ObjectiveTo evaluate the effectiveness of stone needle thermocompression and massage compared to flurbiprofen gel patch in relieving chronic musculoskeletal pain in the shoulder and back， and to explore the potential mediating mechanism through muscle elasticity. MethodsA total of 120 patients with chronic musculoskeletal pain in the shoulder and back were randomly assigned to either stone needle group or flurbiprofen group， with 60 patients in each. The stone needle group received stone needle thermocompression and massage for 30 minutes， three times per week； the flurbiprofen group received flurbiprofen gel patch twice daily. Both groups were treated for 2 weeks. Pain improvement， as the primary outcome， was assessed using the Global Pain Scale （GPS） at baseline， after 2 weeks of treatment， and again 2 weeks post-treatment. To explore potential mechanisms， a mediator analysis was conducted by measuring changes in superficial and deep muscle elasticity using musculoskeletal ultrasound at baseline and after the 2-week treatment period. ResultsThe stone needle group showed significantly greater pain relief than the flurbiprofen group 2 weeks post-treatment. After adjusting for confounders related to pain duration， the between-group mean difference was -8.8 ［95% CI （-18.2， -0.7）， P＜0.05］. Part of the therapeutic effect was mediated by changes in deep muscle elasticity， with a mediation effect size of -1.5 ［95% CI （-2.0， -0.9）， P = 0.024］， accounting for 17.9% of the total effect. ConclusionStone needle thermocompression and massage can effectively relieve chronic musculoskeletal pain in the shoulder and back， partly through a mediating effect of improved deep muscle elasticity.

Alzheimer’s disease (AD) is a central neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment, and there is a lack of effective drugs to treat AD clinically. Existing medications for the treatment of AD, such as Tacrine, Donepezil, Rivastigmine, and Aducanumab, only serve to delay symptoms and but not cure disease. To add insult to injury, these medications are associated with very serious adverse effects. Therefore, it is urgent to explore effective therapeutic drugs for AD. Recently, studies have shown that a variety of enzyme inhibitors, such as cholinesterase inhibitors, monoamine oxidase (MAO)inhibitors, secretase inhibitors, can ameliorate cholinergic system dysfunction, Aβ production and deposition, Tau protein hyperphosphorylation, oxidative stress damage, and the decline of synaptic plasticity, thereby improving AD symptoms and cognitive function. Some plant extracts from natural sources, such as Umbelliferone, Aaptamine, Medha Plus, have the ability to inhibit cholinesterase activity and act to improve learning and cognition. Isochromanone derivatives incorporating the donepezil pharmacophore bind to the catalytic active site (CAS) and peripheral anionic site (PAS) sites of acetylcholinesterase (AChE), which can inhibit AChE activity and ameliorate cholinergic system disorders. A compound called Rosmarinic acid which is found in the Lamiaceae can inhibit monoamine oxidase, increase monoamine levels in the brain, and reduce Aβ deposition. Compounds obtained by hybridization of coumarin derivatives and hydroxypyridinones can inhibit MAO-B activity and attenuate oxidative stress damage. Quinoline derivatives which inhibit the activation of AChE and MAO-B can reduce Aβ burden and promote learning and memory of mice. The compound derived from the combination of propargyl and tacrine retains the inhibitory capacity of tacrine towards cholinesterase, and also inhibits the activity of MAO by binding to the FAD cofactor of monoamine oxidase. A series of hybrids, obtained by an amide linker of chromone in combine with the benzylpiperidine moieties of donepezil, have a favorable safety profile of both cholinesterase and monoamine oxidase inhibitory activity. Single domain antibodies (such as AAV-VHH) targeted the inhibition of BACE1 can reduce Aβ production and deposition as well as the levels of inflammatory cells, which ultimately improve synaptic plasticity. 3-O-trans-p-coumaroyl maslinic acid from the extract of Ligustrum lucidum can specifically inhibit the activity of γ-secretase, thereby rescuing the long-term potentiation and enhancing synaptic plasticity in APP/PS1 mice. Inhibiting γ-secretase activity which leads to the decline of inflammatory factors (such as IFN-γ, IL-8) not only directly improves the pathology of AD, but also reduces Aβ production. Melatonin reduces the transcriptional expression of GSK-3β mRNA, thereby decreasing the levels of GSK-3β and reducing the phosphorylation induced by GSK-3β. Hydrogen sulfide can inhibitGSK-3β activity via sulfhydration of the Cys218 site of GSK-3β, resulting in the suppression of Tau protein hyperphosphorylation, which ameliorate the motor deficits and cognitive impairment in mice with AD. This article reviews enzyme inhibitors and conformational optimization of enzyme inhibitors targeting the regulation of cholinesterase, monoamine oxidase, secretase, and GSK-3β. We are hoping to provide a comprehensive overview of drug development in the enzyme inhibitors, which may be useful in treating AD.

