ObjectiveTo investigate the ameliorative effects and related mechanisms of the Zuogui Jiangtang Shuxin prescription （ZJSP） on glucose and lipid metabolism disorders in MKR mice with diabetic cardiomyopathy （DCM）， with a focus on elucidating its regulatory role on the adenosine monophosphate-activated protein kinase （AMPK）/forkhead box protein O1 （FoxO1）/cluster of differentiation 36 （CD36） signaling pathway and lipid deposition. MethodsFifty 8-week-old male MKR mice were fed a high-fat diet for four weeks and then intraperitoneally injected with streptozotocin （STZ） while maintaining a high-fat diet to establish a DCM model. The mice were randomly divided into the model group， the low-dose（14.43 g·kg^-1）and high-dose（28.86 g·kg^-1） ZJSP groups， and the metformin group （0.25 g·kg^-1）， with age-matched FVB mice as a normal control group. Each group received intragastric administration of normal saline or corresponding concentrations of ZJSP at equal volumes. After four weeks， fasting blood glucose （FBG） and cardiac function were measured. Blood was collected from the eyeballs under anesthesia to detect fasting insulin （FINS） and blood lipid levels. Myocardial tissue morphology was observed by hematoxylin-eosin （HE） staining， and lipid deposition in the heart was assessed using oil red O staining. Real-time quantitative polymerase chain reaction （Real-time PCR） was used to measure the mRNA expression levels of AMPK， FoxO1， and CD36 in myocardial tissues. Western blot was employed to detect the protein expression levels of AMPK， p-AMPK， FoxO1， p-FoxO1， and CD36. ResultsCompared with the control group， the model group showed significantly increased levels of FBG and FINS （P<0.01）， elevated levels of triglycerides （TG）， total cholesterol （TC）， and low-density lipoprotein cholesterol （LDL-C） （P<0.01）， and significantly decreased left ventricular ejection fraction （EF） and fractional shortening （FS） values （P<0.01）. HE staining revealed marked cardiomyocyte hypertrophy， disarray， and widened intercellular spaces in myocardial tissues. Oil Red O staining showed extensive red deposition areas and fine lipid droplet accumulation in the myocardial tissue. AMPK mRNA expression was decreased， while FoxO1 and CD36 mRNA expressions were significantly increased （P<0.01）. The p-AMPK/AMPK protein expression ratio in myocardial tissues was significantly reduced， while the p-FoxO1/FoxO1 protein expression ratio and CD36 protein expression levels were significantly increased （P<0.01）. Compared with the model group， all treatment groups exhibited significantly reduced FBG （P<0.01）， decreased FINS and blood lipid levels （TG， TC， LDL-C） （P<0.05， P<0.01）， improved cardiac function （P<0.05）， noticeable amelioration of myocardial histopathological morphology and lipid deposition， increased AMPK mRNA expression （P<0.01）， with significantly downregulated FoxO1 and CD36 mRNA expressions （P<0.01）， elevated p-AMPK/AMPK protein expression levels in myocardial tissue （P<0.05）， significantly decreased p-FoxO1/FoxO1 ratios （P<0.01）， and downregulated CD36 protein expression levels （P<0.05， P<0.01）. ConclusionZJSP exerts a protective effect on the heart in type 2 DCM of MKR mice， and its mechanism may be associated with the regulation of the AMPK/FoxO1/CD36 signaling pathway.

