Effects of honokiol protects against chronic kidney disease via BNIP3/NIX and FUNDC1-mediated mitophagy and AMPK pathways.

BACKGROUND: Chronic kidney disease (CKD) is a serious health threat worldwide. Defective mitophagy has been reported to induce mitochondrial dysfunction, which is closely associated with CKD pathogenesis. Honokiol (HKL) is a bioactive component of Magnolia officinalis that has multiple efficacies. Our study aimed to investigate the effect of HKL on a CKD rat model and explore the possible mechanisms of mitophagy mediated by Bcl-2 interacting protein 3 and BNIP3-like (NIX) (also known as the BNIP3/NIX pathway) and FUN14 domain-containing 1 (the FUNDC1 pathway) and the role of the AMP-activated protein kinase (AMPK) pathway. METHODS: A CKD rat model was established by feeding the animals dietary adenine (0.75% w/w, 3 weeks). Simultaneously, the treatment group was given HKL (5 mg/kg/day, 4 weeks) by gavage. Renal function was assessed by measuring serum creatinine (Scr) and blood urea nitrogen (BUN) levels. Pathological changes were analyzed by periodic acid-Schiff (PAS) and Masson's trichrome staining. Protein expression was evaluated by Western blotting and immunohistochemistry. RESULTS: HKL treatment ameliorated the decline in renal function and reduced tubular lesions and interstitial fibrosis in CKD rats. Accordingly, the renal fibrosis markers Col-IV and α-SMA were decreased by HKL. Moreover, HKL suppressed the upregulation of the proapoptotic proteins Bad and Bax and Cleaved caspase-3 expression in CKD rats. Furthermore, HKL suppressed BNIP3, NIX and FUNDC1 expression, leading to the reduction of excessive mitophagy in CKD rats. Additionally, AMPK was activated by adenine, and HKL reversed this change and significantly decreased the level of activated AMPK (phosphorylated AMPK, P-AMPK). CONCLUSION: HKL exerted a renoprotective effect on CKD rats, which was possibly associated with BNIP3/NIX and FUNDC1-mediated mitophagy and the AMPK pathway.

The effects of natural products and bioactive ingredients of traditional Chinese medicine on apoptosis of ovarian granulosa cells.

Abnormal ovarian function is the main manifestation of female reproductive toxicity. Granulosa cells (GCs) play an important role in determining the fate of follicles and are the main effector cells of the female reproductive system. Excessive apoptosis of GCs leads to pathological folliculogenesis and further reproductive damage. However, drugs available for treatment of female reproductive toxicity are limited. Recent studies have confirmed that various natural products and bioactive ingredients of traditional Chinese medicine (TCM) can inhibit apoptosis of GCs and protect ovarian function. In this review, the mechanisms underlying the proapoptotic and antiapoptotic effects of natural products and bioactive ingredients of TCM on the proliferation, function, and apoptosis of GCs are summarized based on the findings of reports published over the past 10 years as reference for the treatment of female reproductive toxicity.

Clinical prognostic role of bioimpedance phase angle in diabetic and non-diabetic hemodialysis patients.

BACKGROUND AND OBJECTIVES: Bioelectrical-impedance analysis (BIA) is frequently used to estimate dry weight in hemodialysis (HD) patients. However, the clinical prognostic significance of BIA indicators is unclear. As a nutritional index, low phase angle (PA) might be an independent risk factor for predicting death in multiple chronic diseases. We performed this study to find relative influence factors of PA and other clinical prognostic significance. METHODS AND STUDY DESIGN: The study involved 87 HD patients, 33 of whom were diabetic and 54 of whom were not. We measured body composition index, body water index and nutritional indicators and collected biochemical criteria. Then, we statistically analyzed the associations of these indices. After 1 year of follow- up, we recorded death, heart failure, hospitalization, cerebrovascular and cardiovascular events and other clinical outcomes. RESULTS: We found a significant difference between the two groups in visceral-fat area, extracellular water/total body water (ECW/TBW) ratio and PA value. Two factors were negatively associated with PA: ECW/TBW ratio and HCO3- before HD. At 1 year, we noted that PA was associated with events such as heart failure or hospitalization. By further stratification and multivariate analysis adjusting for age, sex and months of dialysis, we found that low PA was an independent predictor of heart failure for diabetic HD patients. CONCLUSIONS: PA value was lower in Diabetic nephropathy (DN) HD patients, than that in non-DN HD patients. PA was mainly negatively associated with ECW/TBW ratio. It is a useful index for predicting heart failure in diabetic HD patients.

