Alternative splicing (AS), a critical mechanism in gene expression regulation, is essential for cellular physiological processes such as proliferation, metabolism, and apoptosis via generating diverse mRNA isoforms and expanding protein diversity. In the field of oncology, AS has been significantly implicated in the regulation of various biological processes involved in tumorigenesis and cancer progression. Specific mutations or expression changes in splicing factors, such as SF3B1, SRSF2, and U2AF1, play key roles in multiple types of cancer. This review summarizes novel therapeutic strategies for cancer targeting alternative splicing, including inhibiting spliceosome components, antisense oligonucleotide (ASO) therapy, and approaches to overcome drug resistance and immune evasion in cancer. These strategies, which modulate the activity of splicing factors and RNA-modifying enzymes, show promise in addressing chemoresistance and enhancing the efficacy of immunotherapy. This review provides a comprehensive exploration of alternative splicing mechanisms, their role in cancer, and their potential as a therapeutic target, highlighting the importance of alternative splicing in cancer research and therapy.

ObjectiveTo investigate the protective effects and mechanisms of Bushen Zhuyun prescription （BSZY） on abortion rats with kidney deficiency-corpus luteum inhibition syndrome. MethodsAn abortion rat model with kidney deficiency-corpus luteum inhibition syndrome was constructed. Pregnant mice aged 8-10 weeks were randomly divided into a control group （Control）， a model group （Model）， low-dose BSZY （BSZY-L）， medium-dose BSZY （BSZY-M）， and high-dose BSZY （BSZY-H） groups （2.57， 5.14， 10.28 g·kg^-¹）， and a Zishen Yutai Pill （ZSYT） group （1.575 g·kg^-¹）. Hematoxylin-eosin （HE） staining was used to evaluate histopathological changes in ovarian and decidual tissue of rats in each group. Enzyme-linked immunosorbent assay （ELISA） was employed to measure levels of estrogen （E₂）， progesterone （P）， luteinizing hormone （LH）， prolactin （PRL）， and follicle-stimulating hormone （FSH） in serum. The candidate targets of BSZY were obtained from the Traditional Chinese Medicine System Pharmacology Platform （TCMSP） and Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine （TCMIP） v2.0 databases， while disease targets for recurrent spontaneous abortion （RSA） were retrieved from GeneCards， DrugBank， Online Mendelian Inheritance in Man （OMIM）， and Therapeutic Target Database （TTD）. The intersection targets were identified by the Venny 2.1.0 platform. Pathway enrichment analysis was conducted based on the Metascape database to predict the potential mechanisms of BSZY. Additionally. Western blot was used to verify the effects of BSZY on the expression of estrogen receptor （ERα）， phosphatidylinositol 3-kinase （PI3K）， and protein kinase B （Akt） and explore its protective mechanism on RSA rats. ResultsCompared with the control group， the model group exhibited significantly decreased uterine， ovarian， and embryonic wet weights （P<0.05， P<0.01）， with an abortion rate of 57.18%. The ovarian tissue showed varying degrees of reduction in primordial follicles， primary follicles， mature follicles， and corpora lutea， along with a large number of atretic follicles. The endometrium was thinner， and decidual tissue exhibited cellular edema and disorganized arrangement. In contrast， compared with the model group， the BSZY groups at all doses and the ZSYT group demonstrated increased uterine， ovarian， and embryonic wet weights， along with a reduced abortion rate. The number of primordial follicles， primary follicles， mature follicles， and corpora lutea increased， while atretic follicles decreased. The endometrium thickened， and decidual tissue displayed normal cellular structure with tight arrangement. Additionally， the model group showed significantly decreased levels of E₂， P， PRL， and FSH in serum （P<0.05， P<0.01）， along with a decreasing trend in LH level. In contrast， the BSZY groups at all doses exhibited significantly elevated levels of E₂， P， LH， PRL， and FSH in serum （P<0.05， P<0.01）. Network pharmacology predictions suggested that BSZY may exert protective effects against abortion in rats by activating the ERα/PI3K/Akt signaling pathway. Western blot results confirmed that BSZY significantly upregulated the expression of ERα， PI3K， and p-Akt proteins （P<0.05， P<0.01）. ConclusionBSZY has a protective effect on the abortion rats with kidney deficiency-corpus luteum inhibition syndrome， possibly by activating the ERα/PI3K/Akt signaling pathway to reduce ovarian apoptosis and regulate endocrine function， thereby lowering the abortion rate.

