Doxorubicin-induced Nephrotoxicity Research Articles

Modulation of the Sirtuin-1 signaling pathway in doxorubicin-induced nephrotoxicity (synergistic amelioration by resveratrol and pirfenidone)

The current study was conducted to determine the precise mechanisms of Sirtuin-1 (Sirt-1), TGF- β (Transforming Growth Factor-β), and long non-coding RNA Metastasis Associated Lung Adenocarcinoma Transcript 1 (LncRNA MALAT-1) in signaling pathways in doxorubicin (DOX)-induced nephrotoxicity. The potential therapeutic effect of Resveratrol and Pirfenidone in DOX toxicity was also assessed. Thirty-six male adult rats were evenly distributed into four groups: Group 1: control rats. Group 2: DOX exposed rats’ group, each animal received 7.5 mg/kg DOX as a single intravenous dose, Group 3: DOX exposed group subjected to oral resveratrol (20 mg/kg/daily for two weeks), Group 4: DOX exposed group subjected to oral Pirfenidone (200 mg/kg once daily for 10 days). At the planned time, animals were sacrificed. Renal tissue was collected to assess matrix metalloproteinase-9 (MMP9), inflammatory and apoptotic markers: tumor necrosis factor-alpha (TNF- β, caspase-3, cyclo-oxygenase-2 (COX-2), and oxidative stress markers: nitric oxide (NO), Glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD). Sirtuin-1 (Sirt-1), TGF-β, and LncRNA MALAT-1 were quantitatively assessed by real-time RT-PCR in the whole blood. Results showed that the DOX group exhibited a significant increase in oxidative stress markers, and inflammatory, and apoptotic markers in the renal tissue. Histologically, the renal tubule lining cells exhibited vacuolar alterations in the cytoplasm, glomerular atrophy, and vascular congestion. Furthermore, renal degeneration was evident, as confirmed by the heightened immuno-expression of MMP9. Exposure to DOX resulted in a significant decrease in Sirtuin-1 (Sirt-1) with a significant increase in the TGFβ, and LncRNA MALAT-1 gene expression. However, pre-treatment with either resveratrol/or Pirefenidone ameliorated the histological renal alterations, regulated the pathways of Sirt-1, TGFβ, and LncRNA MALAT-1, and decreased all oxidative stress, inflammatory and apoptotic markers. In conclusion, DOX exposure leads to renal toxicity by inducing renal degeneration, oxidative stress, and apoptosis. Administration of either resveratrol or Pirfenidone counteracted these changes and protected the kidney against DOX-induced renal damage.

Comparative effects of incretin-based therapy on doxorubicin-induced nephrotoxicity in rats: the role of SIRT1/Nrf2/NF-κB/TNF-α signaling pathways.

Introduction: Nephrotoxicity represents a major complication of using doxorubicin (DOX) in the management of several types of cancers. Increased oxidative stress and the activation of inflammatory mediators play outstanding roles in the development of DOX-induced kidney damage. This study aimed to investigate whether the two pathways of incretin-based therapy, glucagon-like peptide-1 receptor agonist (presented as semaglutide, SEM) and dipeptidyl peptidase-4 inhibitor (presented as alogliptin, ALO), differentially protect against DOX-induced nephrotoxicity in rats and to clarify the underlying molecular mechanisms. Methods: Adult male rats were divided into six groups: control (received the vehicle), DOX (20mg/kg, single I.P. on day 8), DOX + ALO (20mg/kg/day, P.O. for 10days), DOX + SEM (12μg/kg/day, S.C. for 10days), ALO-alone, and SEM-alone groups. At the end of the study, the animals were sacrificed and their kidney functions, oxidative stress, and inflammatory markers were assessed. Kidney sections were also subjected to histopathological examinations. Results: The co-treatment with either ALO or SEM manifested an improvement in the kidney functions, as evidenced by lower serum concentrations of creatinine, urea, and cystatin C compared to the DOX group. Lower levels of MDA, higher levels of GSH, and increased SOD activity were observed in either ALO- or SEM-treated groups than those observed in the DOX group. DOX administration resulted in decreased renal expressions of sirtuin 1 (SIRT1) and Nrf2 with increased NF-κB and TNF-α expressions, and these effects were ameliorated by treatment with either ALO or SEM. Discussion: Co-treatment with either ALO or SEM showed a renoprotective effect that was mediated by their antioxidant and anti-inflammatory effects via the SIRT1/Nrf2/NF-κB/TNF-α pathway. The fact that both pathways of the incretin-based therapy demonstrate an equally positive effect in alleviating DOX-induced renal damage is equally noteworthy.

