ObjectiveTo investigate the effect of different exercise interventions on metabolism and liver parameters in patients with metabolic dysfunction-associated fatty liver disease （MAFLD）， and to provide evidence-based recommendations for clinical exercise rehabilitation. MethodsThis study was conducted according to the PRISMA guidelines， and the protocol was registered on the PROSPERO platform， with a registration number of CRD42025641717. PubMed， Web of Science， Scopus， Wiley Online Library， CNKI， Wanfang Data， and VIP were searched for related articles published up to September 2024. The Cochrane tool for assessing risk of bias was used to assess the quality of articles， and Stata MP 17.0 was used to perform the network meta-analysis. ResultsA total of 57 articles were included， involving 2 648 patients. The results showed that aerobic exercise combined with resistance exercise had the best effect in improving body mass index （mean difference ［WMD］=-0.97， 95% confidence interval ［CI］： -1.66 to -0.28］， P<0.05， surface under the cumulative ranking curve ［SUCRA］=85.4） and triglycerides （WMD=-29.6， 95%CI： -46.66 to 12.54， P<0.05， SUCRA=87.3）； resistance exercise was the optimal intervention method for improving total cholesterol （WMD=-15.99， 95%CI： -24.19 to -7.79， P<0.05， SUCRA=79.9） and glutamine transaminase （WMD=-8.08， 95%CI： -12.13 to -4.02， P<0.05， SUCRA=87.3）； low-intensity aerobic exercise had the best effect in improving aspartate aminotransferase （WMD=-4.3， 95%CI： -8.45 to -0.15， P<0.05， SUCRA=73.5）， gamma-glutamyl transpeptidase （GGT） （WMD=-3.26， 95%CI： -7.79 to 1.27， P>0.05， SUCRA=82.3）， and glycated hemoglobin （HbA1c） （WMD=-0.6， 95%CI： -2.02 to 0.82， P>0.05， SUCRA=78.8）； moderate-intensity aerobic exercise was the optimal intervention modality to improve Homeostasis Model Assessment of Insulin Resistance （WMD=-0.92， 95%CI： -1.51 to -0.33， P<0.05， SUCRA=69.4）. It should be noted that there were no significant differences in HbA1c and GGT across different exercise interventions （all P>0.05）， suggesting that there was currently no sufficient statistical evidence to support that exercise could improve these two indicators. ConclusionBased on the comprehensive league table and cumulative probability ranking， aerobic exercise combined with resistance exercise， resistance exercise， and low- and moderate-intensity aerobic exercise may be the best exercise modality for improving key indicators in MAFLD patients， and targeted exercise modalities should be selected for intervention against different indicators； however， due to limitations of the original studies， further studies are needed for validation and exploration.

Abstract Liver metastasis is one of the most common complications of advanced lung cancer and an important factor influencing patient prognosis and survival. Currently, there are limited effective treatment options for lung cancer patients with liver metastasis, leading to short survival and poor prognosis. In-depth studies of the related molecular mechanisms are crucial for advancing clinical translation and optimizing therapeutic strategies. In recent years, more and more studies of the mechanisms of liver metastasis in lung cancer have performed, particularly in areas such as the roles of different proteins, cell-cell interactions, and changes in the tumor microenvironment. This review summarizes the current understanding of the basic process of lung cancer liver metastasis, regulatory proteins, signaling pathways, tumor microenvironment changes, and clinical treatment progress. Emerging evidence highlights the critical involvement of TGF-β/smad signaling pathway and integrin family proteins in promoting lung cancer liver metastasis. In the tumor microenvironment, various cell types including mononuclear phagocytes, fibroblasts, and hepatocytes contribute to this metastatic process. Clinically, the combination of immunotherapy with chemotherapy, radiotherapy, and antiangiogenic therapy has shown potential to improve treatment outcomes. Furthermore, targeted therapy against specific pathways, proteins, and cells within the tumor microenvironment, as well as the integration of multiple treatment modalities, holds promise for becoming effective strategies in the future clinical management of lung cancer liver metastasis.

Nanotechnologies seek to overcome inherent deficiencies of conventional diagnosis and treatment, which attracted sustained attention and a limited number of nanomedicines approved by the FDA. However, the critical gaps in clinical translation remain, and nanomedicines that were initially heralded as magic bullets have yet to reach their realistic potential. The major obstacles of fabrication technologies may be overlooked in the nanoparticles' journey. Suboptimal manufacturing strategies partly hampered the inefficient transformation. In this review, we discuss the nanoparticle manufacturing strategies of "Top-Down" and "Bottom-Up" on precise nanoscale fabrication, including artificial intelligence introduced to guided nanomedicine fabrication for accelerating the transformation. Re-engineering existing nanomedicine fabrication, individual manufacturing, and modular technology might highlight the dilemmas of nanomedicines to meet their initial expectations.

