Background:This study seeks to identify and assess the severity of drug-related problems (DRPs), analyze risk factors and evaluate the impact of DRPs on the health-related quality of life (HRQoL) among elderly multimorbid inpatients with stroke in the Comprehensive Stroke Center (CSC) in China. Methods:A two-year retrospective study was conducted at a tertiary hospital among elderly multimorbid inpatients with stroke. Medication review, HRQoL assessment and stroke-associated clinical scales assessment by clinical pharmacists or the medical team. Results:An analysis of 592 patients revealed 576 DRPs. The mean age of patients was 73.64 ± 7.96 years old. 583 (55.6%) cases had at least one DRP, with an average of 1.53 ± 0.94 DRPs per patient. The most common multimorbidity pattern was co-existing hypertension and stroke (17.4%). "Drug selection, C1" emerged as the predominant cause of DRPs (54.0%; 311/576), followed by "Patient related, C7" (18.2%; 105/576). Most DRPs (79.3%, 457/576) were low severity (B-D); the remaining 20.7% (119/576) were high severity (E-H). Increased hospital length of stays (LOS) and coexisting atrial fibrillation were identified as significant factors influencing the occurrence of DRPs (p < 0.05). The quantity of DRPs showed a weak negative correlation with HRQoL scores (r = -0.291, p < 0.001), as well as moderate positive correlations with both the mRS scores (r = 0.304, p < 0.001) and the NIHSS scores (r = 0.306, p < 0.001). Conclusion:DRPs are prevalent among elderly multimorbid inpatients with stroke in CSC and are mainly caused by drug selection and patient-related problems. Prolonged hospitalization days and the presence of atrial fibrillation were identified as significant risk factors for occurrence of DRPs in elderly multimorbid inpatients with stroke. Pharmaceutical services of medication review could assist in the identification of DRPs at the CSC.

Codonopsis pilosula Nannf. polysaccharides (CPPs) exhibit diverse pharmacological activities including immunomodulatory, anticancer, neuroprotective, metabolic, antimicrobial, antiviral, antifatigue, antihypoxia, and osteogenic/anti-osteoporotic effects, yet research in the field has been largely descriptive, lacking a unified framework to predict function from structure. This review provides a critical synthesis of the literature, arguing that the multifaceted bioactivity of CPPs—including immunomodulatory, anticancer, neuroprotective, and metabolic effects—is principally governed by definable structure-activity relationships (SAR). We systematically analyze how key structural parameters—molecular weight, monosaccharide composition, glycosidic linkages, and chemical modifications (e.g., sulfation, selenylation, phosphorylation)—dictate specific biological responses. Low molecular weight fractions and modified derivatives demonstrate enhanced immunomodulatory and antioxidant capacities by optimizing receptor interactions and free radical scavenging, while pectic-type structures rich in galacturonic acid are pivotal for anticancer and prebiotic activities. Specific glycosidic motifs are crucial for activating neuroprotective and osteogenic pathways such as Nrf2, Wnt/β-catenin, and BACE1 inhibition. The precise manipulation of CPP structures enables targeted efficacy, ranging from gut microbiota modulation and enzyme inhibition (α-amylase/α-glucosidase) to the induction of pyroptosis in cancer cells. We further highlight critical research gaps—including non-standardized characterization, limited pharmacokinetic data, and unmet clinical needs—and propose a transition from descriptive studies to rational structure-based design. This SAR-driven approach positions CPPs as promising candidates for engineered nutraceuticals and multi-target therapeutics in precision medicine.

