Zuo et al. identified a novel post-translational modification-protein pyruvylation-and revealed that pyruvate, a glycolysis metabolite, induces STAT1 pyruvylation at Lys201, which blocks signal transducer and activator of transcription 1 (STAT1)-signal transducer and activator of transcription 2 (STAT2) binding to suppress type I interferon signaling and antiviral immunity. This study provides new insights into antiviral therapy for patients with metabolic diseases.

Promoting thermogenesis in adipose tissue to enhance energy expenditure is widely regarded as a promising strategy for obesity treatment. However, the development of effective thermogenic drugs remains challenging. Our screenings identified the natural compound Akebia Saponin D (ASD) as a potent brown fat thermogenesis activator in mice, showing effects through mitochondrial brown fat uncoupling protein 1 (UCP1)-dependent pathways. ASD was found to significantly mitigate high-fat diet-induced obesity and enhance the mitochondrial quality of brown adipocytes to promote thermogenesis. Utilizing human protein microarrays, cellular thermal shift assay, and drug affinity responsive target stability, along with microscale thermophoresis and molecular docking analysis, we identified ubiquitin carboxyl-terminal hydrolase 4 (USP4) as a direct target of ASD. ASD interacts with USP4 and promotes the deubiquitination of peroxisome proliferator-activated receptor gamma, thus inhibiting its proteasomal degradation and enhancing the transcriptional activation of UCP1 in brown adipocytes. Additionally, USP4 knockdown was shown to attenuate brown fat thermogenesis induced by ASD. In summary, our findings demonstrate that ASD promotes brown fat thermogenesis by targeting USP4, highlighting its potential as a promising natural small molecule for obesity treatment.

Although immune checkpoint inhibitor-based immunotherapy has shown clinical efficacy in various cancer types, its efficacy in pancreatic cancer remains limited. This limitation is primarily attributed to the dense stromal tumor microenvironment (TME) and highly immunosuppressive TME of pancreatic cancer. The dense stromal TME forms a physical barrier that severely hinders the penetration and accumulation of therapeutic agents and immune cells. Additionally, it collaborates with the immunosuppressive TME to weaken immune responses against tumors. To overcome these challenges, a piezoelectric nanoparticle system, BTO@BAL, was developed, which combined piezoelectric nanomaterial barium titanate (BTO), a targeting peptide, and an amphiphilic prodrug molecule. The prodrug molecule is composed of a small-molecule PD-L1 inhibitor (BMS1166) and a nitric oxide (NO) donor (Arg)9, linked by a thioketal bond. Upon ultrasound (US)-triggered piezocatalysis, BTO continuously generated reactive oxygen species (ROS) in the hypoxic TME. On the one hand, ROS oxidized (Arg)9 to release NO, which degraded the dense stromal barrier of pancreatic cancer, remodeled the TME, improved tumor mechanical properties, and reduced stiffness. Combined with the targeted peptide, this strategy synergistically improved drug delivery efficiency. Furthermore, the combined action of ROS and NO enhanced the immunogenicity of pancreatic cancer, promoting the activation and maturation of local dendritic cells, thereby strengthening antitumor immune responses. On the other hand, ROS induced thioketal bond cleavage to release BMS1166, effectively down-regulating PD-L1 expression on KPC cells, reshaping the immunosuppressive TME of pancreatic cancer, and further amplifying the efficacy of immunotherapy. This strategy integrated US-triggered piezocatalysis with gas therapy, greatly enhancing pancreatic cancer immunotherapy and offering a theoretical foundation for developing tumor theranostic platforms.

