Chrysophanol-mediated trx-1 activation attenuates renal fibrosis through inhibition of the JNK/Cx43 signaling pathway.

PURPOSE: This study aimed to investigate the inhibitory effect of chrysophanol on renal fibrosis and its molecular mechanism. METHODS: Initially, potential targets of chrysophanol were predicted through network pharmacology analysis, and a protein-protein interaction network of these targets was constructed using Venn diagrams and the STRING database. GO enrichment analysis predicted the biological process of chrysophanol in treating renal fibrosis. Subsequently, both in vivo and in vitro experiments were conducted using unilateral ureteral obstruction (UUO) induced CKD mouse model and HK-2 cell model, respectively. In the mouse model, different doses of chrysophanol were administered to assess its renal protective effects through biochemical indicators, histological examination, and immunofluorescence staining. In the cell model, the regulatory effect of chrysophanol on the Trx-1/JNK/Cx43 pathway was evaluated using western blotting and flow cytometry. RESULTS: Chrysophanol treatment significantly ameliorated renal dysfunction and histopathological damage in the UUO mouse model, accompanied by a reduction in serum oxidative stress markers. Furthermore, chrysophanol markedly upregulated the expression of Trx-1 in renal tissues and inhibited the activation of the JNK/Cx43 signaling pathway. At the cellular level, chrysophanol enhanced the activity of Trx-1 and downregulated the JNK/Cx43 signaling pathway, thereby inhibiting TGF-ß induced oxidative stress and cell apoptosis. CONCLUSION: This study demonstrated a significant inhibitory effect of chrysophanol on renal fibrosis, mediated by the activation of Trx-1 to inhibit the JNK/Cx43 pathway. These findings provide experimental support for the potential use of chrysophanol as a therapeutic agent for renal fibrosis.

Ultrasound-guided microwave ablation for secondary hyperparathyroidism: a systematic review and meta-analysis.

OBJECTIVES: Microwave ablation (MWA) is used for the treatment of severe secondary hyperparathyroidism (SHPT), but its efficacy and safety still remained unclear. This study aimed to investigate the efficacy and safety of ultrasound (US)-guided MWA in patients with SHPT. METHODS: The PubMed, Cochrane library, Embase, China national knowledge infrastructure (CNKI) and Wanfang databases were searched to identify published studies that evaluated the efficacy and safety of US-guided MWA in patients with SHPT. The primary outcomes were parathyroid hormone (PTH), serum calcium and phosphorus levels. RESULTS: A total of 26 studies with 932 patients were identified. The PTH levels showed significant reduction at 1 month [weighted mean difference (WMD) = 945.33, 95% CI: 797.15∼1093.52] and 6 months (WMD = 1,151.91, 95% CI: 990.93∼1312.89) after MWA of SHPT patients. The serum calcium (WMD = 0.39, 95% CI: 0.30 ∼ 0.48) and phosphorus levels (WMD = 0.64, 95% CI: 0.43 ∼ 0.85) showed significant reduction at 6 months after MWA of SHPT patients. The most common complications observed were hypocalcemia (35.2%) and transient hoarseness (9.2%). No other major complications or death occurred in our study patients. CONCLUSION: These findings suggest MWA as a safe and effective minimally invasive technique for the management of SHPT. PTH, calcium, and phosphorus levels were significantly reduced at 1 and 6 months after MWA.

Improved oral bioavailability and anti-chronic renal failure activity of chrysophanol via mixed polymeric micelles.

AIMS: This study was designed to prepare chrysophanol-loaded micelles (CLM) to improve the oral bioavailability, targetability and anti-chronic renal failure (CRF) activity of chrysophanol (CH). METHODS: The preparation of CLM was achieved via thin-film dispersion technique. The in vitro release of CLM compared with free CH was measured in phosphate buffer solution (PBS) containing 0.5%w/v sodium dodecyl sulphate (pH 6.8) while the pharmacokinetic and anti-CRF activity study was also conducted in rats. Moreover, the tissue distribution of CLM was investigated in the mice. RESULTS: The CLM had particle size (PS) of 29.64 ± 0.71 nm, and encapsulation efficiency (EE) of 90.48 ± 1.22%w/w. The cumulative release rate of CH from the micellar system was significantly higher than that of the free CH (86%m/m vs. 15%m/m, p < 0.01). In vivo pharmacokinetic studies showed that the bioavailability of CLM after oral administration was substantially improved (about 3.4 times) compared with free drugs (p < 0.01). Also, it was observed that CLM accumulated well in the liver and brain. Moreover, in vitro renal podocytes study showed that CLM had better protection against renal podocyte damage than the free CH. In addition, CLM significantly (p < 0.01) reduced levels of blood urea nitrogen (BUN), kidney injury molecule-1 (Kim-1), and serum creatinine (SCr), which obviously improved kidney damage in rats with CRF. CONCLUSIONS: Collectively, these findings suggest that mixed micelles may be used as a promising drug delivery system for oral bioavailability improvement and concomitantly enhance the anti-CRF activity of CH, as well as provide a basis for the clinical application of CH.

