- Biomedical Research Institute of New Mexico, New Mexico Veterans Affairs (VA) Health Care System, 1501 San Pedro Dr. SE, Albuquerque, NM 87108, USA
| | - Amanda Carroll-Portillo
- Division of Gastroenterology and Hepatology, Department of Medicine, University of New Mexico, Albuquerque, NM 87131, USA
| | - Cristina N Coffman
- Biomedical Research Institute of New Mexico, New Mexico Veterans Affairs (VA) Health Care System, 1501 San Pedro Dr. SE, Albuquerque, NM 87108, USA
| | - Henry C Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, University of New Mexico, Albuquerque, NM 87131, USA
- Medicine Service, New Mexico Veterans Affairs (VA) Health Care System, 1501 San Pedro Dr. SE, Albuquerque, NM 87108, USA
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4
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Falvo S, Santillo A, Di Fiore MM, Venditti M, Grillo G, Latino D, Baccari I, Petito G, Chieffi Baccari G. New Insights into D-Aspartate Signaling in Testicular Activity. Cells 2024; 13:1400. [PMID: 39195288 DOI: 10.3390/cells13161400] [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: 07/20/2024] [Revised: 08/19/2024] [Accepted: 08/20/2024] [Indexed: 08/29/2024] Open
Abstract
D-aspartate (D-Asp) is an amino acid found in high concentrations in the testis and pituitary gland. Increasing evidence suggests that D-Asp promotes spermatogenesis by activating testosterone production in the Leydig cells via LH release from the pituitary gland. In vitro studies indicate that D-Asp may also influence steroidogenesis and spermatogenesis through autocrine and paracrine signals. D-Asp enhances StAR and steroidogenic enzyme expressions, facilitating testicular cell proliferation via the GluR/ERK1/2 pathway. Moreover, it supports spermatogenesis by enhancing the mitochondrial function in spermatocytes, aiding in the metabolic shift during meiosis. Enhanced mitochondrial function, along with improved MAM stability and reduced ER stress, has been observed in Leydig and Sertoli cells treated with D-Asp, indicating potential benefits in steroidogenesis and spermatogenesis efficiency. Conversely, D-Asp exerts a notable anti-apoptotic effect in the testis via the AMPAR/AKT pathway, potentially mediated by antioxidant enzyme modulation to mitigate testicular oxidative stress. This review lays the groundwork for future investigations into the molecules promoting spermatogenesis by stimulating endogenous testosterone biosynthesis, with D-amino acids emerging as promising candidates.
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Affiliation(s)
- Sara Falvo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania 'Luigi Vanvitelli', 81100 Caserta, Italy
| | - Alessandra Santillo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania 'Luigi Vanvitelli', 81100 Caserta, Italy
| | - Maria Maddalena Di Fiore
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania 'Luigi Vanvitelli', 81100 Caserta, Italy
| | - Massimo Venditti
- Department of Experimental Medicine, University of Campania 'Luigi Vanvitelli', 80138 Napoli, Italy
| | - Giulia Grillo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania 'Luigi Vanvitelli', 81100 Caserta, Italy
| | - Debora Latino
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania 'Luigi Vanvitelli', 81100 Caserta, Italy
| | - Isabella Baccari
- Department of Experimental Medicine, University of Campania 'Luigi Vanvitelli', 80138 Napoli, Italy
| | - Giuseppe Petito
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania 'Luigi Vanvitelli', 81100 Caserta, Italy
| | - Gabriella Chieffi Baccari
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania 'Luigi Vanvitelli', 81100 Caserta, Italy
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Khezri MR, Hsueh H, Mohammadipanah S, Khalili Fard J, Ghasemnejad‐Berenji M. The interplay between the PI3K/AKT pathway and circadian clock in physiologic and cancer-related pathologic conditions. Cell Prolif 2024; 57:e13608. [PMID: 38336976 PMCID: PMC11216939 DOI: 10.1111/cpr.13608] [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: 09/01/2023] [Revised: 12/15/2023] [Accepted: 01/25/2024] [Indexed: 02/12/2024] Open
Abstract
The circadian clock is responsible for the regulation of different cellular processes, and its disturbance has been linked to the development of different diseases, such as cancer. The main molecular mechanism for this issue has been linked to the crosstalk between core clock regulators and intracellular pathways responsible for cell survival. The PI3K/AKT signalling pathway is one of the most known intracellular pathways in the case of cancer initiation and progression. This pathway regulates different aspects of cell survival including proliferation, apoptosis, metabolism, and response to environmental stimuli. Accumulating evidence indicates that there is a link between the PI3K/AKT pathway activity and circadian rhythm in physiologic and cancer-related pathogenesis. Different classes of PI3Ks and AKT isoforms are involved in regulating circadian clock components in a transcriptional and functional manner. Reversely, core clock components induce a rhythmic fashion in PI3K and AKT activity in physiologic and pathogenic conditions. The aim of this review is to re-examine the interplay between this pathway and circadian clock components in normal condition and cancer pathogenesis, which provides a better understanding of how circadian rhythms may be involved in cancer progression.
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Affiliation(s)
- Mohammad Rafi Khezri
- Reproductive Health Research Center, Clinical Research InstituteUrmia University of Medical SciencesUrmiaIran
| | - Hsiang‐Yin Hsueh
- The Ohio State University Graduate Program in Molecular, Cellular and Developmental BiologyThe Ohio State UniversityColumbusOhioUSA
| | - Somayeh Mohammadipanah
- Reproductive Health Research Center, Clinical Research InstituteUrmia University of Medical SciencesUrmiaIran
| | - Javad Khalili Fard
- Department of Pharmacology and Toxicology, Faculty of PharmacyTabriz University of Medical SciencesTabrizIran
| | - Morteza Ghasemnejad‐Berenji
- Department of Pharmacology and Toxicology, Faculty of PharmacyUrmia University of Medical SciencesUrmiaIran
- Research Center for Experimental and Applied Pharmaceutical SciencesUrmia University of Medical SciencesUrmiaIran
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Wei BR, Zhao YJ, Cheng YF, Huang C, Zhang F. Helicobacter pylori infection and Parkinson's Disease: etiology, pathogenesis and levodopa bioavailability. Immun Ageing 2024; 21:1. [PMID: 38166953 PMCID: PMC10759355 DOI: 10.1186/s12979-023-00404-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 12/11/2023] [Indexed: 01/05/2024]
Abstract
Parkinson's disease (PD), a neurodegenerative disorder with an unknown etiology, is primarily characterized by the degeneration of dopamine (DA) neurons. The prevalence of PD has experienced a significant surge in recent years. The unidentified etiology poses limitations to the development of effective therapeutic interventions for this condition. Helicobacter pylori (H. pylori) infection has affected approximately half of the global population. Mounting evidences suggest that H. pylori infection plays an important role in PD through various mechanisms. The autotoxin produced by H. pylori induces pro-inflammatory cytokines release, thereby facilitating the occurrence of central inflammation that leads to neuronal damage. Simultaneously, H. pylori disrupts the equilibrium of gastrointestinal microbiota with an overgrowth of bacteria in the small intestinal known as small intestinal bacterial overgrowth (SIBO). This dysbiosis of the gut flora influences the central nervous system (CNS) through microbiome-gut-brain axis. Moreover, SIBO hampers levodopa absorption and affects its therapeutic efficacy in the treatment of PD. Also, H. pylori promotes the production of defensins to regulate the permeability of the blood-brain barrier, facilitating the entry of harmful factors into the CNS. In addition, H. pylori has been found to induce gastroparesis, resulting in a prolonged transit time for levodopa to reach the small intestine. H. pylori may exploit levodopa to facilitate its own growth and proliferation, or it can inflict damage to the gastrointestinal mucosa, leading to gastrointestinal ulcers and impeding levodopa absorption. Here, this review focused on the role of H. pylori infection in PD from etiology, pathogenesis to levodopa bioavailability.
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Affiliation(s)
- Bang-Rong Wei
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal Centre, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yu-Jia Zhao
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal Centre, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yu-Feng Cheng
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal Centre, Zunyi Medical University, Zunyi, Guizhou, China
| | - Chun Huang
- The Fifth People's Hospital of Chongqing, Chongqing, China
| | - Feng Zhang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal Centre, Zunyi Medical University, Zunyi, Guizhou, China.
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7
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Yang Y, Xu M, Yuan W, Feng Y, Hou Y, Fang F, Duan S, Bai L. Network Pharmacology and Molecular Docking Analysis on Mechanisms of Scutellariae Radix in the Treatment of Cerebral Ischemia-reperfusion Injury. Comb Chem High Throughput Screen 2024; 27:2712-2725. [PMID: 37855354 DOI: 10.2174/0113862073258863230921180641] [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: 05/17/2023] [Revised: 07/25/2023] [Accepted: 08/18/2023] [Indexed: 10/20/2023]
Abstract
BACKGROUND Multiple brain disorders are treated by Scutellaria Radix (SR), including cerebral ischemia-reperfusion (CI/R). However, more studies are needed to clarify the molecular mechanism of SR for CI/R. METHODS The active substances and potential targets of SR and CI/R-related genes were obtained through public databases. Overlapping targets of SR and CI/R were analyzed using proteinprotein interaction (PPI) networks. GO and KEGG enrichment analyses were performed to predict the pathways of SR against CI/R, and the key components and targets were screened for molecular docking. The results of network pharmacology analysis were verified using in vitro experiments. RESULTS 15 components and 64 overlapping targets related to SR and CI/R were obtained. The top targets were AKT1, IL-6, CAS3, TNF, and TP53. These targets have been studied by GO and KEGG to be connected to a number of signaling pathways, including MAPK, PI3K-Akt pathway, and apoptosis. Molecular docking and cell experiments helped to further substantiate the network pharmacology results. CONCLUSION The active compound of SR was able to significantly decrease the apoptosis of HT- 22 cells induced by OGD/R. This finding suggests that SR is a potentially effective treatment for CI/R by modulating the MAPK and PI3K-Akt pathways.
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Affiliation(s)
- Yang Yang
- Department of Pharmacy, Xi'an No.1 Hospital, The First Affiliated Hospital of Northwest University, China
| | - Mengrong Xu
- Department of Pharmacy, Xi'an No.1 Hospital, The First Affiliated Hospital of Northwest University, China
| | - Wenting Yuan
- Department of College of Life Sciences, Northwest University, No. 229, North Taibai Road, Beilin District, China
| | - Yue Feng
- Department of College of Life Sciences, Northwest University, No. 229, North Taibai Road, Beilin District, China
| | - Yongqiang Hou
- Department of Pharmacy, Xi'an No.1 Hospital, The First Affiliated Hospital of Northwest University, China
| | - Fei Fang
- Deparment of Central Lab, Xi'an No.1 Hospital, The First Affiliated Hospital of Northwest University, China
| | - Shiwan Duan
- Department of Pharmacy, Xi'an No.1 Hospital, The First Affiliated Hospital of Northwest University, China
| | - Lu Bai
- Department of Pharmacy, Xi'an No.1 Hospital, The First Affiliated Hospital of Northwest University, China
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Kuonqui K, Campbell AC, Sarker A, Roberts A, Pollack BL, Park HJ, Shin J, Brown S, Mehrara BJ, Kataru RP. Dysregulation of Lymphatic Endothelial VEGFR3 Signaling in Disease. Cells 2023; 13:68. [PMID: 38201272 PMCID: PMC10778007 DOI: 10.3390/cells13010068] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/20/2023] [Accepted: 12/26/2023] [Indexed: 01/12/2024] Open
Abstract
Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3), a receptor tyrosine kinase encoded by the FLT4 gene, plays a significant role in the morphogenesis and maintenance of lymphatic vessels. Under both normal and pathologic conditions, VEGF-C and VEGF-D bind VEGFR3 on the surface of lymphatic endothelial cells (LECs) and induce lymphatic proliferation, migration, and survival by activating intracellular PI3K-Akt and MAPK-ERK signaling pathways. Impaired lymphatic function and VEGFR3 signaling has been linked with a myriad of commonly encountered clinical conditions. This review provides a brief overview of intracellular VEGFR3 signaling in LECs and explores examples of dysregulated VEGFR3 signaling in various disease states, including (1) lymphedema, (2) tumor growth and metastasis, (3) obesity and metabolic syndrome, (4) organ transplant rejection, and (5) autoimmune disorders. A more complete understanding of the molecular mechanisms underlying the lymphatic pathology of each disease will allow for the development of novel strategies to treat these chronic and often debilitating illnesses.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Babak J. Mehrara
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Raghu P. Kataru
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
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Elkhawaga SY, Elshafei A, Elkady MA, Yehia AM, Abulsoud AI, Abdelmaksoud NM, Elsakka EGE, Ismail A, Mokhtar MM, El-Mahdy HA, Hegazy M, Elballal MS, Mohammed OA, Abdel-Reheim MA, El-Dakroury WA, Abdel Mageed SS, Elrebehy MA, Shahin RK, Zaki MB, Doghish AS. Possible role of miRNAs in pheochromocytoma pathology - Signaling pathways interaction. Pathol Res Pract 2023; 251:154856. [PMID: 37806171 DOI: 10.1016/j.prp.2023.154856] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 09/21/2023] [Accepted: 10/03/2023] [Indexed: 10/10/2023]
Abstract
Pheochromocytoma (PCC) is a type of neuroendocrine tumor that originates from adrenal medulla or extra-adrenal chromaffin cells and results in the production of catecholamine. Paroxysmal hypertension and cardiovascular crises were among the clinical signs experienced by people with PCC. Five-year survival of advanced-stage PCC is just around 40% despite the identification of various molecular-level fundamentals implicated in these pathogenic pathways. MicroRNAs (miRNAs, miRs) are a type of short, non-coding RNA (ncRNA) that attach to the 3'-UTR of a target mRNA, causing translational inhibition or mRNA degradation. Evidence is mounting that miRNA dysregulation plays a role in the development, progression, and treatment of cancers like PCC. Hence, this study employs a comprehensive and expedited survey to elucidate the potential role of miRNAs in the development of PCC, surpassing their association with survival rates and treatment options in this particular malignancy.