In recent decades, the prevalence of hyperuricemia and gout has increased dramatically due to lifestyle changes. The drugs currently recommended for hyperuricemia are associated with adverse reactions that limit their clinical use. In this study, we report that berberine (BBR) is an effective drug candidate for the treatment of hyperuricemia, with its mechanism potentially involving the modulation of gut microbiota and its metabolite, succinic acid. BBR has demonstrated good therapeutic effects in both acute and chronic animal models of hyperuricemia. In a clinical trial, oral administration of BBR for 6 months reduced blood uric acid levels in 22 participants by modulating the gut microbiota, which led to an increase in the abundance of Bacteroides and a decrease in Clostridium sensu stricto_1. Furthermore, Bacteroides fragilis was transplanted into ICR mice, and the results showed that Bacteroides fragilis exerted a therapeutic effect on uric acid similar to that of BBR. Notably, succinic acid, a metabolite of Bacteroides, significantly reduced uric acid levels. Subsequent cell and animal experiments revealed that the intestinal metabolite, succinic acid, regulated the upstream uric acid synthesis pathway in the liver by inhibiting adenosine monophosphate deaminase 2 (AMPD2), an enzyme responsible for converting adenosine monophosphate (AMP) to inosine monophosphate (IMP). This inhibition resulted in a decrease in IMP levels and an increase in phosphate levels. The reduction in IMP led to a decreased downstream production of hypoxanthine, xanthine, and uric acid. BBR also demonstrated excellent renoprotective effects, improving nephropathy associated with hyperuricemia. In summary, BBR has the potential to be an effective treatment for hyperuricemia through the gut-liver axis.

Hereditary myopathy with early respiratory failure is a titin （TTN）-related myopathy caused by mutations in the A-band of the TTN gene.This condition is characterized by distinctive clinical and pathological features， as well as a typical skeletal muscle involvement pattern. We report a 43-year-old male patient with progressive distal limb weakness over the past three years. The initial symptom was difficulty in lifting both feet， followed by difficulty in extending the dorsum of both hands one year later. However， the patient never experienced dyspnea. The patient's past medical history was unremarkable， and there was no family history of inherited diseases.His parents were healthy. Physical examination revealed wrist drop and noticeable atrophy of the tibialis anterior in both calves. Muscle strength in the lower limbs was graded at 4 for proximal muscles and 2 for distal muscles.Laboratory tests showed a creatine kinase level of 375U/L（normal range：50~310）. Electromyography revealed myogenic injury in the bilateral tibialis anterior and the right extensor digitorum communis. Magnetic resonance imaging of the muscles showed isolated involvement of the semitendinosus muscle with severe fatty infiltration， along with significant fatty degeneration of the anterior calf muscles. Muscle biopsy of the proband showed subsarcolemmal “necklace-like” cytoplasmic bodies and the “erasure” phenomenon on NADH enzyme histochemistry. Both electrocardiogram and echocardiography showed no abnormalities. Exome sequencing of the proband identified a missense mutation in the TTN gene， c.95358C>G， p.Asn31786Lys. Sanger sequencing confirmed that the mutation was absent in both parents of the proband， indicating a de novo mutation.

Childhood is a critical period for growth and development, and the oral microbiota, as the second most diverse microbial community in the human body, plays a pivotal role in maintaining children's health. Recent studies have demonstrated that dysbiosis of the oral microbiota not only contributes to oral diseases such as dental caries and periodontitis but may also influence the development of children's skeletal, nervous, digestive, cardiovascular, and immune systems through mechanisms involving inflammatory responses, metabolic regulation, and cross-organ communication networks. This review systematically examines the role of the oral microbiota in childhood growth and development and, guided by the core principles of the "active health" model, proposes multiple intervention strategies—including probiotics, xylitol, and mouthwashes—to optimize children's health through early oral microbiota modulation.

