Capsaicin inhibits A7r5 cell senescence via the mitochondrial carrier protein Slc25a12.

Aging of vascular smooth muscle cells (VSMCs) is the principal factor responsible for the loss of vascular function, and continuous exposure to high glucose is one of the key factors contributing to the aging of VSMCs. This study established a high glucose-induced senescence model of the A7r5 cell line and used transcriptome sequencing to screen the regulatory target genes of high glucose-induced cellular senescence. The study revealed that the expression of the Slc25a12 gene, which belongs to the solute carrier family 25 member 12, was notably reduced following damage caused by high glucose levels. This inhibition was shown to cause mitochondrial malfunction and cellular senescence. The encoded product of the Slc25a12 gene is a mitochondrial carrier protein that binds to calcium and aids in transporting aspartate for glutamate exchange within the inner mitochondrial membrane. Mitochondrial dysfunction compromises the cell's capacity to resist oxidation and repair damage, and is an inherent element in hastening cellular aging. Moreover, our findings validated that the transient receptor potential vanilloid 1 (TRPV1) agonist capsaicin hindered the decrease in Slc25a12 expression, prevented mitochondrial dysfunction, and blocked cellular senescence. Could the regulation of Slc25a12 expression by capsaicin restore cellular mitochondrial function and restrict senescence? In vitro tests have verified that interference with A7r5 Slc25a12 noticeably diminishes capsaicin's effectiveness in repairing mitochondrial function and inhibiting senescence. The findings indicate that capsaicin delays mitochondrial dysfunction and therefore hinders cellular senescence by regulating the mitochondrial membrane protein Slc25a12 in the A7r5 cell line.

Predictive value of serum lncRNA MALAT1 for the recurrence of persistent atrial fibrillation after radiofrequency ablation.

Objective: The authors investigated the predictive value of MALAT1 for persistent atrial fibrillation (PAF) recurrence after radiofrequency ablation. Methods: Serum MALAT1 level was determined. The correlation between MALAT1 and high-sensitivity C-reactive protein/left atrial diameter (LAD) was analyzed. The predictive value of MALAT1 was evaluated. The postoperative recurrence rate in patients with high/low MALAT1 was compared. Independent risk factors for postoperative recurrence were analyzed. Results: MALAT1 was elevated in PAF patients and positively correlated with high-sensitivity C-reactive protein/LAD. MALAT1/high-sensitivity C-reactive protein/LAD were enhanced in patients with recurrent PAF. Patients with high MALAT1 had a higher recurrence rate. Upregulated MALAT1 was an independent risk factor for postoperative PAF recurrence. Conclusion: Serum MALAT1 level >2.03 predicts postoperative recurrence of PAF, and PAF patients with high MALAT1 have a higher risk of postoperative recurrence.

Atrial fibrillation (AF) is a common cardiac arrhythmia (abnormal heartbeat), which usually manifests as an irregular and rapid rhythm. In severe cases, AF can lead to cardiovascular diseases such as thromboembolism (narrowing and blockage of blood vessels) and heart failure (impaired pumping function of the heart). Cardiac radiofrequency ablation is a common method used to treat AF. However, patients with PAF still have a high rate of late recurrence after the operation, so there is an urgent need to identify suitable biochemical markers for predicting the postoperative recurrence of PAF. lncRNAs are a type of noncoding nucleic acid; they do not encode proteins, have various biological functions and are widely distributed in living organisms. The lncRNA MALAT1 has been considered a potential therapeutic target and biomarker in several cardiovascular diseases. This study demonstrated that the serum level of MALAT1 in PAF patients was significantly higher than that in normal subjects and MALAT1 level was elevated in patients with recurrent PAF compared with patients without recurrence. The authors also found that serum MALAT1 could predict whether PAF will recur after operation, with a high accuracy. In addition, PAF patients with high expression of serum MALAT1 had a higher risk of postoperative recurrence. In summary, serum level of lncRNA MALAT1 can help predict postoperative recurrence of PAF and a high level of MALAT1 is indicative of a higher risk of postoperative recurrence. Analysis of serum lncRNA MALAT1 level in PAF patients before surgery can predict postoperative recurrence, and intervention programs that lower the MALAT1 level can be implemented to reduce the risk of postoperative recurrence of PAF and increase the success rate of the operation. This study has important implications for reducing the recurrence rate after radiofrequency ablation in PAF patients.

