Protective effect of Clinacanthus nutans in cisplatin-induced nephrotoxicity on human kidney cell (PCS-400-010) elucidated by an LCMS-based metabolomics approach.

Cisplatin-induced nephrotoxicity has been widely reported in numerous studies. The objective of this study is to assess the potential nephroprotective effects of Clinacanthus nutans (Burm. f.) Lindau (Acanthaceae) leaf extracts on human kidney cells (PCS-400-010) in vitro using an LCMS-based metabolomics approach. Orthogonal partial least square-discriminant analysis identified 16 significantly altered metabolites when comparing the control and pre-treated C. nutans cisplatin-induced groups. These metabolites were found to be associated with glycerophospholipid, purine, and amino acid metabolism, as well as the glycolysis pathway. Pre-treatment with C. nutans aqueous extract (125 µg/mL) for 24 h, followed by 48 h of cisplatin induction in PCS-400-010 cells, demonstrated a nephroprotective effect, particularly involving the regulation of amino acid metabolism.

Integration of network pharmacology and intestinal flora to investigate the mechanism of action of Chinese herbal Cichorium intybus formula in attenuating adenine and ethambutol hydrochloride-induced hyperuricemic nephropathy in rats.

CONTEXT: Cichorium intybus L. (Asteraceae) formula (CF) has been applied as a folk medicine to treat hyperuricemic nephropathy (HN). However, the exact mechanism remains unclear. OBJECTIVE: To explore the therapeutic effect and mechanism of CF on HN. MATERIALS AND METHODS: Through network pharmacological methods, the targets of the active component of CF against HN were obtained. Subsequently, Male Wistar rats were divided into control, HN, allopurinol (50 mg/kg), CF high-dose (8.64 g/kg) and CF low-dose (2.16 g/kg) groups. The HN model was induced via intragastric administration of adenine (100 mg/kg) and ethambutol hydrochloride (250 mg/kg) for 3 weeks. After CF treatment, biochemical indicators including UA, UREA and CREA were measured. Then, HE staining, qRT-PCR and gut microbiota analysis were conducted to further explore the mechanism. RESULTS: The network pharmacology identified 83 key targets, 6 core genes and 200 signalling pathways involved in the treatment of HN. Compared to the HN group, CF (8.64 g/kg) significantly reduced the levels of UA, UREA and CREA (from 2.4 to 1.57 µMol/L, from 15.87 to 11.05 mMol/L and from 64.83 to 54.83 µMol/L, respectively), and mitigated renal damage. Furthermore, CF inhibited the expression of IL-6, TP53, TNF and JUN. It also altered the composition of gut microbiota, and ameliorated HN by increasing the relative abundance of some probiotics. CONCLUSIONS: This work elucidated the therapeutic effect and underlying mechanism by which CF protects against HN from the view of the biodiversity of the intestinal flora, thus providing a scientific basis for the usage of CF.

Design, synthesis and bioactive evaluation of geniposide derivatives for antihyperuricemic and nephroprotective effects.

Hyperuricemia is a principal factor mediating gout and kidney damage, and xanthine oxidase (XOD) is a key enzyme in the pathogenesis of hyperuricemia. In this context, a series of geniposide derivatives were designed and synthesized, and antihyperuricemic and nephroprotective effects of all derivatives was evaluated in vitro and in vivo. Compound 2e emerged as the most potent XOD inhibitor, with an IC50 value of 6.67 ± 0.46 µM. Simultaneously, cell viability, ROS generation, and SOD levels assay showed that compound 2e could repair the damage of HKC cells by inhibiting the oxidative stress response. The results of the study indicated compound 2e significantly decreased uric acid levels by inhibiting the XOD activity, and repaired kidney damage by inhibiting the expression of TLR4/TLR2/MyD88/NF-κB and NALP3/ASC/caspase-1 signaling pathways. Enzyme inhibition kinetics suggested that compound 2e functioned via reversible mixed competitive inhibition. Moreover, a molecular docking study was performed to gain insight into the binding mode of compound 2e with XOD. These results suggest that geniposide derivatives were potential to be developed into a novel medicine to reveal healthy benefits in natural prevention and reduction risk of hyperuricemia and kidney damage.

