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Periferakis A, Periferakis AT, Troumpata L, Periferakis K, Georgatos-Garcia S, Touriki G, Dragosloveanu CDM, Caruntu A, Savulescu-Fiedler I, Dragosloveanu S, Scheau AE, Badarau IA, Caruntu C, Scheau C. Pinosylvin: A Multifunctional Stilbenoid with Antimicrobial, Antioxidant, and Anti-Inflammatory Potential. Curr Issues Mol Biol 2025; 47:204. [PMID: 40136458 PMCID: PMC11941527 DOI: 10.3390/cimb47030204] [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: 02/14/2025] [Revised: 03/13/2025] [Accepted: 03/15/2025] [Indexed: 03/27/2025] Open
Abstract
Stilbenoids are a category of plant compounds exhibiting notable health-related benefits. After resveratrol, perhaps the most well-known stilbenoid is pinosylvin, a major phytochemical constituent of most plants characterised by the pine spines among others. Pinosylvin and its derivatives have been found to exert potent antibacterial and antifungal effects, while their antiparasitic and antiviral properties are still a subject of ongoing research. The antioxidant properties of pinosylvin are mostly based on its scavenging of free radicals, inhibition of iNOS and protein kinase C, and promotion of HO-1 expression. Its anti-inflammatory properties are based on a variety of mechanisms, such as COX-2 inhibition, NF-κB and TRPA1 activation inhibition, and reduction in IL-6 levels. Its anticancer properties are partly associated with its antioxidant and anti-inflammatory potential, although a number of other mechanisms are described, such as apoptosis induction and matrix metalloproteinase inhibition. A couple of experiments have also suggested a neuroprotective potential. A multitude of ethnomedical and ethnobotanical effects of pinosylvin-containing plants are reported, like antimicrobial, antioxidant, anti-inflammatory, hepatoprotective, and prokinetic actions; many of these are corroborated by recent research. The advent of novel methods of artificial pinosylvin synthesis may facilitate its mass production and adoption as a medical compound. Finally, pinosylvin may be a tool in promoting environmentally friendly pesticide and insecticide policies and be used in land remediation schemes.
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Affiliation(s)
- Argyrios Periferakis
- Department of Physiology, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Akadimia of Ancient Greek and Traditional Chinese Medicine, 16675 Athens, Greece
- Elkyda, Research & Education Centre of Charismatheia, 17675 Athens, Greece
| | - Aristodemos-Theodoros Periferakis
- Department of Physiology, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Elkyda, Research & Education Centre of Charismatheia, 17675 Athens, Greece
| | - Lamprini Troumpata
- Department of Physiology, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Konstantinos Periferakis
- Akadimia of Ancient Greek and Traditional Chinese Medicine, 16675 Athens, Greece
- Pan-Hellenic Organization of Educational Programs (P.O.E.P.), 17236 Athens, Greece
| | - Spyrangelos Georgatos-Garcia
- Tilburg Institute for Law, Technology, and Society (TILT), Tilburg University, 5037 DE Tilburg, The Netherlands
- Corvers Greece IKE, 15124 Athens, Greece
| | - Georgia Touriki
- Faculty of Law, Democritus University of Thrace, 69100 Komotini, Greece
| | - Christiana Diana Maria Dragosloveanu
- Department of Ophthalmology, Faculty of Dentistry, The “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Ophthalmology, Clinical Hospital for Ophthalmological Emergencies, 010464 Bucharest, Romania
| | - Ana Caruntu
- Department of Oral and Maxillofacial Surgery, “Carol Davila” Central Military Emergency Hospital, 010825 Bucharest, Romania
- Department of Oral and Maxillofacial Surgery, Faculty of Dental Medicine, Titu Maiorescu University, 031593 Bucharest, Romania
| | - Ilinca Savulescu-Fiedler
- Department of Internal Medicine, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Internal Medicine and Cardiology, Coltea Clinical Hospital, 030167 Bucharest, Romania
| | - Serban Dragosloveanu
- Department of Orthopaedics and Traumatology, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Orthopaedics, “Foisor” Clinical Hospital of Orthopaedics, Traumatology and Osteoarticular TB, 021382 Bucharest, Romania
| | - Andreea-Elena Scheau
- Department of Radiology and Medical Imaging, “Foisor” Clinical Hospital of Orthopaedics, Traumatology and Osteoarticular TB, 021382 Bucharest, Romania
| | - Ioana Anca Badarau
- Department of Physiology, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Constantin Caruntu
- Department of Physiology, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Dermatology, “Prof. N.C. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania
| | - Cristian Scheau
- Department of Physiology, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Radiology and Medical Imaging, “Foisor” Clinical Hospital of Orthopaedics, Traumatology and Osteoarticular TB, 021382 Bucharest, Romania
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Park MK, Choi BY, Kho AR, Lee SH, Hong DK, Kang BS, Lee CJ, Yang HW, Woo SY, Park SW, Kim DY, Jung HH, Yang WI, Suh SW. L-theanine ameliorates traumatic-brain-injury-induced hippocampal neuronal death in rats. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 139:156457. [PMID: 40023064 DOI: 10.1016/j.phymed.2025.156457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 04/01/2024] [Accepted: 02/01/2025] [Indexed: 03/04/2025]
Abstract
BACKGROUND Traumatic brain injury (TBI) is a major health concern, often resulting in significant brain damage and functional impairments. A key contributing factor to TBI-induced neuronal injury is the overactivation of AMPA glutamate receptors, leading to an increased influx of calcium and zinc ions. This study investigates the neuroprotective potential of l-theanine, known for its antioxidant potential and ability to enhance glutathione synthesis, against hippocampal damage in a TBI rat model. METHODS Rats subjected to TBIs were treated with two dosages of l-theanine (100 and 200 mg/kg) and an AMPA receptor inhibitor, NBQX (30 mg/kg). The neuronal damage assessment, conducted 24 h post-injury, involved a histological analysis, focusing on the factors of neuronal death, oxidative damage, and glial cell activation. The statistical analysis included the performance of an ANOVA followed by a Bonferroni post hoc test, with the data presented as mean ± SEM values and the significance determined at p < 0.05. RESULTS Treatment with l-theanine was observed to significantly mitigate the zinc accumulation, neuronal death, and cognitive impairments associated with TBI. These benefits are likely attributed to the inhibition of AMPA receptor activity and reduction in neuroinflammation, possibly enhanced as a result of increased glutathione production. CONCLUSION This study suggests that l-theanine can perform a neuroprotective role in TBI, modulating AMPA receptor activation and diminishing neuroinflammation. Its antioxidant and anti-inflammatory properties further enhance the material's potential use as a therapeutic agent for reducing hippocampal damage caused as a result of a TBI.
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Affiliation(s)
- Min Kyu Park
- Department of Physiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea.
| | - Bo Young Choi
- Institute of Sport Science, Hallym University, Chuncheon, 24252, Republic of Korea; Department of Physical Education, Hallym University, Chuncheon, 24252, Republic of Korea.
| | - A Ra Kho
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
| | - Song Hee Lee
- Department of Physiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea.
| | - Dae Ki Hong
- Department of Physiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
| | - Beom Seok Kang
- Department of Physiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea.
| | - Chang Jun Lee
- Department of Physiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea.
| | - Hyun Wook Yang
- Department of Physiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea.
| | - Seo Young Woo
- Department of Physiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea.
| | - Se Wan Park
- Department of Physiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea.
| | - Dong Yeon Kim
- Department of Physiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea.
| | - Hyun Ho Jung
- Department of Physiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea.
| | - Won Il Yang
- Institute of Sport Science, Hallym University, Chuncheon, 24252, Republic of Korea; Department of Physical Education, Hallym University, Chuncheon, 24252, Republic of Korea; Department of Sport Industry Studies, Yonsei University, Seoul, 03722, Republic of Korea.
| | - Sang Won Suh
- Department of Physiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea.
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Arkinson C, Dong KC, Gee CL, Martin A. Mechanisms and regulation of substrate degradation by the 26S proteasome. Nat Rev Mol Cell Biol 2025; 26:104-122. [PMID: 39362999 PMCID: PMC11772106 DOI: 10.1038/s41580-024-00778-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/23/2024] [Indexed: 10/05/2024]
Abstract
The 26S proteasome is involved in degrading and regulating the majority of proteins in eukaryotic cells, which requires a sophisticated balance of specificity and promiscuity. In this Review, we discuss the principles that underly substrate recognition and ATP-dependent degradation by the proteasome. We focus on recent insights into the mechanisms of conventional ubiquitin-dependent and ubiquitin-independent protein turnover, and discuss the plethora of modulators for proteasome function, including substrate-delivering cofactors, ubiquitin ligases and deubiquitinases that enable the targeting of a highly diverse substrate pool. Furthermore, we summarize recent progress in our understanding of substrate processing upstream of the 26S proteasome by the p97 protein unfoldase. The advances in our knowledge of proteasome structure, function and regulation also inform new strategies for specific inhibition or harnessing the degradation capabilities of the proteasome for the treatment of human diseases, for instance, by using proteolysis targeting chimera molecules or molecular glues.
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Affiliation(s)
- Connor Arkinson
- California Institute for Quantitative Biosciences, University of California at Berkeley, Berkeley, CA, USA
- Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA
- Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA
| | - Ken C Dong
- Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA
| | - Christine L Gee
- California Institute for Quantitative Biosciences, University of California at Berkeley, Berkeley, CA, USA
- Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA
- Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA
| | - Andreas Martin
- California Institute for Quantitative Biosciences, University of California at Berkeley, Berkeley, CA, USA.
- Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA.
- Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA.
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Mishra AP, Kumar R, Harilal S, Nigam M, Datta D, Singh S, Waranuch N, Chittasupho C. Demystifying the management of cancer through smart nano-biomedicine via regulation of reactive oxygen species. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:497-532. [PMID: 39480523 DOI: 10.1007/s00210-024-03469-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 09/17/2024] [Indexed: 11/02/2024]
Abstract
Advancements in therapeutic strategies and combinatorial approaches for cancer management have led to the majority of cancers in the initial stages to be regarded as treatable and curable. However, certain high-grade cancers in the initial stages are still regarded as chronic and difficult to manage, requiring novel therapeutic strategies. In this era of targeted and precision therapy, novel strategies for targeted delivery of drug and synergistic therapies, integrating nanotherapeutics, polymeric materials, and modulation of the tumor microenvironment are being developed. One such strategy is the study and utilization of smart-nano biomedicine, which refers to stimuli-responsive polymeric materials integrated with the anti-cancer drug that can modulate the reactive oxygen species (ROS) in the tumor microenvironment or can be ROS responsive for the mitigation as well as management of various cancers. The article explores in detail the ROS, its types, and sources; the antioxidant system, including scavengers and their role in cancer; the ROS-responsive targeted polymeric materials, including synergistic therapies for the treatment of cancer via modulating the ROS in the tumor microenvironment, involving therapeutic strategies promoting cancer cell death; and the current landscape and future prospects.
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Affiliation(s)
- Abhay Prakash Mishra
- Cosmetics and Natural Products Research Centre, Department of Pharmaceutical Technology, Naresuan University, Phitsanulok, 65000, Thailand
| | - Rajesh Kumar
- Faculty of Pharmaceutical Sciences, Kerala University of Health Sciences, Kerala, 680596, India.
| | - Seetha Harilal
- Faculty of Pharmaceutical Sciences, Kerala University of Health Sciences, Kerala, 680596, India
| | - Manisha Nigam
- Department of Biochemistry, Hemvati Nandan Bahuguna Garhwal University, Srinagar Garhwal, Uttarakhand, 246174, India
| | - Deepanjan Datta
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal Karnataka, 576104, India
| | - Sudarshan Singh
- Office of Research Administration, Chiang Mai University, Chiang Mai, 50200, Thailand.
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, 50200, Thailand.
| | - Neti Waranuch
- Cosmetics and Natural Products Research Centre, Department of Pharmaceutical Technology, Naresuan University, Phitsanulok, 65000, Thailand
| | - Chuda Chittasupho
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, 50200, Thailand
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Ha Y, Kang W, Roh J, Jung Y, Lee H, Park T. Acetyl tributyl citrate attenuates 5-fluorouracil-induced inflammation, oxidative stress, and apoptosis in human keratinocytes. Biochem Pharmacol 2024; 230:116606. [PMID: 39489222 DOI: 10.1016/j.bcp.2024.116606] [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: 07/09/2024] [Revised: 10/15/2024] [Accepted: 10/31/2024] [Indexed: 11/05/2024]
Abstract
5-Fluorouracil (5-FU) is a commonly used chemotherapy drug that effectively destroys cancer cells. Despite its widespread use and efficacy, it also presents considerable challenges, particularly with adverse effects on rapidly dividing normal cells, such as keratinocytes. These detrimental effects are attributed to inflammatory, oxidative, and apoptotic potentials, leading to severe skin disorders. Due to the lack of specific remedies for 5-FU-induced dermatological side effects, conventional treatments are applied instead, which provide limited relief and have drawbacks. This study investigated the impact of acetyl tributyl citrate (ATBC) in 5-FU-treated human keratinocytes. The findings indicated that ATBC substantially reduced inflammation caused by 5-FU, as demonstrated by nuclear translocation of nuclear factor kappa B and expression of its downstream genes, including tumor necrosis factor, interleukin 1 beta (IL1B), and IL6. ATBC also markedly decreased oxidative stress, indicated by reactive oxygen species levels and the antioxidant gene expression such as superoxide dismutase 1 (SOD1), SOD2, and heme oxygenase 1 in 5-FU-treated cells. Furthermore, ATBC attenuated 5-FU-induced apoptosis, as determined by lactate dehydrogenase release and Annexin V/propidium iodide flow cytometry, with the potential involvement of interferon-related genes. Following this, protein kinase C delta was predicted as a possible molecular target of ATBC. These findings propose ATBC as a therapeutic agent for managing the cutaneous side effects associated with 5-FU treatment.
