The evolutionary arms race between life and pathogens drives diversification in immune system signaling mechanisms. Recent research has found that the TIR protein of the bacterial type II Thoeris defense system can produce a novel “hybrid” immune signaling molecule—histidine-ADP-ribose (His-ADPR). This molecule, formed by the direct linkage of an amino acid and a nucleotide, challenges the traditional view that TIR enzymes generate only pure nucleotide derivatives. This signal is specifically recognized by the Macro domain of an effector protein, triggering the transmembrane domain to disrupt the membrane for defense. The study further reveals that phages can evade immunity by expressing “signal sponge” proteins that bind and sequester His-ADPR. This offensive-defensive pressure drives TIR enzymes to continuously expand their “chemical arsenal” of signaling molecules. The discovery not only confirms the shared biochemical core of bacterial TIR signaling molecules (based on NAD⁺ modification), but also highlights their remarkable chemical plasticity and evolutionary innovative capacity. It provides a new perspective for understanding the origin and diversity of immune signaling.

OBJECTIVE To investigate the effect of plasma trough concentration of venetoclax and its influencing factors in patients with acute myeloid leukemia （AML）. METHODS After 5 days of venetoclax administration， venous blood samples were collected from AML patients before the next dose. Plasma trough concentrations of venetoclax were determined using high-performance liquid chromatography-tandem mass spectrometry. Spearman correlation was used to assess the correlations between venetoclax plasma trough concentration and various parameters （including patients’ general information， venetoclax-related indicators， liver function indicators， kidney function indicators， and blood routine indicators）. Multiple linear regression analysis was performed to identify independent factors influencing plasma trough concentration of venetoclax. Using efficacy as dependent variable [complete remission （CR）+partial remission （PR） vs. no remission （NR）]， univariate and multivariate binary Logistic regression analyses were conducted to identify factors affecting efficacy. The receiver operating characteristic （ROC） curve was used to evaluate the predictive value of venetoclax plasma trough concentration for clinical efficacy （assessed as CR）. RESULTS A total of 172 venetoclax plasma trough concentration measurements from 101 patients were included in this study. The median plasma trough concentration of venetoclax was 2.38 （1.18， 3.85） μg/mL； the median sampling time for plasma trough concentration of venetoclax was 10 （7， 15） d； the duration of venetoclax use was （34±12） d. Multiple linear regression analysis showed that alkaline phosphatase （ B ＝14.65， 95%CI： 5.35-23.95， P ＝0.002）， total bilirubin （ B ＝－101.71， 95%CI： －197.16 to －6.25， P ＝0.037）， and white blood cell count （ B ＝－106.84， 95%CI： －187.61 to －26.07， P ＝0.010） were independent factors influencing plasma trough concentration of venetoclax. Due to patient attrition during treatment， 114 venetoclax plasma trough concentration measurements from 69 patients were included for efficacy evaluation. The results showed that 46 patients （66.7%） achieved CR， 11 patients （15.9%） achieved PR， and 12 patients （17.4%） were NR. Multivariate binary Logistic regression analysis showed that age， hemoglobin， venetoclax plasma trough concentration， hematocrit， and mean corpuscular hemoglobin were independent factors affecting patient efficacy （ P ＜0.05）. ROC curve analysis showed that the cut-off value of plasma trough concentration of venetoclax for predicting patient efficacy （assessed as CR） was 1.68 μg/mL （AUC＝0.66， 95%CI： 0.54-0.78， P ＝0.014）. CONCLUSIONS There is considerable inter-individual variability in plasma trough concentration of venetoclax among AML patients. Plasma trough concentration of venetoclax is significantly correlated with alkaline phosphatase， total bilirubin， and white blood cell count. Plasma trough concentration of venetoclax is an independent factor affecting patient’s efficacy， and when the cut-off value for predicting CR is above 1.68 μg/mL， better effects may be achieved.

