Background Pyrethroid pesticides (PYRs) can cross the placental barrier to cause intrauterine fetal exposure, which may lead to developmental immunotoxicity (DIT). However, the specific effect of maternal PYR exposure during pregnancy on the cellular immune function of 1-year-old children remains unclear. Objective To explore the effect of PYRs exposure throughout the entire pregnancy on peripheral blood lymphocytes in 1-year-old children and potential sensitive window period of PYRs exposure. Methods A birth cohort was established by enrolling pregnant women in their first trimester and following them and their infants until one year of age. Ultra-high performance liquid chromatography-tandem mass spectrometry was used to detect the levels of PYRs metabolites, including 3-phenoxybenzoic acid (3PBA), 4-fluoro-3-phenoxybenzoic acid (4F3PBA), and cis-3-(2,2-dichlorovinyl)-2,2- dimethylcyclopropane carboxylic acid (cis-DBCA), in the urine of pregnant women during the first trimester (gestational weeks 6-12), the second trimester (gestational weeks 21-24), and the third trimester (gestational weeks 33-36). Peripheral blood leukocyte and lymphocyte counts were measured in children at 12 months of age using the Coulter principle combined with flow cytometry. Exposure levels of PYRs metabolites in each trimester were divided into low, moderate, and high exposure groups based on the 25th (P₂₅) and 75th (P₇₅) percentiles. Meanwhile, participants were classified as having repeated high or low exposure if their metabolite levels were > P₇₅ or <P₂₅ in at least two trimesters, respectively, while all others were categorized as having repeated moderate exposure. Generalized linear models were used to analyze the associations between trimester-specific and repeated PYRs metabolite exposure levels and the peripheral blood white blood cell (WBC) and lymphocyte counts in children aged 1 year. Results A total of 336 mother-child pairs were included in this study. For the pregnant women, the total detection rates of maternal urinary 3PBA, 4F3PBA, and cis-DBCA across the three trimesters of pregnancy were 80.5%, 100.0%, and 81.3%, respectively; and median creatinine-corrected concentrations were 0.24, 0.36, and 0.42 μg·g⁻¹, respectively. In children aged 1 year, the mean WBC and lymphocyte counts in peripheral blood were (8.9±2.0)×10⁹·L⁻¹ and (5.7±1.6)×10⁹·L⁻¹, respectively. The results of the generalized linear model analysis indicated that compared to the low exposure group, the high cis-DBCA exposure group during the third trimester of pregnancy had significantly lower peripheral blood WBC count (β=−0.87, 95%CI: −1.51, −0.23) and lymphocyte count (β=−0.64, 95%CI: −1.15, −0.13); and the repeated high-exposure group of cis-DBCA had significantly lower peripheral blood WBC count (β=−1.34, 95%CI: −2.34, −0.34) and lymphocyte count (β=−0.80, 95%CI: −1.60, −0.01) than the repeated low exposure group. Similarly, the repeated moderate-exposure group of cis-DBCA had a significantly lower peripheral blood WBC count (β=−0.83, 95%CI: −1.59, −0.07) than the repeated low exposure group. Conclusion High maternal exposure to PYRs with cis-DBCA as the major metabolite exposure is associated with decreased peripheral leukocyte and lymphocyte counts in children aged 1 year, and repeated high-level exposure throughout gestation appears to exacerbate DIT in offspring. The third trimester of pregnancy maybe a sensitive window for children's DIT induced by exposure to PYRs during pregnancy.

