Xuebijing injection and its bioactive components alleviate nephrotic syndrome by inhibiting podocyte inflammatory injury.

Xuebijing injection (XBJ) is widely used to treat nephrotic syndrome (NS) in clinic, but its bioactive components and therapeutic mechanism are still unclear. In this study, the bioactive components of XBJ were determined by ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF/MS). The therapeutic effect of XBJ on NS was evaluated in BALB/c mice induced by adriamycin (ADR, 10 mg/kg) via a single tail vein. The protective effect of XBJ and its bioactive components on podocytes was demonstrated using mouse podocytes (MPC-5) induced by lipopolysaccharide (LPS, 4 µg/mL). The results show that 33 components of XBJ were identified. Furthermore, 12 bioactive components were detected in blood, including protocatechuic acid, salvianolic acid C, benzoyloxypaeoniflorin, danshensu, salvianolic acid A, salvianolic acid B, catechin, caffeic acid, galloylpaeoniflorin, oxypaeoniflorin, hydroxysafflor yellow A, rosmarinic acid. The relative content (%) of the bioactive components were 59.32, 16.01, 9.97, 9.73, 8.72, 8.31, 7.92, 6.54, 1.54, 1.30, 0.68 and 0.59 in this order. After XBJ treatment, the renal function, hyperlipidemia and renal pathological damage were improved in NS model mice. Moreover, the levels of nephrin and desmin which are functional proteins in podocytes were reversed, and the levels of pro-inflammatory factors were reduced by XBJ. Interestingly, protocatechuic acid and salvianolic acid C also showed good protective effects on podocyte function and reduced the level of inflammation in LPS-induced MPC-5. The study is the first time to elucidate the bioactive components of XBJ and its potential therapeutic mechanism for treating NS by protecting podocyte function.

Association between cognitive function and body composition in older adults: data from NHANES (1999-2002).

Aim: To investigate the association between cognitive function and body composition in older adults. Methods: We collected data on 2080 older adults (>60 years of age) from the National Health and Nutrition Examination Survey (NHANES) for the years 1999-2000 and 2001-2002. Candidate variables included: demographic data (sex, age, race, education level, marital status, poverty-to-income ratio), alcohol consumption, cardiovascular disease, diabetes, osteoporosis, total bone mineral density, and total fat mass. A logistic regression model was established to analyze the association between cognitive function and body composition in older adults. In addition, stratified logics regression analysis was performed by sex and age. Results: Bone mineral density significantly affects cognitive function in older adults (p<0.01). When examining the data according to sex, this correlation is present for women (p < 0.01). For men, though, it is not significant (p = 0.081). Stratified by age, total bone mineral density was significantly correlated with cognitive function in 60-70 and 70-80 years old people, but not in older adults older than 80 years(for 60-70 years old, p = 0.019; for 70-80 years old, p = 0.022). There was no significant correlation between total bone mineral density and cognitive function (p = 0.575). Conclusion: The decrease of total bone mineral density was significantly correlated with cognitive decline in the older adults, especially among women and older people in the 60 to 80 age group. There was no connection between total fat mass, total percent fat, total lean mass, appendicular lean mass, appendicular lean mass /BMI and cognitive function in the older adults.

Endoplasmic reticulum stress-related protein GRP78 and CHOP levels in synovial fluid correlate with disease progression of primary knee osteoarthritis: A cross-sectional study.

BACKGROUND: Endoplasmic reticulum (ER) stress has been shown to play an important role in osteoarthritis (OA). OBJECTIVE: This study was aimed at assessing the relationship of endoplasmic reticulum (ER) stress-related glucose-regulated protein 78 (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP) concentrations in the serum/synovial fluid (SF) with disease severity of primary knee osteoarthritis (pkOA). METHODS: Patients with pkOA together with healthy individuals were consecutively recruited from our hospital. The levels of GRP78 and CHOP in serum / SF were detected using enzyme-linked immunosorbent assay. The levels of IL-6 and MMP-3 were also examined. Radiographic progression of pkOA was evaluated based on Kellgren-Lawrence (K-L) grades. Receiver Operating Characteristic (ROC) curves were used to assess the diagnostic value of GRP78/CHOP levels with regard to K-L grades. The assessment of clinical severity was conducted using the visual analogue scale (VAS), Oxford knee score (OKS), and Lequesne algofunctional index (LAI). RESULTS: A total of 140 pkOA patients and 140 healthy individuals were included. Serum GRP78 and CHOP levels in pkOA patients were not significantly different from those in healthy individuals. The SF GRP78 and CHOP levels in healthy controls were not detected due to ethical reasons. Compared to those with K-L grade 2 and 3, the pkOA patients with K-L grade 4 had higher GRP78 and CHOP levels in the SF with statistical significance. In addition, the pkOA patients with K-L grade 3 exhibited drastically upregulated GRP78 and CHOP concentrations in the SF compared to those with K-L grade 2. Positive correlations of GRP78 and CHOP levels with K-L grades, IL-6, and MMP-3 levels in the SF were observed. ROC curve analysis indicated that both GRP78 and CHOP levels may act as decent indicators with regard to OA. GRP78 and CHOP concentrations in the SF were positively correlated with VAS/LAI score and negatively associated with OKS score. CONCLUSION: The study indicated that GRP78 and CHOP levels in the SF but not the serum were positively correlated with disease severity of pkOA.