ObjectiveTo investigate the ameliorative effects and related mechanisms of the Zuogui Jiangtang Shuxin prescription （ZJSP） on glucose and lipid metabolism disorders in MKR mice with diabetic cardiomyopathy （DCM）， with a focus on elucidating its regulatory role on the adenosine monophosphate-activated protein kinase （AMPK）/forkhead box protein O1 （FoxO1）/cluster of differentiation 36 （CD36） signaling pathway and lipid deposition. MethodsFifty 8-week-old male MKR mice were fed a high-fat diet for four weeks and then intraperitoneally injected with streptozotocin （STZ） while maintaining a high-fat diet to establish a DCM model. The mice were randomly divided into the model group， the low-dose（14.43 g·kg^-1）and high-dose（28.86 g·kg^-1） ZJSP groups， and the metformin group （0.25 g·kg^-1）， with age-matched FVB mice as a normal control group. Each group received intragastric administration of normal saline or corresponding concentrations of ZJSP at equal volumes. After four weeks， fasting blood glucose （FBG） and cardiac function were measured. Blood was collected from the eyeballs under anesthesia to detect fasting insulin （FINS） and blood lipid levels. Myocardial tissue morphology was observed by hematoxylin-eosin （HE） staining， and lipid deposition in the heart was assessed using oil red O staining. Real-time quantitative polymerase chain reaction （Real-time PCR） was used to measure the mRNA expression levels of AMPK， FoxO1， and CD36 in myocardial tissues. Western blot was employed to detect the protein expression levels of AMPK， p-AMPK， FoxO1， p-FoxO1， and CD36. ResultsCompared with the control group， the model group showed significantly increased levels of FBG and FINS （P<0.01）， elevated levels of triglycerides （TG）， total cholesterol （TC）， and low-density lipoprotein cholesterol （LDL-C） （P<0.01）， and significantly decreased left ventricular ejection fraction （EF） and fractional shortening （FS） values （P<0.01）. HE staining revealed marked cardiomyocyte hypertrophy， disarray， and widened intercellular spaces in myocardial tissues. Oil Red O staining showed extensive red deposition areas and fine lipid droplet accumulation in the myocardial tissue. AMPK mRNA expression was decreased， while FoxO1 and CD36 mRNA expressions were significantly increased （P<0.01）. The p-AMPK/AMPK protein expression ratio in myocardial tissues was significantly reduced， while the p-FoxO1/FoxO1 protein expression ratio and CD36 protein expression levels were significantly increased （P<0.01）. Compared with the model group， all treatment groups exhibited significantly reduced FBG （P<0.01）， decreased FINS and blood lipid levels （TG， TC， LDL-C） （P<0.05， P<0.01）， improved cardiac function （P<0.05）， noticeable amelioration of myocardial histopathological morphology and lipid deposition， increased AMPK mRNA expression （P<0.01）， with significantly downregulated FoxO1 and CD36 mRNA expressions （P<0.01）， elevated p-AMPK/AMPK protein expression levels in myocardial tissue （P<0.05）， significantly decreased p-FoxO1/FoxO1 ratios （P<0.01）， and downregulated CD36 protein expression levels （P<0.05， P<0.01）. ConclusionZJSP exerts a protective effect on the heart in type 2 DCM of MKR mice， and its mechanism may be associated with the regulation of the AMPK/FoxO1/CD36 signaling pathway.

Objective : To explore the effect of dendrobium officinale polysaccharides(DOP) on necrotizing enterocolitis(NEC) in neonatal mice and to preliminarily explore the potential molecular mechanisms. Methods : Seven-day-old C57BL/6J mice were randomly divided into four groups: control(CTRL) group, necrotizing enterocolitis(NEC) group, low-dose DOP treatment(DOPL+NEC) group and high-dose DOP treatment(DOPH+NEC) group. The NEC model was established by hypoxia, cold stimulation, hypertonic feeding and intraperitoneal injection of lipopolysaccharide(LPS). At the end of the experiment, the small intestine tissues were collected. The general condition of the mice was observed, and body weight was recorded. Hematoxylin-eosin(HE) staining was used to observe pathological changes in the small intestine tissues. The expression levels of E-cadherin, Occludin and Claudin-1 were detected by immunohistochemistry and Western blot. The concentrations of tumor necrosis factor-α(TNF-α), interleukin(IL)-1β, IL-6 and IL-10 were measured by ELISA. The levels of lactate dehydrogenase(LDH), malondialdehyde(MDA), superoxide dismutase(SOD) and glutathione(GSH) were detected using commercial kits. The expression levels of nuclear factor erythroid 2-related factor 2(Nrf2) and heme oxygenase-1(HO-1) proteins were detected by immunohistochemistry and Western blot. Results : ompared with the CTRL group , the NEC group exhibited decreased body weight and increased HE pathological scores (P < 0. 01 or P < 0. 001) . The protein expression levels of E-cadherin , Occludin and Claudin-1 were reduced (P < 0. 