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With the development of large numbers of novel organophosphate esters (OPEs) alternatives, it is imperative to screen and identify those with high priority. In this study, surface water, biofilms, and freshwater snails were collected from the flow-in rivers of Taihu Lake Basin, China. Screened by target, suspect, and nontarget analysis, 11 traditional and 14 novel OPEs were identified, of which 5 OPEs were first discovered in Taihu Lake Basin. The OPE concentrations in surface water ranged from 196 to 2568 ng/L, with the primary homologue tris(2,4-ditert-butylphenyl) phosphate (TDtBPP) being newly identified, which was likely derived from the transformation of tris(2,4-ditert-butylphenyl) phosphite. The majority of the newly identified OPEs displayed substantially higher bioaccumulation and biomagnification potentials in the biofilm-snail food chain than the traditional ones. Quantitative structure-property relationship models revealed both hydrophobicity and polarity influenced the bioaccumulation and biomagnification of the OPEs, while electrostatic attraction also had a contribution to the bioaccumulation in the biofilm. TDtBPP was determined as the utmost priority by toxicological priority index scheme, which integrated concentration, bioaccumulation, biomagnification, acute toxicity, and endocrine disrupting potential of the identified OPEs. These findings provide novel insights into the behaviors of OPEs and scientific bases for better management of high-risk pollutants in aquatic ecosystem.
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Ésteres , Organofosfatos , Contaminantes Químicos del Agua , Relación Estructura-Actividad Cuantitativa , Animales , Monitoreo del Ambiente , China , CaracolesRESUMEN
Sirtuins (Sirts) are a family of nicotinamide adenine dinucleotide-dependent protein deacetylases that share diverse cellular functions. Increasing evidence shows that Sirts play a critical role in podocyte injury, which is a major determinant of proteinuria-associated renal disease. Membranous nephropathy (MN) is a typical glomerular disease in which podocyte damage mediates proteinuria development. In this study we investigated the molecular mechanisms underlying the regulatory roles of Sirt in podocyte injury in MN patients, rats with cationic bovine serum albumin (CBSA)-induced MN and zymosan activation serum (ZAS)-stimulated podocytes. Compared with healthy controls, MN patients showed significant reduction in intrarenal Sirt1 and Sirt6 protein expression. In CBSA-induced MN rats, significant reduction in intrarenal Sirt1, Sirt3 and Sirt6 protein expression was observed. However, only significant decrease in Sirt6 protein expression was found in ZAS-stimulated podocytes. MN patients showed significantly upregulated protein expression of Wnt1 and ß-catenin and renin-angiotensin system (RAS) components in glomeruli. CBSA-induced MN rats exhibited significantly upregulated protein expression of intrarenal Wnt1 and ß-catenin and their downstream gene products as well as RAS components. Similar results were observed in ZAS-stimulated podocytes. In ZAS-stimulated podocytes, treatment with a specific Sirt6 activator UBCS039 preserved the protein expression of podocin, nephrin and podocalyxin, accompanied by significant inhibition of the protein expression of ß-catenin and its downstream gene products, including Snail1 and Twist; treatment with a ß-catenin inhibitor ICG-001 significantly preserved the expression of podocyte-specific proteins and inhibited the upregulation of downstream ß-catenin gene products accompanied by significant suppression of the protein expression of RAS components. Thus, we demonstrate that Sirt6 ameliorates podocyte injury by blocking RAS signalling via the Wnt1/ß-catenin pathway. Sirt6 is a specific therapeutic target for the treatment of podocyte damage-associated renal disease.
