This study aimed to investigate the effect of harpagoside(HA) on ethanol(ET)-and high-glucose(HG)-exacerbated pyroptosis in rat insulinoma cells(INS-1) and its underlying mechanism. INS-1 were cultured and assigned to the following groups: normal glucose(NG), HG, HG+ET(100 mmol·L~(-1))(abbreviated as ET), HG+ET+HA(12.5, 25, 50 μmol·L~(-1))(abbreviated as HA), and HG+ET+HA(50 μmol·L~(-1))+AMP-activated protein kinase(AMPK) inhibitor compound C(comp.C, 2 μmol·L~(-1))(abbreviated as comp.C) to verify the mechanism of HA. CCK-8 assay was employed to evaluate cell viability. The formation of pyroptotic bodies was quantified under a microscope. Dichlorofluorescein diacetate probe was used to detect intracellular reactive oxygen species(ROS) levels. Western blot analysis was performed to determine the phosphorylation level of AMPK as well as the expression and activation of Nod-like receptor protein 3(NLRP3)/gasdermin D(GSDMD)-related proteins. Molecular docking was utilized to predict the binding affinity between HA and AMPK. Time-resolved fluorescence resonance energy transfer(TR-FRET) assay was applied to measure the effect of HA on the kinase activity of recombinant AMPK protein. The results demonstrated that compared with the NG group, the HG group showed decreased cell viability, increased number of pyroptotic bodies, reduced AMPK activity, and elevated ROS levels along with upregulated expression and activation of NLRP3/GSDMD-related proteins. Compared with the HG group, ET exposure further exacerbated these changes. Compared with the ET group, HA ameliorated the above abnormalities. Meanwhile, molecular docking analysis revealed that the binding affinity between HA and AMPK was-6.59 kcal·mol~(-1). TR-FRET assay indicated that HA enhanced the kinase activity of AMPK protein. After pretreatment of INS-1 with comp.C, the ameliorative effects of HA on the above abnormalities were abolished. In conclusion, HA ameliorates the ET-and HG-exacerbated pyroptosis in INS-1 by activating the AMPK signaling pathway.

This study aims to explore the effects and mechanisms of Shenqi Jiangtang Granules(SJG) in improving sarcopenia in type 2 diabetes mellitus(T2DM) by regulating glucose and lipid metabolism disorders and mitophagy in skeletal muscle. Firstly, the modified T2DM with sarcopenia rat models characterized by glucose and lipid metabolism disorders and sarcopenia were established. After modeling successfully, the model rats received either the low-dose of SJG(L-SJG), the high-dose of SJG(H-SJG), rosiglitazone(RSG), or normal saline(as a vehicle) via gavage for 8 weeks, respectively. In the in vivo study, for the model rats, diabetic phenotypic characteristics, glucose and lipid metabolism indicators were examined; sarcopenia indicators including gastrocnemius mass coefficient, forelimb grip strength, gastrocnemius histopathological features, and the protein expression levels and extent of muscle atrophy markers such as Atrogin-1 and MURF-1 in gastrocnemius were also detected. Additionally, mitochondrial morphology and the protein expression levels of mitophagy markers including Tom20, Beclin1, LC3Ⅱ/LC3Ⅰ, P62 in gastrocnemius, insulin resistance(IR) indicators, and the protein expression levels of key signaling molecules in the insulin receptor substrate 1(IRS1)/phosphatidylinositol 3-kinase(PI3K)/serine-threonine kinase(AKT) pathway in gastrocnemius were assessed, respectively. Secondly, in the in vitro study, the C2C12 myotube cells were treated with high glucose(HG) combined with palmitic acid(PA), followed by intervention with H-SJG-containing serum, RSG, or a mitophagy agonist named by CCCP. The protein expression levels and intensity of mitophagy markers, IR indices, and the protein expression levels of key signaling molecules of the IRS1/PI3K/AKT pathway in cells were detected. In addition, in the network pharmacology and non-targeted muscle metabolomics studies, the "Chinese medicine-component-target" network of SJG was constructed using Cytoscape 3.10.1. The OMIM and Gene Cards databases were used to integrate targets related to T2DM and sarcopenia. The DAVID database was applied to perform Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses on the intersection targets of SJG, T2DM, and sarcopenia. Non-targeted metabolomics was adopted to analyze the characteristics of gastrocnemius in rats, screen the potential biomarkers, and enrich the related metabolic pathways. The results of the above-mentioned study indicated that the effect of SJG in ameliorating sarcopenia in T2DM might be associated with regulation of mitophagy, IR, and the PI3K/AKT signaling pathway. More importantly, the in vivo results showed that both SJG and RSG could improve diabetic phenotypic characteristics, glucose and lipid metabolism disorders, sarcopenia, mitochondrial morphology and the protein expression levels of mitophagy markers in gastrocnemius, IR, and the protein expression levels of key signaling molecules in the IRS1/PI3K/AKT pathway in the model rats. The in vitro results showed that both H-SJG and RSG could improve mitophagy, IR, and activation of the IRS1/PI3K/AKT pathway in the C2C12 myotube cells treated with HG combined with PA, and their effects were generally similar to those of a mitophagy agonist. In conclusion, the authors clarified in this study that SJG can ameliorate sarcopenia in T2DM through multiple targets; its mechanisms are closely related to regulating glucose and lipid metabolism disorder, increasing mitophagy in skeletal muscle, inhibiting IR, and activating the IRS1/PI3K/AKT pathway; its effects are equivalent to the euglycemic agent RSG. This study provides pharmacological evidence for exploring "conventional drugs in new use", namely, the scientific connotation of SJG in treating T2DM with sarcopenia in the clinic.