Non-high-density lipoprotein cholesterol may predict the cardio-cerebrovascular risk in patients on maintenance hemodialysis.

BACKGROUND: Non-high-density lipoprotein cholesterol (non-HDL-C) may be an independent risk factor for cardio-cerebrovascular disease (CVD); however, the cutoff level in patients on maintenance hemodialysis (MHD) is unknown. METHODS: This was a retrospective multicenter study of MHD patients treated at 10 dialysis centers in Guangdong Province from July 1, 2016, to April 1, 2017. Laboratory test data were collected and CVD complications and outcomes recorded. RESULTS: In total, 1288 eligible patients were included in this study; the non-HDL-C interquartile range was 2.76 (2.24-3.45) mmol/L. Over a median follow-up time of 24 months, 141 patients developed CVD. The non-HDL-C level was a principal risk factor for such events (P < 0.05; 95% confidence interval 0.800-0.842). The maximum Youden index was 0.549 and the best cutoff > 3.39 mmol/L. CONCLUSION: Higher baseline non-HDL-C levels may increase the CVD risk in MHD patients. Thus, non-HDL-C effectively predicts CVD.

Chemical characterisation and quantification of the major constituents in the Chinese herbal formula Jian-Pi-Yi-Shen pill by UPLC-Q-TOF-MS/MS and HPLC-QQQ-MS/MS.

INTRODUCTION: Jian-Pi-Yi-Shen pill (JPYSP) is a Chinese medicine formula developed for the treatment of anaemic patients with chronic kidney disease (CKD). OBJECTIVE: To investigate the chemical profile of JPYSP in the treatment of renal anaemia. METHODS: A method coupling ultra-performance liquid chromatography with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) was established to characterise the chemical constituents present in JPYSP. Subsequently, a high-performance liquid chromatography method coupled with triple-quadrupole tandem mass spectrometry (HPLC-QQQ-MS/MS) was developed to quantify the major constituents from the identified compounds related to the treatment of CKD and anaemia. RESULTS: A total of 71 compounds were tentatively identified from JPYSP, including saponins, flavonoids, sesquiterpenoids, coumarins, phenylpropanoids, anthranones, anthraquinones, tannins, phenolic acids and others. Amongst them, 12 compounds (i.e. astragaloside IV, calycosin, calycosin 7-O-glucoside, salvianolic acid A, rosmarinic acid, rhein, liquiritin, formononetin, atractylenolide I, dioscin, tanshinone IIA, and acteoside) were further quantified simultaneously by HPLC-QQQ-MS/MS. CONCLUSION: The newly developed approach is suitable for the chemical profiling analysis and quality control of JPYSP, and could lead to additional pharmacodynamic studies involving the components of JPYSP.

Jian-Pi-Yi-Shen Formula ameliorates chronic kidney disease: involvement of mitochondrial quality control network.

BACKGROUND: Jian-Pi-Yi-Shen Formula (JPYSF), a Chinese herbal decoction with the efficacies of 'fortify the spleen and tonify the kidney' and 'activate blood and resolve stasis', is effective for the treatment of chronic kidney disease in clinic. However, the underlying mechanism remains unclear. The aim of this study was to investigate the therapeutic effects and possible mechanisms of JPYSF on retarding chronic kidney disease progression in 5/6 nephrectomized (5/6 Nx) rats. METHODS: Perindopril (4 mg/kg/d) and JPYSF (2.72 g/kg/d) were administrated by gavage to 5/6 Nx rats daily for 6 weeks. The therapeutic effects of JPYSF were evaluated by renal function, pathological injury, and fibrosis. The protein levels associated with mitochondrial quality control network were measured by Western blot and immunofluorescence analysis. RESULTS: 5/6 Nx rats showed obvious decline in renal function as evidenced by increased serum creatinine, blood urea nitrogen, and urinary protein excretion, and significant injury in kidney structure as evidenced by glomerular hypertrophy, tubular atrophy, and interstitial fibrosis. Administration of JPYSF for 6 weeks could improve renal function and ameliorate kidney structure injury in 5/6 Nx rats. Furthermore, the remnant kidneys of 5/6 Nx rats showed unbalanced mitochondrial quality control network manifested as decreased mitochondrial biogenesis, fusion, and mitophagy, and increased mitochondrial fission. Treatment of JPYSF could restore aforesaid aspects of mitochondrial quality control network. CONCLUSIONS: These results indicate that JPYSF can notably ameliorate 5/6 Nx-induced chronic kidney disease, which may be related with modulation of mitochondrial quality control network.

