Microbiota-derived acetate attenuates neuroinflammation in rostral ventrolateral medulla of spontaneously hypertensive rats.

BACKGROUND: Increased neuroinflammation in brain regions regulating sympathetic nerves is associated with hypertension. Emerging evidence from both human and animal studies suggests a link between hypertension and gut microbiota, as well as microbiota-derived metabolites short-chain fatty acids (SCFAs). However, the precise mechanisms underlying this gut-brain axis remain unclear. METHODS: The levels of microbiota-derived SCFAs in spontaneously hypertensive rats (SHRs) were determined by gas chromatography-mass spectrometry. To observe the effect of acetate on arterial blood pressure (ABP) in rats, sodium acetate was supplemented via drinking water for continuous 7 days. ABP was recorded by radio telemetry. The inflammatory factors, morphology of microglia and astrocytes in rostral ventrolateral medulla (RVLM) were detected. In addition, blood-brain barrier (BBB) permeability, composition and metabolomics of the gut microbiome, and intestinal pathological manifestations were also measured. RESULTS: The serum acetate levels in SHRs are lower than in normotensive control rats. Supplementation with acetate reduces ABP, inhibits sympathetic nerve activity in SHRs. Furthermore, acetate suppresses RVLM neuroinflammation in SHRs, increases microglia and astrocyte morphologic complexity, decreases BBB permeability, modulates intestinal flora, increases fecal flora metabolites, and inhibits intestinal fibrosis. CONCLUSIONS: Microbiota-derived acetate exerts antihypertensive effects by modulating microglia and astrocytes and inhibiting neuroinflammation and sympathetic output.

Hydrogen Sulfide Ameliorates Heart Aging by Downregulating Matrix Metalloproteinase-9.

PURPOSE: Aging contributes significantly to cardiovascular diseases and cardiac dysfunction, leading to the upregulation of matrix metalloproteinase-9 (MMP-9) in the heart and a significant decrease in hydrogen sulfide (H2S) content, coupled with impaired cardiac diastolic function. This study explores whether supplementing exogenous hydrogen sulfide during aging ameliorates the decline in H2S concentration in the heart, suppresses MMP-9 expression, and improves the age-associated impairment in cardiac morphology and function. METHODS: We collected plasma from healthy individuals of different ages to determine the relationship between aging and H2S and MMP-9 levels through Elisa detection and liquid chromatography-tandem mass spectrometry (LC/MC) detection of plasma H2S content. Three-month-old mice were selected as the young group, while 18-month-old mice were selected as the old group, and sodium hydrosulfide (NaHS) was injected intraperitoneally from 15 months old until 18 months old as the old + NaHS group. Plasma MMP-9 content was detected using Elisa, plasma H2S content, cardiac H2S content, and cystathionine gamma-lyase (CSE) activity were detected using LC/MC, and cardiac function was detected using echocardiography. Heart structure was assessed using hematoxylin and eosin staining, Masone staining was used to detect the degree of cardiac fibrosis, while western blot was used to detect the expression of MMP-9, CSE, and aging marker proteins. Knockdown of MMP-9 and CSE in H9c2 cells using small interfering RNA was carried out to determine the upstream-downstream relationship between MMP-9 and CSE. RESULTS: H2S content in the plasma of healthy individuals decreases with escalating age, whereas MMP-9 level rises with age progression. Aging leads to a decrease in H2S levels in the heart and plasma of mice, severe impairment of cardiac diastolic function, interstitial relaxation, and fibrosis of the heart. Supplementing with exogenous H2S can improve these phenomena. CONCLUSION: H2S maintains the structure and function of the heart by inhibiting the expression of MMP-9 during the aging process.

Inducible Fgf13 ablation alleviates cardiac fibrosis via regulation of microtubule stability.