As a microbial therapy method, fecal microbiota transplantation (FMT) has attracted the attention of researchers in recent years. As one of the most direct and effective methods to improve gut microbiota, FMT achieves therapeutic benefits by transplanting functional gut microbiota from healthy human feces into the intestines of patients to reconstruct new gut microbiota. FMT has been proven to be an effective treatment for gastrointestinal diseases such as Clostridium difficile infection, irritable bowel syndrome, and inflammatory bowel disease. In addition, the clinical and basic research of FMT outside the gastrointestinal system is also emerging. It is worth noting that there is bidirectional communication between the gut microbial community and the central nervous system (CNS) through the gut-brain axis. Some gut bacteria can synthesize and release neurotransmitters such as glutamate, gamma-aminobutyric acid (GABA) and dopamine. Imbalanced gut microbiota may interfere with the normal levels of these neurotransmitters, thereby affecting brain function. Gut microbiota can also produce metabolites that may cross the blood-brain barrier and affect CNS function. FMT may affect the occurrence and development of CNS and its related diseases by reshaping the gut microbiota of patients through a variety of pathways such as nerves, immunity, and metabolites. This article introduces the development of FMT and the research status of FMT in China, and reviews the basic and clinical research of FMT in neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease), neurotraumatic diseases (spinal cord injury, traumatic brain injury) and stroke from the characteristics of three types of nervous system diseases, the characteristics of intestinal flora, and the therapeutic effect and mechanism of fecal microbiota transplantation, summarize the common mechanism of fecal microbiota transplantation in the treatment of CNS diseases and the therapeutic targets. We found that the common mechanisms of FMT in the treatment of nervous system diseases may include the following 3 categories through summary and analysis. (1) Gut microbiota metabolites, such as SCFAs, TMAO and LPS. (2) Inflammatory factors and immune inflammatory pathways such as TLR-MyD88 and NF-κB. (3) Neurotransmitter 5-HT. In the process of reviewing the studies, we found the following problems. (1) In basic researches on the relationship between FMT and CNS diseases, there are relatively few studies involving the autonomic nervous system pathway. (2) Clinical trial studies have shown that FMT improves the severity of patients’ symptoms and may be a promising treatment for a variety of neurological diseases. (3) The improvement of clinical efficacy is closely related to the choice of donor, especially emphasizing that FMT from healthy and young donors may be the key to the improvement of neurological diseases. However, there are common challenges in current research on FMT, such as the scientific and rigorous design of FMT clinical trials, including whether antibiotics are used before transplantation or different antibiotics are used, as well as different FMT processes, different donors, different functional analysis methods of gut microbiota, and the duration of FMT effect. Besides, the safety of FMT should be better elucidated, especially weighing the relationship between the therapeutic benefits and potential risks of FMT carefully. It is worth mentioning that the clinical development of FMT even exceeds its basic research. Science and TIME rated FMT as one of the top 10 breakthroughs in the field of biomedicine in 2013. FMT therapy has great potential in the treatment of nervous system diseases, is expected to open up a new situation in the medical field, and may become an innovative weapon in the medical field.

Using column chromatography methods including the macroporous adsorbent resin, MCI gel CHP 20P, ODS-A-HG, Sephadex LH-20, combined with chromatographic separation methods such as TLC and reversed-phase HPLC, three glycosides (1-3) and two peptides including two new compounds were isolated from the ethanol extract of arthropod Scolopendra subspinipes mutilans. Their structures were identified as colosides A and B (1 and 2), 3,4-dihydroxyquinoline-4-O-β-D-glucopyranoside (3), aurantiamide (4), cyclo (L-phe-L-val) (5) by UV, NMR and HR-ESI-MS spectroscopic techniques.