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Enfermedades Renales , Podocitos , Humanos , Ratas , Animales , beta Catenina/metabolismo , Podocitos/metabolismo , Sirtuina 1/metabolismo , Sistema Renina-Angiotensina , Enfermedades Renales/metabolismo , ProteinuriaRESUMEN
A fullerene-polysaccharide supramolecular hydrogel was constructed by carrying out a co-assembly of fullerene@hydroxypropyl-ß-cyclodextrin, chitosan and bentonite, and displayed good antioxidant and antiglycation properties, and hence showed promising cosmetics applications. Benefitting from the cyclodextrin hydrophobic cavity, hydroxypropyl-ß-cyclodextrin formed a stoichiometric 2 : 1 complex with fullerene, effectively enhancing the water solubility and biological activity of fullerene, and the encapsulation ratio of the prepared fullerene was calculated to be 79%. Results of oxygen radical absorbance capacity and pyrogallol autoxidation experiments showed high antioxidant activity displayed by the fullerene@HP-ß-CD inclusion complex. The supramolecular inclusion was further co-assembled, using multiple hydrogen bonds and electrostatic interactions, with chitosan and bentonite to form a supramolecular hydrogel; this hydrogel was successfully used in antiglycation, with a glycation end products inhibition rate of 43.99% at a 10% sample concentration. Therefore, the fullerene-polysaccharide ternary co-assembly supramolecular hydrogel showed good antioxidant and antiglycation abilities, and the construction of the polysaccharide supramolecular hydrogel provided a new perspective for raw materials to consider in cosmetics applications.
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PURPOSE: The risk of thromboembolic events is elevated in patients with nephrotic syndrome, and warfarin use has been associated with an increased risk of bleeding. Indobufen, a selective cyclooxygenase-1 inhibitor, is currently being evaluated for the prevention of thromboembolic events in nephrotic syndrome. This study aimed to compare the efficacy and safety of indobufen with that of warfarin in patients with nephrotic syndrome. MATERIALS AND METHODS: This multicenter, randomized, three-arm, open-label, parallel controlled trial involved a total of 180 adult patients with nephrotic syndrome from four centers in China. Patients were randomly assigned to receive 100 mg indobufen (bid), 200 mg indobufen (bid), and 3 mg warfarin (qd) daily for 12 weeks. The primary endpoints included thromboembolic and bleeding events, while laboratory results and adverse events constituted secondary endpoints. RESULTS: No thromboembolic events occurred in the high-/low-dose indobufen and warfarin groups. Moreover, the use of a low dose of indobufen significantly reduced the risk of minor bleeding events compared with warfarin use (2% versus 18%, p < .05). Finally, adverse events were more frequent in warfarin-treated patients. CONCLUSIONS: This study found that indobufen therapy provided equivalent effects in preventing thromboembolic events compared with warfarin therapy, while low dose of indobufen was associated with a reduced risk of bleeding events, thus it should be recommended for the prevention of thromboembolic events in clinical practice in patients with nephrotic syndrome. TRIAL REGISTRATION NUMBER: ChiCTR-IPR-17013428.
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Fibrilación Atrial , Síndrome Nefrótico , Tromboembolia , Adulto , Humanos , Warfarina/efectos adversos , Fibrinolíticos/uso terapéutico , Síndrome Nefrótico/complicaciones , Síndrome Nefrótico/tratamiento farmacológico , Síndrome Nefrótico/inducido químicamente , Anticoagulantes , Tromboembolia/prevención & control , Tromboembolia/inducido químicamente , Hemorragia/inducido químicamente , Hemorragia/complicaciones , Resultado del TratamientoRESUMEN
Chronic kidney disease (CKD) results in significant dyslipidemia and profound changes in lipid and lipoprotein metabolism. The associated dyslipidemia, in turn, contributes to progression of CKD and its cardiovascular complications. To gain an in-depth insight into the disorders of lipid metabolism in advanced CKD, we applied UPLC-HDMS-based lipidomics to measure serum lipid metabolites in 180 patients with advanced CKD and 120 age-matched healthy controls. We found significant increases in the levels of total free fatty acids, glycerolipids, and glycerophospholipids in patients with CKD. The levels of free fatty acids, glycerolipids, and glycerophospholipids directly correlated with the level of serum triglyceride and inversely correlated with the levels of total cholesterol and eGFR. A total of 126 lipid species were identified from positive and negative ion modes. Out of 126, 113 identified lipid species were significantly altered in patients with CKD based on the adjusted FDR method. These results pointed to profound disturbance of fatty acid and triglyceride metabolisms in patients with CKD. Logistic regression analysis showed strong correlations between serum methyl hexadecanoic acid, LPC(24:1), 3-oxooctadecanoic acid, and PC(20:2/24:1) levels with eGFR and serum creatinine levels (R > 0.8758). In conclusion, application of UPLC-HDMS-based lipidomic technique revealed profound changes in lipid metabolites in patients with CKD. The observed increases in serum total fatty acids, glycerolipids, and glycerophospholipids levels directly correlated with increased serum triglyceride level and inversely correlated with the eGFR and triglyceride levels.
