Therapeutic implication of targeting mitochondrial drugs designed for efferocytosis dysfunction.

Efferocytosis refers to the process by which phagocytes remove apoptotic cells and related apoptotic products. It is essential for the growth and development of the body, the repair of damaged or inflamed tissues, and the balance of the immune system. Damaged efferocytosis will cause a variety of chronic inflammation and immune system diseases. Many studies show that efferocytosis is a process mediated by mitochondria. Mitochondrial metabolism, mitochondrial dynamics, and communication between mitochondria and other organelles can all affect phagocytes' clearance of apoptotic cells. Therefore, targeting mitochondria to modulate phagocyte efferocytosis is an anticipated strategy to prevent and treat chronic inflammatory diseases and autoimmune diseases. In this review, we introduced the mechanism of efferocytosis and the pivoted role of mitochondria in efferocytosis. In addition, we focused on the therapeutic implication of drugs targeting mitochondria in diseases related to efferocytosis dysfunction.

Mitochondria-Associated Organelle Crosstalk in Myocardial Ischemia/Reperfusion Injury.

Organelle damage is a significant contributor to myocardial ischemia/reperfusion (I/R) injury. This damage often leads to disruption of endoplasmic reticulum protein regulatory programs and dysfunction of mitochondrial energy metabolism. Mitochondria and endoplasmic reticulum are seamlessly connected through the mitochondrial-associated endoplasmic reticulum membrane (MAM), which serves as a crucial site for the exchange of organelles and metabolites. However, there is a lack of reports regarding the communication of information and metabolites between mitochondria and related organelles, which is a crucial factor in triggering myocardial I/R damage. To address this research gap, this review described the role of crosstalk between mitochondria and the correlative organelles such as endoplasmic reticulum, lysosomal and nuclei involved in reperfusion injury of the heart. In summary, this review aims to provide a comprehensive understanding of the crosstalk between organelles in myocardial I/R injury, with the ultimate goal of facilitating the development of targeted therapies based on this knowledge.

Cell death in atherosclerosis.

A complex and evolutionary process that involves the buildup of lipids in the arterial wall and the invasion of inflammatory cells results in atherosclerosis. Cell death is a fundamental biological process that is essential to the growth and dynamic equilibrium of all living things. Serious cell damage can cause a number of metabolic processes to stop, cell structure to be destroyed, or other irreversible changes that result in cell death. It is important to note that studies have shown that the two types of programmed cell death, apoptosis and autophagy, influence the onset and progression of atherosclerosis by controlling these cells. This could serve as a foundation for the creation of fresh atherosclerosis prevention and treatment strategies. Therefore, in this review, we summarized the molecular mechanisms of cell death, including apoptosis, pyroptosis, autophagy, necroptosis, ferroptosis and necrosis, and discussed their effects on endothelial cells, vascular smooth muscle cells and macrophages in the process of atherosclerosis, so as to provide reference for the next step to reveal the mechanism of atherosclerosis.

Turmeric-Derived Nanoparticles Functionalized Aerogel Regulates Multicellular Networks to Promote Diabetic Wound Healing.

Regulation of excessive inflammation and impaired cell proliferation is crucial for healing diabetic wounds. Although plant-to-mammalian regulation offers effective approaches for chronic wound management, the development of a potent plant-based therapeutic presents challenges. This study aims to validate the efficacy of turmeric-derived nanoparticles (TDNPs) loaded with natural bioactive compounds. TDNPs can alleviate oxidative stress, promote fibroblast proliferation and migration, and reprogram macrophage polarization. Restoration of the fibroblast-macrophage communication network by TDNPs stimulates cellular regeneration, in turn enhancing diabetic wound healing. To address diabetic wound management, TDNPs are loaded in an ultralight-weight, high swelling ratio, breathable aerogel (AG) constructed with cellulose nanofibers and sodium alginate backbones to obtain TDNPs@AG (TAG). TAG features wound shape-customized accessibility, water-adaptable tissue adhesiveness, and capacity for sustained release of TDNPs, exhibiting outstanding performance in facilitating in vivo diabetic wound healing. This study highlights the potential of TDNPs in regenerative medicine and their applicability as a promising solution for wound healing in clinical settings.