A Chinese herbal decoction, Jian-Pi-Yi-Shen, regulates the expressions of erythropoietin and pro-inflammatory cytokines in cultured cells.

BACKGROUND: A Chinese herbal formula, namely Jian-Pi-Yi-Shen (JPYS), has been clinically prescribed for patients with chronic kidney disease associated-anemia, and which can improve the patient's immunological system. However, the mechanisms of JPYS involved in anemia and immune response have not been investigated. To study the role of JPYS in regulating hematopoietic and immunological functions, we investigated its activities on the expressions of erythropoietin and pro-inflammatory cytokines in cultured cells. METHODS: The standardized herbal extracts of JPYS (0-30 µg/ml) were applied onto cultured cells for 24-48 h. Total RNA was collected from the treated cells and subjected to real-time quantitative PCR analysis. Cultured HEK293T cells, transfected with a construct composed of hypoxia response element tagged with a luciferase gene, i.e. pHRE-Luc, were treated with JPYS extracts (1-30 µg/ml) for 24 h. The cell lysates were subjected to luciferase assay. RESULTS: The treatment with JPYS extract onto cultured HEK293T cells induced erythropoietin expression in a dose-dependent manner, having the highest response by ~ 50% of increase. In parallel, application of JPYS extract for 24 h stimulated expressions of interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α in cultured RAW 264.7 macrophages. In contrast, the pretreatment with JPYS extract suppressed expressions of IL-1ß, IL-6, and TNF-α in lipopolysaccharide-induced macrophages. CONCLUSIONS: These results confirmed the hematopoietic function of JPYS in regulating erythropoietin expression, as well as the bidirectional immune-modulatory roles of JPYS by regulating the expression of pro-inflammatory cytokines in cultures.

Exogenous nitric oxide-induced postharvest disease resistance in citrus fruit to Colletotrichum gloeosporioides.

BACKGROUND: Nitric oxide (NO) is an important signaling molecule involved in numerous plant responses to biotic and abiotic stresses. To investigate the effects of NO on the control of postharvest anthracnose caused by Colletotrichum gloeosporioides in citrus fruit and its possible mechanisms, citrus fruit were treated with an NO donor. RESULTS: The results showed that exogenous NO released from 50 µmol L(-1) sodium nitroprusside aqueous solution could effectively reduce the disease incidence and lesion diameter of citrus fruit inoculated with C. gloeosporioides during storage at 20 °C. Exogenous NO could regulate hydrogen peroxide levels, stimulate the synthesis of phenolic compounds, and induce phenylalanine ammonia-lyase, peroxidase, polyphenol oxidase, catalase activities, and the ascorbate-glutathione cycle. Furthermore, exogenous NO could inhibit weight loss, improve the ascorbic acid and titratable acidity content, and delay the increase in total soluble solids content in citrus fruit during storage at 20 °C. CONCLUSIONS: The results suggest that the use of exogenous NO is a potential method for inducing the disease resistance of fruit to fungal pathogens and for extending the postharvest life of citrus fruit.

Autophagy inhibitors promoted aristolochic acid I induced renal tubular epithelial cell apoptosis via mitochondrial pathway but alleviated nonapoptotic cell death in mouse acute aritolochic acid nephropathy model.

