Effect of Dietary Fiber Supplementation on Metabolic Endotoxemia: A Protocol for Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Introduction: Metabolic endotoxemia (ME) is the main cause of sub-clinical chronic inflammation, which subsequently triggers the onset of several chronic diseases. However, recent reports have indicated that dietary fiber (DF) contributes significantly to ameliorating ME and inflammation. This protocol aims to provide an outline of all procedures in synthesizing the available data on the effect of DF against ME. Methods: Following the PRISMA 2020 guidelines for preparing protocols, this protocol was registered in the International Prospective Registry of Systematic Reviews (PROSPERO) with registration number (CRD42023417833). In this review, we specifically focused on the inclusion of clinical trials that met the following criteria: they were published or available as preprints, employed random, quasi-random, or cross-over designs, and were exclusively documented in the English language. Clinical medical subject headings (MeSH) as search terms were used on prominent databases such as MEDLINE, COCHRANE library, PubMed, World Health Organization International Clinical Trials Registry Platforms, and US National Institutes of Health Ongoing Trials Register Clinicaltrials.gov. Results and discussion: This protocol will guide the exploration of articles that report changes in ME biomarkers in subjects supplemented with DF. The findings of this protocol will ensure a comprehensive evaluation of available evidence, provide a quantitative summary, identify patterns and trends, enhance statistical power, and address heterogeneity, which collectively will clarify the optimal types, doses, and duration of DF interventions for managing ME and low-grade inflammation. Ethics and dissemination: The quantitative data of clinical trials will be collected, and a meta-analysis will be performed using RevMan V.5.3 software. Therefore, no ethical approval is required.

Induction of Apoptosis and Modulation of Caspase Activity on MCF-7 Human Breast Cancer Cells by Bioactive Fractionated Cocoa Leaf Extract.

BACKGROUND: The objective of this study was to investigate the potential anti-proliferative activities of a methanolic extract of cocoa leaves (CL) obtained through sequential partition and fractionation against MCF-7 breast cancer cells.  Methods: The methanolic extract of CL was partitioned in three separated solvents (hexane, dichloromethane, and methanol). Hexane partition was the most potent against MCF-7 cells growth with the lowest IC50 value. Then, it was subjected to two fractionation procedures, resulting in the identification of the CL bioactive fraction (II-F7) with potent toxicity against MCF-7 cells. RESULTS: Further investigation into CL bioactive fraction (II-F7) revealed significant dose-dependent growth inhibitory effects on MCF-7 cells, which were attributed to the induction of apoptosis, as evidenced by the presence of apoptotic bodies, fragmented DNA, and disruption of mitochondrial membrane potential. Additionally, treatment with CL bioactive fraction (II-F7) upregulated the expression of pro-apoptotic genes (DDIT3, GADD45G and HRK) and significantly increased the activities of caspase-8 and caspase-9. CONCLUSION: Overall, this study suggests that bioactive fraction (II-F7) from CL extract has significant and selective cytotoxicity against MCF-7 cells through inducing apoptosis and has potential as a therapeutic agent for breast cancer treatment.

The effects of consuming a Mediterranean style diet on associated COVID-19 severity biomarkers in obese/overweight adults: A systematic review.

Background: COVID-19 severity is strongly associated with high Body Mass Index (BMI) (≥25kg/m2) amongst adults and elevated inflammatory markers have enabled prediction of disease progression. The composition of a Mediterranean diet provides favourable outcomes on weight reduction and inflammatory markers. Aim: This systematic review aimed to investigate the effects of consuming a Mediterranean diet on BMI and inflammatory markers of obese/overweight adults (≥18 years) at risk of developing severe COVID-19 outcomes. Methods: PubMed Central, Cochrane Library and MEDLINE databases were searched to identify randomised controlled trials published between January 2010 to August 2021 evaluating the impact of Mediterranean diet on BMI and inflammatory markers in overweight/obese adults. The review followed the PRISMA checklist, used Cochrane Collaboration search strategies, and is PROSPERO registered (CRD42021277070). Two authors independently screened and evaluated studies for methodological quality. Papers were extracted and included based eligibility, despite risk of bias scores. Results: Of 65 extracted records, six studies met the eligibility criteria and were included. Reductions in BMI, TNF-α, IL-6 and hs-CRP were reported amongst most findings, the majority of which were significant. Conclusion: The main findings indicate a hypocaloric, fibre dense Mediterranean diet is a short-term (<4 months) mitigation strategy to significantly reduce BMI and inflammatory markers amongst overweight/obese adults at risk of developing severe COVID-19 outcomes. Further research is now needed to examine the role of Mediterranean diet in COVID-19 prevalence, severity, morbidity and mortality.

