Based on the etiology and clinical diagnostic criteria of type 2 diabetes mellitus （T2DM）， identification and typing of treatment from the perspective of traditional Chinese and western medicine， the criteria for evaluating the clinical compatibility of traditional Chinese and western medicine in animal models of T2DM were set up. The literature was reviewed to sort out and analyze the existing commonly used modeling methods， summarize the mechanism， compare the advantages and disadvantages， and calculate the consistency between the animal model and the clinical symptoms， syndromes， and indicators from the perspective of traditional Chinese and western medicine. The authors found that spontaneous animal models and high-fat diets combined with multiple low-dose streptozotocin （STZ） induction models were more in line with modern medical pathogenesis of T2DM. However， it fails to form some special syndromes required for traditional Chinese medicine （TCM） research. In addition， there are many methods of combining the etiology and pathogenesis of TCM， which can be divided into three categories： intervention carried out by drug administration， behavioral stimulation， or environmental changes according to TCM， or use of hormones according to clinical evidence and combination of the two methods mentioned above. All of them can successfully establish different types of animal models. However， different methods of establishing syndrome models have their own advantages and disadvantages， and there is no unified standard for the stability and evaluation of syndrome models. As for the clinical consistency criteria of traditional Chinese and western medicine established in this paper， the animal model with 100% consistency has not been calculated due to the conditions of incomplete symptoms and syndromes described in the studies and different selection indicators. Consequently， the establishment of a simple， easy-to-use， and affordable T2DM animal model with both traditional Chinese and western medicine disease characteristics and the improvement of the Chinese and western medicine evaluation system for different evidence types are of great significance for the future development of TCM research on T2DM.

Based on the etiology and clinical diagnostic criteria of type 2 diabetes mellitus （T2DM）， identification and typing of treatment from the perspective of traditional Chinese and western medicine， the criteria for evaluating the clinical compatibility of traditional Chinese and western medicine in animal models of T2DM were set up. The literature was reviewed to sort out and analyze the existing commonly used modeling methods， summarize the mechanism， compare the advantages and disadvantages， and calculate the consistency between the animal model and the clinical symptoms， syndromes， and indicators from the perspective of traditional Chinese and western medicine. The authors found that spontaneous animal models and high-fat diets combined with multiple low-dose streptozotocin （STZ） induction models were more in line with modern medical pathogenesis of T2DM. However， it fails to form some special syndromes required for traditional Chinese medicine （TCM） research. In addition， there are many methods of combining the etiology and pathogenesis of TCM， which can be divided into three categories： intervention carried out by drug administration， behavioral stimulation， or environmental changes according to TCM， or use of hormones according to clinical evidence and combination of the two methods mentioned above. All of them can successfully establish different types of animal models. However， different methods of establishing syndrome models have their own advantages and disadvantages， and there is no unified standard for the stability and evaluation of syndrome models. As for the clinical consistency criteria of traditional Chinese and western medicine established in this paper， the animal model with 100% consistency has not been calculated due to the conditions of incomplete symptoms and syndromes described in the studies and different selection indicators. Consequently， the establishment of a simple， easy-to-use， and affordable T2DM animal model with both traditional Chinese and western medicine disease characteristics and the improvement of the Chinese and western medicine evaluation system for different evidence types are of great significance for the future development of TCM research on T2DM.