ObjectiveEstablish a deep learning ultrasound radiomics model based on destruction-replenishment contrast-enhanced ultrasound (DR-CEUS) for the early prediction of acute kidney injury (SA-AKI).MethodThis paper proposes a deep learning ultrasound radiomics model (DLUR). Deep learning models were separately established using ResNet18, ResNet50, ResNext18, and ResNext50 networks. Based on the features extracted from the fully connected layers of the optimal model, a deep learning ultrasound radiomics model (DLUR) was established using three classification models (built with 3 classifiers). The predictive performance of the best DLUR model was compared with the visual assessments of two groups of ultrasound physicians with varying levels of experience. The performance of each model and the ultrasound physicians was evaluated by assessing the receiver operating characteristic (ROC) curves. The area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were subsequently calculated.ResultsCompared to the ResNet18 model, the DLUR model based on logistic regression (DLUR-LR) demonstrated the best predictive performance, showing a Net Reclassification Improvement (NRI) value of 0.210 (p < 0.05). The Integrated Discrimination Improvement (IDI) value for the corresponding stage was 0.169 (p < 0.05). Additionally, the performance of the DLUR-LR model also surpassed that of senior ultrasound physicians (AUC, 0.921 vs. 0.829, p < 0.05).ConclusionBy combining deep learning and ultrasound radiomics, a deep learning ultrasound radiomics model with outstanding predictive efficiency and robustness has demonstrated excellent capability in the early prediction of acute kidney injury (SA-AKI).

Shotgun metagenomics has become a pivotal technology in microbiome research, enabling in-depth analysis of microbial communities at both the high-resolution taxonomic and functional levels. This approach provides valuable insights of microbial diversity, interactions, and their roles in health and disease. However, the complexity of data processing and the need for reproducibility pose significant challenges to researchers. To address these challenges, we developed EasyMetagenome, a user-friendly pipeline that supports multiple analysis methods, including quality control and host removal, read-based, assembly-based, and binning, along with advanced genome analysis. The pipeline also features customizable settings, comprehensive data visualizations, and detailed parameter explanations, ensuring its adaptability across a wide range of data scenarios. Looking forward, we aim to refine the pipeline by addressing host contamination issues, optimizing workflows for third-generation sequencing data, and integrating emerging technologies like deep learning and network analysis, to further enhance microbiome insights and data accuracy. EasyMetageonome is freely available at https://github.com/YongxinLiu/EasyMetagenome.

This study proposes a new method B-mode ultrasound to assess right hemidiaphragm mobility during maximal respiration in healthy adults. In 29 healthy volunteers, the mean and coefficient of variation of diaphragmatic excursion measured by M-mode and a new B-mode measurements were compared, and their agreement was assessed using the Bland-Altman analysis. Intra-observer and inter-observer agreement were analyzed using intraclass correlation coefficients (ICC) in 15 healthy volunteers. The mean values for diaphragmatic mobility using M-mode and B-mode ultrasound methods were 6.03 ± 1.21 cm and 3.97 ± 0.93 cm, respectively, with coefficients of variation of 0.1103 ± 0.0627 and 0.0772 ± 0.0347. The Bland-Altman plot showed the consistency of the two methods. The ICCs for the first and second M-mode measurements by the senior physician, compared with those by the junior physician, were 0.851 (95% CI: 0.615-0.947), 0.671 (95% CI: 0.177-0.883), and 0.659 (95% CI: 0.168-0.877). For the B-mode ultrasound measurements, the corresponding ICC values were 0.812 (95% CI: 0.533-0.933), 0.832 (95% CI: 0.464-0.945), and 0.701 (95% CI: 0.208-0.896)." Measurements of diaphragmatic excursion using B-mode ultrasound show strong agreement with M-mode ultrasound in healthy volunteers, in addition to demonstrating lower variability and higher reproducibility.

NETosis plays a pivotal role in the innate immune response after diabetic myocardial infarction (MI), exerting a profound influence on the overall pathological process and potential recovery outcomes. The metabolism of diabetic cardiomyocyte actively creates a specialized micro environment for the innate immune response after MI. However, the mechanism by which cardiac metabolism drives NETosis remains unclear. Utilizing public databases of human MI sc-RNA datasets, we discovered that cardiomyocyte PDK4 expression mediates the intensification of glycolysis, which is strongly correlated with NETosis. Through mass spectrometry imaging and phenotype assessment, we ascertained that specific knockout of PDK4 in cardiomyocytes (PDK4fl/flMyh6Cre, male, 6 weeks) led to a reduction in NETosis by restraining micro environmental lactate (LA) production. In addition, the role of LA in promoting NETosis has been further corroborated by in vivo/in vitro experiments involving LA supplementation and its absence. Moreover, LA redirects neutrophil metabolic flux from glycolysis to the pentose-phosphate pathway (PPP). Mechanistically, LA triggers metabolic remodeling through the PRMT9-mediated methylation of PFKL at the R301 residue, resulting in PFKL inactivation and the consequent restriction of glycolysis. Our findings reveal the crucial role of cardiomyocyte metabolism in NETosis, shedding light on the role of LA as a vital signaling molecule in the crosstalk between cardiomyocytes and neutrophils. Importantly, we screened pitavastatin, a potential inhibitor of PDK4 among the FDA-approved drugs, and verified that it can alleviate NETosis in diabetic MI, which provides a rationale for drug selection in diabetic MI patients.

