Non-alcoholic fatty liver disease and sleep disorders.

Studies have shown that non-alcoholic fatty liver disease (NAFLD) may be associated with sleep disorders. In order to explore the explicit relationship between the two, we systematically reviewed the effects of sleep disorders, especially obstructive sleep apnea (OSA), on the incidence of NAFLD, and analyzed the possible mechanisms after adjusting for confounding factors. NAFLD is independently associated with sleep disorders. Different sleep disorders may be the cause of the onset and aggravation of NAFLD. An excessive or insufficient sleep duration, poor sleep quality, insomnia, sleep-wake disorders, and OSA may increase the incidence of NAFLD. Despite that some research suggests a unidirectional causal link between the two, specifically, the onset of NAFLD is identified as a result of changes in sleep characteristics, and the reverse relationship does not hold true. Nevertheless, there is still a lack of specific research elucidating the reasons behind the higher risk of developing sleep disorders in individuals with NAFLD. Further research is needed to establish a clear relationship between NAFLD and sleep disorders. This will lay the groundwork for earlier identification of potential patients, which is crucial for earlier monitoring, diagnosis, effective prevention, and treatment of NAFLD.

Roles of pyroptosis in atherosclerosis pathogenesis.

Pyroptosis is a pro-inflammatory type of regulated cell death (RCD) characterized by gasdermin protein-mediated membrane pore formation, cell swelling, and rapid lysis. Recent studies have suggested that pyroptosis is closely related to atherosclerosis (AS). Previous studies reported that pyroptosis involving endothelial cells (ECs), macrophages, and smooth muscle cells (SMCs) plays an important role in the formation and development of AS. Pyroptosis not only causes local inflammation but also amplifies the inflammatory response and it aggravates plaque instability, leading to plaque rupture and thrombosis, eventually resulting in acute cardiovascular events. In this review, we clarified some novel pathways and mechanics and presented some potential drugs.

Role of miRNAs in Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by autoimmunity, synovial inflammation and joint destruction. Pannus formation in the synovial cavity can cause irreversible damage to the joint and cartilage and eventually permanent disability. Current conventional treatments for RA have limitations regarding efficacy, safety and cost. microRNA (miRNA) is a type of non-coding RNA (ncRNA) that regulates gene expression at the post-transcriptional level. The dysregulation of miRNA has been observed in RA patients and implicated in the pathogenesis of RA. miRNAs have emerged as potential biomarkers or therapeutic agents. In this review, we explore the role of miRNAs in various aspects of RA pathophysiology, including immune cell imbalance, the proliferation and invasion of fibroblast-like synovial (FLS) cell, the dysregulation of inflammatory signaling and disturbance in angiogenesis. We delve into the regulatory effects of miRNAs on Treg/Th17 and M1/M2 polarization, the activation of the NF-κB/NLRP3 signaling pathway, neovascular formation, energy metabolism induced by FLS-cell-induced energy metabolism, apoptosis, osteogenesis and mobility. These findings shed light on the potential applications of miRNAs as diagnostic or therapeutic biomarkers for RA management. Furthermore, there are some strategies to regulate miRNA expression levels by utilizing miRNA mimics or exosomes and to hinder miRNA activity via competitive endogenous RNA (ceRNA) network-based antagonists. We conclude that miRNAs offer a promising avenue for RA therapy with unlimited potential.

Nitric Oxide Synthases in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe joint damage and disability. However, the specific mechanism of RA has not been thoroughly clarified over the past decade. Nitric oxide (NO), a kind of gas messenger molecule with many molecular targets, is demonstrated to have significant roles in histopathology and homeostasis. Three nitric oxide synthases (NOS) are related to producing NO and regulating the generation of NO. Based on the latest studies, NOS/NO signaling pathways play a key role in the pathogenesis of RA. Overproduction of NO can induce the generation and release of inflammatory cytokines and act as free radical gas to accumulate and trigger oxidative stress, which can involve in the pathogenesis of RA. Therefore, targeting NOS and its upstream and downstream signaling pathways may be an effective approach to managing RA. This review clearly summarizes the NOS/NO signaling pathway, the pathological changes of RA, the involvement of NOS/NO in RA pathogenesis and the conventional and novel drugs based on NOS/NO signaling pathways that are still in clinical trials and have good therapeutic potential in recent years, with an aim to provide a theoretical basis for further exploration of the role of NOS/NO in the pathogenesis, prevention and treatment of RA.

