Nano Ellagic Acid Counteracts Cisplatin-Induced Upregulation in OAT1 and OAT3: A Possible Nephroprotection Mechanism

Cisplatin is an anticancer drug commonly used for solid tumors. However, it causes nephrotoxicity. OAT1 and OAT3 are organic anion transporters known to contribute to the uptake of cisplatin into renal tubular cells. The present study was designed to examine the protective role of ellagic acid nanoformulation (ellagic acid nano) on cisplatin-induced nephrotoxicity in rats, and the role of OAT1/OAT3 in this effect. Four groups of male Wistar rats were used (n = 6): (1) control, (2) cisplatin (7.5 mg/kg single dose, intraperitoneal), (3) cisplatin + ellagic acid nano (1 mg/kg), and (4) cisplatin + ellagic acid nano (2 mg/kg). Nephrotoxic rats treated with ellagic acid nano exhibited a significant reduction in elevated serum creatinine, urea, and oxidative stress marker, malondialdehyde (MDA). Additionally, ellagic acid nano restored renal glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Ellagic acid nano improved the histopathological changes induced by cisplatin, such as tubular dilatation, necrosis, and degeneration. Interestingly, OAT1 and OAT3 showed significantly lower expression at both mRNA and protein levels following ellagic acid nano treatment relative to the cisplatin-exposed group. These findings reveal a potential inhibitory role of ellagic acid antioxidant on OAT1 and OAT3 expression and thus explains its nephroprotective effect against cisplatin nephrotoxicity.

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Macrophage migration inhibitory factor may play a protective role in osteoarthritis

Arthritis Research & Therapy ◽

10.1186/s13075-021-02442-w ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Ming Liu ◽

Zikun Xie ◽

Guang Sun ◽

Liujun Chen ◽

Dake Qi ◽

...

Keyword(s):

Polymerase Chain Reaction ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Protective Role ◽

Macrophage Migration ◽

Chain Reaction ◽

Protein Levels ◽

Tnf Α ◽

Polymerase Chain

Abstract Background Osteoarthritis (OA) is the most prevalent form of arthritis and the major cause of disability and overall diminution of quality of life in the elderly population. Currently there is no cure for OA, partly due to the large gaps in our understanding of its underlying molecular and cellular mechanisms. Macrophage migration inhibitory factor (MIF) is a procytokine that mediates pleiotropic inflammatory effects in inflammatory diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, data on the role of MIF in OA is limited with conflicting results. We undertook this study to investigate the role of MIF in OA by examining MIF genotype, mRNA expression, and protein levels in the Newfoundland Osteoarthritis Study. Methods One hundred nineteen end-stage knee/hip OA patients, 16 RA patients, and 113 healthy controls were included in the study. Two polymorphisms in the MIF gene, rs755622, and -794 CATT5-8, were genotyped using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) and PCR followed by automated capillary electrophoresis, respectively. MIF mRNA levels in articular cartilage and subchondral bone were measured by quantitative polymerase chain reaction. Plasma concentrations of MIF, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) were measured by enzyme-linked immunosorbent assay. Results rs755622 and -794 CATT5-8 genotypes were not associated with MIF mRNA or protein levels or OA (all p ≥ 0.19). MIF mRNA level in cartilage was lower in OA patients than in controls (p = 0.028) and RA patients (p = 0.004), while the levels in bone were comparable between OA patients and controls (p = 0.165). MIF protein level in plasma was lower in OA patients than in controls (p = 3.01 × 10−10), while the levels of TNF-α, IL-6 and IL-1β in plasma were all significantly higher in OA patients than in controls (all p ≤ 0.0007). Multivariable logistic regression showed lower MIF and higher IL-1β protein levels in plasma were independently associated with OA (OR per SD increase = 0.10 and 8.08; 95% CI = 0.04–0.19 and 4.42–16.82, respectively), but TNF-α and IL-6 became non-significant. Conclusions Reduced MIF mRNA and protein expression in OA patients suggested MIF might have a protective role in OA and could serve as a biomarker to differentiate OA from other joint disorders.

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Protective Role of Leptadenia Hastata on the Haematological and Biochemical Alterations in Adrenaline-Induced Hypertensive Rats

Iranian Jornal of Toxicology ◽

10.32598/ijt.14.1.25 ◽

2020 ◽

Vol 14 (1) ◽

pp. 25-32

Author(s):

Adewuyi Hassan Abdulsalam ◽

◽

Muhammad L. Hadiza ◽

Onukogu Stella Chiamaka ◽

Ibrahim Jonathan ◽

...

