Oxidative Renal Injury Research Articles

Aloe ferox leaf gel extracts attenuate redox imbalance in oxidative renal injury and stimulates glucose uptake, whilst inhibiting key enzymes linked to diabetes and obesity

The worldwide prevalence of diabetes and obesity is growing rapidly. Both metabolic disorders are linked to chronic adverse complications, which include kidney dysfunctions. Medicinal plants play a crucial role in traditional healthcare, especially in developing countries. Aloe ferox, native to South Africa, has a long history of medicinal use, but its pharmacological potential is less studied compared to other Aloe species, necessitating further investigation. Therefore, the present study was conducted to determine the antioxidative, anti-obesogenic, and antidiabetic effects of A. ferox leaf gel extracts using in vitro, ex vivo, and in silico experimental models, with oxidative renal damage induced by ferrous sulfate (FeSO4). A. ferox leaf gel extracts exhibited strong antioxidant activity, inhibited digestive enzymes, and significantly improved glucose uptake. The aqueous extract demonstrated better antioxidant efficacy, leading to higher reduced glutathione (GSH) level, and superoxide dismutase (SOD) and catalase enzymes activity, along with a concurrent reduction of nitric oxide (NO) and malondialdehyde (MDA) levels. Likewise, the aqueous extract showed more potent in vitro DPPH, NO, and OH• radical scavenging activity with IC50 values of 3.64 ±0.3 μg/mL, 110.73±0.1 μg/mL, and 331.13 ±0.7 μg/mL, respectively. The aqueous extract had better inhibition of the enzyme α-amylase (IC50 = 25.73±2.5 µg/mL), whilst the ethanolic extract inhibited α-glucosidase (IC50 =663.2±0.3 µg/ml), and pancreatic lipase (IC50 =122.01±5.9 µg/mL) more strongly. Incubation of the extracts with yeast cells stimulated glucose uptake dose dependently, when ethanolic extract (IC50 = 308.01±0.7 µg/mL) showed the better activity compared to the aqueous extract (IC50 = 338.79±7.05 µg/mL). Furthermore, LC-MS analysis led to the identification of many compounds, when chlorogenic acid demonstrated a stronger molecular interaction with the active site amino acids of α-amylase and catalase compared to other compounds. However, Aloin B showed the highest affinity with α-glucosidase and 5-Hydroxyaloin A showed the lowest binding energy with lipase, and SOD enzyme. These results suggest the reno-protective effects of A. ferox leaf gel extracts against FeSO4-induced oxidative stress along with its anti-hyperglycaemic activity. Given these observed effects, A. ferox leaf gel could indeed be valuable in developing natural therapies and potential drug development for the management of these disorders. Further studies in animal models are needed to ascertain the results of this study.

A comparative study of the efficiency of mitochondria-targeted antioxidants MitoTEMPO and SKQ1 under oxidative stress

MitoTEMPO (MT) and Visomitin (SKQ1) are regareded as mitochondria-targeted antioxidants, which inhibit production of mitochondrial reactive oxygen species (ROS). However, the differences in function between MT and SKQ1 remain unexplored. Herein, we investigated the differential potency of MT and SKQ1 in mitigating oxidative stress under different conditions. The results indicated that high levels of SKQ1 induced cell death. The appropriate concentrations of MT and SKQ1 can prevent or rescue cell damage triggered by hydrogen peroxide (H2O2) and menadione (MEN). MT and SKQ1 reduced ROS levels and reversed the down-regulation of antioxidant defence genes and enzymes. These effects can alleviate the damage to lipids, proteins, and deoxyribonucleic acid (DNA) caused by oxidative stress and restore adenosine 5′ triphosphate (ATP) generation. Subsequently, we found that MT administration in ischemic reperfusion kidney injury in mice provided superior renal protection compared to SKQ1, as evidenced by reduced plasma levels of kidney injury markers, improved renal morphology, decreased apoptosis, restored mitochondrial function, and enhanced antioxidant capacity. Overall, our findings suggest that MT is safer and has greater potential than SKQ1 as a therapeutic agent to mitigate oxidative stress damage or oxidative renal injury.

Nephroprotective effect of Ginsenoside Rg1 in lipopolysaccharide-induced sepsis in mice through the SIRT1/NF-κB signaling.