Hashimoto's thyroiditis (HT) is a chronic autoimmune disorder primarily driven by T cell. The apoptosis of the follicular thyroid cells plays an important role in HT apart from the lymphocyte-mediated cytotoxicity. Advanced oxidation protein products (AOPPs), resulting from oxidative stress, are known to be involved in various inflammatory diseases. However, their role in HT development has not been explored. Here, we discovered that AOPP levels were significantly elevated in thyroid tissues of both HT patients (Ctrl 4.12 +/- 0.56, HT 30.00 +/- 2.78; p < 0.0001) and experimental autoimmune thyroiditis (EAT) mice (Ctrl 8.37 +/- 1.43, HT 55.82 +/- 2.87; p < 0.0001), accompanied by extensive thyroid follicular epithelial cell apoptosis in HT patients (Ctrl 32.16 +/- 1.79, HT 147.10 +/- 13.32; p < 0.0001) and EAT mice (Ctrl 66.78 +/- 6.72, HT 249.10 +/- 9.77; p < 0.0001). In vitro study showed that AOPPs induced reactive oxygen species (ROS) production via nicotinamide adenine dinucleotide phosphate oxidase (NOX), leading to apoptosis in human thyroid follicular epithelial cell (Nthy-ori 3-1). Treatment with apocynin, a NOX inhibitor, reduced AOPP-induced ROS production and apoptosis in Nthy-ori 3-1 cells, and in turn alleviated thyroid follicular epithelial cell apoptosis and autoimmune thyroiditis symptoms in mice. Mechanistically, AOPP treatment activated JNK pathway, leading to the downregulation of Bcl-2, upregulation of Bax, the mitochondrial membrane potential depolarization and consequently triggered the activation of mitochondria-dependent intrinsic apoptosis pathway. Collectively, our findings highlight the promotive roles of AOPP in HT and provide an attractive therapeutic target for HT therapy.

Ethnopharmacological relevanceSaffron, a traditional Chinese medicine, is derived from Crocus sativus L. stigmas and has been reported to possess neuroprotective properties and potentially contribute to the inhibition of apoptosis and inflammation. Safranal, a potent monothyral aldehyde, is a main component of saffron that has been reported to have antiepileptic activity. However, the specific mechanism by which safranal suppresses epileptic seizures via its antiapoptotic and anti-inflammatory properties is unclear.AimTo evaluate the effect of safranal on seizure severity, inflammation, and postictal neuronal apoptosis in a mouse model of pentetrazole (PTZ)-induced seizures and explore the underlying mechanism involved.Materials and methodsThe seizure stage and latency of stage 2 and 4 were quantified to assess the efficacy of safranal in mitigating PTZ-induced epileptic seizures in mice. Electroencephalography (EEG) was employed to monitor epileptiform afterdischarges in each experimental group. The cognitive abilities and motor functions of the mice were evaluated using the novel object recognition test and the open field test, respectively. Neurons were quantified using hematoxylin and eosin staining. Additionally, bioinformatics tools were utilized to predict the interactions between safranal and specific target proteins. Glycogen synthase kinase-3β (GSK-3β), mitochondrial apoptosis-related proteins, and inflammatory factor levels were analyzed through western blotting. Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) concentrations in brain tissue were assessed by ELISA.ResultsSafranal decreased the average seizure stage and increased the lantency of stage 2 and 4 seizures in PTZ-induced epileptic mice. Additionally, safranal exhibited neuroprotective effects on hippocampal CA1 and CA3 neurons and reduced hyperactivity caused by postictal hyperexcitability. Bioinformatics analysis revealed that safranal can bind to five specific proteins, including GSK-3β. By promoting Ser9 phosphorylation and inhibiting GSK-3β activity, safranal effectively suppressed the NF-κB signaling pathway. Moreover, the findings indicate that safranal treatment can decrease TNF-α and IL-1β levels in the cerebral tissues of epileptic mice and downregulate mitochondrial apoptosis-related proteins, including Bcl-2, Bax, Bak, Caspase 9, and Caspase 3.ConclusionSafranal can suppress the NF-κB signaling pathway and mitochondrial-dependent apoptosis through GSK-3β inactivation, suggesting that it is a promising therapeutic agent for epilepsy treatment.

Biological studies on the endocannabinoid system (ECS) have suggested that monoacylglycerol lipase (MAGL), an essential enzyme responsible for the hydrolysis of 2-arachidonoylglycerol (2 -AG), is a novel target for developing antidepressants. A decrease of 2 -AG levels in the hippocampus of the brain has been observed in depressive -like models induced by chronic stress. Herein, employing a structure -based approach, we designed and synthesized a new class of (piperazine-1-carbonyl) quinolin-2(1H)-one derivatives as potent, reversible and selective MAGL inhibitors. And detailed structure -activity relationships (SAR) studies were discussed. Compound 27 (IC50 = 10.3 nM) exhibited high bioavailability (92.7%) and 2 -AG elevation effect in vivo. Additionally, compound 27 exerted rapid antidepressant effects caused by chronic restraint stress (CRS) and didn't show signs of addictive properties in the conditioned place preference (CPP) assays. Our study is the first to report that reversible MAGL inhibitors can treat chronic stress -induced depression effectively, which may provide a new potential therapeutic strategy for the discovery of an original class of safe, rapid antidepressant drugs.

