The irrational use of antibiotics has favored the emergence of resistant bacteria, posing a serious threat to global health. To counteract antibiotic resistance, this research seeks to identify novel antimicrobials derived from essential oils that operate through several mechanisms. It aims to evaluate the quality and composition of essential oils from Origanum compactum and Origanum elongatum; test their antimicrobial activity against various strains; explore their synergies with commercial antibiotics; predict the efficacy, toxicity, and stability of compounds; and understand their molecular interactions through docking and dynamic simulations. The essential oils were extracted via hydrodistillation from the flowering tops of oregano in the Middle Atlas Mountains in Morocco. Gas chromatography combined with mass spectrometry (GC-MS) was used to examine their composition. Nine common antibiotics were chosen and tested alone or in combination with essential oils to discover synergistic effects against clinically important and resistant bacterial strains. A comprehensive in silico study was conducted, involving molecular docking and molecular dynamics simulations (MD). O. elongatum oil includes borneol (8.58%), p-cymene (42.56%), thymol (28.43%), and carvacrol (30.89%), whereas O. compactum oil is mostly composed of γ-terpinene (22.89%), p-cymene (15.84%), thymol (10.21%), and (E)-caryophyllene (3.63%). With O. compactum proving to be the most potent, these essential oils showed antibacterial action against both Gram-positive and Gram-negative bacteria. Certain antibiotics, including ciprofloxacin, ceftriaxone, amoxicillin, and ampicillin, have been shown to elicit synergistic effects. To fight resistant bacteria, the essential oils of O. compactum and O. elongatum, particularly those high in thymol and (E)-caryophyllene, seem promising when combined with antibiotics. These synergistic effects could result from their ability to target the same bacterial proteins or facilitate access to target sites, as suggested by molecular docking simulations. Molecular dynamics simulations validated the stability of the examined protein–ligand complexes, emphasizing the propensity of substances like thymol and (E)-caryophyllene for particular target proteins, opening the door to potentially effective new therapeutic approaches against pathogens resistant to multiple drugs.

Background and Objectives: Autism is a developmental disability characterized by impairment of motor functions and social communication together with the development of repetitive or stereotyped behaviors. Neither the exact etiology or the curative treatment of autism are yet completely explored. The goals of this study were to evaluate the possible effects of perindopril on a rat model of autism and to elucidate the possible molecular mechanisms that may contribute to these effects. Materials and Methods: In a rat model of sodium valproate (VPA)-induced autism, the effect of postnatal administration of different doses of perindopril on growth and motor development, social and repetitive behaviors, sirtuin-1, oxidative stress and inflammatory markers, PI3K/Akt/GSK-3β pathway, JAK2/STAT3 axis, and PPAR-gamma signaling in the hippocampal tissues were investigated. The histopathological and electron microscopic changes elicited by administration of the different treatments were also investigated. Results: Perindopril dose-dependently combatted the effects of prenatal exposure to VPA on growth and maturation, motor development, and social and repetitive behaviors. In addition, the different doses of perindopril ameliorated the effects of prenatal exposure to VPA on sirtuin-1, oxidative stress and inflammatory markers, PI3K/Akt/GSK-3β pathway, JAK2/STAT3 axis, and PPAR-gamma signaling. These effects had a mitigating impact on VPA-induced histopathological and electron microscopic changes in the hippocampal tissues. Conclusions: Perindopril may emerge as a promising agent for amelioration of the pathologic changes of autism spectrum disorders.

Methotrexate (METX) is a widely used chemotherapeutic and immunosuppressive agent, frequently employed as a first-line treatment for various malignancies and autoimmune disorders. Despite its clinical efficacy, METX is known to induce cardiotoxicity primarily through mechanisms involving oxidative stress, inflammation, and apoptosis. Apigenin (API), a natural dietary flavonoid, exhibits potent antioxidant and anti-inflammatory properties. The current study evaluated the protective effects of API against METX-induced cardiotoxicity in mice, focusing on the modulation of transforming growth factor-β (TGF-β)/(SMAD2) signaling. Molecular docking was done to investigate the possible inhibition of TGF-β by API and bioinformatic tools were utilized to investigate the correlation between the target proteins. Male Swiss albino mice were randomly distributed to four groups: Group I: a saline group, Group II: a METX control group (20 mg/kg, per week), Group III: METX + API (40 mg/kg, per day) and Group IV: METX + API (80 mg/kg, per day, via oral gavage); the study continued for three weeks. Our findings suggest that API administration significantly mitigated METX cardiotoxicity and serum CK-MB, likely through attenuation of the inflammatory cytokines (NF-κB, IL-1β, TNF-α, and IL-6) and suppression of cardiac TGF-β/SMAD2 signaling. The congruence between bioinformatics and experimental validation findings strongly highlighted API as a promising therapeutic candidate for alleviating METX cardiotoxicity. While the current data reveals key underlying molecular mechanisms for API's cardioprotective effect, further comprehensive studies across diverse cardiotoxicity models are essential to fully elucidate cardioprotective effect of API.

