Objective To investigate the effects of metformin(Met)on the proliferation of pancreatic cancer cells under different glucose concentration culture conditions,and to find the potential role of miR-139-5p in the process.Methods PANC-1 cells were treated with different concentrations of metformin(0/5/10/20 mmol/L)in 25 mmol/L(high-glucose group,HG)or 5 mmol/L(normal-glucose group,NG)glucose culture,cell proliferation,apoptosis,migration and cell cycle were detected after 48 h.The expression of miR-139-5p was quantitatively detected by RT-qPCR,and the miR-139-5p mimics were transfected into PANC-1 cells to clarify the role of miR-139-5p.Results Metformin inhibited the proliferation,promoted apoptosis,and induced S phase and G2/M phase arrest of PANC-1 cells under in high glucose and normal glucose culture conditions,and its anti-proliferation and pro-apoptosis effects were more significant in the normal glucose groups.The expression of miR-139-5p was up-regu-lated by metformin treatment in normal but not in high glucose culture.Further studies showed that miR-139-5p mimics inhibited of PANC-1 cells proliferation without metformin pre-incubation and enhanced the anti-prolifera-tion effect of 5 mmol/L metformin.The pro-apoptotic effect of 10 mmol/L metformin in normal glucose culture conditions.Conclusions In normal-glucose culture conditions,metformin can inhibit proliferation,induce apop-tosis and cell cycle arrest of PANC-1 cells more significantly than in higher-glucose culture,which may be partly related to the up-regulation of miR-139-5p.

Objective To identify the relationship between physical activity,insulin resistance and cardiovascular risk in individuals with different glucose tolerance status and to provide evidence for exercise intervention in people with different glucose tolerance status.Methods A total of 691 patients with different glucose metabolism status were recruited as subjects of the research.Spearman correlation analysis was used to study the relationship between exercise frequency and insulin resistance,insulin sensitivity,neck circumference(NC)and neck circumference height ratio(NHtR)in the subjects with different glucose metabolism status,the relationship between NC and insu-lin resistance and insulin sensitivity in different glucose metabolism groups.Results 171(62.9%)Subjects with diabetes were intervened by exercised every day.Spearman correlation analysis showed the correlation between exer-cise frequency and tri-glyceride triglyceride-glucose index(TyG index)(r=-0.120,P＜0.05)and NC(r=-0.168,P＜0.05)were negatively correlated.In subjects with diabetes,NC was positively correlated with triglyc-erides(TG)(r=-0.100,P＜0.05),homeostasis model assessment of insulin resistance(HOMA-R)(r=-0.163,P＜0.05),total cholesterol/high-density lipoprotein(TC/HDL-C)(r=-0.214,P＜0.05)and TyG index(r=-0.156,P＜0.05).Conclusions Increased frequency of exercise is associated with reduced NC,improved insulin resistance,and cardiovascular risk factors in subjects of our team with newly diagnosed diabetes.Exercise has no significant effect on insulin resistance of subjects with normal glucose tolerance and pre-diabetes.

Mitochondrial diabetes mellitus (MDM) is a genetically heterogeneous disorder caused by mitochondrial DNA (mtDNA) or nuclear DNA mutations, characterized by multi-system involvement and diverse clinical phenotypes. We report a pediatric case presenting with growth retardation followed by subsequent development of diabetes mellitus. Systematic evaluation revealed concurrent bilateral sensorineural hearing loss, bilateral basal ganglia calcification, and electroencephalographic abnormalities. A post-exercise lactate test demonstrated significant elevation of serum lactate levels immediately after physical exertion. Genetic analysis identified a large-scale mitochondrial DNA deletion spanning from m.8649 to m.16084. This case report is complemented by a literature review focusing on the pathogenesis, genetic characteristics, and therapeutic approaches of mitochondrial diabetes, with particular emphasis on mitochondrial disorders exhibiting large-scale mtDNA deletions alongside diabetic manifestations. Our comprehensive analysis aims to enhance clinical understanding and inform diagnostic strategies for this complex disease entity.