Resveratrol may dose-dependently modulate nephrin and OTULIN levels in a doxorubicin-induced nephrotoxicity model

One of the most important side effects of Doxorubicin (DOX), a chemotherapeutic agent, is nephrotoxicity. The purpose of this study is to determine whether different doses of natural polyphenol Resveratrol (RSV) show antioxidative, anti-inflammatory or antiapoptotic effects in kidney tissue in DOX-induced nephrotoxicity and to detect how nephrin and OTULIN levels are affected in this process. A total of six equal groups made up of the 42 Sprague-Dawley rats utilized in the study (n = 7) were randomly assigned. Except for the control group (no treatment), all treatments were given intraperitoneally to the DOX (15 mg/kg), DOX + RSV I (15 mg/kg DOX+ 1 mg/kg/day RSV), DOX + RSV II (15 mg/kg DOX+ 5 mg/kg/day RSV), RSV I and RSV II groups. Kidney tissues taken from rats sacrificed on the fifteenth day were analyzed biochemically, histologically and immunohistochemically. Accordingly, it was determined that nephrin and OTULIN levels decreased in kidney tissue in DOX-induced nephrotoxicity. Furthermore, DOX caused oxidative stress, inflammation, and apoptosis, as well as histopathological changes in kidney tissue. However, it was observed that DOX-induced changes were regulated by RSV application. RSV was demonstrated to have antioxidant, anti-inflammatory and anti-apoptotic properties in dose-dependent DOX-induced nephrotoxicity. RSV may exert nephroprotective effects by modulating DOX-induced altered nephrin and OTULIN levels.

Betaine alleviates doxorubicin-induced nephrotoxicity by preventing oxidative insults, inflammation, and fibrosis through the modulation of Nrf2/HO-1/NLRP3 and TGF-β expression.

Doxorubicin (Dox) is an anthracycline antibiotic used to treat various cancers and shows severe toxicity in multiple organ systems, including kidneys. Evidence shows that betaine's antioxidant and anti-inflammatory properties could prevent the onset of several disorders. Hence, the present study aims to investigate the therapeutic potential of betaine on Dox-induced nephrotoxicity (DIN). Nephrotoxicity was induced in male Sprague Dawley rats using Dox at a dose of 4 mg/kg (cumulative dose: 20 mg/kg) by the intraperitoneal route and cotreated with betaine through oral gavage (200 and 400 mg/kg) for 28 days. At the end of the experiment, biochemical, oxidative stress parameters, histopathology, and qRT-PCR were performed. DIN was indicated by elevated serum creatinine, urea, and decreased albumin levels representing kidney damage; the histopathological lesions (increased capsular space, renal tubule damage, and fibrosis) in renal tissues supported these biochemical findings. Interestingly, betaine treatment improves these alterations in Dox-treated rats. Further, betaine treatment decreases the lipid peroxidation and nitrite concentration and increases the superoxide dismutases and catalase enzyme concentration in Dox-treated rats. Fascinatingly, at the molecular level, DIN in rats shows upregulation of the Nrf2/HO-1 gene, while betaine treatment attenuated its expression along with the downregulation of inflammatory genes (NLRP3, TLR-4, TNF-α, and IL-6) and fibrosis-related genes (TGF-β and Acta2) expression in Dox-treated rats. These results showed that betaine has reno-protective properties by reducing inflammatory and fibrotic mediators and enhancing antioxidant capacity in the renal tissue of rats treated with Dox. We believe betaine can be exploited as a dietary supplement to attenuate DIN.