Insight into modulators of sphingosine-1-phosphate receptor and implications for cardiovascular therapeutics.

Cardiovascular disease is the leading cause of death worldwide, and it's of great importance to understand its underlying mechanisms and find new treatments. Sphingosine 1-phosphate (S1P) is an active lipid that exerts its effects through S1P receptors on the cell surface or intracellular signal, and regulates many cellular processes such as cell growth, cell proliferation, cell migration, cell survival, and so on. S1PR modulators are a class of modulators that can interact with S1PR subtypes to activate receptors or block their activity, exerting either agonist or functional antagonist effects. Many studies have shown that S1P plays a protective role in the cardiovascular system and regulates cardiac physiological functions mainly through interaction with cell surface S1P receptors (S1PRs). Therefore, S1PR modulators may play a therapeutic role in cardiovascular diseases. Here, we review five S1PRs and their functions and the progress of S1PR modulators. In addition, we focus on the effects of S1PR modulators on atherosclerosis, myocardial infarction, myocardial ischaemia/reperfusion injury, diabetic cardiovascular diseases, and myocarditis, which may provide valuable insights into potential therapeutic strategies for cardiovascular disease.

T7 expression plasmids for producing a recombinant human G1P[8] rotavirus comprising RIX4414 sequences of the RV1 (Rotarix , GSK) vaccine strain.

The live oral rotavirus RV1 (Rotarix) vaccine is formulated from the human G1P[8] RIX4414 virus. Based on RIX4414 sequences, T7 expression plasmids were constructed that supported recovery of recombinant RIX4414-like viruses by reverse genetics. These plasmids will advance the study of the RV1 vaccine, possibly allowing improvements to its efficacy.

NIR-II Responsive Nanohybrids Incorporating Thermosensitive Hydrogel as Sprayable Dressing for Multidrug-Resistant-Bacteria Infected Wound Management.

Developing an effective dressing against bacterial infection and synchronously addressing wound complications, such as bleeding, long-term inflammation, and reinfection, are highly desirable in clinical practice. In this work, a second near-infrared (NIR-II) responsive nanohybrid consisting of imipenem encapsulated liposome with gold-shell and lipopolysaccharide (LPS)-targeting aptamer, namely ILGA, is constructed for bacteria elimination. Benefiting from the delicate structure, ILGA exhibits strong affinity and a reliable photothermal/antibiotic therapeutic effect toward multidrug-resistant Pseudomonas aeruginosa (MDR-PA). Furthermore, by incorporating ILGA with a thermosensitive hydrogel poly(lactic-co-glycolic acid)-polyethylene glycol-poly(lactic-co-glycolic acid) (PLGA-PEG-PLGA), a sprayable dressing ILGA@Gel was prepared, which enables a quick on-demand gelation (10 s) for wound hemostasis and offers excellent photothermal/antibiotic efficacy to sterilize the infected wound. Additionally, ILGA@Gel provides satisfactory wound-healing environments by reeducating wound-associated macrophages for inflammation alleviation and forming a gel layer to block exogenous bacterial reinfection. This biomimetic hydrogel reveals excellent bacteria eradication and wound recovery effectiveness, demonstrating its promising potential for managing complicated infected wounds.

[Retracted] Oxidized­low density lipoprotein accumulates cholesterol esters via the PKCα­adipophilin­ACAT1 pathway in RAW264.7 cells.

Following the publication of the above paper, a concerned reader drew to the Editor's attention that the "con" and "ox­LDL" panels in Fig. 1E on p. 3602, and various data panels included in Figs. 3 and 5 on p. 3604, contained apparent anomalies, including what appeared to be matching patternings of cellular data either within the same figure panels or comparing among the data panels. After having conducted an independent investigation in the Editorial Office, the Editor of Molecular Medicine Reports has determined that the above paper should be retracted from the Journal on account of a lack of confidence in the overall authenticity of the data. After having consulted the authors in this regard, they agreed with the decision to retract this paper. The Editor deeply regrets any inconvenience that has been caused to the readership of the Journal. [Molecular Medicine Reports 12: 3599­3606, 2015; DOI: 10.3892/mmr.2015.3864.