[The use of herbal supplement Renotinex based on terpenes for the complex treatment of patients with urinary stone disease].

AIM: to evaluate the efficiency of dietary supplements Renotinex for the complex treatment of patients with urinary stone disease who undergone to extracorporeal shock wave lithotripsy (ESWL). MATERIALS AND METHODS: a total of 60 patients with uncomplicated form of the urinary stone disease with the first stone episode (of size up to 1 cm) were evaluated. Patients were divided into two groups of 30 people and treated by ESWL. In the first group, patients additionally received Renotinex. In the second group, standard complex therapy (antispasmodics, analgesics, non-steroidal anti-inflammatory drugs) was prescribed. The urinary level of 2-microglobulin and serum level of tocopherol were considered as markers of damage and inflammation. Pain intensity was assessed using visual analogue scale. Follow-up studies were carried out on the 1st, 7th and 14th day of therapy. Duration of treatment and follow-up was 1 month. The average number of ESWL sessions was 2.6 in both groups. RESULTS: according to the study, it was established that components of Renotinex had antiseptic, antispasmodic, anti-inflammatory effects on the genitourinary system, enhancing renal blood flow and decreasing the permeability of the kidney capillaries. In addition, Renotinex has diuretic effect and nephroprotective effect, and improves renal function, alleviating aggressive therapeutic influence of ESWL. Antioxidant and nephroprotective effect are among the main mechanisms of action of Renotinex. CONCLUSION: In patients who received Renotinex as dietary supplements fragments after ESWL pass twice as fast, while in patients who did not receive Renotinex, there was more pronounced damage to the kidney parenchyma diagnosed by urine level of 2-microglobulin. The serum concentration of vitamin E increases, while taking Renotinex, which may prevent the peroxidation of polyunsaturated lipids in cell membranes and enhances the nephroprotective effect of Renotinex.

Rosuvastatin Attenuates acute nephrotoxicity through modulation of oxidative stress in Sprague Dawley rats.

OBJECTIVE: To assess the reno-protective effect of rosuvastatin on gentamicin-induced nephrotoxicity in rats. METHODS: The prospective experimental study was conducted at the College of Medicine, Mustansiriya University, Baghdad, Iraq, from March to July, 2018, and comprised Sprague Dawley male rats aged 3-4 months and weighing 200-400g each. The rats were divided into 3 equal groups which were treated for 14 days. Group1 was treated with distilled water plus normal saline, Group2 with distilled water plus gentamicin, and Group3 with rosuvastatin plus gentamicin. Parameters measured were blood urea, serum creatinine, serum malondialdehyde, superoxide dismutase, glutathione reductase, neutrophil gelatinase associated lipocalin, kidney injury molecule-1, interleukin- 18 and Cystatin-c. SPSS 20 was used for data analysis. RESULTS: Of the 30 rats, there were 10(33.3%) in each of the three groups. Rosuvastatin produced significant renoprotective effect through reduction of blood urea, kidney injury molecule-1 and interleukin-18 (p<0.01) compared to the gentamicin group. CONCLUSIONS: Rosuvastatin was found to be a reno-protective against gentamicin-induced nephrotoxicity through modulation of pro-inflammatory and oxidative/anti-oxidant pathways.

HPLC Analysis and In Vivo Renoprotective Evaluation of Hydroalcoholic Extract of Cucumis melo Seeds in Gentamicin-Induced Renal Damage.

