Objective To investigate the effect and underlying mechanism of miR-137 on athero-sclerosis(AS)plaques in apolipoprotein E(ApoE)gene knockout(ApoE)mice.Methods Sixty ApoE-/-mice were fed with high-fat diet for 12 weeks to establish an AS model.Then they were assigned into AS group,negative control group,miR-137 group,Ad negative control group,and combination group,with 12 mice in each group;Another 12 wild-type C57BL/6 mice fed with chow diet were subjected as the Control group.Fully automated biochemical analyzer was applied to detect serum lipid levels,including total cholesterol(TC),triglycerides(TG),low-density lipo-protein cholesterol(LDL-C),and high-density lipoprotein cholesterol(HDL-C).ELISA was con-ducted to detect the levels of serum inflammatory factors,including TNF-α,IL-4,IL-6,and IL-10.HE staining was used to observe the morphological changes of mouse aortic tissue.Oil red O stai-ning was employed to observe the overall formation of aortic plaques.Immunofluorescence stai-ning was utilized to detect the expression of inducible nitric oxide synthase(iNOS)and arginase-1(Arg-1)in the aortic tissue.Real-time qPCR was applied to detect the mRNA expression of miR-137 and sex determining region Y box protein 4(SOX4)in the aorta.Results The miR-137 group has significantly lower serum levels of TG,TC,LDL-C,TNF-α and IL-6,and higher levels of HDL-C,IL-10 and IL-4 when compared with the AS group and negative control group(P＜0.05).The combination treatment resulted in increased serum levels of TG,TC,LDL-C,TNF-αand IL-6,while decreased levels of HDL-C,IL-10 and IL-4 in comparison with the Ad negative control group(P＜0.05).Larger aortic plaque area,more severe overall aortic plaque injury and stronger iNOS fluorescence intensity were observed in the AS group than the control group(P＜0.05).Treatment of miR-137 reversed above histological changes,resulting in smaller aortic plaque area,attenuated overall aortic plaque injury,decreased iNOS fluorescence intensity,and elevated Arg-1 fluorescence intensity when compared with the AS group and negative control group(P＜0.05).Compared with the Ad negative control group,the aortic plaque area,overall aortic plaque injury and iNOS fluorescence intensity were increased,while the Arg-1 fluorescence intensity was significantly decreased in the combined group(P＜0.05).Double luciferase assay showed that the luciferase activity of SOX4-containing wild-type cells was significantly decreased after transfection of miR-137 mimics when compared with transfection of mimics negative control(0.37±0.05 vs 1.00±0.08,P＜0.05).Conclusion Overexpression of miR-137 inhibits the activa-tion of rat sarcoma/mitogen-activated protein kinase pathway probably by down-regulating SOX4 expression,and then suppress M1 macrophage polarization and promote M2 macrophage polariza-tion,reduces inflammatory response and the formation of AS plaques.

Gliomas are the most common primary neuroepithelial tumors of the central nervous system in adults, of which glioblastoma is the deadliest subtype. Apart from the intrinsically indestructible characteristics of glioma (stem) cells, accumulating evidence suggests that the tumor microenvironment also plays a vital role in the refractoriness of glioblastoma. The primary functions of platelets are to stop bleeding and regulate thrombosis under physiological conditions. Furthermore, platelets are also active elements that participate in a variety of processes of tumor development, including tumor growth, invasion, and chemoresistance. Glioma cells recruit and activate resting platelets to become tumor-educated platelets (TEPs), which in turn can promote the proliferation, invasion, stemness, and chemoresistance of glioma cells. TEPs can be used to obtain genetic information about gliomas, which is helpful for early diagnosis and monitoring of therapeutic effects. Platelet membranes are intriguing biomimetic materials for developing efficacious drug carriers to enhance antiglioma activity. Herein, we review the recent research referring to the contribution of platelets to the malignant characteristics of gliomas and focusing on the molecular mechanisms mediating the interaction between TEPs and glioma (stem) cells, as well as present the challenges and opportunities in targeting platelets for glioma therapy.
Humans ; Glioma/metabolism* ; Blood Platelets/physiology* ; Brain Neoplasms/pathology* ; Tumor Microenvironment