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Affiliation(s)
- Samy Y Elkhawaga
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr 11231, Cairo, Egypt
| | - Ahmed Elshafei
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr 11231, Cairo, Egypt
| | - Mohamed A Elkady
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr 11231, Cairo, Egypt
| | - Amr Mohamed Yehia
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr 11231, Cairo, Egypt
| | - Ahmed I Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr 11231, Cairo, Egypt; Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Nourhan M Abdelmaksoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Elsayed G E Elsakka
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr 11231, Cairo, Egypt
| | - Ahmed Ismail
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr 11231, Cairo, Egypt
| | - Mahmoud Mohamed Mokhtar
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr 11231, Cairo, Egypt
| | - Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr 11231, Cairo, Egypt.
| | - Maghawry Hegazy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr 11231, Cairo, Egypt
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt
| | - Osama A Mohammed
- Department of Clinical Pharmacology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Mustafa Ahmed Abdel-Reheim
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62521, Egypt.
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt
| | - Sherif S Abdel Mageed
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt
| | - Reem K Shahin
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt
| | - Mohamed Bakr Zaki
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt; Faculty of Pharmacy (Boys), Al-Azhar University, Nasr 11231, Cairo, Egypt.
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10
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Wu W, Xia X, Tang L, Luo J, Xiong S, Ma G, Lei H. Phosphoinositide 3-kinase as a therapeutic target in angiogenic disease. Exp Eye Res 2023; 236:109646. [PMID: 37716399 DOI: 10.1016/j.exer.2023.109646] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/30/2023] [Accepted: 09/05/2023] [Indexed: 09/18/2023]
Abstract
Phosphoinositide 3-kinases (PI3Ks) generate lipids that control multitudinous intracellular cell signaling events which participate in cell survival and proliferation. In addition, PI3K signaling also contributes to metabolism, immunity, angiogenesis and cardiovascular homeostasis, and many diseases. The diverse actions of PI3K stem from the existence of their various isoforms and a variety of protein effectors. Hence, PI3K isoform-specific inhibitors have already achieved a wonderful effect on treating cancer. Herein, we summarize the molecular mechanism of PI3K inhibitors in preventing the permeability of vessels and neovascularization. Additionally, we briefly illustrate how PI3K signaling modulates blood vessel growth and discuss the different roles that PI3K isoforms play in angiogenesis.
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Affiliation(s)
- Wenyi Wu
- Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Ophthalmology, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
| | - Xiaobo Xia
- Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Ophthalmology, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Luosheng Tang
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jing Luo
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Siqi Xiong
- Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Ophthalmology, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Gaoen Ma
- Department of Ophthalmology, The First Affiliated Hospital of Hainan Medical University, Haikou, 571199, China.
| | - Hetian Lei
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, China.
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11
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Cherkasova V, Ilnytskyy Y, Kovalchuk O, Kovalchuk I. Transcriptome Analysis of Cisplatin, Cannabidiol, and Intermittent Serum Starvation Alone and in Various Combinations on Colorectal Cancer Cells. Int J Mol Sci 2023; 24:14743. [PMID: 37834191 PMCID: PMC10572413 DOI: 10.3390/ijms241914743] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 09/26/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
Platinum-derived chemotherapy medications are often combined with other conventional therapies for treating different tumors, including colorectal cancer. However, the development of drug resistance and multiple adverse effects remain common in clinical settings. Thus, there is a necessity to find novel treatments and drug combinations that could effectively target colorectal cancer cells and lower the probability of disease relapse. To find potential synergistic interaction, we designed multiple different combinations between cisplatin, cannabidiol, and intermittent serum starvation on colorectal cancer cell lines. Based on the cell viability assay, we found that combinations between cannabidiol and intermittent serum starvation, cisplatin and intermittent serum starvation, as well as cisplatin, cannabidiol, and intermittent serum starvation can work in a synergistic fashion on different colorectal cancer cell lines. Furthermore, we analyzed differentially expressed genes and affected pathways in colorectal cancer cell lines to understand further the potential molecular mechanisms behind the treatments and their interactions. We found that synergistic interaction between cannabidiol and intermittent serum starvation can be related to changes in the transcription of genes responsible for cell metabolism and cancer's stress pathways. Moreover, when we added cisplatin to the treatments, there was a strong enrichment of genes taking part in G2/M cell cycle arrest and apoptosis.
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Affiliation(s)
| | | | - Olga Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada; (V.C.); (Y.I.)
| | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada; (V.C.); (Y.I.)
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12
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Kichina JV, Maslov A, Kandel ES. PAK1 and Therapy Resistance in Melanoma. Cells 2023; 12:2373. [PMID: 37830586 PMCID: PMC10572217 DOI: 10.3390/cells12192373] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 09/23/2023] [Accepted: 09/27/2023] [Indexed: 10/14/2023] Open
Abstract
Malignant melanoma claims more lives than any other skin malignancy. While primary melanomas are usually cured via surgical excision, the metastatic form of the disease portents a poor prognosis. Decades of intense research has yielded an extensive armamentarium of anti-melanoma therapies, ranging from genotoxic chemo- and radiotherapies to targeted interventions in specific signaling pathways and immune functions. Unfortunately, even the most up-to-date embodiments of these therapies are not curative for the majority of metastatic melanoma patients, and the need to improve their efficacy is widely recognized. Here, we review the reports that implicate p21-regulated kinase 1 (PAK1) and PAK1-related pathways in the response of melanoma to various therapeutic modalities. Ample data suggest that PAK1 may decrease cell sensitivity to programmed cell death, provide additional stimulation to growth-promoting molecular pathways, and contribute to the creation of an immunosuppressive tumor microenvironment. Accordingly, there is mounting evidence that the concomitant inhibition of PAK1 enhances the potency of various anti-melanoma regimens. Overall, the available information suggests that a safe and effective inhibition of PAK1-dependent molecular processes would enhance the potency of the currently available anti-melanoma treatments, although considerable challenges in implementing such strategies still exist.
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Affiliation(s)
- Julia V. Kichina
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Elm & Carlton St., Buffalo, NY 14263, USA
| | - Alexei Maslov
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Elm & Carlton St., Buffalo, NY 14263, USA
| | - Eugene S. Kandel
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Elm & Carlton St., Buffalo, NY 14263, USA
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13
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Yehia AM, Elsakka EGE, Abulsoud AI, Abdelmaksoud NM, Elshafei A, Elkhawaga SY, Ismail A, Mokhtar MM, El-Mahdy HA, Hegazy M, Elballal MS, Mohammed OA, El-Husseiny HM, Midan HM, El-Dakroury WA, Zewail MB, Abdel Mageed SS, Moustafa YM, Mostafa RM, Elkady MA, Doghish AS. Decoding the role of miRNAs in multiple myeloma pathogenesis: A focus on signaling pathways. Pathol Res Pract 2023; 248:154715. [PMID: 37517169 DOI: 10.1016/j.prp.2023.154715] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 07/21/2023] [Accepted: 07/24/2023] [Indexed: 08/01/2023]
Abstract
Multiple myeloma (MM) is a cancer of plasma cells that has been extensively studied in recent years, with researchers increasingly focusing on the role of microRNAs (miRNAs) in regulating gene expression in MM. Several non-coding RNAs have been demonstrated to regulate MM pathogenesis signaling pathways. These pathways might regulate MM development, apoptosis, progression, and therapeutic outcomes. They are Wnt/β-catenin, PI3K/Akt/mTOR, P53 and KRAS. This review highlights the impending role of miRNAs in MM signaling and their relationship with MM therapeutic interventions.
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Affiliation(s)
- Amr Mohamed Yehia
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Elsayed G E Elsakka
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Ahmed I Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt; Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Nourhan M Abdelmaksoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Ahmed Elshafei
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Samy Y Elkhawaga
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Ahmed Ismail
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Mahmoud Mohamed Mokhtar
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| | - Maghawry Hegazy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Osama A Mohammed
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt; Department of Clinical Pharmacology, Faculty of Medicine, Bisha University, Bisha 61922, Saudi Arabia
| | - Hussein M El-Husseiny
- Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukh, Elqaliobiya 13736, Egypt; Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai Cho, Fuchu-shi, Tokyo 183-8509, Japan
| | - Heba M Midan
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Moataz B Zewail
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Sherif S Abdel Mageed
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Yasser M Moustafa
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | | | - Mohamed A Elkady
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
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14
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Tian L, Wu W, Yu T. Graph Random Forest: A Graph Embedded Algorithm for Identifying Highly Connected Important Features. Biomolecules 2023; 13:1153. [PMID: 37509188 PMCID: PMC10377046 DOI: 10.3390/biom13071153] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/26/2023] [Accepted: 06/30/2023] [Indexed: 07/30/2023] Open
Abstract
Random Forest (RF) is a widely used machine learning method with good performance on classification and regression tasks. It works well under low sample size situations, which benefits applications in the field of biology. For example, gene expression data often involve much larger numbers of features (p) compared to the size of samples (n). Though the predictive accuracy using RF is often high, there are some problems when selecting important genes using RF. The important genes selected by RF are usually scattered on the gene network, which conflicts with the biological assumption of functional consistency between effective features. To improve feature selection by incorporating external topological information between genes, we propose the Graph Random Forest (GRF) for identifying highly connected important features by involving the known biological network when constructing the forest. The algorithm can identify effective features that form highly connected sub-graphs and achieve equivalent classification accuracy to RF. To evaluate the capability of our proposed method, we conducted simulation experiments and applied the method to two real datasets-non-small cell lung cancer RNA-seq data from The Cancer Genome Atlas, and human embryonic stem cell RNA-seq dataset (GSE93593). The resulting high classification accuracy, connectivity of selected sub-graphs, and interpretable feature selection results suggest the method is a helpful addition to graph-based classification models and feature selection procedures.
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Affiliation(s)
- Leqi Tian
- School of Data Science, The Chinese University of Hong Kong, Shenzhen 518172, China
- Shenzhen Research Institute of Big Data, Shenzhen 518172, China
| | - Wenbin Wu
- School of Data Science, The Chinese University of Hong Kong, Shenzhen 518172, China
| | - Tianwei Yu
- School of Data Science, The Chinese University of Hong Kong, Shenzhen 518172, China
- Shenzhen Research Institute of Big Data, Shenzhen 518172, China
- Guangdong Provincial Key Laboratory of Big Data Computing, Shenzhen 518172, China
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15
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Yan L, Du H, Li Y, Li X, Sun L, Cao C. Identification and characterization of key genes in insulin signaling pathway as molecular targets for controlling the fall webworm, Hyphantria cunea. PEST MANAGEMENT SCIENCE 2023; 79:899-908. [PMID: 36317953 DOI: 10.1002/ps.7268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Revised: 10/22/2022] [Accepted: 10/28/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND The insulin signaling pathway is closely related to metabolism, growth, reproductive capacity and lifespan of insects. However, the physiological function of the insulin signaling pathway is little known in Hyphantria cunea. RESULTS Five insulin signaling pathway genes (HcInR, HcPI3K, HcAKT, HcFOXO and HcTOR) in H. cunea were identified and characterized in this study. The spatiotemporal expression profiles of the genes showed that HcInR, HcAKT, HcPI3K and HcTOR expressions were higher at the egg stage than those in other development stages, whereas HcFOXO was highly expressed in the adult stage; all of these genes were highly expressed in the larval digestive system, especially in the midgut and hindgut. After RNA interference (RNAi) of the five genes in 5th instar H. cunea larvae, weight gain and survival rate (except in the siHcAKT-injected group) were significantly decreased, and the developmental duration of larval and pupal stages were prolonged. In addition, knockdown of five genes in 7th instar larvae decreased the pupation rate, survival rate and oviposition capacity, and resulted in abnormal development during larval-pupal transition. CONCLUSION Our findings indicate that the insulin signaling pathway plays essential roles in growth and development and the molting process in H. cunea, providing an important basis for developing new potentially molecular targets for RNAi-based pest control and understanding the mechanism of H. cunea outbreak. © 2022 Society of Chemical Industry.
