[Mechanism of Fushen Granules treat peritoneal dialysis-related peritonitis by regulating TLR4/NF-κB pathway:based on network pharmacology and animal experiments].

Network pharmacology was employed to probe into the mechanism of Fushen Granules in treating peritoneal dialysis-rela-ted peritonitis(PDRP) in rats. The main active components of Fushen Granules were searched against the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and their targets were predicted. PDRP-related targets were retrieved from DisGeNET and other databases. The common targets shared by the drug and the disease were identified by the online tool, and protein-protein interaction(PPI) network of the common targets. The obtained 276 common targets were imported into DAVID for GO function enrichment and KEGG pathway enrichment. The main signaling pathway of Fushen Granules in the treatment of PDRP was predicted as Toll-like receptor 4(TLR4)/nuclear factor(NF)-κB. The rat model of uremia was induced by 5/6 nephrectomy. From two weeks after operation, the rat model of peritoneal dialysis(PD) was established by intraperitoneal injection of 20 mL dialysate with 1.25% glucose every day. The sham operation group and model group received 2 mL normal saline by gavage every day. The rats in Fushen Gra-nules groups were administrated with 2 mL solutions of low-(0.54 g·kg~(-1)), medium-(1.08 g·kg~(-1)) and high-dose(2.16 g·kg~(-1)) Fushen Granules every day. The bifico group received 2 mL(113.4 mg·kg~(-1)) of bifico solution every day. At the end of the 8th week, the levels of serum creatinine(Scr) and blood urea nitrogen(BUN) in each group were measured. The serum levels of hypersensitive C reactive protein(hs-CRP), tumor necrosis factor(TNF)-α, and interleukin(IL)-6 were measured, and the pathological changes in the colon tissue were observed by hematoxylin-eosin(HE) staining. The serum levels of lipopolysaccharide(LPS) and lipopolysaccharide-binding protein(LBP) of rats were measured, and the expression levels of LBP, TLR4, NF-κB p65, inhibitor of κB kinase α(IκBα), TNF-α, and IL-1ß in the colon tissue were determined. Compared with sham operation group, the model group had abnormal structure of all layers of colon tissue, sparse and shorter intestinal villi, visible edema in mucosal layer, wider gap, obvious local inflammatory cell infiltration, significantly decreased body weight(P<0.01), and significantly increased kidney function index(Scr, BUN) content(P<0.01). Serum levels of inflammatory cytokines(hs-CRP, TNF-α, IL-6), LPS and LBP were significantly increased(P<0.01), protein expressions of LBP, TLR4, NF-κB p65, TNF-α and IL-1ß were significantly increased(P<0.01), and protein expressions of IκBα were significantly decreased(P<0.01). Compared with model group, intestinal villi damage in colonic tissue of rats in low-, medium-and high-dose Fushen Granules groups and bifico group were alleviated to different degrees, edema in submucosa was alleviated, space was narrowed, and inflammatory cell infiltration in lamina propria was reduced. The contents of renal function index(Scr, BUN) and serum inflammatory factors(hs-CRP, TNF-α, IL-6) were significantly decreased(P<0.05 or P<0.01) in medium-and high-dose Fushen Granules groups and bifico group(P<0.05 or P<0.01). Serum LPS and LBP contents in Fushen Granules group and bifico group were significantly decreased(P<0.01), protein expressions of LBP, TLR4, NF-κB p65, TNF-α and IL-1ß in Fushen Granules group were significantly decreased(P<0.05 or P<0.01), and protein expressions of IκBα were significantly increased(P<0.01). The expression of LBP protein in bifico group was significantly decreased(P<0.01). The results suggest that Fushen Granules can protect the residual renal function of PD rats, reduce the inflammatory response, and protect the colon tissue. Based on network pharmacology, TLR4/NF-κB pathway may be the main signaling pathway of Fushen granule in the treatment of PDRP. The results showed that Fushen Granules could improve intestinal inflammation and protect intestinal barrier to prevent PDRP by regulating the expression of key factors in TLR4/NF-κB pathway in colon of PD rats.

Involvement of CB2 signalling pathway in the development of osteoporosis by regulating the proliferation and differentiation of hBMSCs.