Objective To investigate the effect and underlying mechanism of miR-137 on athero-sclerosis(AS)plaques in apolipoprotein E(ApoE)gene knockout(ApoE)mice.Methods Sixty ApoE-/-mice were fed with high-fat diet for 12 weeks to establish an AS model.Then they were assigned into AS group,negative control group,miR-137 group,Ad negative control group,and combination group,with 12 mice in each group;Another 12 wild-type C57BL/6 mice fed with chow diet were subjected as the Control group.Fully automated biochemical analyzer was applied to detect serum lipid levels,including total cholesterol(TC),triglycerides(TG),low-density lipo-protein cholesterol(LDL-C),and high-density lipoprotein cholesterol(HDL-C).ELISA was con-ducted to detect the levels of serum inflammatory factors,including TNF-α,IL-4,IL-6,and IL-10.HE staining was used to observe the morphological changes of mouse aortic tissue.Oil red O stai-ning was employed to observe the overall formation of aortic plaques.Immunofluorescence stai-ning was utilized to detect the expression of inducible nitric oxide synthase(iNOS)and arginase-1(Arg-1)in the aortic tissue.Real-time qPCR was applied to detect the mRNA expression of miR-137 and sex determining region Y box protein 4(SOX4)in the aorta.Results The miR-137 group has significantly lower serum levels of TG,TC,LDL-C,TNF-α and IL-6,and higher levels of HDL-C,IL-10 and IL-4 when compared with the AS group and negative control group(P＜0.05).The combination treatment resulted in increased serum levels of TG,TC,LDL-C,TNF-αand IL-6,while decreased levels of HDL-C,IL-10 and IL-4 in comparison with the Ad negative control group(P＜0.05).Larger aortic plaque area,more severe overall aortic plaque injury and stronger iNOS fluorescence intensity were observed in the AS group than the control group(P＜0.05).Treatment of miR-137 reversed above histological changes,resulting in smaller aortic plaque area,attenuated overall aortic plaque injury,decreased iNOS fluorescence intensity,and elevated Arg-1 fluorescence intensity when compared with the AS group and negative control group(P＜0.05).Compared with the Ad negative control group,the aortic plaque area,overall aortic plaque injury and iNOS fluorescence intensity were increased,while the Arg-1 fluorescence intensity was significantly decreased in the combined group(P＜0.05).Double luciferase assay showed that the luciferase activity of SOX4-containing wild-type cells was significantly decreased after transfection of miR-137 mimics when compared with transfection of mimics negative control(0.37±0.05 vs 1.00±0.08,P＜0.05).Conclusion Overexpression of miR-137 inhibits the activa-tion of rat sarcoma/mitogen-activated protein kinase pathway probably by down-regulating SOX4 expression,and then suppress M1 macrophage polarization and promote M2 macrophage polariza-tion,reduces inflammatory response and the formation of AS plaques.

Objective In this study,Knoevenagel derivatives of curcumin were synthesized,and their oil-water partition coefficient were determined.Our aim is to provide an experimental basis for further development of curcumin derivatives.Methods Two Knoevenagel derivatives of curcumin,including 4-(thiophen-2-ylidene)curcumin(3a)and 4-(pyridine-4-ylidene)curcumin(3b),were obtained by using the methylene group of curcumin as the modification site and purified by column chromatography.The structures of these derivatives were confirmed by nuclear magnetic resonance spectroscopy(NMR),infrared(IR)and high-resolution liquid mass spectrometry(HRLC-MS).The oil-water partition coefficient of the derivatives in n-octanol aqueous solution was determined by quantitative analysis using HPLC.Results Knoevenagel derivatives of curcumin were successfully synthesis.The oil-water partition coefficients(lgPap)of curcumin derivatives 3a and 3b are 0.96 and 0.82,respectively.Compared with the oil-water partition coefficient of curcumin(lgPap=3.85),it suggested that curcumin derivatives showed better water solubility than curcumin.Conclusion Compared to the curcumin prototype,Knoevenagel derivatives of curcumin increased water solubility and improved bioavailability.Thus,it may provide experimental basis for introducing heteroarylene moiety of the methylene position of curcumin to enhance pharmacological activity.

Hepatic stellate cells (HSCs) represent a significant component of hepatocellular carcinoma (HCC) microenvironments which play a critical role in tumor progression and drug resistance. Tumor-on-a-chip technology has provided a powerful in vitro platform to investigate the crosstalk between activated HSCs and HCC cells by mimicking physiological architecture with precise spatiotemporal control. Here we developed a tri-cell culture microfluidic chip to evaluate the impact of HSCs on HCC progression. On-chip analysis revealed activated HSCs contributed to endothelial invasion, HCC drug resistance and natural killer (NK) cell exhaustion. Cytokine array and RNA sequencing analysis were combined to indicate the iron-binding protein LIPOCALIN-2 (LCN-2) as a key factor in remodeling tumor microenvironments in the HCC-on-a-chip. LCN-2 targeted therapy demonstrated robust anti-tumor effects both in vitro 3D biomimetic chip and in vivo mouse model, including angiogenesis inhibition, sorafenib sensitivity promotion and NK-cell cytotoxicity enhancement. Taken together, the microfluidic platform exhibited obvious advantages in mimicking functional characteristics of tumor microenvironments and developing targeted therapies.

