Traditional treatment for type 1 diabetes mellitus （T1DM） primarily involves insulin replacement， yet some patients encounter issues such as significant blood glucose fluctuations， high risk of hypoglycemia， and weight gain. In recent years， the adjuvant therapeutic role of non-insulin hypoglycemic drugs in T1DM has gradually gained attention. This article reviews the mechanisms of action and clinical research progress of five types of non-insulin hypoglycemic drugs in the treatment of T1DM： amylin analogues （pramlintide）， biguanides （metformin）， sodium-glucose co-transporter 2 inhibitor， dipeptidyl peptidase-4 inhibitor， and glucagon-like peptide-1 receptor agonist. It is found that these drugs can enhance clinical benefits for T1DM patients by improving insulin sensitivity， delaying gastric emptying， promoting urinary glucose excretion， and regulating incretin levels， thereby reducing glycated hemoglobin levels， decreasing insulin dosage， and managing body weight. Simultaneously， these drugs also present limitations such as low patient compliance due to complex dosing regimens， increased risk of diabetic ketoacidosis， and heterogeneity in glycemic control. Future research could focus on developing individualized treatment strategies， combining pharmacogenomics with novel biomarkers to precisely identify subpopulations of patients who may benefit， and delving into the potential value of these drugs in delaying diabetic vascular complications and improving patients’ quality of life.

Immunotherapy following transplantation has long been a central focus in both anti-rejection strategies and the induction of immune tolerance. Regulatory B cells (Bregs) can directly suppress the immune system via the interaction between programmed cell death protein 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1). Additionally, Bregs exert indirect immunosuppressive effects through the secretion of cytokines such as interleukin-10 (IL-10), transforming growth factor-β (TGF-β), and granzyme B (GrB), among which IL-10 plays a particularly critical role. This review summarizes recent progress in the classification, functional characteristics, and activation mechanisms of Bregs, as well as their potential applications in transplantation immunotherapy, aiming to provide a theoretical foundation for Breg-targeted strategies in transplant immune modulation.

Acute kidney injury(AKI)is a syn-drome characterized by rapid decline in renal excre-tory function.Its pathogenesis is still unclear.Stud-ies have shown that macrophages are major play-ers in AKI inflammation,regulating tissue damage and regeneration repair.During AKI inflammation,macrophages can be activated into different func-tional phenotypes through molecular and signaling pathways,regulate different molecules and signal-ing pathways,and determine the progression of AKI.In this paper,the activation of macrophages and the molecular signaling pathways involved in the regulation of AKI in the past five years are re-viewed,and the mechanism of action of macro-phages in AKI is determined,which provides ideas for the study of macrophages as therapeutic tar-gets.

Acute kidney injury(AKI)is a syn-drome characterized by rapid decline in renal excre-tory function.Its pathogenesis is still unclear.Stud-ies have shown that macrophages are major play-ers in AKI inflammation,regulating tissue damage and regeneration repair.During AKI inflammation,macrophages can be activated into different func-tional phenotypes through molecular and signaling pathways,regulate different molecules and signal-ing pathways,and determine the progression of AKI.In this paper,the activation of macrophages and the molecular signaling pathways involved in the regulation of AKI in the past five years are re-viewed,and the mechanism of action of macro-phages in AKI is determined,which provides ideas for the study of macrophages as therapeutic tar-gets.

Immunotherapy following transplantation has long been a central focus in both anti-rejection strategies and the induction of immune tolerance. Regulatory B cells (Bregs) can directly suppress the immune system via the interaction between programmed cell death protein 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1). Additionally, Bregs exert indirect immunosuppressive effects through the secretion of cytokines such as interleukin-10 (IL-10), transforming growth factor-β (TGF-β), and granzyme B (GrB), among which IL-10 plays a particularly critical role. This review summarizes recent progress in the classification, functional characteristics, and activation mechanisms of Bregs, as well as their potential applications in transplantation immunotherapy, aiming to provide a theoretical foundation for Breg-targeted strategies in transplant immune modulation.