Caffeine, Coffee, Tea and Risk of Rheumatoid Arthritis: Systematic Review and Dose-Response Meta-analysis of Prospective Cohort Studies.

OBJECTIVE: Prospective cohort studies on coffee, tea and caffeine in relation to the risk of rheumatoid arthritis (RA) have shown conflicting results. The aim of this study was to conduct a dose-response meta-analysis of cohort studies on the association between dietary caffeine, different types of coffee and tea consumption and the risk of RA. METHODS: PubMed/Medline, Scopus and EMBASE were searched up to July 2021 to identify relevant studies that had considered different types of coffee (caffeinated or decaffeinated), tea or caffeine exposure with RA as the main, or one of the, outcome(s). Two authors independently screened 742 publications. Finally, five prospective cohort studies were included in our meta-analysis. Pooled relative risks (RRs) were calculated by using a fixed-effects model. We also performed linear and non-linear dose-response analyses to examine the dose-response relations. RESULTS: Comparing extreme categories, we found a positive, significant association between coffee (RR: 1.30; 95% CI: 1.04-1.62; I 2 = 0%, n = 5) and decaffeinated coffee (RR: 1.89; 95% CI: 1.35-2.65; I 2 = 38.1%, n =3) consumption and risk of RA. One additional cup of coffee consumed per day was associated with an increased risk of RA by 6% (95% CI: 1.02-1.10; I 2 = 0%). This increase in the risk of RA for one cup/d of decaffeinated coffee was 11% (95% CI: 1.05-1.18; I 2 = 38). No significant association was observed between caffeinated coffee, tea or caffeine intake and the risk of RA. CONCLUSION: We found that a higher intake of coffee and decaffeinated coffee was associated with increased risk of RA. No significant association between caffeinated coffee, tea or caffeine intake and the risk of RA was observed. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=227665, identifier: CRD42021227665.

Association between dietary acid load and clinical features of migraine headaches among Iranian individuals.

There is limited evidence regarding the possible role of dietary acid load (DAL) in the pathophysiology of migraine headaches. Therefore, we sought to examine DAL in relation to the clinical features of migraine including headache frequency, severity and duration, headache impact test-6 (HIT-6), and serum levels of nitric oxide (NO). In the present cross-sectional study, 262 patients (38 men and 224 women aged 20-50 years) were recruited through a simple random sampling method. Dietary intakes were obtained by using a validated 168-item semi-quantitative food frequency questionnaire (FFQ). DAL was then calculated by two different methods; potential renal acid load (PRAL) and net endogenous acid production (NEAP). In total, 262 patients with a mean (SE) age of 36.1 (0.53) and a BMI of 25.55 (0.21) were included in the current study. After controlling for potential confounders, a higher DAL was positively associated with headache frequency in those with the highest DAL score compared to the lowest (PRAL; ß = 2.33; 95% CI 0.78, 3.88; NEAP; ß = 1.74; 95% CI 0.13, 3.34). Increasing NEAP from 28.96 to 35.89 resulted in a 3.43 and 2.74 increment in HIT-6 scores in the crude (95% CI 1.35, 5.52) and fully-adjusted models (95% CI 0.40, 5.07), respectively. Moreover, a higher dietary PRAL was significantly associated with migraine-related disability, as shown by HIT-6, in subjects of the third tertile compared to those in the first tertile after controlling for confounders (ß = 2.42; 95% CI 0.13, 4.70). In conclusion, our study highlighted the importance of the acid-base properties of a diet in the pathophysiology of migraine headaches. However, further well-designed studies are needed to confirm our findings.

Biological and pharmacological effects and nutritional impact of phytosterols: A comprehensive review.

