Aya H. Al-Najjar

Introduction: Myelotoxicity is a common adverse effect of vincristine and other chemotherapeutic drugs. Hesperetin is a bioactive flavanone with anti-inflammatory activity. This study was planned to examine the hesperetin protecting effect against vincristine induced myelosuppression and splenic inflammation in mice and test whether this effect is mediated through the suppression of Toll-like receptor 4 (TLR4)/myeloid differentiation primary response-88 (MYD88)/nuclear factor-kappa B (NF-κB) signaling pathways. Methods: Bioinformatics tools were used to establish the rationale of the study and molecular docking defined the potential binding of hesperetin to TLR4. Mice were allocated into different experimental groups: Group 1: was the saline mice, Group 2; mice were injected with vincristine (0.1 mg/kg, i. p) for 5 days per week, Group 3; mice received vincristine (as in Group 2) plus hesperetin (100 mg/kg, p. o.) and Group 4; mice received hesperetin (100 mg/kg, p. o.) only; the experiment continued for 2 weeks. Results: The mouse experiment showed that vincristine produced significant decreases in hematological parameters (mainly leukocytes dropped to 4.6 ± 0.32 and platelets dropped to 799.6 ± 25.46 versus 9.48 ± 0.19 and 1654 ± 273.26 × 10 ^˄ 9/L in the saline group, p less than 0.05) and bone marrow hypocellularity (dropped to ∼30–40% compared to 95%–100% in the saline group). The spleens showed white pulp lymphoid depletion, red pulp mild hypocellularity, greater immunostaining for MYD88, and greater content for TLR4, NF-κB, MYD88, TNF-α and IL-1β proteins. Results of molecular docking showed that hesperetin is an interesting complementarity with the TLR4/MD2 interface which was a good rationale for the experimental validation. The mouse experiment showed that hesperetin prevented the decrease hematological parameters, enhanced the bone marrow cellularity to 80%–90%, and the splenic architecture. Hesperetin further inhibited the increases in the target proteins (TLR4, NF-κB, MYD88, TNF-α and IL-1β) significantly. Discussion: The present data documents the novel role of hesperetin in mitigating myelotoxicity of vincristine through modulation of TLR4/MYD88/NF-κB signaling and a direct binding to TLR4 was proposed by molecular docking. This highlights possible usefulness of this combination after adequate clinical studies.

Background: Manganism, a central nervous system dysfunction correlated with neurological deficits such as Parkinsonism, is caused by the substantial collection of manganese chloride (MnCl₂) in the brain.Objectives: To explore the neuroprotective effects of natural compounds, namely, micronized zeolite clinoptilolite (ZC) and punicalagin (PUN), either individually or in combination, against MnCl₂‐induced Parkinson's disease (PD).Methods: Fifty male albino rats were divided into 5 groups (Gps). Gp I was used as the control group, and the remaining animals received MnCl₂ (Gp II–Gp V). Rats in Gps III and IV were treated with ZC and PUN, respectively. Gp V received both ZC and PUN as previously reported for the solo‐treated plants.Results: ZC and/or PUN reversed the depletion of monoamines in the brain and decreased acetyl choline esterase activity, which primarily adjusted the animals' behavior and motor coordination. ZC and PUN restored the balance between glutamate/γ‐amino butyric acid content and markedly improved the brain levels of brain‐derived neurotrophic factor and nuclear factor erythroid 2‐related factor 2/heme oxygenase‐1 and decreased glycogen synthase kinase‐3 beta activity. ZC and PUN also inhibited inflammatory and oxidative markers, including nuclear factor kappa‐light‐chain‐enhancer of activated B cells, Toll‐like receptor 4, nucleotide‐binding domain, leucine‐rich‐containing family, pyrin domain‐containing‐3 and caspase‐1. Bcl‐2‐associated X‐protein and B‐cell leukemia/lymphoma 2 protein (Bcl‐2) can significantly modify caspase‐3 expression. ZC and/or PUN ameliorated PD in rats by decreasing the levels of endoplasmic reticulum (ER) stress markers (p‐protein kinase‐like ER kinase (PERK), glucose‐regulated protein 78, and C/EBP homologous protein (CHOP)) and enhancing the levels of an autophagy marker (Beclin‐1).Discussion and Conclusion: ZC and/or PUN mitigated the progression of PD through their potential neurotrophic, neurogenic, anti‐inflammatory, antioxidant, and anti‐apoptotic activities and by controlling ER stress through modulation of the PERK/CHOP/Bcl‐2 pathway.

Cholestasis is one of the major determinants which causes hepatic injury and might lead to liver complications. In cholestasis, toxic bile acids accumulate with decrease in the capacity of detoxification. It can be stimulated experimentally by bile duct ligation (BDL) to block the bile flow from the liver. As for the treatment, lactoferrin (LF), the iron-binding glycoprotein, has been evaluated in various studies for the treatment of infections, inflammation, and cancer. This study aims to illustrate the curative effects of LF on BDL-induced hepatic injury in rats. Animals were randomly allocated into 4 groups: the first group is the control sham; the subjects of the second group have been subjected to a surgery of BDL; the latter procedure has been induced in the third group, 14 days later, they have been subjected to the treatment with LF (300 mg/kg/day, po) for two weeks; as for the last group, LF has been administered (300mg/kg/day, po) for two weeks. BDL elevated biomarkers of hepatocellular damage (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) and obstructive cholestatic injury (gamma-glutamyl transferase (γ-GT) and total bilirubin). In addition, it provoked oxidative stress manifested by increase in hepatic MDA and reduction of SOD with down-regulation of Nrf2/HO-1 pathway. LF treatment ameliorated these effects through its antioxidant activity by activation of Nrf2/HO-1 pathway that leads to decrease in hepatic MDA and elevation of SOD. In conclusion; lactoferrin alleviated hepatic injury induced by BDL via activating Nrf2 gene expression that might be led back to its antioxidant properties.