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Affiliation(s)
- Liqiong Yan
- Key Laboratory of Sustainable Forest Ecosystem Management-Ministry of Education, Northeast Forestry University, Harbin, China
| | - Hui Du
- Key Laboratory of Sustainable Forest Ecosystem Management-Ministry of Education, Northeast Forestry University, Harbin, China
| | - Ye Li
- Key Laboratory of Sustainable Forest Ecosystem Management-Ministry of Education, Northeast Forestry University, Harbin, China
| | - Xue Li
- Key Laboratory of Sustainable Forest Ecosystem Management-Ministry of Education, Northeast Forestry University, Harbin, China
| | - Lili Sun
- Key Laboratory of Sustainable Forest Ecosystem Management-Ministry of Education, Northeast Forestry University, Harbin, China
| | - Chuanwang Cao
- Key Laboratory of Sustainable Forest Ecosystem Management-Ministry of Education, Northeast Forestry University, Harbin, China
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16
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Pan F, Li P, Hao G, Liu Y, Wang T, Liu B. Enhancing Milk Production by Nutrient Supplements: Strategies and Regulatory Pathways. Animals (Basel) 2023; 13:ani13030419. [PMID: 36766308 PMCID: PMC9913681 DOI: 10.3390/ani13030419] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 01/10/2023] [Accepted: 01/23/2023] [Indexed: 01/28/2023] Open
Abstract
The enhancement of milk production is essential for dairy animals, and nutrient supplements can enhance milk production. This work summarizes the influence of nutrient supplements-including amino acids, peptides, lipids, carbohydrates, and other chemicals (such as phenolic compounds, prolactin, estrogen and growth factors)-on milk production. We also attempt to provide possible illuminating insights into the subsequent effects of nutrient supplements on milk synthesis. This work may help understand the strategy and the regulatory pathway of milk production promotion. Specifically, we summarize the roles and related pathways of nutrients in promoting milk protein and fat synthesis. We hope this review will help people understand the relationship between nutritional supplementation and milk production.
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Affiliation(s)
- Fengguang Pan
- Laboratory of Nutrition and Functional Food, College of Food Science and Engineering, Jilin University, Changchun 130062, China
| | - Peizhi Li
- Laboratory of Nutrition and Functional Food, College of Food Science and Engineering, Jilin University, Changchun 130062, China
| | - Guijie Hao
- Key Laboratory of Healthy Freshwater Aquaculture, Ministry of Agriculture and Rural Affairs, Huzhou 313001, China
- Key Laboratory of Fish Health and Nutrition of Zhejiang Province, Zhejiang Institute of Freshwater Fisheries, Huzhou 313001, China
| | - Yinuo Liu
- Key Laboratory of Genetics and Breeding, Zhejiang Institute of Freshwater Fisheries, Huzhou 313001, China
| | - Tian Wang
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China
- Correspondence: (T.W.); (B.L.)
| | - Boqun Liu
- Laboratory of Nutrition and Functional Food, College of Food Science and Engineering, Jilin University, Changchun 130062, China
- Correspondence: (T.W.); (B.L.)
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17
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Liang Y, Zhang D, Gong J, He W, Jin J, He Q. Mechanism study of Cordyceps sinensis alleviates renal ischemia–reperfusion injury. OPEN CHEM 2022. [DOI: 10.1515/chem-2022-0237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Abstract
Cordyceps sinensis (C. sinensis) is a kind of traditional Chinese medicine commonly used to protect renal function and relieve kidney injury. This study aimed to reveal the renal protective mechanism of C. sinensis in renal ischemia–reperfusion injury (RIRI). First, we obtained 8 active components and 99 common targets of C. sinensis against RIRI from public databases. Second, we have retrieved 38 core targets through STRING database analysis. Third, Gene Ontology analysis of 38 core targets is indicated that C. sinensis treatment RIRI may related hormone regulation, oxidative stress, cell proliferation, and immune regulation. Kyoto Encyclopedia of Genes and Genomes enrichment analysis of 38 core targets is indicated that C. sinensis treatment RIRI may involve in PI3K–Akt, HIF-1, and MAPK signaling pathways, as well as advanced glycation end product (AGE)–receptor for AGE (RAGE) signaling pathway in diabetic complications. Lastly, molecular docking was used to detect the binding activity and properties of active components and core target using molecular docking. And the results showed that eight active components of C. sinensis had low affinity with core targets. In conclusion, C. sinensis may improve RIRI by regulating oxidative stress and immunity through PI3K–Akt, HIF-1, and MAPK pathways.
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Affiliation(s)
- Yan Liang
- Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College , Hangzhou , Zhejiang, 310014 , China
| | - Di Zhang
- Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College , Hangzhou , Zhejiang, 310014 , China
| | - Jianguang Gong
- Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College , Hangzhou , Zhejiang, 310014 , China
| | - Wenfang He
- Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College , Hangzhou , Zhejiang, 310014 , China
| | - Juan Jin
- Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College , Hangzhou , Zhejiang, 310014 , China
| | - Qiang He
- Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College , Hangzhou , Zhejiang, 310014 , China
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18
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Chen L, Lin X, Lei Y, Xu X, Zhou Q, Chen Y, Liu H, Jiang J, Yang Y, Zheng F, Wu B. Aerobic glycolysis enhances HBx-initiated hepatocellular carcinogenesis via NF-κBp65/HK2 signalling. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:329. [PMID: 36411480 PMCID: PMC9677649 DOI: 10.1186/s13046-022-02531-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 10/31/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Aerobic glycolysis has been recognized as one of the growth-promoting metabolic alterations of cancer cells. Emerging evidence indicates that nuclear factor κB (NF-κB) plays significant roles in metabolic adaptation in normal cells and cancer cells. However, whether and how NF-κB regulates metabolic reprogramming in hepatocellular carcinoma (HCC), specifically hepatitis B virus X protein (HBx)-initiated HCC, has not been determined. METHODS A dataset of the HCC cohort from the TCGA database was used to analyse the expression of NF-κB family members. Expression of NF-κBp65 and phosphorylation of NF-κBp65 (p-p65) were detected in liver tissues from HBV-related HCC patients and normal controls. A newly established HBx+/+/NF-κBp65f/f and HBx+/+/NF-κBp65Δhepa spontaneous HCC mouse model was used to investigate the effects of NF-κBp65 on HBx-initiated hepatocarcinogenesis. Whether and how NF-κBp65 is involved in aerobic glycolysis induced by HBx in hepatocellular carcinogenesis were analysed in vitro and in vivo. RESULTS NF-κBp65 was upregulated in HBV-related HCC, and HBx induced NF-κBp65 upregulation and phosphorylation in vivo and in vitro. Hepatocyte-specific NF-κBp65 deficiency remarkably decreased HBx-initiated spontaneous HCC incidence in HBx-TG mice. Mechanistically, HBx induced aerobic glycolysis by activating NF-κBp65/hexokinase 2 (HK2) signalling in spontaneous hepatocarcinogenesis, and overproduced lactate significantly promoted HCC cell pernicious proliferation via the PI3K (phosphatidylinositide 3-kinase)/Akt pathway in hepatocarcinogenesis. CONCLUSION The data elucidate that NF-κBp65 plays a pivotal role in HBx-initiated spontaneous HCC, which depends on hyperactive NF-κBp65/HK2-mediated aerobic glycolysis to activate PI3K/Akt signalling. Thus, phosphorylation of NF-κBp65 will be a potential therapeutic target for HBV-related HCC.
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Affiliation(s)
- Lingjun Chen
- grid.412558.f0000 0004 1762 1794Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630 Guangdong Province China ,grid.484195.5Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630 Guangdong Province China
| | - Xianyi Lin
- grid.412558.f0000 0004 1762 1794Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630 Guangdong Province China ,grid.484195.5Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630 Guangdong Province China
| | - Yiming Lei
- grid.412558.f0000 0004 1762 1794Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630 Guangdong Province China ,grid.484195.5Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630 Guangdong Province China
| | - Xuan Xu
- grid.412558.f0000 0004 1762 1794Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630 Guangdong Province China ,grid.484195.5Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630 Guangdong Province China
| | - Qi Zhou
- grid.412558.f0000 0004 1762 1794Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630 Guangdong Province China ,grid.484195.5Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630 Guangdong Province China
| | - Yan Chen
- grid.412558.f0000 0004 1762 1794Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630 Guangdong Province China ,grid.484195.5Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630 Guangdong Province China
| | - Huiling Liu
- grid.412558.f0000 0004 1762 1794Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630 Guangdong Province China ,grid.484195.5Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630 Guangdong Province China
| | - Jie Jiang
- grid.412558.f0000 0004 1762 1794Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630 Guangdong Province China ,grid.484195.5Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630 Guangdong Province China
| | - Yidong Yang
- grid.412558.f0000 0004 1762 1794Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630 Guangdong Province China ,grid.484195.5Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630 Guangdong Province China
| | - Fengping Zheng
- grid.412558.f0000 0004 1762 1794Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630 Guangdong Province China ,grid.484195.5Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630 Guangdong Province China
| | - Bin Wu
- grid.412558.f0000 0004 1762 1794Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630 Guangdong Province China ,grid.484195.5Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630 Guangdong Province China
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19
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Abou Daher A, Alkhansa S, Azar WS, Rafeh R, Ghadieh HE, Eid AA. Translational Aspects of the Mammalian Target of Rapamycin Complexes in Diabetic Nephropathy. Antioxid Redox Signal 2022; 37:802-819. [PMID: 34544257 DOI: 10.1089/ars.2021.0217] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significance: Despite the many efforts put into understanding diabetic nephropathy (DN), direct treatments for DN have yet to be discovered. Understanding the mechanisms behind DN is an essential step in the development of novel therapeutic regimens. The mammalian target of rapamycin (mTOR) pathway has emerged as an important candidate in the quest for drug discovery because of its role in regulating growth, proliferation, as well as protein and lipid metabolism. Recent Advances: Kidney cells have been found to rely on basal autophagy for survival and for conserving kidney integrity. Recent studies have shown that diabetes induces renal autophagy deregulation, leading to kidney injury. Hyper-activation of the mTOR pathway and oxidative stress have been suggested to play a role in diabetes-induced autophagy imbalance. Critical Issues: A detailed understanding of the role of mTOR signaling in diabetes-associated complications is of major importance in the search for a cure. In this review, we provide evidence that mTOR is heavily implicated in diabetes-induced kidney injury. We suggest possible mechanisms through which mTOR exerts its negative effects by increasing insulin resistance, upregulating oxidative stress, and inhibiting autophagy. Future Directions: Both increased oxidative stress and autophagy deregulation are deeply embedded in DN. However, the mechanisms controlling oxidative stress and autophagy are not well understood. Although Akt/mTOR signaling seems to play an important role in oxidative stress and autophagy, further investigation is required to uncover the details of this signaling pathway. Antioxid. Redox Signal. 37, 802-819.
