Maggot Kinase and Natural Thrombolytic Proteins.

Thrombolytic enzymes constitute a class of proteases with antithrombotic functions. Derived from natural products and abundant in nature, certain thrombolytic enzymes, such as urokinase, earthworm kinase, and streptokinase, have been widely used in the clinical treatment of vascular embolic diseases. Fly maggots, characterized by their easy growth and low cost, are a traditional Chinese medicine recorded in the Compendium of Materia Medica. These maggots can also be used as raw material for the extraction and preparation of thrombolytic enzymes (maggot kinase). In this review, we assembled global research reports on natural thrombolytic enzymes through a literature search and reviewed the functions and structures of natural thrombolytic enzymes to provide a reference for natural thrombophilic drug screening and development.

Fenofibrate improves hepatic steatosis, insulin resistance, and shapes the gut microbiome via TFEB-autophagy in NAFLD mice.

Non-alcoholic fatty liver disease (NAFLD) is a major liver disease subtype worldwide, is commonly associated with insulin resistance and obesity. NAFLD is characterized by an excessive hepatic lipid accumulation, as well as hepatic steatosis. Fenofibrate is a peroxisome proliferator-activated receptor α agonist widely used in clinical therapy to effectively ameliorate the development of NAFLD, but its mechanism of action is incompletely understood. Here, we found that fenofibrate dramatically modulate the gut microbiota composition of high-fat diet (HFD)-induced NAFLD mouse model, and the change of gut microbiota composition is dependent on TFEB-autophagy axis. Furthermore, we also found that fenofibrate improved hepatic steatosis, and increased the activation of TFEB, which severed as a regulator of autophagy, thus, the protective effects of fenofibrate against NAFLD are depended on TFEB-autophagy axis. Our study demonstrates the host gene may influence the gut microbiota and highlights the role of TFEB and autophagy in the protective effect of NAFLD. This work expands our understanding of the regulatory interactions between the host and gut microbiota and provides novel strategies for alleviating obesity.

Integrative bioinformatics analysis to screen key genes and signalling pathways related to ferroptosis in obesity.

Ferroptosis is closely associated with the development of disease in the body. However, there are few studies on ferroptosis-related genes (FRGs) in obesity. Therefore, key genes and signalling pathways related to ferroptosis in obesity were screened. Briefly, the RNA sequencing data of obesity and the non-obesity human samples and 259 FRGs were downloaded from GEO database and FerrDb database, respectively. The obesity-related module genes were firstly screened by weighted gene co-expression network analysis (WGCNA) and crossed with differentially expressed genes (DEGs) of obesity/normal samples and FRGs to obtain obesity-ferroptosis related (OFR) DEGs. Then, key genes were screened by PPI network. Next, the correlation of key genes and differential immune cells between obesity and normal samples were further explored by immune infiltration analysis. Finally, microRNA (miRNA)-messenger RNA (mRNA), transcription factor (TF)-mRNA networks and drug-gene interaction networks were constructed. As a result, 17 OFR DEGs were obtained, which mainly participated in processes such as lipid metabolism or adipocyte differentiation. The 4 key genes, STAT3, IL-6, PTGS2, and VEGFA, constituted the network. M2 macrophages, T cells CD8, mast cells activated, and T cells CD4 memory resting had significant differences between obesity and normal samples. Moreover, 51 miRNAs and 164 drugs were predicted for 4 key genes. All in all, this study has screened 4 FRGs, including IL-6, VEGFA, STAT3, and PTGS2, in obesity patients.

Immobilization of Horseradish Peroxidase for Phenol Degradation.

The use of enzymes to degrade environmental pollutants has received wide attention as an emerging green approach. Horseradish peroxidase (HRP) can efficiently catalyze the degradation of phenol in the environment; however, free HRP exhibits poor stability and temperature sensitivity and is easily deactivated, which limit its practical applications. In this study, to improve their thermal stability, HRP enzymes were immobilized on mesoporous molecular sieves (Al-MCM-41). Specifically, Al-MCM-41(W) and Al-MCM-41(H) were prepared by modifying the mesoporous molecular sieve Al-MCM-41 with glutaraldehyde and epichlorohydrin, respectively, and used as carriers to immobilize HRP on their surface, by covalent linkage, to form the immobilized enzymes HRP@Al-MCM-41(W) and HRP@Al-MCM-41(H). Notably, the maximum reaction rate of HRP@Al-MCM-41(H) was increased from 2.886 × 105 (free enzyme) to 5.896 × 105 U/min-1, and its half-life at 50 °C was increased from 745.17 to 1968.02 min; the thermal stability of the immobilized enzyme was also significantly improved. In addition, we elucidated the mechanism of phenol degradation by HRP, which provides a basis for the application of this enzyme to phenol degradation.