Preparation of Fraxetin Long Circulating Liposome and Its Anti-enteritis Effect.

This study sought to improve the oral bioavailability and enhance the anti-enteritis effect of fraxetin by incorporating it into long circulating liposomes (F-LC-Lipo). The optimal formulation of F-LC-Lipo was obtained via orthogonal design. The particle size, morphology, encapsulation efficiency, stability, and anti-enteritis effect of F-LC-Lipo were evaluated. The particle size of F-LC-Lipo was 166.65 ± 8.75 nm with entrapment efficiency (EE) of 92.18 ± 0.17%. The release rate in different dissolution media (pH 1.2 HCl, DDW, and pH 7.4 PBS) was significantly higher than that of fraxetin solution. Compared with the free fraxetin solution, F-LC-Lipo increased oral bioavailability of fraxetin by 4.43 times (443%). More importantly, F-LC-Lipo could improve the levels of interleukin-1 beta (IL-1ß), IL-6, malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), prostaglandin E2 (PEG2), and IL-10 in rats with enteritis. Overall, these results suggested that LC-Lipo may serve as a potential carrier for improving the solubility and oral bioavailability of fraxetin as well as improving its enteritis effect.

[Network pharmacological analysis and preliminary validation of mechanisms of Baitouweng Decoction in treatment of ulcerative colitis].

The aim of this paper was to explore the pharmacological mechanism of Baitouweng Decoction in the treatment of ulcerative colitis(UC) by network pharmacology and to preliminarily verify the related targets by animal experiments. Cytoscape software was used to construct "ingredient-target-disease" network through TCMSP, GeneCards and Uniprot databases. The protein interaction network was constructed using STRING database, and the core targets were speculated. The GO and KEGG enrichment analysis was conducted using R software. Autodock Vina software was used for molecular docking of ingredients and core targets. UC mice induced by dextran sodium sulfate(DSS) were treated by Baitouweng Decoction. The pathological changes of colon tissues were observed by HE staining, and the expression levels of related genes were analyzed by immunohistochemistry.The results showed that 26 active ingre-dients and 30 core targets were found in Baitouweng Decoction through network pharmacology. GO enrichment analysis showed that these genes mainly affected nuclear receptor activity, transcription factor activity, steroid hormone receptor activity, ubiquitin-like protein ligase binding, protein heterodimerization activity, transcription cofactor binding and other biological processes. KEGG enrichment analysis showed that P53 signaling pathway, EGFR signaling pathway, TNF signaling pathway, PI3 K-AKT signaling pathway and some cancer-related pathways were enriched. Molecular docking showed that EGFR, PPARG, CASP3, NOS3, caspase-9, CCND1, ADH, IL6 and NFKB1 were better docked with active ingredients. The experiments verified that Baitouweng Decoction could improve the colon pathology of mice, and EGFR is one of the related targets. Our study suggested that Baitouweng Decoction could treat UC through multiple targets and pathways, which provided a theoretical basis for future research.

Isoliquiritin Ameliorates Ulcerative Colitis in Rats through Caspase 3/HMGB1/TLR4 Dependent Signaling Pathway.

