Mitochondrial dysfunction in chondrocytes is a key pathogenic factor in osteoarthritis (OA), but directly modulating mitochondria in vivo remains a significant challenge. This study is the first to verify a correlation between mitochondrial dysfunction and the downregulation of the FOXO3 gene in the cartilage of OA patients, highlighting the potential for regulating mitophagy via FOXO3 gene modulation to alleviate OA. Consequently, we developed a chondrocyte-targeting CRISPR/Cas9-based FOXO3 gene-editing tool (FoxO3) and integrated it within a nanoengineered 'truck' (NETT, FoxO3-NETT). This was further encapsulated in injectable hydrogel microspheres (FoxO3-NETT@SMs) to harness the antioxidant properties of sodium alginate and the enhanced lubrication of hybrid exosomes. Collectively, these FoxO3-NETT@SMs successfully activate mitophagy and rebalance mitochondrial function in OA chondrocytes through the Foxo3 gene-modulated PINK1/Parkin pathway. As a result, FoxO3-NETT@SMs stimulate chondrocytes proliferation, migration, and ECM production in vitro, and effectively alleviate OA progression in vivo, demonstrating significant potential for clinical applications.

To promote the development of extracellular vesicles of herbal medicine especially the establishment of standardization, led by the National Expert Committee on Research and Application of Chinese Herbal Vesicles, research experts in the field of herbal medicine and extracellular vesicles were invited nationwide with the support of the Expert Committee on Research and Application of Chinese Herbal Vesicles, Professional Committee on Extracellular Vesicle Research and Application, Chinese Society of Research Hospitals and the Guangdong Engineering Research Center of Chinese Herbal Vesicles. Based on the collation of relevant literature, we have adopted the Delphi method, the consensus meeting method combined with the nominal group method to form a discussion draft of "Consensus statement on research and application of Chinese herbal medicine derived extracellular vesicles-like particles (2023)". The first draft was discussed in online and offline meetings on October 12, 14, November 2, 2022 and April and May 2023 on the current status of research, nomenclature, isolation methods, quality standards and research applications of extracellular vesicles of Chinese herbal medicines, and 13 consensus opinions were finally formed. At the Third Academic Conference on Research and Application of Chinese Herbal Vesicles, held on May 26, 2023, Kewei Zhao, convenor of the consensus, presented and read the consensus to the experts of the Expert Committee on Research and Application of Chinese Herbal Vesicles. The consensus highlights the characteristics and advantages of Chinese medicine, inherits the essence, and keeps the righteousness and innovation, aiming to provide a reference for colleagues engaged in research and application of Chinese herbal vesicles at home and abroad, decode the mystery behind Chinese herbal vesicles together, establish a safe, effective and controllable accurate Chinese herbal vesicle prevention and treatment system, and build a bridge for Chinese medicine to the world.

