Multiple myeloma (MM) remains an incurable hematological malignancy, even with the clinical success of proteasome inhibitors (PIs). The compensatory upregulation of HDAC6 following proteasome inhibition offers a strong rationale for dual targeting. However, a systematic comparison of different zinc-binding groups (ZBGs) within a non-covalent scaffold has been lacking. Here, we designed a series of non-covalent dual HDAC6/proteasome inhibitors based on a carfilzomib-derived scaffold, incorporating either a hydroxamic acid or an ortho-aminoanilide ZBG with linkers of varying lengths. Our SAR analysis revealed a clear division of labor: the R1 position dominates proteasome inhibition (IC50 = 2.6-8.1 nM, comparable to MG-132 at 10.8 nM), whereas HDAC6 activity is highly dependent on the choice of ZBG and cap group. For instance, the ortho-aminoanilide ZBG confers potent HDAC6 inhibition only when paired with a 2-chlorobenzyl cap (IC50 = 29.8 nM); with a tetralin cap, it is essentially inactive (IC50 > 5 μM). In contrast, the hydroxamic acid ZBG delivers moderate HDAC6 activity (130-280 nM) across both cap groups. Among the nine compounds, H-07 emerged as the most balanced dual inhibitor, with proteasome IC50 = 4.2 nM and HDAC6 IC50 = 29.8 nM. In RPMI-8226 cells, H-07 increased ac-α-tubulin and ac-histone H3 levels and induced PARP cleavage-findings consistent with engagement of both HDAC6 and class I HDACs, in addition to the expected effects from proteasome inhibition. Molecular dynamics simulations provided plausible binding modes for both targets. Despite this promising in vitro profile, a substantial loss of potency was observed in cell-based functional assays: the cellular proteasome IC50 of H-07 was 6.768 μM, representing a > 1600-fold increase relative to its enzymatic IC50 (4.2 nM). This marked shift is consistent with the limited membrane permeability frequently associated with polar peptidomimetic scaffolds, and it underscores a key limitation that must be addressed in future optimization efforts. Nevertheless, this work establishes a clear SAR framework and identifies key determinants for the rational optimization of this class of non-covalent dual inhibitors.

Cathepsins play critical roles in various physiopathological processes, with several reported to be associated with nonalcoholic fatty liver disease (NAFLD). Herein, we investigated the expression patterns of the cathepsin family in human and mouse livers, cultured hepatocytes, and their roles in NAFLD. Public datasets of NAFLD patients and controls were analyzed to examine hepatic cathepsin expression in human livers. RT-qPCR assessed these genes in mouse livers, HepG2, Hepa1-6, and mouse primary cells. Despite different expression patterns, CTSA, CTSB, CTSD, CTSH, and CTSL were consistently highly expressed across all samples. Notably, steatosis patients and diabetic mice exhibited significantly increased hepatic expression of four cathepsins. Among these, we first observed elevated CTSG and CTSW, with CTSG showing the most pronounced increase. Moreover, hepatic CTSG was increased and positively correlated with disease severity in NASH patients. CTSG was also upregulated in HepG2 cells treated with high glucose or free fatty acids. In vitro, CTSG overexpression promoted, while its knockdown reduced lipid accumulation. In vivo, hepatic CTSG overexpression significantly induced lipid deposition, impaired glucose tolerance, and elevated HOMA-IR. Mechanistically, CTSG upregulated key lipid synthesis genes (ACC, SCD1) and downregulated those involved in lipid oxidation (PPARα, Lcad) and secretion (MTTP) by suppressing Akt. Furthermore, Akt activation alleviated lipid deposition induced by CTSG overexpression, while Akt inhibition abolished the beneficial effect of CTSG knockdown. This study is the first to reveal the expression patterns of the cathepsin family in human and mouse livers, and identifies that hepatic CTSG is elevated in NAFLD and can promote lipid deposition, supporting CTSG as a novel potential therapeutic target for NAFLD.