BACKGROUND: Isoliquiritin belongs to flavanol glycosides and has a strong antiinflammatory activity. This study sought to investigate the anti-inflammatory effect of isoliquiritin and its underlying mechanism. METHODS: The inflammatory (trinitro-benzene-sulfonic acid-TNBS-induced ulcerative colitis (UC)) model was established to ascertain the effect of isoliquiritin on the caspase-3/HMGB1/TLR4 pathway in rats. We also explored its protective effect on intestinal inflammation and its underlying mechanism using the LPS-induced inflammation model of Caco-2 cells. Besides, Deseq2 was used to analyze UCassociated protein levels. RESULTS: Isoliquiritin treatment significantly attenuated shortened colon length (induced by TNBS), disease activity index (DAI) score, and body weight loss in rats. A decrease in the levels of inflammatory mediators (IL-1ß, I IL-4, L-6, IL-10, PGE2, and TNF-α), coupled with malondialdehyde (MDA) and superoxide dismutase (SOD), was observed in colon tissue and serum of rats after they have received isoliquiritin. Results of techniques (like western blotting, real-time PCR, immunohistochemistry, and immunofluorescence-IF) demonstrated the potential of isoliquiritin to decrease expressions of key genes in the TLR4 downstream pathways, viz., MyD88, IRAK1, TRAF6, NF-κB, p38, and JNK at mRNA and protein levels as well as inhibit HMGB1 expression, which is the upstream ligand of TLR4. Bioinformational analysis showed enteritis to be associated with a high expression of HMGB1, TLR4, and caspase-3. CONCLUSION: Isoliquiritin could reduce intestinal inflammation and mucosal damage of TNBS-induced colitis in rats with a certain anti-UC effect. Meanwhile, isoliquiritin treatment also inhibited the expression of HMGB1, TLR4, and MyD88 in LPS-induced Caco-2 cells. These results indicated that isoliquiritin could ameliorate UC through the caspase-3/HMGB1/TLR4-dependent signaling pathway.

Construction of chrysophanol loaded nanoparticles with N-octyl-O-sulfate chitosan for enhanced nephroprotective effect.

Natural occurring anthraquinone like chrysophanol has been studied because of its anti-diabetic, anti-tumor, anti-inflammatory, hepatoprotective and neuroprotective properties. Nonetheless, its poor water solubility and unstable nature are big concerns in achieving efficient delivery and associated pharmacokinetic and pharmacodynamic effects. Herein, this study sought to solve the above-mentioned problem through development of chrysophanol-loaded nanoparticles to enhance the bioavailability of chrysophanol and to evaluate its anti-renal fibrosis effect in rats. After synthesis of a safe N-octyl-O-sulfate chitosan, we used it to prepare chrysophanol-loaded nanoparticles through dialysis technique before we performed and physical characterization. Also, we tested the stability of the nanoparticles for 21 days at 4 °C and room temperature (25 °C) and evaluated their pharmacokinetics and anti-renal fibrosis effect in rat model of chronic kidney disease (CKD). In terms of results, the nano-preparation demonstrated an acceptable narrow size distribution, wherein the encapsulation rate, size, polydispersed index (PDI) and electrokinetic potential at room temperature were respectively 83.41±0.89 %, 364.88±13.62 nm, 0.192±0.015 and 23.78±1.39 mV. During 21 days of storage, we observed that size of particles and electrokinetic potential altered slightly but the difference was statistically insignificant (p > 0.05). Also, in vitro release studies showed that the formulation reached 84.74 % at 24 h. Chrysophanol nanoparticles showed a 2.57-fold increase in bioavailability compared to unformulated chrysophanol. More importantly, chrysophanol nanoparticles demonstrated certain renal internalization properties and anti-renal fibrosis effects, which could ultimately result in reduced blood-urea nitrogen (BUN), kidney-injury molecule-1 (KIM-1) and serum creatinine (SCr) levels in model rats. In conclusion, the prepared chrysophanol-loaded nanoparticles potentially increased bioavailability and enhanced nephroprotective effects of chrysophanol.

Immunosuppressive treatment for idiopathic membranous nephropathy: An updated network meta-analysis.

This network meta-analysis (NMA) aims to investigate the efficacy and safety of different pharmacological treatments for idiopathic membranous nephropathy (IMN). Thirty-four relevant studies were extracted from PubMed, Embase, Cochrane database, and MEDLINE. Treatment with tacrolimus (TAC), cyclophosphamide (CTX), mycophenolate mofetil, chlorambucil (CHL), cyclosporin A (CSA), steroids, rituximab (RTX), and conservative therapy were compared. Outcomes were measured using remission rate and incidence of side effects. Summary estimates were expressed as the odds ratio (OR) and 95% confidence intervals (CIs). The quality of findings was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. In the direct meta-analysis for comparison of complete remission (CR) rate, the curative effect of RTX is inferior to CTX (OR 0.37; CI 0.18, 0.75). In the NMA of CR rate, the results showed that the curative effects of CTX, CHL, and TAC were significantly higher than those of the control group. The efficacy of RTX is not inferior to the CTX (OR 0.81; CI 0.32, 2.01), and the level of evidence was moderate; CSA was not as effective as RTX, and the difference was statistically significant with moderate evidence (OR 2.98, CI 1.00, 8.91). In summary, we recommend CTX and RTX as the first-line drug for IMN treatment.