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Dislipidemias/sangre , Metabolismo de los Lípidos/genética , Insuficiencia Renal Crónica/sangre , Triglicéridos/sangre , Adulto , Anciano , Colesterol/sangre , Dislipidemias/genética , Dislipidemias/patología , Ácidos Grasos/sangre , Femenino , Glicerofosfolípidos/sangre , Humanos , Lípidos/sangre , Lipoproteínas/sangre , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patologíaRESUMEN
BACKGROUND AND PURPOSE: Membranous nephropathy (MN) is an immune-mediated glomerular disease in adults. Antibody- and antigen-bonding mechanisms have been largely clarified, but the subepithelium immune complex deposition-mediated downstream molecular mechanisms are currently unresolved. Increasing evidence has suggested that gut microbiota contribute to MN pathogenesis. EXPERIMENTAL APPROACH: In this study, we identified alterations in faecal gut microbiota and serum metabolites that mediate an aryl hydrocarbon receptor (AhR) mechanism in cationic bovine serum albumin (CBSA)-induced MN rats and in patients with idiopathic MN (IMN). KEY RESULTS: Impaired renal function correlated with the relative abundance of reduced faecal probiotics, Lactobacillus and Bifidobacterium, and altered serum levels of tryptophan-produced indole derivatives (TPIDs) in MN rats. Further results showed that reduced relative abundance of five probiotics, namely Lactobacillus johnsonii, Lactobacillus murinus, Lactobacillus vaginalis, Lactobacillus reuteri and Bifidobacterium animalis, positively correlated with decreased levels of indole-3-pyruvic acid, indole-3-aldehyde and tryptamine and negatively correlated with increased levels of indole-3-lactic acid and indole-3-acetic acid in serum of MN rats. Altered five probiotics and five TPIDs also were observed in patients with IMN. Further studies showed that MN rats exhibited a significant increase in intrarenal mRNA expression of AhR and its target genes CYP1A1, CYP1A2 and CYP1B1, which were accompanied by protein expression of down-regulated cytoplasmic AhR, but up-regulated nuclear AhR, in MN rats and IMN patients. CONCLUSION AND IMPLICATIONS: Activation of the intrarenal AhR signalling pathway may involve five TPIDs. These data suggest that gut microbiota could influence MN through TPIDs that engage host receptors.
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Microbioma Gastrointestinal , Glomerulonefritis Membranosa , Indoles , Lactobacillus , Receptores de Hidrocarburo de Aril , Lactobacillus/fisiología , Glomerulonefritis Membranosa/microbiología , Triptófano/farmacología , Indoles/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Humanos , Animales , Ratas , Masculino , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
Accumulated evidence suggested that gut microbial dysbiosis interplayed with progressive chronic kidney disease (CKD). However, no available therapy is effective in suppressing progressive CKD. Here, using microbiomics in 480 participants including healthy controls and patients with stage 1-5 CKD, we identified an elongation taxonomic chain Bacilli-Lactobacillales-Lactobacillaceae-Lactobacillus-Lactobacillus johnsonii correlated with patients with CKD progression, whose abundance strongly correlated with clinical kidney markers. L. johnsonii abundance reduced with progressive CKD in rats with adenine-induced CKD. L. johnsonii supplementation ameliorated kidney lesion. Serum indole-3-aldehyde (IAld), whose level strongly negatively correlated with creatinine level in CKD rats, decreased in serum of rats induced using unilateral ureteral obstruction (UUO) and 5/6 nephrectomy (NX) as well as late CKD patients. Treatment with IAld dampened kidney lesion through suppressing aryl hydrocarbon receptor (AHR) signal in rats with CKD or UUO, and in cultured 1-hydroxypyrene-induced HK-2 cells. Renoprotective effect of IAld was partially diminished in AHR deficiency mice and HK-2 cells. Our further data showed that treatment with L. johnsonii attenuated kidney lesion by suppressing AHR signal via increasing serum IAld level. Taken together, targeting L. johnsonii might reverse patients with CKD. This study provides a deeper understanding of how microbial-produced tryptophan metabolism affects host disease and discovers potential pathways for prophylactic and therapeutic treatments for CKD patients.
