ObjectiveThis study aimed to investigate the action mechanism by which Banxia Xiexintang （BXT） inhibits epithelial-mesenchymal transition （EMT） in chronic atrophic gastritis （CAG） rats by regulating the interleukin-17（IL-17）/extracellular regulated protein kinases（ERK）/CCAAT enhancer binding protein β（C/EBPβ）signaling pathway， thereby providing new theoretical evidence for the treatment of CAG with classic traditional Chinese medicine formulas. MethodsA CAG rat model was established by using the combined factor method. After successful modeling， the rats were randomly divided into the model group， low-， medium-， and high-dose groups （0.549， 1.098， 2.196 g·kg^-1， respectively） of BXT， and the positive drug group （vitacoenzyme， 0.3 g·kg^-1）. A normal control group was also set up. After 8 weeks of intervention， the pathological changes of gastric tissue were evaluated. The enzyme-linked immunosorbent assay （ELISA） was used to detect the contents of IL-17， tumor necrosis factor-α （TNF-α）， cyclooxygenase-2 （COX-2）， and C/EBPβ in serum， as well as the contents of EMT markers in gastric mucosal tissue including E-cadherin， N-cadherin， and vimentin. The immunohistochemistry method was employed to determine the localization and protein expression levels of IL-17， p-ERK， and C/EBPβ in gastric mucosal tissue. Western blot was used to detect the protein expressions of C/EBPβ， ERK， and its phosphorylated form （p）-ERK in gastric mucosa. Real-time polymerase chain reaction （Real-time PCR） was applied to measure the mRNA expression levels of ERK， COX-2， and C/EBPβ in gastric mucosa. ResultsCompared with those in the normal control group， the rats in the model group showed gastric mucosal glandular atrophy and inflammatory cell infiltration. The protein and their related mRNA expressions of C/EBPβ， ERK， and p-ERK in gastric mucosa were significantly increased （P<0.05，P<0.01）. The levels of IL-17， TNF-α， COX-2， and C/EBPβ in serum were significantly increased （P<0.01）. The contents of N-cadherin and vimentin in gastric mucosal tissue were significantly increased， while the content of E-cadherin was significantly decreased （P<0.01）. Compared with the model group， after intervention with different doses of BXT， the pathological damage of the gastric mucosa was improved to varying degrees. The protein and mRNA expressions of C/EBPβ， ERK， and p-ERK in gastric mucosa were significantly reduced （P<0.05，P<0.01）. The levels of IL-17， TNF-α， COX-2， and C/EBP β in serum were significantly decreased （P<0.01）. The contents of N-cadherin and vimentin in gastric mucosa tissue were decreased， while the content of E-cadherin was increased （P<0.05，P<0.01）. ConclusionBXT can effectively improve the pathological damage of gastric mucosal tissue in CAG rats. Its action mechanism may be related to reducing the levels of IL-17 and TNF-α in serum， regulating the IL-17/ERK/C/EBPβ signaling pathway and inhibiting the EMT process.

