A comprehensive review of miR-21 in liver disease: Big impact of little things.

microRNAs (miRNAs), a class of non-coding RNA with 20-24 nucleotides, are defined as the powerful regulators for gene expression. miR-21 is a multifunctional miRNA enriched in the circulatory system and multiple organs, which not only serves as a non-invasive biomarker in disease diagnosis, but also participates in many cellular activities. In various chronic liver diseases, the increase of miR-21 affects glycolipid metabolism, viral infection, inflammatory and immune cell activation, hepatic stellate cells activation and tissue fibrosis, and autophagy. Moreover, miR-21 is also a liaison in the deterioration of chronic liver disease to hepatocellular carcinoma (HCC), and it impacts on cell proliferation, apoptosis, migration, invasion, angiogenesis, immune escape, and epithelial-mesenchymal transformation by regulating target genes expression in different signaling pathways. In current research on miRNA therapy, some natural products can exert the hepatoprotective effects depending on the inhibition of miR-21 expression. In addition, miR-21-based therapeutic also play a role in regulating intracellular miR-21 levels and enhancing the efficacy of chemotherapy drugs. Herein, we systemically summarized the recent progress of miR-21 on biosynthesis, biomarker function, molecular mechanism and miRNA therapy in chronic liver disease and HCC, and looked forward to outputting some information to enable it from bench to bedside.

Kaempferol efficacy in metabolic diseases: Molecular mechanisms of action in diabetes mellitus, obesity, non-alcoholic fatty liver disease, steatohepatitis, and atherosclerosis.

The incidence of metabolic diseases has progressively increased, which has a negative impact on human health and life safety globally. Due to the good efficacy and limited side effects, there is growing interest in developing effective drugs to treat metabolic diseases from natural compounds. Kaempferol (KMP), an important flavonoid, exists in many vegetables, fruits, and traditional medicinal plants. Recently, KMP has received widespread attention worldwide due to its good potential in the treatment of metabolic diseases. To promote the basic research and clinical application of KMP, this review provides a timely and comprehensive summary of the pharmacological advances of KMP in the treatment of four metabolic diseases and its potential molecular mechanisms of action, including diabetes mellitus, obesity, non-alcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), and atherosclerosis. According to the research, KMP shows remarkable therapeutic effects on metabolic diseases by regulating multiple signaling transduction pathways such as NF-κB, Nrf2, AMPK, PI3K/AKT, TLR4, and ER stress. In addition, the most recent literature on KMP's natural source, pharmacokinetics studies, as well as toxicity and safety are also discussed in this review, thus providing a foundation and evidence for further studies to develop novel and effective drugs from natural compounds. Collectively, our manuscript strongly suggested that KMP could be a promising candidate for the treatment of metabolic diseases.

Protective mechanism of Paeonol on central nervous system.

Cerebrovascular diseases involve neuronal damage, resulting in degenerative neuropathy and posing a serious threat to human health. The discovery of effective drug components from natural plants and the study of their mechanism are a research idea different from chemical synthetic medicines. Paeonol is the main active component of traditional Chinese medicine Paeonia lactiflora Pall. It widely exists in many medicinal plants and has pharmacological effects such as anti-atherosclerosis, antiplatelet aggregation, anti-oxidation, and anti-inflammatory, which keeps generally used in the treatment of cardiovascular and cerebrovascular diseases. Based on the therapeutic effects of Paeonol for cardiovascular and cerebrovascular diseases, this article reviewed the pharmacological effects of Paeonol in Alzheimer's disease, Parkinson's disease, stroke, epilepsy, diabetes encephalopathy, and other neurological diseases, providing a reference for the research of the mechanism of Paeonol in central nervous system diseases.

Comparative Pharmacokinetic Study of Rhubarb Anthraquinones in Normal and Nonalcoholic Fatty Liver Disease Rats.

