OBJECTIVE:To evaluate the potential contribution of glycyrrhizin (GLZ) to mitigate the testicular toxicity linked to cisplatin (CIS) intoxication. METHODS:40 mature male Wistar albino rats (Rattus norvegicus albinus) were randomly divided into 4 equal groups (n = 10) for 60 days: the control group, CIS-treated group (single dose of 7 mg/kg, IP), GLZ-treated group (25 mg/kg, PO), and GLZ plus CIS-treated group. Blood and testis samples were examined using biochemical, histological, and immunohistochemical techniques. Semen samples were also obtained, and any abnormalities were reported. RESULTS:Serum follicle-stimulating hormone, luteinizing hormone, and testosterone levels were all markedly reduced by CIS. Oxidative stress and a significant reduction in levels of the antioxidant enzymes glutathione peroxidase, superoxide dismutase, and catalase were linked to CIS. Immunohistochemically, CIS showed diffuse, significantly positive immunolocalizations against the anti-caspase 3 antibody, indicating widespread apoptosis within the testicular parenchyma. Histopathologically, CIS showed diffuse coagulative necrosis of spermatogenic cells, necrotic Sertoli cells, intertubular edema, and Leydig cell hyperplasia. Moreover, CIS revealed a noteworthy increase in sperm abnormalities. Pre-coadministration and posttreatment with GLZ mitigated the majority of these detrimental consequences, and serum levels of antioxidant enzymes, luteinizing hormone, follicle-stimulating hormone, and testosterone were significantly elevated. CONCLUSIONS:Glycyrrhizin has been proven to be a strong antioxidant as well as antiapoptotic and cytoprotective against CIS testicular damage. CLINICAL RELEVANCE:The described model is a tool to evaluate the testicular protective impact of GLZ.

Background: Gold nanoparticles (GNPs) have garnered significant attention in the biomedicine field due to their exceptional electrical, mechanical, chemical, and optical characteristics. The interaction of these remarkable potentials with biological tissues carries a risk of toxicity. Quercetin (Qur) is a natural flavonoid and exhibits numerous pharmacological impacts, especially anti-inflammatory, anti-apoptotic, and antioxidant. Objective: This investigation aimed to clarify the potential cardiotoxicity induced by different diameters of spherical GNPs as well as to evaluate the possible cardioprotective roles of Qur against the most toxic diameter of GNPs. Methods: Rats were randomly grouped and treated with or without sphere GNPs (10, 20 and 50 nm) and Qur (200 mg/kg b.wt.). Heart and blood samples were collected and subjected to histological, immunohistochemical and biochemical investigations. Results: When compared to the groups treated with 20 and 50 nm, the 10 nm GNPs dramatically increased the levels of cardiac biomarkers, including Troponin I, Creatine kinase isoenzyme-MB (CK-MB), CK-Total, lactate dehydrogenase (LDH). Histopathologically, 10 nm GNPs exhibited severe cardiomyocytes degenerations, atrophy, disorganization of myocardial fibers, focal hemorrhage, congested blood vessels and interstitial inflammatory cells infiltrations. Immunohistochemically, 10 nm GNPs exhibited strongly positive expressions against anti-caspase-3 antibody confirming extensive apoptosis of cardiomyocytes. However, the majority of these pathological changes were significantly improved upon Qur treatment. Conclusion: The size of GNPs is crucial to their toxicological impact on cardiac tissues where 10 nm GNPs can induce severe histological damage, potent cytotoxicity, and apoptosis rather than larger particles. Otherwise, pre-co-treatment with Qur revealed a significant cardioprotective effect against GNPs cardiotoxicity.

In the original publication [...].

Otitis media with effusion (OME) is a recurrent middle ear inflammatory condition. It may be complicated by acquired hearing loss and speech impairment especially in children. Accordingly, the current study aimed to assess the role of cytokines and the imbalance of Th17/Tregs in the pathogenesis of OME. Additionally, the protective effect of astaxanthin and its mechanisms related to Notch1/ Hes1/mTORC1/S6K1 signalling were investigated. Methods: Forty-eight children were grouped as follow: G1: control healthy group G2: acute otitis media (AOM) group, G3: OME group. In the lipopolysaccharide (LPS) induced OME rat model, 15 rats were randomised into: G1: normal control group, G2: LPS group, and G3: astaxanthin treated group. Results: Biochemical analysis of the children's peripheral blood samples showed that IL1 beta, IL-2, IL-4, IL-6, IL-17, and IL-23 were significantly elevated, while TGF-beta was significantly decreased in AOM and OME patients (group 2 and 3). In the LPS- induced OME rat model, astaxanthin treatment resulted in suppression of IL-17, IL-6, TNF-alpha, Muc5A, TFF3, NICD, Hes1, mTORC1, and S6K1 in rat middle ear mucosa. Furthermore, astaxanthin significantly downregulated ROR gamma while upregulating FoxP3 and restored the balance between Th17/Tregs. Moreover, astaxanthin improved the histopathological picture of the inflamed middle ear mucosa. Conclusions: Proinflammatory cytokines as well as Th17/Tregs imbalance play a crucial role in the pathogenesis of AOM and OME. Additionally, astaxanthin alleviated LPS- induced OME in rats through suppression of Notch1/ Hes1/mTORC1/S6K1 pathway, and regulation of Th17/Tregs.