The aim of the present study was to explore the potential mechanism underlying the involvement of CB2 in osteoporosis. Micro-CT was utilized to examine femur bone architecture. Also, real-time PCR and Western blot analysis were utilized to detect the effect of 2-AG on the expression of CB2 and Notch, or the interaction between CB2 and Notch 2. 2-AG treatment up-regulated BMD, Tb.Sp and SMI in OVX mice, whereas proportion of bone volume in total volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N) and bone mineral density (BMD) were decreased in 2-AG-treated OVX mice. Accordingly, 2-AG administration up-regulated Notch 1 expression in OVX mice but had no effect on CB2 and Notch 2 expression. Meanwhile, 2-AG administration promoted the differentiation of hBMSCs in OVX mice, while exhibiting no effect on the proliferation of hBMSCs. Furthermore, in the cellular models, 2-AG treatment also up-regulated Notch 1 expression but had no effect on CB2 and Notch 2 expression, while Notch 1 shRNA had no effect on CB2 and Notch 2 expression. 2-AG promoted cell proliferation and differentiation, which were inhibited by Notch 1 shRNA. NICD had no effect on CB2 level but increased Notch 1 expression, and CB2 shRNA decreased CB2 and Notch 1 expression. Finally, CB2 shRNA inhibited cell proliferation and differentiation, whereas NICD promoted proliferation and differentiation of hBMSCs. Our results provided further evidence for the association of CB2 gene with BMD and osteoporosis, and identified CB2 as a promising target for the treatment of osteoporosis.

Importance of non-medical reasons for dropout in patients on peritoneal dialysis.

BACKGROUND: To describe the associated factors for non-medical reasons for dropout in peritoneal dialysis (PD) patients. METHODS: A retrospective cohort study was performed using registry data of adult patients commencing PD as their initial renal replacement therapy in one hospital-facilitated PD center in Taiwan between 2014 and 2018. The collected data included socio-demographics and relevant medical and PD-related parameters. Kaplan-Meier analysis was used to determine the impact of non-medical reasons and medical reasons on PD dropout. RESULTS: The analysis included 224 PD patients, of whom 37 dropped out for non-medical reasons and 187 for medical reasons during the study period. There was significant difference between the two cohorts in age (62.3 years vs. 56.1 years, P = 0.010) and PD vintage (median 3.4 years vs. 4.8 years, P = 0.001). Diabetes was more predominant in the cohort for non-medical reasons than in the one for medical reasons (54.1% vs. 27.3% respectively, P = 0.001). In non-medical reason cohort, two leading reasons given for dropping out were lacking of caregivers (n = 12) and losing confidence (n = 10), whereas PD-related peritonitis (n = 101) was the main medical reason for PD dropout. Using Kaplan-Meier curve analysis, patients in the non-medical reason cohort demonstrated higher cumulative dropout rate compared to patients in the medical reason cohort during a 10-year period (P < 0.001). CONCLUSIONS: The main characteristics of PD dropout patients for non-medical reasons are age, diabetes, patients' perception and caregiver support.

Comparison of Solute Clearance, Hospitalization Rate, and Aortic Arch Calcification between Online Hemodiafiltration and High-Flux Hemodialysis: A 6-Year Observational Study.

BACKGROUND/AIMS: Studies on the long-term clinical benefits of hemodiafiltration (HDF) and high-flux hemodialysis (HFHD) are very limited. This study aimed to investigate the hospitalization rate and aortic arch calcification (AAC) of these two dialysis modalities over 6 years. METHODS: Participants who received regular HDF and HFHD in one hospital-facilitated hemodialysis center were prospectively enrolled after matching for age, sex, and diabetes between January 2009 and December 2014. Medical records were reviewed retrospectively on demographics, laboratory variables, calcified scores in aortic arch measured by chest radiography, and rates of hospital admission. Cox proportional hazard regression and linear regression were used to obtain the outcome results. RESULTS: The HDF and HFHD groups consisted of 108 and 102 participants, respectively. Levels of laboratory variables including small soluble solutes and Kt/V were not statistically different over the 6-year period between the HDF and HFHD groups. Calcified scores of the aortic arch increased over 6 years in both groups. The changes in the mean calcified scores were significant when compared between the two groups (0.44-1.82 in HFHD, 0.79-1.8 in HDF, respectively, p = 0.008). Hospitalization rates were 735 per 1,000 patients in the HDF group and 852 per 1,000 patients in the HFHD group, respectively. No significant difference was observed in frequency and days of hospitalization between HDF and HFHD. CONCLUSION: Hospitalization rates and AAC were observed to be equal for HDF and HFHD.

Time-varying serum albumin levels and all-cause mortality in prevalent peritoneal dialysis patients: a 5-year observational study.