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Affiliation(s)
- Yoojeong Ha
- Department of Food and Nutrition, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Wesuk Kang
- Department of Food and Nutrition, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Jiyun Roh
- Department of Food and Nutrition, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Yearim Jung
- Department of Food and Nutrition, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Hyunbin Lee
- Department of Food and Nutrition, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Taesun Park
- Department of Food and Nutrition, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
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Shiota M, Ushijima M, Tsukahara S, Nagakawa S, Okada T, Tanegashima T, Kobayashi S, Matsumoto T, Eto M. Oxidative stress in peroxisomes induced by androgen receptor inhibition through peroxisome proliferator-activated receptor promotes enzalutamide resistance in prostate cancer. Free Radic Biol Med 2024; 221:81-88. [PMID: 38762061 DOI: 10.1016/j.freeradbiomed.2024.05.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 05/14/2024] [Accepted: 05/16/2024] [Indexed: 05/20/2024]
Abstract
Androgen receptor (AR)-targeting therapy induces oxidative stress in prostate cancer. However, the mechanism of oxidative stress induction by AR-targeting therapy remains unclear. This study investigated the mechanism of oxidative stress induction by AR-targeting therapy, with the aim to develop novel therapeutics targeting oxidative stress induced by AR-targeting therapy. Intracellular reactive oxygen species (ROS) was examined by fluorescence microscopy and flow cytometry analysis. The effects of silencing gene expression and small molecule inhibitors on gene expression and cytotoxic effects were examined by quantitative real-time PCR and cell proliferation assay. ROS induced by androgen depletion co-localized with peroxisomes in prostate cancer cells. Among peroxisome-related genes, PPARA was commonly induced by AR inhibition and involved in ROS production via PKC signaling. Inhibition of PPARα by specific siRNA and a small molecule inhibitor suppressed cell proliferation and increased cellular sensitivity to the antiandrogen enzalutamide in prostate cancer cells. This study revealed a novel pathway by which AR inhibition induced intracellular ROS mainly in peroxisomes through PPARα activation in prostate cancer. This pathway is a promising target for the development of novel therapeutics for prostate cancer in combination with AR-targeting therapy such as antiandrogen enzalutamide.
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Affiliation(s)
- Masaki Shiota
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
| | - Miho Ushijima
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
| | - Shigehiro Tsukahara
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
| | - Shohei Nagakawa
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
| | - Tatsunori Okada
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
| | - Tokiyoshi Tanegashima
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
| | - Satoshi Kobayashi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
| | - Takashi Matsumoto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
| | - Masatoshi Eto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
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Wang N, Zhang C. Oxidative Stress: A Culprit in the Progression of Diabetic Kidney Disease. Antioxidants (Basel) 2024; 13:455. [PMID: 38671903 PMCID: PMC11047699 DOI: 10.3390/antiox13040455] [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: 02/27/2024] [Revised: 04/01/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
Diabetic kidney disease (DKD) is the principal culprit behind chronic kidney disease (CKD), ultimately developing end-stage renal disease (ESRD) and necessitating costly dialysis or kidney transplantation. The limited therapeutic efficiency among individuals with DKD is a result of our finite understanding of its pathogenesis. DKD is the result of complex interactions between various factors. Oxidative stress is a fundamental factor that can establish a link between hyperglycemia and the vascular complications frequently encountered in diabetes, particularly DKD. It is crucial to recognize the essential and integral role of oxidative stress in the development of diabetic vascular complications, particularly DKD. Hyperglycemia is the primary culprit that can trigger an upsurge in the production of reactive oxygen species (ROS), ultimately sparking oxidative stress. The main endogenous sources of ROS include mitochondrial ROS production, NADPH oxidases (Nox), uncoupled endothelial nitric oxide synthase (eNOS), xanthine oxidase (XO), cytochrome P450 (CYP450), and lipoxygenase. Under persistent high glucose levels, immune cells, the complement system, advanced glycation end products (AGEs), protein kinase C (PKC), polyol pathway, and the hexosamine pathway are activated. Consequently, the oxidant-antioxidant balance within the body is disrupted, which triggers a series of reactions in various downstream pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), transforming growth factor beta/p38-mitogen-activated protein kinase (TGF-β/p38-MAPK), nuclear factor kappa B (NF-κB), adenosine monophosphate-activated protein kinase (AMPK), and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. The disease might persist even if strict glucose control is achieved, which can be attributed to epigenetic modifications. The treatment of DKD remains an unresolved issue. Therefore, reducing ROS is an intriguing therapeutic target. The clinical trials have shown that bardoxolone methyl, a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, blood glucose-lowering drugs, such as sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists can effectively slow down the progression of DKD by reducing oxidative stress. Other antioxidants, including vitamins, lipoic acid, Nox inhibitors, epigenetic regulators, and complement inhibitors, present a promising therapeutic option for the treatment of DKD. In this review, we conduct a thorough assessment of both preclinical studies and current findings from clinical studies that focus on targeted interventions aimed at manipulating these pathways. We aim to provide a comprehensive overview of the current state of research in this area and identify key areas for future exploration.
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Affiliation(s)
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Tang S, An X, Sun W, Zhang Y, Yang C, Kang X, Sun Y, Jiang L, Zhao X, Gao Q, Ji H, Lian F. Parallelism and non-parallelism in diabetic nephropathy and diabetic retinopathy. Front Endocrinol (Lausanne) 2024; 15:1336123. [PMID: 38419958 PMCID: PMC10899692 DOI: 10.3389/fendo.2024.1336123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 01/23/2024] [Indexed: 03/02/2024] Open
Abstract
Diabetic nephropathy (DN) and diabetic retinopathy (DR), as microvascular complications of diabetes mellitus, are currently the leading causes of end-stage renal disease (ESRD) and blindness, respectively, in the adult working population, and they are major public health problems with social and economic burdens. The parallelism between the two in the process of occurrence and development manifests in the high overlap of disease-causing risk factors and pathogenesis, high rates of comorbidity, mutually predictive effects, and partial concordance in the clinical use of medications. However, since the two organs, the eye and the kidney, have their unique internal environment and physiological processes, each with specific influencing molecules, and the target organs have non-parallelism due to different pathological changes and responses to various influencing factors, this article provides an overview of the parallelism and non-parallelism between DN and DR to further recognize the commonalities and differences between the two diseases and provide references for early diagnosis, clinical guidance on the use of medication, and the development of new drugs.
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Affiliation(s)
- Shanshan Tang
- College of Traditional Chinese Medicine, Changchun University of Traditional Chinese Medicine, Changchun, China
| | - Xuedong An
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Wenjie Sun
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuehong Zhang
- Fangshan Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Cunqing Yang
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaomin Kang
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuting Sun
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Linlin Jiang
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Xuefei Zhao
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Qing Gao
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Hangyu Ji
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Fengmei Lian
- Guang’an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
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Kumar N, Thorat ST, Patole PB, Gite A, Reddy KS. Protective role of selenium and selenium-nanoparticles against multiple stresses in Pangasianodon hypophthalmus. FISH PHYSIOLOGY AND BIOCHEMISTRY 2024; 50:239-258. [PMID: 37656302 DOI: 10.1007/s10695-023-01231-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 08/16/2023] [Indexed: 09/02/2023]
Abstract
Pollution and climate change pose significant threats to aquatic ecosystems, with adverse impacts on aquatic animals, including fish. Climate change increases the toxicity of metal in aquatic ecosystems. To understand the severity of metal pollution and climate change, an experiment was conducted to delineate the mitigation potential of selenium (Se) and selenium nanoparticles (Se-NPs) against lead (Pb) and high temperature stress in Pangasianodon hypophthalmus. For the experiment, five isonitrogenous and isocaloric diets were prepared, varying in selenium supplementation as Se at 0, 1, and 2 mg kg-1 diet, and Se-NPs at 1 and 2 mg kg-1 diet. The fish in stressor groups were exposed to Pb (1/20th of LC50 concentration, 4 ppm) and high temperature (34 °C) throughout the experiment. The results demonstrated that dietary supplementation of Se at 1 and 2 mg kg-1 diet, as well as Se-NPs at 1 mg kg-1 diet, significantly reduced (p < 0.01) the levels of lactate dehydrogenase and malate dehydrogenase in both liver and muscle tissues. Additionally, the levels of alanine aminotransferase and aspartate aminotransferase in both gill and liver tissues were significantly decreased (p < 0.01) with the inclusion of Se and Se-NPs in the diets. Furthermore, the enzymes glucose-6-phosphate dehydrogenase in gill and liver tissues, fructose 1,6-bisphosphatase in liver and muscle tissues, and acid phosphatase in liver tissue were remarkably reduced (p < 0.01) due to the supplementation of Se and Se-NPs. Moreover, dietary supplementation of Se and Se-NPs significantly enhanced (p < 0.01) the activity of pyruvate kinase, glucokinase, hexokinase, alkaline phosphatase, ATPase, protease, amylase, lipase, and RNA/DNA ratio in the fish. Histopathological examination of gill and liver tissues also indicated that Se and Se-NPs protected against structural damage caused by lead and high-temperature stress. Moreover, the study examined the bioaccumulation of selenium and lead in muscle, water, and diets. The aim of the study revealed that Se and Se-NPs effectively protected the fish from lead toxicity and high-temperature stress, while also improving the function of cellular metabolic enzymes in P. hypophthalmus.
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Affiliation(s)
- Neeraj Kumar
- ICAR-National Institute of Abiotic Stress Management, Baramati, 413 115, Pune, India.
| | | | - Pooja Bapurao Patole
- ICAR-National Institute of Abiotic Stress Management, Baramati, 413 115, Pune, India
| | - Archana Gite
- ICAR-National Institute of Abiotic Stress Management, Baramati, 413 115, Pune, India
| | - Kotha Sammi Reddy
- ICAR-National Institute of Abiotic Stress Management, Baramati, 413 115, Pune, India
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Anees S, Ahmad M, Ashraf S, Bhat AH, Hamid R, Ganie SA. Bioactive fractions from Allium humile alleviate the risk of high fat diet induced atherosclerosis in albino Wistar rats by inhibiting protein kinase C. Fitoterapia 2024; 172:105775. [PMID: 38097019 DOI: 10.1016/j.fitote.2023.105775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 12/07/2023] [Accepted: 12/07/2023] [Indexed: 12/19/2023]
Abstract
Atherosclerosis is a global concern that worsens with age, and plants that are effective medicinal herbs can give a viable alternative. PKC is a key factor in cardiovascular and other disorders; targeting it can reduce the risk of these diseases. We evaluated Allium humile for PKC inhibition and therapeutic efficacy against atherosclerosis. Soxhlet extraction was done to obtain extracts (hexane, ethyl acetate, methanol, ethanol and aqueous) and then tested for DPPH radical scavenging and PKC inhibitory activity. The methanolic extract was more active than the other extracts, so it was subjected to column chromatography, and seventeen fractions were obtained. Only 11, 12, and 15 showed good activity against PKC. Wistar rats were divided into six groups and each group received high fat diet for 30 days. Then the three potent fractions (10 mg/kg) were administered for 15 days along with high fat diet. Fraction II had the highest effectiveness (P < 0.0001) in decreasing lipid levels, lipid peroxidation, reducing IL-6 and TNF-α expression, and raising nitric oxide. This also demonstrated a decrease in PKC activity, as well as a decrease in the formation of the lipoidal layer in the aorta wall and rupture of the intima and media as validated by histological analysis. The two compounds, phytol acetate and cyanidin 3-(6″-o-malonyllaminaribioside) were characterised in fraction II by NMR and HRMS and cyanidin 3-(6″-o-malonyllaminaribioside) inhibited PKC more efficiently. Thus, Allium humile has strong anti-atherogenic activity as well as the ability to inhibit PKC both in vitro and in vivo.
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Affiliation(s)
- Suhail Anees
- Department of Clinical Biochemistry, University of Kashmir, Srinagar, India
| | - Muzaffar Ahmad
- Department of Biochemistry, University of Kashmir, Srinagar, India
| | - Suhail Ashraf
- Department of Clinical Biochemistry, University of Kashmir, Srinagar, India
| | | | - Rabia Hamid
- Department of Nanotechnology, University of Kashmir, Srinagar, India.
| | - Showkat Ahmad Ganie
- Department of Clinical Biochemistry, University of Kashmir, Srinagar, India.
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11
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Mansour HM, Mohamed AF, Khattab MM, El-Khatib AS. Pazopanib ameliorates rotenone-induced Parkinsonism in rats by suppressing multiple regulated cell death mechanisms. Food Chem Toxicol 2023; 181:114069. [PMID: 37820786 DOI: 10.1016/j.fct.2023.114069] [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: 03/20/2023] [Revised: 09/16/2023] [Accepted: 09/27/2023] [Indexed: 10/13/2023]
Abstract
Parkinson's disease (PD) is characterized by motor impairments and progressive dopaminergic neuronal death in the substantia nigra (SN). Recently, the involvement of other regulated cell death (RCD) machineries has been highlighted in PD. Necroptosis is controlled by p-RIPK1, p-RIPK3, and p-MLKL and negatively regulated by caspase-8. Ferroptosis is characterized by iron overload and accumulation of reactive oxygen species. Interestingly, the molecular chaperone complex HSP90/CDC37 has been reported to directly regulate necroptosis, ferroptosis, and some PD-associated proteins. We investigated the potential anti-necroptotic and anti-ferroptotic effects of the anti-cancer drug pazopanib, uncovering the HSP90/CDC37 complex as a master RCD modulator in rotenone-induced Parkinsonism in rats. Oral administration of 15 mg/kg pazopanib to rotenone-intoxicated rats for three weeks improved motor deficits, debilitated histopathological changes, and increased striatal dopaminergic levels. Pazopanib suppressed LRRK2 and c-Abl. Pazopanib displayed an anti-necroptotic effect through inhibition of the p-RIPK1/p-RIPK3/p-MLKL pathway and activation of caspase-8. Moreover, pazopanib inhibited the ferroptotic p-VEGFR2-PKCβII-PLC-γ-ACSL-4 pathway, iron, 4-HNE, and PTGS2 while increasing GPX-4 and GSH levels. Taken together, the current research sheds light on the repositioning of pazopanib targeting HSP90/CDC37 and its multiple RCD mechanisms, which would offer a new perspective for therapeutic strategies in PD.
