LncRNAs associated with oxidative stress in diabetic wound healing: Regulatory mechanisms and application prospects.

Diabetes is a group of chronic diseases with blood glucose imbalance, and long-term hyperglycaemia causes sustained damage to various organs of the body, resulting in vascular lesions, neuropathy and impaired wound healing. Diabetic wound formation involves a variety of complex mechanisms, and they are characterized by a persistent chronic inflammatory response, degradation of angiogenesis and imbalance of extracellular matrix regulation, all of which are related to oxidative stress. Additionally, repair and healing of diabetic wounds require the participation of a variety of cells, cytokines, genes, and other factors, which together constitute a complex biological regulatory network. Recent studies have shown that long noncoding RNAs (lncRNAs) can be involved in the regulation of several key biological pathways and cellular functions demonstrating their critical role in diabetic wound healing. LncRNAs are a major family of RNAs with limited or no protein-coding function. Numerous studies have recently reported a strong link between oxidative stress and lncRNAs. Given that both lncRNAs and oxidative stress have been identified as potential drivers of diabetic wound healing, their link in diabetic wound healing can be inferred. However, the specific mechanism of oxidative stress related to lncRNAs in diabetic wound healing is still unclear, and elucidating the functions of lncRNAs in these processes remains a major challenge. This article reviews the mechanisms of lncRNAs related to oxidative stress in several stages of diabetic wound healing and discusses diagnostic and treatment potential of lncRNAs to treat diabetic wounds by improving oxidative stress, as well as the challenges of using lncRNAs for this purpose. It is hoped that these results will provide new targets and strategies for the diagnosis and treatment of impaired wound healing in diabetic patients.

Interactions between PCSK9 and NLRP3 inflammasome signaling in atherosclerosis.

Atherosclerosis is an early pathological basis of numerous cardiovascular events that result in death or disability. Recent studies have described PCSK9 as a novel target for the treatment of atherosclerosis; PCSK9 is capable of degrading LDLR on the surface of hepatocytes through the regulation of lipid metabolism, and it can function as a novel inflammatory modulator in atherosclerosis. Inflammasomes are important intracellular multiprotein complexes that promote the inflammatory response in atherosclerosis. Among inflammasomes, the NLRP3 inflammasome is particularly notable because of its important role in the development of atherosclerotic disease. After activation, NLRP3 forms a complex with ASC and pro-caspase-1, converting pro-caspase-1 into activated caspase-1, which may trigger the release of IL-1ß and IL-18 and contribute to the inflammatory response. Several recent studies have indicated that there may be interactions between PCSK9 and the NLRP3 inflammasome, which may contribute to the inflammatory response that drives atherosclerosis development and progression. On the one hand, the NLRP3 inflammasome plays an important role via IL-1ß in regulating PCSK9 secretion. On the other hand, PCSK9 regulates caspase-1-dependent pyroptosis by initiating mtDNA damage and activating NLRP3 inflammasome signaling. This paper reviews the mechanisms underlying PCSK9 and NLRP3 inflammasome activation in the context of atherosclerosis. Furthermore, we describe the current understanding of the specific molecular mechanism underlying the interactions between PCSK9 and NLRP3 inflammasome signaling as well as the drug repositioning events that influence vascular cells and exert beneficial antiatherosclerotic effects. This review may provide a new therapeutic direction for the effective prevention and treatment of atherosclerosis in the clinic.

The role of MicroRNA networks in tissue-specific direct and indirect effects of metformin and its application.

Metformin is a first-line oral antidiabetic agent that results in clear benefits in relation to glucose metabolism and diabetes-related complications. The specific regulatory details and mechanisms underlying these benefits are still unclear and require further investigation. There is recent mounting evidence that metformin has pleiotropic effects on the target tissue development in metabolic organs, including adipose tissue, the gastrointestinal tract and the liver. The mechanism of actions of metformin are divided into direct effects on target tissues and indirect effects via non-targeted tissues. MicroRNAs (miRNAs) are a class of endogenous, noncoding, negative gene regulators that have emerged as important regulators of a number of diseases, including type 2 diabetes mellitus (T2DM). Metformin is involved in many aspects of miRNA regulation, and metformin treatment in T2DM should be associated with other miRNA targets. A large number of miRNAs regulation by metformin in target tissues with either direct or indirect effects has gradually been revealed in the context of numerous diseases and has gradually received increasing attention. This paper thoroughly reviews the current knowledge about the role of miRNA networks in the tissue-specific direct and indirect effects of metformin. Furthermore, this knowledge provides a novel theoretical basis and suggests therapeutic targets for the clinical treatment of metformin and miRNA regulators in the prevention and treatment of cancer, cardiovascular disorders, diabetes and its complications.

