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.

Omicron variant genome evolution and phylogenetics.

Following the discovery of the SARS-CoV-2 Omicron variant (B.1.1.529), the global COVID-19 outbreak has resurfaced after appearing to be relentlessly spreading over the past 2 years. This new variant showed marked degree of mutation, compared with the previous SARS-CoV-2 variants. This study investigates the evolutionary links between Omicron variant and recently emerged SARS-CoV-2 variants. The entire genome sequences of SARS-CoV-2 variants were obtained, aligned using Clustal Omega, pairwise comparison was computed, differences, identity percent, gaps, and mutations were noted, and the identity matrix was generated. The phylogenetics of Omicron variants were determined using a variety of evolutionary substitution models. The ultrametric and metric clustering methods, such as UPGMA and neighbor-joining (NJ), using nucleotide substitution models that allowed the inclusion of nucleotide transitions and transversions as Kimura 80 models, revealed that the Omicron variant forms a new monophyletic clade that is distant from other SARS-CoV-2 variants. In contrast, the NJ method using a basic nucleotide substitution model such as Jukes-Cantor revealed a close relationship between the Omicron variant and the recently evolved Alpha variant. Based on the percentage of sequence identity, the closest variants were in the following order: Omicron, Alpha, Gamma, Delta, Beta, Mu, and then the SARS-CoV-2 USA isolate. A genome alignment with other variants indicated the greatest number of gaps in the Omicron variant's genome ranging from 43 to 63 gaps. It is possible, given their close relationship to the Alpha variety, that Omicron has been around for much longer than predicted, even though they created a separate monophyletic group. Sequencing initiatives in a systematic and comprehensive manner is highly recommended to study the evolution and mutations of the virus.

Green Synthesis of Silver Nanoparticles by the Cyanobacteria Synechocystis sp.: Characterization, Antimicrobial and Diabetic Wound-Healing Actions.

Green nanotechnology is now accepted as an environmentally friendly and cost-effective advance with various biomedical applications. The cyanobacterium Synechocystis sp. is a unicellular spherical cyanobacterium with photo- and hetero-trophic capabilities. This study investigates the ability of this cyanobacterial species to produce silver nanoparticles (AgNPs) and the wound-healing properties of the produced nanoparticles in diabetic animals. METHODS: UV-visible and FT-IR spectroscopy and and electron microscopy techniques investigated AgNPs' producibility by Synechocystis sp. when supplemented with silver ion source. The produced AgNPs were evaluated for their antimicrobial, anti-oxidative, anti-inflammatory, and diabetic wound healing along with their angiogenesis potential. RESULTS: The cyanobacterium biosynthesized spherical AgNPs with a diameter range of 10 to 35 nm. The produced AgNPs exhibited wound-healing properties verified with increased contraction percentage, tensile strength and hydroxyproline level in incision diabetic wounded animals. AgNPs treatment decreased epithelialization period, amplified the wound closure percentage, and elevated collagen, hydroxyproline and hexosamine contents, which improved angiogenesis factors' contents (HIF-1α, TGF-ß1 and VEGF) in excision wound models. AgNPs intensified catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities, and glutathione (GSH) and nitric oxide content and reduced malondialdehyde (MDA) level. IL-1ß, IL-6, TNF-α, and NF-κB (the inflammatory mediators) were decreased with AgNPs' topical application. CONCLUSION: Biosynthesized AgNPs via Synechocystis sp. exhibited antimicrobial, anti-oxidative, anti-inflammatory, and angiogenesis promoting effects in diabetic wounded animals.

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.

Geraniol Averts Methotrexate-Induced Acute Kidney Injury via Keap1/Nrf2/HO-1 and MAPK/NF-κB Pathways.

OBJECTIVES: Geraniol, a natural monoterpene, is an essential oil component of many plants. Methotrexate is an anti-metabolite drug, used for cancer and autoimmune conditions; however, clinical uses of methotrexate are limited by its concomitant renal injury. This study investigated the efficacy of geraniol to prevent methotrexate-induced acute kidney injury and via scrutinizing the Keap1/Nrf2/HO-1, P38MAPK/NF-κB and Bax/Bcl2/caspase-3 and -9 pathways. METHODS: Male Wister rats were allocated into five groups: control, geraniol (orally), methotrexate (IP), methotrexate and geraniol (100 and 200 mg/kg). RESULTS: Geraniol effectively reduced the serum levels of creatinine, urea and Kim-1 with an increase in the serum level of albumin when compared to the methotrexate-treated group. Geraniol reduced Keap1, escalated Nrf2 and HO-1, enhanced the antioxidant parameters GSH, SOD, CAT and GSHPx and reduced MDA and NO. Geraniol decreased renal P38 MAPK and NF-κB and ameliorated the inflammatory mediators TNF-α, IL-1ß, IL-6 and IL-10. Geraniol negatively regulated the apoptotic mediators Bax and caspase-3 and -9 and increased Bcl2. All the biochemical findings were supported by the alleviation of histopathological changes in kidney tissues. CONCLUSION: The current findings support that co-administration of geraniol with methotrexate may attenuate methotrexate-induced acute kidney injury.

