Identification of Oxidative Stress-Related Biomarkers for Pain-Depression Comorbidity Based on Bioinformatics.

Oxidative stress has been identified as a major factor in the development and progression of pain and psychiatric disorders, but the underlying biomarkers and molecular signaling pathways remain unclear. This study aims to identify oxidative stress-related biomarkers and signaling pathways in pain-depression comorbidity. Integrated bioinformatics analyses were applied to identify key genes by comparing pain-depression comorbidity-related genes and oxidative stress-related genes. A total of 580 differentially expressed genes and 35 differentially expressed oxidative stress-related genes (DEOSGs) were identified. By using a weighted gene co-expression network analysis and a protein-protein interaction network, 43 key genes and 5 hub genes were screened out, respectively. DEOSGs were enriched in biological processes and signaling pathways related to oxidative stress and inflammation. The five hub genes, RNF24, MGAM, FOS, and TKT, were deemed potential diagnostic and prognostic markers for patients with pain-depression comorbidity. These genes may serve as valuable targets for further research and may aid in the development of early diagnosis, prevention strategies, and pharmacotherapy tools for this particular patient population.

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.

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.

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.

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.

Erratum: CD151 promotes Colorectal Cancer progression by a crosstalk involving CEACAM6, LGR5 and Wnt signaling via TGFß1: Erratum.

[This corrects the article DOI: 10.7150/ijbs.53657.].

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.

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.

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.