Exploring causal association between circulating inflammatory cytokines and functional outcomes following ischemic stroke: A bidirectional Mendelian randomization study.

OBJECTIVES: Previous observational studies have indicated correlations between various inflammatory cytokines and functional outcomes following ischemic stroke (IS); however, the causality remains unclear. We aimed to further evaluate the causal association between 41 circulating inflammatory cytokines and functional outcomes following IS. METHODS: Two-sample bidirectional Mendelian randomization (MR) analysis was used in this study. The genetic variation of 41 circulating inflammatory cytokines were derived from genome-wide association study (GWAS) data of European ancestry (n = 8293). The corresponding genetic association of functional outcomes following IS were derived from European ancestry GWAS data (n = 6021). RESULTS: Inverse variance weighted (IVW) analysis showed that genetically predicted increased levels of regulation and activation in normal T-cell expression and secretion factor (RANTES/CCL5) and eosinophilic chemotactic factor (EOTAXIN/CCL11) were positively correlated with the increased adverse functional outcomes (modified Rankin Scale [mRS≥3] following IS (OR: 1.40, 95% CI: 1.002-1.96, p = 0.049; OR: 1.33, 95% CI: 1.15-1.54, p = 0.0001). Interleukin 18 (IL-18) level might be the downstream consequence of adverse functional outcomes following IS (ß: -0.09, p = 0.039). Other inflammatory cytokines and functional outcomes following IS did not appear to be causally related. CONCLUSIONS: This study suggests a causality between inflammation and adverse functional outcomes following IS. RANTES (CCL5) and EOTAXIN (CCL11) may be the upstream factors of adverse functional outcomes following IS, while IL-18 may be the downstream effect of adverse functional outcomes following IS. Whether these cytokines can be used to predict or improve adverse functional outcomes after IS requires further researches.

Palladium-catalyzed [4 + 2] cycloaddition of 2-methylidenetrimethylene carbonate or methylene cyclic carbamate with sulfamate-derived cyclic imines.

A palladium-catalyzed [4 + 2] cycloaddition of 2-methylidenetrimethylene carbonate or methylene cyclic carbamate with sulfamate-derived cyclic imines has been successfully developed under mild reaction conditions, affording pharmacologically interesting oxazine or hydropyrimidine derivatives in high yields (up to 99% yield). Furthermore, the cycloaddition reactions could be efficiently scaled up and several synthetic transformations were accomplished for the construction of other useful 1,3-oxazine and hydropyrimidinone derivatives.

Effects of triclosan exposure on stem cells from human exfoliated deciduous teeth (SHED) fate.

Triclosan (TCS), a widely used broad-spectrum antibacterial agent and preservative, is commonly found in products and environments. Widespread human exposure to TCS has drawn increasing attention from researchers concerning its toxicological effect. However, minimal studies have focused on the impact of TCS exposure on human stem cells. Therefore, the aim of the present study was to evaluate the effects of TCS exposure on stem cells from human exfoliated deciduous teeth (SHED) and its molecular mechanisms. A series of experimental methods were conducted to assess cell viability, morphology, proliferation, differentiation, senescence, apoptosis, mitochondrial function, and oxidative stress after SHED exposure to TCS. Furthermore, transcriptome analysis was applied to investigate the response of SHED to different concentrations of TCS exposure and to explore the molecular mechanisms. We demonstrated that TCS has a dose-dependent proliferation and differentiation inhibition of SHED, while promoting cellular senescence, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and oxidative stress, as well as significantly induces apoptosis and autophagy flux inhibition at high concentrations. Interestingly, no significant morphological changes in SHED were observed after TCS exposure. Transcriptome analysis of normal and TCS-induced SHED suggested that SHED may use different strategies to counteract stress from different concentrations of TCS and showed significant differences. We discovered that TCS mediates cellular injury of SHED by enhancing the expression of PTEN, thereby inhibiting the phosphorylation levels of PI3K and AKT as well as mTOR expression. Collectively, our findings provide a new understanding of the toxic effects of TCS on human stem cell fate, which is important for determining the risk posed by TCS to human health.

