Date palm seed extract and herbal mixture mitigate gentamicin-induced renal injury in mice: Role of Protease-activated receptors (PARs) and Retinoid X receptor alpha (RXR-α)

Amri J., Alaee M., Babaei R., Salemi Z., Meshkani R., Ghazavi A., Akbari A., Salehi M.

One of the major complications of diabetes is diabetic nephropathy, and often many patients suffer from diabetic nephropathy. That is why it is important to find the mechanisms that cause nephropathy and its treatment. This study was designed to examine the antidiabetic effects of biochanin A (BCA) and evaluate its effects on oxidative stress markers and the expression of transforming growth factor-β1 (TGF-β1) and protease-activated receptors-2 (PAR-2) genes in the kidney of type 1 diabetic rats. After induction of diabetes using streptozotocin (STZ), 55 mg/kg bw dose, rats were randomly divided into four groups with six rats in each group as follows: normal group: normal control receiving normal saline and a single dose of citrate buffer daily; diabetic control group: diabetic control receiving 0.5% dimethyl sulfoxide daily; diabetic+BCA (10 mg/kg) group: diabetic rats receiving biochanin A at a dose of 10 mg/kg bw daily; diabetic+BCA (15 mg/kg) group: diabetic rats receiving biochanin A at a dose of 15 mg/kg bw daily. TGF-β1 and PAR-2 gene expression was assessed by real-time. Spectrophotometric methods were used to measure biochemical factors: fast blood glucose (FBG), urea, creatinine, albumin, lipids profiles malondialdehyde (MDA), and superoxide dismutase (SOD). The course of treatment in this study was 42 days. The results showed that in the diabetic control group, FBG, serum urea, creatinine, expression of TGF-β1 and PAR-2 genes, and the levels of MDA in kidney tissue significantly increased and SOD activity in kidney tissue and serum albumin significantly decreased compared to the normal group (p < 0.001). The results showed that administration of biochanin A (10 and 15 mg/kg) after 42 days significantly reduced the expression of TGF-β1 and PAR-2 genes and FBG, urea, creatinine in serum compared to the diabetic control group (p < 0.001), also significantly increased serum albumin compared to the diabetic control group (p < 0.001). The level of MDA and SOD activity in the tissues of diabetic rats that used biochanin A (10 and 15 mg/kg) was significantly reduced and increased, respectively, compared to the diabetic control group (p < 0.001). Also, the result showed that in the diabetic control group lipids profiles significantly is disturbed compared to the normal group (p < 0.001), the results also showed that biochanin A (10 and 15 mg/kg) administration could significantly improved the lipids profile compared to the control diabetic group (p < 0.001). It is noteworthy that it was found that the beneficial effects of the biochanin A were dose dependent. In conclusion, administration of biochanin A for 42 days has beneficial effect and improves diabetes and nephropathy in diabetic rats. So probably biochanin A can be used as an adjunct therapy in the treatment of diabetes.

Zrouri H., Elbouzidi A., Bouhrim M., Bencheikh N., Kharchoufa L., Ouahhoud S., Ouassou H., El Assri S., Choukri M.

<p class="Default">In Morocco, Raphanus sativus is a widespread traditional medicinal plant used to treat various kidney diseases such as nephropathy.</p><p class="Mabstract"><strong>Objective</strong>:<strong> </strong>The present study aims to evaluate the protective effect of the <em>R. sativus </em>aqueous extract against the gentamicin-induced acute nephrotoxicity in rats.</p><p class="Mabstract"><strong>Methods</strong>: Rats were randomly separated into four groups (n=6; ♂/ ♀=1). The control group was treated only with distilled water (10 mL/kg; <em>p.o</em>). The gentamicin group was treated with distilled water (10 mL/kg; <em>p.o</em>) and injected intraperitoneally by the gentamicin (80 mg/kg; <em>i.p</em>). <em>R. sativus </em>groups were treated with the aqueous extracts of this plant at a dose of (200 or 400 mg/kg; <em>p.o</em>) and injected by the gentamicin (80 mg/kg; <em>i.p</em>). The plasma Creatinine, Urea, Uric Acid, Albumin, Total Protein, Alanine transaminase, Aspartate transaminase, and Calcium levels were measured. The urinary creatinine, urinary Calcium, urinary volume, water intake, creatinine clearance, body weight gain, relative right kidney weight, and kidney malondialdehydes were determined.</p><p class="Mabstract"><strong>Results</strong>: This study showed that the daily pretreatment with <em>R. sativus</em> aqueous extract at two doses of 200 and 400 mg/kg, p.o prevented the rats from the gentamicin-induced nephrotoxicity. Moreover, the <em>R. sativus </em>aqueous extract showed a high amount of polyphenols and flavonoids and a significant antioxidant activity.</p><p class="Mabstract"><strong>Conclusion</strong>: <em>R. sativus </em>aqueous extract, as a novel natural product, may have preventive properties against gentamicin-induced nephrotoxicity in rats. The present study describes new areas of investigation to introduce better therapeutic agents for renal disorders and dysfunction.</p>

Shebeko S.K., Chernykh V.V., Zupanets K.O.