ObjectiveTo classify subtypes among middle-aged and elderly type 2 diabetes mellitus (T2DM) patients aged between 35‒74 years in Shanghai suburbs, to compare their characteristics and analyze incidence risk for cerebrovascular disease among these subtypes, so as to promote personalized and precise treatment of T2DM. MethodsA total of 7 792 patients with T2DM who completed a baseline survey from 2016 and 2019 were selected as the research subjects, based on the data from a natural population cohort and biobank in Shanghai suburbs. Patients were stratified by gender and clustered into subtypes using k-means method based on baseline parameters including the age at T2DM diagnosis, body mass index (BMI), fasting blood glucose, and triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C). Patients were followed up until March 31, 2023. Multivariate Cox regression models were used to analyze the association between subtypes and incidence risk for cerebrovascular disease, and those with cerebrovascular disease within 1 year of follow-up survey were excluded from sensitivity analysis. ResultsAmong the 7 792 patients with T2DM, 3 615 were males and 4 177 were females. Stratified by gender, 4 subgroups were identified through k-means clustering analysis, namely poor blood glucose control subgroup, severe insulin-resistant subgroup, younger onset subgroup, and older onset subgroup. The median follow-up time was 4.30 years, during which 1 960 cerebrovascular disease events were observed (844 in males, 1 116 in females). After adjusting for smoking, alcohol consumption, weekly exercise, family history of diabetes mellitus, and duration of diabetes mellitus, among male patients, the incidence risk for cerebrovascular disease was lower in the younger onset subgroup (HR=0.59, 95%CI: 0.48‒0.73, P<0.001), poor blood glucose control subgroup (HR=0.81, 95%CI: 0.65‒1.00, P=0.046), and severe insulin-resistant subgroup (HR=0.61, 95%CI: 0.50‒0.75, P<0.001), compared to the older onset subgroup. While among female patients, the incidence risk for cerebrovascular disease was also lower in the younger onset subgroup (HR=0.68, 95%CI: 0.57‒0.80, P<0.001), poor blood glucose control subgroup (HR=0.73, 95%CI: 0.60‒0.89, P=0.002), and severe insulin-resistant subgroup (HR=0.72, 95%CI: 0.61‒0.85, P<0.001), compared to the older onset subgroup. Results of the sensitivity analysis were consistent with the main findings. ConclusionAmong middle-aged and elderly T2DM patients in suburban Shanghai, both male and female patients have the highest incidence risk for cerebrovascular disease in the older onset subgroup. Subtyping of T2DM patients can help to identify the high-risk populations of cerebrovascular disease.

Platinum-based chemotherapy resistance is a key factor of poor prognosis and recurrence in hepatocellular carcinoma (HCC). Herein, RNAseq analysis revealed that elevated tubulin folding cofactor E (TBCE) expression is associated with platinum-based chemotherapy resistance. High expression of TBCE contributes to worse prognoses and earlier recurrence among liver cancer patients. Mechanistically, TBCE silencing significantly affects cytoskeleton rearrangement, which in turn increases cisplatin-induced cycle arrest and apoptosis. To develop these findings into potential therapeutic drugs, endosomal pH-responsive nanoparticles (NPs) were developed to simultaneously encapsulate TBCE siRNA and cisplatin (DDP) to reverse this phenomena. NPs (siTBCE + DDP) concurrently silenced TBCE expression, increased cell sensitivity to platinum treatment, and subsequently resulted in superior anti-tumor effects both in vitro and in vivo in orthotopic and patient-derived xenograft (PDX) models. Taken together, NP-mediated delivery and the co-treatment of siTBCE + DDP proved to be effective in reversing chemotherapy resistance of DDP in multiple tumor models.

Digestive system malignant tumor is one of the common malignant tumors in humans,and its high morbidity and low survival rate at advanced stages bring heavy disease burden to patients,families and society.However,current tumor screening technologies are not suitable for screening in large-scale populations and long-term follow-up because of the invasiveness or complexity.Thus,liquid biopsy,which based on biomarkers such as circulating tumor DNA,circulating tumor cells,exosomes and other new biomarkers,has broad prospects for development in tumor screening.Exosome,secreted by living cells,is a type of extracellular vesicle with the lipid bilayer.Compared to other biomarkers,exosome has the advantages of high stability,wide distribution,and high quantity.The various proteins carried by exosome can reflect the characteristics of the origin cells,and exosome has important research value for the early diagnosis of tumors.This article reviews the studies of exosomal proteins as biomarkers for early diagnosis of digestive system malignant tumors in the past five years,and summarizes the characteristics and limitations of the above studies,so as to provide reference for promoting the clinical transformation of exosomal proteins.