Repetitive transcranial magnetic stimulation for cerebellar ataxia: a systematic review and meta-analysis.

Background: Repetitive transcranial magnetic stimulation, a non-invasive brain stimulation technique, can manage cerebellar ataxia (CA) by suppressing cerebral cortical excitability. Hence, this study aimed to summarize the efficacy and safety of rTMS for CA patients by meta-analysis. Methods: The PubMed, Embase, Web of Science, and Cochrane Library databases were searched for eligible studies published till 20 May 2023. Weighted mean difference (MD) and 95% confidence intervals (CIs) were used to assess the effect of rTMS treatment. Additionally, the quality of the included studies and the risk of bias were evaluated using the Physiotherapy Evidence Database (PEDro) scale. Results: Overall, eight studies involving 278 CA patients were included in this meta-analysis. rTMS could significantly improve the Scale for the Assessment and Rating of Ataxia (SARA) (MD: -2.00; 95% CI: -3.97 to -0.02, p = 0.05), International Cooperative Ataxia Rating Scale (ICARS) (MD: -3.96; 95% CI: -5.51 to -2.40, p < 0.00001), Timed Up-and-Go test (TUG) (MD: -1.54; 95% CI: -2.24 to -0.84, p < 0.0001), 10-m walk test (10 MWT) (MD10-m steps: -2.44; 95% CI: -4.14 to -0.73, p = 0.005), and Berg Balance Scale (BBS) (MD: 2.59; 95% CI: 1.15-4.03, p = 0.0004) as compared to sham stimulation. Active rTMS was not significantly different from sham rTMS in changing the duration (MD10-m time: -1.29; 95% CI: -7.98 to 5.41, p = 0.71). No severe adverse events were observed in both sham stimulation and active rTMS groups. Conclusion: This meta-analysis provides limited evidence that rTMS may be beneficial in treating CA patients. However, these findings should be treated with caution due to the limitations of the smaller sample size and the inconsistent approach and target of rTMS treatment. Therefore, more large-scale RCTs are required to further validate our analytical findings. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=295726, identifier: CRD42022295726.

Macrophage-derived exosomes promote activation of NLRP3 inflammasome and autophagy deficiency of mesangial cells in diabetic nephropathy.

Dysfunction of mesangial cells plays a significant role in the glomerular lesions and is implicated in the pathophysiology of diabetic nephropathy (DN). Macrophages infiltration is the main pathological feature of DN, which can ultimately lead to renal inflammation. Recent studies suggest that the crosstalk between kidney resident cells and inflammatory cells influences the development of DN, and that controlling this crosstalk may help treat DN. Here, we found that DN mice appeared renal pathological damage, including dilation of mesangial matrix and significant infiltration of macrophages, accompanied by increased inflammatory response, NLRP3 inflammasome activation and autophagy deficiency. Additionally, mesangial cells internalized exosomes from high glucose (HG) treated macrophage, resulting the activation of inflammatory cytokines and NLRP3 inflammasome and deficiency of autophagy in vitro and in vivo. Moreover, C57BL/6 mice injected HG-stimulated macrophages-derived exosomes exhibited renal dysfunction and mesangial matrix expansion. Taken together, the present study demonstrated that mesangial cells responded to HG treated macrophage-derived exosomes by promoting the activation of NLRP3 inflammasome and autophagy deficiency, thereby participating in the development of DN.

Paeoniflorin suppresses kidney inflammation by regulating macrophage polarization via KLF4-mediated mitophagy.

