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Objectives: The primary objective of the Peritoneal Dialysis Telemedicine-assisted Platform Cohort (PDTAP) Study is to explore potential predictors and their effects on patient survival, technique survival, and the occurrence of infectious and noninfectious complications. Design: The PDTAP study is a national-level cohort study in China. A newly developed PD telemedicine application provided a unique and convenient way to collect multicenter, structured data across units. Setting: The PDTAP study was underway in 27 hospitals from 14 provinces located at 7 geographical regions (northwest, northeast, north, central, southwest, southeast, and south) in China. Participants: Our study aims to enroll at least 7000 adult patients with end-stage renal disease receiving PD. Methods: Approval has been obtained through the ethics committees of all hospitals. All participants signed the informed consent form after the center had received ethics board approval in accordance with the Declaration of Helsinki. Main outcome measures: Patient survival, technique survival, hospitalization, and the occurrence of infectious and noninfectious complications. Conclusions: The PDTAP study aims to explore potential predictors and their effects on patient survival, technique survival, and infectious and noninfectious complications using a newly developed PD telemedicine system to collect multicenter, structured data in real-world practice. Substantial and transformable findings in relation to PD practices were expected. This study also developed a national-level infrastructure for further collaboration and ancillary investigation.

Background and objectives Several clinical practice guidelines noted the potential benefits of urate-lowering therapy on cardiovascular disease and CKD progression; however, the effect of this regimen remains uncertain. In this systematic review, we aimed to evaluate the efficacy of urate-lowering therapy on major adverse cardiovascular events, all-cause mortality, kidney failure events, BP, and GFR. Design, setting, participants, & measurements We systematically searched MEDLINE, Embase, and the Cochrane databases for trials published through July 2020. We included prospective, randomized, controlled trials assessing the effects of urate-lowering therapy for at least 6 months on cardiovascular or kidney outcomes. Relevant information was extracted into a spreadsheet by two authors independently. Treatment effects were summarized using random effects meta-analysis. Results We identified 28 trials including a total of 6458 participants with 506 major adverse cardiovascular events and 266 kidney failure events. Overall urate-lowering therapy did not show benefits on major adverse cardiovascular events (risk ratio, 0.93; 95% confidence interval, 0.74 to 1.18) and all-cause mortality (risk ratio, 1.04; 95% confidence interval, 0.78 to 1.39) or kidney failure (risk ratio, 0.97; 95% confidence interval, 0.61 to 1.54). Nevertheless, urate-lowering therapy attenuated the decline in the slope of GFR (weighted mean difference, 1.18 ml/min per 1.73 m2 per year; 95% confidence interval, 0.44 to 1.91) and lowered the mean BP (systolic BP: weighted mean difference, −3.45 mm Hg; 95% confidence interval, −6.10 to −0.80; diastolic BP: weighted mean difference, −2.02 mm Hg; 95% confidence interval, −3.25 to −0.78). There was no significant difference (risk ratio, 1.01; 95% confidence interval, 0.94 to 1.08) in the risk of adverse events between the participants receiving urate-lowering therapy and the control group. Conclusions Urate-lowering therapy did not produce benefits on the clinical outcomes, including major adverse cardiovascular events, all-cause mortality, and kidney failure. Thus, there is insufficient evidence to support urate lowering in patients to improve kidney and cardiovascular outcomes.

Background: The aim of this study was to estimate the attributable risk for all-cause mortality in hypertensive adults living in Beijing, China. Methods: We conducted a prospective cohort study on the basis of the disease risk prediction model, which included 3006 hypertensive patients aged 50 and over who participated in the annual health examination from thirty-eight community health centers were randomly selected from all 53 community health centers in Dongcheng district of Beijing in China. This cohort study was conducted from January 1, 2013 to June 31, 2018 in these community health centers. Data included age, gender, education level, BMI, smoking and drinking status, renal function, diabetes mellitus (DM), coronary heart disease, levels of blood pressure, use of medications, and blood lipid levels. Results: the follow-up time was 4.90 ± 0.51 years. There were significant survival differences by gender, renal function (eGFR > 90 vs. 60–90 vs. 12 years), coronary heart disease (CHD) (CHD vs. NO CHD). In the multivariate Cox proportional hazard analysis, the prognostic factors of all-cause mortality in hypertensive patients were male [HR 1.662, 95% CI 1.110–2.489, p = 0.014], educational level

