This study provides a comprehensive computational exploration of the inhibitory activity and metabolic pathways of 8-methoxypsoralen (8-MP), a furocoumarin derivative used for treating various skin disorders, on cytochrome P450 (P450). Employing quantum chemical DFT calculations, molecular docking, and molecular dynamics (MD) simulations analyses, the biotransformation mechanisms and the active site binding profile of 8-MP in CYP1B1 were investigated. Three plausible inactivation mechanisms were minutely scrutinized. Further analysis explored the formation of reactive metabolites in subsequent P450 metabolic processes, including covalent adduct formation through nucleophilic addition to the epoxide, 8-MP epoxide hydrolysis, and non-CYP-catalyzed epoxide ring opening. Special attention was paid to the catalytic effect of residue Phe268 on the mechanism-based inactivation (MBI) of P450 by 8-MP. Energetic profiles and facilitating conditions revealed a slight preference for the C4′=C5′ epoxidation pathway, while recognizing a potential kinetic competition with the 8-OMe demethylation pathway due to comparable energy demands. The formation of covalent adducts via nucleophilic addition, particularly by phenylalanine, and the generation of potentially harmful reactive metabolites through autocatalyzed ring cleavage are likely to contribute significantly to P450 metabolism of 8-MP. Our findings highlight the key role of Phe268 in retaining 8-MP within the active site of CYP1B1, thereby facilitating initial oxygen addition transition states. This research offers crucial molecular-level insights that may guide the early stages of drug discovery and risk assessment related to the use of 8-MP.

The emergence of bacteria that are resistant to several antibiotics has represented a serious hazard to human health globally. Bioactive metabolites from medicinal plants have a wide spectrum of therapeutic possibilities against resistant bacteria. Therefore, this study was performed to investigate the antibacterial efficacy of various extracts of three medicinal plants as Salvia officinalis L., Ziziphus spina-christi L., and Hibiscus sabdariffa L. against pathogenic Gram-negative Enterobacter cloacae (ATCC13047), Pseudomonas aeruginosa (RCMB008001), Escherichia coli (RCMB004001), and Gram-positive Staphylococcus aureus (ATCC 25923), bacteria using the agar-well diffusion method. Results revealed that, out of the three examined plant extracts, the methanol extract of H. sabdariffa L. was the most effective against all tested bacteria. The highest growth inhibition (39.6 ± 0.20 mm) was recorded against E. coli. Additionally, the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of the methanol extract of H. sabdariffa were detected in the case of all tested bacteria. Moreover, an antibiotic susceptibility test revealed that all tested bacteria showed multidrug resistance (MDR). While 50% of tested bacteria were sensitive and 50% were intermediately sensitive to piperacillin/tazobactam (TZP) based on the inhibition zone but still less than the extract. Synergistic assay demonstrated the promising role of using a combination of H. sabdariffa L. and (TZP) against tested bacteria. A surface investigation using a scanning electron microscope of the E. coli treated with TZP, extract, or a combination of the two revealed extremely considerable bacterial cell death. In addition, H. sabdariffa L. has a promising anticancer role versus Caco-2 cells with IC₅₀ of 17.51 ± 0.07 µg/mL and minimal cytotoxicity upon testing versus Vero cells with CC₅₀ of 165.24 ± 0.89 µg/mL. Flow cytometric analysis confirmed that H. sabdariffa extract significantly increased the apoptotic rate of Caco-2-treated cells compared to the untreated group. Furthermore, GC-MS analysis confirmed the existence of various bioactive components in the methanol hibiscus extract. Utilizing molecular docking with the MOE-Dock tool, binding interactions between n-Hexadecanoic acid, hexadecanoic acid-methyl ester, and oleic acid, 3-hydroxypropyl ester were evaluated against the target crystal structures of E. coli (MenB) (PDB ID:3T88) and the structure of cyclophilin of a colon cancer cell line (PDB ID: 2HQ6). The observed results provide insight into how molecular modeling methods might inhibit the tested substances, which may have applications in the treatment of E. coli and colon cancer. Thus, H. sabdariffa methanol extract is a promising candidate to be further investigated for developing alternative natural therapies for infection treatment.

Background/Objectives: Myocardial infarction (MI) and diabetes pose significant health challenges globally, necessitating the development of innovative medication strategies to improve outcomes in affected populations. This research aimed to determine the defensive impact of ferulic acid (FA) against isoproterenol-induced myocardial infarction (MI) in diabetic rats. Methods: A group of male rats was partitioned into five distinct groups: control group, diabetic group, diabetic + MI, diabetic + MI + 20 mg/kg FA, and diabetic + MI + 40 mg/kg FA. The experimental groups received isoproterenol (ISO) subcutaneously at a dosage of 50 mg/kg body weight for two consecutive days. Results: The outcome was severe cardiac toxicity, as shown by changes in electrocardiogram (ECG) rhythm and a substantial increase in blood cardiac enzymes such as creatinine kinase (CK-MB), cardiac troponin I (cTnI), and lactate dehydrogenase (LDH). Additionally, there was a surge in inflammatory cytokines, like tumor necrosis factor-alpha (TNF-α), and a disruption of the antioxidant system, evidenced by a rise in malondialdehyde (MDA) content. Moreover, there was a rise in cardiac receptor of advanced glycation end products (RAGE). Treatment with FA with escalating dosages of 20 and 40 mg/kg b.w. effectively mitigated changes in serum cardiac enzymes and improved the cellular architecture, which was evaluated by histopathological examination. Conclusions: In conclusion, in a dose-dependent manner, FA successfully showed a cardioprotective effect against ISO-induced cardiac toxicity in diabetic rats, as shown by the improvement in ECG findings, normalization of serum cardiac biomarkers, and augmentation of the endogenous antioxidant system. Therefore, the aforementioned data indicate that ferulic acid may potentially have a protective effect on MI patients who have diabetes mellitus.

