Uncovering the Therapeutic Potential of Phosphocreatine in Diabetic Retinopathy: Mitigating Mitochondrial Dysfunction and Apoptosis via JAK2/STAT3 Signaling Pathway.

Diabetic retinopathy (DR) stands as a prevalent complication of diabetes mellitus, causing damage to the delicate retinal capillaries and potentially leading to visual impairment. While the exact underlying cause of DR remains elusive, compelling research suggests that mitochondrial energy deficiency and the excessive generation of reactive oxygen species (ROS) play pivotal roles in its pathogenesis. Recognizing that controlling hyperglycemia alone fails to reverse the defects in retinal mitochondria induced by diabetes, current strategies seek to restore mitochondrial function as a means of safeguarding against DR. To address this pressing issue, a comprehensive study was undertaken to explore the potential of phosphocreatine (PCr) in bolstering mitochondrial bioenergetics and providing protection against DR via modulation of the JAK2/STAT3 signaling pathway. Employing rat mitochondria and RGC-5 cells, the investigation meticulously assessed the impact of PCr on ROS production, mitochondrial membrane potential, as well as the expression of crucial apoptotic and JAK2/STAT3 signaling pathway proteins, utilizing cutting-edge techniques such as high-resolution respirometry and western blotting. The remarkable outcomes revealed that PCr exerts a profound protective influence against DR by enhancing mitochondrial function and alleviating diabetes-associated symptoms and biochemical markers. Notably, PCr administration resulted in an upregulation of antiapoptotic proteins, concomitant with a downregulation of proapoptotic proteins and the JAK2/STAT3 signaling pathway. These significant findings firmly establish PCr as a potential therapeutic avenue for combating diabetic retinopathy. By augmenting mitochondrial function and exerting antiapoptotic effects via the JAK2/STAT3 signaling pathway, PCr demonstrates promising efficacy both in vivo and in vitro, particularly in counteracting the oxidative stress engendered by hyperglycemia. In summary, our study sheds light on the potential of PCr as an innovative therapeutic strategy for diabetic retinopathy. By bolstering mitochondrial function and exerting protective effects via the modulation of the JAK2/STAT3 signaling pathway, PCr holds immense promise in ameliorating the impact of DR in the face of oxidative stress induced by hyperglycemia.

Fisetin's Promising Antitumor Effects: Uncovering Mechanisms and Targeting for Future Therapies.

Background Cancer remains a critical global health challenge and a leading cause of mortality. Flavonoids found in fruits and vegetables have gained attention for their potential anti-cancer properties. Fisetin, abundantly present in strawberries, apples, onions, and other plant sources, has emerged as a promising candidate for cancer prevention. Epidemiological studies linking a diet rich in these foods to lower cancer risk have sparked extensive research on fisetin's efficacy. Objective This review aims to comprehensively explore the molecular mechanisms of fisetin's anticancer properties and investigate its potential synergistic effects with other anticancer drugs. Furthermore, the review examines the therapeutic and preventive effects of fisetin against various cancers. Methods A systematic analysis of the available scientific literature was conducted, including research articles, clinical trials, and review papers related to fisetin's anticancer properties. Reputable databases were searched, and selected studies were critically evaluated to extract essential information on fisetin's mechanisms of action and its interactions with other anticancer drugs. Results Preclinical trials have demonstrated that fisetin inhibits cancer cell growth through mechanisms such as cell cycle alteration, induction of apoptosis, and activation of the autophagy signaling pathway. Additionally, fisetin reduces reactive oxygen species levels, contributing to its overall anticancer potential. Investigation of its synergistic effects with other anticancer drugs suggests potential for combination therapies. Conclusion Fisetin, a bioactive flavonoid abundant in fruits and vegetables, exhibits promising anticancer properties through multiple mechanisms of action. Preclinical trials provide a foundation for further exploration in human clinical trials. Understanding fisetin's molecular mechanisms is vital for developing novel, safe, and effective cancer prevention and treatment strategies. The potential synergy with other anticancer drugs opens new avenues for combination therapies, enhancing cancer management approaches and global health outcomes.

Procyanidins: A promising anti-diabetic agent with potential benefits on glucose metabolism and diabetes complications.

Diabetes mellitus (DM) is a complex disease with alarming worldwide health implications and high mortality rates, largely due to its complications such as cardiovascular disease, nephropathy, neuropathy, and retinopathy. Recent research has shown that procyanidins (PC), a type of flavonoid, have strong antioxidant and free radical elimination effects, and may be useful in improving glucose metabolism, enhancing pancreatic islet cell activity, and decreasing the prevalence of DM complications. This review article presents a systematic search for peer-reviewed articles on the use of PC in the treatment of DM, without any language restrictions. The article also discusses the potential for PC to sensitise DM medications and improve their efficacy. Recent in vivo and in vitro studies have demonstrated promising results in improving the biological activity and bioavailability of PC for the treatment of DM. The article concludes by highlighting the potential for novel materials and targeted drug delivery methods to enhance the pharmacokinetics and bioactivity of PC, leading to the creation of safer and more effective anti-DM medications in the future.

Phosphocreatine Improves Cardiac Dysfunction by Normalizing Mitochondrial Respiratory Function through JAK2/STAT3 Signaling Pathway In Vivo and In Vitro.

Diabetic cardiomyopathy (DCM) is one of the common cardiovascular complications in patients with diabetes. Accumulating evidence has demonstrated that DCM is thoroughly related to mitochondrial energy impairment and increases the generation of reactive oxygen species (ROS). Therefore, an ongoing study is developing strategies to protect cardiac mitochondria from diabetic complications, especially from hyperglycemia. Phosphocreatine (PCr) plays a major metabolic role in cardiac muscular cells including intracellular concentration of ATP which affects the activity of the myocardium. We hypothesized that PCr might improve oxidative phosphorylation and electron transport capacity in mitochondria impaired by hyperglycemia in vivo and in vitro. Also, we aimed to evaluate the protective effect of PCr against DCM through the JAK2/STAT3 signaling pathway. The mitochondrial respiratory capacity from rats and H9C2 cells was measured by high-resolution respirometry (HRR). Expressions of proteins Bax, Bcl-2, caspase 3, caspase 9, cleaved caspase 3, and cleaved caspase 9, as well as JAK2/STAT3 signaling pathways, were determined by western blotting. ROS generation and mitochondrial membrane potential (MMP) were measured with fluorescent probes. Type 1 diabetes mellitus was induced in Wistar male rats by a single intraperitoneal injection of streptozotocin (STZ) (80 mg/kg body weight). Our results revealed that PCr possessed protective effects against DCM injury by improving the mitochondrial bioenergetics and by positively exerting protective effects against DCM in vivo and in vitro, not only improving diabetes symptom, resulting in changes of cardiac tissue using hematoxylin and eosin (H&E) stain, but also ameliorating biochemical changes. Moreover, PCr increased Bcl-2, caspase 3, and caspase 9 protein expressions and decreased Bax, cleaved caspase 3, and cleaved caspase 9 expressions as well as the JAK2/STAT3 signaling pathway. In conclusion, PCr improves mitochondrial functions and exerts an antiapoptotic effect in vivo and in vitro exposed to oxidative stress by hyperglycemia through the JAK2/STAT3 signaling pathway. Our findings suggest that PCr medication is a possible therapeutic strategy for cardioprotection.