Objective To investigate the correlation between interleukin 1β gene-511C/T polymorphism of and essential hypertension in the Yi ethnic group of Yunnan province.Methods-511C/T polymorphism of interleukin 1β gene was detected by PCR-RFLP in 85 Yi patients with essential hypertension(EH group)and 106 Yi healthy people(control group)in Shuanghe Township,Jinning County,Yunnan Province.Genotype and allele frequencies were analyzed by SPSS 27.0 software,and association analysis was performed.Results The frequency distribution of CC,CT and TT genotypes at the mutation site 511 of the IL-1βgene in EH group was 18.82%,44.71%and 36.47%,respectively,and it was 5.66%,26.42%and 67.92%in the control group.The difference in genotype frequency between the two groups was statistically significant(P＜0.05).The allele frequency of C and T in EH group was 41.18%and 58.82%,respectively,and the allele frequency of C and T in control group was 18.87%and 81.13%.The frequency difference of alleles between the two groups was statistically significant(P＜0.05).Both genotype frequency and allele frequency found in males and females had statistical differences(P＜0.05).Conclusions The distribution of IL-1β gene-511C/T polymorphism is related to the incident of essential hyper-tension among the Yi ethnic group Yunnan Province,and is the susceptibility gene of the Yi ethnic group to essen-tial hypertension.

Objective To explore whether dexmedetomidine(DEX)can alleviate exertional heatstroke(EHS)-induced rhabdomyolysis(RM)in rats by activating adrenergic α2 receptors,and to explore its potential mechanism based on the reactive oxygen species(ROS)/NOD-like receptor protein 3(NLRP3)/interleukin-1β(IL-1β)pathway.Methods Thirty-six male Sprague-Dawley(SD)rats,after a 7-day acclimatization training,were randomly divided into six groups:control group(CN group),EHS group,low-dose DEX group(EHS+low DEX group),high-dose DEX group(EHS+high DEX group),DEX combined with yohimbine(YOH)group(EHS+high DEX+YOH group),and YOH group(EHS+YOH),with six rats in each group.Before modeling,EHS+high DEX+YOH group and EHS+YOH group were intraperitoneally injected with YOH at 1 mg/kg,while the other four groups were injected intraperitoneally with an equal dose of physiological saline(0.9%NS).During modeling,except for CN group,the other 5 groups of rats were subjected to heat exercise in a high-temperature and high-humidity chamber to construct an EHS rat model.After successful modeling,EHS+low DEX group was intraperitoneally injected with DEX at 10 μg/kg,EHS+high DEX group and EHS+high DEX+YOH group were intraperitoneally injected with DEX at 30 μg/kg,and CN group,EHS group and DEX+YOH group were intraperitoneally injected with equal doses of saline.After 6 h of observation,all rats were anesthetized,and their blood from the abdominal aorta and gastrocnemius muscle tissue were taken.Enzyme-linked immunosorbent assay(ELISA)was used to detect the expression levels of serum tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),IL-1β and myoglobin(MB)in rats;biochemical assay kit was used to measure the level of creatine kinase(CK)in rat serum;HE staining was used to observe pathological changes in rat gastrocnemius muscle tissues;transmission electron microscopy was used to observe ultrastructural changes in gastrocnemius muscle;2′,7′-dichlorofluorescent yellow diacetate(DCFH-DA)fluorescent probe was used to detect the level of reactive oxygen species(ROS);and Western blotting was performed to detect the expression levels of NOD-like receptors 3(NLRP3),aspartic protease-1(caspase-1)and adrenergic α2A receptor(ADRA2A).Results Compared with CN group,the levels of serum IL-6,IL-1β,TNF-α,CK and MB in EHS group rats were significantly elevated(P<0.01).HE staining results revealed that the gastrocnemius muscle tissues of rats in EHS group had these pathological manifestations such as disarray of muscle fibrous structure,hemorrhage,edema,and infiltration of inflammatory cells.Transmission electron microscopy results showed that the ultrastructure of the gastrocnemius muscle in EHS group exhibited myofibroblasts with swelling and enlarging in size,cytoplasmic vacuolization,and mitochondria with obvious swelling,degranulation,and disappearance of double cristae.Compared with CN group,the expression levels of ROS,NLRP3,and caspase-1 in gastrocnemius of rats in EHS group significantly increased(P<0.01);Compared with EHS group,the levels of TNF-α,IL-6,IL-1β,CK,MB and the expression levels of ROS,NLRP3,caspase-1 in gastrocnemius tissue of rats in EHS+low DEX group and EHS+high DEX group decreased in a dose-dependent manner(P<0.05),and the pathological damage observed with HE staining and transmission electron microscopy was alleviated by DEX.After YOH pretreatment,compared with the EHS+high DEX group,the serum levels of TNF-α,IL-6,IL-1β,CK,MB and ROS,NLRP3 and caspase-1 in the gastrocnemius muscle tissue of rats in EHS+high DEX+YOH group relatively increased(P<0.05),and the pathological damage observed with HE staining and transmission electron microscopy was exacerbated.The expression of ADRA2A in gastrocnemius muscle of EHS group significantly decreased compared with CN group(P<0.01),and the expression of ADRA2A in muscle of rats in DES+low DEX group and EHS+high DEX group was higher than that in EHS group(P<0.05).Conclusions DEX can alleviate EHS-induced RM by activating ADRA2A,potentially through inhibiting the ROS-dependent NLRP3/IL-1β inflammatory pathway.

