The increasing prevalence of aging has led to a rising incidence of comorbidity of sarcopenia and obesity, posing significant burdens on socioeconomic and public health. Current research has systematically explored the pathogenesis of each condition; however, the mechanisms underlying their comorbidity remain unclear. This study reviews the current literature on sarcopenia and obesity in the aging population, focusing on their shared biological mechanisms, which include loss of autophagy, abnormal macrophage function, mitochondrial dysfunction, and reduced sex hormone secretion. It also identifies metabolic mechanisms such as insulin resistance, vitamin D metabolism abnormalities, dysregulation of iron metabolism, decreased levels of nicotinamide adenine dinucleotide, and gut microbiota imbalances. Additionally, this study also explores the important role of genetic factors, such as alleles and microRNAs, in the co-occurrence of sarcopenia and obesity. A better understanding of these mechanisms is vital for developing clinical interventions and preventive strategies.
Humans ; Sarcopenia/physiopathology* ; Obesity/physiopathology* ; Aging/physiology* ; Autophagy/physiology* ; Insulin Resistance ; Comorbidity ; Vitamin D/metabolism* ; Gonadal Steroid Hormones/metabolism* ; Gastrointestinal Microbiome ; Mitochondria ; MicroRNAs

OBJECTIVES: To assess the preliminary efficacy and safety of a dose-intensified C5VD regimen (cisplatin, 5-fluorouracil, vincristine, and doxorubicin) in children with locally advanced hepatoblastoma. METHODS: This prospective study enrolled 24 children with newly diagnosed, locally advanced hepatoblastoma who received the dose-intensified C5VD regimen at Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, and Shanghai Children's Hospital between January 2020 and December 2023. Clinical characteristics, treatment outcomes, and chemotherapy-related toxicities were analyzed. RESULTS: Of the 24 patients, 13 were male and 11 were female, with a median age at diagnosis of 18.7 months (range: 3.5-79.4 months). All patients achieved complete macroscopic resection of hepatic lesions without liver transplantation. Serum alpha-fetoprotein levels decreased significantly after two chemotherapy cycles. During a median follow-up of 38.4 months (range: 15.8-50.7 months), all patients maintained continuous complete remission, with 3-year event-free survival and overall survival rates of 100%. Across 144 chemotherapy cycles, the incidence rates of grade 3-4 neutropenia, thrombocytopenia, and infections were 97%, 77%, and 71%, respectively; no treatment-related deaths occurred. Notably, 5 patients (21%) developed Brock grade ≥3 hearing loss, of whom 1 required a hearing aid. CONCLUSIONS The dose-intensified C5VD regimen demonstrates significant efficacy with an overall favorable safety profile in the treatment of newly diagnosed, locally advanced pediatric hepatoblastoma. Grade 3-4 myelosuppression and infection are the predominant toxicities. However, high‑dose cisplatin-induced ototoxicity remains a concern, highlighting the need for improved otoprotective strategies.
Humans ; Hepatoblastoma/pathology* ; Male ; Female ; Infant ; Liver Neoplasms/pathology* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Child, Preschool ; Prospective Studies ; Doxorubicin/adverse effects* ; Child ; Cisplatin/adverse effects* ; Vincristine/adverse effects* ; Fluorouracil/adverse effects*

Dendritic cells (DCs) serve as the primary antigen-presenting cells in autoimmune diseases, like rheumatoid arthritis (RA), and exhibit distinct signaling profiles due to antigenic diversity. Type II collagen (CII) has been recognized as an RA-specific antigen; however, little is known about CII-stimulated DCs, limiting the development of RA-specific therapeutic interventions. In this study, we show that CII-stimulated DCs display a preferential gene expression profile associated with migration, offering a new perspective for targeting DC migration in RA treatment. Then, saikosaponin D (SSD) was identified as a compound capable of blocking CII-induced DC migration and effectively ameliorating arthritis. Optineurin (OPTN) is further revealed as a potential SSD target, with Optn deletion impairing CII-pulsed DC migration without affecting maturation. Function analyses uncover that OPTN prevents the proteasomal transport and ubiquitin-dependent degradation of C-C chemokine receptor 7 (CCR7), a pivotal chemokine receptor in DC migration. Optn-deficient DCs exhibit reduced CCR7 expression, leading to slower migration in CII-surrounded environment, thus alleviating arthritis progression. Our findings underscore the significance of antigen-specific DC activation in RA and suggest OPTN is a crucial regulator of CII-specific DC migration. OPTN emerges as a promising drug target for RA, potentially offering significant value for the therapeutic management of RA.