Promoter hypermethylation and comprehensive regulation of ncRNA lead to the down-regulation of ZNF880, providing a new insight for the therapeutics and research of colorectal cancer.

The human genome encodes more than 350 kinds of Krüppel-associated box (KRAB) domain-containing zinc-finger proteins (KZFPs), KRAB-type ZNF transcription factor family (KZNF) plays a vital role in gene regulatory networks. The KZNF family members include a large number of highly homologous genes, gene subtypes and pseudogenes, and their expression has a high degree of tissue specificity and precision. Due to the high complexity of its regulatory network, the KZNF gene family has not been researched in sufficient, and the role of its members in the occurrence of cancer is mostly unexplored. In this study, ZNF880 was significantly associated with overall survival (OS) and disease-free survival (DFS) in colorectal carcinoma (CRC) patients. Low ZNF880 expression resulted in shorter OS and DFS. Combined with Colon adenocarcinoma (COAD) and Rectum adenocarcinoma (READ) data collection in the TCGA database, we found that ZNF880 was significantly down-regulated in CRC. Further analysis of the sequence variation of ZNF880 in CRC showed that ZNF880 accumulated a large number of SNV in the C2H2 domain and KRAB domain, while promoter region of ZNF880 also showed high methylation in COAD and READ. Combined with the Cbioportal and TIMER databases, the expression of mutant ZNF880 was significantly lower in COAD compared to the wild type. Simultaneously, the lncRNA-miRNA-ZNF880 ceRNA regulatory network was constructed through co-expression and miRNAs target gene prediction, demonstrating the precision of the ZNF880 regulatory network. In addition, the decreased expression of ZNF880 caused the significant immune infiltration decreases of CD8 + cells in COAD. In contrast, the immune infiltration of CD4 + cells and macrophages in COAD is positively correlated with ZNF880. Finally, through protein-protein interaction (PPI) network analysis and transcription factor target gene prediction, we screened out the genes most likely to be related to the function of ZNF880. CENPK, IFNGR2, REC8 and ZBTB17 were identified as the most closely functioning genes with ZNF880, which may indicate that ZNF880 has important links with the formation of cell centromere, tumor immunity, cell cycle and other pathways closely related to the occurrence of CRC. These studies show that the down-regulation of ZNF880 gene is closely related to CRC, and the targeted change of the expression of its regulatory molecules (miRNA and lncRNA) may be a new perspective for CRC treatment.

Gut microbiome determines therapeutic effects of OCA on NAFLD by modulating bile acid metabolism.

Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease, had no approved pharmacological agents yet. Obeticholic acid (OCA), a novel bile acid derivative, was demonstrated to ameliorate NAFLD-related manifestations. Regarding the role of gut-liver axis in liver disease development, this study aimed to explore the potential role of gut microbiota in the treatment of OCA in NAFLD mice induced by the high-fat diet (HFD). Antibiotic-induced microbiome depletion (AIMD) and fecal microbiota transplantation (FMT) confirmed the critical role of gut microbiota in OCA treatment for NAFLD by effectively alleviating histopathological lesions and restoring liver function impaired by HFD. Metagenomic analysis indicated that OCA intervention in HFD mice remarkably increased the abundance of Akkermansia muciniphila, Bifidobacterium spp., Bacteroides spp., Alistipes spp., Lactobacillus spp., Streptococcus thermophilus, and Parasutterella excrementihominis. Targeted metabolomics analysis indicated that OCA could modulate host bile acids pool by reducing levels of serum hydrophobic cholic acid (CA) and chenodeoxycholic acid (CDCA), and increasing levels of serum-conjugated bile acids, such as taurodeoxycholic acid (TDCA) and tauroursodesoxycholic acid (TUDCA) in the HFD-fed mice. Strong correlations were observed between differentially abundant microbes and the shifted bile acids. Furthermore, bacteria enriched by OCA intervention exhibited much greater potential in encoding 7alpha-hydroxysteroid dehydrogenase (7α-HSDs) producing secondary bile acids rather than bile salt hydrolases (BSHs) mainly responsible for primary bile acid deconjugation. In conclusion, this study demonstrated that OCA intervention altered gut microbiota composition with specially enriched gut microbes modulating host bile acids, thus effectively alleviating NAFLD in the mice.

