Structural insights into adhesion GPCR ADGRL3 activation and Gq, Gs, Gi, and G12 coupling.

Adhesion G-protein-coupled receptors (aGPCRs) play key roles in a diversity of physiologies. A hallmark of aGPCR activation is the removal of the inhibitory GAIN domain and the dipping of the cleaved stalk peptide into the ligand-binding pocket of receptors; however, the detailed mechanism remains obscure. Here, we present cryoelectron microscopy (cryo-EM) structures of ADGRL3 in complex with Gq, Gs, Gi, and G12. The structures reveal unique ligand-engaging mode, distinctive activation conformation, and key mechanisms of aGPCR activation. The structures also reveal the uncharted structural information of GPCR/G12 coupling. A comparison of Gq, Gs, Gi, and G12 engagements with ADGRL3 reveals the key determinant of G-protein coupling on the far end of αH5 of Gα. A detailed analysis of the engagements allows us to design mutations that specifically enhance one pathway over others. Taken together, our study lays the groundwork for understanding aGPCR activation and G-protein-coupling selectivity.

Network physics of attractive colloidal gels: Resilience, rigidity, and phase diagram.

Colloidal gels exhibit solid-like behavior at vanishingly small fractions of solids, owing to ramified space-spanning networks that form due to particle-particle interactions. These networks give the gel its rigidity, and with stronger attractions the elasticity grows as well. The emergence of rigidity can be described through a mean field approach; nonetheless, fundamental understanding of how rigidity varies in gels of different attractions is lacking. Moreover, recovering an accurate gelation phase diagram based on the system's variables has been an extremely challenging task. Understanding the nature of colloidal clusters, and how rigidity emerges from their connections is key to controlling and designing gels with desirable properties. Here, we employ network analysis tools to interrogate and characterize the colloidal structures. We construct a particle-level network, having all the spatial coordinates of colloids with different attraction levels, and also identify polydisperse rigid fractal clusters using a Gaussian mixture model, to form a coarse-grained cluster network that distinctly shows main physical features of the colloidal gels. A simple mass-spring model then is used to recover quantitatively the elasticity of colloidal gels from these cluster networks. Interrogating the resilience of these gel networks shows that the elasticity of a gel (a dynamic property) is directly correlated to its cluster network's resilience (a static measure). Finally, we use the resilience investigations to devise [and experimentally validate] a fully resolved phase diagram for colloidal gelation, with a clear solid-liquid phase boundary using a single volume fraction of particles well beyond this phase boundary.

Downregulation of Wtap causes dilated cardiomyopathy and heart failure.

RNA binding proteins have been shown to regulate heart development and cardiac diseases. However, the detailed molecular mechanisms is not known. In this study, we identified Wilms' tumor 1-associating protein (WTAP, a key regulatory protein of the m6A RNA methyltransferase complex) as a key regulator of heart function and cardiac diseases. WTAP is associated with heart development, and its expression is downregulated in both human and mice with heart failure. Cardiomyocyte-specific knockout of Wtap (Wtap-CKO) induces dilated cardiomyopathy, heart failure and neonatal death. Although WTAP deficiency in the heart decreases METTL3 (methyltransferase-like 3) protein levels, cardiomyocyte-specific overexpression of Mettl3 in Wtap-CKO mice does not rescue the phenotypes of Wtap-CKO mice. Instead, WTAP deficiency in the heart decreases chromatin accessibility in the promoter regions of Mef2a (myocyte enhancer factor-2α) and Mef2c, leading to reduced mRNA and protein levels of these genes and lower expression of their target genes. Conversely, WTAP directly binds to the promoter of the Mef2c gene and increases its promoter luciferase activity and expression. These data demonstrate that WTAP plays a key role in heart development and cardiac function by maintaining the chromatin accessibility of cardiomyocyte specific genes.

Hepatocyte-specific Wtap deficiency promotes hepatocellular carcinoma by activating GRB2-ERK depending on downregulation of proteasome-related genes.

