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Human Reproduction Update Jul 2023Regulated cell death is a fundamental component of numerous physiological processes; spanning from organogenesis in utero, to normal cell turnover during adulthood, as... (Review)
Review
BACKGROUND
Regulated cell death is a fundamental component of numerous physiological processes; spanning from organogenesis in utero, to normal cell turnover during adulthood, as well as the elimination of infected or damaged cells throughout life. Quality control through regulation of cell death pathways is particularly important in the germline, which is responsible for the generation of offspring. Women are born with their entire supply of germ cells, housed in functional units known as follicles. Follicles contain an oocyte, as well as specialized somatic granulosa cells essential for oocyte survival. Follicle loss-via regulated cell death-occurs throughout follicle development and life, and can be accelerated following exposure to various environmental and lifestyle factors. It is thought that the elimination of damaged follicles is necessary to ensure that only the best quality oocytes are available for reproduction.
OBJECTIVE AND RATIONALE
Understanding the precise factors involved in triggering and executing follicle death is crucial to uncovering how follicle endowment is initially determined, as well as how follicle number is maintained throughout puberty, reproductive life, and ovarian ageing in women. Apoptosis is established as essential for ovarian homeostasis at all stages of development and life. However, involvement of other cell death pathways in the ovary is less established. This review aims to summarize the most recent literature on cell death regulators in the ovary, with a particular focus on non-apoptotic pathways and their functions throughout the discrete stages of ovarian development and reproductive life.
SEARCH METHODS
Comprehensive literature searches were carried out using PubMed and Google Scholar for human, animal, and cellular studies published until August 2022 using the following search terms: oogenesis, follicle formation, follicle atresia, oocyte loss, oocyte apoptosis, regulated cell death in the ovary, non-apoptotic cell death in the ovary, premature ovarian insufficiency, primordial follicles, oocyte quality control, granulosa cell death, autophagy in the ovary, autophagy in oocytes, necroptosis in the ovary, necroptosis in oocytes, pyroptosis in the ovary, pyroptosis in oocytes, parthanatos in the ovary, and parthanatos in oocytes.
OUTCOMES
Numerous regulated cell death pathways operate in mammalian cells, including apoptosis, autophagic cell death, necroptosis, and pyroptosis. However, our understanding of the distinct cell death mediators in each ovarian cell type and follicle class across the different stages of life remains the source of ongoing investigation. Here, we highlight recent evidence for the contribution of non-apoptotic pathways to ovarian development and function. In particular, we discuss the involvement of autophagy during follicle formation and the role of autophagic cell death, necroptosis, pyroptosis, and parthanatos during follicle atresia, particularly in response to physiological stressors (e.g. oxidative stress).
WIDER IMPLICATIONS
Improved knowledge of the roles of each regulated cell death pathway in the ovary is vital for understanding ovarian development, as well as maintenance of ovarian function throughout the lifespan. This information is pertinent not only to our understanding of endocrine health, reproductive health, and fertility in women but also to enable identification of novel fertility preservation targets.
Topics: Adult; Animals; Female; Humans; Apoptosis; Granulosa Cells; Mammals; Oocytes; Ovarian Follicle; Ovary; Regulated Cell Death; Homeostasis
PubMed: 36857094
DOI: 10.1093/humupd/dmad005 -
Antioxidants (Basel, Switzerland) Jul 2023Ethanol consumption triggers oxidative stress by generating reactive oxygen species (ROS) through its metabolites. This process leads to steatosis and liver... (Review)
Review
Ethanol consumption triggers oxidative stress by generating reactive oxygen species (ROS) through its metabolites. This process leads to steatosis and liver inflammation, which are critical for the development of alcoholic liver disease (ALD). Autophagy is a regulated dynamic process that sequesters damaged and excess cytoplasmic organelles for lysosomal degradation and may counteract the harmful effects of ROS-induced oxidative stress. These effects include hepatotoxicity, mitochondrial damage, steatosis, endoplasmic reticulum stress, inflammation, and iron overload. In liver diseases, particularly ALD, macroautophagy has been implicated as a protective mechanism in hepatocytes, although it does not appear to play the same role in stellate cells. Beyond the liver, autophagy may also mitigate the harmful effects of alcohol on other organs, thereby providing an additional layer of protection against ALD. This protective potential is further supported by studies showing that drugs that interact with autophagy, such as rapamycin, can prevent ALD development in animal models. This systematic review presents a comprehensive analysis of the literature, focusing on the role of autophagy in oxidative stress regulation, its involvement in organ-organ crosstalk relevant to ALD, and the potential of autophagy-targeting therapeutic strategies.
