Autophagy and mitophagy as potential therapeutic targets in diabetic heart condition:Harnessing the power of nanotheranostics

Autophagy and mitophagy pose unresolved challenges in understanding the pathology of diabetic heart condition(DHC),which encompasses a complex range of cardiovascular issues linked to diabetes and associated cardiomyopathies.Despite significant progress in reducing mortality rates from cardiovascular diseases(CVDs),heart failure remains a major cause of increased morbidity among diabetic patients.These cellular processes are essential for maintaining cellular balance and removing damaged or dysfunctional components,and their involvement in the development of diabetic heart disease makes them attractive targets for diagnosis and treatment.While a variety of conventional diagnostic and therapeutic strategies are available,DHC continues to present a significant challenge.Point-of-care diagnostics,supported by nanobiosensing techniques,offer a promising alternative for these complex scenarios.Although conventional medications have been widely used in DHC patients,they raise several concerns regarding various physiological aspects.Modern medicine places great emphasis on the application of nanotechnology to target autophagy and mitophagy in DHC,offering a promising approach to deliver drugs beyond the limitations of traditional therapies.This article aims to explore the potential connections between autophagy,mitophagy and DHC,while also discussing the promise of nanotechnology-based theranostic interventions that specifically target these molecular pathways.

Current therapeutic modalities and chemopreventive role of natural products in liver cancer:Progress and promise

Liver cancer is a severe concern for public health officials since the clinical cases are increasing each year,with an estimated 5-year survival rate of 30%–35%after diagnosis.Hepatocellular carcinoma(HCC)constitutes a significant subtype of liver cancer(approximate75%)and is considered primary liver cancer.Treatment for liver cancer mainly depends on the stage of its progression,where surgery including,hepatectomy and liver transplantation,and ablation and radiotherapy are the prime choice.For advanced liver cancer,various drugs and immunotherapy are used as first-line treatment,whereas second-line treatment includes chemotherapeutic drugs from natural and synthetic origins.Sorafenib and lenvatinib are first-line therapies,while regorafenib and ramucirumab are secondline therapy.Various metabolic and signaling pathways such as Notch,JAK/STAT,Hippo,TGF-β,and Wnt have played a critical role during HCC progression.Dysbiosis has also been implicated in liver cancer.Drug-induced toxicity is a key obstacle in the treatment of liver cancer,necessitating the development of effective and safe medications,with natural compounds such as resveratrol,curcumin,diallyl sulfide,and others emerging as promising anticancer agents.This review highlights the current status of liver cancer research,signaling pathways,therapeutic targets,current treatment strategies and the chemopreventive role of various natural products in managing liver cancer.

Insight into the liver dysfunction in COVID-19 patients: Molecular mechanisms and possible therapeutic strategies

As of June 2022,more than 530 million people worldwide have become ill with coronavirus disease 2019(COVID-19).Although COVID-19 is most commonly associated with respiratory distress(severe acute respiratory syndrome),metaanalysis have indicated that liver dysfunction also occurs in patients with severe symptoms.Current studies revealed distinctive patterning in the receptors on the hepatic cells that helps in viral invasion through the expression of angiotensinconverting enzyme receptors.It has also been reported that in some patients with COVID-19,therapeutic strategies,including repurposed drugs(mitifovir,lopinavir/ritonavir,tocilizumab,etc.)triggered liver injury and cholestatic toxicity.Several proven indicators support cytokine storm-induced hepatic damage.Because there are 1.5 billion patients with chronic liver disease worldwide,it becomes imperative to critically evaluate the molecular mechanisms concerning hepatotropism of COVID-19 and identify new potential therapeutics.This review also designated a comprehensive outlook of comorbidities and the impact of lifestyle and genetics in managing patients with COVID-19.