Physical exercise attenuates age-related muscle atrophy and exhibits anti-ageing effects via the adiponectin receptor 1 signalling.

BACKGROUND: Although the adiponectin signalling exerts exercise-mimicking effects, whether this pathway contributes to the anti-ageing benefits of physical exercise has not been established yet. METHODS: Swim exercise training and wheel running were used to measure lifespan in the nematode Caenorhabditis elegans and skeletal muscle quality in mice, respectively. Muscle weight, muscle fibre cross-sectional area (CSA) and myonuclei number were used to evaluate muscle mass. RNA sequencing (RNA-Seq) analysis of skeletal muscle in exercised mice was used to study the underlying mechanisms. Western blot and immunofluorescence were performed to explore autophagy- and senescence-related markers. RESULTS: The C. elegans adiponectin receptor PAQR-1/AdipoR1, but not PAQR-2/AdipoR2, was activated (3.55-fold and 3.48-fold increases in p-AMPK on Days 1 and 6, respectively, P < 0.001), which was involved in lifespan extension in exercised worms. Exercise training increased skeletal muscle mass index (1.29-fold, P < 0.01), muscle weight (1.75-fold, P < 0.001), myonuclei number (1.33-fold, P < 0.05), muscle fibre CSA (1.39-fold, P < 0.05) and capillary abundance (2.19-fold, P < 0.001 for capillary density; 1.58-fold, P < 0.01 for capillary number) in aged mice. Physical exercise reduced protein (2.94-fold, P < 0.001) and mRNA levels (1.70-fold, P < 0.001) of p16INK4a , a marker for cellular senescence, in skeletal muscle of aged mice. These beneficial effects of exercise on skeletal muscle of mice were dependent on AdipoR1. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis for differentially expressed genes in skeletal muscle between exercised mice with and without AdipoR1 knockdown by RNA-Seq analysis revealed that several KEGG pathways, such as 'AMPK signalling pathway' (P < 0.001), 'FOXO signalling pathway' (P < 0.001) and 'autophagy' (P < 0.001) were overrepresented. Knockdown of FoxO3a inhibited exercise-mediated beneficial effects on skeletal muscle quality of mice by inhibiting autophagy/mitophagy (3.81-fold reduction in LC3-II protein, P < 0.001; 1.53-fold reduction in BNIP3 protein, P < 0.05). Knockdown of daf-16, the FoxO homologue in C. elegans, reduced autophagy (2.77-fold and 2.06-fold reduction in GFP::LGG-1 puncta in seam cells and the intestine, respectively, P < 0.05) and blocked lifespan extension by exercise in worms. CONCLUSIONS: Our findings provide insights into how the AdipoR1 pathway has an impact on the anti-ageing benefits of exercise and implicate that activation of the AdipoR1 signalling may represent a potential therapeutic strategy for reducing age-related loss of skeletal muscle.

Attach importance to the individualized treatment of adult portal hypertension based on etiology and pathogenesis: A review.

There are many factors that can cause portal hypertension and secondary symptoms such as ascites, splenomegaly, and variceal hemorrhage, can seriously affect patients' quality of life and even threaten their lives. In this paper, we summarize various causes of portal hypertension based on etiology and pathogenesis and give individualized treatment strategies in order to remind clinicians to pay attention to the identification of different causes and select corresponding treatment, so that patients are provided with the optimal treatment strategies and benefit from them.

Fagopyrum dibotrys extract alleviates hepatic steatosis and insulin resistance, and alters autophagy and gut microbiota diversity in mouse models of high-fat diet-induced non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a major global health concern with increasing prevalence, with a lack of currently available effective treatment options; thus, the investigation of novel therapeutic approaches is necessary. The study aimed to investigate the outcomes and mechanisms of action of Fagopyrum dibotrys extract (FDE) in a high-fat diet (HFD)-induced mouse model of obesity. The findings showed that FDE supplementation attenuated glucose tolerance, insulin resistance (IR), hepatic steatosis, and abnormal lipid metabolism. In addition, FDE also promoted autophagic activity and inhibited the phosphorylation of transcription factor EB in HFD-fed mice. Furthermore, gut microbiota characterization via 16S rRNA sequencing revealed that the supplementation of FDE increased Bacteroidetes and Verrucomicrobia populations while decreased Firmicutes, thus modifying the gut microbiome. FDE also increased the relative abundance of Akkermansia. Our findings suggest that FDE may protect against HFD-induced NAFLD by activating autophagy and alleviating dysbiosis in the gut microbiome. FDE may be beneficial as a nutraceutical treatment for NAFLD.