  Objective  By summarizing the clinical characteristics and follow-up outcomes of 5 patients with immune checkpoint inhibitor induced diabetes mellitus (ICI-DM) and reviewing the relevant literatures, the article aims at providing reference to clinicians in the diagnosis and treatment of the ICI-DM.  Methods  Clinical data of 5 patients with ICI-DM who were admitted to Peking Union Medical College Hospital from December 2018 to February 2023 and did retrospectively analyzed.  Results  Five patients with a mean age of (65±7)years received treatment by the programmed cell death 1 (PD-1) or its ligand inhibitor (PD-L1). The median time from the first immunotherapy to the discovery of elevated plasma glucose was 100 (43, 210)days, and the median cycle of immunotherapy was 7 (2.5, 10.5). The onset of the illness of all the 5 patients started with diabetic ketosis or ketoacidosis. At the onset, urine ketone bodies were positive, random plasma glucose was (36.36±15.89)mmol/L, glycosylated hemoglobin A1c (HbA1c)was (8.6%±0.66%), arterial blood pH was (7.28±0.16), and the median fasting C-peptide level was 0.09 (0.05, 0.32)μg/L. Five patients had an onset plasma glucose level of grade 3 or 4.Then, ICI treatment was discontinued in all patients and insulin therapy started. The daily dosage of insulin was (56±20)IU, supplemented with hypoglycemic drugs. After treatment, urine ketone body turned negative, pH value increased to normal range, and random plasma glucose decreased significantly (the median difference of random blood glucose before and after treatment was 21.30 mmol/L, P=0.043) showing that the treatment was effective. During the follow-up, all patients continued to use insulin. The PD-1 or PD-L1 inhibitors were restarted after hyperglycemia remission. The tumor condition was under control.  Conclusions  ICI-DM mainly occurs in patients who receive treatment with PD-1 or PD-L1 inhibitors usually with acute hyperglycemia whose laboratory tests indicate insulin secretion defects. Some patients had positive islet cell antibodies, glutamic acid decarboxylase antibodies and autoantibodies.Patients with positive autoantibodies needed early diagnosis and continuous insulin treatment. ICI treatment can be restarted after endocrinologists brought the blood glucose under control.

Objective:Both type 1 diabetes and type 2 diabetes are associated with abnormal bone metabolism, but they have different pathogenic mechanisms. Sclerostin(SOST), Dickkopf-related protein 1(DKK-1), and irisin are newly discovered factors involved in the regulation of bone metabolism. This study aims to compare the differences in serum levels of SOST, DKK-1, and irisin between patients with type 1 diabetes and type 2 diabetes.Methods:This cross-sectional study included 101 patients with type 1 diabetes who visited the Endocrinology Department of Peking Union Medical College Hospital from 2017 to 2019, as well as 55 patients with type 2 diabetes and 59 individuals with normal glucose tolerance who were confirmed through an oral glucose tolerance test as part of the Beijing Changping Community Type 2 Diabetes Management Program from 2014 to 2015. Enzyme-linked immunosorbent assay(ELISA) was used to measure the levels of SOST, DKK-1, and irisin.Results:There were more female participants than male participants, with an average age of 49 years. The group with type 1 diabetes had a longer duration of illness( P<0.001) and higher HbA 1C levels( P<0.001) compared to the group with type 2 diabetes, and there was no statistical difference in age between the two groups. Both the type 1 diabetes and type 2 diabetes groups had lower levels of serum procollagen type 1 N-terminal propeptide(P1NP) compared to the control group [(8 579±400)pg/mL, (7 268±552)pg/mL vs(10 051±618)pg/mL, P=0.039, P=0.001]; But the β isomer of C-terminal cross-linking telopeptide of type 1 collagen(β-CTX) showed no statistical difference compared to the control group. Patients with type 1 diabetes and type 2 diabetes had higher SOST than controls [(129.7±6.8)pg/mL, (104.8±6.8)pg/mL vs(85.9±5.3)pg/mL, P<0.001, P=0.030], the differences between the type 1 diabetes group and the control group lost statistical significance after adjusting for factors such as fasting blood glucose and lipid levels. There was no significant difference in SOST between type 1 diabetes and type 2 diabetes groups. There was no significant difference in DKK-1 among three groups, but DKK-1 in type 1 diabetes group was lower or tended to be lower than that in type 2 diabetes group. Serum irisin in patients with type 1 diabetes was higher than that in controls and patients with type 2 diabetes[(16.6±0.7)ng/mL vs (9.6±0.6)ng/mL, (9.8±0.6)ng/mL, both P<0.001], but there was no significant difference in irisin level between type 2 diabetes and controls. Conclusions:Patients with both type 1 and type 2 diabetes showed inhibition of the bone formation marker P1NP, while the bone resorption marker β-CTX did not significantly change. SOST levels were elevated or showed an increasing trend in both type 1 and type 2 diabetes patients, which may be related to the inhibition of bone formation. Additionally, type 1 diabetes patients had increased levels of irisin, which may be involved in abnormal bone turnover.