Objective: To characterize perioperative dynamic changes in immune-cell phenotypes and inflammatory cytokines in patients undergoing CPB (cardiopulmonary bypass) cardiac surgery, and to explore their associations with postoperative outcomes. Methods: In this prospective cohort study, 120 adult patients who underwent elective cardiac surgery under CPB at West China Hospital from May 2022 to March 2023 were enrolled. Perioperative immune-cell phenotypes and concentrations of 40 inflammation-related cytokines were measured. The primary outcomes were the sequential organ failure assessment (SOFA) score at 24 h after surgery and ΔSOFA (the peak SOFA score within 48 h after surgery minus the preoperative SOFA score). Secondary outcomes included major adverse cardiovascular events (MACE), acute kidney injury (AKI), respiratory failure, severe liver injury, and infection. Results: The mean age of enrolled patients was 57±10 years. Of these, 52% (62/120) were male and 90% (108/120) underwent valve surgery. During the rewarming to the end of CPB, neutrophil counts rapidly increased (7.39×10 /L vs preoperative 3.07×10 /L, P<0.001), with significant upregulation of CD11b (7.30×10 /L vs preoperative 3.05×10 /L, P<0.001) and CD54 (7.15×10 /L vs preoperative 2.99×10 /L, P<0.001). Lymphocyte counts increased at the end of CPB (1.75×10 /L vs preoperative 1.12×10 /L, P<0.001) but decreased significantly at 24 h after surgery (0.59×10 /L vs preoperative 1.12×10 /L, P<0.001). Plasma analysis showed that multiple pro-inflammatory cytokines increased during CPB and remained elevated up to 24 h after surgery; five chemokines and the anti-inflammatory cytokine IL-10 peaked at the end of CPB. The SOFA score increased from 1 (1, 2) preoperatively to 7 (5, 10) at 24 h after surgery, with a ΔSOFA of 6 (4, 8). Within 30 days after surgery, 48 patients (40.0%) developed AKI, 17 (14.2%) developed infection, 4 (3.3%) developed severe liver injury, 3 (2.5%) developed respiratory failure, and 3 (2.5%) experienced MACE. During the 2-year follow-up, 8 patients (6.7%) experienced MACE and 5 (4.2%) died. Conclusion: Multi-organ dysfunction is common after cardiac surgery under CPB (median ΔSOFA, 6), accompanied by perioperative activation of multiple immune-cell subsets and upregulation of pro-inflammatory, anti-inflammatory, and chemotactic mediators. This study provides data-driven evidence and research clues for further investigation of the associations between CPB-related immune perturbations and postoperative organ dysfunction and clinical outcomes.

Background Per- and poly-fluoroalkyl substances (PFAS) can influence gestational diabetes mellitus (GDM); however, current studies on their association are limited and have yielded inconsistent findings. Objective To investigate the association between maternal exposure to PFAS, as measured by urinary concentrations in early pregnancy, and the risk of developing GDM. Methods Based on the Wuhu Birth Cohort in Anhui Province conducted between 2020 and 2023, this study included 1910 pregnant women. Urine samples were collected during the first trimester, and a 75 g oral glucose tolerance test (OGTT) was completed at 24–28 gestational weeks. The concentrations of six PFAS in urine were measured using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Participants were categorized into low, medium, and high exposure groups according to tertiles of individual PFAS concentrations. Logistic regression analysis was employed to assess the potential impact of early-pregnancy PFAS exposure levels on the risk of GDM, with stratified analyses by maternal age and fetal sex. A generalized weighted quantile sum regression (gWQS) model was applied to evaluate the relative weight distribution of the six PFAS in their mixture effect. Results The logistic regression results revealed that both medium exposure to perfluorohexane sulfonate (PFHxS) (OR=1.475, 95%CI: 1.040, 2.093) and high exposure to perfluorononanoic acid (PFNA) (OR=1.430, 95%CI: 1.013, 2.018) were positively associated with diagnosed GDM. This association was more pronounced among women older than 28 years. Among pregnant women carrying male fetuses, high-level exposures to per fluorohexanoic acid (PFHxA) (OR=1.708, 95%CI: 1.006, 2.899) and PFHxS (OR=2.116, 95%CI: 1.247, 3.584) showed positive associations with diagnosed GDM. In contrast, among those carrying female fetuses, moderate perfluorooctanesulfonic acid (PFOS) exposure was associated with a lower risk of GDM (OR=0.542, 95%CI: 0.311, 0.946). The gWQS results demonstrated that PFOS (0.48) and perfluorobutane sulfonate (PFBS) (0.34) contributed the most to the mixture effect. Conclusion Early-pregnancy exposure to PFAS (particularly PFHxS and PFNA) may be an etiological factor for GDM, with maternal age and fetal sex potentially acting as effect modifiers in this association.

Natural product-based drug combinations (NPDCs) present distinctive advantages in treating complex diseases. While high-throughput screening (HTS) and conventional computational methods have partially accelerated synergistic drug combination discovery, their applications remain constrained by experimental data fragmentation, high costs, and extensive combinatorial space. Recent developments in artificial intelligence (AI), encompassing traditional machine learning and deep learning algorithms, have been extensively applied in NPDC identification. Through the integration of multi-source heterogeneous data and autonomous feature extraction, prediction accuracy has markedly improved, offering a robust technical approach for novel NPDC discovery. This review comprehensively examines recent advances in AI-driven NPDC prediction, presents relevant data resources and algorithmic frameworks, and evaluates current limitations and future prospects. AI methodologies are anticipated to substantially expedite NPDC discovery and inform experimental validation.