Pharmacological effects of the Cassia Seed on atherosclerosis: A meta-analysis based on network pharmacology.

BACKGROUND: The aim of this study was to shed light on the active ingredients and potential targets of Cassia Seed about anti-atherosclerosis based on network pharmacology. METHODS: The active ingredients and potential targets of Cassia Seed were obtained from traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) and SwissTargetPrediction database. Then, atherosclerosis-related targets were screened via GeneCards, online mendelian inheritance in man, therapeutic target database and DrugBank database. The common targets and protein-protein interaction (PPI) network was later identified and built. Furthermore, we used the database for annotation, visualization and integrated discovery (DAVID) database server to accomplish the enrichment analysis. The compounds-targets-pathways network was ultimately constructed by Cytoscape. RESULTS: A total of 14 active ingredients and 475 related targets were sifted from Cassia Seed. Among 574 potential atherosclerotic targets, there were 99 targets overlapped with those of Cassia Seed. Topological analysis with Cytoscape revealed that proto-oncogene tyrosine-protein kinase proto-oncogene tyrosine-protein kinase Src, transcription factor AP-1 (JUN), mitogen-activated protein kinase 8 (MAPK8), mitogen-activated protein kinase 14 (MAPK14) and catenin beta-1 were considered as the hub gene. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis suggested that the Cassia Seed had the potential to influence varieties of biological processes and pathways, including positive regulation of smooth muscle cell proliferation, inflammatory response, tumor necrosis factor (TNF) signaling pathway, vascular endothelial growth factor (VEGF) signaling pathway and arachidonic acid (ARA) metabolism. CONCLUSION: Taken together, our findings support that anti-atherosclerosis effects of Cassia Seed are characterized by multi-component, multi-target and multi-path mechanism of action.

Mitochondrial Dysfunction in Rheumatoid Arthritis.

Rheumatoid arthritis, a chronic autoimmune disease with complex etiology, is characterized by excessive proliferation of synovial cells, massive production of inflammatory cells and cartilage destruction. Studies have shown that mitochondrial dysfunction plays an important role in promoting the occurrence of RA. Mitochondria with normal structure and function are essential for the normal survival of chondrocytes and synovial cells. Once mitochondrial function is destroyed, it will affect the survival, activation and differentiation of immune cells and non-immune cells involved in the pathogenesis of RA, thus leading to the occurrence of RA. However, the mechanism of mitochondrial dysfunction in RA remains unclear. This article reviews the method of mitochondrial dysfunction leading to RA, the effects of mitochondrial dysfunction on immune cells, the etiology of mitochondrial dysfunction in RA, and the pathology of mitochondrial dysfunction in RA. We also outline some drugs that can exert therapeutic effects on RA which are associated with modulating mitochondrial activity. The understanding and summary of mitochondrial dysfunction in RA may provide new research directions for pathological intervention and prevention of RA.

Roles of autophagy in rheumatoid arthritis.

Autophagy, a vital mechanism restricted in tissues, exerts its cytoprotective role through the degradation mechanism of damaged or aging organelles, harmful protein aggregates and intracellular pathogens, followed by energy furnishment. However, dysfunctional autophagy is associated with the development of autoimmune diseases such as rheumatoid arthritis (RA). In pathological conditions, autophagy may be involved in the maturation, survival and proliferation of various immune and non-immune cells and plays a key role in the pathogenesis of RA. Furthermore, autophagy appears to be involved in the citrullination of T lymphocytes and the presentation of citrullinated peptides, which are presented to T lymphocytes via the major histocompatibility complex, causing immune responses and chronic inflammation, as well as bone and cartilage destruction associated with apoptosis resistance of RA fibroblast-like synoviocyte (RAFLS) and osteoclastogenesis. In this review, we have summarised the roles of autophagy in the pathogenesis of RA including citrullination, immune tolerance break, osteoclastogenesis, RA FLS cell dysplasia, apoptosis resistance, together with the therapeutic potentials of autophagy regulators.