During sepsis, the kidney is one of the most vulnerable organs. Sepsis-associated acute kidney injury (S-AKI) is hallmarked by renal inflammation, apoptosis, and oxidative injury. Ginsenoside Rg1 (Rg1) is a natural product that possesses abundant pharmacological actions and protects against many sepsis-related diseases. Nevertheless, its role and related mechanism in S-AKI remain to be determined. S-AKI was induced using lipopolysaccharide (LPS, 10 mg/kg) via a single intraperitoneal injection. Rg1 (200 mg/kg) was intraperitoneally administered for 3 consecutive days before LPS treatment. For histopathological examination, murine kidney tissues were stained with hematoxylin and eosin. Tubular injury score was calculated to evaluate kidney injury. Serum creatinine and BUN levels were measured for assessing renal dysfunction. The levels and activities of oxidative stress markers (MDA, 4-HNE, PC, GSH, SOD, and CAT) in renal tissue were measured by corresponding kits. Renal cell apoptosis was detected by TUNEL staining. The protein levels of apoptosis-related markers (Bcl-2, Bax, and Cleaved caspase-3), proinflammatory factors, SIRT1, IκBα, p-NF-κB p65, and NF-κB p65 in kidneys were determined using western blotting. Immunofluorescence staining was employed to assess p-NF-κB p65 expression in renal tissues. LPS-induced injury of kidneys and renal dysfunction in mice were ameliorated by Rg1. Rg1 also impeded LPS-evoked renal cell apoptosis in kidneys. Moreover, Rg1 attenuated LPS-triggered inflammation and oxidative stress in kidneys by inhibiting proinflammatory cytokine release, enhancing antioxidant levels and activities, and reducing lipid peroxidation. However, all these protective effects of Rg1 in LPS-induced AKI mice were reversed by EX527, an inhibitor of sirtuin 1 (SIRT1). Mechanistically, Rg1 upregulated SIRT1 protein expression, increased SIRT1 activity, and inactivated NF-κB signaling in the kidney of LPS-induced AKI mice, which was also reversed by EX527. Rg1 ameliorates LPS-induced kidney injury and suppresses renal inflammation, apoptosis, and oxidative stress in mice via regulating the SIRT1/NF-κB signaling.

Elucidating ascorbate and aldarate metabolism pathway characteristics via integration of untargeted metabolomics and transcriptomics of the kidney of high-fat diet-fed obese mice.

Obesity is a major independent risk factor for chronic kidney disease and can activate renal oxidative stress injury. Ascorbate and aldarate metabolism is an important carbohydrate metabolic pathway that protects cells from oxidative damage. However the effect of oxidative stress on this pathway is still unclear. Therefore, the primary objective of this study was to investigate the ascorbate and aldarate metabolism pathway in the kidneys of high-fat diet-fed obese mice and determine the effects of oxidative stress. Male C57BL/6J mice were fed on a high-fat diet for 12 weeks to induce obesity. Subsequently, non-targeted metabolomics profiling was used to identify metabolites in the kidney tissues of the obese mice, followed by RNA sequencing using transcriptomic methods. The integrated analysis of metabolomics and transcriptomics revealed the alterations in the ascorbate and aldarate metabolic pathway in the kidneys of these high-fat diet-fed obese mice. The high-fat diet-induced obesity resulted in notable changes, including thinning of the glomerular basement membrane, alterations in podocyte morphology, and an increase in oxidative stress. Metabolomics analysis revealed 649 metabolites in the positive-ion mode, and 470 metabolites in the negative-ion mode. Additionally, 659 differentially expressed genes (DEGs) were identified in the obese mice, of which 34 were upregulated and 625 downregulated. Integrated metabolomics and transcriptomics analyses revealed two DEGs and 13 differential metabolites in the ascorbate and aldarate metabolic pathway. The expression levels of ugt1a9 and ugt2b1 were downregulated, and the ascorbate level in kidney tissue of obese mice was reduced. Thus, renal oxidative stress injury induced by high-fat diet affects metabolic regulation of ascorbate and aldarate metabolism in obese mice. Ascorbate emerged as a potential marker for predicting kidney damage due to high-fat diet-induced obesity.

Selenium protects against Pb-induced renal oxidative injury in weaning rats and human renal tubular epithelial cells through activating NRF2