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Affiliation(s)
- Alaa Abou Daher
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Sahar Alkhansa
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - William S Azar
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,Department of Physiology and Biophysics, Georgetown University Medical School, Washington, District of Columbia, USA
| | - Rim Rafeh
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Hilda E Ghadieh
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
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20
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Yu J, Qi H, Wang Z, Zhang Z, Song E, Song W, An R. RAB3D, upregulated by aryl hydrocarbon receptor (AhR), promotes the progression of prostate cancer by activating the PI3K/AKT signaling pathway. Cell Biol Int 2022; 46:2246-2256. [DOI: 10.1002/cbin.11910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 07/31/2022] [Accepted: 09/08/2022] [Indexed: 11/06/2022]
Affiliation(s)
- Jingsong Yu
- Department of Urology The First Affiliated Hospital of Harbin Medical University Harbin China
| | - Haipeng Qi
- Department of Urology The First Affiliated Hospital of Harbin Medical University Harbin China
| | - Zheng Wang
- Department of Urology The First Affiliated Hospital of Harbin Medical University Harbin China
| | - Ze Zhang
- Department of Urology The First Affiliated Hospital of Harbin Medical University Harbin China
| | - Erlin Song
- Department of Urology The First Affiliated Hospital of Harbin Medical University Harbin China
| | - Wenting Song
- Department of Management Office Heilongjiang Academy of Medical Sciences Harbin China
| | - Ruihua An
- Department of Urology The First Affiliated Hospital of Harbin Medical University Harbin China
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21
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Gao Q, Deng H, Yang Z, Yang Q, Zhang Y, Yuan X, Zeng M, Guo M, Zeng W, Jiang X, Yu B. Sodium danshensu attenuates cerebral ischemia–reperfusion injury by targeting AKT1. Front Pharmacol 2022; 13:946668. [PMID: 36188542 PMCID: PMC9520076 DOI: 10.3389/fphar.2022.946668] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 08/22/2022] [Indexed: 12/02/2022] Open
Abstract
The beneficial properties of Sodium Danshensu (SDSS) for controlling cerebral ischemia and reperfusion injury (CIRI) are elucidated here both in vivo and in vitro. SDSS administration significantly improved the viability of P12 cells, reduced lactate dehydrogenase (LDH) leakage, and decreased the apoptosis rate following exposure to an oxygen-glucose deprivation/reoxygenation (OGD) environment. In addition, the results of a HuprotTM human protein microarray and network pharmacology indicated that AKT1 is one of the main targets of SDSS. Moreover, functional experiments showed that SDSS intervention markedly increased the phosphorylation level of AKT1 and its downstream regulator, mTOR. The binding sites of SDSS to AKT1 protein were confirmed by Autodock software and a surface plasmon resonance experiment, the result of which imply that SDSS targets to the PH domain of AKT1 at ASN-53, ARG-86, and LYS-14 residues. Furthermore, knockdown of AKT1 significantly abolished the role of SDSS in protecting cells from apoptosis and necrosis. Finally, we investigated the curative effect of SDSS in a rat model of CIRI. The results suggest that administration of SDSS significantly reduces CIRI-induced necrosis and apoptosis in brain samples by activating AKT1 protein. In conclusion, SDSS exerts its positive role in alleviating CIRI by binding to the PH domain of AKT1 protein, further resulting in AKT1 activation.
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Affiliation(s)
- Qing Gao
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hao Deng
- Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhengfei Yang
- College of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan, China
| | - Qiuyue Yang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yilin Zhang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiaopeng Yuan
- Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
| | - Miao Zeng
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Maojuan Guo
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wenyun Zeng
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xijuan Jiang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- *Correspondence: Xijuan Jiang, ; Bin Yu,
| | - Bin Yu
- International Exchanges Department and International Education College, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- *Correspondence: Xijuan Jiang, ; Bin Yu,
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22
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Sun K, Wang X, Zhang X, Shi X, Gong D. The antagonistic effect of melatonin on TBBPA-induced apoptosis and necroptosis via PTEN/PI3K/AKT signaling pathway in swine testis cells. ENVIRONMENTAL TOXICOLOGY 2022; 37:2281-2290. [PMID: 35665993 DOI: 10.1002/tox.23595] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 05/16/2022] [Accepted: 05/21/2022] [Indexed: 06/15/2023]
Abstract
Tetrabromobisphenol A (TBBPA) is a widely used industrial brominated flame retardant, which can endanger animal and human health, including cytotoxicity, endocrine disruption, reproductive toxicity and so on. Melatonin (MT) is a noteworthy free radical scavenger and an antioxidant to alleviate oxidative stress. To investigate the cytotoxic of TBBPA on swine testis cells (ST cells), as well as the antagonistic effect of MT, we established TBBPA exposure and MT antagonistic models, used flow cytometry and AO/EB staining methods to detect apoptosis and necroptosis, used DCFH-DA method to examine the content of reactive oxygen species (ROS) and investigated the expression of associated genes using RT-PCR and Western blot. According to our findings, TBBPA exposure induced cell death in ST cells. TBBPA increased ROS levels, thus increasing PTEN expression and decreasing PI3K and AKT expression. Apoptosis-related factors (Caspase-3, Bax, Cyt-c, and Caspase-9) and necroptosis-related factors (RIPK1, RIPK3, and MLKL) were considerably elevated, in addition to the reduced expression of BCL-2 and Caspase-8. We also found that MT inhibited apoptosis and necroptosis in TBBPA-induced ST cells and effectively resolved the abnormal expression of related signaling pathways. In summary, the above results indicate that MT alleviates the disorder of PTEN/PI3K/AKT signaling pathway via inhibiting ROS overproduction, thereby mitigating apoptosis and necroptosis caused by TBBPA. This research provides a theoretical basis for further understanding of the toxicity of TBBPA and the detoxification of MT against environmental toxics.
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Affiliation(s)
- Kexin Sun
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Xu Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Xinyu Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Xu Shi
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Duqiang Gong
- College of Animal Science and Technology, College of Jilin Agricultural Science and Technology University, Jilin, China
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23
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Mechanisms of solid lipid nanoparticles-triggered signaling pathways in eukaryotic cells. Colloids Surf B Biointerfaces 2022; 220:112863. [DOI: 10.1016/j.colsurfb.2022.112863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 09/04/2022] [Accepted: 09/19/2022] [Indexed: 11/17/2022]
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24
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Wu YH, Chou CY. Collagen XI Alpha 1 Chain, a Novel Therapeutic Target for Cancer Treatment. Front Oncol 2022; 12:925165. [PMID: 35847935 PMCID: PMC9277861 DOI: 10.3389/fonc.2022.925165] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 05/31/2022] [Indexed: 01/13/2023] Open
Abstract
The extracellular matrix (ECM) plays an important role in the progression of cancer. Collagen is the most abundant component in ECM, and is involved in the biological formation of cancer. Although type XI collagen is a minor fibrillar collagen, collagen XI alpha 1 chain (COL11A1) expression has been found to be upregulated in a variety of human cancers including colorectal, esophagus, glioma, gastric, head and neck, lung, ovarian, pancreatic, salivary gland, and renal cancers. High levels of COL11A1 usually predict poor prognosis, owing to its association with angiogenesis, invasion, and drug resistance in cancer. However, little is known about the specific mechanism through which COL11A1 regulates tumor progression. Here, we have organized and summarized recent developments regarding the interactions between COL11A1 and intracellular signaling pathways and selected therapeutic agents targeting COL11A1, as these indicate its potential as a target for treatment of cancers, especially epithelial ovarian cancer.
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Affiliation(s)
- Yi-Hui Wu
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan.,Department of Nursing, Min-Hwei Junior College of Health Care Management, Tainan, Taiwan
| | - Cheng-Yang Chou
- Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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25
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Different prenatal supplementation strategies and its impacts on reproductive and nutrigenetics assessments of bulls in finishing phase. Vet Res Commun 2022; 47:457-471. [PMID: 35750996 DOI: 10.1007/s11259-022-09963-y] [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: 03/04/2022] [Accepted: 06/18/2022] [Indexed: 10/17/2022]
Abstract
This study investigated the effect of different prenatal nutrition approaches in 126 pregnant Nellore cows on reproductive and nutrigenetic traits of the male offspring during the finishing phase. For that purpose, three nutritional treatments were used in these cows during pregnancy: PP - protein-energy supplementation in the final third, FP - protein-energy supplementation during the entire pregnancy, and NP - (control) only mineral supplementation. The male progeny (63 bulls; 665 ± 28 days of age) were evaluated for scrotal circumference, seminal traits, number of Sertoli cells and testicular area. We performed a genomic association (700 K SNPs) for scrotal circumference at this age. In addition, a functional enrichment was performed in search of significant metabolic pathways (P < 0.05) with inclusion of genes that are expressed in these genomic windows by the MetaCore software. With the exception of major sperm defects (P < 0.1), the other phenotypes showed no difference between prenatal treatments. We found genes and metabolic pathways (P < 0.05) that are associated with genomic windows (genetic variance explained >1%) in different treatments. These molecular findings indicate that there is genotype-environment interaction among the different prenatal treatments and that the FP treatment showed greater major sperm defects compared to the NP treatment.
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26
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Zhang L, Li B, Li W, Jiang J, Chen W, Yang H, Pan D. miR-107 Attenuates Sepsis-Induced Myocardial Injury by Targeting PTEN and Activating the PI3K/AKT Signaling Pathway. Cells Tissues Organs 2022; 212:523-534. [PMID: 35717938 DOI: 10.1159/000525476] [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: 02/18/2022] [Accepted: 06/08/2022] [Indexed: 11/19/2022] Open
Abstract
Sepsis is a public health problem worldwide. This study investigated the mechanism of miR-107 on sepsis-induced myocardial injury. Sepsis rat models were established by cecal ligation and puncture (CLP), and the cell model was established using lipopolysaccharide (LPS)-induced cardiomyocytes. Cardiac function indexes of rats were measured using echocardiography. Pathological changes in the rat myocardium were observed using histological staining. Expression of miR-107 in the serum of rats and in cardiomyocytes was detected after the treatment with miR-107 mimic and/or pcDNA3.1-PTEN, followed by assessment of cell cycle, proliferation, and apoptosis. Binding sites of miR-107 and PTEN were predicted. PTEN, PI3K, p-PI3K, AKT, and p-AKT levels in LPS-induced cardiomyocytes were measured. miR-107 was significantly downregulated in the serum of CLP rats and LPS-induced cardiomyocytes. miR-107 overexpression remarkably improved cardiac function and histological changes, decreased inflammatory factors, and alleviated the sepsis-induced myocardial injury in rats. In LPS-induced cardiomyocytes, miR-107 overexpression increased cardiomyocyte proliferation, inhibited apoptosis, and enhanced the proportion of cardiomyocytes arrested in S and G2/M phases. miR-107 targeted PTEN. PTEN overexpression partially reversed the inhibition of miR-107 mimic on cardiomyocyte apoptosis. miR-107 overexpression activated the PI3K/AKT pathway by inhibiting PTEN. To conclude, miR-107 activates the PI3K/AKT pathway by inhibiting PTEN, thus attenuating sepsis-induced myocardial injury and LPS-induced cardiomyocyte apoptosis.
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Affiliation(s)
- Lin Zhang
- Department of Cardiology, Guilin People's Hospital, Guilin, China
| | - Bin Li
- Department of Cardiology, Guilin People's Hospital, Guilin, China
| | - Wei Li
- Department of Cardiology, Guilin People's Hospital, Guilin, China
| | - Jingbo Jiang
- Department of Cardiology, Guilin People's Hospital, Guilin, China
| | - Wei Chen
- Department of Cardiology, Guilin People's Hospital, Guilin, China
| | - Huayun Yang
- Department of Cardiology, Guilin People's Hospital, Guilin, China
| | - Diguang Pan
- Department of Cardiology, Guilin People's Hospital, Guilin, China
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27
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Ždralević M, Giannattasio S. Mitochondrial Research: Yeast and Human Cells as Models. Int J Mol Sci 2022; 23:ijms23126654. [PMID: 35743096 PMCID: PMC9224154 DOI: 10.3390/ijms23126654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 06/13/2022] [Indexed: 01/27/2023] Open
Affiliation(s)
- Maša Ždralević
- Faculty of Medicine, University of Montenegro, Kruševac bb, 81000 Podgorica, Montenegro;
| | - Sergio Giannattasio
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, 70126 Bari, Italy
- Correspondence: ; Tel.: +39-080-5929816
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28
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Metabolic Impact of MKP-2 Upregulation in Obesity Promotes Insulin Resistance and Fatty Liver Disease. Nutrients 2022; 14:nu14122475. [PMID: 35745205 PMCID: PMC9228271 DOI: 10.3390/nu14122475] [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: 04/13/2022] [Revised: 06/08/2022] [Accepted: 06/13/2022] [Indexed: 11/23/2022] Open
Abstract
The mechanisms connecting obesity with type 2 diabetes, insulin resistance, nonalcoholic fatty liver disease, and cardiovascular diseases remain incompletely understood. The function of MAPK phosphatase-2 (MKP-2), a type 1 dual-specific phosphatase (DUSP) in whole-body metabolism, and how this contributes to the development of diet-induced obesity, type 2 diabetes (T2D), and insulin resistance is largely unknown. We investigated the physiological contribution of MKP-2 in whole-body metabolism and whether MKP-2 is altered in obesity and human fatty liver disease using MKP-2 knockout mice models and human liver tissue derived from fatty liver disease patients. We demonstrate that, for the first time, MKP-2 expression was upregulated in liver tissue in humans with obesity and fatty liver disease and in insulin-responsive tissues in mice with obesity. MKP-2-deficient mice have enhanced p38 MAPK, JNK, and ERK activities in insulin-responsive tissues compared with wild-type mice. MKP-2 deficiency in mice protects against diet-induced obesity and hepatic steatosis and was accompanied by improved glucose homeostasis and insulin sensitivity. Mkp-2−/− mice are resistant to diet-induced obesity owing to reduced food intake and associated lower respiratory exchange ratio. This was associated with enhanced circulating insulin-like growth factor-1 (IGF-1) and stromal cell-derived factor 1 (SDF-1) levels in Mkp-2−/− mice. PTEN, a negative regulator of Akt, was downregulated in livers of Mkp-2−/− mice, resulting in enhanced Akt activity consistent with increased insulin sensitivity. These studies identify a novel role for MKP-2 in the regulation of systemic metabolism and pathophysiology of obesity-induced insulin resistance and fatty liver disease.