Keyword(s):

Elevated Serum ◽

Protective Role ◽

Protective Effects ◽

Hypertensive Rats ◽

Bioactive Constituents ◽

Once Daily ◽

Biochemical Alterations ◽

The Mean ◽

Normal Controls

Background: Leptadenia hastata (L. Hastata) is a plant used for various diseases in Nigeria. This study evaluated the protective effects of L. hastate on the haematological and biochemical alterations in adrenaline-induced hypertensive rats. Methods: Twenty-five rats were divided equally into five groups (A-E). Groups A-D were given 0.5 mg/kg adrenaline, groups A and B were treated with 100 and 200 mg/kg the extract of L. Hastata, respectively, while groups C and D were treated with 5 mg/kg amlodipine (standard control) and normal saline (untreated control), respectively. Group E were given distilled water (normal controls). The adrenaline was injected intraperitoneally while the extract was given orally once daily for seven days. Results: Treatment with 100 and 200 mg/kg of the extract significantly reduced the elevated serum albumin, ALP, ALT, AST, chloride, sodium and creatinine, cholesterol and LDL concentrations compared with the untreated hypertensive rats. The bicarbonate level, WBC and RBC counts, mean cell hemoglobin and packed cell value were higher in rats treated with the extract compared with the untreated hypertensive rats. The mean cell value, HDL, triglyceride, urea, potassium, total and direct bilirubin concentrations in experimental groups were not significantly different from those in the controls (P<0.05). Conclusion: Our results suggest that treatment of the hypertensive rats with the extract of L. Hastata protects against renal, hepatic and cardiac damages, thus it could be considered as a natural anti-hypertensive agent. Further studies are required to identify the bioactive constituents and the mechanism(s) of action.

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Hepato & nephro protective effects of naringenin-loaded tpgs polymeric nanosuspension against cisplatin-induced toxicity

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v10i4.1544 ◽

2019 ◽

Vol 10 (4) ◽

pp. 2755-2764

Author(s):

Sumathi Rajamani ◽

Gobinath Kalyanasundaram ◽

Tamizharasi Sengodan ◽

Sivakumar Thangavelu ◽

Nikhitha K Shanmukhan ◽

...

Keyword(s):

Antioxidant Activities ◽

Aqueous Solubility ◽

Protective Role ◽

Chemotherapeutic Agents ◽

Glycol Succinate ◽

High Pressure Homogenization ◽

Protective Effects ◽

Male Wistar Rats ◽

Nephroprotective Effect

Cisplatin (Cis-Diammineplatinum (II) dichloride/CIS) is one of the most potent chemotherapeutic agents widely used in treatment of various cancers. Naringenin (NAR), a natural flavonoid, protect against CIS-induced injury in rats without hampering CIS beneficial cytotoxic activity. Even though NAR exhibits therapeutic potency, clinical evolution of the molecule is embarrassed because of very less aqueous solubility which corresponds to low availability at the site of the tumor. In our former analysis, nanosuspension of naringenin (NARNS) was developed by the method of high-pressure homogenization. The study had been continued to evaluate the protective role of D-α-Tocopheryl polyethylene glycol succinate (TPGS) coated NARNS, against oxidative stress-induced hepato and nephrotoxicity in male Wistar rats upon CIS treatment. Induction of acute hepato and neprotoxicity was done by intraperitoneal injection (i.p) injection of CIS (7 mg/kg of body weight) and administration of NAR and NARNS. Administration of NARNS virtually suppressed CIS-induced and liver injury evidenced by a reduction of lipid peroxidation level, blood urea nitrogen, serum uric acid, creatinine and elevated enzymatic antioxidant activities of superoxide dismutase, catalase, and glutathione peroxidase in rats liver tissue. Histological studies substantiated the biochemical parameters. The study suggests that NARNS has strong hepato and nephroprotective effect compared to NAR.