Hepatocellular carcinoma (HCC) is widely recognized as one of the three leading causes of cancer-related death worldwide. Glycyrrhetinic acid (GA) exhibits potent anti-HCC activity, but its poor aqueous solubility limits its clinical application. At high concentrations, nitric oxide (NO) exerts cytotoxic effects on tumor cells. In this study, an ultrasound-assisted albumin nanoparticle system co-loaded with GA and NO (SNO-HSA-GA) was developed for synergistic HCC therapy. The optimized formulation exhibited an average particle size of 232.4 ± 6.2 nm, a zeta potential of -31.2 ± 1.5 mV, and a GA loading of 11.86 ± 1.05

BACKGROUND:Graves' orbitopathy (GO) is a sight-threatening disease associated with thyroid dysfunction, with an unmet medical need for early diagnosis and treatment. Orbital fibroblasts (OFs) proliferation and migration play central roles in the pathogenesis of GO. Homocysteine (Hcy) has been demonstrated to be related to thyroid function, but its role in GO remains unclear. In this study, we aimed to investigate the role of Hcy in GO progression and its effects on OFs. METHODS:A total of 131 patients with Graves' disease (GD) were enrolled, of which 68 suffered from GO, with 40 having inactive GO and 28 having active GO. Serum Hcy levels were measured using ELISA assays. Primary cultured OFs were established from orbital connective tissues. Cell proliferation was quantified using CCK-8 assays, while wound healing assays were used to evaluate OFs migration. Western blotting was used to measure Akt signaling pathway. RESULTS:Under a matched thyroid function state, serum Hcy levels were significantly higher in GO patients than in GD. More interestingly, active GO patients had significantly elevated Hcy levels compared to inactive GO patients. Furthermore, serum Hcy levels correlated positively with clinical activity scores in GO patients. In vitro, Hcy stimulated OFs proliferation and migration under both physiological and inflammatory conditions. Mechanistically, Hcy activated the Akt signaling pathway in OFs under these conditions. CONCLUSIONS:This study supports the potential role of Hcy as a novel biomarker for GO progression. Furthermore, Hcy stimulates OFs proliferation and migration, suggesting its potential as a therapeutic target for GO treatment.

To investigate the diagnostic value of dual-energy computed tomography (DECT)–derived quantitative parameters combined with morphological features for assessing subtle orbital tissue changes in Graves’ ophthalmopathy (GO), and to evaluate their feasibility as imaging biomarkers throughout the disease course. Data from patients suspected of having GO were retrospectively collected. All these patients underwent DECT scans and had no history of thyroid function treatment or other medical history, which may have affected the measurement of orbital tissues. Three clinical features, four morphological features, and twenty-four DECT parameters were measured. The overall data were divided into training and test cohorts. Univariate and multivariate analyses were applied to select relevant parameters and construct a nomogram. Among the 206 patients suspected of having GO, 134 patients were diagnosed as positive for GO (GO+), and 72 patients were diagnosed as negative (GO-) according to relevant diagnostic criteria. (1) The average thickness, average width, weighted average thickness and weighted average width of orbital muscles significantly differed between the GO + and GO- groups (p < 0.05). (2) The minimum and average values of electron density in orbital muscles and lacrimal glands were significantly different (p < 0.05). (3) A nomogram was constructed to predict the risk of GO, and the area under the curve, sensitivity, and specificity in the training and test cohorts were 0.812, 92.1