BACKGROUND AND OBJECTIVES: Cucumis melo, of family Cucurbitaceae, has traditionally been used to treat variety of kidney disorders. However to best of our knowledge there is no scientific study available that validates its renaoprotective uses. Therefore, this study aimed to evaluate nephroprotective effects of hydroalcoholic extract of Cucumis melo seeds (CMHE) and to identify its phytoconstituents. MATERIALS AND METHODS: HPLC was performed to identify key phytochemicals of CMHE. Gentamicin (100 mg/kg/day, i.p) was administered to induce nephrotoxicity in Swiss albino mice for 8 days. Gentamicin (100 mg/kg/day, i.p) and oral CMHE were co-administered to mice at doses of 250 and 500 mg/kg to evaluate protective effects of CMHE. Normal control group mice were administered normal saline. Changes in body weights, biochemical and histopathological studies were conducted to establish nephroprotective effects of CMHE. Results: HPLC analysis indicated presence of quercetin, m-coumaric acid, gallic acid, chlorogenic acid, and trans-4-hydroxy-3-methoxy cinnamic acid in CMHE. Mice treated with CMHE showed significant increase in body weight and decrease in kidney weight as compared with toxic control group. Dose-dependent significant decrease in total blood urea nitrogen, serum creatinine, serum urea, and uric acid levels were observed in CMHE-treated groups as compared with toxic control group. Histopathological analysis of CMHE-treated groups showed improvement in kidney structures as compared with toxic control group. Conclusions: Biochemical, histopathological, and phytochemical screening of hydroalcoholic extract of Cucumis melo seeds suggest that it has nephroprotective potential. Furthermore, standardization of extract against identified phytochemicals, as well as long-term toxicological studies are suggested before commencement of clinical trials.

Nephroprotective effect of N-acetylglucosamine in rats with acute kidney injury.

The article presents the results of the study of the nephroprotective effect of N-acetylglucosamine (NAG) under the development of experimental acute kidney injury (AKI). The study was conducted on a model of acute glycerol nephrosis in rats. NAG was studied at a dose of 50 mg/kg at daily parenteral administration during 1 week compared to quercetin, which was administered intraperitoneally at a dose of 34 mg/kg. The efficiency of the drugs was assessed by the functional state of animals, the renal excretory function and the nitrogen metabolism indices. The NAG effect on rats with AKI caused a reduction of the mortality rate, an increase in diuresis, a reduction of proteinuria, an increase in creatinine and urea excretion, which indicates the normalization of the renal excretory function and nitrogen metabolism. At the same time, NAG has statistically significantly exceeded the effect of quercetin in the majority of indices and, therefore, the level of efficiency. Thus, NAG is an efficient agent for AKI treatment, which can be used at parenteral route of administration.

Nephroprotective effect of cranberry (Vaccinium oxycoccos) in streptozocin-induced diabetic nephropathy in mice.

OBJECTIVES: Diabetic nephropathy is a chief reason of mortality particularly in individuals with renal dysfunction. The current research was aimed to assess the nephroprotective portion of Vaccinium oxycoccos toward mice diabetic nephropathy induced by streptozotocin (STZ). V. oxycoccos was purchased and used for hydroalcoholic extraction. METHODS: Sixty male mice were subjected to STZ-intraperitoneal injection (45 mg/kg). After diabetes induction, mice were divided into five groups of diabetic control (received only STZ), non-diabetic control (received only citrate buffer), two V. oxycoccos treatment (received V. oxycoccos extract (200 and 400 mg/kg) oral daily by gavage), and metformin treatment (received metformin (500 mg/kg) oral daily by gavage). Glucose and weight of mice were checked weekly. RESULTS: After 28 days, the effect of V. oxycoccos extract on serum and urine parameters were assessed. STZ caused significant decreased in the mice body weight. Mice treated with the V. oxycoccos (400 mg/kg) harbored the lowest weight loss at day 28 (70.2±1.38 g). STZ caused significant increase in the mice FBS. Mice treated with the V. oxycoccos (400 mg/kg) harbored the lowest FBS at day 28 (189.2±1.20 mg/dL). Treatment of mice with V. oxycoccos (400 mg/kg) caused the lowest increase in the levels of cholesterol, HbA1c and triglycerides compared to the diabetic control mice. Compared to the diabetic control group, mice treated with V. oxycoccos (400 mg/kg) had the highest HDL, insulin, SOD, and GSH (p<0.05). The lowest serum BUN, CR, and UR were found in mice treated with V. oxycoccos (400 mg/kg). Anti-inflammatory effects of V. oxycoccos (400 mg/kg) was shown by the lowest TNF-α, IL-6, and TGF-ß1 concentration in mice treated with V. oxycoccos (400 mg/kg). CONCLUSIONS: The current study disclosed that treatment with V. oxycoccos resulted in substantial development in the serum and urine parameters and also antioxidant and anti-inflammatory response of STZ-induced diabetic mice.

Phytochemical, acute toxicity and renal protective appraisal of Ajuga parviflora hydromethanolic leaf extract against CCl4 induced renal injury in rats.

