Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases, but no effective anti-fibrotic therapy is currently available. Glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP1R) are both peptide hormone receptors involved in energy metabolism of epithelial cells. However, their role in intestinal fibrosis and the underlying mechanisms remain largely unexplored. Herein GCGR and GLP1R were found to be reduced in the stenotic ileum of patients with Crohn's disease as well as in the fibrotic colon of mice with chronic colitis. The downregulation of GCGR and GLP1R led to the accumulation of the metabolic byproduct lactate, resulting in histone H3K9 lactylation and exacerbated intestinal fibrosis through epithelial-to-mesenchymal transition (EMT). Dual activating GCGR and GLP1R by peptide 1907B reduced the H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis in vivo. We uncovered the role of GCGR/GLP1R in regulating EMT involved in intestinal fibrosis via histone lactylation. Simultaneously activating GCGR/GLP1R with the novel dual agonist peptide 1907B holds promise as a treatment strategy for alleviating intestinal fibrosis.

OBJECTIVE To explore the mechanism of Compound lizard powder reducing cisplatin resistance in gastric cancer by regulating glycolytic activity based on phosphoinositide 3-kinase（PI3K）/protein kinase B（Akt） signaling pathway. METHODS Human gastric cancer MKN45 and MKN45/DDP （cisplatin-resistant） cells were cultured in vitro and intervened with different mass concentrations of cisplatin （0.1， 0.2， 0.4， 0.8， 1.6， 3.2 μg/mL） to detect the survival rate， half inhibitory concentration （IC50） and drug resistance index. MKN45/DDP cells were inoculated subcutaneously in the right anterior axilla of nude mice to prepare a transplanted tumor model of gastric cancer. After successful modeling， they were randomly divided into model group， cisplatin group （0.002 g/kg）， Compound lizard powder group （2.8 g/kg） and combination group （the same dose as each single drug group）， with 8 nude mice in each group. Each administration group was given relevant solution， twice a week （cisplatin， i.p.） or twice a day （Compound lizard powder， i. g.）， for 4 consecutive weeks. During the experiment， the body weight of nude mice was monitored， and tumor volume and inhibitory rate of tumor were calculated. The levels of inflammatory factors （tumor necrosis factor- α， interleukin-6） in tumor tissue， the mRNA and protein expressions of multidrug resistance-associated protein 1 （MRP1）， P-glycoprotein （P-gp）， glucose transporter-1 （GLUT1） and lactate dehydrogenase A （LDHA）， as well as the protein expressions of PI3K， phosphorylated PI3K （p-PI3K）， Akt， phosphorylated Akt （p-Akt）， hexokinase-2 （HK2） and pyruvate kinase M2 （PKM2） were all detected. RESULTS With the intervention of different concentrations of cisplatin， the survival rate of MKN45/DDP-resistant cells was significantly higher than that of MKN45 parent cells （P＜0.05）. IC50 value of MKN45/DDP and MKN45 cells were（1.052 0±0.221 9） and （0.372 1±0.238 0）μg/mL， and the drug resistant index was 2.827. Compared with the model group， cisplatin group， Compound lizard powder group and combination group all had certain inhibitory effects on the tumor growth in nude mice； the inhibitory rates of tumor increased significantly （P＜0.05）； the levels of inflammatory factors， the mRNA and protein expressions of MRP1， P-gp， GLUT1 and LDHA （except for cisplatin group）， the phosphorylation levels of PI3K and Akt protein （except for cisplatin group） as well as the protein expressions of HK2 and PKM2 were decreased significantly， while the combination group was significantly better than the cisplatin group （P＜0.05）. CONCLUSIONS Compound lizard powder may inhibit tumor growth in transplanted tumor model nude mice with gastric cancer-resistant cells by reducing the secretion of tumor-related inflammatory factors， inhibiting the expression of glycolysis， drug resistance-related proteins and genes， inhibiting the activation of the PI3K/Akt signaling pathway， thus having a certain effect of enhancing cisplatin efficacy and reversing drug resistance.