This study aimed to comprehensively examine the association of gallstones, cholecystectomy, and cancer risk. Multivariable logistic regressions were performed to estimate the observational associations of gallstones and cholecystectomy with cancer risk, using data from a nationwide cohort involving 239 799 participants. General and gender-specific two-sample Mendelian randomization (MR) analysis was further conducted to assess the causalities of the observed associations. Observationally, a history of gallstones without cholecystectomy was associated with a high risk of stomach cancer (adjusted odds ratio (aOR)=2.54, 95% confidence interval (CI) 1.50-4.28), liver and bile duct cancer (aOR=2.46, 95% CI 1.17-5.16), kidney cancer (aOR=2.04, 95% CI 1.05-3.94), and bladder cancer (aOR=2.23, 95% CI 1.01-5.13) in the general population, as well as cervical cancer (aOR=1.69, 95% CI 1.12-2.56) in women. Moreover, cholecystectomy was associated with high odds of stomach cancer (aOR=2.41, 95% CI 1.29-4.49), colorectal cancer (aOR=1.83, 95% CI 1.18-2.85), and cancer of liver and bile duct (aOR=2.58, 95% CI 1.11-6.02). MR analysis only supported the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer. This study added evidence to the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer, highlighting the importance of cancer screening in individuals with gallstones.
Humans ; Mendelian Randomization Analysis ; Gallstones/complications* ; Female ; Male ; Cholecystectomy/statistics & numerical data* ; Middle Aged ; Risk Factors ; Aged ; Adult ; Neoplasms/etiology* ; Stomach Neoplasms/epidemiology*

Alcoholic steatohepatitis (ASH) is a liver disease characterized by steatosis, inflammation, and necrosis of the liver tissue as a result of excessive alcohol consumption. Pregnane X receptor (PXR) is a xenobiotic nuclear receptor best known for its function in the transcriptional regulation of drug metabolism and disposition. Clinical reports suggested that the antibiotic rifampicin, a potent human PXR activator, is a contraindication in alcoholics, but the mechanism was unclear. In this study, we showed that the hepatic expression of fatty acid binding protein 4 (FABP4) was uniquely elevated in ASH patients and a mouse model of ASH. Pharmacological inhibiting FABP4 attenuated ASH in mice. Furthermore, treatment of mice with the mouse PXR agonist pregnenolon-16α-carbonitrile (PCN) induced the hepatic and circulating levels of FABP4 and exacerbated ASH in a PXR-dependent manner. Our mechanism study established FABP4 as a transcriptional target of PXR. Treatment with andrographolide, a natural compound and dual inhibitor of PXR and FABP4, alleviated mice from ASH. In summary, our results showed that the PXR-FABP4 gene regulatory axis plays an important role in the progression of ASH, which may have accounted for the contraindication of rifampicin in patients of alcoholic liver disease. Pharmacological inhibition of PXR and/or FABP4 may have its promise in the clinical management of ASH.

BACKGROUND:Studies have shown that insulin-like growth factor 1/platelet-derived growth factor has an inhibitory effect on fibroblast apoptosis.miR-141-3p in bone marrow stromal cells increases with age and has a relationship with the activation of inflammatory signaling pathways,suggesting that it may be a therapeutic target for lumbar disc herniation. OBJECTIVE:To explore the effects of miR-141-3p on dorsal root ganglion inflammation and lower limb pain in rats with lumbar disc herniation by regulating insulin-like growth factor 1/platelet-derived growth factor. METHODS:Fifty male Sprague-Dawley rats,SPF level,were randomly divided into normal group,model group,miR-NC group,miR-141-3p inhibitor group and miR-141-3p mimics group,with 10 rats in each group.Except for the normal group,animal models of lumbar disc herniation were established in rats by autologous nucleus pulposus transplantation.After successful modeling,rats in the miR-NC,miR-141-3p inhibitor and miR-141-3p mimics groups were injected intrathecally with 10 μL of 20 μmol/L miR-NC,miR-141-3p inhibitor,miR-141-3p mimics,once a day for 28 days,respectively,while those in the normal and model groups were injected with the same volume of saline at the same location at the same time.Paw withdrawal thermal latency threshold was used to evaluate lower limb pain in rats.The mRNA expression of miR-141-3p in dorsal root ganglion tissue was detected by real-time fluorescence quantitative PCR,the levels of inflammatory factors in dorsal root ganglion tissue were detected by ELISA,and the expression of insulin-like growth factor 1/platelet-derived growth factor in dorsal root ganglion tissue was detected by western blot.The correlation between miR-141-3p and insulin-like growth factor 1/platelet-derived growth factor was analyzed. RESULTS AND CONCLUSION:There were no significant differences in all indexes between the miR-NC group and the model group.Paw withdrawal thermal latency threshold was significantly lower in the model group than in the normal group(P＜0.05),significantly lower in the miR-141-3p inhibitor group than the miR-NC group(P＜0.05),and significantly higher in the miR-141-3p mimics group than in the miR-141-3p inhibitor group(P＜0.05).The mRNA expression of miR-141-3p in dorsal root ganglion tissue was significantly lower in the model group than in the normal group(P＜0.05),significantly lower in the miR-141-3p inhibitor group than in the miR-NC group(P＜0.05),and significantly higher in the miR-141-3p mimics group than in the miR-141-3p inhibitor group(P＜0.05).The levels of tumor necrosis factor α,interleukin 1β,and interleukin 1 in dorsal root ganglion tissue were significantly higher in the model group than in the normal group(P＜0.05),significantly higher in the miR-141-3p inhibitor group than in the miR-NC group(P＜0.05),and significantly lower in the miR-141-3p mimics group than in the miR-141-3p inhibitor group(P＜0.05).The protein expressions of insulin-like growth factor 1 and platelet-derived growth factor in dorsal root ganglion tissue were significantly lower in the model group than in the normal group(P＜0.05),significantly lower in the miR-141-3p inhibitor group than in the miR-NC group(P＜0.05),and significantly higher in the miR-141-3p mimics group than in the miR-141-3p inhibitor group(P＜0.05).The expressions of insulin-like growth factor 1 and platelet-derived growth factor showed a positive correlation with miR-141-3p(r=0.904,P＜0.001;r=0.879,P＜0.001).To conclude,miR-141-3p can significantly improve lower limb pain and inhibit inflammation in dorsal root ganglia in rats with lumbar disc herniation,and its mechanism may be related to the promotion of insulin-like growth factor 1/platelet-derived growth factor expression.