Aristolochic acid I (AAI) can induce renal tubular epithelial cells (RTECs) autophagy, which thereby extenuates apoptosis in vitro. In this study, we aimed to determine whether the in vitro data also apply to the AAI-induced pathologic condition in vivo. BALB/c mice were treated with AAI, autophagy inhibitors [3-methyladenine (3MA) or chloroquine diphosphate salt (CQ)], and AAI plus the inhibitors for consecutive 5 days, respectively. Mice were euthanized on day 3 and 5. AAI induced RTECs autophagy was confirmed by electron microscopy and western blot. The results showed induction of apoptotic RTECs and up-regulation of mitochondrial and endoplasmic reticulum stress-related proteins in AAI-treated mice at both of the two time points. There were more apoptotic RTECs in AAI + inhibitor groups, which might be due to increased mitochondrial stress-related proteins (cytochrome C and apoptotic protease activating factor 1, APAF-1). On day 5, severe tubulointerstitial injuries induced by AAI led to a significant decline in kidney function. There were numerous autolysosomes in dying RTECs of the AAI group. Autophagy inhibitors increased AAI-induced RTECs mitochondrial apoptosis by increasing mitochondrial stress-related proteins, but they partially mitigated the AAI-induced severe renal tubulointerstitial injury. These results confirmed that AAI could induce autophagy in RTECs, which prevented apoptosis via mitochondrial pathway in vivo. However, continuous stimulation with AAI induced excess autophagy, which ultimately resulted in AAI-induced cell death. It suggested that apoptosis wasn't the main culprit in acute aristolochic acid nephropathy mice model.

JinChan YiShen TongLuo Formula ameliorate mitochondrial dysfunction and apoptosis in diabetic nephropathy through the HIF-1α-PINK1-Parkin pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The JinChan YiShen TongLuo (JCYSTL) formula, a traditional Chinese medicine (TCM), has been used clinically for decades to treat diabetic nephropathy (DN). TCM believes that the core pathogenesis of DN is "kidney deficiency and collateral obstruction," and JCYSTL has the effect of "tonifying kidney and clearing collateral," thus alleviating the damage to kidney structure and function caused by diabetes. From the perspective of modern medicine, mitochondrial damage is an important factor in DN pathogenesis. Our study suggests that the regulation of mitophagy and mitochondrial function by JCYSTL may be one of the internal mechanisms underlying its good clinical efficacy. AIM OF THE STUDY: This study aimed to investigate the mechanisms underlying the renoprotective effects of JCYSTL. MATERIALS AND METHODS: Unilateral nephrectomy combined with low-dose streptozotocin intraperitoneally injected in a DN rat model and high glucose (HG) plus hypoxia-induced HK-2 cells were used to explore the effects of JCYSTL on the HIF-1α/mitophagy pathway, mitochondrial function and apoptosis. RESULTS: JCYSTL treatment significantly decreased albuminuria, serum creatinine, blood urea nitrogen, and uric acid levels and increased creatinine clearance levels in DN rats. In vitro, medicated serum containing JCYSTL formula increased mitochondrial membrane potential (MMP); improved activities of mitochondrial respiratory chain complexes I, III, and IV; decreased the apoptotic cell percentage and apoptotic protein Bax expression; and increased anti-apoptotic protein Bcl-2 expression in HG/hypoxia-induced HK-2 cells. The treatment group exhibited increased accumulation of PINK1, Parkin, and LC3-II and reduced P62 levels in HG/hypoxia-induced HK-2 cells, whereas in PINK1 knockdown HK-2 cells, JCYSTL did not improve the HG/hypoxia-induced changes in Parkin, LC3-II, and P62. When mitophagy was impaired by PINK1 knockdown, the inhibitory effect of JCYSTL on Bax and its promoting effect on MMP and Bcl-2 disappeared. The JCYSTL-treated group displayed significantly higher HIF-1α expression than the model group in vivo, which was comparable to the effects of FG-4592 in DN rats. PINK1 knockdown did not affect HIF-1α accumulation in JCYSTL-treated HK-2 cells exposed to HG/hypoxia. Both JCYSTL and FG-4592 ameliorated mitochondrial morphological abnormalities and reduced the mitochondrial respiratory chain complex activity in the renal tubules of DN rats. Mitochondrial apoptosis signals in DN rats, such as increased Bax and Caspase-3 expression and apoptosis ratio, were weakened by JCYSTL or FG-4592 administration. CONCLUSION: This study demonstrates that the JCYSTL formula activates PINK1/Parkin-mediated mitophagy by stabilizing HIF-1α to protect renal tubules from mitochondrial dysfunction and apoptosis in diabetic conditions, presenting a promising therapy for the treatment of DN.