BackgroundLead (Pb) poisoning posing a crucial health risk, especially among children, causing devastating damage not only to brain development, but also to kidney function. Thus, an urgent need persists to identify highly effective, safe, and low-toxicity drugs for the treatment of Pb poisoning. The present study focused on exploring the protective effects of Se on Pb-induced nephrotoxicity in weaning rats and human renal tubular epithelial cells, and investigated the possible mechanisms. MethodsForty weaning rats were randomly divided into four groups in vivo: control, Pb-exposed, Pb+Se and Se. Serum creatinine (Cr), urea nitrogen (BUN) and hematoxylin and eosin (H&E) staining were performed to evaluate renal function. The activities of antioxidant enzymes in the kidney tissue were determined. In vitro experiments were performed using human renal tubular epithelial cells (HK-2 cells). The cytotoxicity of Pb and Se was detected by 3-(4,5-dimethylthiazol-2yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Inverted fluorescence microscope was used to investigate cell morphological changes and the fluorescence intensity of reactive oxygen species (ROS). The oxidative stress parameters were measured by a multi-detection reader. Nuclear factor-erythroid-2-related factor (NRF2) signaling pathways were measured by Western blot and reverse transcription polymerase chain reaction (RT-PCR) in HK-2 cells. ResultsWe found that Se alleviated Pb-induced kidney injury by relieving oxidative stress and reducing the inflammatory index. Se significantly increased the activity of the antioxidant enzymes glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT), whereas it decreased the excessive release of malondialdehyde (MDA) in the kidneys of weaning rats and HK-2 cells. Additionally, Se enhanced the antioxidant defense systems via activating the NRF2 transcription factor, thereby promoting the to downstream expression of heme oxygenase 1. Furthermore, genes encoding glutamate-cysteine ligase synthetase catalytic (GCLC), glutamate-cysteine ligase synthetase modifier (GCLM) and NADPH quinone oxidoreductase 1 (NQO1), downstream targets of NRF2, formed a positive feedback loop with NRF2 during oxidative stress responses. The MTT assay results revealed a significant decrease in cell viability with Se treatment, and the cytoprotective role of Se was blocked upon knockdown of NRF2 by small interfering RNA (siRNA). MDA activity results also showed that NRF2 knockdown inhibited the NRF2-dependent transcriptional activity of Se. ConclusionsOur findings demonstrate that Se ameliorated Pb-induced nephrotoxicity by reducing oxidative stress both in vivo and in vitro. The molecular mechanism underlying Se’s action in Pb-induced kidney injury is related to the activation of the NRF2 transcription factor and the activity of antioxidant enzymes, ultimately suppressing ROS accumulation.

Cucurbit[8]uril-Based Supramolecular Probe for the Detection of 3-Nitrotyrosine in Human Serum and Plasma.

The biomarker 3-nitrotyrosine (3-NT) is widely recognized as an indicator of renal oxidative stress injury, making its detection crucial for the early identification of renal insufficiency. This study presents the design and synthesis of a tetraphenylstyrene imidazole derivative (TIPE-MI), which is utilized to create a supramolecular probe in conjunction with cucurbit[8]uril (Q[8]) through host-guest interactions. The resulting supramolecular self-assembly exhibits excellent optical properties and has been employed for the specific detection of 3-NT through fluorescence quenching. The introduction of 3-NT resulted in a decreased fluorescence intensity of the yellow fluorescent probe, which gradually transitioned from bright yellow to light yellow and then became colorless as the 3-NT concentration was increased. A portable detection platform was devised to augment the efficiency of detection. In order to facilitate biological applications, we have substantiated the probe's exceptional precision in detecting 3-NT in biological samples, encompassing human serum and plasma. The probe also exhibited negligible cytotoxicity. The accumulation of the probe in renal cells elicited a fluorescence signal, thereby indicating the prospective viability of this system for visual detection with renal cytocompatibility.

Cannabinoid receptor 2 (CB2) agonists and L-arginine ameliorate diabetic nephropathy in rats by suppressing inflammation and fibrosis through NF-κβ pathway.

Diabetic nephropathy (DN) is a condition that leads to end-stage chronic kidney disease characterized by inflammation and a deficiency ofnitric oxide (NO).Cannabinoid receptor (CB2) activation by specific agonist reduces nuclear factor kappa beta (NF-κβ) expression. Beta caryophyllene (BCP), a natural CB2 receptor activator, protects kidney function in several diseases. L-Arginine (LA) modulates several physiological processes by donating nitric oxide (NO). Hence, we tested a novel BCP-LA combination to treat DN and investigated its molecular mechanisms. BCP, LA, and combinations of both were evaluated in LPS-induced RAW 264.7 macrophage inflammation as well as in streptozotocin (55mg/kg)-induced diabetes in SD rats. Diabetic rats were administered200 mg/kg of BCP, 100mg/kg of LA, and combination of both orally for 28days. Biochemical markers and inflammatory cytokines were assessed in plasma; also, kidney tissue was examined for renal oxidative stress injury, NF-κβ expression, and histology. After 28days of treatment, BCP and LA combination significantly lowered plasma glucose levels than the disease control group. BCP and LA also normalized renal markers and oxidative stress of diabetic rats. Plasma and RAW macrophage cell lines showed reduced levels of IL-6 and TNF-α (P < 0.001). Histopathological evaluations revealed that BCP and LA together decreased renal fibrosis and collagen deposition also improved nephrotic indices. Meanwhile, the effect of BCP and LA together significantly reduced the NF-κβ (P < 0.01) against diabetic rats. These results indicate that the innovative regimen BCP with LA may be a therapeutic treatment for DN, as it protects kidney tissue from diabetes via NF-κβ inhibition.

