Ursolic acid alleviates lupus nephritis by suppressing SUMO1-mediated stabilization of NLRP3.

BACKGROUND: Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease that affects multiple organs and cause a wide range of severe clinical manifestations, including lupus nephritis (LN), which is a major risk factor for morbidity and mortality in individual with SLE. Ursolic acid (UA) is a natural compound with favorable anti-inflammatory properties and has been employed to treat multiple disease, including inflammatory diseases, diabetes, and Parkinson's disease. However, its therapeutic potential on LN and the underlying mechanisms remains unclear. PURPOSE: This aim of this study was to investigate the impact of UA on LN and its underlying mechanism. METHODS: MRL/lpr lupus-prone mouse model was used and UA was administered orally for 8 weeks. Dexamethasone was used as a positive control. After 8 weeks of administration, the spleen-to-body-weight ratio, renal function, urine albumin excretion, cytokines levels, and the deposition of immune complex were measured. The primary mouse glomerular mesangial cells (GMCs) and SV40-MES-13 were stimulated by lipopolysaccharide (LPS), either alone or in combination with nigericin, to establish an in vitro model. The activation of NLRP3 inflammasome were investigated both in vivo and in vitro using qRT-PCR, immunoblotting, and immunofluorescence. RESULTS: Our results revealed that UA prominently alleviated LN in MRL/lpr lupus-prone mice, leading to a significant reduction in proteinuria production, infiltration of immune cells infiltration, and histopathological damage in the renal tissue. In addition, UA exerted inhibitory effects on the secretion of IL-1ß, IL-18, and caspase-1, pyroptosis, and ASC speck formation in primary mouse GMCs and SV40-MES-13 cells. Furthermore, UA facilitated the degradation of NLRP3 by suppressing SUMO1-mediated SUMOylation of NLRP3. CONCLUSION: UA possess a therapeutical effect on LN in MRL/lpr mice by enhancing the degradation of NLRP3 through inhibition of SUMO1-mediated SUMOylation of NLRP3. Our findings provide a basis for proposing UA as a potential candidate for the treatment of LN.

Impact of transcranial electrical stimulation on serum neurotrophic factors and language function in patients with speech disorders.

BACKGROUND: Speech disorders have a substantial impact on communication abilities and quality of life. Traditional treatments such as speech and psychological therapies frequently demonstrate limited effectiveness and patient compliance. Transcranial electrical stimulation (TES) has emerged as a promising non-invasive treatment to improve neurological functions. However, its effectiveness in enhancing language functions and serum neurofactor levels in individuals with speech disorders requires further investigation. AIM: To investigate the impact of TES in conjunction with standard therapies on serum neurotrophic factor levels and language function in patients with speech disorders. METHODS: In a controlled study spanning from March 2019 to November 2021, 81 patients with speech disorders were divided into a control group (n = 40) receiving standard speech stimulation and psychological intervention, and an observation group (n = 41) receiving additional TES. The study assessed serum levels of ciliary neurotrophic factor (CNTF), glial cell-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF), as well as evaluations of motor function, language function, and development quotient scores. RESULTS: After 3 wk of intervention, the observation group exhibited significantly higher serum levels of CNTF, GDNF, BDNF, and NGF compared to the control group. Moreover, improvements were noted in motor function, cognitive function, language skills, physical abilities, and overall development quotient scores. It is worth mentioning that the observation group also displayed superior performance in language-specific tasks such as writing, reading comprehension, retelling, and fluency. CONCLUSION: This retrospective study concluded that TES combined with traditional speech and psychotherapy can effectively increase the levels of neurokines in the blood and enhance language function in patients with speech disorders. These results provide a promising avenue for integrating TES into standard treatment methods for speech disorders.

[Clinical and Mechanism Research Progress in Amelioration of Mild Cognitive Impairment via Meditation].