The inflammatory proliferation of fibroblast-like synoviocytes (FLSs) and functional imbalances in T lymphocytes play critical roles in the pathogenesis of rheumatoid arthritis (RA). The clinical efficacy of Huayu Tongbi Fang (HYTB, a traditional herbal formula) in RA treatment has been validated. In this study, we aimed to explore the regulatory mechanisms of HYTB on the proliferation and differentiation of T lymphocytes, and the inhibitory effect of HYTB on inflammatory proliferation of FLSs. The RCS-364 (Rat FLSs) cells were cocultured with rat splenic lymphocytes that were induced by interleukin-1β in Transwell chambers. After freeze-dried HYTB powder treatment, the percentage of T-cell subset and apoptosis rates of FLSs were measured using flow cytometry. Furthermore, protein expression of key molecules of NF-κB and JAK/STAT signaling pathways was quantified using Western blot. The granulocyte-macrophage colony-stimulating factor (GM-CSF) was measured using enzyme-linked immunosorbent assay. The results showed that HYTB could inhibit the inflammatory proliferation of FLSs through inducing cell apoptosis. Additionally, HYTB treatment could intervene in the proliferation and differentiation of T lymphocytes and regulate protein expression of key molecules in NF-κB and JAK/STAT cell signaling pathways. Moreover, it could inhibit FLS activation by suppressing GM-CSF production by T cells and FLSs. Therefore, the HYTB formula should be used as a traditional medicine against RA in modern complementary and alternative therapies.

ObjectivesDry weight assessment (DWA) is an important part of dialysis and fluid management in patients receiving renal replacement therapy. With the development of bioimpedance analysis (BIA), the development of the direct segmental multi-frequency BIA (DSM-BIA) has provided a more convenient measure for DWA of dialysis patients, but its accuracy remains unclear. This study was designed to evaluate the application of DSM-BIA in DWA of continuous ambulatory peritoneal dialysis (CAPD) patients.DesignThis is a cross-sectional study. Using the conventional BIA as a reference, we examined the accuracy of the DSM-BIA technique for assessing dry weight in CAPD patients and analyzed the potential factors influencing their fluid volume status.Setting and Participants:A total of 31 patients with end-stage renal disease receiving CAPD and 310 healthy volunteers were recruited for this study.MethodsThe intraclass correlation coefficients (ICC) and Bland-Altman plots were used to assess the consistency between DSM-BIA and the conventional BIA for DWA. Univariate and multivariate linear regression analyses were used to explore the influencing factors associated with the edema index.ResultsDSM-BIA and the conventional BIA technology were consistent in DWA in CAPD patients (ICC female 0.972, ICC male 0.882, ICC total 0.960). Similarly, Bland-Altman plots showed good agreements between the two methods in DWA for both genders. Univariate and multivariate linear regression analysis showed both eGFR level (P = 0.04) and serum NT-pro BNP concentration (P = 0.007) were positively correlated with the ratio of extracellular water to total body water (ECW/TCW).ConclusionsDSM-BIA in DWA has good accuracy in clinical applications and has potential application value for fluid volume management in CAPD patients.

Mitochondrial dysfunction, which is directly involved in Parkinson's disease (PD), is characterized by the production of reactive oxygen species (ROS) and aberrant energy metabolism. Thus, regulating mitochondrial function might be an effective strategy to treat PD. However, the blood-brain barrier (BBB) presents a significant challenge for the intracerebral delivery of drugs. Here, we synthesized a zeolitic imidazolate framework 8-coated Prussian blue nanocomposite (ZIF-8@PB), which was encapsulated with quercetin (QCT), a natural antioxidant, to treat PD. ZIF-8@PB-QCT exhibited superior near-infrared radiation (NIR) response and penetrated through the BBB to the site of mitochondrial damage guided by the photothermal effect. In the mice model of PD, the QCT released from ZIF-8@PB-QCT significantly increased the adenosine triphosphate levels, reduced the oxidative stress levels, and reversed dopaminergic neuronal damage as well as PD-related behavioral deficits without any damage to the normal tissues. Furthermore, we explored the underlying neuroprotective mechanism of ZIF-8@PB-QCT that was mediated by activating the PI3K/Akt signaling pathway. Thus, combined with noninvasive NIR radiation, the biocompatible ZIF-8@PB-QCT nanocomposite could be used to treat neurodegenerative diseases.