N-(2-hydroxy phenyl) acetamide ameliorate inflammation and doxorubicin-induced nephrotoxicity in rats

Doxorubicin (DOX) is an anthracyclin antibiotic used for the treatment of various cancers. Nephrotoxicity is among the serious side effects of DOX, therefore, DOX-induced nephrotoxic model has been widely used to study nephropathies. The objectives of this study is to investigate the possible anti-inflammatory and nephroprotective effects of salicylic acid derivative, N-(2-hydroxy phenyl) acetamide (NA-2), in a rat model of DOX-induced nephrotoxicity. The in vitro anti-inflammatory potential of NA-2 was manifested by whole blood oxidative burst and nitric oxide (NO) assays with no toxicity on normal human fibroblast (BJ) cells, human embryonic kidney (HEK-293) cells, and normal monkey kidney epithelial (Vero) cells. The in vivo study included five groups: Normal control, DOX (6 mg/kg DOX-i.v.via tail vein), NA-2 treated control-i.p., NA-2/DOX treated-i.p., and prednisolone/DOX treated. After 7 days of DOX administration, rats with urinary protein level of >50 mg/kg/day were selected. Treatment group rats received i.p. doses of NA-2 (10 mg/kg/day) for 3 weeks with weekly monitoring of urinary protein excretion and body weights. mRNA expression of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, and kidney injury molecule (KIM)-1 was analyzed by quantitative polymerase chain reaction (qPCR). Protein expressions were analyzed by immunohistochemistry. NA-2 attenuated DOX-induced changes in serum and urine levels, and improved inflammatory profile of the renal tissue. Histopathological findings revealed protective effects of NA-2 showing lesser lesions. We conclude that NA-2 is able to protect against DOX-induced renal damage functionally, biochemically and histopathologically with corresponding improvement in the kidney inflammatory profile.

Dapagliflozin protects against doxorubicin-induced nephrotoxicity associated with nitric oxide pathway—A translational study

Doxorubicin (Dox) is a potent anticancer agent, but its associated organ toxicity, including nephrotoxicity, restricts clinical applications. Dapagliflozin (DAPA), a sodium–glucose cotransporter-2 inhibitor, has been shown to slow the progression of kidney disease in patients with and without diabetes. However, the effect of DAPA to counteract Dox-induced nephrotoxicity remains uncertain. Therefore, in this study, we aimed to elucidate the effects of DAPA in mitigating Dox-induced nephrotoxicity. We analyzed the Taiwan National Health Insurance Database to evaluate the incidence of renal failure among breast cancer patients receiving Dox treatment compared to those without. After adjusting for age and comorbidities, we found that the risk of renal failure was significantly higher in Dox-treated patients (incidence rate ratio, 2.45; confidence interval, 1.41–4.26; p = 0.0014). In a parallel study, we orally administered DAPA to Sprague–Dawley rats for 6 weeks, followed by Dox for 4 weeks. DAPA ameliorated Dox-induced glomerular atrophy, renal fibrosis, and dysfunction. Furthermore, DAPA effectively suppressed Dox-induced apoptosis and reactive oxygen species production. On a cellular level, DAPA in HK-2 cells mitigated Dox-mediated suppression of the endothelial NOS pathway and reduced Dox-induced activities of reactive oxygen species and apoptosis-associated proteins. DAPA improved Dox-induced apoptosis and renal dysfunction, suggesting its potential utility in preventing nephrotoxicity in patients with cancer undergoing Dox treatment.

Gossypetin mitigates doxorubicin-induced nephrotoxicity: A histopathological and biochemical evaluation

Doxorubicin (DOX) is an anticancer agent that is generally used to treat wide range of malignancies. Gossypetin (GTIN) is a well-known bioflavonoid that shows multiple therapeutical potentials. The experiment aimed toelucidate the nephroprotective impact of GTIN against renal damage caused by DOX. 24 Sprague-Dawley (SD) rats were separated into 4 groups: Control, DOX (3 mg/kg i.p.), DOX + GTIN (3 mg/kg i.p. + 30 mg/kg by oral gavage), and GTIN (30 mg/kg. orally) for the evaluation of renal markers, apoptotic markers, antioxidant and inflammatory profile. The outcomes of the experiment apprised that DOX exposure induced a pronounced decrease in enzymatic activities of antioxidants including glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione reductase (GSR), catalase (CAT), glutathione-S-transferase (GST) as well as glutathione (GSH) accompanied by an increment in reactive oxygen species (ROS) as well as malondialdehyde (MDA) levels. Likewise, DOX intoxication promoted escalation in the urea, kidney injury molecule-1 (KIM-1), creatinine, as well as neutrophil gelatinase-associated lipocalin (NGAL) level, on the other hand instigating a remarkable decline in creatinine clearance level. DOX induction brought a considerable escalation in interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), nuclear factor kappa-B (NF-κB) as well as cyclooxygenase-2 (COX-2). In addition, DOX administration depicted a considerable raised in Caspase-9, Bax as well as Caspase-3 levels, while lowered Bcl-2 level. DOX treatment also prompted histomorphological impairment. GTIN + DOX co-treatment ameliorated all the above-stated damages in the kidneys. In conclusion, GTIN can effectively mitigate the renal impairments induced by DOX-prompted nephrotoxicity.