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Lactobacillus johnsonii , Insuficiencia Renal Crónica , Insuficiencia Renal Crónica/microbiología , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/patología , Animales , Ratas , Humanos , Ratones , Masculino , Lactobacillus johnsonii/genética , Indoles , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Microbioma Gastrointestinal , FemeninoRESUMEN
Considerable achievements were realized in illuminating underlying pathological mechanisms of patients with idiopathic membranous nephropathy (IMN). Although IMN patients are well diagnosed before they reach renal failure, no currently available drug intervention is effective in halting IMN progression. In this study, we assess Moshen granule (MSG) effect on IMN patients and cationic bovine serum albumin (CBSA)-induced rats. Increasing studies has indicated that activation of aryl hydrocarbon receptor (AHR) was related to oxidative stress and inflammation. We further determine MSG effect on AHR, nuclear factor ÆB (NF-ÆB) and nuclear factor erythroid 2-related factor 2 (Nrf2) in the CBSA-induced rats. MSG markedly reduces proteinuria and improves kidney function in both IMN patients and rats induced by CBSA. MSG markedly inhibits increased mRNA expressions of intrarenal AHR and its four downstream target genes including CYP1A1, CYP1A2, CYP1B1 and COX-2 compared with untreated CBSA-induced rats. This is accompanied by markedly downregulated protein expressions of p-IÆBα and NF-ÆB p65 and its downstream gene products including MCP-1, COX-2, 12-LOX, iNOS, p47phox and p67phox, while markedly preserves protein expressions of Nrf2 and its downstream gene products including catalase, HO-1, GCLM, GCLC, MnSOD and NQO1 in the kidney tissues. These data suggests MSG blunts podocyte damage through inhibiting activation of NF-ÆB/Nrf2 pathway via AHR signaling. This finding may provide a promising therapy for treatment of IMN through oxidative stress and inflammation.
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Membranous nephropathy (MN) patients are diagnosed by the presence of phospholipase A2 receptor (PLA2R) before they progress to renal failure. However, the subepithelium-like immunocomplex deposit-mediated downstream molecular pathways are poorly understood. The aryl hydrocarbon receptor (AHR), NF-ÆB and Nrf2 pathways play central roles in the pathogenesis and progression of chronic kidney disease. However, their mutual effects on MN require further examination. Thus, we investigated the effect of AHR signalling on the NF-ÆB and Nrf2 pathways in IMN patients, cationic bovine serum albumin (CBSA)-injected rats and zymosan activation serum (ZAS)-treated podocytes. IMN patients show significantly decreased serum total protein and albumin levels, increased urine protein levels and intrarenal IgG4 and PLA2R protein expression in glomeruli compared with controls. IMN patients exhibited increased mRNA expression of intrarenal AHR and its target genes, including CYP1A1, CYP1A2, CYP1B1 and COX-2. This increase was accompanied by significantly upregulated protein expression of CD3, NF-ÆB p65 and COX-2 and significantly downregulated Nrf2 and HO-1 expression. Similarly, CBSA-induced rats showed severe proteinuria and activated intrarenal AHR signalling. This was accompanied by significantly upregulated protein expression of intrarenal p-IκBα, NF-κB p65 and its gene products, including COX-2, MCP-1, iNOS, 12-LOX, p47phox and p67phox, and significantly downregulated protein expression of Nrf2 and its gene products, including HO-1, catalase, GCLC, GCLM, MnSOD and NQO1. These results were further verified in ZAS-induced podocytes. Treatment with the AHR antagonist CH223191 and AHRsiRNA significantly preserved podocyte-specific protein expression and improved the NF-ÆB and Nrf2 pathways in ZAS-induced podocytes. In contrast, similar results were obtained in ZAS-induced podocytes treated with the NF-ÆB inhibitor BAY 11-7082 and NF-κBp65 siRNA. However, neither method had a significant effect on AHR signalling. Collectively, these results indicate that the NF-ÆB pathway is a downstream target of AHR signalling. Our findings suggest that blocking AHR signalling inhibits oxidative stress and inflammation, thereby improving proteinuria and renal injury.
