Ameliorative effects of vanillin against pentylenetetrazole-induced epilepsy and associated memory loss in mice: The role of Nrf2/HO-1/NQO1 and HMGB1/RAGE/TLR4/NFκB pathways.

BACKGROUND: Epilepsy is a severe neurological disorder associated with substantial morbidity and mortality. Vanillin (Van) is a natural phenolic aldehyde with beneficial pharmacological properties. This study investigated the neuroprotective effects of Van in epilepsy and elucidated its mechanism of action. METHODS: Swiss albino mice were divided into the following five groups: "normal group", 0.9 % saline; "pentylenetetrazole (PTZ) group", intraperitoneal administration of 35 mg/kg PTZ on alternate days up to 42 days; and "PTZ + Van 20", "PTZ + Van 40", and "PTZ + sodium valproate (Val)" groups received PTZ injections in conjunction withVan 20 mg, Van 40 mg/kg, and Val 300 mg/kg, respectively. Behavioural tests and hippocampal histopathological analysis were performed in all groups. The Nrf2/HO-1/NQO1 and HMGB1/RAGE/TLR4/NFκB pathways, oxidative stress, neuro-inflammation, and apoptotic markers were analysed. Furthermore, brain acetylcholinesterase (AChE) activity and levels of dopamine (DA), gamma-aminobutyric acid GABA, and serotonin 5-HT were assessed. RESULTS: Van prolonged seizure manifestations and improved electroencephalogram (EEG)criteriain conjunction with 100 mg/kg PTZ once daily. Van administration increased Nrf2/HO-1/NQO1 levels, with subsequent attenuation of malondialdehyde (MDA) and nitric oxide (NO) levels with elevated glutathione (GSH) levels and intensified superoxide dismutase (SOD) and catalase activities. Van reduced the gene and protein expression of HMGB1/RAGE/TLR4/NFκB and decreased the levels of inflammatory and apoptotic markers. In addition, Van reduced AChE activity, and elevated glial fibrillary acidic proteins (GFAP) increased neurotransmitter and brain-derived neurotrophic factors (BDNF). CONCLUSION: By increasing Nrf2/HO-1/NQO1 levels and downregulating the HMGB1/RAGE/TLR4/ NFκB pathway, Van offered protection in PTZ-kindled mice with subsequent attenuation in lipid peroxidation, upregulation in antioxidant enzyme activities, and reduction in inflammation and apoptosis.

Zingiber officinale rhizome extracts mediated ni nanoparticles and its promising biomedical and environmental applications.

BACKGROUND: Zingiber officinale, generally known as ginger, contains bioactive phytochemicals, including gingerols and shogaols, that may function as reducing agents and stabilizers for the formation of nickel nanoparticles (Ni-NPs). Ginger extract-mediated nickel nanoparticles were synthesized using an eco-friendly method, and their antibacterial, antioxidant, antiparasitic, antidiabetic, anticancer, dye degrading, and biocompatibility properties were investigated. METHODS: UV-visible spectroscopy, fourier transform infrared spectroscopy, X-ray powder diffraction, energy-dispersive X-ray spectroscopy, and scanning electron microscopy were used to validate and characterize the synthesis of Ni-NPs. Agar well diffusion assay, alpha-amylase and glucosidase inhibitory assay, free radical scavenging assay, biocompatibility assay, and MTT assay were used to analyse the biomedical importance of Ni-NPs. RESULTS: SEM micrograph examinations revealed almost aggregates of Ni-NPs; certain particles were monodispersed and spherical, with an average grain size of 74.85 ± 2.5 nm. Ni-NPs have successfully inhibited the growth of Pseudomonas aeruginosa, Escherichia coli, and Proteus vulgaris by inducing membrane damage, as shown by the absorbance at 260 nm (A260). DPPH (2,2-diphenyl-1-picrylhydrazyl) free radicals were successfully scavenged by Ni-NPs at an inhibition rate of 69.35 ± 0.81% at 800 µg/mL. A dose-dependent cytotoxicity of Ni-NPs was observed against amastigote and promastigote forms of Leishmania tropica, with significant mortality rates of 94.23 ± 1.10 and 92.27 ± 1.20% at 1.0 mg/mL, respectively. Biocompatibility studies revealed the biosafe nature of Ni-NPs by showing RBC hemolysis up to 1.53 ± 0.81% at 400 µg/mL, which is considered safe according to the American Society for Materials and Testing (ASTM). Furthermore, Ni-NPs showed antidiabetic activity by inhibiting α-amylase and α-glucosidase enzymes at an inhibition rate of 22.70 ± 0.16% and 31.23 ± 0.64% at 200 µg/mL, respectively. Ni-NPs have shown significant cytotoxic activity by inhibiting MCF-7 cancerous cells up to 68.82 ± 1.82% at a concentration of 400 µg/mL. The IC50 for Ni-NPs was almost 190 µg/mL. Ni-NPs also degraded crystal violet dye up to 86.1% at 2 h of exposure. CONCLUSIONS: In conclusion, Zingiber officinale extract was found successful in producing stable nanoparticles. Ni-NPs have shown substantial biomedical activities, and as a result, we believe these nanoparticles have potential as a powerful therapeutic agent for use in nanomedicine.