New Tiaoxin Recipe alleviates energy metabolism disorders in an APPswe/PS1DE9 mouse model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a typical neurodegenerative disease with a complex etiology. Until now, there has been no effective treatment available for AD; however, improving energy dysmetabolism, the key pathological event in the early stage of AD, can effectively delay the progression of AD. OBJECTIVE: This paper aims to investigate the therapeutic effect and potential mechanism of the new Tiaoxin recipe on early AD. METHODS: APP/PS1 mice were divided into a model group, a new Tiaoxin recipe group, and a donepezil group, and C57/BL mice were used for the control group. Mouse cognitive and learning abilities were tested using the Morris water maze test and a new object-recognition experiment. The 42 amino acid form of amyloid ß peptide (Aß1-42) content was detected by enzyme-linked immunosorbent assay, the senile plaque area was detected by thioflavin S staining, and the senescence-associated ß-galactosidase (SA-ß-gal)-positive area was detected by chemical staining. Also, the adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NAD+), and nicotinamide adenine dinucleotide hydride (NADH) contents were detected using a biochemical method, and the cluster of differentiation 38 (CD38) and silent mating-type information regulation 2 homolog 3 (SIRT3) protein expression levels were detected by immunofluorescence and Western blot analysis. RESULTS: Compared with those of the control group, the learning and memory abilities of the model group were impaired; the senile plaque deposition, Aß1-42 content, and SA-ßgal-positive staining area were increased; the ATP concentration, NAD+ concentration, and NAD+/NADH ratio were decreased; the CD38 protein expression level was increased; and the SIRT3 protein expression level was decreased. Following intervention with the new Tiaoxin recipe, the learning and memory abilities were improved; the senile plaque deposition, Aß1-42 content, and SA-ßgal-positive area were reduced; the ATP concentration, NAD+ concentration, and NAD+/NADH ratio were increased; CD38 protein expression was decreased, and SIRT3 protein expression was increased. CONCLUSION: This study shows that the new Tiaoxin Recipe can improve cognitive ability and reduce the Aß1-42 content and senile plaque deposition in APP/PS1 mice, which may occur through the downregulation of CD38 protein expression, upregulation of SIRT3 protein expression, restoration of the NAD+ level, promotion of ATP synthesis, mitigation of energy metabolism disorders.

Aß promotes CD38 expression in senescent microglia in Alzheimer's disease.

BACKGROUND: In Alzheimer's disease (AD), the neuroinflammatory response mediated by the activation of senescent microglia is closely related to energy dysmetabolism. However, the mechanism underlying the interaction between the energy metabolism of aging microglia and neuroinflammation remains unclear. METHODS: We used biochemical methods, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and western blot to determine the effects and mechanism of CD38 knockdown on energy metabolism and neuroinflammation in Aß1-40 injured BV2 cells. Using AD model mice, we detected CD38 enzyme activity, energy metabolism factors (ATP, NAD +, and NAD + /NADH), and neuroinflammatory factors (IL-1ß, IL-6, and TNF-α) following the addition of CD38 inhibitor. Using a combination of biochemical analysis and behavioral testing, we analyzed the effects of the CD38 inhibitor on energy metabolism disorder, the neuroinflammatory response, and the cognition of AD mice. RESULTS: Following Aß1-40 injury, SA-ß-Gal positive cells and senescence-related proteins P16 and P21 increased in BV2 cells, while energy-related molecules (ATP, NAD +, and NAD + /NADH) and mitochondrial function (mitochondrial ROS and MMP) decreased. Further studies showed that CD38 knockdown could improve Aß1-40-induced BV2 cells energy dysmetabolism and reduce the levels of IL-1ß, IL-6, and TNF-α. In vivo results showed an increase in senile plaque deposition and microglial activation in the hippocampus and cortex of 34-week-old APP/PS1 mice. Following treatment with the CD38 inhibitor, senile plaque deposition decreased, the number of Iba1 + BV2 cells increased, the energy metabolism disorder was improved, the proinflammatory cytokines were reduced, and the spatial learning ability was improved. CONCLUSIONS: Our results confirm that senescent microglia appeared in the brain of 34-week-old APP/PS1 mice, and that Aß1-40 can induce senescence of BV2 cells. The expression of CD38 increases in senescent BV2 cells, resulting in energy metabolism disorder. Therefore, reducing CD38 expression can effectively improve energy metabolism disorder and reduce proinflammatory cytokines. Following intervention with the CD38 inhibitor in APP/PS1 mice, the energy metabolism disorder was improved in the hippocampus and cortex, the level of proinflammatory cytokines was reduced, and cognitive impairment was improved.