Background Gestational weight gain is closely related to maternal and infant health outcomes. Pregnant women are simultaneously exposed to four metals—lithium (Li), vanadium (V), uranium (U), and bismuth (Bi)—through inhalation of fine particulate matter and consumption of contaminated food and water. Existing studies suggest that exposure to these metals may be associated with gestational weight gain. However, no study has yet explored the complex relationships between exposure to mixtures of these four metals and weight gain at different stages of pregnancy. Objective To investigate the associations between mixed exposure to Li, V, U, and Bi in early pregnancy and the average weekly gestational weight gain during both early pregnancy and mid-to-late pregnancy. Methods This prospective study recruited eligible women in early pregnancy from an obstetrics clinic of a tertiary hospital in Jinan, China, between September 2021 and July 2023. Pre-pregnancy weight, current weight (at 11⁺⁰ to 13⁺⁶ weeks of gestation), and spot urine samples (≥5.0 mL) were collected at enrollment. Urinary concentrations of Li, V, Bi, and U were determined using inductively coupled plasma mass spectrometry. Participants were followed up in late pregnancy (≥28 weeks of gestation) to collect information on physical activity via questionnaire; weight measurements at the last antenatal visit (35⁺⁰ to 37⁺⁶ weeks of gestation) were obtained from the hospital information system. After adjusting for covariates, multiple linear regression and generalized additive models were used to assess the associations of individual metals with weekly weight gain in early pregnancy and in mid-to-late pregnancy. Bayesian kernel machine regression (BKMR) and quantile-based g-computation (Qgcomp) were applied to evaluate the joint effects of the metal mixture exposure on weekly weight gain at the two gestational stages. Results A total of 313 pregnant women were included. The geometric means of urinary Li, V, U, and Bi concentrations were 37.07, 0.20, 0.06, and 0.04 μg·L⁻¹, respectively; after creatinine adjustment, the corresponding values were 46.82, 0.25, 0.07, and 0.05 μg·g⁻¹ (Cr). The mean weekly gestational weight gain was (0.19±0.25) kg in early pregnancy and (0.53 ± 0.18) kg in mid-to-late pregnancy. Both multiple linear regression and generalized additive models showed that urinary V concentration was positively associated with average weekly gestational weight gain in early pregnancy, while no significant associations were found for other metals or for gestational weight gain in mid-to-late pregnancy. In the BKMR model with early-pregnancy weight gain as the outcome, V had the strongest association [posterior inclusion probability (PIP)=0.773]. When other metals were fixed at their medians, V showed a positive non-linear association with the outcome. A significant single-metal effect of V and its interaction with Li were observed. Compared with the 50th percentile of the metal mixture, the average weekly weight gain in early pregnancy increased by 0.016 (95%CI: 0.003, 0.029) and 0.018 (95%CI: 0.001, 0.036) at the 60th and 65th percentiles, respectively; conversely, at the 25th percentile, it decreased by 0.026 (95%CI: 0.002, 0.050). Overall, the joint effect of the metal mixture on early- pregnancy weight gain showed an upward trend. In the BKMR model for mid-to-late pregnancy gestational weight gain, all PIPs were<0.5, and no significant single-metal effects, interactions, or joint effects were identified. Qgcomp results confirmed a positive association between the metal mixture and early-pregnancy weight gain (b=0.031, 95%CI: 0.010, 0.051; P<0.01), with V contributing the highest positive weight (0.71). No significant association was found for weight gain in mid-to-late pregnancy (b=0.007, P=0.339). Conclusion Higher levels of co-exposure to the Li, V, Bi, and U metal mixture during early pregnancy may be associated with increased average weekly weight gain in early pregnancy. Among these metals, V exhibits a predominant role and appears to interact with Li. No association is observed between early-pregnancy metal mixture exposure and average weekly gestational weight gain in mid-to-late pregnancy. These findings suggest that monitoring and managing metal exposure during early pregnancy may be crucial for the rational regulation of gestational weight gain.