Graves’ orbitopathy (GO) is a sight-threatening organ-specific autoimmune disease with complicated pathogenesis. Gut microbiota-derived tryptophan (Trp) metabolites play important roles in immune-related diseases, but their role in GO remains unknown. Trp metabolism-associated gut flora was analyzed by 16 S sequencing in GO patients and controls. Serum metabolomics profiling was performed to assess Trp metabolic pathway. Trp metabolites levels were measured by ELISA in 401 serum samples from a case-control study, and their effects on inflammation and proliferation in orbital fibroblasts were evaluated in vitro. Trp metabolism-associated gut flora, including phylum Firmicutes and genus Anaerostipes, were significantly down-regulated in GO patients. Serum metabolomics revealed significant enrichment of Trp metabolic pathway in both GO and Graves’ disease (GD) groups. Serum levels of indolepropionic acid (IPA), indole-3-lactate (ILA), and indoleacetic acid (IAA) were significantly decreased in both GD and GO patients compared to controls, with IAA levels further reduced in GO compared to GD patients. Notably, active GO patients had significantly lower IAA levels compared to inactive ones. Moreover, the levels of IAA were negatively correlated with clinical activity score and serum thyrotropin receptor antibody (TRAb) in GO patients. In vitro, IPA, ILA, and IAA mitigated TNFα-induced inflammation and proliferation in orbital fibroblasts by suppressing the Akt signaling pathway. Trp metabolites IAA maybe a novel biomarker for GO progression. And IPA, ILA and IAA may play a protective role in GO by regulating inflammation and proliferation in orbital fibroblasts, suggesting their potential as therapeutic targets for GO treatment.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world, mainly because of its powerful pro-connective tissue proliferation matrix and immunosuppressive tumor microenvironment (TME), which promote tumor progression and metastasis. In addition, the extracellular matrix leads to vascular collapse, increased interstitial fluid pressure, and obstruction of lymphatic return, thereby hindering effective drug delivery, deep penetration, and immune cell infiltration. Therefore, reshaping the TME to enhance tumor perfusion, increase deep drug penetration, and reverse immune suppression has become a key therapeutic strategy. Traditional therapies for PDAC, including surgery, radiation, and chemotherapy, face significant limitations. Surgery is challenging due to tumor location and growth, while chemotherapy and radiation are hindered by the dense extracellular matrix and immunosuppressive TME. In recent years, the advancement of nanotechnology has provided new opportunities to improve drug efficacy. Nanoscale drug delivery systems (NDDSs) provide several advantages, including improved drug stability in vivo, enhanced tumor penetration, and reduced systemic toxicity. However, the clinical translation of nanotechnology in PDAC therapy faces several challenges. These include the need for precise targeting and control over drug release, potential immune responses to the nanocarriers, and the scalability and cost-effectiveness of production. This article provides an overview of the latest nanobased methods for achieving better therapeutic outcomes and overcoming drug resistance. We pay special attention to TME-targeted therapy in the context of PDAC, discuss the advantages and limitations of current strategies, and emphasize promising new developments. By emphasizing the enormous potential of NDDSs in improving the treatment outcomes of patients with PDAC, while critically discussing the limitations of traditional therapies and the challenges faced by nanotechnology in achieving clinical breakthroughs, our review paves the way for future research in this rapidly developing field.

Objective:Investigating the antialcoholic liver injury properties of Rabdosia rubescens and its effect on the expression of CYP7A1 and levels of autophagy. Materials and Methods:Male C57BL/6 mice were randomly divided into three groups, namely, the control group (Lieber-DeCarli standard diet), model group (Lieber-DeCarli ethanol diet), and treatment group (Rabdosia rubescens at concentrations of 50 mg/kg, 100 mg/kg, and 200 mg/kg). The mice were fed their respective diets for 10 days, with the treatment group receiving the corresponding concentration of Rabdosia rubescens. On the 11th day, all the mice except those in the control group were given 30% EtOH. Nine hours later, the mice were sacrificed and their blood serum and liver tissue were collected for analysis. The effect of Rabdosia rubescens on alcohol-induced liver damage was evaluated by testing serum biochemical indicators, liver bile acid content, liver tissue histopathological changes, liver LC3 and p62 immunohistochemical staining, liver inflammatory factors, and CYP7A1, SREBP, FAS, LC3, Beclin-1, ATG7, and p62 expressions. Results:Compared with the model group, Rabdosia rubescens was found to significantly reduce the levels of ALT, AST, TG, TC, and TBA in the serum of mice with alcoholic liver injury (p < 0.05 or p < 0.01). Rabdosia rubescens was found to significantly reduce the level of apoptosis in H&E-stained liver tissue sections. Rabdosia rubescens also significantly reduced the levels of TNF-α and IL-1β in the livers of mice (p < 0.001). Rabdosia rubescens was found to induce the expression of LC3, Beclin-1, and ATG7 proteins and mRNA, while inhibiting the expression of CYP7A1, SREBP, FAS, and p62 proteins and mRNA (p < 0.05 or p < 0.01). Conclusion:Rabdosia rubescens has been shown to relieve alcohol-induced liver damage in mice by reducing levels of CYP7A1, alleviating cholestasis and reducing inflammation. It can also reduce alcohol-induced liver damage by decreasing fat synthesis and inducing autophagy.