Healthcare Professionals and Undergraduate Students' Knowledge Toward Drug-Food Interactions in the Eastern Region of Saudi Arabia.

Introduction: Drug and Food Interactions (DFI) arise when particular nutrients in food interact with drugs when consumed concurrently, consequently resulting in alterations in the pharmacokinetics, pharmacodynamics, and therapeutic effectiveness of the drug. This study aimed to evaluate the information and understanding of healthcare providers (HCPs) about common DFI. Methods: A cross-sectional study was achieved by a self-administered online-based questionnaire to gather data from HCPs in eastern region of Saudi Arabia between Sep. to Oct. 2022. The questionnaire integrated questions related to HCP demographic features and knowledge of DFI. The DFI section included questions that assessed the general knowledge of DFI and knowledge of specific food and drug interactions. Results: A total of 401 participants completed the study questionnaire; 41.4% were undergraduate students, 37.2% were pharmacists, 10.5% were nurses, and 9.5% were doctors. Unfortunately, HCPs are unable to recognize several food types that may interact with medications, which may lead to undesirable consequences associated with an enormous financial burden. For instance, only 27.9% of the HCPs stated that patients on monoamine oxidase inhibitors should avoid cheese. In addition, only approximately 11% of HCPs knew that patients on levothyroxine should avoid cauliflower, those taking digoxin should avoid wheat bran, those taking lithium should avoid cola, and those on heparin should avoid calcium-rich food. Overall knowledge was significantly higher among pharmacists and others HCPs with more than 5 years of experience. Discussion and Conclusion: This study demonstrated a low level of knowledge regarding specific food and drug interactions among healthcare providers in the eastern region of Saudi Arabia.

Multifunctional Spirogyra-hyalina-Mediated Barium Oxide Nanoparticles (BaONPs): Synthesis and Applications.

This research aims to biosynthesize Barium oxide nanoparticles (BaONPs) for biomedical applications, using Spirogyra hyalina as a stabilizing and reducing agent. UV-visible spectroscopy, Fourier transform infrared spectroscopy (FTIR), energy-dispersive X-ray, X-ray diffraction (XRD), and scanning electron microscopy (SEM) were used to physiochemically characterize the barium oxide nanoparticles, while antibacterial, minimum inhibitory concentration, antifungal, free radicle scavenging, and anti-inflammatory assay were performed to assess the therapeutic potential of the synthesized BaONPs. Fourier transform infrared spectroscopy revealed bands at 615 and 692 cm-1 that corresponded to the formation of BaONPs. Scanning electron microscopy revealed the spherical and flower-shaped morphology of BaONPs having an average diameter of 64.01 ± 2.0 nm. Both Gram-positive and Gram-negative bacterial growth was halted by the barium nanoparticles, demonstrating their efficacy up to 19.12 ± 0.31 mm against E. coli, 18.83 ± 0.44 mm against Klebsiella pneumoniae, 17.31 ± 0.59 mm against P. aeruginosa, 16.56 ± 0.37 mm against S. aureus, and 15.75 ± 0.38 mm against S. epidermidis, respectively. The minimum inhibitory concentration was 9.0, 6.3, 5.5, 4.5, and 2.0 µg/mL for S. aureus, Klebsiella pneumoniae, S. epidermidis, P. aeruginosa, and E. coli, respectively. BaONPs were not that effective against fungal strains such as Rhizoctonia solani, Fusarium solani, and Fusarium proliferatum. The BaONPs exhibited potent anti-inflammatory and antioxidant activity through inhibiting cyclooxygenases type 1 (43.12 ± 1.21%) and 2 (41.23 ± 1.56%), and DPPH free radicles up to 43.52 ± 0.29% at 400 µg/mL. In conclusion, the biomolecules derived from Spirogyra hyalina have demonstrated remarkable ability to generate stable nanoparticles, offering promising prospects for their utilization as therapeutic agents and coating materials in various biomedical applications.

Aceclofenac/Citronellol Oil Nanoemulsion Repurposing Study: Formulation, In Vitro Characterization, and In Silico Evaluation of Their Antiproliferative and Pro-Apoptotic Activity against Melanoma Cell Line.