Abstract Microglia-associated neuroinflammation plays a role in secondary brain injury after traumatic brain injury (TBI). Hydrogen gas (H2) promotes microglial M2 polarization and alleviates neuroinflammation across brain disorders. However, little is known about the mechanism and target of H2 in treating neuroinflammation of TBI. In the present study, H2 inhalation conferred an improved neurological outcome after TBI by significantly decreasing neuroinflammation and activating microglial M2 polarization via inhibition of histone deacetylase 5 (HDAC5) expression. Furthermore, an AMPK inhibitor activated expression of HDAC5 and downstream GSK3β/AKT signaling; H2 treatment reversed these effects and rescued neurological function in vitro and in vivo. Mechanistically, H2 down-regulated GSK3β histone H3 acetylation levels through AMPK activation. Altogether, these data indicate that H2 inhalation inhibits neuroinflammation and rescues neurological function after TBI by promoting M2 polarization of microglia through GSK3β/AKT signaling and AMPK-dependent mediation of HDAC5. Our findings reveal novel targets for inhibiting neuroinflammation, and highlights the potential of H2 therapy for TBI.

ETHNOPHARMACOLOGICAL RELEVANCE:Sumu (Lignum sappan), the dry heartwood of Caesalpinia sappan L., is a traditional Chinese medicine used as an analgesic and anti-inflammatory agent. AIM OF THE STUDY:The study aspired to discover natural phosphodiesterase 4 (PDE4) inhibitors with dual anti-inflammatory and antioxidant activities from Sumu for the treatment of chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS:To accurately and efficiently identify natural PDE4 inhibitors from Sumu, molecular docking and molecular dynamics (MD) analysis methods were used for structure-based virtual screening of a self-built database of primary polyphenols in Sumu. According to the previous studies of Sumu and the free radical scavenging mechanism of polyphenols, the reported antioxidant components from Sumu and the potential antioxidants with the antioxidant pharmacophore of catechol and π-conjugated moieties were selected from the potential PDE4 inhibitors predicted by docking. Sappanone A, a potential PDE4 inhibitor with antioxidant activity from Sumu, was selected, calculated and synthesized to evaluate its dual anti-inflammatory and antioxidant functions in vitro and in vivo studies. Herein sappanone A was assayed for its inhibitory effects against PDE4 enzyme activity, tumor necrosis factor-alpha (TNF-α) production induced by lipopolysaccharide (LPS) in RAW264.7 macrophages and malondialdehyde (MDA) production induced by Fe2+ in mouse lung homogenate; sappanone A was also assayed for its abilities of radical (DPPH) scavenging, reducing Fe3+ and complexing Fe2+ in vitro. Additionally, LPS-induced acute lung injury (ALI) in mice was used to evaluate its anti-inflammatory activity as a PDE4 inhibitor in vivo, and the levels of TNF-α and total protein in bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) activity in the lung were assayed. RESULTS:The present study predicted and validated that sappanone A was a promising PDE4 inhibitor from Sumu with dual anti-inflammation and antioxidant activities from Sumu. In vitro, sappanone A remarkably inhibited PDE4 enzyme activity and reduced TNF-α production induced by LPS in RAW264.7 macrophages and MDA production induced by Fe2+ in mouse lung homogenate. Meanwhile, it showed outstanding abilities of scavenging DPPH radicals, reducing Fe3+ and complexing Fe2+. In vivo, sappanone A (25 mg/kg and 50 mg/kg, i.p., twice daily for 7 days) distinctly prevented LPS-induced ALI in mice by reducing the levels of TNF-α and total protein in BALF and MPO activity in the lung. CONCLUSION:Sappanone A is a natural PDE4 inhibitor with dual anti-inflammatory and antioxidant activities from the traditional Chinese medicine Sumu, which may be a promising therapeutic agent to prevent the vicious cycle of COPD inflammation and oxidative stress.