Liver fibrosis is a key intermediate stage in the progression of chronic liver disease to end-stage liver cirrhosis. Mortality rises expo nentially once it reaches decompensated liver disease. In a healthy liver microenvironment, hepatocytes, Kupffer cells, hepatic stellate cells (HSCs), liver sinusoidal endothelial cells, and other cells interact with extracellular matrix (ECM) to maintain cell stability and liver function. Different types of liver injury (such as viral hepatitis and alcoholic liver injury) can cause liver fibrosis. Liver injury signals acti vate Kupffer cells and recruit immune cells, leading to liver inflammation. This inflammation, together with liver injury, stimulates the activation of HSCs. Activated HSCs migrate to injury sites and secrete ECM. The ECM increase and stiffening contribute to fibrosis. Microenvironment changes alter cell phenotypes, perpetuating HSC activation. This article explores liver fibrosis mechanisms, reviews cellular and microenvironmental changes, summarizes fibrosis characteristics, and provides insights for clinical treatment. Cite this article as: Zou X, Ke Y, Shao Y, Liu S, Shi T. Liver fibrosis: interactions between cells and microenvironments. Turk J Gastroenterol. 2025;36(11):711-722.

Ganoderma mushrooms are popularly used as dietary supplements to promote health around the world. However, their potential applications for the prevention and treatment of obesity needs to be further investigated. In this study, we isolated a novel triterpenoid from Ganoderma resinaceum, Resinacein S (Res S), and determined its absolute configuration. We reported that Res S treatment significantly inhibited the high-fat HF diet-induced body weight gain though increased thermogenesis and energy metabolism. Specifically, treatment with Res S promoted brown adipose tissue activation and browning of inguinal white adipose tissue, improving whole-body glucose and lipid homeostasis. Mechanistically, Res S treatment induced the expression of thermogenic genes and related protein, for example, uncoupling protein 1 and mitochondrial biogenesis in a cell-autonomous manner by activating the AMPK-PGC1α signaling pathway. These findings identify Res S as a potential therapeutic alternative for obesity in the setting of its increasingly high prevalence. HIGHLIGHTS: Resinacein S (Res S) exhibited potent anti-obesity effects in high-fat diet-fed mice; Res S treatment significantly promoted brown adipose tissue activation and browning of inguinal white adipose tissue; Res S treatment stimulated UCP1 expression and enhanced mitochondrial function; Res S induced adipocyte thermogenic activity through activating the AMPK-PGC1α axis.

Osteoporosis, a prevalent metabolic bone disorder, exhibits an age-related increase in incidence, profoundly impacting patients’ quality of life. Recent studies have underscored the fundamental role of mitochondria in bone metabolism, emphasizing the intricate link mitochondrial dysfunction and the viability and functionality of bone cells. Beyond their role in energy production, mitochondria are critical in modulating cellular apoptosis, oxidative stress, and calcium ion homeostasis, all of which are essential for maintaining bone health. Emerging evidence suggests that mitochondrial dysfunction plays an integral role in the pathogenesis of osteoporosis, yet significant challenges persist in this field. This review seeks to elucidate the critical role of mitochondria in osteoporosis research, examine their intricate relationship with bone metabolism, and synthesize current research advances alongside future directions. Ultimately, it aims to offer novel insights for the prevention and treatment of osteoporosis.