Mild cognitive impairment(MCI)has a high risk of progressing to dementia,with no recommended therapies.Recent studies have shown that meditation has huge potential to improve the cognitive function,with low cost and high safety,being suitable to be applied in the treatment of neurological and psychotic disorders.This paper reviews the application and prospects of meditation in treating MCI from the concept,clinical efficacy,and mechanism of meditation,aiming to provide reference for future clinical studies.

Sex differences in the association of the uric acid to high-density lipoprotein cholesterol ratio with coronary artery disease risk among Chinese nondialysis patients with CKD stages 3-5.

BACKGROUND AND AIMS: Evidence has indicated that serum uric acid (UA) and high-density lipoprotein cholesterol (HDL-C) are positively and negatively associated with coronary artery disease (CAD). The UA to HDL-C ratio (UHR) has recently drawn attention as a new predictor for metabolic syndrome, inflammation and atherosclerosis. However, the association between the UHR and CAD in nondialysis chronic kidney disease (CKD) patients is still unclear. METHODS AND RESULTS: We retrospectively analysed 733 733 nondialysis patients with CKD stage 3-5 who received their first coronary artery angiography (CAG), including 510 participants with CAD. All laboratory indicators were collected within one week before CAG. The median UHR of CAD and non-CAD patients was 15.52% and 12.29%, respectively. In multivariate analysis, female patients with a high UHR were 4.7 times more at risk of CAD than those with a lower UHR. Meanwhile, the positive association of the UHR with the severity of coronary artery stenosis (CAS) persisted significantly in female CAD subjects but not in males. In addition, receiver operating characteristic (ROC) curves were constructed for CAD and severe CAS. The area under the curve (AUC) for the UHR was higher than that for UA and HDL-C alone in female patients [UHR (AUC): 0.715 for CAD and 0.716 for severe CAS]. CONCLUSIONS: An elevated UHR was independently related to an increased CAD risk and the severity of CAS in nondialysis female patients with CKD stage 3-5, and was more predictive of the onset of CAD and the severity of CAS than UA or HDL-C alone.

Investigation of targets and anticancer mechanisms of covalently acting natural products by functional proteomics.

Eriocalyxin B (EB), 17-hydroxy-jolkinolide B (HJB), parthenolide (PN), xanthatin (XT) and andrographolide (AG) are terpenoid natural products with a variety of promising antitumor activities, which commonly bear electrophilic groups (α,ß-unsaturated carbonyl groups and/or epoxides) capable of covalently modifying protein cysteine residues. However, their direct targets and underlying molecular mechanisms are still largely unclear, which limits the development of these compounds. In this study, we integrated activity-based protein profiling (ABPP) and quantitative proteomics approach to systematically characterize the covalent targets of these natural products and their involved cellular pathways. We first demonstrated the anti-proliferation activities of these five compounds in triple-negative breast cancer cell MDA-MB-231. Tandem mass tag (TMT)-based quantitative proteomics showed all five compounds commonly affected the ubiquitin mediated proteolysis pathways. ABPP platform identified the preferentially modified targets of EB and PN, two natural products with high anti-proliferation activity. Biochemical experiments showed that PN inhibited the cell proliferation through targeting ubiquitin carboxyl-terminal hydrolase 10 (USP10). Together, this study uncovered the covalently modified targets of these natural products and potential molecular mechanisms of their antitumor activities.

Matrine suppresses NLRP3 inflammasome activation via regulating PTPN2/JNK/SREBP2 pathway in sepsis.