Fibroblast growth factor (FGF) isoform 13, a distinct type of FGF, boasts significant potential for therapeutic intervention in cardiovascular dysfunctions. However, its impact on regulating fibrosis remains unexplored. This study aims to elucidate the role and mechanism of FGF13 on cardiac fibrosis. Here, we show that following transverse aortic constriction (TAC) surgery, interstitial fibrosis and collagen content increase in mice, along with reduced ejection fraction and fractional shortening, augmented heart mass. However, following Fgf13 deletion, interstitial fibrosis is decreased, ejection fraction and fractional shortening are increased, and heart mass is decreased, compared with those in the TAC group. Mechanistically, incubation of cardiac fibroblasts with transforming growth factor ß (TGFß) increases the expressions of types I and III collagen proteins, as well as α-smooth muscle actin (α-SMA) proteins, and enhances fibroblast proliferation and migration. In the absence of Fgf13, the expressions of these proteins are decreased, and fibroblast proliferation and migration are suppressed, compared with those in the TGFß-stimulated group. Overexpression of FGF13, but not FGF13 mutants defective in microtubule binding and stabilization, rescues the decrease in collagen and α-SMA protein and weakens the proliferation and migration function of the Fgf13 knockdown group. Furthermore, Fgf13 knockdown decreases ROCK protein expression via microtubule disruption. Collectively, cardiac Fgf13 knockdown protects the heart from fibrosis in response to haemodynamic stress by modulating microtubule stabilization and ROCK signaling pathway.

Modulation of Kv7 Channel Currents by Echinocystic Acid.

Modulation of KCNQ-encoded voltage-gated potassium Kv7/M channel function represents an attractive strategy to treat neuronal excitability disorders such as epilepsy, pain, and depression. The Kv7 channel group includes five subfamily members (Kv7.1-Kv7.5). Pentacyclic triterpenes display extensive pharmacological activities including antitumor, anti-inflammatory, and antidepression effects. In this study, we investigated the effects of pentacyclic triterpenes on Kv7 channels. Our results show that echinocystic acid, ursonic acid, oleanonic acid, demethylzeylasteral, corosolic acid, betulinaldehyde, acetylursolic acid, and α-boswellic acid gradually exert decreasing degrees of Kv7.2/Kv7.3 channel current inhibition. Echinocystic acid was the most potent inhibitor, with a half-maximal inhibitory concentration (IC50) of 2.5 µM. It significantly shifted the voltage-dependent activation curve in a positive direction and slowed the time constant of activation for Kv7.2/Kv7.3 channel currents. Furthermore, echinocystic acid nonselectively inhibited Kv7.1-Kv7.5 channels. Taken together, our findings indicate that echinocystic acid is a novel and potent inhibitor that could be used as a tool to further understand the pharmacological functions of neuronal Kv7 channels. SIGNIFICANCE STATEMENT: Pentacyclic triterpenes reportedly have multiple potential therapeutic uses such as anticancer, anti-inflammatory, antioxidant, and antidepression effects. In the present study, we show that echinocystic acid, ursonic acid, oleanonic acid, and demethylzeylasteral inhibit Kv7.2/Kv7.3 channels to varying degrees. Of these, echinocystic acid was the most potent Kv7.2/Kv7.3 current inhibitor and inhibited Kv7.1-Kv7.5 currents in a nonselective manner.

Perfluorooctane sulfonate promotes atherosclerosis by modulating M1 polarization of macrophages through the NF-κB pathway.

