Objective: To investigate the effects of Zuogui Jiangtang Jieyu Formula (ZGJTJYF) on histone H3 lysine 18 lactylation (H3K18la) in the hippocampus of rats with diabetes mellitus complicated with depression (DD) and predict the regulatory genes of H3K18la. Methods: Male Sprague-Dawley rats were divided into control, model, and positive drug (metformin [0.18 g/kg] and fluoxetine [1.8 mg/kg]) groups, and the three groups were treated with high, medium, and low ZGJTJYF doses (20.52, 10.26, and 5.13 g/kg, respectively), with 10 rats per group. After treatment, the forced swimming and water maze tests were performed to assess depressive-like behaviors and cognitive function. An enzyme-linked immunosorbent assay was used to measure blood insulin, glycosylated hemoglobin, lactate levels, and lactate content in the hippocampus. Western blotting was used to detect H3K18la expression in the hippocampus. Cleavage Under Targets and lagmentation(CUT&Tag) experiments targeted hippocampal H3K18la epigenetic modification regions to analyze the transcription factors bound by H3K18la. Kyoto Encyclopedia of Genes and Genomes and Protein-Protein Interaction networks were constructed to identify key pathways and target genes regulated by H3K18la. Results: Compared with the normal group, the model group rats showed prolonged immobility time in the forced swim test, increased escape latency in the water maze experiment, decreased target quadrant distance ratio (P<0.01), increased serum lactate content, and decreased lactate content in hippocampal homogenate (P<0.01), as well as decreased H3K18la protein expression in the hippocampus (P<0.01). Compared with the model group, ZGJTJYF reduced the immobility time in the forced swim test and the escape latency in the water maze test (P<0.01), while the distance ratio in the target quadrant increased (P<0.01) in model rats. Lowered fasting blood glucose, insulin, and glycosylated hemoglobin levels (P<0.05, P<0.01) were also observed. ZGJTJYF also increased the lactate content and H3K18la protein expression in hippocampal homogenate (P<0.05, P<0.01). The DNA sequences bound by H3K18la were predominantly enriched at the transcription start sites. ZGJTJYF modulated H3K18la-associated pathways, including cell adhesion junctions, tumor growth factor-beta (TGF-β) signaling, stem cell pluripotency regulation, mitogen-activated protein kinase(MAPK) signaling pathway, and insulin resistance, leading to the identification of 12 target genes. Conclusion ZGJTJYF enhances hippocampal lactate levels and H3K18la modification in DD rats, which may regulate neural cell interactions, neurogenic stem cell function, TGF-β signaling, MAPK signaling, and insulin resistance pathways.

As common drug delivery materials,polymers possess the advantages of a simple preparation method,adjustable chemical structure,and excellent biocompatibility.They are widely used in the responsive drug delivery for various diseases,especially in drug delivery of colon diseases.Utilizing the adjustable characteristics of polymers,drug delivery systems based on pH response,microbial enzyme response,reactive oxygen species response,and bio-adhesion have been constructed,showing excellent efficacy in the treatment of colitis.This article reviews the research progress of polymer-based targeted drug delivery systems in the treatment of colitis and discusses its research and application prospects.