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Glomerulonefritis Membranosa , Animales , Ratas , Ciclooxigenasa 2/metabolismo , Glomerulonefritis Membranosa/genética , Glomerulonefritis Membranosa/metabolismo , Glomerulonefritis Membranosa/patología , Inflamación/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo , Proteinuria , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Humanos , Podocitos/metabolismoRESUMEN
Chronic kidney disease (CKD) was a major public health problem worldwide. Renal fibrosis, especially tubulointerstitial fibrosis, is final manifestation of CKD. Many studies have demonstrated that TGF-ß/Smad signaling pathway plays a crucial role in renal fibrosis. Therefore, targeted inhibition of TGF-ß/Smad signaling pathway can be used as a potential therapeutic measure for tubulointerstitial fibrosis. At present, a variety of targeting TGF-ß1 and its downstream Smad proteins have attracted attention. Natural products used as potential therapeutic strategies for tubulointerstitial fibrosis have the characteristics of acting on multiple targets by multiple components and few side effects. With the continuous research and technique development, more and more molecular mechanisms of natural products have been revealed, and there are many natural products that inhibited tubulointerstitial fibrosis via TGF-ß/Smad signaling pathway. This review summarized the role of TGF-ß/Smad signaling pathway in tubulointerstitial fibrosis and natural products against tubulointerstitial fibrosis by targeting TGF-ß/Smad signaling pathway. Additionally, many challenges and opportunities are presented for inhibiting renal fibrosis in the future.
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Chronic kidney diseases usually cause renal interstitial fibrosis, the prevention, delay, and treatment of which is a global research hotspot. However, no definite treatment options are available in modern medicine. Chinese herbal medicine has a long history, rich varieties, and accurate treatment effects. Hitherto, many Chinese herbal medicine studies have emerged to improve renal interstitial fibrosis. This paper reviews the mechanisms of renal interstitial fibrosis and recent studies on the disease intervention with Chinese herbal medicine through literature search, intend to reveal the importance of Chinese herbal medicine in renal interstitial fibrosis. The results show that Chinese herbal medicine can improve renal interstitial fibrosis, and the effects of Chinese herbal medicine on specific pathological mechanisms underlying renal interstitial fibrosis have been explored. Additionally, the limitations and advantages of Chinese herbal medicine in the treatment of renal interstitial fibrosis, possible research directions, and new targets of Chinese herbal medicine are discussed to provide a basis for studies of renal interstitial fibrosis.