Objective: To investigate the efficacy of antibacterial peptides in the adjuvant therapy of stage Ⅲ periodontitis. Methods: Fifty-one patients were randomly divided into simple mechanical curettage group, minocycline hydrochloride group and antibacterial peptide group according to the treatment mode. Three groups received periodontal sequential treatment, and after the ultrasonic supragingival scaling, they were performed with curettage, root surface planing, polishing and flushing. After treatment in the minocycline hydrochloride group and the biological antibacterial peptide group, minocycline hydrochloride ointment and biological antibacterial peptide periodontal gel were injected into the periodontal pocket respectively. The mechanical curettage group did not take medicine. Periodontal checklists at baseline and 90 d after treatment were recorded to compare differences of the three groups in periodontal probing depth (PD), bleeding index (BI) and attachment level (AL). Enzyme-linked immunosorbent assay (ELSIA) was used to detect the change of tumour necrosis factor-α (TNF-α), interleukin (IL)-1β by collecting the gingival crevicular fluid of the three sets at baseline, 7 d after treatment and 90 d after treatment. Results: There was no statistically significant difference in periodontal clinical examination indexes(PD,BI,AL) and contents of TNF-α and IL-1β in the gingival crevicular fluid between the three groups at baseline (P>0.05). At 7 and 90 d after treatment, all indexes in the three groups were improved compared with those before treatment. The comparison between groups showed that in periodontal pockets with PD≤5 mm, there was no statistically significant difference in the indicators between the three groups. In periodontal pockets with PD≥6 mm, the minocycline hydrochloride group and the bio-antibacterial peptide group had no statistically significant difference in various indicators, but they were all better than the mechanical scaling group. Conclusion Basic periodontal therapy is an important treatment for stage Ⅲ periodontitis. Minocycline hydrochloride and biological antibacterial peptides are both effective adjuvant drugs for deep periodontal pockets with PD≥6 mm.

Objective: To explore method for isolating and culturing human epidermal stem cells ( EPSCs) in vitro and isolating and purifying epidermal stem cell exsomes ( EPSCs-Exo) by optimizing the technical process． Method: Firstly，the improved separating enzyme was used to isolate the EPSCs derived from human skin tissue．Then，an improved serum-free culture medium and 10 specific factors were combined to construct optimized 2D culture medium which could stimulate the growth of EPSCs，promote the secretion of EPSCs-Exo，maintain the stemness and proliferation of EPSCs，and delay the differentiation and maturation of EPSCs． Further，the conditions of differential centrifugation was optimized，and then the human EPSCs-Exo was successfully extracted with high efficiency and high purity． Results: The human skin tissue was confirmed with the expressions of markers for epidermal cells． EPSCs were verified with high expression levels of integrin-α6，integrin-β1，P63 and CK19 by immunofluorescence staining and Western blot． The nanoparticle tracking analysis results showed the particles separated for EPSCs supernatant was saucepan with the detected diameter between 30 － 150 nm． The Western blot results showed the positive expression of membrane markers Tsg101，CD9 and CD63 and the negative expression of intracellular markers Calnexin and GAPDH． Conclusion The results show that the human-derived EPSCs have been successfully isolated and cultured in vitro，and the EPSCs-Exo have been successfully isolated and identified．