Jian-Pi-Yi-Shen formula ameliorates renal fibrosis-induced anemia in rats with chronic kidney disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Jian-Pi-Yi-Shen (JPYS) formula is an effective herbal therapy against renal injury, and JPYS has been clinically applied to ameliorate chronic kidney disease (CKD) and CKD-associated anemia. Increasing evidence supports the link between renal fibrosis and anemia in CKD. JPYS possessed anti-fibrosis effects in experimental CKD. Nevertheless, research on the mechanisms of JPYS in ameliorating renal anemia (RA) through suppressing renal fibrosis remains to be clarified. AIM OF THE STUDY: Our study here was carried out to investigate the mechanisms of JPYS in protecting against RA. MATERIALS AND METHODS: An adenine-induced anemia model in rats with CKD at three different time points was established, and bio-samples taken from each group were analyzed. Biochemical analysis was employed to detect kidney function and hematological parameters. Masson staining was used to evaluate renal fibrosis of rats. Western blot and immunohistochemistry were utilized to evaluate the expressions of fibrotic markers, erythropoietin (EPO) and hypoxia inducible factor-2α (HIF-2α) in the kidneys of rats. Subsequently, transcriptomic analysis was conducted to disclose the possible mechanisms of JPYS in treating RA. Finally, the expression levels of key targets were analyzed and validated by using Western blot and enzyme-linked immunosorbent assay (ELISA). RESULTS: JPYS treatment improved kidney function, suppressed renal fibrosis and enhanced hematological parameters in CKD rats. Moreover, JPYS treatment restored the increased expression levels of fibrotic markers and the declined EPO with time dependence. In parallel, data indicated JPYS treatment stimulated the translocation of HIF-2α into nucleus in the renal interstitium and thus promoted the expression of EPO. Transcriptomic profiling disclosed that activations of both nuclear factor kappa B (NF-κB) and transforming growth factor-ß (TGF-ß)/Smad pathways were closely associated with RA. Ultimately, experimental validation results presented that the increased expressions of target proteins from the above-mentioned two pathways in the kidneys were decreased significantly after JPYS treatment. CONCLUSION: Our findings suggest that JPYS may improve RA by alleviating renal fibrosis, and the mechanisms of which involve in inhibiting the NF-κB and TGF-ß/Smad pathways.

A novel enzyme-based functional correlation algorithm for multi-omics reveals the potential mechanisms of traditional Chinese medicines: Taking Jian-Pi-Yi-Shen formula as an example.

The integrated analysis of host metabolome and intestinal microbiome is an opportunity to explore the complex therapeutic mechanisms of traditional Chinese medicines. Currently, researchers mainly employ various statistical correlation analytical methods to investigate metabolome-microbiome correlations. However, these conventional correlation techniques often focus on statistical correlations and their biological meanings are always ignored, especially the functional relevance between them. Here, we developed a novel enzyme-based functional correlation (EBFC) algorithm to further improve the interpretability and the identified scope of microbe-metabolite correlations based on the conventional Spearman's analysis. The proposed EBFC algorithm is successfully utilized to reveal the therapeutic mechanisms of Jian-Pi-Yi-Shen (JPYS) formula on the treatment of adenine-induced chronic kidney disease (CKD) rats. JPYS, a TCM formula for treating CKD, has beneficial clinical effects. We tentatively revealed the potential mechanism of JPYS for treating CKD rats from the perspective of the serum metabolome, gut microbiome, and their interactions. Specifically, 11 metabolites and 19 bacterial genera in the CKD rats were significantly regulated to approaching normal status after JPYS treatment, suggesting that JPYS could ameliorate the pathological symptoms of CKD rats by reshaping the disturbed metabolome and gut microbiota. Further correlation analysis between the significantly perturbed metabolites, microbiota, and the related enzymes provided more strong evidence for the study of host metabolism-microbiota interactions and the therapeutic mechanism of JPYS on CKD rats. In conclusion, these findings will help us to deeply understand the pathogenesis of CKD and provide new insights into the therapeutic mechanism of JPYS.