BACKGROUND AND OBJECTIVES: Rhubarb anthraquinones contain five main components, that is, rhein, emodin, aloe-emodin, chrysophanol, and physcion, which demonstrate good therapeutic effects on nonalcoholic fatty liver disease (NAFLD). However, research on its pharmacokinetics in NAFLD remains lacking. This study aimed to investigate the pharmacokinetic differences of rhubarb anthraquinones in normal and NAFLD rats. METHODS: This study developed an NAFLD rat model by high-fat diet feeding for 6 weeks. Normal and NAFLD groups were orally administered different rhubarb anthraquinones doses (37.5, 75, and 150 mg/kg). The concentration of the rhein, emodin, aloe-emodin, chrysophanol, and physcion in plasma was determined by high-performance liquid chromatography-ultraviolet. RESULTS: The results revealed significant differences in pharmacokinetic behavior between normal and NAFLD rats. Compared with normal rats, NAFLD rats demonstrated significantly increased maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0 → ∞) of rhubarb anthraquinones (P < 0.05), as well as significantly prolonged time to reach maximum plasma concentration (Tmax), terminal elimination half-life (t1/2), and mean residence time (MRT) of rhubarb anthraquinones (P < 0.05). CONCLUSIONS: This study indicates significant differences in the pharmacokinetics of rhubarb anthraquinones between the physiological and NAFLD states of rats. Rhubarb anthraquinone demonstrated a longer retention time and slower absorption rate in NAFLD rats and exhibited higher bioavailability and peak concentration. This finding provides important information for guiding the clinical use of rhubarb anthraquinones under pathological conditions.

Forsythiaside A alleviates acute lung injury by inhibiting inflammation and epithelial barrier damages in lung and colon through PPAR-γ/RXR-α complex.

INTRODUCTION: Acute lung injury (ALI) is a lung disease characterized by inflammation and still requires further drug development. Forsythiaside A as the active compound of Forsythiae Fructus has the therapeutic potential for ALI. OBJECTIVE: To investigate the mechanism of forsythiaside A in treating ALI through PPAR-γ and its conjugate RXR-α based on gut-lung axis. METHODS: This study constructed in vitro and in vivo injury models using LPS and TNF-α. Forsythiaside A was used for the drug treatment, and RXR-α inhibitor UVI3003 was used to interfere with PPAR-γ/RXR-α complexes in the cells. HE staining was used for histopathological examination. Serum endotoxin contents were determined using limulus lysate kit. IHC staining and Western blot were conducted to assess the protein expressions. ELISA was applied to examine the content of pro-inflammatory cytokines in the cell supernatants. The protein interactions were analyzed via CO-IP. RESULTS: In vivo results showed that forsythiaside A regulated PPAR-γ/RXR-α and inhibited TLR4/MAPK/NF-κB and MLCK/MLC2 signal pathways, thus inhibiting inflammation and epithelial barrier damages of lung and colon in ALI mice induced by intratracheal LPS. PPAR-γ/RXR-α were promoted by forsythiaside A in lungs, whereas inhibited by forsythiaside A in colons. Additionally, in vitro results showed that forsythiaside A suppressed inflammation and epithelial barrier damages in macrophages and lung/colon epithelial cells, by manipulating PPAR-γ/RXR-α to suppress the LPS- and TNF-α-induced activation of TLR4/MAPK/NF-κB and NF-κB/MLCK/MLC2 signal pathways. Moreover, further mechanism study indicated that forsythiaside A showed a cell-specific regulatory effect on PPAR-γ/RXR-α complex. Specifically, the PPAR-γ/RXR-α protein interactions were promoted by forsythiaside A in LPS-induced macrophages RAW264.7 and TNF-α-induced lung epithelial cells A549, but inhibited by forsythiaside A in TNF-α-induced colon epithelial cells SW620. CONCLUSION: In the treatment of ALI, Forsythiaside A inhibited inflammation and epithelial barrier damages of lung and colon through its regulation on PPAR-γ/RXR-α complex.

The protective effect of forsythiaside A on 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced cholestatic liver injury in mice: Based on targeted metabolomics and molecular biology technology.