BACKGROUND: Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Abnormal activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome plays a vital role in the pathogenesis of sepsis. Matrine is proved to show good anti-inflammatory properties, whereas its effect and the underlying molecular machinery on sepsis remains unclear. PURPOSE: The aim of this study is to evaluate the effect and mechanism of Matrine on sepsis. STUDY DESIGN: THP-1 cells and J774A.1 cells were stimulated by lipopolysaccharide (LPS) with nigericin or adenosine triphosphate (ATP) to establish an in vitro model. Cecal ligation and puncture (CLP)-induced sepsis mouse model was used. Matrine was given by gavage. METHODS: To investigate the NLRP3 inflammasome activation, phorbol myristate acetate (PMA)-induced THP-1 cells were first primed with LPS and then stimulated by matrine, followed by treatment with nigericin or ATP. The concentration of interleukin 1ß (IL-1ß) and interleukin 18 (IL-18) in the cell culture supernatant was detected. The mechanism was explored by cell death assay, immunoblots and immunofluorescence in vitro. C57BL/6 mice were intragastrically administered with matrine for 5 days before CLP. The therapeutic effect of matrine was evaluated by symptoms, pathological analysis, ELISA and RT-qPCR. RESULTS: Our results revealed that matrine inhibited IL-1ß and IL-18 secretion, suppressed caspase-1 activation, reduced cell death, and blocked ASC speck formation upon NLRP3 inflammasome activation. Furthermore, matrine restrains NLRP3 inflammasome activation as well as pyroptosis through regulating the protein tyrosine phosphatase non-receptor type 2 (PTPN2)/JNK/SREBP2 signaling. Matrine also prominently improved the symptoms and pathological changes with reduced levels of TNF-α, IL-1ß, and IL-6 in the lung tissues and serum in a dose-dependent manner. CONCLUSION: Matrine effectively alleviates the symptoms of CLP-induced sepsis in mice, restrains NLRP3 inflammasome activation by regulating PTPN2/JNK/SREBP2 signaling pathway, and may become a promising therapeutic agent for sepsis treatment.

IL-37 improves mice myocardial infarction via inhibiting YAP-NLRP3 signaling mediated macrophage programming.

OBJECTIVE: Myocardial infarction is the highest cause of cardiovascular death. Previous studies found that patients with myocardial infarction have elevated serum IL-37 and IL-37 treatment significantly alleviates adverse remodeling in myocardial infarction mice. However, the underlying mechanism of IL-37 in myocardial infarction is still unknown. Here we explored the underlying mechanism of IL-37 in attenuating myocardial infarction. METHODS: The myocardial infarction mice model was constructed by left anterior descending ligation and then submitted to recombinant IL-37 administration. The histology and cardiac function were detected by HE & Masson staining and echocardiography, respectively. The macrophage phenotypes were analyzed by flow cytometry and real-time PCR. The cytokines in serum and cell culture supernatant were determined by ELISA. In addition, THP-1 cells were used in vitro to investigate the underlying mechanisms. RESULTS: Infarcted mice showed increased inflammatory cell infiltration and impaired cardiac function. IL-37 treatment alleviated pro-inflammatory macrophage infiltration, tissue injury, and collagen deposition in hearts on day 3 and 7 after infarction in mice. In addition, IL-37 application modulated the balance between M1 and M2 macrophages in infarcted hearts. In vitro, THP-1 cell line polarization was also regulated by IL-37, companied by YAP phosphorylation and NLRP3 inactivation. Verteporfin, a YAP inhibitor, could abolish IL-37-induced NLRP3 inhibition and M2 macrophage polarization. CONCLUSION: Our results demonstrated that IL-37 achieves a favorable therapeutical function on myocardial infarction by modulating YAP-NLRP3 mediated macrophage programming, providing a promising drug for the treatment of myocardial infarction.

Yixin Ningshen Tablet Alleviates Comorbidity of Myocardial Infarction and Depression by Enhancing Myocardial Energy Metabolism and Increasing Availability of Monoamine Neurotransmitter.