Synergistic antitumor efficacy of PD-1-conjugated PTX- and ZSQ-loaded nanoliposomes against multidrug-resistant liver cancers.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor chemotherapeutic efficiency due to multidrug resistance (MDR); it is very important to develop a targeted nanocarrier for the treatment of HCC. In this study, a programmed death ligand 1 (PD-L1)-conjugated nanoliposome was constructed for co-delivery of paclitaxel (PTX) and P-glycoprotein (P-gp) inhibitor zosuquidar (ZSQ) to overcome MDR in human HCC cells and tumors in vivo. Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) were used to examine the nanoparticles morphology and size; PD-1-conjugated PTX and ZSQ-loaded nanoliposomes (PD-PZLP) revealed a spherical shape with a size of 139.5 ± 10.7 nm. Then, the physicochemical properties, as well as the drug loading capacity, release profile, cellular uptake, and cytotoxicity of the dual drug-encapsulated nanoliposomes were characterized. PD-PZLP displayed a high drug loading capacity of 20 ~ 30% for both PTX and ZSQ; the drug release of PTX and ZSQ in pH 5.0 was significantly faster than in pH 7.4. Cellular uptake study demonstrated PD-PZLP had higher internalization efficiency than non-targeted PZLP. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and reactive oxygen species (ROS) analysis demonstrated that PD-PZLP triggered an excessive ROS reaction and cell apoptosis compared with that of free PTX or ZSQ, which was also consistent with the cell antiproliferative effects in MTT assay. Furthermore, PD-PZLP could enhance synergistic antitumor effects on 7721/ADM xenograft tumor model, which also significantly alleviated hepatotoxicity as evident from the decreased aspartate transaminase (AST) and alanine transaminase (ALT) levels. Overall, PD-PZLP exhibited high loading capacity, significant synergistic effects, promising antitumor efficacy, and the lowest toxicity, which provide a promising strategy to overcome MDR in HCC.

Treatment of Modified Dahuang Fuzi Decoction on Cognitive Impairment Induced by Chronic Kidney Disease through Regulating AhR/NF-κB/JNK Signal Pathway.

Aim: An increasing widespread of chronic kidney disease (CKD) has been established lately around the globe. In addition to renal function loss, CKD can also cause cognitive impairment (CI). Modified Dahuang Fuzi Decoction (MDFD) is used as a traditional Chinese therapy for CKD. The effect of MDFD on cognitive impairment induced by chronic kidney disease (CKD-CI), and therapeutic mechanisms were investigated. Methods: The CKD animals' model was developed in the 5/6 nephrectomized mice. Sham operation and model groups received normal saline, while positive control and MDFD high/medium/low dose received Aricept (10 mg/kg/day) and different doses of MDFD (24, 16, and 8 g/kg/day), respectively. Cognitive function was detected with the Morris water maze test, while related factors were determined by ELISA. Histopathology and mechanism were studied using HE, western blot, and qRT-PCR. Results: In the CKD-CI mice model, escape latency decreased significantly, whereas time of crossing platform and time spent within the platform quadrant increased substantially (P < 0.05) after MDFD treatment. Moreover, renal function and brain injury in CKD-CI improved dose-dependently, while the effect of MDFD-L was worse. Proteins such as aryl hydrocarbon receptor, nuclear factor-kappa B and c-Jun-N-terminal kinase, and mRNA in the kidney and brain of all the treatment groups decreased substantially (P < 0.05). Expression of tropomyosin receptor kinase B and brain-derived neurotrophic factor at protein and mRNA levels in the brain were significantly enhanced (P < 0.05). Conclusion: MDFD presumably activated the BDNF/TrkB pathway by inhibiting the AhR/NF-κB/JNK signaling pathway to treat CKD-CI.

Efficacy of Urate-Lowering Therapy in Patients With Chronic Kidney Disease: A Network Meta-Analysis of Randomized Controlled Trials.

