BACKGROUND:Post and core restoration is a common choice for tooth defects,but the repair effects of various post and core materials are different. OBJECTIVE:To evaluate the stress distribution at the post and core,tooth root,and bonding agent site of post and core models made of different elastic modulus post and core materials using finite element method. METHODS:A three-dimensional root canal treated maxillary central incisor model was built using three-dimensional modeling software,which was restored with a full ceramic crown.The post and core materials in the restoration used nanoceramic resin(elastic modulus=12.8 GPa),composite resin(elastic modulus=16 GPa),hybrid ceramic(elastic modulus=34.7 GPa),glass ceramic(elastic modulus=95 GPa),titanium alloy(elastic modulus=112 GPa),and zirconia(elastic modulus=209.3 GPa).The model was fixed in cortical bone.A 100 N concentrated force of 45° from the long axis of the tooth was applied to 1/3 of the crown and tongue side of the central incisor.The stress distribution of the post and core,dentin,and tooth-root bonding agent in the model was repaired by the maximum principal stress criterion. RESULTS AND CONCLUSION:(1)When the post and core materials with higher elastic modulus was used,the post-core stress in the repair model was more concentrated.When the elastic modulus of the post and core materials(nanoceramic resin and composite resin)was close to dentin,the stress distribution of the post and core was more uniform.The stress distribution of dentin in all restoration models was similar regardless of post and core materials.When the post and core with higher elastic modulus was used,more stress concentration was shown at the post and root bonding agent in the repair model.(2)The maximum stress values at the post and core,tooth root,and the bonding agent site of post and tooth root in the nanoceramic resin model were 31.00,33.21,and 0.51 MPa,respectively.The maximum stress values at the post and core,tooth root,and the bonding agent between the post and tooth root in the composite resin model were 36.84,33.14,and 0.59 MPa,respectively.In the mixed ceramic model,the maximum stress values at the post and core,tooth root,and the bonding agent between the post and tooth root were 64.05,32.83,and 1.00 MPa,respectively.In the glass ceramic model,the maximum stress values at the post and core,tooth root,and the bonding agent between the post and tooth root were 112.30,32.69,and 1.73 MPa,respectively.In the titanium alloy model,the maximum stress values of the post and core,tooth root,and the bonding agent between the post and tooth root were 120.00,32.17,and 1.86 MPa,respectively.In the zirconia model,the maximum stress values of the post and core,tooth root,and the bonding agent between the post and tooth root were 148.80,31.85,and 2.28 MPa,respectively.(3)The higher the elastic modulus of the post and core material,the higher the maximum stress at the post and core during restoration.The elastic modulus of the post and core material had no significant effect on the maximum stress of the dental bonding agent and dentin.

Exercise-induced metabolic remodeling is a fundamental adaptive process whereby the body reorganizes systemic and cellular metabolism to meet the dynamic energy demands posed by physical activity. Emerging evidence reveals that such remodeling not only enhances energy homeostasis but also profoundly influences immune function through complex molecular interactions involving glucose, lipid, and protein metabolism. This review presents an in-depth synthesis of recent advances, elucidating how exercise modulates immune regulation via metabolic reprogramming, highlighting key molecular mechanisms, immune-metabolic signaling axes, and the authors’ academic perspective on the integrated “exercise-metabolism-immunity” network. In the domain of glucose metabolism, regular exercise improves insulin sensitivity and reduces hyperglycemia, thereby attenuating glucose toxicity-induced immune dysfunction. It suppresses the formation of advanced glycation end-products (AGEs) and interrupts the AGEs-RAGE-inflammation positive feedback loop in innate and adaptive immune cells. Importantly, exercise-induced lactate, traditionally viewed as a metabolic byproduct, is now recognized as an active immunomodulatory molecule. At high concentrations, lactate can suppress immune function through pH-mediated effects and GPR81 receptor activation. At physiological levels, it supports regulatory T cell survival, promotes macrophage M2 polarization, and modulates gene expression via histone lactylation. Additionally, key metabolic regulators such as AMPK and mTOR coordinate immune cell energy balance and phenotype; exercise activates the AMPK-mTOR axis to favor anti-inflammatory immune cell profiles. Simultaneously, hypoxia-inducible factor-1α (HIF-1α) is transiently activated during exercise, driving glycolytic reprogramming in T cells and macrophages, and shaping the immune landscape. In lipid metabolism, exercise alleviates adipose tissue inflammation by reducing fat mass and reshaping the immune microenvironment. It promotes the polarization of adipose tissue macrophages from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype. Moreover, exercise alters the secretion profile of adipokines—raising adiponectin levels while reducing leptin and resistin—thereby influencing systemic immune balance. At the circulatory level, exercise improves lipid profiles by lowering pro-inflammatory free fatty acids (particularly saturated fatty acids) and triglycerides, while enhancing high-density lipoprotein (HDL) function, which has immunoregulatory properties such as endotoxin neutralization and macrophage cholesterol efflux. Regarding protein metabolism, exercise triggers the expression of heat shock proteins (HSPs) that act as intracellular chaperones and extracellular immune signals. Exercise also promotes the secretion of myokines (e.g., IL-6, IL-15, irisin, FGF21) from skeletal muscle, which modulate immune responses, facilitate T cell and macrophage function, and support immunological memory. Furthermore, exercise reshapes amino acid metabolism, particularly of glutamine, arginine, and branched-chain amino acids (BCAAs), thereby influencing immune cell proliferation, biosynthesis, and signaling. Leucine-mTORC1 signaling plays a key role in T cell fate, while arginine metabolism governs macrophage polarization and T cell activation. In summary, this review underscores the complex, bidirectional relationship between exercise and immune function, orchestrated through metabolic remodeling. Future research should focus on causative links among specific metabolites, signaling pathways, and immune phenotypes, as well as explore the epigenetic consequences of exercise-induced metabolic shifts. This integrated perspective advances understanding of exercise as a non-pharmacological intervention for immune regulation and offers theoretical foundations for individualized exercise prescriptions in health and disease contexts.