OBJECTIVE: To investigate the therapeutic effect of Yixin Ningshen Tablet (YXNS) on comorbidity of myocardial infarction (MI) and depression in rats and explore the underlying mechanism. METHODS: The Sprague-Dawley rats were randomly divided into 5 groups with 7 rats in each group according to their weights, including control, model, fluoxetine (FLXT, 10 mg/kg), low-dose YXNS (LYXNS, 100 mg/kg), and high-dose YXNS (HYXNS, 300 mg/kg) groups. All rats were pretreated with corresponding drugs for 12 weeks. The rat model of MI and depression was constructed by ligation of left anterior descending coronary artery and chronic mild stress stimulation. The echocardiography, sucrose preference test, open field test, and forced swim test were performed. Myocardial infarction (MI) area and myocardial apoptosis was also detected. Serum levels of interleukin (IL)-6, IL-1ß, tumor necrosis factor-α (TNF-α), 5-hydroxytryptamine (5-HT), adrenocorticotrophic hormone (ACTH), corticosterone (CORT), and norepinephrine (NE) were determined by enzyme linked immunosorbent assay. The proteins of adenosine 5'-monophosphate -activated protein kinase (AMPK), p-AMPK, peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and nuclear respiratory factor 1 (NRF1) in heart were detected by Western blot analysis. The expression levels of TNF-α, IL-6, indoleamine 2,3-dioxygenase (IDO1), kynurenine 3-monooxygenase (KMO), and kynureninase (KYNU) in hippocampus were detected by real-time quantitative polymerase chain reaction. RESULTS: Compared with the model group, the cardiac function of rats treated with YXNS improved significantly (P<0.01). Meanwhile, YXNS effectively reduced MI size and cardiomyocytes apoptosis of rats (P<0.01 or P<0.05), promoted AMPK phosphorylation, and increased PGC-1α protein expression (P<0.01 or P<0.05). HYXNS significantly increased locomotor activity of rats, decreased the levels of TNF-α, IL-6 and IL-1ß, and increased the serum levels of 5-HT, NE, ACTH, and CORT (all P<0.05). Moreover, HYXNS decreased the mRNA expressions of IDO1, KMO and KYNU (P<0.05). CONCLUSIONS: YXNS can relieve MI by enhancing myocardial energy metabolism. Meanwhile, YXNS can alleviate depression by resisting inflammation and increasing availability of monoamine neurotransmitters. It may be used as a potential drug to treat comorbidity of MI and depression.

Total glucosides of Paeony restores intestinal barrier function through inhibiting Lyn/Snail signaling pathway in colitis mice.

BACKGROUND: Inflammatory bowel disease (IBD) is an autoimmune disease. The pathogenesis of IBD is complicated and intestinal mucosal barrier damage is considered as the trigger factor for the initiation and recurrence of IBD. Total Glucosides of Paeony (TGP) has shown good inhibitory effects on immune-inflammation in clinic studies. However, its effect and mechanism on IBD are largely unknown. PURPOSE: The purpose of this study is to evaluate the effect and mechanism of TGP on IBD. STUDY DESIGN: DSS-induced colitis mouse model was used. TGP was given by gavage. Caco-2 cells were stimulated by outer membrane vesicles (OMV) to establish an in vitro model. METHODS: C57BL/6 mice were divided into normal control group, model group, mesalazine group, paeoniflorin (PA) group, high-dose group of TGP, and low-dose group of TGP. The model was induced with 2.5% DSS for 7 days, and TGP was intragastrically administered for 10 days. The therapeutic effect of TGP was evaluated by symptoms, histochemical analysis, RT-qPCR and ELISA. The mechanism was explored by intestinal permeability, Western blot and immunofluorescence in vivo and in vitro. RESULTS: Our results showed that TGP could significantly improve the symptoms and pathological changes, with reduced levels of TNF-α, IL-17A, IL-23 and IFN-γ in the colon tissues and serum under a dose-dependent manner. TGP also reduced the intestinal permeability and restored the protein expression of tight junction and adherens junction proteins of intestinal epithelial cells in vivo and in vitro. Furthermore, TGP could inhibit the expression of p-Lyn and Snail and prevent Snail nuclear localization, thereby maintaining tight and adherens junctions. CONCLUSION: TGP effectively improves the symptoms of DSS-induced colitis in mice, protects the intestinal epithelial barrier by inhibiting the Lyn/Snail signaling pathway, and maybe a promise therapeutic agent for IBD treatment.

