A Comparative GC/MS Analysis of Citrus Essential Oils: Unveiling the Potential Benefits of Herb-Drug Interactions in Preventing Paracetamol-Induced Hepatotoxicity.

Our study aimed to test the potential of Citrus oils in protecting against paracetamol (PAR)-induced hepatotoxicity. The essential oils of Pineapple sweet orange (OO), Murcott mandarin (MO), Red grapefruit (GO), and Oval kumquat (KO) were investigated using gas chromatography coupled with mass spectrometry (GC/MS). Twenty-seven compounds were identified, with monoterpene hydrocarbons being abundant class. d-Limonene had the highest percentage (92.98 %, 92.82 %, 89.75 %, and 94.46 % in OO, MO, GO, and KO, respectively). Hierarchical cluster analysis (HCA) and principal components analysis (PCA) revealed that octanal, linalool, germacrene D, and d-limonene were the principal discriminatory metabolites that segregated the samples into three distinct clusters. In vitro antioxidant capacities were ranged from 1.2-12.27, 1.79-5.91, and 235.05-585.28 µM Trolox eq/mg oil for 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic (ABTS), ferric-reducing antioxidant power (FRAP), and oxygen radical absorbance capacity (ORAC), respectively. In vivo, citrus oils exhibited a significant reduction in alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and nitric oxide (NO). Additionally, there was an increase in glutathione reductase (GSH), and the liver architecture was nearly normal. Molecular docking revealed that d-limonene exhibited a good inhibitory interaction with cytochrome P450 (CYP450) isoforms 1A2, 3A4, and 2E1, with binding energies of -6.17, -4.51, and -5.61 kcal/mol, respectively.

Taming Food-Drug Interaction Risk: Potential Inhibitory Effects of Citrus Juices on Cytochrome Liver Enzymes Can Safeguard the Liver from Overdose Paracetamol-Induced Hepatotoxicity.

Paracetamol overdose is the leading cause of drug-induced hepatotoxicity worldwide. Because of N-acetyl cysteine's limited therapeutic efficacy and safety, searching for alternative therapeutic substitutes is necessary. This study investigated four citrus juices: Citrus sinensis L. Osbeck var. Pineapple (pineapple sweet orange), Citrus reticulata Blanco × Citrus sinensis L. Osbeck (Murcott mandarin), Citrus paradisi Macfadyen var. Ruby Red (red grapefruit), and Fortunella margarita Swingle (oval kumquat) to improve the herbal therapy against paracetamol-induced liver toxicity. UHPLC-QTOF-MS/MS profiling of the investigated samples resulted in the identification of about 40 metabolites belonging to different phytochemical classes. Phenolic compounds were the most abundant, with the total content ranked from 609.18 to 1093.26 µg gallic acid equivalent (GAE)/mL juice. The multivariate data analysis revealed that phloretin 3',5'-di-C-glucoside, narirutin, naringin, hesperidin, 2-O-rhamnosyl-swertisin, fortunellin (acacetin-7-O-neohesperidoside), sinensetin, nobiletin, and tangeretin represented the crucial discriminatory metabolites that segregated the analyzed samples. Nevertheless, the antioxidant activity of the samples was 1135.91-2913.92 µM Trolox eq/mL juice, 718.95-3749.47 µM Trolox eq/mL juice, and 2304.74-4390.32 µM Trolox eq/mL juice, as revealed from 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid, ferric-reducing antioxidant power, and oxygen radical absorbance capacity, respectively. The in vivo paracetamol-induced hepatotoxicity model in rats was established and assessed by measuring the levels of hepatic enzymes and antioxidant biomarkers. Interestingly, the concomitant administration of citrus juices with a toxic dose of paracetamol effectively recovered the liver injury, as confirmed by normal sections of hepatocytes. This action could be due to the interactions between the major identified metabolites (hesperidin, hesperetin, phloretin 3',5'-di-C-glucoside, fortunellin, poncirin, nobiletin, apigenin-6,8-digalactoside, 6',7'-dihydroxybergamottin, naringenin, and naringin) and cytochrome P450 isoforms (CYP3A4, CYP2E1, and CYP1A2), as revealed from the molecular docking study. The most promising compounds in the three docking processes were hesperidin, fortunellin, poncirin, and naringin. Finally, a desirable food-drug interaction was achieved in our research to overcome paracetamol overdose-induced hepatotoxicity.

