OBJECTIVE: To investigate the therapeutic potential of pseudolaric acid B (PAB) on non-alcoholic fatty liver disease (NAFLD) and its underlying molecular mechanism in vitro and in vivo. METHODS: Eight-week-old male C57BL/6J mice (n=32) were fed either a normal chow diet (NCD) or a high-fat diet (HFD) for 8 weeks. The HFD mice were divided into 3 groups according to a simple random method, including HFD, PAB low-dose [10 mg/(kg·d), PAB-L], and PAB high-dose [20 mg/(kg·d), PAB-H] groups. After 8 weeks of treatment, glucose metabolism and insulin resistance were assessed by oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Biochemical assays were used to measure the serum and cellular levels of total cholesterol (TC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). White adipose tissue (WAT), brown adipose tissue (BAT) and liver tissue were subjected to hematoxylin and eosin (H&E) staining or Oil Red O staining to observe the alterations in adipose tissue and liver injury. PharmMapper and DisGeNet were used to predict the NAFLD-related PAB targets. Peroxisome proliferator-activated receptor alpha (PPARα) pathway involvement was suggested by Kyoto Encyclopedia of Genes and Genomes (KEGG) and search tool Retrieval of Interacting Genes (STRING) analyses. Luciferase reporter assay, cellular thermal shift assay (CETSA), and drug affinity responsive target stability assay (DARTS) were conducted to confirm direct binding of PAB with PPARα. Molecular dynamics simulations were applied to further validate target engagement. RT-qPCR and Western blot were performed to assess the downstream genes and proteins expression, and validated by PPARα inhibitor MK886. RESULTS: PAB significantly reduced serum TC, TG, LDL-C, AST, and ALT levels, and increased HDL-C level in HFD mice (P<0.01). Target prediction analysis indicated a significant correlation between PAB and PPARα pathway. PAB direct target binding with PPARα was confirmed through luciferase reporter assay, CETSA, and DARTS (P<0.05 or P<0.01). The target engagement between PAB and PPARα protein was further confirmed by molecular dynamics simulations and the top 3 amino acid residues, LEU321, MET355, and PHE273 showed the most significant changes in mutational energy. Subsequently, PAB upregulated the genes expressions involved in lipid metabolism and mitochondrial biogenesis downstream of PPARα (P<0.05 or P<0.01). Significantly, the PPARα inhibitor MK886 effectively reversed the lipid-lowering and PPARα activation properties of PAB (P<0.05 or P<0.01). CONCLUSION PAB mitigates lipid accumulation, ameliorates liver damage, and improves mitochondrial biogenesis by binding with PPARα, thus presenting a potential candidate for pharmaceutical development in the treatment of NAFLD.
Animals ; PPAR alpha/metabolism* ; Non-alcoholic Fatty Liver Disease/pathology* ; Male ; Mice, Inbred C57BL ; Lipid Metabolism/drug effects* ; Diterpenes/therapeutic use* ; Organelle Biogenesis ; Diet, High-Fat ; Humans ; Mice ; Liver/metabolism* ; Insulin Resistance ; Mitochondria/metabolism* ; Molecular Docking Simulation

Chronic visceral pain is a persistent and debilitating condition arising from dysfunction or sensitization of the visceral organs and their associated nervous pathways. Increasing evidence suggests that imbalances in central nervous system function play an essential role in the progression of visceral pain, but the exact mechanisms underlying the neural circuitry and molecular targets remain largely unexplored. In the present study, the ventral tegmental area (VTA) was shown to mediate visceral pain in mice. Visceral pain stimulation increased c-Fos expression and Ca²⁺ activity of glutamatergic VTA neurons, and optogenetic modulation of glutamatergic VTA neurons altered visceral pain. In particular, the upregulation of NMDA receptor 2A (NR2A) subunits within the VTA resulted in visceral pain in mice. Administration of a selective NR2A inhibitor decreased the number of visceral pain-induced c-Fos positive neurons and attenuated visceral pain. Pharmacology combined with chemogenetics further demonstrated that glutamatergic VTA neurons regulated visceral pain behaviors based on NR2A. In summary, our findings demonstrated that the upregulation of NR2A in glutamatergic VTA neurons plays a critical role in visceral pain. These insights provide a foundation for further comprehension of the neural circuits and molecular targets involved in chronic visceral pain and may pave the way for targeted therapies in chronic visceral pain.
Animals ; Male ; Visceral Pain/metabolism* ; Up-Regulation/physiology* ; Ventral Tegmental Area/metabolism* ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors* ; Neurons/drug effects* ; Mice, Inbred C57BL ; Mice ; Proto-Oncogene Proteins c-fos/metabolism* ; Chronic Pain/metabolism* ; Glutamic Acid/metabolism*

