BACKGROUND: 3D-printing is widely used in regenerative medicine and is expected to achieve vaginal morphological restoration and true functional reconstruction. Mesenchymal stem cells-derived exosomes (MSCs-Exos) were applyed in the regeneration of various tissues. The current study aimed to explore the effctive of MSCs-Exos in vaginal reconstruction. METHODS: In this work, hydrogel was designed using decellularized extracellular matrix (dECM) and gelatin methacrylate (GelMA) and silk fibroin (SF). The biological scaffolds were constructed using desktop-stereolithography.The physicochemical properties of the hydrogels were evaluated; Some experiments have been conducted to evaluate exosomes’ effect of promotion vaginal reconstruction and to explore the mechanism in this process. RESULTS: It was observed that the sustained release property of exosomes in the hydrogel both in vitro and in vitro.The results revealed that 3D scaffold encapsulating exosomes expressed significant effects on the vascularization and musule regeneration of the regenerative vagina tissue. Also, MSCs-Exos strongly promoted vascularization in the vaginal reconstruction of rats, which may through the PI3K/AKT signaling pathway. CONCLUSION The use of exosome-hydrogel composites improved the epithelial regeneration of vaginal tissue, increased angiogenesis, and promoted smooth muscle tissue regeneration. 3D-printed, lumenal scaffold encapsulating exosomes might be used as a cell-free alternative treatment strategy for vaginal reconstruction.

BACKGROUND: Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a severe congenital disorder characterized by vaginal hypoplasia caused by dysplasia of the Müllerian duct. Patients with MRKH syndrome often require nonsurgical or surgical treatment to achieve satisfactory vaginal length and sexual outcomes. The extracellular matrix has been successfully used for vaginal reconstruction. METHODS: In this study, we developed a new biological material derived from porcine vagina (acellular vaginal matrix, AVM) to reconstruct the vagina in Bama miniature pigs. The histological characteristics and efficacy of acellularization of AVM were evaluated, and AVM was subsequently transplanted into Bama miniature pigs to reconstruct the vaginas. RESULTS: Macroscopic analysis showed that the neovaginas functioned well in all Bama miniature pigs with AVM implants. Histological analysis and electrophysiological evidence indicated that morphological and functional recovery was restored in normal vaginal tissues. Scanning electron microscopy showed that the neovaginas had mucosal folds characteristics of normal vagina. No significant differences were observed in the expression of CK14, HSP47, and a-actin between the neovaginas and normal vaginal tissues. However, the expression of estrogen receptor (ER) was significantly lower in the neovaginas than in normal vaginal tissues. In addition, AVM promoted the expression of b-catenin, c-Myc, and cyclin D1. These results suggest that AVM might promotes vaginal regeneration by activating the b-catenin/cMyc/cyclin D1 pathway. CONCLUSION This study reveals that porcine-derived AVM has potential application for vaginal regeneration.

OBJECTIVE: To investigate the mechanism of self-efficacy between self-management ability and self-management behavior and its differences among patients with different disease courses through mediation tests. METHODS: In the study, 489 patients with type 2 diabetes who attended the endocrinology departments of four hospitals in Shanxi Province and Inner Mongolia Autonomous Region from July to September 2022 were enrolled as the study population. They were investigated by General Information Questionnaire, Diabetes Self-Management Scale, Chinese version of Diabetes Empowerment Simplified Scale, and Diabetes Self-Efficacy Scale. Mediation analyses were performed using the linear regression model, Sobel test, and Bootstrap test in the software Stata version 15.0 and divided the patients into different disease course groups for subgroup analysis according to whether the disease course was > 5 years. RESULTS: In this study, the score of self-management behavior in the patients with type 2 diabetes was 6.16±1.41, the score of self-management ability was 3.99±0.74, and the score of self-efficacy was 7.05±1.90. The results of the study showed that self-efficacy was positively correlated with self-management ability (r=0.33) as well as self-management behavior (r=0.47) in the patients with type 2 diabetes (P < 0.01). The mediating effect of self-efficacy accounted for 38.28% of the total effect of self-management ability on self-management behaviors and was higher in the behaviors of blood glucose monitoring (43.45%) and diet control (52.63%). The mediating effect of self-efficacy accounted for approximately 40.99% of the total effect for the patients with disease course ≤ 5 years, while for the patients with disease course > 5 years, the mediating effect accounted for 39.20% of the total effect. CONCLUSION Self-efficacy enhanced the effect of self-management ability on the behavior of the patients with type 2 diabetes, and this positive effect was more significant for the patients with shorter disease course. Targeted health education should be carried out to enhance patients' self-efficacy and self-management ability according to their disease characteristics, to stimulate their inner action, to promote the development of their self-management behaviors, and to form a more stable and long-term mechanism for disease management.
Humans ; Diabetes Mellitus, Type 2/therapy* ; Self Efficacy ; Self-Management ; Blood Glucose Self-Monitoring ; Blood Glucose ; Self Care