Aceclofenac (ACF) is a widely used non-steroidal anti-inflammatory drug (NSAID) known for its effectiveness in treating pain and inflammation. Recent studies have demonstrated that ACF possesses antiproliferative properties, inhibiting the growth of cancer cells in various cancer cell lines. Citronellol, a monoterpenoid alcohol found in essential oils, exhibits antioxidant properties and activities such as inhibiting cell growth and acetylcholinesterase inhibition. In this study, the objective was to formulate and evaluate an aceclofenac/citronellol oil nanoemulsion for its antiproliferative effects on melanoma. The optimal concentrations of citronellol oil, Tween 80, and Transcutol HP were determined using a pseudoternary phase diagram. The formulated nanoemulsions were characterized for droplet size, zeta potential, thermophysical stability, and in vitro release. The selected formula (F1) consisted of citronellol oil (1 gm%), Tween 80 (4 gm%), and Transcutol HP (1 gm%). F1 exhibited a spherical appearance with high drug content, small droplet size, and acceptable negative zeta potential. The amorphous state of the drug in the nanoemulsion was confirmed by Differential Scanning Calorimetry, while FTIR analysis indicated its homogenous solubility. The nanoemulsion showed significant antiproliferative activity, with a lower IC50 value compared to aceclofenac or citronellol alone. Flow cytometric analysis revealed cell cycle arrest and increased apoptosis induced by the nanoemulsion. In silico studies provided insights into the molecular mechanism underlying the observed antitumor activity. In conclusion, the developed aceclofenac/citronellol oil nanoemulsion exhibited potent cytotoxicity and pro-apoptotic effects, suggesting its potential as a repurposed antiproliferative agent for melanoma treatment. In a future plan, further animal model research for validation is suggested.

Bio-Stimulant for Improving Simmondsia chinensis Secondary Metabolite Production, as Well as Antimicrobial Activity and Wound Healing Abilities.

Simmondsia chinensis is a dioecious, long-lived perennial shrub. Its leaves contain several antioxidant flavonoids that have numerous pharmacological effects. Various strategies have been explored to propagate jojoba with enhanced pharmacological values. This research evaluates the bio-stimulatory impacts of He-Ne laser seed irradiation on seed germination, plantlet growth, and alteration of the composition and bioactivities of phytochemicals in jojoba plants. Jojoba seeds were irradiated for 5, 10, and 15 min before in vitro germination. Germination, growth, and multiplication parameters were recorded during germination, multiple-shoot induction, and rooting stages. The wound healing and antimicrobial activities of methanolic extracts from plant lines obtained from the non-irradiated (control) and 10 min irradiated seeds were compared by excision wound model in Wistar male rats and zone of inhibition assay. Our study revealed that laser irradiation increased seed germination, with the highest percentage observed in seeds irradiated for 10 min. Plant lines from the 10 min irradiated seeds produced more explants with higher explant heights and numbers of leaves, more roots, and higher photosynthetic pigment contents than those of control and other laser testings. By comparing plant extracts from the control and 10 min treatments, we observed that extracts from the 10 min treatment exhibited higher percentages of wound contraction and shorter epithelialization periods. In addition, these extracts also resulted in higher levels of angiogenesis elements (VEGF, TGF-ß1, and HIF-1α) and reduced the inflammation regulators (IL-1ß, IL-6, TNF-α, and NFκB) in the experimental rats. In concordance, extracts from the 10 min treatment also explained raised antibacterial activities towards Staphylococcus aureus and Escherichia coli. Our findings show that pre-sowing seed treatment with a He-Ne laser (632.8 nm) could be a good technique for stimulating S. chinensis plant growth and increasing the impact compound levels and biological activities.

Antibacterial and Antibiofilm Activity of Ficus carica-Mediated Calcium Oxide (CaONPs) Phyto-Nanoparticles.

The significance of nanomaterials in biomedicines served as the inspiration for the design of this study. In this particular investigation, we carried out the biosynthesis of calcium oxide nanoparticles (CaONPs) by employing a green-chemistry strategy and making use of an extract of Ficus carica (an edible fruit) as a capping and reducing agent. There is a dire need for new antimicrobial agents due to the alarming rise in antibiotic resistance. Nanoparticles' diverse antibacterial properties suggest that they might be standard alternatives to antimicrobial drugs in the future. We describe herein the use of a Ficus carica extract as a capping and reducing agent in the phyto-mediated synthesis of CaONPs for the evaluation of their antimicrobial properties. The phyto-mediated synthesis of NPs is considered a reliable approach due to its high yield, stability, non-toxicity, cost-effectiveness and eco-friendliness. The CaONPs were physiochemically characterized by UV-visible spectroscopy, energy-dispersive X-ray (EDX), scanning-electron microscopy (SEM), X-ray diffraction (XRD), and Fourier-transform infrared spectroscopy (FTIR). The biological synthesis of the calcium oxide nanoparticles revealed a characteristic surface plasmon resonance peak (SPR) at 360 nm in UV-Vis spectroscopy, which clearly revealed the successful reduction of the Ca2+ ions to Ca0 nanoparticles. The characteristic FTIR peak seen at 767 cm-1 corresponded to Ca-O bond stretching and, thus, confirmed the biosynthesis of the CaONPs, while the scanning-electron micrographs revealed near-CaO aggregates with an average diameter of 84.87 ± 2.0 nm. The antibacterial and anti-biofilm analysis of the CaONPs showed inhibition of bacteria in the following order: P. aeruginosa (28 ± 1.0) > S. aureus (23 ± 0.3) > K. pneumoniae (18 ± 0.9) > P. vulgaris (13 ± 1.6) > E. coli (11 ± 0.5) mm. The CaONPs were shown to considerably inhibit biofilm formation, providing strong evidence for their major antibacterial activity. It is concluded that this straightforward environmentally friendly method is capable of synthesizing stable and effective CaONPs. The therapeutic value of CaONPs is indicated by their potential as a antibacterial and antibiofilm agents in future medications.