Wilm's tumor 1-associating protein (WTAP), a regulatory protein of the m6A methyltransferase complex, has been found to play a role in regulating various physiological and pathological processes. However, the in vivo role of WTAP in the pathogenesis of hepatocellular carcinoma (HCC) is unknown. In this study, we have elucidated the crucial role of WTAP in HCC progression and shown that hepatic deletion of Wtap promotes HCC pathogenesis through activation of multiple signaling pathways. A single dose of diethylnitrosamine injection causes more and larger HCCs in hepatocyte-specific Wtap knockout (Wtap-HKO) mice than Wtapflox/flox mice fed with either normal chow diet or a high-fat diet. Elevated CD36, IGFBP1 (insulin-like growth factor-binding protein 1), and chemokine (C-C motif) ligand 2 (CCL2) expression leads to steatosis and inflammation in the Wtap-HKO livers. The hepatocyte proliferation is dramatically increased in Wtap-HKO mice, which is due to higher activation of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription-3 signaling pathways. Hepatic deletion of Wtap activates the ERK signaling pathway by increasing the protein stability of GRB2 and ERK1/2, which is due to the decreased expression of proteasome-related genes. Restoring PSMB4 or PSMB6 (two key components of the proteasome) leads to the downregulation of GRB2 and ERK1/2 in Wtap-HKO hepatocytes. Mechanistically, WTAP interacts with RNA polymerase II and H3K9ac to maintain expression of proteasome-related genes. These results demonstrate that hepatic deletion of Wtap promotes HCC progression through activating GRB2-ERK1/2-mediated signaling pathway depending on the downregulation of proteasome-related genes especially Psmb4 and Psmb6.

BGL3 lncRNA mediates retention of the BRCA1/BARD1 complex at DNA damage sites.

Long non-coding RNAs (lncRNAs) are emerging regulators of genomic stability and human disease. However, the molecular mechanisms by which nuclear lncRNAs directly contribute to DNA damage responses remain largely unknown. Using RNA antisense purification coupled with quantitative mass spectrometry (RAP-qMS), we found that the lncRNA BGL3 binds to PARP1 and BARD1, exhibiting unexpected roles in homologous recombination. Mechanistically, BGL3 is recruited to DNA double-strand breaks (DSBs) by PARP1 at an early time point, which requires its interaction with the DNA-binding domain of PARP1. BGL3 also binds the C-terminal BRCT domain and an internal region (amino acids 127-424) of BARD1, which mediates interaction of the BRCA1/BARD1 complex with its binding partners such as HP1γ and RAD51, resulting in BRCA1/BARD1 retention at DSBs. Cells depleted for BGL3 displayed genomic instability and were sensitive to DNA-damaging reagents. Overall, our findings underscore the biochemical versatility of RNA as a mediator molecule in the DNA damage response pathway, which affects the accumulation of BRCA1/BARD1 at DSBs.

A network pharmacology- and transcriptomics-based investigation reveals an inhibitory role of ß-sitosterol in glioma via the EGFR/MAPK signaling pathway.

Glioma is characterized by rapid cell proliferation, aggressive invasion, altered apoptosis and a poor prognosis. ß-Sitosterol, a kind of phytosterol, has been shown to possess anticancer activities. Our current study aims to investigate the effects of ß-sitosterol on gliomas and reveal the underlying mechanisms. Our results show that ß-sitosterol effectively inhibits the growth of U87 cells by inhibiting proliferation and inducing G2/M phase arrest and apoptosis. In addition, ß-sitosterol inhibits migration by downregulating markers of epithelial-mesenchymal transition (EMT). Mechanistically, network pharmacology and transcriptomics approaches illustrate that the EGFR/MAPK signaling pathway may be responsible for the inhibitory effect of ß-sitosterol on glioma. Afterward, the results show that ß-sitosterol effectively suppresses the EGFR/MAPK signaling pathway. Moreover, ß-sitosterol significantly inhibits tumor growth in a U87 xenograft nude mouse model. ß-Sitosterol inhibits U87 cell proliferation and migration and induces apoptosis and cell cycle arrest in U87 cells by blocking the EGFR/MAPK signaling pathway. These results suggest that ß-sitosterol may be a promising therapeutic agent for the treatment of glioma.

A Framework for Determining the Optimal Vibratory Frequency of Graded Gravel Fillers Using Hammering Modal Approach and ANN.