ObjectiveTo investigate the contamination status of ochratoxin A (OTA) in commercially available food products in Shanghai, and to assess OTA exposure levels and the associated non-carcinogenic and carcinogenic risks among pregnant women by integrating dietary consumption data of this population. MethodsThe levels of OTA contamination in 1 520 food samples collected in Shanghai from 2022 to 2023 were determined using liquid chromatography-tandem mass spectrometry. An exposure assessment model was developed based on the dietary consumption levels of pregnant women from the 2016‒2017 Shanghai Pregnant Women Dietary Monitoring Survey to calculate the estimated daily intake (EDI) of OTA, the margin of exposure for non-carcinogenic toxicity (MOE₁), and the margin of exposure for carcinogenic toxicity (MOE₂). An MOE₁ greater than 200 and an MOE₂ greater than 10 000 indicate that the non-carcinogenic toxicity and carcinogenic toxicity resulting from exposure are negligible, respectively. For samples with OTA contamination levels below the limit of detection (LOD), which accounted for more than 80% of the samples, the OTA levels were assigned values of 0 and LOD, respectively, for subsequent calculations. ResultsThe detection rates of OTA in cereals, nuts, dried fruits, and alcohol samples collected in 2022 were 2.03%, 0, 0, and 0, respectively. The OTA detection rates in cereals, nuts, dried fruits, beans, and alcohol samples collected in 2023 were 2.50%, 0.39%, 2.47%, 1.67%, and 13.33%, respectively. For pregnant women in Shanghai in 2022, simulation results indicated that when assigning a value of 0 and the LOD, theP₅₀ values of EDI for dietary OTA exposure were 0.05 and 0.72 ng·(kg·d)^-1, respectively, and the P₉₅ values of EDI for dietary OTA exposure were 0.25 and 2.40 ng·(kg·d)^-1, respectively. For pregnant women in Shanghai in 2023, the P₅₀ values of EDI for dietary OTA exposure were 0.04 and 1.00 ng·(kg·d)^-1, respectively, and the P₉₅ values of EDI for dietary OTA exposure were 0.23 and 2.67 ng·(kg·d)^-1, respectively, both substantially below the tolerable daily intake (TDI) for OTA [17 ng·(kg·d)^-1]. The EDI for dietary OTA exposure in 100.0% of Shanghai pregnant women was lower than the TDI, indicating an overall low level of dietary OTA exposure among this population. For 100.0% of pregnant women, the MOE₁ for dietary OTA exposure exceeded 200. When assigned a value of 0, the MOE₂ for 100.0% of pregnant women in both 2022 and 2023 exceeded10 000. When assigned the LOD value, 72.3% and 81.8% of pregnant women in 2022 and 2023, respectively, had an MOE₂ exceeding 10 000. ConclusionFrom 2022 to 2023, samples of cereals, nuts, dried fruits, beans, and alcohol sold in Shanghai exhibited varying degrees of OTA contamination. The overall EDI of OTA exposure among pregnant women in Shanghai remained at a low level. The non-carcinogenic and carcinogenic risks associated with OTA exposure were generally low and at controllable levels.

OBJECTIVE To explore the efficacy and safety of toludesvenlafaxine in the treatment of patients with major depressive disorder （MDD） with anhedonia. METHODS This retrospective study included 160 patients with MDD with anhedonia who were treated at Hebei Mental Health Center from May 2023 to August 2025. These patients were divided into a control group （ n ＝81） and an observation group （ n ＝79） according to treatment regimens. All patients received transcranial magnetic stimulation therapy. On this basis，the control group was treated with Sertraline Hydrochloride Tablets， while the observation group received Toludesvenlafaxine Hydrochloride Sustained-Release Tablets，with an 8-week continuous treatment course.To compare t he clinical total effective rate， anhedonia remission rate，the severity of depressive symptoms，degree of anhedonia，cognitive function，social function and quality of life between the two groups before and after treatment， the incidence of adverse reactions during treatment was recorded simultaneously. RESULTS After treatment，the total effective rate and anhedonia remission rate of the observation group were significantly higher than the control group （ P ＜0.05）. At the 4th and 8th weeks of treatment， the scores of Snaith-Hamilton Pleasure Scale， Hamilton Depression Rating Scale-17 Items， and Sheehan Disability Scale of both groups were significantly lower than those before treatment in the same group， and the observation group was significantly lower than the control group （ P ＜0.05）； the scores of Montreal Cognitive Assessment and Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form were significantly higher than those before treatment in the same group， and the observation group was significantly higher than the control group （ P ＜0.05）. There was no statistically significant difference in the overall incidence of adverse reactions between the two groups （ P ＞0.05）. CONCLUSIONS Toludesvenlafaxine can significantly improve depressive symptoms， cognitive function， and social function in MDD patients with anhedonia，with good safety.