A Comparative Phylogenetic Analysis on the Chloroplast Genome in Different Reynoutria japonica Populations.

Reynoutria japonica Houtt., a traditional medicine herb of the Polygonaceae family, has been used since ancient times in China due to its various pharmacological effects. Chloroplast genomes are conservative and play an essential role in population diversity analysis. However, there are few studies on the chloroplast genome of R. japonica. In this study, the complete chloroplast genomes of three R. japonica from different regions were performed by next-generation sequencing technology. The results revealed that the lengths of the three chloroplast genomes are between 163,371~163,372 bp, and they have a highly conserved structure with a pair of inverted repeat (IR) regions (31,121 bp), a large single-copy (LSC) region (87,571~87,572 bp), and a small single-copy (SSC) region (13,558 bp). In total, 132 genes were annotated, including 8 rRNA genes, 37 tRNA genes, and 87 protein-coding genes. The phylogenetic analysis strongly revealed that 13 populations of R. japonica form a monophyly, and Fallopia multiflora (Polygonaceae) is its closest species. The two species diverged at ~20.47 million years ago, and R. japonica in China could be further divided into two major groups based on genetic structure analysis. In addition, several potential loci with suitable polymorphism were identified as molecular markers. Our study provides important genetic resources for further development and utilization of R. japonica germplasm, as well as some new insights into the evolutionary characteristics of this medicinal plant.

Protective Effects of Polydatin from Grapes and Reynoutria japonica Houtt. on Damaged Macrophages Treated with Acetaminophen.

The unregulated use of acetaminophen (APAP), an antipyretic and analgesic drug, harms hepatocytes and kidney cells, leading to liver failure and acute kidney injury. Herein, we investigate whether APAP damages macrophages in the immune system by observing its effects on macrophage proliferation and apoptosis. Using proteomics, we analyzed the effects of APAP on macrophage protein expression profiles and evaluated whether polydatin, the active ingredient in grapes and wine, can repair the damaged cells. The results showed that APAP alters the morphology and physiological processes of macrophages, inhibits macrophage proliferation, and promotes apoptosis. We observed 528 differentially expressed proteins when 500 µg/mL APAP was administered to the cells. These proteins are involved in biological processes including cell division, apoptosis, and acute phase response. Overall, our findings demonstrate that APAP harms the immune system by damaging macrophages and that polydatin can repair this damage.

[Genome structure and variation of Reynoutria japonica Houtt. chloroplast genome].

Reynoutria japonica Houtt., belonging to Polygoneae of Polygonaceae, is a Chinese medicinal herb with the functions of draining dampness and relieving jaundice, clearing heat and detoxifying, dispersing blood stasis and relieving pain, and relieving cough and resolving phlegm. In this study, we carried out high-throughput sequencing for the chloroplast genome sequences of five cultivars of R. japonica and analyzed the genome structure and variations. The chloroplast genomes of the five R. japonica cultivars had two sizes (163 376 bp and 163 371 bp) and a typical circular tetrad structure composed of a large single-copy (LSC) region of 85 784 bp, a small single-copy (SSC) region of 18 616 bp, and a pair of inverted repeat (IR) regions (IRa/IRb) which are spaced apart. A total of 161 genes were obtained by annotation, which consisted of 106 protein-coding genes, 10 rRNA-coding genes, and 45 tRNA-coding genes. The total GC content was 36.7%. Specifically, the GC content in the LSC, SSC, and IR regions were 34.8%, 30.7%, and 42.7%, respectively. Comparison of the whole chloroplast genome among the five cultivars showed that trnk-UUU, rpoC1, petD, rpl16, ndhA, and rpl12 in coding regions had sequence variations. In the phylogenetic tree constructed for the 11 samples of Polygoneae, the five cultivars of R. japonica clustered into one clade near the root and was a sister group of Fallopia multiflora (Thunb.).

Nomenclatural and taxonomic notes on Rubusdavidianus Kuntze and R.viburnifolius Franch.

