Mechanisms of gelofusine protection in an in vitro model of polymyxin B-associated renal injury.

Polymyxins are a last-resort treatment option for multidrug-resistant gram-negative bacterial infections, but they are associated with nephrotoxicity. Gelofusine was previously shown to reduce polymyxin-associated kidney injury in an animal model. However, the mechanism(s) of renal protection has not been fully elucidated. Here, we report the use of a cell culture model to provide insights into the mechanisms of renal protection. Murine epithelial proximal tubular cells were exposed to polymyxin B. Cell viability, lactate dehydrogenase (LDH) release, polymyxin B uptake, mitochondrial superoxide production, nuclear morphology, and apoptosis activation were evaluated with or without concomitant gelofusine. A megalin knockout cell line was used as an uptake inhibition control. Methionine was included in selected experiments as an antioxidant control. A polymyxin B concentration-dependent reduction in cell viability was observed. Increased viability was observed in megalin knockout cells following comparable polymyxin B exposures. Compared with polymyxin B exposure alone, concomitant gelofusine significantly increased cell viability as well as reduced LDH release, polymyxin B uptake, mitochondrial superoxide, and apoptosis. Gelofusine and methionine were more effective at reducing renal cell injury in combination than either agent alone. In conclusion, the mechanisms of renal protection by gelofusine involve decreasing cellular drug uptake, reducing subsequent oxidative stress and apoptosis activation. These findings would be valuable for translational research into clinical strategies to attenuate drug-associated acute kidney injury.NEW & NOTEWORTHY Gelofusine is a gelatinous saline solution with the potential to attenuate polymyxin-associated nephrotoxicity. We demonstrated that the mechanisms of gelofusine renal protection involve reducing polymyxin B uptake by proximal tubule cells, limiting subsequent oxidative stress and apoptosis activation. In addition, gelofusine was more effective at reducing cellular injury than a known antioxidant control, methionine, and a megalin knockout cell line, indicating that gelofusine likely has additional pharmacological properties besides only megalin inhibition.

Antibacterial, antidiabetic, acute toxicity, antioxidant, and nephroproductive competence of extracts of Lannea coromandelica fruit through in-vitro and in-vivo animal model investigation.

The anti-dermatophytic (Proteus vulgaris, Klebsiella pneumoniae, Enterobacter aerogenes, Propionibacterium acnes, Staphylococcus aureus, and Streptococcus pyogenes) and nephroprotective activities of methanol and aqueous extracts obtained from Lannea coromandelica fruit were investigated through in-vitro (agar well diffusion method) and in-vivo (animal model) study. The methanol extract showed considerable antibacterial activity against selective bacterial pathogens at increased concentration (15.0 mg mL-1) in the following order P. vulgaris (35.2 ± 1.6 mm) > E. aerogenes (32.1 ± 2.1 mm) > K. pneumoniae (29.3±2 mm) > P. acnes (28.2 ± 2.4 mm) > S. aureus (25.5 ± 2.4 mm) > S. pyogenes (24.3 ± 2.1 mm) than aqueous extract. The MIC values of this methanol and aqueous extract was found as 2.5-7.5 mg mL-1 and 5.0 to 1.0 mg mL-1 respectively. Different treatment sets (A-E) on a rat-based animal model study revealed that the methanol extract has excellent antioxidant and nephroprotective activity, as well as favorable effects on essential biochemical substances involved in active metabolic activities. As demonstrated by histopathological and microscopic examination, the biologically active chemical present in methanol extract had a positive effect on serum markers, enzyme, and non-enzyme-based antioxidant activities, as well as lowering the toxicity caused by EG in the rat (as nephroprotective activity) renal cells.

Water-soluble phenolics from Phoenix dactylifera fruits as potential reno-protective agent against cisplatin-induced toxicity: pre- and post-treatment strategies.