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The protective role of alpha-lipoic acid on long-term exposure of rats to the combination of chlorpyrifos and deltamethrin pesticides

Toxicology and Industrial Health ◽

10.1177/0748233715616553 ◽

2016 ◽

Vol 33 (2) ◽

pp. 159-170 ◽

Cited By ~ 9

Author(s):

Chidiebere Uchendu ◽

Suleiman F Ambali ◽

Joseph O Ayo ◽

King AN Esievo

Keyword(s):

Lipoic Acid ◽

Lethal Dose ◽

Liver Homogenate ◽

Experimental Period ◽

Protective Role ◽

Serum Glucose ◽

Group I ◽

Male Wistar Rats

The study was aimed at evaluating the protective role of α-lipoic acid (ALA) on long-term exposure of rats to the combination of chlorpyrifos (CPF) and deltamethrin (DLT). Forty-two (42) male Wistar rats were divided into 6 exposure groups with 7 animals in each group: (I) soya oil (2 ml kg−1), (II) ALA (60 mg kg−1), (III) DLT (6.25 mg kg−1), (IV) CPF (4.75 mg kg−1), (V) (CPF + DLT) DLT (6.25 mg kg−1) and CPF (4.75 mg kg−1; 1/20th of the previously determined median lethal dose) and (VI) (ALA + CPF + DLT) pretreated with ALA (60 mg kg−1) and then co-exposed to CPF and DLT, 45 min later. The regimens were administered by gavage once daily for a period of 16 weeks. Sera obtained from blood collected at the end of the experimental period were used for the evaluation of serum glucose, total protein, albumin, urea, creatinine and the activities of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase and acetylcholinesterase. The liver homogenate was used to assay for the activities of superoxide dismutase and glutathione peroxidase and the concentrations of malondialdehyde, cytokine and tumour necrotic factor α. The result showed that the combination of CPF and DLT resulted in marked alterations of these biochemical parameters in most cases compared to either of the pesticides singly, supplementation with ALA ameliorated these alterations.

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Upregulation of Mitochondrial Redox Sensitive Proteins in LPS-Treated Stefin B-Deficient Macrophages

Cells ◽

10.3390/cells8121476 ◽

2019 ◽

Vol 8 (12) ◽

pp. 1476 ◽

Cited By ~ 1

Author(s):

Mojca Trstenjak Prebanda ◽

Janja Završnik ◽

Boris Turk ◽

Nataša Kopitar Jerala

Keyword(s):

Redox Homeostasis ◽

Redox Status ◽

Protective Role ◽

Protein Levels ◽

Lps Challenge ◽

Pyrin Domain ◽

Cysteine Cathepsins ◽

Peroxiredoxin 3 ◽

Superoxide Dismutase 2

Stefin B (cystatin B) is an intracellular inhibitor of cysteine cathepsins and mutations in the stefin B gene, resulting in the development of Unverricht–Lundborg disease, which is a form of myoclonic epilepsy. It was suggested that a key mechanism behind stefin B-mediated disease progression was impaired redox homeostasis. Stefin B-deficient mice were found more sensitive to lipopolysaccharide (LPS)-induced sepsis as a consequence of increased expression of caspase-11 and Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing (NLRP nflammasome activation and higher levels of mitochondrial reactive oxygen species (ROS). In the present study, we investigated if LPS-triggered oxidative stress affected the protein levels and redox status of redox sensitive proteins—thioredoxin, peroxiredoxins, and superoxide dismutases in macrophages and spleens of LPS-injected mice. LPS challenge was found to result in a marked elevation in mitochondrial peroxiredoxin 3 (Prx3), sulfiredoxin, and superoxide dismutase 2 (Sod2) in stefin B-deficient macrophages and spleens. We determined that sulfiredoxin is targeted to mitochondria after LPS challenge. In conclusion, the upregulation of mitochondrial redox-sensitive proteins Prx3 and Sod2 in stefin B-deficient cells implies a protective role of stefin B in mitochondrial function.

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Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion of para-aminohippurate after ischemic acute renal failure in rats

AJP Renal Physiology ◽

10.1152/ajprenal.00473.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. F1599-F1605 ◽

Cited By ~ 64

Author(s):

R. Schneider ◽

C. Sauvant ◽

B. Betz ◽

M. Otremba ◽

D. Fischer ◽

...

Keyword(s):