Intermittent theta burst stimulation (iTBS), a time-saving and cost-effective repetitive transcranial magnetic stimulation regime, has been shown to improve cognition in patients with Alzheimer's disease (AD). However, the specific mechanism underlying iTBS-induced cognitive enhancement remains unknown. Previous studies suggested that mitochondrial functions are modulated by magnetic stimulation. Here, we showed that iTBS upregulates the expression of iron-sulfur cluster assembly 1 (ISCA1, an essential regulatory factor for mitochondrial respiration) in the brain of APP/PS1 mice. In vivo and in vitro studies revealed that iTBS modulates mitochondrial iron-sulfur cluster assembly to facilitate mitochondrial respiration and function, which is required for ISCA1. Moreover, iTBS rescues cognitive decline and attenuates AD-type pathologies in APP/PS1 mice. The present study uncovers a novel mechanism by which iTBS modulates mitochondrial respiration and function via ISCA1-mediated iron-sulfur cluster assembly to alleviate cognitive impairments and pathologies in AD. We provide the mechanistic target of iTBS that warrants its therapeutic potential for AD patients.
Humans ; Mice ; Animals ; Transcranial Magnetic Stimulation ; Alzheimer Disease/therapy* ; Cognitive Dysfunction/therapy* ; Cognition ; Sulfur ; Iron ; Iron-Sulfur Proteins ; Mitochondrial Proteins

Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APC^min/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

Background Environmental noise pollution is serious, and there are few studies on the effects of long-term noise exposure during sleep on cognitive function and possible biological clock mechanism. Objective To explore the cognitive impairment induced by noise exposure during sleep in mice and possible biological clock mechanism, and to provide a theoretical basis for the protection against noise exposure. Methods Twenty male C57BL/6J mice were randomly divided into a control group and a noise-exposed group, 10 mice in each group. The noise-exposed group was exposed to sleep-period noise using a noise generator for 12 h (08:00–20:00) per day for a total of 30 d. The calibrated noise intensity was set at 90 dB. No intervention was imposed on the control group. At the end of the noise exposure, cognitive function of mice was examined using the new object recognition experiment and the open field test, and the hippocampal tissue damage of mice were evaluated by Nissl staining, ionized calcium binding adaptor molecule 1 (Iba1) immunofluorescence staining, and real-time fluorescence quantitative PCR for inflammatory factors and biological clock genes. Oxidative stress indicators in the hippocampus of mice were also detected by assay kit. Results After noise exposure during sleep period, the results of new object recognition experiment showed that the discrimination index of mice in the noise-exposed group was 0.06±0.04, which was significantly lower than that of the control group (0.65±0.13) (P<0.05). The results of open field test showed that the central activity distance of the noise-exposed group was (242.20±176.10) mm, which was significantly lower than that of the control group, (1548.00±790.30) mm (P < 0.05), and the central activity time of the noise-exposed group was (0.87±0.64) s, which was significantly lower than that of the control group, (6.00±2.86) s (P < 0.05). The Nissl staining results showed that compared with the control group, neurons in the hippocampus of the noise-exposed mice were shrunken, deeply stained, disorganized, and loosely connected. The immunofluorescence results showed that microglia in the hippocampus of the noise-exposed mice were activated and the expression of Iba1 was significantly increased compared with those of the control group (P<0.05). The real-time PCR results of showed that the mRNA levels of the biological clock genes Clock, Per2, and Rev-erbα were significantly increased compared with those of the control group (P<0.05), and the mRNA level of Per1 was significantly decreased compared with that of the control group (P<0.05); and the mRNA levels of IL-18, IL-6, iNOS, and NLRP3 in the hippocampal tissues of mice were significantly increased compared with those of the control group (P<0.05). The results of oxidative stress evaluation showed that compared with the control group, reduced glutathione content was significantly reduced in the noise-exposed group (P<0.001). Conclusion Noise exposure during sleep period can lead to the destabilization of biological clock genes in hippocampal tissues and trigger hippocampal neuroinflammation, which can lead to the activation of microglia and cause cognitive impairment in mice.