Nephrotoxicity is the major side effect of cisplatin, an effective platinum-based chemotherapeutic drug that is applicable in the treatment of several solid-tissue cancers. Studies have indicated that certain water-soluble phenolics offer renal protection. Thus, this study investigates the role of pre and post-treatment of rats with water-soluble phenolics from Phoenix dactylifera (PdP) against nephrotoxicity induced by cisplatin. Rats were either orally pretreated or post-treated with 200 mg/kg body weight of PdP before or after exposure to a single therapeutic dose of cisplatin (5 mg/kg body weight) for 7 successive days intraperitoneally. The protective effects of PdP against Cisplatin-induced nephrotoxicity was based on the evaluation of various biochemical and redox biomarkers, together with histopathological examination of kidney tissues. The composition, structural features, and antioxidative influence of PdP were determined based on chromatographic, spectroscopic, and in vitro antioxidative models. Cisplatin single exposure led to a substantial increase in the tested renal function biomarkers (uric acid, creatinine, and urea levels), associated with an increase in malondialdehyde indicating lipid peroxidation and a significant decline (p < 0.05) in reduced glutathione (GSH) levels in the renal tissue when compared with the control group. A marked decline exists in the kidney antioxidant enzymes (catalase, SOD, and GPx). Nevertheless, treatment with PdP significantly suppressed the heightened renal function markers, lipid peroxidation, and oxidative stress. Spectroscopic analysis revealed significant medicinal phenolics, and in vitro tests demonstrated antioxidative properties. Taken together, results from this study indicate that pre- and/or post-treatment strategies of PdP could serve therapeutic purposes in cisplatin-induced renal damage.

Nephroprotective effects of coriander (Coriandrum sativum) leaves aqueous extracts in aristolochic acid-intoxicated zebrafish embryos.

Coriander is a notable medicinal plant known for its diverse properties, including anti-inflammatory, antioxidant, anticancer, analgesic, and anti-diabetic effects. Despite its recognized health benefits, research on its nephroprotective properties is limited. This study aimed to investigate the potential nephroprotective properties of an aqueous extract derived from coriander leaves using an aristolochic acid-intoxicated zebrafish model. To assess kidney abnormalities induced by aristolochic acid (AA), we utilized the transgenic line Tg(wt1b:egfp), which expresses green fluorescent protein (GFP) in the kidney. Our previous report indicated that AA exposure leads to acute renal failure in zebrafish characterized by kidney malformation and impaired renal function. However, pretreatment of coriander extract (CE) can mitigate kidney malformations induced by AA. In addition, CE pretreatment reduces the accumulation of red blood cells in the glomerular region. To verify the nephroprotective effects of CE, we analyzed renal function by measuring the glomerular filtration rate in zebrafish embryos. Results indicate that CE partially mitigates renal function impairment caused by AA exposure, suggesting its potential to attenuate AA-induced renal failure. Mechanistically, pretreatment with CE reduces the expression of proinflammatory and proapoptotic genes induced by AA. This suggests that CE likely alleviates acute renal failure by reducing inflammation and apoptosis. As a result, we regard zebrafish as a valuable model for screening natural compounds that have the potential to alleviate AA-induced nephrotoxicity.

In vivo hepatoprotective and nephroprotective effects of Stenocarpus sinuatus leaf extract against ifosfamide-induced toxicity in rats.

Ifosfamide (IFOS) is a broad-spectrum chemotherapeutic agent that has been extensively used for breast cancer and other solid tumors. Unfortunately, its use is associated with toxicities of several organs. Stenocarpus sinuatus is an Australian tree belonging to the Proteaceae family. In the current study, the phytochemical constituents of S. sinuatus methanol leaf extract (SSLE) were assessed. In addition, the protective effect of SSLE against IFOS-induced nephrotoxicity and hepatotoxicity was evaluated. Rats were randomly divided into six groups: control, IFOS (50 mg/kg), IFOS + SSLE (100 mg/kg), IFOS + SSLE (200 mg/kg), IFOS + SSLE (400 mg/kg), and SSLE (400 mg/kg). Hepatoprotective and nephroprotective potency of SSLE was assessed using different biochemical parameters. The phytochemical investigation resulted in the isolation of four flavonoid glycosides (kaempferol 3-O-ß- d-glucopyranosyl-(1→2)-α- l-rhamnopyranoside, kaempferol 3-O-α-rhamnopyranoside, isorhamnetin 3-O-ß- d-glucopyranosyl-(1→2)-α- l-rhamnopyranoside, and quercetin 3-O-ß- d-glucopyranosyl-(1→2)-α- l-rhamnopyranoside) and a coumarin (scopoletin). This is the first report on the isolated compounds from the genus Stenocarpus. SSLE showed enhancement of kidney and liver functions and reduction of oxidative stress and inflammation. The histopathology of the investigated organs confirmed the protective effect of SSLE. In conclusion, SSLE is considered as a promising candidate that can be used in defense against the toxic effects of IFOS after further clinical trials.