Aß promotes CD38 expression in senescent microglia in Alzheimer's disease

BACKGROUND: In Alzheimer's disease (AD), the neuroinflammatory response mediated by the activation of senescent microglia is closely related to energy dysmetabolism. However, the mechanism underlying the interaction between the energy metabolism of aging microglia and neuroinflammation remains unclear. METHODS: We used biochemical methods, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and western blot to determine the effects and mechanism of CD38 knockdown on energy metabolism and neuroinflammation in Aß1-40 injured BV2 cells. Using AD model mice, we detected CD38 enzyme activity, energy metabolism factors (ATP, NAD +, and NAD +/NADH), and neuroinflammatory factors (IL-1ß, IL-6, and TNF-α) following the addition of CD38 inhibitor. Using a combination of biochemical analysis and behavioral testing, we analyzed the effects of the CD38 inhibitor on energy metabolism disorder, the neuroinflammatory response, and the cognition of AD mice. RESULTS: Following Aß1-40 injury, SA-ß-Gal positive cells and senescence-related proteins P16 and P21 increased in BV2 cells, while energy-related molecules (ATP, NAD +, and NAD +/NADH) and mitochondrial function (mitochondrial ROS and MMP) decreased. Further studies showed that CD38 knockdown could improve Aß1-40-induced BV2 cells energy dysmetabolism and reduce the levels of IL-1ß, IL-6, and TNF-α. In vivo results showed an increase in senile plaque deposition and microglial activation in the hippocampus and cortex of 34-week-old APP/PS1 mice. Following treatment with the CD38 inhibitor, senile plaque deposition decreased, the number of Iba1 +BV2 cells increased, the energy metabolism disorder was improved, the proinflammatory cytokines were reduced, and the spatial learning ability was improved. CONCLUSIONS: Our results confirm that senescent microglia appeared in the brain of 34-week-old APP/PS1 mice, and that Aß1-40 can induce senescence of BV2 cells. The expression of CD38 increases in senescent BV2 cells, resulting in energy metabolism disorder. Therefore, reducing CD38 expression can effectively improve energy metabolism disorder and reduce proinflammatory cytokines. Following intervention with the CD38 inhibitor in APP/PS1 mice, the energy metabolism disorder was improved in the hippocampus and cortex, the level of proinflammatory cytokines was reduced, and cognitive impairment was improved.

[Effects of miR-133b on oxLDL-induced vascular endothelial cell injury by targeting SGTB].

Objective: To investigate the effect of microRNA-133b (miR-133b) on oxidized low density lipoprotein (oxLDL) induced vascular endothelial cell injury by targeting small protein molecules rich in glutamine 34-tetrapeptide repeats (SGTB). Methods: Human umbilical vein endothelial cells (EVC-304) were induced by 100 µg/ml oxLDL for 24 h to construct a vascular endothelial cell injury model. EVC-304 cells were divided into control group, oxLDL group (oxLDL treatment), oxLDL+miR-NC group (transfectted with 20 nmol/L miR-NC+oxLDL treatment), oxLDL+miR-133b group (transfectted with 20 nmol/L miR-133b mimics +oxLDL treatment), oxLDL+si-NC group (transfectted with 20 nmol/L si-NC+oxLDL treatment), oxLDL+si-SGTB group (transfected with 20 nmol/L si-SGTB+oxLDL treatment), oxLDL+miR-133b+ pcDNA group (transfected with 20 nmol/L si-SGTB and pcDNA+oxLDL), oxLDL+miR-133b+pcDNA-SGTB group (transfected with 20 nmol/L si-SGTB and pcDNA-SGTB), 9 wells in each group. Real-time quantitative PCR (qRT-PCR) and Western blot were used to detect the expression levels of miR-133b and SGTB; flow cytometry was used to detect cell apoptosis; kits were used to detect malondialdehyde (MDA) content and the activities of superoxide disproportionation enzyme (SOD) and glutathione peroxidase (GSH-Px). The expression levels of Bcl-2 and Bax protein were detected by Western blot. The dual luciferase reporter gene assay and Western blot were used to verify the targeted and regulatory between miR-133b and SGTB. Results: Compared with the control group, the expressions of miR-133b and Bcl-2 in EVC-304 cells were decreased significantly after oxLDL induction, while the expression levels of SGTB and Bax were sincreased ignificantly (P＜0.05), the MDA content and apoptosis rate were increased significantly (P＜0.05), and the activities of SOD and GSH-Px were decreased significantly (P＜0.05). Over-expression of miR-133b or interfering with SGTB inhibited oxLDL-induced apoptosis and oxidative stress in EVC-304 cells (P＜ 0.05). miR-133b directly bound to SGTB, miR-133b overexpression significantly down-regulated SGTB expression (P＜0.05), miR-133b inhibition significantly up-regulated SGTB expression (P＜0.05) Over-expression of SGTB reversed the effect of over-expressing miR-133b on oxLDL-induced vascular endothelial cell injury (P＜0.05). Conclusion: miR-133b could attenuate oxidative stress damage and apoptosis induced by oxLDL in vascular endothelial cells by targeting and inhibiting SGTB expression.