Introduction Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus (DM) and the primary cause of end-stage renal disease. Routine medication might result in adverse effects which limit their usage. Laboratory studies have shown that Xiao Zheng San Jie (XZSJ) granules is effective in reducing the levels of urinary protein and blood creatinine in rats with DKD. Hence, we aim to conduct a clinical trial to determine the efficacy and safety of XZSJ granules among patients with DKD Stage IV, who present with the syndromes of qi deficiency and blood stasis. The purpose of this paper is to report the methodology of this trial.Methods and analysisThis is a randomised, double-blind, placebo-controlled, multi-centre clinical trial. A total of 72 patients with DKD Stage IV who have the syndromes of qi deficiency and blood stasis will be randomly assigned to either intervention or placebo group. In addition to routine medication, the intervention group will be given XZSJ formula (in granules) and the control group will be given placebo for 12-weeks. Data collected at baseline as well as weeks 4, 8 and 12 will be recorded in case report forms and subsequently entered into EpiData 3.1 electronic database. Adverse events will also be documented. Primary outcomes – estimated glomerular filtration rate, urinary albumin-to-creatinine ratio, and serum creatinine – will be assessed after 12 weeks. Ethics and disseminationThis trial has been approved by the Research Ethics Committee of Dongzhimen Hospital (DZMEC-KY-2018-60). Informed consent will be obtained from all participants. Results of this study will be disseminated to the public through academic conferences and peer-reviewed journals.DiscussionThis trial might provide information on an effective method for the treatment of DKD, especially for patients who present with the syndromes of qi deficiency and blood stasis. We hope that this trial will serve as a reference for the conception of high-quality Traditional Chinese Medicine trials in the future, which incorporate syndrome diagnosis into the study design.Trial registration Chinese Clinical Trial Registry, ChiCTR1900021391. Registered 18 February 2018, http://www.chictr.org.cn/showproj.aspx?proj=36106.

Valsartan has the potential to attenuate neointimal hyperplasia and to suppress the inflammatory response. This study aimed to evaluate the role of valsartan in neointimal hyperplasia and the toll-like receptor 4 (TLR4)-nitric oxide synthase (NOS) pathway in the balloon-injured rat aorta. Forty-eight Wistar rats were randomly allocated to three groups: sham control (control), balloon-injured group (surgery), and balloon-injured+valsartan-treated group (valsartan). Rats were killed at 14 and 28 days after balloon-injury, and then the aortic tissues were collected for morphometric analysis as well as for measurements of the mRNA or protein expression of angiotensin II, angiotensin II type 1 (AT1) receptor, angiotensin II type 2 (AT2) receptor, TLR4, endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), serine/arginine-rich splicing factor 1(SRSF1) and extracellular signal regulated kinase (ERK). Valsartan at a dose of 20 mg/kg/day markedly decreased neointimal hyperplasia in the aorta of balloon-injured rats, and significantly reduced the mRNA or protein expression of TLR4, AT1 receptor, SRSF1 and phosphorylated-ERK (p-ERK) as well as the aortic levels of iNOS (all p

Obesity and related metabolic disorders are associated with intestinal microbiota dysbiosis, disrupted intestinal barrier and chronic inflammation. Shen-Yan-Fang-Shuai formula (SYFSF) is a traditional Chinese herbal formula composed of Astragali Radix, Radix Angelicae Sinensis, Rheum Officinale Baill, and four other herbs. In this study, we identified that SYFSF treatment prevented weight gain, low-grade inflammation and insulin resistance in high-fat diet (HFD)-fed mice. SYFSF also substantially improved gut barrier function, reduced metabolic endotoxemia, as well as systemic inflammation. Sequencing of 16S rRNA genes obtained from fecal samples demonstrated that SYFSF attenuated HFD-induced gut dysbiosis, seen an decreased Firmicutes to Bacteroidetes ratios. Microbial richness and diversity were also higher in the SYFSF-treated HFD group. Furthermore, similar therapeutic effects and changes in gut microbiota profile caused by SYFSF could be replicated by fecal microbiota transfer (FMT). Taken together, our study highlights the efficacy of SYFSF in preventing obesity and related metabolic disorders. Its therapeutic effect is associated with the modulation of gut microbiota, as a prebiotic.

Purpose Restenosis is the main complication after percutaneous coronary intervention. The proliferation of new intima contributes to the process. In this study, we aimed to explore the effect of olmesartan on intimal thickening after balloon injury and possible mechanism. Methods Aortic endothelial denudation model was made by a 2F balloon catheter. Thirty-six rats were randomly allocated into three groups: Control (n = 12) Surgery (n = 12, received vascular balloon injury) and Olmesartan (n = 12, received 3 mg.kg-1.d-1olmesartan after injury). Fourteen and 28 days after injury, HE staining was used to assess the aortic endothelial injury. Radioimmunological method was used to examine the level of angiotensin II (Ang II). Western blotting and reverse transcription polymerse chain reaction (RT-PCR) were employed to detect the protein and mRNA level of Apelin/APJ. Results After vascular balloon injury, the proliferation of vascular smooth muscle cells and the intimal thickening were increased. The mRNA and protein level of Ang II, AT1, Apelin and APJ mRNA were promoted by vascular balloon injury. Olmesartan decreased the proliferation of vascular smooth muscle cells and the intimal thickening. Olmesartan decreased the expression of Ang II and AT1, but further increased the expression of Apelin and APJ. Balloon injury also induced the activation of Extracellular signal-regulated kinase (ERK) signaling and olmesartan decreased the effect. Conclusion Olmesartan inhibits the intimal thickening through activating Apelin/APJ and inhibiting AngII-AT1 and ERK pathway.