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29
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D’Incal C, Broos J, Torfs T, Kooy RF, Vanden Berghe W. Towards Kinase Inhibitor Therapies for Fragile X Syndrome: Tweaking Twists in the Autism Spectrum Kinase Signaling Network. Cells 2022; 11:cells11081325. [PMID: 35456004 PMCID: PMC9029738 DOI: 10.3390/cells11081325] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/01/2022] [Accepted: 04/03/2022] [Indexed: 12/12/2022] Open
Abstract
Absence of the Fragile X Mental Retardation Protein (FMRP) causes autism spectrum disorders and intellectual disability, commonly referred to as the Fragile X syndrome. FMRP is a negative regulator of protein translation and is essential for neuronal development and synapse formation. FMRP is a target for several post-translational modifications (PTMs) such as phosphorylation and methylation, which tightly regulate its cellular functions. Studies have indicated the involvement of FMRP in a multitude of cellular pathways, and an absence of FMRP was shown to affect several neurotransmitter receptors, for example, the GABA receptor and intracellular signaling molecules such as Akt, ERK, mTOR, and GSK3. Interestingly, many of these molecules function as protein kinases or phosphatases and thus are potentially amendable by pharmacological treatment. Several treatments acting on these kinase-phosphatase systems have been shown to be successful in preclinical models; however, they have failed to convincingly show any improvements in clinical trials. In this review, we highlight the different protein kinase and phosphatase studies that have been performed in the Fragile X syndrome. In our opinion, some of the paradoxical study conclusions are potentially due to the lack of insight into integrative kinase signaling networks in the disease. Quantitative proteome analyses have been performed in several models for the FXS to determine global molecular processes in FXS. However, only one phosphoproteomics study has been carried out in Fmr1 knock-out mouse embryonic fibroblasts, and it showed dysfunctional protein kinase and phosphatase signaling hubs in the brain. This suggests that the further use of phosphoproteomics approaches in Fragile X syndrome holds promise for identifying novel targets for kinase inhibitor therapies.
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Affiliation(s)
- Claudio D’Incal
- Protein Chemistry, Proteomics and Epigenetic Signaling (PPES), Department of Biomedical Sciences, University of Antwerp, 2000 Antwerp, Belgium; (C.D.); (J.B.); (T.T.)
- Department of Medical Genetics, University of Antwerp, 2000 Antwerp, Belgium;
| | - Jitse Broos
- Protein Chemistry, Proteomics and Epigenetic Signaling (PPES), Department of Biomedical Sciences, University of Antwerp, 2000 Antwerp, Belgium; (C.D.); (J.B.); (T.T.)
| | - Thierry Torfs
- Protein Chemistry, Proteomics and Epigenetic Signaling (PPES), Department of Biomedical Sciences, University of Antwerp, 2000 Antwerp, Belgium; (C.D.); (J.B.); (T.T.)
| | - R. Frank Kooy
- Department of Medical Genetics, University of Antwerp, 2000 Antwerp, Belgium;
| | - Wim Vanden Berghe
- Protein Chemistry, Proteomics and Epigenetic Signaling (PPES), Department of Biomedical Sciences, University of Antwerp, 2000 Antwerp, Belgium; (C.D.); (J.B.); (T.T.)
- Correspondence: ; Tel.: +0032-(0)-32-652-657
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30
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Miao R, Fang X, Wei J, Wu H, Wang X, Tian J. Akt: A Potential Drug Target for Metabolic Syndrome. Front Physiol 2022; 13:822333. [PMID: 35330934 PMCID: PMC8940245 DOI: 10.3389/fphys.2022.822333] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 02/07/2022] [Indexed: 12/21/2022] Open
Abstract
The serine/threonine kinase Akt, also known as protein kinase B (PKB), is one of the key factors regulating glucose and lipid energy metabolism, and is the core focus of current research on diabetes and metabolic diseases. Akt is mostly expressed in key metabolism-related organs and it is activated in response to various stimuli, including cell stress, cell movement, and various hormones and drugs that affect cell metabolism. Genetic and pharmacological studies have shown that Akt is necessary to maintain the steady state of glucose and lipid metabolism and a variety of cellular responses. Existing evidence shows that metabolic syndrome is related to insulin resistance and lipid metabolism disorders. Based on a large number of studies on Akt-related pathways and reactions, we believe that Akt can be used as a potential drug target to effectively treat metabolic syndrome.
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Affiliation(s)
- Runyu Miao
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,Graduate College, Beijing University of Chinese Medicine, Beijing, China
| | - Xinyi Fang
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,Graduate College, Beijing University of Chinese Medicine, Beijing, China
| | - Jiahua Wei
- Graduate College, Changchun University of Chinese Medicine, Changchun, China
| | - Haoran Wu
- Graduate College, Beijing University of Chinese Medicine, Beijing, China
| | - Xinmiao Wang
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiaxing Tian
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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31
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d-aspartate and N-methyl-d-aspartate promote proliferative activity in mouse spermatocyte GC-2 cells. Reprod Biol 2022; 22:100601. [PMID: 35032869 DOI: 10.1016/j.repbio.2021.100601] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 12/29/2021] [Accepted: 12/31/2021] [Indexed: 12/29/2022]
Abstract
D-Aspartate (D-Asp) and its methylated form N-methyl-d-aspartate (NMDA) promote spermatogenesis by stimulating the biosynthesis of sex steroid hormones. d-Asp also induces spermatogonia proliferation directly by activating the ERK/Aurora B pathway. In the present study, a mouse spermatocyte-derived cell line (GC-2) which represents a stage between preleptotene spermatocyte and round spermatids was exposed to 200 μM d-Asp or 50 μM NMDA for 30 min, 2 h, and 4 h to explore the influence of these amino acids on cell proliferation and mitochondrial activities occurring during this process. By Western blotting analyses, the expressions of AMPAR (GluA1-GluA2/3 subunits), cell proliferation as well as mitochondria functionality markers were determined at different incubation times. The results revealed that d-Asp or NMDA stimulate proliferation and meiosis in the GC-2 cells via the AMPAR/ERK/Akt pathway, which led to increased levels of the PCNA, p-H3, and SYCP3 proteins. The effects of d-Asp and NMDA on the mitochondrial functionality of the GC-2 cells strongly suggested an active role of these amino acids in germ cell maturation. In both d-Asp- and NMDA-treated GC-2 cells mitochondrial biogenesis as well as mitochondrial fusion are increased while mitochondria fission is inhibited. Finally, the findings showed that NMDA significantly increased the expressions of the CII, CIII, CIV, and CV complexes of oxidative phosphorylation system (OXPHOS), whereas d-Asp induced a significant increase in the expressions only of the CIV and CV complexes. The present study provides novel insights into the mechanisms underlying the role of d-Asp and NMDA in promoting spermatogenesis.
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32
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Gehrand AL, Phillips J, Welhouse KD, Siddiqui H, Schulgit M, Hoffman J, Hunt H, Raff H. Glucocorticoid Receptor Antagonist Alters Corticosterone and Receptor-sensitive mRNAs in the Hypoxic Neonatal Rat. Endocrinology 2022; 163:6429713. [PMID: 34791109 DOI: 10.1210/endocr/bqab232] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Indexed: 11/19/2022]
Abstract
Hypoxia, a common stressor with preterm birth, increases morbidity and mortality associated with prematurity. Glucocorticoids (GCs) are administered to the preterm infant to improve oxygenation; prolonged use of GCs remains controversial. We evaluated a selective glucocorticoid receptor (GR) antagonist (CORT113176) in our neonatal rat model of human prematurity to assess how fasting and hypoxia-induced increases in neonatal corticosterone affects endogenous hormones and endocrine pancreas function. Neonatal rat pups at postnatal day (PD) 2, PD8, and PD15 were pretreated with CORT113176 and, after 60 minutes of separation and fasting, exposed to hypoxia (8% O2) or control (normoxia) for 30 or 60 minutes while fasting was continued. Plasma corticosterone, ACTH, glucose, and insulin were measured and fasting Homeostatic Model Assessment of Insulin Resistance was calculated. Glucocorticoid and insulin receptor-sensitive gene mRNAs were analyzed in liver, muscle, and adipose to evaluate target tissue biomarkers. CORT113176 pretreatment augmented baseline and hypoxia-induced increases in corticosterone and attenuated hypoxia-induced increases in insulin resistance at PD2. Normoxic and hypoxic stress increased the hepatic GR-sensitive gene mRNAs, Gilz and Per1; this was eliminated by pretreatment with CORT113176. CORT113176 pretreatment decreased baseline insulin receptor-sensitive gene mRNAs Akt2, Irs1, Pik3r1, and Srebp1c at PD2. We show that CORT113176 variably augments the stress-induced increases in corticosterone concentrations (attenuation of negative feedback) and that GR is critical for hepatic responses to stress in the hypoxic neonate. We also propose that measurement of Gilz and Per1 mRNA expression may be useful to evaluate the effectiveness of GR antagonism.
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Affiliation(s)
- Ashley L Gehrand
- Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Advocate Aurora Research Institute, Milwaukee, WI 53215, USA
| | - Jonathan Phillips
- Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Advocate Aurora Research Institute, Milwaukee, WI 53215, USA
| | - Kyle D Welhouse
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Hana Siddiqui
- Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Advocate Aurora Research Institute, Milwaukee, WI 53215, USA
| | - Matthew Schulgit
- Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Advocate Aurora Research Institute, Milwaukee, WI 53215, USA
| | | | - Hazel Hunt
- Corcept Therapeutics, Menlo Park, CA 94025, USA
| | - Hershel Raff
- Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Advocate Aurora Research Institute, Milwaukee, WI 53215, USA
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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33
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Zhang BH, Liu H, Yuan Y, Weng XD, Du Y, Chen H, Chen ZY, Wang L, Liu XH. Knockdown of TRIM8 Protects HK-2 Cells Against Hypoxia/Reoxygenation-Induced Injury by Inhibiting Oxidative Stress-Mediated Apoptosis and Pyroptosis via PI3K/Akt Signal Pathway. Drug Des Devel Ther 2021; 15:4973-4983. [PMID: 34916780 PMCID: PMC8670861 DOI: 10.2147/dddt.s333372] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 11/30/2021] [Indexed: 11/23/2022] Open
Abstract
Background Acute kidney injury (AKI) emerges as an acute and critical disease. Tripartite motif 8 (TRIM8), one number of the TRIM protein family, is proved to participate in ischemia/reperfusion (I/R) injury. However, whether TRIM8 is involved in renal I/R injury and the associated mechanisms are currently unclear. Purpose This study aimed to investigate the precise role of TRIM8 and relevant mechanisms in renal I/R injury. Materials and Methods In this study, human renal proximal tubular epithelial cells (HK-2 cells) underwent 12 hours of hypoxia and 2 h, 3 h or 4 h of reoxygenation to establish an in vitro hypoxia/reoxygenation (H/R) model. The siRNAs specific to TRIM8 (si-TRIM8) were transfected into HK-2 cells to knockdown TRIM8. The cell H/R model included various groups including Control, H/R, H/R+DMSO, H/R+NAC, si-NC+H/R, si-TRIM8+H/R and si-TRIM8+LY294002+H/R. The cell viability and levels of reactive oxygen species (ROS), hydrogen peroxide (H2O2), mRNA, apoptotic proteins, pyroptosis-related proteins and PI3K/AKT pathway-associated proteins were assessed. Results In vitro, realtime-quantitative PCR and western-blot analysis showed that the mRNA and protein expression of TRIM8 were obviously upregulated after H/R treatment in HK-2 cells. Compared with the H/R model group, knockdown of TRIM8 significantly increased cell viability and reduced the levels of ROS, H2O2, apoptotic proteins (Cleaved caspasebase-3 and BAX) and pyroptosis-related proteins (NLRP3, ASC, Caspase-1, Caspase-11, IL-1β and GSDMD-N). Western-blot analysis also authenticated that PI3K/AKT pathway was activated after TRIM8 inhibition. The application of 5 mM N-acetyl-cysteine, one highly efficient ROS inhibitor, significantly suppressed the expression of apoptotic proteins and pyroptosis-related proteins. Moreover, the combined treatment of TRIM8 knockdown and LY294002 reversed the effects of inhibiting oxidative stress. Conclusion Knockdown of TRIM8 can alleviate H/R-induced oxidative stress by triggering the PI3K/AKT pathway, thus attenuating pyropyosis and apoptosis in vitro.