Objective To explore the current status and potential subtypes of frailty among family caregivers of patients with dementia,and to analyze the related influencing factors of different subtypes.Methods Dementia patients and their family caregivers in 8 community health service centers in Shanghai from June to October 2023 were recruited by convenience sampling.General information questionnaire,Tilburg Frailty Indicator(TFI),Pittsburgh Sleep Quality Index(PSQI),Self-Rating Depression Scale(SDS),Zarit Caregiver Burden Interview(ZBI),and Connor-Davidson Resilience Scale(CD-RISC)were conducted for investigation.Latent profile analysis was used to explore the potential subtypes of frailty among family caregivers of patients with dementia.The influencing factors associated with the potential subtypes were identified by univariate analysis and multivariate Logistic regression analysis.Results A total of 470 family caregivers of patients with dementia were surveyed,and 46.17％of them suffered from frailty.Frailty among family caregivers of patients with dementia can be classified into 3 potential subtypes:comprehensive-low frailty subtype(70.64％),psychosocial-medium frailty subtype(19.57％),and physical-high frailty subtype(9.79％).Family caregivers of patients with dementia who had poor sleep quality and suffered from 2 or more chronic diseases were more likely to be classified into the physical-high frailty subtype(P＜0.05).Family caregivers of patients with dementia who had higher levels of depression,lower mastery levels of caregiving knowledge and skills and spousal caregivers were more likely to be classified into the psychosocial-medium frailty subtype(P＜0.05).Family caregivers of patients with dementia who had higher levels of resilience were more likely to be classified into the comprehensive-low frailty subtype(P＜0.05).Conclusion The incidence of frailty among family caregivers of patients with dementia is at a high level with significant heterogeneity.It is suggested that medical staff should pay attention to the frailty of family caregivers,with a focus on family caregivers in the psychosocial-medium frailty subtype or physical-high frailty subtype,and take timely and targeted interventions according to the characteristics and influencing factors of different subtypes,so as to prevent or delay the occurrence and development of frailty.

The onset of primary hepatic carcinoma (PHC) is usually occult, and early symptoms are not obvious. Most patients are at advanced stages of disease at diagnosis, and the prognosis is poor. Paraneoplastic syndrome (PNS) refers to the clinical manifestations indirectly caused by tumor metabolites or abnormal immune reactions that cannot be explained by the primary lesion, local tumor spread or distant metastasis. Hypercholesterolemia, hypercalcemia and hypoglycemia are the most commonly seen clinical presentations of PNS in PHC patients. Adequate understanding of PNS is of great importance in early diagnosis and treatment of PHC. In this review, we summarized the clinical manifestations and prognostic mechanisms of PNS in patients with PHC.

Cell Cycle Proteins ; Microtubule-Associated Proteins

Nanoparticles (NPs) have shown potential in cancer therapy, while a single administration conferring a satisfactory outcome is still unavailable. To address this issue, the dissolving microneedles (DMNs) were developed to locally deliver functionalized NPs with combined chemotherapy and photothermal therapy (PTT).

OBJECTIVE: To observe the effects of on the expression of β-tubulin Ⅲ and glial fibrillary acidic protein (GFAP) and the proliferation and differentiation of murine neural stem cells (NSCs) . METHODS: An immortalized murine NSC line was divided into model control (MC) group, 10% drug-containing serum group (NLXT group), and 10% Naoluoxintong drug-containing serum with inhibitor Y27632 group (Y-27632 group) with corresponding treatments. The activity of the NSCs was detected after the treatments using MTT assay, and the migration of the cells was observed with Transwell assay. The expressions of β-tubulin Ⅲ, GFAP and MAP-2 proteins in the cells were detected with immunoblotting, and the expressions of DCX, NEUN, and β-tubulin Ⅲ were also detected with immunofluorescence assay. RESULTS: Compared with that in MC group, the number of migrated cells in NLXT group and Y-27632 group increased significantly at 1 day and 3 days after induction ( < 0.05). The survival rate and the number of migrated cells in NLXT group and Y-27632 group increased significantly on day 7 ( < 0.01). Compared with those in MC group, the expressions of β-tubulin Ⅲ, MAP2 and GFAP protein in NLXT group and Y-27632 group were significantly increased on days 3 ( < 0.01) and 7 ( < 0.05). The numbers of β-tubulinⅢ/ GFAP, BrdU/DCX, and BrdU/NEUN labeled cells in the NLXT group and Y-27632 group were significantly greater than those in the MC group. CONCLUSIONS promotes the proliferation and differentiation of murine NSCs by regulating the expressions of β-tubulinⅢ/GFAP.
Animals ; Cell Differentiation ; Cell Proliferation ; Glial Fibrillary Acidic Protein ; Mice ; Neural Stem Cells ; Tubulin

Objective To study the different ischemic characteristics of cerebral gray matter and deep white matter in patients with chronic cerebral artery severe stenosis or occlusion. Methods A retrospective study was conducted on 30 patients with chronic unilateral cerebral artery severe stenosis or occlusion from April 2014 to April 2018 in our hospital. Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time of peak time (TTP) and time to delay(TTD) of cerebral cortex gray matter and deep white matter in the blood supply area of the responsible artery (the affected side) and the contralateral hemisphere (the healthy side) were measured. Statistical analysis of the perfusion parameters of cerebral cortex gray matter and deep white matter in the affected side and contralateral side were performed using SPSS13.0 software package. T test was used for variance homogeneity, and t′test was used for variance discrepancy, and P<0.05 was statistically significant. Results The average values of CBF and CBV of the ipsilateral and contralateral cerebral cortex were increased than those of ipsilateral and contralateral cerebral deep white matter respectively(P<0.01). MTT, TTP and TTD of the ipsilateral and contralateral cerebral cortex were decreased than that of ipsilateral and contralateral cerebral deep white matter (P<0.01); CBF of ipsilateral cerebral cortex and CBV of ipsilateral cerebral deep white matter were not different from those of the contralateral cerebral cortex and deep white matter respectively, but CBF of ipsilateral cerebral deep white matter is decreased than that of the contralateral deep white matter (P<0.01). CBV of ipsilateral cerebral cortex is increased than that of the contralateral cerebral cortex (P<0.01). MTT, TTP and TTD of ipsilateral cerebral cortex and deep white matter were increased than those of contralateral cerebral cortex and deep white matter respectively(P<0.01). Conclusion Deep cerebral white matter perfusion decreased more significantly than cortical gray matter in the supply region of chronic cerebral artery severe stenosis or occlusion. CT perfusion imaging can quantify the degree of chronic cerebral ischemia and can provide quantitative diagnostic information for clinical treatment and efficacy evaluation.