The Effect of Exercise on Doxorubicin-Induced Nephrotoxicity in Male and Female Rats

Doxorubicin (DOX) is a first-line chemotherapeutic agent used to treat a wide range of malignancies including breast and lymphatic cancers. However, the clinical use of DOX is limited due to off-target toxicity to healthy organs. DOX-induced nephrotoxicity is established in both cancer patients and experimental models, where it is hypothesized that oxidative damage to renal cells increases glomerular capillary permeability and tubular atrophy. In contrast, endurance exercise preconditioning has the potential to reduce renal edema and inflammation, improving glomerular filtration rate and urine creatinine clearance rate. Therefore, the purpose of this study was to investigate whether exercise preconditioning can protect against DOX-induced nephrotoxicity and elucidate differences between male and female rats. Young-adult male and female Sprague-Dawley rats were randomly separated into 4 groups: i) sedentary saline; ii) sedentary DOX (20 mg/kg IP); iii) exercise-trained saline; and iv) exercise-trained DOX. Exercise trained animals underwent 2 weeks of treadmill preconditioning for (5 days/wk, 60 min/day, 30 m/min @ 0% grade). Animals received saline or DOX 24hrs after the final exercise bout, followed by endpoint 48hrs post-treatment. Evaluation of inflammatory markers within the urine (i.e. IP10, AGP and NGAL) demonstrated elevated levels in DOX-treated males and females, regardless of exercise. Male rats receiving DOX had elevated levels of clusterin which was not found in female rodents suggesting a possible sex-difference. Moreover, urine creatinine levels were significantly increased following DOX treatment and reduced with exercise in males, with no significant differences in females. In summary, animals treated with doxorubicin had higher levels of markers for inflammation and renal disease, with minimal effects of exercise preconditioning to prevent these changes. Additionally, males demonstrated higher levels of renal toxicity suggesting that females may have a greater resistance to DOX-induced nephrotoxicity.R01 HL153140R01 HL144858 R01 HL144858 and R01 HL153140 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Modulatory Role of Autophagy in Metformin Therapeutic Activity toward Doxorubicin-Induced Nephrotoxicity

Doxorubicin (DOX) is a frequent chemotherapeutic drug used to treat various malignant tumors. One of the key factors that diminish its therapeutic importance is DOX-induced nephrotoxicity. The first-line oral antidiabetic drug is metformin (Met), which also has antioxidant properties. The purpose of our study was to investigate the underlying molecular mechanisms for the potential protective effects of Met on DOX-triggered nephrotoxicity. Four animal groups were assigned as follows; animals received vehicle (control group), 200 mg/kg Met (Met group), DOX 15 mg/kg DOX (DOX group), and a combination of DOX and Met (DOX/Met group). Our results demonstrated that DOX administration caused marked histological alterations of widespread inflammation and tubular degeneration. Notably, the DOX-induced dramatic up-regulation of the nuclear factor-kappa B/P65 (NF-κB/P65), microtubule-associated protein light chain 3B (LC3B), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-1beta (IL-1β), 8-hydroxy-2' -deoxyguanosine (8-OHdG), and Beclin-1 in renal tissue. A marked increase in the malondialdehyde (MDA) tissue level and a decrease in the total antioxidant capacity (TAC) were also recorded in DOX-exposed animals. Interestingly, Met could minimize all histopathological changes as well as the disruptions caused by DOX in the aforementioned measures. Thus, Met provided a workable method for suppressing the nephrotoxicity that occurred during the DOX regimen via the deactivation of the Beclin-1/LC3B pathway.