Green nanocoating-based polysaccharides decorated with ZnONPs doped Egyptian kaolinite for antimicrobial coating paper.

Paper coating plays an important role in the paper properties, printability and application. The nanocoating is a multifunction layer that provides the paper with unique features. In this work, nanocoating formulas were prepared using a green method and component. The nanocoating formulas were based on biopolymers nanostarch NSt and nanochitosan NCh (NCS) decorated with Egyptian kaolinite Ka doped with zinc nanoparticles NCS@xka/ZnONPs (x represents different ratios) support for multifunctional uses. The nanocoating formulas were characterized using a physiochemical analysis as well as a topographical study. FTIR, XRD, SEM and TEM techniques were used. Additionally, the antimicrobial activity of the tested samples was assessed against six microorganisms including Gram-negative and Gram-positive bacteria. The prepared nanocoating formulas affirmed excellent antimicrobial activity as a broad-spectrum antimicrobial active agent with excellent activity against all representative microbial communities. The nanocoating with the highest ratio of Ka/ZnONPs (NCS@40 ka/ZnONPs) showed excellent antimicrobial activity with an inhibition percentage of more than 70% versus all microorganisms presented. The paper was coated with the prepared suspensions and characterized concerning optical, mechanical and physical properties. When Ka/ZnONPs were loaded into NCS in a variety of ratios, the characteristics of coated paper were enhanced compared to blank paper. The sample NCS@40 ka/ZnONPs increased tensile strength by 11%, reduced light scattering by 12%, and improved brightness and whiteness by 1%. Paper coated with NCh suspension had 35.32% less roughness and 188.6% less porosity. When coated with the sample NCS@10 ka/ZnONPs, the coated paper's porosity was reduced by 94% and its roughness was reduced by 10.85%. The greatest reduction in water absorptivity was attained by coating with the same sample, with a reduction percentage of 132%.

Therapeutic efficacy of Nano-formulation of lactoperoxidase and lactoferrin via promoting immunomodulatory and apoptotic effects.

This study identifies promising potential of a novel and safer nanocombination of bovine milk lactoperoxidase (LPO) and lactoferrin (LF) to target breast cancer in vitro and in adult female albino rat model. Favorable selective anticancer effects of the prepared nanocombination were observed, in a dose-dependent manner, against both MCF-7 and MDA cell lines, sparing normal HFB-4 cells. The administration of LPO + LFNPs markedly improved the induced-breast cancer disorders, prolonged survival and reduced the values of serum TNF-α, IL1ß, CD4+, ALAT, ASAT, urea, creatinine, cholesterol and triglycerides with remarkable elevation in mammary SOD and GPx activity and GSH level. Moreover, the histopathological findings showed that LPO + LFNPs succeeded in prevention of mammary gland tumorigenesis. Superior efficacy of LPO + LFNPs was observed against pro-inflammatory cytokines through their anti-inflammatory and immunomodulatory properties. The treatment of LPO + LFNPs more significantly modulated the apoptosis and enhanced the expression of cell cycle regulator genes, which demonstrates a successful tumor therapy in vitro and in vivo. Therefore, this study provided evidence that the chemo-preventive feature of LPO + LFNPs may offer a novel alternative therapy for the treatment of breast cancer through enhances apoptosis pathway, improvement of immune response, reduction of inflammation and restoration of the impaired oxidative stress.

Protective effect of cannabinoids on gastric mucosal lesions induced by water immersion restrain stress in rats.