This study aimed to explore the effects and mechanisms of Supplemented Shenqi Dihuang Decoction Formula(SSDDF) in ameliorating renal aging(RA) and tubulointerstitial fibrosis(TIF) in diabetic kidney disease(DKD) by inhibiting ferroptosis, in comparison with empagliflozin(EMPA), a novel hypoglycemic agent. For the in vivo experiment, a type 2 DKD rat model with histopathological characteristics of RA and TIF was established. After successful modeling, the model rats were divided into the low-dose SSDDF(SSDDF-L) group, high-dose SSDDF(SSDDF-H) group, EMPA group and normal saline control group, and were administrated by gavage for six consecutive weeks for intervention. For the in vitro experiment, a senescent model of renal tubular epithelial cells was constructed by treating NRK-52E cells with high glucose(HG), which was then intervened with SSDDF-L containing serum, SSDDF-H containing serum, EMPA, as well as ferroptosis and iron metabolism inhibitors. In both in vivo and in vitro studies, aging phenotypes and related physiological indicators including body weight(BW) and blood glucose(BG), renal injury indicators including serum creatinine(Scr), blood urea nitrogen(BUN) and urinary N-acetyl-β-D-glucosaminidase(UNAG), aging characteristics of renal tissues and cells including senescence-associated β-galactosidase(SA-β-gal) staining and protein expression of klotho and p16, TIF pathological features and cellular fibrotic injury, senescence-associated secretory phenotype(SASP), and ferroptosis characteristics(lipid peroxidation-dependent ferroptosis detected by Ferro Orange fluorescent probe and mitochondrial transmission electron microscopy) were examined and compared. Meanwhile, an "SSDDF-component-target" network was constructed via network pharmacology, and Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses were combined to screen the core signaling pathways. Non-targeted metabolomics was adopted to analyze the characteristics of renal tissues, screen potential biomarkers and enrich related metabolic pathways.The results indicated that the effect of SSDDF in ameliorating RA and TIF in DKD rats might be associated with the regulation of ferroptosis signaling pathways. In the in vivo experiment, SSDDF ameliorated the aging phenotypes, BW, BG, UNAG levels, as well as RA and TIF in DKD model rats, with SSDDF-H exerting a superior effect to SSDDF-L; notably, SSDDF-H showed a better effect than EMPA in improving Scr and BUN levels. SSDDF also ameliorated renal lipid peroxidation-dependent ferroptosis in DKD rats, where SSDDF-H had a better effect than SSDDF-L and an equivalent effect to EMPA. In the in vitro experiment, SSDDF-H containing serum multi-targetedly improved HG-induced senescence, fibrotic injury, SASP expression, ferroptosis marker levels and mitochondrial ultrastructural damage in renal tubular epithelial cells, with its effect comparable to that of ferroptosis or iron metabolism inhibitors. In conclusion, both SSDDF and EMPA can multi-targetedly ameliorate RA and TIF in DKD model rats with similar anti-aging and anti-fibrotic effects, and their core mechanism is the inhibition of renal lipid peroxidation-dependent ferroptosis. Based on this, the clinical establishment of a combined therapy regimen of SSDDF plus EMPA featured by "coordination of traditional Chinese and Western medicine" for elderly patients with DKD is expected to exert a dual synergistic effect in anti-aging and anti-fibrosis.