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Affiliation(s)
- Heba M Mansour
- Central Administration of Biological, Innovative Products, and Clinical Studies, Egyptian Drug Authority, EDA, Giza, Egypt
| | - Ahmed F Mohamed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Faculty of Pharmacy, King Salman International University (KSIU), South Sinai, 46612, Egypt.
| | - Mahmoud M Khattab
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Aiman S El-Khatib
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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12
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Pozzi G, Presta V, Masselli E, Condello G, Cortellazzi S, Arcari ML, Micheloni C, Vitale M, Gobbi G, Mirandola P, Carubbi C. Interplay between Protein Kinase C Epsilon and Reactive Oxygen Species during Myogenic Differentiation. Cells 2023; 12:1792. [PMID: 37443826 PMCID: PMC10340168 DOI: 10.3390/cells12131792] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 06/22/2023] [Accepted: 06/30/2023] [Indexed: 07/15/2023] Open
Abstract
Reactive oxygen species (ROS) are currently recognized as a key driver of several physiological processes. Increasing evidence indicates that ROS levels can affect myogenic differentiation, but the molecular mechanisms still need to be elucidated. Protein kinase C (PKC) epsilon (PKCe) promotes muscle stem cell differentiation and regeneration of skeletal muscle after injury. PKCs play a tissue-specific role in redox biology, with specific isoforms being both a target of ROS and an up-stream regulator of ROS production. Therefore, we hypothesized that PKCe represents a molecular link between redox homeostasis and myogenic differentiation. We used an in vitro model of a mouse myoblast cell line (C2C12) to study the PKC-redox axis. We demonstrated that the transition from a myoblast to myotube is typified by increased PKCe protein content and decreased ROS. Intriguingly, the expression of the antioxidant enzyme superoxide dismutase 2 (SOD2) is significantly higher in the late phases of myogenic differentiation, mimicking PKCe protein content. Furthermore, we demonstrated that PKCe inhibition increases ROS and reduces SOD2 protein content while SOD2 silencing did not affect PKCe protein content, suggesting that the kinase could be an up-stream regulator of SOD2. To support this hypothesis, we found that in C2C12 cells, PKCe interacts with Nrf2, whose activation induces SOD2 transcription. Overall, our results indicate that PKCe is capable of activating the antioxidant signaling preventing ROS accumulation in a myotube, eventually promoting myogenic differentiation.
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Affiliation(s)
- Giulia Pozzi
- Department of Medicine and Surgery (DiMeC), University of Parma, Via Gramsci, 14, 43126 Parma, Italy; (G.P.); (V.P.); (E.M.); (G.C.); (M.L.A.); (C.M.); (M.V.); (C.C.)
| | - Valentina Presta
- Department of Medicine and Surgery (DiMeC), University of Parma, Via Gramsci, 14, 43126 Parma, Italy; (G.P.); (V.P.); (E.M.); (G.C.); (M.L.A.); (C.M.); (M.V.); (C.C.)
| | - Elena Masselli
- Department of Medicine and Surgery (DiMeC), University of Parma, Via Gramsci, 14, 43126 Parma, Italy; (G.P.); (V.P.); (E.M.); (G.C.); (M.L.A.); (C.M.); (M.V.); (C.C.)
| | - Giancarlo Condello
- Department of Medicine and Surgery (DiMeC), University of Parma, Via Gramsci, 14, 43126 Parma, Italy; (G.P.); (V.P.); (E.M.); (G.C.); (M.L.A.); (C.M.); (M.V.); (C.C.)
| | - Samuele Cortellazzi
- Department of Medicine and Surgery (DiMeC), University of Parma, Via Gramsci, 14, 43126 Parma, Italy; (G.P.); (V.P.); (E.M.); (G.C.); (M.L.A.); (C.M.); (M.V.); (C.C.)
| | - Maria Luisa Arcari
- Department of Medicine and Surgery (DiMeC), University of Parma, Via Gramsci, 14, 43126 Parma, Italy; (G.P.); (V.P.); (E.M.); (G.C.); (M.L.A.); (C.M.); (M.V.); (C.C.)
| | - Cristina Micheloni
- Department of Medicine and Surgery (DiMeC), University of Parma, Via Gramsci, 14, 43126 Parma, Italy; (G.P.); (V.P.); (E.M.); (G.C.); (M.L.A.); (C.M.); (M.V.); (C.C.)
| | - Marco Vitale
- Department of Medicine and Surgery (DiMeC), University of Parma, Via Gramsci, 14, 43126 Parma, Italy; (G.P.); (V.P.); (E.M.); (G.C.); (M.L.A.); (C.M.); (M.V.); (C.C.)
- Italian Foundation for Research in Balneotherapy (FoRST), 00198 Rome, Italy
| | - Giuliana Gobbi
- Department of Medicine and Surgery (DiMeC), University of Parma, Via Gramsci, 14, 43126 Parma, Italy; (G.P.); (V.P.); (E.M.); (G.C.); (M.L.A.); (C.M.); (M.V.); (C.C.)
| | - Prisco Mirandola
- Department of Medicine and Surgery (DiMeC), University of Parma, Via Gramsci, 14, 43126 Parma, Italy; (G.P.); (V.P.); (E.M.); (G.C.); (M.L.A.); (C.M.); (M.V.); (C.C.)
| | - Cecilia Carubbi
- Department of Medicine and Surgery (DiMeC), University of Parma, Via Gramsci, 14, 43126 Parma, Italy; (G.P.); (V.P.); (E.M.); (G.C.); (M.L.A.); (C.M.); (M.V.); (C.C.)
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Jovanović M, Kovačević S, Brkljačić J, Djordjevic A. Oxidative Stress Linking Obesity and Cancer: Is Obesity a 'Radical Trigger' to Cancer? Int J Mol Sci 2023; 24:ijms24098452. [PMID: 37176160 PMCID: PMC10179114 DOI: 10.3390/ijms24098452] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/24/2023] [Accepted: 05/01/2023] [Indexed: 05/15/2023] Open
Abstract
Obesity is on the rise worldwide, and consequently, obesity-related non-communicable diseases are as well. Nutritional overload induces metabolic adaptations in an attempt to restore the disturbed balance, and the byproducts of the mechanisms at hand include an increased generation of reactive species. Obesity-related oxidative stress causes damage to vulnerable systems and ultimately contributes to neoplastic transformation. Dysfunctional obese adipose tissue releases cytokines and induces changes in the cell microenvironment, promoting cell survival and progression of the transformed cancer cells. Other than the increased risk of cancer development, obese cancer patients experience higher mortality rates and reduced therapy efficiency as well. The fact that obesity is considered the second leading preventable cause of cancer prioritizes the research on the mechanisms connecting obesity to cancerogenesis and finding the solutions to break the link. Oxidative stress is integral at different stages of cancer development and advancement in obese patients. Hypocaloric, balanced nutrition, and structured physical activity are some tools for relieving this burden. However, the sensitivity of simultaneously treating cancer and obesity poses a challenge. Further research on the obesity-cancer liaison would offer new perspectives on prevention programs and treatment development.
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Affiliation(s)
- Mirna Jovanović
- Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia
| | - Sanja Kovačević
- Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia
| | - Jelena Brkljačić
- Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia
| | - Ana Djordjevic
- Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia
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14
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Xu C, Wang H, Zhou L, Yan B. Phenotypic and transcriptomic shifts in roots and leaves of rice under the joint stress from microplastic and arsenic. JOURNAL OF HAZARDOUS MATERIALS 2023; 447:130770. [PMID: 36640509 DOI: 10.1016/j.jhazmat.2023.130770] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/27/2022] [Accepted: 01/09/2023] [Indexed: 06/17/2023]
Abstract
Co-contamination of soil from microplastics (MP) and arsenic (As) is becoming more prevalent, posing a severe threat to agricultural productivity. However, how this joint pollution affects crop growth needs to be better understood. To assess this, we investigated the transcriptomic and phenotypic patterns of rice (Oryza sativa) to MP, As, and their mixtures. The results revealed that, compared to As, MP had much less impact on rice growth, while the MP-As mixture decreased rice's aboveground biomass and altered As's biodistribution in rice tissues. Transcriptome further corroborated this pattern: 13 (294), 4195 (1842), and 3112 (2063) genes differentially regulated in response to MP, As, and their mixtures were observed in root (leaf) tissues, respectively. The joint application of MP and As produced a synergistic effect on crucial metabolic processes, such as carbohydrate, carboxylic acid, oxoacid, organic acid, amino acid, and tetrapyrrole metabolism. Moreover, we found that the joint stress reprogrammed the expression of hub genes encoding photosynthetic enzymes, protein kinases, and transcription factors, which likely reflect a transcript-driven tradeoff strategy between rice growth and defense. Together, these results strongly indicate that MP aggravated the As-induced toxicity in rice plants, which may impact the crop's acclimation to other abiotic field environments.
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Affiliation(s)
- Chanchan Xu
- Institute of Environmental Research at Greater Bay Area, Key Laboratory for Water Quality and Conservation of the Pearl River Delta, Ministry of Education, Guangzhou University, Guangzhou 510006, China
| | - Haiqing Wang
- Institute of Environmental Research at Greater Bay Area, Key Laboratory for Water Quality and Conservation of the Pearl River Delta, Ministry of Education, Guangzhou University, Guangzhou 510006, China
| | - Li Zhou
- Institute of Environmental Research at Greater Bay Area, Key Laboratory for Water Quality and Conservation of the Pearl River Delta, Ministry of Education, Guangzhou University, Guangzhou 510006, China.
| | - Bing Yan
- Institute of Environmental Research at Greater Bay Area, Key Laboratory for Water Quality and Conservation of the Pearl River Delta, Ministry of Education, Guangzhou University, Guangzhou 510006, China.
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15
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Ghareghomi S, Moosavi-Movahedi F, Saso L, Habibi-Rezaei M, Khatibi A, Hong J, Moosavi-Movahedi AA. Modulation of Nrf2/HO-1 by Natural Compounds in Lung Cancer. Antioxidants (Basel) 2023; 12:antiox12030735. [PMID: 36978983 PMCID: PMC10044870 DOI: 10.3390/antiox12030735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 03/08/2023] [Accepted: 03/13/2023] [Indexed: 03/19/2023] Open
Abstract
Oxidative stresses (OSs) are considered a pivotal factor in creating various pathophysiological conditions. Cells have been able to move forward by modulating numerous signaling pathways to moderate the defects of these stresses during their evolution. The company of Kelch-like ECH-associated protein 1 (Keap1) as a molecular sensing element of the oxidative and electrophilic stress and nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) as a master transcriptional regulator of the antioxidant response makes a master cytoprotective antioxidant pathway known as the Keap1/Nrf2 pathway. This pathway is considered a dual-edged sword with beneficial features for both normal and cancer cells by regulating the gene expression of the array of endogenous antioxidant enzymes. Heme oxygenase-1 (HO-1), a critical enzyme in toxic heme removal, is one of the clear state indicators for the duality of this pathway. Therefore, Nrf2/HO-1 axis targeting is known as a novel strategy for cancer treatment. In this review, the molecular mechanism of action of natural antioxidants on lung cancer cells has been investigated by relying on the Nrf2/HO-1 axis.
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Affiliation(s)
- Somayyeh Ghareghomi
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran 1417466191, Iran; (S.G.); (F.M.-M.)
| | - Faezeh Moosavi-Movahedi
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran 1417466191, Iran; (S.G.); (F.M.-M.)
| | - Luciano Saso
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, 00185 Rome, Italy
- Correspondence: (L.S.); (M.H.-R.); (A.A.M.-M.); Tel.: +39-06-4991-2481 (L.S.); +98-21-6111-3214 (M.H.-R.); +98-21-6640-3957 (A.A.M.-M.); Fax: +39-06-4991-2481 (L.S.); +98-21-6697-1941 (M.H.-R.); +98-21-6640-4680(A.A.M.-M.)
| | - Mehran Habibi-Rezaei
- School of Biology, College of Science, University of Tehran, Tehran 1417466191, Iran
- Center of Excellence in NanoBiomedicine, University of Tehran, Tehran 1417466191, Iran
- Correspondence: (L.S.); (M.H.-R.); (A.A.M.-M.); Tel.: +39-06-4991-2481 (L.S.); +98-21-6111-3214 (M.H.-R.); +98-21-6640-3957 (A.A.M.-M.); Fax: +39-06-4991-2481 (L.S.); +98-21-6697-1941 (M.H.-R.); +98-21-6640-4680(A.A.M.-M.)
| | - Ali Khatibi
- Department of Biotechnology, Faculty of Biological Sciences, Alzahra University, Tehran 1993893973, Iran;
| | - Jun Hong
- School of Life Sciences, Henan University, Kaifeng 475000, China;
| | - Ali A. Moosavi-Movahedi
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran 1417466191, Iran; (S.G.); (F.M.-M.)
- UNESCO Chair on Interdisciplinary Research in Diabetes, University of Tehran, Tehran 1417466191, Iran
- Correspondence: (L.S.); (M.H.-R.); (A.A.M.-M.); Tel.: +39-06-4991-2481 (L.S.); +98-21-6111-3214 (M.H.-R.); +98-21-6640-3957 (A.A.M.-M.); Fax: +39-06-4991-2481 (L.S.); +98-21-6697-1941 (M.H.-R.); +98-21-6640-4680(A.A.M.-M.)
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16
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Colacci A, Corvi R, Ohmori K, Paparella M, Serra S, Da Rocha Carrico I, Vasseur P, Jacobs MN. The Cell Transformation Assay: A Historical Assessment of Current Knowledge of Applications in an Integrated Approach to Testing and Assessment for Non-Genotoxic Carcinogens. Int J Mol Sci 2023; 24:ijms24065659. [PMID: 36982734 PMCID: PMC10057754 DOI: 10.3390/ijms24065659] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/08/2023] [Accepted: 03/11/2023] [Indexed: 03/18/2023] Open
Abstract
The history of the development of the cell transformation assays (CTAs) is described, providing an overview of in vitro cell transformation from its origin to the new transcriptomic-based CTAs. Application of this knowledge is utilized to address how the different types of CTAs, variously addressing initiation and promotion, can be included on a mechanistic basis within the integrated approach to testing and assessment (IATA) for non-genotoxic carcinogens. Building upon assay assessments targeting the key events in the IATA, we identify how the different CTA models can appropriately fit, following preceding steps in the IATA. The preceding steps are the prescreening transcriptomic approaches, and assessment within the earlier key events of inflammation, immune disruption, mitotic signaling and cell injury. The CTA models address the later key events of (sustained) proliferation and change in morphology leading to tumor formation. The complementary key biomarkers with respect to the precursor key events and respective CTAs are mapped, providing a structured mechanistic approach to represent the complexity of the (non-genotoxic) carcinogenesis process, and specifically their capacity to identify non-genotoxic carcinogenic chemicals in a human relevant IATA.