(1) Background: this research aims at studying the nephroprotective properties of BNO 2103 in a model of chromate-induced renal failure in rats and at proving the possibility of using BNO 2103 in clinical practice for the complex treatment of chronic kidney disease (CKD). (2) Methods: fifty rats divided into five groups were studied. The drugs BNO 2103, Prednisolone and Lespephril were administered within 20 days. The excretory function and the functional state of kidneys, blood biochemical parameters and indicators of nitrogen metabolism were determined. (3) Results: under the influence of BNO 2103, there was a significant improvement in renal excretory function, in nitrogen metabolism and blood biochemical parameters compared with the control pathology group. BNO 2103 also outperformed the comparators in most indicators. (4) Conclusions: BNO 2103 has demonstrated nephroprotective, hypoazotemic and diuretic effects; and can be used to implement to the combined therapy of CKD.

M. Eldeeb H., A. Mohamme H., S. M. Saji M., Elnaeem M. S., S. Al-Omar M., A. Mobark M., S. Ahmed A.

Kilany O., Abdou R., El-Beltagy M., Mohammad H.

Hussain M.I., Semreen M.H., Shanableh A., Khattak M.N., Saadoun I., Ahmady I.M., Mousa M., Darwish N., Radeef W., Soliman S.S.

The biochemical composition, secondary metabolites (phenolic compounds, flavonoids) and antimicrobial potential of different varieties of Emirati date (Phoenix dactylifera L.) pits were investigated. Total phenolic acids (TPC) and total flavonoid contents (TFC) of the different date pits were measured using a Folin–Ciocalteau reagent. Different organic solvents [(n-hexane; H2O: EtOH (1:1); ethyl acetate; acetone: Water (1:1); and methanol: Chloroform (1:1)] were compared to evaluate the phytotoxicity of Ajwa, Fard, Khalas, Khodari, Abu Maan, Lulu, and Mabroom date pits. The antimicrobial activity of the date pit extracts were evaluated by means of agar-well diffusion assay on Staphylococcus aureus (ATCC 29123), Escherichia coli (ATCC 25922) and Candida albicans (ATCC 66027). Minimum inhibitory concentrations (MICs) were measured following clinical laboratory standardization institute (CLSI) protocol. The biochemical analyses of date pits indicate that TPC were ranged from 7.80 mg of equivalent gallic acid⁄100 g dry weight in Ajwa to 4.65 mg in Mabroom. The TFC were ranged between 1.6–4.54 mg of equivalent catechin⁄100 g dry weight. Ajwa pit extract showed good quality traits (higher protein, lower ash content, and intermediate dietary fiber). The results indicate that the ethyl acetate extract of Khalas and Khodari inhibited S. aureus with an inhibition zone diameter of 20 mm and MIC of 10 mg/mL. Abu Mann pit extract inhibited the S. aureus and also decreased the population of E. coli. The diameter of inhibition zone was 15, 16, and 18 mm after treatment with Ajwa extracts, while the MICs were 7.5 and 5 mg/mL. The MeOH: CFM extract of Abu Mann and Ajwa was more potent against E. coli bacteria than any other extract. This work demonstrates that the Emirati date pits extract has antimicrobial (antibacterial, antifungal) potential and can be used as phytotoxic natural compounds.

ALrajhi M., AL-Rasheedi M., Eltom S.E., Alhazmi Y., Mustafa M.M., Ali A.M.

Antibiotic resistance is one of the biggest hazards globally that is leading to prolonged hospital stay, inflated medical expenditures and increased morbidity and mortality. Many natural compounds ...

Alzahrani S, Ezzat W, Elshaer R E, Abd El-Lateef A S, Mohammad H M F, Elkazaz A Y, Toraih E, Zaitone S A

Shukla A.S., Jha A.K., Kumari R., Rawat K., Syeda S., Shrivastava A.

