Ischemia/reperfusion injury (IRI) permeates a variety of diseases and is a ubiquitous concern in every transplantation proceeding, from whole organs to modest grafts. Given its significance, efforts to evade the damaging effects of both ischemia and reperfusion are abundant in the literature and they consist of several strategies, such as applying pre-ischemic conditioning protocols, improving protection from preservation solutions, thus providing extended cold ischemia time and so on. In this review, we describe many of the latest pharmacological approaches that have been proven effective against IRI, while also revisiting well-established concepts and presenting recent pathophysiological findings in this ever-expanding field. A plethora of promising protocols has emerged in the last few years. They have been showing exciting results regarding protection against IRI by employing drugs that engage several strategies, such as modulating cell-surviving pathways, evading oxidative damage, physically protecting cell membrane integrity, and enhancing cell energetics.

https://www.mdpi.com/1422-0067/20/20/5034/pdf

Ischemia/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies.

Chlorogenic acids (CGAs), a group of hydroxycinnamates, are generally abundant in everyday foods and beverages, most prominently in certain coffee drinks. Among them, the chlorogenic acid (CGA), also termed as 5-O-caffeoylquinic acid (5-CQA), is one of the most abundant, highly functional polyphenolic compounds in the human diet. The evidence of its health benefits obtained from clinical studies, as well as basic research, indicates an inverse correlation between 5-CQA consumption and a lower risk of metabolic syndromes and chronic diseases. This review focuses on the beneficial properties for health and mechanisms of action of 5-CQA, starting with its history, isomers, dietary sources, processing effects, preparation methods, pharmacological safety evaluation, and bioavailability. It also provides the possible molecular mechanistic bases to explain the health beneficial effects of 5-CQA including neuroprotective, cardiovascular protective, gastrointestinal protective, renoprotective, hepatoprotective, glucose and lipid metabolism regulatory, and anticarcinogenic effects. The information summarized here could aid in the basic and clinical research on 5-CQA as a natural dietary additive, potential drug candidate, as well as a natural health promoter.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/1541-4337.12620

Chlorogenic acid: A comprehensive review of the dietary sources, processing effects, bioavailability, beneficial properties, mechanisms of action, and future directions.

Ischemic stroke caused by arterial occlusion is the most common type of stroke, which is among the most frequent causes of disability and death worldwide. Current treatment approaches involve achieving rapid reperfusion either pharmacologically or surgically, both of which are time-sensitive; moreover, blood flow recanalization often causes ischemia/reperfusion injury. However, even though neuroprotective intervention is urgently needed in the event of stroke, the exact mechanisms of neuronal death during ischemic stroke are still unclear, and consequently, the capacity for drug development has remained limited. Multiple cell death pathways are implicated in the pathogenesis of ischemic stroke. Here, we have reviewed these potential neuronal death pathways, including intrinsic and extrinsic apoptosis, necroptosis, autophagy, ferroptosis, parthanatos, phagoptosis, and pyroptosis. We have also reviewed the latest results of pharmacological studies on ischemic stroke and summarized emerging drug targets with a focus on clinical trials. These observations may help to further understand the pathological events in ischemic stroke and bridge the gap between basic and translational research to reveal novel neuroprotective interventions.

Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications.

Diabetes affects a large population of the world. Lifestyle, obesity, dietary habits, and genetic factors contribute to this metabolic disease. A target pathway to control diabetes is the 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. AMPK is a heterotrimeric protein with α, β, and γ subunits. In several studies, AMPK activation enhanced glucose uptake into cells and inhibited intracellular glucose production. Impairment of AMPK activity is present in diabetes, according to some studies. Drugs used in the treatment of diabetes, such as metformin, are also known to act through regulation of AMPK. Thus, drugs that activate and regulate AMPK are potential candidates for the treatment of diabetes. In addition, many patients encounter important adverse effects, like hypoglycemia, while using allopathic drugs. As a result, the investigation of plant-derived natural drugs that lack adverse side effects and treat diabetes is necessary. Natural products like berberine, quercetin, resveratrol, and so forth have shown significant potential in regulating and activating the AMPK pathway which can lead to manage diabetes mellitus and its complications.

