Cancer progression is accompanied by significant metabolic alterations. We developed a novel computational approach to identify cancer-related risk metabolic subpathways (CMSubpathway). By leveraging the topology of large-scale metabolic pathway gene networks, we initially identified metabolic subpathways and then refined them by taking into account pathway activity dysregulation, prognostic efficacy, and classification performance. We employed the CMSubpathway to extensively identify cancer-related metabolic subpathways across 21 cancer types. Ultimately, 12 risk metabolic subpathways were identified in six cancer types. Subsequently, the 12 overlapping genes of risk metabolic subpathways were identified as the core metabolic module genes. Utilizing the public CRISPR knockout screening datasets sourced from DepMap, we further supported our hypothesis that the essential roles of ADH5, ALDH1B1, and ALDH7A1 in breast cancer cell growth and development. The core metabolic module and its associated genes exhibited significant down-regulation at both the transcriptome and proteome levels based on data from tissues, blood, and single cells. The activity of this core metabolic module was associated with the immune infiltration levels of multiple immune cells, especially T cells. Notably, an abnormal core metabolic module was observed in CD8 T cell subtypes, with the stem-like CD8 T cell subtype showing high metabolic activity and exhaustion markers. Thus, we established a method for identifying risk metabolic subpathways in cancers, which helps to identify more precise biomarkers for cancer patients.

Exercise in heart failure with preserved ejection fraction (HFpEF) remains a hot topic, although current treatment strategies have not been shown to improve the long-term prognosis of HFpEF. Previous studies have mostly focused on the roles of endurance training, the mechanisms underlying long-term voluntary exercise have not been elucidated. The purpose of the present analysis was to evaluate alterations in cardiac function in HFpEF mice (HFpEF-Sed) after 6 weeks of voluntary running (HFpEF-Ex), investigate mechanisms, and compare the effects with fluoxetine (HFpEF-FLX). We found that voluntary exercise, instead of fluoxetine intervention, significantly improved left ventricular end-diastolic internal diameter (LVIDd) and the rate of change in anterior wall thickness (ATW) in HFpEF mice. The exercise capacity of HFpEF-Sed mice was significantly reduced, but prolonged voluntary running significantly reversed the expression of myocardial BNP, TNF-α, and IL-6, α-MHC, and β-MHC in HFpEF-Sed mice, along with myocardial fiber disorders accompanied by massive inflammatory cell infiltrates. Importantly, myocardial Complex III and Complex V, Mfn2, Drp1, p62, and LC3 II/I expression in HFpEF-Sed mice were all significantly different from those of normal mice, whereas voluntary exercise significantly reversed these expressions. These findings strongly suggest that long-term voluntary exercise is effective in avoiding acute and chronic energy stress in HFpEF-Sed mice, which is consistent with the mechanism of current first-line treatment for HFpEF. This notion was further supported by electron microscopy results, which showed no pathological features in cardiomyocyte mitochondrial morphology after prolonged voluntary exercise. Additionally, fluoxetine was found to inhibit depressive-like behavior in HFpEF mice.

Most antirheumatic drugs with high toxicity exhibit a narrow therapeutic window due to their nonspecific distribution in the body, leading to undesirable side effects and reduced patient compliance. To in response to these challenges, prodrug-based nanoparticulate drug delivery systems (PNDDS), which combines prodrug strategy and nanotechnology into a single system, resulting their many advantages, including stability for prodrug structure, the higher drug loading capacity of the system, improving the target activity and bioavailability, and reducing their untoward effects. PNDDS have gained attention as a method for relieving arthralgia syndrome of rheumatoid arthritis in recent years. This article systematically reviews prodrug-based nanocarriers for rheumatism treatment, including Nano systems based on prodrug-encapsulated nanomedicines and conjugate-based nanomedicines. It provides a new direction for the clinical treatment of rheumatoid arthritis.