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Affiliation(s)
- Annamaria Colacci
- Agency for Prevention, Environment and Energy, Emilia-Romagna (Arpae), Via Po 5, I-40139 Bologna, Italy
- Correspondence:
| | - Raffaella Corvi
- European Commission, Joint Research Centre (JRC), I-21027 Ispra, Italy
| | - Kyomi Ohmori
- Chemical Division, Kanagawa Prefectural Institute of Public Health, Chigasaki 253-0087, Japan
- Research Initiatives and Promotion Organization, Yokohama National University, Yokohama 240-8501, Japan
| | - Martin Paparella
- Division of Medical Biochemistry, Biocenter, Medical University of Innsbruck, A-6020 Innbruck, Austria
| | - Stefania Serra
- Agency for Prevention, Environment and Energy, Emilia-Romagna (Arpae), Via Po 5, I-40139 Bologna, Italy
| | | | - Paule Vasseur
- Universite de Lorraine, CNRS UMR 7360 LIEC, Laboratoire Interdisciplinaire des Environnements Continentaux, 57070 Metz, France
| | - Miriam Naomi Jacobs
- Radiation, Chemical and Environmental Hazards, UK Health Security Agency, Harwell Science and Innovation Campus, Chilton OX11 0RQ, UK
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Mukherjee I, Biswas S, Singh S, Talukdar J, Alqahtani MS, Abbas M, Nag TC, Mridha AR, Gupta S, Sharma JB, Kumari S, Dhar R, Karmakar S. Monosodium Glutamate Perturbs Human Trophoblast Invasion and Differentiation through a Reactive Oxygen Species-Mediated Pathway: An In-Vitro Assessment. Antioxidants (Basel) 2023; 12:antiox12030634. [PMID: 36978882 PMCID: PMC10045473 DOI: 10.3390/antiox12030634] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/19/2023] [Accepted: 02/21/2023] [Indexed: 03/08/2023] Open
Abstract
The overproduction of reactive oxygen species (ROS) has been associated with various human diseases. ROS exert a multitude of biological effects with both physiological and pathological consequences. Monosodium glutamate (MSG), a sodium salt of the natural amino acid glutamate, is a flavor-enhancing food additive, which is widely used in Asian cuisine and is an ingredient that brings out the “umami” meat flavor. MSG consumption in rats is associated with ROS generation. Owing to its consumption as part of the fast-food culture and concerns about its possible effects on pregnancy, we aimed to study the impact of MSG on placental trophoblast cells. MSG exposure influenced trophoblast invasion and differentiation, two of the most critical functions during placentation through enhanced production of ROS. Similar findings were also observed on MSG-treated placental explants, as confirmed by elevated Nrf2 levels. Ultrastructural studies revealed signs of subcellular injury by MSG exposure. Mechanistically, MSG-induced oxidative stress with endoplasmic reticulum stress pathways involving Xbp1s and IRE1α was observed. The effect of MSG through an increased ROS production indicates that its long-term exposure might have adverse health effect by compromising key trophoblast functions.
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Affiliation(s)
- Indrani Mukherjee
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India
- Amity Institute of Biotechnology (AIB), Amity University, Noida 201301, India
| | - Subhrajit Biswas
- Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University, Noida 201301, India
| | - Sunil Singh
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Joyeeta Talukdar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Mohammed S. Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha 61421, Saudi Arabia
- BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester LE1 7RH, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha 61421, Saudi Arabia
- Electronics and Communications Department, College of Engineering, Delta University for Science and Technology, Gamesa 35712, Egypt
| | - Tapas Chandra Nag
- Department of Anatomy, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Asit Ranjan Mridha
- Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Surabhi Gupta
- Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Jai Bhagwan Sharma
- Department of Obstetrics & Gynaecology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Supriya Kumari
- Department of Obstetrics & Gynaecology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Ruby Dhar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India
- Correspondence: (R.D.); (S.K.); Tel.: +91-9999612564 (S.K.)
| | - Subhradip Karmakar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India
- Correspondence: (R.D.); (S.K.); Tel.: +91-9999612564 (S.K.)
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18
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Hammerling U, Kim YK, Quadro L. Quantum chemistry rules retinoid biology. Commun Biol 2023; 6:227. [PMID: 36854887 PMCID: PMC9974979 DOI: 10.1038/s42003-023-04602-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 02/16/2023] [Indexed: 03/02/2023] Open
Abstract
This Perspective discusses how retinol catalyzes resonance energy transfer (RET) reactions pivotally important for mitochondrial energy homeostasis by protein kinase C δ (PKCδ). PKCδ signals to the pyruvate dehydrogenase complex, controlling oxidative phosphorylation. The PKCδ-retinol complex reversibly responds to the redox potential of cytochrome c, that changes with the electron transfer chain workload. In contrast, the natural retinoid anhydroretinol irreversibly activates PKCδ. Its elongated conjugated-double-bond system limits the energy quantum absorbed by RET. Consequently, while capable of triggering the exergonic activating pathway, anhydroretinol fails to activate the endergonic silencing path, trapping PKCδ in the ON position and causing harmful levels of reactive oxygen species. However, physiological retinol levels displace anhydroretinol, buffer cyotoxicity and potentially render anhydroretinol useful for rapid energy generation. Intriguingly, apocarotenoids, the primary products of the mitochondrial β-carotene,9'-10'-oxygenase, have all the anhydroretinol-like features, including modulation of energy homeostasis. We predict significant conceptual advances to stem from further understanding of the retinoid-catalyzed RET.
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Affiliation(s)
- Ulrich Hammerling
- Department of Food Science, Rutgers Center for Lipid Research and Institute of Food Nutrition and Health, Rutgers University, New Brunswick, NJ, USA.
| | - Youn-Kyung Kim
- Department of Food Science, Rutgers Center for Lipid Research and Institute of Food Nutrition and Health, Rutgers University, New Brunswick, NJ, USA
| | - Loredana Quadro
- Department of Food Science, Rutgers Center for Lipid Research and Institute of Food Nutrition and Health, Rutgers University, New Brunswick, NJ, USA.
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Berner J, Miebach L, Herold L, Höft H, Gerling T, Mattern P, Bekeschus S. Gas Flow Shaping via Novel Modular Nozzle System (MoNoS) Augments kINPen-Mediated Toxicity and Immunogenicity in Tumor Organoids. Cancers (Basel) 2023; 15:cancers15041254. [PMID: 36831596 PMCID: PMC9953918 DOI: 10.3390/cancers15041254] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 02/03/2023] [Accepted: 02/13/2023] [Indexed: 02/18/2023] Open
Abstract
Medical gas plasma is an experimental technology for anticancer therapy. Here, partial gas ionization yielded reactive oxygen and nitrogen species, placing the technique at the heart of applied redox biomedicine. Especially with the gas plasma jet kINPen, anti-tumor efficacy was demonstrated. This study aimed to examine the potential of using passive flow shaping to enhance the medical benefits of atmospheric plasma jets (APPJ). We used an in-house developed, proprietary Modular Nozzle System (MoNoS; patent-pending) to modify the flow properties of a kINPen. MoNoS increased the nominal plasma jet-derived reactive species deposition area and stabilized the air-plasma ratio within the active plasma zone while shielding it from external flow disturbances or gas impurities. At modest flow rates, dynamic pressure reduction (DPR) adapters did not augment reactive species deposition in liquids or tumor cell killing. However, MoNoS operated at kINPen standard argon fluxes significantly improved cancer organoid growth reduction and increased tumor immunogenicity, as seen by elevated calreticulin and heat-shock protein expression, along with a significantly spurred cytokine secretion profile. Moreover, the safe application of MoNoS gas plasma jet adapters was confirmed by their similar-to-superior safety profiles assessed in the hen's egg chorioallantoic membrane (HET-CAM) coagulation and scar formation irritation assay.
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Affiliation(s)
- Julia Berner
- ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Straße 2, 17489 Greifswald, Germany
- Department of Oral, Maxillofacial and Plastic Surgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Straße, 17475 Greifswald, Germany
| | - Lea Miebach
- ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Straße 2, 17489 Greifswald, Germany
- Department of General, Visceral, Thoracic and Vascular Surgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Straße, 17475 Greifswald, Germany
| | - Luise Herold
- ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Straße 2, 17489 Greifswald, Germany
- Department of Oral, Maxillofacial and Plastic Surgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Straße, 17475 Greifswald, Germany
| | - Hans Höft
- Department of Plasma Diagnostics, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Straße 2, 17489 Greifswald, Germany
| | - Torsten Gerling
- ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Straße 2, 17489 Greifswald, Germany
- Diabetes Competence Centre Karlsburg (KDK), Leibniz Institute for Plasma Science and Technology (INP), Greifswalder Straße 11, 17495 Karlsburg, Germany
| | - Philipp Mattern
- ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Straße 2, 17489 Greifswald, Germany
- Diabetes Competence Centre Karlsburg (KDK), Leibniz Institute for Plasma Science and Technology (INP), Greifswalder Straße 11, 17495 Karlsburg, Germany
| | - Sander Bekeschus
- ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Straße 2, 17489 Greifswald, Germany
- Correspondence: ; Tel.: +49-3834-554-3948
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Phosphorylation of the Human DNA Glycosylase NEIL2 Is Affected by Oxidative Stress and Modulates Its Activity. Antioxidants (Basel) 2023; 12:antiox12020355. [PMID: 36829914 PMCID: PMC9952225 DOI: 10.3390/antiox12020355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 01/25/2023] [Accepted: 01/29/2023] [Indexed: 02/05/2023] Open
Abstract
The DNA glycosylase NEIL2 plays a central role in maintaining genome integrity, in particular during oxidative stress, by recognizing oxidized base lesions and initiating repair of these via the base excision repair (BER) pathway. Post-translational modifications are important molecular switches that regulate and coordinate the BER pathway, and thereby enable a rapid and fine-tuned response to DNA damage. Here, we report for the first time that human NEIL2 is regulated by phosphorylation. We demonstrate that NEIL2 is phosphorylated by the two kinases cyclin-dependent kinase 5 (CDK5) and protein kinase C (PKC) in vitro and in human SH-SY5Y neuroblastoma cells. The phosphorylation of NEIL2 by PKC causes a substantial reduction in NEIL2 repair activity, while CDK5 does not directly alter the enzymatic activity of NEIL2 in vitro, suggesting distinct modes of regulating NEIL2 function by the two kinases. Interestingly, we show a rapid dephosphorylation of NEIL2 in response to oxidative stress in SH-SY5Y cells. This points to phosphorylation as an important modulator of NEIL2 function in this cellular model, not least during oxidative stress.
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Selenium Nanoparticles Can Influence the Immune Response Due to Interactions with Antibodies and Modulation of the Physiological State of Granulocytes. Pharmaceutics 2022; 14:pharmaceutics14122772. [PMID: 36559266 PMCID: PMC9783826 DOI: 10.3390/pharmaceutics14122772] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/02/2022] [Accepted: 12/09/2022] [Indexed: 12/14/2022] Open
Abstract
Currently, selenium nanoparticles (SeNPs) are considered potential immunomodulatory agents and as targets for activity modulation are granulocytes, which have the most abundant population of immune blood cells. The present study aims to evaluate the cytotoxic effect and its effect on the functional responses of granulocytes. In addition to the intrinsic activity of SeNPs, we studied the activity of the combination of SeNPs and IgG antibodies. Using laser ablation and fragmentation, we obtained nanoparticles with an average size of 100 nm and a rather narrow size evolution. The resulting nanoparticles do not show acute toxicity to primary cultures of fibroblasts and hepatocytes, epithelial-like cell line L-929 and granulocyte-like culture of HL-60 at a concentration of 109 NPs/mL. SeNPs at a concentration of 1010 NPs/mL reduced the viability of HL-60 cells by no more than 10% and did not affect the viability of the primary culture of mouse granulocytes, and did not have a genotoxic effect on progenitor cells. The addition of SeNPs can affect the production of reactive oxygen species (ROS) by mouse bone marrow granulocytes, modulate the proportion of granulocytes with calcium spikes and enhance fMLF-induced granulocytes degranulation. SeNPs can modulate the effect of IgG on the physiological responses of granulocytes. We studied the expression level of genes associated with inflammation and cell stress. SeNPs increase the expression of catalase, NF-κB, Xrcc5 and some others; antibodies enhance the effect of SeNPs, but IgG without SeNPs decreases the expression level of these genes. This fact can be explained by the interaction between SeNPs and IgG. It has been established that antibodies interact with SeNPs. We showed that antibodies bind to the surface of selenium nanoparticles and are present in aqueous solutions in a bound form from DLS methods, ultraviolet-visible spectroscopy, vibrational-rotational spectrometry, fluorescence spectrometry, and refractometry. At the same time, in a significant part of the antibodies, a partial change in the tertiary and secondary structure is observed. The data obtained will allow a better understanding of the principles of the interaction of immune cells with antibodies and SeNPs and, in the future, may serve to create a new generation of immunomodulators.
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22
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Redox-Activation of Neutrophils Induced by Pericardium Scaffolds. Int J Mol Sci 2022; 23:ijms232415468. [PMID: 36555108 PMCID: PMC9779008 DOI: 10.3390/ijms232415468] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/24/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
Implantation of scaffolds causes a local inflammatory response whereby the early recruitment of neutrophils is of great importance not only for fighting the infection, but also for facilitating effective regeneration. We used luminol-dependent chemiluminescence, flow cytometry, ELISA, and confocal microscopy to assess the responses of neutrophils after the exposure to the scaffold-decellularized bovine pericardium (collagen type I) crosslinked with genipin (DBPG). We demonstrated that DBPG activated neutrophils in whole blood causing respiratory burst, myeloperoxidase (MPO) secretion, and formation of neutrophil extracellular trap-like structures (NETs). In addition, we studied platelets, another important player of the immediate immune host response. We found that platelets triggered redox-activation of isolated neutrophils by the pericardium scaffold, and likely participate in the NETs formation. Free radicals generated by neutrophils and hypochlorous acid produced by MPO are potent oxidizing agents which can oxidatively degrade biological structures. Understanding the mechanisms and consequences of redox activation of neutrophils by pericardium scaffolds is important for the development of new approaches to increase the efficiency of tissue regeneration.