RS-5645 attenuates inflammatory cytokine storm induced by SARS-CoV-2 spike protein and LPS by modulating pulmonary microbiota.

An inflammatory cytokine storm is considered an important cause of death in severely and critically ill COVID-19 patients, however, the relationship between the SARS-CoV-2 spike (S) protein and the host's inflammatory cytokine storm is not clear. Here, the qPCR results indicated that S protein induced a significantly elevated expression of multiple inflammatory factor mRNAs in peripheral blood mononuclear cells (PBMCs), whereas RS-5645 ((4-(thiophen-3-yl)-1-(p-tolyl)-1H-pyrrol-3-yl)(3,4,5-trimethoxyphenyl)methanone) attenuated the expression of the most inflammatory factor mRNAs. RS-5645 also significantly reduced the cellular ratios of CD45+/IFNγ+, CD3+/IFNγ+, CD11b+/IFNγ+, and CD56+/IFNγ+ in human PBMCs. In addition, RS-5645 effectively inhibited the activation of inflammatory cells and reduced inflammatory damage to lung tissue in mice. Sequencing results of 16S rRNA v3+v4 in mouse alveolar lavage fluid showed that there were 494 OTUs overlapping between the alveolar lavage fluid of mice that underwent S protein+ LPS-combined intervention (M) and RS-5645-treated mice (R), while R manifested 64 unique OTUs and M exhibited 610 unique OTUs. In the alveoli of group R mice, the relative abundances of microorganisms belonging to Porphyromonas, Rothia, Streptococcus, and Neisseria increased significantly, while the relative abundances of microorganisms belonging to Psychrobacter, Shimia, and Sporosarcina were significantly diminished. The results of KEGG analysis indicated that the alveolar microbiota of mice in the R group can increase translation and reduce the activity of amino acid metabolism pathways. COG analysis results indicated that the abundance of proteins involved in ribosomal structure and biogenesis related to metabolism was augmented in the alveolar microbiota of the mice in the R group, while the abundance of proteins involved in secondary metabolite biosynthesis was significantly reduced. Therefore, our research results showed that RS-5645 attenuated pulmonary inflammatory cell infiltration and the inflammatory storm induced by the S protein and LPS by modulating the pulmonary microbiota.

Symptoms Based on Deficiency Syndrome in Traditional Chinese Medicine Might Be Predictor of Frailty in Elderly Community Dwellers.

BACKGROUND: The most widely used frailty phenotype and frailty indexes are either time-consuming or complicated, thus restricting their generalization in clinical practice; and therefore, an easier and faster screening tool is needed to be developed. OBJECTIVE: To select sensitive symptoms in traditional Chinese medicine (TCM) and study whether they can improve the risk prediction of frailty. METHODS: This is a cross-sectional study enrolling 2249 Chinese elderly community dwellers. Data were collected via face-to-face inquiries, anthropometric measurements, laboratory tests, and community health files. Frailty was the main outcome measure, and it was evaluated by Fried's frailty phenotype (FP). The ordinal logistic regression model was used to identify the factors associated with frailty. The risk assessment plot was used to compare the discriminative ability for frailty among models with and without TCM symptoms. RESULTS: The identified sensitive influential factors for frailty included age, education level, dietary habits, chronic obstructive pulmonary disease, diabetes, cerebral infarction, osteoporosis, cold limbs, lethargy and laziness in speaking and moving, weakness of lower limbs, slow movement, dry mouth and throat, and glazed expression. The risk prediction for "frailty cumulative components ≥1" was not significantly increased, while for "frailty cumulative components ≥2", a new model developed with the above selected TCM symptoms had a higher AUC than the baseline model without it (0.79 VS 0.81, P=0.002). And the NRI and IDI for the new model were 41.4% (P=0.016) and 0.024% (P=0.041), respectively. CONCLUSION: This research might provide an easier and faster way for early identification and risk prediction of frailty in elderly community dwellers.