Perfluorooctane sulfonate (PFOS) is a widely used and distributed perfluorinated compounds and is reported to be harmful to cardiovascular health; however, the direct association between PFOS exposure and atherosclerosis and the underlying mechanisms remain unknown. Therefore, this study aimed to investigate the effects of PFOS exposure on the atherosclerosis progression and the underlying mechanisms. PFOS was administered through oral gavage to apolipoprotein E-deficient (ApoE-/-) mice for 12 weeks. PFOS exposure significantly increased pulse wave velocity (PWV) and intima-media thickness (IMT), increased aortic plaque burden and vulnerability, and elevated serum lipid and inflammatory cytokine levels. PFOS promoted aortic and RAW264.7 M1 macrophage polarization, which increased the secretion of nitric oxide synthase (iNOS) and pro-inflammatory factors (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and interleukin-1ß [IL-1ß]), and suppressed M2 macrophage polarization, which decreased the expression of CD206, arginine I (Arg-1), and interleukin-10 (IL-10). Moreover, PFOS activated nuclear factor-kappa B (NF-κB) in the aorta and macrophages. BAY11-7082 was used to inhibit NF-κB-alleviated M1 macrophage polarization and the inflammatory response induced by PFOS in RAW264.7 macrophages. Our results are the first to reveal the acceleratory effect of PFOS on the atherosclerosis progression in ApoE-/- mice, which is associated with the NF-κB activation of macrophages to M1 polarization to induce inflammation.

Liquiritigenin Attenuated Collagen-Induced Arthritis and Cardiac Complication via Inflammation and Fibrosis Inhibition in Mice.

Rheumatoid arthritis (RA) is a common autoimmune disease with increased cardiovascular disease risk. Liquiritigenin (LG) is a triterpene with anti-inflammatory properties. Our study aimed to explore the effect of LG on RA and the cardiac complication. Collagen-induced arthritis (CIA) mice with LG treatment exhibited obvious alleviation in histopathological changes, accompanied by the decreased expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-17A in synovium and serum. LG attenuated cartilage destruction by reducing matrix metalloproteinase (MMP)-3 and MMP-13 expression in the synovium of CIA mice. The echocardiography results proved the alleviation of cardiac dysfunction in CIA mice. The electrocardiogram, biochemical, and histochemical analysis proved the cardioprotection effect of LG against RA. The decreased expression of inflammatory factors (TNF-α, IL-1ß, and IL-6) and fibrotic markers (fibronectin, Collagen I, and Collagen III) in cardiac tissues of CIA mice further corroborated the attenuation of myocardial inflammation and fibrosis by LG. Mechanistic studies showed that LG could inhibit transforming growth factor ß-1 (TGF-ß1) and phos-Smad2/3 expression in cardiac tissues of CIA mice. Our study suggested that LG could relieve RA and its cardiac complication probably by inhibiting the TGF-ß1/Smad2/3 pathway. All these suggested that LG might be a potential candidate for RA and its cardiac complication therapy.

Identification of Signature Genes of Dilated Cardiomyopathy Using Integrated Bioinformatics Analysis.

Dilated cardiomyopathy (DCM) is characterized by left ventricular or biventricular enlargement with systolic dysfunction. To date, the underlying molecular mechanisms of dilated cardiomyopathy pathogenesis have not been fully elucidated, although some insights have been presented. In this study, we combined public database resources and a doxorubicin-induced DCM mouse model to explore the significant genes of DCM in full depth. We first retrieved six DCM-related microarray datasets from the GEO database using several keywords. Then we used the "LIMMA" (linear model for microarray data) R package to filter each microarray for differentially expressed genes (DEGs). Robust rank aggregation (RRA), an extremely robust rank aggregation method based on sequential statistics, was then used to integrate the results of the six microarray datasets to filter out the reliable differential genes. To further improve the reliability of our results, we established a doxorubicin-induced DCM model in C57BL/6N mice, using the "DESeq2" software package to identify DEGs in the sequencing data. We cross-validated the results of RRA analysis with those of animal experiments by taking intersections and identified three key differential genes (including BEX1, RGCC and VSIG4) associated with DCM as well as many important biological processes (extracellular matrix organisation, extracellular structural organisation, sulphur compound binding, and extracellular matrix structural components) and a signalling pathway (HIF-1 signalling pathway). In addition, we confirmed the significant effect of these three genes in DCM using binary logistic regression analysis. These findings will help us to better understand the pathogenesis of DCM and may be key targets for future clinical management.

Potential molecular mechanism of cardiac hypertrophy in mice induced by exposure to ambient PM2.5.