Mechanism and recent updates on insulin-related disorders

Insulin,a small protein with 51 amino acids synthesized by pancreatic β-cells,is crucial to sustain glucose homeostasis at biochemical and molecular levels.Numerous metabolic dysfunctions are related to insulin-mediated altered glucose homeostasis.One of the significant pathophysiological conditions linked to the insulin associated disorder is diabetes mellitus(DM)(type 1,type 2,and gestational).Insulin resistance(IR)is one of the major underlying causes of metabolic disorders despite its association with several physiological conditions.Metabolic syndrome(MS)is another pathophysiological condition that is associated with IR,hypertension,and obesity.Further,several other pathophysiological disorders/diseases are associated with the insulin malfunctioning,which include polycystic ovary syndrome,neuronal disorders,and cancer.Insulinomas are an uncommon type of pancreatic β-cell-derived neuroendocrine tumor that makes up 2% of all pancreatic neoplasms.Literature revealed that different biochemical events,molecular signaling pathways,microRNAs,and microbiota act as connecting links between insulin disorder and associated pathophysiology such as DM,insuloma,neurological disorder,MS,and cancer.In this review,we focus on the insulin-related disorders and the underlying mechanisms associated with the pathophysiology.

Therapeutic potential and pharmacological mechanism of visnagin

Visnagin is a furanochromone and one of the most important compound in the Ammi visnaga(L.)Lam(a synonym of Visnaga daucoides Gaertn.)plant,which is used to cure various ailments.Many investigations into the bioactive properties of visnagin have been studied to date.The literature on visnagin demonstrates its biological properties,including anti-inflammatory,anti-diabetic,and beneficial effects in cardiovascular and renal diseases.Moreover,visnagin improves sperm quality parameters,stimulates steroidogenesis,and increases serum gonadotropins and testosterone levels,while decreasing proinflammatory cytokines,oxidative damage,genomic instability,and it modulates apoptosis.Thus,visnagin has emerged as an exciting lead for further research,owing to its potential in various unmet clinical needs.The current review summarized its basic structure,pharmacokinetics,and pharmacological effects,focusing on its mechanisms of action.The review will help to understand the potential of visnagin as an alternative treatment strategy for several diseases and provide insight into research topics that need further exploration for visnagin’s safe clinical use.

Thr231磷酸化对顺式和反式tau蛋白226-236多肽六聚体结构的影响

目的:研究Thr231磷酸化对于顺-反式tau异构体构象以及聚集行为的影响,探讨可能的在阿尔茨海默病和相关疾病中的毒性关联。方法:采用副本交换分子动力学模拟分析Tau蛋白226-246多肽片段六聚体的相互作用和结构。采用NAMD和CHARMM36分子力场的隐式溶剂化GBIS模型。使用了温度分布从300K到450K的56个模拟副本,每个模拟副本的模拟时间为200 ns,总模拟时间为11200 ns。结果:天然态时Thr231-Pro232是顺式和反式Tau226-236六聚体的相互作用中心,尽管顺式和反式tau多肽六聚体中肽链间有着不同的主链相互作用。反式比顺式tau多肽更易形成主链间氢键,226VAVVR231T部分在顺反式tau中均有4-10%的²结构,而反式tau多肽²结构略多。虽然反式tau蛋白多肽比顺式更为伸展末端距较长,但顺式和反式Tau226-236六聚体具有类似的表面积和回转半径。Thr231磷酸化完全破坏了顺式tau中主链间的氢键和²结构,反式Tau226-236六聚体中主链间的氢键和²结构也随Thr231磷酸化而减少,但影响较小。磷酸化Thr231在顺-反式Tau226-236六聚体中都易与Arg230形成盐桥。Thr231磷酸化促使顺式Tau226-236六聚体中VAVV部分有较大的疏水暴露面积,而这一作用在反式Tau226-236六聚体中较小。结论:Thr231磷酸化对顺式和反式Tau226-236六聚体结构有不同的影响,但是缺乏清晰的局部结构区别。Thr231磷酸化后六聚体中VAVV部分疏水暴露面积的差异和顺反式Tau226-236末端距的明显差别需要在全长Tau蛋白单体和寡聚体中进一步研究。