Drug-induced liver injury(DILI)is one of the major challenges in drug development and clinical practice,and effective prevention and con-trol measures remain lacking.Research has shown that DILI is primarily mediated by immune respons-es.Human leukocyte antigen(HLA)alleles are cur-rently the strongest genetic factors reported to be associated with DILI.Due to the low positive predic-tive value of HLA alleles,preemptive HLA genetic screening has limited clinical utility in preventing DILI.However,its high negative predictive value makes it valuable for DILI diagnosis and causality assessment.In recent years,polymorphisms in im-mune-related genes-such as those involved in anti-gen processing and presentation pathways,T-cell receptors,immunostimulatory molecules,and cyto-kines-have been found to be associated with DILI.Future studies combining these genes with HLA analysis may provide deeper mechanistic insights into DILI and facilitate their translational applica-tion in clinical practice,ultimately improving drug safety.

Objective To investigate the predictive value of atherosclerotic index of plasma(AIP)for the risk of coronary heart disease(CHD)in patients with nonalcoholic fatty liver disease(NAFLD).Methods A retrospective analysis was conducted in 299 patients with NAFLD.Based on presence or absence of CHD,the patients were divided into NAFLD with CHD group(n=177)and NAFLD group(n=122).Clinical data were collected from both groups,and AIP was calculat-ed.Multivariate Logistic regression analysis was performed to explore the independent risk factors for CHD in patients with NAFLD.Receiver operating characteristic(ROC)curves were plotted to evalu-ate the predictive value of AIP for the risk of CHD in patients with NAFLD.Results The NAFLD with CHD group had a higher proportion of males,smokers,and higher levels of alanine aminotrans-ferase(ALT),aspartate aminotransferase(AST),fasting plasma glucose(FPG),triglycerides(TG),low-density lipoprotein cholesterol(LDL-C),γ-glutamyltransferase(GGT),uric acid(UA),and AIP than the NAFLD group.The NAFLD with CHD group also had lower levels of high-density lipoprotein cholesterol(HDL-C)than the NAFLD group(P＜0.05).Multivariate Logistic regression analysis revealed that males(OR=2.548,95％CI,1.402 to 4.632,P=0.002),high levels of AST(OR=1.038,95％CI,1.002 to 1.077,P=0.041),high levels of LDL-C(OR=1.811,95％CI,1.242 to 2.640,P=0.002),and high AIP(OR=16.117,95％CI,1.874 to 138.609,P=0.011)were independent risk factors for CHD in patients with NAFLD(P＜0.05).ROC curve analysis showed that AIP had an area under the curve of 0.746(95％CI,0.688 to 0.804)for pre-dicting CHD in patients with NAFLD,with a sensitivity of 76.3％and a specificity of 73.0％.Conclusion AIP is an independent influencing factor for CHD in patients with NAFLD and has certain predictive value for the risk of CHD in these patients.

Recently,diffusion models have emerged as a promising paradigm for molecular design and optimization.However,most diffusion-based molecular generative models focus on modeling 2D graphs or 3D geom-etries,with limited research on molecular sequence diffusion models.The International Union of Pure and Applied Chemistry(IUPAC)names are more akin to chemical natural language than the simplified molecular input line entry system(SMILES)for organic compounds.In this work,we apply an IUPAC-guided conditional diffusion model to facilitate molecular editing from chemical natural language to chemical language(SMILES)and explore whether the pre-trained generative performance of diffusion models can be transferred to chemical natural language.We propose DiffIUPAC,a controllable molecular editing diffusion model that converts IUPAC names to SMILES strings.Evaluation results demonstrate that our model out-performs existing methods and successfully captures the semantic rules of both chemical languages.Chemical space and scaffold analysis show that the model can generate similar compounds with diverse scaffolds within the specified constraints.Additionally,to illustrate the model's applicability in drug design,we conducted case studies in functional group editing,analogue design and linker design.

Recently, diffusion models have emerged as a promising paradigm for molecular design and optimization. However, most diffusion-based molecular generative models focus on modeling 2D graphs or 3D geometries, with limited research on molecular sequence diffusion models. The International Union of Pure and Applied Chemistry (IUPAC) names are more akin to chemical natural language than the Simplified Molecular Input Line Entry System (SMILES) for organic compounds. In this work, we apply an IUPAC-guided conditional diffusion model to facilitate molecular editing from chemical natural language to chemical language (SMILES) and explore whether the pre-trained generative performance of diffusion models can be transferred to chemical natural language. We propose DiffIUPAC, a controllable molecular editing diffusion model that converts IUPAC names to SMILES strings. Evaluation results demonstrate that our model outperforms existing methods and successfully captures the semantic rules of both chemical languages. Chemical space and scaffold analysis show that the model can generate similar compounds with diverse scaffolds within the specified constraints. Additionally, to illustrate the model's applicability in drug design, we conducted case studies in functional group editing, analogue design and linker design.

Drug-induced liver injury(DILI)is one of the major challenges in drug development and clinical practice,and effective prevention and con-trol measures remain lacking.Research has shown that DILI is primarily mediated by immune respons-es.Human leukocyte antigen(HLA)alleles are cur-rently the strongest genetic factors reported to be associated with DILI.Due to the low positive predic-tive value of HLA alleles,preemptive HLA genetic screening has limited clinical utility in preventing DILI.However,its high negative predictive value makes it valuable for DILI diagnosis and causality assessment.In recent years,polymorphisms in im-mune-related genes-such as those involved in anti-gen processing and presentation pathways,T-cell receptors,immunostimulatory molecules,and cyto-kines-have been found to be associated with DILI.Future studies combining these genes with HLA analysis may provide deeper mechanistic insights into DILI and facilitate their translational applica-tion in clinical practice,ultimately improving drug safety.