Artificial Intelligence ; Biological Products/chemistry* ; Humans ; Drug Combinations ; Drug Discovery/methods* ; Machine Learning ; Algorithms

Increasing evidence has underscored the significance of post-stroke alterations along gut-brain axis, while its role in pathogenesis and treatment of ischemic stroke (IS) remains largely unexplored. This study aimed to elucidate the therapeutic effects and action targets of Panax notoginseng saponins (PNS) on IS and explore a novel pathogenesis and treatment strategy of IS via profiling the microbial community and metabolic characteristics along gut-brain axis. Our findings revealed for the first time that the therapeutic effect of PNS on IS was microbiota-dependent. Ischemia/reperfusion (I/R) modeling significantly down-regulated Lactobacilli in rats, and PNS markedly recovered Lactobacilli, particularly Lactobacillus reuteri (L.Reu). Metabolomics showed a significant reduction in serum histidine (HIS) in clinical obsolete IS patients and rehabilitation period I/R rats. Meanwhile, the L.Reu colonization in I/R rats exhibited significant neuroprotective activity and greatly increased HIS in serum, gut microbiota, and brain. Moreover, exogenous HIS demonstrated indirect neuroprotective effects through metabolizing to histamine. Notably, vagus nerve severance in I/R rats was performed to investigate HIS's neuroprotective mechanism. The results innovatively revealed that PNS could promote HIS synthesis in gut by enhancing L.Reu proportion, thereby increasing intracerebral HIS through peripheral pathway. Consequently, our data provided novel insights into HIS metabolism mediated by L.Reu in the pathogenesis and treatment of IS.

Stearoyl-coenzyme A desaturase 1 (SCD1) catalyzes the rate-limiting step of de novo lipogenesis and modulates lipid homeostasis. Although numerous SCD1 inhibitors were tested for treating metabolic disorders both in preclinical and clinic studies, the tissue-specific roles of SCD1 in modulating obesity-associated metabolic disorders and determining the pharmacological effect of chemical SCD1 inhibition remain unclear. Here a novel role for intestinal SCD1 in obesity-associated metabolic disorders was uncovered. Intestinal SCD1 was found to be induced during obesity progression both in humans and mice. Intestine-specific, but not liver-specific, SCD1 deficiency reduced obesity and hepatic steatosis. A939572, an SCD1-specific inhibitor, ameliorated obesity and hepatic steatosis dependent on intestinal, but not hepatic, SCD1. Mechanistically, intestinal SCD1 deficiency impeded obesity-induced oxidative stress through its novel function of inducing metallothionein 1 in intestinal epithelial cells. These results suggest that intestinal SCD1 could be a viable target that underlies the pharmacological effect of chemical SCD1 inhibition in the treatment of obesity-associated metabolic disorders.