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Affiliation(s)
- Bang-Hua Zhang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China.,Hubei Key Laboratory of Digestive System Disease, Wuhan, Hubei, People's Republic of China
| | - Hao Liu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China.,Hubei Key Laboratory of Digestive System Disease, Wuhan, Hubei, People's Republic of China
| | - Yan Yuan
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China.,Hubei Key Laboratory of Digestive System Disease, Wuhan, Hubei, People's Republic of China
| | - Xiao-Dong Weng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China
| | - Yang Du
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China
| | - Hui Chen
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China
| | - Zhi-Yuan Chen
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China
| | - Lei Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China
| | - Xiu-Heng Liu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China
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Eroglu EC, Tunug S, Geckil OF, Gulec UK, Vardar MA, Paydas S. Discovery of metabolomic biomarkers for discriminating platinum-sensitive and platinum-resistant ovarian cancer by using GC-MS. EUROPEAN JOURNAL OF MASS SPECTROMETRY (CHICHESTER, ENGLAND) 2021; 27:235-248. [PMID: 34806450 DOI: 10.1177/14690667211057996] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
This study aims to determine ovarian cancer (OC) patients with platinum resistance for alternative treatment protocols by using metabolomic methodologies. Urine and serum samples of platinum-resistant and platinum-sensitive OC were analyzed using GC-MS. After data processing of GC-MS raw data, multivariate analyses were performed to interpret complex data for biologically meaningful information and to identify the biomarkers that cause differences between two groups. The biomarkers were verified after univariate, multivariate, and ROC analysis. Finally, metabolomic pathways related to group separations were specified. The results of biomarker analysis showed that 3,4-dihydroxyphenylacetic acid, 4-hydroxybutyric acid, L-threonine, D- mannose, and sorbitol metabolites were potential biomarkers in urine samples. In serum samples, L-arginine, linoleic acid, L-glutamine, and hypoxanthine were identified as important biomarkers. R2Y, Q2, AUC, sensitivity and specificity values of platinum-resistant and sensitive OC patients' urine and serum samples were 0.85, 0.545, 0.844, 91.30%, 81.08 and 0.570, 0.206, 0.743, 77.78%, 74.28%, respectively. In metabolic pathway analysis of urine samples, tyrosine metabolism and fructose and mannose metabolism were found to be statistically significant (p < 0.05) for the discrimination of the two groups. While 3,4-dihydroxyphenylacetic acid, L-tyrosine, and fumaric acid metabolites were effective in tyrosine metabolism. D-sorbitol and D-mannose metabolites were significantly important in fructose and mannose metabolism. However, seven metabolomic pathways were significant (p < 0.05) in serum samples. In terms of p-value, L-glutamine in the nitrogen metabolic pathway from the first three pathways; L-glutamine and pyroglutamic acid metabolites in D-glutamine and D-glutamate metabolism. In the arginine and proline metabolic pathway, L-arginine, L-proline, and L-ornithine metabolites differed significantly between the two groups.
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Affiliation(s)
- Evren C Eroglu
- Department of Biotechnology, 37506Cukurova University, Adana, Turkey
- Alata Horticultural Research Institute, Mersin, Turkey
| | - Sule Tunug
- Department of Gynecological Oncology, 37506Cukurova University, Adana, Turkey
| | - Omer Faruk Geckil
- Department of Gynecological Oncology, 37506Cukurova University, Adana, Turkey
| | | | - Mehmet Ali Vardar
- Department of Gynecological Oncology, 37506Cukurova University, Adana, Turkey
| | - Semra Paydas
- Department of Oncology, 37506Cukurova University, Adana, Turkey
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Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT. Int J Mol Sci 2021; 22:ijms222111376. [PMID: 34768807 PMCID: PMC8583472 DOI: 10.3390/ijms222111376] [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: 07/24/2021] [Revised: 10/05/2021] [Accepted: 10/14/2021] [Indexed: 11/16/2022] Open
Abstract
Hyperactivity of serine-threonine kinase AKT is one of the most common molecular abnormalities in cancer, where it contributes to poor outcomes by facilitating the growth and survival of malignant cells. Despite its well-documented anti-apoptotic effects, hyperactivity of AKT is also known to be stressful to a cell. In an attempt to better elucidate this phenomenon, we observed the signs of proteotoxic stress in cells that harbor hyperactive AKT or have lost its principal negative regulator, PTEN. The activity of HSF1 was predictably elevated under these circumstances. However, such cells proved more sensitive to various regimens of heat shock, including the conditions that were well-tolerated by syngeneic cells without AKT hyperactivity. The sensitizing effect of hyperactive AKT was also seen in HSF1-deficient cells, suggesting that the phenomenon does not require the regulation of HSF1 by this kinase. Notably, the elevated activity of AKT was accompanied by increased levels of XBP1, a key component of cell defense against proteotoxic stress. Interestingly, the cells harboring hyperactive AKT were also more dependent on XBP1 for their growth. Our observations suggest that proteotoxic stress conferred by hyperactive AKT represents a targetable vulnerability, which can be exploited by either elevating the stress above the level tolerated by such cells or by eliminating the factors that enable such tolerance.
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Two Sides to Every Story: Herpes Simplex Type-1 Viral Glycoproteins gB, gD, gH/gL, gK, and Cellular Receptors Function as Key Players in Membrane Fusion. Viruses 2021; 13:v13091849. [PMID: 34578430 PMCID: PMC8472851 DOI: 10.3390/v13091849] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/02/2021] [Accepted: 09/04/2021] [Indexed: 12/21/2022] Open
Abstract
Herpes simplex virus type-1 (HSV-1) and type-2 (HSV-2) are prototypical alphaherpesviruses that are characterized by their unique properties to infect trigeminal and dorsal root ganglionic neurons, respectively, and establish life-long latent infections. These viruses initially infect mucosal epithelial tissues and subsequently spread to neurons. They are associated with a significant disease spectrum, including orofacial and ocular infections for HSV-1 and genital and neonatal infections for HSV-2. Viral glycoproteins within the virion envelope bind to specific cellular receptors to mediate virus entry into cells. This is achieved by the fusion of the viral envelope with the plasma membrane. Similarly, viral glycoproteins expressed on cell surfaces mediate cell-to-cell fusion and facilitate virus spread. An interactive complex of viral glycoproteins gB, gD/gH/gL, and gK and other proteins mediate these membrane fusion phenomena with glycoprotein B (gB), the principal membrane fusogen. The requirement for the virion to enter neuronal axons suggests that the heterodimeric protein complex of gK and membrane protein UL20, found only in alphaherpesviruses, constitute a critical determinant for neuronal entry. This hypothesis was substantiated by the observation that a small deletion in the amino terminus of gK prevents entry into neuronal axons while allowing entry into other cells via endocytosis. Cellular receptors and receptor-mediated signaling synergize with the viral membrane fusion machinery to facilitate virus entry and intercellular spread. Unraveling the underlying interactions among viral glycoproteins, envelope proteins, and cellular receptors will provide new innovative approaches for antiviral therapy against herpesviruses and other neurotropic viruses.
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Dynamic Regulation of Cysteine Oxidation and Phosphorylation in Myocardial Ischemia-Reperfusion Injury. Cells 2021; 10:cells10092388. [PMID: 34572037 PMCID: PMC8469016 DOI: 10.3390/cells10092388] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/06/2021] [Accepted: 09/07/2021] [Indexed: 02/02/2023] Open
Abstract
Myocardial ischemia-reperfusion (I/R) injury significantly alters heart function following infarct and increases the risk of heart failure. Many studies have sought to preserve irreplaceable myocardium, termed cardioprotection, but few, if any, treatments have yielded a substantial reduction in clinical I/R injury. More research is needed to fully understand the molecular pathways that govern cardioprotection. Redox mechanisms, specifically cysteine oxidations, are acute and key regulators of molecular signaling cascades mediated by kinases. Here, we review the role of reactive oxygen species in modifying cysteine residues and how these modifications affect kinase function to impact cardioprotection. This exciting area of research may provide novel insight into mechanisms and likely lead to new treatments for I/R injury.
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Phanaksri T, Yingchutrakul Y, Roytrakul S, Prasopdee S, Kunjantarachot A, Butthongkomvong K, Tesana S, Sathavornmanee T, Thitapakorn V. Plasma checkpoint protein 1 (Chk1) as a potential diagnostic biomarker for opisthorchiasis and cholangiocarcinoma. Cancer Biomark 2021; 33:43-55. [PMID: 34366327 DOI: 10.3233/cbm-210170] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Patients infected with a parasite often develop opisthorchiasis viverrini, which often progresses into cholangiocarcinoma (CCA) due to the asymptomatic nature of the infection. Currently, there are no effective diagnostic methods for opisthorchiasis or cholangiocarcinoma. OBJECTIVE The aim of this study was to identify the host-responsive protein that can be developed as a diagnostic biomarker of opisthorchiasis and cholangiocarcinoma. METHODS Plasma samples were collected from non-OVCCA, OV, and CCA subjects, and the proteomes were investigated by LC-MS/MS. Venn diagrams and protein network prediction by STITCH were used to identify the potential biomarkers. The level of candidate protein, the plasma checkpoint protein 1 (Chk1), was measured by indirect enzyme-linked immunosorbent assay (ELISA). RESULTS Chk1 was present in the center of the protein network analysis in both the OV and CCA groups. In addition, the plasma Chk1 levels were significantly increased in both groups (P< 0.05). The sensitivity of the opisthorchiasis viverrini and cholangiocarcinoma was 59.38% and 65.62%, respectively, while the specificity of both was 85.71%. CONCLUSION Chk1 was identified by differential plasma proteomes and was increased in O. viverrini-infected and cholangiocarcinoma-derived plasma samples. Higher levels of plasma Chk1 levels may serve as a potential diagnostic biomarker for opisthorchiasis and cholangiocarcinoma.
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Affiliation(s)
- Teva Phanaksri
- Research Unit in Opisthorchiasis, Cholangiocarcinoma, and Neglected Parasitic Diseases, Chulabhorn International College of Medicine (CICM), Thammasat University, Pathumthani, Thailand
| | | | - Sittiruk Roytrakul
- Proteomics Research Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), NSTDA, Pathumthani, Thailand
| | - Sattrachai Prasopdee
- Research Unit in Opisthorchiasis, Cholangiocarcinoma, and Neglected Parasitic Diseases, Chulabhorn International College of Medicine (CICM), Thammasat University, Pathumthani, Thailand
| | - Anthicha Kunjantarachot
- Research Unit in Opisthorchiasis, Cholangiocarcinoma, and Neglected Parasitic Diseases, Chulabhorn International College of Medicine (CICM), Thammasat University, Pathumthani, Thailand
| | | | - Smarn Tesana
- Research Unit in Opisthorchiasis, Cholangiocarcinoma, and Neglected Parasitic Diseases, Chulabhorn International College of Medicine (CICM), Thammasat University, Pathumthani, Thailand
| | | | - Veerachai Thitapakorn
- Research Unit in Opisthorchiasis, Cholangiocarcinoma, and Neglected Parasitic Diseases, Chulabhorn International College of Medicine (CICM), Thammasat University, Pathumthani, Thailand
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Brosinsky P, Bornbaum J, Warga B, Schulz L, Schlüter KD, Ghigo A, Hirsch E, Schulz R, Euler G, Heger J. PI3K as Mediator of Apoptosis and Contractile Dysfunction in TGFβ 1-Stimulated Cardiomyocytes. BIOLOGY 2021; 10:biology10070670. [PMID: 34356525 PMCID: PMC8301398 DOI: 10.3390/biology10070670] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/09/2021] [Accepted: 07/13/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND TGFβ1 is a growth factor that plays a major role in the remodeling process of the heart by inducing cardiomyocyte dysfunction and apoptosis, as well as fibrosis thereby restricting heart function. TGFβ1 mediates its effect via the TGFβ receptor I (ALK5) and the activation of SMAD transcription factors, but TGFβ1 is also known as activator of phosphoinositide-3-kinase (PI3K) via the non-SMAD signaling pathway. The aim of this study was to investigate whether PI3K is also involved in TGFβ1-induced cardiomyocytes apoptosis and contractile dysfunction. METHODS AND RESULTS Incubation of isolated ventricular cardiomyocytes with TGFβ1 resulted in impaired contractile function. Pre-incubation of cells with the PI3K inhibitor Ly294002 or the ALK5 inhibitor SB431542 attenuated the decreased cell shortening in TGFβ1-stimulated cells. Additionally, TGFβ-induced apoptosis was significantly reduced by the PI3K inhibitor Ly294002. Administration of a PI3Kγ-specific inhibitor AS605240 abolished the TGFβ effect on apoptosis and cell shortening. This was also confirmed in cardiomyocytes from PI3Kγ KO mice. Induction of SMAD binding activity and the TGFβ target gene collagen 1 could be blocked by the PI3K inhibitor Ly294002, but not by the specific PI3Kγ inhibitor AS605240. CONCLUSIONS TGFβ1-induced SMAD activation, cardiomyocyte apoptosis, and impaired cell shortening are mediated via both, the ALK5 receptor and PI3K, in adult cardiomyocytes. PI3Kγ specifically contributes to apoptosis induction and impairment of contractile function independent of SMAD signaling.