OBJECTIVE: Hepatocellular carcinoma (HCC) is sensitive to ferroptosis, a new form of programmed cell death that occurs in most tumor types. However, the mechanism through which ferroptosis modulates HCC remains unclear. This study aimed to investigate the oncogenic role and prognostic value of FANCD2 and provide novel insights into the prognostic assessment and prediction of immunotherapy. METHODS: Using clinicopathological parameters and bioinformatic techniques, we comprehensively examined the expression of FANCD2 macroscopically and microcosmically. We conducted univariate and multivariate Cox regression analyses to identify the prognostic value of FANCD2 in HCC and elucidated the detailed molecular mechanisms underlying the involvement of FANCD2 in oncogenesis by promoting iron-related death. RESULTS: FANCD2 was significantly upregulated in digestive system cancers with abundant immune infiltration. As an independent risk factor for HCC, a high FANCD2 expression level was associated with poor clinical outcomes and response to immune checkpoint blockade. Gene set enrichment analysis revealed that FANCD2 was mainly involved in the cell cycle and CYP450 metabolism. CONCLUSION To the best of our knowledge, this is the first study to comprehensively elucidate the oncogenic role of FANCD2. FANCD2 has a tumor-promoting aspect in the digestive system and acts as an independent risk factor in HCC; hence, it has recognized value for predicting tumor aggressiveness and prognosis and may be a potential biomarker for poor responsiveness to immunotherapy.
Humans ; Carcinoma, Hepatocellular/diagnosis* ; Liver Neoplasms/diagnosis* ; Immunotherapy ; Fanconi Anemia Complementation Group D2 Protein/metabolism* ; Prognosis ; Male ; Female ; Middle Aged ; Biomarkers, Tumor/metabolism*

Stent entrapment is a rare complication of percutaneous coronary intervention.In recent years,with the development of distal radial artery puncture technology,the rare complications related to distal radial artery have been gradually understood.This article describes a patient who underwent coronary intervention through a distal radial approach,and the stent was dislodged and trapped in the far radial artery.The patient came to our hospital for stent implantation because of acute extensive anterolateral myocardial infarction.During the intervention,the balloon could not be filled when the stent was released from the left anterior descending artery,and the retracting stent could not be used to remove the guide catheter.The stent was dislodged and embedded in the distal vessel.The sheath was inserted through the proximal radial reverse puncture,and the stent was captured with a snare and removed.

Stent entrapment is a rare complication of percutaneous coronary intervention.In recent years,with the development of distal radial artery puncture technology,the rare complications related to distal radial artery have been gradually understood.This article describes a patient who underwent coronary intervention through a distal radial approach,and the stent was dislodged and trapped in the far radial artery.The patient came to our hospital for stent implantation because of acute extensive anterolateral myocardial infarction.During the intervention,the balloon could not be filled when the stent was released from the left anterior descending artery,and the retracting stent could not be used to remove the guide catheter.The stent was dislodged and embedded in the distal vessel.The sheath was inserted through the proximal radial reverse puncture,and the stent was captured with a snare and removed.

Objective To explore the effects of Peiyuan Yishen Antai Decoction on cell senescence and decidualization of aged mice with recurrent spontaneous abortion(RSA)based on P53/P21 signaling pathway;To discuss its mechanism in the treatment of RSA.Methods 8-9 month old CBA/J female mice were randomly divided into aging model group(normal saline 0.3 mL/d),Chinese materia medica group(18.72 g/kg)and dydrogesterone group(2.6 mg/kg).6-8 week old CBA/J female mice were assigned to a reproductive age blank group(normal saline 0.3 mL/d),with five mice in each group.After administering the corresponding solutions by gavage for 2 weeks,the reproductive age blank group mice were housed in cages with BALB/c male mice,while the remaining groups were housed in cages with DBA/2 male mice.After confirming the presence of vaginal plug,gavage was continued until the 9th day of pregnancy for sampling.Mice embryo loss rate was observed,HE staining was used to observe the morphology of uterine decidua,immunohistochemistry was used to detect the localization and expression of aging related protein Pi6INK4a in decidua tissue,RT-PCR and Western blot were used to detect the mRNA and protein expressions of P53,P21,insulin-like growth factor binding protein 1(IGFBP-1)and prolactin(PRL)in decidual tissue.Results Compared with the reproductive age blank group,the embryo loss rate of the aging model group significantly increased(P＜0.05),the irregular endometrial cells were vacuolated,the number of glands and blood vessels was reduced,the expression of P16INK4a in decidual tissue significantly increased(P＜0.05),and the expressions of P53,P21 mRNA and protein significantly increased(P＜0.05),the mRNA and protein expressions of IGFBP-1 and PRL significantly decreased(P＜0.05).Compared with the aging model group,the Chinese materia medica group and the dydrogesterone group showed an decreasing trend in embryo loss rate in mice,the arrangement of cells in the decidua tissue was relatively neat,and the number of blood vessels and glands increased,the expression of P16INK4a in decidua tissue was significantly decreased(P＜0.05),the mRNA and protein expressions of P53 and P21 were significantly decreased(P＜0.05),while the mRNA and protein expressions of IGFBP-1 and PRL significantly increased(P＜0.05).Conclusion Peiyuan Yishen Antai Decoction can improve the aging status of endometrial stromal cells in aged RSA model mice by regulating the P53/P21 signaling pathway,promote decidualization process,and thus exert a protective effect on pregnancy.