Objective:To investigate the mechanism of microRNA-597-3p ( miR-579-3p) in improving hypoxic-ischemic encephalopathy (HIE) by regulating the interleukin-1 receptor-associated kinase 1 (IRAK1)/tumor necrosis factor receptor-associated factor 6 (TRAF6)/transforming growth factor-β-activated kinase 1 (TAK1)/nuclear factor-κB (NF-κB) signaling pathway. Methods:Peripheral blood of healthy neonates ( n=5) and HIE newborns ( n=5) from June 2023 to June 2024 in the No.215 Hospital of Shaanxi Nuclear Industry were collected. The differential expression of miRNA in peripheral blood of neonates with HIE was analyzed by next-generation sequencing. The oxygen-glucose deprivation (OGD) method was used to establish the HIE cell model, which was designated as the OGD group, while cells without OGD treatment served as the control group. Rat adrenal pheochromocytoma PC12 cells were transfected with miR-579-3p mimic (mimic), mimic negative control (mimic-NC), miR-579-3p inhibitor (inhibitor), inhibitor negative control (inhibitor-NC), respectively, and divided into the mimic group, mimic-NC group, inhibitor group, inhibitor-NC group. On the basis of mimic group and inhibitor group, IRAK1 overexpression plasmid ( oeIRAK1) and IRAK1 small interfering RNA plasmid ( siIRAK1) were transfected respectively, which were divided into oeIRAK1 group and siIRAK1 group. The relative expression level of mRNA was detected by real-time reverse transcription-PCR. The absorbance ( A) value was detected by cell counting kit-8 assay. The apoptosis rate was detected by Annexin Ⅴ-fluorescein isothiocyanate/propidium iodide double staining. The relative expression of protein was detected by Western blotting. The levels of pro-inflammatory factors and anti-oxidative stress factors were detected by enzyme-linked immunosorbent assay. Bioinformatics analysis was used to predict the binding site between miR-579-3p and IRAK1, and the dual-luciferase reporter assay was performed to validate their targeting relationship. A total of 12 7-day-old SD rats were selected and randomly divided into the HIE group and the sham group by the random number table method. In the HIE group, the right common carotid artery of rats was permanently occluded, followed by hypoxia exposure, whereas rats in the sham group only underwent common carotid artery exposure without ligation or hypoxia treatment. Immunohistochemical staining was used to detect the expression of protein in brain tissue of HIE rats. The least significant difference t-test was used for comparison between the two groups, and one-way analysis of variance was used for comparison between multiple groups. Results:Compared with the healthy neonates, a total of 278 differentially expressed miRNAs were detected in the peripheral blood of neonates with HIE, among which miR-579-3p showed the most significant downregulation. The relative expression level of miR-579-3p in the mimic group (15.78±1.93) was significantly higher than that in the mimic-NC group (1.00±0.14) ( P<0.01), and in the inhibitor group (0.29±0.14) was significantly lower than that in inhibitor-NC group (1.00±0.14) ( P<0.01). The A value in the mimic group (0.89±0.09) was significantly higher than that in the mimic-NC group (0.52±0.08) ( P<0.01), and in the inhibitor group (0.30±0.05 ) was significantly lower than that in the inhibitor-NC group (0.56±0.07) ( P<0.05). The apoptosis rate of mimic group [(7.47±1.53)%] was significantly lower than that in the mimic-NC group [(30.97±3.47)%] ( P<0.05), and in the inhibitor group [(49.05±4.21)%] was significantly lower than that in the inhibitor-NC group [(35.51±3.64)%] ( P<0.01). The relative expression level of cysteine aspartic acid specific protease-3 ( Caspase-3) and B-cell lymphoma-2 (Bcl-2) associated X protein ( Bax) (1.21±0.10, 1.40±0.13), the relative expression of cleaved Caspase-3 and Bax (1.00±0.13, 1.13±0.09), the levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α [(45.15±5.14, 38.34±5.69) pg/mg] in the mimic group were significantly lower than those in the mimic-NC group [2.10±0.14, 2.37±0.16, 2.29±0.09, 2.27±0.12, (95.67±9.05, 63.99±5.24) pg/mg] (all P<0.01). The relative expression level of Bcl-2 and Claspin (1.03±0.09, 1.00±0.04), the relative expression of Bcl-2 and Claspin (1.21±0.06, 0.94±0.09), the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) [(67.65±6.86, 