Background and aims The mechanism of cholestatic liver injury (CLI) is unclear, and effective therapies are lacking. While peroxisome proliferator-activated receptor alpha (PPARα) agonists show potential hepatoprotective effect and pyroptosis is implicated in hepatocellular damage, how PPARα activation mitigates lithocholic acid (LCA)-induced pyroptosis remains unknown. Methods The hepatoprotective effect of PPARα agonists was evaluated in a mouse model of intrahepatic cholestasis induced by LCA. Liver injury was assessed via serum biochemistry, hematoxylin and eosin and TUNEL staining, and electron microscopy. Pyroptosis pathways were analyzed using real-time quantitative polymerase chain reaction, Western blot, and co-immunoprecipitation. Results Combined morphological, histopathological, and biochemical analyses confirmed that PPARα activation protects against CLI. Compared with LCA treatment alone, PPARα activation significantly attenuated the elevation of serum lactate dehydrogenase (LDH), the increased TUNEL-positive cells, and the formation of hepatocyte membrane pores. Mechanistically, PPARα activation suppressed both NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis and apoptosis protease-activating factor-1 (APAF-1)/CASPASE-3/GSDME-mediated pyroptosis. Furthermore, PPARα agonist pretreatment inhibited activation of the nuclear factor-kappa B (NF-κB) and forkhead box O1 (FOXO1) signaling pathways. Conclusions PPARα protects against LCA-induced CLI by inhibiting both NLRP3 inflammasome-mediated pyroptosis associated with NF-κB and APAF-1/CASPASE-3/GSDME-mediated pyroptosis associated with the FOXO1 signaling pathway.

Countries in the Southeast Asian region have revised their national food-based dietary guidelines (FBDGs) in response to the public health and nutrition priorities. As a continuous effort to facilitate regional networking, the Southeast Asia Public Health Nutrition Network publishes this review as an update of its previous publication in 2016. This review provides an updated descriptive overview of current FBDGs for the general adult population in Brunei Darussalam, Indonesia, Malaysia, the Philippines, Thailand, and Vietnam. It summarises and compares commonalities and differences in key dietary messages and visual communication tools across countries. The findings indicate strong regional alignment on core dietary recommendations, including consuming a balanced and varied diet with foods from all food groups, prioritising vegetables and fruits, prioritising minimally processed grains or whole grains starchy staples, practising moderation in protein intake from both animal and plant sources, limiting foods high in fats/oils, sugar and salt, being physically active and maintaining a healthy body weight. Pictorial food guides, such as food pyramids and healthy plates, are widely used, with variations in design that reflect cultural contexts to enhance public understanding. While countries acknowledge the importance of FBDGs, effective dissemination and adoption remain challenging due to limited resources, weak cross-sectoral collaboration, and unsupportive food environments. This review highlights the need for stronger communication strategies, improved understanding of consumer barriers, systematic monitoring and evaluation, inclusion of guidance on away-from-home meals, strengthened multi-stakeholder collaboration across the food supply chain, and enhanced regional collaboration to support effective FBDGs implementation in Southeast Asia.