Cholestasis is a disorder of bile secretion and excretion caused by a variety of etiologies. At present, there is a lack of functional foods or drugs that can be used for intervention. Forsythiaside A (FTA) is a natural phytochemical component isolated from the medicinal plant Forsythia suspensa (Thunb.) Vahl, which has a significant hepatoprotective effect. In this study, we investigated whether FTA could alleviate liver injury induced by cholestasis. In vitro, FTA reversed the decrease in viability of human intrahepatic bile duct epithelial cells, the decrease in antioxidant enzymes (SOD1, CAT and GSH-Px), and cell apoptosis induced by lithocholic acid. In vivo, FTA protected mice from 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver injury, abnormal serum biochemical indexes, abnormal bile duct hyperplasia, and inflammatory infiltration. Furthermore, FTA treatment alleviated liver fibrosis by inhibiting collagen deposition and HSC activation. The metabonomic results showed that DDC-induced bile acid disorders in the liver and serum were reversed after FTA treatment, which may benefit from the activation of the FXR/BSEP axis. In addition, FTA treatment increased the levels of antioxidant enzymes in the serum and liver. Meanwhile, FTA treatment inhibited ROS and MDA levels and cleaved caspase 3 protein expression, thereby reducing DDC-induced hepatic oxidative stress and apoptosis. Further studies showed that the antioxidant effects of FTA were dependent on the activation of the BRG1/NRF2/HO-1 axis. In a word, FTA has a significant hepatoprotective effect on cholestatic liver injury, and can be further developed as a functional food or drug to prevent and treat cholestatic liver injury.

Phillygenin Ameliorates Carbon Tetrachloride-Induced Liver Fibrosis: Suppression of Inflammation and Wnt/ß-Catenin Signaling Pathway.

Liver fibrosis (LF) is caused by the chronic wound healing response to liver injury from various origins. Among the causes, inflammatory response is the central trigger of LF. Phillygenin (PHI) is a lignan derived from Forsythia suspensa, which has significant anti-inflammatory properties. However, the effect of PHI on improving LF and the underlying mechanism have rarely been studied. In this study, we used carbon tetrachloride (CCl4) to establish a mouse model of LF. Through histological analysis of liver tissue, and measurement of the levels of hepatocyte damage markers (ALT, AST, TBIL, TBA) and four indicators of LF (Col IV, HA, LN, PC-III) in serum, it was shown that PHI improved liver function and reduced the progress of LF. Subsequently, the detection of fibrogenic biomarkers in liver tissue showed that PHI inhibited the activation of hepatic stellate cells (HSCs). Next, the expression of inflammatory markers in liver tissue/serum was detected by immunohistochemistry, RT-qPCR, and ELISA, suggesting that PHI inhibited inflammation during LF. Similarly, in vitro experiments also confirmed that PHI could inhibit lipopolysaccharide-induced inflammatory responses in RAW264.7 cells, which showed strong anti-inflammatory effects. In addition, the results of network pharmacology, molecular docking, RT-qPCR and western blot confirmed that PHI could alleviate CCl4-induced LF by inhibiting the Wnt/ß-catenin pathway. In conclusion, our research showed that PHI curbed LF through inhibition of HSC activation and collagen accumulation via inhibiting multiple profibrogenic factors, modulating a variety of inflammatory factors, and suppressing the Wnt/ß-catenin pathway.

Protective effects of dietary quercetin on cerebral ischemic injury: pharmacology, pharmacokinetics and bioavailability-enhancing nanoformulations.

Cerebral ischemia, as an ischemic stroke-like disease, has become a health problem of global concern. Studies have found that oxidative stress, inflammation, apoptosis, and impaired blood-brain barrier (BBB) and ion channel regulation are the basis for the development of cerebral ischemia pathology. Quercetin, a flavonoid compound, commonly found in the daily diet and in some Chinese herbal medicines, including vegetables, fruits, and tea, is one of the most prominent dietary antioxidants. Modern pharmacological studies have shown that quercetin can effectively protect against cerebral ischemic injury, and its mechanisms may involve antioxidant, anti-inflammatory, anti-apoptotic, BBB protection, ion channel regulation, cell excitatory glutamate toxicity alleviation and cognitive impairment recovery activities. However, the low bioavailability of quercetin and the presence of the BBB structure limit the therapeutic efficacy. There have been studies targeting the delivery of quercetin to the injury site through nanotechnology to enhance the therapeutic effect of quercetin. This review discusses and reviews the pharmacological activity, pharmacokinetic characteristics, and targeted delivery nanosystems of quercetin in protecting against cerebral ischemic injury, and provides information on various downstream signaling pathways regulated by quercetin, such as PI3k/Akt, MAPK, and Sirt1. We hope to provide a scientific basis for the development and application of quercetin in the field of cerebral ischemia.