Influence of spinal cord injury on core regions of motor function.

Functional electrical stimulation is an effective way to rebuild hindlimb motor function after spinal cord injury. However, no site map exists to serve as a reference for implanting stimulator electrodes. In this study, rat models of thoracic spinal nerve 9 contusion were established by a heavy-impact method and rat models of T6/8/9 spinal cord injury were established by a transection method. Intraspinal microstimulation was performed to record motion types, site coordinates, and threshold currents induced by stimulation. After transection (complete injury), the core region of hip flexion migrated from the T13 to T12 vertebral segment, and the core region of hip extension migrated from the L1 to T13 vertebral segment. Migration was affected by post-transection time, but not transection segment. Moreover, the longer the post-transection time, the longer the distance of migration. This study provides a reference for spinal electrode implantation after spinal cord injury. This study was approved by the Institutional Animal Care and Use Committee of Nantong University, China (approval No. 20190225-008) on February 26, 2019.

Prognostic Factors Analysis and Nomogram Construction of Dual Primary Lung Cancer: A Population Study.

As a special type of lung cancer, multiple primary lung cancer (MPLC) has unique biological characteristics, and its research remains limited. The aim of our research was to identify prognostic factors and construct a prognostic nomogram of dual primary lung cancer (DPLC). A population cohort study of patients with DPLC was conducted using the extracted data from the Surveillance, Epidemiology, and End Results (SEER) database. Relevant survival variables were identified using the Cox proportional hazard model. Prognostic nomogram was performed and its predictive performance was validated via the modeling and validating cohort data. Additionally, propensity score matching (PSM) was also applied to evaluate whether surgery affected the OS of this study population. 5411 eligible DPLC patients were included in this study cohort, with 41.0% of 3-year OS rate and 27.7% of 5-year OS rate. Age, sex, race, grade, stage, lymph node (LN) metastasis, histological type, primary site, and surgery were considered to be prognostic factors of OS. The C-indexes of the established nomogram were 0.70 (95% CI (0.69, 0.71)) in the modeling group and 0.70 (95% CI (0.68, 0.72)) in the validation group, which showed an ideal model discrimination ability. AUC and calibration plots of 3- and 5-year OS also proved the good performance of the established nomogram. After 1 : 1 PSM, surgery can potentially reduce the risk of OS (HR = 0.63, 95% CI: 0.56-0.72) of DPLC. The prognostic nomogram with reliable performance was developed to predict 3- and 5-year OS rates, which could assist clinicians to make more reasonable survival prediction for DPLC patients. For patients without absolute surgical contraindications, surgery should be actively considered.

Astragaloside IV reverses simvastatin-induced skeletal muscle injury by activating the AMPK-PGC-1α signalling pathway.

In this study, we investigated the effect of astragaloside IV on skeletal muscle energy metabolism disorder caused by statins and explored the possible mechanisms. High-fat diet-fed apolipoprotein E knockout (ApoE-/- ) mice performed aerobic exercise and were administered simvastatin, simvastatin + trimetazidine, or simvastatin + astragaloside IV by gavage. At the end of treatment, exercise performance was assessed by the hanging grid test, forelimb grip test, and running tolerance test. Moreover, plasma lipid and creatine kinase concentrations were measured. After sacrifice, the gastrocnemius muscle was used to assess muscle morphology, and energy metabolism was evaluated by determining the concentration of lactic acid and the storage capacity of adenosine triphosphate and glycogen. Mitochondrial function was assessed by measuring mitochondrial complex III and citrate synthase activity and membrane potential. In addition, oxidative stress was assessed by determining the level of hydrogen peroxide. Finally, using western blotting and reverse transcription polymerase chain reaction, we explored the mechanism of astragaloside IV in alleviating simvastatin-induced muscle injury. Our results demonstrated that astragaloside IV reversed simvastatin-induced muscle injury without affecting the lipid-lowering effect of simvastatin. Moreover, astragaloside IV promoted the phosphorylation of AMPK and activated PGC-1α, which upregulated the expression of NRF1 to enhance energy metabolism and inhibit skeletal muscle cell apoptosis.