Ochratoxin A (OTA) is ubiquitous in the food and feed fields. It has strong hepatotoxicity and nephrotoxicity, seriously threatening the health of humans and animals. Enzymatic degradation of mycotoxins is considered to be a promising method to control mycotoxin contaminations. In this study, a new ochratoxin A amidohydrolase from Microbulbifer thermotolerans (MiADH) was obtained. After heterologous expression in Escherichia coli and purification, the recombinant protein was studied regarding the hydrolysis activity, hydrolysis products, enzymatic properties, and substrate binding mode. MiADH can degrade OTA into ochratoxin α (OTα) and phenylalanine, demonstrating a detoxifying ability. It demonstrated the best performance at 70 ℃ and pH 8.0, and Cu²⁺ had the strongest inhibitory effect on the activity of MiADH. MiADH with good thermal stability exhibited huge potential for industrial application. Rational design guided by three-dimensional structural models and substrate docking analysis revealed the important amino acids affecting substrate binding and obtained multiple mutants with improved activity. Among these mutants, V324A had the highest activity, which was 4.2-fold that of the wild type. The identification of MiADH enriches the ochratoxin A degradation enzyme library and provides a new candidate enzyme for the biological detoxification of ochratoxin A in the food and feed industry.
Amidohydrolases/chemistry* ; Ochratoxins/metabolism* ; Substrate Specificity ; Escherichia coli/metabolism* ; Recombinant Proteins/metabolism* ; Actinomycetales/genetics*

Bombesin receptor subtype-3 (BRS3) is an orphan G protein-coupled receptor (GPCR) that plays critical roles in energy homeostasis, glucose metabolism, and insulin secretion. Recent structural studies have elucidated BRS3 signaling mechanisms using synthetic ligands, including BA1 and MK-5046. However, the molecular basis of BRS3 activation by bioactive natural compounds and their derivatives, particularly those derived from traditional Chinese medicine, remains unclear. Here, we present high-resolution cryogenic electron microscopy (cryo-EM) structures of the human BRS3-G_q complex in both unliganded and active states bound by two herb-derived compounds (DSO-5a and oridonin), at resolutions of 2.9, 2.8, and 2.9 Å, respectively. These structures display distinct ligand recognition patterns between DSO-5a and oridonin. Although both compounds bind to the orthosteric pocket, they differentially engage the interaction network of BRS3, as demonstrated by mutagenesis studies assessing calcium mobilization and inositol phosphate 1 (IP1) accumulation. These findings enhance our understanding of BRS3 activation and provide valuable insights into the development of small-molecule BRS3 modulators with therapeutic potential.

Petroleum hydrocarbon pollution has become one of the global environmental problems, posing a serious threat to the environment and human health. Microbial remediation plays an important role in the remediation of petroleum hydrocarbon-contaminated environment. Nevertheless, the stress factors present in the environment polluted by petroleum hydrocarbons limit the effectiveness of microbial remediation. This paper reviews the common stress factors in petroleum hydrocarbon-polluted environment and the response mechanisms of microorganisms to these factors. Furthermore, we introduce the methods to improve microbial tolerance, such as irrational modification, rational modification based on systems biology tools or tolerance mechanisms, and the construction of microbial consortia. The application of these methods is expected to improve the viability and remediation efficiency of microorganisms in petroleum hydrocarbon-contaminated environment and provide new perspectives and technical support for environmental remediation.
Biodegradation, Environmental ; Petroleum/metabolism* ; Hydrocarbons/isolation & purification* ; Bacteria/genetics* ; Environmental Pollutants/isolation & purification* ; Petroleum Pollution

Objective:To evaluate the effectiveness of diaphragm ultrasound in predicting the success of extubation from tracheotomy in patients with acquired brain injury.Methods:A retrospective analysis was conducted on 51 brain-injured patients. They were divided into an extubation failure group and an extubation success group. The results of ultrasound examination of the diaphragm in the 2 groups were analyzed by univariate analysis, and the independent variables with significance were further subjected to multivariate logistic regression analysis. R software was applied to build the diaphragm indicators showing significant predictive power into a histogram model. The predictive value of this nomogram model was assessed using the receiver operating characteristics (ROC) curve.Results:The univariate analysis revealed significant differences between the two groups in terms of diaphragm excursion, diaphragm thickening fraction and diaphragm excursion-time index. The multivariate logistic regression analysis and the nomogram showed that those three variables are independent influencing factors predicting the success of decannulation. The areas under the ROC curves confirmed that finding.Conclusions:Diaphragm excursion, diaphragm thickening fraction and the diaphragm excursion-time index are useful independent predictors of the success of decannulation among brain injury patients.

Objective To investigate the correlation between skeletal muscle fat content and diabetic peripheral neuropathy(DPN)in patients with type 2 diabetes mellitus(T2DM).Methods 290 patients with T2DM admitted to our hospital were enrolled in this study from January 2023 to February 2024 and divided into two groups according to whether they were complicated with DPN:simple T2DM group(T2DM,n=98)and T2DM with DPN group(DPN,n=192).The general data,biochemical indexes and fat distribution indexes measured based on quantitative CT were compared between the two groups.Spearman correlation was used to analyze the relationship between fat distribution indexes and DPN,logistic regression analysis of influencing factors of T2DM complicated with DPN.Results Age,DM duration,WHR,FIns,insulin resistance index(HOMA-IR)and FF were higher in DPN group than in T2DM group(P<0.05).Ca,subcutaneous abdominal fat area(SFA)and liver fat content were lower in DPN group than in T2DM group(P<0.05).Spearman correlation analysis showed that DPN was negatively correlated with SFA and liver fat content(r=-0.127,-0.123,P<0.05),and positively correlated with FF(r=0.117,P<0.05).Logistic regression analysis showed that without adjusting for confounding factors and adjusting for DM duration,WHR,HOMA-IR,Ca,SFA and liver fat content,FF was an influential factor for DPN in T2DM patients.Conclusions Skeletal muscle FF was associated with DPN in patients with T2DM.