Nephroprotective and Anti-Diabetic Potential of Beta vulgaris L. Root (Beetroot) Methanolic Extract in a Rat Model of Type 2 Diabetes Mellitus.

Background and Objectives: Diabetes mellitus is a chronic metabolic disease associated with several complications, including that of kidney disease. Plant-based dietary products have shown promise in mitigating these effects to improve kidney function and prevent tissue damage. This study assessed the possible favorable effects of beetroot extract (BE) in improving kidney function and preventing tissue damage in diabetic rats. Materials and Methods: Type 2 diabetes mellitus (T2DM) was induced using a low dose of streptozotocin (STZ). Both control and rats with pre-established T2DM were divided into six groups (each consisting of eight rats). All treatments were given by gavage and continued for 12 weeks. Fasting blood glucose levels, serum fasting insulin levels, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), serum triglycerides, cholesterol, low-density lipoprotein-cholesterol, serum and urinary albumin, and creatinine and urea levels were measured. Apart from this, glutathione, malondialdehyde, superoxide dismutase, tumor necrosis factor-α, and interleukine-6 in the kidney homogenates of all groups of rats were measured, and the histopathological evaluation of the kidney was also performed. Results: It was observed that treatment with BE increased body weight significantly (p ≤ 0.05) to be similar to that of control groups. Fasting glucose, insulin, HOMA-IR levels, and lipid profile in the plasma of the pre-established T2DM rats groups decreased to p ≤ 0.05 in the BE-treated rats as the BE concentration increased. Treatment with BE also improved the renal levels of oxidative stress and inflammatory markers, urinary albumin, and serum creatinine and urea levels. Unlike all other groups, only the kidney tissues of the T2DM + BE (500 mg/kg) rats group showed normal kidney tissue structure, which appears to be similar to those found in the kidney tissues of the control rats groups. Conclusion: we found that streptozotocin administration disturbed markers of kidney dysfunction. However, Beta vulgaris L. root extract reversed these changes through antioxidant, anti-inflammatory, and antiapoptotic mechanisms.

[Nephroprotective value of N-acetylcysteine for patients with concomitant trauma, as well as other aspects of the use of this drug in clinical practice].

An analysis and review of domestic and foreign literature on the role of N-acetylcysteine in the correction of oxidative stress, as well as the problem of oxidative stress, and protection against free radicals are presented in the article. The important role of N-acetylcysteine in replenishing the intracellular glutathione level, which is the main cell antioxidant, has been shown, as well as the potential use of N-acetylcysteine for various pathological conditions and diseases. The relevance of concomitant injury and renal dysfunction, and the experience of the clinical use of N-acetylcysteine as a nephroprotector in patients with concomitant injury in the clinic of the Department of Faculty and Endoscopic Surgery of KBSU named after Kh.M. Berbekov are also described. After reviewing the literature, based on the results of many experimental studies, we can conclude that this pharmacological substance is a very promising for replenishing the intracellular glutathione pool, and it becomes possible to include it in the combined therapy of a number of human diseases.

An integrated strategy by absorbed component characterization, pharmacokinetics, and activity evaluation for identification of potential nephroprotective substances in Zhu-Ling decoction.