Akebia saponin D (ASD) is a bioactive triterpenoid saponin extracted from Dipsacus asper Wall. ex DC.. This study aimed to investigate the effects of ASD on allergic airway inflammation. Human lung epithelial BEAS-2B cells and bone marrow-derived mast cells (BMMCs) were pretreated with ASD (50, 100 and 200 μΜ) and AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) (1 mM), and then stimulated with lipopolysaccharide (LPS) or IL-33. Pretreatment with ASD and AICAR significantly inhibited TNF-α and IL-6 production from BEAS-2B cells, and IL-13 production from BMMCs. Moreover, pretreatment with ASD and AICAR significantly increased p-AMPK expression in BEAS-2B cells. Inhibition of AMPK by siRNA and compound C partly abrogated the suppression effect of ASD on TNF-α, IL-6, and IL-13 production. Asthma murine model was induced by ovalbumin (OVA) challenge and treated with ASD (150 and 300 mg/kg) or AICAR (100 mg/kg). Infiltration of eosinophils, neutrophils, monocytes, and lymphocytes, and production of TNF-α, IL-6, IL-4, and IL-13 were attenuated in ASD and AICAR treated mice. Lung histopathological changes were also ameliorated after ASD and AICAR treatment. Additionally, it showed that treatment with ASD and AICAR increased p-AMPK expression in the lung tissues. In conclusion, ASD exhibited protective effects on allergic airway inflammation through the induction of AMPK activation.

Sonodynamic therapy for pancreatic cancer is always limited to poor drug delivery and resistance. The insufficient drug delivery is mostly associated with the abundant fibrotic stroma which consisting of a natural physical barrier. In addition, the activated DNA repair pathway associated with reactive oxygen (ROS) therapy greatly resist and weaken the SDT efficacy. Based on these facts, we herein presented an ultrasound responsive microbubble system of PARP1 siRNA-Pyropheophorbide/SNO (P-PPaS MBs), which were self-assembled by lipids covalently conjugated with Pyropheophorbide, DSPE-PEG2000-SNO, and DC-Chol, while the PARP1 siRNA was absorbed onto the surface of microbubbles. Upon local ultrasound irradiation, the in situ micro-nano conversion induced cavitation effect and spatial–temporal controlled release of NO mediated by ROS generated from pyropheophorbide could facilitate the deeper penetration of sonosensitizer and siRNA at pancreatic tumor sites. SDT could effectively kill tumor cells, while PARP1 inhibition blocked the DNA repair pathway to further enhance the tumor killing efficiency. Therefore, controlled NO self-supply and gene therapy assisted SDT had the potential to be an effective strategy for deeper pancreatic cancer therapy.

我国约有慢性乙肝病毒感染者8600万,其中约3200万为慢性乙型肝炎患者,另外5400万为乙肝病毒携带者.每位乙肝病毒感染者的背后都有一个家庭.如果家中有慢性乙肝病毒感染者,家庭成员既不要惧怕,也不能大意,要科学、正确对待.