Cardiac hypertrophy could be induced by ambient fine particulate matter (PM2.5) exposure. Since cardiac hypertrophy represents an early event leading to heart dysfunction, it is necessary to explore the molecular mechanisms, which are largely unknown. In the present study, an ambient particulate matter exposure mice model was established to explore its adverse effects related to the heart and the potential mechanisms. Forty-eight male C57BL/6 mice were randomly subjected to three groups: filtered air group, unfiltered air group and concentrated air group, and were exposed for 8 and 16 weeks, 6 h/day, respectively. In vitro experiments, the cardiac muscle cell line (HL-1) was treated with PM2.5 (0, 25, 50 and 100 µg/mL) for 24 h. In the present study, cardiac hypertrophy was occurred in vivo and vitro after exposure to PM2.5. Mechanistically, circ_0001859 could sponge miR-29b-3p, which could interact with 3'UTRs of Ctnnb1 (gene name of ß-catenin). And Ctnnb1 expression was transcriptionally inhibited by si-circ_0001859 or miR-29b-3p mimic in HL-1 cells. Additionally, miR-29b-3p inhibitor could also make a reversion about the inhibition effect of circ_0001859 silencing on Ctnnb1 mRNA level in HL-1 cells. Functionally, knockout of circ_0001859 or overexpression of miR-29b-3p could inhibit LEF1/IGF-2R pathway and alleviate the progress of hypertrophy induced by PM2.5 in HL-1 cells. And miR-29b-3p inhibitor could reverse the inhibition effect of circ_0001859 silencing on hypertrophic response induced by PM2.5 in HL-1 cells. Consequently, the data demonstrated that circRNA_0001859 promoted the process of cardiac hypertrophy through suppressing miR-29b-3p leading to enhance Ctnnb1 level, and activated downstream pathway molecules LEF1/IGF-2R.

Pd-Catalyzed Direct C-H Functionalization/Annulation of BODIPYs with Alkynes to Access Unsymmetrical Benzo[ b]-Fused BODIPYs: Discovery of Lysosome-Targeted Turn-On Fluorescent Probes.

A highly efficient palladium-catalyzed direct C-H functionalization/annulation of BODIPYs with alkynes has been developed for the first time to construct a series of unsymmetrical benzo[ b]-fused BODIPYs from readily available starting materials. These unsymmetrical benzo[ b]-fused BODIPYs exhibit remarkably red-shifted emissions and larger Stokes shifts than classical BODIPY dyes. Cell imaging experiments and cytotoxicity assays demonstrate that BODIPYs 4c and 4d have specific lysosome-labeling capacities, turn-on fluorescence emissions in cells, and low cytotoxicity.

Polarization dynamic patterns of vector solitons in a graphene mode-locked fiber laser.

Multiple polarization dynamic patterns of vector solitons, including fundamental solitons, bunched solitons, loosely or tightly bound states and harmonic mode locking have been observed experimentally in an erbium-doped fiber ring laser with graphene as a saturable absorber. By carefully adjusting the pump power and the orientation of the intra-cavity polarization controller, either polarization rotation or polarization locked operation have all been achieved for the above vector solitons. This is the first time that high order harmonic mode locking of polarization rotation vector solitons has been achieved. The signal to noise ratio of our system was ~51 dB, which indicates that the laser operated with high stability.

Different polarization dynamic states in a vector Yb-doped fiber laser.

Different polarization dynamic states in an unidirectional, vector, Yb-doped fiber ring laser have been observed. A rich variety of dynamic states, including group velocity locked polarization domains and their splitting into regularly distributed multiple domains, polarization locked square pulses and their harmonic mode locking counterparts, and dissipative soliton resonances have all been observed with different operating parameters. We have also shown experimentally details of the conditions under which polarization-domain-wall dark pulses and bright square pulses form.

Flexible operability and amplification of gray pulses.