An efficient strategy for the identification of potential nephroprotective substances in Zhu-Ling decoction has been established with the integration of absorbed components characterization, pharmacokinetics, and activity evaluation. A qualitative method was developed to characterize the chemical constituents absorbed components in vivo of Zhu-Ling decoction by using ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry. A quantitative method was established and validated for the simultaneous determination of eight compounds in rat plasma by using ultra-performance liquid chromatography-triple quadruple tandem mass spectrometry. Finally, the nephroprotective activities of absorbed components with high exposure were assessed by cell survival rate, superoxide dismutase, and malondialdehyde activities in hydrogen peroxide-induced Vero cells. As a result, 111 compounds in Zhu-Ling decoction and 36 absorbed components were identified in rat plasma and urine, and poricoic acid A, poricoic acid B, alisol A, 16-oxo-alisol A, and dehydro-tumulosic acid had high exposure levels in rat plasma. Finally, poricoic acid B, poricoic acid A, 16-oxo-alisol A, and dehydro-tumulosic acid showed remarkable nephroprotective activity against Vero cells damage induced by hydrogen peroxide. Besides, superoxide dismutase and malondialdehyde activities were obviously regulated in hydrogen peroxide-induced Vero cells by treatment with the four compounds mentioned above. Therefore, these four compounds were considered to be effective substances of Zhu-Ling decoction due to their relatively high exposure in vivo and biological activity. This study provided a chemical basis for the action mechanism of Zhu-Ling decoction in the treatment of chronic kidney diseases.

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.

Thymoquinone Ameliorates Carfilzomib-Induced Renal Impairment by Modulating Oxidative Stress Markers, Inflammatory/Apoptotic Mediators, and Augmenting Nrf2 in Rats.

Chemotherapy-induced kidney damage is an emerging problem that restricts cancer treatment effectiveness. The proteasome inhibitor carfilzomib (CFZ) is primarily used to treat multiple myeloma and has been associated with severe renal injury in humans. CFZ-induced nephrotoxicity remains an unmet medical need, and there is an urgent need to find and develop a nephroprotective and antioxidant therapy for this condition. Thymoquinone (TQ) is a bioactive compound that has been isolated from Nigella sativa seeds. It has a wide range of pharmacological properties. Therefore, this experimental design aimed to study the effectiveness of TQ against CFZ-induced renal toxicity in rats. The first group of rats was a normal control (CNT); the second group received CFZ (4 mg/kg b.w.); the third and fourth groups received TQ (10 and 20 mg/kg b.w.) 2 h before receiving CFZ; the fifth group received only TQ (20 mg/kg b.w.). This experiment was conducted for 16 days, and at the end of the experiment, blood samples and kidney tissue were collected for biochemical assays. The results indicated that administration of CFZ significantly enhanced serum marker levels such as BUN, creatinine, and uric acid in the CFZ group. Similarly, it was also noticed that CFZ administration induced oxidative stress by reducing antioxidants (GSH) and antioxidant enzymes (CAT and SOD) and increasing lipid peroxidation. CFZ treatment also enhanced the expression of IL-1ß, IL-6, and TNF-α production. Moreover, CFZ increased caspase-3 concentrations and reduced Nrf2 expression in the CFZ-administered group. However, treatment with 10 and 20 mg/kg TQ significantly decreased serum markers and increased antioxidant enzymes. TQ treatment considerably reduced IL-1ß, IL-6, TNF-α, and caspase-3 concentrations. Overall, this biochemical estimation was also supported by histopathological outcomes. This study revealed that TQ administration significantly mitigated the negative effects of CFZ treatment on Nrf2 expression. Thus, it indicates that TQ may have utility as a potential drug to prevent CFZ-induced nephrotoxicity in the future.

Determination of Hypoglycemic, Hypolipidemic and Nephroprotective Effects of Berberis Calliobotrys in Alloxan-Induced Diabetic Rats.