Objective To investigate the changes in the tumor microenvironment of pancreatic cancer(PDAC)complicated with diabetes mellitus(DM)in a mouse model of hyperglycemia and orthotopic pancreatic cancer by analyzing transcriptome and single-cell transcriptome data in order to identify potential therapeutic targets.Method By integrating single-cell transcriptome and bulk transcriptome data,bioinformatics analysis was conducted to compare the characteristics of tumor cells and tumor immune microenvironment between PDAC patients with DM(DM group)and those without DM(non-DM group).Twenty male C57BL/6 mice(6 weeks old,weighing 18～20 g)were randomly divided into a hyperglycemic group[STZ group,continuous intraperitoneal injection of 50 mg/kg streptozocin(STZ)(final concentration of 1％)dissolved in citrate buffer],and a control group(Control group,an equivalent volume of citrate buffer without STZ at the same time points),with 10 mice in each group.Tail-tip blood glucose level was measured to monitor glycemic status.After orthotopic inoculation of pancreatic cancer cells in both Control and STZ groups,tumor-infiltrating immune cells were harvested.Flow cytometry was employed to determine the effects of hyperglycemia on:total CD8+T cell and Treg cell populations;CD8+T cell subsets expressing Ki67,TNF-α,granzyme B(GZMB)and IFN-γ;surface expression of PD-1,lymphocyte activation gene-3(LAG-3)and T cell immunoglobulin and mucin domain-3(Tim-3)on CD8+T cells;programmed death-ligand 1(PD-L1)expression on tumor cells;and tumor-associated macrophage surface expression of major histocompatibility complex classⅠ(MHC-Ⅰ)and cluster of differentiation 206(CD206).Results Bioinformatics analysis revealed that,compared to the non-DM group,the genes significantly up-regulated in the DM group were associated with poor prognosis(P＜0.001).The proportion of type 2 ductal cells was increased in the DM group,exhibiting higher levels of copy number variation(P＜0.001).In the tumor immune microenvironment of the DM group,there was an increase in the proportion of Treg cells(P＜0.05)and an elevated exhaustion score for CD8+T cells(P＜0.001),accompanied by down-regulated expression of effector molecules,up-regulated expression of inhibitory checkpoints,and a significant increase in the M2 score of M2-like macrophages(P＜0.001).Animal experiments and flow cytometry found that,compared to the Control group,the STZ group had a shorter survival time(P＜0.001),with decreased proportions of total CD8+T cells(P＜0.01)and CD8+T cells expressing Ki67,TNF-α,GZMB and IFN-γ(P＜0.01),increased proportion of Treg cells(P＜0.001),up-regulated expression of PD-1,LAG-3 and Tim-3 on the surface of CD8+T cells(P＜0.001),and up-regulation of PD-L1 on tumor cell surface(P＜0.001)and enhanced expression of CD206 on the surface of tumor-associated macrophages,while down-regulated expression of MHC-Ⅰ(P＜0.001).Conclusion High glucose promotes the formation of an immunosuppressive microenvironment in PDAC,and targeting type 2 ductal cells and immunosuppressive cells in the tumor microenvironment,combined with dual immune checkpoint antibody therapy,may improve patient prognosis.