Lignans derived from Eucommia ulmoides Oliver (Eucommia lignans) inhibit the progression of inflammatory diseases, while their effect on the progression of diabetic nephropathy (DN) remained unclear. This work was designed to assess the function of Eucommia lignans in DN. The major constituents of Eucommia lignans were analyzed by UPLC-Q-TOF-MS/MS. The binding between Eucommia lignans and aldose reductase (AR) was predicted by molecular docking. Eucommia lignans (200, 100, and 50 mg·kg^-1) were used in model animals to evaluate their renal function changes. Rat glomerular mesangial cells (HBZY-1) were transfected with sh-AR, sh-AMPK, and oe-AR in the presence of high glucose (HG) or HG combined with Eucommia lignans to evaluate whether Eucommia lignans affected HG-induced cell injury and mitochondrial dysfunction through the AR/Nrf2/HO-1/AMPK axis. Eucommia lignans significantly attenuated the progression of DN in vivo. Eucommia lignans notably reversed HG-induced upregulation of inflammatory cytokines and mitochondrial injury, while downregulating the levels of Cyto c, caspase 9, AR, and NOX4 in HBZY-1 cells. In contrast, HG-induced downregulation of Nrf2, HO-1 and p-AMPKα levels were abolished by Eucommia lignans. Meanwhile, knockdown of AR exerted similar therapeutic effect of Eucommia lignans on DN progression, and AR overexpression reversed the effect of Eucommia lignans. Eucommia lignans alleviated renal injury through the AR/Nrf2/HO-1/AMPK axis. Thus, these findings might provide evidence for the use of Eucommia lignans in treating DN.
Animals ; Rats ; AMP-Activated Protein Kinases/genetics* ; Diabetes Mellitus ; Diabetic Nephropathies/prevention & control* ; Eucommiaceae/metabolism* ; Lignans/therapeutic use* ; Molecular Docking Simulation ; NF-E2-Related Factor 2/metabolism* ; Tandem Mass Spectrometry

The human leukocyte antigen (HLA) molecules encoded within the human major histocompatibility complex are a group of highly conserved cell surface proteins, which are related to antigen recognition. HLA genes display a high degree of genetic polymorphism, which is the basis of individual differences in immunity. Specific HLA genotypes have been highly associated with typical adverse drug reactions. HLA-A*31:01 and HLA-B*15:02 are associated with carbamazepine-induced severe cutaneous adverse reactions, HLA-B*57:01 is related to abacavir-induced drug-induced hypersensitivity syndrome and flucloxacillin/pazopanib-induced drug-induced liver injury, while HLA-B*35:01 is a potential biomarker for predicting polygonum multiflorum-induced liver injury. It is not clear how small drug molecules to interact with HLA molecules and T cell receptors (TCR). There are four mechanistic hypotheses, including the hapten/prohapten theory, the pharmacological interaction concept, the altered peptide repertoire model, and the altered TCR repertoire model.
Drug-Related Side Effects and Adverse Reactions/genetics* ; Genotype ; HLA Antigens/genetics* ; Humans ; Polymorphism, Genetic

AIM: To evaluate the bioequivalence of the test and reference preparations of solifenacin succinate tablets administered once orally under fasting and fed conditions in Chinese healthy volunteers. METHODS: The study was designed as single-center, randomized, open, self-crossover and twenty four healthy volunteers were recruited respectively in fasting and fed conditions. Subjects were assigned to receive a single oral of the test or reference formulation per period at a dose of 10 mg. The plasma concentration of solifenacin was analyzed by LC-MS/MS. The major pharmacokinetic parameters were calculated by WinNonlin 7.0, then the bioequivalence was evaluated.RESULTS: The main pharmacokinetic parameters of a single oral solifenacin succinate under fasting condition for test and reference preparation were as follows: C

Rituximab is the main monoclonal antibody for targeted therapy currently. With more rituximab biosimilars appearing and clinical evaluation need increasing, it is crucial to develop rapid and effective quantitative methods to determine the rituximab blood concentration in biological matrices for drug metabolism and pharmacokinetics (DMPK) analysis. This article reviewed the application of ligand binding method (LBA), liquid chromatography-tandem mass spectrometry (LC-MS/MS) and emerging quantitative technology to detect the blood concentration of Rituximab, which may provide valuable information for the analysts and testers when developing quantitative methods for rituximab and its biosimilars.

Objective: To assess the expression of miR-21, miR-221, and miR-222 in exosomes of CAL27 tongue squamous cell carcinoma cells. Methods : CAL27 tongue squamous cell carcinoma cells and normal human oral keratinocytes (HOKs) were cultured, and then, the cultured supernatant was collected to separate the exosomes. Exosomes were detected by electron microscopy, and the expression levels of miR-21, miR-221, and miR-222 in the exosomes of tongue cancer cells were measured by qRT-PCR. Results: Exosomes existed in the cultured supernatants of CAL27 cells and HOKs. Additionally, the expression levels of miR-21, miR-221, and miR-222 in the exosomes of CAL27 cells were significantly enhanced compared with those in the HOK exosomes (P < 0.05). Conclusion The expression levels of miR-21, miR-221, and miR-222 were markedly enhanced in the exosomes of CAL27 tongue squamous cell carcinoma cells.