OBJECTIVE To study the effects of the curcumin derivative bisdemethoxycurcumin （BC） promoting neuronal differentiation of neuroblastoma cells Neuro-2a （N2a） in mice and its mechanism. METHODS The effects of BC （1， 2， 4， 6， 8， 10 μmol/L） on the viability of N2a cells were detected by MTT assay to determine the concentration range of drug treatment. The control group， retinoic acid （RA） group （10 μmol/L） and BC groups （1， 2 and 4 μmol/L） were set up， and the length of neural protrusions of the differentiated cells was measured and the cell differentiation rate was calculated after 48 h and 72 h of culture. Compared with 0 min group， Western blot was used to detect the phosphorylation levels of protein kinase B （Akt）， extracellular- signal regulated kinase 1/2 （ERK1/2）， and p38 mitogen-activated protein kinase （p38） proteins in cells treated by 4 μmol/L BC for 5， 15， 30， 60， 120 min. After intervention with inhibitors LY294002 （LY） and PD98059 （PD）， the effects of BC on Akt and ERK1/2 protein phosphorylation levels and promoting neural differentiation were further validated. RESULTS According to the MTT experiment， the BC concentrations for subsequent induction of cell differentiation were determined to be 1， 2， and 4 μmol/L. After 48 hours of differentiation， compared with the control group， the cell differentiation rate in RA group and BC 1， 2 and 4 μmol/L groups， the length of cellular neural processes wjxhhxx413@163.com in the BC 4 μmol/L group significantly increased （P＜0.05 or P＜0.01）；after inducing differentiation of BC for 72 hours，compared with the control group， the cell differentiation rate and the length of cellular neural processes in the RA group， the cell differentiation rate in the BC 4 μmol/L group， and the length of cellular neural processes in the BC 2 μmol/L group all significantly increased （P＜0.05 or P＜0.01）.Compared with the 0 min group， the phosphorylation levels of Akt， ERK1/2， and p38 proteins in cells of the 5， 15， 30， 60 and 120 min groups increased to varying degrees after treated by 4 μmol/L BC， and some differences were statistically significant （P＜0.05 or P＜0.01）. After adding the inhibitor LY/PD， compared with the BC group， the phosphorylation level of ERK1/2 protein in the PD+BC group cells were significantly reduced （P＜0.01）， and the cell differentiation rates in the LY group， LY+BC group， PD group， and PD+BC group was significantly reduced （P＜0.01）. CONCLUSIONS BC promotes N2a cell differentiation mainly by increasing cell differentiation rate and neural protrusion length. The mechanism may be related to the activation of mitogen-activated protein kinase/ ERK and PI3K/Akt signaling pathways.

Renal fibrosis, especially tubulointerstitial fibrosis, is the most common pathway of all chronic kidney diseases progressing to end-stage renal diseases. Several adaptive reactions occur in renal tubular epithelial cells after chronic injury, such as changes in glycolipid metabolism, unfolded protein response, autophagy and senescence, epithelial-to-mesenchymal transition and G2/M cell cycle arrest. Maladaptive repair mechanisms can induce tubulointerstitial fibrosis. This article will discuss the molecular mechanism of these adaptive responses of renal tubular epithelial cells driving renal tubulointerstitial fibrosis, and provide a basis for exploring new drug targets for renal tubulointerstitial fibrosis.