We have investigated experimentally the flexible production and amplification of gray pulses for the first time to our knowledge. Switchable wavelengths, tunable pulse-widths, and adjustable contrasts have all been obtained in a fiber laser. Amplification of gray pulses was also experimentally investigated in detail. The contrast of the pulses could also be increased in an amplifier. The robust stability that results from the interactions between adjacent harmonic mode locking counterparts of gray pulses was found to last for up to ten hours. To the best of our knowledge, the gray pulses trains we have generated are the most stable achieved to date in an all-fiber laser system. This finding can be used as a guide for the establishment of robust gray pulses as laser sources.

Toxicological Responses of Chlorella vulgaris to Dichloromethane and Dichloroethane.

The aim of this study was to evaluate the acute toxicity effects of dichloromethane and dichloroethane on Chlorella vulgaris at the physiological and molecular level. Data showed that the cell number, chlorophyll a, and total protein content gradually decreased with increasing dichloromethane and dichloroethane concentrations over a 96-h exposure. Lower doses of two organic solvents had stimulatory effects on catalase and superoxide dismutase activity. Malondialdehyde showed a concentration-dependent increase in response to dichloromethane and dichloroethane exposure. Electron microscopy also showed that there were some chloroplast abnormalities in response to different concentrations of dichloromethane and dichloroethane exposure. Real-time polymerase chain reaction assay demonstrated that dichloromethane and dichloroethane reduced the transcript abundance of psaB, whereas that of psbC changed depending on the toxicant after 24 h of exposure. Dichloromethane and dichloroethane affected the activity of antioxidant enzymes, disrupted the chloroplast ultrastructure, and reduced transcription of photosynthesis-related genes in C. vulgaris, leading to metabolic disruption and cell death.

Pectin-based double network hydrogels as local depots of celastrol for enhanced antitumor therapy.

In this study, A double-network (DN) hydrogel composed of a physical glycyrrhizic acid (GA) network and a chemically crosslinked pectin-based network was fabricated as a local depot of celastrol (CEL) for cancer treatment. The obtained DN hydrogel possessed excellent mechanical performance, flexibility, biocompatibility, biodegradability and self-healing property. Furthermore, the release profile of CEL loaded DN hydrogel maintained a controlled and sustained release of CEL for a prolonged period. Finally, in vivo animal experiments demonstrated that the DN hydrogel could significantly enhance the therapeutic efficiency of CEL in CT-26 tumor-bearing mice upon intratumoral injection while effectively alleviate the toxicity of the CEL. In summary, this injectable pectin-based double network hydrogels are ideal delivery vehicle for tumor therapy.

FGF13 deficiency ameliorates calcium signaling abnormality in heart failure by regulating microtubule stability.

Calcium signaling abnormality in cardiomyocytes, as a key mechanism, is closely associated with developing heart failure. Fibroblast growth factor 13 (FGF13) demonstrates important regulatory roles in the heart, but its association with cardiac calcium signaling in heart failure remains unknown. This study aimed to investigate the role and mechanism of FGF13 on calcium mishandling in heart failure. Mice underwent transaortic constriction to establish a heart failure model, which showed decreased ejection fraction, fractional shortening, and contractility. FGF13 deficiency alleviated cardiac dysfunction. Heart failure reduces calcium transients in cardiomyocytes, which were alleviated by FGF13 deficiency. Meanwhile, FGF13 deficiency restored decreased Cav1.2 and Serca2α expression and activity in heart failure. Furthermore, FGF13 interacted with microtubules in the heart, and FGF13 deficiency inhibited the increase of microtubule stability during heart failure. Finally, in isoproterenol-stimulated FGF13 knockdown neonatal rat ventricular myocytes (NRVMs), wildtype FGF13 overexpression, but not FGF13 mutant, which lost the binding site of microtubules, promoted calcium transient abnormality aggravation and Cav1.2 downregulation compared with FGF13 knockdown group. Generally, FGF13 deficiency improves abnormal calcium signaling by inhibiting the increased microtubule stability in heart failure, indicating the important role of FGF13 in cardiac calcium homeostasis and providing new avenues for heart failure prevention and treatment.