01 or P < 0. 001) . The concentrations of TNF-α, IL-1βand IL-6 increased , while the concentration of IL-10 decreased (P < 0. 01) . The levels of MDA and LDH increased , while the levels of GSH and SOD decreased (P < 0. 01) . The protein expression levels of Nrf2 and HO-1 increased ( P < 0. 05 or P < 0. 01) . In contrast , DOP intervention groups showed increased body weight and decreased HE scores (P < 0. 05 or P < 0. 01) . The protein expression levels of E-cadherin , Occludin and Claudin-1 increased (P < 0. 05 or P < 0. 01 or P < 0. 01) . The concentrations of TNF-α, IL-1βand IL-6 decreased(P < 0. 05 or P < 0. 01 ) , while the concentration of IL-10 increased ( P < 0. 01) . The levels of MDA and LDH decreased , while the levels of GSH and SOD increased ( P < 0. 05 or P < 0. 01) . The protein expression levels of Nrf2 and HO-1 further increased (P < 0. 05 or P < 0. 01) . Conclusion DOP can ameliorate the pathological damage of necrotizing enterocolitis and enhance the intestinal mucosal barrier function in NEC mice . Additionally , it can also reduce oxidative stress injury and intestinal inflammation in NEC mice . The mechanism may be associated with the activation of the Nrf2/HO-1 pathway by DOP.

Objective To compare the clinical effect of left atrial appendage(LAA)plus atrial septal defect(ASD)closure therapy and ASD closure therapy in treating ASD associated with atrial fibrillation(AF).Methods A total of 102 patients with ASD complicated by non-valvular AF,who were admitted to the General Hospital of Northern Theater Command of China from January 2016 to December 2023,were enrolled in this study.Of the 102 patients,simultaneous one-stop interventional transcatheter LAA plus ASD closure was performed in 52(LAA+ASD closure group)and ASD closure was performed in 50.(ASD closure group).The perioperative and postoperative 30 d,90 d,180 d clinical safety and efficacy were compared between the two groups.Telephone follow-up was conducted,the complications such as embolization and bleeding were recorded,and the medium-to-long-term follow-up results were compared between the two groups.Results The immediate surgical success rate in both groups was 100％.The immediate postoperative monitoring showed that the occlusion effect was satisfactory.In LAA plus ASD closure group,LACBES LAA occluder was used in 27 patients and LAmbre LAA occluder was adopted in 25.There were no statistically significant differences in the patients' baseline characteristics between the two groups(all P＞0.05).In the LAA+ASD closure group,3 patients developed cardiac tamponade,among them 2 patients were cured after pericardiocentesis drainage and one patient was referred to the surgery department to receive occluder removal and intracardiac repair.Medium-to-long-term follow-up was conducted in 101 patients with a median follow-up period of 37.6 months.The incidence of embolic events in the LAA+ASD closure group was lower than that in the ASD closure group(3.9％vs.18.0％,P=0.028).The incidence of bleeding events in the ASD closure group was higher than that in the LAA+ASD closure group(16.00％vs.1.96％,P=0.016).Kaplan-Meier analysis indicated that the risk of occurring embolic events and bleeding events in the LAA+ASD closure group was strikingly lower than that in the ASD closure group(HR=4.295 and 7.888 respectively,95％CI:1.317-14.010 and 2.135-29.140 respectively,P=0.040 9 and P=0.020 8 respectively).Conclusion Simultaneous interventional transcatheter LAA plus ASD closure can effectively prevent embolic events such as stroke,etc.in patients with ASD complicated by AF,and its bleeding risk is lower than simple ASD closure.

The interaction between m⁶A-methylated RNA and chromatin modification remains largely unknown. We found that targeted inhibition of bromodomain-containing protein 4 (BRD4) by siRNA or its inhibitor (JQ1) significantly decreases mRNA m⁶A levels and suppresses the malignancy of breast cancer (BC) cells via increased expression of demethylase AlkB homolog 5 (ALKBH5). Mechanistically, inhibition of BRD4 increases the mRNA stability of ALKBH5 via enhanced binding between its 3' untranslated regions (3'UTRs) with RNA-binding protein RALY. Further, BRD4 serves as a scaffold for ubiquitin enzymes tripartite motif containing-21 (TRIM21) and ALKBH5, resulting in the ubiquitination and degradation of ALKBH5 protein. JQ1-increased ALKBH5 then demethylates mRNA of extra spindle pole bodies like 1 (ESPL1) and reduces binding between ESPL1 mRNA and m⁶A reader insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), leading to decay of ESPL1 mRNA. Animal and clinical studies confirm a critical role of BRD4/ALKBH5/ESPL1 pathway in BC progression. Further, our study sheds light on the crosstalks between histone modification and RNA methylation.