Rotavirus NSP1 Subverts the Antiviral Oligoadenylate Synthetase-RNase L Pathway by Inducing RNase L Degradation.

The interferon (IFN)-inducible 2',5'-oligoadenylate synthetase (OAS)-RNase L pathway plays a critical role in antiviral immunity. Group A rotaviruses, including the simian SA11 strain, inhibit this pathway through two activities: an E3-ligase related activity of NSP1 that degrades proteins necessary for IFN signaling, and a phosphodiesterase (PDE) activity of VP3 that hydrolyzes the RNase L-activator 2',5'-oligoadenylate. Unexpectedly, we found that a recombinant (r) SA11 double mutant virus deficient in both activities (rSA11-VP3H797R-NSP1ΔC17) retained the ability to prevent RNase L activation. Mass spectrometry led to the discovery that NSP1 interacts with RNase L in rSA11-infected HT29 cells. This interaction was confirmed through copulldown assay of cells transiently expressing NSP1 and RNase L. Immunoblot analysis showed that infection with wild-type rSA11 virus, rSA11-VP3H797R-NSP1ΔC17 double mutant virus, or single mutant forms of the latter virus all resulted in the depletion of endogenous RNase L. The loss of RNase L was reversed by addition of the neddylation inhibitor MLN4924, but not the proteasome inhibitor MG132. Analysis of additional mutant forms of rSA11 showed that RNase L degradation no longer occurred when either the N-terminal RING domain of NSP1 was mutated or the C-terminal 98 amino acids of NSP1 were deleted. The C-terminal RNase L degradation domain is positioned upstream and is functionally independent of the NSP1 domain necessary for inhibiting IFN expression. Our studies reveal a new role for NSP1 and its E3-ligase related activity as an antagonist of RNase L and uncover a novel virus-mediated strategy of inhibiting the OAS-RNase L pathway. IMPORTANCE For productive infection, rotavirus and other RNA viruses must suppress interferon (IFN) signaling and the expression of IFN-stimulated antiviral gene products. Particularly important is inhibiting the interferon (IFN)-inducible 2',5'-oligoadenylate synthetase (OAS)-RNase L pathway, as activated RNase L can direct the nonspecific degradation of viral and cellular RNAs, thereby blocking viral replication and triggering cell death pathways. In this study, we have discovered that the simian SA11 strain of rotavirus employs a novel strategy of inhibiting the OAS-RNase L pathway. This strategy is mediated by SA11 NSP1, a nonstructural protein that hijacks E3 cullin-RING ligases, causing the ubiquitination and degradation of host proteins essential for IFN induction. Our analysis shows that SA11 NSP1 also recognizes and causes the ubiquitination of RNase L, an activity resulting in depletion of endogenous RNase L. These data raise the possibility of using therapeutics targeting cellular E3 ligases to control rotavirus infections.

Targeted Mitochondrial Drugs for Treatment of Ischemia-Reperfusion Injury.

Ischemia-reperfusion injury is a complex hemodynamic pathology that is a leading cause of death worldwide and occurs in many body organs. Numerous studies have shown that mitochondria play an important role in the occurrence mechanism of ischemia-reperfusion injury and that mitochondrial structural abnormalities and dysfunction lead to the disruption of the homeostasis of the whole mitochondria. At this time, mitochondria are not just sub-organelles to produce ATP but also important targets for regulating ischemia-reperfusion injury; therefore, drugs targeting mitochondria can serve as a new strategy to treat ischemia-reperfusion injury. Based on this view, in this review, we discuss potential therapeutic agents for both mitochondrial structural abnormalities and mitochondrial dysfunction, highlighting the application and prospects of targeted mitochondrial drugs in the treatment of ischemia-reperfusion injury, and try to provide new ideas for the clinical treatment of the ischemia-reperfusion injury.