Abstract Denitrosylase S-nitrosoglutathione reductase (GSNOR) regulates the equilibrium of total cellular S-nitrosylation levels, a key redox-based post-translational modification that is frequently dysregulated in various diseases. However, the effects and underlying mechanisms of GSNOR on brain microvascular endothelial cells (BMECs) under hypoxia conditions are unknown. In this study, a photothrombosis model was used to induced cerebral ischemia injury in the male C57BL6 mice injury. BMECs were subjected with oxygen-glucose deprivation (OGD) for 6 h to establish the ischemic cell models in vitro. Increased GSNOR levels and S-nitrosylation dysfunctions were observed in cerebral ischemic injury. GSNOR knockdown rescued OGD-induced ischemic injury in BMECs. HIF-1α S-nitrosylation was significantly increased in BMECs after GSNOR knockdown. We investigated the effects of GSNOR on mitochondrial functions and revealed the relationship between HIF-1α translocation and downstream signaling, including mitochondrial bioenergetic functions and activation of mitophagy in BMECs. GSNOR knockdown alleviated OGD-induced mitochondrial impairments. Moreover, GSNOR reduced excessive mitochondrial reactive oxygen species (ROS) production, thereby, alleviating mitochondrial oxidative stress. GSNOR knockdown also enhanced the disturbance of cellular bioenergetic functions and BNIP3L/NIX-mediated mitophagy. Expression levels of mitophagy-related proteins, such as LC3B, BNIP3L/NIX, and FUNDC1were significantly elevated in GSNOR knockdown detected by western blot. These results suggest that the knockdown of GSNOR knockdown alleviates mitochondrial toxicity by promoting HIF-1α S-nitrosylation-associated repair of mitochondrial functions and activating mitophagy in BMECs. Understanding the protective effects of GSNOR provides a novel strategy for developing potential therapies targets for ischemic injury in BMECs.

IntroductionThe incidence of osteoporosis (OP) keeps increasing due to global aging of the population. Therefore, identifying the diagnostic and prognostic biomarkers of OP is of great significance. MethodsmRNA data from OP and non-OP samples were obtained from GEO database, which were divided into training set (GSE35959) and testing sets (GSE7158, GSE62402, GSE7429 and GSE56815). Gene modules most significantly related to OP were revealed using weighted gene co-expression network analysis (WGCNA) and differentially expressed genes (DEGs) between OP and normal samples in training set were identified using limma R package. Thereafter, above two gene sets were intersected to obtain the genes potentially related to OP. Protein-protein interaction (PPI) pairs were screened by STRING database and visualized using Cytoscape, while the plug-in cytoHubba was used to screen hub genes by determining their topological parameters. Afterwards, a diagnostic model was constructed using those hub genes, whose creditability was further evaluated by testing sets. ResultsThe results of WGCNA analysis found the Black module was most significantly related to OP, which included altogether 1286 genes. Meanwhile, 2771 DEGs were discovered between OP patients and the normal controls. After taking the intersection, 479 genes were identified potentially correlated with the development of OP. Subsequently, six hub genes were discovered through PPI network construction and node topological analysis. Finally, we constructed a support vector machine model based on these six genes, which can accurately classified training and testing set samples into OP and normal groups. ConclusionOur current study constructed a six hub genes-based diagnostic model for OP. Our findings may shed some light on the research of the early diagnosis for OP and had certain practical significance.

Alpha-naphthylisothiocyanate (ANIT) is a typical hepatotoxicant that causes cholestasis, which causes toxic bile acid accumulation in the liver and leads to liver injury. Picroside II (PIC), one of the dominant effective components extracted from Picrorhiza scrophulariiflora Pennell, exhibits many pharmacological effects. However, the role of AMP-activated protein kinase (AMPK)-Farnesoid X receptor (FXR) pathway in the hepatoprotective effect of PIC against ANIT-induced cholestasis remains largely unknown. This study aimed to investigate the mechanisms of PIC on ANIT-induced cholestasis in vivo and in vitro. Our results showed that PIC protected against ANIT-induced liver injury in primary mouse hepatocytes, and decreased serum biochemical markers and lessened histological injuries in mice. ANIT inhibited FXR and its target genes of bile acid synthesis enzymes sterol-12 alpha-hydroxylase (CYP8B1), and increase bile acid uptake transporter Na + -dependent taurocholate transporter (NTCP), efflux transporter bile salt export pump (BSEP) and bile acid metabolizing enzymes UDP-glucuronosyltransferase 1a1 (UGT1A1) expressions. PIC prevented its downregulation of FXR, NTCP, BSEP and UGT1A1, and further reduced CYP8B1 by ANIT. Furthermore, ANIT activated AMPK via ERK1/2-LKB1 pathway. PIC inhibited ERK1/2, LKB1 and AMPK phosphorylation in ANIT-induced cholestasis in vivo and in vitro. AICAR, an AMPK agonist, blocked PIC-mediated changes in FXR, CYP8B1 and BSEP expression in vitro. Meanwhile, U0126, an ERK1/2 inhibitor, further repressed ERK1/2-LKB1-AMPK pathway phosphorylation. In conclusion, PIC regulated bile acid-related transporters and enzymes to protect against ANIT-induced liver injury, which related to ERK1/2-LKB1-AMPK pathway. Thus, this study extends the understanding of the anti-cholestasis effect of PIC and provides new therapeutic targets for cholestasis treatment.