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23
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Biswas S, Ray Banerjee E. Probiotic treatment of inflammatory bowel disease: Its extent and intensity. World J Immunol 2022; 12:15-24. [DOI: 10.5411/wji.v12.i2.15] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/09/2022] [Accepted: 08/17/2022] [Indexed: 02/05/2023] Open
Abstract
Free radicals (reactive oxygen species, superoxides and hydroxyl radicals) lead to the development of oxidative stress because of imbalance in the amount of antioxidants. Continued development of oxidative stress leads to chronic diseases in humans. The instability in the antioxidant activities and accumulation of oxidative stress due to free radicals may occur in diseases like inflammatory bowel disease (IBD). Antioxidants are substances that inhibit or delay the mechanism of oxidation of molecules mediated by free radicals and also transform into lesser-active derivatives. Probiotics are defined as live microorganisms that show beneficial effects on inflamed intestine and balance the inflammatory immune responses in the gut. Probiotic strains have been reported to scavenge hydroxyl radicals and superoxide anions that are abundantly produced during oxidative stress. The most widely studied probiotic strains are Streptococcus, Bifidobacterium and Lactobacillus. Probiotics cultured in broth have shown some amount of antioxidant activities. Fermented milk and soy milk, which possess starter microorganisms (probiotics), tends to increase the antioxidant activities many-fold. This review aims to discuss the in vivo and in vitro antioxidant activities of specific probiotics with various assays with respect to IBD.
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Affiliation(s)
- Saheli Biswas
- Department of Zoology, University of Calcutta, Kolkata 700019, West Bengal, India
| | - Ena Ray Banerjee
- Department of Zoology, University of Calcutta, Kolkata 700019, West Bengal, India
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Aytekin Sahin G, Karabulut D, Unal G, Sayan M, Sahin H. Effects of probiotic supplementation on very low dose AFB1-induced neurotoxicity in adult male rats. Life Sci 2022; 306:120798. [PMID: 35843344 DOI: 10.1016/j.lfs.2022.120798] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 07/07/2022] [Accepted: 07/08/2022] [Indexed: 12/24/2022]
Abstract
AIMS Aflatoxin B1 (AFB1) is the most toxic and common form of AF found in food and feed. Although AFB1 exposure has toxic effects on many organs, studies on the brain are limited. Moreover, to the best of our knowledge, there is no study on the effect of probiotics on AFB1-induced neurotoxicity. Therefore, we aimed to evaluate the possible effects of probiotics on AFB1-induced neurotoxicity in the brain. MAIN METHODS Thirty-two adult male Wistar rats were divided into four groups: Vehicle (VEH), Probiotic (PRO) (2.5 × 1010 CFU/day VSL#3, orally), Aflatoxin B1 (AFB1) (25 μg/kg/week AFB1, orally), and Aflatoxin B1 + Probiotic (AFB1 + PRO) (2.5 × 1010 CFU/day VSL#3 + 25 μg/kg/week AFB1, orally). At the end of eight weeks, rats were behaviorally evaluated by the open field test, novel object recognition test, and forced swim test. Then, oxidative stress and inflammatory markers in brain tissues were analyzed. Next, brain sections were processed for Hematoxylin&Eosin staining and NeuN and GFAP immunostaining. KEY FINDINGS Probiotic supplementation tended to decrease oxidative stress and inflammatory markers compared to the AFB1 group. Besides, brain tissues had more normal histological structures in VEH, PRO, and AFB1 + PRO groups than in the AFB1 group. Moreover, in probiotic groups, GFAP immunoreactivity intensity was decreased, while NeuN-positive cell number increased in brain tissues compared to the AFB1 group. SIGNIFICANCE Probiotics seem to be effective at reducing the neurotoxic effects of AFB1. Thus, our study suggested that especially Bifidobacterium and Lactobacillus species can improve AFB1-induced neurotoxicity with their antioxidant and anti-inflammatory effects.
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Affiliation(s)
- Gizem Aytekin Sahin
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Nuh Naci Yazgan University, Kayseri, Turkey.
| | - Derya Karabulut
- Department of Histology and Embryology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Gokhan Unal
- Department of Pharmacology, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey
| | - Meryem Sayan
- Department of Histology and Embryology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Habibe Sahin
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Erciyes University, Kayseri, Turkey
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Mercury-Induced Oxidative Stress Response in Benthic Foraminifera: An In Vivo Experiment on Amphistegina lessonii. BIOLOGY 2022; 11:biology11070960. [PMID: 36101341 PMCID: PMC9312061 DOI: 10.3390/biology11070960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/22/2022] [Accepted: 06/01/2022] [Indexed: 11/17/2022]
Abstract
The evaluation of the effects of pollution (e.g., Hg pollution) is a difficult task and relies mostly on biomonitoring based on bioindicators. The application of biomarkers may represent a complementary or alternative approach in environmental biomonitoring. Mercury is known to pose a significant health hazard due to its ability to cross cellular membranes, bioaccumulate, and biomagnify. In the present research, the effects of short-term (i.e., 24 h) Hg exposure in the symbiont-bearing benthic foraminiferal species Amphistegina lessonii are evaluated using several biomarkers (i.e., proteins and enzymes). Mercury leads to significant changes in the biochemistry of cells. Its effects are mainly associated with oxidative stress (i.e., production of reactive oxygen species: ROS), depletion of glutathione (GSH), and alteration of protein synthesis. Specifically, our findings reveal that exposure to Hg leads to the consumption of GSH by GPx and GST for the scavenging of ROS and the activation of antioxidant-related enzymes, including SOD and GSH-enzymes (GST, GSR, GPx, and Se-GPx), that are directly related to a defense mechanism against ROS. The Hg exposure also activates the MAPK (e.g., p-p38) and HSP (e.g., HSP 70) pathways. The observed biochemical alterations associated with Hg exposure may represent effective and reliable proxies (i.e., biomarkers) for the evaluation of stress in A. lessonii and lead to a possible application for the detection of early warning signs of environmental stress in biomonitoring.
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Rodrigues BM, Mathias LS, Deprá IDC, Cury SS, de Oliveira M, Olimpio RMC, De Sibio MT, Gonçalves BM, Nogueira CR. Effects of Triiodothyronine on Human Osteoblast-Like Cells: Novel Insights From a Global Transcriptome Analysis. Front Cell Dev Biol 2022; 10:886136. [PMID: 35784485 PMCID: PMC9248766 DOI: 10.3389/fcell.2022.886136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 05/06/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Thyroid hormones play a significant role in bone development and maintenance, with triiodothyronine (T3) particularly being an important modulator of osteoblast differentiation, proliferation, and maintenance. However, details of the biological processes (BPs) and molecular pathways affected by T3 in osteoblasts remain unclear.Methods: To address this issue, primary cultures of human adipose-derived mesenchymal stem cells were subjected to our previously established osteoinduction protocol, and the resultant osteoblast-like cells were treated with 1 nm or 10 nm T3 for 72 h. RNA sequencing (RNA-Seq) was performed using the Illumina platform, and differentially expressed genes (DEGs) were identified from the raw data using Kallisto and DESeq2. Enrichment analysis of DEGs was performed against the Gene Ontology Consortium database for BP terms using the R package clusterProfiler and protein network analysis by STRING.Results: Approximately 16,300 genes were analyzed by RNA-Seq, with 343 DEGs regulated in the 1 nm T3 group and 467 upregulated in the 10 nm T3 group. Several independent BP terms related to bone metabolism were significantly enriched, with a number of genes shared among them (FGFR2, WNT5A, WNT3, ROR2, VEGFA, FBLN1, S1PR1, PRKCZ, TGFB3, and OSR1 for 1nM T3; and FZD1, SMAD6, NOG, NEO1, and ENG for 10 nm T3). An osteoblast-related search in the literature regarding this set of genes suggests that both T3 doses are unfavorable for osteoblast development, mainly hindering BMP and canonical and non-canonical WNT signaling.Conclusions: Therefore, this study provides new directions toward the elucidation of the mechanisms of T3 action on osteoblast metabolism, with potential future implications for the treatment of endocrine-related bone pathologies.
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Affiliation(s)
- Bruna Moretto Rodrigues
- Department of Internal Medicine, Medical School Botucatu, São Paulo State University (UNESP), Botucatu, Brazil
| | - Lucas Solla Mathias
- Department of Internal Medicine, Medical School Botucatu, São Paulo State University (UNESP), Botucatu, Brazil
| | - Igor de Carvalho Deprá
- Department of Internal Medicine, Medical School Botucatu, São Paulo State University (UNESP), Botucatu, Brazil
| | - Sarah Santiloni Cury
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, Brazil
| | - Miriane de Oliveira
- Department of Internal Medicine, Medical School Botucatu, São Paulo State University (UNESP), Botucatu, Brazil
| | | | - Maria Teresa De Sibio
- Department of Internal Medicine, Medical School Botucatu, São Paulo State University (UNESP), Botucatu, Brazil
| | - Bianca Mariani Gonçalves
- Department of Internal Medicine, Medical School Botucatu, São Paulo State University (UNESP), Botucatu, Brazil
| | - Célia Regina Nogueira
- Department of Internal Medicine, Medical School Botucatu, São Paulo State University (UNESP), Botucatu, Brazil
- *Correspondence: Célia Regina Nogueira,
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Haslem L, Hays JM, Hays FA. p66Shc in Cardiovascular Pathology. Cells 2022; 11:cells11111855. [PMID: 35681549 PMCID: PMC9180016 DOI: 10.3390/cells11111855] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/30/2022] [Accepted: 06/01/2022] [Indexed: 02/06/2023] Open
Abstract
p66Shc is a widely expressed protein that governs a variety of cardiovascular pathologies by generating, and exacerbating, pro-apoptotic ROS signals. Here, we review p66Shc’s connections to reactive oxygen species, expression, localization, and discuss p66Shc signaling and mitochondrial functions. Emphasis is placed on recent p66Shc mitochondrial function discoveries including structure/function relationships, ROS identity and regulation, mechanistic insights, and how p66Shc-cyt c interactions can influence p66Shc mitochondrial function. Based on recent findings, a new p66Shc mitochondrial function model is also put forth wherein p66Shc acts as a rheostat that can promote or antagonize apoptosis. A discussion of how the revised p66Shc model fits previous findings in p66Shc-mediated cardiovascular pathology follows.
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Affiliation(s)
- Landon Haslem
- Biochemistry and Molecular Biology Department, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (L.H.); (J.M.H.)
| | - Jennifer M. Hays
- Biochemistry and Molecular Biology Department, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (L.H.); (J.M.H.)
| | - Franklin A. Hays
- Biochemistry and Molecular Biology Department, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (L.H.); (J.M.H.)
- Stephenson Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Correspondence:
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Singh R, Sharma A, Saji J, Umapathi A, Kumar S, Daima HK. Smart nanomaterials for cancer diagnosis and treatment. NANO CONVERGENCE 2022; 9:21. [PMID: 35569081 PMCID: PMC9108129 DOI: 10.1186/s40580-022-00313-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/26/2022] [Indexed: 05/14/2023]
Abstract
Innovations in nanomedicine has guided the improved outcomes for cancer diagnosis and therapy. However, frequent use of nanomaterials remains challenging due to specific limitations like non-targeted distribution causing low signal-to-noise ratio for diagnostics, complex fabrication, reduced-biocompatibility, decreased photostability, and systemic toxicity of nanomaterials within the body. Thus, better nanomaterial-systems with controlled physicochemical and biological properties, form the need of the hour. In this context, smart nanomaterials serve as promising solution, as they can be activated under specific exogenous or endogenous stimuli such as pH, temperature, enzymes, or a particular biological molecule. The properties of smart nanomaterials make them ideal candidates for various applications like biosensors, controlled drug release, and treatment of various diseases. Recently, smart nanomaterial-based cancer theranostic approaches have been developed, and they are displaying better selectivity and sensitivity with reduced side-effects in comparison to conventional methods. In cancer therapy, the smart nanomaterials-system only activates in response to tumor microenvironment (TME) and remains in deactivated state in normal cells, which further reduces the side-effects and systemic toxicities. Thus, the present review aims to describe the stimulus-based classification of smart nanomaterials, tumor microenvironment-responsive behaviour, and their up-to-date applications in cancer theranostics. Besides, present review addresses the development of various smart nanomaterials and their advantages for diagnosing and treating cancer. Here, we also discuss about the drug targeting and sustained drug release from nanocarriers, and different types of nanomaterials which have been engineered for this intent. Additionally, the present challenges and prospects of nanomaterials in effective cancer diagnosis and therapeutics have been discussed.
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Affiliation(s)
- Ragini Singh
- College of Agronomy, Liaocheng University, Liaocheng, 252059, Shandong, China.
| | - Ayush Sharma
- Amity Center for Nanobiotechnology and Nanomedicine (ACNN), Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, 303002, Rajasthan, India
| | - Joel Saji
- Amity Center for Nanobiotechnology and Nanomedicine (ACNN), Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, 303002, Rajasthan, India
| | - Akhela Umapathi
- Amity Center for Nanobiotechnology and Nanomedicine (ACNN), Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, 303002, Rajasthan, India
| | - Santosh Kumar
- Shandong Key Laboratory of Optical Communication Science and Technology, School of Physics Science and Information Technology, Liaocheng University, Liaocheng, 252059, Shandong, China
| | - Hemant Kumar Daima
- Amity Center for Nanobiotechnology and Nanomedicine (ACNN), Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, 303002, Rajasthan, India.
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Sulforaphane Suppresses the Nicotine-Induced Expression of the Matrix Metalloproteinase-9 via Inhibiting ROS-Mediated AP-1 and NF-κB Signaling in Human Gastric Cancer Cells. Int J Mol Sci 2022; 23:ijms23095172. [PMID: 35563563 PMCID: PMC9099819 DOI: 10.3390/ijms23095172] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 04/28/2022] [Accepted: 05/02/2022] [Indexed: 02/01/2023] Open
Abstract
Sulforaphane, a natural phytochemical compound found in various cruciferous vegetables, has been discovered to present anti-cancer properties. Matrix metalloproteinase-9 (MMP-9) plays a crucial role in gastric cancer metastasis. However, the role of sulforaphane in MMP-9 expression in gastric cancer is not yet defined. Nicotine, a psychoactive alkaloid found in tobacco, is associated with the development of gastric cancer. Here, we found that sulforaphane suppresses the nicotine-mediated induction of MMP-9 in human gastric cancer cells. We discovered that reactive oxygen species (ROS) and MAPKs (p38 MAPK, Erk1/2) are involved in nicotine-induced MMP-9 expression. AP-1 and NF-κB are the critical transcription factors in MMP-9 expression. ROS/MAPK (p38 MAPK, Erk1/2) and ROS functioned as upstream signaling of AP-1 and NF-κB, respectively. Sulforaphane suppresses the nicotine-induced MMP-9 by inhibiting ROS-mediated MAPK (p38 MAPK, Erk1/2)/AP-1 and ROS-mediated NF-κB signaling axes, which in turn inhibit cell invasion in human gastric cancer AGS cells. Therefore, the current study provides valuable evidence for developing sulforaphane as a new anti-invasion strategy for human gastric cancer therapy.