BACKGROUND: Macrophages M1 polarization involved in the process of renal inflammatory injury, is a well-established hallmark of chronic kidney disease (CKD). Paeoniflorin (PF), a water-soluble monoterpene glycoside extracted from Paeonia lactiflora, revealed renal anti-inflammatory activities in our previous study. However, the potential molecular mechanism of PF on CKD remains unknown. PURPOSE: The present study aims to investigate the regulation of PF on macrophage polarization in CKD. METHODS: A CKD model was established by cationic bovine serum albumin and a murine macrophage cell line RAW264.7 induced with lipopolysaccharide (LPS) were used to clarify the underlying mechanisms of PF in CKD. RESULTS: Results showed that PF exhibited favorable protective effects on CKD model mice by promoting renal function, ameliorating renal pathological injury and podocyte damage. Furthermore, PF inhibited the infiltration of M1 macrophage marker CD68 and iNOS in kidney tissue, but increased the proportion of M2 macrophage marker CD206. In RAW264.7 cells stimulated with LPS, the levels of cytokines including IL-6, IL-1ß, TNF-α, MCP-1 were lessened under PF treatment, while the levels of Arg1, Fizz1, IL-10 and Ym-1 were augmented. These results indicated that PF promoted macrophage polarization from M1 to M2 in vivo and in vitro. More importantly, PF repaired the damaged mitochondria through increasing mitochondrial membrane potential and reducing ROS accumulation. The mitophagy-related proteins PINK1, Parkin, Bnip3, P62 and LC3 were up-regulated by PF, accompanied by the incremental expressions of Krüppel-like transcription factor 4 (KLF4). Moreover, the promotion of mitophagy and inhibition of M1 macrophage polarization owing to PF were reversed by mitophagy inhibitor Mdivi-1 or silencing KLF4. CONCLUSION: Overall, PF suppressed renal inflammation by promoting macrophage polarization from M1 to M2 and inducing mitophagy via regulating KLF4. It is expected to provide a new strategy for exploring the effects of PF in treating CKD.

Danshen injection induces autophagy in podocytes to alleviate nephrotic syndrome via the PI3K/AKT/mTOR pathway.

BACKGROUND: Danshen injection (DSI) is an agent extracted from the Salvia miltiorrhiza Bunge, a natural drug commonly used to alleviate kidney diseases. However, the material basis and therapeutic effects of DSI on nephrotic syndrome (NS) remain unclear. PURPOSE: To investigate the material basis of DSI and the therapeutic effects and underlying mechanisms of NS. METHODS: NS models were established using adriamycin-induced BALB/c mice and lipopolysaccharide-induced mouse podocytes (MPC-5). Following DSI and prednisone administration, kidney coefficients, 24 h urine protein, blood urea nitrogen, and serum creatinine levels were tested. Histomorphology was observed by periodic acid-Schiff staining and hematoxylin and eosin staining of the kidney sections. The glomerular basement membrane and autophagosomes of the kidneys were observed using transmission electron microscopy. Nephrin and desmin levels in the glomeruli were tested using immunohistochemistry. The viability of MPC-5 cells was tested using cell counting kit-8 after chloroquine and rapamycin administration in combination with DSI. The in vivo and in vitro protein levels of phosphatidylinositol 3-kinase (PI3K), AKT, phosphorylated AKT (Ser473), mammalian target of rapamycin (mTOR), microtubule-associated protein light chain 3 (LC3), beclin1, cleaved caspase-3, and caspase-3 were detected using western blotting. RESULTS: Our results showed that DSI contained nine main components: caffeic acid, danshensu, lithospermic acid, rosmarinic acid, salvianolic acid A, salvianolic acid B, salvianolic acid C, salvianolic acid D, and 3, 4-Dihydroxybenzaldehyde. In in vivo studies, the NS mice showed renal function and pathological impairment. Podocytes were damaged, with decreased levels of autophagy and apoptosis, accompanied by inhibition of the PI3K/AKT/mTOR signaling. DSI administration resulted in improved renal function and pathology in NS mice, with the activation of autophagy and PI3K/AKT/mTOR signaling in the kidneys. Additionally, podocytes were less damaged and intracellular autophagosomes were markedly increased. In vitro studies have shown that DSI activated MPC-5 autophagy and reduced apoptosis via the PI3K/AKT/mTOR pathway. CONCLUSION: Collectively, this study demonstrated that DSI activated podocyte autophagy and reduced apoptosis via the PI3K/AKT/mTOR signaling, ultimately attenuating NS. Our study clarified the main components of DSI and elucidated its therapeutic effects and potential mechanisms for NS, providing new targets and agents for the clinical treatment of NS.

Sustained delivery of gambogic acid from mesoporous rod-structure hydroxyapatite for efficient in vitro cancer therapy.