Abelmoschus manihot-derived extracellular vesicle-like particles(AM-EVLPs), as a novel natural nano-delivery system, have a precise protective effect on podocytes. This study aims to verify the effects in vivo and in vitro of AM-EVLPs in protecting against podocyte injury using a modified rat model with diabetic kidney disease(DKD) and a high-glucose(HG)-induced podocyte model, and then to explore its therapeutic targets based on the pathological mechanisms of "mitochondria-endoplasmic reticulum coupling" and tumor protein 53(P53)-mediated oxeiptosis. The first, AM-EVLPs were extracted from fresh flower petals of Abelmoschus manihot using ultracentrifugation combined with density gradient centrifugation. The second, in the in vivo study, the modified DKD rat model was established. After successful modeling, the DKD model rats were randomly divided into 4 groups, including the model group, the low-dose AM-EVLPs(L-AM-EVLPs)-treated group, the high-dose AM-EVLPs(H-AM-EVLPs)-treated group, and total flavones of Abelmoschus manihot(TFA)-treated group, receiving corresponding drugs for consecutive 4 weeks. In the in vitro study, mouse podocytes(MPC5 cells) were exposed to HG and subsequently treated with L-AM-EVLPs, H-AM-EVLPs, empagliflozin(EMPA), P53 small interfering RNA(P53-siRNA), or P53-overexpressing lentivirus(P53-OE), respectively. Using the DKD model rats, blood glucose, urinary albumin, liver and kidney function-related indicators were observed. Additionally, glomerular histopathological features, foot process and mitochondrial ultrastructure, the protein expression levels of podocyte-specific structural molecules(podocin and nephrin),renal reactive oxygen species(ROS) levels, as well as the protein expression levels of oxeiptosis-related proteins including P53, Kelch-like ECH-associated protein 1(KEAP1), phosphoglycerate mutase family member 5(PGAM5), and apoptosis-inducing factor/mitochondria-associated 1(AIFM1) were detected, respectively. Furthermore, the differential expression proteomic profile of diabetic kidneys was also analyzed. Using the HG-induced podocyte model, the protein expression levels of podocin and nephrin, the degree of mitochondria-endoplasmic reticulum coupling, the binding intensity of the IP3R1-GRP75-VDAC1 complex, mitochondrial calcium ion(Ca~(2+)) concentration, mitochondrial reactive oxygen species(mtROS) levels, and the protein expression levels of key signaling molecules in the KEAP1/PGAM5/AIFM1 signaling axis were detected. The in vivo results showed that, for the DKD model rats, AM-EVLPs dose-dependently improved urinary albumin, blood urea nitrogen(BUN), and serum creatinine(Scr) levels; reduced glomerular cell proliferation, ECM deposition, and collagen deposition; ameliorated foot process fusion and mitochondrial ultrastructural damage; upregulated the protein expression levels of podocin and nephrin; reduced mtROS levels; and reversed the aberrant protein expression levels of key signaling molecules in the oxeiptosis pathway, including P53, KEAP1, PGAM5, and p-AIFM1. In which, the ameliorative effect of H-AM-EVLPs was superior to that of TFA. Additionally, proteomic analysis of diabetic kidneys revealed that differentially expressed proteins were enriched in pathways related to oxidative stress, programmed cell death, endoplasmic reticulum-mitochondria coupling, and P53-related signaling pathways. The in vitro results showed that AM-EVLPs improved the protein expression levels of podocin and nephrin in podocytes, dissociated the IP3R1-GRP75-VDAC1, restored mitochondria-endoplasmic reticulum coupling homeostasis, inhibited mitochondrial calcium ion overload and mtROS generation. In which, the ameliorative effects of H-AM-EVLPs were superior to those of EMPA. More importantly, the treatment of AM-EVLPs or P53-siRNA could downregulate the protein expression levels of KEAP1 and PGAM5, and upregulate the protein expression level of p-AIFM1 under HG conditions in the in vitro study, while P53-OE reversed the regulatory effects of AM-EVLPs on the protein expression levels of the above-mentioned signaling molecules, suggesting that AM-EVLPs could inhibit podocyte oxeiptosis by targeting P53 to regulate the KEAP1/PGAM5/AIFM1 signaling axis activation. In conclusion, this study demonstrated that AM-EVLPs precisely ameliorate HG-induced podocyte injury, and their effects are achieved by targeted regulation of "mitochondria-endoplasmic reticulum coupling" and P53-mediated oxeiptosis. These findings provide pharmacological evidence for AM-EVLPs as a novel natural nano-delivery system for precision therapy of podocyte injury in DKD.