BACKGROUND: In this study, we investigated the association of time-varying serum albumin levels with mortality over a 5-year period in one cohort of patients undergoing long-term peritoneal dialysis (PD) therapy. METHODS: The participants in this study enrolled 302 patients who underwent long-term PD at a single PD center in Taiwan. We reviewed medical records from 2011 to 2015 retrospectively. Time-averaged albumin level and serum albumin reach rate (defined as the percentage of serum albumin measurements that reached ≥3.5 g/dL) were applied as the predictor variables in the first 2 years (2011-2012). All-cause mortality was used as the outcome variable in the subsequent 3 years (2013-2015). Hazard function of all-cause mortality in the study participants was examined by using Cox proportional hazard regression models . RESULTS: Patients with different albumin reach rates (75-< 100%, 50-< 75%, 1-< 50%) did not exhibit a significantly increased risk for all-cause mortality. Patients with a 0% albumin reach rate exhibited a significantly increased risk for all-cause mortality (hazard ratio [HR] 7.59, 95% confidence interval [CI], 2.38-24.21) by fully adjusted analysis. Patients with time-averaged albumin levels of < 3.5 g/dL (HR 15.49, 95% CI 1.74-137.72) exhibited a higher risk for all-cause mortality than those with serum albumin levels ≥4.0 g/dL. CONCLUSIONS: This study demonstrated that higher serum albumin reach rates and higher time-averaged serum albumin levels are associated with a lower mortality rate over a 5-year period among patients undergoing long-term PD.

Long-term efficacy, safety and biocompatibility of a novel sirolimus eluting iron bioresorbable scaffold in a porcine model.

Iron is considered as an attractive alternative material for bioresorbable scaffolds (BRS). The sirolimus eluting iron bioresorbable scaffold (IBS), developed by Biotyx Medical (Shenzhen, China), is the only iron-based BRS with an ultrathin-wall design. The study aims to investigate the long-term efficacy, safety, biocompatibility, and lumen changes during the biodegradation process of the IBS in a porcine model. A total of 90 IBSs and 70 cobalt-chromium everolimus eluting stents (EES) were randomly implanted into nonatherosclerotic coronary artery of healthy mini swine. The multimodality assessments including coronary angiography, optical coherence tomography, micro-computed tomography, magnetic resonance imaging, real-time polymerase chain reaction (PCR), and histopathological evaluations, were performed at different time points. There was no statistical difference in area stenosis between IBS group and EES group at 6 months, 1year, 2 years and 5 years. Although the scaffolded vessels narrowed at 9 months, expansive remodeling with increased mean lumen area was found at 3 and 5 years. The IBS struts remained intact at 6 months, and the corrosion was detectable at 9 months. At 5 years, the iron struts were completely degraded and absorbed in situ, without in-scaffold restenosis or thrombosis, lumen collapse, aneurysm formation, and chronic inflammation. No local or systemic toxicity and abnormal histopathologic manifestation were found in all experiments. Results from real-time PCR indicated that no sign of iron overload was reported in scaffolded segments. Therefore, the IBS shows comparable efficacy, safety, and biocompatibility with EES, and late lumen enlargement is considered as a unique feature in the IBS-implanted vessels.

Solvent effect and hydrogen bond interaction on tautomerism, vibrational frequencies, and Raman spectra of guanine: a density functional theoretical study.

Stable structures and Raman spectra of guanine have been investigated by density functional theory (DFT). Focusing on solvent effect and hydrogen bonding interaction, we have calculated the two keto-amino tautomers G17K and G19K as well as their guanine-water complexes and tetramers. The results show G17K is more stable than G19K in the gas phase, whereas in polar solvents G19K dominates. The vibrational fundamentals of G17K have been reassigned based on normal-mode analysis, since the previous assignment was limited to the G19K only. In the Raman spectra, the modes of the ring breathing vibration and those in the fingerprint region (from 1000 to 1600 cm(-1)) affected by the solvent effect and the hydrogen bonding interaction dramatically. The band at 1163 cm(-1) of G17K in gas has a large blue shift when water molecule forms hydrogen bonds with N7-H16 and C6═O13 sites. The blue shift can be explained by the influence of hydrogen bonding interaction along with shortening the N1-C6 bond distance. In addition, the dominant existing tautomer in polycrystalline and powder guanine is proposed to be G17K, whose calculated vibrational frequencies agree with the experimental Raman spectra reported before.

[Effect of shenshuning recipe on the extracellular matrix accumulation of the peritoneal fibrosis rats].