Evaluation of Protective Effects of Polyphenols of the Marine Brown Alga Ecklonia cava against Potassium Bromate Induced Nephrotoxicity in Rats

Pharmacognosy Research,2023,15,3,544-550.DOI:10.5530/pres.15.3.057Published:June 2023Type:Original Article Authors:Moqbel Ali Moqbel Redhwan, Suman Samaddar, Hariprasad MG, Sumaia Abdulbari Ahmed Ali Hard, Gitima Deka, and Anyembe Godfrey Author(s) affiliations:Moqbel Ali Moqbel Redhwan1,*, Suman Samaddar2, Hariprasad MG3, Sumaia Abdulbari Ahmed Ali Hard4, Gitima Deka5, Anyembe Godfrey6 1Department of Pharmacology, KLE College of Pharmacy, Bangalore, Karnataka, INDIA. 2BGS GIMS Research Institute, BGS Global Institute of Medical Sciences, Bengaluru, Karnataka, INDIA. 3Department of Pharmacology, KLE College of Pharmacy, Bangalore, Karnataka, INDIA. 4Department of Pharmaceutics, KLE College of Pharmacy, Bangalore, Karnataka, INDIA. 5Department of Pharmacy, Yeungnam University, Gyeongsangbuk-do, SOUTH KOREA. 6Department of Pharmacology, Karnataka College of Pharmacy, Bangalore, Karnataka, INDIA. Abstract:Background: Ecklonia cava is a kelp (brown algae) genus belonging to Lessoniaceae with plenty of Eckol-type phlorotannins. It exhibits antioxidant, anti-inflammatory, and antibacterial activity. Objectives: This study investigated Ecklonia cava (EC) polyphenols for their protective effects against KBrO3-induced nephrotoxicity in rats. Materials and Methods: The polyphenolic fraction was isolated from EC. Group, I was control (untreated), and group II was administered KBrO3 (135 mg/kg b.w) intragastric for four weeks. Group III was administered ECPP (200 mg/kg b.w) concurrently with KBrO3 (135 mg/kg b.w) orally, and Group VI was administered Rutin (100 mg/ kg b.w) along with KBrO3 (135 mg/kg b.w) orally. The protective effects of ECPP on KBrO3-induced nephrotoxicity in rats were assessed for the biochemical parameters of serum, various antioxidant enzymes, and histopathological changes in kidneys. Results: The level of serum of Blood Urea Nitrogen (BUN), uric acid, and creatinine was suggestively augmented (p<0.001) when treated by KBrO3. The activity of antioxidant enzymes, superoxide dismutase, catalase, glutathione peroxidase, and FRAP (ferric ion reducing antioxidant parameter) were diminished (p<0.001). At the same time, lipid peroxidation and nitric oxide were raised (p<0.001) with KBrO3 treatment in the kidneys. In addition, the protein carbonyl level was amplified (p<0.001) with KBrO3 administration. Histological studies presented renal damage in KBrO3-treated animals where tissue injury was abridged in ECPP pretreatment groups. Conclusion: These results suggest that ECPP functions as an antioxidant in vivo by scavenging reactive oxygen species, which helps preclude oxidative renal injury in rats treated with KBrO3. Keywords:Antioxidant, Ecklonia cava, Nephroproductive activity, Polyphenols, Potassium bromate.View:PDF (1.04 MB)

NEAT1 Regulates Calcium Oxalate Crystal-Induced Renal Tubular Oxidative Injury via miR-130/IRF1.

Aims: Calcium oxalate (CaOx) crystal deposition induces damage to the renal tubular epithelium, increases epithelial adhesion, and contributes to CaOx nephrocalcinosis. The long noncoding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) is thought to be involved in this process. In this study, we aimed to investigate the mechanism by which NEAT1 regulates renal tubular epithelium in response to inflammatory and oxidative injury triggered by CaOx crystals. Results: As CaOx crystals were deposited in mouse kidney tissue, the expression of NEAT1 was significantly elevated and positively correlated with interferon regulatory factor 1 (IRF1), Toll-like receptor 4 (TLR4), and NF-κB. NEAT1 targets and inhibits miR-130a-3p as a competitor to endogenous RNA. miR-130 binds to and exerts inhibitory effects on the 3'-untranslated region of IRF1. After transfected with silence-NEAT1, IRF1, TLR4, and NF-κB were also variously inhibited, and oxidative damage in renal calcinosis was subsequently attenuated. When we simultaneously inhibited NEAT1 and miR-130, renal tubular injury was exacerbated. Innovation and Conclusion: We found that the lncRNA NEAT1 can enhance IRF1 signaling through targeted repression of miR-130a-3p and activate TLR4/NF-κB pathways to promote oxidative damage during CaOx crystal deposition. This provides an explanation for the tubular epithelial damage caused by CaOx crystals and offers new ideas and drug targets for the prevention and treatment of CaOx nephrocalcinosis. Antioxid. Redox Signal. 38, 731-746.

Sodium thiosulfate through preserving mitochondrial dynamics ameliorates oxidative stress induced renal apoptosis and ferroptosis in 5/6 nephrectomized rats with chronic kidney diseases.