Insights into serum metabolic biomarkers for early detection of incident diabetic kidney disease in Chinese patients with type 2 diabetes by random forest.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD) worldwide. Early detection is critical for the risk stratification and early intervention of progressive DKD. Serum creatinine (sCr) and urine output are used to assess kidney function, but these markers are limited by their delayed changes following kidney pathology, and lacking of both sensitivity and accuracy. Hence, it is essential to illustrate potential diagnostic indicators to enhance the precise prediction of early DKD. A total of 194 Chinese individuals include 30 healthy participants (Stage 0) and 164 incidents with type 2 diabetes (T2D) spanning from DKD's Stage 1a to 4 were recruited and their serums were subjected for untargeted metabolomic analysis. Random forest (RF), a machine learning approach, together with univariate linear regression (ULR) and multivariate linear regression (MvLR) analysis were applied to characterize the features of untargeted metabolites of DKD patients and to identify candidate DKD biomarkers. Our results indicate that 2-(α-D-mannopyranosyl)-L-tryptophan (ADT), succinyladenosine (SAdo), pseudouridine and N,N,N-trimethyl-L-alanyl-L-proline betaine (L-L-TMAP) were associated with the development of DKD, in particular, the latter three that were significantly elevated in Stage 2-4 T2D incidents. Each of the four metabolites in combination with sCr achieves better performance than sCr alone with area under the receiver operating characteristic curve (AUC) of 0.81-0.91 in predicting DKD stages. An average of 3.9 years follow-up study of another cohort including 106 Stage 2-3 patients suggested that "urinary albumin-to-creatinine ratio (UACR) + ADT + SAdo" can be utilized for better prognosis evaluation of early DKD (average AUC = 0.9502) than UACR without sexual difference.

Lisinopril protects against the adriamycin nephropathy and reverses the renalase reduction: potential role of renalase in adriamycin nephropathy.

AIMS: To investigate the potential role of renalase in adriamycin nephropathy and the effect of lisinopril on the regulation of renalase. METHODS: Adriamycin nephropathy was induced in male Wistar rats (n=12) by a single injection of adriamycin at 2 mg/kg body weight. Rats were then randomly assigned to a model group or a treatment group, to which were administered distilled water or the angiotensin converting enzyme inhibitor lisinopril, respectively, for 12 weeks. Six normal rats served as controls. At the end of study, physiological parameters and systolic blood pressure were measured. Glomerulosclerosis and tubulointerstitial injury were assessed by histopathology Renalase protein expression in kidney was quantified by immunohistochemistry and immunoblotting. The serum concentration and urinary excretion of renalase were determined by enzyme-linked immunosorbent assay. RESULTS: In model group rats, proteinuria and systolic blood pressure were elevated. Increased serum renalase concentration was observed; however, renalase protein expression in the kidney was significantly decreased. Compared with the model group, decreased proteinuria, lower systolic blood pressure, and fewer morphologic lesions were detected in the treatment group. Although levels of serum renalase were similar, accumulation of renalase in urine and kidney tissue increased notably in the treatment group compared with the model group. CONCLUSIONS: This study suggests that renalase may be involved in the process of adriamycin-induced renal injuries. Lisinopril may attenuate adriamycin-induced kidney injury by controlling blood pressure, which may be partially attributed to the renalase expression and secretion.

Study of workshop network stability based on pinning control in disturbance environment.

In the production process, the manufacturing behavior and all the essential factors are affected by several disturbance factors, showing a complex dynamic fluctuation law. It makes the stability control process a difficult problem in environmental constraints. In this paper, the workshop production process is considered, and an improved coupled map lattice workshop production network state model is proposed. On this basis, the controller with the function of resource load protection is designed, and the network state model of the workshop based on the pinning control is developed. Three kinds of stability control strategies, SAC (Self-adaption Control) , SC (Self-acting Control) and PC (Pinning Control) , are designed based on disturbance triggering behavior and node state transition rules. In addition, two control effect evaluation indexes, RTS (Recovery Time Steps) and NFT (Node Failure Times) are designed. Considering the actual production data of diesel fuel injection system parts production workshop as example, the model is simulated and verified. The results show that under different disturbance intensities, compared with the SAC strategy, the RTS-Average value of the PC strategy is reduced by 29.83% on average, and the NFT-Average values are reduced by 46.9% on average. This proves that the pinning control strategy has certain advantages in controlling time length and propagation scale of disturbance propagation.

Effects of hypoxia-inducible factor prolyl hydroxylase inhibitors versus erythropoiesis-stimulating agents on iron metabolism and inflammation in patients undergoing dialysis: A systematic review and meta-analysis.