PPARα Targeting GDF11 Inhibits Vascular Endothelial Cell Senescence in an Atherosclerosis Model.

Atherosclerosis (AS) is a complex vascular disease that seriously harms the health of the elderly. It is closely related to endothelial cell aging, but the role of senescent cells in atherogenesis remains unclear. Studies have shown that peroxisome proliferator-activated receptor alpha (PPARα) inhibits the development of AS by regulating lipid metabolism. Our previous research showed that PPARα was involved in regulating the repair of damaged vascular endothelial cells. Using molecular biology and cell biology approaches to detect senescent cells in atherosclerosis-prone apolipoprotein E-deficient (Apoe -/-) mice, we found that PPARα delayed atherosclerotic plaque formation by inhibiting vascular endothelial cell senescence, which was achieved by regulating the expression of growth differentiation factor 11 (GDF11). GDF11 levels declined with age in several organs including the myocardium, bone, central nervous system, liver, and spleen in mice and participated in the regulation of aging. Our results showed that PPARα inhibited vascular endothelial cell senescence and apoptosis and promoted vascular endothelial cell proliferation and angiogenesis by increasing GDF11 production. Taken together, these results demonstrated that PPARα inhibited vascular endothelial cell aging by promoting the expression of the aging-related protein GDF11, thereby delaying the occurrence of AS.

Ferroptosis in a sarcopenia model of senescence accelerated mouse prone 8 (SAMP8).

As a systemic syndrome characterized by age-associated degenerative skeletal muscle atrophy, sarcopenia leads to a risk of adverse outcomes in the elderly. Age-related iron accumulation is found in the muscles of sarcopenia animal models and patients, but the role of iron in sarcopenia remains poorly understood. It has been recently found that iron overload in several diseases is involved in ferroptosis, an iron- dependent form of programmed cell death. However, whether this excess iron can result in ferroptosis in muscles is still unclear. In our present study, we found that ferric citrate induced ferroptosis in C2C12 cells, as well as impaired their differentiation from myoblasts to myotubes. Due to the decreased muscle mass and fiber size, 40-week-old senescence accelerated mouse prone 8 (SAMP8) mice were used as a sarcopenia model, in whose muscles the iron content and markers of ferroptosis were found to increase, compared to 8-week- old SAMP8 controls. Moreover, our results showed that iron overload upregulated the expression of P53, which subsequently repressed the protein level of Slc7a11 (solute carrier family 7, member 11), a known ferroptosis-related gene. The downregulation of Slc7a11 then induced the ferroptosis of muscle cells through the accumulation of lipid peroxidation products, which may be one of the causes of sarcopenia. The findings in this study indicate that iron plays a key role in triggering P53- Slc7a11-mediated ferroptosis in muscles, and suggest that targeting iron accumulation and ferroptosis might be a therapeutic strategy for treating sarcopenia.

MicroRNA-146b-5p overexpression attenuates premature ovarian failure in mice by inhibiting the Dab2ip/Ask1/p38-Mapk pathway and γH2A.X phosphorylation.

OBJECTIVE: To examine the role of high-fat and high-sugar (HFHS) diet-induced oxidative stress, which is a risk factor for various diseases, in premature ovarian failure (POF). MATERIALS AND METHODS: Ovarian granulosa cells (OGCs) were isolated from mice and cultured in medium supplemented with HFHS and poly (lactic-co-glycolic acid) (PLGA)-cross-linked miR-146b-5p nanoparticles (miR-146@PLGA). RNA and protein expression levels were examined using quantitative real-time polymerase chain reaction and Western blotting, respectively. HFHS diet-induced POF model mice were administered miR-146@PLGA. RESULTS: The ovarian tissue of mice fed a HFHS diet exhibited the typical pathological characteristics of POF. HFHS supplementation induced oxidative stress injury in the mouse OGCs, activation of the Dab2ip/Ask1/p38-Mapk signalling pathway and phosphorylation of γH2A.X in vitro and in vivo. The results of the luciferase reporter assay revealed that miR-146 specifically downregulated p38-Mapk14 expression. Meanwhile, co-immunoprecipitation and Western blot analyses revealed that HFHS supplementation upregulated nuclear p38-Mapk14 expression and consequently enhanced γH2A.X (Ser139) phosphorylation. The HFHS diet-induced POF mouse model treated with miR-146@PLGA exhibited downregulated p38-Mapk14 expression in the OGCs, mitigated OGC ageing and alleviated the symptoms of POF. CONCLUSIONS: This study demonstrated that HFHS supplementation activates the Dab2ip/Ask1/p38-Mapk signalling pathway and promotes γH2A.X phosphorylation by inhibiting the expression of endogenous miR-146b-5p, which results in OGC ageing and POF development.