Cognitive enhancing effects of pazopanib in D­galactose/ovariectomized Alzheimer's rat model: insights into the role of RIPK1/RIPK3/MLKL necroptosis signaling pathway.

Necroptosis, a programmed form of necrotic cell death carried out by receptor-interacting serine/threonine protein kinase 1 (RIPK1) and RIPK3, has been found to be implicated in the pathogenesis of Alzheimer's disease (AD). An FDA-approved anti-cancer drug, pazopanib, is reported to possess potent inhibitory effect against necroptosis via interfering with RIPK1. So far, there are no existing data on the influence of pazopanib on necroptotic pathway in AD. Thus, this study was designed to explore the impact of pazopanib on cognitive impairment provoked by ovariectomy (OVX) together with D-galactose (D-Gal) administration in rats and to scrutinize the putative signaling pathways underlying pazopanib-induced effects. Animals were allocated into four groups; the first and second groups were exposed to sham operation and administered normal saline and pazopanib (5 mg/kg/day, i.p.), respectively, for 6 weeks, while the third and fourth groups underwent OVX then were injected with D-Gal (150 mg/kg/day, i.p.); concomitantly with pazopanib in the fourth group for 6 weeks. Pazopanib ameliorated cognitive deficits as manifested by improved performance in the Morris water maze besides reversing the histological abnormalities. Pazopanib produced a significant decline in p-Tau and amyloid beta (Aß) plaques. The neuroprotective effect of pazopanib was revealed by hampering neuroinflammation, mitigating neuronal death and suppressing RIPK1/RIPK3/MLKL necroptosis signaling pathway. Accordingly, hindering neuroinflammation and the necroptotic RIPK1/RIPK3/MLKL pathway could contribute to the neuroprotective effect of pazopanib in D-Gal/OVX rat model. Therefore, this study reveals pazopanib as a valuable therapeutic agent in AD that warrants future inspection to provide further data regarding its neuroprotective effect.

Identification of Novel Cyclooxygenase-1 Selective Inhibitors of Thiadiazole-Based Scaffold as Potent Anti-Inflammatory Agents with Safety Gastric and Cytotoxic Profile.

Major obstacles faced by the use of nonsteroidal anti-inflammatory drugs (NSAID) are their gastrointestinal toxicity induced by non-selective inhibition of both cyclooxygenases (COX) 1 and 2 and their cardiotoxicity associated with a certain class of COX-2 selective inhibitors. Recent studies have demonstrated that selective COX-1 and COX-2 inhibition generates compounds with no gastric damage. The aim of the current study is to develop novel anti-inflammatory agents with a better gastric profile. In our previous paper, we investigated the anti-inflammatory activity of 4-methylthiazole-based thiazolidinones. Thus, based on these observations, herein we report the evaluation of anti-inflammatory activity, drug action, ulcerogenicity and cytotoxicity of a series of 5-adamantylthiadiazole-based thiazolidinone derivatives. The in vivo anti-inflammatory activity revealed that the compounds possessed moderate to excellent anti-inflammatory activity. Four compounds 3, 4, 10 and 11 showed highest potency (62.0, 66.7, 55.8 and 60.0%, respectively), which was higher than the control drug indomethacin (47.0%). To determine their possible mode of action, the enzymatic assay was conducted against COX-1, COX-2 and LOX. The biological results demonstrated that these compounds are effective COX-1 inhibitors. Thus, the IC50 values of the three most active compounds 3, 4 and 14 as COX-1 inhibitors were 1.08, 1.12 and 9.62 µΜ, respectively, compared to ibuprofen (12.7 µΜ) and naproxen (40.10 µΜ) used as control drugs. Moreover, the ulcerogenic effect of the best compounds 3, 4 and 14 were evaluated and revealed that no gastric damage was observed. Furthermore, compounds were found to be nontoxic. A molecular modeling study provided molecular insight to rationalize the COX selectivity. In summary, we discovered a novel class of selective COX-1 inhibitors that could be effectively used as potential anti-inflammatory agents.