BACKGROUND:The diabetic microenvironment can cause excessive M1 polarization of macrophages,and this hyperglycemic inflammatory state can inhibit osteogenic differentiation of bone marrow mesenchymal stem cells,thus affecting the healing of diabetic bone defects.Studies have indicated that mogroside V possesses anti-inflammatory,antioxidant,and hypoglycemic properties.However,its potential to modulate M1 polarization of macrophages and osteogenic differentiation of bone marrow mesenchymal stem cells under high glucose and inflammatory condition remains unclear. OBJECTIVE:To explore the effect of mogroside V on regulating M1 macrophage polarization and its effect on osteogenic differentiation of bone marrow mesenchymal stem cells under high glucose and inflammatory condition. METHODS:Murine diabetic models were established using C57BL/6 mice.Bone marrow-derived macrophages were isolated from tibia and fibula of normal and diabetic mice,and cultured in low-glucose and high-glucose media.Then M1 polarization of bone marrow-derived macrophages was induced using lipopolysaccharide and interferon-γ.Bone marrow-derived macrophages were treated with 160,320,and 640 μmol/L mogroside V.Flow cytometry was employed to determine the proportion of F4/80+CD86+cells.qRT-PCR was utilized to assess mRNA expression levels of inducible nitric oxide synthase,interleukin 1β,and interleukin 6.ELISA was employed to evaluate tumor necrosis factor-α secretion in bone marrow-derived macrophage supernatants.Bone marrow mesenchymal stem cells were isolated from tibia and fibula of C57BL/6 suckling mice,and induced osteogenic differentiation using low-or high-glucose osteogenic induction medium.Bone marrow mesenchymal stem cells were treated with M1 macrophage-conditioned mediums with or without 320 μmol/L mogroside V in osteogenic differentiation process.qRT-PCR was employed to assess the mRNA expression of alkaline phosphatase,Runt-related factor 2,osteocalcin,and osteopontin on day 14 after osteogenic induction.Alizarin red staining and quantitative analysis were conducted to evaluate calcium deposition on day 21 after osteogenic induction. RESULTS AND CONCLUSION:(1)Flow cytometry results showed that with the treatment of 320 and 640 μmol/L mogroside V,the proportion of F4/80+CD86+bone marrow-derived macrophages was significantly lower than that in the high-glucose control group(P<0.05).(2)qRT-PCR results showed that with the treatment of 160,320,and 640 μmol/L mogroside V,the mRNA expression levels of inducible nitric oxide synthase and interleukin 6 were significantly lower than that in the high-glucose control group(P<0.05).With the treatment of 320 and 640 μmol/L mogroside V,the mRNA expression level of interleukin 1β was significantly lower than that in the high-glucose control group(P<0.05).(3)ELISA results exhibited that with the treatment of 160,320,and 640 μmol/L mogroside V,the tumor necrosis factor-α secretion level was significantly lower than that in the high-glucose control group(P<0.05).(4)With the treatment of 320 μmol/L mogroside V,calcium salt deposition was increased in bone marrow mesenchymal stem cells under high glucose and inflammatory conditions(P<0.05),and the mRNA relative expression levels of alkaline phosphatase,Runt-related factor 2,and osteopontin were increased(P<0.05).These findings indicate that mogroside V can promote osteogenic differentiation of bone marrow mesenchymal stem cells by inhibiting the M1 polarization of bone marrow-derived macrophages under high glucose and inflammatory conditions and reducing the generation of inflammatory factors.

Objective:To investigate the relationship between thyroid autoimmunity and pregnancy outcome in patients with unexplained recurrent abortion.Methods:A retrospective cohort study of 354 patients with normal thyroid function with recurrent abortion of unknown cause admitted to Sun Yat-sen Memorial Hospital, Sun Yat-sen University from January 2015 to June 2022 was used to detect thyroid antibody and thyroid function levels during pregnancy or early pregnancy. They were divided into TAI group ( n=144) and non-TAI group ( n=210) according to whether thyroid autoimmunity (TAI) was complicated or not. Tracking pregnancy outcomes. Results:Compared with the non-TAI group, the TAI group had a higher proportion of pregnancy outcomes resulting in miscarriage [42.4%(61/144) vs 27.1%(57/210), P=0.004]. In patients with unexplained recurrent abortion, TAI significantly increased the risk of spontaneous abortion [ OR(95% CI): 2.13(1.34, 3.41), P=0.001]. Positive TPOAb or TgAb also increased the risk of spontaneous abortion [ OR(95% CI): 2.18(1.37, 3.50), P=0.001; OR(95% CI): 2.33(1.31, 4.13), P=0.004]. TAI, TPOAb and TgAb had no significant interaction with age ( P=0.482, 0.724, 0.740). Conclusions:TAI is positively associated with the risk of spontaneous abortion in patients with unexplained recurrent abortion. TAI may be a potential risk factor for unexplained recurrent abortion, expanding the diagnosis and treatment of unexplained recurrent abortion.