Introduction and Objective: Data from human and animal studies demonstrated that the gut microbiota influences various diseases, including type 1 diabetes (T1D) and type 2 diabetes. However, to date, there are only a few clinical studies exploring the role of gut microbiota in Diabetic ketoacidosis patients, while none of the studies have compared the bacterial communities between Diabetic ketoacidosis patients and patients with diabetic ketosis and high glucose state. Methods: In the current study, the gut microbiota-related changes were characterized by 16S rRNA-based microbial profiling among patients with DKA, DK, as well as matched diabetic controls. Results: The diagram revealed that 495 OTUs were common to all fecal samples. Furthermore, 214 OTUs were identified in the DK group, 172 OTUs in diabetes group. At the phylum level, Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria were the predominant phyla in patients with DK as well as healthy controls. At the genus level, the proportion of Bacteroides was maximal in both groups, while the proportion of Lactobacillales was down-regulated in patients with DK. At the phylum and genus levels, the intestinal microbiota composition of the DK patients was changed as compared to that of the healthy controls. The LEfSe analysis demonstrated ten discriminative features (LDA score > 3, p < 0.05). The members of s_Faecalibacterium_prausnitzii and Oscillospirales were enriched in samples from healthy controls, whereas Gammaproteobacteria and Proteobacteria were enriched in DKA patients significantly. Conclusion: In summary, the current study, for the first time, presented distinct features of the intestinal microbiota in patients with DKA and DK. These results would aid in establishing the principles guiding DKA treatment. However, additional studies are essential to understand the mechanism underlying this disease and intestinal microbiota. Disclosure T. Shi: None. Funding National Natural Science Foundation of China (82200937)

Pharmaceutical contaminants are causing great attention for the public people, urgently requiring to be eliminated from the environment. Herein, commercial pharmaceutical carbamazepine was chosen as a model to be degraded by a heterogeneous Fenton system using natural pyrite as catalyst. The catalyst was characterized by X‐ray diffraction apparatus, high‐resolution transmission electron microscopy, and X‐ray photoelectron spectroscopy. The elements composition and chemical states of pyrite changed significantly after the Fenton reaction, which promoted the production of active species in the electron transfer process. The degradation efficiency of carbamazepine (2.5 mg/L) can reach 99.71% after 30 min with 0.3 g/L of pyrite and 5 mM of H2O2, respectively. The reaction system was suitable for a wide range of pH (3–9). The environmental adaptability examination of pyrite showed that humic acid (HA) had inhibitory effects on the degradation of carbamazepine. While the changes of degradation efficiency of carbamazepine were inconspicuous in the presence of and , indicating strong anti‐interference to environment common anions. Free‐radical capturers suggested that hydroxyl radical (∙OH), superoxide radical (), and singlet oxygen (1O2) participated in the degradation of carbamazepine. This research has offered a new strategy of “treating wastes with wastes” to use pyrite to remove emerging pollutants.

Pregnancy requires metabolic adaptations in order to meet support fetal growth with nutrient availability. In this study, the influence of pregnancy on metabolically active organs (adipose tissues in particular) was investigated. Our results showed that maternal weight and adipose mass presented dynamic remodeling in the periparturient mice. Meanwhile, pregnancy mice displayed obvious glucose intolerance and insulin resistance in late pregnancy as compared to non-pregnancy, which were partially reversed at parturition. Further analyses revealed that different fat depots exhibited site-specific adaptions of morphology and functionality as pregnancy advanced. Brown and inguinal white adipose tissue (BAT and IngWAT) exhibited obviously decreased thermogenic activity; by contrast, gonadal white adipose tissue (GonWAT) displayed remarkably increased lipid mobilization. Notably, we found that mammary gland differentiation was enhanced in IngWAT, followed by BAT but not in GonWAT. These result indicated that brown and white adipose tissues might synergistically play a crucial role in maintaining the maximum of energy supply for mother and fetus, which facilitates the mammary duct luminal epithelium development as well as the growth and development of fetus. Accompanied with adipose adaptation, however, our results revealed that the liver and pancreas also displayed significant metabolic adaptability, which together tended to trigger the risk of maternal metabolic diseases. Importantly, pregnancy-dependent obesity in our mice model resembled the disturbed metabolic phenotypes of pregnant women such as hyperglyceridemia and hypercholesterolemia. Our findings in this study could provide valuable clues for better understanding the underlying mechanisms of metabolic maladaptation and facilitate the development of the prevention and treatment of metabolic diseases.