Computer aided diabetic retinopathy detection based on ophthalmic photography: a systematic review and Meta-analysis.

AIM: To ensure the diagnostic value of computer aided techniques in diabetic retinopathy (DR) detection based on ophthalmic photography (OP). METHODS: PubMed, EMBASE, Ei village, IEEE Xplore and Cochrane Library database were searched systematically for literatures about computer aided detection (CAD) in DR detection. The methodological quality of included studies was appraised by the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2). Meta-DiSc was utilized and a random effects model was plotted to summarize data from those included studies. Summary receiver operating characteristic curves were selected to estimate the overall test performance. Subgroup analysis was used to identify the efficiency of CAD in detecting DR, exudates (EXs), microaneurysms (MAs) as well as hemorrhages (HMs), and neovascularizations (NVs). Publication bias was analyzed using STATA. RESULTS: Fourteen articles were finally included in this Meta-analysis after literature review. Pooled sensitivity and specificity were 90% (95%CI, 85%-94%) and 90% (95%CI, 80%-96%) respectively for CAD in DR detection. With regard to CAD in EXs detecting, pooled sensitivity, specificity were 89% (95%CI, 88%-90%) and 99% (95%CI, 99%-99%) respectively. In aspect of MAs and HMs detection, pooled sensitivity and specificity of CAD were 42% (95%CI, 41%-44%) and 93% (95%CI, 93%-93%) respectively. Besides, pooled sensitivity and specificity were 94% (95%CI, 89%-97%) and 87% (95%CI, 83%-90%) respectively for CAD in NVs detection. No potential publication bias was observed. CONCLUSION: CAD demonstrates overall high diagnostic accuracy for detecting DR and pathological lesions based on OP. Further prospective clinical trials are needed to prove such effect.

Total Glucosides of Paeony protects against collagen-induced mouse arthritis via inhibiting follicular helper T cell differentiation.

BACKGROUND: The development of rheumatoid arthritis (RA) is related to germinal center (GC) response and autoreactive T cells, which mediate adaptive immunity and play an important role in stimulating the production of autoantibodies and pro-inflammatory cytokines by B cells and macrophages. Total Glucosides of Paeony (TGP) has anti-inflammatory, immunomodulatory and analgesic effects and is widely used to treat RA. However, few studies investigated whether the therapeutic effect of TGP is associated with the inhibition of autoimmune response. PURPOSE: The aim of this study was to investigate the effects and mechanisms of TGP on RA. STUDY DESIGN: Type II collagen-induced arthritis (CIA) mouse model was used, and TGP and paeoniflorin were intragastrically treated. METHODS: DBA/1 mice were divided into 5 groups: control, model, positive drug (paeoniflorin) and high- and low-dose TGP group. After 21 days of intragastric administration, the pathological change, inflammation expression and molecular mechanism of each group of mice were detected by Micro-CT, histochemical analysis, ELLSA, Western blot, RT-qPCR and flow cytometry. RESULTS: Our study found that TGP treatment effectively improved inflammation and joint destruction in CIA mice. It reduced the production of serum IgG2a and pro-inflammatory cytokines, including serum interleukin (IL)-21, tumor necrosis factor (TNF)-α and IL-6, and the phosphorylation of NF-κB p65 and STAT3 in a dose-dependent manner. More importantly, TGP could suppress the frequency of germinal center B cells and Tfh cells in the spleen. CONCLUSION: TGP can not only improve symptoms, but also inhibit bone destruction. The therapeutic effect of TGP on CIA is mainly achieved by inhibiting spleen Tfh cell differentiation and GC formation through STAT3 signaling pathway.

Genome-wide analysis reveals alcohol dehydrogenase 1C and secreted phosphoprotein 1 for prognostic biomarkers in lung adenocarcinoma.