OBJECTIVE: To compare the effects of different materials for partial sciatic nerve ligation on glial cell activation in the spinal cord in a rat model of chronic constriction injury (CCI). METHODS: SD rats were randomly divided into the sham group (=15), silk suture CCI group (=15) and chromic catgut CCI group (=14). The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) of the rats were detected at 3, 7, 11 and 15 days after the operation. The changes in the sciatic nerve, the activation of spinal cord glial cells and the expression of inflammatory factors were observed using Western blotting and RT-PCR. RESULTS: At 3 to 15 days after the surgery, MWT and TWL of the rats were significantly lower in silk suture group and chromic catgut group than in the control group ( < 0.05), and was significantly lower in chromic catgut group than in the silk suture group ( < 0.05) at 3 days after the surgery. The results of sciatic nerve myelin staining showed that the sciatic nerve was damaged and demyelinated in both the ligation groups. The expressions of CD11b, GFAP, IL-1β and TNF-α in the two ligation groups were similar and all significantly higher than those in the control group ( < 0.05). IL-6 mRNA level was significantly higher in chromic catgut group than in the silk suture group ( < 0.05). CONCLUSIONS The CCI models established by partial sciatic nerve ligation with silk suture and chromic catgut all show glial activation, and the inflammatory response is stronger in chromic catgut group.
Animals ; Constriction ; Neuroglia ; Rats ; Rats, Sprague-Dawley ; Sciatic Nerve ; Spinal Cord

Objective TosummarizeMRIfeaturesofadultreversiblespleniallesionsyndrome(RESLES)andevaluateitsdiagnosticvalue. Methods ClinicalandMRIdataof15patientswithRESLESwereanalyzedretrospectively.Primarydiseasesandcausesincluded:encephalitis disease,cerebrovasculardiseases,metabolicandelectrolytedisorders.Theclinicalsymptomswereheadache,dizziness,changeofconsciousness, epilepticseizuresandothernonspecificneurologicsymptoms.Thecranialimagingexaminationwasperformedat3.0T/1.5TsuperconductingMR, includingT1WI,T2WI,T2FLAIRandDWI,inwhich7casesunderwentMRIenhancedscanand5casesunderwentMRAexamination.Results Among15patients,MRIfindingsofallpatientswerecharacterizedbythecharacteristic"boomerangsign"ortheovoidabnormalitysignalinthe corporiscallosisplenium,whichwaspresentedascytotoxicedema.Besides,4ofthem werecombinedwithposteriorreversibleencephalopathy syndrome(PRES),whichwascharacterizedbyvasogenicedemainthebilateraloccipital,temporal,parietallobeandcerebellarhemisphere.The clinicalsymptomsofallpatientsimprovedafterreasonabletreatment.Conclusion MRIcharacteristicfindingofadultreversiblesple-niallesionsyndromeisthecytotoxicedemaofthecorpuscallosum,whichcanbeshowedas"boomerangsign"orovalform.Imagingfindingsand clinicalsymptomsarereversible.Thecorrectunderstandingofthisdiseaseisofgreatsignificancetoclinicalrationaldiagnosisandtreatment.