Proteolysis-targeting chimeras (PROTACs) represent a promising class of drugs that can target disease-causing proteins more effectively than traditional small molecule inhibitors can, potentially revolutionizing drug discovery and treatment strategies. However, the links between in vitro and in vivo data are poorly understood, hindering a comprehensive understanding of the absorption, distribution, metabolism, and excretion (ADME) of PROTACs. In this work, ¹⁴C-labeled vepdegestrant (ARV-471), which is currently in phase III clinical trials for breast cancer, was synthesized as a model PROTAC to characterize its preclinical ADME properties and simulate its clinical pharmacokinetics (PK) by establishing a physiologically based pharmacokinetics (PBPK) model. For in vitro-in vivo extrapolation (IVIVE), hepatocyte clearance correlated more closely with in vivo rat PK data than liver microsomal clearance did. PBPK models, which were initially developed and validated in rats, accurately simulate ARV-471's PK across fed and fasted states, with parameters within 1.75-fold of the observed values. Human models, informed by in vitro ADME data, closely mirrored postoral dose plasma profiles at 30 mg. Furthermore, no human-specific metabolites were identified in vitro and the metabolic profile of rats could overlap that of humans. This work presents a roadmap for developing future PROTAC medications by elucidating the correlation between in vitro and in vivo characteristics.

ObjectiveTo investigate the features of liver histopathological damage in patients with indeterminate phase of chronic HBV infection， as well as the timing for initiating antiviral therapy in such patients. MethodsA retrospective screening was performed for the patients with chronic HBV infection who were hospitalized in The Fifth Medical Center of Chinese PLA General Hospital and underwent liver biopsy from March 2018 to April 2022， among whom the patients who met the criteria for indeterminate phase defined in Chinese guidelines for chronic hepatitis B prevention and treatment （2022 edition） were enrolled， and their clinical data were collected. Liver histopathological stage was determined using the Scheuer scoring system， with stages 0 — 4 for inflammation grade （G） and stages 0 — 4 for fibrosis degree （S）， and the patients were divided into groups based on the presence of significant necroinflammation （≥G2） and significant liver fibrosis （≥S2）. The independent samples t-test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups； the chi-square test or the Fisher’s exact test was used for comparison of categorical data between two groups. A Spearman’s rank correlation analysis was used to investigate the correlation between liver histopathology and clinical factors， and the Logistic regression model was used to identify the independent influencing factors for significant necroinflammation and liver fibrosis. ResultsA total of 271 patients with indeterminate phase of chronic HBV infection were enrolled， among whom 61 （22.5%） had significant necroinflammation （≥G2） and 124 （45.8%） had significant liver fibrosis （≥S2）. The Logistic regression analysis showed that alanine aminotransferase ≥30 U/L （for male patients） or ≥19 U/L （for female patients） （odds ratio ［OR］=2.69， 95% confidence interval ［CI］： 1.39 — 5.21， P=0.003）， HBV DNA ≥2 000 IU/mL （OR=2.75， 95%CI： 1.38 — 5.48， P=0.004）， and liver stiffness measurement （LSM） ≥6.0 kPa （OR=4.57， 95%CI： 2.17 — 9.62， P<0.001） were independent risk factors for significant inflammation. HBV DNA ≥2 000 IU/mL （OR=1.82， 95%CI： 1.01 — 3.32， P=0.049） and LSM ≥6.0 kPa （OR=2.06， 95%CI： 1.23 — 3.43， P=0.006） were independent influencing factors for significant liver fibrosis. ConclusionAmong the patients with indeterminate phase of chronic HBV infection， a substantial proportion of patients have significant liver histopathological damage. Antiviral therapy should be initiated in a timely manner for patients with high-risk factors.

As an important strategy in antiviral drug development, nucleoside analogs (NAs) have attracted considerable attention due to their unique mechanisms of action and favorable safety profile. This review systematically summarizes recent advances in the mechanisms of action of NAs, focusing on the following four aspects: (1) Targeting viral polymerases, inhibiting viral replication through mechanisms such as non-absolute termination, delayed chain termination and induction of viral RNA mutations in addition to classical chain termination, which has been newly discovered; (2) Regulating RNA methylation modifications—for instance, competitively inhibiting methyltransferases, which significantly reduces viral replication efficiency; (3) Depleting nucleotide pools—by affecting host cell purine nucleotide synthesis pathways, thereby indirectly inhibiting viral replication; and (4) Immunomodulatory functions—including activation of the STING pathway to promote interferon production. Furthermore, this review systematically discusses the breakthrough progress in prodrug technologies for addressing key clinical challenges such as drug resistance and off-target toxicity of NAs. These advances provide crucial technical support for the clinical translation of NAs. These advances provide key technical support for the clinical translation of NAs. This review clarifies the multi-target action rules of NAs and provides a theoretical framework for the design of next-generation broad-spectrum antiviral agents.