Green magnetite/carbonized spent coffee (MG/CFC) composite was synthesized from natural pyrite and characterized as an adsorbent and catalyst in photo-Fenton’s oxidation system of Congo red dye (C.R). The absorption behavior was illustrated based on the steric and energetic parameters of the advanced Monolayer equilibrium model of one energetic site (R² > 0.99). The structure exhibits 855 mg/g as effective site density which induces its C.R saturation adsorption capacity to 436.1 mg/g. The change in the number of absorbed C.R per site with temperature (n = 1.53 (293) to 0.51 (313 K)) suggests changes in the mechanism from multimolecular (up to 2 molecules per site) to multianchorage (one molecule per more than one site) processes. The energetic studies (ΔE = 6.2–8.2 kJ/mol) validate the physical uptake of C.R by MG/CFC which might be included van der Waals forces, electrostatic attractions, and hydrogen bonding. As a catalyst, MG/CFC exhibits significant activity during the photo-Fenton’s oxidation of C.R under visible light. The complete oxidation of C.R was detected after 105 min (5 mg/L), 120 min (10 mg/L), 135 min (15 mg/L), 180 min (20 mg/L), and 240 min (25 mg/L) using MG/CFC at 0.2 g/L dosage and 0.1 mL of H₂O₂. Increasing the dosage up to 0.5 g/L reduce the complete oxidation interval of C.R (5 mg/L) down to 30 min while the complete mineralization was detected after 120 min. The acute and chronic toxicities of the treated samples demonstrate significant safe products of no toxic effects on aquatic organisms as compared to the parent C.R solution.

Lead (Pb) is a common pollutant that is not biodegradable and gravely endangers the environment and human health. Annona squamosa fruit has a wide range of medicinal uses owing to its phytochemical constituents. This study evaluated the effect of treatment with A. squamosa fruit extract (ASFE) on testicular toxicity induced in male rats by lead acetate. The metal-chelating capacity and phytochemical composition of ASFE were determined. The LD₅₀ of ASFE was evaluated by probit analysis. Molecular docking simulations were performed using Auto Dock Vina. Forty male Sprague Dawley rats were equally divided into the following groups: Gp1, a negative control group; Gp2, given ASFE (350 mg/kg body weight (b. wt.)) (1/10 of LD₅₀); Gp3, given lead acetate (PbAc) solution (100 mg/kg b. wt.); and Gp4, given PbAc as in Gp3 and ASFE as in Gp2. All treatments were given by oro-gastric intubation daily for 30 days. Body weight changes, spermatological parameters, reproductive hormone levels, oxidative stress parameters, and inflammatory biomarkers were evaluated, and molecular and histopathological investigations were performed. The results showed that ASFE had promising metal-chelating activity and phytochemical composition. The LD₅₀ of ASFE was 3500 mg/kg b. wt. The docking analysis showed that quercetin demonstrated a high binding affinity for JAK-1 and STAT-3 proteins, and this could make it a more promising candidate for targeting the JAK-1/STAT-3 pathway than others. The rats given lead acetate had defective testicular tissues, with altered molecular, biochemical, and histological features, as well as impaired spermatological characteristics. Treatment with ASFE led to a significant mitigation of these dysfunctions and modulated the JAK-1/STAT-3/SOCS-1 axis in the rats.

Metronidazole is the primary antimicrobial drug for treating acute and chronic vaginal pathogens during pregnancy; however, there has been insufficient research on placental disorders, early pregnancy loss, and preterm birth. Here, the potential activity of metronidazole on pregnancy outcomes was investigated. 130 mg/kg body weight of metronidazole was orally given individually to pregnant rats on gestation days 0–7, 7–14, and 0–20. Pregnancy outcome evaluations were carried out on gestation day 20. It was demonstrated that metronidazole could induce maternal and fetal hepatotoxicity. There is a significant increase in the activities of maternal hepatic enzymes (ALT, AST, and ALP), total cholesterol, and triglycerides compared with the control. These biochemical findings were evidenced by maternal and fetal liver histopathological alterations. Furthermore, metronidazole caused a significant decrease in the number of implantation sites and fetal viability, whereas it caused an increase in fetal lethality and the number of fetal resorptions. In addition, a significant decrease in fetal weight, placental weight, and placental diameter was estimated. Macroscopical examination revealed placental discoloration and hypotrophy in the labyrinth zone and the degeneration of the basal zone. The fetal defects are related to exencephaly, visceral hernias, and tail defects. These findings suggest that the administration of metroniazole during gestation interferes with embryonic implantation and fetal organogenesis and enhances placental pathology. We can also conclude that metronidazole has potential maternal and fetal risks and is unsafe during pregnancy. Additionally, it should be strictly advised and prescribed, and further consideration should be given to the associated health risks.