To address the uncertainty of optimal vibratory frequency fov of high-speed railway graded gravel (HRGG) and achieve high-precision prediction of the fov, the following research was conducted. Firstly, commencing with vibratory compaction experiments and the hammering modal analysis method, the resonance frequency f0 of HRGG fillers, varying in compactness K, was initially determined. The correlation between f0 and fov was revealed through vibratory compaction experiments conducted at different vibratory frequencies. This correlation was established based on the compaction physical-mechanical properties of HRGG fillers, encompassing maximum dry density ρdmax, stiffness Krd, and bearing capacity coefficient K20. Secondly, the gray relational analysis algorithm was used to determine the key feature influencing the fov based on the quantified relationship between the filler feature and fov. Finally, the key features influencing the fov were used as input parameters to establish the artificial neural network prediction model (ANN-PM) for fov. The predictive performance of ANN-PM was evaluated from the ablation study, prediction accuracy, and prediction error. The results showed that the ρdmax, Krd, and K20 all obtained optimal states when fov was set as f0 for different gradation HRGG fillers. Furthermore, it was found that the key features influencing the fov were determined to be the maximum particle diameter dmax, gradation parameters b and m, flat and elongated particles in coarse aggregate Qe, and the Los Angeles abrasion of coarse aggregate LAA. Among them, the influence of dmax on the ANN-PM predictive performance was the most significant. On the training and testing sets, the goodness-of-fit R2 of ANN-PM all exceeded 0.95, and the prediction errors were small, which indicated that the accuracy of ANN-PM predictions was relatively high. In addition, it was clear that the ANN-PM exhibited excellent robust performance. The research results provide a novel method for determining the fov of subgrade fillers and provide theoretical guidance for the intelligent construction of high-speed railway subgrades.

Current Status of Novel Multifunctional Targeted Pt(IV) Compounds and Their Reductive Release Properties.

Platinum-based drugs are widely used in chemotherapy for various types of cancer and are considered crucial. Tetravalent platinum (Pt(IV)) compounds have gained significant attention and have been extensively researched among these drugs. Traditionally, Pt(IV) compounds are reduced to divalent platinum (Pt(II)) after entering cells, causing DNA lesions and exhibiting their anti-tumor effect. However, the available evidence indicates that some Pt(IV) derivatives may differ from the traditional mechanism and exert their anti-tumor effect through their overall structure. This review primarily focuses on the existing literature regarding targeted Pt(II) and Pt(IV) compounds, with a specific emphasis on their in vivo mode of action and the properties of reduction release in multifunctional Pt(IV) compounds. This review provides a comprehensive summary of the design and synthesis strategies employed for Pt(II) derivatives that selectively target various enzymes (glucose receptor, folate, telomerase, etc.) or substances (mitochondria, oleic acid, etc.). Furthermore, it thoroughly examines and summarizes the rational design, anti-tumor mechanism of action, and reductive release capacity of novel multifunctional Pt(IV) compounds, such as those targeting p53-MDM2, COX-2, lipid metabolism, dual drugs, and drug delivery systems. Finally, this review aims to provide theoretical support for the rational design and development of new targeted Pt(IV) compounds.

Deficiency of WTAP in islet beta cells results in beta cell failure and diabetes in mice.

AIMS/HYPOTHESIS: N6-methyladenosine (m6A) mRNA methylation and m6A-related proteins (methyltransferase-like 3 [METTL3], methyltransferase-like 14 [METTL14] and YTH domain containing 1 [YTHDC1]) have been shown to regulate islet beta cell function and the pathogenesis of diabetes. However, whether Wilms' tumour 1-associating protein (WTAP), a key regulator of the m6A RNA methyltransferase complex, regulates islet beta cell failure during pathogenesis of diabetes is largely unknown. The present study aimed to investigate the role of WTAP in the regulation of islet beta cell failure and diabetes. METHODS: Islet beta cell-specific Wtap-knockout and beta cell-specific Mettl3-overexpressing mice were generated for this study. Blood glucose, glucose tolerance, serum insulin, glucose-stimulated insulin secretion (both in vivo and in vitro), insulin levels, glucagon levels and beta cell apoptosis were examined. RNA-seq and MeRIP-seq were performed, and the data were well analysed. RESULTS: WTAP was downregulated in islet beta cells in type 2 diabetes, due to lipotoxicity and chronic inflammation, and islet beta cell-specific deletion of Wtap (Wtap-betaKO) induced beta cell failure and diabetes. Wtap-betaKO mice showed severe hyperglycaemia (above 20 mmol/l [360 mg/dl]) from 8 weeks of age onwards. Mechanistically, WTAP deficiency decreased m6A mRNA modification and reduced the expression of islet beta cell-specific transcription factors and insulin secretion-related genes by reducing METTL3 protein levels. Islet beta cell-specific overexpression of Mettl3 partially reversed the abnormalities observed in Wtap-betaKO mice. CONCLUSIONS/INTERPRETATION: WTAP plays a key role in maintaining beta cell function by regulating m6A mRNA modification depending on METTL3, and the downregulation of WTAP leads to beta cell failure and diabetes. DATA AVAILABILITY: The RNA-seq and MeRIP-seq datasets generated during the current study are available in the Gene Expression Omnibus database repository ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE215156 ; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE215360 ).