Role of noncoding RNAs and untranslated regions in cancer: A review.

Cancer is one of the most prevalent diseases worldwide, and poses a threat to human health. Noncoding RNAs (ncRNAs) constitute most transcripts, but they cannot be translated into proteins. Studies have shown that ncRNAs can act as tumor suppressors or oncogenes. This review describes the role of several ncRNAs in various cancers, including microRNAs (miRNAs) such as the miR-34 family, let-7, miR-17-92 cluster, miR-210, and long noncoding RNAs (lncRNAs) such as HOX transcript antisense intergenic RNA (HOTAIR), Metastasis associated lung adenocarcinoma transcript 1 (MALAT1), H19, NF-κB-interacting lncRNA (NKILA), as well as circular RNAs (circRNAs) and untranslated regions (UTRs), highlighting their effects on cancer growth, invasion, metastasis, angiogenesis, and apoptosis. They function as tumor suppressors or oncogenes that interfere with different axes and pathways, including p53 and IL-6, which are involved in the progression of cancer. The characteristic expression of some ncRNAs in cancer also allows them to be used as biomarkers for early diagnosis and therapeutic candidates. There is a complex network of interactions between ncRNAs, with some lncRNAs and circRNAs acting as competitive endogenous RNAs (ceRNAs) to decoy miRNAs and repress their expression. The ceRNA network is a part of the ncRNA network and numerous ncRNAs work as nodes or hubs in the network, and disruption of their interactions can cause cancer development. Therefore, the balance and stabilization of this network are important for cancer diagnosis and treatment.

New progress in understanding roles of nitric oxide during hepatic ischemia-reperfusion injury.

Hepatic ischemia-reperfusion injury (HIRI) is a major clinical cause of morbidity and mortality in liver surgery and transplantation. Many studies have found that nitric oxide (NO) plays an important role in the HIRI and its increase or decrease can affect the progression and outcome of HIRI. However, the role of NO in HIRI is controversial and complicated. NO derived by endothelial NO synthase (eNOS) shows a protective role in HIRI, while excessive NO derived by inducible NO synthase (iNOS) accelerates inflammation and increases oxidative stress, further aggravating HIRI. Nevertheless, the overexpression of eNOS may exacerbate HIRI and iNOS-derived NO in some cases reduces HIRI. Here we review the new progress in the understanding of the roles of NO during HIRI: (1) NO possesses different roles in HIRI by increasing NO bioavailability, down-regulating leukotriene C4 synthase, inhibiting the activation of the nuclear factorκB (NFκB) pathway, enhancing cell autophagy, and reducing inflammatory cytokines and reactive oxygen species (ROS). And NO has both protective and deleterious effects by regulating apoptotic factors; (2) eNOS promotes NO production and suppresses its own overexpression, exerting a hepatoprotective effect reversely. Its activation is regulated by the PI3K/Akt and KLF2/AMPK pathways; and (3) iNOS derived NO mainly has deteriorating effects on HIRI, while it may have a protective function under some conditions. Their expression should reach a balance to reduce the adverse side and make NO protective in the treatment of HIRI. Thus, it can be inferred that NO modulating drugs may be a new direction in the treatment of HIRI or may be used as an adjunct to mitigate HIRI for the purpose of protecting the liver.

Roles of Nitric Oxide in Brain Ischemia and Reperfusion.

Brain ischemia and reperfusion (I/R) is one of the most severe clinical manifestations of ischemic stroke, placing a significant burden on both individuals and society. The only FDA-approved clinical treatment for ischemic stroke is tissue plasminogen activator (t-PA), which rapidly restores cerebral blood flow but can have severe side effects. The complex pathological process of brain I/R has been well-established in the past few years, including energy metabolism disorders, cellular acidosis, doubling of the synthesis or release of excitotoxic amino acids, intracellular calcium homeostasis, free radical production, and activation of apoptotic genes. Recently, accumulating evidence has shown that NO may be strongly related to brain I/R and involved in complex pathological processes. This review focuses on the role of endogenous NO in pathological processes in brain I/R, including neuronal cell death and blood brain barrier disruption, to explore how NO impacts specific signaling cascades and contributes to brain I/R injury. Moreover, NO can rapidly react with superoxide to produce peroxynitrite, which may also mediate brain I/R injury, which is discussed here. Finally, we reveal several therapeutic approaches strongly associated with NO and discuss their potential as a clinical treatment for ischemic stroke.