Anticancer drugs are now frequently being combined with dietary phytochemicals/nutraceuticals in an effort to enhance their antitumor efficacy while lowering their toxic effects. This forced the research to shift toward traditional medical practices with some advancement, that is, the use of nutraceuticals such as catechins. Catechins and their gallate esters are a class of polyphenolic compounds that has recently attracted a great deal of attention because of its beneficial effect on human health. They are functionally versatile and regulate a number of biological pathways to deal with various physiological or pathophysiological pathways. Catechins are mostly known for their potent antioxidants activity; however, depending on the doses, they may also show prooxidant effects. Reports on green tea catechin-mediated modulation of several key cellular functions associated with strong chemoprotective and chemosensitizing properties have been often ascribed to both anti- and prooxidant activities. Catechins hit multiple targets in cancer therapy and are also found to be useful in managing multidrug-resistant tumors. Catechins have been shown to suppress several key pathways linked to oncogenesis, including those involved in cell survival, proliferation, and invasion, along with angiogenesis. They are also helpful against disorders involving lipid and glucose metabolism such as type 2 diabetes and obesity and could also alleviate the risk of cardiovascular diseases. The beneficial effects of catechins especially EGCG have been reported from in vitro and in vivo studies in model organisms and from some pilot studies in preclinical and clinical trials. Catechins, potent antioxidants with biological activity relevant to the prevention and treatment of cancer, are actively being tried in combination with many chemotherapeutic drugs in order to increase the efficacy of the chemotherapeutic drugs and to ameliorate the drug-associated side effects.

Al Suleimani Y.M., Abdelrahman A.M., Karaca T., Manoj P., Ashique M., Nemmar A., Ali B.H.

This study aimed at investigating the possible ameliorative effects of sitagliptin in mice with gentamicin (GEN) nephrotoxicity. Sitagliptin was given to the animals at an oral dose of 10mgkg-1 per day for 10days, and in some of these mice, GEN was injected intraperitoneally at a dose of 100mgkg-1 per day during the last seven days of the treatment. Nephrotoxicity was evaluated histopathologically by light microscopy and biochemically by measuring several indices in plasma, urine and renal cortex homogenates. GEN treatment induced nephrotoxicity as evidenced by significantly (P

Yang H., Li W., Wang L., Li W., Sun H., He X., Zhang J.

Background/Aims: This study measured the effect of Sika deer (Cervus nippon Temminck) antler protein (SDAPR), glycoproteins (SDAG), and polysaccharides (SDAPO) on cisplatin-induced cytotoxicity in HEK 293 cells, and investigated the effect of SDAPR against cisplatin-induced nephrotoxicity in mice. Methods: Cell viability was measured by MTT assay. ICR mice were randomly divided into five groups: control, cisplatin with vehicle, and cisplatin with SDAPR at three concentrations: 5, 10, or 20 mg/kg, p.o., 10 d. Cisplatin was injected on 7th day (25 mg/kg, i.p.). Renal function, oxidative stress, levels of inflammatory factors, and expression of apoptosis-related proteins were measured in vivo. Renal tissues were stained with TUNEL and H&E to observe renal cell apoptosis and pathological changes. Results: Pretreatment with SDAPR (125-2000 µg/mL) significantly improved cell viability, with an EC50 of approximately 1000 µg/mL. SDAPR also ameliorated cisplatin-induced histopatholo- gic changes, and decreased blood urea nitrogen (BUN) and creatinine (Cr) (P < 0.05). Western blotting analysis showed SDAPR clearly decreased expression levels of cleaved-caspase-3 and Bax, and increased the expression level of Bcl-2 (P < 0.01). Additionally, SDAPR markedly regulated oxidative stress markers and inflammatory cytokines (P<0.05). TUNEL staining showed decreased apoptosis after SDAPR treatment (P < 0.01). Conclusions: These results indicate that SDAPR can be an effective dietary supplement, to relieve cisplatin-induced nephrotoxicity by improved antioxidase activity, suppressed inflammation, and inhibited apoptosis in vivo.

Liu Y., Ji P., Lv H., Qin Y., Deng L.

Gentamicin modified chitosan film (CS-GT) was produced using a three-step procedure comprising: (i) the chitosan solution was air-dried to form a chitosan (CS) film, (ii) using citric acid to generate the amide and carboxyl groups on the surface of CS, (iii) the CS with surface carboxyl groups was modified by grafting of gentamicin. After modification, this CS-GT film has excellent hydrophilicity and biocompatibility. It is very evident that the gentamicin grafting treatment significantly improves the antibacterial properties of the CS film. Our preliminary results suggest that this novel gentamicin modified chitosan film, which can be prepared in large quantities and at low cost, should have potential application in biomedical applications.

Chashmi N.A., Emadi S., Khastar H.