Introduction: The aim of this study was to investigate the effects of the compound Lactobacillus acidophilus in combination with montmorillonite powder on the inflammatory response in children with rotavirus enteritis (RVE). Methods: A total of 94 children with RVE admitted to our hospital between June 2021 and April 2023 were selected and divided into two groups using a random digit table method. Each group consisted of 47 children. Both groups were administered standard symptomatic treatment upon admission. The control group was additionally administered montmorillonite powder, while the observation group was administered compound L. acidophilus tablets in addition to the treatment administered to the control group. Both the treatments were administered for a duration of 5 days. Parameters such as clinical efficacy, symptom relief time (diarrhea, vomiting, fever, dehydration), inflammatory response (C-reactive protein [CRP]), and adverse reactions (constipation, bloating, drowsiness, skin allergy, dry mouth) were compared between the two groups. Results: Posttreatment, the observation group exhibited a significantly higher total effective rate (95.74%) compared to the control group (78.72%). The symptom relief time for diarrhea ([2.23 +/- 0.48] days), vomiting ([1.38 +/- 0.25] days), fever ((1.91 +/- 0.68) days), and dehydration ([2.74 +/- 0.53] days) in the observation group were all significantly shorter than those in the control group ([3.42 +/- 0.71] days, [2.65 +/- 0.54] days, [2.76 +/- 0.84] days, and [4.60 +/- 0.89] days), respectively. The posttreatment CRP levels in the observation group were (5.26 +/- 1.32) mg/L, lower than those in the control group (7.45 +/- 1.58) mg/L, although this difference was not statistically significant. The incidence of adverse reactions was 14.89% in the observation group and 8.51% in the control group, with no significant difference between the groups. Conclusion: The combination of compound L. acidophilus and montmorillonite effectively shortens the symptom recovery time and improves inflammatory response in children with RVE, while maintaining a high safety profile.

目的 本研究拟结合网络药理学方法及肝细胞实验研究,筛选具有肝保护作用中药有效成分并对其机制进行探讨.方法 筛选ETCM、TCMSP、ETCM、TCMID数据库中有肝保护作用中药及有效成分,再建立对乙酰氨基酚(APAP)肝损伤模型验证.通过SwissTargetPrediction平台,预测有效成分作用靶点.与DisGeNET、OMIM、Gene-Card 平台筛选肝损伤靶点取交集,再通过STRING、Cytoscape3.7.2构建蛋白相互作用网络和药物-靶点互作网络,筛选核心靶点.最终通过APAP诱导人正常肝细胞(LO2)损伤模型进行作用机制的验证.结果 通过ETCM、TCMSP、ETCM、TCMID数据库,筛选出13味中药,337个活性成分,高频出现活性成分27个,借助文献及APAP肝损伤模型验证,确定原阿片碱进行后续研究.通过构建蛋白相互作用网络和化合物-靶点互作网络,最终筛选出 JAK2、PIK3CD、PIK3CB、PIK3CA、SIRT1、SYK等6个核心靶点.结合文献检索,选取SIRT1为目标靶点.细胞实验表明,原阿片碱明显增加损伤肝细胞SIRT1表达(P＜0.01),原阿片碱各组SIRT1下游因子NRF2、HO-1、SOD2表达均较模型组显著升高(P＜0.05),ROS含量明显降低(P＜0.01).结论 利用网络药理学成功筛选出具有肝保护作用的原阿片碱,并进行验证.其作用机制与激活SIRT1/NRF2信号通路,减轻APAP诱导的细胞氧化损伤有关.

