Antioxidants have valuable effects on the process of spermatogenesis, particularly with diabetes mellitus (DM). Therefore, the present study investigated the impact and the intracellular mechanisms by which thymoquinone (TQ) works against diabetes-induced testicular deteriorations in rats. Wistar male rats (n = 60) were randomly allocated into four groups; Control, Diabetic (streptozotocin (STZ)-treated rats where diabetes was induced by intraperitoneal injection of STZ, 65 mg/kg), Diabetic + TQ (diabetic rats treated with TQ (50 mg/kg) orally once daily), and TQ (non-diabetic rats treated with TQ) for 12 weeks. Results revealed that TQ significantly improved the sperm parameters with a reduction in nitric oxide (NO) and malondialdehyde (MDA) levels in testicular tissue. Also, it increased testicular reduced glutathione (GSH) levels and superoxide dismutase (SOD) activity. Interestingly, TQ induced downregulation of testicular inducible nitric oxide synthase (iNOS) and nuclear factor kappa-B (NF-κB) and significantly upregulated the aromatase protein expression levels in testicles in comparison with the diabetic rats. In conclusion, TQ treatment exerted a protective effect against reproductive dysfunction induced by diabetes not only through its powerful antioxidant and hypoglycemic effects but also through its downregulation of testicular iNOS and NF-κB along with upregulation of aromatase expression levels in diabetic rats.

Triple-negative breast cancers (TNBCs) comprise 10−15% of all breast cancers but with more resistance affinity against chemotherapeutics. Although doxorubicin (DOX) is the recommended first choice, it has observed cardiotoxicity together with apparent drug resistance. The anti-hyperglycemic drug, empagliflozin (EMP), was recently indicated to have in vitro anticancer potential together with its previously reported cardioprotective properties related to calmodulin inhibition. In this study, we carried out molecular docking studies which revealed the potential blocking of the calmodulin receptor by EMP through its binding with similar crucial amino acids compared to its cocrystallized inhibitor (AAA) as a proposed mechanism of action. Moreover, combination of DOX with EMP showed a slightly lower cytotoxic activity against the MDA-MB-231 cell line (IC 50 = 1.700 ± 0.121) compared to DOX alone (IC 50 = 1.230 ± 0.131), but it achieved a more characteristic arrest in the growth of cells by 4.67-fold more than DOX alone (with only 3.27-fold) in comparison to the control as determined by cell cycle analysis, and at the same time reached an increase in the total apoptosis percentage from 27.05-to 29.22-fold, compared to DOX alone as indicated by Annexin V-FITC apoptosis assay. Briefly, the aforementioned in vitro studies in addition to PCR of pro-and antiapoptotic genes (mTOR, p21, JNK, Bcl2, and MDR1) suggest the chemosensitization effect of EMP combination with DOX which can reduce the required therapeutic dose of DOX in TNBC and eventually will decrease its toxic side effects (especially cardiotoxicity), along with decreasing the chemoresistance of TNBC cells to DOX treatment.

Gastric ulcers are a major problem worldwide with no effective treatment. The objective of this study was to evaluate the use of manuka honey in the treatment of acetic acid-induced chronic gastric ulcers in rats. Different groups of rats were treated with three different concentrations of honey. Stomachs were checked macroscopically for ulcerative lesions in the glandular mucosa and microscopically for histopathological alterations. Treatment with manuka honey significantly reduced the ulcer index and maintained the glycoprotein content. It also reduced the mucosal myeloperoxidase activity, lipid peroxidation (MDA), and the inflammatory cytokines (TNF-α, IL-1β, and IL-6) as compared to untreated control group. In addition, honey-treated groups showed significant increase in enzymatic (GPx and SOD) and nonenzymatic (GSH) antioxidants besides levels of the anti-inflammatory cytokine IL-10. Flow cytometry studies showed that treatment of animals with manuka honey has normalized cell cycle distribution and significantly lowered apoptosis in gastric mucosa. In conclusion, the results indicated that manuka honey is effective in the treatment of chronic ulcer and preservation of mucosal glycoproteins. Its effects are due to its antioxidant and anti-inflammatory properties that resulted in a significant reduction of the gastric mucosal MDA, TNF-α, IL-1β, and IL-6 and caused an elevation in IL-10 levels.

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