OBJECTIVES: This study aimed to determine the impact of cannabinoid agonists and antagonists on the mucosal lesion progress in the stomach induced by water-immersion restraint stress (WIRS). MATERIALS AND METHODS: Rats subjected to WIRS for 4 hr were treated with Dimethyl sulfoxide (DMSO), CBR1 agonist (NADA, 1 mg/kg), CBR1 antagonist (Rimonabant, 1 mg/kg), CBR2 agonist (GW405833 1 mg/kg) or CBR2 antagonist (AM630, 1 mg/kg SC) 30 min before WIRS. Microscopic lesions, oxidative stress, inflammatory cytokines biomarkers, and (Myeloperoxidase) MPO in gastric tissues were determined. RESULTS: Results indicated development of severe gastric lesions with a substantial increase in the contents of (nitric oxide) NO, (malondialdehyde) MDA, (interleukin-1 beta) IL-1ß, MPO, (tumor necrosis factor-alpha) TNF-α, and a significant fall in the content of GSH and the activity of PON-1 after WIRS. CONCLUSION: Treatment with NADA and AM630 protected gastric tissues against ulcers as demonstrated by a decrease in the contents of MDA, TNF-α, MPO, and IL-1ß along with an increase in the content of PON-1 activity and GSH in the stomach tissues. On the other hand, treatment with SR141716A or GW405833 showed no protective effects on ulcers development. It seems that cannabinoids exert their antioxidant potential and anti-inflammatory effects against WIRS-induced gastric ulcers by activation of CB1R.

Anticholinesterase activity and metabolite profiling of Syagrus romanzoffiana (Cham.) Glassman leaves and fruits via UPLC-QTOF-PDA-MS.

The purpose of this study is to provide a complete metabolic profile of the hydroalcoholic extracts of the leaves and fruits of Syagrus romanzoffiana (Cham.) Glassman via UPLC-QTOF-PDA-MS and to evaluate their anticholinesterase activities in a model of Alzheimer disease. The current study has identified 39 metabolites belonging to various chemical classes (i.e. flavonols, phenolic acids, fatty acids, stilbenoids and lignans). While the fatty acids predominated in both leaves and fruits, the stilbenoids were more predominant in leaves. Their neuroprotective effect was comparable to Aricept; the standard drug used in treatment of Alzheimer disease. Both extracts significantly decreased the acetylcholinesterase activity and improved the histopathological changes in the cerebral cortex and cerebellum of rat model of aluminium chloride-induced Alzheimer disease. In light of the current study, Syagrus romanzoffiana (Cham.) Glassman is recommended as promising candidate for palliative treatment in Alzheimer disease through inhibition of the acetylcholinesterase activity.

Pulse Pressure Variation-Guided Fluid Therapy during Supratentorial Brain Tumour Excision: A Randomized Controlled Trial.

BACKGROUND: Goal-directed fluid therapy (GDFT) improved patient outcomes in various surgical procedures; however, its role during mass brain resection was not well investigated. AIM: In this study, we evaluated a simple protocol based on intermittent evaluation of pulse pressure variation for guiding fluid therapy during brain tumour resection. METHODS: Sixty-one adult patients scheduled for supratentorial brain mass excision were randomized into either GDFT group (received intraoperative fluids guided by pulse pressure variation) and control group (received standard care). Both groups were compared according to the following: brain relaxation scale (BRS), mean arterial pressure, heart rate, urine output, intraoperative fluid intake, postoperative serum lactate, and length of hospital stay. RESULTS: Demographic data, cardiovascular data (mean arterial pressure and heart rate), and BRS were comparable between both groups. GDFT group received more intraoperative fluids {3155 (452) mL vs 2790 (443) mL, P = 0.002}, had higher urine output {2019 (449) mL vs 1410 (382) mL, P < 0.001}, and had lower serum lactate {0.9 (1) mmol versus 2.5 (1.1) mmol, P = 0.03} compared to control group. CONCLUSION: In conclusion, PPV-guided fluid therapy during supratentorial mass excision, increased intraoperative fluids, and improved peripheral perfusion without increasing brain swelling.

