Pharmacotranscriptomic profiles, which capture drug-induced changes in gene expression, offer vast potential for computational drug discovery and are widely used in modern medicine. However, current computational approaches neglected the associations within gene‒gene functional networks and unrevealed the systematic relationship between drug efficacy and the reversal effect. Here, we developed a new genome-scale functional module (GSFM) transformation framework to quantitatively evaluate drug efficacy for in silico drug discovery. GSFM employs four biologically interpretable quantifiers: GSFM_Up, GSFM_Down, GSFM_ssGSEA, and GSFM_TF to comprehensively evaluate the multi-dimension activities of each functional module (FM) at gene-level, pathway-level, and transcriptional regulatory network-level. Through a data transformation strategy, GSFM effectively converts noisy and potentially unreliable gene expression data into a more dependable FM active matrix, significantly outperforming other methods in terms of both robustness and accuracy. Besides, we found a positive correlation between RS_GSFM and drug efficacy, suggesting that RS_GSFM could serve as representative measure of drug efficacy. Furthermore, we identified WYE-354, perhexiline, and NTNCB as candidate therapeutic agents for the treatment of breast-invasive carcinoma, lung adenocarcinoma, and castration-resistant prostate cancer, respectively. The results from in vitro and in vivo experiments have validated that all identified compounds exhibit potent anti-tumor effects, providing proof-of-concept for our computational approach.

OBJECTIVES: To explore the therapeutic mechanism of compound Centella asiatica formula (CCA) for alleviating Schistosoma japonicum (Sj)-induced liver fibrosis in mice. METHODS: The active components and targets of CCA were identified using the TCMSP database with cross-analysis of Sj-related liver fibrosis targets. A "drug-component-target-pathway-disease" network was constructed using Cytoscape 3.9.1. Functional enrichment analysis (GO/KEGG) was performed using DAVID. Molecular docking study was carried out to validate interactions between the core targets and the key compounds. For experimental validation of the results, 36 mice were divided into control group, Sj-infected model group, and CCA-treated groups. In the latter two groups, liver fibrosis was induced via abdominal infection with Sj cercariae for 8 weeks, followed by 8 weeks of daily treatment with CCA decoction or saline. Hepatic pathology of the mice was assessedwith HE and Masson staining, and hepatic expressions of collagen-I and collagen-III were detected using immunohistochemistry; serum IL-6 and TNF-α levels were determined with ELISA. Hepatic expressions of TLR4 and MyD88 proteins were analyzed with Western blotting. RESULTS: We identified a total of 107 bioactive CCA components and 791 targets, including 37 intersection targets linked to Sj-induced fibrosis. The core targets included TNF, TP53, JUN, MMP9, and CXCL8, involving the IL-17 signaling, lipid metabolism, TLR4/MyD88 axis, and cancer pathways. Molecular docking study confirmed strong binding affinity between quercetin (a primary CCA component) and TNF/TP53/JUN/MMP9. In Sj-infected mouse models, CCA treatment significantly attenuated hepatic inflammatory cell infiltration, reduced collagen-I and collagen-III deposition, improved tissue architecture, reduced serum IL-6 and TNF-α levels, and downregulated TLR4 and MyD88 expressions in the liver. CONCLUSIONS CCA mitigates Sj-induced liver fibrosis by targeting TNF, TP53, JUN, and MMP9 to modulate the TLR4/MyD88 pathway, thereby suppressing pro-inflammatory cytokine release, inhibiting hepatic stellate cell activation, reducing collagen deposition, and preventing granuloma formation in the liver.
Animals ; Toll-Like Receptor 4/metabolism* ; Mice ; Myeloid Differentiation Factor 88/metabolism* ; Schistosoma japonicum ; Liver Cirrhosis/parasitology* ; Schistosomiasis japonica ; Signal Transduction ; Molecular Docking Simulation ; Inflammation ; Centella/chemistry* ; Drugs, Chinese Herbal/pharmacology* ; Tumor Necrosis Factor-alpha/metabolism*

High mobility group box 1 (HMGB1), when released extracellularly, plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system. In experimental autoimmune encephalomyelitis (EAE), a condition that models multiple sclerosis, the levels of extracellular HMGB1 and interleukin-33 (IL-33) have been found to be inversely correlated. However, the mechanism by which IL-33 deficiency enhances HMGB1 release during EAE remains elusive. Our study elucidates a potential signaling pathway whereby the absence of IL-33 leads to increased binding of P300/CBP-associated factor with HMGB1 in the nuclei of astrocytes, upregulating HMGB1 acetylation and promoting its release from astrocyte nuclei in the spinal cord of EAE mice. Conversely, the addition of IL-33 counteracts the TNF-α-induced increase in HMGB1 and acetylated HMGB1 levels in primary astrocytes. These findings underscore the potential of IL-33-associated signaling pathways as a therapeutic target for EAE treatment.
Animals ; Encephalomyelitis, Autoimmune, Experimental/metabolism* ; Astrocytes/metabolism* ; Interleukin-33/metabolism* ; HMGB1 Protein/metabolism* ; Acetylation ; Mice, Knockout ; Mice, Inbred C57BL ; p300-CBP Transcription Factors/metabolism* ; Mice ; Spinal Cord/metabolism* ; Cells, Cultured ; Female ; Signal Transduction