Aims: This study aimed to evaluate the effects of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) on iron metabolism and inflammation in dialysis-dependent chronic kidney disease (DD-CKD) patients. Methods: PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov websites were searched for randomized controlled trials (RCTs) investigating HIF-PHIs versus ESAs for DD-CKD patients. Key findings: Twenty studies with 14,737 participants were included in the meta-analysis, which demonstrated no significant difference in the effect of transferrin saturation and ferritin between HIF-PHIs and the ESAs group (MD, 0.65; 95%CI, -0.45 to 1.75; very low certainty; SMD, -0.03; 95% CI, -0.13 to 0.07; low certainty). However, HIF-PHIs significantly increased the iron (MD, 2.30; 95% CI, 1.40 to 3.20; low certainty), total iron-binding capacity (SMD, 0.82; 95% CI, 0.66 to 0.98; low certainty), and transferrin (SMD, 0.90; 95%CI, 0.74 to 1.05; moderate certainty) levels when compared with the ESAs group. In contrast, the hepcidin level and dosage of intravenous iron were significantly decreased in the HIF-PHIs group compared with the ESAs group (MD, -15.06, 95%CI, -21.96 to -8.16; low certainty; MD, -18.07; 95% CI, -30.05 to -6.09; low certainty). The maintenance dose requirements of roxadustat were independent of baseline CRP or hsCRP levels with respect to the effect on inflammation. Significance: HIF-PHIs promote iron utilization and reduce the use of intravenous iron therapy. Furthermore, HIF-PHIs, such as roxadustat, maintain the erythropoietic response independent of the inflammatory state. Thus, HIF-PHIs may be an alternative treatment strategy for anemia in DD-CKD patients, where ESA is hyporesponsive due to iron deficiency and inflammation.

Jian-Pi-Yi-Shen formula restores iron metabolism from dysregulation in anemic rats with adenine-induced nephropathy.

ETHNOPHARMACOLOGICAL RELEVANCE: Jian-Pi-Yi-Shen (JPYS) is a herbal decoction being used to relieve the symptoms of chronic kidney disease (CKD) and its complications, including anemia, for over twenty years. Nonetheless, it is unclear how JPYS influences renal anemia and iron metabolism. AIM OF THE STUDY: An analysis of network pharmacology, chemical profiling, and in vivo experiments was conducted to identify the impact of JPYS on JAK2-STAT3 pathway and iron utilization in renal anemia and CKD. MATERIALS AND METHODS: The chemical properties of JPYS and its exposed ingredients were detected in vivo. And based on the aforesaid chemical compounds, the potential targets and signaling pathways of JPYS for renal anemia treatment were predicted by network pharmacology. Afterward, an adenine-feeding animal model of CKD-related anemia was developed to verify the mechanism by which JPYS modulates iron recycling to treat renal anemia. Renal injury was estimated by serum creatinine (Scr), blood urea nitrogen (BUN), histopathological examinations and fibrosis degree. Western blot, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry approaches were utilized to assess the levels of JAK2, STAT3 and iron metabolism-related factors. RESULTS: There were 164 active ingredients identified in JPYS, including prototypes and metabolites in vivo were identified in JPYS, and 21 core targets were found through network pharmacology based on topological characteristics. Combined with the core targets and pathway enrichment analysis, the majority of the candidate targets were associated with the JAK2-STAT3 signaling pathways. Experimental results indicated that JPYS treatment significantly decreased the expression of BUN and Scr, restored renal pathological damage, down-regulated fibrosis degree, and improved hematological parameters such as red blood cell, hemoglobin and hematocrit in CKD rats. Furthermore, JPYS significantly restored iron metabolism from dysregulation by increasing the levels of iron and ferritin in the serum, inhibiting the production of hepcidin in liver and serum, and regulating transferrin receptor 1 in bone marrow. Meanwhile, the expression of JAK2 and STAT3 was suppressed by JPYS treatment. CONCLUSIONS: Based on these results, JPYS reduces hepcidin levels by inhibiting the activation of JAK2-STAT3 signaling, thereby protecting against iron deficiency anemia.

Insights into the mechanisms of triptolide nephrotoxicity through network pharmacology-based analysis and RNA-seq.