Large inter-individual and intra-individual differences in the expression and activity of drug-metabolizing enzymes(DMEs)contribute to unpredictable drug response and toxicity,which is a challenge facing precision medicine.Nuclear receptor-mediated transcriptional regulation and epigenetic mechanisms including histone modifications,non-coding RNAs,and DNA methylation can help to explain the individual variability in DME expressions.However,several questions remain unanswered.Recently,epitranscriptomics,an emerging field,provides new insights into the regulation of gene expression.As the most abundant RNA modification in eukaryotes,N6-methyladenosine(m6A)modifi-cation plays key roles in various physiological and pathological processes.This review summarizes the recent progress in m6A modification-mediated individual variability in DME expression in terms of the role of m6A modification in regulating basal expression of DMEs,crosstalk between m6A modification and nuclear receptors during the ontogeny of DMEs,and the contribution of m6A modification to xenobi-otic exposure-mediated changes in DME expression.This review aims to provide data for the elucida-tion of individual variations in drug metabolism in clinic.

Objective:To evaluate the effect of trans-nasal humidified rapid insufflation ventilatory exchange (THRIVE) on the early postoperative atelectasis in patients undergoing prolonged non-intubated intravenous anesthesia for gastrointestinal endoscopic procedures.Methods:In this randomized double-blind controlled trial, 150 patients of either sex, aged 18-80 yr, with American Society of Anesthesiologists Physical Status classification Ⅰ or Ⅱ and body mass index of 18-30 kg/m 2, scheduled for endoscopic mucosal resection of multiple colorectal polyps at Northern Jiangsu People′s Hospital Affiliated to Yangzhou University from February 18 to June 15, 2024, were divided into 2 groups ( n=75 each) using simple random allocation: THRIVE group (group T) and conventional oxygen therapy group (group C). In group T, the oxygen flow rate was 10 L/min before anesthesia induction and increased to 50 L/min after induction until the end of operation, and the inhaled oxygen concentration was 100%. Group C used conventional mask oxygen inhalation, with an oxygen flow rate of 10 L/min during anesthesia induction and maintenance. Lung ultrasonography was performed immediately before anesthesia induction and after the end of surgery, and the modified lung ultrasound score and diaphragm mobility during quiet breathing were recorded to assess the occurrence of atelectasis and diaphragmatic dysfunction. The lowest intraoperative SpO 2 value, adverse events during surgery and in the postanesthesia care unit (PACU), duration of PACU stay, adverse events within 7 days after operation, hospitalization duration, and satisfaction scores of both patients and endoscopists were recorded. Results:Compared with group C, the postoperative modified lung ultrasound score and incidence of atelectasis and diaphragmatic dysfunction were significantly decreased, the lowest intraoperative SpO 2 value was increased, the incidence of hypoxemia was decreased, the duration of PACU stay was shortened, and endoscopists′ satisfaction scores were increased ( P<0.05), and no statistically significant changes were observed in diaphragm mobility, incidence of other intraoperative adverse events, incidence of adverse events during PACU stay and within 7 days after operation, or patients′ satisfaction scores in group T ( P>0.05). Conclusions:THRIVE can reduce the risk of early postoperative atelectasis and intraoperative hypoxemia, thereby promoting postoperative recovery of patients undergoing gastrointestinal endoscopy under long-term non-intubated anesthesia.

OBJECTIVE To observe the clinical efficacy of Gandou Fumu Decoction(GDFMD)combined with swallowing func-tion training on Wilson's disease with dysphagia of phlegm stasis type.METHODS Sixty-eight WD patients in The First Affiliated Hospital of Anhui University of Chinese Medicine were randomly equally divided into a control group(34 cases)and a treatment group(34 cases)during October 2021 to October 2024.Control group patients were treated with basic therapy such as copper drainage and swallowing training,while patients in the treatment group received additional GDFMD.The scores of traditional Chinese medicine(TCM)syndrome scores,Water Swallow Test(WST),Standardized Swallowing Assessment(SSA),Functional Oral Intake Scale(FOIS),Barthel Scale were observed before and after the treatment.24-hour urinary copper,superoxide dismutase(SOD)and malon-dialdehyde(MDA)levels were measured in both groups.RESULTS After treatment,the TCM syndrome scores,SSA,WST scale scores and blood MDA levels of the two groups of patients were significantly reduced(P<0.05,P<0.01),and the treatment group was better than the control group(P<0.05);FOIS,Barthel scale scores,24-hour urine copper content and serum SOD level in both groups were significantly increased(P<0.05,P<0.01),and the treatment group was better than the control group(P<0.05).CON-CLUSION The combined therapy of Gandou Fumu Decoction with swallowing training can improve the swallowing function on Wil-son's disease with dysphagia of phlegm stasis type and enhance the copper removing.The mechanism may be related to improving the level of antioxidant stress.