Objective: Several COVID-19 patients have overlapping comorbidities. The independent role of each component contributing to the risk of COVID-19 is unknown, and how some non-cardiometabolic comorbidities affect the risk of COVID-19 remains unclear. Methods: A retrospective follow-up design was adopted. A total of 1,160 laboratory-confirmed patients were enrolled from nine provinces in China. Data on comorbidities were obtained from the patients' medical records. Multivariable logistic regression models were used to estimate the odds ratio ( Results: Overall, 158 (13.6%) patients were diagnosed with severe illness and 32 (2.7%) had unfavorable outcomes. Hypertension (2.87, 1.30-6.32), type 2 diabetes (T2DM) (3.57, 2.32-5.49), cardiovascular disease (CVD) (3.78, 1.81-7.89), fatty liver disease (7.53, 1.96-28.96), hyperlipidemia (2.15, 1.26-3.67), other lung diseases (6.00, 3.01-11.96), and electrolyte imbalance (10.40, 3.00-26.10) were independently linked to increased odds of being severely ill. T2DM (6.07, 2.89-12.75), CVD (8.47, 6.03-11.89), and electrolyte imbalance (19.44, 11.47-32.96) were also strong predictors of unfavorable outcomes. Women with comorbidities were more likely to have severe disease on admission (5.46, 3.25-9.19), while men with comorbidities were more likely to have unfavorable treatment outcomes (6.58, 1.46-29.64) within two weeks. Conclusion Besides hypertension, diabetes, and CVD, fatty liver disease, hyperlipidemia, other lung diseases, and electrolyte imbalance were independent risk factors for COVID-19 severity and poor treatment outcome. Women with comorbidities were more likely to have severe disease, while men with comorbidities were more likely to have unfavorable treatment outcomes.
Adult ; Aged ; COVID-19/virology* ; China/epidemiology* ; Comorbidity ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Severity of Illness Index ; Treatment Outcome

With the deepening of research, proteomics has developed into a science covering the study of all the structural and functional characteristics of proteins and the dynamic change rules. The essence of various biological activities is revealed from the perspectives of the biological structure, functional activity and corresponding regulatory mechanism of proteins by proteomics. Among them, phospholipid-binding protein is one of the hotspots of proteomics, especially annexin A1, which is widely present in various tissues and cells of the body. It has the capability of binding to phospholipid membranes reversibly in a calcium ion dependent manner. In order to provide possible research ideas for researchers, who are interested in this protein, the biological effects of annexin A1, such as inflammatory regulation, cell signal transduction, cell proliferation, differentiation and apoptosis are described in this paper.

The treatment of late stage hepatocellular carcinoma (HCC) presently remains a great challenge. A very few drugs have been recently approved for clinical use except sorafenib and lenvatinib. After decades of failure and experience with molecular targeted and immunosuppressive therapy, immune checkpoint inhibitors are becoming one of the potentially effective therapies for patients with HCC, whose tumor is in the middle and late stages. Moreover, immune checkpoint is one of the main mechanisms of tumor immune evasion; of which programmed cell death protein 1 and its ligand (PD1/PD-L1) are important immune checkpoint targets, and its related pathway has shown to have an antitumor effect in a variety of solid or hematologic tumors and its inhibitors can effectively exert antitumor immunosuppressive effects. This review summarizes the current role of PD1/PD-L1 inhibitors in the treatment of late stage HCC, and explores the forecasting value of combined therapy strategy for HCC.