Objective: To design and establish a new method for flow cytometry-based detection of commonly observed highly expressed antigens on red blood cells, and to further evaluate the differences and distribution characteristics of antigen expression levels between ABO blood type homozygotes and heterozygotes in healthy individuals. Methods: Residual blood samples after donor blood type identification by Shanghai Blood Center in April 2024 were collected. Among them, samples of 19 homozygous and 19 heterozygous individuals of type A and type B were selected. Then the expression level of ABO antigen on red blood cells were detected using the new method established in this study and the traditional aldehyde fixed red blood cell method. Both methods were tested independently three times and the results were compared. Results: The mean values of the three detection results of the new method was (×10 /RBC): AA homozygous 3.3±0.5, AO heterozygous 2.8±0.3, BB homozygous 3.6±0.3, BO heterozygous 3.1±2.8. The mean values of the three detection results of the aldehyde fixation method were AA homozygous 5.9±0.9, AO heterozygous 5.0±1.4, BB homozygous 3.8±0.6, and BO heterozygous 3.3±0.4. The average antigen distribution of each genotype followed a normal distribution. Comparing the average antigen expression levels of homozygotes and heterozygotes, both methods showed that A/B homozygotes had higher antigen levels than heterozygotes, with AA being 1.17 to 1.18 times that of AO and BB being 1.15 to 1.16 times that of BO. Comparing the inter batch differences in the three test results of two methods, the new method showed no significant difference in the three test results for four genotypes (P>0.05). The aldehyde fixation method showed significant differences in the test results for all three genotypes (P<0.01) except for BB homozygotes (P>0.05). The reliability and reproducibility of the new method were better than those of the traditional aldehyde fixation method. Conclusion: The antigen expression level of ABO homozygotes is higher than that of heterozygotes, and the difference in antigen level between type A homozygotes and heterozygotes is slightly higher than that of type B. The new method is superior to traditional aldolization fixation methods.

Objective To investigate the effect of long noncoding RNAMCTP1-AS1 on the proliferation and invasion of cervical cancer cells and its related mechanisms.Methods The Cancer Genome Atlas database was used to analyze the expression of MCTP1-AS1 in cervical cancer tissues and normal cervical tissues,and the correlation between the expression level of MCTP1-AS1 and the pathological stage of cervical cancer patients was analyzed.The expression of MCTP1-AS1 in cervical cancer cell lines HCC1106,HCC94,SiHa,Hela,C33A and normal cervical epithelial cells H8 was detected.Hela cells were transfected with pcDNA-Ctrl plasmid(Ctrl group)and pcDNA-MCTP1-AS1 plasmid(MCTP1-AS1 group),respectively.the proliferation and invasion ability of Hela cells were detected,respectively.the expression of proliferation proteins CDK2 and Cyclin A and invasion proteins N-cadherin and ZEB1 in Hela cells were detected,the targeting relationship between MCTP1-AS1 and miR-10a-5p were verified.The expression of miR-10a-5p in Hela cells was detected.Results Compared with normal cervical tissue,the expression of MCTP1-AS1 in cervical cancer tissue was significantly decreased(P＜0.01).The expression level of MCTP1-AS1 was negatively correlated with the pathological stage of cervical cancer patients(P＜0.01).Compared with H8 cells,the expression of MCTP1-AS1 in cervical cancer cell lines HCC1106,HCC94,SiHa,Hela,and C33A were significantly decreased(P＜0.01).Compared to Ctrl group,overexpression of MCTP1-AS1 significantly reduced the levels of proliferative proteins CDK2 and Cyclin A,as well as invasive proteins N-cadherin and ZEB1 in Hela cells.MCTP1-AS1 directly binds to miR-10a-5p(P＜0.01).Compared to Ctrl group,MCTP1-AS1 group showed a significant decrease in miR-10a-5p expression in Hela cells(P＜0.01).Conclusion MCTP1-AS1 expression is downregulated in cervical cancer tissues and cells,and MCTP1-AS1 expression is negatively correlated with the pathological stage of cervical cancer patients.MCTP1-AS1 inhibits the proliferation and invasion of cervical cancer cells by targeting miR-10a-5p.