Objective To investigate the efficacy of varying doses of methylprednisolone(MP)on mice with acute exacerbations of chronic obstructive pulmonary disease(AECOPD)induced with influenza A virus(IAV).Methods Mouse model of COPD was established using LPS combined with smoking for 12 weeks,and then these COPD mice were treated with administration of 40 μL IAV via nasal drip to establish a AECOPD model.A total of 15 AECOPD mice were randomly divided into low-,medium-and high-dose MP groups,oseltamivir group and blank group.The body weight and survival time were monitored within 10 d after IAV infection.On days 1,3,and 5 post-treatment,lung function was assessed using whole-body plethysmography(WBP),inflammatory factors in bronchoalveolar lavage fluid(BALF)were quantified with ELISA,viral titers in BALF were determined using plaque assays,and colony-forming units were evaluated with blood agar plates.Immunofluorescence analysis:① Pulmonary immunofluorescence assay:Mice were randomly categorized into(n=4):LPS 1-day group,LPS 3-day group,and LPS+MP treatment group.All groups received an initial dose of LPS via atomization;subsequently,the LPS+MP treatment group received a single gavage dose of MP.Lung tissues were harvested from the 1-day LPS group on 1 d post-treatment,and from the 3-day LPS and LPS+MP groups on 3 d for immunofluorescence staining.② Cellular immunofluorescence assay:Mouse bone marrow neutrophils were classified into blank control(no intervention),LPS stimulation(LPS group),MP intervention with LPS stimulation(LPS+MP group),and MP intervention alone(MP group).The above cells were collected in 4 h after corresponding interventions for subsequent cellular immunofluorescence analysis.Results ①The medium-dose MP group demonstrated the most significant improvement in survival rate,weight recovery,and lung function when compared to other groups(P＜0.05).② Treatment of medium-dose MP obviously reduced the levels of IL-6 and neutrophil extracellular traps(NETs)(P＜0.05),while,elevated inflammatory factors and NETs were observed in the high-dose MP group on day 5 post-treatment.③ Notable decline in the lung injury score was found in the medium-dose MP group than the other groups(P＜0.05).④The high-dose MP group exhibited substantial bacterial proliferation and delayed viral clearance since day 5 after treatment.Conclusion Medium-dose MP shows best efficacy in treatment of IAV-induced AECOPD,and the dose neither delays viral clearance nor increases the risk of bacterial infection following viral infection.

Objective To investigate the impact of adequate lumen preparation on the 12-month primary patency rate of drug-eluting stents(DES)in patients with lower extremity arteriosclerosis obliterans(ASO)and to identify risk and protective factors for in-stent restenosis.Methods A retrospective cohort study was conducted on 141 patients who underwent DES implantation for ASO at the Department of Vascular Surgery of the First Affiliated Hospital of Chongqing Medical University between April 2022 and April 2024.According to post-percutaneous transluminal angioplasty(PTA)dissection grade[severe dissection is defined as type C or higher based on National Heart,Lung,and Blood Institute(NHLBI)criteria]and residual stenosis rate(severe stenosis is defined as≥30%),the patients were categorized into an adequate preparation group(no severe dissection or severe residual stenosis;n=59)and an inadequate preparation group(n=82).DES primary patency at 12 months was assessed by color Doppler ultrasonography or angiography,defined as a peak systolic velocity ratio≤2.4 on duplex ultrasound or angiographic stenosis<50%.Kaplan-Meier analysis was used to compare intergroup differences in DES patency rate and freedom from clinically driven target lesion revascularization(CD-TLR).Multivariate logistic regression analysis was employed to identify risk and protective factors for DES restenosis and to evaluate the risk contributions of post-PTA dissection and residual stenosis to DES restenosis.Results Post-PTA,vascular dissection occurred in 94.3%(133/141)of treated limbs,among which 42.1%(56/133)were severe dissections,and severe residual stenosis was present in 44.0%(62/141)of limbs.Kaplan-Meier analysis revealed that the 12-month primary patency rate was significantly higher in the adequate preparation group than the inadequate group(HR=0.322,95%CI:0.132～0.789,P=0.013),while no significant difference was found in the rate of freedom from CD-TLR(HR=0.608,95%CI:0.187～1.937,P=0.407).Multivariate logistic regression analysis identified adequate lumen preparation(OR=0.228,95%CI:0.069～0.747,P=0.015)and Rutherford category 2～3(OR=0.205,95%CI:0.058～0.725,P=0.014)as independent protective factors against DES restenosis.The patency rate in the subgroup with coexisting severe dissection and residual stenosis was significantly lower than that in the uncomplicated group(55.6%vs 89.8%,P<0.001),with a 7.067-fold increased risk of re-stenosis(95%CI:2.424～20.602,P<0.001).Conclusion Adequate lumen preparation significantly improves the 12-month primary patency rate of DES.It,along with Rutherford category 2～3,serves as an independent protective factor against in-stent restenosis.Concurrent severe dissection and significant residual stenosis should be actively avoided during the procedure.