UDP-glucuronosyltransferases (UGTs) are a family of phase II drug metabolizing enzymes that catalyze glucuronidation of numerous endogenous and exogenous substrates. Carbon tetrachloride (CCl4) is widely used to develop liver injuries mimicking human liver diseases. However, effects of CCl4 on the expression and activities of UGTs and the mechanism have not been fully elucidated. The present study aims to elucidate the dysregulation patterns of major UGTs induced by CCl4. Biochemical and histopathological results showed that CCl4 exerted hepatotoxicity in rats. The mRNA levels of UGTs were all significantly reduced in acute liver injury rats. However, mRNA levels of UGT1A1, 1A6, 2B1 and 2B2 were up-regulated while the UGT2B3, 2B6 and 2B12 levels were reduced in chronic CCl4-induced liver fibrosis rats. The protein expression of UGT1A1, 1A6 and 2B were decreased in acute liver injury rats. UGT1A1 and 1A6 proteins were increased, whereas UGT2B protein was reduced in liver fibrosis rats. In addition, CCl4 inhibited the enzyme activities of UGTs in rats. Moreover, the dysregulation of UGTs was accompanied by the decreased mRNA expression of Nrf2, CAR, FXR, PXR, PPAR-α and their corresponding target genes, except for Nrf2, HO-1, AhR and CYP1A1 in liver fibrosis rats. These findings suggest that dysregulation of UGTs under CCl4 exposure is isoform-specific, which could have a complex impact on drug efficacy and endogenous metabolism. Different exposure durations of CCl4 (single vs multiple doses) could have differential effects on rat hepatic UGTs expression.

BACKGROUD:Cholestasis, accompanied by the accumulation of bile acids in body, may ultimately cause liver failure and cirrhosis. There have been limited therapies for cholesteric disorders. Therefore, development of appropriate therapeutic drugs for cholestasis is required. Picroside II is a bioactive component isolated from Picrorhiza scrophulariiflora Pennell, its mechanistic contributions to the anti-cholestasis effect have not been fully elucidated, especially the role of picroside II on bile acid homeostasis via nuclear receptors remains unclear.PURPOSE:This study was designed to investigate the hepatoprotective effect of picroside II against alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury and elucidate the mechanisms in vivo and in vitro.METHODS:The ANIT-induced cholestatic mouse model was used with or without picroside II treatment. Serum and bile biochemical indicators, as well as liver histopathological changes were examined. siRNA, Dual-luciferase reporter, quantitative real-time PCR and Western blot assay were used to demonstrate the farnesoid X receptor (FXR) pathway in the anti-cholestasis effects of picroside II in vivo and in vitro.RESULTS:Picroside II exerted hepatoprotective effect against ANIT-induced cholestasis by impaired hepatic function and tissue damage. Picroside II increased bile acid efflux transporter bile salt export pump (Bsep), uptake transporter sodium taurocholate cotransporting polypeptide (Ntcp), and bile acid metabolizing enzymes sulfate transferase 2a1 (Sult2a1) and UDP-glucuronosyltransferase 1a1 (Ugt1a1), whereas decreased the bile acid synthesis enzymes cholesterol 7α-hydroxylase (Cyp7a1) and oxysterol 12α-hydroxylase (Cyp8b1). In addition, expression of FXR and the target gene Bsep was increased, whereas aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor alpha (PPARα) and their corresponding target genes were not significantly influenced by picroside II under cholestatic conditions. Furthermore, regulation of transporters and enzymes involved in bile acid homeostasis by picroside II were abrogated by FXR silencing in mouse primary cultured hepatocytes. Dual-luciferase reporter assay performed in HepG2 cells demonstrated FXR activation by picroside II.CONCLUSION:Our findings demonstrate that picroside II exerts protective effect on ANIT-induced cholestasis possibly through FXR activation that regulates the transporters and enzymes involved in bile acid homeostasis. Picroside II might be an effective approach for the prevention and treatment of cholestatic liver diseases.