PubMed: 37507963
DOI: 10.3390/antiox12071425 -
Frontiers in Immunology 2023Diabetic kidney disease (DKD) is a chronic inflammatory condition that affects approximately 20-40% of individuals with diabetes. Sodium-glucose co-transporter 2... (Review)
Review
Diabetic kidney disease (DKD) is a chronic inflammatory condition that affects approximately 20-40% of individuals with diabetes. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors, emerging as novel hypoglycemic agents, have demonstrated significant cardiorenal protective effects in patients with DKD. Initially, it was believed that the efficacy of SGLT-2 inhibitors declined as the estimated glomerular filtration rate (eGFR) decreased, which led to their preferential use in DKD patients at G1-G3 stages. However, recent findings from the DAPA-CKD and EMPA-KIDNEY studies have revealed equally beneficial cardiorenal effects of SGLT-2 inhibitors in individuals at stage G4 DKD, although the underlying mechanism behind this phenomenon remains unclear. In this comprehensive analysis, we provide a systematic review of the mechanisms and functioning of SGLT-2 inhibitors, potential renal protection mechanisms, and the therapeutic efficacy and safety of SGLT-2 inhibitors in kidney diseases, with a particular focus on stage G4 DKD. Gaining a deeper understanding of the renal protective effect of SGLT-2 inhibitors and their underlying mechanisms is highly significance for the successful utilization of these inhibitors in the treatment of diverse kidney disorders.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Diabetic Nephropathies; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Kidney
PubMed: 37809091
DOI: 10.3389/fimmu.2023.1213473 -
Phytomedicine : International Journal... Nov 2023Verbascoside is a natural and water-soluble phenylethanoid glycoside found in several medicinal plants. It has extensive pharmacological effects, including antioxidative... (Review)
Review
BACKGROUND
Verbascoside is a natural and water-soluble phenylethanoid glycoside found in several medicinal plants. It has extensive pharmacological effects, including antioxidative and antineoplastic actions, and a wide range of therapeutic effects against depression.
PURPOSE
In this review, we appraised preclinical and limited clinical evidence to fully discuss the anti-depression capacity of verbascoside and its holistic characteristics that can contribute to better management of depression in vivo and in vitro models, as well as, its toxicities and medicinal value.
METHODS
This review was prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A systematic review of 32 preclinical trials published up to April 2023, combined with a comprehensive bioinformatics analysis of network pharmacology and molecular docking, was conducted to elucidate the antidepressant mechanism of action of verbascoside. Studies included in the systematic review were obtained from 7 electronic databases: PubMed, Scopus, Web of Science, Cochrane, ResearchGate, ScienceDirect, and Google Scholar.
RESULTS
Studies on the antidepressant effects of verbascoside showed that various pharmacological mechanisms and pathways, such as modulating the levels of monoamine neurotransmitters, inhibiting hypothalamic-pituitary-adrenal (HPA) axis hyperfunction and promoting neuroprotection may be involved in the process of its action against depression. Verbascoside promotes dopamine (DA) biosynthesis by promoting the expression of tyrosine hydroxylase mRNA and protein, upregulates the expression of 5-hydroxytryptamine receptor 1B (5-HT1B), prominence protein, microtubule-associated protein 2 (MAP2), hemeoxygenase-1 (HO-1), SQSTM1, Recombinant Autophagy Related Protein 5 (ATG5) and Beclin-1, and decreases the expression of caspase-3 and a-synuclein, thus exerting antidepressant effects. We identified seven targets (CCL2, FOS, GABARAPL1, CA9, TYR, CA12, and SQSTM1) and three signaling pathways (glutathione metabolism, metabolism of xenobiotics by cytochrome P450, fluid shear stress and atherosclerosis) as potential molecular biological sites for verbascoside.
CONCLUSIONS
These findings provide strong evidence that verbascoside exerts its antidepressant effects through various pharmacological mechanisms. However, further multicentre clinical case-control and molecularly targeted fishing studies are required to confirm the clinical efficacy of verbascoside and its underlying direct targets.
