epsis is a systemic inflammatory response syndrome triggered by infection， and its high mortality rate is closely associated with immune imbalance， particularly the imbalance in the differentiation of helper T cell （Th） cell subsets [Th1， Th2， Th17， regulatory T cell （Treg） ] . In recent years， traditional Chinese medicine （TCM）， with its characteristics of multi-component and multi-target actions， has demonstrated unique advantages in regulating Th cell differentiation and function， as well as correcting immune imbalances in sepsis， offering new perspectives for immunotherapy of sepsis. This review summarizes relevant studies on the regulation of Th cell differentiation for sepsis treatment by TCM monomers and active ingredients （such as Astragalus membranaceus ， Scutellaria baicalensis ， Coptis chinensis ， Rheum palmatum ， Ganoderma lucidum ， Ginkgo biloba ， and Cistanche deserticola ）， the alcohol extract of Dai Baijie， and TCM formulas and preparations categorized as blood-activating and stasis-removing， purgative and laxative， warming and tonifying yang， and tonifying qi and nourishing yin. The results indicate that these TCM monomers， active ingredients， extracts， formulas， and preparations can regulate the Th1/Th2 and Th17/Treg balance， target the differentiation balance of Th cell subsets， alleviate inflammatory responses， or improve immune suppression， thereby exerting therapeutic effects on sepsis.

Objective To investigate the effects of super early enteral nutrition support on postoperative serum miR-124 levels,inflammatory markers,immune function,nutritional status,and short-term and long-term rehabilitation outcomes in patients with severe traumatic brain injury(STBI).Methods A total of123 STBI patients admitted to our hospital from January 2021 to December 2022 were selected.According to the start time of enteral nutrition,patients were divided into super early enteral nutrition group,late enteral nutrition group and parenteral nutrition group.We collect clinical data from each group and detected serum miR-124 and inflammatory factors,immune indicator,nutritional indicators levels before and after treatment,as well as postoperative complications and prognosis.Results Compared with the parenteral group and the late intestinal group,the levels of miR-124,inflammatory factors and the proportion of CD8+T cells in the super early intestinal group were significantly reduced,while the proportion of CD4+/CD8+cells was significantly increased,with statistical differences(all P＜0.05).Compared with the parenteral group,the levels of albumin,prealbumin,and transferrin in intestinal groups were significantly increased with statistical differences(both P＜0.05).Compared with the late intestinal group,the levels of albumin and prealbumin in the super early intestinal group were significantly increased,with statistical differences(both P＜0.05),while there was no significant difference in transferrin levels between two groups(P＞0.05).There was no significant difference in the incidence of various complications during hospitalization among all groups(all P＞0.05).The total incidence of complications in the super early intestinal group was significantly lower than that in the parenteral group and late intestinal group with statistical differences(both P＜0.05).During the follow-up period,there was no significant difference in prognosis,disability,and mortality among three groups(all P＞0.05).Compared with the parenteral group,the GOS scores of the intestinal groups were significantly reduced with statistical differences(P＜0.05).There was no statistically significant difference in GOS scores between two groups(P＞0.05).Conclusion Super early enteral nutrition support is effective in treating patients with STBI,which can effectively improve the patient's nutritional status,enhance immune function,suppress inflammatory reactions,help repair nerve injuries,and enhance rehabilitation effects.

