Autophagy is a fundamental cellular process that eliminates molecules and subcellular elements, including nucleic acids, proteins, lipids and organelles, via lysosome-mediated degradation to promote homeostasis, differentiation, development and survival. While autophagy is intimately linked to health, the intricate relationship among autophagy, aging and disease remains unclear. This Review examines several emerging features of autophagy and postulates how they may be linked to aging as well as to the development and progression of disease. In addition, we discuss current preclinical evidence arguing for the use of autophagy modulators as suppressors of age-related pathologies such as neurodegenerative diseases. Finally, we highlight key questions and propose novel research avenues that will likely reveal new links between autophagy and the hallmarks of aging. Understanding the precise interplay between autophagy and the risk of age-related pathologies across organisms will eventually facilitate the development of clinical applications that promote long-term health. This Review synthesizes recent research on the mechanisms and roles of autophagy in health, aging and disease and discusses how drugs that modulate the process of autophagy could be used to suppress age-associated diseases.

/pdf/autophagy-in-healthy-aging-and-disease-1ngjbtg7gj.pdf

Autophagy in healthy aging and disease

Natural products for the treatment of type 2 diabetes mellitus: Pharmacology and mechanisms.

The release of reactive oxygen species (ROS) and the generation of oxidative stress are considered critical factors for the pathogenesis of diabetes mellitus (DM), a disorder that is growing in prevalence and results in significant economic loss. New therapeutic directions that address the detrimental effects of oxidative stress may be especially warranted to develop effective care for the millions of individuals that currently suffer from DM. The mechanistic target of rapamycin (mTOR), silent mating type information regulation 2 homolog 1 (S. cerevisiae) (SIRT1), and Wnt1 inducible signaling pathway protein 1 (WISP1) are especially justified to be considered treatment targets for DM since these pathways can address the complex relationship between stem cells, trophic factors, impaired glucose tolerance, programmed cell death pathways of apoptosis and autophagy, tissue remodeling, cellular energy homeostasis, and vascular biology that greatly impact the biology and disease progression of DM. The translation and development of these pathways into viable therapies will require detailed understanding of their proliferative nature to maximize clinical efficacy and limit adverse effects that have the potential to lead to unintended consequences.

/pdf/new-insights-for-oxidative-stress-and-diabetes-mellitus-3ew7ddhg71.pdf

New Insights for Oxidative Stress and Diabetes Mellitus.

Neurodegenerative disorders are significantly increasing in incidence as the age of the global population continues to climb with improved life expectancy. At present, more than 30 million individuals throughout the world are impacted by acute and chronic neurodegenerative disorders with limited treatment strategies. The mechanistic target of rapamycin (mTOR), also known as the mammalian target of rapamycin, is a 289 kDa serine/threonine protein kinase that offers exciting possibilities for novel treatment strategies for a host of neurodegenerative diseases that include Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, stroke and trauma. mTOR governs the programmed cell death pathways of apoptosis and autophagy that can determine neuronal stem cell development, precursor cell differentiation, cell senescence, cell survival and ultimate cell fate. Coupled to the cellular biology of mTOR are a number of considerations for the development of novel treatments involving the fine control of mTOR signalling, tumourigenesis, complexity of the apoptosis and autophagy relationship, functional outcome in the nervous system, and the intimately linked pathways of growth factors, phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), AMP activated protein kinase (AMPK), silent mating type information regulation two homologue one (Saccharomyces cerevisiae) (SIRT1) and others. Effective clinical translation of the cellular signalling mechanisms of mTOR offers provocative avenues for new drug development in the nervous system tempered only by the need to elucidate further the intricacies of the mTOR pathway.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bcp.12804

Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders.

Studies regarding macroautophagic/autophagic regulation in endothelial cells (ECs) under diabetic conditions are very limited. Clinical evidence establishes an endothelial protective effect...

https://www.tandfonline.com/doi/pdf/10.1080/15548627.2019.1569913

Metformin alleviates hyperglycemia-induced endothelial impairment by downregulating autophagy via the Hedgehog pathway

Cardiovascular complications are the major causes of death in patients with diabetes mellitus. Several studies have demonstrated that endothelial progenitor cells (EPCs), adult stem cells contributing to the regeneration of vascular endothelium, are dysfunctional under diabetic condition resulting in impaired peripheral circulation and delayed wound healing. In this study, we investigated the cellular alteration of EPCs under high glucose condition, to elucidate the mechanisms underlying diabetes-associated EPC dysfunction. EPCs were isolated from bone marrow and cultured in normal glucose (5.5 mM)- or high glucose (HG; 30 mM)-containing medium. High glucose treated-EPCs showed decreased ability to form tubule-like networks in Matrigel compared to EPCs under normal glucose, which matched well to the clinical observation of diabetic EPC dysfunction. Conversion of LC3-I to LC3-II was increased in EPCs under HG condition, showing that HG induced autophagy in EPCs. Flow cytometric analysis revealed generation of oxidative stress and disruption of mitochondrial permeability in HG exposed EPCs. Increased mitochondrial oxidative stress was also observed by mitochondria-specific superoxide indicator, MitoSOX(TM). Taken together, we demonstrated that autophagy and mitochondrial impairment were induced in EPCs under high glucose condition, giving a new insight into the mechanism underlying dysfunction of diabetic EPCs. We hope that our finding can contribute to the development of a new treatment option for cardiovascular complications in diabetic patients.