Exendin-4 inhibits atrial arrhythmogenesis in a model of myocardial infarction-induced heart failure via the GLP-1 receptor signaling pathway.

Glucagon-like peptide-1 receptor (GLP-1 receptor) agonists are considered to exert cardioprotective effects in models of acute and chronic heart disease. The present study aimed to investigate the role of exendin-4 (a GLP-1 receptor agonist) in atrial arrhythmogenesis in a model of myocardial infarction (MI)-induced heart failure and to elucidate the mechanisms underlying its effects. For this purpose, male Sprague-Dawley rats underwent sham surgery or left anterior descending artery ligation prior to being treated with saline/exendin-4/exendin-4 plus exendin9-39 (an antagonist of GLP-1 receptor) for 4 weeks. The effects of exendin-4 on atrial electrophysiology, atrial fibrosis and PI3K/AKT signaling were assessed. Rats with MI exhibited depressed left ventricular function, an enlarged left atrium volume, prolonged action potential duration, elevated atrial tachyarrhythmia inducibility, decreased conduction velocity and an increased total activation time, as well as total activation time dispersion and atrial fibrosis. However, these abnormalities were attenuated by treatment with the GLP-1 receptor agonist, exendin-4. Moreover, the expression levels of collagen I, collagen III, transforming growth factor-ß1, phosphorylated PI3K and AKT levels in atrial tissues were upregulated in rats with MI. These changes were also attenuated by exendin-4. It was also found that these exedin-4-mediated attenutations were mitigated by the co-administration of exendin9-39 with exendin-4. Overall, the findings of the present study suggested that exendin-4 decreases susceptibility to atrial arrhythmogenesis, improves conduction properties and exerts antifibrotic effects via the GLP-1 receptor signaling pathway. These findings provide evidence for the potential use of GLP-1R in the treatment of atrial fibrillation.

TET2-mediated Cdkn2A DNA hydroxymethylation in midbrain dopaminergic neuron injury of Parkinson's disease.

It has been reported that abnormal epigenetic modification is associated with the occurrence of Parkinson's disease (PD). Here, we found that a ten-eleven translocation 2 (TET2), a staff of the DNA hydroxylases family, was increased in dopaminergic neurons in vitro and in vivo. Genome-wide mapping of DNA 5-hydroxymethylcytosine (5-hmC)-sequencing has revealed an aberrant epigenome 5-hmC landscape in 1-methyl-4-phenylpyridinium iodide (MPP+)-induced SH-SY5Y cells. The TET family of DNA hydroxylases could reverse DNA methylation by oxidization of 5-methylcytosine (5-mC) to 5-hmC. However, the relationship between modification of DNA hydroxymethylation and the pathogenesis of PD is not clear. According to the results of 5-hmC-sequencing studies, 5-hmC was associated with gene-rich regions in the genomes related to cell cycle, especially gene-cyclin-dependent kinase inhibitor 2A (Cdkn2A). Downregulation of TET2 expression could significantly rescue MPP+-stimulated SH-SY5Y cell damage and cell cycle arrest. Meanwhile, knockdown of Tet2 expression in the substantia nigra pars compacta of MPTP-induced PD mice resulted in attenuated MPTP-induced motor deficits and dopaminergic neuronal injury via p16 suppression. In this study, we demonstrated a critical function of TET2 in PD development via the CDKN2A activity-dependent epigenetic pathway, suggesting a potential new strategy for epigenetic therapy.

Fisetin regulates gut microbiota to decrease CCR9+/CXCR3+/CD4+ T-lymphocyte count and IL-12 secretion to alleviate premature ovarian failure in mice.