Acute pancreatitis (AP) is a life-threatening gastrointestinal disorder for which no effective pharmacological treatments are currently available. One of the pharmacological targets that merits further research is the neurokinin 1 receptor (NK1R), which is found on pancreatic acinar cells and responds to the neuropeptide substance P (SP) that participates in AP. Although a few studies have stated the involvement of SP/NK1R in neurogenic inflammation in AP development, the regulatory mechanism remains unclear. In this study, we found that following activation of NK1R by SP, β-arrestin1, a scaffold protein of NK1R, down-regulated transcription of Adss, Adsl, and Ampd in the purine nucleotide cycle, thereby inhibiting mitochondrial function through fumarate depletion. Interestingly, we identified magnolol as a new and natural NK1R inhibitor with a non-nitrogenous biphenyl core structure. It exhibited a beneficial effect on AP by restoring purine nucleotide cycle metabolic enzymes and fumarate levels. Our study not only provides new therapeutic strategies, leading compounds, and drug translation possibilities for AP, but also provides important clues for the study of downstream mechanisms driven by SP in other diseases.

Objective: To investigate the chemical compositions of Maxing Shigan Decoction (麻杏石甘汤, MXSGD) and elucidate its anti-influenza A virus (IAV) mechanism from prediction to validation. Methods: Ultra high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to analyze the chemical compositions of MXSGD. Network pharmacology theories were used to screen and identify shared targets of both the potential targets of active ingredients of MXSGD and IAV. A protein-protein interaction (PPI) network was then constructed, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The binding stability between core bioactive compounds and key targets was validated by molecular docking and dynamic simulations. A total of 24 BALB/c mice were infected with IAV to build IAV mouse models. After successful modelling, the mouse models were randomly divided into model, MXSGD high-dose (2.8 g/kg), MXSGD low-dose (1.4 g/kg), and oseltamivir (20.14 mg/kg) groups, with an additional normal mice as control group (n = 6 per group). The treatments were administered by gavage daily between 8:00 a.m. and 10:00 a.m. for five consecutive days. Upon completion of the administration, the body weight ratio, lung index, protein content in the bronchoalveolar lavage fluid (BALF), and the levels of inflammatory factors including interleukin (IL)-6 and tumor necrosis factor (TNF)-α in mice were measured to preliminarily analyze the therapeutic efficacy of MXSGD against IAV infection. Furthermore, the expression levels of mechanistic target of rapamycin (mTOR), hypoxia inducible factor (HIF)-1α, and vascular endothelial growth factor (VEGF) proteins in the HIF-1 signaling pathway, which was enriched by network pharmacology, were detected by Western blot. Results: A total of 212 chemical components in MXSGD were identified by the UPLC-MS/MS method. These chemical components can be classified into 9 primary categories and 31 secondary categories. After intersecting the chemical component targets with IAV-related targets, a total of 567 potential MXSGD components targeting IAV were identified. The construction of PPI network and the results of both GO and KEGG enrichment analyses revealed that the anti-IAV effects of MXSGD were associated with multiple pathways, including apoptosis, TNF, HIF-1, and IL-17 signaling pathways. The results of molecular docking demonstrated that the binding energies between the core compound 1-methoxyphaseollin and key targets including HIF-1α, mTOR, and VEGF were all lower than – 5.0 kcal/mol. Furthermore, molecular dynamics simulations confirmed the structural stability of the resulting complexes. Animal experiments showed that compared with the normal controls, IAV-infected mice showed significantly reduced body weight ratio, markedly increased lung index, protein content in BALF, and the levels of inflammatory factors such as IL-6 and TNF-α (P < 0.01), thereby causing damage to the lung tissue; consequently, the expression levels of mTOR, HIF-1α, and VEGF proteins in the lung tissues of these mice were significantly elevated (P < 0.01). However, after MXSGD treatment, the mouse models presented a significant increase in body weight ratio, as well as marked decreases in lung index, protein content in BALF, and the levels of inflammatory factors including IL-6 and TNF-α (P < 0.01). Furthermore, the therapy alleviated IAV-induced injuries and significantly downregulated the expression levels of mTOR, HIF-1α, and VEGF proteins in lung tissues (P < 0.01 or P < 0.05). Conclusion MXSGD exerts anti-IAV effects through multi-component, multi-target, and multi-pathway synergism. Among them, 1-methoxyphaseollin is identified as a potential key component, which alleviates virus-induced lung injury and inflammatory response via the regulation of HIF-1 signaling pathway, providing experimental evidence for the clinical application of MXSGD.