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Chronic kidney disease (CKD) is a major worldwide public health problem. The increase in the number of patients with CKD and end-stage kidney disease requesting renal dialysis or transplantation will progress to epidemic proportions in the next several decades. Although blocking the renin-angiotensin system (RAS) has been used as a first-line standard therapy in patients with hypertension and CKD, patients still progress towards end-stage kidney disease, which might be closely associated with compensatory renin expression subsequent to RAS blockade through a homeostatic mechanism. The Wnt/ß-catenin signalling pathway is the master upstream regulator that controls multiple intrarenal RAS genes. As Wnt/ß-catenin regulates multiple RAS genes, we inferred that this pathway might also be implicated in blood pressure control. Therefore, discovering new medications to synchronously target multiple RAS genes is necessary and essential for the effective treatment of patients with CKD. We hypothesized that Shenkang injection (SKI), which is widely used to treat CKD patients, might ameliorate CKD by inhibiting the activation of multiple RAS genes via the Wnt/ß-catenin signalling pathway. To test this hypothesis, we used adenine-induced CKD rats and angiotensin II (AngII)-induced HK-2 and NRK-49F cells. Treatment with SKI inhibited renal function decline, hypertension and renal fibrosis. Mechanistically, SKI abrogated the increased protein expression of multiple RAS elements, including angiotensin-converting enzyme and angiotensin II type 1 receptor, as well as Wnt1, ß-catenin and downstream target genes, including Snail1, Twist, matrix metalloproteinase-7, plasminogen activator inhibitor-1 and fibroblast-specific protein 1, in adenine-induced rats, which was verified in AngII-induced HK-2 and NRK-49F cells. Similarly, our results further indicated that treatment with rhein isolated from SKI attenuated renal function decline and epithelial-to-mesenchymal transition and repressed RAS activation and the hyperactive Wnt/ß-catenin signalling pathway in both adenine-induced rats and AngII-induced HK-2 and NRK-49F cells. This study first revealed that SKI repressed epithelial-to-mesenchymal transition by synchronously targeting multiple RAS elements by blocking the hyperactive Wnt/ß-catenin signalling pathway.
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Membranous nephropathy (MN) is the most common cause of nephrotic syndrome among adults, which is the leading glomerular disease that recurs after kidney transplantation. Treatment for MN remained controversial and challenging, partly owing to absence of sensitive and specific biomarkers and effective therapy for prediction and diagnosis of disease activity. MN starts with the formation and deposition of circulating immune complexes on the outer area in the glomerular basement membrane, leading to complement activation. The identification of autoantibodies against the phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing protein 7A (THSD7A) antigens illuminated a distinct pathophysiological rationale for MN treatments. Nowadays, detection of serum anti-PLA2R antibodies and deposited glomerular PLA2R antigen can be routinely applied to MN. Anti-PLA2R antibodies exhibited much high specificity and sensitivity. Measurement of PLA2R in immune complex deposition allows for the diagnosis of PLA2R-associated MN in patients with renal biopsies. In the review, we critically summarized newer diagnosis biomarkers including PLA2R and THSD7A tests and novel promising therapies by using traditional Chinese medicines such as Astragalus membranaceus, Tripterygium wilfordii, and Astragaloside IV for the treatment of MN patients. We also described unresolved questions and future challenges to reveal the diagnosis and treatments of MN. These unprecedented breakthroughs were quickly translated to clinical diagnosis and management. Considerable advances of detection methods played a critical role in diagnosis and monitoring of treatment.
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BACKGROUND AND PURPOSE: In chronic kidney disease (CKD), patients inevitably reach end-stage renal disease and require renal transplant. Evidence suggests that CKD is associated with metabolite disorders. However, the molecular pathways targeted by metabolites remain enigmatic. Here, we describe roles of 1-hydroxypyrene in mediating renal fibrosis. EXPERIMENTAL APPROACH: We analysed 5406 urine and serum samples from patients with Stage 1-5 CKD using metabolomics, and 1-hydroxypyrene was identified and validated using longitudinal and drug intervention cohorts as well as 5/6 nephrectomised and adenine-induced rats. KEY RESULTS: We identified correlations between the urine and serum levels of 1-hydroxypyrene and the estimated GFR in patients with CKD onset and progression. Moreover, increased 1-hydroxypyrene levels in serum and kidney tissues correlated with decreased renal function in two rat models. Up-regulated mRNA expression of aryl hydrocarbon receptor and its target genes, including CYP1A1, CYP1A2 and CYP1B1, were observed in patients and rats with progressive CKD. Further we showed up-regulated mRNA expression of aryl hydrocarbon receptor and its three target genes, plus up-regulated nuclear aryl hydrocarbon receptor protein levels in mice and HK-2 cells treated with 1-hydroxypyrene, which caused accumulation of extracellular matrix components. Treatment with aryl hydrocarbon receptor short hairpin RNA or flavonoids inhibited mRNA expression of aryl hydrocarbon receptor and its target genes in 1-hydroxypyrene-induced HK-2 cells and mice. CONCLUSION AND IMPLICATIONS: Metabolite 1-hydroxypyrene was demonstrated to mediate renal fibrosis through activation of the aryl hydrocarbon receptor signalling pathway. Targeting aryl hydrocarbon receptor may be an alternative therapeutic strategy for CKD progression.