Objective To specifically extract and analyze nascent proteins synthesized by bone marrow mesenchymal stem cells(BMSCs)after transplantation into ischemic hearts using a technique employing mutant methionyl-tRNA synthetase(MetRSL247G)for nascent protein labeling,in order to explore the potential mechanisms of action in BMSCs post-transplantation.Methods Point mutation at position 274 of the MetRS gene in BMSCs was induced via lentiviral infection to enable azidonorleucine(ANL)-mediated labeling of nascent proteins in BMSCs.The labeling efficiency was verified by means of fluorescent non-canonical amino-acid tagging(FUNCAT).Thirty healthy female C57BL/6J mice(8-10 weeks old)were divided into control and experimental groups,with 15 mice in each group.The acute myocardial infarction model was constructed by ligating the left anterior descending coronary artery in experimental group,while control mice underwent only thoracotomy without coronary ligation.After modeling,both groups received intramyocardial injections of MetRSL247G-modified BMSCs(MetRSL247G-BMSCs)at 3 different sites in the peri-infarct ischemic region.Mice were intraperitoneally injected with ANL every 6 hours for 4 times on postoperative days 0,2,and 6(n=5 for each time point)respectively,euthanized 24 h after the last injection,and cardiac tissues were isolated.The newly synthesized and labeled proteins produced by BMSCs after transplantation into the myocardium of experimental and control groups were collected,using an enrichment technique for ANL-tagged proteins and liquid chromatography-tandem mass spectrometry(LC-MS)analysis.Gene ontology(GO)analysis,Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis,protein-protein interaction(PPI)analysis,and heatmap visualization analysis were performed to identify differentially expressed proteins at the 3 time points and screen key pathways and genes.Results Under fluorescence microscopy,the MetRSL247G lentivirus-infected BMSCs were observed to be labelled with mCherry signals,confirming the successful construction of the MetRSL247G-BMSCs cell line.Green fluorescent signals were detected only in nascent proteins in culture medium containing both MetRSL247G-BMSCs and ANL,validating the sensitivity and specificity of the labeling method.GO analysis revealed that differentially expressed proteins were primarily involved in basic cellular biological processes such as extracellular exosome formation,extracellular matrix organization,and focal adhesion.KEGG and PPI analyses indicated that the differential proteins were mainly involved in complement and coagulation cascade pathway,actin cytoskeleton regulation pathway,and apoptosis pathway.Heatmap analysis showed significantly upregulated expression of anti-apoptosis and cell adhesion-related factors in experimental group on day 1(P＜0.05),upregulated anti-apoptotic factors,pro-apoptotic factors,and cell adhesion-related factors on day 3(P＜0.05),and upregulated anti-apoptotic factors,cell differentiation-related factors,and cell adhesion-related factors on day 7(P＜0.05)compared with control group.Expression of apoptosis-inducing factor 1 was significantly downregulated on days 1 and 7(P＜0.05).On day 3,most differentially expressed proteins,including anti-apoptosis factors(Protein S100-A11,Clusterin,Gelsolin),pro-apoptosis factor(Cathepsin B),cell differentiation-related factor(Transgelin-2),and cell adhesion-related factors(Cofilin-1,Periostin,Fibronectin)were significantly upregulated(P＜0.05).Conclusions The MetRSL247G mutation enables BMSCs to incorporate ANL and synthesize labeled proteins,confirming the feasibility of this nascent protein labeling technique.Nascent proteins of BMSCs in ischemic myocardium primarily contribute to extracellular exosome secretion and extracellular matrix organization.BMSCs may adapt to and respond to ischemic and hypoxic environments by influencing complement and coagulation cascades,activating inflammatory factors,regulating actin cytoskeleton structure,and modulating apoptosis,thereby maintaining the survival of BMSCs.