Objective To explore the relationship between plantar fascia stiffness and windlass mechanism and their impact on the arch,and provide a biomechanical mechanism explanation for plantar fascia and arch-related diseases.Methods A foot-plate model with 30° flexion angle at the metatarsophalangeal joint was constructed.The musculoskeletal model combined with the three-dimensional finite element analysis method was used,and the dynamic data of the foot during walking at the speed of 5 km/h was obtained using dual fluoroscopic imaging system(DFIS).The finite element model was verified,and the influence of plantar fascia stiffness on the capstan mechanism and arch-related mechanical parameters was explored.Results The finite element simulation analysis results were highly consistent with the foot data obtained by DFIS,confirming the validity of the model.With the increase of plantar fascia stiffness,the windlass effect and the stiffness of the longitudinal arch of the foot both showed an increasing trend,but the flexion angle of the metatarsophalangeal joint decreased,the distal stress of the plantar fascia gradually decreased,and the proximal stress increased;when the plantar fascia stiffness was 25％-150％,the width of the transverse arch of the foot increased with the increase of plantar fascia stiffness,while the height of the transverse arch decreased with the increase of plantar fascia stiffness;when the plantar fascia stiffness was 150％-200％,the width of the transverse arch of the foot decreased,the height increased,and the stiffness also increased.Conclusions An increase in plantar fascia stiffness can enhance the windlass mechanism to some extent,but it also leads to a reduction in metatarsophalangeal joint flexion.The stiffness of the plantar fascia affects the metatarsophalangeal joint flexion,thereby impacting the windlass mechanism and the distal tensile force of the plantar fascia.Together with the ground reaction force at the distal end of the metatarsals,these factors collectively influence the stiffness of the transverse arch of the foot.

OBJECTIVE To explore the association of the expressions of tissue forkhead box transcription factor(FOX)F2,angiopoietin-like protein 4(ANGPTL4)and FOXP3 with the pathological features and recurrence of the cervical cancer patients with human papillomavirus(HPV)infection undergoing radical hysterectomy.METHODS Totally 69 cervical cancer patients with HPV infection who underwent radical hysterectomy in Danzhou People's Hospital from Nov.2018 to Jul.2021 were randomly assigned as the cervical cancer group,meanwhile,72 patients who had cervical intraepithelial neoplasia(CIN)were chosen as the CIN group.The patients of the cer-vical cancer group were divided into the recurrence group with 25 cases and the no recurrence group with 44 cases according to the prognosis.The levels of tissue FOXF2,ANGPTL4 and FOXP3 were compared among the groups.The levels of FOXF2,ANGPTL4 and FOXP3 were compared among the cervical cancer patients with dif-ferent clinical pathological features,and the pathological features were compared among the patients with different treatment outcomes.The values of the three indexes in diagnosis of the postoperative recurrence in the cervical cancer patients with HPV infection undergoing radical resection were analyzed.RESULTS There were significant differences in the levels of tissue FOXF2 mRNA,ANGPTL4 mRNA and FOXP3 mRNA between the cervical cancer group and the CIN group(P＜0.05).There were significant differences in the levels of FOXF2 mRNA,ANGPTL4 mR-NA and FOXP3 mRNA among the cervical cancer patients with HPV infection who varied in federation international of gynecology and obstetrics(FIGO)stage,lymphatic metastasis and infiltration depth(P＜0.05).There were significant differences in the FIGO stage,lymphatic metastasis,infiltration depth,FOXF2 mRNA level,ANGPTL4 mRNA level and FOXP3 mRNA level between the recurrence group and the no recurrence group(P＜0.05).The area under the curve(AUC)value of the joint detection of FOXF2 mRNA,ANGPTL4 mRNA and FOXP3 mRNA was higher than that of the single detection in diagnosis of the postoperative recurrence in the cervical cancer patients with HPV infection under-going radical resection(P＜0.05).CONCLUSIONS The cervical cancer patients with HPV infection undergoing radi-cal resection show the abnormal expressions of tissue FOXF2 mRNA,ANGPTL4 mRNA and FOXP3 mRNA.There is association between the three indexes and the FIGO stage,lymphatic metastasis and infiltration depth.The joint detection of the three indexes has high value in diagnosis of the postoperative recurrence.