Objective To evaluate the efficacy and safety of oprinon hydrochloride in increasing cardiac pump function and stabilizing hemodynamics and preventing common complications after cardiac valve replacement. Methods Sixty-two patients were admitted to the First Affiliated Hospital of Zhengzhou University from January to August 2018 to undergo cardiac valve replacement operation, post-operatively, 32 patients using oprinon hydrochloride were in the observation group and 30 patients using milrinone were in the control group. Both groups received basic treatment, additionally the observation group was given oprinon hydrochloride intravenous pump injection for 48 hours and the control group was given milrinone intravenous pump injection for 48 hours. The changes of vital signs (blood pressure, heart rate, respiratory rate), cardiac function, hemodynamics, biochemical indexes, electrocardiogram, cardiac color Doppler ultrasound and adverse reactions were observed before and after treatment in the two groups. The incidence of cardiovascular events (worsening, re-hospitalization and death) was followed up 1 month after discharge. Results The left ventricular ejection fraction (LVEF), central venous pressure (CVP), arterial oxygen saturation (SaO2), arterial partial pressure of oxygen (PaO2), N-terminal B-type natriuria (NT-proBNP), lactic acid, serum creatinine (SCr), blood sodium and potassium of the two groups after treatment were not statistically significant compared with those before treatment [LVEF: the control group was 0.52±0.09 vs. 0.60±0.09, the observation group was 0.62±0.12 vs. 0.50±0.11;CVP (mmHg, 1 mmHg = 0.133 kPa): the control group was 11.2±2.8 vs. 13.0±2.9, the observation group was 13.0±2.5 vs. 10.5±3.6; SaO2: the control group was 0.98 (0.90, 0.99) vs. 0.99 (0.98, 1.00), the observation group was 0.95 (0.94, 0.98) vs. 0.96 (0.90, 1.00); PaO2(mmHg): the control group was 100.5 (63.8, 135.3) vs. 99.5 (82.3, 179.5), the observation group was 95.0 (85.5, 129.0) vs. 75.5 (59.0, 138.3); NT-proBNP (pg/L): the control group was 1.45 (1.34, 3.31) vs. 0.92 (0.42, 1.81), the observation group was 0.47 (0.35, 1.37) vs. 2.07 (1.27, 4.44); lactic acid (mmol/L): the control group was 3.6 (2.4, 4.5) vs. 1.4 (1.2, 3.1), the observation group was 1.3 (1.1, 2.1) vs. 3.1 (1.4, 3.7); SCr (μmol/L): the control group was 106.7±35.9 vs. 84.4±20.3, the observation group was 96.5±40.7 vs. 77.1±23.1; sodium (mmol/L):the control group was 141.4±7.2 vs. 143.6±4.2, the observation group was 142.9±3.6 vs. 140.5±4.5; potassium (mmol/L): the control group was 4.6±0.9 vs. 4.8±0.6, the observation group was 4.8±0.6 vs. 4.1±0.6, all P > 0.05];the comparisons between the following indicators in levels before and after treatment in the two groups had statistical significant differences: the peripheral arterial pressure (PAP), white blood cell count (WBC), hemoglobin (Hb), platelet count (PLT), alanine aminotransferas (ALT) and aspartate aminotransferase (AST) [PAP (mmHg): the control group was 33.0 (24.0, 59.3) vs. 38.0 (34.8, 46.0), the observation group was 30.0 (25.0, 32.0) vs. 53.5 (29.3, 66.5); WBC (×109/L):the control group was 12.2 (10.4, 13.9) vs. 5.7 (4.4, 8.6), the observation group was: 8.4 (3.7, 11.8) vs. 8.6 (5.7, 12.4); Hb (g/L): the control group was 95.6±12.9 vs. 130.3±15.0, the observation group was 111.1±22.6 vs. 112.4±24.6; PLT (×109/L): the control group was 95.2±21.3 vs. 168.7±32.6, the observation group was 146.3±68.1 vs. 132.7±45.1;ALT (U/L): the control group was 36.5 (15.3, 80.5) vs. 14.0 (11.0, 19.0), the observation group was 15.0 (10.0, 32.3) vs. 20.3 (12.0, 35.8); AST (U/L): the control group was 33.0 (20.0, 83.0) vs. 16.5 (16.7, 28.8), the observation group was 35.5 (12.3, 56.8) vs. 75.5 (45.3, 140.3), all P < 0.05]; after treatment, the urea nitrogen (BUN) level in control group was higher than that before treatment (mmol/L: 11.4±4.7 vs. 7.1±2.5), while BUN in the observation group was decreased (mmol/L: 6.5 ±3.3 vs. 9.1±3.8), there was statistical significant difference in BUN level between the two groups after treatment (P < 0.05). The levels of systolic blood pressure and respiratory rate after treatment in the two groups were significantly higher than those before treatment (all P < 0.05). After treatment, the diastolic blood pressure in the observation group was increased, but there was no significant difference in the control group before and after treatment, and the diastolic blood pressure in the observation group after treatment was higher than that in the control group (mmHg: 67.8±9.9 vs. 62.0±10.5, P < 0.05). According to the New York Heart Association Heart (NYHA) function efficacy assessment score, the total effective rate of the observation group was higher than that of the control group [93.7% (30/32) vs. 83.3% (25/30), P > 0.05]. There was no statistical significant difference in the incidence of adverse reactions between the observation group and the control group [12.5% (4/32) vs. 30.0% (9/30), P > 0.05]. The patients in the two groups were followed up for one month after discharge, 9 cases (30.0%) in the control group were re-hospitalized due to heart failure, and 3 cases (9.4%) in the observation group were re-hospitalized due to heart failure, there was no statistical significant difference between the two groups in re-hospitalization rate (P > 0.05). Conclusion Oprinone hydrochloride can effectively improve cardiac function and maintain hemodynamic stability of patients after heart valve replacement surgery.