Cysteinyl aspartate specific proteinase (caspase)-6 belongs to the caspase family and plays a vital role in mediating cell death. Under certain conditions, three pathways of programmed cell death (PCD), including apoptosis, necroptosis and pyroptosis (PANoptosis), transform one way into another, with enormous therapeutic potential. Initially, scholars reported that caspase-6 is a caspase executor that mediates apoptosis. With the ceaseless exploration of the PCD types, studies have demonstrated that caspase-6 mediates pyroptosis by regulating gasdermin D and mediates necroptosis by regulating mixed lineage kinase domain-like. By regulating PANoptosis, caspase-6 plays a crucial role in tumorigenesis in humans and mediates anti-tumour immunity. Therefore, a comprehensive understanding of caspase-6 function in cancer via PANoptosis is important for the prevention and therapy of tumours. This article summarized the function of caspase-6 in PANoptosis and its impact on cancer development, providing targets and strategies for tumour treatment.

Cancer has currently become a serious public health issue in many countries worldwide, and tumors of the digestive system have attracted an increasing number of researchers' due to their numerous types, high proportion and wide area of occurrence. While tumors of the digestive system suffer from high mortality rates, leading to untimely diagnosis and a poor prognosis, making it necessary to update current treatment approaches such as surgery, radiation therapy, and chemotherapy. This highlights the importance of exploring novel therapeutic ideas and targets. Traditional Chinese medicine has a long history of clinical use due to its low toxicity and multi-factor targeting of multiple pathways. As a kind of traditional Chinese herb, S. nigrum Linn. is highly regarded for its proven antitumor activity. The aim of this study was to comprehensively recapitulate and analyze the anti-cancer effects and molecular mechanisms of treatment of gastrointestinal tumors with S. nigrum Linn. extracts and related compounds, including classical signaling pathways mediated by them as well as noncoding RNA pathways associated with tumor suppression. Components that have been found to be responsible for the anti-cancer activity of S. nigrum Linn. include solanine, solasonine, solamargine, a-L-rhhamnopyranose, uttroside B, degalactotigonin, glycoprotein, and other compounds. The underlying mechanisms of anti-cancer activity reflected in this study include apoptosis, cell cycle arrest, autophagy, anti-angiogenesis, suppression of metastasis and invasion, immune escape, and increased sensitivity to radiotherapy. S. nigrum Linn. has great potential in the treatment of tumors of the digestive system, and through further clinical trials and pharmacological mechanisms it has the potential to become a uniform and standardized anti-tumor drug.

The effects of ginger on gastrointestinal disorders such as ulcerative colitis have been widely investigated using experimental models; however, the mechanisms underlying its therapeutic actions are still unknown. In this study, we investigated the correlation between the therapeutic effects of ginger and the regulation of the gut microbiota. We used dextran sulfate sodium (DSS) to induce colitis and found that ginger alleviated colitis-associated pathological changes and decreased the mRNA expression levels of interleukin-6 and inducible nitric oxide synthase in mice. 16s rRNA sequencing analysis of the feces samples showed that mice with colitis had an intestinal flora imbalance with lower species diversity and richness. At the phylum level, a higher abundance of pathogenic bacteria, Proteobacteria and firmicutes , were observed; at the genus level, most samples in the model group showed an increase in Lachnospiraceae_NK4A136_group . The overall analysis illustrated an increase in the relative abundance of Lactobacillus_murinus , Lachnospiraceae_bacterium_615 , and Ruminiclostridium_ sp ._KB18. These increased pathogenic bacteria in model mice were decreased when treated with ginger. DSS-treated mice showed a lower abundance of Muribaculaceae , and ginger corrected this disorder. The bacterial community structure of the ginger group analyzed with Alpha and Beta indices was similar to that of the control group. The results also illustrated that altered intestinal microbiomes affected physiological functions and adjusted key metabolic pathways in mice. In conclusion, this research presented that ginger reduced DSS-induced colitis severity and positively regulated the intestinal microbiome. Based on the series of data in this study, we hypothesize that ginger can improve diseases by restoring the diversity and functions of the gut microbiota.

肝纤维化是肝损伤后修复反应的失衡,其发生机制尚未明确.复制与人类肝纤维化相似的动物模型是深入研究肝纤维化发病机制与药物治疗的重要基础.该文主要针对胆汁淤积、毒物诱导、代谢障碍、酒精损伤、免疫异常及血吸虫等致肝纤维化模型复制方法进行综述,以供肝纤维化研究者选择参考.