Objective To use AI-assisted motor dysfunction assessment for quantitative evaluation of motor function in Parkinson's disease(PD)and multiple system atrophy-Parkinsonian type(MSA-P)in order to achieve accurate differential diagnosis.Methods A total of 105 participants aged ≥60 years were consecutively enrolled from the First and Third Medical Centers of Chinese PLA General Hospital between January and September 2024.Based on diagnostic criteria,they were divided into a PD group(48 cases),a MSA-P group(31 cases),and a control group(26 cases).The general information was collected,and the motor function was evaluated with Move-ment Dysfunction Assessment Software in order to assess the diagnostic value of the AI-assisted assessment in differentiating between PD and MSA-P.Results Significantly differences were observed among the three groups in terms of facial expression indicators,bilateral finger tapping frequency,bilateral hand movement frequency,right hand movement amplitude change rate,bilat-eral palm flipping frequency,bilateral toe tapping frequency,freezing load of bilateral toe tapping,bilateral leg flexibility frequency,right leg flexibility amplitude change rate,freezing load of bilat-eral leg flexibility,upright extension angular velocity,turnaround time,forward step frequency,backward step frequency,forward average stride length,backward average stride length,forward average walking speed,backward average walking speed,forward average step width,backward average step width,bilateral postural tremor frequency,bilateral postural tremor maximum am-plitude,bilateral action tremor frequency,bilateral action tremor maximum amplitude,and com-parison of bilateral resting tremor frequency(P＜0.05,P＜0.01).The MSA-P group exhibited significantly lower blink frequency,maximum amplitude and frequency of facial tremors,upright extension angular velocity,and step frequency,while higher ratio of mouth opening duration and longer turnaround time when compared with the PD group(P＜0.05,P＜0.01).The AUC value of the combined nine motor function indicators and the five facial expression indicators in differ-entiating PD from MSA-P was 0.943(95％CI:0.895-0.991,P=0.000)and 0.925(95％CI:0.870-0.981,P=0.000),respectively,both better than that of individual indicators.Conclusion Combi-nation assessment of facial expression,posture,gait with AI assistance can contribute to the dif-ferential diagnosis of PD and MSA-P.

Objective To systematically evaluate the effect of inspiratory muscle training(IMT)on weaning outcomes in patients with weaning failure.Methods Literatures in Chinese and English were retrieved from databases such as PubMed,Cochrane Library,Web of Science,Embase,CNKI,VIP,Wanfang data and CBM for researches on the effect of IMT in mechanical ventila-tion weaning failure,from the inception of the databases to October 22,2024.The methodological quality of the researches was evaluated with PEDro scale,and data were extracted for a systematic review.Results Nine randomized controlled trials were included,published between 2011 and 2023,from Brazil,China,the United States,Iran and Australia,with a total of 499 patients.The scores of the PEDro scale ranged five to eight.The population included patients with prolonged weaning,difficult weaning and tracheostomy.The IMT methods included threshold load training and tapered flow resistance training.The training intensity was 30%to 80%of maximal inspiratory pressure(MIP),and some researches did not set the training intensity based on MIP.The pro-gression of intensity varied widely across researches.The intervention frequency ranged from five to 30 breaths per set,with at least one minute rest between sets,two to six sets per session,one to two sessions per day,and five to seven days per week.The duration of the intervention ranged from successful weaning,one week after weaning,extubation,or four days to eight weeks.Regarding the efficacy of the intervention,IMT was not benefi-cial for the duration of mechanical ventilation and intensive care unit(ICU)length of stay on weaning failure pa-tients.However,the effect of IMT on weaning successful rates,duration of weaning,MIP and mortality was in-consistent.Conclusion IMT can not improve the duration of mechanical ventilation and ICU length of stay for weaning failure pa-tients,and there is still debate regarding its effect on successful rate of weaning,duration of weaning,MIP and mortality.