Objective:This study aims to explore the application effect of anticipatory risk intervention combined with health education under LEARNS mode in elderly patients with chronic heart failure(CHF).Methods:This randomized controlled enrolled 126 elderly CHF patients admitted in Panzhihua Central Hospital between January 2022 and February 2023.They were divided into control group(n=63)and intervention group(n=63).All patients received routine nursing care,patients in control group received additional health education under LEARNS mode,compared to those in intervention group receiving additional anticipatory risk intervention based on control group,both groups were intervened for 2 months.Physiological indexes,negative emotion,quality of life,sleep quality,disease perception&control and self-efficacy,as well as incidence of adverse events,were compared between two groups.Results:Compared with patients in control group after intervention,those in intervention group had signif-icant lower systolic blood pressure(SBP)[(119.84±8.60)mmHg vs.(129.49±9.24)mmHg],diastolic blood pressure(DBP)[(81.59±5.08)mmHg vs.(88.51±6.36)mmHg],N terminal pro brain natriuretic peptide(NT-proBNP)[(2604.46±204.80)ng/L vs.(3024.87±212.27)ng/L],scores of Self-Rating Anxiety Scale(SAS)[(55.90±2.43)points vs.(60.11±2.62)points],Self-Rating Depression Scale(SDS)[(57.03±2.56)points vs.(61.54±2.66)points],Minnesota Living with Heart Failure Questionnaire(MLHFQ)[(52.05±6.32)points vs.(60.46±7.10)points]and Pittsburgh Sleep Quality Index(PSQI)[(9.00±1.65)points vs.(11.05±1.96)points],and significant higher left ventricular ejection fraction(LVEF)[(51.83±7.28)％vs.(47.57±5.98)％],scores of Control Attitude Scale-Revised(CAS-R)[(35.59±2.97)points vs.(30.60±3.52)points]and Gen-eral Self-Efficacy Scale(GSES)[(36.98±4.21)points vs.(30.52±4.14)points](P＜0.001 all).Incidence of adverse events in intervention group was significantly lower than that of control group(3.17％vs.12.70％,P=0.048).Conclusion:Anticipatory risk intervention combined with health education under the LEARNS model could effectively improve the physiological indexes,quality of life and sleep,enhance disease perception and self-effica-cy,and reduce negative emotion and incidence of adverse events in elderly CHF patients.

Objective:This study aims to explore the application effect of anticipatory risk intervention combined with health education under LEARNS mode in elderly patients with chronic heart failure(CHF).Methods:This randomized controlled enrolled 126 elderly CHF patients admitted in Panzhihua Central Hospital between January 2022 and February 2023.They were divided into control group(n=63)and intervention group(n=63).All patients received routine nursing care,patients in control group received additional health education under LEARNS mode,compared to those in intervention group receiving additional anticipatory risk intervention based on control group,both groups were intervened for 2 months.Physiological indexes,negative emotion,quality of life,sleep quality,disease perception&control and self-efficacy,as well as incidence of adverse events,were compared between two groups.Results:Compared with patients in control group after intervention,those in intervention group had signif-icant lower systolic blood pressure(SBP)[(119.84±8.60)mmHg vs.(129.49±9.24)mmHg],diastolic blood pressure(DBP)[(81.59±5.08)mmHg vs.(88.51±6.36)mmHg],N terminal pro brain natriuretic peptide(NT-proBNP)[(2604.46±204.80)ng/L vs.(3024.87±212.27)ng/L],scores of Self-Rating Anxiety Scale(SAS)[(55.90±2.43)points vs.(60.11±2.62)points],Self-Rating Depression Scale(SDS)[(57.03±2.56)points vs.(61.54±2.66)points],Minnesota Living with Heart Failure Questionnaire(MLHFQ)[(52.05±6.32)points vs.(60.46±7.10)points]and Pittsburgh Sleep Quality Index(PSQI)[(9.00±1.65)points vs.(11.05±1.96)points],and significant higher left ventricular ejection fraction(LVEF)[(51.83±7.28)％vs.(47.57±5.98)％],scores of Control Attitude Scale-Revised(CAS-R)[(35.59±2.97)points vs.(30.60±3.52)points]and Gen-eral Self-Efficacy Scale(GSES)[(36.98±4.21)points vs.(30.52±4.14)points](P＜0.001 all).Incidence of adverse events in intervention group was significantly lower than that of control group(3.17％vs.12.70％,P=0.048).Conclusion:Anticipatory risk intervention combined with health education under the LEARNS model could effectively improve the physiological indexes,quality of life and sleep,enhance disease perception and self-effica-cy,and reduce negative emotion and incidence of adverse events in elderly CHF patients.