Objective: To establish the immortalized mouse brain microvascular pericytes model and to apply to the cerebrovascular toxicants screening study. Methods: Brain pericytes were isolated from 3 weeks of mice by tissue digestion. Immortalized pericyte cell line was constructed by infecting with LT retrovirus. Monoclone was selected to purify the immortalized pericyte cell line. The pericyte characteristics and purity were explored by immunocytochemistry. Cell proliferation was measured by using the Pomega MTS cell Proliferation Colorimetric Assay Kit. Pericytes were treated with 0, 160, 320, 640, 1 280, 2 560 μmol/L lead acetate, 0, 5, 10, 20, 40, 80 μmol/L cadmium chloride and 0, 5, 10, 20, 40, 80 μmol/L sodium arsenite in 24 hours. Cell toxicity of each group was determined by MTS assay, median lethal dose (LD₅₀) was calculated in linear regression. Results: Mouse brain pericytes were successfully isolated by tissue separation and enzyme digestion method. After immortalized by LT retroviruses, monoclone was selected and expanded to establish pericyte cell line. The brain pericytes exhibited typical long spindle morphology and positive staining for α-SMA and Vimentin. The proliferation of brain pericytes cell lines was very slowly, and the doubling time was about 48 hours. The proliferation of immortalized brain pericytes cell lines was very quickly, and the doubling time was about 24 hours. After lead acetate, cadmium chloride and sodium arsenite treatment for 24 hours respectively, gradual declines in cell viability were observed. The LD₅₀ of lead acetate was 2 025.0 μmol/L, the LD₅₀ of cadmium chloride was 36.6 μmol/L, and the LD₅₀ of sodium arsenite was 33.2 μmol/L. Conclusion The immortalized mouse brain microvascular pericyte model is established successfully by infecting with LT retrovirus, and can be applied to screen cerebrovascular toxicants. The toxicity of these toxicants to immortalized mouse brain microvascular pericyte is in sequence: sodium arsenite,cadmium chloride, lead acetate.

Objective: To investigate the effects of cerebral cavernous malformation 3 (CCM3) gene knockout on the lead exposure-induced blood-brain barrier malfunction in mice brain, and the relationship between CCM3 knockout and the Alzheimer's disease (AD). Methods: Wide type (WT) mice and CCM3⁺/- mice were divided into 4 groups, control group and lead exposed group in WT as well as CCM3^+/- mice. Lead exposed groups were treated with 0.05% lead acetate in drinking water for 12 weeks, while control group drink deionized water freely. Blood lead and brain lead levels in each group were detected by graphite furnace atomic absorption spectrometry. The brain tissue of each group was made into paraffin sections, whose morphology were observed by HE staining. The expression of Aβ_1-42 in brain tissue was detected by immunohistochemistry and the brain capillaries were labeled by VRGFR2. The protein expression of Claudin-5, ZO-1, and p-Tau was detected by Western blot. The brain tissue RNA was extracted and the relative expression of LRP-1 mRNA was detected by qRT-PCR. Results: The levels of blood lead WT (216.07±84.16) and CCM3^+/- (189.64±101.86) μg/L in lead exposed group were higher than those in control group WT (19.52±11.46) and CCM3^+/- (11.79±8.20) μg/L, the difference was statistically significant (t=4.18, P=0.006; t=3.79, P=0.016). The levels of brain lead WT (1.78±0.69) and CCM3^+/- (1.74±0.66) μg/L were higher than those in control group WT (1.06±0.87) and CCM3^+/- (0.97±0.64) μg/L, the difference was statistically significant (t=3.67, P=0.018; t=3.88, P=0.015). The HE staining showed no obvious lesions in the brain of each group of mice. The results of immunohistochemistry showed that there was no Aβ₁-42 deposition in the brain of mice in each group. The numbers of microvessels in the brain of CCM3^+/- mice in the lead exposed group were decreased. Compared with the relative expression levels of Claudin-5 (WT: 1.30±0.03, CCM3^+/-: 1.07±0.08) in control group mice brain, the relative expression of Claudin-5 (WT: 0.96±0.04, CCM3^+/-: 0.59±0.01) was decreased with statistical significance (F=199.27, P<0.001). The relative expression level of LRP-1 gene mRNA in brain of lead exposed group (WT: 0.32±0.10, CCM3^+/-: 0.06±0.01) was higher than that of unexposed group (WT:1.00±0.06, CCM3^+/-:2.12±0.18), the difference was statistically significant (F=288.29, P<0.001). The relative expression level of LRP-1 gene mRNA in brain of CCM3⁺/- mice exposed to lead was lower than that of WT mice ((0.06±0.01)vs(0.32±0.10), t=26.90, P<0.001). Conclusion The mice did not show significant AD-like lesions under low-does lead exposure, but resulted in early damage of brain blood-brain barrier and early changes of AD-like lesions in mice, with CCM3^+/- mice being sensitive to lead exposure stronger than that of WT mice, suggesting that deletion of CCM3 gene may be one of the potential risk factors for accelerating the development of AD in mice exposed to lead.