Many plants of the Berberis genus have been reported pharmacologically to possess anti-diabetic potential, and Berberis calliobotrys has been found to be an inhibitor of α-glucosidase, α-amylase and tyrosinase. Thus, this study investigated the hypoglycemic effects of Berberis calliobotrys methanol extract/fractions using in vitro and In vivo methods. Bovine serum albumin (BSA), BSA-methylglyoxal and BSA-glucose methods were used to assess anti-glycation activity in vitro, while in vivo hypoglycemic effects were determined by oral glucose tolerance test (OGTT). Moreover, the hypolipidemic and nephroprotective effects were studied and phenolics were detected using high performance liquid chromatography (HPLC). In vitro anti-glycation showed a significant reduction in glycated end-products formation at 1, 0.25 and 0.5 mg/mL. In vivo hypoglycemic effects were tested at 200, 400 and 600 mg/kg by measuring blood glucose, insulin, hemoglobin (Hb) and HbA1c. The synergistic effect of extract/fractions (600 mg/kg) with insulin exhibited a pronounced glucose reduction in alloxan diabetic rats. The oral glucose tolerance test (OGTT) demonstrated a decline in glucose concentration. Moreover, extract/fractions (600 mg/kg) exhibited an improved lipid profile, increased Hb, HbA1c levels and body weight for 30 days. Furthermore, diabetic animals significantly exhibited an upsurge in total protein, albumin and globulin levels, along with a significant improvement in urea and creatinine after extract/fractions administration for 42 days. Phytochemistry revealed alkaloids, tannins, glycosides, flavonoids, phenols, terpenoids and saponins. HPLC showed the presence of phenolics in ethyl acetate fraction that could be accountable for pharmacological actions. Therefore, it can be concluded that Berberis calliobotrys possesses strong hypoglycemic, hypolipidemic and nephroprotective effects, and could be a potential therapeutic agent for diabetes treatment.

Lysophosphatidylcholine-based liposome to improve oral absorption and nephroprotective effects of astaxanthin.

BACKGROUND: The present study was aimed to develop astaxanthin (AX)-loaded liposomes by the utilization of soybean phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) to improve the nutraceutical properties of AX. AX-loaded liposomes consisting of PC (PC/AX) and LPC (LPC/AX) were evaluated in terms of particle size distribution, morphology, release characteristics, pharmacokinetic behavior, and nephroprotective effects in a rat model of acute kidney injury. RESULTS: PC/AX and LPC/AX had uniform size distributions with a mean particle size of 254 and 148 nm, respectively. Under pH 6.8 conditions, both liposomes exhibited improved dissolution behavior of AX compared with crystalline AX (cAX). In particular, LPC/AX showed a sevenfold higher release of AX than PC/AX. After the oral administration of LPC/AX (33.2 mg AX kg-1 ) to rats, there was a significant increase in systemic exposure to AX, as evidenced by a 15-fold higher AUC0-24 h than PC/AX. However, the oral absorption of AX in the cAX group was negligible. Based on the results of histological analysis and measurement of plasma biomarkers, LPC/AX exhibited improved nephroprotective effects of AX in the rat model of kidney injury. CONCLUSION: From these observations, a strategic application of the LPC-based liposomal approach might be a promising option to improve the nutraceutical properties of AX. © 2022 Society of Chemical Industry.

Lifelong effect of therapy in young patients with the COL4A5 Alport missense variant p.(Gly624Asp): a prospective cohort study.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEis) have evolved as a first-line therapy for delaying end-stage renal failure (ESRF) in Alport syndrome (AS). The present study tested the hypothesis of a superior nephroprotective potential of an early ACEi intervention, examining a cohort with the COL4A5 missense variant p.(Gly624Asp). METHODS: In this observational cohort study (NCT02378805), 114 individuals with the identical gene variant were explored for age at ESRF and life expectancy in correlation with treatment as endpoints. RESULTS: All 13 untreated hemizygous patients developed ESRF (mean age 48.9 ± 13.7 years), as did 3 very late treated hemizygotes (51.7 ± 4.2 years), with a mean life expectancy of 59.2 ± 9.6 years. All 28 earlier-treated [estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2] hemizygous patients were still alive and still had not reached ESRF. Therapy minimized the annual loss of their GFR, similar to the annual loss in healthy individuals. Of 65 heterozygotes, 4 untreated individuals developed ESRF at an age of 53.3 ± 20.7 years. None of the treated heterozygous females developed ESRF. CONCLUSIONS: For the first time, this study shows that in AS, early therapy in individuals with missense variants might have the potential to delay renal failure for their lifetime and thus to improve life expectancy and quality of life without the need for renal replacement therapy. Some treated patients have reached their retirement age with still-functioning kidneys, whereas their untreated relatives have reached ESRF at the same or a younger age. Thus, in children with glomerular haematuria, early testing for Alport-related gene variants could lead to timely nephroprotective intervention.