Revealment study on the regulation of lipid metabolism by Lingguizhugan Decoction in heart failure treatment based on integrated lipidomics and proteomics.

Lingguizhugan Decoction (LGZGD) is a classical traditional Chinese medicine prescription. Our previous studies found that disorders of lipid metabolism were reversed by LGZGD in heart failure (HF) mice. This study aimed to reveal the regulation of lipid metabolism of LGZGD. A mice model of HF was established by intraperitoneal injection of doxorubicin. The components of LGZGD were identified with the UHPLC-QTOF-MS method. The regulation of lipid metabolism by LGZGD was detected by serum lipidomics and heart tissue proteomics. Molecular docking was further performed to screen active components. A total of 78 compounds in LGZGD were identified. Results of lipidomics showed that 37 lipids illustrated a significant recovery trend to normal after the treatment of LGZGD. Results of proteomics demonstrated that 55 proteins were altered by the administration of LGZGD in HF mice. After enrichment analysis, the Prakg2/Ucp2/Plin1 axis on the Apelin pathway plays a vital role in HF treatment by LGZGD. Nine active components exhibited the outstanding ability of binding to the apelin receptor with MM-GBSA value lower than -60 Kcal/mol. In conclusion, all results combined together revealed that multi-component in the LGZGD had beneficial effects on the HF through ameliorating lipid disorders, which provides a novel insight into the cardioprotective effects of LGZGD and its clinical application.

Mechanism of YY1 mediating autophagy dependent ferroptosis in PM2.5 induced cardiac fibrosis.

Epidemiological studies have demonstrated strong associations between exposure to ambient fine particulate matter (PM2.5) and cardiac disease. To investigate the potential mechanism of cardiac fibrosis induced by PM2.5, we established PM2.5 exposure models in vivo and in vitro, and then cardiac fibrosis was evaluated. The ferroptosis and ferritinophagy was detected to characterize the effects of PM2.5 exposure. The results indicated that PM2.5 exposure could induce cardiac fibrosis in mice. YY1 was induced by PM2.5 exposure and then increased NCOA4, a cargo receptor for ferritinophagy, which interacted with FHC and promoted the transport of ferritin to the autophagosome for degradation. The release of large amounts of free iron from ferritinophagy led to lipid peroxidation directly via the Fenton reaction, thereby triggering ferroptosis. Moreover, siNCOA4 could partly restore the FHC protein level in HL-1 cells and inhibit the occurrence of downstream ferroptosis. Functionally, NCOA4 knockdown inhibited ferroptosis and alleviated HL-1 cell death induced by PM2.5. Ferroptosis inhibitor (Ferrostatin-1) could reverse the promoting effect of ferritinophagy mediated ferroptosis on cardiac fibrosis induced by PM2.5 exposure in mice. Our study indicated that PM2.5 induced cardiac fibrosis through YY1 regulating ferritinophagy-dependent ferroptosis.

Integration of miRNA and mRNA analysis reveals the role of ribosome in to anti-artificial aging in sweetcorn.

Sweetcorn is a kind of maize with high sugar content and has poor seed aging tolerance, which seriously limits its production. However, few studies have explored the artificial aging (AA) tolerance by miRNA-mRNA integration analysis in sweetcorn. Here, we characterized the physiological, biochemical and transcriptomic changes of two contrasting lines K62 and K107 treated with AA during time series. Both the germination indexes and antioxidant enzymes showed significant difference between two lines. The MDA content of AA-tolerant genotype K62 was significantly lower than that of K107 on the fourth and sixth day. Subsequently, 157 differentially expressed miRNAs (DEMIs) and 8878 differentially expressed mRNAs (DEMs) were identified by RNA-seq analysis under aging stress. The "ribosome" and "peroxisome" pathways were enriched to respond to aging stress, genes for both large units and small ribosomal subunits were significantly upregulated expressed and higher translation efficiency might exist in K62. Thirteen pairs of miRNA-target genes were obtained, and 8 miRNA-mRNA pairs might involve in ribosome protein and translation process. Our results elucidate the mechanism of sweetcorn response to AA at miRNA-mRNA level, and provide a new insight into sweetcorn AA response to stress.