Oral supplementation with geranium oil or anise oil ameliorates depressed rat-related symptoms through oils antioxidant effects.

Background Depression is a psychiatric disease condition and the chronic mild stress (CMS) model is a well-known and valuable animal model of depression. Geranium oil and anise oil were chosen for such a study. The aim of this research was to establish the geranium oil and anise oil effect to ameliorate CMS-related symptoms. Methods This research included 80 male albino rats each group of 10 rats and the animals were divided into two major groups: normal and CMS. The normal group was subdivided into four (control, geranium oil, anise oil and venlafaxine drug) subgroups treated orally with saline, geranium oil, anise oil and venlafaxine drug, respectively, for 4 weeks. The CMS group was subdivided into four (CMS without any treatment, CMS + geranium oil, CMS + anise oil and CMS + venlafaxine drug) subgroups treated orally with geranium oil, anise oil and venlafaxine drug, respectively, for 4 weeks. Results The sucrose consumption in sucrose preference test, the distance traveled test and center square entries test were decreased, while center square duration test, immobility time in tail suspension test and floating time in forced swimming test were increased in CMS. The superoxide dismutase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase and catalase levels decreased but malondialdehyde and nitric oxide levels increased in brain cerebral cortex and hippocampus areas in CMS. The oral intake of geranium oil and anise oil pushes all these parameters to approach the control levels. These results were supported by histopathological investigations of both brain cerebral cortex and hippocampus tissues. Conclusions Geranium oil and anise oil ameliorate CMS-related symptoms and this effect were related to the antioxidant effects of oils.

Role of ashwagandha methanolic extract in the regulation of thyroid profile in hypothyroidism modeled rats.

This study aimed to evaluate the anti-hypothyroidism potential of ashwagandha methanolic extract (AME). This target was performed through induction of animal model of hypothyroidism by propylthiouracil. After 1 month from treatments, blood samples were collected for biochemical determinations, and liver and kidney were removed for the determination of oxidative stress markers and thyroid gland was removed for histopathological examination. The total phenolic compounds in the extract and the in vitro radical scavenging activity of extract were also determined. The results revealed that the induction of hypothyroidism by propylthiouracil induced a significant increase in serum TSH level but it induced significant decreases in the levels of total T3, free T3, free T4, and total T4 hormones compared with the control values. Also, serum glucose, Il-6, and body weight gain increased significantly while Il-10 and blood hemoglobin levels showed significant decrease. Induction of hypothyroidism increased also the levels of hepatic and renal MDA and NO and decreased significantly the values of GSH, GPx and Na+/ K+-ATPase. Both AME and the anti-hypothyroidism drug significantly ameliorated the changes occurred in the levels of the above parameters and improved histological picture of thyroid gland but with different degrees; where ashwagandha methanolic extract showed the strongest effect. We can conclude that ashwagandha methanolic extract treatment improves thyroid function by ameliorating thyroid hormones and by preventing oxidative stress.

Modulation of gastric acid secretion by cannabinoids in rats.

The current study aimed to evaluate the role of cannabinoid receptors in the regulation of gastric acid secretion and oxidative stress in gastric mucosa. To fulfill this aim, gastric acid secretion stimulated with histamine (5 mg/kg, subcutaneous [SC]), 2-deoxy- d-glucose (D-G) (200 mg/kg, intravenous) or -carbachol (4 µg/kg, SC) in the 4-hour pylorus-ligated rats. The CB1R agonist ( N-arachidonoyl dopamine, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D-G and carbachol but not in histamine, reduced pepsin content, and increased mucin secretion. Furthermore, it decreased malondialdehyde (MDA) and nitric oxide (NO) contents with an increase in glutathione (GSH) and paraoxonase 1 (PON-1). Meanwhile, CB2R antagonist (AM630, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D-G and reduced MDA and NO contents with an increase in GSH and PON-1. Meanwhile, CB1R antagonist rimonabant or CB2R agonist GW 405833 had no effect on stimulated gastric acid secretion. Therefore, both CB1R agonist and CB2R antagonist may exert antisecretory and antioxidant potential in the stomach.