多糖是大多数中药材的主要成分之一.近年来,多糖的功效逐渐成为生命科学领域研究的热点,然而其药代动力研究尚处于起步阶段.本文对多糖的分类、生物分析方法、药代动力学研究进展进行综述,以期为多糖药代动力学的进一步研究提供参考.

Osteoarthritis (OA) is the most prevalent joint disease and is one of the major causes of disability in the world. There has been an increase in the incidence of OA, which is associated with an aging population, sedentary lifestyle, and reduced physical activity. Due to the complex OA pathogenesis, there are limited diagnostic tools. OA is a degenerative joint disorder with a recognized inflammatory component, usually described as abnormal expression of inflammatory factors. For instance, interleukin 6 (IL-6) has been shown to be upregulated in serum and synovial fluid among patients with OA. Most of the inflammatory factors have been associated with the expression of long noncoding RNAs (lncRNAs). However, the role of the novel lncRNA Fer-1-like protein 4 (FER1L4) in OA is yet to be determined. Here, we interrogated the expression profile of FER1L4 in patients with OA to define its potential application as a diagnostic marker. We collected synovial fluid and blood samples from both OA cases and normal controls. Using qRT-PCR, we evaluated the expression of FER1L4 in plasma and synovial fluid. On the other hand, the expression of IL-6 in plasma and synovial fluid was assessed using ELISA. Besides, the effect of age, gender or disease stage in the expression of the FER1L4 in plasma was also estimated. Moreover, the receiver operating characteristic (ROC) curves were used to determine the impact of FER1L4 in OA cases compared with the normal controls. In addition, we analyzed the correlation between FER1L4 and IL-6 through Pearson correlation analysis. Also, IL-6 expression in overexpressed FER1L4 samples was detected in chondrocytes through western blot analysis, while FER1L4 expression following endogenous IL-6 exposure was detected by qRT-PCR. Our data showed that whereas lncRNA FER1L4 is downregulated in OA patients, IL-6 is upregulated. The plasma FER1L4 levels among the OA cases were suppressed with disease progression and old age, and the down-regulation could efficiently discriminate OA patients from normal subjects. In addition, upregulation of FER1L4 inhibited IL-6 expression in human chondrocyte cells, and treatment with different concentrations of exogenous IL-6 did not affect the expression of FER1L4. Taken together, our data demonstrates that FER1L4 could efficiently identify OA cases from normal subjects, and can also modulate the expression of IL-6 in human chondrocytes.

With the advancement of imaging technology, systemic disease control rate and survival rate, the morbidity of brain metastases (BMs) from non-small cell lung cancer (NSCLC) has been riding on a steady upward trend (40%), but management of BMs from NSCLC remains obscure. Systemic therapy is anticipated to offer novel therapeutic avenues in the management of NSCLC BMs, and radiotherapy (RT) and immunotherapy have their own advantages. Recently, it was confirmed that immune checkpoint inhibitors (ICIs) and RT could mutually promote the efficacy in the treatment of BMs from NSCLC. In this paper, we provide a review on current understandings and practices of separating or combining ICIs and RT, which could provide a reference for the coming laboratory and clinical studies and contribute to the development of new approaches in NSCLC BMs.

