BACKGROUND: Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. METHODS: We generated an microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t -test were used to analyze the data. RESULTS: Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. CONCLUSIONS Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.
Animals ; MicroRNAs/metabolism* ; Angiotensin II/toxicity* ; Mice ; Renal Insufficiency, Chronic/chemically induced* ; Mice, Knockout ; Disease Models, Animal ; Male ; Signal Transduction/genetics* ; LIM Domain Proteins/genetics* ; Mice, Inbred C57BL ; Cell Line ; Humans

Proximity labeling catalyzed by promiscuous enzymes,such as APEX2,has emerged as a powerful approach to characterize multiprotein complexes and protein-protein interactions.How-ever,current methods depend on the expression of exogenous fusion proteins and cannot be applied to identify proteins surrounding post-translationally modified proteins.To address this limitation,we developed a new method to label proximal proteins of interest by antibody-mediated protein A-ascorbate peroxidase 2(pA-APEX2)labeling(AMAPEX).In this method,a modified protein is bound in situ by a specific antibody,which then tethers a pA-APEX2 fusion protein.Activation of APEX2 labels the nearby proteins with biotin;the biotinylated proteins are then purified using streptavidin beads and identified by mass spectrometry.We demonstrated the utility of this approach by profiling the proximal proteins of histone modifications including H3K27me3,H3K9me3,H3K4me3,H4K5ac,and H4K12ac,as well as verifying the co-localization of these iden-tified proteins with bait proteins by published ChIP-seq analysis and nucleosome immunoprecipi-tation.Overall,AMAPEX is an efficient method to identify proteins that are proximal to modified histones.

Objective To investigate the efficacy and safety of domestic bortezomibˉbased chemotherapy for patients with multiple myeloma (MM). Methods The clinical data of 60 MM patients treated with domestic bortezomibˉbased chemotherapy regimen (the observation group) in the First Affiliated Hospital of Zhengzhou University from April 2018 to October 2018 were retrospectively analyzed, which were compared with 112 MM patients treated with original treatment regimen (the control group) at the same hospital from November 2010 to November 2014. According to the disease stage, the patients were divided into newly diagnosed MM (NDMM) group and relapsed refractory MM (RRMM) group, and efficacy and adverse reactions of domestic bortezomib were evaluated. Results The total response rate (ORR) of the observation group was 71.7% (43/60), severe complete response (sCR) + complete response (CR) rate was 16.7% (10/60), very good partial response (VGPR) rate was 18.3% (11/60), and partial response (PR) rate was 36.7% (22/60). The ORR of NDMM group (45 cases) and RRMM group (15 cases) was 82.2% (37/45) and 40.0% (6/15), respectively, and the difference was statistically significant (χ2＝ 9.877, P < 0.05). There was no significant difference between ISS stage Ⅰ+Ⅱ and stage Ⅲ [ORR: 75.7% (28/37) vs. 65.2% (15/23), respectively; χ2＝0.764, P >0.05]. ORR and CR rates in the NDMM group and RRMM group of the observation group and the control group were not statistically different (all P>0.05). In the treatment of bortezomibˉbased chemotherapy, the common adverse reaction was peripheral neuropathy, mostly belonging to grade 1-2. Other side effects included hematocytopenia, gastrointestinal events and herpes zoster, which could be alleviated or restored to normality after supportive treatments. One patient died of pulmonary infection, respiratory failure and septic shock during the intermittent period of chemotherapy. Conclusion ORR of domestic bortezomibˉbased chemotherapy in treatment of the patients with MM is high, and the incidence of adverse reactions shows no significant increase compared with original drugs.

OBJECTIVETo compare the clinical efficacy of treating different diseases with the same acupuncture comprehensive therapy and intramuscular injection of ranibizumab in the treatment of macular edema, and to explore an effective treatment.

METHODSA retrospective study was conducted, ①Acupuncture combined with EA at Xinming one (Extra), Sizhukong (TE 23), Tongziliao (GB 1), once every other day; ②acupoint injection, alternation with compound anisodine and mecobalamine injection at Qiuhou (EX-HN 7), Taiyang (EX-HN 5), once every other day; ③auricular acupressure at yan (LO), gan (CO), shen (CO) and other points; ④plum-blossom needle at Zhengguang 1 (Extra), Zhengguang 2 (Extra), once every other day were given in the acupuncture group (20 cases, 24 affected eyes). Intramuscular injection of 0.5 mg ranibizumab was given in the ranibizumab group (22 cases, 23 affected eyes). The macular foveal thickness, early treatment diabetic retinopathy study of (ETDRS) visual acuity chart, self-evaluation scores of visual function impairment ophthalmopathy patient's quality of life scale were observed before treatment, after 3, 6, 9 and 12 months of treatment, and the clinical efficacy was evaluated.

RESULTS①At all the observation time points of the treatment, the macular thickness was lower than that before treatment in the two groups (all <0.05), and there was no significant difference between the acupuncture group and the ranibizumab group (all >0.05). ②Visual acuity was higher than that before treatment at all the time points in the two groups (all <0.05). After 3-months treatment, there was no statistical significance between the two groups (>0.05). After 6, 9, and 12 months treatment, the visual acuity in the acupuncture group was better than that in the ranibizumab group (<0.05, <0.01). ③At all the time points, the quality of life scores were lower than those before treatment in the two groups (all <0.05). There was no statistical significance in the ranibizumab group compared with those before treatment (all >0.05). In 3, 6, 9 and 12 months of treatment, the quality of life scores in the acupuncture group was better than those in the ranibizumab group (<0.05, <0.01). ④The total effective rate of the acupuncture group was 79.2% (19/24), which was better than 30.4% (7/23) in the ranibizumab group (<0.05). ⑤The improvement of visual acuity before and after treatment was negatively correlated with the course of disease (<0.05), ie, the longer the disease course of the eyes, the worse the visual acuity and the worse the effect.