Chronic kidney disease (CKD) progression may be evoked through dysregulated mitochondrial dynamics enhanced oxidative stress and inflammation contributing to high cardiovascular morbidity and mortality. Previous study has demonstrated sodium thiosulfate (STS, Na2S2O3) could effectively attenuate renal oxidative injury in the animal model of renovascular hypertension. We explored whether the potentially therapeutic effect of STS is available on the attenuating CKD injury in thirty-six male Wistar rats with 5/6 nephrectomy. We determined the STS effect on reactive oxygen species (ROS) amount in vitro and in vivo by an ultrasensitive chemiluminescence-amplification method, ED-1 mediated inflammation, Masson's trichrome stained fibrosis, mitochondrial dynamics (fission and fusion) and two types of programmed cell death, apoptosis and ferroptosis by western blot and immunohistochemistry. Our in vitro data showed STS displayed the strongest scavenging ROS activity at the dosage of 0.1 g. We applied STS at 0.1 g/kg intraperitoneally 5 times/week for 4 weeks to these CKD rats. CKD significantly enhanced the degree in arterial blood pressure, urinary protein, BUN, creatinine, blood and kidney ROS amount, leukocytes infiltration, renal 4-HNE expression, fibrosis, dynamin-related protein 1 (Drp1) mediated mitochondrial fission, Bax/c-caspase 9/c-caspase 3/poly (ADP-ribose) polymerase (PARP) mediated apoptosis, iron overload/ferroptosis and the decreased xCT/GPX4 expression and OPA-1 mediated mitochondrial fusion. STS treatment significantly ameliorated oxidative stress, leukocyte infiltration, fibrosis, apoptosis and ferroptosis and improved mitochondrial dynamics and renal dysfunction in CKD rats. Our results suggest that STS as drug repurposing strategy could attenuate CKD injury through the action of anti-mitochondrial fission, anti-inflammation, anti-fibrosis, anti-apoptotic, and anti-ferroptotic mechanisms.

Evaluating the role of polysaccharide extracted from Pleurotus columbinus on cisplatin-induced oxidative renal injury

This research aimed to examine the antioxidant polysaccharide activity (PsPc-3) derived from Pleurotus columbinus (P. columbinus) on oxidative renal injury (ORI) induced by cisplatin (CP). The principal components of crude polysaccharide were assessed. We studied the preventive impact of polysaccharide on cisplatin-induced renal damage in this study. For 21 days, we employed the CP-induced ORI rat model and divided the rats into four groups: control, CP alone, polysaccharide post CP (100 mg/kg) orally, and CP + polysaccharide (pre and post). The chemical characterization of the polysaccharide fraction PsPc-3 stated that protein was not present. PsPc-3 contained 7.2% uronic acid as assessed as 0% sulfate. PsPc-3 hydrolysate structured of Galacturonic:Glucose:Xylose and their molar proportions were 1:4:5, respectively. The average molecular weight (Mw) and molecular mass (Mn) per molecule of PsPc-3 were 5.49 × 104 g/mol and Mn of 4.95 × 104 g/mol respectively. DPPH radical scavenging activity was demonstrated by the polysaccharide of 65.21–95.51% at 10 mg/ml with IC50 less than 10 mg/ml. CP increased serum urea to 92.0 mg/dl and creatinine up to 1.0 mg/dl, with a concurrent decrease in the levels of total protein to 4.0 mg/dl. Besides, Also, CP-induced ORI raised levels of malondialdehyde (MDA), alkaline phosphatase (ALP), and renal hormones (renin and aldosterone), with a decline in antioxidants compared to control rats. In addition, in the presence of CP, interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) levels increased. PsPc-3 decreased these changes dramatically. PsPc-3 improves pathological renal damage caused by CP and decreases tubular apoptosis measured by DNA ladder formation and cleaved caspase- 3. These findings showed that PsPc-3 isolated from P. columbinus protects and inhibits tubular apoptosis in cisplatin-induced ORI. Furthermore, PsPc-3 has no influence on the anticancer efficacy of CP in rats. Thus, PsPc-3 derived from P. columbinus might provide a novel therapy method for cisplatin-induced nephrotoxicity.

Paricalcitol Ameliorates Acute Kidney Injury in Mice by Suppressing Oxidative Stress and Inflammation via Nrf2/HO-1 Signaling.