The inflammatory response mediated by microglia plays a critical role in the progression of ischemic stroke. Phosphoinositide 3-kinase gamma (PI3Kγ) has been implicated in multiple inflammatory and autoimmune diseases, making it a promising target for therapeutic intervention. The aim of this study was to evaluate the efficacy of 8e, a hydrogen sulfide (H2S) releasing derivative of 3-n-butylphthalide (NBP), on brain damage and PI3Kγ signaling following cerebral ischemia injury. 8e significantly reduced sensorimotor deficits, focal infarction, brain edema and neural apoptosis at 72 h after transient middle cerebral artery occlusion (tMCAO). The NOX2 isoform of the NADPH oxidase family is considered a major enzymatic source of superoxide. We found that the release of superoxide, together with the expression of NOX2 subunits p47phox, p-p47phox, and the upstream PI3Kγ/AKT signaling were all down-regulated by 8e, both in the penumbral region of the rat brain and in the primary cultured microglia subjected to oxygen-glucose deprivation (OGD). With the use of siRNA and pharmacological inhibitors, we further demonstrated that 8e regulates the formation of superoxide in activated microglia through the PI3Kγ/AKT/NOX2 signaling pathway and subsequently prevents neuronal death in neighboring neurons. Our experimental data indicate that 8e is a potential candidate for the treatment of ischemic stroke and PI3Kγ-mediated neuroinflammation.

Alzheimer's disease (AD) is a complex neurodegenerative disorder with cognitive impairment and major neuropathologic hallmark of amyloid-beta (Aβ) peptides. Risperidone, an atypical antipsychotic, can improve concentration and cognitive deficit in schizophrenia patients. In this study, behavior tests including Morris Water Maze test, Step-through passive avoidance test, Open Field test, Step-Down test, Hole-Board test and Novel object recognition test were preformed to examine the effect of Risperidone on Aβ1-42-induced cognitive dysfunction in both long-term and short-term memory. Furthermore, ELISA assay was conducted to measure the levels of Aβ1-42, BACE1 and p-Tau in the hippocampus and cortex. Moreover, primary cortical neuron was cultured in vitro, and the cell viability, mitochondrial membrane potential, and the level of p-Akt, GSK3β and Caspase-3 protein were measured. For behavior tests, the results showed that Risperidone significantly reversed the Aβ1-42-induced dysfunction in learning, memory, locomotor activity and exploratory behavior. As detected by ELISA assay, risperidone decreased the levels of Aβ1-42, BACE1 and p-Tau in the hippocampus and cortex of AD model mice. Biochemical assay showed that Risperidone reversed the Aβ1-42-induced decrease of cell viability and mitochondrial membrane potential in cultured cortical neurons. The expression of p-Akt was increased, whereas the expression of GSK3β and Caspase-3 were decreased. These results suggested that Risperidone may be used as a promising candidate for AD treatment, for its effects of inhibiting Aβ generation and improving cognitive impairment in mice.

NOSH-NBP, a novel nitric oxide (NO) and hydrogen sulfide (H2S)-releasing hybrid, protects brain from ischemic stroke. This study mainly aimed to investigate the therapeutic effect of NOSH-NBP on ischemic stroke and the underlying mechanisms. In vivo, transient middle cerebral artery occlusion (tMCAO) was performed in C57BL/6 mice, with NO-NBP and H2S-NBP as controls. NO and H2S scavengers, carboxy-PTIO and BSS, respectively, were used to quench NO and H2S of NOSH-NBP. In vitro, BV2 microglia/BMDM were induced to the M1/2 phenotype, and conditioned medium (CM) experiments in BV2 microglia, neurons and b.End3 cerebral microvascular endothelial cells (ECs) were performed. Microglial/macrophage activation/polarization was assessed by flow cytometry, Western blot, RT-qPCR, and ELISA. Neuronal and EC survival was measured by TUNEL, flow cytometry, MTT and LDH assays. Transmission electron microscopy, EB extravasation, brain water content, TEER measurement and Western blot were used to detect blood-brain barrier (BBB) integrity and function. Interestingly, NOSH-NBP significantly reduced cerebral infarct volume and ameliorated neurological deficit, with superior effects compared with NO-NBP and/or H2S-NBP in mice after tMCAO. Both NO and H2S-releasing groups contributed to protection by NOSH-NBP. Additionally, NOSH-NBP decreased neuronal death and attenuated BBB dysfunction in tMCAO-treated mice. Furthermore, NOSH-NBP promoted microglia/macrophage switch from an inflammatory M1 phenotype to the protective M2 phenotype in vivo and in vitro. Moreover, the TLR4/MyD88/NF-κB pathway and NLRP3 inflammasome were involved in the inhibitory effects of NOSH-NBP on M1 polarization, while peroxisome proliferator activated receptor gamma signaling contributed to NOSH-NBP induced M2 polarization. These findings indicated that NOSH-NBP is a potential therapeutic agent that preferentially promotes microglial/macrophage M1-M2 switch in ischemic stroke.