Therapeutic treatment with phosphodiesterase-4 inhibitors alleviates kidney injury and renal fibrosis by increasing MMP-9 in a doxorubicin-induced nephrotoxicity mouse model

Nephrotic syndrome (NS) is associated with kidney dysfunction and is an important cause of morbidity and mortality in industrialized countries. Here, we evaluated the effects of the phosphodiesterase-4 (PDE-4) inhibitors rolipram and roflumilast on a doxorubicin-induced NS model. Early-stage rolipram treatment preserved glomerular filtration barrier function, as indicated by reduced serum protein and albumin loss and the prevention of hypercholesterolemia. These effects were associated with reduced glomerular and tubular lesions and abrogated renal cell apoptosis. In addition, rolipram treatment reduced inflammation, which was characterized by a decrease in macrophage accumulation and reduced levels of CCL2 and TNF in the kidneys. Rolipram also reduced renal fibrosis, which was associated with decreased α-smooth muscle actin (α-SMA) area and increased metalloproteinase 9 (MMP9) activity in renal tissue. Late-stage rolipram or roflumilast treatment preserved glomerular filtration barrier function, as characterized by reduced serum albumin loss, decreased proteinuria, and the prevention of hypercholesterolemia. Importantly, only roflumilast treatment was associated with a reduction in glomerular and tubular lesions at this time point. In addition, both rolipram and roflumilast reduced renal tissue fibrosis and MMP9 activity in renal tissue.

Doxorubicin-induced nephrotoxicity model in Wistar rats: Characterization of biochemical parameters, histological and immunohistochemical assessment

The Ceylon Journal of Science is a peer-reviewed journal published quarterly by the University of Peradeniya, Sri Lanka in March, June, September and December. It is aimed at publishing high quality research articles on topics related to different disciplines in Science. The journal accepts original research articles, book reviews, reviews and mini-reviews, short communications, opinions, research notes, and commentaries and notes. The Journal has its own website https://site.pdn.ac.lk/cjs/. The journal strictly adheres to publication ethics as emphasized by the Committee on Publication Ethics (COPE). It is indexed in Sri Lanka Journals Online (SLJOL), Directory of Open Access Journals (DOAJ), Google Scholar and Zoological Records. According to the Google Scholar;H5-Index: 12H5-Median: 15According to the Exaly (1970 – 2021);Impact Factor: 0.6 (top 19%)Extended IF: 0.6 (top 19%)H-Index: 8 (top 28%)Citations/paper: 1.42

Antioxidant Activity of Cichorium intybus Extract in Concomitant Use with Melatonin Against Doxorubicin-induced Nephrotoxicity

Background: Doxorubicin is preferred to cure many malignancies. Its nephrotoxicity is a dangerous nature that is to operate with a warning. Antioxidants accompanied by anticancer could moderate the various side effects. Objectives: Cichorium intybus has nephron-protective effects. Melatonin stands as an antioxidant equivalent to others. The repairing effects of C. intybus-melatonin against the toxicity effects of doxorubicin on the kidneys were studied. Methods: Thirty 20 g to 25 g, balb/c mice were divided into 5 identical groups (n: 6). The research was grouped as control saline; DOX with the injection of doxorubicin; Chicory with the administration of the C. intybus complete extract following DOX; melatonin with the administration of the melatonin following DOX; both: With the administration of the chicory and melatonin following DOX. The histopathological study was set to determine degeneration, inflammation, and necrosis. Results: The mean of each histological phenomenon in the control group was significantly lower than in the DOX group. In the histopathology, we saw that all the treating groups, including C. intybus extract-received, melatonin-received, both of them received improved better than the doxorubicin-received group. The best improving mean was seen in the latter group. The DOX-induced nephrotoxicity could be improved by using the C. intybus extract and melatonin synchronously as therapeutic care. Conclusions: Synchronous administration of the chicory and melatonin has a healing potency against doxorubicin-induced nephrotoxicity.