Supplementary_Table_1 for The Peritoneal Dialysis Telemedicine-assisted Platform Cohort (PDTAP) Study: Design and methods by Tiantian Ma, Zhikai Yang, Shaomei Li, Huaying Pei, Jinghong Zhao, Yi Li, Zibo Xiong, Yumei Liao, Zhanzheng Zhao, Jing Xiao, Ying Li, Qiongzhen Lin, Zhaoxia Zheng, Liping Duan, Gang Fu, Shanshan Guo, Wenbo Hu, Yulin Li, Fuyun Sun, Nan Zhao, Qin Wang, Tianrong Ji, Beiru Zhang, Rui Yu, Li Hao, Guiling Liu, Li Zuo, Huiping Zhao, Caili Wang, Lirong Deng, Hongyu Chen, Li Li, Yulan Shen, Yong Zhang, Lihua Wang, Yan Yan, Zhigang Ma, Yingping Li, Xianchao Zhang, Xuejian Wang, Yirong Liu, Xinying Gao, Zhonggao Xu, Li Zhang, Shutong Du, Cui Zhao, Xiaoli Chen, Hongyi Li, Yingli Yue, Shanshan Chen, Yingchun Ma, Yuanyuan Wei, Jingwei Zhou, Jie Lv, Yingdong Zheng, Sainan Zhu, Minghui Zhao and Jie Dong in Peritoneal Dialysis International

A derivative formula, DGBX, which is composed of three herbs (Radix astragali,Radix Angelicae sinensis, andCoptis chinensisFranch), is derived from a famous Chinese herbal formula, Danggui Buxue Tang (DBT) (Radix astragaliandRadix Angelicae sinensis). We aimed to investigate the effects of DGBX on the regulation of the balance between proliferation and apoptosis of hematopoietic stem cells (HSCs) due to the aberrant immune response in a mouse model of aplastic anemia (AA). Cyclosporine (CsA), an immunosuppressor, was used as the positive control. Our results indicated that DGBX could downregulate the production of IFNγin bone marrow cells by interfering with the binding between SLAM and SAP and the expressions of Fyn and T-bet. This herbal formula can also inhibit the activation of Fas-mediated apoptosis, interferon regulatory factor-1-induced JAK/Stat, and eukaryotic initiation factor 2 signaling pathways and thereby induce proliferation and attenuate apoptosis of HSCs. In conclusion, DGBX can relieve the immune-mediated destruction of HSCs, repair hematopoietic failure, and recover the hematopoietic function of HSCs in hematogenesis. Therefore, DGBX can be used in traditional medicine against AA as a complementary and alternative immunosuppressive therapeutic formula.

Over the past several decades, natural products with poly-pharmacological profiles have demonstrated promise as novel therapeutics for various complex diseases, including cancer. Berberine (PubChem CID: 2353), a soliloquies quaternary alkaloid, has been validated to exert powerful effects in many cancers. However, the underlying molecular mechanism is not yet fully elucidated. In this study, we summarized the molecular effects of berberine against multiple cancers based on current available literatures. Furthermore, a systems pharmacology infrastructure was developed to discover new cancer indications of berberine and explore their molecular mechanisms. Specifically, we incorporated 289 high-quality protein targets of berberine by integrating experimental drug–target interactions (DTIs) extracted from literatures and computationally predicted DTIs inferred by network-based inference approach. Statistical network models were developed for identification of new cancer indications of berberine through integration of DTIs and curated cancer significantly mutated genes (SMGs). High accuracy was yielded for our statistical models. We further discussed three typical cancer indications (hepatocarcinoma, lung adenocarcinoma, and bladder carcinoma) of berberine with new mechanisms of actions (MOAs) based on our systems pharmacology framework. In summary, this study systematically provides a powerful strategy to identify potential anti-cancer effects of berberine with novel mechanisms from a systems pharmacology perspective.

Staphylopine is a newly identified broad-spectrum metallophore for metal acquisition, and it plays important roles in the survival and virulence of Staphylococcus aureus and other pathogens in the metal-scarce environment in hosts. CntK catalyzes the first step of staphylopine synthesis by converting L-histidine to D-histidine to provide an essential building block of staphylopine. Herein, the crystal structures of S. aureus CntK (SaCntK) and its C72S variant are determined at 1.82 and 1.58 A resolution, respectively. SaCntK forms a homodimer and each subunit contains a two-domain α/β structure. Its overall structure resembles diaminopimelate epimerase, although their sequence identities are lower than 22%. SaCntK is specific for histidine, whereas other proteinogenic amino acids, with the exception of arginine, do not show any binding with SaCntK. Structural modeling suggested that residues Asn16, Glu46, Gln47 and Glu208 are responsible for specific substrate binding, and their substitutions significantly reduced the binding of histidine to SaCntK. Structural modeling suggested SaCntK uses a two-base catalytic mechanism, which has been observed in many cofactor-independent racemases. Our study provides critical insights into the structure and functions of CntK in staphylopine synthesis, which makes it helpful for developing potential antibiotics targeting the staphylopine-mediated metal acquisition process in bacteria.