Objective:This study aimed to compare the clinical efficacy of da Vinci robot-assisted subtotal colectomy with laparoscopic surgery in the treatment of slow transit constipation.Methods:A retrospective cohort study was performed. The clinical and follow-up data of 95 patients with slow transit constipation who underwent robotic or laparoscopic subtotal colectomy at the First Affiliated Hospital of Harbin Medical University from July, 2022 to August, 2024 and had a follow-up period of 6 months were retrospectively analyzed. Patients were divided into a robotic surgery group (43 cases) and a laparoscopic surgery group (52 cases) according to surgical approaches. All patients underwent preoperative colonic transit study, barium enema radiography, defecography, and colonoscopy to confirm the diagnosis of slow transit constipation. There were no statistically significant differences in baseline data between the two groups (all P>0.05). Primary observation indicators included Wexner constipation score, gastrointestinal quality of life score, and the time of first ambulation after surgery. Secondary observation indicators included operation time, intraoperative blood loss, first defecation time, length of hospital stay, postoperative defecation frequency, postoperative complications, surgical satisfaction, and postoperative pain. The Wexner constipation score was evaluated at 6 months after surgery as well, and a total score of 15 or above was defined as constipation; the higher the score, the more severe the constipation. The gastrointestinal quality of life index was also evaluated at 6 months after surgery; the lower the score, the poorer the quality of life. Pain assessment was conducted on the 2nd day after surgery using the visual analogue scale (VAS) for self-assessment, and here a higher score indicated greater pain intensity. Observe the patients' intraoperative and pastoperative conditions. Results:Both groups completed the surgery unevenifullg without conversion to laparotomy, and no severe intraoperative complications occurred. Compared to the laparoscopic surgery group, the robotic surgery group had significantly shorter first ambulation time ([18.5±1.3] hours vs. [24.5±0.6] hours, t=-30.437, P<0.001), first defecation time ([21.2±2.2] hours vs. [24.9±0.9] hours, t=-10.818, P<0.001), and hospital stay ([7.8±1.5] days vs. [9.4±3.3] days, t=-3.069, P=0.003), all P<0.05. There were no statistically significant differences between the two groups in terms of operation time, intraoperative blood loss, postoperative pain score, defecation frequency, or incidence of postoperative complications (all P>0.05). Follow-up at 6 months post-operation also showed no statistically significant differences between the two groups in terms of Wexner score, gastrointestinal quality of life score, daily defecation frequency, or surgical satisfaction (all P>0.05). When comparing the follow-up scores between postoperative and preoperative periods in each group, both Wexner scores (laparoscopic group: [2.2±1.2] vs. [17.7±0.9], t=83.580, P<0.001; robotic group: [2.6±1.2] vs. [17.5±0.8], t=69.274, P<0.001) and gastrointestinal quality of life scores (laparoscopic group: [108.6±4.4] vs. [76.0±4.6], t=-41.442, P<0.001; robotic group: [109.3±6.1] vs. [77.8±6.4], t=-29.939, P<0.001) were significantly improved. No additional complications or recurrence were observed in both groups at 6 months post-operation. Conclusion:Compared to laparoscopic subtotal colectomy, da Vinci robot-assisted subtotal colectomy for slow transit constipation is associated with faster postoperative recovery and shorter hospital stays, and the operative times and therapeutic efficacy are similar between the two approaches.