Low sodium intake ameliorates hypertension and left ventricular hypertrophy in mice with primary aldosteronism.

The goal of this paper is to elucidate the effects of sodium restriction on hypertension and left ventricular (LV) hypertrophy in a mouse model with primary aldosteronism (PA). Mice with genetic deletion of TWIK-related acid-sensitive K (TASK)-1 and TASK-3 channels (TASK-/-) were used as the animal model of PA. Parameters of the LV were assessed using echocardiography and histomorphology analysis. Untargeted metabolomics analysis was conducted to reveal the mechanisms underlying the hypertrophic changes in the TASK-/- mice. The TASK-/- adult male mice exhibited the hallmarks of PA, including hypertension, hyperaldosteronism, hypernatremia, hypokalemia, and mild acid-base balance disorders. Two weeks of low sodium intake significantly reduced the 24-h average systolic and diastolic BP in TASK-/- but not TASK+/+ mice. In addition, TASK-/- mice showed increasing LV hypertrophy with age, and 2 weeks of the low-sodium diet significantly reversed the increased BP and LV wall thickness in adult TASK-/- mice. Furthermore, a low-sodium diet beginning at 4 weeks of age protected TASK-/- mice from LV hypertrophy at 8-12 weeks of age. Untargeted metabolomics demonstrated that the disturbances in heart metabolism in the TASK-/- mice (e.g., Glutathione metabolism; biosynthesis of unsaturated fatty acids; amino sugar and nucleotide sugar metabolism; pantothenate and CoA biosynthesis; D-glutamine and D-glutamate metabolism), some of which were reversed after sodium restriction, might be involved in the development of LV hypertrophy. In conclusion, adult male TASK-/- mice exhibit spontaneous hypertension and LV hypertrophy, which are ameliorated by a low-sodium intake.

Integrated metabolomics and network analysis reveal changes in lipid metabolisms of tripterygium glycosides tablets in rats with collagen-induced arthritis.

Tripterygium glycosides tablets (TGT) are the commonly used preparation for rheumatoid arthritis (RA). However, the changes in TGT on RA are still unclear at the metabolic level. This study aimed to reveal the biological processes of TGT in collagen-induced arthritis (CIA) rats through integrated metabolomics and network analysis. First, the CIA model in rats was established, and the CIA rats were given three doses of TGT. Then, the endogenous metabolites in the serum from normal rats, CIA rats, and CIA rats treated with varying doses of TGT were detected by UHPLC-QTOF-MS/MS. Next, univariate and multivariate statistical analyses were performed to find the differential metabolites. Finally, differential metabolites, metabolic pathways, and hub genes were analyzed integrally to reveal the biological processes of TGT in CIA rats. The paw diameter, arthritis score, immunoglobulin G (IgG) concentration, CT image, and histological assay showed that TGT had evident therapeutic effects on CIA rats. Untargeted metabolomics revealed that TGT could ameliorate the down-regulation of lipid levels in CIA rats. Four key differential metabolites were found including LysoP(18:0), LysoPA(20:4), LysoPA(18:2), and PS(O-20:0/17:1). The glycerophospholipid metabolic pathway was perturbed in treating CIA with TGT. A total of 24 genes, including PLD1, LPCAT4, AGPAT1, and PLA2G4A, were found to be the hub genes of TGT in CIA rats. In conclusion, the integrated analysis provided a novel and holistic perspective on the biological processes of TGT in CIA rats, which could give helpful guidance for further TGT on RA. Future studies based on human samples are necessary.