BACKGROUND: Degenerative kidney diseases are mostly associated with oxidative stress. Natural products are considered as the antioxidants enrich food that can restrict the progress of oxidative stress induced disorders. Therefore, the present study was aimed to evaluate the renal protective effect of Ajuga parviflora leaf extract in carbon tetrachloride intoxicated rats. METHODS: The hydromethanolic extract of A. parviflora leaves was obtained by extracting twice in 60% methanol. The principal bioactive constituents were detected by LC/MS analysis. Toxicity of plant extract was assessed using brine shrimp lethal toxicity test and acute toxicity model on healthy Sprague-Dawley male rats. Nephroprotective effects of plant extract were also evaluated on rats by inducing CCl4 renal toxicity in comparison with positive control and naïve groups. The dose of A. parviflora administered to animal was 100, 200 and 300 mg/kg. All administrations were given orally on an alternate day basis for 30 days. Urine and serum biomarkers were analyzed, along with antioxidant enzymes. Finally, the DNA damages, lipid peroxides, hydrogen peroxides and nitrites were assessed in rat's renal tissue. The histopathology alterations in renal tissues were further studied for kidney damages. RESULTS: The LC/MS analysis confirmed the presence of different important pharmacological compounds in A. parviflora methanolic leaf extract. The key bioactive compounds include pyocyanin, zonisamide, D Saccharic acid, altretamine, carbocyclic thromboxane A2, Sinapyl alcohol, and vitamin C. The important polypeptides identified include Lys-Tyr-Lys, His-His-Lys, Met-Asp-Arg, Phe-Val-Arg, and PyroGlu-Val-Arg. The LD50 of A. parviflora was found to be > 1000 µg/mL. A. parviflora administration significantly subsides CCl4 toxicity in rats, reduced the elevated level of RBCs, pus and epithelial cells. The abnormal elevated level of specific gravity, creatinine, urobilinogen, urea and albumin were also reduced to normal physiological level. The reduced urinary protein and pH were also normalized. The serum urobilinogen, urea and total bilirubin levels were also reversed to normal levels while the diminished albumin and total protein levels also came to normal. The important phase I and II enzyme levels were also reversed in A. parviflora administered rats. The H2O2, thiobarbituric acid reactive substance (TBARS) and nitrite levels were significantly decreased. Furthermore, the damaged DNA and histopathological changes in CCl4 exposed rats were also highly significantly reversed after the administration of A. parviflora. All effects were significant (P < 0.05) and highly significant (P < 0.005) at 100 and 300 mg/kg respectively. CONCLUSION: The restored urine and serum profile of various parameters to normal physiological levels suggests that the A. parviflora has potential antioxidant and repairing potential in renal disorders.

NMR and LCMS analytical platforms exhibited the nephroprotective effect of Clinacanthus nutans in cisplatin-induced nephrotoxicity in the in vitro condition.

BACKGROUND: Clinacanthus nutans (C. nutans) Lind. locally known as Belalai Gajah or Sabah snake grass is a medicinal plant belonging to Acanthaceae family. In Asia, this plant is traditionally used for treating skin rashes, insects and snake bites, diabetes mellitus, fever and for diuretic effect. C. nutans has been reported to possess biological activities including anti-oxidant, anti-inflammation, anti-cancer, anti-diabetic and anti-viral activities. METHODS: Proton Nuclear Magnetic Resonance (1H NMR) and Liquid Chromatography Mass Spectroscopy (LCMS) coupled with multivariate data analysis were employed to characterize the metabolic variations of intracellular metabolites and the compositional changes of the corresponding culture media in rat renal proximal tubular cells (NRK-52E). RESULTS: NMR and LCMS analysis highlighted choline, creatine, phosphocholine, valine, acetic acid, phenylalanine, leucine, glutamic acid, threonine, uridine and proline as the main metabolites which differentiated the cisplatin-induced group of NRK-52E from control cells extract. The corresponding media exhibited lactic acid, glutamine, glutamic acid and glucose-1-phosphate as the varied metabolites. The altered pathways perturbed by cisplatin nephrotoxic on NRK-52E cells included changes in amino acid metabolism, lipid metabolism and glycolysis. CONCLUSION: The C. nutans aqueous extract (1000 µg/mL) exhibited the most potential nephroprotective effect against cisplatin toxicity on NRK-52E cell lines at 89% of viability. The protective effect could be seen through the changes of the metabolites such as choline, alanine and valine in the C. nutans pre-treated samples with those of the cisplatin-induced group.