To seek out novel promising biomarkers for predicting lung adenocarcinoma (LUAD) prognosis, we conducted this study. First, 279 upregulated and 37 downregulated differentially expressed genes were obtained from LUAD and para-carcinoma tissues by the Affymetrix GeneChip Human Transcriptome Array. Then, we randomly classified samples of LUAD data set GSE31210 as training and testing sets in a 1:1 ratio. Alcohol dehydrogenase 1C (ADH1C) and secreted phosphoprotein 1 (SPP1) were finally identified correlating with the LUAD survival through least absolute shrinkage and selection operator penalized Cox proportion hazards regression model, and applied to build a 2-gene signature related to prognosis in training set. Univariate and multivariable survival analyses suggested that overall survival (OS) and relapse-free survival (RFS) in the 2-gene signature low-risk group were better than the high-risk group. Kaplan-Meier curves proved that elevated ADH1C expression and reduced SPP1 expression were related to better OS and RFS. Besides, the SPP1 expressed higher in LUAD than para-carcinoma tissues using quantitative reverse transcription polymerase chain reaction assay. Finally, the association between the two genes and clinicopathological parameters in 80 LUAD were analyzed, it is suggested that SPP1 was relevant to epidermal growth factor receptor mutation. These findings indicated that ADH1C and SPP1 might be novel promising biomarkers for predicting LUAD prognosis.

Ginsenoside Rg1 protects against H2O2­induced neuronal damage due to inhibition of the NLRP1 inflammasome signalling pathway in hippocampal neurons in vitro.

Oxidative stress and neuroinflammation are important in the pathogenesis of ageing and age­related neurodegenerative diseases, including Alzheimer's disease. NADPH oxidase 2 (NOX2) is a major source of reactive oxygen species (ROS) in the brain. The nucleotide­binding oligomerisation domain (NOD)­like receptor protein 1 (NLRP1) inflammasome is responsible for the formation of pro­inflammatory molecules in neurons. Whether the NOX2­NLRP1 inflammasome signalling pathway is involved in neuronal ageing and age­related damage remains to be elucidated. Ginsenoside Rg1 (Rg1) is a steroidal saponin found in ginseng. In the present study, the primary hippocampal neurons were treated with H2O2 (200 µM) and Rg1 (1, 5 and 10 µM) for 24 h to investigate the protective effects and mechanisms of Rg1 on H2O2­induced hippocampal neuron damage, which mimics age­related damage. The results showed that H2O2 treatment significantly increased ROS production and upregulated the expression of NOX2 and the NLRP1 inflammasome, and led to neuronal senescence and damage to hippocampal neurons. Rg1 decreased ROS production, reducing the expression of NOX2 and the NLRP1 inflammasome in H2O2­treated hippocampal neurons. Furthermore, Rg1 and tempol treatment significantly decreased neuronal apoptosis and the expression of ß­galactosidase, and alleviated the neuronal senescence and damage induced by H2O2. The present study indicates that Rg1 may reduce NOX2­mediated ROS generation, inhibit NLRP1 inflammasome activation, and inhibit neuronal senescence and damage.