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Receptores de Hidrocarburo de Aril , Insuficiencia Renal Crónica , Animales , Citocromo P-450 CYP1A1/genética , Fibrosis , Humanos , Ratones , Pirenos , Ratas , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/tratamiento farmacológicoRESUMEN
The dinuclear title compound, [Fe(2)(C(2)H(4)S(2))(C(24)H(20)OP(2))(CO)(5)] or (µ-SCH(2)CH(2)S-µ)Fe(2)(CO)(5)[Ph(2)PP(O)Ph(2)], con-tains a butterfly-shaped Fe(2)S(2) core in which the Feâ¯Fe separation is 2.5275â (6)â Å. One of the Fe atoms is also coordinated to three carbonyl ligands and the other to two carbonyl ligands and one phosphane ligand [Ph(2)PP(O)Ph(2)]. Both Fe-atom geometries could be described as grossly distorted octa-hedral and the Ph(2)PP(O)Ph(2) ligand lies trans to the Feâ¯Fe link.
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The title compound, C(8)H(9)N(3)S, is almost planar (r.m.s. deviation = 0.019â Å) apart from the terminal -NH(2) grouping [deviation of the N atom = 0.286â (2)â Å]. In the crystal, mol-ecules are linked by N-Hâ¯N hydrogen bonds, generating (001) sheets.
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Diabetic kidney disease (DKD) is the primary cause of chronic kidney disease that inevitably progress to end-stage kidney disease. Intervention strategies such as blood glucose control is effective for preventing DKD, but many patients with DKD still reach end-stage kidney disease. Although comprehensive mechanisms shed light on the progression of DKD, the most compelling evidence has highlighted that hyperglycemia-related advanced glycation end products (AGEs) formation plays a central role in the pathogenesis of DKD. Pathologically, accumulation of AGEs-mediated receptor for AGEs (RAGE) triggers oxidative stress and inflammation, which is the major deleterious effect of AGEs in host and intestinal microenvironment of diabetic and ageing conditions. The activation of AGEs-mediated RAGE could evoke nicotinamide adenine dinucleotide phosphate oxidase-induced reactive oxygen and nitrogen species production and subsequently give rise to oxidative stress in DKD and ageing kidney. Therefore, targeting RAGE with its ligands mediated oxidative stress and chronic inflammation is considered as an additional intervention strategy for DKD and ageing kidney. In this review, we summarize AGEs/RAGE-mediated oxidative stress and inflammation signaling pathways in DKD and ageing kidney, discussing opportunities and challenges of targeting at AGEs/RAGE-induced oxidative stress that could hold the promising potential approach for improving DKD and ageing kidney.