Topics: Glycosides; Molecular Docking Simulation; Neuroprotection; Sequestosome-1 Protein
PubMed: 37657207
DOI: 10.1016/j.phymed.2023.155027 -
European Journal of Medicinal Chemistry Dec 2023Targeted protein degradation (TPD) has emerged as a promising therapeutic approach with potential advantages over traditional occupancy-based inhibitors in terms of... (Review)
Review
Targeted protein degradation (TPD) has emerged as a promising therapeutic approach with potential advantages over traditional occupancy-based inhibitors in terms of dosing, side effects and targeting "undruggable" proteins. Targeted degraders can theoretically bind any nook or cranny of targeted proteins to drive degradation. This offers convenience versus the small-molecule inhibitors that must function in a well-defined pocket. The degradation process depends mainly on two cell self-destruction mechanisms, namely the ubiquitin-proteasome system and the lysosomal degradation pathway. Various TPD strategies (e.g., proteolytic-targeting chimeras, molecular glues, lysosome-targeting chimeras, and autophagy-targeting chimeras) have been developed. These approaches hold great potential for targeting dysregulated proteins, potentially offering therapeutic benefits. In this article, we systematically review the mechanisms of various TPD strategies, potential applications to drug discovery, and recent advances. We also discuss the benefits and challenges associated with these TPD strategies, aiming to provide insight into the targeting of dysregulated proteins and facilitate their clinical applications.
Topics: Proteolysis; Proteasome Endopeptidase Complex; Autophagy; Drug Discovery; Lysosomes
PubMed: 37778240
DOI: 10.1016/j.ejmech.2023.115839 -
Frontiers in Pharmacology 2023To summarize and clarify the current research status and indicate possible future directions in the field of autophagy in ischemic stroke, we performed a comprehensive...
To summarize and clarify the current research status and indicate possible future directions in the field of autophagy in ischemic stroke, we performed a comprehensive and multidimensional bibliometric analysis of the literature in this field published from 2011 to 2022. We retrieved articles on the field of autophagy in ischemic stroke published between 2011 and 2022 from Web of Science Core Collection (WOSCC). VOSviewer (version 1.6.19) and CiteSpace (version 6.2.R2 Basic) were used to identify the leading topics as well as generate visual maps of Countries/regions, organizations, authors, journals, and keyword networks in the related field. A total of 568 publications were contained in this research. The journal with the most publications were Front Pharmacol, Mol Neurobiol, and Neuroscience. China was the most productive country with respect to co-authorship, with the Capital Med Univ being the organization with the most. co-authorships. In terms of authorship analysis, eight of the top 10 most contributive authors were from China. The co-occurring author keywords can be divided into three main clusters, including "protective effect of autophagy in ischemic stroke," "autophagy-targeted therapy for ischemic stroke," and "mitochondrial function in cerebral ischemia-reperfusion injury". This bibliometric analysis helps us reveal the current research hotspots in the research field of autophagy in ischemic stroke and guide future research directions. Subsequent trends in this special field are likely to identify and develop novel autophagy-targeted therapy strategies to effectively prevent and treat ischemic stroke.
PubMed: 37731738
DOI: 10.3389/fphar.2023.1232114 -
Journal of Hazardous Materials Oct 2023Phthalates (PAEs) are widely used for their excellent ability to improve plastic products. As an essential endocrine axis that regulates the reproductive system, whether... (Review)
Review
Phthalates (PAEs) are widely used for their excellent ability to improve plastic products. As an essential endocrine axis that regulates the reproductive system, whether dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis is involved in reproductive toxicity mediated by environmental endocrine disruptors PAEs has become a hot topic of widespread concern. This study systematically reviewed the adverse effects of multiple PAEs on the HPG axis in different models and objectively discussed the possible underlying mechanisms. The abnormal release of gonadotropin-releasing hormone and gonadotropin, dysfunction of sex hormone receptors and steroid hormone synthesis, and general damage, including cell proliferation, oxidative stress, apoptosis, and autophagy have been confirmed to be involved in this process. Although it is widely established that PAEs induce HPG axis dysfunction, the specific mechanisms involved remain unclear. From a systematic review of relevant publications, it appears that the abnormal expression of peroxisome proliferator-activated, aryl hydrocarbon, and insulin receptors mediated by PAEs is key upstream event that induces these adverse outcomes; however, this inference needs to be further verified. Overall, this study aimed to provide reliable potential biomarkers for future environmental risk assessment and epidemiological investigation of PAEs.