Renal Failure ◽

Acute Renal Failure ◽

Organic Anion ◽

Organic Anions ◽

Organic Anion Transporters ◽

Protein Levels ◽

Anion Transporters ◽

Pah Clearance ◽

Ischemic Acute Renal Failure

Ischemic acute renal failure (iARF) was described to reduce renal extraction of the organic anion para-aminohippurate (PAH) in humans. The rate-limiting step of renal organic anion secretion is its basolateral uptake into proximal tubular cells. This process is mediated by the organic anion transporters OAT1 and OAT3, which both have a broad spectrum of substrates including a variety of pharmaceutics and toxins. Using a rat model of iARF, we investigated whether impairing the secretion of the organic anion PAH might be associated with downregulation of OAT1 or OAT3. Inulin and PAH clearance was determined starting from 6 up to 336 h after ischemia-reperfusion (I/R) injury. Net secretion of PAH was calculated and OAT1 as well as OAT3 expression was analyzed by RT-PCR and Western blotting. Inulin and PAH clearance along with PAH net secretion were initially diminished after I/R injury with a gradual recovery during follow-up. This initial impairment after iARF was accompanied by decreased mRNA and protein levels of OAT1 and OAT3 in clamped animals compared with sham-operated controls. In correlation to the improvement of kidney function, both mRNA and protein levels of OAT1 and OAT3 were upregulated during the follow-up. Thus decreased expression of OAT1 and OAT3 is sufficient to explain the decline of PAH secretion after iARF. As a result, this may have substantial impact on excretion kinetics and half-life of organic anions. As a consequence, the biological effects of a variety of organic anions may be affected after iARF.

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Major role of organic anion transporters in the uptake of phenolsulfonphthalein in the kidney

European Journal of Pharmacology ◽

10.1016/s0014-2999(03)02111-3 ◽

2003 ◽

Vol 475 (1-3) ◽

pp. 85-92 ◽

Cited By ~ 13

Author(s):

Shirou Itagaki ◽

Mitsuru Sugawara ◽

Michiya Kobayashi ◽

Sachiho Nishimura ◽

Michio Fujimoto ◽

...

Keyword(s):

Organic Anion ◽

Organic Anion Transporters ◽

Anion Transporters

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Role of Organic Anion Transporters in the Pharmacokinetics of Zonampanel, an α-Amino-3-hydroxy-5-methylisoxazole-4-propionate Receptor Antagonist, in Rats

Drug Metabolism and Disposition ◽

10.1124/dmd.107.019828 ◽

2008 ◽

Vol 36 (8) ◽

pp. 1496-1504 ◽

Cited By ~ 13

Author(s):

Tsuyoshi Minematsu ◽

Tadashi Hashimoto ◽

Toshiko Aoki ◽

Takashi Usui ◽

Hidetaka Kamimura

Keyword(s):

Receptor Antagonist ◽

Organic Anion ◽

Organic Anion Transporters ◽

Anion Transporters

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Protective Effect of Quercetin on Melphalan-Induced Oxidative Stress and Impaired Renal and Hepatic Functions in Rat

Chemotherapy Research and Practice ◽

10.1155/2014/936526 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 8

Author(s):

Ebenezer Tunde Olayinka ◽

Ayokanmi Ore ◽

Olaniyi Solomon Ola ◽

Oluwatobi Adewumi Adeyemo

Keyword(s):

Anticancer Agents ◽

Hepatic Function ◽

Protective Role ◽

Glutathione S Transferase ◽

Drug Induced ◽

Treatment Groups ◽

Plasma Bilirubin ◽

Male Wistar Rats ◽

Mda Content

One major challenge with the use of anticancer agents is the phenomenon of drug-induced toxicity. Melphalan (MPLN) is an alkylating anticancer agent, while quercetin (QCT) is an antioxidant. We investigated the protective role of quercetin against MPLN-induced toxicity. Twenty-five male Wistar rats (160–170 g) were randomized into five treatment groups; (I) control, (II) MPLN (0.2 mg/kg b.w.), (III) pre-treated with QCT (20 mg/kg b.w.) for 7 days followed by MPLN (0.2 mg/kg b.w.) for 7 days, (IV) cotreated with QCT (20 mg/kg b.w.) and MPLN (0.2 mg/kg b.w.) for 7 days, and (V) QCT (20 mg/kg b.w.) alone. MPLN caused a significant increase in plasma bilirubin, urea, and creatinine by 122.2%, 102.3%, and 188%, respectively (P<0.05). Similarly, plasma ALP, ALT, AST, and γ-GT activities increased significantly by 57.9%, 144.3%, 71.3%, and 307.2%, respectively, relative to control. However, pre or cotreatment with QCT ameliorated the levels of renal and hepatic function indices. Hepatic ascorbic acid and GSH and activities of glutathione-S-transferase, SOD, and catalase decreased significantly by 36.2%, 188%, 46.5%, 34.4%, and 55.2%, respectively, followed by increase in MDA content by 46.5% relative to control. Pre- and cotreatment with QCT reestablished the hepatic antioxidant status and lipid peroxidation. Overall, quercetin protected against MPLN-induced renal and hepatic toxicity in rats.

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