Objective To investigate the effect of Anchusa italica Retz.extract on cough variant asthma(CVA)and its mechanism of action.Methods Forty-eight SD rats of each eight were randomly divided into blank group(equal amount of saline),model group(equal amount of saline),control group(250 mg·kg-1 prednisone acetate)and experimental-A1,-A5,-A7 groups(61.1 mg·kg-1 Anchusa italica Retz.extract A1,48.8 mg·kg-1 Anchusa italica Retz.extract A5,201.8 mg·kg-1 Anchusa italica Retz.extract A7),continuous gavage for 28 d;except for the blank group,the other groups were made with ovalbumin-complete Freund's adjuvant.The number of cough times of each rat was observed.The changes in the expression of Toll-like receptor 4(TLR4),myeloid differentiation factor(MyD88)and nuclear factor κB(NF-κB)proteins were observed in the lung tissue.Results The cough times in the blank group,model group,control group and experimental-A1,-A5,-A7 groups were 1.10±0.22,8.33±1.24,3.08±0.65,3.31±0.99,3.08±1.02 and 3.06±0.68;the relative expression levels of TLR4 protein were 0.61±0.01,0.84±0.04,0.66±0.02,0.64±0.04,0.64±0.03 and 0.69±0.02;the relative expression levels of MyD88 protein were 0.54±0.08,0.86±0.06,0.71±0.06,0.65±0.05,0.64±0.08 and 0.70±0.06;the relative expression levels of p-NF-κB protein were 0.48±0.11,0.94±0.06,0.80±0.08,0.68±0.04,0.68±0.06 and 0.78±0.09.Compared with the experimental-A1,-A5,-A7 groups,control group,normal group,the differences were statistically significant in the model group(all P＜0.05).Conclusion The extract of Anchusa Italica Retz.can inhibit the symptoms of CVA rats,and the mechanism may be related to the inhibition of TLR4/MyD88/NF-κB signaling pathway.

Objective To investigate the molecular mechanism of action of isoglycoside-4'-O-apigenin(1 → 2)glucoside(licraside)intervention in alleviating cholestasis.Methods Farnesol X receptor(FXR)was silenced in human HepG2 cells using lentivirus,and bilirubin and α-isothiocyanate(ANIT)were used to induce HepG2 cells to construct a hypercholate-hyperbilirubin model.The effects of licraside on cell viability,biochemical indices contents and the expression level of FXR and its downstream related proteins in the model were investigated.HepG2 cells and FXR-silenced HepG2 cells were divided into normal,model and experimental groups.Bilirubin and probenecid were added to all groups except the normal group,and 80 μmol·L-1 licraside was added to the experimental group.After 24 h of culture,cell viability and the levels of total bile acids(TBA),bilirubin and other biochemical indices were examined in each group;the protein expression levels of FXR and bile salt efflux pump(BSEP)were examined in each group by Western blot assay.Results The cell viability in HepG2 cells normal group,HepG2 cells model group,HepG2 cells experimental group,siFXR-HepG2 cells normal group,siFXR-HepG2 cells model group and siFXR-HepG2 cells experimental group were(100.00±17.15)％,(39.41±2.91)％,(70.79±3.74)％,(81.41±5.12)％,(33.49±2.69)％and(44.08±4.82)％;the levels of TBA were(7.98±5.87),(46.18±10.93),(9.25±7.20),(11.18±3.36),(38.28±5.12)and(34.79±5.39)μmol·L-1;the levels of total bilirubin were(5.21±3.27),(40.29±24.88),(5.21±2.64),(12.00±4.64),(56.36±14.85)and(15.39±5.56)μmol·L-1;the relative expression levels of FXR protein were 1.00±0.10,0.81±0.07,1.11±0.09,0.10±0.02,0.12±0.02 and 0.10±0.04;the relative expression levels of BSEP protein were 1.00±0.17,0.81±0.02,0.88±0.03,0.70±0.09,0.49±0.07 and 0.60±0.10.The differences of the above indexes in the HepG2 cells experimental group compared with the model group were statistically significant(P＜0.001,P＜0.01);except for TBA,the differences of the above indexes in siFXR-HepG2 cells experimental group compared with the model group were statistically significant(P＜0.001,P＜0.01).Conclusion Licraside can effectively reduce the biochemical indices level of hypercholate-hyperbilirubin cell model.This effect is achieved by agonizing of FXR protein expression,increase the efflux of bile acid salt and then reduce the synthesis of bile acids,and eventually achieve the effect of alleviating the cholestasis.