Factitious thyrotoxicosis is the presence of excess circulating thyroid hormone from an exogenous source. It can be iatrogenic or it can occur due to intentional thyroid hormone misuse or abuse. It can also occur due to accidental ingestion, pharmacy error, or inadvertent exposure to unlabeled thyroid hormone in supplements or contaminated hamburger meat. Consequences range from mild thyrotoxic symptoms to more serious or life-threatening sequelae including thyrotoxic periodic paralysis, seizure, coma, arrhythmias, myocardial infarction, and thyroid storm. If unclear from the history, differentiating factitious thyrotoxicosis from other etiologies of thyroid hormone excess is challenging, and may require radioactive iodine uptake and serum thyroglobulin testing. In most cases, treatment simply consists of stopping the exogenous thyroid hormone exposure with subsequent monitoring. However, in cases of massive acute poisoning with thyroid hormone, gastric decontamination strategies and inpatient care in a monitored setting with measures to reduce circulating T3 levels may be needed.

Among people with HIV (PWH), initiating antiretroviral therapy (ART) is associated with weight gain that might increase the risk of cardiometabolic outcomes. We estimated the effect of hypothetical interventions to restrict increases in body mass index (BMI) in the two years after ART initiation on the 7-year risk of incident type-2 diabetes mellitus (T2DM) among PWH in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) clinical cohorts using the parametric extended g-formula. Among 13,822 normal weight or overweight PWH (BMI ≥18.5 and ≤29.9 kg/m2) who initiated ART between 2012-2021, the 7-year risk of T2DM was 5.6% (95% confidence interval [CI]: 4.8%, 6.3%). Compared to no intervention on BMI, if BMI increase during the first 2 years was capped at 5% of baseline BMI, the risk ratio (RR) for T2DM risk was 0.94 (95% CI, 0.86, 1.03); if BMI was capped at 29.9 kg/m2, RR=0.88 (95% CI, 0.80, 0.97); and if PWH were prevented from gaining any weight over the first 2 years, RR=0.81 (95% CI, 0.72, 0.92). These results provide preliminary evidence to promote studies of real weight maintenance interventions among PWH initiating ART.

Insulin is a central regulator of metabolic homoeostasis with diverse, tissue-specific actions across multiple organs. Despite major advances in insulin formulations, current therapies rely on systemic delivery and do not reproduce the physiological distribution of endogenous insulin, resulting in non-physiological tissue exposure and associated metabolic limitations. In this perspective, we discuss emerging strategies aimed at achieving tissue-selective insulin action, including molecular engineering of insulin analogues, modulation of insulin receptor isoform specificity and targeted delivery approaches. Attention is given to hepato-preferential, muscle-directed, brain-targeted and adipose-modulating strategies, highlighting their mechanistic basis, therapeutic potential and inherent limitations. While proof of principle has been established for several approaches, challenges remain in balancing tissue selectivity with whole-body metabolic control. Advances in protein design and delivery technologies may ultimately enable the development of next-generation insulin therapies that better mimic physiological insulin action and improve clinical outcomes in metabolic and neurodegenerative diseases.

Dupuytren's disease is a benign fibroproliferative condition of the palmar fascia, characterized by onset of nodules that develop into cords causing irreducible digital contracture. Prevalence increases with age. It mainly affects males of Northern European origin. Etiopathogenesis is multifactorial, combining genetic predisposition and environmental factors such as alcohol consumption, smoking, microtrauma and diabetes. Management is based on precise clinical assessment, with Tubiana classification and diathesis screening, to adapt therapeutic strategy. In the early stages, monitoring may be combined with medical treatment (radiotherapy, collagenase, corticosteroids, anti-TNF) aimed at slowing progression. In case of functional impairment or significant retraction, several surgical options are available: percutaneous fasciotomy, limited or segmental fasciectomy, dermofasciectomy with skin grafting, or even phalangectomy in severe recurrent cases. This narrative review provides an up-to-date summary of epidemiological, pathophysiological and therapeutic data, emphasizing the importance of a decision-tree that takes account of the progression, diathesis and severity of the contracture.