Critical examinations of specimens, with literature reviews, have shown that Rubusdavidianus is conspecific with R.lambertianus. Therefore, we treat R.davidianus as a new synonym within Rubus. We propose a new name, Rubusloirensis Ti R. Huang nom. nov. to replace the later homonym of R.pycnanthus Genev. Additionally, lectotypification of three names, R.davidianus Kuntze, R.malifolius Focke and R.viburnifolius Franch., are designated here after examination of previous works.

The Identity of Rubuspekinensis Focke and R.crataegifolius Bunge (Rosaceae).

A critical examination of specimens, with literature and a field survey have shown that Rubuspekinensis is conspecific with R.crataegifolius. Their morphological variations range can be defined as: leaves at the base may be ovate, suborbicular, narrowly ovate, entire, at the middle, ovate, narrowly ovate, oblong-lanceolate, palmately 3-lobed or 5-lobed and at the top, ovate, lanceolate, entire or 3-lobed; flowers solitary in the axillae or several flowers clustered at the terminal of branchlets or formed into short racemes. Therefore, we treat the former species as a synonym for the latter one.

Immobilized Crosslinked Pectinase Preparation on Porous ZSM-5 Zeolites as Reusable Biocatalysts for Ultra-Efficient Hydrolysis of ß-Glycosidic Bonds.

In this study, we immobilized pectinase preparation on porous zeolite ZSM-5 as an enzyme carrier. We realized this immobilized enzyme catalyst, pectinase preparation@ZSM-5, via a simple combined strategy involving the van der Waals adsorption of pectinase preparation followed by crosslinking of the adsorbed pectinase preparation with glutaraldehyde over ZSM-5. Conformal pectinase preparation coverage of various ZSM-5 supports was achieved for the as-prepared pectinase preparation@ZSM-5. The porous pectinase preparation@ZSM-5 catalyst exhibited ultra-efficient biocatalytic activity for hydrolyzing the ß-glycosidic bonds in the model substrate 4-nitrophenyl ß-D-glucopyranoside, with a broad operating temperature range, high thermal stability, and excellent reusability. The relative activity of pectinase preparation@ZSM-5 at a high temperature (70 °C) was nine times higher than that of free pectinase preparation. Using thermal inactivation kinetic analysis based on the Arrhenius law, pectinase preparation@ZSM-5 showed higher activation energy for denaturation (315 kJ mol-1) and a longer half-life (62 min-1) than free pectinase preparation. Moreover, a Michaelis-Menten enzyme kinetic analysis indicated a higher maximal reaction velocity for pectinase preparation@ZSM-5 (0.22 µmol mg-1 min-1). This enhanced reactivity was attributed to the microstructure of the immobilized pectinase preparation@ZSM-5, which offered a heterogeneous reaction system that decreased the substrate-pectinase preparation binding affinity and modulated the kinetic characteristics of the enzyme. Additionally, pectinase preparation@ZSM-5 showed the best ethanol tolerance among all the reported pectinase preparation-immobilized catalysts, and an activity 247% higher than that of free pectinase preparation at a 10% (v/v) ethanol concentration was measured. Furthermore, pectinase preparation@ZSM-5 exhibited potential for practical engineering applications, promoting the hydrolysis of ß-glycosidic bonds in baicalin to convert it into baicalein. This was achieved with a 98% conversion rate, i.e., 320% higher than that of the free enzyme.

Metformin Alleviates Hepatic Steatosis and Insulin Resistance in a Mouse Model of High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease by Promoting Transcription Factor EB-Dependent Autophagy.

Nonalcoholic fatty liver disease (NAFLD) results from an abnormal accumulation of lipids within hepatocytes, and is commonly associated with obesity, insulin resistance, and hyperlipidemia. Metformin is commonly used to treat type 2 diabetes mellitus and, in recent years, it was found to play a potential role in the amelioration of NAFLD. However, the mechanisms underlying the protective effect of metformin against NAFLD remain largely unknown. Transcription factor EB (TFEB) is a master transcriptional regulator of lysosomal biogenesis and autophagy and, when activated, is effective against disorders of lipid metabolism. However, the role of TFEB in hepatic steatosis is not well understood. In this report, we demonstrate that the activity of TFEB is reduced in the liver of mice fed a high-fat diet. Metformin treatment significantly reverses the activity of TFEB, and the protective effect of metformin against hepatic steatosis and insulin resistance is dependent on TFEB. We show that metformin-induced autophagy is regulated by TFEB, and our findings reveal that TFEB acts as a mediator, linking metformin with autophagy to reverse NAFLD, and highlight that TFEB may be a promising molecular target for the treatment of NAFLD.

