Cellular senescence, a state of irreversible growth arrest triggered by various stressors, engages in a category of pathological processes, whereby senescent cells accumulate in mitotic tissues. Senolytics as novel medicine against aging and various diseases through the elimination of senescent cells has emerged rapidly in recent years. Exercise is a potent anti‐aging and anti‐chronic disease medicine, which has shown the capacity to lower the markers of cellular senescence over the past decade. However, whether exercise is a senolytic medicine for aging and various diseases remains unclear. Here, we have conducted a systematic review of the published literature studying the senolytic effects of exercise or physical activity on senescent cells under various states in both human and animal models. Exercise can reduce the markers of senescent cells in healthy humans, while it lowered the markers of senescent cells in obese but not healthy animals. The discrepancy between human and animal studies may be due to the relatively small volume of research and the variations in markers of senescent cells, types of cells/tissues, and health conditions. These findings suggest that exercise has senolytic properties under certain conditions, which warrant further investigations.
Metformin is one of the most widely used drugs for type 2 diabetes and it also exhibits cardiovascular protective activity. However, the underlying mechanism of its action is not well understood. Here, we used an adult zebrafish model of heart cryoinjury, which mimics myocardial infarction in humans, and demonstrated that autophagy was significantly induced in the injured area. Through a systematic evaluation of the multiple cell types related to cardiac regeneration, we found that metformin enhanced the autophagic flux and improved epicardial, endocardial and vascular endothelial regeneration, accelerated transient collagen deposition and resolution, and induced cardiomyocyte proliferation. Whereas, when the autophagic flux was blocked, then all these processes were delayed. We also showed that metformin transiently enhanced the systolic function of the heart. Taken together, our results indicate that autophagy is positively involved in the metformin-induced acceleration of heart regeneration in zebrafish and suggest that this well-known diabetic drug has clinical value for the prevention and amelioration of myocardial infarction.
Background - Human heterotaxy is a group of congenital disorders characterized by misplacement of one or more organs according to the left-right axis. The genetic causes of human heterotaxy are highly heterogeneous. Methods - We performed exome sequencing in a cohort of 26 probands with heterotaxy followed by gene burden analysis for the enrichment of novel rare damaging mutations. Transcription activator-like effector nuclease (TALEN) was used to generate somatic loss-of-function mutants in a zebrafish model. Ciliary defects were examined by whole-mount immunostaining of acetylated α-tubulin. Results - We identified a significant enrichment of novel rare damaging mutations in the CC2D1A gene. Seven occurrences of CC2D1A mutations were found to affect four highly conserved amino acid residues of the protein. Functional analyses in the TALEN-mediated zebrafish knock-out models and identified heterotaxy phenotypes of the cardiovascular and gastrointestinal systems in both somatic and germline mutants. Defective cilia were identified by whole-mount immunostaining of acetylated α-tubulin. These abnormalities were rescued by wild-type cc2d1a mRNA, but not cc2d1a mutant mRNA, strongly suggesting a loss-of-function mechanism. On the other hand, over-expression of cc2d1a orthologous mutations cc2d1a P559L and cc2d1a G808V (orthologous to human CC2D1A P532L and CC2D1A G781V) did not affect embryonic development. Conclusions - Using a zebrafish model, we were able to establish a novel association of CC2D1A with heterotaxy and ciliary dysfunction in the F2 generation via a loss-of-function mechanism. Future mechanistic studies are needed for a better understanding of the role of CC2D1A in left-right patterning and ciliary dysfunction.
Background: Infiltration of macrophages into the central nervous system (CNS) is involved in many neurological disorders, such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and autism. Despite extensive studies into neuroinflammation associated macrophage infiltration into the CNS, its underlying mechanisms and pathological roles remain unclear, especially when triggered by peripheral inflammation. Methods: To further elucidate the role and mechanism of peripheral inflammation in neurological disorders, we exploited interleukin 1 beta (il1b) mutant transgenic zebrafish (Danio rerio) with fluorescent protein expression restricted to macrophages to track the macrophage migration under peripheral inflammation following tail amputation.Results: We found that macrophage infiltration into the brain of zebrafish embryo following peripheral tissue injury can be alleviated via genetically targeting il1b. In addition, through circulation-independent migration, macrophages infiltrate brains with evidence of increased apoptosis. We further identified the expression of camk2g1 in the brains of zebrafish with hyperactive behavior following peripheral tissue injury. This il1b-regulated protein is associated with neuropsychiatry disorders. Conclusion: These findings demonstrated that peripheral tissue injury induces il1b-mediated macrophage infiltration into the brain and a hyperactive behavior.
Autophagy is a dynamic process that regulates the selective and nonselective degradation of cytoplasmic components, such as damaged organelles and protein aggregates inside lysosomes to maintain tissue homeostasis. Different types of autophagy including macroautophagy, microautophagy, and chaperon-mediated autophagy (CMA) have been implicated in a variety of pathological conditions, such as cancer, aging, neurodegeneration, and developmental disorders. Furthermore, the molecular mechanism and biological functions of autophagy have been extensively studied in vertebrate hematopoiesis and human blood malignancies. In recent years, the hematopoietic lineage-specific roles of different autophagy-related (ATG) genes have gained more attention. The evolution of gene-editing technology and the easy access nature of hematopoietic stem cells (HSCs), hematopoietic progenitors, and precursor cells have facilitated the autophagy research to better understand how ATG genes function in the hematopoietic system. Taking advantage of the gene-editing platform, this review has summarized the roles of different ATGs at the hematopoietic cell level, their dysregulation, and pathological consequences throughout hematopoiesis.
Objective: Doxycycline hyclate is a broad spectrum antibiotic with activity against a wide range of gram-positive and gram-negative bacteria and it is widely used as a pharmacological agent. A simple, selective, linear, precise and accurate ultraviolet detection (UV) method has been developed and applied for the determination of doxycycline hyclate in different pharmaceutical samples. Methods: Acid-base analysis and titrimetric method were utilized to determine the value of pH and moisture content of purchased pharmaceutical samples. A mixture of methanol and hydrochloric acid (0.01N Methanolic HCl) was used to determine the biochemical properties of doxycycline hyclate. UV detector set at 349 nm was used to monitor the effluent. The purified water was used as solvent. Results: In 1% aqueous solution of doxycycline, three samples (4th, 5th and 7th) showed lower pH values of 1.97, 1.98, and 1.99 respectively. Furthermore, the same samples indicated the additional moisture contents of 2.81%, 2.85% and 2.83% respectively while considering the acceptance level (1.4% to 2.8%). The method proved to be linear (R2=0.993), precise (RSD=0.79% for inter-day precision), accurate (Recovery=100.59%) and selective regarding possible impurities and excipients of the samples. The doxycycline content obtained in the sample analysis was within the range of 84.05% to 85.80%. Conclusion: The optimized and validated method may be successfully employed to perform routine quality control analyses. Investigation of the pH, moisture content and potency of doxycycline hyclate in different samples give a general view of local pharmacies trade and ensure that the method applied here was validated for this kind of analysis.
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