The major contribution of myocardial damage to global mortalities raises debate regarding the exploration of new therapeutic strategies for its treatment. Therefore, our study investigated the counteracting effect of tiron against isoprenaline (ISO)-mediated cardiac infarction in mice. Tiron was administered to mice for 7 days prior to two consecutive injections of ISO on days 8 and 9 of the treatment protocol. Tiron significantly reduced the levels of CK-MB, LDH, and AST in serum samples of ISO-challenged mice. A considerable increase in the cardiac antioxidant response was observed in tiron-treated mice, as indicated by depletion of MDA and enhancement of antioxidant activities. Furthermore, tiron induced a marked decrease in NLRP3, ASC, and caspase-1 levels accompanied by weak immune reactions of IL-1β, NF-κB, TLR4, and iNOS in the infarct cardiac tissues. Histopathological screening validated these variations observed in the cardiac specimens. Thus, tiron clearly mitigated the oxidative and inflammatory stress by repressing the NLRP3 inflammasome and the TLR4/NF-κB/iNOS signaling cascade.

Background: Nootkatone (NK), a bioactive sesquiterpene ketone, is a major ingredient in grapefruit that has distinguished biological activities. Melamine (MM), a food adulterant, was reported to induce toxic effects including renal disorders. Hence, this protocol was devoted to evaluate the renoprotective impact of NK toward MM-evoked renal damage. Methods: Rats were either exposed to MM (700 mg/kg) or a combination of MM and two doses of NK (5 and 10 mg/kg). Results: The results showed that NK therapy notably decreased the kidney functional parameters, along with KIM-1 and NGAL expressions of MM group. Furthermore, a decrease in MDA and NO levels as well as an elevation in SOD, CAT, GSH, and SOD and NRF2 mRNA expression in the NK group demonstrated NK's ability to enhance the renal antioxidant defense of the MM group. Significant suppression in renal inflammatory markers was achieved by NK via lessening of IL-1 beta and TNF-alpha, besides downregulation of NF-kappa B and IL-1 beta expressions. NK also downregulated vimentin, nestin, and desmin in the MM group. Additionally, in response to the MM exposure, NK hindered renal apoptosis by decreasing caspase-3 expression and restoring renal histopathological features. Conclusion: These outcomes suggest that NK can be considered as a prospective candidate to guard against MM exposure-mediated renal toxic effects.

Melamine (ML) is a common environmental contaminant, commonly used in food fraud, representing a serious health hazard and jeopardizing human and animal health. Recently, nootkatone (NK), a naturally occurring sesquiterpenoid, has garnered considerable attention due to its potential therapeutic advantages. We investigated the potential mechanisms underlying the protective effects of NK against ML-induced liver injury in rats. Five groups were utilized: control, ML, NK10, ML-NK5, and ML-NK10. ML induced substantial hepatotoxicity, including considerable alterations in biochemical parameters and histology. The oxidative distress triggered by ML increased the generation of malondialdehyde (MDA) and nitric oxide (NO) and decreased levels of reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) activities. In addition, decreased expression of nuclear factor-erythroid 2-related factor 2 (Nrf2) and increased nuclear factor kappa beta (NF-κB) expression levels were observed in hepatocytes, which indicated the occurrence of inflammatory changes following ML exposure. These alterations were alleviated by NK supplementation in a dose-dependent manner. The data revealed that the favorable effects of NK were attributed, at least in part, to its antioxidant and anti-inflammatory properties. Moreover, our results were supported by molecular docking studies that revealed a good fit and interactions between NK and antioxidant enzymes. Thus, the current study demonstrated that NK is a potential new food additive for the prevention or treatment of ML-induced toxicity.