GBP5 promotes liver injury and inflammation by inducing hepatocyte apoptosis.

Liver injury is the first step in causing fibrosis, cirrhosis, and liver cancer, leading to mortality. However, the drivers of progressive liver injury are still incompletely defined. Here, we identify GBP5 as a major factor causing liver injury and inflammation. We show that the expression of GBP5 is abnormally elevated in the damaged liver, and its expression depends at least partially on the NF-κB-inducing kinase (NIK)/NF-κB2 signaling pathway. Knockout of Gbp5 ameliorates D-galactosamine/lipopolysaccharide (GalN/LPS)-induced liver injury and inflammation. Conversely, liver-specific overexpression of GBP5 induces liver injury and inflammation. Mechanistically, GBP5 induces hepatocyte apoptosis through the activation of both calpain/caspase 12/caspase 3 and TNFα/caspase 8/caspase 3 signaling pathways. Inhibition of either calpain activity or caspase 3 prevents GBP5-induced cell death. Our data demonstrate that GBP5 expression is induced by toxins or the NIK signaling pathway, which promotes both extrinsic and intrinsic apoptosis signaling pathways and further induces liver injury, providing a novel drug target for the treatment of liver injury and inflammation.

Nature-inspired designs for disordered acoustic bandgap materials.

We introduce an amorphous mechanical metamaterial inspired by how cells pack in biological tissues. The spatial heterogeneity in the local stiffness of these materials has been recently shown to impact the mechanics of confluent biological tissues and cancer tumor invasion. Here we use this bio-inspired structure as a design template to construct mechanical metamaterials and show that this heterogeneity can give rise to amorphous cellular solids with large, tunable acoustic bandgaps. Unlike acoustic crystals with periodic structures, the bandgaps here are directionally isotropic and robust to defects due to their complete lack of positional order. Possible ways to manipulate bandgaps are explored with a combination of the tissue-level elastic modulus and local stiffness heterogeneity of cells. To further demonstrate the existence of bandgaps, we dynamically perturb the system with an external sinusoidal wave in the perpendicular and horizontal directions. The transmission coefficients are calculated and show valleys that coincide with the location of bandgaps. Experimentally this design should lead to the engineering of self-assembled rigid acoustic structures with full bandgaps that can be controlled via mechanical tuning and promote applications in a broad area from vibration isolations to mechanical waveguides.

Peptide-anchored neutrophil membrane-coated biomimetic nanodrug for targeted treatment of rheumatoid arthritis.

Macrophage polarization determines the production of cytokines that fuel the initiation and evolution of rheumatoid arthritis (RA). Thus, modulation of macrophage polarization might represent a potential therapeutic strategy for RA. However, coordinated modulation of macrophages in the synovium and synovial fluid has not been achieved thus far. Herein, we develop a biomimetic ApoA-I mimetic peptide-modified neutrophil membrane-wrapped F127 polymer (R4F-NM@F127) for targeted drug delivery during RA treatment. Due to the high expression of adhesion molecules and chemokine receptors on neutrophils, the neutrophil membrane coating can endow the nanocarrier with synovitis-targeting ability, with subsequent recruitment to the synovial fluid under the chemotactic effects of IL-8. Moreover, R4F peptide modification further endows the nanocarrier with the ability to target the SR-B1 receptor, which is highly expressed on macrophages in the synovium and synovial fluid. Long-term in vivo imaging shows that R4F-NM@F127 preferentially accumulates in inflamed joints and is engulfed by macrophages. After loading of the anti-inflammatory drug celastrol (Cel), R4F-NM@F127-Cel shows a significant reduction in hepatotoxicity, and effectively inhibits synovial inflammation and alleviates joint damage by reprogramming macrophage polarization. Thus, our results highlight the potential of the coordinated targeted modulation of macrophages as a promising therapeutic option for the treatment of RA.