Background: Several clinical practice guidelines noted the potential benefits of urate-lowering therapy (ULT) on cardiovascular disease (CVD) and chronic kidney disease (CKD) progression, however effect of this regimen remains much uncertainty. In this systematic review, we aimed to evaluate the efficacy of ULT on major adverse cardiovascular events(MACEs), all-cause mortality and kidney failure events. Methods: We systematically searched MEDLINE, Embase, and the Cochrane databases for trials published through April 2019. We included prospective, randomized, controlled trials assessing the effects of ULT on cardiovascular or renal outcomes. We extracted published data and did a meta-analysis of urate-lowering therapy on relative risks (RRs) of major adverse cardiovascular events, all-cause mortality, kidney failure events, and adverse events. Summary estimates of RR reductions were calculated with a random effects model. Findings: We identified 28 trials including a total of 9194 participants, of which 5070 participants received ULT, 4104 participants received placebo, usual-care or no treatment. Finally, 1279 MACEs, 377 deaths and 87 kidney failure events were recorded. Among all the population with 3103 (34·18%) participants having chronic kidney disease and 5718 (61·14%) having cardiovascular disease or stroke, ULT reduced the risk of MACEs [risk ratio (RR) 0·80, 95% confidence interval (CI) 0·67-0·95; I2 = 42·7%] and all-cause mortality (RR 0·80, 95% CI 0·66-0·97; I2 =0·0%), but had no effect on kidney failure (RR 1·04, 95%CI 0·43-2·42; I2 =64·4%). There was no significant difference (RR=0·99, 95% CI 0·95 to 1·03; I2 =55·7%) in the risk of adverse events between the participants receiving ULT and the control group. Interpretation: ULT has a beneficial effect on reducing the risk of MACEs and all-cause mortality. However, there is insufficient evidence to support an effect of ULT in reducing risk of kidney failure events. Funding Statement: This work was funded by National Key Research and Development Program of China (2018YFC1314004). JL was supported by the grant from the National Natural Science Foundation of China (no. 81270795), JZ was supported by the National Natural Science Foundation of China (81874401). Dr Badve is supported by a John Chalmers Clinical Research Fellowship with the support of Servier from The George Institute for Global Health. Declaration of Interests: Dr Badve reports grants from the National Health and Medical Research Council of Australia, personal fees from Bayer AG and Amgen Australia, and nonfinancial support from Bayer AG. Other authors listed in this paper declare no competing interests. Ethics Approval Statement: This study is registered with PROSPERO, number CRD42018104227.

Diabetic kidney disease (DKD) is a global pandemic, and microinflammation has been reported as an important pathogenic factor of DKD. Traditional Chinese Medicine (TCM) has been used in the treatment of DKD for thousands of years, and modern Chinese medicine studies have found that herbal medicines with heat-clearing property have a curative anti-inflammation effect in DKD. This article reviews the new clinical and experimental progress made in herbal medicines with heat-clearing property, in the treatment of DKD, as well as their safety aspects.

Background Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus and the primary cause of end-stage renal disease. Existing therapies for DKD are not sufficiently effective. We report the protocol of a pragmatic randomized controlled trial of the use of traditional Chinese herbal medicine to treat patients with DKD. Methods/design This will be a multicenter randomized controlled trial. A total of 266 patients with DKD (106 with early stage, 80 with middle-stage, and 80 with advanced-stage disease) with an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m2will be included. Participants with DKD of each stage will be randomly allocated at a 1:1 ratio to either the experimental group, which will receive Xiaozhen formula and basic treatment, or the control group, which will receive basic treatment only. The study duration will be 24 weeks. The primary outcome will be urinary microalbumin excretion rate for early stage DKD, 24-h urinary protein for middle-stage DKD, and eGFR for advanced-stage DKD. Adverse events will also be evaluated. Data for all outcome indicators will be collected at baseline and weeks 4, 12, and 24. Discussion This study will provide evidence of the effectiveness and safety of traditional Chinese herbal medicine in treating patients with DKD. Trial registration Chinese Clinical Trials Registry: ChiCTR-IOR-16010072. Registered on 2 December 2016. Electronic supplementary material The online version of this article (10.1186/s13063-018-2749-6) contains supplementary material, which is available to authorized users.