Inspired by the critical role of nanocarrier in biomaterials modification, we synthesized a mesoporous rod-structure hydroxyapatite (MR-HAp) nanoparticles for boosting gambogic acid (GA) bioavailability in cells and improving the tumor therapy. As expected, the GA loading ratio of MR-HAp was up to about 96.97% and GA-loaded MR-HAp (MR-HAp/GA) demonstrates a sustained release performance. Furthermore, a substantial improvement was observed in inhibiting the cell proliferation and inducing the apoptosis of HeLa cells, as the cell viability was decreased to 89.6% and the apoptosis was increased to 49.2% when the cells treated with MR-HAp/GA at a GA concentration of 1 µg/mL for 72 h. The remarkable inhibition effect of cell proliferation and the enhanced inducing apoptosis are attributed to the increasing intracellular reactive oxygen species level and reduced mitochondrial membrane potential. This result provides a promising and facile approach for highly efficient tumor treatment.

Cu(II) carboxylate arene C─H functionalization: Tuning for nonradical pathways.

We report carbon-hydrogen acetoxylation of nondirected arenes benzene and toluene, as well as related functionalization with pivalate and 2-ethylhexanoate ester groups, using simple copper(II) [Cu(II)] salts with over 80% yield. By changing the ratio of benzene and Cu(II) salts, 2.4% conversion of benzene can be reached. Combined experimental and computational studies results indicate that the arene carbon-hydrogen functionalization likely occurs by a nonradical Cu(II)-mediated organometallic pathway. The Cu(II) salts used in the reaction can be isolated, recycled, and reused with little change in reactivity. In addition, the Cu(II) salts can be regenerated in situ using oxygen and, after the removal of the generated water, the arene carbon-hydrogen acetoxylation and related esterification reactions can be continued, which leads to a process that enables recycling of Cu(II).

Salvianolic acid B attenuates membranous nephropathy by activating renal autophagy via microRNA-145-5p/phosphatidylinositol 3-kinase/AKT pathway.

The abnormal proliferation and inflammatory response of the mesangial cells play a crucial role in the progression of membranous nephropathy (MN). Herein, this study aimed to investigate the therapeutic effect of Salvianolic acid B (SalB) on MN-induced mesangial abnormalities and its underlying mechanisms. MN models were established in cationic bovine serum albumin-induced Sprague-Dawley rats and lipopolysaccharide-induced human mesangial cells (HMCs). Following SalB and microRNA-145-5p antagomir treatment, kidney function was investigated by 24-hours urine protein, serum creatinine, and blood urea nitrogen. Pathological changes of kidney were investigated by Periodic acid Schiff staining. CD68 and IgG were detected by immunofluorescence in glomerulus. Mesangial autophagosomes were observed by transmission electron microscope. MicroRNA-145-5p inhibitor, mimic, LY294002, and SalB were used to treat with HMCs. In kidney and HMCs, IL-1 ß, IL-2, IL-6, TNF-α and microRNA-145-5p was detected by quantitative real-time PCR. Phosphatidylinositol 3-kinase (PI3K), phosphorylated AKT, AKT, beclin1, and microtubule-associated protein light chain 3 (LC3) levels were detected by Western blot. HMCs proliferation and cycle were detected by Cell Counting Kit-8 and flow cytometry. LC3 were detected by LC3-dual-fluorescent adenovirus in HMCs. Our results showed that SalB significantly ameliorated kidney function and pathological changes. Furthermore, it significantly alleviated proliferation, inflammation and activated autophagy in mesangial cells. Moreover, microRNA-145-5p antagomir accentuated MN while microRNA-145-5p inhibitor and LY294002 encouraged proliferation and inflammation through PI3K/AKT pathway in HMCs. Collectively, our study demonstrated that SalB activated renal autophagy to reduce cell proliferation and inflammation of MN, which was mediated by microRNA-145-5p to inhibit PI3K/AKT pathway, and ultimately attenuated MN.

Scalp acupuncture enhances local brain regions functional activities and functional connections between cerebral hemispheres in acute ischemic stroke patients.