PURPOSE: The goal of this study was to systematically review the efficacy and safety of urate-lowering therapy in patients with chronic kidney disease (CKD). METHODS: PubMed, the Cochrane Central Registration of Controlled Trials, and EMBASE databases and several websites were electronically searched to collect randomized clinical trials on the efficacy of urate-lowering therapy in CKD from inception to December 31, 2020. The key primary end points were uric acid or estimated glomerular filtration rate (eGFR) levels; the safety end points were death, renal event, cardiovascular event, and gastrointestinal event. A Bayesian network meta-analysis was conducted with the use of ADDIS and R software. FINDINGS: A total of 17 randomized clinical trials involving 2059 patients were included. The results of network meta-analysis showed that urate-lowering therapy could reduce urate levels in patients with CKD. Febuxostat was the most effective treatment in lowering urate levels according to the rank probability. Urate-lowering therapy has the tendency to delay the decline of eGFR, but the difference was not statistically significant. Ranking probability showed that benzbromarone, febuxostat, and allopurinol ranked higher than placebo in reducing the decline of eGFR. There were no statistically significant differences between groups in the incidence of all adverse effects. IMPLICATIONS: All urate-lowering therapies could reduce the urate level in patients with CKD, but the benefit of such therapy in renal disease is still unclear. PROSPERO identifier: CRD42020222601.

Dual-targeted colon-based integrated micelle drug delivery system for treatment of ulcerative colitis.

Emodin (EMO) is an active ingredient of Chinese traditional medicine with the potential to reportedly treat ulcerative colitis (UC). However, the solubility of EMO in water is poor coupled with low oral bioavailability, whilst existing conventional oral preparations of the drug lack targeting ability. Thus, this work sought to design and fabricate a mannose modified colon targeted micelle drug delivery system comprising quantum dots (QDs) and EMO to obtain Eu-CS-Man-Ps-P(HEMA-DMAM)/EMO-QDs, which exhibited stable physicochemical properties, smaller average sized droplets (226.22 ± 1.83 nm), better polydispersity (PDI = 0.060 ± 0.005), negative ζ-potential (-19.19 ± 0.89 mV) and high efficiency of encapsulation (95.14 ± 0.23%). We observed Eu-CS-Man-Ps-P(HEMA-DMAM)/EMO-QDs to be an effective approach for the improvement of EMO solubility in an aqueous medium with an increased oral bioavailability (3.23 times higher than native drug) of the drug. Besides, the micelle could increase the retention and release of EMO in colonic ulcers through multi-stage targeting, improve oral bioavailability, regulate the expression of inflammatory factors and repair damaged tissues, which helped us to achieve the design goal of integrated diagnosis and treatment of UC. Conclusively, the therapeutic effect of EMO was enhanced through an integrated micelle, which exhibited good prospects in improving solubility and oral biological availability.

Eriodictyol suppresses the malignant progression of colorectal cancer by downregulating tissue specific transplantation antigen P35B (TSTA3) expression to restrain fucosylation.

Eriodictyol is a natural flavonoid with many pharmacological effects, such as anti-oxidation, anti-inflammation, anti-tumor, and neuroprotection. Besides, it has been reported that flavonoids play an important role in protein glycosylation. The fucosylation structure is closely associated with processes of various tumor metastases. TSTA3 is involved in the de novo synthesis and can convert cellular GDP-D-mannose into GDP-L-fucose. It was predicted on the STITCH database that eriodictyol interacted with TSTA3. In addition, literature has confirmed that TSTA3 is upregulated in CRC and can regulate the proliferation and migration of breast cancer cells. Herein, the precise effects of eriodictyol on the clone-forming, proliferative, migratory and invasive abilities of CRC cells as well as EMT process were assessed. Moreover, the correlation among eriodictyol, TSTA3, and fucosylation in these malignant behaviors of CRC cells was evaluated, in order to elucidate the underlying mechanism. The current work discovered that eriodictyol inhibited the viability, clone-formation, proliferation, migration, invasion, and EMT of CRC cells, and that these inhibitory effects of eriodictyol on the malignant behavior of CRC cells were reversed by TSTA3 overexpression. Additionally, eriodictyol suppresses fucosylation by downregulating the TSTA3 expression. Results confirmed that fucosylation inhibitor (2-F-Fuc) inhibited clone formation, proliferation, migration, invasion, as well as EMT of CRC cells and eriodictyol treatment further reinforced the suppressing effects of 2-F-Fuc on the malignant behavior of CRC cells. We conclude that eriodictyol suppresses the clone-forming, proliferative, migrative and invasive abilities of CRC cells as well as represses the EMT process by downregulating TSTA3 expression to restrain fucosylation.