Objective:To investigate the clinical features of amoebic enteritis with acquired immunodeficiency syndrome (AIDS) patients.Methods:The clinical data of patients diagnosed of amoebic enteritis in Beijing Ditan Hospital, Capital Medical University from April 2011 to October 2019 were collected. They were divided into amoebic enteritis group and amoebic enteritis with AIDS group. The laboratory indexes, pathological examination and colonoscopic appearance of the two groups were analyzed retrospectively. The clinical characteristics of amoeba enteritis with AIDS patient were summarized. Pearson chi-square test, continuous calibration chi-square test, Fisher′s exact test, independent sample t test and Mann-Whitney U test were used for statistical analysis. Results:A total of 53 patients with amoebic enteritis were included, including 31 cases in amoebic enteritis group and 22 cases in amoebic enteritis with AIDS group. The detection rate of amoebic trophozoite in cases feces in amoebic enteritis with AIDS group was lower than that in amebic enteritis group (68.2%(15/22) vs 96.8%(30/31)) with statistical significance ( χ2=6.13, P=0.013). The detection rate of amoebic trophozoite by colonoscopy in amoebic enteritis with AIDS was higher than that in amebic enteritis group (7/15 vs 1/16) with statistical significance (Fisher′s exact test, P=0.015). Amoebic enteritis with AIDS cases had lower levels of red blood cell count ((3.48±0.80)×10 12/L vs (4.11±0.81)×10 12/L), hemoglobin ((102.40±25.74) g/L vs (121.52±22.73) g/L), albumin ((29.07±5.94) g/L vs (35.48±6.92) g/L), CD4 + T-lymphocyte counts (76.00 (26.25, 228.50)/μL vs 514.50 (444.00, 752.25)/μL) than patients with amoebic enteritis, which were all statistically significant ( t=2.80, 2.86, 3.52 and Z=-5.27, respectively, all P<0.050). And amoebic enteritis with AIDS cases had higher level of alanine aminotransferase (ALT) (21.00 (12.85, 41.33) U/L vs 13.40 (9.40, 22.40) U/L, Z=-2.32, P=0.020). The results of colonoscopy showed that amoebic enteritis with AIDS cases had higher rate of intestinal mucosa ulcer than amoebic enteritis cases ((11/15 vs 5/16) Fisher′s exact test, P=0.032). Conclusions:Amoebic enteritis with AIDS cases have lower levels of red blood cells, hemoglobin, albumin and CD4 + T-lymphocyte counts and higher levels of ALT. Amoebic enteritis with AIDS cases have higher rate of intestinal mucosa ulcer detected by colonoscopy. Colonoscopy combined with biopsy play an important role in the diagnosis of amoebic enteritis with AIDS patients.

原发性硬化性胆管炎(primary sclerosing cholangitis,PSC)是一种以多灶性胆管狭窄和进展性肝病为特征的胆汁淤积性肝病[1-2].PSC 好发于男性患者,确诊年龄在20～57岁,欧美国家报道患病率3.85/10万～16.2/10万,亚洲报道患病率0.95/10万～3.85/10万不等[3-4].PSC临床表现复杂多样,除肝脏受累外,还可合并炎症性肠病(inflammatory bowel disease,IBD),发生胆管癌及结直肠癌风险也会升高[5-6].PSC诊断上缺乏特异性诊断标志物,特别需要和IgG4相关硬化性胆管炎(IgG4-related scle-rosing cholangitis,IgG4-SC)及其他继发性硬化性胆管炎(secondary sclerosing cholangitis,SSC)等相鉴别.近年来相关学会先后发布了PSC诊疗相关指南规范,微生态及组学研究用于PSC的诊断与鉴别诊断也不断进展[7-8],本文拟就相关内容阐述如下.

酒精性肝病(alcoholic liver disease,ALD)是危害我国人民健康的主要肝脏疾病之一.党的十八大以来,我国肝病领域研究人员与全球同道一起围绕ALD进行深入研究并取得重要进展.在ALD发病机制领域,进一步阐明了基因多态性、肠道微生态和铁死亡在酒精性肝病中的重要作用.在ALD诊疗领域,针对ALD维持戒酒、重症酒精性肝炎药物治疗及ALD肝移植等方面工作不断突破.但我国ALD防控形势依旧严峻,仍需针对ALD的发病机制与诊疗进行深入研究,以期切实改善ALD患者预后,进一步降低ALD的社会负担.