OBJECTIVE: To observe the effect of Shenshuning Recipe (SR) on the peritoneal function, accumulation of extracellular matrix (ECM), and the expression of transforming growth factor-beta1 (TGF-beta1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in the peritoneal fibrosis rats. METHODS: The peritoneal fibrosis correlating peritoneal dialysis SD rat model was induced by injecting erythromycin and peritoneal dialysate. They were randomly divided into 4 groups according to body weight, i.e., the 1.50% peritoneal dialysate group (Group B), the 1.50% peritoneal dialysate + SR group (Group C), the 4.25% peritoneal dialysate group (Group D), and the 4.25% peritoneal dialysate +SR group (Group E), 15 in each group. Besides, another 15 rats was taken as the blank control group (n = 15, Group A). SR at the daily dose of 43.93 g/kg was given to rats in Group C and E by gastrogavage, while equal volume of normal saline was given to rats in other groups by gastrogavage. The changes of glucose in the peritoneal fluid were detected. The ultra filtration volume (UF)and mass transfer of glucose (MTG) were calculated. The pathomorphological changes of the peritoneum were observed. The distribution of collagen fiber, fibroblast count, collagen I (Col I), expressions of TIMP-1 and TGF-beta1 were determined. RESULTS: At the end of the 6th week, statistical difference was shown in UF [(-3.3 +/- 14.2) mL] and [(-2.0 +/- 10.7) mL], MTG [(18.1 +/- 0.8) mmol/kg] and [(16.1 +/- 1.2) mmol/kg], collagen fiber [(4 721.3 +/- 541.0)%] and [(6502.7 +/- 877.4)%], fibroblast [(0.087 +/- 0.010)/mm2] and [(0.131 +/- 0.042)/mm2], Col I [(187.5 +/- 36.9)%] and [(289.7 +/- 95.6)%], TIMP-1 [(2.57 +/- 0.94)%] and [(3.63 +/- 0.29)%], and TGF-beta1 [(104.0 +/- 20.7) ng/L] and [(108.2 +/- 17.5) ng/L] between Group C and Group E, when compared with the peritoneal dialysate group at the same concentration (P < 0.05, P < 0.01). CONCLUSION: SR could postpone the development of peritoneal fibrosis in peritoneal dialysis SD rats possibly through inhibiting expressions of TGF-beta1 and TIMP-1, and hindering the over-accumulation of ECM.

Plasmon-Mediated Photoelectrochemical Hot-Hole Oxidation Coupling Reactions of Adenine on Nanostructured Silver Electrodes.

Surface-enhanced Raman spectroscopy (SERS) has been widely applied in the identification and characterization of DNA structures with high efficiency. Especially, the SERS signals of the adenine group have exhibited high detection sensitivity in several biomolecular systems. However, there is still no unanimous conclusion regarding the interpretation of some special kinds of SERS signals of adenine and its derivatives on silver colloids and electrodes. This Letter presents a new photochemical azo coupling reaction for adenyl residues, in which the adenine is selectively oxidized to (E)-1,2-di(7H-purin-6-yl) diazene (azopurine) in the presence of silver ions, silver colloids, and electrodes of nanostructures under visible light irradiation. The product, azopurine, is first found to be responsible for the SERS signals. This photoelectrochemical oxidative coupling reaction of adenine and its derivatives is promoted by plasmon-mediated hot holes and is regulated by positive potentials and pH of solutions, which opens up new avenues for studying azo coupling in the photoelectrochemistry of adenine-containing biomolecules on electrode surfaces of plasmonic metal nanostructures.

Evaluation of Renal Impairment in Patients with Diabetic Kidney Disease by Integrated Chinese and Western Medicine.

OBJECTIVE: To investigate the factors related to renal impairment in patients with diabetic kidney disease (DKD) from the perspective of integrated Chinese and Western medicine. METHODS: Totally 492 patients with DKD in 8 Chinese hospitals from October 2017 to July 2019 were included. According to Kidney Disease Improving Global Outcomes (KDIGO) staging guidelines, patients were divided into a chronic kidney disease (CKD) 1-3 group and a CKD 4-5 group. Clinical data were collected, and logistic regression was used to analyze the factors related to different CKD stages in DKD patients. RESULTS: Demographically, male was a factor related to increased CKD staging in patients with DKD (OR=3.100, P=0.002). In clinical characteristics, course of diabetes >60 months (OR=3.562, P=0.010), anemia (OR=4.176, P<0.001), hyperuricemia (OR=3.352, P<0.001), massive albuminuria (OR=4.058, P=0.002), atherosclerosis (OR=2.153, P=0.007) and blood deficiency syndrome (OR=1.945, P=0.020) were factors related to increased CKD staging in patients with DKD. CONCLUSIONS: Male, course of diabetes >60 months, anemia, hyperuricemia, massive proteinuria, atherosclerosis, and blood deficiency syndrome might indicate more severe degree of renal function damage in patients with DKD. (Registration No. NCT03865914).

[Preparation and characterization of mono PEGylated recombinant human interferon omega].