Currently, there are no studies reporting the efficacy of fisetin in premature ovarian failure (POF). In this study, using mouse and Caenorhabditis elegans models, we found that fisetin not only significantly reversed ovarian damage in POF mice, but also effectively increased C. elegans lifespan and fertility. Subsequently, we carried out 16S rRNA v3+v4 sequencing using fresh feces samples from each group of mice. Results showed that although there was no significant difference in the number of gut microbiomes between the different groups of mice, fisetin affected the diversity and distribution of gut microbiota in POF mice. Alpha and beta diversity analyses showed that in the gut of POF mice in the fisetin group, the bacterial count of uncultured_bacterium_f_Lachnospiraceae was significantly increased, while that of Akkermansia was significantly decreased. Finally, flow cytometry analysis showed that the numbers of CCR9+/CXCR3+/CD4+ T lymphocytes in the peripheral blood of POF mice in the fisetin group were significantly reduced, along with the number of CD4+/interleukin (IL)-12+ cells. Therefore, our data suggested that fisetin regulates the distribution and bacterial counts of Akkermansia and uncultured_bacterium_f_Lachnospiracea in POF mice, and reduces peripheral blood CCR9+/CXCR3+/CD4+ T-lymphocyte count and IL-12 secretion to regulate the ovarian microenvironment and reduce inflammation, thus exerting therapeutic effects against POF.

Study of the Distribution of Epicardial Vagal Ganglion and the Relationship Between Delayed Enhancement Magnetic Resonance Imaging and Radiofrequency Ablation in Patients with Atrial Fibrillation.

This article presents a retrospective study of patients undergoing radiofrequency ablation of atrial fibrillation (AF); analyzes the characteristics of heart rate variability (HRV) in patients; and explores the role of delayed enhancement magnetic resonance imaging and autonomic nervous system function, changes in autonomic nervous system function, and recurrence of AF after radiofrequency ablation to understand the effect of denervation of the autonomic nervous system on the efficacy of radiofrequency ablation of AF. The study found that there were no significant differences in clinical baseline characteristics, mean heart rate, and HRV indicators between patients without relapse and patients with relapse (P > 0.05). The overall HRV index was significantly reduced after surgery as well as before surgery. In the relapse-free group, the high-frequency power that responded to vagal tone was more significant, the low-frequency/high-frequency power ratio increased, and other HRV indicators were significantly reduced; in the relapse group, mean heart rate increased, sympathetic response to the low-frequency power of nerve tension was significantly reduced, and the low-frequency/high-frequency power ratio was decreased. The difference was statistically significant (P < 0.05). Therefore, sympathetic and parasympathetic nerve function were significantly reduced after radiofrequency ablation of the pulmonary veins in patients with AF. Reducing vagus nerve tension may inhibit early recurrence of paroxysmal AF in patients after left atrial ring pulmonary vein ablation.

Identification of a novel regulatory pathway for PPARα by RNA-seq characterization of the endothelial cell lipid peroxidative injury transcriptome.

Endothelial dysfunction caused by endothelial cell injuries is the initiating factor for atherosclerosis (AS), and lipid peroxidative injury is one of a dominant factor for AS pathogenesis. Using RNA-seq, we compared changes in transcriptome expression before and after endothelial cell injury, and found 311 differentially expressed genes (DEGs), of which 258 genes were upregulated and 53 genes were downregulated. The protein-protein interactions (PPIs) between the genes were analysed using the STRING database, and a PPI network of DEGs was constructed. The relationship distributions among these PPIs were analysed by performing network node statistics. We found that in the top 20 DEGs with high connected protein nodes in the PPI network, 16 were upregulated and 4 were downregulated. Gene ontology (GO) functional enrichment analysis and KEGG pathway enrichment analysis on the DEGs were also performed. By comparing the upregulated expressed genes with high connected protein nodes in the PPI network to those related to endothelial cell lipid damage and repair in the GO analysis, we identified seven genes (NOX4, PPARA, CCL2, PDGFB, IL8, VWF, CD36) and verified their expression levels by real-time polymerase chain reaction. The protein interactions between the seven genes were then analysed using the STRING database. The results predicted that CCL2 interacts with NOX4, PPARα, PDGFß and VWF individually. Thus, we examined the protein expression levels of CCL2, NOX4, PPARα, PDGFß and VWF, and found that the expression levels of all proteins were significantly upregulated after the lipid peroxidative injury, with CCL2 and PPARα exhibiting the highest expression levels. Therefore, we investigated the interregulatory relationship between CCL2 and PPARα and their roles in the repair of endothelial cell injury. With the help of gene overexpression and knockdown techniques, we discovered that PPARα promotes the repair of endothelial cell injury by upregulating CCL2 expression in human umbilical vein endothelial cells but that CCL2 cannot regulate PPARα expression. Therefore, we believe that PPARα participates in the repair of endothelial cell lipid peroxidative injury through regulating the expression of CCL2.

Tiaoxin Recipe, a Chinese herbal formula, inhibits microRNA-34a expression in the APPswe/PS1ΔE9 mouse model of Alzheimer's disease.