Effective and targeted prevention and treatment methods for acute kidney injury (AKI), a common clinical complication, still needs to be explored. Paricalcitol is a biologically active chemical that binds to vitamin D receptors in the body to exert anti-oxidant and anti-inflammatory effects. However, the molecular mechanism of the effect of paricalcitol on AKI remains unclear. The current study uses a paricalcitol pretreatment with a mouse AKI model induced by cisplatin to detect changes in renal function, pathology and ultrastructure. Results showed that paricalcitol significantly improved renal function in mice and reduced inflammatory cell infiltration and mitochondrial damage in renal tissue. Furthermore, paricalcitol markedly suppressed reactive oxygen species and malondialdehyde levels in the kidneys of AKI mice and increased the levels of glutathione, superoxide dismutase, Catalase and total anti-oxidant capacity. In addition, we detected renal necrosis and inflammation-related proteins in AKI mice by immunofluorescence and Western blot, and found that their levels were markedly decreased after paricalcitol pretreatment. Moreover, paricalcitol promotes nuclear factor erythroid 2-related factor 2 (Nrf2) in the nucleus and activates the Nrf2/heme oxygenase-1 (HO-1) signaling pathway; while HO-1 is inhibited, the protective effect of paricalcitol on the kidney is attenuated. In conclusion, paricalcitol exerts a renoprotective effect by decreasing renal oxidative injury and inflammation through Nrf2/HO-1 signaling, providing a new insight into AKI prevention.

The effect of Myrtus communis L. extract on nephrolithiasis model in rats.

Nephrolithiasis is a common urological disease that can lead to renal failure. Oxidative stress has been shown to be a contributing factor for nephrolithiasis and many agents have been studied to prevent and treat oxidative stress-related nephrolithiasis and renal damage. Myrtus communis (MC) extract has been shown to be an important antioxidant in different animal models. In this study, MC extract was administered preventively or therapeutically to rats with kidney stones, and its effectiveness was investigated. Wistar albino rats were divided into four groups (n=8); control (C), ethylene glycol (EG), EG+preventive MC, and EG+curative MC groups. The nephrolithiasis model was created by adding 0.75% EG to drinking water for 8 weeks. Ultimately, 24-hour urine was collected to measure calcium, citrate, and creatinine levels. After decapitation, kidney tissues were harvested for histological analyses, measurement of osteopontin and 8-hydroxydeoxyguanosine (8-OHdG) levels, and N-acetyl-β-glucosaminidase (NAG), myeloperoxidase (MPO) and caspase-3 activities. In 24-hour urine samples, calcium, citrate and creatinine levels were decreased in the EG group, while oxalate levels were increased and in treatment groups these parameters returned to control levels. MPO, 8-OHdG, caspase-3 and NAG activity were significantly increased in tissue and these changes were reversed in both MC groups. Histological findings also supported the biochemical parameters. MC can reduce oxidative stress and histopathological changes in kidney tissues in rat nephrolithiasis model when used as either a preventive or therapeutic agent. If supported with further clinical trials, MC might have clinical implications in preventing oxidative renal cell injury and ultimately kidney stone formation.

Vitamin D-vitamin D receptor alleviates oxidative stress in ischemic acute kidney injury via upregulating glutathione peroxidase 3.

Vitamin D receptor was previously reported to be protective in acute kidney injury (AKI) with the mechanism unclear, while the role of renal localized glutathione peroxidase 3 (GPX3) was not illustrated. The present study aims to investigate the role of GPX3 as well as its correlation with vitamin D-vitamin D receptor (VD-VDR) in ischemia-reperfusion (I/R)-induced renal oxidative stress injury. We showed that the expression of GPX3 and VDR were consistently decreased in renal tissues of I/R-related AKI patients and mice models. VDR agonist paricalcitol could reverse GPX3 expression and inhibit oxidative stress in I/R mice or hypoxia-reoxygenation (H/R) insulted HK-2 cells. VDR deficiency resulted in aggregated oxidative stress and severer renal injury accompanied by further decreased renal GPX3, while tubular-specific VDR overexpression remarkably reduced I/R-induced renal injury with recovered GPX3 in mice. Neither serum selenium nor selenoprotein P was affected by paricalcitol administration nor Vdr modification in vivo. In addition, inhibiting GPX3 abrogated the protective effects of VD-VDR in HK-2 cells, while GPX3 overexpression remarkably attenuated H/R-induced oxidative stress and apoptosis. Mechanistic probing revealed the GPX3 as a VDR transcriptional target. Our present work revealed that loss of renal GPX3 may be a hallmark that promotes renal oxidative stress injury and VD-VDR could protect against I/R-induced renal injury via inhibition of oxidative stress partly by trans-regulating GPX3. In addition, maintenance of renal GPX3 could be a therapeutic strategy for ischemic AKI.

Dioscin Protects against Cisplatin-Induced Acute Kidney Injury by Reducing Ferroptosis and Apoptosis through Activating Nrf2/HO-1 Signaling.