Background: The association of changes in metabolic syndrome (MetS) with cognitive function remains unclear. We explored this association using prospective and Mendelian randomization (MR) studies. Methods: MetS components including high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), waist circumference (WC), fasting plasma glucose (FPG), and triglycerides were measured at baseline and two follow-ups, constructing a MetS index. Immediate, delayed memory recall, and cognitive function along with its dimensions were assessed by immediate 10- word recall test (IWRT) and delayed 10-word recall test (DWRT), and mini-mental state examination (MMSE), respectively, at baseline and follow-ups. Linear mixed-effect model was used. Additionally, the genome-wide association study (GWAS) of MetS was conducted and one-sample MR was performed to assess the causality between MetS and cognitive function. Results: Elevated MetS index was associated with decreasing annual change rates (decrease) in DWRT and MMSE scores, and with decreases in attention, calculation and recall dimensions. HDL-C was positively associated with an increase in DWRT scores, while SBP and FPG were negatively associated. HDL-C showed a positive association, whereas WC was negatively associated with increases in MMSE scores, including attention, calculation and recall dimensions. Interaction analysis indicated that the association of MetS index on cognitive decline was predominantly observed in low family income group. The GWAS of MetS identified some genetic variants. MR results showed a non-significant causality between MetS and decrease in DWRT, IWRT, nor MMSE scores. Conclusion Our study indicated a significant association of MetS and its components with declines in memory and cognitive function, especially in delayed memory recall.

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Qualitative and quantitative analysis methods for chemical components of different processed products of Corni Fructus were established to systematically characterize and identify these components, and the content of the main differential components was determined. The chemical components of different processed products of Corni Fructus were collected using ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS). Through analysis of self-built databases, literature, and reference standards, a total of 93 components were obtained, including 19 iridoids, 15 flavonoids, 16 organic acids, eight triterpenoids, eight tannins, four amino acids, two polysaccharides, five olefins, and 16 other compounds. Additionally, by using multivariate statistical methods, the differential components between different processed products of Corni Fructus were screened under the conditions of VIP>1.0 and FC<0.5 or FC>2.0 and P<0.05. The PCA and OPLS-DA results showed differences in the chemical components between different processed products of Corni Fructus. A total of 21 differential components were screened, including tartaric acid, morroniside, and rutin. On this basis, ultra-high performance liquid chromatography-triple quadrupole tandem mass spectrometry(UPLC-QqQ-MS/MS) was used to determine the content of 10 main common differential components, including gallic acid, morroniside, ursolic acid, loganin, swertiamarin, rutin, 5-hydroxymethylfurfural, cornuside Ⅰ, quercetin, and oleanolic acid. The above 10 components showed a good linear relationship within the determined concentration range, with the precision, stability, repeatability, and sample recovery rate all meeting the requirements. Compared with that in Corni Fructus, the content of iridoid glycosides in wine-prepared Corni Fructus and wine-and honey-prepared Corni Fructus decreased, while the content of gallic acid, rutin, quercetin, 5-hydroxymethylfurfural, ursolic acid, and oleanolic acid increased. Compared with wine-prepared Corni Fructus, wine-and honey-prepared Corni Fructus showed varying degrees of increase in all other components, except for a slight decrease in gallic acid content. In summary, this study clarified the influence of different processing methods on the chemical components of Corni Fructus, providing a theoretical basis for the scientific connotation, overall quality evaluation, and clinically rational application of Corni Fructus processing in the future.
Tandem Mass Spectrometry/methods* ; Chromatography, High Pressure Liquid/methods* ; Cornus/chemistry* ; Drugs, Chinese Herbal/chemistry* ; Fruit/chemistry*