Objective To evaluate the differences in efficacy,safety and economics of vancomycin hydrochloride for injection between two manufacturers based on real-world data.Methods A total of 6 757 cases of intravenous use of vancomycin hydrochloride for injection from different manufacturers between January 1,2013 and December 31,2019 in the Affiliated Drum Tower Hospital of Nanjing University Medical School were retrospectively analyzed,and 5308 cases were matched by 1∶1 propensity score method,including 2 654 cases in the group A(domestic drug group)and 2 654 cases in group B(the innovator drug group).The differences in efficacy and safety between the two groups were compared.Cost-effectiveness analysis was used to compare the drug economics of the two groups.Results There were no significant differences in clinical cure rate,bacterial clearance rate,and incidence of adverse events between the two groups(P>0.05).In terms of economics,the average cost of vancomycin per capita,average daily cost of vancomycin and average cost of antibiotics per capita were significantly different between the two groups(P<0.05),and the cost of group B was higher than that of group A.Conclusion The efficacy and safety of vancomycin hydrochloride for injection were consistent between the two manufacturers.

Background::Concerns exist regarding the risk of infections in patients with spondyloarthritis (SpA) treated with biologics. We assessed the risk of infections of biological and targeted drugs in patients with SpA by performing a meta-analysis based on randomized controlled trials (RCTs).Methods::A systematic literature search was conducted in PubMed, Embase, Web of Science, the Cochrane Library, and China Biology Medicine Disc for RCTs evaluating the risk of infections of biological therapy in patients with SpA from inception through August 9, 2021. We calculated a pooled Peto odds ratio (OR) for infections in biologics-treated patients vs. placebo patients. The risk of bias on the included RCTs was assessed by using the Cochrane Risk of Bias Tool. Results::In total, 62 studies were included in this meta-analysis. Overall, the risk of infection (Peto OR: 1.16, 95% confidence interval [CI]: 1.07-1.26, P < 0.001), serious infection (Peto OR: 1.65, 95% CI: 1.26-2.17, P < 0.001), upper respiratory tract infection (URTI) (Peto OR: 1.17, 95% CI: 1.04-1.32, P = 0.008), nasopharyngitis (Peto OR: 1.25, 95% CI: 1.10-1.42, P < 0.001), and Candida infection (Peto OR: 2.64, 95% CI: 1.48-4.71, P = 0.001) were increased in SpA patients treated with biologics compared with placebo. Sensitivity analysis based on biologics classes was conducted, and results demonstrated that compared with placebo, there was a higher risk of infection for tumor necrosis factor (TNF)-α inhibitors (Peto OR: 1.38, 95% CI: 1.13-1.68, P = 0.001) and interleukin (IL)-17 inhibitors (Peto OR: 1.55, 95% CI: 1.08-2.22, P = 0.018) in axial SpA, and for Janus kinase inhibitors in peripheral SpA (Peto OR: 1.39, 95% CI: 1.14-1.69, P = 0.001); higher risk of serious infection for IL-17 inhibitors in peripheral SpA (Peto OR: 3.46, 95% CI: 1.26-9.55, P = 0.016) and axial SpA (Peto OR: 2.01, 95% CI: 1.38-2.91, P < 0.001); higher risk of URTI for TNF-α inhibitors in axial SpA (Peto OR: 1.37, 95% CI: 1.05-1.78, P= 0.019), and for apremilast in peripheral SpA (Peto OR: 1.60, 95% CI: 1.08-2.36, P = 0.018); higher risk of nasopharyngitis for TNF-α inhibitors in axial SpA (Peto OR: 1.41, 95% CI: 1.05-1.90, P = 0.022) and peripheral SpA (Peto OR: 1.49, 95% CI: 1.09-2.05, P = 0.013), and for IL-17 inhibitors in axial SpA (Peto OR: 1.35, 95% CI: 1.01-1.82, P = 0.044); higher risk of herpes zoster for Janus kinase inhibitors in peripheral SpA (Peto OR: 2.18, 95% CI: 1.03-4.62, P = 0.043); higher risk of Candida infection for IL-17 inhibitors in peripheral SpA (Peto OR: 2.52, 95% CI: 1.31-4.84, P= 0.006). Conclusions::This meta-analysis shows that biological therapy in patients with SpA may increase the risk of infections, including serious infections, URTI, nasopharyngitis, and Candida infection, which should be paid attention to in our clinical practice.