Role of Cholinergic Signaling in Alzheimer's Disease.

Acetylcholine, a neurotransmitter secreted by cholinergic neurons, is involved in signal transduction related to memory and learning ability. Alzheimer's disease (AD), a progressive and commonly diagnosed neurodegenerative disease, is characterized by memory and cognitive decline and behavioral disorders. The pathogenesis of AD is complex and remains unclear, being affected by various factors. The cholinergic hypothesis is the earliest theory about the pathogenesis of AD. Cholinergic atrophy and cognitive decline are accelerated in age-related neurodegenerative diseases such as AD. In addition, abnormal central cholinergic changes can also induce abnormal phosphorylation of ttau protein, nerve cell inflammation, cell apoptosis, and other pathological phenomena, but the exact mechanism of action is still unclear. Due to the complex and unclear pathogenesis, effective methods to prevent and treat AD are unavailable, and research to explore novel therapeutic drugs is various and active in the world. This review summaries the role of cholinergic signaling and the correlation between the cholinergic signaling pathway with other risk factors in AD and provides the latest research about the efficient therapeutic drugs and treatment of AD.

Amyloidosis in Alzheimer's Disease: Pathogeny, Etiology, and Related Therapeutic Directions.

The amyloid hypothesis of Alzheimer's disease has long been the predominant theory, suggesting that Alzheimer's disease is caused by the accumulation of amyloid beta protein (Aß) in the brain, leading to neuronal toxicity in the central nervous system (CNS). Because of breakthroughs in molecular medicine, the amyloid pathway is thought to be central to the pathophysiology of Alzheimer's disease (AD). Currently, it is believed that altered biochemistry of the Aß cycle remains a central biological feature of AD and is a promising target for treatment. This review provides an overview of the process of amyloid formation, explaining the transition from amyloid precursor protein to amyloid beta protein. Moreover, we also reveal the relationship between autophagy, cerebral blood flow, ACHE, expression of LRP1, and amyloidosis. In addition, we discuss the detailed pathogenesis of amyloidosis, including oxidative damage, tau protein, NFTs, and neuronal damage. Finally, we list some ways to treat AD in terms of decreasing the accumulation of Aß in the brain.

Hepatic Lipid Metabolism Disorder and Atherosclerosis.

Lipid metabolism disorder plays a fundamental role in the pathogenesis of atherosclerosis. As the largest metabolic organ of the human body, the liver has a key role in lipid metabolism by influencing fat production, fat decomposition, and the intake and secretion of serum lipoproteins. Numerous clinical and experimental studies have indicated that the dysfunction of hepatic lipid metabolism is closely related to the onset of atherosclerosis. However, the identity and functional role of hepatic lipid metabolism responsible for these associations remain unknown. This review presented that cholesterol synthesis, cholesterol transport, and the metabolism of triglycerides, lipoproteins, and fatty acids are all associated with hepatic lipid metabolism and atherosclerosis. Moreover, the roles of gut microbiota, inflammatory response, and oxidative stress in the pathological association between hepatic lipid metabolism and atherosclerosis are also discussed. This significant evidence strongly supports that hepatic lipid metabolism disorders may increase the risk of atherosclerosis.

Atherosclerosis: The Culprit and Co-victim of Vascular Dementia.

Vascular dementia (VD), a cerebrovascular disease which causes cognitive impairment, is one of the significant factors that affects the quality of senectitude. Atherosclerosis (AS) is a chronic inflammatory syndrome and closely associated with VD. Analyzing the role of AS in VD contribute greatly to its early detection and prevention, but their relationship has not been integrated into a complete network. This review summarizes AS biomarkers as VD predictors for the first time and describes the direct mechanisms of AS causing VD from five aspects: vascular morphogenesis, hemodynamic change, neurovascular unit damage (NVU), oxidative stress, and microRNA (miRNA). Finally, it discriminates the relationship between AS and VD in common risk factors which can be disease or some molecules. In particular, these data imply that the role of AS in VD is not only a pathogenic factor but also a comorbidity in VD. This review aims to bring new ideas for the prediction and treatment of VD.