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Affiliation(s)
- Paulin Brosinsky
- Institute of Physiology, Justus-Liebig-University Giessen, 35392 Giessen, Germany; (P.B.); (J.B.); (B.W.); (L.S.); (K.-D.S.); (R.S.); (G.E.)
| | - Julia Bornbaum
- Institute of Physiology, Justus-Liebig-University Giessen, 35392 Giessen, Germany; (P.B.); (J.B.); (B.W.); (L.S.); (K.-D.S.); (R.S.); (G.E.)
| | - Björn Warga
- Institute of Physiology, Justus-Liebig-University Giessen, 35392 Giessen, Germany; (P.B.); (J.B.); (B.W.); (L.S.); (K.-D.S.); (R.S.); (G.E.)
| | - Lisa Schulz
- Institute of Physiology, Justus-Liebig-University Giessen, 35392 Giessen, Germany; (P.B.); (J.B.); (B.W.); (L.S.); (K.-D.S.); (R.S.); (G.E.)
| | - Klaus-Dieter Schlüter
- Institute of Physiology, Justus-Liebig-University Giessen, 35392 Giessen, Germany; (P.B.); (J.B.); (B.W.); (L.S.); (K.-D.S.); (R.S.); (G.E.)
| | - Alessandra Ghigo
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy; (A.G.); (E.H.)
| | - Emilio Hirsch
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy; (A.G.); (E.H.)
| | - Rainer Schulz
- Institute of Physiology, Justus-Liebig-University Giessen, 35392 Giessen, Germany; (P.B.); (J.B.); (B.W.); (L.S.); (K.-D.S.); (R.S.); (G.E.)
| | - Gerhild Euler
- Institute of Physiology, Justus-Liebig-University Giessen, 35392 Giessen, Germany; (P.B.); (J.B.); (B.W.); (L.S.); (K.-D.S.); (R.S.); (G.E.)
| | - Jacqueline Heger
- Institute of Physiology, Justus-Liebig-University Giessen, 35392 Giessen, Germany; (P.B.); (J.B.); (B.W.); (L.S.); (K.-D.S.); (R.S.); (G.E.)
- Correspondence: ; Tel.: +49-641-99-47215
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Mitochondrial ATP-Sensitive K+ Channel Opening Increased the Airway Smooth Muscle Cell Proliferation by Activating the PI3K/AKT Signaling Pathway in a Rat Model of Asthma. Can Respir J 2021; 2021:8899878. [PMID: 34336047 PMCID: PMC8289566 DOI: 10.1155/2021/8899878] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 11/13/2020] [Indexed: 12/02/2022] Open
Abstract
Abnormal proliferation of airway smooth muscle cells (ASMCs) leads to airway remodeling and the development of asthma. This study aimed to assess whether mitochondrial ATP-sensitive K+ (mitoKATP) channels regulated the proliferation of ASMCs by regulating the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway in asthmatic rats. Forty-eight Sprague Dawley rats were immunized with ovalbumin-containing alum to establish the asthma models. The ASMCs were isolated and identified by phase-contrast microscopic images and immunohistochemical staining for α-smooth muscle actin. The ASMCs were treated with a potent activator of mitoKATP, diazoxide, or an inhibitor of mitoKATP, 5-hydroxydecanoate (5-HD). Rhodamine-123 (R-123) was used for detecting the mitochondrial membrane potential (Δψm). The proliferation of ASMCs was examined by the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. The protein and mRNA expressions of AKT and p-AKT were detected using western blotting and quantitative real-time PCR. The results showed that diazoxide enhanced the mitoKATP channel opening in ASMCs in the rat model of asthma, while 5-HD impeded it. Diazoxide also increased ASMC proliferation in the rat model of asthma, whereas 5-HD alleviated it. However, LY294002, a PI3K/AKT pathway inhibitor, reversed the functional roles of diazoxide in the proliferation ability of ASMCs in the rat model of asthma. Furthermore, treatment with diazoxide induced the phosphorylation of AKT, and treatment with 5-HD decreased the phosphorylation of AKT in ASMCs in the rat model of asthma. In conclusion, the mitoKATP channel opening increased the proliferation of ASMCs by activating the PI3K/AKT signaling pathway in a rat model of asthma.
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Falvo S, Rosati L, Di Fiore MM, Di Giacomo Russo F, Chieffi Baccari G, Santillo A. Proliferative and Apoptotic Pathways in the Testis of Quail Coturnix coturnix during the Seasonal Reproductive Cycle. Animals (Basel) 2021; 11:ani11061729. [PMID: 34207904 PMCID: PMC8226535 DOI: 10.3390/ani11061729] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 05/27/2021] [Accepted: 05/31/2021] [Indexed: 11/30/2022] Open
Abstract
Simple Summary The quail Coturnix coturnix exhibits an annual cycle of testis size, sexual steroid production, and spermatogenesis. The testicular levels of both 17β-estradiol (E2) and androgens are higher during the reproductive period compared to the non-reproductive period, suggesting that estrogens act in synergy with the androgens for the initiation of spermatogenesis. Therefore, the present study aimed to investigate the estrogen responsive system in quail testis in relation to the reproduction seasons, with a focus on the molecular pathways activated in both active and regressive quail testes. The results indicated that estrogens participated in the activation of mitotic and meiotic events during the reproductive period by activating the ERK1/2 and Akt-1 pathways. In the non-reproductive period, when the E2/ERα levels are low, ERK1/2 and Akt-1 pathways remain inactive and apoptotic events occur. Our results suggest that the activation or inhibition of these molecular pathways plays a crucial role in the physiological switch “on/off” of the testicular activity in male quail during the seasonal reproductive cycle. Abstract The quail Coturnix coturnix is a seasonal breeding species, with the annual reproductive cycle of its testes comprising an activation phase and a regression phase. Our previous results have proven that the testicular levels of both 17β-estradiol (E2) and androgens are higher during the reproductive period compared to the non-reproductive period, which led us to hypothesize that estrogens and androgens may act synergistically to initiate spermatogenesis. The present study was, therefore, aimed to investigate the estrogen responsive system in quail testis in relation to the reproduction seasonality, with a focus on the molecular pathways elicited in both active and regressive quail testes. Western blotting and immunohistochemistry analysis revealed that the expression of ERα, which is the predominant form of estrogen receptors in quail testis, was correlated with E2 concentration, suggesting that increased levels of E2-induced ERα could play a key role in the resumption of spermatogenesis during the reproductive period, when both PCNA and SYCP3, the mitotic and meiotic markers, respectively, were also increased. In the reproductive period we also found the activation of the ERK1/2 and Akt-1 kinase pathways and an increase in second messengers cAMP and cGMP levels. In the non-reproductive phase, when the E2/ERα levels were low, the inactivation of ERK1/2 and Akt-1 pathways favored apoptotic events due to an increase in the levels of Bax and cytochrome C, with a consequent regression of the gonad.
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Affiliation(s)
- Sara Falvo
- Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Università degli Studi della Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (S.F.); (M.M.D.F.); (F.D.G.R.); (G.C.B.)
| | - Luigi Rosati
- Dipartimento di Biologia, Università degli Studi di Napoli “Federico II”, 80138 Napoli, Italy;
| | - Maria Maddalena Di Fiore
- Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Università degli Studi della Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (S.F.); (M.M.D.F.); (F.D.G.R.); (G.C.B.)
| | - Federica Di Giacomo Russo
- Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Università degli Studi della Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (S.F.); (M.M.D.F.); (F.D.G.R.); (G.C.B.)
| | - Gabriella Chieffi Baccari
- Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Università degli Studi della Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (S.F.); (M.M.D.F.); (F.D.G.R.); (G.C.B.)
| | - Alessandra Santillo
- Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Università degli Studi della Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (S.F.); (M.M.D.F.); (F.D.G.R.); (G.C.B.)
- Correspondence:
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The N 6-methyladenosine demethylase ALKBH5 negatively regulates the osteogenic differentiation of mesenchymal stem cells through PRMT6. Cell Death Dis 2021; 12:578. [PMID: 34088896 PMCID: PMC8178363 DOI: 10.1038/s41419-021-03869-4] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/11/2021] [Accepted: 05/11/2021] [Indexed: 12/23/2022]
Abstract
N6-methyladenosine (m6A) modification is widespread in messenger RNAs and increasing evidence suggests the crucial roles of m6A in cell differentiation and tissue development. However, whether m6A modulates the osteogenic differentiation of mesenchymal stem cells (MSCs) has not been fully elucidated. Here we show that conditional knockout of the demethylase Alkbh5 in bone marrow MSCs strengthened bone mass in mice. Loss- and gain-of-function studies demonstrated that ALKBH5 negatively regulates the osteogenic differentiation of MSCs in vitro. At a mechanistic level, meRIP-seq and RNA-seq in MSCs following knockdown of ALKBH5 revealed changes in transcripts of PRMT6 containing consensus m6A motifs required for demethylation by ALKBH5. Furthermore, we found that ALKBH5 accelerates the degradation rate of PRMT6 mRNA in an m6A-dependent manner, and that the ALKBH5-PRMT6 axis regulates the osteogenesis of MSCs, mainly through activation of the PI3K/AKT pathway. Thus, our work reveals a different facet of the novel ALKBH5-PRMT6 axis that modulates the osteogenic differentiation of MSCs, which can serve as a target to improve the clinical use of MSCs.
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Olmo IG, Olmo RP, Gonçalves ANA, Pires RGW, Marques JT, Ribeiro FM. High-Throughput Sequencing of BACHD Mice Reveals Upregulation of Neuroprotective miRNAs at the Pre-Symptomatic Stage of Huntington's Disease. ASN Neuro 2021; 13:17590914211009857. [PMID: 33906482 PMCID: PMC8718118 DOI: 10.1177/17590914211009857] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Huntington’s disease (HD) is a genetic disorder marked by transcriptional alterations that result in neuronal impairment and death. MicroRNAs (miRNAs) are non-coding RNAs involved in post-transcriptional regulation and fine-tuning of gene expression. Several studies identified altered miRNA expression in HD and other neurodegenerative diseases, however their roles in early stages of HD remain elusive. Here, we deep-sequenced miRNAs from the striatum of the HD mouse model, BACHD, at the age of 2 and 8 months, representing the pre-symptomatic and symptomatic stages of the disease. Our results show that 44 and 26 miRNAs were differentially expressed in 2- and 8-month-old BACHD mice, respectively, as compared to wild-type controls. Over-representation analysis suggested that miRNAs up-regulated in 2-month-old mice control the expression of genes crucial for PI3K-Akt and mTOR cell signaling pathways. Conversely, miRNAs regulating genes involved in neuronal disorders were down-regulated in 2-month-old BACHD mice. Interestingly, primary striatal neurons treated with anti-miRs targeting two up-regulated miRNAs, miR-449c-5p and miR-146b-5p, showed higher levels of cell death. Therefore, our results suggest that the miRNAs altered in 2-month-old BACHD mice regulate genes involved in the promotion of cell survival. Notably, over-representation suggested that targets of differentially expressed miRNAs at the age of 8 months were not significantly enriched for the same pathways. Together, our data shed light on the role of miRNAs in the initial stages of HD, suggesting a neuroprotective role as an attempt to maintain or reestablish cellular homeostasis.
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Affiliation(s)
- Isabella G Olmo
- Department of Biochemistry and Immunology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, Belo Horizonte, Brazil
| | - Roenick P Olmo
- Department of Biochemistry and Immunology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, Belo Horizonte, Brazil.,CNRS UPR9022, Inserm U1257, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Strasbourg, France
| | - André N A Gonçalves
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, Universidade de São Paulo, São Paulo, Brazil
| | - Rita G W Pires
- Department of Physiological Sciences, Center for Health Sciences, Universidade Federal do Espirito Santo, Vitoria, Brazil
| | - João T Marques
- Department of Biochemistry and Immunology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, Belo Horizonte, Brazil.,CNRS UPR9022, Inserm U1257, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Strasbourg, France
| | - Fabíola M Ribeiro
- Department of Biochemistry and Immunology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, Belo Horizonte, Brazil
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Contribution of Yeast Studies to the Understanding of BCL-2 Family Intracellular Trafficking. Int J Mol Sci 2021; 22:ijms22084086. [PMID: 33920941 PMCID: PMC8071328 DOI: 10.3390/ijms22084086] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/12/2021] [Accepted: 04/13/2021] [Indexed: 12/24/2022] Open
Abstract
BCL-2 family members are major regulators of apoptotic cell death in mammals. They form an intricate regulatory network that ultimately regulates the release of apoptogenic factors from mitochondria to the cytosol. The ectopic expression of mammalian BCL-2 family members in the yeast Saccharomyces cerevisiae, which lacks BCL-2 homologs, has been long established as a useful addition to the available models to study their function and regulation. In yeast, individual proteins can be studied independently from the whole interaction network, thus providing insight into the molecular mechanisms underlying their function in a living context. Furthermore, one can take advantage of the powerful tools available in yeast to probe intracellular trafficking processes such as mitochondrial sorting and interactions/exchanges between mitochondria and other compartments, such as the endoplasmic reticulum that are largely conserved between yeast and mammals. Yeast molecular genetics thus allows the investigation of the role of these processes on the dynamic equilibrium of BCL-2 family members between mitochondria and extramitochondrial compartments. Here we propose a model of dynamic regulation of BCL-2 family member localization, based on available evidence from ectopic expression in yeast.