58.07±5.20) U/mg] in the mimic group were significantly higher than those in the mimic-NC group [(0.51±0.05, 0.52±0.02, 0.58±0.05, 0.46±0.07, 42.08±5.86, 29.80±4.85) U/mg] ( P<0.05, 0.01). The relative expression level of Caspase-3 and Bax (2.72±0.16, 2.97±0.10), the relative expression of cleaved Caspase-3 and Bax (3.25±0.17, 2.76±0.16), the levels of IL-6 and TNF-α [(122.80±11.59, 92.58±7.56) pg/mg] in the inhibitor group were significantly higher than those in the inhibitor-NC group [(1.86±0.14, 2.12±0.10, 2.35±0.15, 1.82±0.15, (88.13±8.59, 68.61±6.17) pg/mg] ( P<0.05, 0.01). The relative expression levels of Bcl-2 and Claspin mRNA (0.17±0.04, 0.20±0.06), the relative expression of Bcl-2 and Claspin proteins (0.11±0.03, 0.13±0.05), the levels of SOD and GSH-Px [(16.62±3.19, 12.01±1.92) U/mg] in the inhibitor group were significantly lower than those in the inhibitor-NC group [0.54±0.05, 0.54±0.05, 0.53±0.10, 0.45±0.07, (38.09±5.47, 30.90±3.87) U/mg] ( P<0.05, 0.01). IRAK1 was identified as a putative target of miR-579-3p. The relative luciferase activity of wild-type IRAK1 in the mimic group (0.45±0.05) was significantly lower than that in the mimic-NC group (1.00±0.08) ( P<0.01). The relative expression levels of IRAK1, TRAF6, TAK1 and NF-κB mRNA in the mimic group (0.96±0.09, 0.96±0.11, 1.34±0.16, 1.74±0.20), the relative expression of IRAK1, TRAF6, TAK1, and phosphorylated NF-κB (p-NF-κB) proteins (0.96±0.20, 1.27±0.19, 1.34±0.18, 1.16±0.19) were all lower than those in the mimic-NC group (1.96±0.17, 1.88±0.24, 2.39±0.23, 2.44±0.20, 2.33±0.22, 2.17±0.24, 2.25±0.28, 2.06±0.28) (all P<0.01). The relative expression levels of IRAK1, TRAF6, TAK1 and NF-κB mRNA in the inhibitor group (2.54±0.15, 2.61±0.13, 2.97±0.15, 2.99±0.20), the relative expression of IRAK1, TRAF6, TAK1 and p-NF-κB proteins (3.73±0.34, 3.17±0.25, 3.68±0.22, 3.29±0.20) were all higher than those in the inhibitor-NC group (1.87±0.18, 1.84±0.19, 2.15±0.24, 2.24±0.26, 2.35±0.23, 1.94±0.25, 2.05±0.27, 2.17±0.29) (all P<0.01). The A value in the oeIRAK1 group (0.66±0.07) was significantly lower than that in the mimic group (0.94±0.10) ( P<0.05), and in the siIRAK1 group (0.51±0.08) was significantly higher than that in the inhibitor group (0.23±0.05) ( P<0.05). The apoptosis rate in the oeIRAK1 group [(23.32±2.40)%] was significantly higher than that in the mimic group [(9.02±1.23)%] ( P<0.05), and in the siIRAK1 group [(28.27±2.57)%] was significantly lower than that in the inhibitor group [(48.96±4.60)%] ( P<0.01). The levels of IL-6 and TNF-α in the oeIRAK1 group [(85.10±6.98, 59.49±5.78) pg/mg] were significantly higher than those in the mimic group [(47.51±8.87, 23.65±3.75) pg/mg], and the levels of SOD and GSH-Px [(49.58±5.63, 41.31±6.21) U/mg] were significantly lower than those in the mimic group [(81.22±6.94, 62.26±5.44) U/mg] ( P<0.05, 0.01). The levels of IL-6 and TNF-α in the siIRAK1 group [(108.25±9.47, 74.87±8.71) pg/mg] were significantly lower than those in the inhibitor group [(142.65±13.88, 104.49±9.18) pg/mg], and the levels of SOD and GSH-Px [(35.87±3.69, 34.89±4.96) U/mg] were significantly higher than those in the inhibitor group [(15.55±3.70, 15.62±3.30) U/mg] ( P<0.05, 0.01). The relative expression level of miR-579-3p in the HIE group (0.47±0.11) was significantly lower than that in the sham group (1.00±0.09) ( P<0.01). The levels of IL-6 and TNF-α in the HIE group [(62.18±6.42, 68.42±4.91) pg/mg] were significantly higher than those in the sham group [(20.77±4.68, 31.16±4.95) pg/mg], and the levels of SOD and GSH-Px [(22.63±3.33, 19.07±2.86) U/mg] were significantly lower than those in the sham group [(47.89±4.58, 56.55±4.45) U/mg] (all P<0.01). The relative levels of TLR4, IRAK1, TRAF6, TAK1, NF-κB, and Caspase-3 mRNA, TLR4, IRAK1, TRAF6, TAK1, p-NF-κB, and cleaved Caspase-3 proteins in the HIE group (1.87±0.24, 2.03±0.21, 2.23±0.20, 1.85±0.18, 1.91±0.20, 2.36±0.20, 2.36±0.28, 2.16±0.28, 1.95±0.27, 2.05±0.26, 2.34±0.24, and 2.72±0.23) were all higher than those in the sham group (1.00±0.15, 1.00±0.11, 1.00±0.09, 1.00±0.05, 1.00±0.12, 1.00±0.15, 1.00±0.15, 1.00±0.21, 1.00±0.10, 1.00±0.14, 1.00±0.19, 1.00±0.16) (all P<0.01), which were consistent with the immunohistochemical staining results. Conclusions:miR-579-3p might alleviate HIE-induced neuronal damage by regulating the IRAK1/TRAF6/TAK1/NF-κB signaling pathway.