Kaempferol Inhibits Zearalenone-Induced Oxidative Stress and Apoptosis via the PI3K/Akt-Mediated Nrf2 Signaling Pathway: In Vitro and In Vivo Studies.

In this study, kaempferol (KFL) shows hepatoprotective activity against zearalenone (ZEA)-induced oxidative stress and its underlying mechanisms in in vitro and in vivo models were investigated. Oxidative stress plays a critical role in the pathophysiology of various hepatic ailments and is normally regulated by reactive oxygen species (ROS). ZEA is a mycotoxin known to exert toxicity via inflammation and ROS accumulation. This study aims to explore the protective role of KFL against ZEA-triggered hepatic injury via the PI3K/Akt-regulated Nrf2 pathway. KFL augmented the phosphorylation of PI3K and Akt, which may stimulate antioxidative and antiapoptotic signaling in hepatic cells. KFL upregulated Nrf2 phosphorylation and the expression of antioxidant genes HO-1 and NQO-1 in a dose-dependent manner under ZEA-induced oxidative stress. Nrf2 knockdown via small-interfering RNA (siRNA) inhibited the KFL-mediated defence against ZEA-induced hepatotoxicity. In vivo studies showed that KFL decreased inflammation and lipid peroxidation and increased H2O2 scavenging and biochemical marker enzyme expression. KFL was able to normalize the expression of liver antioxidant enzymes SOD, CAT and GSH and showed a protective effect against ZEA-induced pathophysiology in the livers of mice. These outcomes demonstrate that KFL possesses notable hepatoprotective roles against ZEA-induced damage in vivo and in vitro. These protective properties of KFL may occur through the stimulation of Nrf2/HO-1 cascades and PI3K/Akt signaling.

Cyanobacteria as Nanogold Factories II: Chemical Reactivity and anti-Myocardial Infraction Properties of Customized Gold Nanoparticles Biosynthesized by Cyanothece sp.

Cyanothece sp., a coccoid, unicellular, nitrogen-fixing and hydrogen-producing cyanobacterium, has been used in this study to biosynthesize customized gold nanoparticles under certain chemical conditions. The produced gold nanoparticles had a characteristic absorption band at 525-535 nm. Two types of gold nanoparticle, the purple and blue, were formed according to the chemical environment in which the cyanobacterium was grown. Dynamic light scattering was implemented to estimate the size of the purple and blue nanoparticles, which ranged from 80 ± 30 nm and 129 ± 40 nm in diameter, respectively. The highest scattering of laser light was recorded for the blue gold nanoparticles, which was possibly due to their larger size and higher concentration. The appearance of anodic and cathodic peaks in cyclic voltammetric scans of the blue gold nanoparticles reflected the oxidation into gold oxide, followed by the subsequent reduction into the nano metal state. The two produced forms of gold nanoparticles were used to treat isoproterenol-induced myocardial infarction in experimental rats. Both forms of nanoparticles ameliorated myocardial infarction injury, with a slight difference in their curative activity with the purple being more effective. Mechanisms that might explain the curative effect of these nanoparticles on the myocardial infarction were proposed. The morphological, physiological, and biochemical attributes of the Cyanothece sp. cyanobacterium were fundamental for the successful production of "tailored" nanoparticles, and complemented the chemical conditions for the differential biosynthesis process. The present research represents a novel approach to manipulate cyanobacterial cells towards the production of different-sized gold nanoparticles whose curative impacts vary accordingly. This is the first report on that type of manipulated gold nanoparticles biosynthesis which will hopefully open doors for further investigations and biotechnological applications.

ß-Caryophyllene as a Potential Protective Agent Against Myocardial Injury: The Role of Toll-Like Receptors.