Synthesis and bioactivity evaluation of novel nuciferine derivatives with antihyperuricemia and nephroprotective effects.

Hyperuricemia is a common metabolic disease with a series of complications. Nuciferine, a typical aporphine alkaloid natural compound extracted from the leaves of Nelumbo nucifera Gaertn., was confirmed to have an antihyperuricemia effect. In the present study, 30 novel nuciferine derivatives were designed and synthesized. The effects of all derivatives on the regulation of URAT1 were studied in a uric acid-induced HK-2 cell model with benzbromarone as a positive control. The results indicated that Compound 1j showed the optimal URAT1 inhibitory activity through repressing PI3K/Akt pathway in HK-2 cells and the inhibitory effect was similar to that of benzbromarone. In addition, in vivo experiments demonstrated that Compound 1j could reduce uric acid levels and ameliorate kidney damage in hyperuricemic mice. On the one hand, Compound 1j could inhibit the expression of URAT1 and GLUT9 to increase the uric acid excretion index. On the other hand, Compound 1j could regulate the TLR4/IκBα/NF-κB signaling pathway to reduce the levels of inflammatory cytokines, thereby alleviating kidney damage. Meanwhile, a molecular docking assay revealed the potential molecular binding power (-9.79 kcal/mol) between Compound 1j and URAT1, which was more tightly bound than the lead compound nuciferine (-7.44 kcal/mol). Based on these results, Compound 1j may be a future drug for the development of new potential antihyperuricemia and nephroprotective drug candidates.

Standardized aqueous stem bark extract of Gmelina arborea roxb. possesses nephroprotection against adriamycin-induced nephrotoxicity in Wistar rats.

Nephrotoxicity is a major limitation of adriamycin (ADR) chemotherapy. We hypothesized that administration of standardized aqueous bark extract of Gmelina arborea Roxb. (GA) (Family; Verbenaceae), a traditional therapeutic agent, may reduce the nephrotoxicity caused by ADR in Wistar rats. The dose-dependent nephroprotective activity of the standardized GA extract was investigated in ADR-induced (20 mg/kg, ip) nephrotoxicity in male Wistar rats (n = 6/group). The lyophilized powder of the aqueous refluxed (4 h) GA extract was administered at 100, 300 and 500 mg/kg doses orally for three consecutive days. Fosinopril sodium (0.09 mg/kg) was used as the positive control. Assessment of biochemical parameters on serum, urine and histopathology on H and E stained kidney sections were done at the end of the intervention. The treatment with GA and fosinopril decreased the elevation of serum creatinine, blood urea nitrogen, cystatin C, ß2-microglobulin and loss of total protein in urine in nephrotoxic rats in a dose-dependent manner (p < 0.05). In contrast, serum concentrations of albumin and total protein were increased significantly (p < 0.05). H and E stained kidney sections showed an attenuation of renal parenchymal injury following the treatment. The aqueous extract of GA demonstrated antioxidant potential in vitro. Present findings conclude that the standardized aqueous extract of GA stem bark exerted a dose-dependent protection against ADR-induced nephrotoxicity in vivo and may be a promising adjunct in ADR chemotherapy.

Nephroprotective effect of persimmon leaves (Diospyros kaki L.f.) against CCl4-induced renal toxicity in Swiss Albino rats.

