Amelioration of Lupus Nephritis by Serum Amyloid P Component Gene Therapy with Distinct Mechanisms Varied from Different Stage of the Disease

BACKGROUND: Our previous study revealed that administration of syngeneic female BALB/c mice with excessive self activated lymphocyte-derived DNA (ALD-DNA) could induce systemic lupus erythematosus (SLE) disease, indicating that overload of self-DNA might exceed normal clearance ability and comprise the major source of autoantigens in lupus mice. Serum amyloid P component (SAP), an acute-phase serum protein with binding reactivity to DNA in mice, was proved to promote the clearance of free DNA and prevent mice against self-antigen induced autoimmune response. It is reasonable to hypothesize that SAP treatment might contribute to alleviation of SLE disease, whereas its role in ALD-DNA-induced lupus nephritis is not fully understood. METHODOLOGY/PRINCIPAL FINDINGS: The ratios of SAP to DNA significantly decreased and were negatively correlated with the titers of anti-dsDNA antibodies in ALD-DNA-induced lupus mice, indicating SAP was relatively insufficient in lupus mice. Herein a pcDNA3-SAP plasmid (pSAP) was genetically constructed and intramuscularly injected into BALB/c mice. It was found that SAP protein purified from the serum of pSAP-treated mice bound efficiently to ALD-DNA and inhibited ALD-DNA-mediated innate immune response in vitro. Treatment of ALD-DNA-induced lupus mice with pSAP in the early stage of SLE disease with the onset of proteinuria reversed lupus nephritis via decreasing anti-dsDNA autoantibody production and immune complex (IC) deposition. Further administration of pSAP in the late stage of SLE disease that had established lupus nephritis alleviated proteinuria and ameliorated lupus nephritis. This therapeutic effect of SAP was not only attributable to the decreased levels of anti-dsDNA autoantibodies, but also associated with the decreased infiltration of lymphocytes and the reduced production of inflammatory markers. CONCLUSION/SIGNIFICANCE: These results suggest that SAP administration could effectively alleviated lupus nephritis via modulating anti-dsDNA antibody production and the inflammation followed IC deposition, and SAP-based intervening strategy may provide new approaches for treating SLE disease

Effect and safety of combined Gegen Qinlian decoction/metformin in the treatment of diabetes mellitus in patients, and its influence on serum C peptide and glycosylated hemoglobin

Purpose: To investigate the clinical efficacy and safety of combined Gegen Qinlian decoction /metformin in the treatment of diabetes mellitus (DM), and its influence on serum C peptide and glycosylated hemoglobin (HbAlc).Methods: One hundred and eighty-six DM patients who received treatment in Tangshan Gongren Hospital, Tangshan City, China from July 2018 to November 2019 were randomly assigned to group X (n = 93) and group Y (n = 93). Group Y was given metformin, while X received a combination of Gegen Qinlian decoction and metformin. Total effectiveness, incidence of adverse reactions, blood glucose, TCM syndrome scores, as well as serum C peptide and HbAlc were determined and compared between the two groups.Results: Compared with group Y, group X had significantly higher treatment effectiveness (p < 0.05), lower incidence of adverse reactions (p < 0.05), significantly lower levels of blood glucose and TCM syndrome score after treatment (p < 0.001), but significantly higher serum C-peptide levels (p < 0.001) and lower levels of HbAlc.Conclusion: the combination of Gegen Qinlian decoction and metformin produces a good anti-diabetic efficacy, with a lower incidence of adverse reactions in patients. Therefore, the combined therapy has potentials for application in clinical practice, but further clinical trials are required

Membrane Vesicles Are the Dominant Structural Components of Ceftazidime-Induced Biofilm Formation in an Oxacillin-Sensitive MRSA