This study aimed to explore the changes in functional connections between cerebral hemispheres and local brain regions functional activities in patients with acute ischemic stroke (AIS) treated with International Standard Scalp Acupuncture (ISSA). Thirty patients with middle cerebral artery AIS in the dominant hemisphere were selected and randomly divided into two groups such as the control group and the scalp acupuncture group, with 15 patients in each group. Patients in the control group were treated with conventional Western medicine, while patients in the scalp acupuncture group received ISSA (acupuncture at the parietal midline [MS5], acupuncture at the left anterior parietotemporal oblique line [MS6] and acupuncture at the left posterior parietotemporal oblique line [MS7]) for one course of treatment. All patients were evaluated for treatment efficacy and received whole brain resting state functional magnetic resonance imaging (Rs-fMRI) scan before and after treatment. The observational indicators included: (a) the National Institutes of Health Stroke Scale (NIHSS) scores and the simplified Fugl-Meyer Assessment (SFMA) scores; (b) analyses of the amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo) and voxel-mirrored homotopic connectivity (VMHC). The results showed a significant difference in the NIHSS scores before and after treatment in the scalp acupuncture group compared with the control group (p < .05), indicating that patients improved better after scalp acupuncture treatment. Compared with the control group, the VMHC, ALFF and ReHo values in the scalp acupuncture group increased after treatment. The VMHC values increased in the brain regions dominated by bilateral BA6 and BA8; the ALFF values increased in the left BA39 and the adjacent superior temporal gyrus and middle temporal gyrus; and the ReHo values increased in the brain regions extending from left middle temporal gyrus (including BA21) to BA37, and the brain regions extending from the left BA40 and angular gyrus to BA7. The present study indicated that scalp acupuncture can specifically strengthen the functional activities of the brain regions related to sensory integration, language processing and motor coordination in the middle aged and elderly patients with AIS of the dominant cerebral hemisphere, and can strengthen bilateral frontal lobe motor control. This study may provide a scientific basis for the clinical application of ISSA treatment in patients with AIS, and may also provide a preliminary research basis for further animal experiments.

Hemispheric Difference of Regional Brain Function Exists in Patients With Acute Stroke in Different Cerebral Hemispheres: A Resting-State fMRI Study.

OBJECTIVE: To explore the different compensatory mechanisms of brain function between the patients with brain dysfunction after acute ischemic stroke (AIS) in the dominant hemisphere and the non-dominant hemisphere based on Resting-state Functional Magnetic Resonance Imaging (Rs-fMRI). METHODS: In this trial, 15 healthy subjects (HS) were used as blank controls. In total, 30 hemiplegic patients with middle cerebral artery acute infarction of different dominant hemispheres were divided into the dominant hemisphere group (DH) and the non-dominant hemisphere group (NDH), scanned by a 3.0 T MRI scanner, to obtain the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) and compare the differences. RESULTS: Compared with the HS, increased ALFF values in the brain areas, such as the bilateral midbrain, were observed in DH. Meanwhile decreased ReHo values in the brain areas, such as the right postcentral gyrus (BA3), were also observed. Enhanced ALFF values in the brain areas, such as the left BA6, and enhanced ReHo values in the brain areas, such as the left precuneus, were observed in the NDH. The ALFF and ReHo values of the right BA9 and precentral gyrus were both increased. Compared with DH, the NDH group showed lower ALFF values in the left supplementary motor area and lower ReHo values in the right BA10. CONCLUSION: After acute infarction in the middle cerebral artery of the dominant hemisphere, a compensation mechanism is triggered in brain areas of the ipsilateral cortex regulating motor-related pathways, while some brain areas related to cognition, sensation, and motor in the contralateral cortex are suppressed, and the connection with the peripheral brain regions is weakened. After acute infarction in the middle cerebral artery of the non-dominant hemisphere, compensatory activation appears in motor control-related brain areas of the dominant hemisphere. After acute middle cerebral artery infarction in the dominant hemisphere, compared with the non-dominant hemisphere, functional specificity in the bilateral supplementary motor area weakens. After acute middle cerebral artery infarction in different hemispheres, there are hemispheric differences in the compensatory mechanism of brain function.

The Role of Ophiopogonin D in Atherosclerosis: Impact on Lipid Metabolism and Gut Microbiota.

Gut microbiota has been proven to play an important role in many metabolic diseases and cardiovascular disease, particularly atherosclerosis. Ophiopogonin D (OPD), one of the effective compounds in Ophiopogon japonicus, is considered beneficial to metabolic syndrome and cardiovascular diseases. In this study, we have illuminated the effect of OPD in ApoE knockout (ApoE[Formula: see text] mice on the development of atherosclerosis and gut microbiota. To investigate the potential ability of OPD to alleviate atherosclerosis, 24 eight-week-old male ApoE[Formula: see text] mice (C57BL/6 background) were fed a high-fat diet (HFD) for 12 weeks, and 8 male C57BL/6 mice were fed a normal diet, serving as the control group. ApoE[Formula: see text] mice were randomly divided into the model group, OPD group, and simvastatin group ([Formula: see text]= 8). After treatment for 12 consecutive weeks, the results showed that OPD treatment significantly decreased the plaque formation and levels of serum lipid compared with those in the model group. In addition, OPD improved oral glucose tolerance and insulin resistance as well as reducing hepatocyte steatosis. Further analysis revealed that OPD might attenuate atherosclerosis through inhibiting mTOR phosphorylation and the consequent lipid metabolism signaling pathways mediated by SREBP1 and SCD1 in vivo and in vitro. Furthermore, OPD treatment led to significant structural changes in gut microbiota and fecal metabolites in HFD-fed mice and reduced the relative abundance of Erysipelotrichaceae genera associated with cholesterol metabolism. Collectively, these findings illustrate that OPD could significantly protect against atherosclerosis, which might be associated with the moderation of lipid metabolism and alterations in gut microbiota composition and fecal metabolites.