Grape Seed Extract Alone or Combined with Atropine in Treatment of Malathion Induced Neuro- and Genotoxicity.

The aim of this study was to investigate the effect of treatment with grape seed extract (GSE) on the neurotoxic and genotoxic effects of acute malathion exposure. Rats received malathion (150 mg/kg by i.p. injection) for two successive days alone or combined with GSE at doses of 150 or 300 mg/kg, orally or with GSE at 300 mg/kg and atropine at a dose of 2 mg/kg, i.p. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide, paraoxonase (PON1) were determined in cortex, striatum, and rest of brain tissue (subcortex). Interleukin-1ß (IL-1ß), and butyrylcholinesterase (BChE) activities were determined in brain regions. Cytogenetic analyses for chromosomal aberrations in somatic and germ cells, micronucleus test, Comet assay, DNA fragmentation of liver cells and histopathological examination of brain and liver sections were also performed. Malathion resulted in an increase in MDA, nitric oxide; a decrease in GSH and PON1 activity in different brain regions. IL-1ß increased, while BChE activity decreased in brain after the administration of malathion. The insecticide also caused marked structural and numerical chromosomal aberrations and increased liver DNA fragmentation. The Comet assay showed a significant increase in DNA damage of peripheral blood lymphocytes. These effects of malathion were alleviated with the administration of GSE alone or combined with atropine. Addition of atropine to treatment with GSE was associated with significant decrease in MDA, BChE and chromosomal aberrations compared with GSE only treatment. Our data indicate that GSE protects against malathion neurotoxic and genotoxic effects, most likely through reducing brain oxidative stress and inflammatory response.

DNA Cytometry and Nuclear Morphometry in Ovarian Benign, Borderline and Malignant Tumors.

BACKDROUND: Ovarian carcinoma is a leading cause of death in gynecological malignancy. Ovarian surface epithelial serous and mucinous tumours are classified as benign, borderline, and malignant. The identification of borderline tumours most likely to act aggressively remains an important clinical issue. AIM: This work aimed to study DNA ploidy and nuclear area in ovarian serous and mucinous; benign, borderline and malignant tumours. MATERIAL AND METHODS: This study included forty ovarian (23 serous and 17 mucinous) tumours. Paraffin blocks were sectioned; stained with haematoxylin and eosin for histopathologic and morphometric studies and with blue feulgen for DNA analysis. RESULTS: All four serous and six out of nine mucinous benign tumours were diploid. All eight serous and five mucinous malignant tumours were aneuploid. Nine of eleven (81.8%) serous and all three mucinous borderline tumours were aneuploid. There were highly significant differences in mean aneuploid cells percentage between serous benign (1.5%), borderline (45.6%) and malignant (74.5%) (p = 0.0001) and between mucinous benign (13.2%) and both borderline (63.7%) and malignant (68.4%) groups (p = 0.0001). There were significant differences in nuclear area between serous benign (26.191%), borderline (45.619%) and malignant (67.634 %) and a significant positive correlation between mean percentage aneuploid value and mean nuclear area in all serous and mucinous groups. CONCLUSION: We suggest that DNA ploidy and nuclear area combined, may be adjuncts to histopathology; in ovarian serous and mucinous benign, borderline and malignant neoplasms; identifying the aggressive borderline tumours.

Cadmium impact and osteoporosis: mechanism of action.