Saccharides from Arctium lappa. L. root (ALR-S) is a high-purity fructosaccharide separated from the medicinal plant Arctium lappa. L. root. These compounds showed many pharmacological effects in previous studies. In the present study, the antithrombotic effects of ALR-S in arterial thrombosis via inhibiting platelet adhesion and rebalancing thrombotic and antithrombotic factor expression and secretion were found in rats and human aortic endothelial cells (HAECs). This study also showed that inhibition of oxidative stress (OS), which is closely involved in the expression of coagulation- and thrombosis-related proteins, was involved in the antithrombotic effects of ALR-S. Furthermore, studies using FeCl3-treated HAECs showed that ALR-S induced the abovementioned effects at least partly by blocking the ERK/NF-κB pathway. Moreover, U0126, a specific inhibitor of ERK, exhibited the same effects with ALR-S on a thrombotic process in FeCl3-injured HAECs, suggesting the thrombotic role of the ERK/NF-κB pathway and the antithrombotic role of blocking the ERK/NF-κB pathway by ALR-S. In conclusion, our study revealed that the ERK/NF-κB pathway is a potential therapeutic target in arterial thrombosis and that ALR-S has good characteristics for the cure of arterial thrombosis via regulating the ERK/NF-κB signaling pathway.

Long non-coding RNAs (lncRNAs) are associated with human diseases. Although lncRNA-disease associations have received significant attention, no online repository is available to collect lncRNA-mediated regulatory mechanisms, key downstream targets, and important biological functions driven by disease-related lncRNAs in human diseases. We thus developed LncTarD (http://biocc.hrbmu.edu.cn/LncTarD/or http://bio-bigdata.hrbmu.edu.cn/LncTarD), a manually-curated database that provides a comprehensive resource of key lncRNA-target regulations, lncRNA-influenced functions, and lncRNA-mediated regulatory mechanisms in human diseases. LncTarD offers (i) 2822 key lncRNA-target regulations involving 475 lncRNAs and 1039 targets associated with 177 human diseases; (ii) 1613 experimentally-supported functional regulations and 1209 expression associations in human diseases; (iii) important biological functions driven by disease-related lncRNAs in human diseases; (iv) lncRNA-target regulations responsible for drug resistance or sensitivity in human diseases and (v) lncRNA microarray, lncRNA sequence data and transcriptome data of an 11 373 pan-cancer patient cohort from TCGA to help characterize the functional dynamics of these lncRNA-target regulations. LncTarD also provides a user-friendly interface to conveniently browse, search, and download data. LncTarD will be a useful resource platform for the further under-standing of functions and molecular mechanisms of lncRNA deregulation in human disease, which will help to identify novel and sensitive biomarkers and therapeutic targets.

Atherosclerosis is a common and complex disease, whose morbidity increased significantly. Here, an integrated approach was proposed to elucidate systematically the pathogenesis of atherosclerosis from a systems biology point of view. Two weighted human signaling networks were constructed based on atherosclerosis related gene expression data of stem cells. Then, 37 candidate Atherosclerosis-risk Modules were detected using four kinds of permutation tests. Five Atherosclerosis-risk Modules (three Absent Modules and two Emerging Modules) enriched in functions significantly associated with disease genes were identified and verified to be associated with the maintenance of normal biological process and the pathogenesis and development of atherosclerosis. Especially for Atherosclerosis-risk Emerging Module P96, it could distinguish between normal and disease samples by Supporting Vector Machine with the average expression value of the module as classification feature. These identified modules and their genes may act as potential atherosclerosis biomarkers. Our study would shed light on the signal transduction of atherosclerosis, and provide new insights to its pathogenesis from the perspective of stem cells.

LncRNAs have emerged as a major class of regulatory molecules involved in normal cellular physiology and disease, our knowledge of lncRNAs is very limited and it has become a major research challenge in discovering novel disease-related lncRNAs in cancers. Based on the assumption that diverse diseases with similar phenotype associations show similar molecular mechanisms, we presented a pan-cancer network-based prioritization approach to systematically identify disease-specific risk lncRNAs by integrating disease phenotype associations. We applied this strategy to approximately 2800 tumor samples from 14 cancer types for prioritizing disease risk lncRNAs. Our approach yielded an average area under the ROC curve (AUC) of 80.66%, with the highest AUC (98.14%) for medulloblastoma. When evaluated using leave-one-out cross-validation (LOOCV) for prioritization of disease candidate genes, the average AUC score of 97.16% was achieved. Moreover, we demonstrated the robustness as well as the integrative importance of this approach, including disease phenotype associations, known disease genes and the numbers of cancer types. Taking glioblastoma multiforme as a case study, we identified a candidate lncRNA gene SNHG1 as a novel disease risk factor for disease diagnosis and prognosis. In summary, we provided a novel lncRNA prioritization approach by integrating pan-cancer phenotype associations that could help researchers better understand the important roles of lncRNAs in human cancers.

Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. The complexity of cancer can be reduced to a small number of underlying principles like cancer hallmarks which could govern the transformation of normal cells to cancer. Besides, the growth and metastasis of cancer often relate to combined effects of long non-coding RNAs (lncRNAs). Here, we performed comprehensive analysis for lncRNA expression profiles and clinical data of six types of human cancer patients from The Cancer Genome Atlas (TCGA), and identified six risk pathways and twenty three lncRNAs. In addition, twenty three cancer risk lncRNAs which were closely related to the occurrence or development of cancer had a good classification performance for samples of testing datasets of six cancer datasets. More important, these lncRNAs were able to separate samples in the entire cancer dataset into high-risk group and low-risk group with significantly different overall survival (OS), which was further validated in ten validation datasets. In our study, the robust and effective cancer biomarkers were obtained from cancer datasets which had information of normaltumor samples. Overall, our research can provide a new perspective for the further study of clinical diagnosis and treatment of cancer.

MicroRNAs (miRNAs/miR) have emerged as a novel class of gene expression modulators in kidney disease. Lupus nephritis (LN) is the predominant cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Hsa‑miR‑371‑5p has previously been reported to be dysregulated in LN using a miRNA microarray analysis. The present study aimed to determine the function and molecular mechanisms of hsa‑miR‑371‑5p in human mesangial cells of LN. Quantitative polymerase chain reaction (qPCR) was used to detect hsa‑miR‑371‑5p expression in LN tissues. Furthermore, the MTT assay and flow cytometric analyses were performed to analyze the effects of hsa‑miR‑371‑5p on mesangial cell proliferation and apoptosis. Bioinformatics analysis, luciferase reporter assay, qPCR and western blotting were also conducted to predict and confirm the target gene of hsa‑miR‑371‑5p in mesangial cells. The results demonstrated that hsa‑miR‑371‑5p expression was markedly downregulated in LN renal tissues compared with in normal kidney tissues. Restoration of hsa‑miR‑371‑5p expression using synthetic hsa‑miR‑371‑5p mimics was able to significantly inhibit mesangial cell proliferation and induce apoptosis. In addition, mechanistic exploration demonstrated that hypoxia‑inducible factor 1α (HIF‑1α) was a direct target gene of hsa‑miR‑371‑5p in mesangial cells. In conclusion, these results suggested that hsa‑miR‑371‑5p is downregulated in LN, and overexpression of hsa‑miR‑371‑5p may inhibit mesangial cell proliferation and promote apoptosis by directly targeting HIF‑1α.

Imperatorin (IMP) is a major constituent of many herbal medicines and possesses anti-osteoporosis activity. The present research work aimed to study the biotransformation processes of IMP and evaluated the anti-osteoporosis activity of the transformed metabolites. Among 18 strains of filamentous fungi screened, Penicillium janthinellum AS 3.510 exhibited good capability to metabolise IMP to the new derivatives. Ten transformed products were isolated and purified, and their structures were identified accurately based on spectroscopic data. Eight metabolites (2–8 and 10) were novel and previously unreported. The major biotransformation reactions involved hydroxylation of the prenyloxy side-chain and the lactone ring-opening reaction of furocoumarin skeleton. In addition, anti-osteoporosis activities of all products (1–10) were evaluated using MC3T3-E1 cells. The results showed that products 5 and 8 had the best bioactivities in increasing MC3T3-E1 cell growth. These products could be used in future therapeutic regimens for treating osteoporosis.