Protective effects of a traditional Chinese herbal formula Jiang-Xian HuGan on Concanavalin A-induced mouse hepatitis via NF-κB and Nrf2 signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Jiang-Xian HuGan (JXHG) formulated by five natural products including Freshwater clam (Corbicula fluminea), Curcuma longa L., Ligustrum lucidum, Eclipta prostrata (L.) L. and Paeonia lactiflora Pall., has exhibited a great hepatoprotective effect. AIM OF THIS STUDY: We investigated the effect of JXHG on concanavalin A (ConA)-induced acute live injury in mice, and to elucidate its underlying molecular mechanisms. MATERIALS AND METHODS: Jiangkanling Capsule (900 mg/kg), low-dose JXHG (LJXHG, 700 mg/kg), high-dose JXHG (HJXHG, 1400 mg/kg) were administered to mice by oral gavage daily for 20 days prior to a single intravenous injection of ConA (20 mg/kg). Liver injury was evaluated by measuring the serum levels of enzymes and cytokines as well as liver histological analysis. We also measured the hepatic expression of cytokines at mRNA levels and the proteins related to NF-κB and Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling pathways. RESULT: Our results showed that JXHG pretreatment significantly alleviated ConA-induced live injury as evidenced by decreased serum levels of glutamic-pyruvic transaminase (ALT) and glutamic oxalacetic transaminase (AST), and reduced hepatocyte apoptosis and mortality. Furthermore, JXHG was able to significantly reduce the serum levels of proinflammatory cytokines, down-regulate the mRNA expression of interleukin-6 (IL-6) and interferon-γ (IFN-γ), and up-regulate IL-10 as well as superoxide-dimutase-1 (SOD1), glutathione reductase (GSR) and Glutathione peroxidase 2 (GPX2) mRNA in the liver tissues after Con A injection. In addition, JXHG pretreatment dramatically suppressed the phosphorylation of NF-κB p65 (p65), increased Nrf2 expression, and decreased the expression ratio of cleaved caspase-3/caspase-3 in liver tissues. CONCLUSION: These results suggest that JXHG protects against ConA-induced acute live injury through inhibiting NF-κB mediated inflammatory pathway and promoting Nrf2 mediated anti-oxidative stress signaling pathway.

S-propargyl-cysteine attenuates inflammatory response in rheumatoid arthritis by modulating the Nrf2-ARE signaling pathway.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder. Hydrogen sulfide (H2S), the third physiological gasotransmitter, is well recognized as an anti-inflammatory mediator in various inflammatory conditions. Herein, we explored the protective effects of S-propargyl-cysteine (SPRC, also known as ZYZ-802), an endogenous H2S modulator, on RA and determined the underlying mechanisms. In the present study, SPRC concentration-dependently attenuated inflammatory mediator expression, reactive oxidase species generation, and the expression and activity of matrix metalloproteinases (MMP)-9 in interleukin (IL)-1ß-induced human rheumatoid fibroblast-like synoviocytes MH7A. In addition, SPRC blocked IL-1ß-mediated migration and invasion of MH7A cells. As expected, the protective effects of SPRC were partially abrogated by DL-propargylglycine (PAG, a H2S biosynthesis inhibitor). In vivo study also demonstrated that SPRC treatment markedly ameliorated the severity of RA in adjuvant-induced arthritis rats, and this effect was associated with the inhibition of inflammatory response. We further identified that SPRC remarkably induced heme oxygenase-1 expression associated with the degradation of Kelch-like ECH-associated protein 1 (Keap1) and nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2); this effect was attributed to the sulfhydrylation of the cysteine residue of Keap1. Our data demonstrated for the first time that SPRC, an endogenous H2S modulator, exerted anti-inflammatory properties in RA by upregulating the Nrf2-antioxidant response element (ARE) signaling pathway.

Rebuilding motor function of the spinal cord based on functional electrical stimulation.

Rebuilding the damaged motor function caused by spinal cord injury is one of the most serious challenges in clinical neuroscience. The function of the neural pathway under the damaged sites can be rebuilt using functional electrical stimulation technology. In this study, the locations of motor function sites in the lumbosacral spinal cord were determined with functional electrical stimulation technology. A three-dimensional map of the lumbosacral spinal cord comprising the relationship between the motor function sites and the corresponding muscle was drawn. Based on the individual experimental parameters and normalized coordinates of the motor function sites, the motor function sites that control a certain muscle were calculated. Phasing pulse sequences were delivered to the determined motor function sites in the spinal cord and hip extension, hip flexion, ankle plantarflexion, and ankle dorsiflexion movements were successfully achieved. The results show that the map of the spinal cord motor function sites was valid. This map can provide guidance for the selection of electrical stimulation sites during the rebuilding of motor function after spinal cord injury.