The amino group PEGylation of rhIFNomega with monomethoxy polyethylene glycol succinimidyl succinate (mPEG-SS, 20 000) was investigated, and the modified mixture was separated and purified by ion exchange chromatography and gel filtration chromatography. Under the optimized purification conditions, the average content ofmono PEG-rhIFNomega in the collect liquid reached 182 microg x mL(-1). The average purified yield of mono PEG-rhIFNomega exceed to 22%, and the purity of mono PEG-rhIFNomega was greater than 98% by SDS-PAGE and RP-HPLC. Relative molecular mass of mono PEG-rhIFNomega was 43 790 detected by MALDI-TOF MS. The apparent molecular mass measured by SDS-PAGE was about 60 810. The purified PEG-rhIFNomega has the characteristics of typical PEGylated protein. Activity reservation rate of mono PEG-rhIFNomega was 15.0%, while the antigenicity decreased by at least 64 folds. In addition, the acid stability, thermal stability and stability in serum and trypsin solution of mono PEG-rhIFNomega were markedly better than those of the rhIFNomega. The pharmacological properties of mono PEG-rhIFNomega were significantly improved. The prepared PEG-rhIFNomega might be developed to a novel safe and long-acting interferon.

Ongoing Clinical Trials in Aging-Related Tissue Fibrosis and New Findings Related to AhR Pathways.

Fibrosis is a pathological manifestation of wound healing that replaces dead/damaged tissue with collagen-rich scar tissue to maintain homeostasis, and complications from fibrosis contribute to nearly half of all deaths in the industrialized world. Ageing is closely associated with a progressive decline in organ function, and the prevalence of tissue fibrosis dramatically increases with age. Despite the heavy clinical and economic burden of organ fibrosis as the population ages, to date, there is a paucity of therapeutic strategies that are specifically designed to slow fibrosis. Aryl hydrocarbon receptor (AhR) is an environment-sensing transcription factor that exacerbates aging phenotypes in different tissues that has been brought back into the spotlight again with economic development since AhR could interact with persistent organic pollutants derived from incomplete waste combustion. In addition, gut microbiota dysbiosis plays a pivotal role in the pathogenesis of numerous diseases, and microbiota-associated tryptophan metabolites are dedicated contributors to fibrogenesis by acting as AhR ligands. Therefore, a better understanding of the effects of tryptophan metabolites on fibrosis modulation through AhR may facilitate the exploitation of new therapeutic avenues for patients with organ fibrosis. In this review, we primarily focus on how tryptophan-derived metabolites are involved in renal fibrosis, idiopathic pulmonary fibrosis, hepatic fibrosis and cardiac fibrosis. Moreover, a series of ongoing clinical trials are highlighted.

Efficacy and safety of Zicuiyin decoction on diabetic kidney disease: A multicenter, randomized controlled trial.

BACKGROUD: Zicuiyin (ZCY) decoction created by Xichun Zhang in the Qing dynasty has been used on diabetes mellitus and complications for more than two centuries in China. Huangkui capsule (HKC) is a listed Chinese patent medicine to treat diabetic kidney disease (DKD). To determine whether ZCY is non-inferior to HKC in the treatment of DKD, a multicenter, parallel-control, open-label, randomized clinical trial was conducted. METHODS: In this clinical trial, 88 DKD patients were recruited at three centers in Tianjin from January 2018 to December 2019. They were randomized to receive HKC (2.5 g, TID) or ZCY (crude drug amount 75 g, 150 ml, BID) for eight weeks based on routine treatment. The primary outcome was the change of estimated glomerular filtration rate (eGFR). The secondary outcomes included change of serum creatinine (SCr), urinary albumin excretion rate, 24 h urinary protein, urinary albumin-creatinine ratio, glycosylated hemoglobin A1c, symptom scores, and microbiota compositions profiles. RESULTS: The change of eGFR in HKC and ZCY groups were -7.08 ± 24.65 and 2.57 ± 18.49 ml/min/1.73 m2, respectively (p < 0.05). The 95% lower confidence limit for the difference between the estimated means was 1.93 ml/min/1.73 m2, establishing the superiority of ZCY. Compared to HKC, ZCY could significantly decrease SCr and symptom scores (p < 0.05). There were no significant differences in other outcomes between the two groups (p > 0.05). ZCY ameliorated gut microbiota dysbiosis, including increased Prevotellaceae and Lactobacillaceae and decreased Enterobacteriales, Clostridiaceae and Micrococcaceae. No severe adverse events were reported in any group. CONCLUSIONS: ZCY had better efficacy in improving and protecting kidney function. It would be an alternative option to treat DKD, especially those who decline eGFR and gut microbiota dysbiosis. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR-OON-17012076. Registered July 21, 2017.