Protein Phosphorylation in Cancer: Role of Nitric Oxide Signaling Pathway.

Nitric oxide (NO), a free radical, plays a critical role in a wide range of physiological and pathological processes. Due to its pleiotropic function, it has been widely investigated in various types of cancers and is strongly associated with cancer development. Mounting pieces of evidence show that NO regulates various cancer-related events, which mainly depends on phosphorylating the key proteins in several signaling pathways. However, phosphorylation of proteins modulated by NO signaling pathway may lead to different effects in different types of cancer, which is complex and remains unclear. Therefore, in this review, we focus on the effect of protein phosphorylation modulated by NO signaling pathway in different types of cancers including breast cancer, lung cancer, prostate cancer, colon cancer, gastric cancer, pancreatic cancer, ovarian cancer, and neuroblastoma. Phosphorylation of key proteins, including p38 MAPK, ERK, PI3K, STAT3, and p53, modified by NO in various signaling pathways affects different cancer-related processes including cell apoptosis, proliferation, angiogenesis, metastasis, and several cancer therapies. Our review links the NO signaling pathway to protein phosphorylation in cancer development and provides new insight into potential targets and cancer therapy.

Astragaloside IV Alleviates Liver Inflammation, Oxidative Stress and Apoptosis to Protect Against Experimental Non-Alcoholic Fatty Liver Disease.

PURPOSE: Non-alcoholic fatty liver disease (NAFLD) is the main form of chronic liver disease in the world. Astragaloside IV (ASIV) has been tested in experimental models of different diseases. The purpose of this study was to evaluate the effect and protective mechanism of ASIV on NAFLD. METHODS: Lipopolysaccharide (LPS)- and palmitate acid (PA)-induced RAW264.7 cells and LO2 cells were used as a NAFLD model. The mice NAFLD model was evaluated by hematoxylin-eosin staining (HE staining), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Liver lipid metabolism was evaluated by triglyceride (TG) and total cholesterol (TC) kits and oil red O staining. Oxidative stress indicators were examined through biochemical methods. Inflammatory factors were explored through enzyme-linked immuno sorbent assay (ELISA), real-time quantitative PCR and oxidative stress indicator kits. The expression levels of 5-LO (5-lipoxygenase) and leukotriene A4 hydrolase (LTA4H) were checked by real-time quantitative PCR and Western blotting. Apoptosis was detected by Annexin V-FITC/PI cell apoptosis detection kit. RESULTS: Our results showed that in vivo ASIV significantly reduced liver tissue damage, and serum AST, ALT and serum TG levels in NAFLD mice. In vitro, ASIV reduced cell supernatant TG and TC content increased by PA treatment, and significantly decreased the accumulation of intracellular lipid droplets induced by PA treatment. Additionally, ASIV reduced reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and restored glutathione peroxidase (GSH-Px) levels in PA-treated LO2 cell supernatant. Furthermore, ASIV inhibited the production of proinflammatory cytokines (IL-6 and TNF-α) in RAW264.7 cells induced by LPS. We also found that ASIV downregulated the expression of 5-LO and LTB4 (leukotriene B4) in NAFLD mice. Moreover, ASIV restored apoptotic protein (Bax and Bcl-2) expression in PA-treated LO2 cells. CONCLUSION: ASIV may reduce liver steatosis, hepatocyte oxidative stress and apoptosis, and decrease liver inflammation, thereby attenuating the progression of NAFLD and thus might be of therapeutic interest.

The Roles of Nitric Oxide Synthase/Nitric Oxide Pathway in the Pathology of Vascular Dementia and Related Therapeutic Approaches.