Objective To explore the potential role of alpinumisoflavone(AIF)in the treatment of temporomandibu-lar joint osteoarthritis(TMJOA)cell model through network pharmacology and molecular docking and to provide a re-search basis for AIF in the treatment of TMJOA.Methods GeneCards,OMIM,DisGeNET,and PharmGKB databases were used to screen TMJOA disease targets,and PharmMapper and HERB were used to retrieve AIF-related targets.The intersection targets of the compounds and diseases were uploaded to the STRING database to obtain the key targets for GO and KEGG enrichment analysis,while the key targets in related signaling pathways were evaluated through mo-lecular docking.Approval was obtained from the Ethics Committee to extract condylar chondrocytes from 3-week-old SD rats.The CCK-8 assay was used to detect AIF cytotoxicity on condylar chondrocytes.Condylar chondrocytes were in-duced with 10 ng/mL interleukin 1β(IL-1β)for 24 h to construct a TMJOA cell model.The experiment was divided in-to three groups:control group,comprising condylar chondrocytes cultured in DMEM for 48 h;IL-1β group,comprising condylar chondrocytes pre-cultured in DMEM for 24 h,after which IL-1β was added to the original culture medium to obtain a medium concentration of 10 ng/mL and allowed to culture for 24 h;and the IL-1β+10 μmol/L AIF group,com-prising condylar chondrocytes pre-cultured in DMEM medium containing 10 μmol/L AIF for 24 h,after which IL-1β was added to the original culture medium to obtain a medium concentration of 10 ng/mL and allowed to culture for 24 h.The effect of AIF on condylar chondrocyte apoptosis in the TMJOA cell model was detected by flow cytometry.The experiment was divided into four groups:control group,IL-1β group,IL-1β+10 μmol/L AIF group,and IL-1β+30 μmol/L AIF group.The IL-1β+30 μmol/L AIF group was pre-cultured in DMEM containing 30 μmol/L AIF for 24 h,after which IL-1β was added to the original culture medium to obtain a medium concentration of 10 ng/mL and allowed to culture for 24 h.The remaining three groups were cultured in the same manner as before.The mRNA and protein ex-pression of apoptosis-associated B-cell leukemia/lymphoma-2(Bcl2),cysteinyl aspartate specific protease 3(caspase-3),matrix degradation-associated a disintegrin and metalloproteinase with thrombospondin motifs 4(ADAMTS4),matrix me-talloproteinase 3(MMP3),and matrix metalloproteinase 13(MMP13)were detected by qPCR and western blot,by AIF in the TMJOA cell model.Results The PharmMapper and HERB database search yielded 300 AIF compound targets.The GeneCards,OMIM,DisGeNET,and PharmGKB databases yielded 378 TMJOA disease targets.Thirty-three poten-tial common targets were obtained by intersecting compounds with disease targets.The common targets were uploaded into the STRING database to obtain 31 key targets that were mainly associated with apoptosis and extracellular matrix degradation.This process may be associated with the MAPK,estrogen,and TNF signaling pathways.The molecular docking results showed that AIF has good binding activity with extracellular signal-regulated kinase 1/2(ERK1/2)and estrogen receptor gene 1/2(ESR1/2),which are key targets in the MAPK and estrogen signaling pathways.The CCK-8 assay showed that AIF had no obvious cytotoxicity to condylar chondrocytes.The cell experiments showed that AIF inhib-ited apoptosis in the IL-1β+10 μmol/L AIF group compared to the IL-1β group.Compared to the IL-1β group in the IL-1β+10 μmol/L AIF group and the IL-1β+30 μmol/L AIF group,AIF upregulated Bcl2 and downregulated caspase-3 mRNA and protein expression and inhibited ADAMTS4,MMP3,and MMP13 mRNA and protein expression.Conclusion AIF inhibited apoptosis in the TMJOA cell model by upregulating Bcl2 and downregulating caspase-3 mRNA and pro-tein expression,and inhibited extracellular matrix degradation induced by IL-1β,thereby delaying TMJOA progression.