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30
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Bhatti JS, Sehrawat A, Mishra J, Sidhu IS, Navik U, Khullar N, Kumar S, Bhatti GK, Reddy PH. Oxidative stress in the pathophysiology of type 2 diabetes and related complications: Current therapeutics strategies and future perspectives. Free Radic Biol Med 2022; 184:114-134. [PMID: 35398495 DOI: 10.1016/j.freeradbiomed.2022.03.019] [Citation(s) in RCA: 223] [Impact Index Per Article: 74.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 03/20/2022] [Accepted: 03/22/2022] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes (T2DM) is a persistent metabolic disorder rising rapidly worldwide. It is characterized by pancreatic insulin resistance and β-cell dysfunction. Hyperglycemia induced reactive oxygen species (ROS) production and oxidative stress are correlated with the pathogenesis and progression of this metabolic disease. To counteract the harmful effects of ROS, endogenous antioxidants of the body or exogenous antioxidants neutralise it and maintain bodily homeostasis. Under hyperglycemic conditions, the imbalance between the cellular antioxidant system and ROS production results in oxidative stress, which subsequently results in the development of diabetes. These ROS are produced in the endoplasmic reticulum, phagocytic cells and peroxisomes, with the mitochondrial electron transport chain (ETC) playing a pivotal role. The exacerbated ROS production can directly cause structural and functional modifications in proteins, lipids and nucleic acids. It also modulates several intracellular signaling pathways that lead to insulin resistance and impairment of β-cell function. In addition, the hyperglycemia-induced ROS production contributes to micro- and macro-vascular diabetic complications. Various in-vivo and in-vitro studies have demonstrated the anti-oxidative effects of natural products and their derived bioactive compounds. However, there is conflicting clinical evidence on the beneficial effects of these antioxidant therapies in diabetes prevention. This review article focused on the multifaceted role of oxidative stress caused by ROS overproduction in diabetes and related complications and possible antioxidative therapeutic strategies targeting ROS in this disease.
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Affiliation(s)
- Jasvinder Singh Bhatti
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India.
| | - Abhishek Sehrawat
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India.
| | - Jayapriya Mishra
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India.
| | - Inderpal Singh Sidhu
- Department of Zoology, Sri Guru Gobind Singh College, Sector 26, Chandigarh, India.
| | - Umashanker Navik
- Department of Pharmacology, Central University of Punjab, Bathinda, India.
| | - Naina Khullar
- Department of Zoology, Mata Gujri College, Fatehgarh Sahib, Punjab, India.
| | - Shashank Kumar
- Department of Biochemistry, School of Basic Sciences, Central University of Punjab, Bathinda, India.
| | - Gurjit Kaur Bhatti
- Department of Medical Lab Technology, University Institute of Applied Health Sciences, Chandigarh University, Mohali, India.
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA; Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA; Department of Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA; Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA; Department of Speech, Language, and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA.
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Lv W, Jin S, Cao D, Wang N, Jin X, Zhang Y. Effects of Luteinizing Hormone Releasing Hormone A2 on Gonad Development in Juvenile Amur Sturgeon, Acipenser schrenckii, Revealed by Transcriptome Profiling Analysis. Front Genet 2022; 13:859965. [PMID: 35401695 PMCID: PMC8989137 DOI: 10.3389/fgene.2022.859965] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 02/22/2022] [Indexed: 11/15/2022] Open
Abstract
Acipenser schrenckii is an economically important aquatic species whose gonads require particularly long times to reach sexual maturity. Luteinizing hormone plays important roles in gonad development, and luteinizing hormone releasing hormone A2 (LH-A2) is used as an oxytocin to promote ovulation in aquaculture of A. schrenckii. In this study, we aimed to determine the effects of LH-A2 on gonad development in juvenile A. schrenckii through transcriptome profiling analysis of the pituitary and gonads after LH-A2 treatment at a dose of 3 μg/kg. The 17β-estradiol (E2) levels gradually increased with LH-A2 treatment time, and significantly differed from those of the control group on days 5 and 7 (p < 0.01). However, the content of testosterone (Testo) gradually decreased with LH-A2 treatment time and showed significant differences on day 3 (p < 0.05), and on days 5 and 7 (p < 0.01), compared to those in the control group. Thus, LH-A2 promotes the secretion of E2 and inhibits the secretion of Testo. Transcriptome profiling analysis revealed a total of 2,883 and 8,476 differentially expressed genes (DEGs) in the pituitary and gonads, respectively, thus indicating that LH-A2 has more regulatory effects on the gonads than the pituitary in A. schrenckii. Signal transduction, global and overview maps, immune system, endocrine system and lipid metabolism were the main enriched metabolic pathways in both the pituitary and gonads. Sixteen important genes were selected from these metabolic pathways. Seven genes were co-DEGs enriched in both signal transduction and endocrine system metabolic pathways. The other co-DEGs were selected from the immune system and lipid metabolism metabolic pathways, and showed mRNA expression changes of >7.0. The expression of five DEGs throughout LH-A2 treatment was verified to show the same patterns of change as those observed with RNA-seq, indicating the accuracy of the RNA-seq in this study. Our findings provide valuable evidence of the regulation of gonad development of juvenile A. schrenckii by LH-A2 and may enable the establishment of artificial techniques to regulate gonad development in this species.
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Affiliation(s)
- Weihua Lv
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China
| | - Shubo Jin
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China
| | - Dingchen Cao
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China
| | - Nianmin Wang
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China
| | - Xing Jin
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China
| | - Ying Zhang
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China
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Zhang HL, Hu BX, Li ZL, Du T, Shan JL, Ye ZP, Peng XD, Li X, Huang Y, Zhu XY, Chen YH, Feng GK, Yang D, Deng R, Zhu XF. PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis. Nat Cell Biol 2022; 24:88-98. [PMID: 35027735 DOI: 10.1038/s41556-021-00818-3] [Citation(s) in RCA: 287] [Impact Index Per Article: 95.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 11/17/2021] [Indexed: 12/12/2022]
Abstract
The accumulation of lipid peroxides is recognized as a determinant of the occurrence of ferroptosis. However, the sensors and amplifying process of lipid peroxidation linked to ferroptosis remain obscure. Here we identify PKCβII as a critical contributor of ferroptosis through independent genome-wide CRISPR-Cas9 and kinase inhibitor library screening. Our results show that PKCβII senses the initial lipid peroxides and amplifies lipid peroxidation linked to ferroptosis through phosphorylation and activation of ACSL4. Lipidomics analysis shows that activated ACSL4 catalyses polyunsaturated fatty acid-containing lipid biosynthesis and promotes the accumulation of lipid peroxidation products, leading to ferroptosis. Attenuation of the PKCβII-ACSL4 pathway effectively blocks ferroptosis in vitro and impairs ferroptosis-associated cancer immunotherapy in vivo. Our results identify PKCβII as a sensor of lipid peroxidation, and the lipid peroxidation-PKCβII-ACSL4 positive-feedback axis may provide potential targets for ferroptosis-associated disease treatment.
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Affiliation(s)
- Hai-Liang Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Bing-Xin Hu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhi-Ling Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Tian Du
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jia-Lu Shan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhi-Peng Ye
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiao-Dan Peng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xuan Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yun Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xian-Ying Zhu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yu-Hong Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Gong-Kan Feng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Dajun Yang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Rong Deng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
| | - Xiao-Feng Zhu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
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Insulin-like Growth Factor II Prevents MPP+ and Glucocorticoid Mitochondrial-Oxidative and Neuronal Damage in Dopaminergic Neurons. Antioxidants (Basel) 2021; 11:antiox11010041. [PMID: 35052545 PMCID: PMC8773450 DOI: 10.3390/antiox11010041] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/19/2021] [Accepted: 12/22/2021] [Indexed: 11/17/2022] Open
Abstract
Stress seems to contribute to Parkinson’s disease (PD) neuropathology, probably by dysregulation of the hypothalamic–pituitary–adrenal axis. Key factors in this pathophysiology are oxidative stress and mitochondrial dysfunction and neuronal glucocorticoid-induced toxicity. The insulin-like growth factor II (IGF-II), a pleiotropic hormone, has shown antioxidant and neuroprotective effects in some neurodegenerative disorders. Our aim was to examine the protective effect of IGF-II on a dopaminergic cellular combined model of PD and mild to moderate stress measuring oxidative stress parameters, mitochondrial and neuronal markers, and signalling pathways. IGF-II counteracts the mitochondrial-oxidative damage produced by the toxic synergistic effect of corticosterone and 1-methyl-4-phenylpyridinium, protecting dopaminergic neurons from death and neurodegeneration. IGF-II promotes PKC activation and nuclear factor (erythroid-derived 2)-like 2 antioxidant response in a glucocorticoid receptor-dependent pathway, preventing oxidative cell damage and maintaining mitochondrial function. Thus, IGF-II is a potential therapeutic tool for treatment and prevention of disease progression in PD patients suffering mild to moderate emotional stress.
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34
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Cheng Y, Chen H. Aberrance of Zinc Metalloenzymes-Induced Human Diseases and Its Potential Mechanisms. Nutrients 2021; 13:nu13124456. [PMID: 34960004 PMCID: PMC8707169 DOI: 10.3390/nu13124456] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/06/2021] [Accepted: 12/09/2021] [Indexed: 12/13/2022] Open
Abstract
Zinc, an essential micronutrient in the human body, is a component in over 300 enzymes and participates in regulating enzymatic activity. Zinc metalloenzymes play a crucial role in physiological processes including antioxidant, anti-inflammatory, and immune responses, as well as apoptosis. Aberrant enzyme activity can lead to various human diseases. In this review, we summarize zinc homeostasis, the roles of zinc in zinc metalloenzymes, the physiological processes of zinc metalloenzymes, and aberrant zinc metalloenzymes in human diseases. In addition, potential mechanisms of action are also discussed. This comprehensive understanding of the mechanisms of action of the regulatory functions of zinc in enzyme activity could inform novel zinc-micronutrient-supply strategies for the treatment of diseases.
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Affiliation(s)
- Yunqi Cheng
- Queen Mary School, Medical College, Nanchang University, Nanchang 330006, China;
- Department of Histology and Embryology, Medical College, Nanchang University, Nanchang 330006, China
| | - Hongping Chen
- Department of Histology and Embryology, Medical College, Nanchang University, Nanchang 330006, China
- Correspondence:
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35
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Lian S, Li S, Zhu J, Xia Y, Do Jung Y. Nicotine stimulates IL-8 expression via ROS/NF-κB and ROS/MAPK/AP-1 axis in human gastric cancer cells. Toxicology 2021; 466:153062. [PMID: 34890707 DOI: 10.1016/j.tox.2021.153062] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/04/2021] [Accepted: 12/06/2021] [Indexed: 02/04/2023]
Abstract
Nicotine, a major alkaloid found in tobacco, is a significant risk factor for gastric cancer. IL-8, a pleiotropic cytokine, plays a vital role in cancer cell metastasis. The role of nicotine in IL-8 expression and the underlying mechanism is currently unknown. Here, we examined the effects of nicotine on IL-8 expression and explored the potential mechanisms in gastric cancer cells. We found that nicotine increases IL-8 expression. Specific inhibitor and mutagenesis studies showed that ROS and MAPK (Erk1/2, p38) were involved in this process. Deletion and site-directed mutagenesis studies indicate the involvement of transcription factor NF-κB and AP-1. ROS and ROS/MAPK (Erk1/2, p38) functioned as the upstream signaling molecules in the activation of NF-κB and AP-1, respectively. AGS gastric cancer cells pretreated with nicotine stimulate angiogenesis in the tumor microenvironment, partially abrogated by silencing IL-8 in AGS cells. In this study, we found that nicotine induces IL-8 expression via ROS/NF-κB and ROS/MAPK (Erk1/2, p38)/AP-1 axis in gastric cancer cells, thus stimulating endothelial cell proliferation and angiogenesis in the tumor microenvironment.
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Affiliation(s)
- Sen Lian
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China.
| | - Shinan Li
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Jun Zhu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Yong Xia
- Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining, Shandong, 272067, China.
| | - Young Do Jung
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
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36
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Basiglio CL, Crocenzi FA, Sánchez Pozzi EJ, Roma MG. Oxidative Stress and Localization Status of Hepatocellular Transporters: Impact on Bile Secretion and Role of Signaling Pathways. Antioxid Redox Signal 2021; 35:808-831. [PMID: 34293961 DOI: 10.1089/ars.2021.0021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Significance: Most hepatopathies are primarily or secondarily cholestatic in nature. Oxidative stress (OS) is a frequent trait among them, and impairs the machinery to generate bile by triggering endocytic internalization of hepatocellular transporters, thus causing cholestasis. This is critical, since it leads to accelerated transporter degradation, which could explain the common post-transcriptional downregulation of transporter expression in human cholestatic diseases. Recent Advances: The mechanisms involved in OS-induced hepatocellular transporter internalization are being revealed. Filamentous actin (F-actin) cytoskeleton disorganization and/or detachment of crosslinking actin proteins that afford transporter stability have been characterized as causal factors. Activation of redox-sensitive signaling pathways leading to changes in phosphorylation status of these structures is involved, including Ca2+-mediated activation of "classical" and "novel" protein kinase C (PKC) isoforms or redox-signaling cascades downstream of NADPH oxidase. Critical Issues: Despite the well-known occurrence of hepatocellular transporter internalization in human hepatopathies, the cholestatic implications of this phenomenon have been overlooked. Accordingly, no specific treatment has been established in the clinical practice for its prevention/reversion. Future Directions: We need to improve our knowledge on the pro-oxidant triggering factors and the multiple signaling pathways that mediate this oxidative injury in each cholestatic hepatopathy, so as to envisage tailor-made therapeutic strategies for each case. Meanwhile, administration of antioxidants or heme oxygenase-1 induction to elevate the hepatocellular levels of the endogenous scavenger bilirubin are promising alternatives that need to be re-evaluated and implemented. They may complement current treatments in cholestasis aimed to enhance transcriptional carrier expression, by providing membrane stability to the newly synthesized carriers. Antioxid. Redox Signal. 35, 808-831.