Objective This study aims to evaluate the therapeutic efficacy of Compound Fufangteng Mixture(CFM)on myocardial fibrosis(MF)and explore its action targets and mechanisms through a combination of animal pharmacodynamics,cell biology,and network pharmacology approaches.Methods Thirty-five male C57BL/6J mice were divided into the normal group,model group,CFM low-dose(0.72 g/kg)group,CFM high-dose(1.44 g/kg)group,and sacubitril valsartan sodium group(20 mg/kg)based on random number table,with 7 mice in each group.Except for the normal group,the mice in the other groups were subcutaneously injected with isoproterenol(20 mg/kg)at multiple points once daily for 21 consecutive days to establish the MF model.The CFM groups were pre-administered by gavage 3 days before modeling,the sacubitril valsartan sodium group was administered starting from the day of modeling,and the normal group and model group were given an equal volume of distilled water.The active ingredients in CFM were analyzed using ultra-performance liquid chromatography(UPLC).On days 7,14,and 21 of modeling,the left ventricular ejection fraction(LVEF),left ventricular fractional shortening(LVFS),left ventricular end-diastolic diameter(LVIDd),and left ventricular end-systolic diameter(LVIDs)of mice were detected by ultrasound.The degree of myocardial fibrosis in mice was assessed by Masson staining.The levels of transforming growth factor-β1(TGF-β1),α-smooth muscle actin(α-SMA),type I collagen(COL I),and type Ⅲcollagen(COL Ⅲ)in the myocardial tissue of mice were detected by enzyme-linked immunosorbent assay(ELISA).The average fluorescence intensity of α-SMA in myocardial tissue was detected by immunofluorescence.In addition,by integrating Cellular Thermal Shift Assay(CETSA),QE proteomic analysis,and network pharmacology techniques,we systematically explored the potential core targets and mechanisms of action by which CFM improves MF,and validated these findings using western blotting analysis.Results Main eight chemical components were identified from CFM.Compared with the normal group,the model group exhibited a decrease in LVEF and LVFS,an increase in LVIDd and LVIDs,a higher heart weight to tibia length ratio,and an increased collagen volume fraction(P<0.05),along with aggravated MF.Concurrently,the myocardial tissue showed elevated levels of TGF-β1,α-SMA,COL I,and COL Ⅲ(P<0.05),with enhanced α-SMA fluorescence signal intensity.In comparison to the model group,all groups of CFM and the sacubitril valsartan sodium group demonstrated an increase in LVEF and LVFS,and a decrease in LVIDd,LVIDs,and the heart weight to tibia length ratio(P<0.05).Simultaneously,the collagen volume fraction decreased,and the levels of TGF-β1,α-SMA,COL I,and COL Ⅲ in myocardial tissue were down-regulated(P<0.05).The degree of MF was reduced,and the fluorescence signal intensity of α-SMA expression was weakened.Furthermore,the combined analysis of CETSA,QE proteomics,and network pharmacology revealed that heat shock protein A family member 8(HSPA8)may be a potential core target for CFM in ameliorating MF.CETSA-western blotting analysis further confirmed that CFM could enhance the thermal stability of HSPA8 protein and down-regulate the relative expression level of HSPA8 protein in mouse myocardial tissue(P<0.05).Conclusion CFM can ameliorate isoproterenol-induced cardiac dysfunction in mice,reduce collagen deposition,and reverse the pathological progression of MF.The underlying mechanism may be associated with the regulation of HSPA8.

As common drug delivery materials,polymers possess the advantages of a simple preparation method,adjustable chemical structure,and excellent biocompatibility.They are widely used in the responsive drug delivery for various diseases,especially in drug delivery of colon diseases.Utilizing the adjustable characteristics of polymers,drug delivery systems based on pH response,microbial enzyme response,reactive oxygen species response,and bio-adhesion have been constructed,showing excellent efficacy in the treatment of colitis.This article reviews the research progress of polymer-based targeted drug delivery systems in the treatment of colitis and discusses its research and application prospects.

Objective:To analyze the burden and trends of noncommunicable chronic disease(NCD) attributable to metabolic factors in China from 1990 to 2021.Methods:Data from the Global Burden of Diseases(GBD) 2021 database were utilized to describe changes in mortality and disability-adjusted life years(DALYs) of NCD in China from 1990 to 2021. Stratified analyses were conducted by age, sex, sociodemographic index(SDI), and related risk factors. Statistical analyses and predictions were conducted using the age-period-cohort model and the Nordpred model.Results:In 2021, the age-standardized mortality rate and age-standardized DALYs rate of NCD attributable to metabolic factors in China were 227.56 per 100 000 and 4 829.39 per 100 000, respectively. Their average annual percentage changes were -0.76%( P<0.001) and -0.77%( P<0.001). Overall, the burden decreased progressively with higher SDI levels. Analysis using the age-period-cohort model indicated reduced birth cohort and period effects for metabolic factor-attributable NCD, while age effects rose significantly. The minimum relative risk( RR) value was observed in the 15-19 age group( RR=0.01), and the maximum RR value occurred in the 95-99 age group( RR=996.86). The overall rising mortality trend indicated that age effects are the predominant driver at present. Projections estimate that by 2046, deaths from metabolic factor-attributable NCD in China will reach 8 189 563, with an age-standardized mortality rate of 236.95 per 100 000. Conclusions:China continues to face a substantial burden of NCD linked to metabolic factors, with older adults, males, and individuals with hypertension, diabetes, and prediabetes identified as key populations requiring targeted interventions.