Myocardial infarction (MI) remains one of the major causes of mortality around the world. A possible mechanism involved in myocardial infarction is the engagement of Toll-like receptors (TLRs). This study was intended to discover the prospective cardioprotective actions of ß-caryophyllene, a natural sesquiterpene, to ameliorate isoproterenol (ISO)-induced myocardial infarction through HSP-60/TLR/MyD88/NFκB pathway. ß-Caryophyllene (100 or 200 mg/kg/day orally) was administered for 21 days then MI was induced via ISO (85 mg/kg, subcutaneous) on 20th and 21st days. The results indicated that ISO induced a significant infarcted area associated with several alterations in the electrocardiogram (ECG) and blood pressure (BP) indices and caused an increase in numerous cardiac indicators such as creatine phosphokinase (CPK), creatine kinase-myocardial bound (CK-MB), lactate dehydrogenase (LDH), and cardiac tropinine T (cTnT). In addition, ISO significantly amplified heat shock protein 60 (HSP-60) and other inflammatory markers, such as TNF-α, IL-Iß, and NFκB, and affected TLR2 and TLR4 expression and their adaptor proteins; Myeloid differentiation primary response 88 (MYD88), and TIR-domain-containing adapter-inducing interferon-ß (TRIF). On the other hand, consumption of ß-caryophyllene significantly reversed the infarcted size, ECG and BP alterations, ameliorated the ISO elevation in cardiac indicators; it also notably diminished HSP-60, and subsequently TLR2, TLR4, MYD88, and TRIF expression, with a substantial reduction in inflammatory mediator levels. This study revealed the cardioprotective effect of ß-caryophyllene against MI through inhibiting HSP-60/TLR/MyD88/NFκB signaling pathways.

Cyanobacteria as Nanogold Factories: Chemical and Anti-Myocardial Infarction Properties of Gold Nanoparticles Synthesized by Lyngbya majuscula.

To the best of our knowledge, cyanobacterial strains from the Arabian Gulf have never been investigated with respect to their potential for nanoparticle production. Lyngbya majuscula was isolated from the AlOqair area, Al-Ahsa Government, Eastern Province, Kingdom of Saudi Arabia. The cyanobacterium was initially incubated with 1500 mg/mL of HAuCl4 for two days. The blue-green strain turned purple, which indicated the intracellular formation of gold nanoparticles. Prolonged incubation for over two months triggered the extracellular production of nanogold particles. UV-visible spectroscopy measurements indicated the presence of a resonance plasmon band at ~535 nm, whereas electron microscopy scanning indicated the presence of gold nanoparticles with an average diameter of 41.7 ± 0.2 nm. The antioxidant and anti-myocardial infarction activities of the cyanobacterial extract, the gold nanoparticle solution, and a combination of both were investigated in animal models. Isoproterenol (100 mg/kg, SC (sub cutaneous)) was injected into experimental rats for three days to induce a state of myocardial infarction; then the animals were given cyanobacterial extract (200 mg/kg/day, IP (intra peritoneal)), gold nanoparticles (200 mg/kg/day, IP), ora mixture of both for 14 days. Cardiac biomarkers, electrocardiogram (ECG), blood pressure, and antioxidant enzymes were determined as indicators of myocardial infarction. The results showed that isoproterenol elevates ST and QT segments and increases heart rate and serum activities of creatine phosphokinase (CPK), creatine kinase-myocardial bound (CP-MB), and cardiac troponin T (cTnT). It also reduces heart tissue content of glutathione peroxidase (GRx) and superoxide dismutase (SOD), and the arterial pressure indices of systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and mean arterial pressure (MAP). Gold nanoparticles alone or in combination with cyanobacterial extract produced an inhibitory effect on isoproterenol-induced changes in serum cardiac injury markers, ECG, arterial pressure indices, and antioxidant capabilities of the heart.