Adrenomedullin Mitigates Doxorubicin-Induced Nephrotoxicity in Rats: Role of Oxidative Stress, Inflammation, Apoptosis, and Pyroptosis.

Doxorubicin (DOX) is an anticancer antibiotic which has various effects in human cancers. It is one of the commonly known causes of drug-induced nephrotoxicity, which results in acute renal injury. Adrenomedullin (ADM), a vasodilator peptide, is widely distributed in many tissues and has potent protective effects. Therefore, the current study aimed to examine the protective potential mechanisms of ADM against DOX-induced nephrotoxicity. A total of 28 male Wistar rats were randomized into four groups: control group, doxorubicin group (15 mg/kg single intraperitoneal injection of DOX), adrenomedullin + doxorubicin group (12 μg/kg/day intraperitoneal injection of ADM) 3 days prior to DOX injection and continuing for 14 days after the model was established, and adrenomedullin group. Kidney function biomarkers, oxidative stress markers, and inflammatory mediators (TNF-α, NLRP3, IL-1β, and IL-18) were assessed. The expressions of gasdermin D and ASC were assessed by real-time PCR. Furthermore, the abundances of caspase-1 (p20), Bcl-2, and Bax immunoreactivity were evaluated. ADM administration improved the biochemical parameters of DOX-induced nephrotoxicity, significantly reduced oxidative damage markers and inflammatory mediators, and suppressed both apoptosis and pyroptosis. These results were confirmed by the histopathological findings and revealed that ADM's antioxidant, anti-inflammatory, anti-apoptotic, and anti-pyroptotic properties may have prospective applications in the amelioration of DOX-induced nephrotoxicity.

Investigation of the multi-targeted protection potential of tannic acid against doxorubicin-induced kidney damage in rats

Doxorubicin (DOX) is an antitumor drug that is powerful but can cause worse outcomes, including nephrotoxicity, and therefore has limited clinical use. Therefore, it is necessary to identify safer agents that can minimize the damage caused by the drug without shifting the treatment performance, in addition to clarifying the underlying mechanisms of DOX-induced aberrant in vivo renal activation. In this study, we tested the prophylactic capacity and mechanisms of action of tannic acid (TA) against DOX-mediated kidney damage in rats and evaluated the nephrotoxic activity of DOX when used with TA. Rats were treated during the two weeks with cumulative (18 mg/kg with six different injections) DOX, daily TA (50 mg/kg), and the DOX + TA combination. Changes in major metabolites and components involved in antioxidant metabolism were evaluated in the kidney tissues of all animals. Further, the gene expression levels of regulatory factors that have critical importance in cell metabolism, inflammation, and apoptosis were investigated. Both biochemical and molecular examinations showed that TA improved DOX-induced dysregulations at both protein and gene levels in the kidneys. Increased lipid peroxidation and decreased glutathione levels were reversed. Consistent with oxidative stress marker metabolites, suppressed antioxidant enzyme activities and transcript levels of antioxidant system members were restored. Of note, combination treatment with TA could overcome doxorubicin-induced gene expressions markedly altered by DOX, suggesting that nephroprotection conferred by TA involved the remodeling of stress resistance, cell metabolism, inflammation, and apoptosis. Collectively, the present in vivo study suggests that TA could be used as a multitarget and effective agent for the mitigation of doxorubicin-induced nephrotoxicity without changing the therapeutic efficacy of the drug.

Insight into the Mechanism of Doxorubicin-induced Nephrotoxicity through Gene Expression Analysis of Oxidative Stress, Kidney Injury and Inflammation Markers

Insight into the Mechanism of Doxorubicin-induced Nephrotoxicity through Gene Expression Analysis of Oxidative Stress, Kidney Injury and Inflammation Markers

The protective impact of berberine against doxorubicin-induced nephrotoxicity in rats