OBJECTIVE To analyze the prevalence of potentially inappropriate medication （PIM） in elderly patients with femoral neck fractures at admission and compare the concordance of 3 evaluation criteria. METHODS A retrospective study was conducted to review the data of elderly patients with femoral neck fractures admitted to the Department of Orthopedics in Northern Jiangsu People’s Hospital from July 2022 to June 2023. The PIMs were identified according to the Criteria of Potentially Inappropriate Medications for Older Adults in China：2017 edition （hereinafter referred to as Chinese criteria）， American Geriatrics Society 2023 Updated AGS Beers Criteria® for Potentially Inappropriate Medication in Older Adults （hereinafter referred to as 2023 Beers criteria）， third version criteria for screening tool of older people’s prescriptions for potentially inappropriate medication （hereinafter referred to as STOPP criteria version 3）. The concordance of the 3 evaluation criteria was compared by using Kappa statistics. RESULTS A total of 246 patients were included in this study； 49 patients （19.92%） with 77 PIMs were detected by the Chinese criteria， 64 patients （26.02%） with 118 PIMs were detected by the 2023 Beers criteria， and 41 patients （16.67%） with 67 PIMs were detected by the STOPP criteria version 3； 22 patients met all three criteria simultaneously. The concordance among the three criteria showed moderate agreement （0.417≤Kappa≤0.486） when compared in pairs. CONCLUSIONS There are certain differences in the PIM evaluated by the three criteria， but the prevalence of PIMs is below 30% according to the different H202134） criteria. Benzodiazepines， antipsychotics， antidepressants， and other drugs may increase the risk of patients falling again.

Bone Transplantation/adverse effects* ; Transplantation, Autologous/adverse effects*

Objective To investigate the therapeutic effect and mechanism of Jianwei Xiaozhang Tablets on rats with precancerous lesions of gastric cancer(PLGC).Methods Forty male SD rats were randomly divided into the normal group,the model group,the folic acid group and the Jianwei Xiaozhang Tablets group,with 10 rats in each group.In addition to the normal group,the other three groups of rats were prepared by gavage with Ranitidine Aqueous Solution combined with N-methyl-N'-nitro-N-nitrosoguanidine(MNNG)solution drinking method for the preparation of PLGC model.After successful modeling,drugs were administered accordingly for 7 weeks.The changes in body mass of rats during modeling and drug administration were recorded,the gross view of the stomach was observed and scored pathologically,the coefficients of spleen and liver were determined,the pathological changes in gastric tissue were observed by hematoxylin-eosin(HE)staining,enzyme-linked immunosorbent assay(ELISA)was used to measure serum gastrin(GAS),motilin(MTL)and glucagon(GC),Alisin Blue-Periodic Acid Schiff's(AB-PAS)staining was used to observe the thickness of the mucosal layer of gastric tissues,the expressions of phosphatidylinositol 3-kinase(PI3K),phosphorylated PI3K(p-PI3K),protein kinase B(Akt),phosphorylated Akt(p-Akt),and endothelial-type nitric oxide synthase(eNOS)proteins in gastric tissues were detected by protein immunoblotting(Western Blot),and the expression of vascular endothelial growth factor A(VEGFA)protein in gastric tissues was detected by immunofluorescence staining.Results Compared with the normal group,the body mass of rats in the model group grew slowly during the experimental period,gastric macroscopic pathological scores were significantly increased(P＜0.01),splenic coefficient and hepatic coefficient were significantly decreased(P＜0.01),the gastric tissues showed cuprocyte hyperplasia and intestinal chemotaxis,gastric tissues'inflammation scores were significantly increased(P＜0.01),the serum GAS content was significantly increased(P＜0.01),and the MTL,GC contents were significantly reduced(P＜0.05),and the thickness of the mucous membrane layer of gastric tissue was significantly reduced(P＜0.05),the protein expression levels of PI3K,p-PI3K,Akt,p-Akt and eNOS were reduced(P＜0.01),and the protein expression level of VEGFA was reduced(P＜0.01);compared with the model group,the above indexes of the Jianwei Xiaozhang Tablets group and the folic acid group were all significantly improved(P＜0.05 or P＜0.01),among which,the Jianwei Xiaozhang Tablets group had a better improvement effect in the proliferation of cup cells and intestinal chemotaxis in gastric tissues,the content of serum GAS,and the thickness of the mucous layer in gastric tissues.Conclusion The mechanism of the improvement of PLGC in rats by Jianwei Xiaozhang Tablets may be related to the activation of the PI3K-Akt-eNOS pathway,which in turn promotes the angiogenesis and repair of gastric damaged tissues.