Therapeutic implications of targeting pyroptosis in Cardiac-related etiology of heart failure.

Heart failure remains a considerable clinical and public health problem, it is the dominant cause of death from cardiovascular diseases, besides, cardiovascular diseases are one of the leading causes of death worldwide. The survival of patients with heart failure continues to be low with 45-60% reported deaths within five years. Apoptosis, necrosis, autophagy, and pyroptosis mediate cardiac cell death. Acute cell death is the hallmark pathogenesis of heart failure and other cardiac pathologies. Inhibition of pyroptosis, autophagy, apoptosis, or necrosis reduces cardiac damage and improves cardiac function in cardiovascular diseases. Pyroptosis is a form of inflammatory deliberate cell death that is characterized by the activation of inflammasomes such as NOD-like receptors (NLR), absent in melanoma 2 (AIM2), interferon-inducible protein 16 (IFI-16), and their downstream effector cytokines: Interleukin IL-1ß and IL-18 leading to cell death. Recent studies have shown that pyroptosis is also the dominant cell death process in cardiomyocytes, cardiac fibroblasts, endothelial cells, and immune cells. It plays a crucial role in the pathogenesis of cardiac diseases that contribute to heart failure. This review intends to summarize the therapeutic implications targeting pyroptosis in the main cardiac pathologies preceding heart failure.

Therapeutic Strategies Targeting Mitochondrial Dysfunction in Sepsis-induced Cardiomyopathy.

Sepsis is an increasingly worldwide problem; it is currently regarded as a complex life-threatening dysfunction of one or more organs as a result of dysregulated host immune response to infections. The heart is one of the most affected organs, as roughly 10% to 70% of sepsis cases are estimated to turn into sepsis-induced cardiomyopathy (SIC). SIC can be defined as a reversible myocardial dysfunction characterized by dilated ventricles, impaired contractility, and decreased ejection fraction. Mitochondria play a critical role in the normal functioning of cardiac tissues as the heart is highly dependent on its production of adenosine triphosphate (ATP), its damage during SIC includes morphology impairment, mitophagy, biogenesis disequilibrium, electron transport chain disturbance, molecular damage from the actions of pro-inflammatory cytokines and many other different impairments that are major contributing factors to the severity of SIC. Although mitochondria-targeted therapies usage is still inadequate in clinical settings, the preclinical study outcomes promise that the implementation of these therapies may effectively treat SIC. This review summarizes the different therapeutic strategies targeting mitochondria structure, quality, and quantity abnormalities for the treatment of SIC.

Targeted mitochondrial drugs for treatment of myocardial ischaemia-reperfusion injury.

Myocardial ischaemia-reperfusion injury (MI/RI) refers to the further damage done to ischaemic cardiomyocytes when restoring blood flow. A large body of evidence shows that MI/RI is closely associated with excessive production of mitochondrial reactive oxygen species, mitochondrial calcium overload, disordered mitochondrial energy metabolism, mitophagy, mitochondrial fission, and mitochondrial fusion. According to the way it affects mitochondria, it can be divided into mitochondrial quality abnormalities and mitochondrial quantity abnormalities. Abnormal mitochondrial quality refers to the dysfunction caused by the severe destruction of mitochondria, which then affects the balance of mitochondrial density and number, causing an abnormal mitochondrial quantity. In the past, most of the reports were limited to the study of the mechanism of myocardial ischaemia-reperfusion injury, some of which involved mitochondria, but no specific countermeasures were proposed. In this review, we outline the mechanisms for treating myocardial ischaemia-reperfusion injury from the direction of mitochondria and focus on targeted interventions and drugs to restore mitochondrial health during abnormal mitochondrial quality control and abnormal mitochondrial quantity control. This is an update in the field of myocardial ischaemia-reperfusion injury.

Prevalence of metabolic syndrome among the adult population in western China and the association with socioeconomic and individual factors: four cross-sectional studies.