Hematological malignancies are a serious disease with a high risk of mortality and a high tendency to recur. The current mainstream treatment methods mainly include chemotherapy, targeted therapy, supportive therapy, and hematopoietic stem cell transplantation. Immune cell therapy can induce the function of immune cells and accurately kill tumors and pathogens. For those refractory patients who experience relapse or have poor response to traditional treatments, the immune cell therapy has good clinical efficacy. This article reviews the latest advances in immune cell therapy for hematological malignancies.

Acute leukemia is a common hematological malignancy.Conventional chemotherapy,targe-ted drug therapy,hematopoietic stem cell transplantation and other treatment methods have made progress,but the mortality rate of patients after recurrence is still high.Adoptive cell therapy(ACT)has emerged as an effective therapeutic option for acute leukemia,particularly chimeric antigen receptor(CAR)T-cell therapy,which has demonstrated remarkable efficacy in treating B-cell acute lymphoblastic leukemia(B-ALL)and ma-lignant lymphoma.However,CAR-T cell therapy may induce cytokine release syndrome.Recent studies have highlighted the potent anti-leukemia effects of CAR-NK cell therapy.This review summarizeed the research progress of ACT employing various immune cells targeting different antigens in the treatment of acute leukemia.

Objective:To prepare pullulan-spermine (PS)-poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) conjugated with CD3 antibody, and to investigate their effects on T cell proliferation and cytokine secretion.Methods:Purulan polysaccharide was sperminized to synthesize PS, hydrophobically modified, and then grafted with PLGA to synthesize PS-PLGA. Infrared spectroscopy and nuclear magnetic resonance hydrogen spectrum were used to characterize the structure of PS-PLGA. PS-PLGA NPs were prepared by ultrasonic dialysis method and then coupled with CD3 antibody to prepare PS-PLGA-CD3 NPs. The morphological features of PS-PLGA-CD3 NPs were observed by the transmission electron microscope. The particle sizes, Zeta potential and dispersive coefficient of the NPs were measured using the dynamic laser particle size analyzer. The amount of coupled CD3 antibody on the surface of the NPs was determined using quantitative fluorescence analysis method. The effects of 1, 10, 50, 100, and 200 μg/ml PS-PLGA-CD3 NPs on T-cell proliferation were determined using cell counting kit-8 method. The effects of 1, 10, 50, 100, 200 μg/ml PS-PLGA-CD3 NPs on secretion of interferon-γ (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor-β (TNF-β) by T cell were determined by enzyme-linked immunosorbent assay. Comparisons were made using independent sample t-test or one-factor analysis of variance. Results:Pullulan and PS showed strong absorption at 2 939 cm ?1, and PS had a weaker absorption peak at 3 384 cm ?1 than pullulan. The proton peaks of spermine appeared at chemical shifts of 1.25 to 1.50, 1.63, and 2.25 to 2.75. The characteristic peaks of PLGA appeared at chemical shifts of 1.50, 3.40, and 4.80 to 5.30. Compared to pullulan, the characteristic peaks of both PS and PLGA appeared in the corresponding intervals for PS-PLGA. The morphology of PS-PLGA-CD3 NPs with spermine substitution at 9.7% was all regular and circular, with a mean particle size of (173.3±24.5) nm, a Zeta potential of (?12.78±3.68) mV, the dispersive coefficient of 0.254±0.101, and the CD3 antibody mass fraction of (52.1±9.4) μg/mg. The differences in cell survival were statistically significant for PS-PLGA-CD3 NPs and PS-PLGA NPs, respectively, after co-incubation with T cell after 24, 48, and 72 h at concentrations of 50, 100, and 200 μg/ml, respectively (all P<0.05). The results of the three concentration comparisons after 24 h of co-incubation were [(129.8±23.1)% vs (95.5±8.9)%, (137.5±22.7)% vs (95.1±15.8)%, and (142.3±25.6)% vs (93.2±9.2)%]; and the results after 48 h were [(145.9±23.7)% vs (95.8±10.6)%, (149.3±23.5)% vs (94.9±16.3)%, and (161.2±26.9)% vs (91.5±8.3)%]; and the results after 72 h were [(147.6±20.1)% vs (95.9±17.8)%, (152.4±22.3)% vs (92.7±16.5)%, and (167.7±25.4)% vs (90.8±17.4)%]. The differences in the levels of IFN-γ, IL-2 and TNF-β were statistically significant (all P<0.05 or 0.01) at 50, 100 and 200 μg/ml concentrations for PS-PLGA-CD3 NPs and PS-PLGA NPs, respectively. For IFN-γ, the results of the comparison of the three concentrations were [(35.7±3.1) ng/ml vs (16.4±6.9) ng/ml, (67.3±5.2) ng/ml vs (19.6±2.8) ng/ml, and (79.0±4.2) ng/ml vs (19.3±2.3) ng/ml]; and for IL-2, the results were [(43.5±8.2) ng/ml vs (12.6±1.9) ng/ml, (53.5±7.8) ng/ml vs (15.8±3.3) ng/ml, and (64.0±8.2) ng/ml vs (17.4±3.8) ng/ml]; and for TNF-β, the results were [(108.4±18.9) pg/ml vs (40.8±1.3) pg/ml, (152.3±28.3) pg/ml vs (56.4±3.7) pg/ml and (185.0±33.6) pg/ml vs (81.6±10.2) pg/ml]. Conclusions:PS-PLGA-CD3 NPs are successfully prepared, which have the function of effectively promoting T cell proliferation and cytokine sectetion.