Anethole Pretreatment Modulates Cerebral Ischemia/Reperfusion: The Role of JNK, p38, MMP-2 and MMP-9 Pathways.

Anethole (AN) is one of the major constituents of several plant oils, demonstrating plentiful pharmacological actions. Ischemic stroke is the main cause of morbidity and death worldwide, particularly since ischemic stroke therapeutic choices are inadequate and limited; thus, the development of new therapeutic options is indispensable. This study was planned to explore the preventive actions of AN in ameliorating cerebral ischemia/reperfusion-induced brain damage and BBB permeability leakage, as well as to explore anethole's potential mechanisms of action. The proposed mechanisms included modulating JNK and p38 as well as MMP-2 and MMP-9 pathways. Sprague-Dawley male rats were randomly assigned into four groups: sham, middle cerebral artery occlusion (MCAO), AN125 + MCAO, and AN250 + MCAO. Animals in the third and fourth groups were pretreated with AN 125 or 250 mg/kg orally, respectively, for two weeks before performing middle cerebral artery occlusion (MCAO)-induced cerebral ischemic/reperfusion surgery. Animals that experienced cerebral ischemia/reperfusion exhibited amplified infarct volume, Evans blue intensity, brain water content, Fluoro-Jade B-positive cells, severe neurological deficits, and numerous histopathological alterations. MCAO animals exhibited elevated MMP-9 and MMP-2 gene expressions, enzyme activities, augmented JNK, and p38 phosphorylation. On the other hand, pretreatment with AN diminished the infarct volume, Evans blue dye intensity, brain water content, and Fluoro-Jade B-positive cells, improved the neurological score and enhanced histopathological examination. AN effectively lowered MMP-9 and MMP-2 gene expression and enzyme activities and diminished phosphorylated JNK, p38. AN decreased MDA content, amplified GSH/GSSG ratio, SOD, and CAT, decreased the serum and brain tissue homogenate inflammatory cytokines (TNF-α, IL-6, IL-1ß), NF-κB, and deterred the apoptotic status. This study revealed the neuroprotective ability of AN against cerebral ischemia/reperfusion in rats. AN boosted blood-brain barrier integrity via modulating MMPs and diminished oxidative stress, inflammation, and apoptosis through the JNK/p38 pathway.

The Hepatoprotective Effect of Two Date Palm Fruit Cultivars' Extracts: Green Optimization of the Extraction Process.

Date palm fruit (Phoenix dactylifera: Arecaceae) is rich in essential nutrients and possesses several pharmacological and medicinal activities. The current study aimed to optimize a water bath-assisted extraction method for two cultivars of date palm fruits, Anbara (An) and Reziz (Rz), and investigated the protective effect of the optimized date palm fruit extract against CCl4-induced liver toxicity in relation to oxidative stress, inflammation, apoptosis, and DNA integrity. The optimization process of two date palm fruit cultivars was applied, using response surface methodology through adjusting three "factors"; time, temperature, and rotation, to allow maximum contents of total phenolic (TPC), total flavonoid (TFC), reducing power (FRAP) and scavenging activity (ABTS) of the extract "responses". Extraction factors' application significantly enhanced TPC, TFC, FRAP, and ABTS responses by 1.30, 1.23, 3.03, and 2.06-fold, respectively in An and 2.18, 1.71, 1.11, and 2.62-fold, respectively in Rz, in relation to the convectional water extraction. Furthermore, co-administered CCl4 with An or Rz optimized extracts enhanced body weight gain, amended hepatic architecture, and diminished collagen fiber accumulation. Furthermore, An or Rz extracts reduced liver enzymes, hydroxyproline, alpha-fetoprotein (AFP), MDA, inflammatory cytokine (TNF-α, NF-κB) levels, and DNA fragmentation, while increasing deteriorated adiponectin (ADP) and antioxidant enzyme (GSH, GPX, NO, and IFN-γ) levels, relative to CCl4-administered animals. The protective effects of An or Rz-optimized extracts were also evidenced by suppressing hepatic fibrosis and improving liver function and structure via modulating oxidative stress, inflammation, and apoptosis, in CCl4-induced hepatic damage. Hence, the optimized extraction process for the two date palm fruits resulted in extracts which are rich in phenolic and flavonoid contents and with an elevated antioxidant power. The presence of these rich extracts could help to explain their proven hepatoprotective activity against CCl4-induced liver toxicity.

Hypericum perforatum L. Nanoemulsion Mitigates Cisplatin-Induced Chemobrain via Reducing Neurobehavioral Alterations, Oxidative Stress, Neuroinflammation, and Apoptosis in Adult Rats.