Acute kidney injury (AKI) is a clinical syndrome with high morbidity and mortality worldwide, and there is currently no effective means to prevent it. Dioscin is naturally present in the dioscoreaceae plants and has antioxidant and anti-inflammatory effects. Here, we found that dioscin is protective against cisplatin-induced AKI. Pathological and ultrastructural observations revealed that dioscin reduced renal tissue lesions and mitochondrial damage. Furthermore, dioscin markedly suppressed reactive oxygen species and malondialdehyde levels in the kidneys of AKI rats and increased the contents of glutathione and catalase. In addition, dioscin dramatically reduced the number of apoptotic cells and the expression of pro-apoptotic proteins in rat kidneys and human renal tubular epithelial cells (HK2). Conversely, the protein levels of anti-ferroptosis including GPX4 and FSP1 in vivo and in vitro were significantly enhanced after dioscin treatment. Mechanistically, dioscin promotes the entry of Nrf2 into the nucleus and regulates the expression of downstream HO-1 to exert renal protection. However, the nephroprotective effect of dioscin was weakened after inhibiting Nrf2 in vitro and in vivo. In conclusion, dioscin exerts a reno-protective effect by decreasing renal oxidative injury, apoptosis and ferroptosis through the Nrf2/HO-1 signaling pathway, providing a new insight into AKI prevention.

The effect of carvacrol on tramadol-induced oxidative renal injury in rats: biochemical and histopathological evaluation

Long-term treatment with tramadol is reported to be toxic to the kidneys. Research shows that tramadol reduces antioxidants and increases oxidants produced in renal tissue. This study aims to investigate the carvacrol effect on tramadol-induced renal injury in rats. The animals were divided into four groups: healthy (HG), individual tramadol (TR), individual carvacrol (CR), and tramadol + carvacrol (TC). Malondialdehyde (MDA), total glutathione (tGSH), glutathione peroxidase (GPO), superoxide dismutase (SOD), total oxidant status (TOS), total antioxidant status (TAS), blood urea nitrogen (BUN), and creatinine (Cr) were measured. Renal tissue was examined histopathologically. MDA, TOS, BUN, and Cr were significantly elevated in group TR and identified as low in group TC compared to group TR but higher than in the HG group. The tGSH, SOD, GPO, and TAS levels were low in group TR and higher in group TC than in group TR but lower than in the HG group. Histological examination of the TR group revealed diffuse necrosis and focal polymorphonuclear leukocytes (PMNLs) in the tubules. In the TC group, tubular atrophy and necrosis were minimal, and PMNL was rare. We observed that tramadol increases oxidants, decreases antioxidants, increases BUN and Cr, and examined whether the toxic effect on renal tissue regressed with carvacrol.

Rhus longipes (Engl.) infusions improve glucose metabolism and mitigate oxidative biomarkers in ferrous sulfate-induced renal injury

Objective: To explore the antioxidant and antidiabetic activities of Rhus longipes (R. longipes) leaf and stem bark aqueous infusions. Methods: R. longipes leaf and stem bark infusions were characterized via gas-chromatography mass-spectroscopy (GC-MS) analysis. In vitro antioxidant and carbohydrate and lipid digestive enzyme inhibitory activities of R. longipes infusions were determined. Additionally, the modulatory effects of R. longipes infusions on intestinal glucose absorption, muscle glucose uptake, and biomarkers of renal oxidative injury were evaluated. Molecular docking was performed to determine the binding affinities of the identified compounds from the leaf and stem bark infusions on carbohydrate and lipid digestive enzymes. Results: GC-MS analysis revealed the presence of several phytocompounds, including palmitoleic acid, octadecanamide, 24,25-dihydroxyvitamin D and L-ascorbic acid. The bark infusion had significantly higher total phenolic contents compared with the leaf infusion, with better DPPH scavenging [IC50: (10.50±1.03) ±g/mL] and ferric reducing [IC50: (9.85±0.32) ±g/mL] activities (P&lt;0.05). Both R. longipes infusions at their highest concentrations significantly increased glucose uptake in yeast suspension and rat psoas muscle with marked suppression of glucose absorption in the rat jejunum (P&lt;0.05). With no cytotoxicity on Vero cells, the infusions lowered lipid peroxidation, increased cellular reduced glutathione concentration, and the activities of superoxide dismutase and catalase in renal homogenate treated with FeSO4. Conclusions: R. longipes shows antioxidant and antidiabetic activities and could be a potential therapeutic candidate for diabetes.

Integrating network pharmacology approach and experimental validation to reveal the alleviation of Shenkangning capsule on chronic nephritis