Objective To establish an allogeneic rat model of endometriosis and to evaluate the effects of gonadotropin-releasing hormone (GnRH) agonist GenSci006 on experimental rat endometriosis. Methods Endometrium from SPF grade donor female SD rats were transplanted onto the abdominal wall of recipient female rats to construct an allogeneic endometriosis model. The rats undergoing sham surgery were divided into the sham group. Three weeks later, the length, width and height of the ectopic endometrium were measured, and the volume of the endometrium (V₁) was calculated before drug administration. The modeling rats were randomly divided into four groups: model group, triptorelin group (0.25 mg/kg), GenSci006-1 group (0.125 mg/kg) and GenSci006-2 group (0.25 mg/kg). Each group had 16 rats and received a single dose of the corresponding drug. The sham group and model group were administered an equal volume of solvent. Three weeks after administration, ectopic endometrium was measured to calculate the volume V₂ and inhibition rate. The effect of GenSci006 on rat uterus and ovarian tissues was assessed by comparing organ coefficients and changes in pathological sections. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of serum estradiol (E₂), progesterone (P₄), follicle stimulating hormone (FSH), and luteinizing hormone (LH). Real-time fluorescent quantitative PCR was used to detect the expression of GnRH receptor (GnRHR) mRNA in the hypothalamus and pituitary. Western blot was used to detect the expression of estradiol receptor alpha (ERα), beta (ERβ) and progesterone receptor (PR) in ectopic endometrium. Results Three weeks after administration, compared with the model group, the body weight of rats in the triptorelin and GenSci006-2 groups significantly increased (P < 0.05), while the volume of ectopic endometrium significantly decreased (P < 0.05). Compared with the sham group, the model group showed no significant changes in uterine and ovarian organ coefficients or endometrial thickness (P > 0.05). Compared with the model group, the uterine organ coefficients and endometrial thickness were significantly reduced in the triptorelin and GenSci006-2 groups (P < 0.05). Compared with the sham group, the serum levels of E₂, P₄, FSH and LH in the model group showed no significant changes (P > 0.05). Compared with the model group, the ovarian organ coefficient and serum P₄ levels of rats in the Triptorelin, GenSci006-1, and GenSci006-2 groups were significantly reduced (P < 0.05), while the serum LH levels of rats in the GenSci006-1 group were significantly increased (P < 0.05). However, there were no significant changes in serum E₂ and FSH levels in each group (P > 0.05). Compared with the model group, the expression levels of GnRHR mRNA in the pituitary tissue of rats in the triptorelin and GenSci006-2 groups were significantly downregulated (P < 0.05), with no significantly changes in the hypothalamus (P > 0.05). There were no significant changes in the expression level of GnRHR mRNA in the hypothalamus or the protein levels of ERα, ERβ and PR in the ectopic endometrial tissue in any group (P > 0.05). Conclusion The allogeneic endometriosis rat model is a suitable animal model for screening and evaluating drugs for treating endometriosis. The volume of ectopic endometrium, inhibition rate, uterine and ovarian organ coefficients, and serum E₂ levels may serve as indicators for detecting drug efficacy.