Objective To explore the effects of Peiyuan Yishen Antai Decoction on cell senescence and decidualization of aged mice with recurrent spontaneous abortion(RSA)based on P53/P21 signaling pathway;To discuss its mechanism in the treatment of RSA.Methods 8-9 month old CBA/J female mice were randomly divided into aging model group(normal saline 0.3 mL/d),Chinese materia medica group(18.72 g/kg)and dydrogesterone group(2.6 mg/kg).6-8 week old CBA/J female mice were assigned to a reproductive age blank group(normal saline 0.3 mL/d),with five mice in each group.After administering the corresponding solutions by gavage for 2 weeks,the reproductive age blank group mice were housed in cages with BALB/c male mice,while the remaining groups were housed in cages with DBA/2 male mice.After confirming the presence of vaginal plug,gavage was continued until the 9th day of pregnancy for sampling.Mice embryo loss rate was observed,HE staining was used to observe the morphology of uterine decidua,immunohistochemistry was used to detect the localization and expression of aging related protein Pi6INK4a in decidua tissue,RT-PCR and Western blot were used to detect the mRNA and protein expressions of P53,P21,insulin-like growth factor binding protein 1(IGFBP-1)and prolactin(PRL)in decidual tissue.Results Compared with the reproductive age blank group,the embryo loss rate of the aging model group significantly increased(P＜0.05),the irregular endometrial cells were vacuolated,the number of glands and blood vessels was reduced,the expression of P16INK4a in decidual tissue significantly increased(P＜0.05),and the expressions of P53,P21 mRNA and protein significantly increased(P＜0.05),the mRNA and protein expressions of IGFBP-1 and PRL significantly decreased(P＜0.05).Compared with the aging model group,the Chinese materia medica group and the dydrogesterone group showed an decreasing trend in embryo loss rate in mice,the arrangement of cells in the decidua tissue was relatively neat,and the number of blood vessels and glands increased,the expression of P16INK4a in decidua tissue was significantly decreased(P＜0.05),the mRNA and protein expressions of P53 and P21 were significantly decreased(P＜0.05),while the mRNA and protein expressions of IGFBP-1 and PRL significantly increased(P＜0.05).Conclusion Peiyuan Yishen Antai Decoction can improve the aging status of endometrial stromal cells in aged RSA model mice by regulating the P53/P21 signaling pathway,promote decidualization process,and thus exert a protective effect on pregnancy.

Aim To investigate the effects of multi-gly-cosides of Tripterygium wilfordii(GTW)on mitochon-drial dynamics-related proteins and the mechanism of nephroprotective effects in IgA nephrophathy(IgAN)rats.Methods SPF grade male SD rats were random-ly divided into the Control group,modelling group,prednisone group(6.25 mg·kg·d-1)and GTW group(6.25 mg·kg·d-1).The IgAN rat model was established by the method of"bovine serum albumin(BSA)+carbon tetrachloride(CCl4)+lipopolysac-charide(LPS)".The total amount of urinary protein(24 h-UTP)and erythrocyte count in urine were meas-ured in 24 h urine.Blood biochemistry of serum albu-min(ALB),alanine aminotransferase(ALT),urea ni-trogen(BUN),and creatinine(Scr)were measured in abdominal aorta of the rats;immunofluorescence and HE staining were used to observe the histopathology of the kidneys;RT-PCR and Western blotting were used to detect the mRNA and protein expression levels of key proteins regulating mitochondrial division and fu-sion:dynamin-related protein 1(Drp1),mitochondrial fusion protein 1(Mfn1),and mitochondrial fusion pro-tein 2(Mfn2),and PTEN-induced putative kinase 1(Pink1),in the kidney tissue of rats.Results GTW significantly reduced urinary erythrocyte count and 24 h-UTP,decreased serum ALT,BUN and Scr levels,in-creased serum ALB levels,improved renal histopatho-logical status in IgAN rats,increased the protein and mRNA expression levels of Mfn1,Mfn2,and Pink1,and decreased the protein and mRNA expression levels of Drp1 in renal tissues.Conclusions GTW may regu-late mitochondrial structure and maintain the dynamic balance of mitochondrial dynamics by promoting the ex-pression of Mfn1,Mfn2,Pink1 and decreasing Drp1.This may result in a reduction in urinary erythrocyte counts and proteinuria,and an improvement in renal function.