Metformin prevents methylglyoxal-induced apoptosis by suppressing oxidative stress in vitro and in vivo.

Methylglyoxal (MGO) is an active metabolite of glucose and plays a prominent role in the pathogenesis of diabetic vascular complications, including endothelial cell apoptosis induced by oxidative stress. Metformin (MET), a widely prescribed antidiabetic agent, appears to reduce excessive reactive oxygen species (ROS) generation and limit cell apoptosis. However, the molecular mechanisms underlying this process are still not fully elucidated. We reported here that MET prevents MGO-induced apoptosis by suppressing oxidative stress in vitro and in vivo. Protein expression and protein phosphorylation were investigated using western blotting, ELISA, and immunohistochemical staining, respectively. Cell viability and apoptosis were assessed by the MTT assay, TUNEL staining, and Annexin V-FITC and propidium iodide double staining. ROS generation and mitochondrial membrane potential (MMP) were measured with fluorescent probes. Our results revealed that MET prevented MGO-induced HUVEC apoptosis, inhibited apoptosis-associated biochemical changes such as loss of MMP, the elevation of the Bax/Bcl-2 ratio, and activation of cleaved caspase-3, and attenuated MGO-induced mitochondrial morphological alterations in a dose-dependent manner. MET pretreatment also significantly suppressed MGO-stimulated ROS production, increased signaling through the ROS-mediated PI3K/Akt and Nrf2/HO-1 pathways, and markedly elevated the levels of its downstream antioxidants. Finally, similar results were obtained in vivo, and we demonstrated that MET prevented MGO-induced oxidative damage, apoptosis, and inflammation. As expected, MET reversed MGO-induced downregulation of Nrf2 and p-Akt. In addition, a PI3K inhibitor (LY-294002) and a Nrf2 inhibitor (ML385) observably attenuated the protective effects of MET on MGO-induced apoptosis and ROS generation by inhibiting the Nrf2/HO-1 pathways, while a ROS scavenger (NAC) and a permeability transition pores inhibitor (CsA) completely reversed these effects. Collectively, these findings broaden our understanding of the mechanism by which MET regulates apoptosis induced by MGO under oxidative stress conditions, with important implications regarding the potential application of MET for the treatment of diabetic vascular complications.

Long Noncoding RNAs as Emerging Regulators of COVID-19.

Coronavirus disease 2019 (COVID-19), which has high incidence rates with rapid rate of transmission, is a pandemic that spread across the world, resulting in more than 3,000,000 deaths globally. Currently, several drugs have been used for the clinical treatment of COVID-19, such as antivirals (radecivir, baritinib), monoclonal antibodies (tocilizumab), and glucocorticoids (dexamethasone). Accumulating evidence indicates that long noncoding RNAs (lncRNAs) are essential regulators of virus infections and antiviral immune responses including biological processes that are involved in the regulation of COVID-19 and subsequent disease states. Upon viral infections, cellular lncRNAs directly regulate viral genes and influence viral replication and pathology through virus-mediated changes in the host transcriptome. Additionally, several host lncRNAs could help the occurrence of viral immune escape by inhibiting type I interferons (IFN-1), while others could up-regulate IFN-1 production to play an antiviral role. Consequently, understanding the expression and function of lncRNAs during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection will provide insights into the development of lncRNA-based methods. In this review, we summarized the current findings of lncRNAs in the regulation of the strong inflammatory response, immune dysfunction and thrombosis induced by SARS-CoV-2 infection, discussed the underlying mechanisms, and highlighted the therapeutic challenges of COVID-19 treatment and its future research directions.