Serum calcium-phosphorus product for predicting the risk of osteoporotic vertebral compression fractures in elderly patients: a retrospective observational study.

BACKGROUND: This study retrospectively analyzed and evaluated the potential correlations of serum calcium, serum phosphorus, and calcium-phosphorus product (Ca-P product) with the incidence of osteoporotic vertebral compression fractures (OVCFs), with the aim of exploring whether the Ca-P product can be used as a serological indicator to predict the risk of OVCFs. METHODS: This study randomly enrolled 400 elderly patients in our hospital with OVCFs and 400 patients with hip and knee arthroplasty due to femoral head necrosis or osteoarthritis from August 2013 to April 2021. Age, sex, past medical history, and admission biochemical indicators, including albumin, blood urea nitrogen, serum creatinine, serum calcium and serum phosphorus, were collected for statistical analysis. RESULTS: Albumin, serum calcium, serum phosphorus, Ca-P product, corrected serum calcium and corrected Ca-P product were lower in the OVCF group than in the non-OVCF group (P < 0.05). Multivariate logistic regression analysis showed that low values of serum calcium, serum phosphorus, Ca-P product, corrected blood calcium, and corrected Ca-P product can all be risk factors for OVCF. The ROC curve showed that the Ca-P product and corrected Ca-P product were effective in predicting the risk of OVCFs. The predictive value of the Ca-P product was the best; the cutoff point was 29.88, the sensitivity was 0.72 and the specificity was 0.62. The cutoff point of the corrected Ca-P product was 30.50, the sensitivity was 0.74, and the specificity was 0.62. CONCLUSION: The Ca-P product and corrected Ca-P product can be used as serological indicators to predict the risk of OVCFs in elderly individuals. Early clinical interventions targeting this risk factor can further reduce the risk of OVCFs. Also, timely and regular testing of the serum calcium and phosphorus level is recommended and encouraged for this group of people.

Chrysophanol, a main anthraquinone from Rheum palmatum L. (rhubarb), protects against renal fibrosis by suppressing NKD2/NF-κB pathway.

PURPOSE: Chronic kidney disease (CKD), characterized as renal dysfunction and multi-system damage, has become a serious public health problem with high prevalence and mortality. Rheum palmatum L. (rhubarb) is one of the most widely used Chinese herb with renal protective activity. However, the active components and underlying mechanisms of rhubarb remain unknown. In this work, we tried to explore the pharmacological mechanism of chrysophanol, a main anthraquinone from rhubarb, against CKD by in vivo and in vitro models. STUDY DESIGN: The therapeutic effect of chrysophanol and its underlying mechanism were investigated using CKD mouse model induced by unilateral ureteral occlusion (UUO), and human kidney 2 (HK-2) cells stimulated by TGF-ß1 in vivo. METHODS: The impact of chrysophanol on renal function, inflammation, fibrosis of CKD mice were evaluated. Then, the protein expressions of FN1, collagen ɑI, α-SMA, NF-κB and naked keratinocyte homolog 2 (NKD2) were investigated. In vitro studies, the inhibition on inflammation and fibrogenesis by chrysophanol was further validated in TGF-ß1-stimulated HK2 cells, and the regulation of chrysophanol on NKD2/NF-κB pathway was analyzed. Moreover, NKD2 was overexpressed in HK-2 cells to confirm the role of NKD2/NF-κB pathway in chrysophanol-mediated efficacy. Finally, the binding mode of chrysophanol with NKD2 was studied using in silico molecular docking and microscale thermophoresis (MST) assay. RESULTS: Chrysophanol could significantly improve the kidney dysfunction, alleviate renal pathology, and reverse the elevated levels of renal fibrosis markers such as FN1, collagen ɑI and α-SMA. Furthermore, chrysophanol effectively inhibited TNF-α, IL-6, and IL-1ß production, and suppressed NF-κB activation and NKD2 expression. The findings of in vitro study were consistent with those of animal expriment. Using NKD2-overexpressing HK-2 cells, we also demonstrated that overexpression of NKD2 significantly compromised the anti-fibrotic effects of chrysophanol. In addition, molecular docking and MST analysis revealed that NKD2 was a direct target of chrysophanol. CONCLUSION: Together, our work demonstrated for the first time that chrysophanol could effectively ameliorate renal fibrosis by inhibiting NKD2/NF-κB pathway. Chrysophanol can potentially prevent CKD by suppressing renal NKD2 expression directly.