JAK/STAT pathway promotes the progression of diabetic kidney disease via autophagy in podocytes.

Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetes and an important cause of end-stage renal disease. Previous studies have shown that the damage to podocyte autophagy is related to the pathogenesis of DKD, and this damage is closely mediated by the Janus kinase (JAK)/signal transductors and the transcription (STAT) signaling pathway. Here, the underlying molecular mechanism of the JAK/STAT signaling pathway regulating podocyte autophagy was investigated. In the present study, compared to controls, DKD mice showed glomerular hypertrophy, increased kidney weight/weight ratio, and increased urinary protein levels, as well as decreased desmin and synaptopodin expression. Meanwhile, levels of triglyceride, total cholesterol, reduced glutathione, and malondialdehyde were also increased in the serum of DKD mice. Further, a lower number of autophagosomes, reduced expression of MAP1LC3 (LC3) in glomeruli, and increased expression of JAK/STAT pathway-related proteins, namely JAK1, JAK2, STAT1, STAT3, STAT5, and STAT6, were observed in DKD mice. In the in vitro experiments, we observed impaired autophagy, enhanced apoptosis, and activated JAK/STAT pathway in podocytes under high glucose conditions. Studies using ruxolitinib inhibitors have showed that suppression of the JAK/STAT pathway in podocytes subjected to high glucose could increase autophagic flux and autophagy-related protein expression. Taken together, the present study demonstrates that high glucose inhibits autophagy by activating the JAK/STAT pathway in mice and podocytes, thereby preventing the efficient removal of damaged proteins and organelles from the body to prevent apoptosis, and ultimately aggravating the progression of podocyte injury and DKD.

Ferulic Acid Ameliorates Atherosclerotic Injury by Modulating Gut Microbiota and Lipid Metabolism.

Atherosclerosis is a leading cause of death worldwide. Recent studies have emphasized the significance of gut microbiota and lipid metabolism in the development of atherosclerosis. Herein, the effects and molecular mechanisms involving ferulic acid (FA) was examined in atherosclerosis using the ApoE-knockout (ApoE-∕-, c57BL/6 background) mouse model. Eighteen male ApoE-/- mice were fed a high-fat diet (HFD) for 12 weeks and then randomly divided into three groups: the model group, the FA (40 mg/kg/day) group and simvastatin (5 mg/kg/day) group. As results, FA could significantly alleviate atherosclerosis and regulate lipid levels in mice. Liver injury and hepatocyte steatosis induced by HFD were also mitigated by FA. FA improved lipid metabolism involving up-regulation of AMPKα phosphorylation and down-regulation of SREBP1 and ACC1 expression. Furthermore, FA induced marked structural changes in the gut microbiota and fecal metabolites and specifically reduced the relative abundance of Fimicutes, Erysipelotrichaceae and Ileibacterium, which were positively correlated with serum lipid levels in atherosclerosis mice. In conclusion, we demonstrate that FA could significantly ameliorate atherosclerotic injury, which may be partly by modulating gut microbiota and lipid metabolism via the AMPKα/SREBP1/ACC1 pathway.

Zhen-Wu-Tang Induced Mitophagy to Protect Mitochondrial Function in Chronic Glomerulonephritis via PI3K/AKT/mTOR and AMPK Pathways.