ObjectiveTo investigate the relationship between Jiaotai pill (JTP), its main component berberine (BBR), and the serotonin (5-HT) system in regulating islet hormone secretion and alleviating pancreatic β-cell dysfunction during type 2 diabetes mellitus (T2DM) progression.MethodsT2DM rat model was established using a high-fat diet and streptozotocin injection. JTP, BBR, and Metformin were intragastrically administered for 35 days. The analyzed indices included blood glucose, blood lipids, islet hormones, and proteins related to 5-HT synthesis, secretion, and transport. Additionally, an in vitro model of glucose injury in islet cells was established to study the effects of JTP and BBR on islet hormone secretion following tryptophan hydroxylase 1 (TPH1) inhibition.ResultsJTP and BBR significantly improved blood glucose and lipid levels and islet morphology in T2DM rats. Both models exhibited reduced islet 5-HT levels and impaired islet hormone secretion. However, the administration of JTP and BBR reversed these effects. Furthermore, JTP and BBR upregulated the expression of TPH1(P = .0194, P = .0413) transglutaminase 2 (TGase2; P = .0492, P = .0349), serotonin transporter (SERT, P = .0090), and 5- hydroxytryptamine 1F receptor (5-HT1FR) in the islet 5-HT pathway (P = .0194). In the cell model, the regulatory effects of JTP and BBR on islet hormone levels were significantly weakened after TPH1 inhibition (P = .001), suggesting that JTP and BBR influence islet hormone secretion through the pancreatic 5-HT system.ConclusionThe islet 5-HT system is correlated with islet hormone secretion dysfunction in T2DM. JTP and BBR can improve islet hormone secretion by activating the TPH1/TGase2/SERT/5-HT1FR pathway in the islet 5-HT system in T2DM rats.

Wilson's disease （WD） is a copper metabolism disorder caused by mutations in the ATP7B gene， with diverse phenotypes and complex pathogenesis. It is one of the few rare diseases that can achieve good clinical efficacy through standardized treatment. Since there are few systematic reviews of this disease， we summarize the pathogenesis and treatment methods of WD from traditional Chinese and western medicine by reviewing the literature related to WD. In western medicine， ATP7B gene mutation is considered as the root cause of WD， which affects copper transport and causes copper metabolism disorders. The excessive copper deposited in the body will result in oxidative stress， defects in mitochondrial function， and cell death. Western medicine treatment of WD relies mainly on drugs， and copper antagonists are the first choice in clinical practice， which are often combined with hepatoprotective and antioxidant therapy. Surgery is a common therapy for the patients with end-stage WD， and gene therapy provides an option for WD patients. According to the traditional Chinese medicine （TCM） theory， WD is rooted in constitutional deficiency and copper accumulation and triggered by dampness-heat accumulation or phlegm combined with stasis. The patient syndrome varies in different stages of the disease， and thus the treatment should be based on syndrome differentiation. The TCM treatment method of nourishing the liver and kidneys and warming the spleen and kidneys can address the root cause. The methods of clearing heat and drying dampness， resolving phlegm and dispelling stasis， and soothing liver and regulating qi movement can be adopted to treat symptoms. On the basis of syndrome differentiation， special prescriptions for the treatment of WD have been formulated， such as Gandou decoction， Gandouling， and Gandou Fumu decoction， which have been widely used in clinical practice. TCM and western medicine have their own advantages and shortcomings. The integrated Chinese and western medicine complementing with each other demonstrates great therapeutic potential. This paper summarizes the pathogenesis and treatment of WD with integrated Chinese and western medicine， aiming to provide a reference for the clinical diagnosis and treatment of this disease.

The heat shock protein 90 (Hsp90) protein family is a cluster of highly conserved molecules that play an important role in maintaining cellular homeostasis. Hsp90 and its co-chaperones regulate a variety of pathways and cellular functions, such as cell growth, cell cycle control and apoptosis. Hsp90 is closely associated with the occurrence and development of tumors and other diseases, making it an attractive target for cancer therapeutics. Inhibition of Hsp90 expression can affect multiple oncogenic pathways simultaneously. Most Hsp90 small molecule inhibitors are in clinical trials due to their low efficacy, toxicity or drug resistance, but they have obvious synergistic anti-tumor effect when used with histone deacetylase (HDAC) inhibitors, tubulin inhibitors or topoisomerase II (Topo II) inhibitors. To address this issue, the design of Hsp90 dual-target inhibitors can improve efficacy and reduce drug resistance, making it an effective tumor treatment strategy. In this paper, the domain and biological function of Hsp90 are briefly introduced, and the design, discovery and structure-activity relationship of Hsp90 dual inhibitors are discussed, in order to provide reference for the discovery of novel Hsp90 dual inhibitors and clinical drug research from the perspective of medicinal chemistry.