BACKGROUND:Temporomandibular joint osteoarthritis is a common oral disease with a high incidence.However,temporomandibular joint osteoarthritis is not easy to be detected in the early stage,and it is difficult to obtain clinical pathological specimens,so it is difficult to carry out related research.The application of digital 3D printing technology to animal models of Temporomandibular joint osteoarthritis increases the consistency of the animal models,thus promoting the study of temporomandibular joint osteoarthritis. OBJECTIVE:To establish a standardized animal model of temporomandibular joint osteoarthritis using novel digital technology. METHODS:According to the different modeling methods of unilateral anterior crossbite,30 female Sprague-Dawley rats were randomly divided into traditional model group,digital model group,and control group(n=10 per group).Cartilage specimens of the condyles were collected at 4 and 8 weeks after modeling.The apparent morphology was observed by stereoscopic microscope.The pathological morphology was observed by hematoxylin-eosin staining and Safranin O/fast green staining.Changes in the expression of interleukin-1β and tumor necrosis factor-α were observed by ELISA,and changes in the expression of aggrecan,type Ⅱ collagen and matrix metalloproteinase-13 were observed by immunohistochemical staining. RESULTS AND CONCLUSION:Different degrees of degeneration were observed in the digital and traditional model groups.The body mass of rats in both the model groups decreased during the 1st week after intervention and subsequently demonstrated growth trend and were significantly lower than that in the control group.The results of stereoscopic microscope showed that at 4 and 8 weeks after modeling,the deformation and defect degree of the digital model group was significantly higher than that of the traditional model group.At these two time points,the Osteoarthritis Research Society International scores of the digital model group and the traditional model group were higher than those of the control group,and the Osteoarthritis Research Society International score of the digital model group was higher than that of the traditional model group(P＜0.05).Histopathological observation showed that the modified Mankin score and Osteoarthritis Research Society International score of the two model groups were significantly higher than those of the control group of the same age at 4 and 8 weeks after modeling(P＜0.05).Immunohistochemical staining results showed that at two time points,compared with the control group of the same age,the expression of aggrecan and type Ⅱ collagen decreased in the traditional model group and the digital model group,while the expression of matrix metalloproteinase 13 increased(P＜0.05).ELISA results showed that the expression levels of inflammatory factors interleukin-1β and tumor necrosis factor-α in the traditional and digital model groups were higher than those in the control group at 8 weeks,and the expression levels of interleukin-1β and tumor necrosis factor-α in the digital model group were higher than those in the traditional model group(P＜0.05).To conclude,the personalized metal tube designed and produced by 3D printing technology can quickly guide the osteoarthritis-like lesions of the temporomandibular joint without repeated trial and adjustment,which is reproducible and suitable for promotion and application.

Objective:To explore the influence of tumor-associated macrophages (TAMs) on endocrine resistance in breast cancer through the forkhead box M1 (FOXM1) /Wnt/ β-catenin pathway. Methods:Tamoxifen-resistant breast cancer cells were cultured, THP-1 cells were induced into macrophages (MΦ), and further induced into TAMs. After being cultured in the conditioned medium (CM) of MCF-7 cells for 24 hours, MΦ were defined as MS cells. After being cultured in the CM of MCF-7R cells for 24 hours, MΦ were defined as MR cells. MCF-7 cells, after being cultured in the CM of macrophages for 24 hours, were defined as MCF-7 (MΦ) cells. MCF-7 cells, after being cultured in the CM of MS cells for 24 hours, were defined as MCF-7 (MS) cells. MCF-7 cells, after being cultured in the CM of MR cells for 24 hours, were defined as MCF-7 (MR) cells. Cell viability and invasion ability were evaluated using CCK-8 and Transwell assays. The protein levels of CD163, Wnt1, β-catenin, and FOXM1 in different groups were examined by qRT-PCR and Western blot. Results:Compared to the MS group (mRNA: 1.49±0.12, protein: 1.15±0.12), CD163 expression was higher in the MR group (mRNA: 2.33±0.16, protein 1.52±0.11) ( t=7.28, P=0.002) ( t=3.94, P=0.017), indicating that tamoxifen-resistant breast cancer cells can induce polarization of more MΦ into TAMs. TAMs increased the expression of FOXM1 in breast cancer cells, which further activated the Wnt/ β-catenin pathway. Compared to the MCF-7 (MΦ) group, the MCF-7 (MS) and MCF-7 (MR) groups showed enhanced cell viability and invasion, with the most significant increase observed in the MCF-7 (MR) group. Compared with MCF-7 (MΦ) cells, the levels of Wnt1, β-catenin, and FOXM1 in MCF-7 (MS) and MCF-7 (MR) cells were significantly increased, with the highest levels observed in the MCF-7 (MR) group with the most TAM polarization. Compared to the MCF-7 group, both the MCF-7 (MR) and MCF-7+pcDNA-FOXM1 groups showed increased levels of Wnt1 and β-catenin, enhanced cell viability and invasion. Compared to the MCF-7 (MR) group, the MCF-7 (MR) + si-FOXM1 group showed reduced levels of Wnt1 and β-catenin, weakened cell viability and invasion. Conclusion:TAMs promote endocrine resistance in breast cancer by upregulating FOXM1 and activating the Wnt/ β-catenin pathway.