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Affiliation(s)
- Cecilia L Basiglio
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, U.N.R., Rosario, Argentina
| | - Fernando A Crocenzi
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, U.N.R., Rosario, Argentina
| | - Enrique J Sánchez Pozzi
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, U.N.R., Rosario, Argentina
| | - Marcelo G Roma
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, U.N.R., Rosario, Argentina
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Averina OV, Poluektova EU, Marsova MV, Danilenko VN. Biomarkers and Utility of the Antioxidant Potential of Probiotic Lactobacilli and Bifidobacteria as Representatives of the Human Gut Microbiota. Biomedicines 2021; 9:1340. [PMID: 34680457 PMCID: PMC8533434 DOI: 10.3390/biomedicines9101340] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 09/12/2021] [Accepted: 09/22/2021] [Indexed: 12/12/2022] Open
Abstract
Lactobacilli and bifidobacteria are an important part of human gut microbiota. Among numerous benefits, their antioxidant properties are attracting more and more attention. Multiple in vivo and in vitro studies have demonstrated that lactobacilli and bifidobacteria, along with their cellular components, possess excellent antioxidant capacity, which provides a certain degree of protection to the human body against diseases associated with oxidative stress. Recently, lactobacilli and bifidobacteria have begun to be considered as a new source of natural antioxidants. This review summarizes the current state of research on various antioxidant properties of lactobacilli and bifidobacteria. Special emphasis is given to the mechanisms of antioxidant activity of these bacteria in the human gut microbiota, which involve bacterial cell components and metabolites. This review is also dedicated to the genes involved in the antioxidant properties of lactobacilli and bifidobacteria strains as indicators of their antioxidant potential in human gut microbiota. Identification of the antioxidant biomarkers of the gut microbiota is of great importance both for creating diagnostic systems for assessing oxidative stress and for choosing strategies aimed at restoring the normal functioning of the microbiota and, through it, restoring human health. In this review, the practical application of probiotic strains with proven antioxidant properties to prevent oxidative stress is also considered.
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Affiliation(s)
- Olga V. Averina
- Vavilov Institute of General Genetics, Russion Academy of Sciences, 119991 Moscow, Russia; (E.U.P.); (M.V.M.); (V.N.D.)
| | - Elena U. Poluektova
- Vavilov Institute of General Genetics, Russion Academy of Sciences, 119991 Moscow, Russia; (E.U.P.); (M.V.M.); (V.N.D.)
| | - Mariya V. Marsova
- Vavilov Institute of General Genetics, Russion Academy of Sciences, 119991 Moscow, Russia; (E.U.P.); (M.V.M.); (V.N.D.)
| | - Valery N. Danilenko
- Vavilov Institute of General Genetics, Russion Academy of Sciences, 119991 Moscow, Russia; (E.U.P.); (M.V.M.); (V.N.D.)
- Institute of Ecology, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia
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du Preez K, Rautenbach Y, Hooijberg EH, Goddard A. Oxidative burst and phagocytic activity of phagocytes in canine parvoviral enteritis. J Vet Diagn Invest 2021; 33:884-893. [PMID: 34148453 DOI: 10.1177/10406387211025513] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Canine parvoviral enteritis (CPE) is a severe disease characterized by systemic inflammation and immunosuppression. The function of circulating phagocytes (neutrophils and monocytes) in affected dogs has not been fully investigated. We characterized the functional capacity of canine phagocytes in CPE by determining their oxidative burst and phagocytic activities using flow cytometry. Blood was collected from 28 dogs with CPE and 11 healthy, age-matched, control dogs. Oxidative burst activity was assessed by stimulating phagocytes with opsonized Escherichia coli or phorbol 12-myristate 13-acetate (PMA) and measuring the percentage of phagocytes producing reactive oxygen species and the magnitude of this production. Phagocytosis was measured by incubating phagocytes with opsonized E. coli and measuring the percentage of phagocytes containing E. coli and the number of bacteria per cell. Complete blood counts and serum C-reactive protein (CRP) concentrations were also determined. Serum CRP concentration was negatively and positively correlated with segmented and band neutrophil concentrations, respectively. Overall, no differences in phagocyte function were found between dogs with CPE and healthy control dogs. However, infected dogs with neutropenia or circulating band neutrophils had decreased PMA-stimulated oxidative burst activity compared to healthy controls. Additionally, CPE dogs with neutropenia or circulating band neutrophils had decreased PMA- and E. coli-stimulated oxidative burst activity and decreased phagocytosis of E. coli compared to CPE dogs without neutropenia or band neutrophils. We conclude that phagocytes have decreased oxidative burst and phagocytic activity in neutropenic CPE dogs and in CPE dogs with circulating band neutrophils.
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Affiliation(s)
- Kelly du Preez
- Section of Clinical Pathology, Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, Pretoria, South Africa
| | - Yolandi Rautenbach
- Section of Clinical Pathology, Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, Pretoria, South Africa
| | - Emma H Hooijberg
- Section of Clinical Pathology, Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, Pretoria, South Africa
| | - Amelia Goddard
- Section of Clinical Pathology, Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, Pretoria, South Africa
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Issac PK, Lite C, Guru A, Velayutham M, Kuppusamy G, Saraswathi NT, Al Olayan EM, Aloufi AS, Elokaby MA, Elumalai P, Arshad A, Arockiaraj J. Tryptophan-tagged peptide from serine threonine-protein kinase of Channa striatus improves antioxidant defence in L6 myotubes and attenuates caspase 3-dependent apoptotic response in zebrafish larvae. FISH PHYSIOLOGY AND BIOCHEMISTRY 2021; 47:293-311. [PMID: 33394283 DOI: 10.1007/s10695-020-00912-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 11/27/2020] [Indexed: 05/02/2023]
Abstract
This study reports the antioxidant property and molecular mechanism of a tryptophan-tagged peptide derived from a teleost fish Channa striatus of serine threonine-protein kinase (STPK). The peptide was tagged with tryptophan to enhance the antioxidant property of STPK and named as IW13. The antioxidant activity of IW13 peptide was investigated using in vitro methods such as DPPH, ABTS, superoxide anion radical scavenging and hydrogen peroxide scavenging assay. Furthermore, to investigate the toxicity and dose response of IW13 peptide on antioxidant defence in vitro, L6 myotubes were induced with generic oxidative stress due to exposure of hydrogen peroxide (H2O2). IW13 peptide exposure was found to be non-cytotoxic to L6 cells in the tested concentration (10, 20, 30, 40 and 50 μM). Also, the pre-treatment of IW13 peptide decreased the lipid peroxidation level and increased glutathione enzyme activity. IW13 peptide treatment upregulated the antioxidant enzyme genes: GPx (glutathione peroxidase), GST (glutathione S transferase) and GCS (glutamine cysteine synthase), in vitro in L6 myotubes and in vivo in zebrafish larvae against the H2O2-induced oxidative stress. The results demonstrated that IW13 renders protection against the H2O2-induced oxidative stress through a cellular antioxidant defence mechanism by upregulating the gene expression, thus enhancing the antioxidant activity in the cellular or organismal level. The findings exhibited that the tryptophan-tagged IW13 peptide from STPK of C. striatus could be a promising candidate for the treatment of oxidative stress-associated diseases.
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Affiliation(s)
- Praveen Kumar Issac
- SRM Research Institute, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu, 603 203, India
| | - Christy Lite
- Endocrine and Exposome Laboratory, Department of Zoology, Madras Christian College, Tambaram, Chennai, Tamil Nadu, 600 059, India
| | - Ajay Guru
- SRM Research Institute, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu, 603 203, India
| | - Manikandan Velayutham
- SRM Research Institute, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu, 603 203, India
| | - Giva Kuppusamy
- Innovation and Technology Advancement Department, GK Aqua Sdn Bhd, Lot 563 Kg Sg Machang Ulu, 71750, Lenggeng, Negeri Sembilan, Malaysia
| | - N T Saraswathi
- Molecular Biophysics Lab, School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, Tamil Nadu, 613 401, India
| | - Ebtesam M Al Olayan
- Department of Zoology, Faculty of Science, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Abeer S Aloufi
- Department of Zoology, Vaccines Research Unit, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Mohamed A Elokaby
- Aquaculture Division, National Institute of Oceanography and Fisheries (NIOF), Alexandria, 21556, Egypt
| | - Preetham Elumalai
- School of Processing Technology, Kerala University of Fisheries and Ocean Studies, Panangad, Kerala, India
| | - Aziz Arshad
- International Institute of Aquaculture and Aquatic Sciences (I-AQUAS), Universiti Putra Malaysia, 71050, Port Dickson, Negeri Sembilan, Malaysia
- Department of Aquaculture, Faculty of Agriculture, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Jesu Arockiaraj
- SRM Research Institute, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu, 603 203, India.
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De Luca E, Perrelli A, Swamy H, Nitti M, Passalacqua M, Furfaro AL, Salzano AM, Scaloni A, Glading AJ, Retta SF. Protein kinase Cα regulates the nucleocytoplasmic shuttling of KRIT1. J Cell Sci 2021; 134:jcs250217. [PMID: 33443102 PMCID: PMC7875496 DOI: 10.1242/jcs.250217] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 12/15/2020] [Indexed: 12/16/2022] Open
Abstract
KRIT1 is a scaffolding protein that regulates multiple molecular mechanisms, including cell-cell and cell-matrix adhesion, and redox homeostasis and signaling. However, rather little is known about how KRIT1 is itself regulated. KRIT1 is found in both the cytoplasm and the nucleus, yet the upstream signaling proteins and mechanisms that regulate KRIT1 nucleocytoplasmic shuttling are not well understood. Here, we identify a key role for protein kinase C (PKC) in this process. In particular, we found that PKC activation promotes the redox-dependent cytoplasmic localization of KRIT1, whereas inhibition of PKC or treatment with the antioxidant N-acetylcysteine leads to KRIT1 nuclear accumulation. Moreover, we demonstrated that the N-terminal region of KRIT1 is crucial for the ability of PKC to regulate KRIT1 nucleocytoplasmic shuttling, and may be a target for PKC-dependent regulatory phosphorylation events. Finally, we found that silencing of PKCα, but not PKCδ, inhibits phorbol 12-myristate 13-acetate (PMA)-induced cytoplasmic enrichment of KRIT1, suggesting a major role for PKCα in regulating KRIT1 nucleocytoplasmic shuttling. Overall, our findings identify PKCα as a novel regulator of KRIT1 subcellular compartmentalization, thus shedding new light on the physiopathological functions of this protein.
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Affiliation(s)
- Elisa De Luca
- Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Torino, Italy
- CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Torino, Italy
- Center for Biomolecular Nanotechnologies, Istituto Italiano di Tecnologia, 73010 Arnesano, Lecce, Italy
| | - Andrea Perrelli
- Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Torino, Italy
- CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Torino, Italy
| | - Harsha Swamy
- Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14642, USA
| | - Mariapaola Nitti
- Department of Experimental Medicine, University of Genoa, 16132 Genova, Italy
| | - Mario Passalacqua
- Department of Experimental Medicine, University of Genoa, 16132 Genova, Italy
| | - Anna Lisa Furfaro
- Department of Experimental Medicine, University of Genoa, 16132 Genova, Italy
| | - Anna Maria Salzano
- Proteomics & Mass Spectrometry Laboratory, ISPAAM, National Research Council, 80147 Napoli, Italy
| | - Andrea Scaloni
- Proteomics & Mass Spectrometry Laboratory, ISPAAM, National Research Council, 80147 Napoli, Italy
| | - Angela J Glading
- Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14642, USA
| | - Saverio Francesco Retta
- Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Torino, Italy
- CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Torino, Italy
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Dükel M, Tavsan Z, Kayali HA. Flavonoids regulate cell death-related cellular signaling via ROS in human colon cancer cells. Process Biochem 2021. [DOI: 10.1016/j.procbio.2020.10.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Ammendola R, Parisi M, Esposito G, Cattaneo F. Pro-Resolving FPR2 Agonists Regulate NADPH Oxidase-Dependent Phosphorylation of HSP27, OSR1, and MARCKS and Activation of the Respective Upstream Kinases. Antioxidants (Basel) 2021; 10:antiox10010134. [PMID: 33477989 PMCID: PMC7835750 DOI: 10.3390/antiox10010134] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/11/2021] [Accepted: 01/14/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Formyl peptide receptor 2 (FPR2) is involved in the pathogenesis of chronic inflammatory diseases, being activated either by pro-resolving or proinflammatory ligands. FPR2-associated signal transduction pathways result in phosphorylation of several proteins and in NADPH oxidase activation. We, herein, investigated molecular mechanisms underlying phosphorylation of heat shock protein 27 (HSP27), oxidative stress responsive kinase 1 (OSR1), and myristolated alanine-rich C-kinase substrate (MARCKS) elicited by the pro-resolving FPR2 agonists WKYMVm and annexin A1 (ANXA1). Methods: CaLu-6 cells or p22phoxCrispr/Cas9 double nickase CaLu-6 cells were incubated for 5 min with WKYMVm or ANXA1, in the presence or absence of NADPH oxidase inhibitors. Phosphorylation at specific serine residues of HSP27, OSR1, and MARCKS, as well as the respective upstream kinases activated by FPR2 stimulation was analysed. Results: Blockade of NADPH oxidase functions prevents WKYMVm- and ANXA1-induced HSP-27(Ser82), OSR1(Ser339) and MARCKS(Ser170) phosphorylation. Moreover, NADPH oxidase inhibitors prevent WKYMVm- and ANXA1-dependent activation of p38MAPK, PI3K and PKCδ, the kinases upstream to HSP-27, OSR1 and MARCKS, respectively. The same results were obtained in p22phoxCrispr/Cas9 cells. Conclusions: FPR2 shows an immunomodulatory role by regulating proinflammatory and anti-inflammatory activities and NADPH oxidase is a key regulator of inflammatory pathways. The activation of NADPH oxidase-dependent pro-resolving downstream signals suggests that FPR2 signalling and NADPH oxidase could represent novel targets for inflammation therapeutic intervention.