Remodeling the hepatic fibrotic microenvironment with emerging nanotherapeutics: a comprehensive review.

Liver fibrosis could be the last hope for treating liver cancer and remodeling of the hepatic microenvironment has emerged as a strategy to promote the ablation of liver fibrosis. In recent years, especially with the rapid development of nanomedicine, hepatic microenvironment therapy has been widely researched in studies concerning liver cancer and fibrosis. In this comprehensive review, we summarized recent advances in nano therapy-based remodeling of the hepatic microenvironment. Firstly, we discussed novel strategies for regulatory immune suppression caused by capillarization of liver sinusoidal endothelial cells (LSECs) and macrophage polarization. Furthermore, metabolic reprogramming and extracellular matrix (ECM) deposition are caused by the activation of hepatic stellate cells (HSCs). In addition, recent advances in ROS, hypoxia, and impaired vascular remodeling in the hepatic fibrotic microenvironment due to ECM deposition have also been summarized. Finally, emerging nanotherapeutic approaches based on correlated signals were discussed in this review. We have proposed novel strategies such as engineered nanotherapeutics targeting antigen-presenting cells (APCs) or direct targeting T cells in liver fibrotic immunotherapy to be used in preventing liver fibrosis. In summary, this comprehensive review illustrated the opportunities in drug targeting and nanomedicine, and the current challenges to be addressed.

Steatosis in metabolic diseases: A focus on lipolysis and lipophagy.

Fatty acids (FAs), as part of lipids, are involved in cell membrane composition, cellular energy storage, and cell signaling. FAs can also be toxic when their concentrations inside and/or outside the cell exceed physiological levels, which is called "lipotoxicity", and steatosis is a form of lipotoxity. To facilitate the storage of large quantities of FAs in cells, they undergo a process called lipolysis or lipophagy. This review focuses on the effects of lipolytic enzymes including cytoplasmic "neutral" lipolysis, lysosomal "acid" lipolysis, and lipophagy. Moreover, the impact of related lipolytic enzymes on lipid metabolism homeostasis and energy conservation, as well as their role in lipid-related metabolic diseases. In addition, we describe how they affect lipid metabolism homeostasis and energy conservation in lipid-related metabolic diseases with a focus on hepatic steatosis and cancer and the pathogenesis and therapeutic targets of AMPK/SIRTs/FOXOs, PI3K/Akt, PPARs/PGC-1α, MAPK/ERK1/2, TLR4/NF-κB, AMPK/mTOR/TFEB, Wnt/ß-catenin through immune inflammation, oxidative stress and autophagy-related pathways. As well as the current application of lipolytic enzyme inhibitors (especially Monoacylglycerol lipase (MGL) inhibitors) to provide new strategies for future exploration of metabolic programming in metabolic diseases.

The role of miR-155 on liver diseases by modulating immunity, inflammation and tumorigenesis.

The liver is a well-known metabolic organ that can be susceptible to external stimuli to affect its normal physiological function. Worldwide, the morbidity and mortality of liver diseases are skyrocketing every year, causing human health crises. Recently, new approaches such as biotechnology have been introduced to achieve optimal treatment and prognostic management of liver diseases. microRNAs (miRNAs), a kind of small non-coding RNA molecule, have the advantages of biodiversity, wide distribution and numerous members. Among these miRNAs, miR-155 is an important regulator of inflammation, immunity and tumorigenesis. In this review, the PubMed and Web of Science databases were searched from 2009 to 2022. After inclusion and exclusion, 64 articles were selected for a systematic review to comprehensively summarize the mechanisms of miR-155 regulating inflammation, immunity and tumorigenesis in liver diseases and liver cancer, covering in vitro, in vivo and clinical studies. Existing preclinical studies and clinical trials have listed that the up-regulation and down-regulation of miR-155 are significant in alcoholic liver injury, viral hepatitis, autoimmune hepatitis, infectious liver injury, liver transplantation and liver cancer. The immune and inflammation effects of miR-155 are manifested by regulating macrophage polarization, NK cell killing, Th17 cell and Th1/Th2 cell differentiation. Additionally, miR-155 is also committed to participating in the cell cycle, invasion and metastasis, immune escape and other processes to promote and intensify the development of liver cancer. In conclusion, miR-155 is not only a biomarker for the diagnosis and prognosis of liver diseases, but also plays a therapeutic role via regulating immunity, inflammation and tumorigenesis.