[Effects of Shensu II Recipe on the expressions of transforming growth factor-beta1, and plasminogen activator inhibitor-1 in the focal segmental glomerulosclerosis rats].

OBJECTIVE: To observe the effects of Shensu II Recipe on the renal function, mesangial extracellular matrix (ECM) accumulation, the expressions of transforming growth factor-beta1, (TGF-beta1), and plasminogen activator inhibitor-1 (PAI-1) in the focal segmental glomerulosclerosis (FSGS) rats. METHODS: FSGS SD rat model was induced by injecting adriamycin. They were randomly divided into the model group, the Western medicine group, and the Chinese medicine group according to body weight. Besides, another 12 rats was taken as the blank control group. Of them, benazepril (0.33 mg/100 g) was given to rats in the Western medicine group by gastrogavage, while Shensu II Recipe (3.5 g/100 g) was given to rats in the Chinese medicine group by gastrogavage. Normal saline was given to rats in the control group and the model group by gastrogavage. Six rats died during the experiment process, among which, one in the control group, two in the model group, one in the Western medicine group, and two in the Chinese medicine group. The changes of 24 h urinary protein (24 hU, pyrogallol red method), blood urea nitrogen (BUN, urease method), serum creatinine (SCr, enzymatic assay of creatinine), serum total protein (TP, biuret colorimetry), serum albumin (ALB, bromocresol green colormetry) were detected. The pathomorphological changes of the glomerulus were observed. Fibronection (FN), collagen IV (Col IV), glomerulus sclerosis index (GSI), ECM/glomerulus area (GA), expressions of TGF-beta1, and PAI-1 were determined by semi-quantitative analysis. RESULTS: At the end of the 12th week, improvement was shown in the Chinese medicine group (24 hU: 38.55 +/- 2.49 mg; BUN:10.87 +/- 1.78 mmol/L; SCr: 51.70 +/- 1.50 micromol/L; TP: 68.28 +/- 2.31 g/L; and ALB: 42.43 +/- 1.95 g/L). The pathomorphological observation showed that the development of glomerulosclerosis (GS) was significantly slowed down. Semi-quantitative analysis showed significant difference when compared with the model group (GSI: 1.68 +/- 0.33 grade; ECM/GA: 7.11% +/- 2.46%; FN: 4.15% +/- 1.55%; Col IV:1.47% +/- 0.48%; TGF-beta1:19.70% +/- 5.05%; PAI-1: 22.57% +/- 10.65%) ( P < 0.05, P < 0.01). CONCLUSION: Shensu II Recipe could postpone the development of GS in FSGS rats possibly through inhibiting the expressions of TGF-beta1 and PAI-1, hindering the over-accumulation of mesangial matrix.

Association study of the functional variants of the GLIS3 gene with risk of knee osteoarthritis.

INTRODUCTION/OBJECTIVES: Osteoarthritis (OA) ranks the most common joint disorder and the leading cause of disability. Growing evidence has revealed that OA has a strong genetic background, except for aging and obesity. The aim of this study is to determine the associations between potential functional variants of the GLIS3 and GLIS3-AS1 gene and risk of knee OA among a Chinese population. METHODS: In this case-control study with 810 knee OA cases and 900 healthy controls, seven selected functional SNPs of the GLIS3 and GLIS3-AS1 gene were evaluated. RESULTS: We found minor alleles of rs10116772 (OR: 0.80, 95% CI: 0.69-0.92, P = 0.002), rs7045410 (OR: 0.74, 95% CI: 0.61-0.92, P = 0.005), and rs7032713 (OR: 0.76, 95% CI: 0.63-0.93, P = 0.006) were significantly associated with decreased risk of knee OA. Results of the dominant and recessive model, stratified analyses using Kellgren-Lawrence (KL) grading presented that the significant associations were not materially changed. Haplotype analysis indicated that haplotype CGT (OR: 0.66, 95% CI: 0.46-0.96, P = 0.031) and ATT (OR: 0.76, 95% CI: 0.6-0.95, P = 0.017) were significantly associated with decreased risk of knee OA. Further, they were also significantly associated with lower expression level of GLIS3, as well as higher expression level of GLIS3-AS1 in the articular cartilage specimens. Genotype-tissue expression (GTEX) data also validated that minor alleles of rs7045410 and rs7032713 were significantly associated with higher expression level of GLIS3-AS1 in thyroid and pituitary tissues (P < 0.001). CONCLUSIONS: These findings revealed the essential role of genetic variants of the GLIS3 and GLIS3-AS1 gene in the occurrence of knee OA together. Key Point • Functional variants of the GLIS3 and GLIS3-AS1 gene were significantly associated with decreased risk of knee OA.