In Silico-Based Repositioning of Phosphinothricin as a Novel Technetium-99m Imaging Probe with Potential Anti-Cancer Activity.

l-Phosphinothricin (glufosinate or 2-amino-4-((hydroxy(methyl) phosphinyl) butyric acid ammonium salt (AHPB)), which is a structural analog of glutamate, is a recognized herbicide that acts on weeds through inhibition of glutamine synthetase. Due to the structural similarity between phosphinothricin and some bisphosphonates (BPs), this study focuses on investigating the possibility of repurposing phosphinothricin as a bisphosphonate analogue, particularly in two medicine-related activities: image probing and as an anti-cancer drug. As BP is a competitive inhibitor of human farnesyl pyrophosphate synthase (HFPPS), in silico molecular docking and dynamic simulations studies were established to evaluate the binding and stability of phosphinothricin with HFPPS, while the results showed good binding and stability in the active site of the enzyme in relation to alendronate. For the purpose of inspecting bone-tissue accumulation of phosphinothricin, a technetium (99mTc)-phosphinothricin complex was developed and its stability and tissue distribution were scrutinized. The radioactive complex showed rapid, high and sustained uptake into bone tissues. Finally, the cytotoxic activity of phosphinothricin was tested against breast and lung cancer cells, with the results indicating cytotoxic activity in relation to alendronate. All the above results provide support for the use of phosphinothricin as a potential anti-cancer drug and of its technetium complex as an imaging probe.

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.

Evaluation of the automated dispensing cabinets users' level of satisfaction and the influencing factors in Al-Ahsa hospitals.

Automated dispensing cabinets (ADCs) are decentralized, computer-controlled systems used to store, distribute, and track medications at the point of care in the wards. Objective: The objective of the current study is to evaluate how healthcare practitioners are satisfied with ADCs and scrutinize some influencing factors that could affect this satisfaction. Material: A cross-sectional survey study was designed and distributed online to healthcare providers in Al-hasa hospitals. Results: A total of 166 participants. Regarding the frequency and pattern of ADC use, around 79.5% used ADC and 85.4% were informed about using ADC on a daily basis. As for the level of satisfaction with ADC, an exact 81.9% gave a high rate for overall satisfaction, 81.3% were highly satisfied with the system's accuracy, and 74.7% were highly satisfied with the time it takes to complete the task. Regarding usability of the system, 69.8% thought it was easy whereas 36.8% agreed that the time required for reloading medication is longer than before ADC. Furthermore, 79.5% agreed that ADC allowed them to accomplish their job safely, and 67.4% agreed that it improved their productivity. Regarding challenges, 74.7% agreed that all drawer types assure safe access and removal of medications, and 18.7% agreed that there is a significant potential for loss of data. Conclusion: This study investigated healthcare staff's perceptions and satisfaction with ADCs in Al-hasa hospitals. The healthcare participants were mostly highly satisfied with the use of the ADCs which translated into better patient care and improved patient safety as well as higher productivity.

Anethole alleviates Doxorubicin-induced cardiac and renal toxicities: Insights from network pharmacology and animal studies.

Doxorubicin (Dox) is widely used as a chemotherapy drug, while anethole (AN) is primarily known as the main aromatic component in various plant species. This research focused on the impact of AN on the cardiac and renal toxicity induced by Dox and to understand the underlying mechanisms. For cardiac toxicity, Wistar rats were categorized into four groups: a Control group; a Dox group, where rats received 2.5 mg/kg of Dox intraperitoneally every other day; and two Dox + AN groups, where animals were administered Dox (2.5 mg/kg/every other day, IP) along with 125 mg/kg or 250 mg/kg of AN, respectively. The renal toxicity study included similar groups, with the Dox group receiving a single dose of 20 mg/kg of Dox intraperitoneally on the tenth day, and the Dox + AN groups receiving 125 mg/kg and 250 mg/kg of AN for two weeks, alongside the same dose of Dox (20 mg/kg, IP, once on the 10th day). Parameters assessed included ECG, cardiac injury markers (CK, CK-MB, and LDH), and kidney function tests (Cr, BUN, uric acid, LDL, Kim-1, NGAL, and CysC). Antioxidant activity, lipid peroxidation, inflammation, and apoptotic markers were also monitored in heart and renal tissues. Gene expression levels of the TLR4/MyD88/NFκB pathway, along with Bax and Bcl-2, were evaluated. Dox significantly altered ECG, elevated cardiac injury markers, and renal function markers. It also augmented gene expressions of TLR4/MyD88/NFκB, amplified oxidative stress, inflammatory cytokines and apoptotic markers. Conversely, AN reduced cardiac injury markers and kidney function tests, improved ECG, diminished TLR4/MyD88/NFκB gene expression, and alleviated oxidative stress by increasing antioxidant enzyme activities and reducing inflammatory cytokines. AN also enhanced Bcl-2 levels and inhibited Bax and the cleavage of caspase-3 and 9. AN countered the lipid peroxidation, oxidative stress, inflammation, and apoptosis induced by Dox, marking it as a potential preventive strategy against Dox-induced nephrotoxic and cardiotoxic injuries.