Objective: To study the different ischemic characteristics of cerebral gray matter and deep white matter in patients with chronic cerebral artery severe stenosis or occlusion. Methods: A retrospective study was conducted on 30 patients with chronic unilateral cerebral artery severe stenosis or occlusion from April 2014 to April 2018 in our hospital. Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time of peak time (TTP) and time to delay(TTD) of cerebral cortex gray matter and deep white matter in the blood supply area of the responsible artery (the affected side) and the contralateral hemisphere (the healthy side) were measured. Statistical analysis of the perfusion parameters of cerebral cortex gray matter and deep white matter in the affected side and contralateral side were performed using SPSS13.0 software package. T test was used for variance homogeneity, and t′ test was used for variance discrepancy, and P<0.05 was statistically significant. Results: The average values of CBF and CBV of the ipsilateral and contralateral cerebral cortex were increased than those of ipsilateral and contralateral cerebral deep white matter respectively(P<0.01). MTT, TTP and TTD of the ipsilateral and contralateral cerebral cortex were decreased than that of ipsilateral and contralateral cerebral deep white matter (P<0.01); CBF of ipsilateral cerebral cortex and CBV of ipsilateral cerebral deep white matter were not different from those of the contralateral cerebral cortex and deep white matter respectively, but CBF of ipsilateral cerebral deep white matter is decreased than that of the contralateral deep white matter (P<0.01). CBV of ipsilateral cerebral cortex is increased than that of the contralateral cerebral cortex (P<0.01). MTT, TTP and TTD of ipsilateral cerebral cortex and deep white matter were increased than those of contralateral cerebral cortex and deep white matter respectively(P<0.01). Conclusion Deep cerebral white matter perfusion decreased more significantly than cortical gray matter in the supply region of chronic cerebral artery severe stenosis or occlusion. CT perfusion imaging can quantify the degree of chronic cerebral ischemia and can provide quantitative diagnostic information for clinical treatment and efficacy evaluation.

Objective:To explore the association and gene-environment interaction between single nu-cleotide polymorphisms (SNPs)involved in cell-cell adhesion and non-syndromic cleft lip with or without cleft palate (NSCL/P)among Chinese population.Methods:A total of 806 NSCL/P trios were drawn by an international consortium,which conducted a genome-wide association study (GWAS)using a case-parent trio design to investigate genes affecting risks to NSCL/P.The transmission disequilibrium test (TDT)was used to explore the association between cell-cell adhesion genes,including CDH1,CT-NNB1,PVRL1,PVRL2,PVRL3,ACTN1,VCL,LEF1,and NSCL/P.Conditional Logistic regression models were used to estimate effects on risk of exposed and unexposed children.Four common maternal exposures including maternal smoking,environmental tobacco smoke,alcohol consumption and multivita-min supplementation during pregnancy were included in this study.Results:A total of 226 SNP markers were tested after quality control in this study.Although 23 SNPs in three genes (CTNNB1,CDH1, ACTN1)showed nominal significant association with NSCL/P in the TDT (P <0.05).There were no sig-nificant evidence of linkage and association that remained in the transmission disequilibrium test after Bonferroni correction(P >0.000 2).Tests for gene-environment interaction yielded significant results be-tween rs7431 27 in ACTN1 and environmental tobacco smoke (P =0.000 1 )with an estimated OR (case |G and E)=2.00(95%CI:1 .23 -3.26)and OR (case |G no E)=0.59 (95%CI:0.38 -0.90).Among the lower P value results in gene-environment tests,there were no significant results be-tween rs1 475034,rs370535,rs227341 9 in ACTN1,rs1 06871 in CTNNB1 and environmental tobacco smoke interaction.There were also no significant results between rs7634000,rs2971 366,rs2634553, rs1 489032,rs762481 2 in PVRL3 and multivitamin supplementation during pregnancy in gene-environ-ment tests(P >0.000 2).Conclusion:There is no association between cell-cell adhesion genes,inclu-ding CDH1,CTNNB1,PVRL1,PVRL2,PVRL3,ACTN1,VCL,LEF1,and NSCL/P when the genes are considered alone.But our results suggest that SNPs in ACTN1 may influence the risk to NSCL/P through gene-environment interaction.