Objective: To investigate the interactive effects of prenatal and postnatal factors on overweight and obesity in preschool children, so as to provide evidence for subsequent planning of prevention strategies and intervention measures. Methods: Between October 2020 and June 2021, a convenience cluster sample of 918 preschool children from four kindergartens in Xuzhou urban area underwent questionnaire surveys and physical examinations. The Chi square test was used to compare intergroup differences in overweight and obesity prevalence. Multivariate Logistic regression analysis was employed to investigate the effects of prenatal and postnatal factors, as well as their interactions, on overweight and obesity in preschool children. Results: The prevalence of overweight and obesity among preschool children was 30.8%, with boys exhibiting a higher rate (37.0%) than girls (24.8%). Statistically significant differences in overweight and obesity prevalence were observed across age groups, genders, paternal pre pregnancy body mass index (BMI), paternal educational level, delivery mode, antibiotic use within the six months after birth, and rapid weight gain during infancy ( χ 2=5.08-17.67, all P <0.05). After adjusting for confounding factors such as age, gender, the only child, parental educational level and parental average monthly income, interaction analysis revealed that when the father was overweight or obese before conception, children delivered by caesarean section had an increased risk of overweight or obesity ( OR= 2.05 , 95%CI =1.02-3.39), and children with rapid weight gain during infancy also had an increased risk ( OR=2.05, 95%CI = 1.08 -3.88) (both P <0.05). Gender stratified analysis revealed that the interaction between paternal pre pregnancy BMI and mode of delivery on overweight and obesity was more pronounced among girls ( OR=4.00, 95%CI=1.51-10.58, P <0.05). While the interaction between the father s pre pregnancy BMI and rapid weight gain during infancy was more pronounced in boys ( OR= 2.85 , 95%CI=1.14-7.08, P <0.05). No significant interactions between prenatal and postnatal factors on overweight and obesity in preschool children were observed (all P >0.05). Conclusions Multiple prenatal and postnatal factors influence overweight and obesity in preschool children. Attention should be paid to mode of delivery and infant weight gain, particularly when the father is overweight or obese, to reduce the risk of overweight and obesity in preschool children.

Objective:To clarify the changes in incidence and mortality of various cancers based on analysis on registration data of malignant tumor incidence and mortality from Dehui City and Yanji City in Jilin Province.Methods:The incidence and mortality data of malignant tumors from 2009 to 2016 in Dehui City and Yanji City in Jilin Province,were collected from the Chinese Cancer Registry Annual Report published by the National Cancer Center.The number of cases,deaths,crude incidence rate,crude mortality rate,age-standardized incidence rate(ASIR),age-standardized mortality rate(ASMR),and annual percentage change(APC)of the malignant tumors were analyzed by cancer sites and genders.Results:From 2009 to 2016,the CIR of malignant tumors in Dehui City(APC=1.2%,P=0.019)and Yanji City(APC=3.6%,P=0.058)showed an increasing trend.After standard population age adjustment,the ASIR in males in Dehui City showed a significant decline(APC=-5.7%,P=0.021),while the ASIR in females exhibited an overall downward trend,but the difference was not significant(APC=-2.2%,P=0.111).In Yanji City,the ASIR in males(APC=-1.4%,P=0.535)and females(APC=0.0%,P=0.988)showed no significant changes.The CMR of malignant tumors in Dehui City(APC=1.9%,P=0.001)and Yanji City(APC=5.9%,P=0.001)showed a continuous upward trend.After age-standardization,the ASMR in males(APC=-3.1%,P=0.100)and females(APC=-4.2%,P=0.053)in Dehui City,as well as in males(APC=-1.3%,P=0.438)in Yanji City,showed a slight downward trend.Although the ASMR in females in Yanji City showed a slight increase,the difference was not statistically significant(APC=0.5%,P=0.838).In 2016,the most common malignant tumor in terms of both incidence and mortality in Dehui City was lung cancer,with a CIR of 60.76/100 000 and a CMR of 46.96/100 000.In Yanji City,the most common malignant tumor was liver cancer,with a CIR of 49.04/100 000 and a CMR of 51.09/100 000.Conclusion:Lung cancer,liver cancer,and gastric cancer are the major malignant tumors threatening residents in Dehui City,Yanji City,and even the entire Jilin Province,and should be prioritized in cancer prevention and control efforts.Early diagnosis and treatment should be strengthened.