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Yang J, Huang H, Xiao D, Duan Y, Zheng Y, Chen Z. Knockdown of TMED3 inhibits cell viability and migration and increases apoptosis in human chordoma cells. Int J Oncol 2021; 58:15. [PMID: 33760171 PMCID: PMC7949631 DOI: 10.3892/ijo.2021.5195] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 01/28/2021] [Indexed: 01/06/2023] Open
Abstract
Chordoma is a rare low‑grade tumor of the axial skeleton. Over previous decades, a range of targeted drugs have been used for treating chordoma, with more specific and effective therapies under investigation. Transmembrane Emp24 protein transport domain containing 3 (TMED3) is a novel gene reported to be a regulator of oncogenesis, cancer development and metastasis; however, its role in chordoma remains unclear. In the present study, the expression of TMED3 was investigated in chordoma cells, and the effect of TMED3 knockdown on chordoma development was examined in vitro and in vivo, followed by exploration of differentially expressed proteins in TMED3‑silenced chordoma cells via an apoptosis antibody array. Reverse transcription‑quantitative PCR and western blot assays were performed to determine the expression levels. It was revealed that TMED3 was highly expressed in chordoma, and that knockdown of TMED3 inhibited cell viability and migration, and enhanced the apoptosis of chordoma cells. Additionally, knockdown of TMED3 inhibited the expression of Bcl‑2, heat shock protein 27, insulin‑like growth factor (IGF)‑I, IGF‑II, IGF binding protein‑2, Livin, Akt, CDK6 and cyclin D1 proteins, whereas MAPK9 was upregulated. Furthermore, a xenograft nude mice model demonstrated that TMED3 expression promoted tumor growth. Collectively, the present findings suggested that knockdown of TMED3 inhibited cell viability and migration, and enhanced apoptosis in chordoma cells, and that TMED3 may be a novel target for chordoma therapy.
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Affiliation(s)
- Jinxing Yang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518035, P.R. China
| | - Hanwen Huang
- Department of Spinal Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Dan Xiao
- Department of Spine Surgery, Orthopedics Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China
| | - Yang Duan
- Department of Spinal Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Yanfang Zheng
- Department of Medical Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong 510095, P.R. China
| | - Zhong Chen
- Department of Spinal Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
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Ge H, Tian M, Pei Q, Tan F, Pei H. Extracellular Matrix Stiffness: New Areas Affecting Cell Metabolism. Front Oncol 2021; 11:631991. [PMID: 33718214 PMCID: PMC7943852 DOI: 10.3389/fonc.2021.631991] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 01/04/2021] [Indexed: 12/12/2022] Open
Abstract
In recent years, in-depth studies have shown that extracellular matrix stiffness plays an important role in cell growth, proliferation, migration, immunity, malignant transformation, and apoptosis. Most of these processes entail metabolic reprogramming of cells. However, the exact mechanism through which extracellular matrix stiffness leads to metabolic reprogramming remains unclear. Insights regarding the relationship between extracellular matrix stiffness and metabolism could help unravel novel therapeutic targets and guide development of clinical approaches against a myriad of diseases. This review provides an overview of different pathways of extracellular matrix stiffness involved in regulating glucose, lipid and amino acid metabolism.
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Affiliation(s)
- Heming Ge
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Mengxiang Tian
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Qian Pei
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Fengbo Tan
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Haiping Pei
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
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Cadmium induces apoptosis of pig lymph nodes by regulating the PI3K/AKT/HIF-1α pathway. Toxicology 2021; 451:152694. [PMID: 33493553 DOI: 10.1016/j.tox.2021.152694] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 01/05/2021] [Accepted: 01/19/2021] [Indexed: 12/21/2022]
Abstract
OBJECTIVE This study was aimed to explore the possible mechanism of environmental metal cadmium (Cd) inducing apoptosis of pig lymph nodes. METHOD 10 healthy 6-week-old weaned piglets were randomly divided into two groups (n = 5 pigs/group). The control group was fed with a basic diet, and the test group was fed with a basic diet of 20 mg/kg CdCl2. RESULTS The Cd deposition in mesenteric lymph nodes (MLN), inguinal lymph nodes (ILN) and submaxillary lymph nodes (SLN) after Cd exposure was 2.37 folds, 1.4 folds and 1.8 folds of the control group, respectively. And the rate of MLN and ILN apoptotic cells in the Cd group was 4.11 folds and 9.18 folds of the control group, respectively. The mRNA levels of SOD1, SOD2, CAT, GPX1 and GSH in the Cd group were reduced. Similarly, the two-phase detoxification enzymes had a significant downward trend. Cd exposure decreased the activities of GSH, GSH-Px, SOD, CAT, and increased H2O2 and MDA levels. The mRNA and protein levels of Drp1 and Mff in the Cd group were higher than the corresponding control group, and the mRNA and protein levels of Mfn1 and Mfn2 were lower than those in the control group. In addition, the mRNA and protein levels of pro-apoptotic genes in the Cd group were lower than those in the control group. Cd can significantly reduce the expression of PI3K, AKT and HIF-1α in the three lymph nodes. In summary, Cd induces oxidative stress and regulates the PI3K/AKT/HIF-1α signal transduction pathway to cause mitochondrial dynamics disorder, which leads to the apoptosis of pig lymph nodes, suggesting that Cd-induced mitochondrial pathway apoptosis is related to Cd pig lymph nodes play an important role in the toxicity mechanism.
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Neutrophil Elastase Deficiency Ameliorates Myocardial Injury Post Myocardial Infarction in Mice. Int J Mol Sci 2021; 22:ijms22020722. [PMID: 33450865 PMCID: PMC7828348 DOI: 10.3390/ijms22020722] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/09/2021] [Accepted: 01/10/2021] [Indexed: 12/17/2022] Open
Abstract
Neutrophils are recruited into the heart at an early stage following a myocardial infarction (MI). These secrete several proteases, one of them being neutrophil elastase (NE), which promotes inflammatory responses in several disease models. It has been shown that there is an increase in NE activity in patients with MI; however, the role of NE in MI remains unclear. Therefore, the present study aimed to investigate the role of NE in the pathogenesis of MI in mice. NE expression peaked on day 1 in the infarcted hearts. In addition, NE deficiency improved survival and cardiac function post-MI, limiting fibrosis in the noninfarcted myocardium. Sivelestat, an NE inhibitor, also improved survival and cardiac function post-MI. Flow cytometric analysis showed that the numbers of heart-infiltrating neutrophils and inflammatory macrophages (CD11b+F4/80+CD206low cells) were significantly lower in NE-deficient mice than in wild-type (WT) mice. At the border zone between intact and necrotic areas, the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells was lower in NE-deficient mice than in WT mice. Western blot analyses revealed that the expression levels of insulin receptor substrate 1 and phosphorylation of Akt were significantly upregulated in NE-knockout mouse hearts, indicating that NE deficiency might improve cardiac survival by upregulating insulin/Akt signaling post-MI. Thus, NE may enhance myocardial injury by inducing an excessive inflammatory response and suppressing Akt signaling in cardiomyocytes. Inhibition of NE might serve as a novel therapeutic target in the treatment of MI.
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Abiko Y, Aoki H, Kumagai Y. Effect of combined exposure to environmental aliphatic electrophiles from plants on Keap1/Nrf2 activation and cytotoxicity in HepG2 cells: A model of an electrophile exposome. Toxicol Appl Pharmacol 2021; 413:115392. [PMID: 33428920 DOI: 10.1016/j.taap.2020.115392] [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: 08/25/2020] [Revised: 12/24/2020] [Accepted: 12/30/2020] [Indexed: 11/25/2022]
Abstract
Electrophiles, ubiquitously found in the environment, modify thiol groups of sensor proteins, leading to activation of redox signaling pathways such as the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor E2 related factor 2 (Nrf2) pathway. Nrf2 activation by exposure to single electrophiles has been established. However, the effect of exposure to a combination of electrophiles on Nrf2 activation has not been well evaluated. The current study examined whether combined exposure to electrophiles enhances the modification of thiol groups and Keap1/Nrf2 activation in HepG2 cells. Six electrophiles [1,2-naphthoquinone (1,2-NQ), 1,4-NQ, 1,4-benzoquinone, (E)-2-hexenal (hexenal), (E)-2-decenal, and (E)-2-butenal] were tested for S-modification of albumin in vitro and for cytotoxicity to HepG2 cells. Interestingly, a mixture of the electrophiles enhanced S-modification of albumin and cytotoxicity compared with exposure to each electrophile separately. Herein, we focused on 1,2-NQ, 1,4-NQ, and hexenal to clarify the combined effect of electrophiles on Keap1/Nrf2 activation in HepG2 cells. A concentration addition model revealed that 1,2-NQ and/or 1,4-NQ additively enhanced hexenal-mediated S-modification of GSH in vitro, whereas the cytotoxicity of hexenal was synergistically increased by simultaneous exposure of HepG2 cells to the NQs. Furthermore, an NQ cocktail (2.5 μM each) that does not activate Nrf2 enhanced hexenal-mediated Nrf2 activation. These results suggest that combined exposure to electrophiles at low concentrations induces stronger activation of redox signaling compared with exposure to each electrophile alone and worsens their cytotoxicity.
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Affiliation(s)
- Yumi Abiko
- Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human, Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Hanako Aoki
- Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human, Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Yoshito Kumagai
- Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human, Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
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Wong H, Levenga J, LaPlante L, Keller B, Cooper-Sansone A, Borski C, Milstead R, Ehringer M, Hoeffer C. Isoform-specific roles for AKT in affective behavior, spatial memory, and extinction related to psychiatric disorders. eLife 2020; 9:e56630. [PMID: 33325370 PMCID: PMC7787664 DOI: 10.7554/elife.56630] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 12/15/2020] [Indexed: 12/12/2022] Open
Abstract
AKT is implicated in neurological disorders. AKT has three isoforms, AKT1/AKT2/AKT3, with brain cell type-specific expression that may differentially influence behavior. Therefore, we examined single Akt isoform, conditional brain-specific Akt1, and double Akt1/3 mutant mice in behaviors relevant to neuropsychiatric disorders. Because sex is a determinant of these disorders but poorly understood, sex was an experimental variable in our design. Our studies revealed AKT isoform- and sex-specific effects on anxiety, spatial and contextual memory, and fear extinction. In Akt1 mutant males, viral-mediated AKT1 restoration in the prefrontal cortex rescued extinction phenotypes. We identified a novel role for AKT2 and overlapping roles for AKT1 and AKT3 in long-term memory. Finally, we found that sex-specific behavior effects were not mediated by AKT expression or activation differences between sexes. These results highlight sex as a biological variable and isoform- or cell type-specific AKT signaling as potential targets for improving treatment of neuropsychiatric disorders.
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Affiliation(s)
- Helen Wong
- Institute for Behavioral Genetics, University of Colorado, Boulder, United States
| | - Josien Levenga
- Institute for Behavioral Genetics, University of Colorado, Boulder, United States
- Linda Crnic Institute, Anschutz Medical Center, Aurora, United States
| | - Lauren LaPlante
- Institute for Behavioral Genetics, University of Colorado, Boulder, United States
| | - Bailey Keller
- Institute for Behavioral Genetics, University of Colorado, Boulder, United States
| | | | - Curtis Borski
- Institute for Behavioral Genetics, University of Colorado, Boulder, United States
| | - Ryan Milstead
- Department of Integrative Physiology, University of Colorado, Boulder, United States
| | - Marissa Ehringer
- Institute for Behavioral Genetics, University of Colorado, Boulder, United States
- Department of Integrative Physiology, University of Colorado, Boulder, United States
| | - Charles Hoeffer
- Institute for Behavioral Genetics, University of Colorado, Boulder, United States
- Linda Crnic Institute, Anschutz Medical Center, Aurora, United States
- Department of Integrative Physiology, University of Colorado, Boulder, United States
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