Background Xian-Fang-Huo-Ming-Yin (XFHM), a traditional herbal formula, has been used to treat sores and carbuncles for hundreds of years in Asia. Nowadays, its clinical effects in treatment of rheumatoid arthritis (RA) have been validated. In this study, we want to study its possible molecular mechanisms of regulating the differentiation of lymphocytes and production of pro-inflammatory cytokines in collagen-induced arthritis (CIA) mice for RA treatment. Methods A high performance liquid chromatography-electrospray ionization/mass spectrometer (HPLC-ESI/MSn) system was used to analyze the constituents of XFHM granules. An arthritics mouse model was induced by collagen and leflunomide (LEF) was used as a positive control medicine. Pathological changes at the metatarsophalangeal joint were studied through Safranin O and immunohistochemical staining. The differentiation of T, B and NK cells was examined by flow cytometry and pro-inflammatory cytokines were assayed using an Inflammation Antibody Array assay. The expression of key molecules of the nuclear factor κB (NF-κB) and Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways in spleen were studied by western-blot analysis. Results In our study. 21 different dominant chemical constituents were identified in XFHM. Treatment with XFHM suppressed the pathological changes in arthrosis of CIA. Additionally, XFHM down-regulated the proliferation and differentiation of CD3+ T cells and CD3−CD19+ B cells significantly. However, XFHM had no significant effect on CD3−NK1.1+ NK cells. Further study showed that the production of pro-inflammatory cytokines had been suppressed by inhibiting the activation of NF-κB and JAK/STAT signaling. Conclusions XFHM can regulate and maintain the immunologic balance of lymphocytic immunity and inhibit the production of pro-inflammatory cytokines, thus suppressing the pathological changes of RA. Therefore, XFHM may be used as an application of traditional medicine against RA in modern complementary and alternative therapeutics. Electronic supplementary material The online version of this article (doi:10.1186/s12906-016-1526-x) contains supplementary material, which is available to authorized users.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and satisfactory therapeutic strategies have not yet been established. The Shen-Yan-Fang-Shuai Formula (SYFSF) is a traditional Chinese formula composed of Astragali radix, Radixangelicae sinensis, Rheum officinale Baill, and four other herbs. It has been widely used as an effective treatment for DKD patients in China. However, little is known about the molecular mechanisms underlying SYFSF’s renoprotection. In this study, we compared the protective effect of SYFSF to irbesartan on the histology and renal cells in type 2 DKD rat model and high-glucose (HG) cultured mesangial cells, respectively. We found that SYFSF could significantly decrease urinary albumin, cholesterol, and triglyceride. And a decrease in serum creatinine was also found in SYFSF-treated group compared with irbesartan-treated rats. In addition, SYFSF inhibited the interstitial expansion and glomerulosclerosis in diabetic rats. Notably, SYFSF markedly downregulated the expression of MCP-1, TGF-β1, collagen IV, and fibronectin in diabetic rat models and HG-induced mesangial cell models. The renoprotection was closely associated with a reduced expression of TNF-α and phosphorylated NF-κBp65. Our study suggests that SYFSF may ameliorate diabetic kidney injury. The observed renoprotection is probably attributable to an inhibition of inflammatory response and extracellular matrix (ECM) accumulation mediated by TNF-α/NF-κBp65 signaling pathway.

The hypoalbuminuric effect of sulodexide (SDX) on diabetic kidney disease (DKD) was suggested by some clinical trials but was denied by the Collaborative Study Group. In this study, the diabetic rats were treated with SDX either from week 0 to 24 or from week 13 to 24. We found that 24-week treatment significantly decreased the urinary protein and HAVCR1 excretion, inhibited the interstitial expansion, and downregulated the renal cell apoptosis and interstitial fibrosis. Renoprotection was also associated with a reduction in renocortical/urinary oxidative activity and the normalization of renal klotho expression. However, all of these actions were not observed when SDX was administered only at the late stage of diabetic nephropathy (from week 13 to 24). In vitro, advanced glycation end products (AGEs) dose-dependently enhanced the oxidative activity but lowered the klotho expression in cultured proximal tubule epithelial cells (PTECs). Also, H2O2 could downregulate the expression of klotho in a dose-dependent manner. However, overexpression of klotho reduced the HAVCR1 production and the cellular apoptosis level induced by AGEs or H2O2. Our study suggests that SDX may prevent the progression of DKD at the early stage by upregulating renal klotho expression, which inhibits the tubulointerstitial injury induced by oxidative stress.

Aims Upregulation of heme oxygenase (HO)-1 plays an important role in vascular protection. Valsartan attenuates neointimal hyperplasia in animal studies. The objective of this study was to examine the role of HO-1 and angiotensin II type 1 (AT 1 ) receptor in the action of valsartan on neointimal hyperplasia in balloon-injured rat aortic arteries. Main methods Thirty-six male Wistar rats were randomly divided into the following three groups with twelve rats in each group: control group, surgery (model) group, and valsartan group. Aortic balloon injury was performed to elicit endothelial denudation with a 2F balloon catheter. On days 14 and 28 after injury, blood was harvested to measure bilirubin levels. Aortic arteries were harvested for morphometry analysis, to determine angiotensin II (Ang II) level, and to analyze mRNA or protein expression. Key findings Compared with the control group, proliferation and intimal thickening of vascular smooth muscle cells (VSMCs) were obvious in the surgery group rats on days 14 and 28 after injury. Valsartan significantly reduced the proliferation and intimal thickening. Additionally, pretreatment with valsartan significantly reduced Ang II levels, AT 1 receptor, and p38 mitogen-activated protein kinase (MAPK) expression. Valsartan increased HO-1 protein and mRNA expression, as well as increased serum bilirubin levels compared with the surgery group. Significance Valsartan treatment decreased neointimal hyperplasia in balloon-injured rats. The mechanism of action might be linked to the upregulation of HO-1, downregulation of AT 1 receptor and inhibition of p38MAPK signal pathway.