Objective To evaluate the feasibility of intravesical instillation of urokinase and heparin sodium in the treatment of bladder clot irrigation.Methods This report discusses the diagnosis and treatment of three patients with bladder blood clot tamponade confirmed by abdominal and pelvic computed tomography(CT)scans enrolled from our hospital during Jun. to Sep. 2024, and discuss the relevant literature.Results A solution containing urokinase(20 000 IU)and heparin sodium(125 000 U)was instilled through a three-way catheter and retained for 30 minutes before drainage. Complete clot dissolution was achieved in all cases, with immediate relief of hypogastric distension and pain. Post-procedural CT showed restored bladder lumen patency. Hemoglobin levels decreased by 2-5 g/L without complications.Conclusion This preliminary trial demonstrated that intravesical instillation of urokinase-heparin provides a safe and effective minimally invasive alternative for bladder clot in irrigation cases.

This study aimed to investigate the underlying mechanisms of Duhuo Jisheng Decoction(DJD) in the prevention and treatment of knee osteoarthritis(KOA). Forty SPF New Zealand rabbits were randomly divided using SPSS 26.0 software into five groups: blank group, model group, low-dose DJD group, high-dose DJD group, and high-dose DJD+phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR) signaling pathway activator group(high-dose DJD+740Y-P group), with eight rabbits in each group. Except for the blank group, the KOA model was established in the other groups using papain injection into the knee joint cavity combined with forced flexion of the knee joint. The day after modeling, the blank group and model group were given normal saline at 10 mL·kg~(-1) by gavage, the low-dose DJD group received DJD at 8.8 g·kg~(-1) by gavage, the high-dose DJD group received DJD at 35.2 g·kg~(-1) by gavage, and the high-dose DJD+740Y-P group received DJD at 35.2 g·kg~(-1) by gavage along with 740Y-P at 0.15 μmoL·kg~(-1) injected via the auricular vein. All groups received treatment continuously for four weeks. After modeling and intervention, behavioral observations were performed for all groups, and after the intervention, imaging assessments of the knee joints were conducted. Cartilage from the knee joints was collected, and gross morphological changes were observed. Pathological changes in cartilage tissue were examined using hematoxylin-eosin(HE) staining. The results of these observations were quantitatively evaluated using the Lequesne MG score, Kellgren-Lawrence(K-L) grading, Pelletier score, and Mankin score. ELISA was used to measure the levels of interleukin-1β(IL-1β), interleukin-18(IL-18), and matrix metalloproteinase 13(MMP13) in cartilage tissue. Real-time RT-PCR was used to detect the mRNA expression levels of PI3K, Akt, mTOR, Nod-like receptor protein 3(NLRP3), cysteine protease 1(caspase-1), and gasdermin D(GSDMD) in cartilage tissue. Western blot was employed to measure the protein expression levels of PI3K, Akt, mTOR, NLRP3, caspase-1, and GSDMD. The results showed that compared with the blank group, the model group exhibited significant knee joint degeneration, increased Lequesne MG score, K-L grading, Pelletier score, and Mankin score, elevated levels of IL-1β, IL-18, and MMP13 in cartilage tissue, activation of PI3K, Akt, and mTOR phosphorylation along with increased mRNA expression levels, and elevated protein and mRNA expression levels of NLRP3, caspase-1, and GSDMD. Compared with the model group, these indicators were reversed in both the low-dose and high-dose DJD groups, with the high-dose group showing greater decline degree than the low-dose DJD group. However, compared with the high-dose DJD group, the improvements in knee joint degeneration were less pronounced in the high-dose DJD+740Y-P group, with increased Lequesne MG score, K-L grading, Pelletier score, Mankin score, elevated levels of IL-1β, IL-18, and MMP13, activation of PI3K, Akt, and mTOR phosphorylation along with increased mRNA expression, and increased protein and mRNA expression levels of NLRP3, caspase-1, and GSDMD. In conclusion, DJD is effective and safe in the treatment of KOA, and its mechanism may be related to the inhibition of PI3K/Akt/mTOR signaling pathway-mediated pyroptosis in cartilage tissue, thereby improving knee joint bone structure, reducing the inflammatory response, and preventing cartilage matrix degradation.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Rabbits ; TOR Serine-Threonine Kinases/genetics* ; Osteoarthritis, Knee/genetics* ; Proto-Oncogene Proteins c-akt/genetics* ; Signal Transduction/drug effects* ; Male ; Disease Models, Animal ; Pyroptosis/drug effects* ; Phosphatidylinositol 3-Kinases/genetics* ; Humans ; Female