CONTEXT: Cadmium (Cd) is a widespread environmental pollutant that is associated with increased risk of osteoporosis. It has been proposed that Cd's toxic effect on bone is exerted via impaired activation of vitamin D, secondary to the kidney effects. OBJECTIVE: The present study was designed to investigate the damaging impact of Cd in drinking water on bone from biochemical and histopathological point of view. MATERIALS AND METHODS: This study was conducted on 30, 3-months-old female Sprague Dawley rats exposed to cadmium chloride in a dose of 50 mg Cd/L in drinking water for 3 months. Serum was taken for determination of calcium, phosphorous levels, parathyroid hormone, 1,25 dihydroxy vitamin D(3), osteocalcin (OC) and bone specific alkaline phosphatase (BALP) activity. RESULTS: The result revealed that Cd administration induces significant increase in serum calcium (Ca), phosphorous (P) and parathyroid hormone (PTH) levels in concomitant with significant reduction in serum vitamin D(3), osteocalcin (OC) levels and bone specific alkaline phosphatase (BALP) activity. CONCLUSION: The present study provided clear evidence that long-term exposure to cadmium chloride produced marked abnormalities in bone biomarkers and increasing risk of fracture.

Effects of biphenyldimethyl-dicarboxylate administration alone or combined with silymarin in the CCL4 model of liver fibrosis in rats.

The effect of biphenyldimethyldicarboxylate (DDB), a synthetic compound, in use for the treatment of chronic hepatitis was studied on hepatic injury caused in rats by administration of carbon tetrachloride (CCl4). Starting at time of administration of the first dose of CCl4, rats received DDB at four dose levels (3, 15, 75 or 375 mg/kg), silymarin (22 mg/kg), a combination of DDB (75 mg/kg) and silymarin (22 mg/kg) or saline (control) once orally daily for 30 days. The administration of DDB in CCl4-treated rats at 75 or 375 mg/kg resulted in 61.2-76.2% decrease in alanine aminotransferase (ALT) and 46.9-60.8% decrease in aspartate aminotransferase (AST), respectively compared with the CCl4 control group. Silymarin treatment resulted in 34.6 and 30% decrease in ALT and AST, while DDB (75 mg/kg) combined with silymarin (22 mg/kg) resulted in 58.2 and 31% decrease in ALT and AST, respectively. Serum creatinine increased by 50% by DDB at 375 mg/kg. After treatment with DDB at 75 or 375 mg/kg or DDB combined with silymarin, the development of liver necrosis and fibrosis caused by CCl4 was markedly reduced, while after DDB combined with silymarin no DNA aneuploid cells could be observed. The decrease in glycogen and protein contents in hepatocytes caused by CCl4 was markedly prevented by co-treatment with DDB at 75 or 375 mg/kg or DDB combined with silymarin. It is concluded that in the model of hepatic injury caused by chronic administration of CCl4 in rats, the synthetic compound DDB, limits hepatocellular injury and exerts antifibrotic effect. Better improvement in protein, DNA, mucopolysaccharide content was seen after both DDB and silymarin compared to DDB alone. It is suggested, therefore, that DDB alone or in combination with silymarin might prove of benefit in the therapy of chronic liver disease. Monitoring of kidney functions in patients taking DDB is warranted.

The protective effect of melatonin against fumonisin-induced renal damage in rats.

The present study was designed to investigate the potential protective effect of melatonin against the renal toxicity of fumonisin in female rats. Six groups of animals were used in this study. The first group served as control. The second group was given melatonin only at a dose level of 10 mg/kg. The third group was fed ration contaminated with fumonisin (100 mg/kg diet). The fourth group was fed ration contaminated with fumonisin (200 mg/kg diet). The fifth group was given daily interperitoneal injection (IP) 10 mg/kg melatonin and fed ration contaminated with fumonisin (100 mg/kg diet). The sixth group was given daily interperitoneal injection of 10 mg/kg melatonin and fed ration contaminated with fumonisin (200 mg/kg diet). The rats were treated for 1 month. Histopathological and histochemical changes in the kidney were investigated. In addition, DNA ploidy was measured in the kidney. Fumonisin administration (100 or 200 mg/Kg diet) to unpretreated control rats caused extensive renal damage as evaluated by histopathology, histochemistry, and/or DNA ploidy measurement. No apparent changes following administration of melatonin. Melatonin coadministration to the fumonisin-administered rats reduced kidney damage and the tissues appeared more or less like the normal. The present study indicates that melatonin has a protective effect in fumonisin-induced renal damage.