In order to investigate the effect and mechanism of action of rosuvastatin on atherosclerotic lesion in a Wistar rat model, 16 Wistar rats were fed a cholesterol-rich, vitamin D 3 overload diet and underwent balloon injury of the aorta. One day prior to injury, half of the rats began rosuvastatin treatment (5 mg/kg/d) via oral gavage. Eight control rats received a basal diet and sham operation. After 14 weeks of treatment, the animals were sacrificed. Blood was collected to measure lipid and angiotensin II (Ang II) levels and morphologic analysis was performed on the aorta. Scavenger receptor-class B type I (SR-BI), Ang II type-1 (AT 1 ) receptor and phosphorylated extracellular signal regulated kinase 1/2 (p-ERK1/2) protein and mRNA levels were measured via Western blot and real time reverse transcriptase polymerase chain reaction, respectively. Spearman's rank correlation was utilized to examine the relationships between SR-BI and Ang II or AT 1 receptor expression. The atherosclerosis model group demonstrated an increase in plasma lipid levels and aortic plaque formation. After 14 weeks of treatment with rosuvastatin, there was a significant decrease in plasma lipid and Ang II levels accompanied by an improvement in aortic lesions. Rosuvastatin increased the expression of SR-BI but significantly inhibited the expression of AT 1 receptor and p-ERK1/2. SR-BI protein expression was inversely correlated with both the level of Ang II and expression of the AT 1 receptor. In conclusion, rosuvastatin attenuates atherosclerosis in the Wistar rat model, and its anti-atherosclerotic activity may be through upregulation of SR-BI expression and inhibition of p-ERK1/2 levels and AT 1 receptor expression.

In traditional Chinese medicine (TCM), xianfanghuomingyin (XFHM) is used to treat autoimmune diseases, including rheumatoid arthritis (RA). Here, we studied the mechanisms underlying its treatment effects, especially its anti-inflammatory effects in a collagen-induced arthritis (CIA) mouse model. We found that cartilage destruction and pannus formation were alleviated by treatment with XFHM. The abnormal differentiation of Th1 and Th17 cells was downregulated significantly by XFHM, and Th2 and Treg cells were upregulated. Moreover, the expression levels of specific cytokines and transcription factors related to Th1 cells (interferonγ[IFNγ], T-bet) and Th17 cells (interleukin- [IL-] 17) and the nuclear receptor retinoic acid receptor-related orphan receptor-gamma (RORγ) were downregulated. Serum IL-4 and GATA-3, which contribute to Th2 cells differentiation, increased significantly after XFHM administration. These results indicate that XFHM can restore the balance of T lymphocytes and reestablish the immunological tolerance to inhibit autoinflammatory disorder of RA. Taken together, XFHM can be used as a complementary or alternative traditional medicine to treat RA.

SAHA (vorinostat, Merck) is a famous clinical drug for zinc-containing histone deacetylase (HDAC) targets against cancer and several other human disorders, whose inhibition mechanism (namely the protonation mechanism) upon binding to HDAC has been debated for more than ten years. It is very challenging to verify experimentally and is still controversial theoretically. The popular "Class-dependent" (namely "Tyr-dependent") hypothesis is that the deprotonation of SAHA is mostly regulated by the conserved Tyr308 in class I HDAC while it is replaced by the His843 in class IIa HDAC. Herein, by elaborate QM(DFT)/MM MD simulations, we exclude the prevalent "Class-dependent" mechanism and advance a novel "Metal-dependent" mechanism, where the remote second metal site (K(+) in most HDAC and Ca(2+) in HDAC2) determines the protonation of SAHA. This proof-of-principle "Metal-dependent" mechanism opens up a new avenue to utilize the second metal site for isoform-selective inhibitor design.