Transcriptome-Based Network Analysis Reveals Hirudin Potentiates Anti-Renal Fibrosis Efficacy in UUO Rats.

Background: Hirudin has been widely used in the treatment of antifibrosis. Previous studies have shown that hirudin can effectively improve the clinical remission rate of chronic kidney disease. However, the mechanism of its renal protection has not been systematically investigated. Methods: In this study, the reliability of UUO-induced renal interstitial fibrosis was evaluated by histopathological verification. High-throughput transcriptome sequencing was used to elucidate the molecular mechanism of hirudin, differentially expressed mRNAs were identified, and their functions were analyzed by GO analysis and GSEA. In addition, the RNA-seq results were validated by in vitro and vivo experiments. Results: We found 322 identical differential expressed genes (IDEs) in the UUO hirudin-treated group compared with the sham group. Functional enrichment analysis indicated that cellular amino acid metabolic processes were the most obvious enrichment pathways in biological processes. In terms of molecular functional enrichment analysis, IDEs were mainly enriched in coenzyme binding, pyridoxal phosphate binding and other pathways. In addition, microbody is the most obvious pathway for cellular components. A total of 115 signaling pathways were enriched, and AMPK, JAK-STAT, and PI3K-Akt signaling pathways were the important signaling pathways enriched. We found that PI3K, p-Akt, and mTOR expression were significantly reduced by hirudin treatment. In particular, our results showed that hirudin could induce a decrease in the expression of autophagy-related proteins such as P62, LC3, Beclin-1 in TGF-ß1-induced NRK-52E cells. Conclusion: Our results suggest that hirudin may protect the kidney by ameliorating renal autophagy impairment through modulating the PI3K/Akt pathway.

Efficacy and safety of Shenyankangfu Tablet, a Chinese patent medicine, for primary glomerulonephritis: A multicenter randomized controlled trial.

BACKGROUND: Shenyankangfu Tablet (SYKFT) is a Chinese patent medicine that has been used widely to decrease proteinuria and the progression of chronic kidney disease. OBJECTIVE: This trial compared the efficacy and safety of SYKFT, for the control of proteinuria in primary glomerulonephritis patients, against the standard drug, losartan potassium. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: This was a multicenter, double-blind, randomized, controlled clinical trial. Primary glomerulonephritis patients, aged 18-70 years, with blood pressure ≤ 140/90 mmHg, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min per 1.73 m2, and 24-hour proteinuria level of 0.5-3.0 g, were recruited in 41 hospitals across 19 provinces in China and were randomly divided into five groups: SYKFT, losartan potassium 50 mg or 100 mg, SYKFT plus losartan potassium 50 mg or 100 mg. MAIN OUTCOME MEASURES: The primary outcome was change in the 24-hour proteinuria level, after 48 weeks of treatment. RESULTS: A total of 735 participants were enrolled. The percent decline of urine protein quantification in the SYKFT group after 48 weeks was 8.78% ± 2.56% (P = 0.006) more than that in the losartan 50 mg group, which was 0.51% ± 2.54% (P = 1.000) less than that in the losartan 100 mg group. Compared with the losartan potassium 50 mg group, the SYKFT plus losartan potassium 50 mg group had a 13.39% ± 2.49% (P < 0.001) greater reduction in urine protein level. Compared with the losartan potassium 100 mg group, the SYKFT plus losartan potassium 100 mg group had a 9.77% ± 2.52% (P = 0.001) greater reduction in urine protein. With a superiority threshold of 15%, neither was statistically significant. eGFR, serum creatinine and serum albumin from the baseline did not change statistically significant. The average change in TCM syndrome score between the patients who took SYKFT (-3.00 [-6.00, -2.00]) and who did not take SYKFT (-2.00 [-5.00, 0]) was statistically significant (P = 0.003). No obvious adverse reactions were observed in any group. CONCLUSION: SYKFT decreased the proteinuria and improved the TCM syndrome scores of primary glomerulonephritis patients, with no change in the rate of decrease in the eGFR. SYKFT plus losartan potassium therapy decreased proteinuria more than losartan potassium therapy alone. TRIAL REGISTRATION NUMBER: NCT02063100 on ClinicalTrials.gov.

Effects of Niaoduqing Particles () on Delaying Progression of Renal Dysfunction: A Post-trial, Open-Label, Follow-up Study.