ObjectiveTo reveal the mechanism of Zuogui Jiangtang Jieyu prescription against damage to hippocampal synaptic microenvironment via suppressing glutamate receptor 2 （GluR2）/Parkin signal-mediated mitophagy in rats with diabetes-related depression （DD）. MethodsEighty male SD rats underwent adaptive feeding for 5 days before the study. Ten rats were randomly assigned to the normal group. The model of DD rats was established with the rest by 2-week high-fat diet + streptozotocin （STZ） tail intravenous injection + 28 days of chronic unpredictable mild stress （CUMS） combined with isolation. The rats were randomly divided into a normal group， a model group， a GluR2 blocker group （5 μg·kg^-1）， a GluR2 agonist group （10 μg·kg^-1）， a metformin + fluoxetine group （0.18 g·kg^-1 metformin + 1.8 mg·kg^-1 fluoxetine）， and high- and low-dose Zuogui Jiangtang Jieyu prescription groups （20.52 and 10.26 g·kg^-1， respectively）. The rats in the GluR2 blocker group and the GluR2 agonist group were continuously injected with CNQX and Cl-HIBO in the dentate gyrus of the hippocampus once a week starting from stress modeling， respectively， while the metformin + fluoxetine group and the high- and low-dose Zuogui Jiangtang Jieyu prescription groups were continuously given intragastric administration for 28 d at the same time of stress modeling. Depression-like behavior was evaluated by open field and forced swimming experiments. The levels of serum insulin and adenosine triphosphate （ATP） in hippocampus were detected by biochemical analysis. The levels of 5-hydroxytryptamine （5-HT） and dopamine （DA） in hippocampus were detected by enzyme-linked immunosorbent assay （ELISA）. The autophagosomes of hippocampal neurons were observed by transmission electron microscopy. The morphology and structure of dendrites and spines of hippocampal neurons were evaluated by Golgi staining. Western blot detected the expression levels of GluR2 and Parkin proteins in hippocampus. The expression levels of GluR2， Parkin， regulating synaptic membrane exocytosis protein 3 （RIMS3）， and postsynaptic density protein 95 （PSD95） in the dentate gyrus of the hippocampus were detected by immunofluorescence. ResultsCompared with the normal group， the model group exhibited reduced total activity distance in the open field and increased immobility time in forced swimming （P<0.01）， lowered levels of serum insulin and ATP， 5-HT， and DA in hippocampus （P<0.01）， increased autophagosomes of hippocampal neurons， significantly damaged morphology and structure of dendrites and spines of hippocampal neurons， decreased expression levels of GluR2， RIMS3， and PSD95 in hippocampus， and an increased Parkin expression level （P<0.05， P<0.01）. Compared with the model group， the GluR2 blocker group and the GluR2 agonist group showed aggravation and alleviation of the above abnormal changes， respectively （P<0.05， P<0.01）. The above depression-like behavior was significantly improved in the high- and low-dose Zuogui Jiangtang Jieyu prescription groups to different degrees. Specifically， the two groups saw elevated levels of serum insulin and ATP， 5-HT， and DA in hippocampus （P<0.05， P<0.01）， restrained increase in autophagosomes and damage to morphology and structure of dendrites and spines of hippocampal neurons， up-regulated protein expression levels of GluR2， RIMS3， and PSD95， and down-regulated Parkin expression level （P<0.05， P<0.01）. ConclusionZuogui Jiangtong Jieyu prescription can ameliorate the mitophagy-mediated damage to hippocampal synaptic microenvironment in DD rats， the mechanism of which might be related to the regulation of GluR2/Parkin signaling pathway.

Clinical data of a patient with alveolar soft part sarcoma (ASPS) treated at Zhongshan Hospital, Fudan University were retrospectively analyzed. The patient was initially diagnosed with abdominal ASPS with multiple lung metastases. After 6 weeks of treatment with nivolumab and ipilimumab, the patient achieved stable disease (SD). In the 7th week, the treatment was changed to a combination of nivolumab (30 mg, d1, q3w), anlotinib (8 mg, d1-14, q3w) and ipilimumab (50 mg, d1, q6w). The patient remained SD at the 12th week. The patient then underwent iliac artery embolization and intensity-modulated radiation therapy for the lesion in the psoas major muscle, while continuing the combination treatment. By the 24th week, the evaluation showed partial remission (PR) of both primary tumor and lung metastases. The patient experienced mild adverse reactions during treatment.