Chlorogenic acid (CGA) and luteolin (Lut) are the predominant constituents of Caulis Lonicerae, which is usually used in the treatment for rheumatoid arthritis (RA).In this study, we investigated whether CGA and Lut could synergistically inhibit the proliferation of fibroblast-like synoviocytes (FLSs) in RA synovial tissues.Rat FLS cells (RSC-364) induced by interleukin (IL)-1β were treated by CGA, Lut or both of them. The apoptosis rates were detected by flow cytometer. Protein expression of key molecules of NF-κB and JAK/STAT signaling pathways were detected by Western blot.Treatment with CGA and Lut inhibited the proliferation of RSC-364 cells stimulated by IL-1β significantly and induced cell apoptosis notably. The ratio of apoptosis in RSC-364 cells induced with IL-1β accompanied by both CGA and Lut increased approximately 7-fold compared with those incubated with IL-1β alone. The results of immunoblot analysis revealed that the key molecules involved in the NF-κB and JAK/STAT-signaling pathways, including NF-κB p50, p100, IKKα/β, gp103, JAK1 and STAT3, were decreased significantly in RSC-364 cells treated by IL-1β plus CAG and Lut compared with those incubated with IL-1β alone. Additionally, the amounts of phospho-IKKα/β and phospho-STAT3 were also decreased significantly in cells treated with CGA and Lut. Furthermore, the synergistic effect of CGA and Lut was superior to the effect of one of these two ingredients.Our finding suggested that the combination of CGA and Lut may be a potential therapeutic treatment for the inflammatory proliferation of synoviocytes in patients with RA.

Rationale: Behcet's disease (BD) is a rare systemic vasculitis disorder that can involve vessels of any size. Patient Concerns: A 60-year-old female had recurrent painful mouth ulcers about 30 years ago and recently presented with abdominal distension, conjunctival congestion, and chest pain in sequence. Diagnoses: The patient was diagnosed with BD according to the International Criteria for Behcet's Disease (ICBD). Interventions: A therapy of glucocorticoids and cyclophosphamide was administered. Outcomes: After a 3-month treatment, follow-up examination showed a depression of the inflammation and a slight decrease of the arterial aneurysms. Lessons: BD patients may get a delayed diagnosis because of the long duration between the first and subsequent manifestations. Suspect patients should be followed-up and the diagnosis of BD should be considered when multiple tissues or organs are involved.

The role of the Mas receptor in the activity of valsartan against intimal hyperplasia is unclear. Herein, we investigated the role of the angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas receptor axis on the activity of valsartan against intimal hyperplasiain balloon-injured rat aortic arteries. Wistar rats were randomized equally into the sham control group, injured group, and injured plus valsartan (20 mg/kg/d)-treated group. Valsartan significantly attenuated the vascular smooth muscle cell proliferation and intimal and medial thickening on days 14 and 28 after injury. The angiotensin-(1-7) levels as well as ACE2 and Mas receptor mRNA/protein expression were significantly decreased in the injured rats, compared to the uninjured rats; meanwhile, the angiotensin II level as well as the ACE and AT1 receptor mRNA/protein expression were increased (all P

Background To validate a gradient-based segmentation method for gross tumor volume(GTV) delineation on 8F-fluorothymidine (FLT)positron emission tomography (PET)/ computer tomography (CT) in esophageal squamous cell cancer through pathologic specimen, in comparison with standardized uptake values (SUV) threshold-based methods and CT. The corresponding impact of this GTV delineation method on treatment planning was evaluated. Methods and materials Ten patients with esophageal squamous cell cancer were enrolled. Before radical surgery, all patients underwent FLT-PET/CT. GTVs were delineated by using four methods. GTVGRAD, GTV1.4 and GTV30%max were segmented on FLT PET using a gradient-based method, a fixed threshold of 1.4 SUV and 30% of SUVmax, respectively. GTVCT was based on CT data alone. The maximum longitudinal tumor length of each segmented GTV was compared with the measured tumor length of the pathologic gross tumor length (LPath). GTVGRAD, GTV1.4 and GTV30%max were compared with GTVCT by overlap index. Two radiotherapy plannings (planGRAD) and (planCT) were designed for each patient based on GTVGRAD and GTVCT. The dose-volume parameters for target volume and normal tissues, CI and HI of planGRAD and planCT were compared. Results The mean ± standard deviation of LPath was 6.47 ± 2.70 cm. The mean ± standard deviation of LGRAD,L1.4, L30%max and LCT were 6.22 ± 2.61, 6.23 ± 2.80, 5.95 ± 2.50,7.17 ± 2.28 cm, respectively. The Pearson correlation coefficients between LPath and each segmentation method were 0.989, 0.920, 0.920 and 0.862, respectively. The overlap indices of GTVGRAD, GTV1.4, GTV30%max when compared with GTVCT were 0.75 ± 0.12, 0.71 ± 0.12, 0.57 ± 0.10, respectively. The V5, V10, V20, V30 and mean dose of total-lung,V30 and mean dose of heart of planGRAD were significantly lower than planCT. Conclusions The gradient-based method provided the closest estimation of target length. The radiotherapy plannings based on the gradient-based segmentation method reduced the irradiated volume of lung, heart in comparison to CT.