OBJECTIVE: To follow up the participants of the randomized clinical trial "Efficacy and Safety of Niaoduqing Particles () for Delaying Moderate-to-Severe Renal Dysfunction", and assess the long-term effects of Niaoduqing Particles on delaying the progression of renal dysfunction. METHODS: Participants, who had previously been randomly assigned to receive Niaoduqing Particles or placebo for 24 weeks (146 cases in each group), were invited to follow-up and all were administered Niaoduqing Particles 5 g thrice daily and 10 g before bedtime for 24 weeks. The primary endpoints were changes in baseline serum creatinine (Scr) and estimated glomerular filtration rate (eGFR) after completion of the open-label treatment period. RESULTS: After the double-blind period, the median (interquartile range) changes in Scr were 1.1 (-13.0-24.1) and 11.7 (-2.6-42.9) µmol/L for the Niaoduqing Particle and placebo groups, respectively (P=0.008), and the median changes in eGFRs were-0.2 (-4.3-2.7) and-2.21 (-5.7-0.8) mL•min-1•1.73 m-2, respectively (P=0.016). There were significant differences in the double-blind period changes in renal function between groups. After the open-label period, the median changes in Scr were 9.0 (-10.0-41.9) and 17.5 (-6.0-50.0) µmol/L for the Niaoduqing Particle and placebo groups according to baseline grouping, respectively (P=0.214), and the median changes in eGFRs were-2.3 (-6.4-1.9) and-3.7 (-7.5-1.1) mL•min-1•1.73 m-2, respectively (P=0.134). There were no statistical differences in the open-label period changes in renal function between groups. The eGFR reduction of participants who accepted Niaoduqing Particle treatment for 48 weeks was projected to 2.5 mL•min-1•1.73 m-2 per year. CONCLUSION: Niaoduqing Particles appear to have long-term efficacy for patients with moderate-to-severe renal dysfunction. Although there was no statistical difference, the early use of Niaoduqing Paticles seems to ameliorate the worsening of renal function. (Trial registration No. ChiCTR-TRC-12002448).

Swimming exercise reduces preference for a high-fat diet by increasing insulin sensitivity in C57BL/6 mice.

The present study examined the effect of 4-week swimming training on the preference for a high-fat diet and insulin sensitivity in mice. C57BL/6 J mice were placed on either a low-fat diet or a choice diet (with both low-fat and high-fat diets available) for 6 weeks. During this period, a group of mice on the free-choice diet were randomly selected to receive a 4-week swimming exercise intervention. Mice that received the swimming exercise intervention showed a reduced preference for the high-fat diet as well as a slower rate of weight gain. Moreover, changes in insulin sensitivity, tyrosine hydroxylase expression in the ventral tegmental area-nucleus accumbens system, and the expression of IRS2, IRS2, and high-fat diet-induced Akt phosphorylation in the nucleus accumbens were delayed in the swimming exercise intervention group. Taken together, these results suggest that swimming exercise regulates the dopaminergic reward system to decrease high-fat diet intake, thereby controlling body weight to prevent obesity, in a manner likely mediated by increased insulin signal transduction in the nucleus accumbens.

Positive association between musclin and insulin resistance in obesity: evidence of a human study and an animal experiment.

BACKGROUND: Musclin is a novel skeletal muscle-derived secretory factor considered to be a potent regulator of the glucose metabolism and therefore may contribute to the pathogenesis of obesity and insulin resistance (IR). METHODS: To test this hypothesis, we examined the plasma musclin levels in overweight/obese subjects and lean controls. Rats on a high fat diet (HFD) were used as the annimal model of obesity. Radioimmunoassay and western blot were used to determine musclin levels in plasma and skeletal muscle. RESULTS: According to radioimmunoassays,the overweight/obese subjects exhibited elevated musclin plasma levels compared with the lean controls (89.49 ± 19.00 ng/L vs 80.39 ± 16.35 ng/L, P < 0.01). The musclin levels were positively correlated with triglyceride, fasting plasma glucose, and homeostasis model assessment of IR levels. These observations were confirmed with a high-fat diet(HFD) rat model. HFD rats also exhibited increased musclin immunoreactivity in plasma (P < 0.01) and in skeletal muscle (P < 0.05), as well as increased musclin mRNA levels in skeletal muscle (P < 0.01). Musclin incubation significantly inhibited muscles 3H-2-DG uptake in the normal diet(ND) group (P < 0.01). The protein expression of glucose transporter type 4 was significantly down regulated by 30% (P < 0.05) in the ND group after soleusmuscle was incubated with musclin compared with the control. Musclin incubation also increased the protein levels of glucose-regulated protein (GRP)78 and GRP94 by 146.8 and 54% (both P < 0.05), respectively, in ND rats. CONCLUSIONS: Our data support the hypothesis that musclin has a strong relationship with obesity-associated IR by impairing the glucose metabolism and, at least in part, through causing endoplasmic reticulum stress.