This study explored the mechanism of Xiangsha Liujunzi Decoction(XSLJZD) in the treatment of functional dyspepsia(FD) based on inositol-requiring enzyme 1(IRE1)/apoptosis signal-regulating kinase 1(ASK1)/c-Jun N-terminal kinase(JNK) pathway-mediated autophagy in interstitial cells of Cajal(ICC). Forty-eight SPF-grade male SD suckling rats were randomly divided into a blank group and a modeling group, and the integrated modeling method(iodoacetamide gavage + disturbance of hunger and satiety + swimming exhaustion) was used to replicate the FD rat model. After the model replications were successfully completed, the rats were divided into a model group, high-dose, medium-dose, and low-dose groups of XSLJZD(12, 6, and 3 g·kg~(-1)·d~(-1)), and a positive drug group(mosapride of 1.35 mg·kg~(-1)·d~(-1)), and the intervention lasted for 14 days. The gastric emptying rate and intestinal propulsion rate of rats in each group were measured. The histopathological changes in the gastric sinus tissue of rats in each group were observed by hematoxylin-eosin(HE) staining. The ultrastructure of ICC was observed by transmission electron microscopy. The immunofluorescence double staining technique was used to detect the protein expression of phospho-IRE1(p-IRE1), TNF receptor associated factors 2(TRAF2), phospho-ASK1(p-ASK1), phospho-JNK(p-JNK), p62, and Beclin1 in ICC of gastric sinus tissue of rats in each group. Western blot was used to detect the related protein expression of gastric sinus tissue of rats in each group. Compared with those in the blank group, the rats in the model group showed decreased body weight, gastric emptying rate, and intestinal propulsion rate, and transmission electron microscopy revealed damage to the endoplasmic reticulum structure and increased autophagosomes in ICC. Immunofluorescence staining revealed that the ICC of gastric sinus tissue showed a significant elevation of p-IRE1, TRAF2, p-ASK1, p-JNK, and Beclin1 proteins and a significant reduction of p62 protein. Western blot revealed that the expression levels of relevant proteins in gastric sinus tissue were consistent with those of proteins in ICC. Compared with the model group, the body weight of rats in the high-dose and medium-dose groups of XSLJZD was increased, and the gastric emptying rate and intestinal propulsion rate were increased. Transmission electron microscopy observed amelioration of structural damage to the endoplasmic reticulum of ICC and reduction of autophagosomes, and the p-IRE1, TRAF2, p-ASK1, p-JNK, and Beclin1 proteins in the ICC of gastric sinus tissue were significantly decreased. The p62 protein was significantly increased. Western blot revealed that the expression levels of relevant proteins in gastric sinus tissue were consistent with those of proteins in ICC. XSLJZD can effectively treat FD, and its specific mechanism may be related to the inhibition of the expression of molecules related to the endoplasmic reticulum stress IRE1/ASK1/JNK pathway in ICC and the improvement of autophagy to promote gastric motility in ICC.
Animals ; Male ; Drugs, Chinese Herbal/administration & dosage* ; Autophagy/drug effects* ; Rats ; Rats, Sprague-Dawley ; Interstitial Cells of Cajal/metabolism* ; Dyspepsia/physiopathology* ; Protein Serine-Threonine Kinases/genetics* ; MAP Kinase Kinase Kinase 5/genetics* ; MAP Kinase Signaling System/drug effects* ; Humans ; Endoribonucleases/genetics* ; Multienzyme Complexes

The traditional Chinese medicine(TCM) industry is a crucial part of China's pharmaceutical sector and plays a strategic role in ensuring public health and promoting economic and social development. In response to the practical demand for high-quality development of the TCM industry, this paper focused on the bottlenecks encountered during the digital and intelligent transformation of TCM production systems. Specifically, it explored technical strategies and methodologies for constructing the best TCM production mode. An innovative artificial intelligence(AI)-centered technical architecture for TCM production was proposed, focusing on key aspects of production management including process modeling, state evaluation, and decision optimization. Furthermore, a series of critical technologies were developed to realize the best TCM production mode. Finally, a novel AI-driven TCM production mode characterized by a closed-loop system of "measurement-modeling-decision-execution" was presented through engineering case studies. This study is expected to provide a technological pathway for developing new quality productive forces within the TCM industry.
Artificial Intelligence ; Drugs, Chinese Herbal ; Medicine, Chinese Traditional/methods* ; Humans

Prostate cancer(PCa) is a common malignant tumor among elderly men, with high incidence and mortality rates worldwide, posing a serious threat to human health. Traditional treatments face limitations, highlighting the urgent need for novel therapeutic strategies. Recent studies on the regulatory mechanisms of micro ribonucleic acid(microRNA, miRNA) in tumor development has identified miRNA as new targets for PCa diagnosis and treatment. Traditional Chinese medicine(TCM), with its multi-mechanism, multi-target, and multi-pathway regulatory properties, shows promising potential in miRNA-based PCa therapy. This review summarized recent findings on miRNA' roles in PCa and research progress of TCM intervention and found that a variety of miRNA played important regulatory roles in cell differentiation, proliferation, apoptosis, invasion, metastasis, immune microenvironment, and drug resistance, and their potential as biomarkers for PCa diagnosis, prognosis, and therapy, indicating the potential to be a biomarker for the diagnosis, prognosis evaluation, and treatment of PCa. The review concluded that the active components of TCM(terpenoids, flavonoids, alkaloids, and others) and compounds(Yishen Tonglong Decoction, Shenhu Decoction, Zhoushi Qiling Decoction, Fuzheng Yiliu Decoction, and Qilan Formula) could regulate the expression of their downstream target genes by acting on specific miRNA and affect the above biological behaviors of PCa cells, thus playing a role in the treatment of PCa. This review aims to provide a theoretical basis for miRNA as potential biomarkers and therapeutic targets for PCa and suggest new avenues for further development of targeted therapy strategies against miRNA.
Humans ; MicroRNAs/metabolism* ; Prostatic Neoplasms/metabolism* ; Male ; Drugs, Chinese Herbal/therapeutic use* ; Medicine, Chinese Traditional ; Animals ; Gene Expression Regulation, Neoplastic/drug effects*