Objective:To screen key genes that co-regulate immune and mitochondrial energy metabolism through bioinformatics methods and to investigate the relationship between the key genes and immune infiltration.Methods:A total of 671 glioma samples (the tumor group) and 5 non-tumor brain tissue samples (the control group) were collected from the Cancer Genome Atlas (TCGA) database on November 13, 2023. Through a comprehensive search of the GeneCards database and immune-related genes (IRG) and mitochondrial energy metabolism-related genes (MEMRG) in previous published literatures, 76 IRG and MEMRG (IR & MEMRG) were obtained by taking the intersection of IRG and MEMRG after merging and deduplicating. The limma package in R software was used to screen the differentially expressed genes (DEG) between the tumor group and the control group. Then, immune-related & mitochondrial energy metabolism-related differentially expressed genes (IR&MEMRDEG) were obtained by intersecting with IR & MEMRG. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted on the IR&MEMRDEG through the clusterProfiler package in R software. The STRINGv12.0 online database (https://cn.string-db.org/) was employed to construct a protein interaction network based on IR&MEMRDEG and to identify the top 5 key core genes. Single-sample gene-set enrichment analysis (ssGSEA) was used to determine the relative abundance of immune cell infiltration in all samples, and the immune cell infiltration matrices for both the tumor and the control groups were acquired. The expression differences in infiltration abundance of the immune cells in the tumor group and the control group were analyzing by using the ggplot2 package in R software. The heat map was drawn by utilizing the R software pheatmap package to show self-correlation of immune cells. The correlation between the top 5 key genes in the protein interaction network and immune cells was calculated by using the Spearman algorithm and the R software ggplot2 package.Results:A total of 3 623 DEGs were identified from the TCGA database in both groups, including 1 711 up-regulated genes and 1 912 down-regulated genes. After taking the intersection of DEG and IR&MEMRG, 11 IR&MEMRDEG were obtained including EIF4EBP1, TP53, IDH1, PRCKZ, CD200, GPI, PGM2, PKLR, AK2, ATP4A, and ALDH3B1. GO enrichment analysis results showed that 11 IR&MEMRDEG were mainly enriched in ADP metabolic process, ATP metabolic process, purine nucleoside diphosphate metabolic process, purine ribonucleoside diphosphate metabolic process, and ribonucleoside diphosphate metabolic process at the biological level; in the fibronectin-1 rich granule, secretory granule lumen, cytoplasmic vesiclelumen, vesiclelumen, and nuclear matrix at the cellular component level; in magnesium ion binding, potassium ion binding, and alkali metal ion binding at the molecular functional level. The KEGG enrichment analysis results showed that 11 IR&MEMRDEGs were mainly enriched in glycolysis/gluconeogenesis, carbon metabolism, insulin signaling pathway, pentose phosphate pathway, starch and sucrose metabolism signaling pathways. The protein interaction network analysis from the STRING database revealed that 5 highest scoring core proteins were identified, namely EIF4EBP1, TP53, IDH1, PRKCZ, and AK2.The immune infiltration abundances of 28 immune cells were calculated by using the ssGSEA algorithm. The infiltration abundance of 15 immune cells in the tumor group was higher than that in the control group, and the differences were statistically significant (all P < 0.05). The findings from the immune infiltration analysis indicated a positive correlation among 15 types of immune cells, in which there was a strongest correlation between effector memory CD8 + T cell and myeloid derived suppressor cells. EIF4EBP1, TP53, IDH1, and AK2 exhibited a positive correlation with a large number of immune cells (all P < 0.05), whereas PRKCZ demonstrated a negative correlation with more immune cells (all P < 0.05). Conclusions:PRKCZ, AK2, and EIF4EBP1 have the potential to be the new targets of immunotherapy for gliomas.