Introduction: Triptolide (TPL) is a promising plant-derived compound for clinical therapy of multiple human diseases; however, its application was limited considering its toxicity. Methods: To explore the underlying molecular mechanism of TPL nephrotoxicity, a network pharmacology based approach was utilized to predict candidate targets related with TPL toxicity, followed by deep RNA-seq analysis to characterize the features of three transcriptional elements include protein coding genes (PCGs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) as well as their associations with nephrotoxicity in rats with TPL treatment. Results & Discussion: Although the deeper mechanisms of TPL nephrotoxcity remain further exploration, our results suggested that c-Jun is a potential target of TPL and Per1 related circadian rhythm signaling is involved in TPL induced renal toxicity.

[Effect of lycopene on the apoptosis of human peripheral endothelial progenitor cells cultivated in high concentration of glucose].

OBJECTIVE: To investigate the effect of lycopene treatment on the proliferation and apoptosis of endothelial progenitor cells (EPCs) incubated in a culture medium with high concentration of glucose. METHODS: Mononuclear cells (MNCs) were isolated from human peripheral blood by Ficoll density gradient centrifugation. After being induced to differentiation, the endothelial progenitor cells (EPC) were identified by FITC-labeled Ulex europaeus agglutinin I and Dil labeled acetylated low density lipoprotein dual stain method. Then MTT assay and flow cytometry were used to assess the proliferation and apoptosis of EPCs. RESULTS: The glucose in a concentration of 33 mmol/L significantly inhibited the proliferation and promoted the apoptosis of EPCs (P < 0.05). The proliferation of EPCs in 10, 30 and 50 microg/ml lycopene groups were significantly higher than the 0 microg/ml group. The rate of apoptosis were significantly lower than the lycopene 0 microg/ml group (P < 0.05). CONCLUSION: High concentration of glucose attenuates the proliferative activity and increases the apoptotic rate of EPCs. Lycopene promotes the proliferation and reduces the apoptosis of EPCs cultivated in high glucose medium.

Network Pharmacology and Experimental Verification Strategies to Illustrate the Mechanism of Jian-Pi-Yi-Shen Formula in Suppressing Epithelial-Mesenchymal Transition.

Jian-Pi-Yi-Shen formula (JPYSF), a traditional Chinese medicine, has been recommended to treat renal fibrosis for decades. Previous studies had shown that JPYSF could inhibit epithelial-mesenchymal transition (EMT), an important regulatory role in renal fibrosis. However, the mechanism of JPYSF action is largely unknown. In this study, network pharmacology and experimental verification were combined to elucidate and identify the potential mechanism of JPYSF against renal fibrosis by suppressing EMT at molecular and pathway levels. Network pharmacology was first performed to explore the mechanism of JPYSF against renal fibrosis targeting EMT, and then a 5/6 nephrectomy (5/6 Nx)-induced rat model of renal fibrosis was selected to verify the predictive results by Masson's trichrome stains and western blot analysis. Two hundred and thirty-two compounds in JPYSF were selected for the network approach analysis, which identified 137 candidate targets of JPYSF and 4,796 known therapeutic targets of EMT. The results of the Gene Ontology (GO) function enrichment analysis included 2098, 88, and 133 GO terms for biological processes (BPs), molecular functions (MFs), and cell component entries, respectively. The top 10 enrichment items of BP annotations included a response to a steroid hormone, a metal ion, oxygen levels, and so on. Cellular composition (CC) is mainly enriched in membrane raft, membrane microdomain, membrane region, etc. The MF of JPYSF analysis on EMT was predominately involved in proximal promoter sequence-specific DNA binding, protein heterodimerization activity, RNA polymerase II proximal promoter sequence-specific DNA binding, and so on. The involvement signaling pathway of JPYSF in the treatment of renal fibrosis targeting EMT was associated with anti-fibrosis, anti-inflammation, podocyte protection, and metabolism regulation. Furthermore, the in vivo experiments confirmed that JPYSF effectively ameliorated interstitial fibrosis and inhibited the overexpression of α-SMA, Wnt3a, and ß-catenin, and increased the expression of E-cadherin by wnt3a/ß-catenin signaling pathway in 5/6 Nx-induced renal fibrosis rats. Using an integrative network pharmacology-based approach and experimental verification, the study showed that JPYSF had therapeutic effects on EMT by regulating multi-pathway, among which one proven pathway was the Wnt3a/ß-catenin signaling pathway. These findings provide insights into the renoprotective effects of JPYSF against EMT, which could suggest directions for further research of JPYSF in attenuating renal fibrosis by suppressing EMT.