OBJECTIVES: This study explored the prevalence of and individual influencing factors for metabolic syndrome (MS) as well as associated socioeconomic factors and regional aggregation. DESIGN: Four cross-sectional surveys were analysed for trends in MS and associations with socioeconomic and individual factors through multilevel logistic regression analyses. The risk associated with nutrient intake was also assessed through a dietary survey in 2015. SETTING: From 2010 to 2018, 8-15 counties/districts of West China were included. PARTICIPANTS: A total of 28 274 adults were included in the prevalence analysis. A total of 23 708 adults were used to analyse the related factors. RESULTS: The overall prevalence of MS ranged from 21.4% to 27.8% over the 8 years, remaining basically stable within the 95% CI. Our study found that the urbanisation rate and hospital beds per 1000 people were positively associated with MS, and the number of doctors in healthcare institutions per 1000 persons was negatively associated with MS. The ORs for females, people with college education and higher and unmarried or single people were 1.49, 0.67 and 0.51, respectively (p<0.05). The ORs of people who smoked at least 20 cigarettes/day, ate more than 100 g of red meat/day, consumed fruit or vegetable juice and drank carbonated soft drinks less than weekly were 1.10, 1.16, 1.19-1.27 and 0.81-0.84, respectively. The ORs rose with increasing sedentary time and decreased with higher physical activity. CONCLUSION: The high burden of MS, unreasonable proportions of energy and micronutrient intake and low percentage of high levels of physical activity were the major challenges to public health in western China. Improving the human resources component of medical services, such as the number of doctors, increasing the availability of public sports facilities and E-health tools and improving individual dietary quality and education might help prevent MS.

cGAS-STING signaling in ischemic diseases.

Double stranded DNA (dsDNA) is known to act as a damage-associated molecular pattern (DAMP) that stimulates the body's innate immune response. In general, cyclicGMP-AMP(cGAMP)synthase(cGAS), a DNA sensor, detects these disease-causing DNA and activates the stimulator of interferon gene (STING), which in turn phosphorylates interferon regulatory factor 3 (IRF3), triggering the synthesis of type I interferon (IFN). During this process, the cGAS-STING pathway interacts with different modes of cell death, including autophagy, apoptosis, pyroptosis, and necroptosis. Importantly, cGAS might get stimulated by self-DNA, such as nuclear DNA (nuDNA) and mitochondrial DNA (mtDNA), which ensures a close association between the cGAS-STING signaling pathway and autoimmune responses. Following an ischemic attack, damaged or necrotic cells release large amounts of self-DNA that subsequently activate cGAS, resulting in a range of consequences related to an injury. The present study presents an overview of studies focused on cGAS-STING signaling and cell death, and summarizes the findings of this pathway with regard to ischemia or ischemia/reperfusion (I/R) in different organs of the body, including heart, brain, liver, kidney, and intestine.

Recent insights into atherosclerotic plaque cell autophagy.

Cardiovascular and cerebrovascular diseases, such as coronary heart disease and stroke, caused by atherosclerosis have become the "number one killer", seriously endangering human health in developing and developed countries. Atherosclerosis mainly occurs in large and medium-sized arteries and involves intimal thickening, accumulation of foam cells, and formation of atheromatous plaques. Autophagy is a cellular catabolic process that has evolved to defend cells from the turnover of intracellular molecules. Autophagy is thought to play an important role in the development of plaques. This review focuses on studies on autophagy in cells involved in the formation of atherosclerotic plaques, such as monocytes, macrophages, endothelial cells, dendritic cells, and vascular smooth muscle cells, indicating that autophagy plays an important role in plaque development. We mainly discuss the roles of autophagy in these cells in maintaining the stability of atherosclerotic plaques, providing a reference for the next steps to unravel the mechanisms of atherogenesis.

Sphingosine 1-phosphate and its receptors in ischemia.