This article reported a case of a newborn with congenital absence of the penis. The prenatal examinations were unremarkable. Physical examination of the newborn revealed abnormal external genitalia, with well-developed scrotum and fully descended testicle in normal size, but without the penis. Postnatal ultrasound showed no obvious signals of uterus and ovaries in pelvis and had normal bilateral testicles and urinary system. The diagnosis was congenital absence of the penis.

Subarachnoid hemorrhage (SAH) is a serious intracranial hemorrhage characterized by acute bleeding into the subarachnoid space. The effects of shikonin, a natural compound from the roots of Lithospermum erythrorhizon, on oxidative stress and blood–brain barrier (BBB) injury in SAH was evaluated in this study. A rat model of SAH was established by endovascular perforation to mimic the rupture of intracranial aneurysms. Rats were then administered 25 mg/kg of shikonin or dimethylsulfoxide after surgery. Brain edema, SAH grade, and neurobehavioral scores were measured after 24 h of SAH to evaluate neurological impairment. Concentrations of the oxidative stress markers superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) in the brain cortex were determined using the corresponding commercially available assay kits. Evans blue staining was used to determine BBB permeability. Western blotting was used to quantify protein levels of tight junction proteins zonula occludens-1, Occludin, and Claudin-5. After modeling, the brain water content increased significantly whereas the neurobehavioral scores of rats with SAH decreased prominently. MDA levels increased and the levels of the antioxidant enzymes GSH and SOD decreased after SAH. These changes were reversed after shikonin administration. Shikonin treatment also inhibited Evans blue extravasation after SAH. Furthermore, reduction in the levels of tight junction proteins after SAH modeling was rescued after shikonin treatment. In conclusion, shikonin exerts a neuroprotective effect after SAH by mitigating BBB injury and inhibiting oxidative stress in the cerebral cortex.

Subarachnoid hemorrhage (SAH) is a serious intracranial hemorrhage characterized by acute bleeding into the subarachnoid space. The effects of shikonin, a natural compound from the roots of Lithospermum erythrorhizon, on oxidative stress and blood–brain barrier (BBB) injury in SAH was evaluated in this study. A rat model of SAH was established by endovascular perforation to mimic the rupture of intracranial aneurysms. Rats were then administered 25 mg/kg of shikonin or dimethylsulfoxide after surgery. Brain edema, SAH grade, and neurobehavioral scores were measured after 24 h of SAH to evaluate neurological impairment. Concentrations of the oxidative stress markers superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) in the brain cortex were determined using the corresponding commercially available assay kits. Evans blue staining was used to determine BBB permeability. Western blotting was used to quantify protein levels of tight junction proteins zonula occludens-1, Occludin, and Claudin-5. After modeling, the brain water content increased significantly whereas the neurobehavioral scores of rats with SAH decreased prominently. MDA levels increased and the levels of the antioxidant enzymes GSH and SOD decreased after SAH. These changes were reversed after shikonin administration. Shikonin treatment also inhibited Evans blue extravasation after SAH. Furthermore, reduction in the levels of tight junction proteins after SAH modeling was rescued after shikonin treatment. In conclusion, shikonin exerts a neuroprotective effect after SAH by mitigating BBB injury and inhibiting oxidative stress in the cerebral cortex.