Male infertility (MI) and male sexual dysfunction (MSD) can often coexist together due to various interplay factors such as psychosexual, sociocultural and relationship dynamics. The presence of each form of MSD can adversely impact male reproduction and treatment strategies will need to be individualized based on patients’ factors, local expertise, and geographical socioeconomic status. The Asia Pacific Society of Sexual Medicine (APSSM) and the Asian Society of Men’s Health and Aging (ASMHA) aim to provide a consensus statement and practical set of clinical recommendations based on current evidence to guide clinicians in the management of MI and MSD within the Asia-Pacific (AP) region. A comprehensive, narrative review of the literature was performed to identify the various forms of MSD and their association with MI. MEDLINE and EMBASE databases were searched for the following English language articles under the following terms: “low libido”, “erectile dysfunction”, “ejaculatory dysfunction”, “premature ejaculation”, “retrograde ejaculation”, “delayed ejaculation”, “anejaculation”, and “orgasmic dysfunction” between January 2001 to June 2022 with emphasis on published guidelines endorsed by various organizations. This APSSM consensus committee panel evaluated and provided evidence-based recommendations on MI and clinically relevant MSD areas using a modified Delphi method by the panel and specific emphasis on locoregional socioeconomic-cultural issues relevant to the AP region. While variations exist in treatment strategies for managing MI and MSD due to geographical expertise, locoregional resources, and sociocultural factors, the panel agreed that comprehensive fertility evaluation with a multidisciplinary management approach to each MSD domain is recommended. It is important to address individual MI issues with an emphasis on improving spermatogenesis and facilitating reproductive avenues while at the same time, managing various MSD conditions with evidence-based treatments. All therapeutic options should be discussed and implemented based on the patient’s individual needs, beliefs and preferences while incorporating locoregional expertise and available resources.