Sphingosine 1-phosphate (S1P), a metabolite of sphingolipids, is mainly derived from red blood cells (RBCs), platelets and endothelial cells (ECs). It plays important roles in regulating cell survival, vascular integrity and inflammatory responses through its receptors. S1P receptors (S1PRs), including 5 subtypes (S1PR1-5), are G protein-coupled receptors and have been proved to mediate various and complex roles of S1P in atherosclerosis, myocardial infarction (MI) and ischemic stroke by regulating endothelial function and inflammatory response as well as immune cell behavior. This review emphasizes the functions of S1PRs in atherosclerosis and ischemic diseases such as MI and ischemic stroke, enabling mechanistic studies and new S1PRs targeted therapies in atherosclerosis and ischemia in the future.

Biotherapeutic-loaded injectable hydrogels as a synergistic strategy to support myocardial repair after myocardial infarction.

Myocardial infarction (MI) has been considered as the leading cause of cardiovascular-related deaths worldwide. Although traditional therapeutic agents including various bioactive species such as growth factors, stem cells, and nucleic acids have demonstrated somewhat usefulness for the restoration of cardiac functions, the therapeutic efficiency remains unsatisfactory most likely due to the off-target-associated side effects and low localized retention of the used therapeutic agents in the infarcted myocardium, which constitutes a substantial barrier for the effective treatment of MI. Injectable hydrogels are regarded as a minimally invasive technology that can overcome the clinical and surgical limitations of traditional stenting by a modulated sol-gel transition and localized transport of a variety of encapsulated cargoes, leading to enhanced therapeutic efficiency and improved patient comfort and compliance. However, the design of injectable hydrogels for myocardial repair and the mechanism of action of bioactive substance-loaded hydrogels for MI repair remain unclear. To elucidate these points, we summarized the recent progresses made on the use of injectable hydrogels for encapsulation of various therapeutic substances for MI treatment with an emphasis on the mechanism of action of hydrogel systems for myocardial repair. Specifically, the pathogenesis of MI and the rational design of injectable hydrogels for myocardial repair were presented. Next, the mechanisms of various biotherapeutic substance-loaded injectable hydrogels for myocardial repair was discussed. Finally, the potential challenges and future prospects for the use of injectable hydrogels for MI treatment were proposed for the purpose of drawing theoretical guidance on the development of novel therapeutic strategies for efficient treatment of MI.

Sphingosine-1-phosphate receptor 3 signaling.

Sphingosine-1-phosphate (S1P) is a bioactive lipid which regulates a series of physiological and pathological processes via binding to five S1P receptors (S1PR1-5). Although S1PR1-3 are widely expressed, the study of S1PRs, however, mainly addressed S1PR1 and S1PR2, and few studies focus on S1PR3-5. In recent years, a growing number of studies have shown that S1PR3 plays an important role in cell proliferation, differentiation, apoptosis, and migration, but its function is still controversial. This is the first comprehensive review paper about the role of S1PR3 signaling in cardiovascular function, tissue fibrosis, cancer, immune response, and neurological function. In addition, existing S1PR3 agonists and antagonists are listed at the end of the article, and we also put forward our opinion on the dispute of S1PR3 function.

Circular RNAs in metabolism and metabolic disorders.

Metabolic syndrome (MetS) is a serious health condition triggered by hyperglycemia, dyslipidemia, and abnormal adipose deposition. Recently, circular RNAs (circRNAs) have been proposed as key molecular players in metabolic homeostasis due to their regulatory effects on genes linked to the modulation of multiple aspects of metabolism, including glucose and lipid homeostasis. Dysregulation of circRNAs can lead to metabolic disorders, indicating that circRNAs represent plausible potential targets to alleviate metabolic abnormalities. More recently, a series of circulating circRNAs have been identified to act as both essential regulatory molecules and biomarkers for the progression of metabolism-related disorders, including type 2 diabetes mellitus (T2DM or T2D) and cardiovascular disease (CVD). The findings of this study highlight the function of circRNAs in signaling pathways implicated in metabolic diseases and their potential as future therapeutics and disease biomarkers.