Vascular dementia (VaD) is the second most common form of dementia worldwide. It is caused by cerebrovascular disease, and patients often show severe impairments of advanced cognitive abilities. Nitric oxide synthase (NOS) and nitric oxide (NO) play vital roles in the pathogenesis of VaD. The functions of NO are determined by its concentration and bioavailability, which are regulated by NOS activity. The activities of different NOS subtypes in the brain are partitioned. Pathologically, endothelial NOS is inactivated, which causes insufficient NO production and aggravates oxidative stress before inducing cerebrovascular endothelial dysfunction, while neuronal NOS is overactive and can produce excessive NO to cause neurotoxicity. Meanwhile, inflammation stimulates the massive expression of inducible NOS, which also produces excessive NO and then induces neuroinflammation. The vicious circle of these kinds of damage having impacts on each other finally leads to VaD. This review summarizes the roles of the NOS/NO pathway in the pathology of VaD and also proposes some potential therapeutic methods that target this pathway in the hope of inspiring novel ideas for VaD therapeutic approaches.

Effects of non-drug treatment on liver cells apoptosis during hepatic ischemia-reperfusion injury.

Hepatic ischemia reperfusion injury (HIRI) is an important cause of liver dysfunction after liver transplantation for the patients suffered from fatty liver, non-alcoholic cirrhosis, or liver cancer. It is closely related to liver cells apoptosis. Therefore, how to maintain the stable state of cell apoptosis is important to protect the liver from HIRI. Drug treatment basically applies some active substances directly or indirectly, reducing HIRI. But their toxic side effects limit the clinical applications. Differently, non-drug treatment means making use of other kinds of measures to reduce the damage, such as non-pharmaceutical preparations, surgical methods, inhalation or perfusion gas, and so on. Non-drug treatments have been shown to balance cell apoptosis and reduce liver damage during HIRI. This review summarized the progresses in the roles of non-drug treatments on liver cells apoptosis during HIRI in recent years, focusing on apoptosis inducing factors, its signal transduction pathway, and downstream molecules, etc., expecting to elucidate non-drug treatments of anti-HIRI more systematically.

Sleep disorders in Alzheimer's disease: the predictive roles and potential mechanisms.

Sleep disorders are common in patients with Alzheimer's disease, and can even occur in patients with amnestic mild cognitive impairment, which appears before Alzheimer's disease. Sleep disorders further impair cognitive function and accelerate the accumulation of amyloid-ß and tau in patients with Alzheimer's disease. At present, sleep disorders are considered as a risk factor for, and may be a predictor of, Alzheimer's disease development. Given that sleep disorders are encountered in other types of dementia and psychiatric conditions, sleep-related biomarkers to predict Alzheimer's disease need to have high specificity and sensitivity. Here, we summarize the major Alzheimer's disease-specific sleep changes, including abnormal non-rapid eye movement sleep, sleep fragmentation, and sleep-disordered breathing, and describe their ability to predict the onset of Alzheimer's disease at its earliest stages. Understanding the mechanisms underlying these sleep changes is also crucial if we are to clarify the role of sleep in Alzheimer's disease. This paper therefore explores some potential mechanisms that may contribute to sleep disorders, including dysregulation of the orexinergic, glutamatergic, and γ-aminobutyric acid systems and the circadian rhythm, together with amyloid-ß accumulation. This review could provide a theoretical basis for the development of drugs to treat Alzheimer's disease based on sleep disorders in future work.

Pharmacological Treatment of Vascular Dementia: A Molecular Mechanism Perspective.

Vascular dementia (VaD) is a neurodegenerative disease, with cognitive dysfunction attributable to cerebrovascular factors. At present, it is the second most frequently occurring type of dementia in older adults (after Alzheimer's disease). The underlying etiology of VaD has not been completely elucidated, which limits its management. Currently, there are no approved standard treatments for VaD. The drugs used in VaD are only suitable for symptomatic treatment and cannot prevent or reduce the occurrence and progression of VaD. This review summarizes the current status of pharmacological treatment for VaD, from the perspective of the molecular mechanisms specified in various pathogenic hypotheses, including oxidative stress, the central cholinergic system, neuroinflammation, neuronal apoptosis, and synaptic plasticity. As VaD is a chronic cerebrovascular disease with multifactorial etiology, combined therapy, targeting multiple pathophysiological factors, may be the future trend in VaD.