Objective: Genome-scale CRISPR-Cas9 knockout coupled with single-cell RNA sequencing (scRNA-seq) has been used to identify functionrelated genes. However, this method may knock out too many genes, leading to low efficiency in finding genes of interest. Insulin secretion is controlled by several electrophysiological events, including fluxes of KATP depolarization and K+ repolarization. It is well known that glucose stimulates insulin secretion from pancreatic f3-cells, mainly via the KATP depolarization channel, but whether other nutrients directly regulate the repolarization K+ channel to promote insulin secretion is unknown. Methods: We used a system involving CRISPR-Cas9-mediated knockout of all 83 K+ channels and scRNA-seq in a pancreatic f3 cell line to identify genes associated with insulin secretion. Results: The expression levels of insulin genes were significantly increased after all -K+ channel knockout. Furthermore, Kcnb1 and Kcnh6 were the two most important repolarization K+ channels for the increase in high-glucose-dependent insulin secretion that occurred upon application of specific inhibitors of the channels. Kcnh6 currents, but not Kcnb1 currents, were reduced by one of the amino acids, lysine, in both transfected cells, primary cells and mice with f3-cell-specific deletion of Kcnh6. Conclusions: Our function-related CRISPR screen with scRNA-seq identifies Kcnh6 as a lysine-specific channel. (c) 2024 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

This study synthesized a series of carbazole compounds and tested their antimicrobial activity. Several of the synthesized compounds demonstrated potent inhibitory effects against Gram-negative bacteria. Molecular docking simulations with the fatty acid synthesis enzyme FabH revealed their potential antimicrobial action by interfering with fatty acid synthesis. Additionally, ADMET analysis confirmed favorable pharmacokinetic properties, providing a foundation for drug development and preclinical research. Furthermore, the optimized compound 2-(9HCarbazol-9-yl)-N-(4-(trifluoromethoxy)phenyl)acetamide was evaluated for its inhibitory and disruptive effects on biofilms using live/dead cell staining. The results demonstrated significant inhibition and disruption of biofilms, enhancing their antimicrobial efficacy. These findings offer valuable clues for the development of new antimicrobial drugs and hold promise for addressing the challenge of antimicrobial resistance with novel therapeutic strategies.

The aim of the study was to investigate the influence of Exenatide combined with Metformin on fasting blood glucose, postprandial glucose, triglycerides, total cholesterol, alanine aminotransferase, aspartate aminotransferase, and intestinal flora in type 2 diabetes mellitus cases with non-alcoholic fatty liver disease. A total of 128 type 2 diabetes mellitus patients with non-alcoholic fatty liver disease, diagnosed from January 2019 to January 2022, were included and randomly assigned to either Group A (n=64) or Group B (n=64). Group A received Metformin, while Group B received Exenatide injection and Metformin. After 24 weeks of treatment, blood glucose indices (fasting blood glucose and postprandial glucose), blood lipid indices (triglycerides and total cholesterol), liver function indices (alanine aminotransferase and aspartate aminotransferase) were all lower in Group B than in Group A (P < 0.001 for all). ---Continue