Phytosterols (PSs), classified into plant sterols and stanols, are bioactive compounds found in foods of plant origin. PSs have been proposed to exert a wide number of pharmacological properties, including the potential to reduce total and low-density lipoprotein (LDL) cholesterol levels and thereby decreasing the risk of cardiovascular diseases. Other health-promoting effects of PSs include anti-obesity, anti-diabetic, anti-microbial, anti-inflammatory, and immunomodulatory effects. Also, anticancer effects have been strongly suggested, as phytosterol-rich diets may reduce the risk of cancer by 20%. The aim of this review is to provide a general overview of the available evidence regarding the beneficial physiological and pharmacological activities of PSs, with special emphasis on their therapeutic potential for human health and safety. Also, we will explore the factors that influence the physiologic response to PSs.

Methyl gallate isolated from Mangifera pajang kernel induces proliferation inhibition and apoptosis in MCF-7 breast cancer cells via oxidative stress

Objective: To determine the lead bioactive compound in kernel extract of Mangifera pajang and its anti-cancer activity against human breast cancer cell lines with positive estrogen receptor (MCF-7). Methods: The methanolic extract of dried powder kernel of Mangifera pajang was exposed to column chromatography for isolation. The structural elucidation of the isolated compound was characterized using infrared, nuclear magnetic resonance, mass spectrometry. Furthermore, cytotoxicity, morphological changes, flow cytometry and cell cycle arrest analyses were performed to examine the mechanism of anti-proliferation and apoptosis induced by methyl gallate against MCF-7. Results: One compound was isolated from the methanolic extract of Mangifera pajang kernel and identified as methyl gallate. The flow cytometric results demonstrated induction of apoptosis in MCF-7 cells by three concentrations of methyl gallate. The cell cycle arrest showed a significant (P<0.05) decrease in cell progression at G 2/M phase of MCF-7 after treatment with 100 μM of methyl gallate. The cell percentage of early and late apoptosis was significant at 10 and 100 μM of methyl gallate. Also, methyl gallate treatment induced up-regulation of reactive oxygen species levels in MCF-7 cells with a reduction in superoxide dismutase levels. Conclusions: These findings indicate that isolated methyl gallate from Mangifera pajang kernel extracts induces growth inhibition and apoptosis in MCF-7 cells via up-regulating oxidative stress pathway.

Methyl gallate isolated from Mangifera pajang kernel induces proliferation inhibition and apoptosis in MCF-7 breast cancer cells via oxidative stress

Objective: To determine the lead bioactive compound in kernel extract of Mangifera pajang and its anti-cancer activity against human breast cancer cell lines with positive estrogen receptor (MCF-7). Methods: The methanolic extract of dried powder kernel of Mangifera pajang was exposed to column chromatography for isolation. The structural elucidation of the isolated compound was characterized using infrared, nuclear magnetic resonance, mass spectrometry. Furthermore, cytotoxicity, morphological changes, flow cytometry and cell cycle arrest analyses were performed to examine the mechanism of anti-proliferation and apoptosis induced by methyl gallate against MCF-7. Results: One compound was isolated from the methanolic extract of Mangifera pajang kernel and identified as methyl gallate. The flow cytometric results demonstrated induction of apoptosis in MCF-7 cells by three concentrations of methyl gallate. The cell cycle arrest showed a significant (P<0.05) decrease in cell progression at G 2/M phase of MCF-7 after treatment with 100 μM of methyl gallate. The cell percentage of early and late apoptosis was significant at 10 and 100 μM of methyl gallate. Also, methyl gallate treatment induced up-regulation of reactive oxygen species levels in MCF-7 cells with a reduction in superoxide dismutase levels. Conclusions: These findings indicate that isolated methyl gallate from Mangifera pajang kernel extracts induces growth inhibition and apoptosis in MCF-7 cells via up-regulating oxidative stress pathway.

Vitamin D and thyroid disorders: a systematic review and Meta-analysis of observational studies.