Objective To investigate the clinical efficacy of Guhong Injection for the treatment of patients with coronary microvascular dysfunction(CMD)of qi stagnation and blood stasis syndrome.Methods Sixty cases of patients with CMD of qi stagnation and blood stasis syndrome who were admitted to Guangdong Provincial Hospital of Chinese Medicine from June 2021 to August 2022 were randomly divided into the control group and the trial group according to the random number table method,with 30 cases in each group.The control group was treated with conventional western medicine,and the trial group was treated with Guhong Injection on the basis of treatment for the control group.The course of treatment for the two groups covered 10 days.The changes in traditional Chinese medicine(TCM)syndrome scores,and levels of lipid indicators,serum inflammatory factors and endothelial factors in the two groups were observed before and after treatment.After treatment,the clinical efficacy of the two groups was evaluated.Results(1)During the trial,three cases in the control group and two cases in the trial group fell off and a total of 55 cases were finally included in the statistical analysis of efficacy,including 27 cases in the control group and 28 cases in the trial group.(2)After 10 days of treatment,the total effective rate of the trial group was 89.29%(25/28),and that of the control group was 40.74%(11/27),and the intergroup comparison(tested by chi-square test)showed that the therapeutic efficacy of the trial group was significantly superior to that of the control group(P<0.01).(3)After treatment,the TCM syndrome scores of patients in both groups were decreased compared with those before treatment(P<0.05),and the decrease in the trial group was significantly superior to that in the control group(P<0.01).(4)After treatment,the levels of lipid indicators triglyceride(TG),total cholesterol(TC),and low-density lipoprotein cholesterol(LDL-C)in the two groups of patients were decreased compared with those before treatment(P<0.05),and the level of high-density lipoprotein cholesterol(HDL-C)was increased compared with that before treatment(P<0.05).The intergroup comparison showed that the decrease of TG,TC,and LDL-C levels as well as the increase of HDL-C level in the trial group was significantly superior to that in the control group(P<0.05 or P<0.01).(5)After treatment,the serum levels of inflammatory factors high-sensitivity C-reactive protein(hs-CRP),interleukin 6(IL-6)and tumor necrosis factor α(TNF-α)in the two groups of patients were decreased compared with those before treatment(P<0.05),and the decrease in the trial group was significantly superior to that in the control group(P<0.01).(6)After treatment,the serum level of endothelial factor nitric oxide(NO)in the two groups of patients was increased(P<0.05)and the serum endothelin 1(ET-1)level was decreased compared with that before treatment(P<0.05),and the increase of serum NO level,as well as the decrease of serum ET-1 level in the trial group was significantly superior to that in the control group(P<0.05 or P<0.01).Conclusion Based on the conventional treatment in western medicine,the application of Guhong Injection in the treatment of patients with CMD of qi stagnation and blood stasis syndrome exerts remarkable efficacy,which can effectively alleviate the symptoms,regulate the levels of blood lipids,reduce the inflammatory response,and improve the endothelial function.

The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating many physiological processes. Activating the AhR-CYP1A1 axis has emerged as a novel therapeutic strategy against various inflammatory diseases. Here, a practical in situ cell-based fluorometric assay was constructed to screen AhR-CYP1A1 axis modulators, via functional sensing of CYP1A1 activities in live cells. Firstly, a cell-permeable, isoform-specific enzyme-activable fluorogenic substrate for CYP1A1 was rationally constructed for in-situ visualizing the dynamic changes of CYP1A1 function in living systems, which was subsequently used for discovering the efficacious modulators of the AhR-CYP1A1 axis. Following screening of a compound library, LAC-7 was identified as an efficacious activator of the AhR-CYP1A1 axis, which dose-dependently up-regulated the expression levels of both CYP1A1 and AhR in multiple cell lines. LAC-7 also suppressed macrophage M1 polarization and reduced the levels of inflammatory factors in LPS-induced bone marrow-derived macrophages. Animal tests showed that LAC-7 could significantly mitigate DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice, and markedly reduced the levels of multiple inflammatory factors. Collectively, an optimized fluorometric cell-based assay was devised for in situ functional imaging of CYP1A1 activities in living systems, which strongly facilitated the discovery of efficacious modulators of the AhR-CYP1A1 axis as novel anti-inflammatory agents.

Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.