Cisplatin (Cis) is a potent chemotherapeutic agent; however, it is linked with oxidative stress, inflammation, and apoptosis, which may harmfully affect the brain. Hypericum perforatum L. (HP L.) is a strong medicinal plant, but its hydrophobic polyphenolic compounds limit its activity. Therefore, our study aimed to investigate the neuroprotective action of HP L. and its nanoemulsion (NE) against Cis-induced neurotoxicity. The prepared HP.NE was subjected to characterization. The droplet size distribution, surface charge, and morphology were evaluated. In addition, an in vitro dissolution study was conducted. Compared to Cis-intoxicated rats, HP L. and HP.NE-treated rats displayed improved motor activity and spatial working memory. They also showed an increase in their antioxidant defense system and a reduction in the levels of pro-inflammatory cytokines in the brain. Moreover, they showed an increase in the expression levels of the PON-3 and GPX genes, which are associated with a reduction in the brain levels of COX-2 and TP-53. These findings were confirmed by reducing the immunohistochemical expression of nuclear factor kappa (NF-ƘB) and enhanced Ki-67 levels. In conclusion, HP L. is a promising herb and could be used as an adjuvant candidate to ameliorate chemotherapeutic-induced neurotoxicity. Moreover, HP.NE has superior activity in lessening Cis-induced oxidative stress, inflammation, and apoptosis in brain tissue.

Myrrh Essential Oil Mitigates Renal Ischemia/Reperfusion-Induced Injury.

BACKGROUND: Ischemia/reperfusion (I/R)-induced renal injury is a common reason for kidney injury in clinical settings; therefore, continuous investigation of novel nephroprotective agents is crucial. Myrrh, the oleoresin exudates generated by the genus Commiphora, display numerous pharmacological actions. This study tried to assess the preventive effects of myrrh essential oil against I/R-induced renal damage. METHODS: Rats were randomized into five groups. In the sham group, the animals were subjected to bilateral renal artery separation with no occlusion. In the sham + myrrh group; the rats were administered myrrh essential oil and then treated similarly to the sham group. Renal I/R group: the animals were challenged with renal I/R. In the myrrh + renal I/R groups, rats were administered 50 or 100 mg/kg of myrrh essential oil orally for three weeks before being confronted with I/R. RESULTS: Serum levels of renal function tests and renal injury biomarkers, including NGAL, KIM-1, and CysC, were amplified in the renal I/R group. Animals that experienced renal I/R exhibited elevated lipid peroxidation (MDA); declined SOD, CAT, and GPx activity; declined GSH content; augmented TLR4/NFκB gene expression; and subsequent enhancement of inflammatory mediators (TNF-α, IFN-γ, IL-1ß, and IL-6). Myrrh reduced renal function tests and injury biomarkers and amended renal histological alterations. Pretreatment with myrrh reduced MDA, elevated the antioxidant enzymes' activities and GSH content, and reduced the TLR4 and NFκB gene expression, leading to subsequent inflammation and apoptosis alleviation. CONCLUSIONS: The outcomes of the present investigation established the protective effect of myrrh essential oil against renal I/R via pointing out the antioxidant, anti-inflammatory, and anti-apoptotic effects of myrrh.

Diosmin Mitigates Gentamicin-Induced Nephrotoxicity in Rats: Insights on miR-21 and -155 Expression, Nrf2/HO-1 and p38-MAPK/NF-κB Pathways.

Gentamicin (GNT) is the most frequently used aminoglycoside. However, its therapeutic efficacy is limited due to nephrotoxicity. Thus, the potential anticipatory effect of Diosmin (DIOS) against GNT-prompted kidney damage in rats together with the putative nephroprotective pathways were scrutinized. Four groups of rats were used: (1) control; (2) GNT only; (3) GNT plus DIOS; and (4) DIOS only. Nephrotoxicity was elucidated, and the microRNA-21 (miR-21) and microRNA-155 (miR-155) expression and Nrf2/HO-1 and p38-MAPK/NF-κB pathways were assessed. GNT provoked an upsurge in the relative kidney weight and serum level of urea, creatinine, and KIM-1. The MDA level was markedly boosted, with a decline in the level of TAC, SOD, HO-1, and Nrf2 expression in the renal tissue. Additionally, GNT exhibited a notable amplification in TNF-α, IL-1ß, NF-κB p65, and p38-MAPK kidney levels. Moreover, caspase-3 and BAX expression were elevated, whereas the Bcl-2 level was reduced. Furthermore, GNT resulted in the down-regulation of miR-21 expression along with an up-regulation of the miR-155 expression. Histological examination revealed inflammation, degradation, and necrosis. GNT-provoked pathological abnormalities were reversed by DIOS treatment, which restored normal kidney architecture. Hence, regulating miR-21 and -155 expression and modulating Nrf2/HO-1 and p38-MAPK/NF-κB pathways could take a vital part in mediating the reno-protective effect of DIOS.

Discovery of novel enasidenib analogues targeting inhibition of mutant isocitrate dehydrogenase 2 as antileukaemic agents.