Objective Inducible isoform of NO synthase(iNOS),coded by NOS2,is one of the antioxidant enzymes. The aim of this study is to explore the association between NOS2 gene polymorphisms and susceptibility of anti-tuberculous drug induced liver injury(ATDILI).Methods Sixteen tagSNP of NOS2 gene were selected using systematic bioinformatic analysis(HWE-P> 0.001, MAF>0.1,r2>0.8).A population based case-control study was performed to genotype 16 tagSNP of NOS2 gene in 461 ATDILI patients and 466 non-ATDILI patients using SNPscanTMtechnology.The genotype and haplotype frequencies were compared between case and control groups.Three genetic models including dominant,recessive and additive models were used to analyze the association between all the selected SNP polymorphisms and susceptibility of ATDILI.Results All the alleles frequencies of these SNP were in Hardy-Weinberg equilibrium.NOS2 rs9906835 G/A genotype,rs944725 T/C genotype, rs3794763 G/A genotype,rs3794764 G/A and A/A genotype,rs6505469 T/A genotype were associated with increased risk for developing ATDILI(all P< 0.05).NOS2 rs9906835,rs944725,rs3794763, rs3794764 and rs6505469 were associated with susceptibility of ATDILI in dominant model(all P<0.05).NOS2 rs944725,rs3794763 and rs3794764 were associated with increased risk for developing ATDILI in recessive model(all P< 0.05).In addition,CGCATT,AC and AAA haplotypes of NOS2 gene were found to have association with susceptibility of ATDILI(all P<0.05).Conclusion Our study showed that NOS2 gene is a susceptible gene of ATDILI.

Objective To explore the incidence and risk factors of anti-tuberculosis (TB) drugs induced liver injury (ATDILI) and to discuss its impact on the treatment outcome of patients treated with first line anti-TB drugs.Methods Among the patients who received anti-TB treatment with directly-observed treatment strategy (DOTS),121 patients with ATDILI and 817 patients without ATDILI were included in this retrospective cohort study.Binary Logistic regression model was used to analyze the risk factors of ATDILI in univariate and multivariate analysis.The x2 test was used to compare the treatment success rates and drug resistant rates.Kaplan-Meier analysis and Log-rank test were used to compare the sputum smear/culture conversion rates and cavity closure rates.Results The incidence of ATDILI was 12.9％ (121/938) in this cohort.Multivariate Logistic regression showed that hepatitis B virus carrier with both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) positive (OR=4.29,95％CI:2.15-8.58,P＜0.01),complicated with systemic lupus erythematosus (OR=3.34,95％CI:1.46-7.63,P=0.004),serum albumin ≤25 g/L (OR=3.14,95％CI:1.50-6.58,P=0.002) and alcoholism (OR=1.79,95％CI:1.14-2.82,P=0.012) were independent risk factors of ATDILI.The treatment failure rate in patients with ATDILI was significantly higher than that in patients without ATDILI (19.1％[24/121] vs8.0％[65/817],OR=2.86,95％CI:1.71-4.78,P＜0.01).The drug resistant rates of two groups were not significant different (4.1％[5/121] vs 1.7％[14/817],P＞0.05).The sputum smear/culture conversion rate (85.4％[41/48] vs 94.0％ [298/317],x2 =38.912,P＜0.01) and cavity closure rate (84.6％[22/26] vs 93.0％[198/213],x2 =20.709,P＜0.01) in patients with ATDILI were both significantly lower than those in patients without ATDILI.Conclusions The incidence of ATDILI is relatively high in hospitalized patients treated with first line anti-TB drugs.ATDILI has negative effects on treatment outcome of TB patient.Hepatitis B carrier with positive HBsAg and HBeAg,systemic lupus erythematosus,albumin ≤25 g/L and alcoholism may increase the risk of developing ATDILI.