Diospyros kaki L.f. fruit and leaves are traditionally used for the treatment of hypertension, angina, internal hemorrhage, antithrombotic and anti-inflammatory effects.In the current study, the protective effects of ethyl acetate (Per-1), n-butanol (Per-2), and aqueous (Per-3) fractions of Diospyros kaki leaves against carbon tetrachloride (CCl4) induced nephrotoxicity in Swiss albino rats were tested. Animal were divided into nine groups; each group consists of six animals. The groups were : group I was untreated and kept as control, group II was treated with CCl4 only, group III (silymarin with CCl4); group IV (Per-1 100 mg/kg with CCl4);group V (Per-1 200 mg/kg with CCl4); group VI (Per-2 100 mg/kg with CCl4); group VII (Per-2 200 mg/kg with CCl4); group VIII (Per-3 100 mg/kg with CCl4); and group IX (Per-3 200 mg/kg with CCl4). Silymarin was used as standard drug. All tested fractions were found active (except Per-1 at low dose of 100 mg/kg) with significant value (p < 0.001) compared to CCl4 only group. Serum creatinine, malondialdehyde (MDA), and uric acid were significantly (p < 0.001) lowered in group VII-IX as compared to CCl4 only group. Similarly, total protein (TP) and non-protein sulfhydryls(NP-SH) level in kidney tissues were significantly (p < 0.001) elevated in the same groups compared to CCl4 only group. Further to check the cardio-protective potential, biochemical parameters such as LDH, creatine kinase, TP, MDA, and NP-SH levels in myocardial tissues were also estimated.These findings confirmed that the n-butanol and aqueous fractions are active and recommended for further bioactive phytoconstituents screening. Repeated column chromatography on silica gel G and sephadex-LH-20 of the active n-butanol fraction, four flavonoids were isolated. Based on the spectroscopic NMR data, compounds were identified as kaempferol (1), quercetin (2), astragalin (3), and rutin (4).

The Protective Effects of Sesamin against Cyclophosphamide-Induced Nephrotoxicity through Modulation of Oxidative Stress, Inflammatory-Cytokines and Apoptosis in Rats.

Cyclophosphamide is an anticancer drug with a wide spectrum of clinical uses, but its typical side effects are multiple complications, including nephron toxicity. The possible molecular mechanism of the nephroprotective action of sesamin (SM) against cyclophosphamide (CP) induced renal toxicity was investigated in rats by understanding oxidative stress and inflammatory cytokines. In this study, rats were arbitrarily grouped into the following four groups: a normal control group (CNT); a CP-induced toxicity group; a treatment group with two doses of sesamin SM10 and SM20; a group with sesamin (SM20) alone. A single dose of CP (150 mg/kg body, i.p.) was administered on day 4 of the experiments, while treatment with SM was given orally for seven days from day 1. The group treated with SM showed a significant protective effect against CP-induced renal damage in rats. Treatment with SM significantly increased the antioxidant enzymes (GSH, CAT, and SOD) and reduced malondialdehyde (MDA) levels. Thus, SM significantly overcame the elevated kidney function markers (creatinine, blood urea nitrogen, and uric acid) by attenuating oxidative stress. The SM also significantly reduced the elevated cytokines (IL-1ß and TNFα) and caspase-3 in the treated group. Histopathological studies confirmed the protective effect of sesamin (SM) on CP-induced nephrotoxicity. In conclusion, the current findings support the nephroprotective effect of sesamin against CP-induced renal injury.

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.

Hepato and nephroprotective activity of methanol extract of Hygrophila spinosa and its antibacterial potential against multidrug resistant Pandoraea sputorum.

This research was aimed to evaluate the phytochemical profile, bactericidal activity of Hygrophila spinosa against multidrug resistant Pandoraea sputorum and assess their antioxidant competence against various radicals and studied their hepatoprotective and nephroprotective activity on HepG2 and HEK 293 cell line. The results showed that the methanol extract has various phytochemical components with reasonable quantity. Fortunately, the multidrug-resistant P. sputorum was sensitive (22.8 ± 0.2 mm of the zone of inhibition) at 15 mg mL-1 concentration of methanol extract. The higher concentration of phenolic and other phytochemical components, showed significant antioxidant activity against ferric, DPPH, hydroxyl, and ABTS radicals, with IC50 values of 71.09, 64.333, 91.157, and 104.931 g mL-1, respectively. Surprisingly, the methanol extract possesses hepato and nephroprotective activity against CCl4 and cisplatin-induced cytotoxicity on HepG2 and HEK 293 cell lines, respectively. It maintains the cell viability as up to 90.48% and 90.35% of HepG2 and EK 293 cell line at the concentration of 20 µg mL-1. The FTIR analysis states that the methanol extract possesses a significant functional group responsible for these multi-potential activities. These results suggest that, the methanol extract of H. spinosa might contain the most significant bioactive components with outstanding medicinal properties.