Chronic glomerulonephritis (CGN) is one of the major causes of end-stage kidney disease. Zhen-wu-tang (ZWT), as a famous Chinese herbal prescription, is widely used in China for CGN therapy in clinic. However, the mechanism of ZWT in CGN has not been fully understood. The present study explored the therapeutic effect and the underlying mechanism of ZWT on mitochondrial function in cationic bovine serum albumin (C-BSA)-induced CGN model rats and tumor necrosis factor (TNF-α)-damaged mouse podocytes. The renal functions were measured by serum creatinine (Scr) and blood urea nitrogen (BUN). Renal pathological changes and ultrastructure of kidney tissues were evaluated by periodic acid-Schiff (PAS) staining and transmission electron microscopy. The levels of antioxidases, including mitochondrial catalase (CAT), superoxide dismutase 2 (SOD2), and peroxiredoxin 3 (PRDX3), in CGN rats were examined by real-time PCR. The mitochondrial functions of podocytes were measured by ATP concentration, mitochondrial membrane potential (MMP), and mitochondrial ROS (mtROS). For mitophagy level detection, the expressions of mitophagy-related proteins, including LC3, p62, heat shock protein 60 (HSP60), and translocase of outer mitochondrial membrane 20 (TOMM20), were measured by Western blot, as the colocation of LC3 and mitochondrial marker COX IV were evaluated by immunofluorescence. Our results manifested that ZWT ameliorated CGN model rats by a remarkable decrease in Scr and BUN, inhibition of mesangial matrix proliferation, protection against foot processes fusion, and basement membrane thickening. More importantly, ZWT protected against mitochondrial dysfunction by increasing the expressions of CAT, SOD2, and PRDX3 in CGN model rats, increased ATP content and MMP in podocytes, and decreased excessive mtROS. Furthermore, ZWT induced mitophagy in CGN through increasing the expression of LC3, and decreasing p62, HSP60, TOMM20, and ZWT also enhanced the colocation of LC3 to the mitochondria. We found that ZWT inhibited the PI3K/AKT/mTOR pathway, which could be disturbed by PI3K inhibitor LY294002 and agonist insulin-like growth factor 1. Moreover, ZWT reversed the inhibition of the AMPK pathway in CGN. Overall, ZWT ameliorated renal mitochondrial dysfunction probably by inducing mitophagy via the PI3K/AKT/mTOR and AMPK pathways.

Dingxin Recipe IV attenuates atherosclerosis by regulating lipid metabolism through LXR-α/SREBP1 pathway and modulating the gut microbiota in ApoE-/- mice fed with HFD.

ETHNOPHARMACOLOGICAL RELEVANCE: Dingxin Recipe (DXR) is a traditional Chinese medicine formula that has been reported to be effective and safe treatment for cardiovascular diseases, such as arrhythmias, coronary heart disease. Dingxin Recipe IV (DXR IV) was further improved from the DXR according to the traditional use. However, the mechanism of DXR IV in atherosclerosis is unclear. AIM OF THE STUDY: This study aimed to illustrate whether DXR IV improve atherosclerosis through modulating the lipid metabolism and gut microbiota in atherosclerosis mice. MATERIALS AND METHODS: 40 male ApoE-/- mice were fed on HFD for 12 weeks and were then treated with DXR IV (1.8, 0.9, or 0.45 g/kg/d) for another 12 weeks. The decroation of DXR IV contains four traditional Chinese medicines: the dried rhizome of Coptis chinensis Franch. (15.09%), the root of Salvia miltiorrhiza Bunge (28.30%), the seed of Ziziphus jujuba Mill. (37.74%) and the fruiting body of Ganoderma lucidum (Leyss.ex Fr.) Karst. (18.87%). 8 male c57BL/6 mice fed a normal diet served as control group. The atherosclerotic plaque was quantified by oil-red O staining and masson trichrome staining. Mice feces were collected. The gut micobiota were detected by 16S rRNA gene sequencing and fecal metabolites were analyzed by 1H NMR spectroscopy. The effect of DXR IV on blood lipids (TG, TC, LDL-C, HDL-C) was investigated. The lipid metabolism related genes were determined by RT-qPCR and western blotting respectively. RESULTS: DXR IV exerted the anti-atherosclerosis effect by inhibiting the excessive cholesterol deposition in aorta and regulating the level of TG, TC, LDL-C and HDL-C. The composition of gut microbiota was changed. Interestingly, the relative abundance of Muribaculaceae and Ruminococcaceae increased after DXR IV administration, whereas the abundance of Erysipelotrichaceae decreased, which have been beneficial to lipid metabolism. Nine potential metabolic biomarkers, including acetate, butyrate, propionate, alanine, succinate, valerate, xylose, choline, glutamate, were identified, which were related to fatty acid metabolism. Further, the pathway of fatty acid was detected by the RT-qPCR and western blotting. Compared with model group, the level of LXR-α and SREBP1 decreased significantly in DXR IV group while LXR-ß, SREBP2 showed no statistical significance. It indicated that DXR IV modulated lipid metabolism by LXR-α/SREBP1 but not LXRß and SREBP2. CONCLUSIONS: DXR IV exhibits potential anti-atherosclerosis effect, which is closely related to lipid metabolism and the gut microbiota. This study may provide novel insights into the mechanism of DXR IV on atherosclerosis and a basis for promising clinical usage.