Arachidonic acid: an evolutionarily conserved signaling molecule modulates plant stress signaling networks.

Fatty acid structure affects cellular activities through changes in membrane lipid composition and the generation of a diversity of bioactive derivatives. Eicosapolyenoic acids are released into plants upon infection by oomycete pathogens, suggesting they may elicit plant defenses. We exploited transgenic Arabidopsis thaliana plants (designated EP) producing eicosadienoic, eicosatrienoic, and arachidonic acid (AA), aimed at mimicking pathogen release of these compounds. We also examined their effect on biotic stress resistance by challenging EP plants with fungal, oomycete, and bacterial pathogens and an insect pest. EP plants exhibited enhanced resistance to all biotic challenges, except they were more susceptible to bacteria than the wild type. Levels of jasmonic acid (JA) were elevated and levels of salicylic acid (SA) were reduced in EP plants. Altered expression of JA and SA pathway genes in EP plants shows that eicosapolyenoic acids effectively modulate stress-responsive transcriptional networks. Exogenous application of various fatty acids to wild-type and JA-deficient mutants confirmed AA as the signaling molecule. Moreover, AA treatment elicited heightened expression of general stress-responsive genes. Importantly, tomato (Solanum lycopersicum) leaves treated with AA exhibited reduced susceptibility to Botrytis cinerea infection, confirming AA signaling in other plants. These studies support the role of AA, an ancient metazoan signaling molecule, in eliciting plant stress and defense signaling networks.

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.

Casuarina glauca branchlets' extract as a potential treatment for ulcerative colitis: chemical composition, in silico and in vivo studies.

Ulcerative colitis (UC) is an inflammatory bowel disease that is often resistant to current treatment options, leading to a need for alternative therapies. Herbal products have shown promise in managing various conditions, including UC. However, the potential of Casuarina glauca branchlets ethanolic extract (CGBRE) in treating UC has not been explored. This study aimed to analyze the chemical composition of CGBRE and evaluate its efficacy in UC treatment through in silico and in vivo experiments. LC-ESI-MS/MS was used to identify 86 compounds in CGBRE, with 21 potential bioactive compounds determined through pharmacokinetic analysis. Network pharmacology analysis revealed 171 potential UC targets for the bioactive compounds, including EGFR, LRRK2, and HSP90 as top targets, which were found to bind to key CGBRE compounds through molecular docking. Molecular docking findings suggested that CGBRE may be effective in the prevention or treatment of ulcerative colitis mediated by these proteins, where key CGBRE compounds exhibited good binding affinities through formation of numerous interactions. In vivo studies in rats with acetic acid-induced UC demonstrated that oral administration of 300 mg/kg CGBRE for 6 days reduced UC symptoms and colonic expression of EGFR, LRRK2, and HSP90. These findings supported the therapeutic potential of CGBRE in UC and suggested the need for further preclinical and clinical investigation.

Anethole's effects against myocardial infarction: The role of TLR4/NFκB and Nrf2/HO1 pathways.

BACKGROUND: Exploring new drugs for the management of myocardial infarction (MI) is crucial, as MI is a major contributor to mortality worldwide. Anethole, a naturally occurring essential oil component, has numerous medicinal, pharmaceutical, and cosmetic purposes. This study explored the potential action of anethole to protect myocytes against MI injure. METHODS: Wistar rats were divided into five groups: normal; anethole; and isoproterenol (ISO) groups in addition to two groups of ISO + anethole (125 and 250 mg/kg). All anethole groups were administered the oil component for 30 days, and all ISO groups were challenged with ISO on the 28th and 29th days. Parameters measured included infracted area, ECG, cardiac markers, the expression of Keap 1, nuclear Nrf2, and heme oxygenase-1, as well as the expression of TLR4 and MYD88 together with subsequent downstream oxidative stress, inflammatory, and apoptotic markers. RESULTS: Anethole reduced infarct region, degenerated cardiac indicators levels, amended ECG alterations, and diminished myocardial necrosis. Anethole reduced Keap-1, activated Nrf2/HO-1 pathway, increased mitochondrial antioxidant enzyme activities, declined the TLR4/MYD88 pathway, and ameliorated myocardial inflammation and cell death markers. CONCLUSION: Anethole may retain a cardio-protective potential by controlling myocardial oxidative stress (through Nrf2 pathway) and diminishing inflammation and apoptosis via the TLR4/MYD88 pathway.

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.