Methicillin-resistant Staphylococcus aureus (MRSA) has received increasing attention in recent years. However, the characteristics and relevant mechanisms of biofilm formation in oxacillin-sensitive MRSA (OS-MRSA) are poorly understood. This study was designed to characterize biofilm formation in OS-MRSA BWSA15 in response to ceftazidime (TZ) by comparing the methicillin-sensitive S. aureus (MSSA) strain BWSA23 and the oxacillin-resistant MRSA (OR-MRSA) strain BWSA11. The biofilms and biofilm-forming cells were observed by electron microscopy. Biofilms grown on microtiter plates were chemically decomposed and analyzed by Fourier transform infrared spectroscopy. The transcriptional regulation of genes associated with methicillin resistance, surface adhesion, fatty acid biosynthesis, and global regulation (sigma B) was investigated. A significant increase in biofilm formation ability (10.21-fold) and aggregation ability (2.56-fold) was observed in BWSA15 upon the treatment with TZ (16 μg/ml). The TZ-induced biofilm formation in BWSA15 was characterized by a disappearance of polysaccharide-like extracellular substances and an appearance of a large number of intercellular MVs from extracellular matrix. Few MVs were identified in the biofilms formed by BWSA11 and BWSA23. There was a significant upregulation of mecA, sigB, and fatty acid biosynthesis-associated genes and downregulation of icaA, icaD, clfA, clfB, and fnaA in BWSA15 upon the treatment with TZ. The formation of intracellular junctions of MVs in the biofilms of BWSA15 was mediated by a significant increase in the proportion of proteins as well as by an increase in the proportion of non-ionized carboxyl groups in fatty acids. This study demonstrated that beta-lactam antibiotics can induce biofilm formation in OS-MRSA, and the biofilm induction in OS-MRSA can mainly be attributed to exposed MVs with increased hydrophobicity rather than polysaccharide intercellular adhesins, cell wall-anchored surface proteins, and extracellular DNA

Curcumin Prevents High Fat Diet Induced Insulin Resistance and Obesity via Attenuating Lipogenesis in Liver and Inflammatory Pathway in Adipocytes

Background: Mechanisms underlying the attenuation of body weight gain and insulin resistance in response to high fat diet (HFD) by the curry compound curcumin need to be further explored. Although the attenuation of the inflammatory pathway is an accepted mechanism, a recent study suggested that curcumin stimulates Wnt signaling pathway and hence suppresses adipogenic differentiation. This is in contrast with the known repressive effect of curcumin on Wnt signaling in other cell lineages. Methodology and Principal Findings: We conducted the examination on low fat diet, or HFD fed C57BL/6J mice with or without curcumin intervention for 28 weeks. Curcumin significantly attenuated the effect of HFD on glucose disposal, body weight/fat gain, as well as the development of insulin resistance. No stimulatory effect on Wnt activation was observed in the mature fat tissue. In addition, curcumin did not stimulate Wnt signaling in vitro in primary rat adipocytes. Furthermore, curcumin inhibited lipogenic gene expression in the liver and blocked the effects of HFD on macrophage infiltration and the inflammatory pathway in the adipose tissue. Conclusions and Significance: We conclude that the beneficial effect of curcumin during HFD consumption is mediated by attenuating lipogenic gene expression in the liver and the inflammatory response in the adipose tissue, in the absence o

Effects of configuration parameters on lateral dynamics of tractor–two trailer combinations

The optimum configuration parameters of tractor–trailer combinations for lateral stability performance are proposed by adjusting the length of dolly and the second trailer’s center of gravity. A linear yaw plane model of vehicle combinations is adopted for dynamic analysis, and the model is calibrated by TruckSim. According to the yaw rate rearward amplification ratio of lateral response index, and combining the simulation results of MATLAB/Simulink, dolly and the second trailer are the dominate factors for lateral stability of vehicle combinations. Simulation results show that the distance between articulation joints of dolly is 1.6 m; simultaneously, the rate of distance between front hitch and center of gravity of the second trailer to its front and rear wheelbase is 0.41 and may gain the best lateral performance. Compared with configuration parameters of the original vehicle combinations, the results also illustrate that the one derived from adjustment approach reduces high-speed rearward amplification ratio by 11.4%. The proposed approach might be used for identifying desired design variables of the tractor–two trailer combinations and provided theoretical basis for stability tests