GSPE reduces lead-induced oxidative stress by activating the Nrf2 pathway and suppressing miR153 and GSK-3ß in rat kidney.

Lead (Pb) is a global environmental health hazard that leads to nephrotoxicity. However, the effective treatment of Pb-induced nephrotoxicity remains elusive. Grape seed procyanidin extract (GSPE) has beneficial properties for multiple biological functions. Therefore, the present study investigated whether GSPE reduced Pb-induced nephrotoxicity as well as the protective mechanism of GSPE in a well-established 35-day Pb induced nephrotoxicity rat model. The results showed that GSPE normalized Pb-induced oxidative stress, histological damage, inflammatory, apoptosis, and changes of miR153 and glycogen synthase kinase 3ß (GSK-3ß) levels in rat kidney. Moreover, GSPE enhanced the induction of phase II detoxifying enzymes (heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1) by increasing nuclear factor-erythroid-2-related factor 2 (Nrf2) expression. This study identifies for the first time that Pb-induced oxidative stress in rat kidney is attenuated by GSPE treatment via activating Nrf2 signaling pathway and suppressing miR153 and GSK-3ß. Nrf2 signaling provides a new therapeutic target for renal injury induced by Pb, and GSPE could be a potential natural agent to protect against Pb-induced nephrotoxicity.

Leonurine ameliorates kidney fibrosis via suppressing TGF-ß and NF-κB signaling pathway in UUO mice.

Fibrosis is one of the characteristic features of chronic kidney disease (CKD). Inflammatory reactions and oxidative stress are implicated in the pathogenesis of fibrosis of CKD. Leonurine (LEO) is one of the active compounds from Herba leonuri. In this study, we further evaluated its renoprotective effect in a mouse unilateral urethral obstruction (UUO), featuring the renal tubulointerstitial fibrosis and inflammation. In this model, pretreat of LEO before ureteral obstruction abolished the expression of fibronectin, suppressed the expression of α-SMA and type I/III collagen and down-regulated vimentin. LEO also modified the cytokine expression of TGF-ß, TNF-α, IL-6 and IL-1ß and suppressed the phosphorylation of Smad3. Moreover, LEO blocked phosphorylation of NF-κB, and inactivated the signaling pathways associated with the progression of kidney inflammatory response. Our data support that LEO is a candidate renoprotective compound for renal fibrosis through targeting the TGF-ß/Smad3 and NF-κB pathway.

Leonurine ameliorates LPS-induced acute kidney injury via suppressing ROS-mediated NF-κB signaling pathway.

Acute kidney injury (AKI) is an abrupt loss of kidney function. Severe AKI requires renal replacement therapy and has high mortality. Leonurine (LEO), an alkaloid isolated from Leonurus cardiaca, has shown biological effects such as antioxidant, anticoagulant, and anti-apoptosis. We have examined the effect of LEO on lipopolysaccharide (LPS)-induced AKI in mice and further studied the mechanism involved. Blood urea nitrogen (BUN), creatinine and cytokine were estimated in the serum or tissue. Kidney tissue specimens were used for biochemical estimations of lipid peroxides (LPO), reduced glutathione (GSH), and reactive oxygen species (ROS). The effects of LEO on LPS-induced renal tissue damage were detected by hematoxylin and eosin (HE) stain and electron microscopy. The production of cytokines in the tissue and blood was measured by ELISA. Protein phosphorylation and protein subcellular localization were tested by Western blot. LEO is protected against LPS-induced AKI, improved animal survival and maintained the redox balance. The beneficial effects of LEO were accompanied by the down-regulation of TNF-α, IL-1, IL-6, IL-8, KIM-1 expression and by the inhibition of the phosphorylation of IκBα and p65 translocalization. These results suggest that LEO may suppress NF-κB activation and inhibit pro-inflammatory cytokine production via decreasing cellular ROS production. Accumulating studies have demonstrated that LEO reduces kidney injury and protects renal functions from LPS-induced kidney injury.