Objective:To explore the value of contrast-enhanced ultrasound (CEUS) combined with Ovarian-Adnexal Reporting and Data System (O-RADS US) risk stratification and management system in differential diagnosis of ovarian-adnexal mass.Methods:Fifty-six patients with ovarian-adnexal mass who received transabdominal transvaginal ultrasound and CEUS in the Third People′s Hospital of Longgang District from September 2018 to January 2021 were enrolled. The images were classified by O-RADS US and diagnosed by CEUS by experienced and senior radiologist. On the basis of O-RADS US classification, the enhancement time, enhancement level and enhancement mode of CEUS were combined to upgrade or degrade the classification results of O-RADS US. The diagnostic accuracy was assessed using ROC curve analysis, the area under the ROC curve (AUC) was calculated. The reproducibility of O-RADS US was assessed by another senior radiologist.Results:The AUC of O-RADS US for diagnosing benign and malignant ovarian-adnexal masses was 0.844(0.722, 0.927), the AUC of CEUS was 0.833(0.710, 0.920), the AUC of O-RADS US combined with CEUS was 0.940(0.842, 0.986) (compared with O-RADS US, P=0.020; compared with CEUS, P=0.031). The intra-class correlation coefficient (ICC) was 0.897(0.824, 0.940) for O-RADS US. Conclusions:CEUS combined with O-RADS US classification can effectively improve the diagnostic efficiency for benign and malignant ovarian-adnexal masses.

BACKGROUND: Concerns exist regarding the potential development of tuberculosis in patients with rheumatoid arthritis (RA) treated with biological and targeted drugs. We assessed systematically whether biological therapy increased the risk of tuberculosis in patients with RA by meta-analysis of randomized controlled trials (RCTs). METHODS: A systematic literature search was conducted in PubMed, Embase, the Cochrane Library, and China Biology Medicine disc for RCTs evaluating biological therapy in patients with RA from inception through August 2021. Traditional meta-analysis and network meta-analysis were performed to compare the risk of tuberculosis for each biologics class in patients with RA. Peto odds ratio (Peto OR) and its 95% confidence interval (CI) were calculated as the primary effect measure. RESULTS: In total, 39 studies with 20,354 patients were included in this meta-analysis, and 82 patients developed tuberculosis. The risk of tuberculosis was increased in patients treated with biologics compared with non-biologics (Peto OR: 3.86, 95% CI: 2.36-6.32, P < 0.001). Also, tumor necrosis factor-α (TNF-α) inhibitors had a higher probability of developing tuberculosis than placebo (Peto OR: 3.98, 95% CI: 2.30-6.88, P < 0.001). However, network meta-analysis demonstrated that there was no significant difference in the risk of tuberculosis for each biologics class in patients with RA. Noticeably, tuberculosis was significantly more common in patients treated with a high dose compared with patients receiving a low dose of tofacitinib (Peto OR: 7.39, 95% CI: 2.00-27.31, P = 0.003). CONCLUSION This meta-analysis demonstrates the evidence of an elevated risk of tuberculosis in patients with RA treated with TNF-α inhibitors, and a dose-dependent elevated risk of tuberculosis in patients treated with tofacitinib.
Antirheumatic Agents/adverse effects* ; Arthritis, Rheumatoid/drug therapy* ; Humans ; Network Meta-Analysis ; Pharmaceutical Preparations ; Randomized Controlled Trials as Topic ; Tuberculosis/drug therapy*

Currently, biomanufacturing technology and industry are receiving worldwide attention. However, there are still great challenges on bioprocess optimization and scale-up, including: lacing the process detection methods, which makes it difficult to meet the requirement of monitoring of key indicators and parameters; poor understanding of cell metabolism, which arouses problems to rationally achieve process optimization and regulation; the reactor environment is very different across the scales, resulting in low efficiency of stepwise scale-up. Considering the above key issues that need to be resolved, here we summarize the key technological innovations of the whole chain of fermentation process, i.e., real-time detection-dynamic regulation-rational scale-up, through case analysis. In the future, bioprocess design will be guided by a full lifecycle in-silico model integrating cellular physiology (spatiotemporal multiscale metabolic models) and fluid dynamics (CFD models). This will promote computer-aided design and development, accelerate the realization of large-scale intelligent production and serve to open a new era of green biomanufacturing.
Bioreactors ; Computer Simulation ; Fermentation ; Hydrodynamics