Nano-drug delivery strategies have been highlighted in cancer treatment, and much effort has been made in the optimization of bioavailability, biocompatibility, pharmacokinetics profiles, and in vivo distributions of anticancer nano-drug delivery systems. However, problems still exist in the delicate balance between improved anticancer efficacy and reduced toxicity to normal tissues, and opportunities arise along with the development of smart stimuli-responsive delivery strategies. By on-demand responsiveness towards exogenous or endogenous stimulus, these smart delivery systems hold promise for advanced tumor-specificity as well as controllable release behavior in a spatial-temporal manner. Meanwhile, the blossom of nanotechnology, material sciences, and biomedical sciences has shed light on the diverse modern drug delivery systems with smart characteristics, versatile functions, and modification possibilities. This review summarizes the current progress in various strategies for smart drug delivery systems against malignancies and introduces the representative endogenous and exogenous stimuli-responsive smart delivery systems. It may provide references for researchers in the fields of drug delivery, biomaterials, and nanotechnology.

Drug delivery systems (DDS) are defined as methods by which drugs are delivered to desired tissues, organs, cells and subcellular organs for drug release and absorption through a variety of drug carriers. Its usual purpose to improve the pharmacological activities of therapeutic drugs and to overcome problems such as limited solubility, drug aggregation, low bioavailability, poor biodistribution, lack of selectivity, or to reduce the side effects of therapeutic drugs. During 2015-2018, significant progress in the research on drug delivery systems has been achieved along with advances in related fields, such as pharmaceutical sciences, material sciences and biomedical sciences. This review provides a concise overview of current progress in this research area through its focus on the delivery strategies, construction techniques and specific examples. It is a valuable reference for pharmaceutical scientists who want to learn more about the design of drug delivery systems.

Objective To express and purify two domains GcⅠand GcⅡof Xinjiang hemorrhagic fever virus (XHFV) glycoprotein, and to study its immunogenicity and the effects on immune response in mice. Methods The prokaryotic expression plasmids of pET28a-GcⅠand pET32a-GcⅡwere constructed and transformed into E. coli BL21, respectively. The expression and purification conditions of rGcⅠand rGcⅡproteins were optimized. The antigenicity of the fusion protein was detected by Western Blot and enzyme-linked immunosorbent assay (ELISA). BALB/c mice were immunized by protein immunization and DNA priming-protein boosting. The mice were randomly divided into 5 groups, including pVAX1-GcⅠ+rGcⅠgroup, pVAX1-GcⅡ+rGcⅡgroup, rGcⅠgroup, rGcⅡgroup and saline group (control group) with 7 mice in each group. The serum antibody titer of mice was detected by indirect ELISA, and the immune effect was evaluated by spleen T lymphocyte proliferation assay and cytokine content determination. Results The fusion proteins rGcⅠand rGcⅡwere purified and obtained, which could react with positive serum of sheep and had good antigenicity. After three immunizations, the IgG levels in the serum of each experimental group were significantly higher than those in the control group (all P<0.001). The serum antibody titers of the experimental groups were reached above 1:12800. Among them, the concentration of Th2 type cytokine interleukin-4 (IL-4) in the spleen cell culture supernatant of rGcⅡ[(79.97±7.47) ng/L] and pVAX1-GcⅡ+rGcⅡgroup [(61.43±9.27) ng/L] was significantly higher than (24.29±3.81) ng/L of the control group, respectively (all P<0.01). The highest mass concentration [(42.46 ±2.60) ng/L] of Th1 type cytokine interferon-γ(IFN-γ) was observed in the pVAX1-GcⅡ+rGcⅡ group, which was significantly higher than (20.33±1.67) ng/L of the control group, and the difference was statistically significant (P<0.001). That showed a significant antigen-specific splenic T lymphocyte proliferation (P<0.001). Conclusions The purified recombinant proteins rGcⅠand rGcⅡhave good immunogenicity, which can make the immune system T lymphocytes tend to Th2 response, and pVAX1-GcⅡ combined with recombinant protein GcⅡ can induce better antigen-specific immune effect. And pVAX1-GcⅡ combined with recombinant protein GcⅡis expected to be used as vaccine candidates for the prevention and control of XHFV.