Objective To explore the effect of gastrodin(GAS)on the polarization of M2 microglia under oxygen and glucose deprivation(OGD)and the effect of p38 MAPK inhibition on the polarization status of microglia.Methods BV2 microglia was divided into the control group(Ctrl),p38 MAPK inhibitor SB203580 group(Ⅰ),OGD group(OGD),OGD+I group,gastrodin treatment group(G+OGD),and G+OGD+Ⅰ group.The expressions of p38 MAPK,phosphorylated p38 MAPK(p-p38 MAPK),M2 microglia marker arginase-1(Arg-1)and chitinase like protein 1/2(YM1/2)were detected by immunofluorescent staining and Western blotting.Results Immunofluorescent staining results showed that the pretreatment with gastrodin reduced the fluorescence expression of p-p38 MAPK in OGD induced BV2 microglia,enhanced the fluorescence expressions of Arg-1 and YM1/2.After pretreatment with SB203580,the fluorescence expressions of p-p38 MAPK further decreased,the fluorescence expressions of Arg-1 and YM1/2 further increased,both were significantly different from the G+OGD group(n=3,P＜0.05).The fluorescence expressions of p38 MAPK in each group was not statistically significant(n=3,P＞0.05).Western blotting results showed that the protein expressions of p-p38 MAPK,Arg-1 and YM1/2 in the OGD group enhanced,compared with that in the control group(n=3,P＜0.05).After the pretreatment with gastrodin,the protein expression of p-p38 MAPK was reduced significantly,the protein expressions of Arg-1 and YM1/2 was enhanced obviously,both were significantly different from the OGD group(n=3,P＜0.05).After pretreatment with SB203580,the protein expressions of p-p38 MAPK was further reduced,the protein expression of Arg-1 and YM1/2 were further enhanced,both were significantly different from the G+OGD group(n=3,P＜0.05).In addition,there was no significant change in p38 MAPK protein expression among groups(n=3,P＞0.05).Conclusion Gastrodin inhibits p38 MAPK signaling activation to promote BV2 microglial polarization towards the M2 phenotype,reducing inflammatory responses and exerting a protective effect.