Targeting AMPK signaling pathway by natural products for treatment of diabetes mellitus and its complications.

Atherosclerosis is the main pathological basis of ischemic cardiovascular and cerebrovascular diseases and has attracted more attention in recent years. Multiple studies have demonstrated that the signal transducer and activator of transcription 3 (STAT3) plays essential roles in the process of atherosclerosis. Moreover, aberrant STAT3 activation has been shown to contribute to the occurrence and development of atherosclerosis. Therefore, the study of STAT3 inhibitors has gradually become a focal research topic. In this review, we describe the crucial roles of STAT3 in endothelial cell dysfunction, macrophage polarization, inflammation, and immunity during atherosclerosis. STAT3 in mitochondria is mentioned as well. Then, we present a summary and classification of STAT3 inhibitors, which could offer potential treatment strategies for atherosclerosis. Furthermore, we enumerate some of the problems that have interfered with the development of mature therapies utilizing STAT3 inhibitors to treat atherosclerosis. Finally, we propose ideas that may help to solve these problems to some extent. Collectively, this review may be useful for developing future STAT3 inhibitor therapies for atherosclerosis.

Targeted inhibition of STAT3 as a potential treatment strategy for atherosclerosis.

5'-AMP-activated protein kinase (AMPK), a member of the serine/threonine (Ser/Thr) kinase group, is universally distributed in various cells and organs. It is a significant endogenous defensive molecule that responds to harmful stimuli, such as cerebral ischemia, cerebral hemorrhage, and, neurodegenerative diseases (NDD). Cerebral ischemia, which results from insufficient blood flow or the blockage of blood vessels, is a major cause of ischemic stroke. Ischemic stroke has received increased attention due to its '3H' effects, namely high mortality, high morbidity, and high disability. Numerous studies have revealed that activation of AMPK plays a protective role in the brain, whereas its action in ischemic stroke remains elusive and poorly understood. Based on existing evidence, we introduce the basic structure, upstream regulators, and biological roles of AMPK. Second, we analyze the relationship between AMPK and the neurovascular unit (NVU). Third, the actions of AMPK in different phases of ischemia and current therapeutic methods are discussed. Finally, we evaluate existing controversy and provide a detailed analysis, followed by ethical issues, potential directions, and further prospects of AMPK. The information complied here may aid in clinical and basic research of AMPK, which may be a potent drug candidate for ischemic stroke treatment in the future.

AMPK: Potential Therapeutic Target for Ischemic Stroke.

AMP-activated protein kinase sparks the fire of cardioprotection against myocardial ischemia and cardiac ageing

Inflammation is an important innate immune response to infection or tissue damage. Inflammasomes are involved in the onset and development of inflammation. The NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome is the best-characterized inflammasome. Recent evidence has indicated the importance of the NLRP3 inflammasome in the pathophysiology of cardiovascular disorders. To further understand the roles of the NLRP3 inflammasome in the cardiovascular system, we provide a comprehensive overview and discuss the remaining questions. First, a summary of NLRP3 inflammasome in the cardiovascular system is introduced. Then, the associations between NLRP3 inflammasome and cardiovascular disorders are presented. Finally, we discuss existing problems and potential directions with this issue. The information compiled here summarizes recent progress, thus potentially aiding in the understanding of the NLRP3 inflammasome in cardiovascular disorders, designing experimental and clinical research about the NLRP3 inflammasome, and promoting therapeutics for cardiovascular disorders.

Chunhu Gu

Papers

AMPK: Potential Therapeutic Target for Ischemic Stroke.

AMP-activated protein kinase sparks the fire of cardioprotection against myocardial ischemia and cardiac ageing

Targeting NLRP3 (Nucleotide-Binding Domain, Leucine-Rich-Containing Family, Pyrin Domain-Containing-3) Inflammasome in Cardiovascular Disorders.