Objective: The present study aims to investigate the alterations of serum proteomic and metabolomic profiles in Chinese patients with severe and active Graves’ Orbitopathy (GO). Materials and Methods: Thirty patients with GO and 30 healthy volunteers were enrolled. The serum concentrations of FT3, FT4, T3, T4, and thyroid-stimulating hormone (TSH) were analyzed, after which TMT labeling-based proteomics and untargeted metabolomics were performed. Metabo- Analyst and Ingenuity Pathway Analysis (IPA) was used for integrated network analysis. A nomogram was established based on the model to explore the disease prediction ability of the identified feature metabolites. Results: One hundred thirteen proteins (19 up-regulated and 94 down-regulated) and 75 metabolites (20 increased and 55 decreased) were significantly altered in GO compared to the control group. By combining the lasso regression, IPA network, and protein-metabolite-disease sub-networks, we extracted feature proteins (CPS1, GP1BA, and COL6A1) and feature metabolites (glycine, glycerol 3-phosphate, and estrone sulfate). The logistic regression analysis revealed that the full model with the prediction factors and three identified feature metabolites had better prediction performance for GO compared to the baseline model. The ROC curve also indicated better prediction performance (AUC = 0.933 vs. 0.789). Conclusion: A new biomarker cluster combined with three blood metabolites with high statistical power can be used to discriminate patients with GO. These findings provide further insights into the pathogenesis, diagnosis, and potential therapeutic targets for this disease.

报道1例在北京同仁医院内分泌科长期随访的长病程正常体重2型糖尿病（T2DM）患者，使用利拉鲁肽治疗后疗效及靶器官保护随访4.5年的结果。患者为53岁男性，糖尿病病史15年，体重指数23.76 kg/m 2，既往曾使用基础胰岛素联合口服药治疗，疗效欠佳入院。入院诊断：T2DM、双眼非增殖期糖尿病视网膜病变、糖尿病周围神经病变、冠状动脉粥样硬化性心脏病、高血压病2级很高危组、外周多动脉粥样硬化。予短期胰岛素强化治疗后调整为精蛋白生物合成人胰岛素16 U、1次/晚联合利拉鲁肽注射液1.2 mg、1次/d，盐酸二甲双胍1 g、2次/d治疗，随访4.5年期间，长期糖化血红蛋白控制基本达标，体重稳定，糖尿病视网膜病变无进展，冠状动脉粥样硬化性心脏病好转。实现兼顾降糖、稳定体重、靶器官保护的多重获益。

ObjectiveArsenic trioxide (ATO) exerts therapeutic effects on various solid tumors, and artesunate (ART) synergizes with antitumor drugs. We herein combined ART and an ATO prodrug (ATOP) in pH-responsive and liver-targeting liposomes to improve targeted hepatocellular carcinoma (HCC) treatment.Methods1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-hydrazone (HYD)-polyethylene glycol (PEG)-glycyrrhetinic acid (GA) (DSPE-HYD-PEG-GA) was synthesized and characterized. The optimal ratio of ART and ATOP was selected. Calcium arsenate nanoparticles (CaAs NPs) and DSPE-HYD-PEG-GA@ART/CaAs NPs liposomes were prepared and their physicochemical properties were characterized. Their intracellular uptake, intracellular localization, uptake pathway identification, cytotoxicity, proapoptotic effects, and relevant mechanisms were studied.ResultsThe DSPE-HYD-PEG-GA was successfully synthesized. The best ratio of ART and ATOP was 7:1. The particle size of CaAs NPs under transmission electron microscopy was 142.39 & PLUSMN; 21.50 nm. Arsenic (As), calcium, and oxygen elements were uniformly distributed in CaAs NPs, and the drug loading and encapsulation efficiency of As are 37.28% and 51.40%, respectively. The liposomes were elliptical, and the particle size was 100.91 & PLUSMN; 39.31 nm. The liposome cell intake was significantly increased in Huh-7 cells. The liposomes entered the cell through macropinocytosis and caveolin-mediated endocytosis and were predominantly distributed in the cytoplasm. They exerted an excellent inhibitory effect on Huh-7 cells and promoted tumor cell apoptosis through lipid peroxidation, mitochondrial membrane potential reduction, and cell-cycle blockage.ConclusionsThe pH-responsive and liver-targeting drug delivery system for the combination delivery of ART with ATOP showed promising effects on hepatocellular carcinoma (HCC).