Offsprings early separated from their mothers may display depression and anxiety behaviors. The objective of this study is to assess the potential of isorhmanetin, known for its anti-inflammatory and antidepressant properties, in mitigating these behaviors in male mice. The experimental mice underwent a 4-h daily maternal separation from postnatal days 2 to 21. Afterwards, mice were given an intraperitoneal injection of isorhamnetin (20 mg/kg/day) from postnatal day 61 for 4 weeks. At 3 months old, both behavioral evaluations and biochemical analyses were carried out. The findings indicated that the isolated mice displayed clear signs of anxiety and depression-like behaviors, along with increased levels of various cytokines (IL-1β, IL-6, and TNF-α) in the hippocampus and decreased levels of Sirt1, accompanied by elevated NF-κB p65 expression. The effects were mitigated by treatment with isorhamnetin, resulting in the normalization of behavior and cytokine levels, as well as the activation of Sirt1 expression in addition to downregulation of NF-κB p65. Isorhamnetin has the potential to be utilized as a treatment for anxiety and depression-like symptoms by adjusting pathways of neuroinflammation and the signaling axis of Sirt1 and NF-κB. This opens the door for further investigation in mitigating the biochemical and behavioral adverse effects induced by separation during the maternal period.

Background: Irinotecan is a potent chemotherapeutic agent used as a neoadjuvant in colorectal cancer liver metastasis and significantly enhances five-year survival rates. Recently, irinotecan-associated hepatotoxicity was a significant concern. Given the limited study in this area, we aimed to identify risk factors associated with irinotecan-induced hepatotoxicity. Methods: This is a retrospective cohort study at King Saud University Medical City in Riyadh. The study encompassed all adult cancer patients who received irinotecan treatment between Jun 2017 and December 2023. The clinical records of patients were reviewed to assess factors associated with hepatotoxicity. Time-to-event analyses were performed using time-varying exposure. Results: The study includes 229 adult cancer patients who received irinotecan-based treatment. Median age was 58 years, and colorectal cancer was the most diagnosed type of cancer (68.6%). Over a median follow-up of 103 days, the incidence of hepatotoxicity was 19.2% (n=44). In the adjusted analysis, higher baseline AST was associated with an increased hazard of hepatotoxicity (HR = 1.01; 95% CI: 1.01–1.02; p = 0.001). Cumulative irinotecan dose showed an inverse association with hepatotoxicity, with lower hazards observed in the medium cumulative dose group (HR = 0.36, 95% CI: 0.14–0.91, p = 0.031) and high cumulative dose group (HR = 0.06, 95% CI: 0.01–0.48, p = 0.008) compared with the low cumulative dose group. Conclusion: In summary, an inverse association was observed between cumulative irinotecan dose and hepatotoxicity. A higher baseline AST was also associated with hepatotoxicity, warranting careful assessment of pretreatment liver enzymes and closer monitoring during the early treatment period. Further studies are needed to validate these findings and investigate additional predictors of irinotecan-related hepatotoxicity.

Background: Carbapenem-resistant Enterobacteriaceae (CRE) prevalence has been increasing in Saudi Arabia, posing a significant public health concern. Antimicrobial stewardship programs (ASPs) play an important role in reducing resistance by ensuring appropriate antibiotic use. Our study aimed to assess the appropriateness of meropenem prescriptions pre-ASP and post-ASP implementation in the Intensive Care Unit (ICU) ward. Method: This is a retrospective quasi-experimental pre–post study conducted over 3 years, from 2020 to 2023 at King Abdullah bin Abdulaziz University Hospital (KAAUH). The study included adult ICU patients who received meropenem therapy. The primary objective was to evaluate the appropriateness of meropenem prescriptions in the ICU before and after ASP implementation. The secondary objectives were to identify reasons for inappropriate prescribing and evaluate the interventions implemented to address inappropriate meropenem use. Result: A total of 113 patients were included: 34 in 2020, 41 in 2022, and 38 in 2023. Appropriate meropenem prescribing increased significantly from 23.5% in 2020 to 26.8% in 2022 and 57.9% in 2023 (p = 0.003), while inappropriate prescribing decreased from 76.5% to 73.2% and 42.1%, respectively. Treatment duration also differed significantly across study periods (p = 0.002), with courses of 7–10 days increasing from 24.2% in 2020 to 53.7% in 2022 and 52.6% in 2023, while courses exceeding 10 days decreased from 51.5% to 12.2% and 18.4%, respectively. Among inappropriate prescriptions, an inappropriate antimicrobial spectrum was the predominant reason (81.9%), with no inappropriate dosing identified. Documented stewardship interventions differed significantly across periods (p < 0.001): de-escalation increased from 0% in 2020 to 43.3% in 2022 and 50.0% in 2023, while prescriptions completed without documented intervention decreased from 69.2% to 23.3% and 18.8%, respectively. Conclusion: ASP implementation was associated with a significant improvement in the appropriateness of meropenem prescribing and a shift toward shorter treatment durations among adult ICU patients. Nevertheless, inappropriate prescribing remained substantial in the second post-implementation year, emphasizing the need for continued antimicrobial stewardship interventions and ongoing monitoring of carbapenem use.