Mutant isocitrate dehydrogenase (IDH) 2 "IDH2m" acquires a neo-enzymatic activity reducing α-ketoglutarate to an oncometabolite, D-2-hydroxyglutarate (2-HG). Three s-triazine series were designed and synthesised using enasidenib as a lead compound. In vitro anticancer screening via National Cancer Institute "NCI" revealed that analogues 6a, 6c, 6d, 7g, and 7l were most potent, with mean growth inhibition percentage "GI%" = 66.07, 66.00, 53.70, 35.10, and 81.15, respectively, followed by five-dose screening. Compounds 6c, 6e, and 7c were established as the best IDH2R140Q inhibitors compared to enasidenib, reporting IC50 = 101.70, 67.01, 88.93, and 75.51 nM, respectively. More importantly, 6c, 6e, and 7c displayed poor activity against the wild-type IDH2, IC50 = 2928, 2295, and 3128 nM, respectively, which implementing high selectivity and accordingly safety. Furthermore, 6c was screened for cell cycle arrest, apoptosis induction, and western blot analysis. Finally, computational tools were applied to predict physicochemical properties and binding poses in IDH2R140Q allosteric site.

The Synergistic Hepatoprotective Activity of Rosemary Essential Oil and Curcumin: The Role of the MEK/ERK Pathway.

BACKGROUND: Curcumin is a natural product obtained from the rhizome of Curcuma longa. Rosemary (Rosmarinus officinalis) is a medicinal and aromatic plant that is widely spread in the Mediterranean region. Both Curcumin and rosemary essential oil are natural products of high medicinal and pharmacological significance. The hepatoprotective effect of both natural products is well-established; however, the mechanism of such action is not fully understood. Thus, this study is an attempt to explore the hepatoprotective mechanism of action of these remedies through their effect on MEK and ERK proteins. Furthermore, the effect of rosemary essential oil on the plasma concentration of curcumin has been scrutinized. MATERIALS AND METHODS: The major constituents of REO were qualitatively and quantitatively determined by GC/MS and GC/FID, respectively. Curcumin and rosemary essential oil were given to mice in a pre-treatment model, followed by induction of liver injury through a high dose of paracetamol. Serum liver enzymes, lipid peroxidation, antioxidant activities, the inflammatory and apoptotic biomarkers, as well as the MEK and ERK portions, were verified. The plasma levels of curcumin were determined in the presence and absence of rosemary essential oil. RESULTS: The major constituents of REO were 1,8-cineole (51.52%), camphor (10.52%), and α-pinene (8.41%). The results revealed a superior hepatoprotective activity of the combination when compared to each natural product alone, as demonstrated by the lowered liver enzymes, lipid peroxidation, mitigated inflammatory and apoptotic biomarkers, and enhanced antioxidant activities. Furthermore, the combination induced the overexpression of MEK and ERK proteins, providing evidence for the involvement of this cascade in the hepatoprotective activity of such natural products. The administration of rosemary essential oil with curcumin enhanced the curcuminoid plasma level. CONCLUSION: The co-administration of both curcumin and rosemary essential oil together enhanced both their hepatoprotective activity and the level of curcumin in plasma, indicating a synergistic activity between both natural products.

Achillea millefolium Essential Oil Mitigates Peptic Ulcer in Rats through Nrf2/HO-1 Pathway.

Extreme ethanol ingestion is associated with developing gastric ulcers. Achillea millefolium (yarrow) is one of the most commonly used herbs with numerous proven pharmacological actions. The goal of the hereby investigation is to explore the gastroprotective action of yarrow essential oil against ethanol-induced gastric ulcers and to reveal the unexplored mechanisms. Rats were distributed into five groups (n = 6); the control group administered 10% Tween 20, orally, for two weeks; the ethanol group administered absolute ethanol (5 mL/kg) to prompt gastric ulcer on the last day of the experiment. Yarrow essential oil 100 or 200 mg/kg + ethanol groups pretreated with yarrow oil (100 or 200 mg/kg, respectively), orally, for two weeks prior to gastric ulcer induction by absolute ethanol. Lanso + ethanol group administered 20 mg/kg lansoprazole, orally, for two weeks prior to gastric ulcer induction by ethanol. Results of the current study showed that ethanol caused several macroscopic and microscopic alterations, amplified lipid peroxidation, pro-inflammatory cytokines, and apoptotic markers, as well as diminished PGE2, NO, and antioxidant enzyme activities. On the other hand, animals pretreated with yarrow essential oil exhibited fewer macroscopic and microscopic modifications, reduced ulcer surface, and increased Alcian blue binding capacity, pH, and pepsin activity. In addition, yarrow essential oil groups exhibited reduced pro-inflammatory cytokines, apoptotic markers, and MDA, restored the PGE2 and NO levels, and recovered the antioxidant enzyme activities. Ethanol escalated Nrf2 and HO-1 expressions, whereas pretreatment of yarrow essential oil caused further intensification in Nrf2 and HO-1. To conclude, the current study suggested yarrow essential oil as a gastroprotective agent against ethanol-induced gastric lesions. This gastroprotective effect could be related to the antioxidant, anti-inflammatory, and anti-apoptotic actions of the essential oil through the instigation of the Nrf2/HO-1 pathway.