Objective To investigate the correlation of the level of circulating endothelial progenitor cells (EPCs) and cerebral atherosclerosis burden (CAB) in patients with large artery atherosclerotic stroke (LAAS) and its predictive effect for LAAS.Metlods Consecutive patients with LAAS and healthy controls were enrolled.Flow cytometry wad used to detect EPC level in peripheral blood.CAB was assessed according to the results of CT angiography or magnetic resonance angiography.Univariate analysis was used to compare the demographic and clinical data in both groups.Multivariate logistic regression analysis was used to identify the correlation of circulating EPC level and LAAS.Results A total of 141 patients with LAAS and 100 controls were enrolled.The constituent ratios of hypertension (65.9％ vs.51.0％;x2 =5.443,P =0.020) and diabetes (27.0％ vs.16.0％;x2 =4.035,P=0.045) of the patents,as well as systolic blood pressure (139.1 ± 1 1.1 mmHg vs.131.6 ± 15.7 mmHg;t =3.549,P =0.003;1 mmHg =0.133 kPa) and fasting blood glucose (5.8 ±2.1 mmol/L vs.5.2 ±2.0 mmol/L;t =2.344,P=0.020) in the patient group were significantly higher than those in the control group,while the circulating EPC level (median,interquartile range) (13[3-32] /ml vs.31 [7-59]/ml;Z=3.913,P=0.001) was significantly lower than the control group.Multivariate logistic regression analysis showed that the decreased circulating EPC level (odd ratio 2.632,95％ confidence interval 1.412-4.907,P=0.002) was an independent risk factor for LAAS after adjusting the confounders.The EPC level in the CAB ＞ 3 group was significantly lower than that in the CAB 1 group (5 [2-19]/ml vs.22 [9-43]/ml;Z =3.338,P =0.011).Spearman rank correlation analysis showed that the EPC level was significantly negatively correlated with CAB (r=-0.257,P=0.002).Conclusions The decreased circulating EPC level was an indenpendent risk factor for the onset of LAAS,and the EPC level was negatively correlated with CAB.

Objective: To study the effect of reduced glutathione on oxidative stress in the patients with type 2 diabetic nephropathy.Methods: 72 patients with type 2 diabetic nephropathy were enrolled,of which 36 were put into the control group and the left 36 were in the treatment group randomly.Patients in treatment group received reduced glutathione and routine insulin therapy,while patients in control group took routine insulin therapy only.Based on which,the indicators involved would be determined.Results: With the treatment of reduced glutathione,the serum hs-CRP,IL-6,TNF-α,Hcy level and 24-hour urine microalbumi significantly increased(P0.05).And serum levels of inflammatory markers hs-CRP,TNF-α,Hcy level significantly decreased in treatment group vs the control group(P0.05).Conclusions: Microinflammation exists in the patients with type 2 diabetic nephropathy,and reduced glutathione can obviously improve the oxidative stress and decreased urinary mALB excretion.

中风“防”重于“治”,基于中医“治未病”思想,对中风先兆积极预防和治疗,是降低中风发病和复发的关键.关于中风先兆的防治,历代论述颇多,从涵义、病机、临床表现及防治等方面概述历代医家的相关认识.

The paper reviewed the correlation between hemorrhagic stroke syndrome and microscopic characteristics of modern medicine from the amount and site of bleeding,degree of edema,laboratory parameters.It pointed out that the standardized syndrome diagnosis is the premise of microscopic characteristics research,revealed the formation mechanism and essential of stroke syndromes.Expect to provide an objective basis for the clinical syndrome.