Comparison of Therapies for Secondary Prophylaxis of Esophageal Variceal Bleeding in Cirrhosis: A Network Meta-analysis of Randomized Controlled Trials.

PURPOSE: The decision regarding the optimal secondary prophylactic treatment for esophageal variceal bleeding (EVB) in hepatic cirrhosis is controversial. A network meta-analysis was conducted to assess the benefits of various treatments for the secondary prophylaxis of EVB in patients with cirrhosis. METHODS: A thorough examination of databases, including EMBASE, PubMed, and Cochrane Database of Controlled Trials, was conducted to identify relevant randomized controlled trials up to December 2019. Key primary outcomes included mortality and rebleeding. Within the identified databases, a network meta-analysis was performed. Results were expressed by using a 95% credible interval (CrI) and odds ratios (ORs). The quality of results was assessed by using the Grading of Recommendations, Assessment, Development and Evaluation approach. FINDINGS: Forty-eight trials with 4415 participants with cirrhosis and portal hypertension who had a history of recent variceal bleeding were included. Carvedilol ranked first (surface under the cumulative ranking curve [SUCRA], 87.4%) in overall survival, and some advantage was suggested; however, the findings were not statistically significant, compared with endoscopic variceal ligation + nonselective beta-blockers (NSBB) (OR, 0.59; CrI, 0.28, 1.3), NSBB + isosorbide mononitrate (OR, 0.67; CrI, 0.33, 1.4), and transjugular intrahepatic portosystemic shunt (TIPS) (OR, 0.52; CrI, 0.24, 1.1). NSBB + isosorbide mononitrate (SUCRA, 63.9%) ranked higher than NSBB + endoscopic variceal ligation (SUCRA, 49.6%) in reducing mortality. TIPS (SUCRA, 98.8%) ranked higher than other treatments in reducing rebleeding but did not confer any survival benefit. IMPLICATIONS: TIPS ranks first in preventing rebleeding of secondary prophylaxis of EVB and carvedilol shows outstanding efficacy in improving survival. International Prospective Register of Systematic Reviews: identifier CRD42019131814.

Baitouweng Decoction Ameliorates Ulcerative Colitis in Mice Partially Attributed to Regulating Th17/Treg Balance and Restoring Intestinal Epithelial Barrier.

Ulcerative colitis (UC) is a chronic intestinal disease with unclear pathogenesis. With an increasing global prevalence over the past two decades, UC poses a serious threat to public health. Baitouweng decoction (BTW), a traditional Chinese medicine, has been shown to have good clinical efficacy for treating intestinal inflammation. Yet, the efficacy of BTW in UC and the underlying mechanism remain unclear. The current study aimed to determine whether BTW suppressed intestinal inflammation in mice and the potential mechanism. We used a dextran sulfate sodium (DSS)-induced murine colitis model to test the anti-inflammatory efficacy of BTW. Clinical symptoms were scored by the disease activity index (DAI), and the colon length and pathological changes in colon tissue were also used to further evaluate the efficacy of BTW. Precisely how BTW affected immune function and the intestinal barrier of UC mice was also examined. BTW significantly reduced DAI score and colonic pathological damage. BTW regulated the balance between T helper (Th)17 and regulatory T (Treg) cells, decreased interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α, and increased IL-10 levels. BTW reduced intestinal permeability of UC mice, increased expression of tight junction proteins (occludin and zonula occludens-1), and decreased expression of phospho-nuclear factor (p-NF)-κB and phospho-extracellular signal-regulated kinase (p-ERK) in the colon. BTW inhibited the ERK/p-NF-κB signaling pathway and suppressed expression of cyclo-oxygenase-2 and inducible NO synthase in lipopolysaccharide-activated RAW 264.7 cells. BTW significantly promoted the synthesis of short-chain fatty acids in the gut, particularly acetate, propionate, isobutyric acid, and isovalerate. The results suggest that BTW can protect against DSS-induced UC. The mechanism may be partially attributed to regulating the balance of Th17/Treg cells and restoring the intestinal epithelial barrier.