Activation of Kir2.1 improves myocardial fibrosis by inhibiting Ca 2+ overload and the TGF-ß1/Smad signaling pathway.

The inwardly rectifying potassium channel Kir2.1 is closely associated with many cardiovascular diseases. However, the effect and mechanism of Kir2.1 in diabetic cardiomyopathy remain unclear. In vivo, we use STZ to establish the model, and ventricular structural changes, myocardial inflammatory infiltration, and myocardial fibrosis severity are detected by echocardiography, histological staining, immunohistochemistry, and western blot analysis, respectively. In vitro, a myocardial fibrosis model is established with high glucose. The Kir2.1 current amplitude, intracellular calcium concentration, fibrosis-related proteins, and TGF-ß1/Smad pathway proteins are detected by whole-cell patch clamp, calcium probes, western blot analysis, and immunofluorescence, respectively. The in vivo results show that compared to diabetic cardiomyopathy, zacopride (a Kir2.1 selective agonist) significantly reduces the left ventricular systolic diameter and diastolic diameter, increases the left ventricular ejection fraction and left ventricular short-axis shortening, improves the degree of cell necrosis, and reduces the expression of myocardial interstitial fibrosis protein and collagen fibre deposition area. The in vitro results show that the current amplitude and protein expression of Kir2.1 are both decreased in the high glucose-induced myocardial fibrosis model. Additionally, zacopride significantly upregulates the expression of Kir2.1 and inhibits the expressions of the fibrosis-related proteins α-SMA, collagen I, and collagen III. Activation of Kir2.1 reduces the intracellular calcium concentration and inhibits the protein expressions of TGF-ß1 and p-Smad 2/3. Activation of Kir2.1 can improve myocardial fibrosis induced by diabetic cardiomyopathy, and the possible mechanism may be related to inhibiting Ca 2+ overload and the TGF-ß1/Smad signaling pathway.

Association of DNA methylation and transcriptome reveals epigenetic etiology of heart failure.

Epigenetic modifications viz. DNA methylation, histone modifications, and RNA-based alterations play a crucial role in the development of cardiovascular diseases. In this study, we investigated DNA methylation with an aim to reveal the epigenetic etiology of heart failure. Sprague-Dawley rats surviving myocardial infarction developed acute heart failure in 1 week. Genomic DNA methylation changes were profiled by bisulfite sequencing, and gene expression levels were analyzed by RNA-seq in failing and sham-operation hearts. A total of 3480 differentially methylated genes in the promoter regions including transcriptional start site and 1934 transcriptome-altered genes were identified in the defected hearts. Common differential genes were enriched by the gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway, and protein-protein interaction for HF phenotypes. Among these, Mettl11b, HDAC3, HDAC11, ubiquitination-related genes, and snoRNAs are new epigenetic classifiers that had not been reported yet, which may be important regulators in HF.

α1 -Adrenoceptors activate the NLRP3 inflammasome through downregulation of Kir2.1 in cardiac inflammation.