Doxorubicin (DOX) is a well-known anti-neoplastic agent that is widely employed to treat several types of malignancies. The current study was designed to investigate the renoprotective potential of berberine (BEB) on the doxorubicin (DOX)-induced nephrotoxicity and renal fibrosis. Rats were allocated into four groups; Negative Control, DOX nephrotoxic-induced group received a single dose of DOX (20 mg/kg, i.p.), BEB-group received (50 mg/kg, p.o.) for 14 days, and co-treatment group BEB + DOX where rats were pre-treated with BEB for 10 successive days, then received a single dose of DOX on the 11th day, followed by 4 days of receiving BEB. DOX resulted in nephrotoxicity manifested by significant increments in urea, creatinine, and kidney injury molecule (KIM-1), these biochemical findings were supported with the histopathological lesions in renal tissues. Moreover, DOX provoked oxidative stress through enhancing renal malondialdehyde (MDA) and hydrogen peroxide (H2O2) contents, and decreased renal catalase (CAT) activity. DOX triggered renal fibrosis represented by increased transforming growth factor beta-1 (TGF-β1) and elevated collagen deposition. DOX stimulated apoptosis and inflammation in renal tissues as confirmed by increased immunoexpression of caspase-3 and NF-κB, respectively. These effects were alleviated by BEB co-treatment. Co-treatment with BEB markedly prohibited DOX-induced oxidative damage, inflammation, apoptosis, and fibrosis in renal tissue. Histopathological and immunohistochemical investigations showed the nephroprotective potential of BEB on renal injury, which was consistent with the biochemical findings. Accordingly, it could be concluded that the nephroprotective potential of BEB against DOX-induced kidney injury and fibrosis might be mediated by the anti-oxidant, anti-inflammatory and anti-fibrosis activities.

The protective effect of metformin and exenatide on doxorubicin-induced nephrotoxicity in rats

Objective The aim was to study the protective effect of metformin and exenatide on doxorubicin (DOX)-induced nephrotoxicity in rats. Background DOX is an effective chemotherapeutic agent used for treatment of various solid as well as hematological neoplasms. Its use is limited owing to well-documented nephrotoxicity. Treatment with metformin and exenatide ameliorates nephrotoxicity in rats through antioxidant and antiapoptotic effects. Materials and methods In this experimental study, rats were divided as follows: group 1 was injected with saline intraperitoneal and orally, group 2 was injected with intraperitoneal DOX (15 mg/kg) and oral saline, group 3 was injected with intraperitoneal DOX and received metformin (250 mg/kg/day) orally, group 4 was injected with intraperitoneal DOX and received exenatide (10 μg/kg twice daily) Sc, and group 5 was injected with intraperitoneal DOX and metformin + exenatide. Basal body weight (Wt.), final body Wt., kidney Wt., kidney index, kidney malondialdehyde (MDA), reduced glutathione (GSH), serum tumor necrosis factor-α (TNF-α), serum albumin, serum urea and creatinine, urinary proteins, histopathological examination of hematoxylin and eosin, and caspase-3 immunostaining were evaluated. Results DOX group showed a significant decrease in body Wt, GSH levels, and serum albumin, with an increase in kidney Wt., kidney index, serum TNF-α, kidney MDA levels, urine proteins, serum urea and creatinine, and caspase-3 immunoexpression compared with the control group. In contrast, metformin-, exenatide-, and metformin + exenatide-treated groups showed significant increase in body Wt. and kidney GSH levels, with a decrease in kidney Wt., serum TNF-α, kidney MDA levels, and caspase-3 immunoexpression compared with DOX group. Conclusion Metformin and exenatide improved DOX nephrotoxicity in rats.

Protective effect of diosmin against doxorubicin-induced nephrotoxicity.

Doxorubicin (Dox) is an anthracycline antibiotic that is primarily used for treating various solid tumors including that of pulmonary, ovary, breast, uterine, cervix, and several blood cancers. However, nephrotoxicity associated with Dox treatment limits its clinical use. Administration of Dox in combination with compounds exhibiting antioxidant properties are being used to minimize the side effects of Dox. Diosmin is a flavonoid glycoside with numerous beneficial properties that is found in the pericarp of many citrus fruits. Diosmin has demonstrated antioxidant, anti-inflammatory, and anti-apoptotic effects in response to various insults, although the exact mechanism remains unknown. Therefore, this study was designed to evaluate the effect of diosmin in preventing kidney damage in response to Dox treatment. Male Wistar rats were randomly divided into four groups: control group, Dox group (20mg/kg, i.p.), Dox plus low-dose diosmin group (100mg/kg orally), and Dox plus high-dose diosmin group (200mg/kg orally). A single intraperitoneal injection of Dox resulted in kidney damage as evidenced by significant alterations in kidney markers, histological abnormalities, and the attenuation of antioxidant defense mechanisms (GSH, SOD, and CAT). Moreover, Dox treatment significantly altered the expression of oxidative stress, inflammatory, and anti-apoptotic protein markers. Diosmin pretreatment alleviated Dox-induced nephrotoxicity by ameliorating the antioxidant mechanism, decreasing inflammation and apoptosis, and restoring kidney architecture. In conclusion, our results indicate that diosmin is a promising therapeutic agent for the prevention of nephrotoxicity associated with DOX.