High Glucose Condition Induces Autophagy in Endothelial Progenitor Cells Contributing to Angiogenic Impairment

Effects of a novel carbocyclic analog of pyrrolo[2,3-d]pyrimidine nucleoside on pleiotropic induction of cell death in prostate cancer cells with different androgen responsiveness.

We previously isolated a novel compound, HY251, with the molecular structure of 3-propyl-2-vinyl-1,2,3,3a,3b,6,7,7a,8,8adecahydrocyclopenta[ a]indene-3,3a,7a,8a-tetraol from the roots of Aralia continentalis. The current study was designed to evaluate the detailed molecular mechanisms underlying the apoptotic induction by HY251 in human ovarian cancer PA-1 cells. TUNEL assay and Western blot analyses revealed an appreciable apoptotic induction in PA-1 cells treated with 60 μM of HY251 for 24 h. This apoptotic induction was associated with caspase-8-dependent Bid cleavage, which in turn resulted in the formation of pro-apoptotic truncated Bid (tBid), and activation of caspase-9 and -3, as well as the cleavage of poly(ADP-ribose) polymerase (PARP). Moreover, we found that this death event was also associated with the significant upregulation and activation of the p53 tumor-suppressor protein through phosphorylation at Ser15. Therefore, we suggest that HY251 may be a potent cancer chemotherapeutic candidate for the treatment of ovarian cancer.

HY251, a novel decahydrocyclopenta[a]indene analog, induces apoptosis via tBid-mediated intrinsic pathway in human ovarian cancer PA-1 cells.

Background Previously, we synthesized a new carbocyclic analog of pyrrolo[2,3-d]pyrimidine nucleoside, designated MCS-C3. Recently, we found that LNCaP androgen-responsive prostate cancer cells treated with MCS-C3 rapidly undergo intrinsic apoptosis through dramatic up-regulation of p21(CIP1). The present study aimed to evaluate the cellular functions and underlying molecular mechanisms of p21(CIP1) on apoptotic induction in LNCaP cells treated with 6 μM MCS-C3. Materials and methods Western blots, flow cytometric assay, immunoprecipitation, and transmission electron microscopy analysis were used to measure apoptotic induction in 6-μM MCS-C3-treated LNCaP cells. Effects of MCS-C3 on gene expression of p21(CIP1) were measured by semi-quantitative real-time polymerase chain reaction, and small interfering RNA transfection. Results MCS-C3 induced appreciable caspase-dependent apoptosis associated with the significant up-regulation of p53-dependent p21(CIP1) in LNCaP cells. Moreover, this apoptotic induction was caused by direct binding of p21(CIP1) to anti-apoptotic B-cell lymphoma 2 (BCL2) protein, and antagonizing BCL2 function. In addition, MCS-C3-mediated apoptotic induction, and up-regulation of p21(CIP1) were almost completely blocked by the treatment of androgen-responsive LNCaP cells with flutamide, an androgen receptor (AR) antagonist. Conclusion We identified that induction of intrinsic apoptosis in LNCaP cells by 6 μM MCS-C3 is associated not only with p53 activation but also with mediation of AR. In the present study, we identified the cellular functions and underlying molecular mechanisms of p53-dependent and AR-associated p21(CIP1) on apoptotic induction via direct binding to BCL2 in LNCaP cells treated with 6 μM MCS-C3.

p21CIP1 Induces Apoptosis via Binding to BCL2 in LNCaP Prostate Cancer Cells Treated with MCS-C3, A Novel Carbocyclic Analog of Pyrrolopyrimidine.

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High Glucose Condition Induces Autophagy in Endothelial Progenitor Cells Contributing to Angiogenic Impairment

Effects of a novel carbocyclic analog of pyrrolo[2,3-d]pyrimidine nucleoside on pleiotropic induction of cell death in prostate cancer cells with different androgen responsiveness.

HY251, a novel decahydrocyclopenta[a]indene analog, induces apoptosis via tBid-mediated intrinsic pathway in human ovarian cancer PA-1 cells.

p21CIP1 Induces Apoptosis via Binding to BCL2 in LNCaP Prostate Cancer Cells Treated with MCS-C3, A Novel Carbocyclic Analog of Pyrrolopyrimidine.