OBJECTIVE: To investigate the effect and underlying mechanisms of Tiaoxin Recipe (a Chinese herbal formula) treatment on Alzheimer's disease (AD). METHODS: Twelve-week-old APPswe/PS1ΔE9 (APP/PS1) double transgenic mice were used as a model of AD-afflicted mice. One group of mice was treated with Tiaoxin Recipe by gastrogavage for 12 weeks, while two other groups were given intraperitoneal injections of nicotinamide adenine dinucleotide or FK866 for 4 weeks. Morris water maze and thioflavin S staining tests were performed to evaluate cognitive impairment and amyloid plaque deposition, respectively. Serum amyloid-ß1-42 (Aß1-42) content was detected using an enzyme-linked immunosorbent assay, and quantitative reverse transcription-polymerase chain reaction was performed to examine the expression levels of microRNA-34a (miR-34a) in cortex and hippocampus samples of the study mice. RESULTS: Compared with the normal control group, the memory and learning abilities of the APP/PS1 model group were found to be impaired (P < 0.01), as shown by the increased levels of senile plaque deposition in cortex and hippocampus (P < 0.01), miR-34a expression (P < 0.01) and serum Aß1-42 content (P < 0.01). Treatment with Tiaoxin Recipe significantly reduced memory impairment (P < 0.01) by reducing amyloid plaque accumulation in cortex and hippocampus (P < 0.01), miR-34a expression (P < 0.01) and serum Aß1-42 content (P < 0.01) in APP/PS1 mice. CONCLUSION: Tiaoxin Recipe is a viable complementary or alternative therapeutic treatment that is capable of delaying the development of early-stage AD by inhibiting the expression of miR-34a.

Anti-atherosclerotic effects of LXRα agonist through induced conversion of M1 macrophage to M2.

Liver X receptor alpha (LXRα) plays important roles in lipid metabolism and inflammation. Therefore, it is essential for protection against atherosclerosis (AS). In AS plaques, the key cells involved in lipid metabolism and inflammation are macrophages. However, the mechanism by which LXRα regulates macrophage involvement in AS formation remains unclear. In this study, we first confirmed the effects of an LXRα agonist (T0901317) and antagonist (GSK2033) on foam cell formation and inflammation in vivo and in vitro. Indeed, T0901317 reduced the number of macrophages in AS plaques and decreased the number of migrated macrophages, as assessed using an in vitro transwell assay. Next, we investigated the relationship between the reduction in macrophages in AS plaques and cytokine levels or foam cell formation. The results show that T0901317 reduced the number of high cholesterol-induced M1 macrophages by converting them into M2 macrophages in vivo and in vitro. Due to this phenotypic transition of macrophages, the inflammatory response was alleviated, and lipid metabolism was enhanced in AS plaques. This effect was achieved by promoting the expression of reverse transporters (ATP-binding cassette transporter member 1 and ATP-binding cassette subfamily G member 1) and inhibiting the phosphorylation of nuclear factor-κB-mediated phosphorylation.

miR-15b induces premature ovarian failure in mice via inhibition of α-Klotho expression in ovarian granulosa cells.

A thorough understanding of epigenetics regulatory mechanisms of premature ovarian failure (POF) is still lacking. Here, we found that cyclophosphamide induced significantly decrease in α-Klotho (Kl) expression in mouse ovarian granulosa cells (mOGCs), suggesting that cyclophosphamide inhibited Kl expression. Cyclophosphamide also significantly accelerated ageing and led to a decline in the pregnancy rate of C. elegans. We subsequently noted that the pathological condition exhibited by Kl-/- mice was similar to that observed in cyclophosphamide-induced POF mice. Furthermore, the mOGCs in both types of mice showed significant signs of oxidative stress damage, including decreased SOD and ATP, increased ROS levels. Detailed analyses revealed that the decreased Kl expression led to the reduced expression of autophagy-related proteins in mOGCs, which resulted in decreased autophagy activity. Finally, we found that cyclophosphamide attenuated the autophagy function of mOGCs via upregulating microRNA-15b expression, which silenced the endogenous Kl mRNA expression and stimulated the activity of the downstream TGFß1/Smad pathway. Therefore, we demonstrated that Kl was one of the key inhibitory factors in the development of POF. It elucidated the underlying epigenetic regulatory mechanism, whereby cyclophosphamide-dependent microRNA-15b inhibited Kl expression, leading to the reduced ability of mOGCs to induce autophagy and ROS scavenging, ultimately causing POF.