Objective To observe the effect of oxycodone hydrochloride combined with parecoxib sodium preemptive analgesia on postoperative pain in patients undergoing gynecologic laparoscopic surgery.Methods The clinical data of patients who underwent gynecological laparoscopic surgery at the General Hospital of Huainan Oriental Hospital Group from July 2021 to February 2023 were retrospectively analyzed and the patients were divided into a control group(parecoxib sodium)and a combined group(oxycodone hydrochloride combined with parecoxib sodium)according to the different preemptive analgesic regimens.The observational indexes of this study included opioid consumption within 24 h postoperatively,visual analog scale(VAS)scores at 0,2,6,12 and 24 h postoperatively,the number of effective presses of the patient controlled analgesiac(PCA),the time of the first press of the PCA,the number of remedial analgesia,the satisfaction of analgesia,and the occurrence of postoperative adverse reactions.Results A total of 80 patients were included in the study,with 39 in the control group and 41 in the combined group.The time of the first press of the analgesic pump was significantly longer in the combined group than in the control group(P＜0.05),while the number of effective presses and sufentanil consumption were significantly lower in the combined group than in the control group(P＜0.05).The difference in the number of remedial analgesia between the two groups was not statistically significant(P＞0.05).The VAS scores at 0 h,2 h and 6 h postoperatively in the combined group were significantly lower than those in the control group(P＜0.05),and the differences between the VAS scores at 12 h and 24 h postoperatively were not statistically significant(P＞0.05).The analgesic satisfaction score of patients in the combined group was significantly higher than that of the control group(P＜0.05),and the difference in the incidence of adverse reactions was not statistically significant(P＞0.05).Conclusion The preemptive analgesia regimen of oxycodone hydrochloride combined with parecoxib sodium significantly reduced the consumption of opioid drugs in patients after gynecological laparoscopic surgery,alleviated postoperative pain,and improved patient satisfaction.