Nephroprotective and nephrotoxic effects of Rhubarb and their molecular mechanisms.

Rhubarb, in the form of a traditional Chinese medicine, is used in the treatment of chronic kidney disease (CKD). Previous studies have demonstrated that Rhubarb possesses a good nephroprotective effect, which primarily protects the kidneys from fibrosis, oxidation, inflammation, autophagy, and apoptosis. However, studies have shown that the long-term inappropriate use of Rhubarb may cause damage to renal function. Therefore, how to correctly understand and scientifically evaluate the pharmacodynamics and toxicity of Rhubarb with regard to CKD is a scientific question that urgently needs to be answered. In this review, we explain and illustrate how Rhubarb exerts its nephroprotective effect against CKD. We also describe the mechanisms of action that may cause its nephrotoxicity. Valuable and practical clinical guidance is proposed with regard to methods for mitigating the nephrotoxicity of Rhubarb.

microRNAs-based diagnostic and therapeutic applications in liver fibrosis.

Liver fibrosis is a process of over-extracellular matrix (ECM) aggregation and angiogenesis, which develops into cirrhosis and hepatocellular carcinoma (HCC). With the increasing pressure of liver fibrosis, new therapeutics to cure this disease requires much attention. Exosome-cargoed microRNAs (miRNAs) are emerging approaches in the precision of the liver fibrotic paradigm. In this review, we outlined the different types of hepatic cells derived miRNAs that drive intra-/extra-cellular interactive communication in liver fibrosis with different physiological and pathological processes. Specifically, we highlighted the possible mechanism of liver fibrosis pathogenesis associated with immune response and angiogenesis. In addition, potential clinical biomarkers and different stem cell transplant-derived miRNAs-based therapeutic strategies in liver fibrosis were summarized in this review. miRNAs-based approaches might help researchers devise new candidates for the cell-free treatment of liver fibrosis. This article is categorized under: RNA in Disease and Development > RNA in Disease.

Carthami flos extract against carbon tetrachloride-induced liver fibrosis via alleviating angiogenesis in mice.

BACKGROUND: Angiogenesis is a pathological phenomenon contribute to the development of chronic liver diseases, and anti-angiogenic therapy is an effective strategy to alleviate liver fibrosis. Carthami flos, a medicinal and edible herb, has the effects of improving blood circulation and regulating angiogenesis. However, the anti-angiogenic effect of Carthami flos in liver fibrosis remains unknown. METHODS: We investigated the protective effect and therapeutic mechanism of Carthami flos extract (CFE) on carbon tetrachloride (CCl4)-induced liver fibrosis in mice. The liver injury and collagen deposition were observed and evaluated by conducting HE, Masson, and Sirius red staining, testing the serum biochemical indexes (ALT, AST, ALP, γ-GT), and measuring the contents of HYP and four indexes of liver fiber (Col-IV, LN, HA, PC-III). Simultaneously, the expressions of α-SMA and Collagen-I were detected to determine the activation of hepatic stellate cells (HSCs). Subsequently, we measured the expressions of angiogenesis-related proteins such as PDGFRB, ERK1/2, p-ERK1/2, MEK, p-MEK, HIF-1α, VEGFA, VEGFR2, AKT and eNOS, and the mRNA levels of PDGFRB and VEGFA. Additionally, immunofluorescence staining and RT-qPCR assays were carried out to ascertain the expressions of continuous endothelial markers CD31, CD34 and vWF, and scanning electron microscope analysis was performed to observe the number of sinusoidal endothelial fenestrations. RESULTS: Herein, we found that CFE could significantly reduce liver injury and collagen deposition, like the same effect of colchicine. CFE significantly alleviated CCl4-induced liver injury and fibrosis, mainly manifested by reducing the levels of ALT, AST, ALP and γ-GT and decreasing the contents of HYP, Col-IV, LN, HA and PC-III. Additionally, CCl4 promoted the activation of HSCs by increasing the expressions of α-SMA and Collagen-I, while CFE could rectify the condition. Moreover, CFE treatment prevented the CCl4-induced the up-regulation of PDGFRB, p-MEK, p-ERK1/2, HIF-1α, VEGFA, VEGFR2, AKT and eNOS, suggesting that CFE might provide the protection against abnormal angiogenesis. In the meantime, the gradual disappearance of sinusoidal capillarization after CFE treatment was supported by the decreased the contents of CD31, CD34 and vWF, as well as the increased number of sinusoidal endothelial fenestrae. CONCLUSION: In this study, the reduction of collagen deposition, the obstruction of HSCs activation, the inactivation of angiogenic signaling pathways and the weakening of hepatic sinusoidal capillarization jointly confirmed that CFE might be promising to resist angiogenesis in liver fibrosis via the PDGFRB/ERK/HIF-1α and VEGFA/AKT/eNOS signaling pathways. Nevertheless, as a potential therapeutic drug, the deeper mechanism of Carthami flos still needs to be further elucidated.