Ethnopharmacological relevanceShenkangning (SKN), a Chinese patent medicine composed by eight Chinese medicinal herbs, is commonly applied to treat chronic glomerulonephritis (CGN) in clinic. However, its mechanism is still not clear now. Aim of the studyThis study is designed to evaluate the SKN-provided alleviation on adriamycin (ADR)-induced nephropathy, to reveal its mechanism by integrating network pharmacology analysis and experimental evidences, and to further find the main drug that makes a major contribution to its efficacy. Materials and methodsADR was intravenously injected to mice to induce focal segmental glomerulosclerosis (FSGS). Renal histological evaluation was conducted. The level of urinary protein, and serum amounts of creatinine, urea nitrogen (BUN) and albumin were detected. The potential mechanisms were predicted by network pharmacology analysis and further validated by Real-time polymerase chain reaction (RT-PCR), Western-blot and enzyme-linked immunosorbent assay (ELISA). ResultsSKN (1, 10 g/kg) improved ADR-induced nephropathy in mice. Network pharmacology results predicted that inflammation and oxidative stress were crucially involved in the SKN-provided amelioration on nephropathy. SKN reduced the activation of nuclear factor-κB (NF-κB) and the expression of some pro-inflammatory cytokines, and increased the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the expression of its downstream genes in ADR-induced nephropathy in mice. Furthermore, SKN also restored the reduced expression of both podocin and synaptopodin, which are podocyte-associated proteins. Further results showed that the toxic drug Danfupian (DFP) had no contribution to the SKN-provided alleviation on ADR-induced nephropathy in mice. After integrating the results from evaluating anti-inflammation, anti-oxidant and anti-injury of podocytes in vitro and from comparing the activity of the whole SKN and SKN without Astragali Radix (Huangqi, HQ) in vivo, we found that HQ played a crucial contribution to the SKN-provided amelioration on ADR-induced nephropathy in mice. ConclusionSKN improved ADR-induced nephropathy through suppressing renal inflammation and oxidative stress injury via abrogating NF-κB activation and activating Nrf2 signaling pathway. HQ played a main contribution to the SKN-provided amelioration on ADR-induced nephropathy.

Assessing the risk factors for myocardial infarction in diet-induced prediabetes: myocardial tissue changes

BackgroundHyperglycaemia is known to result in oxidative stress tissue injury and dysfunction. Interestingly, studies have reported hepatic and renal oxidative stress injury during prediabetes; however, any injury to the myocardium during prediabetes has not been investigated. Hence this study aims to assess changes in the myocardial tissue in an HFHC diet-induced model of prediabetes.MethodsMale Sprague Dawley rats were randomly grouped into non-prediabetes and prediabetes (n = 6 in each group) and consumed a standard rat chow or fed a high-fat-high-carbohydrate diet respectively for a 20-week prediabetes induction period. Post induction, prediabetes was confirmed using the ADA criteria. Aldose reductase, NADH oxidase 1, superoxide dismutase, glutathione peroxide, cardiac troponins were analysed in cardiac tissue homogenate using specific ELISA kits. Lipid peroxidation was estimated by determining the concentration of malondialdehyde in the heart tissue homogenate according to the previously described protocol. Myocardial tissue sections were stained with H&E stain and analysed using Leica microsystem. All data were expressed as means ± SEM. Statistical comparisons were performed with Graph Pad instat Software using the Student's two-sided t-test. Pearson correlation coefficient was calculated to assess the association. Value of p < 0.05 was considered statistically significant.ResultsThe prediabetes group showed a markedly high oxidative stress as indicated by significantly increased NADH oxidase 1 and malondialdehyde while superoxide dismutase and glutathione peroxide were decreased compared to non-prediabetes group. There was no statistical difference between cardiac troponin I and T in the non-prediabetes and prediabetes groups. Cardiac troponins had a weak positive association with glycated haemoglobin.ConclusionThe findings of this study demonstrate that prediabetes is associated with myocardial injury through oxidative stress. Future studies are to investigate cardiac contractile function and include more cardiac biomarkers.

Effect of Tangshen formula on alleviating oxidative renal injury in UUO mice by downregulated expression of NADPH oxidase

ObjectiveTo explore the effect of Tangshen formula on the oxidative renal injury in UUO mice. MethodSeven-week-old male mice C57BL/6N were selected and randomly divided into sham-surgery group, UUO model group (UUO-7d and UUO-14d), Tangshen formula (TF) group (UUO + TF-7d and UUO + TF-14d) and fosinopril group (UUO + fosinopril-7d, UUO + fosinopril-14d). The model were established after 5d medication, and continuous postoperative medications for 7d or 14d were also carried out. The renal pathology was observed, the MDA concentration and SOD activity of renal tissue and serum were evaluated, along with the expression of NADPH oxidase in renal tissue. ResultCompared with that of sham-surgery group, the inflammatory cells in renal interstitium of UUO mice is characterized by diffuse infiltration and dramatical proliferation of collagen fibers, while the introduction of Tangshen formula helps to alleviate this situation, which decreases MDA concentration (all P < 0.001 for renal tissue and serum) but increases SOD activity (P < 0.001 in renal tissue, P < 0.05 in serum), as well as downregulates the expression of Nox4 (P < 0.001) and phosphorylated p47phox (P < 0.001) in renal tissue. ConclusionTangshen formula alleviates the pathological injury of renal tissue in UUO mice and fibrosis of renal interstitium, the underlying mechanism is relative to the downregulated expression of NADPH oxidase, upon which the oxidative stress level of kidney and serum in UUO mice is decreased.