Objective:To explore the value of interpretable machine learning model in predicting the prognoses of patients with acute ischemic stroke..Methods:A total of 296 patients with acute ischemic stroke who received intravenous thrombolysis in Zhanjiang Central Hospital, Guangdong Medical University from March 2020 to October 2023 were selected. Prognosis was assessed 3 months after follow-up using modified Rankin scale (scores of 0-2: good prognosis; scores of 3-6: poor prognosis). Clinical data were collected and analyzed retrospectively, and independent influencing factors for prognoses were analyzed by multivariate Logistic regression. These patients were randomly divided into training dataset ( n=178) and test dataset ( n=118) in a 3:2 ratio; independent influencing factors were used as characteristic variables to train these 10 machine learning models, including Logistic regression, random forest, support vector machine, naive Bayesian model, linear discriminant analysis, mixture discriminant analysis, flexible discriminant analysis, gradient boosting machine, extreme gradient boosting, and category boosting. Prediction performance of these 10 machine learning models were evaluated using calibration curve, precise-recall curve, precision-recall gain curve and receiver operating characteristic (ROC) curve. Interpretation and visualization were added via Shapley Additive exPlanation (SHAP) to the machine learning models (including global interpretation and local interpretation). Results:Of the 296 patients, 72 had a poor prognosis. Age ( OR=1.039, 95% CI: 1.008-1.072, P=0.015), National Institute of Health Stroke Scale score ( OR=1.213, 95% CI: 1.000-1.337, P<0.001), Glasgow Coma Scale score ( OR=0.470, 95% CI: 0.289-0.765, P=0.002), Stroke Prognostic Instrument-Ⅱ score ( OR=1.257, 95% CI: 1.043-1.516, P=0.016,), C-reactive protein ( OR=1.709, 95% CI: 1.398-2.087, P<0.001) and platelet count ( OR=0.988, 95% CI: 0.978-0.998, P=0.016) were independent influencing factors for prognoses. Among the 10 machine learning algorithms, calibration curve (C-inder: 0.896), precise-recall curve (area under the curve [AUC]: 0.791), precision-recall gain curve (AUC: 0.363), and ROC curve (AUC: 0.856) in both the training and test sets confirmed that the XGBoost model has the highest performance in predicting prognoses. SHAP visualisation diagram indicated that order of importance was C-reactive protein, National Institutes of Health Stroke Scale, platelet count, Glasgow Coma Scale, Stroke Prediction Tool-II, and age. SHAP scatter plot visualized the contribution direction of these 6 characteristic variables, with bimodal distribution. SHAP dependence plot indicated dependence between values of 6 characteristic variables and SHAP values, with C-reactive protein enjoying the most significant trend. SHAP plot provided local interpretation for individual sample, making the extreme gradient enhancement model more transparent and interpretable. Conclusion:XGBoost model incorporating age, National Institute of Health Stroke Scale, Glasgow Coma Scale, Stroke Prognostic Instrument-Ⅱ, C-reactive protein, and platelet count can differentiate poor prognosis from good prognosis in patients with acute ischemic stroke with high accuracy; on this basis, the model interpretation and visualization combined with SHAP are helpful to understand the contribution and direction of each characteristic variable to the prediction results.

Acute lymphoblastic leukemia (ALL) is the most common malignant neoplastic disease in children. With the continuous improvement in diagnosis and treatment, there has been an increasing number of ALL children who achieve long-term survival after complete remission; however, a considerable proportion of these children have cognitive impairment, which has a serious adverse impact on their learning, employment, and social life. This article reviews the latest research on cognitive impairment in children with ALL from the aspects of the influencing factors, detection techniques, and prevention/treatment methods for cognitive impairment.
Child ; Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy* ; Remission Induction ; Cognitive Dysfunction/etiology*

This article reports two cases of children with B-cell acute lymphoblastic leukemia (B-ALL) complicated by invasive fungal disease (IFD) who received bridging treatment using blinatumomab. Case 1 was a 4-month-old female infant who experienced recurrent high fever and limb weakness during chemotherapy. Blood culture was negative, and next-generation sequencing (NGS) of peripheral blood, bronchoalveolar lavage fluid, and cerebrospinal fluid were all negative. Chest CT and cranial MRI revealed obvious infection foci. Case 2 was a 2-year-old male patient who experienced recurrent high fever with multiple inflammatory masses during chemotherapy. Candida tropicalis was detected in peripheral blood and abscess fluid using NGS, while blood culture and imaging examinations showed no obvious abnormalities. After antifungal and blinatumomab therapy, both cases showed significant improvement in symptoms, signs, and imaging, and B-ALL remained in continuous remission. The report indicates that bridging treatment with blinatumomab in children with B-ALL complicated by IFD can rebuild the immune system and control the underlying disease in the presence of immunosuppression and severe fungal infection.
Child, Preschool ; Female ; Humans ; Infant ; Male ; Antibodies, Bispecific/therapeutic use* ; Invasive Fungal Infections/drug therapy* ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Remission Induction