CONCLUSIONAcupuncture comprehensive treatment can effectively treat macular edema, significantly improve the patient's vision, improve the subjective experience and the quality of life, and the shorter the course of the disease the more significant effect. Acupuncture comprehensive treatment is better than intramuscular injection of ranibizumab.

Objective To observethe clinical efficacy of comprehensive acupuncture treatment in treating primary open-angle glaucoma, and to objectively evaluate the therapeutic efficacy.Method Twenty-eight patients (53 eyes) who received acupuncture treatment were recruited. By adopting a self-control design, the changes of intraocular tension, mean defect (MD) of vision field, mean sensitivity (MS), vision, and score of Quality of Life Scale for Patients with Visual Impairment (QLSPVI) were observed after 3-month acupuncture treatment.ResultThe intraocular tension of the 28 patients declined obviously after the treatment (P<0.01); MD, MS and vision didn't show significant improvements after the treatment (P>0.05); the QLSPVI score dropped significantly after the treatment (P<0.01);the total effective rate was 86.8%; the therapeutic efficacy wasn't correlated with age, disease duration, and treatment duration (P>0.05).Conclusion Acupuncture treatment can effectively reduce the intraocular tension, control the deterioration of MD and MS, maintain the level of vision, and enhance the quality of life of patients with primary open-angle glaucoma; with the same disease duration, the longer the treatment, the better the therapeutic efficacy.

Objective To investigate the survival of islet isograft in NOD mice treated with islet antigen-specific regulatory T cells.Methods GAD-65 antigen pulsed immature dendritic cells (imDC) were used to induce naive T cells into islet antigen-specific regulatory T cells.NOD mice which had progressed to type 1 diabetes (T1DM),as the recipients,received islet isografts (500 IEQ) under renal capsule from NOD mice without T1DM.In NOD mice in control group without transplantation,the changes in blood glucose (BG) were observed.NOD mice in simple islet transplantation group were given islet isograft without Treg infusion.In experiment group,NOD mice were infused with 1 × 106 islet antigen-specific regulatory T cells on the 1st day before transplantation,subsequently underwent islet isotransplantation.The survival of the islet isograft was evaluated by BG levels and the pathological changes were observed.Results BG levels were sustained above 11.1 mmol/L in control group.In simple islet transplantation group,BG level was decreased to the normal level in 1 ～2 days after transplantation,and began to rebound in 7～ 17 days posttransplantation and maintained at the preoperative level.The mean survival of the islet isograft in the NOD mice was (12.2 ± 2.6) day;In experiment group,BG level was decreased to the normal level in 1 ～2 days after transplantation,rebounded above 11.1 mmol/L in some mice on the 27th day after transplantation,and rebounded above 11.1 rnmol/L on the 43th day in all mice.The mean survival of the islet isograft in the NOD mice was (35.2 ± 4.3) days,which was significantly prolonged compared to simple islet transplantation group (P＜ 0.01).In simple islet transplantation group,the islet isograft was infiltrated by many lymph cells and damaged severely,and only few residual islet cells secreted insulin without complete islet existing in insulin staining.The islet isograft in experiment group was intact on the 15th day,with little lymph cell infiltration and a great number of islets secreting insulin.Conclusion Infusion of islet antigen-specific regulatory T cells induced by imDC and islet antigen GAD-65 in vitro could delay the destruction of autoimmune system and prolong the islet isograft survival in NOD mice.

There are increasing experimental evidences and clinical data showing that inflammatory reaction plays an important role in the production and development of atherosclerosis. Inflammatory process promotes the production and release of inflammatory factors by activation of monocytes and stimulation of endothelial cells, which stimulate the migration and proliferation of vascular smooth muscle cells. Hydrolases and cytokines are released from the activated and stimulated cells to increase local lesion and form atherosclerotic plaque with the development of inflammation. So, on the basis of the new pathogenesis of atherosclerosis,scientists try to interfere with atherosclerosis by anti-inflammatory pathway. This paper reviews the progress of drugs against atherosclerosis by the modulation of C reaction protein ,CD40-CD40L,infection and NF-?B.

AIM To observe the protective effect of quercetin on vascular endothelial cells injured by homocysteine in rabbits. METHODS The model of the vascular endothelial cells of rabbits injured by homocysteine was established; 50 mg?kg -1, 100 mg?kg -1 and 200 mg?kg -1 of quercetin were orally adminstered. After 30 days, the number of CEC, levels of MDA and NO,SOD activity in the serum were determined; ET concentration in the plasma was detected. The thoracic aorta was isolated to observe the vascular reactivity to nitroglycerin and ACh and tissue change. RESULTS The number of CEC, levels of MDA and ET were decreased and levels of SOD and NO were significantly increased in the quercetin-administered group compared with the injured group.Non-endothelium dependent relaxation of vessel caused by nitroglycerin was similar in all groups. Endothelium dependent relaxation caused by ACh was reduced in the injured group,whileas the relaxation trended to the normal degree in the quercetin-administered group. Pathological examination showed that quercetin was effective on the injured endothelial cells. CONCLUSION Quercetin produces protective effect on the injured vascular endothelial cells by homocysteine in rabbits.