Objective To investigate whether quercetin inhibits pyroptosis of mouse fibroblast NIH-3T3 cells by regulating the NLRP3/caspase-1/GSDMD signaling pathway.Methods NIH-3T3 cells were treated with quercetin or MCC950(a specific inhibitor of NLRP3)before stimulation with lipopolysaccharide(LPS)and ATP to induce cell pyroptosis.The optimal quercetin concentration and duration were screened using the CCK-8assay after testing various concentrations and times.Morphological changes of the treated cells was observed,and the levels of IL-18 and IL-1β in the cell culture supernatant were detected with ELISA;the protein expressions of NLRP3,cleaved caspase-1,and GSDMD-N and the mRNA levels of NLRP3,caspase-1 and GSDMD were detected using Western blotting and qRT-PCR.The changes in cell pyroptosis were examined with TUNEL staining and LDH release assay.Results The CCK-8 assay indicated that 24-hour treatment with 20 μmol/L quercetin yielded the most favorable results.LPS and ATP stimulation of NIH-3T3 cells induced obvious swelling,cell membrane rupture and leakage of cell contents,significantly increased IL-18 and IL-1β levels,and enhanced protein expressions of NLRP3,cleaved caspase-1 and GSDMD-N and mRNA levels of NLRP3,caspase-1 and GSDMD.LPS and ATP stimulation also caused a significant increment of TUNEL-positive cell counts and LDH release in NIH-3T3 cells.Treatment with quercetin or MCC950 significantly reduced cell pyroptosis induced by LPS and ATP,lowered the concentrations of IL-18 and IL-1β,decreased the expression levels of NLRP3,caspase-1/cleaved caspase-1,GSDMD/GSDMD-N,and reduced the number of TUNEL-positive cells and LDH release.Conclusion Quercetin suppresses pyroptosis of mouse fibroblasts stimulated with LPS and ATP and reduces secretion of inflammatory cytokines by inhibiting the NLRP3/caspase-1/GSDMD pathway.

Objective Hypertriglyceridemic waist(HW),hypertriglyceridemic waist-to-height ratio(HWHtR),and waist-to-hip ratio(WHR)have been shown to be indicators of cardiometabolic risk factors.However,it is not clear which indicator is more suitable for children and adolescents.We aimed to investigate the relationship between HW,HWHtR,WHR,and cardiovascular risk factors clustering to determine the best screening tools for cardiometabolic risk in children and adolescents. Methods This was a national cross-sectional study.Anthropometric and biochemical variables were assessed in approximately 70,000 participants aged 6-18 years from seven provinces in China.Demographics,physical activity,dietary intake,and family history of chronic diseases were obtained through questionnaires.ANOVA,x2 and logistic regression analysis was conducted. Results A significant sex difference was observed for HWHtR and WHR,but not for HW phenotype.The risk of cardiometabolic health risk factor clustering with HW phenotype or the HWHtR phenotype was significantly higher than that with the non-HW or non-HWHtR phenotypes among children and adolescents(HW:OR = 12.22,95%CI:9.54-15.67;HWHtR:OR = 9.70,95%CI:6.93-13.58).Compared with the HW and HWHtR phenotypes,the association between risk of cardiometabolic health risk factors(CHRF)clustering and high WHR was much weaker and not significant(WHR:OR = 1.14,95%CI:0.97-1.34). Conclusion Compared with HWHtR and WHR,the HW phenotype is a more convenient indicator with higher applicability to screen children and adolescents for cardiovascular risk factors.

Objective This study aimed to evaluate whether the onset of the plateau phase of slow hepatitis B surface antigen decline in patients with chronic hepatitis B treated with intermittent interferon therapy is related to the frequency of dendritic cell subsets and expression of the costimulatory molecules CD40,CD80,CD83,and CD86. Method This was a cross-sectional study in which patients were divided into a natural history group(namely NH group),a long-term oral nucleoside analogs treatment group(namely NA group),and a plateau-arriving group(namely P group).The percentage of plasmacytoid dendritic cell and myeloid dendritic cell subsets in peripheral blood lymphocytes and monocytes and the mean fluorescence intensity of their surface costimulatory molecules were detected using a flow cytometer. Results In total,143 patients were enrolled(NH group,n = 49;NA group,n = 47;P group,n = 47).The results demonstrated that CD141/CD1c double negative myeloid dendritic cell(DNmDC)/lymphocytes and monocytes(%)in P group(0.041[0.024,0.069])was significantly lower than that in NH group(0.270[0.135,0.407])and NA group(0.273[0.150,0.443]),and CD86 mean fluorescence intensity of DNmDCs in P group(1832.0[1484.0,2793.0])was significantly lower than that in NH group(4316.0[2958.0,5169.0])and NA group(3299.0[2534.0,4371.0]),Adjusted P all<0.001. Conclusion Reduced DNmDCs and impaired maturation may be associated with the onset of the plateau phase during intermittent interferon therapy in patients with chronic hepatitis B.