Dietary intervention with a low glycemic index and full nutritional support is emerging as an effective strategy for diabetes management. Here, we found that the treatment of a novel compound dietary fiber and high-grade protein diet (CFP) improved glycemic control and insulin resistance in streptozotocin-induced diabetic mice, with a similar effect to liraglutide. In addition, CFP treatment ameliorated diabetes-related metabolic syndromes, such as hyperlipidemia, hepatic lipid accumulation and adipogenesis, systemic inflammation, and diabetes-related kidney damage. These results were greatly associated with enhanced gut barrier function and altered gut microbiota composition and function, especially those bacteria, microbial functions, and metabolites related to amino acid metabolism. Importantly, no adverse effect of CFP was found in our study, and CFP exerted a wider arrange of protection against diabetes than liraglutide. Thereby, fortification with balanced dietary fiber and high-grade protein, like CFP, might be an effective strategy for the management and treatment of diabetes.

Apolipoproteins (Apos) play an important role in regulating plasma lipid concentration. Complex disorders of Apos are highly related with diabetes mellitus, cardiovascular and other diseases. Direct measures of lipoprotein fractions for risk assessment suffer from inaccuracy in the dyslipidemia and pathological states. Therefore, a reliable precise assay will be of high clinical utility. LC-MS/MS methods with multiple reaction monitoring modes have proven suitable for multiplexed quantification. We aimed to develop a simple, cost-effective and amenable LC-MS/MS assay for quantification of ApoA-I, ApoE and ApoJ in human plasma. Standards were constructed from substitute matrix and proteotypic peptides for external calibration and corresponding stable isotope labeled peptides were added as internal standards to remove matrix effects. Analytical validation of the assay included the assessment of linearity, accuracy (RE: -3.02% to 5.32%), intra-assay precision (RSD: 2.50% to 6.56%), inter-assay precision (RSD: 0.78% to 6.68%), spiking recovery rate (accuracy: 87.17% to 112.71%), matrix effect (accuracy: 88.03% to 114.87%), and reproducibility and repeatability of sample preparation (RSD: 1.95% to 7.26%). The performance of proteotypic peptides ApoA-I, ApoE and ApoJ was sufficient for triplex quantitation within a linear range from 16.26 to 1626.41 pmol mL-1, 1.03 to 103.35 pmol mL-1 and 0.86 to 86.46 pmol mL-1 respectively. For all quantified peptides, the determination coefficient (R 2) was >0.997. Besides, the validated LC-MS/MS method has been successfully applied to the quantification of plasma samples in diabetes mellitus and cardiovascular diseases. We anticipate that this assay may provide an alternative method for future clinical applications.

Cases of unpredictable, idiosyncratic liver damage of moxifloxacin (MXF) have been occasionally reported. However, the health effects of MXF exposure remain controversial. The current study examined the metabolic phenotypes and intestinal flora characteristics of hepatotoxicity induced by MXF. Rats were administered moxifloxacin hydrochloride tablets at doses of 36, 72, and 108 mg/kg body weight/day for 21 days. The levels of tricarboxylic acid cycle intermediates were decreased, whereas those of lipids (arachidonic acid, hexadecanoic acid, and linoleic acid) were increased, reflecting disorders of energy–related and lipid metabolism. Enrichment analysis of the differential metabolites suggested that butanoate metabolism was associated with MXF–induced liver injury. 16S rRNA sequencing uncovered that the diversity of gut intestinal was decreased in MXF–treated rats. Specifically, the abundance of Muribaculaceae was increased, whereas that of Lachnospiraceae, a family of butyrate–producing bacteria, was decreased. The combined serum metabonomics and gut microbiome datasets illustrated the involvement of butanoic acid and energy metabolism in the regulatory changes of the gut–liver axis associated with MXF–induced liver injury. The regulation of endogenous small molecules and intestinal flora during drug–induced liver injury was first described from the perspective of the gut–liver axis, providing a research basis for the mechanism of clinical drug–induced liver injury.