Buyang Huanwu Decoction(BYHWD), as one of the classic formulas in traditional Chinese medicine(TCM) for the treatment of cerebral ischemic stroke(CIS), has demonstrated definite effects in clinical practice. However, the material basis and mechanism of treatment have not been systematically elucidated. This study employed network pharmacology and molecular docking to analyze the potential targets and mechanisms of blood-and brain-penetrating active components of BYHWD in reducing cell apoptosis in CIS. Cell experiments were then carried out to validate the prediction results. In the experiments, five active components including hydroxysafflor yellow A( HSYA), tetramethylpyrazine( TMP), astragaloside Ⅳ( AS-Ⅳ), amygdalin( AMY), and paeoniflorin(PF) were selected to explore the pharmacological effects of BYHWD. HT22 cells were treated with BYHWD, and the cell counting kit-8(CCK-8) method was employed to examine the toxic and side effects of BYHWD. A cell model of oxygen-glucose deprivation/reoxygenation( OGD/R) was constructed, with apoptosis and pyroptosis as the main screening indicators. The levels of lactate dehydrogenase(LDH) and glutathione(GSH) were measured to assess the cell membrane integrity. Flow cytometry was employed to detect apoptosis, and the activities of caspase-3 and caspase-1 were measured to clarify the status of apoptosis and pyroptosis. ELISA was employed to determine the levels of interleukin(IL)-1β and IL-18 to confirm pyroptosis. HSYA and AMY were identified in this study as the active components regulating apoptosis and pyroptosis. TUNEL was employed to detect the apoptosis rate, and Western blot was employed to determine the expression levels of apoptosis-related proteins B-cell lymphoma-2(Bcl-2), Bcl-2-associated X protein(Bax), and caspase-3, which confirmed that the anti-apoptotic effect of the combined component group was superior to that of the single component groups. The molecular docking results revealed strong binding affinity of HSYA and AMY with SDF-1α and CXCR4.AMD3100, a selective antagonist of CXCR4, was then used for intervention. The results of Western blot showed alterations in the expression levels of apoptosis-associated proteins, SDF-1α, and CXCR4. In conclusion, HSYA and AMY influence cellular apoptosis by modulating the SDF-1α/CXCR4 signaling cascade.
Drugs, Chinese Herbal/chemistry* ; Apoptosis/drug effects* ; Animals ; Neurons/cytology* ; Mice ; Molecular Docking Simulation ; Cell Line ; Glucose/metabolism* ; Humans ; Neuroprotective Agents/pharmacology*

Ganoderic acid is a class of lanostane-type triterpenoids found in Ganoderma species, and is one of the most important pharmacologically active components in G. lucidum, exhibiting antioxidant, anti-neuropsychiatric, anti-tumor, and immune-enhancing properties. The content of ganoderic acid in G. lucidum is very low, and the traditional extraction process is complex, yielding minimal amounts at high cost. The biosynthetic pathway of G. lucidum triterpenoids(GLTs), including the synthesis of different structural forms of ganoderic acid from lanosterol, as well as the molecular regulatory mechanisms involving key regulatory enzyme genes and their functions, are not yet fully understood. With the continuous development of synthetic biology technologies, there has been a deeper understanding of the biosynthesis and metabolic regulation pathways of ganoderic acid and its derivatives at the molecular level. Research has explored the key regulatory enzyme genes related to ganoderic acid biosynthesis and their functions. Moreover, through the optimization of synthetic biology and culture conditions, large-scale production and preparation of GLTs at the cellular level have been achieved. This paper reviews and analyzes the latest research progress on the biosynthesis pathways and metabolic regulation of GLTs, focusing on the configuration of ganoderic acid and its derivatives, the biosynthetic pathways, key enzyme genes, transcription factors related to ganoderic acid biosynthesis, signal transduction mechanisms, and factors affecting triterpenoid biotransformation. This review is expected to provide a theoretical basis and technical reference for improving the efficient production of triterpenoid pharmacological components and the exploitation and utilization of G. lucidum resources.
Triterpenes/chemistry* ; Reishi/chemistry* ; Biosynthetic Pathways ; Lanosterol