NEW FINDINGS: What is the central question of this study? What is the mechanism of cardiac inflammation induced by α1 -adrenoceptor stimulation by NLRP3 inflammasome activation? What is the main finding and its importance? In the mechanism of cardiac inflammation induced by α1 -adrenoceptor overactivation, Kir2.1 exerts cardioprotective and anti-inflammatory effects by inhibiting the activation of the NLRP3 inflammasome. ABSTRACT: Overstimulation of sympathetic nerves in cardiovascular diseases can lead to impaired cardiomyocyte function and potential heart failure, which activates not only the ß-adrenoceptors but also the α1 -adrenoceptors (α1 -AR). A previous report indicated that NLRP3 inflammasome activation is involved in cardiac inflammation induced by the α1 -AR agonist phenylephrine (PE), but the mechanism is still unknown. Here, we aimed to study whether Kir2.1 is involved in cardiac inflammation caused by PE. The results from in vitro experiments showed that PE upregulated the expression levels of NLRP3, caspase-1, interleukin (IL)-18 and IL-1ß and downregulated the expression level of Kir2.1 in H9C2 cells. The Kir2.1 agonist zacopride downregulated the expression of NLRP3, caspase-1, IL-1ß and IL-18, and the Kir2.1 inhibitor ML133 upregulated their expression. To further explore the mechanism, we found that zacopride downregulated the protein expression level of p-p65 and that ML133 upregulated it. Moreover, the nuclear factor-κB (NF-κB) signalling pathway inhibitor curcumenol reversed the expression of NLRP3 inflammasomes caused by PE in H9C2 cells. In in vivo experiments, the protein expression level of Kir2.1 in the PE group was significantly decreased, and the activation of Kir2.1 by zacopride reduced cardiac inflammation. In short, Kir2.1 is involved in α1 -AR overactivation, which induces cardiac inflammation, through the NF-κB signalling pathway, and activating Kir2.1 can downregulate NLRP3 inflammation and exert cardioprotective effects induced by zacopride.

Palladium-Catalyzed Asymmetric [3 + 2] Annulation of Vinylethylene Carbonates with Alkenes Installed on Cyclic N-Sulfonyl Imines: Highly Enantio- and Diastereoselective Construction of Chiral Tetrahydrofuran Scaffolds Bearing Three Vicinal and Quaternary Stereocenters.

A multisubstituted tetrahydrofuran building block bearing three vicinal chiral carbon centers widely exists in a broad spectrum of bioactive natural products, and the development of efficient and convenient methods to establish this skeleton remains a challenging task. Herein, we have developed an efficient method for the construction of significant tetrahydrofuran scaffolds bearing three vicinal and α-quaternary chiral carbon stereocenters through Pd-catalyzed asymmetric [3 + 2] annulation of vinylethylene carbonates with alkenes installed on cyclic N-sulfonyl imines. A series of multisubstituted tetrahydrofuran derivatives are obtained in high efficiencies with excellent enantioselectivities and diastereoselectivities. Density functional theory (DFT) studies are accomplished to rationalize the stereocontrol of the annulation process and disclose that methanol could be applied to stabilize the reactive zwitterionic π-allylpalladium via the H-bond interaction.

Highly diastereo- and enantioselective synthesis of multisubstituted allylic amino acid derivatives by allylic alkylation of a chiral glycine-based nickel complex and vinylethylene carbonates.

The asymmetric synthesis of multisubstituted allylic amino acid derivatives was accomplished by the allylic alkylation of a chiral glycine-based nickel complex with vinylethylene carbonates. High enantioselectivities and diastereoselectivities were obtained under mild reaction conditions. The gram-scale synthesis was carried out with a good yield and high enantioselectivity, indicating that the method is a highly efficient route to chiral multisubstituted allylic amino acid derivatives.

Effect of thermal treatment on aroma compound formation in yeast fermented pork hydrolysate supplemented with xylose and cysteine.

BACKGROUND: The present study has revealed an innovative method of coupling enzyme hydrolysis, yeast fermentation and thermal treatment to transform pork trimmings into a seasoning product. The pork trimmings were first enzymatically hydrolysed and fermented into liquid pork hydrolysates, followed by adding xylose and cysteine, then heat treatment. RESULTS: Approximately 28% of xylose and 7% of glucose were consumed, and amino acids increased by around 31% after thermal treatment. The heated yeast fermented pork hydrolysates possessed a characteristic 'savoury, roasted-meat and fruity sweet' aroma as a result of the formation of thermally induced sulfur-containing volatiles such as 2-furfurylthiol, as well as retention of yeast generated esters including isoamyl acetate and hexyl acetate. CONCLUSION: The heat-treated fermented pork hydrolysates impart an attractive and innovative aroma because of yeast fermentation and heat treatment. The innovative heated fermented pork hydrolysates could be further processed into a nutritional and savoury pork broth and/or a meat sauce. © 2021 Society of Chemical Industry.

[Bioinformatics analysis of the microRNA expression profile in the peripheral blood lymphocytes of Kazakh patients with essential hypertension in Xinjiang].