Quercetin alleviates ethanol-induced hepatic steatosis in L02 cells by activating TFEB translocation to compensate for inadequate autophagy.

This study aimed to investigate the therapeutic effect of quercetin on ethanol-induced hepatic steatosis in L02 cells and elucidate the potential mechanism. In brief, L02 cells were pretreated with or without ethanol (3%) for 24 h, then treated quercetin (80, 40, 20 µM) for 24 h. The transfection procedure was performed with transcription factor EB (TFEB) small interfering RNA (siRNA TFEB) for 24 h. Our results showed that quercetin autophagic flux in the L02 cells, via upregulating of microtubule associated protein light chain 3B (LC3-II) and lysosome-associated membrane protein 1 (LAMP1), then downregulating of protein sequestosome 1 (SQSTM1/p62). Mechanistically, quercetin activated TFEB nuclear translocation, contributing to lysosomal biogenesis and autophagic activation. Accordingly, the genetic inhibition of TFEB-dependent autophagy decreased ethanol-induced fat accumulation in L02 cells via regulating fatty acid ß oxidation and lipid synthesis. Subsequently, quercetin-induced TFEB-dependent autophagic activation was also linked to inhibit oxidative stress via suppressing reactive oxygen species (ROS), enhancing activities of antioxidant enzymes, and promoting nuclear transfer of the nuclear factor E2-related factor 2 (Nrf2) translocation. Thus, we uncovered a novel protective mechanism against ethanol-induced hepatic steatosis and oxidative stress through TFEB-mediated lysosomal biogenesis and discovered insufficient autophagy as a novel previously unappreciated autophagic flux.

Emerging roles of Sirtuins in alleviating alcoholic liver Disease: A comprehensive review.

Sirtuins (SIRTs), a NAD+ family of dependent deacetylases, are involved in the regulation of various human diseases. Recently, accumulating evidence has uncovered number of substrates and crucial roles of SIRTs in the pathogenesis of alcoholic liver disease (ALD). However, systematic reports are still lacking, so this review provides a comprehensive profile of the crucial physiological functions of SIRTs and its role in attenuating ALD, including alcoholic liver steatosis, steatohepatitis, and fibrosis. SIRTs play beneficial roles in energy/lipid metabolism, oxidative stress, inflammatory response, mitochondrial homeostasis, autophagy and necroptosis of ALD via regulating multiple signaling transduction pathways such as AMPK, LKB1, SREBP1, Lipin1, PGC-1α, PPARα/γ, FoxO1/3a, Nrf2/p62, mTOR, TFEB, RIPK1/3, HMGB1, NFATc4, NF-κB, TLR4, NLRP3, P2X7R, MAPK, TGF1ß/Smads and Wnt/ß-catenin. In addition, the mechanism and clinical application of natural/ synthetic SIRTs agonists in ALD are summarized, which provide a new idea for the treatment of ALD and basic foundation for further studies into target drugs.