Objective:This study aimed to compare the clinical efficacy of da Vinci robot-assisted subtotal colectomy with laparoscopic surgery in the treatment of slow transit constipation.Methods:A retrospective cohort study was performed. The clinical and follow-up data of 95 patients with slow transit constipation who underwent robotic or laparoscopic subtotal colectomy at the First Affiliated Hospital of Harbin Medical University from July, 2022 to August, 2024 and had a follow-up period of 6 months were retrospectively analyzed. Patients were divided into a robotic surgery group (43 cases) and a laparoscopic surgery group (52 cases) according to surgical approaches. All patients underwent preoperative colonic transit study, barium enema radiography, defecography, and colonoscopy to confirm the diagnosis of slow transit constipation. There were no statistically significant differences in baseline data between the two groups (all P>0.05). Primary observation indicators included Wexner constipation score, gastrointestinal quality of life score, and the time of first ambulation after surgery. Secondary observation indicators included operation time, intraoperative blood loss, first defecation time, length of hospital stay, postoperative defecation frequency, postoperative complications, surgical satisfaction, and postoperative pain. The Wexner constipation score was evaluated at 6 months after surgery as well, and a total score of 15 or above was defined as constipation; the higher the score, the more severe the constipation. The gastrointestinal quality of life index was also evaluated at 6 months after surgery; the lower the score, the poorer the quality of life. Pain assessment was conducted on the 2nd day after surgery using the visual analogue scale (VAS) for self-assessment, and here a higher score indicated greater pain intensity. Observe the patients' intraoperative and pastoperative conditions. Results:Both groups completed the surgery unevenifullg without conversion to laparotomy, and no severe intraoperative complications occurred. Compared to the laparoscopic surgery group, the robotic surgery group had significantly shorter first ambulation time ([18.5±1.3] hours vs. [24.5±0.6] hours, t=-30.437, P<0.001), first defecation time ([21.2±2.2] hours vs. [24.9±0.9] hours, t=-10.818, P<0.001), and hospital stay ([7.8±1.5] days vs. [9.4±3.3] days, t=-3.069, P=0.003), all P<0.05. There were no statistically significant differences between the two groups in terms of operation time, intraoperative blood loss, postoperative pain score, defecation frequency, or incidence of postoperative complications (all P>0.05). Follow-up at 6 months post-operation also showed no statistically significant differences between the two groups in terms of Wexner score, gastrointestinal quality of life score, daily defecation frequency, or surgical satisfaction (all P>0.05). When comparing the follow-up scores between postoperative and preoperative periods in each group, both Wexner scores (laparoscopic group: [2.2±1.2] vs. [17.7±0.9], t=83.580, P<0.001; robotic group: [2.6±1.2] vs. [17.5±0.8], t=69.274, P<0.001) and gastrointestinal quality of life scores (laparoscopic group: [108.6±4.4] vs. [76.0±4.6], t=-41.442, P<0.001; robotic group: [109.3±6.1] vs. [77.8±6.4], t=-29.939, P<0.001) were significantly improved. No additional complications or recurrence were observed in both groups at 6 months post-operation. Conclusion:Compared to laparoscopic subtotal colectomy, da Vinci robot-assisted subtotal colectomy for slow transit constipation is associated with faster postoperative recovery and shorter hospital stays, and the operative times and therapeutic efficacy are similar between the two approaches.

Chemical modifications of nitrogenous bases or ribosemoieties are common in RNA molecules and these RNA modifications regu-late tumor progression by modulating gene expression in malignancies.Therefore,delving into the role of RNA modifications in tumor pro-gression is essential for understanding tumor progression mechanisms and developing intervention strategies.Mitochondria are crucial for maintaining the energy state of malignant tumor cells.Recent studies have indicated that RNA modifications and tumor mitochondria are closely connected,implying that mitochondrial function within tumors can be disrupted due to RNA modifications.This article focuses on the role and underlying mechanisms of RNA modifications in tumor mitochondria,offering crucial insights for a deeper understanding of the reg-ulatory mechanisms of tumor metabolism and the development of new innovative therapeutic strategies.