Gentamicin (GM) is an effective and common antibiotic against severe gram-negative infections. However, its nephrotoxic action has limited the extent of its use. The aim of this study was to investigate the protective effects of hydroxytyrosol (HT) on gentamicin induced nephrotoxicity in mice.Male mice (n = 27) were randomly assigned to three groups: (1) Sham, (2) GM (100 mg/kg for 7 days) (3) GM + HT (2 mg/kg BW; gastric gavages, for 7 days). 24-h urine samples were collected on day 8 and then animal were anesthetized. The blood and kidney tissue samples were collected.Gentamicin led to increase in plasma BUN and creatinine, fractional excretion of sodium and potassium and decrease in creatinine clearance and urine flow rate. SOD and GSH levels were reduced and MDA was increased in the GM group compared with the sham group. In GM + HT group, plasma BUN and creatinine, fractional excretion of Na, creatinine clearance and urine flow rate were decreased in contrast to GM group. Increase in SOD and GSH activity and decrease in MDA compared to GM group were seen.Findings suggest that HT partly protected the kidneys from gentamicin induced nephrotoxicity and it is partly due to antioxidant effect of HT.

Oe Y., Hayashi S., Fushima T., Sato E., Kisu K., Sato H., Ito S., Takahashi N.

Objective— The role of hypercoagulability in the pathogenesis of diabetic nephropathy (DN) remains elusive. We recently reported the increased infiltration of macrophages expressing tissue factor in diabetic kidney glomeruli; tissue factor activates coagulation factor X (FX) to FXa, which in turn stimulates protease-activated receptor 2 (PAR2) and causes inflammation. Approach and Results— Here, we demonstrated that diabetes mellitus increased renal FX mRNA, urinary FXa activity, and FX expression in glomerular macrophages. Administration of an oral FXa inhibitor, edoxaban, ameliorated DN with concomitant reductions in the expression of PARs ( Par1 and Par2 ) and of proinflammatory and profibrotic genes. Diabetes mellitus induced PAR2, and lack of Par2 ameliorated DN. FXa or PAR2 agonist increased inflammatory cytokines in endothelial cells and podocytes in vitro. Conclusions— We conclude that enhanced FXa and PAR2 exacerbate DN and that both are promising targets for preventing DN. Alleviating inflammation is probably more important than inhibiting coagulation per se when treating kidney diseases using anticoagulants.

El-Shaibany A., AL-Habori M., Al-Tahami B., Al- Massarani S.

Purpose : To investigate the anti-hyperglycaemic activity of methanol extract of Tribulus terrestris L. Zygophyllaceae in glucose-loaded normal rabbits. Methods: The animals were randomly assigned to 4 groups (n = 5) and treated with a single oral dose. Group 1 served as normal control group and received distilled water; group 2 served as hyperglycaemic control; group 3 was treated with glibenclamide (5 mg/kg, aqueous suspension) and served as reference standard; group 4 received methanol extract of Tribulus terrestris L. (250 mg/kg). Groups 3 and 4 were orally treated with glucose (5 g/kg) after 1 h of drug and extract administration, respectively. Fasting blood glucose (FBG) was determined prior to (0 h) and at 30 min, 1, 2 and 3 h after dosing for acute toxicity study. Results: On comparing within groups, a single dose of the methanol extract of Tribulus terrestris L. lowered FBG to levels comparable to that of glibenclamide (36 vs. 55 %), and reaching the initial level (0 h) at 2 h. FBG were significantly (p < 0.05) lowered at 2 and 3 h in both glibenclamide (45.5 and 56.9 %) and extract (45.7 and 52.7 %) groups as compared with their respective glucose levels at 0.5 h. On the other hand, on comparing between groups, both glibenclamide and methanol extract significantly (p < 0.05, p < 0.001) lowered the rise in blood glucose at 1 h (33.9 and 22.5 %), 2 h (62.8 and 59.16 %), and 3 h (64.6 and 57.1 %) with respect to the hyperglycaemic control group. Conclusion: The methanol extract of the aerial parts of Tribulus terrestris L. possesses potential antihyperglycaemic activity in glucose loaded normal rabbits. Further studies on various organic solvents fractions and isolated compounds from this plant are required. Keywords: Tribulus terrestris L., Zygophyllaceae, Anti-hyperglycaemic activity, Fasting blood glucose, Acute toxicity

Manai S., Boulila A., Silva A.S., Barbosa-Pereira L., Sendón R., Khwaldia K.

Date palm by-products are characterized by their abundance and richness in valuable functional compounds such as dietary fibers, phenolics, tocopherols, and carotenoids. They offer an attractive resource for multiple industries, including food, packaging, cosmetics, and pharmaceuticals, contributing to the development of a sustainable palm date value chain through a circular economy approach. Leveraging their established phytochemical, nutritional, and health-promoting attributes, date palm by-products and their functional compounds have found applications as additives in food formulations and packaging systems, enhancing functional and bioactive properties while extending the shelf life of food products. This comprehensive review aims to discuss the most relevant studies on key functional and bioactive compounds obtained from date by-products. It also addresses safety and toxicity concerns associated with date palm by-products. The review explores various extraction techniques employed for the recovery of bioactive compounds, with a focus on eco-friendly extraction methods, and investigates their potential roles in food formulations and packaging systems.