This study aimed to investigate the differential expression profiles of microRNAs (miRNAs) in peripheral blood lymphocytes between patients with essential hypertension and healthy individuals in Xinjiang Kazakh and to provide insight into the mechanism involved in the pathogenesis of hypertension in this ethnic group. From April 2016 to May 2019, 30 Kazakh patients with essential hypertension in the inpatient and outpatient departments of Cardiology, First Affiliated Hospital of Shihezi University were used as the hypertension group; 30 healthy Kazakh patients were used as the control group. The miRNA expression profiles in peripheral blood lymphocytes of 6 Kazakh hypertensive patients and 6 matched healthy individuals were compared, and the differentially expressed miRNAs were analyzed by cluster analysis, GSEA enrichment analysis, target gene prediction, target gene annotation and other bioinformatics analyses. In addition, qRT-PCR was used to verify the differentially expressed miRNAs. The results showed that compared with the control group, 73 differentially expressed miRNAs were identified in the hypertension group, of which 39 miRNAs were up-regulated and 34 miRNAs were down-regulated. A total of 11 miRNAs related to hypertension were screened by GSEA enrichment analysis, including hsa-miR-100-5p, hsa-miR-150-5p, hsa-miR-299-5p, hsa-miR-299-3p, hsa-miR-296-5p, hsa-miR-196b-5p, hsa-miR-503-5p, hsa-miR-628-5p, hsa-miR-874-3p, hsa-miR-543 and hsa-miR-940. qRT-PCR test found that the expression of hsa-miR-100-5p, hsa-miR-299-5p, hsa-miR-299-3p, hsa-miR-196b-5p, hsa-miR-503-5p, hsa-miR-628-5p and hsa-miR-543 was up-regulated, while the expression of hsa-miR-150-5p, hsa-miR-296-5p, hsa-miR-874-3p and hsa-miR-940 was down-regulated in the hypertension group compared with the control group. The expression trend in the gene chip was consistent with the results verified by qRT-PCR. Using online database to predict target genes of 11 miRNAs related to hypertension, we found that a total of 1 647 target genes might be regulated by these 11 miRNAs. GO function enrichment showed that (a) in biological processes, the predicted hypertension related target genes are mainly relevant to nervous system development, cellular localization, regulation of cellular metabolic process, generation of neurons and positive regulation of biological process; (b) In terms of cellular components, they are mainly related to membrane-bounded organelle, cytoplasm, intracellular membrane-bounded organelle, synapse part, neuron part, and nucleoplasm; (c) In terms of molecular function, they are mainly related to protein binding, transcription regulatory region DNA binding, RNA polymerase II regulatory region DNA binding, transcription regulator activity, and ion binding. KEGG enrichment analysis showed that the p53 signaling pathway, adrenergic signaling in cardiomyocytes, cAMP signaling pathway, TGF-ß signaling pathway, endocrine and other factor-regulated calcium reabsorption, mTOR signaling pathway, and aldosterone-regulated sodium reabsorption may be related to the occurrence and development of hypertension. In conclusion, there are significant differences in the expression of miRNAs in peripheral blood lymphocytes between Kazakh patients with essential hypertension and healthy people. The differentially expressed miRNAs may be related to the occurrence and development of essential hypertension in Kazakh. However, the underlying mechanism needs to be further explored and verified.

Liver X receptors conserve the therapeutic target potential for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic multi-system autoimmune disease with extremely complex pathogenesis. Significantly altered lipid paradox related to the inflammatory burden is reported in RA patients, inducing 50% higher cardiovascular risks. Recent studies have also demonstrated that lipid metabolism can regulate many functions of immune cells in which metabolic pathways have altered. The nuclear liver X receptors (LXRs), including LXRα and LXRß, play a central role in regulating lipid homeostasis and inflammatory responses. Undoubtedly, LXRs have been considered as an attractive therapeutic target for the treatment of RA. However, there are some contradictory effects of LXRs agonists observed in previous animal studies where both pro-inflammatory role and anti-inflammatory role were revealed for LXRs activation in RA. Therefore, in addition to updating the knowledge of LXRs as the prominent regulators of lipid homeostasis, the purpose of this review is to summarize the effects of LXRs agonists in RA-associated immune cells, to explore the underlying reasons for the contradictory therapeutic effects of LXRs agonists observed in RA animal models, and to discuss future strategy for the treatment of RA with LXRs modulators.