It is believed that the occurrence and development of squamous cell carcinoma （SCC） is closely associated with inflammatory responses. The theory of fire and heat， advocated by LIU Wansu， provides significant clinical guidance for understanding the pathogenesis and treatment of SCC. Based on this theory， the pathological mechanisms and clinical characteristics of SCC at different stages were analyzed. In the precancerous and early stages， the primary pathogenesis is qi stagnation leading to internal generation of constrained heat； in post-surgery， the condition shifts to qi deficiency with latent yin fire； during the treatment phase， the pathogenesis involves accumulation of pathogenic factors， excess toxins， and severe heat toxicity； in the late stage， the main pathology is yin deficiency with toxic heat， and phlegm-stasis obstruction of the internal organs. Corresponding stage-based treatment strategies are proposed. In the early stage， regulating qi movement to dissipate constrained heat； for post-surgery， tonifying qi and raising yang to dispel latent fire； during treatment stage， clearing heat and detoxifying to eliminate cancerous toxins； and in the late stage， nourishing yin and unblocking the bowels to clear deficiency heat.

Cancer is a major chronic disease that threatens human health, while traditional Chinese medicine (TCM) is a unique method for cancer prevention and treatment in China. After about 70 years of innovation and development, TCM has made constant progress in areas such as the clinical diagnosis, treatment, evidence-based researches, and mechanism exploration of cancer. It has special advantages in aspects such as reducing toxicity, enhancing treatment efficacy, managing symptoms, accelerating recovery, preventing recurrence and metastasis, and prolonging advanced-stage survival. However, there are still bottlenecks for TCM in cancer care. This paper cuts in the key links between TCM and western medicine in their combined application in cancer prevention and treatment, and take the original TCM theories on cancer as the lead, high-quality evidence-based researches as the drive, and analysis on the dynamic mechanism as the core, to show the advantages and effects of TCM in cancer treatment in an all-round way. It also aims to provide novel strategies for sustainable and innovative development and for formulation of comprehensive schemes that integrate TCM and western medicine for cancer prevention and treatment.

Objective:To investigate the role of vitamin E succinate (VES) in inducing autophagy of human gastric cancer cells by activating calcium redistribution through inositol 1, 4, 5-trisphosphate receptors (IP 3R) pathway. Methods:Human gastric cancer lines MKN28 (moderately differentiated) and MKN45 (poorly differentiated) cells were cultured in vitro in March 2022. Gastric cancer cells were treated with VES at different doses for 24 h, and cell viability was measured by CCK-8 method to determine VES dose for subsequent study. The experiment was set up with solvent control group (0.1% ethanol), VES dose groups, 100 nmol/L rapamycin (RAPA) as autophagy positive control group (RAPA group), 15 μg/ml tunicamycin (TM) was used as the endoplasmic reticulum stress (ERS) positive control group (TM group), 10 μmol/ml 2-aminoethyl diphenylborinate (2-APB group) was used to inhibit IP 3R (2-APB group) and VES+2-APB group. The occurrence of autophagosomes in gastric cancer cells was observed by transmission electron microscopy, and microtubule associated protein 1 light chain 3 (LC3), Beclin1, IP 3R, glucose-regulated protein 75 (Grp75), voltage-dependent anion channel 1 (VDAC1) protein expression was detected by western blotting. Fluo-4 AM was used to label intracellular calcium ions, Rhod-2 AM was used to label mitochondrial calcium ions, and the fluorescence intensity of calcium ions was observed by fluorescence microscope. One-way analysis of variance was used to compare the means among multiple groups, and LSD- t method was used for pairwise comparison. Results:CCK-8 results showed that compared with solvent control group, the proliferation rates of MKN28 cells in 10-100 μg/ml VES group and MKN45 cells in 20-100 μg/ml VES group were significantly decreased ( P<0.05). Subsequent VES dosages were determined according to the growth curve, MKN28 was 5, 10, 20, 40 μg/ml, and MKN45 was 10, 20, 40, 80 μg/ml. The results of transmission electron microscopy and fluorescence showed that autophagosomes were formed in MKN28 cells in 5 and 20 μg/ml VES groups and MKN45 cells in 10 and 40 μg/ml VES groups, and the fluorescence intensity of calcium ions in cytoplasm and mitochondria was significantly higher than that in solvent control group ( P<0.05). Compared with solvent control group, LC3, Beclin1, IP 3R, Grp75 and VDAC1 protein expressions of MKN28 cells in 20 and 40 μg/ml VES groups and MKN45 cells in 40 and 80 μg/ml VES groups were significantly increased ( P<0.05). After inhibiting IP 3R with 2-APB, the expression levels of IP 3R, Grp75 and VDAC1 in two kinds of gastric cancer cells in VES+2-APB group were significantly decreased compared with VES group ( P<0.05). The fluorescence results showed that the fluorescence intensity of cytoplasmic and mitochondrial calcium ions in VES+2-APB groups was significantly lower than that in VES group ( P<0.05). Compared with VES group, LC3 and Beclin1 protein expressions in two kinds of gastric cancer cells in VES+2-APB groups were significantly decreased ( P<0.05) . Conclusion:VES may activate intracellular calcium redistribution through IP 3R-Grp75-VDAC1 calcium channel and induce autophagy in gastric cancer cells.