Objective To find out whether inpatients with acute ischaemic stroke and atrial fibrillation (AF) have higher rate of renal dysfunction than without AF,and analyze risk factors associated with renal dysfunction.Method 374 patients with acute ischaemic stroke and AF were enrolled,which cases have complete data.500 patients were randomly selected as the non-AF group.To compare the prevalence of renal dysfunction [eGFR ＜ 60 mL/(min· 1.73 m2)] of two groups.Non-conditional Logistic regression analysis was used to detemmine the factors associated with renal dysfunction.Results 374 patients in AF group,114 (30.5％) were renal dysfunction;500 patients in non-AF group,75 (15％) were renal dysfunction (P =0.000,OR =2.485).The eGFR of AF and non-AF group was (77.75 ± 39.89) mL/(min· 1.73 m2) and (96.93±39.14) mL/(min · 1.73 m2).In Logis tic regression analysis,heart dysfunction (OR =2.057),hypertension (OR =1.826),diabetes (OR =1.897),hypevuricemia (OR =3.161) were found to be associated with renal dysfunction.Conclusions Adult patients with acute ischaemic stroke and AF have a higher rate of renal dysfunction than acute ischaemic stroke without AF.Heart dysfunction,hypertension,diabetes,hyperuricemia were factors associated with renal dysfunction.

Objective To examine the effects of gross tumor volume (GTV) and radiation dose on the prognosis of hepatocellular carcinoma (HCC) patients treated with whole body gamma knife.Methods The clinical data of 69 HCC patients who underwent body gamma knife treatment from January 2012 to June 2015 in the Radiotherapy Center of the PLA General Hospital were retrospectively reviewed.Based on a 50% or 60% isodose coverage of the planning target volume (PTV), patients were treated with a radiation dose of 4-5 Gy per fraction, and a total marginal dose of 36-50 Gy (median dose 45 Gy).Short-term efficacy, overall survival (OS), and the adverse effect of the treatment were evaluated.The optimal cut-off tumor volume was identified using the receiver operating characteristic curve, and survival was determined by the Kaplan-Meier method.Univariate and multivariate analyses were performed using the log-rank test and Cox proportional hazards regression model, respectively.Results The overall short-term response rate of the 69 patients was 67%.The 1-and 2-year OS rates were 62% and 40%, respectively, with a median survival of 18.6 months.The multivariate analysis showed that gross tumor volume (GTV)<93 cm3(P=0.013) and short-term efficacy of radiotherapy (P=0.000) were significant independent prognostic factors for survival.When GTV was<93 cm3, prognosis was significantly better in patients treated with a dose of ≥45 Gy than in those with<45 Gy (P=0.019).In contrast, radiation dose had no significant effect on survival among patients with GTV>93 cm3(P=0.665).Conclusions GTV is an independent prognostic factor for overall survival of HCC patients.Although high-dose radiotherapy provides survival benefits to patients with small GTV, it is not necessarily suitable for patients with large GTV.