Topics: Reproduction; Gonadotropin-Releasing Hormone; Gonads; Endocrine System; Gonadal Steroid Hormones
PubMed: 37557049
DOI: 10.1016/j.jhazmat.2023.132182 -
Cell Biology International Nov 2023Breast cancer is a commonly known cancer type and the leading cause of cancer death among females. One of the unresolved problems in cancer treatment is the increased... (Review)
Review
Breast cancer is a commonly known cancer type and the leading cause of cancer death among females. One of the unresolved problems in cancer treatment is the increased resistance of the tumor to existing treatments, which is a direct result of apoptotic defects. Calculating an alternative to cell death (autophagy) may be the ultimate solution to maximizing cancer cell death. Our aim in this study was to investigate the potential of free nanoparticles (un-drug-loaded) in the induction or inhibition of autophagy and consider this effect on the therapy process. When the studies met the inclusion criteria, the full texts of all relevant articles were carefully examined and classified. Of the 25 articles included in the analysis, carried out on MCF-7, MDA-MB-231, MDA-MB-231-TXSA, MDA-MB-468, SUM1315, and 4T1 cell lines. Twenty in vitro studies and five in vivo/in vitro studies applied five different autophagy tests: Acridine orange, western blot, Cyto-ID Autophagy Detection Kit, confocal microscope, and quantitative polymerase chain reaction. Nanoparticles (NPs) in the basic format, including Ag, Au, Y O , Se, ZnO, CuO, Al, Fe, vanadium pentoxide, and liposomes, were prepared in the included articles. Three behaviors of NPs related to autophagy were seen: induction, inhibition, and no action. Screened and presented data suggest that most of the involved free NPs (metallic NPs) in this systematic review had reactive oxygen species-mediated pathways with autophagy induction (36%). Also, PI3K/Akt/mTOR and MAPK/ERK signaling pathways were mentioned in just four studies (16%). An impressive percentage of studies (31%) did not examine the NP-related autophagy pathway.
PubMed: 37671447
DOI: 10.1002/cbin.12081 -
Journal of Drug Targeting Sep 2023Renal fibrosis, characterised by glomerulosclerosis and tubulointerstitial fibrosis, is a typical pathological alteration in the progression of chronic kidney disease... (Review)
Review
Renal fibrosis, characterised by glomerulosclerosis and tubulointerstitial fibrosis, is a typical pathological alteration in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD). However, the limited and expensive options for treating renal fibrosis place a heavy financial burden on patients and healthcare systems. Therefore, it is significant to find an effective treatment for renal fibrosis. Ferroptosis, a non-traditional form of cell death, has been found to play an important role in acute kidney injury (AKI), tumours, neurodegenerative diseases, and so on. Moreover, a growing body of research suggests that ferroptosis might be a potential target of renal fibrosis. Meanwhile, mitophagy is a type of selective autophagy that can selectively degrade damaged or dysfunctional mitochondria as a form of mitochondrial quality control, reducing the production of reactive oxygen species (ROS), the accumulation of which is the main cause of renal fibrosis. Additionally, as a receptor of mitophagy, NIX can release beclin1 to induce mitophagy, which can also bind to solute carrier family 7 member 11 (SLC7A11) to block the activity of cystine/glutamate antitransporter (system Xc-) and inhibit ferroptosis, thereby suggesting a link between mitophagy and ferroptosis. However, there have been only limited studies on the relationship among mitophagy, ferroptosis and renal fibrosis. In this paper, we review the mechanisms of mitophagy, and describe how ferroptosis and mitophagy are related to renal fibrosis in an effort to identify potential novel targets for the treatment of renal fibrosis.
Topics: Humans; Mitophagy; Ferroptosis; Acute Kidney Injury; Cystine; Mitochondria
PubMed: 37607069
DOI: 10.1080/1061186X.2023.2250574 -
Heart Failure Reviews Jan 2024Iron overload increases the production of harmful reactive oxygen species in the Fenton reaction, which causes oxidative stress in the body and lipid peroxidation in the... (Review)
Review
Iron overload increases the production of harmful reactive oxygen species in the Fenton reaction, which causes oxidative stress in the body and lipid peroxidation in the cell membrane, and eventually leads to ferroptosis. Diabetes is associated with increased intracellular oxidative stress, inflammation, autophagy, microRNA alterations, and advanced glycation end products (AGEs), which cause cardiac remodeling and cardiac diastolic contractile dysfunction, leading to the development of diabetic cardiomyopathy (DCM). While these factors are also closely associated with ferroptosis, more and more studies have shown that iron-mediated ferroptosis is an important causative factor in DCM. In order to gain fresh insights into the functions of ferroptosis in DCM, this review methodically summarizes the traits and mechanisms connected with ferroptosis and DCM.
Topics: Humans; Diabetic Cardiomyopathies; Ferroptosis; MicroRNAs; Autophagy; Diastole; Reactive Oxygen Species; Diabetes Mellitus
PubMed: 37555989
DOI: 10.1007/s10741-023-10336-z