Objective To explore the effect of sorafenib on HeLa cell proliferation by inducing cell apoptosis and autophagy and its impact on drug resistance.Methods The drug-resistant cell strains were constructed through in-termittent induction method,with concentrations of 0,2.5,5.0,7.5,10.0,15.0,20.0 μmol/L.HeLa cells were incubated with increasing concentrations of sorafenib with each concentration for 1 week.The drug-resistant cell strains with stable passages were collected.MTT assay was used to detect the effect of sorafenib on cell prolifer-ation.Cell cycle distribution was analyzed by flow cytometry.The change in the expression of drug-resistant and ap-optotic genes in the parents and drug-resistant cell strains under different drug concentrations was examined by semi-quantitative PCR.The changes of apoptotic related marker proteins LC3-Ⅰ and LC3-Ⅱ were detected by Westernblot.Results Stable drug-resistant strains were successfully obtained;Drug-treated cells were more blocked in the G1 phase.In drug-resistant cells,the expression of apoptosis suppressor gene Bcl-2 was significantly decreased and the apoptotic gene Bax as well as the drug-resistant genes were all significantly increased(P＜0.05).The LC3-Ⅱ/LC3-Ⅰ ratio of drug-resistant cells was significantly higher than that of parent cells(P＜0.05).Conclusions Sorafenib may block the cell cycle,suppress malignant cell proliferation and promote autophage.On one hand,autophagy participates in the development of cell drug resistance and promotes cell survival.On the other hand,drug-induced autophagy may activate some of apoptotic signaling pathway in drug-resistant cells and promote the reversal of cell drug resistance.

OBJECTIVE To investigate the effect of pachymic acid （PA） on renal function and fibrosis in chronic renal failure （CRF） rats and its potential mechanism based on the Ras homolog gene family member A （RhoA）/Rho-associated coiled-coil forming protein kinase （ROCK） signaling pathway. METHODS Using male SD rats as subjects， the CRF model was established by 5/6 nephrectomy； the successfully modeled rats were divided into model group， PA low-dose， medium-dose and high-dose groups （5， 10， 20 mg/kg PA）， high-dose PA+ROCK pathway activator lysophosphatidic acid （LPA） group （20 mg/kg PA+1 mg/kg LPA）， with 15 rats in each group. Another 15 rats were selected as the sham operation group with only the kidney exposed but not excised. The rats in each drug group were gavaged and/or injected with the corresponding liquid via the caudal vein， once a day， for 12 consecutive weeks. During the experiment， the general condition of rats was observed in each group. After the last administration， the serum renal function indexes （blood urea nitrogen， serum creatinine， uric acid） of rats in each group were detected， the renal histopathological changes were observed； the renal tubule injury score and the area of renal fibrosis were quantified. The levels of oxidative stress indexes [malondialdehyde （MDA）， superoxide dismutase （SOD）] and inflammatory factors （tumor necrosis factor-α， interleukin-1β， interleukin-6）， the positive expression rates of connective tissue growth factor （CTGF） and collagen Ⅰ were detected as well as the expression levels of pathway-related proteins （RhoA， ROCK1） and fibrosis- related proteins （transforming growth factor-β1， bare corneum homologs 2， α-smooth muscle actin） were determined. RESULTS Compared with the sham operation group， the rats in model group had reduced diet， smaller body size， listless spirit and sluggish response， reduced and atrophied glomeruli， dilated renal tubules with chaotic structure， and a large number of inflammatory cells infiltrated interstitium； the serum levels of renal function indexes， renal tubule injury score， renal fibrosis area proportion， the levels of MDA and inflammatory factors， the positive expression rates of CTGF and collagen Ⅰ， and the expression levels of pathway-related proteins and fibrosis-related proteins in renal tissues were significantly increased， while SOD level was significantly decreased （P＜0.05）. Compared with the model group， the general condition and pathological injuries of kidney tissue of rats in PA groups were improved to varying degrees，and the above quantitative indexes were significantly improved in a dose-dependent manner （P＜0.05）. LPA could significantly reverse the improvement effect of PA on the above indicators （P＜0.05）. CONCLUSIONS PA can improve renal function and alleviate renal fibrosis in CRF rats， which may be related to inhibiting the activation of RhoA/ROCK signaling pathway.