Spermidine, a natural polyamine and physiological autophagy inducer, is involved in various physiological processes. However, the impact and mechanism of spermidine on nonalcoholic steatohepatitis (NASH) remains unclarified. We found that daily spermidine intake was significantly lower in volunteers with liver dysfunction than the healthy controls, and the serum and fecal spermidine levels were negatively correlated with the NASH phenotypes. Spermidine supplementation significantly attenuated hepatic lipid accumulation, insulin resistance, hepatic inflammation, and fibrosis in NASH mice induced by a western diet. The ameliorating effect of spermidine on lipid accumulation might be partly regulated by thyroid hormone-responsive protein (THRSP) signaling and autophagy. Moreover, spermidine altered the profile of hepatic bile acids (BAs) and microbial composition and function. Furthermore, spermidine reversed the progression of hepatic steatosis, inflammation, and fibrosis in mice with preexisting NASH. Therefore, spermidine ameliorates NASH partly through the THRSP signaling and the gut microbiota-mediated metabolism of BAs, suggesting that spermidine might be a viable therapy for NASH.

慢性乙型肝炎治疗的关键是抗病毒治疗.临床上长期使用阿德福韦酯或富马酸替诺福韦二吡呋酯抗病毒治疗的慢性乙型肝炎患者可发生范科尼综合征等罕见不良反应,临床上多采用恩替卡韦作为挽救治疗方案.但对于恩替卡韦治疗失败的范科尼综合征患者,后续抗病毒治疗的证据尚不多见.现报道1例恩替卡韦治疗失败的范科尼综合征患者,采用丙酚替诺福韦治疗有效,并对相关文献进行复习,为此类患者的治疗提供依据.

Metabolic syndrome (MetS) is a complex, multifactorial disease which lead to an increased risk of cardiovascular disease, type 2 diabetes, and stroke. However, selective, and potent drugs for the treatment of MetS are still lacking. Previous studies have found that Akebia saponin D (ASD) has beneficial effects on metabolic diseases such as obesity, atherosclerosis, and non-alcoholic fatty liver disease (NAFLD). Therefore, our study was designed to determine the effect and mechanism of action of ASD against MetS in a high-fat diet (HFD) induced mouse model. ASD significantly decreased plasma lipid and insulin resistance in these mice, and a targeted approach using metabolomic analyses of plasma and feces indicated that glucose and lipids in these mice crossed the damaged intestinal barrier into circulation. Furthermore, ASD was able to increase lipid excretion and inhibit intestinal epithelial lipid absorption. Results for gut microbiota composition showed that ASD significantly reduced HFD-associated Alistipes, Prevotella, and enhanced the proportions of Butyricimonas, Ruminococcus, and Bifidobacterium. After 14 weeks of ASD/fecal microbiota transplantation (FMT) interventions the developed gut barrier dysfunction was restored. Additionally, RNA-seq revealed that ASD reduced the lipid-induced tight junction (TJ) damage in intestinal epithelial cells via down-regulation of the PPAR-γ-FABP4 pathway in vitro and that use of the PPAR-γ inhibitor (T0070907) was able to partially block the effects of ASD, indicating that the PPAR-γ/FABP4 pathway is a critical mediator involved in the improvement of MetS. Our results demonstrated that ASD not only modifies the gut microbiome but also ameliorates the HFD-induced gut barrier disruption via down-regulation of the PPAR-γ-FABP4 pathway. These findings suggest a promising, and novel therapeutic strategy for gut protection against MetS.

酒精性肝病是危害我国人民健康的主要肝脏疾病之一.我国酒精性肝病发病率呈上升趋势.酒精性肝病的病因是过量饮酒,但其发病机制涉及乙醇代谢、氧应激损伤、免疫损伤及肠道微生态紊乱.目前,酒精性肝病,特别是酒精性肝炎的发病机制尚未完全阐明.酒精性肝病患者由于首诊时间较晚、戒酒困难及合并多系统损害等因素,整体预后不佳.目前针对酒精性肝病多学科诊疗体系尚不完善,针对酒精性肝病患者有效治疗药物尚不足.亟需我们深入开展酒精性肝病相关基础与临床研究,规范并优化酒精性肝病患者的诊疗以改善患者预后.