Objective:To evaluate the efficacy of eculizumab in treating hematopoietic stem cell transplantation-associated thrombotic microangiopathy (TA-TMA) .Methods:This retrospective study included 11 patients who developed TA-TMA after allogeneic hematopoietic stem cell transplantation and subsequently received eculizumab treatment at Peking University People′s Hospital between June 2018 and May 2024. The incidence of TA-TMA, treatment details, and clinical outcomes were analyzed.Results:Among the 11 included patients [4 males, 7 females; median age: 29 years (range: 9-56) ], underlying diseases were severe aplastic anemia (SAA) in 5 patients, acute lymphoblastic leukemia (ALL) in 3 patients, and acute myeloid leukemia (AML) in 3 patients. The median time to TA-TMA diagnosis was 48 days post-transplantation (range: 4-213 days), and all patients met the diagnostic criteria for high-risk TA-TMA. The median interval from TA-TMA diagnosis to the initiation of eculizumab treatment was 12 days (range: 1-56 days). Patients received a median of 3 doses of eculizumab (range: 1-14). Ten of the 11 patients were assessed as having no response (NR) to eculizumab at the end of treatment or at death. One patient achieved a partial response (PR) but subsequently died after TA-TMA relapsed due to infection. At the last follow-up, all patients were either lost to follow-up or had died. The median follow-up duration was 88 days (range: 33-326 days), and the median time from TA-TMA diagnosis to the last follow-up was 31 days (range: 21-113 days) .Conclusion:Eculizumab demonstrated poor efficacy in this TA-TMA cohort. This might be attributable to the critical and complex condition of the patients, delayed initiation of eculizumab treatment, and insufficient dosage.

Objective:To investigate the clinicopathological and molecular genetic characteristics of pan cytokeratin (CKpan)-positive EWSR1/FUS::CREB fusion malignant tumors in abdominopelvic cavity.Methods:Four cases of malignant tumor with CKpan-positive EWSR1/FUS::CREB fusion were selected from January 2019 to July 2024 in the Department of Pathology, Tianjin Medical University Cancer Hospital, Tianjin, China. Their clinical, pathological, and immunohistochemical characteristics were examined. Their molecular genetic characteristics were analyzed using fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS).Results:Among the 4 patients, there were 2 males and 2 females, aged 44, 44, 48 and 66 years, respectively. The tumor sites included 1 case located between the stomach and transverse colon, 1 case on the serous surface of the gastric wall, 1 case in the transverse mesocolon, and 1 case in transverse mesocolon and small mesentery. The clinical manifestations were mostly abdominal distension and abdominal pain. The maximum diameter of the tumor in the surgical resection specimen was 3.5-8.5 cm. The tumor′s cut surface was grayish-white and gray-yellow in color, with medium consistency. Microscopically, the tumor cells were mainly composed of epithelioid tumor cells, and 2 of the tumors showed that tumor cells arranged in a solid sheet or multinodular pattern, and the cytoplasm of the tumor cells was abundant, lightly stained, and the boundaries were unclear, accompanied by the formation of capsules or microcapsules, and lymphocyte and plasma cell sleeves were seen. In one case, the pseudopapillary arrangement was present, and the tumor cells were radially distributed around the fibrovascular axis. In another case, it was arranged in a pseudoacinar pattern, and the nest was surrounded by slender reticular fibers. Immunohistochemistry showed that tumor cells expressed CKpan (4/4) and WT1 (4/4, including 1 focal positive). Vimentin, CK8/18, D2-40 and S-100 were expressed in various intensities, while Calretinin was locally positive or negative. FISH showed that 2 cases had EWSR1 break-apart and 2 cases had FUS break-apart. NGS confirmed the presence of EWSR1::CREM fusion (1 case) and FUS::CREM fusion (2 cases), respectively. Except for 1 recently diagnosed case, 3 cases were followed up: 1 patient died due to tumor recurrence and metastasis (overall survival was 33 months), and 2 patients survived (1 case had recurrence 58 months after surgery, and 1 case had no recurrence or metastasis after surgery).Conclusions:CKpan-positive EWSR1/FUS::CREB fusion malignant tumor is a rare malignancy tumor with undetermined classification that tends to occur in the abdominopelvic cavity and often involves the gastrointestinal tract. Molecular testing such as FISH and NGS is helpful for a definitive diagnosis.

Objective:To analyze the death cases in Beijing municipal hospitals, identify possible medical quality issues in unexpected death cases, so as to provide a basis for medical quality management in medical institutions.Methods:A total of 432 death cases from Beijing municipal hospitals were included, and their acute physiology and chronic health status were evaluated. Based on the evaluation results and the death risk level determined by the diagnosis-related groups, an average of 10 cases were selected from each hospital. A total of 186 cases from 20 hospitals were selected for clinical diagnosis and treatment process evaluation, those cases with problems in the diagnosis and treatment process were defined as unexpected deaths.Results:According to expert judgment, 19.89% (37/186) of the examined deaths had medical quality issues. The main medical quality issues included delayed diagnosis and treatment of patient condition changes (15 cases), inadequate preoperative evaluation (12 cases), failure to consult as required(11 cases), and inadequate prevention of venous thromboembolism (7 cases).Conclusions:Medical institutions should attach importance to the analysis of death cases, address the medical quality issues in the diagnosis and treatment of unexpected death cases, continuously improve medical quality management.