Autophagy induced by H. pylori VacA regulated the survival mechanism of the SGC7901 human gastric cancer cell line.

BACKGROUND: Vacuolating cytotoxin (VacA) is an important virulence factor of Helicobacter pylori (H. pylori). It was previously believed that VacA can trigger the cascade of apoptosis on mitochondria to lead to cell apoptosis. Recently, it was found that VacA can induce autophagy. However, the molecular mechanism by which VacA induces autophagy is largely unknown. OBJECTIVE: We aimed to explore the molecular mechanism of autophagy induced by H. pylori in gastric cancer cells and the effect of autophagy on the survival of gastric cancer cells. METHODS: The autophagy of human gastric cancer cell line SGC7901 was detected by Western blot and RT-PCR in the treatment of VacA protein of H. pylori. The relationship between autophagy and reactive oxygen species (ROS) in the proliferation of gastric cancer cells were studied by gene expression silences (siRNA) and CM-H2DCFDA (DCF) staining. RESULTS: The results showed that VacA protein secreted by H. pylori in the supernatant stimulated autophagy in SGC7901 cells. After VacA protein treatment, the mRNA expressions of BECN1, ATG7 and PIK3C3, were up-regulated. ATG7 silencing by siRNA inhibited VacA-induced autophagy. Furthermore, our data demonstrated that VacA protein increased ROS levels. Addition of the antioxidant N-acetyl-L-cysteine (NAC) suppressed the levels of ROS, leading to inhibition of autophagy. CONCLUSIONS: H. pylori VacA is a key toxin that induces autophagy by increased ROS levels. And our findings demonstrated that VacA significantly inhibited proliferation in SGC7901 cells.

Octaketide Synthase from Polygonum cuspidatum Implements Emodin Biosynthesis in Arabidopsis thaliana.

Plant anthranoids are medicinally used for their purgative properties. Their scaffold was believed to be formed by octaketide synthase (OKS), a member of the superfamily of type III polyketide synthase (PKS) enzymes. Here, a cDNA encoding OKS of Polygonum cuspidatum was isolated using a homology-based cloning strategy. When produced in Escherichia coli, P. cuspidatum octaketide synthase (PcOKS) catalyzed the condensation of eight molecules of malonyl-CoA to yield a mixture of unphysiologically folded aromatic octaketides. However, when the ORF for PcOKS was expressed in Arabidopsis thaliana, the anthranoid emodin was detected in the roots of transgenic lines. No emodin was found in the roots of wild-type A. thaliana. This result indicated that OKS is the key enzyme of plant anthranoids biosynthesis. In addition, the root growth of the transgenic A. thaliana lines was inhibited to an extent that resembled the inhibitory effect of exogenous emodin on the root growth of wild-type A. thaliana. Immunochemical studies of P. cuspidatum plants detected PcOKS mainly in roots and rhizome, in which anthranoids accumulate. Co-incubation of E. coli - produced PcOKS and cell-free extract of wild-type A. thaliana roots did not form a new product, suggesting an alternative, physiological folding of PcOKS and its possible interaction with additional factors needed for anthranoids assembling in transgenic A. thaliana. Thus, transgenic A. thaliana plants producing PcOKS provide an interesting system for elucidating the route of plant anthranoid biosynthesis.

Fenofibrate Improves Insulin Resistance and Hepatic Steatosis and Regulates the Let-7/SERCA2b Axis in High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease Mice.

Fenofibrate is widely used in clinical therapy to effectively ameliorate the development of non-alcoholic fatty liver disease (NAFLD); however, its specific molecular mechanism of action remains largely unknown. MicroRNAs (miRNAs) are key mediators in regulating endoplasmic reticulum (ER) stress during NAFLD, and the deregulation of miRNAs has been demonstrated in NAFLD pathophysiology. The present study aimed to identify whether fenofibrate could influence miRNA expression in NAFLD and investigate the specific mechanism of action of fenofibrate in lipid metabolism disorder-associated diseases. We found that fenofibrate alleviated ER stress and increased the levels of SERCA2b, which serves as a regulator of ER stress. Additionally, the levels of let-7 miRNA were regulated by fenofibrate; let-7 was found to target the 3' untranslated region of SERCA2b. The present data suggest that the protective effects of fenofibrate against insulin resistance and its suppressive activity against excessive hepatic lipid accumulation may be related to the alteration of the let-7/SERCA2b axis and alleviation of ER stress.