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Diabetes Mellitus , Nefropatías Diabéticas , Envejecimiento , Productos Finales de Glicación Avanzada/metabolismo , Humanos , Riñón/metabolismo , Estrés Oxidativo , Receptor para Productos Finales de Glicación Avanzada/metabolismoRESUMEN
The Wnt/ß-catenin signaling pathway plays important roles in embryonic development and tissue homeostasis. Wnt signaling is induced, and ß-catenin is activated, associated with the development and progression of renal fibrosis. Wnt/ß-catenin controls the expression of various downstream mediators such as snail1, twist, matrix metalloproteinase-7, plasminogen activator inhibitor-1, transient receptor potential canonical 6, and renin-angiotensin system components in epithelial cells, fibroblast, and macrophages. In addition, Wnt/ß-catenin is usually intertwined with other signaling pathways to promote renal interstitial fibrosis. Actually, given the crucial of Wnt/ß-catenin signaling in renal fibrogenesis, blocking this signaling may benefit renal interstitial fibrosis. There are several antagonists of Wnt signaling that negatively control Wnt activation, and these include soluble Fzd-related proteins, the family of Dickkopf 1 proteins, Klotho and Wnt inhibitory factor-1. Furthermore, numerous emerging small-molecule ß-catenin inhibitors cannot be ignored to prevent and treat renal fibrosis. Moreover, we reviewed the knowledge focusing on anti-fibrotic effects of natural products commonly used in kidney disease by inhibiting the Wnt/ß-catenin signaling pathway. Therefore, in this review, we summarize recent advances in the regulation, downstream targets, role, and mechanisms of Wnt/ß-catenin signaling in renal fibrosis pathogenesis. We also discuss the therapeutic potential of targeting this pathway to treat renal fibrosis; this may shed new insights into effective treatment strategies to prevent and treat renal fibrosis.
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Aging as one of intrinsic biological processes is a risk factor for many chronic diseases. Kidney disease is a global problem and health care burden worldwide. The diagnosis of kidney disease is currently based on serum creatinine and urea levels. Novel biomarkers may improve diagnostic accuracy, thereby allowing early prevention and treatment. Over the past few years, advances in genome analyses have identified an emerging class of noncoding RNAs that play critical roles in the regulation of gene expression and epigenetic reprogramming. Long noncoding RNAs (lncRNAs) are pervasively transcribed in the genome and could bind DNA, RNA and protein. Emerging evidence has demonstrated that lncRNAs played an important role in all stages of kidney disease. To date, only some lncRNAs were well identified and characterized, but the complexity of multilevel regulation of transcriptional programs involved in these processes remains undefined. In this review, we summarized the lncRNA expression profiling of large-scale identified lncRNAs on kidney diseases including acute kidney injury, chronic kidney disease, diabetic nephropathy and kidney transplantation. We further discussed a number of annotated lncRNAs linking with complex etiology of kidney diseases. Finally, several lncRNAs were highlighted as diagnostic biomarkers and therapeutic targets. Targeting lncRNAs may represent a precise therapeutic strategy for progressive renal fibrosis.
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Enfermedades Renales/patología , Riñón/metabolismo , ARN Largo no Codificante/metabolismo , Envejecimiento , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/patología , Proteína Forkhead Box O1/química , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Humanos , Enfermedades Renales/genética , Enfermedades Renales/terapia , Trasplante de Riñón , ARN Largo no Codificante/genéticaRESUMEN
BACKGROUND: The combination of Traditional Chinese medicine and Western medicine (TCM+WM) has been widely used in the treatment of glomerulosclerosis, but the results are still controversial. This study will assess the clinical efficacy of TCM+WM for glomerulosclerosis and provide evidence-based medical data via meta-analysis. METHOD: The MEDLINE, EMBASE, PubMed, Cochrane Central Registry of Controlled Trials, and multiple Chinese databases (Wan Fang, CNKI, and VIP) were searched for randomized controlled trials (RCT) that compared the effects of WM and TCM+WM. Review Manager 5.3 software was used for the meta-analysis of selected studies, and appropriate tests were performed to determine the quality, heterogeneity and sensitivity of these studies. RESULTS: Sixteen RCTs met the inclusion criteria and were selected for the analysis. Compared with the placebo or WM-treated glomerulosclerosis patients, TCM+WM intervention significantly improved renal function indices including 24-hour urine protein quantity (24âh U-Pro), serum creatinine (Scr), blood urea nitrogen (BUN), creatinine clearance (Ccr). In addition, the serum albumin (ALB), triglyceride (TG), and cholesterol (CHOL) levels were also significantly improved (Pâ<â.05) in patients receiving the combination therapy. Finally, the combination of TCM+WM reduced the indices of glomerulosclerosis more effectively compared with WM alone. CONCLUSION: The combination of TCM+WM can significantly improve the renal function and prognosis of patients with glomerulosclerosis.