Cardamom Extract Alleviates the Oxidative Stress, Inflammation and Apoptosis Induced during Acetaminophen-Induced Hepatic Toxicity via Modulating Nrf2/HO-1/NQO-1 Pathway.

Acetaminophen (APAP) is the most extensively used and safest analgesic and antipyretic drug worldwide; however, its toxicity is associated with life-threatening acute liver failure. Cardamom (CARD), a sweet, aromatic, commonly used spice, has several pharmacological actions. In the current study, we tried to explore the chemical composition and the hepato-protective effect of ethanolic aqueous extract of CARD to mitigate APAP-induced hepatic toxicity and elucidate its underlying mechanism of action. MATERIAL AND METHODS: Aqueous CARD extract was subjected to LC-TOF-MS analysis to separate and elucidate some of its components. In vivo animal experiments involved five groups of animals. In the normal and cardamom groups, mice were administered either saline or CARD (200 mg/kg), respectively, orally daily for 16 days. In the APAP group, the animals were administered saline orally daily for 15 days, and on the 16th day, animals were administered APAP (300 mg/kg) IP for the induction of acute hepatic failure. In the CARD 200 + APAP group, mice were administered CARD (200 mg/kg) for 15 days, followed by APAP on the 16th day. RESULTS: The aqueous extract of CARD showed several compounds, belonging to polyphenol, flavonoids, cinnamic acid derivatives and essential oil components. In the in vivo investigations, APAP-induced impaired liver function, several histopathological alterations, oxidative stress and inflammatory and apoptotic status signified severe hepatic failure. Whereas, pretreatment with the CARD extract prior to APAP administration diminished serum levels of the hepatic function test and augmented Nrf2 nucleoprotein and HO-1 and NQO-1. CARD down-regulated MDA, inflammatory mediators (IL-1ß, IL-6, TNF-α and NF-κB) and apoptotic markers (caspase 3 and 9 and Bax) and amplified the activities of SOD, catalase, GSH-Px and GSH-R in hepatic tissue samples. CONCLUSION: CARD extract mitigated the hepatic toxicity induced by APAP. The underlying mechanism of action of such hepato-protective action may be through upregulation of the Nrf2/HO-1/NQO-1 pathway with subsequent alleviation of the oxidative stress, inflammation and apoptosis induced by APAP. Many of the compounds identified in the CARD extract could be attributed to this pharmacological action of the extract.

Ameliorative Effect of D-Carvone against Hepatic Ischemia-Reperfusion-Induced Injury in Rats.

BACKGROUND: D-carvone is a monoterpene that exists in the essential oils of several plant species. Hepatic ischemia-reperfusion (Hep I/R) takes place clinically during different scenarios of liver pathologies. The aim of the current investigation is to disclose the hepato-protective actions of carvone against Hep I/R-induced damage and to reveal the underlying mechanism. MATERIAL AND METHODS: Rats were assigned into five groups: sham and carvone plus sham groups, in which rats were administered either saline or carvone orally for three weeks prior to the induction of Hep I/R. In the Hep I/R group, rats were administered saline orally prior to the Hep I/R induction operation. The carvone 25 plus Hep I/R and Carvone 50 plus Hep I/R groups were administered carvone (25 and 50 mg/kg, respectively) for three weeks, followed by the induction of Hep I/R. RESULTS: Liver ischemic animals demonstrated impaired liver function, several histopathological variations, and reduced levels of antioxidant enzyme activities. Furthermore, the Hep I/R groups showed the elevated gene expression of high-mobility group box 1 (HMGB1), toll-like receptors 4 (TLR4), nuclear factor kappa B (NFκB), and LR family pyrin domain containing 3 (NLP3), with subsequent escalated adhesion molecule 1 (ICAM-1), neutrophil infiltration, and several inflammatory mediators, including interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α), as well as apoptotic markers. Pretreatment with D-carvone alleviated ischemia/reperfusion-induced impaired liver function, diminished the histopathological deviations, and augmented the antioxidant enzymes. In addition, D-carvone mitigated the gene expression of HMGB1, TLR4, NFκB, and NLP3, with a subsequent reduction in ICAM-1, neutrophils infiltration, inflammatory mediators, and apoptotic markers. CONCLUSION: Rats pretreated with D-carvone exhibited hepato-protective actions against Hep I/R-induced damage via the downregulation of HMGB1, TLR4, NFκB, NLP3, associated inflammatory mediators, and apoptotic markers.