Melamine (ML), a chemical substance of high nitrogen content, is used as a food adulterant. Former evidences implied that ML could induce a variety of toxic effects including neurotoxicity and cognitive impairment. Therefore, the aim of this study was to delineate the protective effect of the nootkatone (NK) against ML-induced neural adverse effects. Rats were orally pretreated with NK (5 and 10 mg/kg) prior to the oral administration of ML (700 mg/kg) for a period of 28 days. Our findings unveiled remarkable alleviating effect of NK on MK-induced neurobehavioral disturbance in open field test. Furthermore, NK lessened ML-caused increases in the acetylcholine esterase level in the brain tissue of exposed rats. NK also decreased the neural oxidative stress as represented by elevated levels of SOD, CAT, and GSH along with decreased MDA and NO levels. Upregulated mRNA expression levels of neural NRF-2 and HO-1 were noticed after NK administration. Remarkable anti-inflammatory impact was prominent by decreased neural IL-1β, and TNF-α along with downregulated NF-κB and TLR-4 gene expression levels in NK-treated rats. Noteworthily, pre-treatment with NK decreased the immune reaction of RAGE and HMGB-1 induced by oral ML exposure. Brain histological examination validated the obtained biochemical and molecular results. To sum up, these outcomes reveal that NK successfully alleviated the neural damage induced by ML via blocking of oxidative stress, and inflammatory signaling pathways. Consequently, our study may suggest NK as a new effective therapeutic supplement for treatment of ML-mediated neurotoxicity in rats via inhibition of HMGB-1-RAGE/TLR-4/NF-κB.

Aflatoxin B1 (AF) is an unavoidable environmental pollutant that contaminates food, feed, and grains, which seriously threatens human and animal health. Arabic gum (AG) has recently evoked much attention owing to its promising therapeutic potential. Thus, the current study was conducted to look into the possible mechanisms beyond the ameliorative activity of AG against AF-inflicted hepatic injury. Male Wistar rats were assigned into four groups: Control, AG (7.5 g/kg b.w/day, orally), AF (200 µg/kg b.w), and AG plus AF group. AF induced marked liver damage expounded by considerable changes in biochemical profile and histological architecture. The oxidative stress stimulated by AF boosted the production of plasma malondialdehyde (MDA) level along with decreases in the total antioxidant capacity (TAC) level and glutathione peroxidase (GPx) activity. Additionally, AF exposure was associated with down-regulation of the nuclear factor erythroid2–related factor2 (Nrf2) and superoxide dismutase1 (SOD1) protein expression in liver tissue. Apoptotic cascade has also been evoked following AF-exposure, as depicted in overexpression of cytochrome c (Cyto c), cleaved Caspase3 (Cl. Casp3), along with enhanced up-regulation of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, inducible nitric oxide synthase (iNOS), and nuclear factor kappa-B transcription factor/p65 (NF-κB/p65) mRNA expression levels. Interestingly, the antioxidant and anti-inflammatory contents of AG may reverse the induced oxidative damage, inflammation, and apoptosis in AF-exposed animals.

Although the combination of antibiotics is generally well-tolerated, they may have nephrotoxic effects. This study investigated whether tigecycline (TG) and gentamicin (GM) co-administration could accelerate renal damage. Male Wistar rats were randomly divided into six experimental groups: the control, TG7 (tigecycline, 7 mg/kg), TG14 (tigecycline, 14 mg/kg), GM (gentamicin, 80 mg/kg), TG7+GM, and TG14+GM groups. The combination of TG and GM evoked renal damage seen by the disruption of kidney function tests. The perturbation of renal tissue was mainly confounded to the TG and GM-induced oxidative damage, which was exhibited by marked increases in renal MDA (malondialdehyde) along with a drastic reduction in GSH (reduced-glutathione) content and CAT (catalase) activity compared to their individual treatments. More obvious apoptotic events and inflammation were also revealed by elevating the annexin-V and interleukin-6 (IL-6) levels, aside from the upregulation of renal PCNA (proliferating cell nuclear antigen) expression in the TG and GM concurrent treatment. The principal component analysis indicated that creatinine, urea, annexin-V, IL-6, and MDA all played a role in discriminating the TG and GM combined toxicity. Oxidative stress, inflammatory response, and apoptosis were the key mechanisms involved in this potentiated toxicity.

New quinazoline derivatives were designed based on the structural modification of the reported inhibitors to enhance their selectivity toward Aurora A. The synthesized compounds were tested over Aurora A, and a cytotoxicity assay was performed over NCI cell lines to select the best candidate for further evaluation. Compound 6e (2-(3-bromophenyl)-8-fluoroquinazoline-4-carboxylic acid) was the most potent compound among the tested derivatives. A Kinase panel assay was conducted for compound 6e over 14 kinases to evaluate its selectivity profile. Further cell cycle and apoptosis analysis were evaluated for compound 6e over the MCF-7 cell line at its IC50 of 168.78 µM. It arrested the cell cycle at the G1 phase and induced apoptosis. Molecular docking was performed to explore the possible binding mode of compound 6e into the active site. It showed significant binding into the main pocket in addition to potential binding interactions with the key amino acid residues. Accordingly, compound 6e can be considered a potential lead for further structural and molecular optimization of the quinazoline-based carboxylic acid scaffold for Aurora A kinase selective inhibition with apoptosis properties.