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Affiliation(s)
| | | | | | - Fabio Cattaneo
- Correspondence: ; Tel.: +39-081-746-2036; Fax: +39-081-746-4359
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Lian S, Li S, Sah DK, Kim NH, Lakshmanan VK, Jung YD. Suppression of Urokinase-Type Plasminogen Activator Receptor by Docosahexaenoic Acid Mediated by Heme Oxygenase-1 in 12- O-Tetradecanoylphorbol-13-Acetate-Induced Human Endothelial Cells. Front Pharmacol 2021; 11:577302. [PMID: 33381031 PMCID: PMC7768974 DOI: 10.3389/fphar.2020.577302] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 10/15/2020] [Indexed: 11/28/2022] Open
Abstract
Urokinase-type plasminogen activator receptor (uPAR) plays a crucial role in inflammation and tumor metastasis. Docosahexaenoic acid (DHA), a representative omega-3 polyunsaturated fatty acid, has been shown to exhibit anti-inflammatory and anti-tumor properties. However, the mechanism by which DHA negatively regulates uPAR expression is not yet understood. The aim of this study was to investigate the effect of DHA on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced uPAR expression and potential role of heme oxygenase-1 (HO-1) in DHA-induced inhibition of uPAR in human endothelial ECV304 cells. Results showed that TPA induced uPAR expression in a time dependent manner, while DHA inhibited uPAR expression in a concentration-dependent manner. Moreover, treatment with DHA induced HO-1 expression in a time- and concentration-dependent manner. In addition, DHA-induced inhibition of uPAR expression and cell invasion in TPA-stimulated cells was reversed by si-HO-1 RNA. Induction of HO-1 by ferric protoporphyrin IX (FePP) inhibited TPA-induced uPAR expression, and this effect was abolished by treatment with the HO-1 inhibitor tin protoporphyrin IX (SnPP). Additionally, carbon monoxide, an HO-1 product, attenuated TPA-induced uPAR expression and cell invasion. Collectively, these data suggest a novel role of DHA-induced HO-1 in reducing uPAR expression and cell invasion in human endothelial ECV304 cells.
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Affiliation(s)
- Sen Lian
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangdong, China
| | - Shinan Li
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Korea
| | - Dhiraj Kumar Sah
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Korea
| | - Nam Ho Kim
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Korea
| | - Vinoth-Kumar Lakshmanan
- Centre for Preclinical and Translational Medical Research (CPTMR), Central Research Facility (CRF), Faculty of Clinical Research, Sri Ramachandra Institute of Higher Education and Research, Chennai, India.,Thumbay Research Institute for Precision Medicine and Department of Biomedical Sciences, Gulf Medical University, Ajman, United Arab Emirates
| | - Young Do Jung
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Korea
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Valenzano MC, Rybakovsky E, Chen V, Leroy K, Lander J, Richardson E, Yalamanchili S, McShane S, Mathew A, Mayilvaganan B, Connor L, Urbas R, Huntington W, Corcoran A, Trembeth S, McDonnell E, Wong P, Newman G, Mercogliano G, Zitin M, Etemad B, Thornton J, Daum G, Raines J, Kossenkov A, Fong LY, Mullin JM. Zinc Gluconate Induces Potentially Cancer Chemopreventive Activity in Barrett's Esophagus: A Phase 1 Pilot Study. Dig Dis Sci 2021; 66:1195-1211. [PMID: 32415564 PMCID: PMC7677901 DOI: 10.1007/s10620-020-06319-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 05/02/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND Chemopreventive effects of zinc for esophageal cancer have been well documented in animal models. This prospective study explores if a similar, potentially chemopreventive action can be seen in Barrett's esophagus (BE) in humans. AIMS To determine if molecular evidence can be obtained potentially indicating zinc's chemopreventive action in Barrett's metaplasia. METHODS Patients with a prior BE diagnosis were placed on oral zinc gluconate (14 days of 26.4 mg zinc BID) or a sodium gluconate placebo, prior to their surveillance endoscopy procedure. Biopsies of Barrett's mucosa were then obtained for miRNA and mRNA microarrays, or protein analyses. RESULTS Zinc-induced mRNA changes were observed for a large number of transcripts. These included downregulation of transcripts encoding proinflammatory proteins (IL32, IL1β, IL15, IL7R, IL2R, IL15R, IL3R), upregulation of anti-inflammatory mediators (IL1RA), downregulation of transcripts mediating epithelial-to-mesenchymal transition (EMT) (LIF, MYB, LYN, MTA1, SRC, SNAIL1, and TWIST1), and upregulation of transcripts that oppose EMT (BMP7, MTSS1, TRIB3, GRHL1). miRNA arrays showed significant upregulation of seven miRs with tumor suppressor activity (-125b-5P, -132-3P, -548z, -551a, -504, -518, and -34a-5P). Of proteins analyzed by Western blot, increased expression of the pro-apoptotic protein, BAX, and the tight junctional protein, CLAUDIN-7, along with decreased expression of BCL-2 and VEGF-R2 were noteworthy. CONCLUSIONS When these mRNA, miRNA, and protein molecular data are considered collectively, a cancer chemopreventive action by zinc in Barrett's metaplasia may be possible for this precancerous esophageal tissue. These results and the extensive prior animal model studies argue for a future prospective clinical trial for this safe, easily-administered, and inexpensive micronutrient, that could determine if a chemopreventive action truly exists.
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Affiliation(s)
- M C Valenzano
- The Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA, 19096, USA
| | - E Rybakovsky
- The Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA, 19096, USA
| | - V Chen
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - K Leroy
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - J Lander
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - E Richardson
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - S Yalamanchili
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - S McShane
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - A Mathew
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - B Mayilvaganan
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - L Connor
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - R Urbas
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - W Huntington
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - A Corcoran
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - S Trembeth
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - E McDonnell
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - P Wong
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - G Newman
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - G Mercogliano
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - M Zitin
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - B Etemad
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - J Thornton
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA
| | - G Daum
- The Department of Pathology, Lankenau Medical Center, Wynnewood, USA
| | - J Raines
- The Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA, 19096, USA
| | | | - L Y Fong
- Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - J M Mullin
- The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA.
- The Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA, 19096, USA.
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
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Role of Protein Kinase C in Immune Cell Activation and Its Implication Chemical-Induced Immunotoxicity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1275:151-163. [PMID: 33539015 DOI: 10.1007/978-3-030-49844-3_6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Protein kinase C (PKCs) isoforms play a key regulatory role in a variety of cellular functions, including cell growth and differentiation, gene expression, hormone secretion, etc. Patterns of expression for each PKC isoform differ among tissues, and it is also clear that different PKCs are often not functionally redundant, for example specific PKCs mediate specific cellular signals required for activation, proliferation, differentiation and survival of immune cells. In the last 20 years, we have been studying the role of PKCs, mainly PKCβ and its anchoring protein RACK1 (Receptor for Activated C Kinase 1), in immune cell activation, and their implication in immunosenescence and immunotoxicity. We could demonstrate that PKCβ and RACK1 are central in dendritic cell maturation and activation by chemical allergens, and their expressions can be targeted by EDCs and anti-inflammatory drugs. In this chapter, current knowledge on the role of PKC in immune cell activation and possible implication in immunotoxicity will be described.
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NOX2-Derived Reactive Oxygen Species in Cancer. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:7095902. [PMID: 33312338 PMCID: PMC7721506 DOI: 10.1155/2020/7095902] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 10/21/2019] [Indexed: 12/16/2022]
Abstract
The formation of reactive oxygen species (ROS) by the myeloid cell NADPH oxidase NOX2 is critical for the destruction of engulfed microorganisms. However, recent studies imply that ROS, formed by NOX2+ myeloid cells in the malignant microenvironment, exert multiple actions of relevance to the growth and spread of neoplastic cells. By generating ROS, tumor-infiltrating myeloid cells and NOX2+ leukemic myeloid cells may thus (i) compromise the function and viability of adjacent cytotoxic lymphocytes, including natural killer (NK) cells and T cells, (ii) oxidize DNA to trigger cancer-promoting somatic mutations, and (iii) affect the redox balance in cancer cells to control their proliferation and survival. Here, we discuss the impact of NOX2-derived ROS for tumorigenesis, tumor progression, regulation of antitumor immunity, and metastasis. We propose that NOX2 may be a targetable immune checkpoint in cancer.
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Feng T, Wang J. Oxidative stress tolerance and antioxidant capacity of lactic acid bacteria as probiotic: a systematic review. Gut Microbes 2020; 12:1801944. [PMID: 32795116 PMCID: PMC7524341 DOI: 10.1080/19490976.2020.1801944] [Citation(s) in RCA: 245] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 07/15/2020] [Indexed: 02/03/2023] Open
Abstract
Lactic acid bacteria (LAB) are the most frequently used probiotics in fermented foods and beverages and as food supplements for humans or animals, owing to their multiple beneficial features, which appear to be partially associated with their antioxidant properties. LAB can help improve food quality and flavor and prevent numerous disorders caused by oxidation in the host. In this review, we discuss the oxidative stress tolerance, the antioxidant capacity related herewith, and the underlying mechanisms and signaling pathways in probiotic LAB. In addition, we discuss appropriate methods used to evaluate the antioxidant capacity of probiotic LAB. The aim of the present review is to provide an overview of the current state of the research associated with the oxidative stress tolerance and antioxidant capacity of LAB.
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Affiliation(s)
- Tao Feng
- Institute of Animal Husbandry and Veterinary Medicine (IAHVM), Beijing Academy of Agriculture and Forestry Sciences (BAAFS), Beijing, China
- Sino-US Joint Laboratory of Animal Science, Beijing Academy of Agriculture and Forestry Sciences, Beijing, China
| | - Jing Wang
- Institute of Animal Husbandry and Veterinary Medicine (IAHVM), Beijing Academy of Agriculture and Forestry Sciences (BAAFS), Beijing, China
- Sino-US Joint Laboratory of Animal Science, Beijing Academy of Agriculture and Forestry Sciences, Beijing, China
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48
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UbK is Involved in the Resistance of Bacillus Subtilis to Oxidative Stress. Curr Microbiol 2020; 77:4063-4071. [DOI: 10.1007/s00284-020-02239-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Accepted: 10/01/2020] [Indexed: 01/08/2023]
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49
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Lima SNP, Cerdeira CD, Santos GB, Fernandes MDM, Giusti-Paiva A, Brigagão MRPL. Tempol modulates the leukocyte response to inflammatory stimuli and attenuates endotoxin-induced sickness behaviour in mice. Arch Physiol Biochem 2020; 126:341-347. [PMID: 30465447 DOI: 10.1080/13813455.2018.1538247] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Background and aims: Lipopolysaccharide (LPS), an endotoxin, is a component of the outer membrane of Gram-negative bacteria that is able to activate the peripheral immune system, leading to changes in signalling pathways that act locally and systemically to achieve adaptive responses. Sickness behaviour is a motivational state in response to endotoxin exposure and includes depressed activity and a reduction of exploratory behaviour, potentially reorganising organism priorities to cope with infectious diseases. We hypothesised that 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol) modulates the leukocyte response to endotoxins and decreases LPS-induced sickness behaviour in mice.Methods: The effects of Tempol on LPS-induced peritonitis and the respiratory burst of neutrophils primed with LPS and triggered by phorbol 12-myristate-13-acetate (PMA) were evaluated. To evaluate the effects of Tempol on sickness behaviour, the mice were submitted to an open field and forced swim tests.Results: Tempol (50-100 μM/106 cells) decreased the respiratory burst of LPS-primed and PMA-stimulated neutrophils in vitro. In vivo, this nitroxide (30 and 100 mg/kg body weight) inhibited leukocyte migration to the peritoneal cavity after LPS administration in mice. Moreover, Tempol pretreatment (30 and 100 mg/kg body weight) before LPS administration also attenuated sickness behavioural changes.Conclusions: Together, these findings shed light on the mechanisms underlying the anti-inflammatory potential and confirm the therapeutic potential of nitroxides.
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Affiliation(s)
- Samuel Nuno Pereira Lima
- Department of Biochemistry (DBq), Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas, Brazil
| | - Cláudio Daniel Cerdeira
- Department of Biochemistry (DBq), Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas, Brazil
| | - Gérsika Bitencourt Santos
- Department of Biochemistry (DBq), Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas, Brazil
| | - Mateus de Mello Fernandes
- Department of Biochemistry (DBq), Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas, Brazil
| | - Alexandre Giusti-Paiva
- Department of Physiology, Institute of Biomedical Sciences; Federal University of Alfenas, Alfenas, Brazil
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Duitama M, Vargas-López V, Casas Z, Albarracin SL, Sutachan JJ, Torres YP. TRP Channels Role in Pain Associated With Neurodegenerative Diseases. Front Neurosci 2020; 14:782. [PMID: 32848557 PMCID: PMC7417429 DOI: 10.3389/fnins.2020.00782] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 07/02/2020] [Indexed: 01/09/2023] Open
Abstract
Transient receptor potential (TRP) are cation channels expressed in both non-excitable and excitable cells from diverse tissues, including heart, lung, and brain. The TRP channel family includes 28 isoforms activated by physical and chemical stimuli, such as temperature, pH, osmotic pressure, and noxious stimuli. Recently, it has been shown that TRP channels are also directly or indirectly activated by reactive oxygen species. Oxidative stress plays an essential role in neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, and TRP channels are involved in the progression of those diseases by mechanisms involving changes in the crosstalk between Ca2+ regulation, oxidative stress, and production of inflammatory mediators. TRP channels involved in nociception include members of the TRPV, TRPM, TRPA, and TRPC subfamilies that transduce physical and chemical noxious stimuli. It has also been reported that pain is a complex issue in patients with Alzheimer's and Parkinson's diseases, and adequate management of pain in those conditions is still in discussion. TRPV1 has a role in neuroinflammation, a critical mechanism involved in neurodegeneration. Therefore, some studies have considered TRPV1 as a target for both pain treatment and neurodegenerative disorders. Thus, this review aimed to describe the TRP-dependent mechanism that can mediate pain sensation in neurodegenerative diseases and the therapeutic approach available to palliate pain and neurodegenerative symptoms throughout the regulation of these channels.
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