Antioxidant and Anti-Inflammatory Effects of Crocin Ameliorate Doxorubicin-Induced Nephrotoxicity in Rats.

Doxorubicin is a drug that belongs to the anthracycline antibiotics. Nephrotoxicity is one of the serious side effects of doxorubicin treatment. Crocin, which is one of the most bioactive components of saffron, has antioxidant, anti-inflammatory, and antitumor effects. The current study was aimed at investigating the possible protective effects of crocin against doxorubicin-induced nephrotoxicity to elucidate the underlying mechanism of this effect. The study included four groups, six rats in each group: normal control, crocin control, doxorubicin, and crocin/doxorubicin. Doxorubicin and crocin/doxorubicin groups received intraperitoneal injections of doxorubicin (3.5 mg/kg twice weekly for 3 weeks). Rats in the crocin control group and the crocin/doxorubicin group were treated with intraperitoneal injections of crocin (100 mg/kg body weight per day) for 3 weeks. Biomarkers of kidney function and oxidative stress as well as the abundance of mRNA for nuclear factor-κβ and inducible nitric oxide synthase were evaluated. In addition, the abundance of cyclooxygenase 2 and tumor necrosis factor α immunoreactivity was evaluated. Crocin treatment had renoprotective effects manifested by significant improvement in kidney function as well as a reduction in the abundance of biomarkers of oxidative stress markers and inflammatory mediators. In conclusion, crocin has a protective effect against doxorubicin-induced nephrotoxicity in rats by serving as an antioxidant and attenuating the expression of NF-κB, iNOS, COX2, and TNFα.

Anti-inflammatory effects of saxagliptin and vildagliptin against doxorubicin-induced nephrotoxicity in rats: attenuation of NLRP3 inflammasome up-regulation and tubulo-interstitial injury.

Background and purpose:The clinical use of the chemotherapeutic drug, doxorubicin (DXR), is significantly limited by its extensive multi-organ toxicity. Dipeptidyl peptidase-4 (DPP4) is over-expressed in oxidative stress, inflammation and apoptosis. DPP4 inhibitors have proven pleiotropic effects. The study investigates the protective effects of some DDP4 inhibitors; namely, saxagliptin (SAX) and vildagliptin (VIL) against DXR-induced nephrotoxicity in rats.Experimental approach:Forty rats were divided into 4 groups. Group I served as normal control. Nephrotoxicity was induced in the remaining 3 groups by single-DXR injection (15 mg/kg, i.p.). Groups III and IV administered oral SAX (10 mg/kg) and VIL (10 mg/kg) for 2 weeks.Findings/Results:DXR-control rats showed deteriorated renal functions, elevated renal inflammatory parameters (tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and inducible nitric oxide synthase (iNOS)), up-regulated nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome and significant tubulointerstitial injury manifested by elevated neutrophil gelatinase-associated lipocalin concentration and distorted renal histopathological pictures. Immunohistochemical studies showed increased iNOS and Bax positivity in renal tissues of DXR-control rats. Treatment with SAX and VIL significantly attenuated DXR-induced nephrotoxicity via alleviation of all the above-mentioned parameters when compared to DXR-control rats.Conclusion and implications:The study elucidated the possible mechanisms beyond DXR-induced nephrotoxicity to be through inflammation plus tubulointerstitial injury. DXR nephrotoxicity has been linked to TNF-α, IL-1β, and NLRP3 inflammasome up-regulation and iNOS expression. The protective role of SAX and VIL in mitigating the tubular injury and inflammatory effects of DXR on renal tissues has been tested and proved.