BACKGROUND: The contribution of vitamin D to thyroid disorders has received paramount attention; however, results are mixed. Hence, we designed a systematic review and meta-analysis to obtain a definitive conclusion. METHODS: The search included PubMed, ISI Web of Science, Scopus, and Google Scholar databases up to March 2021 to collect available papers reporting the relationship between serum levels of vitamin D and thyroid disorders. The pooled effect was reported as weighted mean difference (WMD) and 95% confidence interval (CI). RESULTS: Out of 6123 datasets, 42 were eligible to get into this systematic review and meta-analysis. Serum vitamin D was markedly lower in autoimmune thyroid diseases (AITD) (WMD - 3.1 ng/dl; 95% CI, - 5.57 to - 0.66; P = 0.013; I2 = 99.9%), Hashimoto's thyroiditis (HT) (WMD - 6.05 ng/dl; 95% CI, - 8.35 to - 3.75; P < 0.001; I2 = 91.0%) and hypothyroidism patients (WMD - 13.43 ng/dl; 95% CI, - 26.04 to - 0.81; P = 0.03; I2 = 99.5%), but not in subjects with Graves' disease (GD) (WMD - 4.14 ng/dl; 95% CI, - 8.46 to 0.17; P = 0.06; I2 = 97.5%). CONCLUSIONS: Our findings suggested lower vitamin D levels in patients with hypothyroidism, AITD, and HT compared to healthy subjects. However, the link between serum vitamin D and GD was only significant among subjects ≥40 years old.

CD105 (Endoglin): A Potential Anticancer Therapeutic Inhibits Mitogenesis and Map Kinase Pathway Activation.

BACKGROUND: CD105 is highly expressed on human activated endothelial cells (ECs), is an important component of the TGF-ß1 receptor complex and is essential for angiogenesis. CD105 expression is up-regulated in activated ECs and is an important potential marker for cancer prognosis. MATERIALS AND METHODS: In vitro rat myoblasts transfected with the L-CD105 and S-CD105 transfectants. The transfectants were treated with TGF-ß1 for the angiogenesis study. RESULTS: L-CD105 affects cell proliferation in the presence and absence of TGF-ß1, and inhibits p-ERK1/2, p-MEK1/2 and p-c-Jun in L-CD105 transfectants compared to controls. The induction of phospho-ERK1/2 following treatment with TGF-ß1 remained significantly lower in L-CD105 transfectants compared to controls. CONCLUSION: L-CD105 inhibits the phosphorylation of ERK1/2, MEK1/2, c-Jun1/2/3, and associated signalling intermediates. CD105 modulates cell growth and TGF-ß1 induced cell signalling through ERK-c-Jun expression.

Honey and its nutritional and anti-inflammatory value.

Inflammation is the main key role in developing chronic diseases including cancer, cardiovascular diseases, diabetes, arthritis, and neurodegenerative diseases which possess a huge challenge for treatment. With massively compelling evidence of the role played by nutritional modulation in preventing inflammation-related diseases, there is a growing interest into the search for natural functional foods with therapeutic and preventive actions. Honey, a nutritional healthy product, is produced mainly by two types of bees: honeybee and stingless bee. Since both types of honey possess distinctive phenolic and flavonoid compounds, there is recently an intensive interest in their biological and clinical actions against inflammation-mediated chronic diseases. This review shed the light specifically on the bioavailability and bioaccessibility of honey polyphenols and highlight their roles in targeting inflammatory pathways in gastrointestinal tract disorders, edema, cancer, metabolic and cardiovascular diseases and gut microbiota.

Acute Inflammation and Oxidative Stress Induced by Lipopolysaccharide and the Ameliorative Effect of Stingless Bee Honey.

BACKGROUND: Systemic acute inflammation is the hallmark of sepsis and is associated with multiple organ dysfunction. OBJECTIVE: This study investigated the potential of Stingless Bee Honey (SBH) to suppress lipopolysaccharide (LPS)-induced systemic acute inflammation in rats and to reveal the probable mechanism of action. METHODS: Rats received 4.6 and 9.2 g/kg SBH for 7 days followed by a single injection of LPS after which blood samples were taken 6h later. RESULTS: LPS induced liver, kidney, heart, and lung injury, were manifested by increased serum transaminases, alkaline phosphatase, creatine kinase, creatinine, and urea, along with multiple histological alterations, particularly leukocyte infiltration. Pro-inflammatory cytokines were elevated in the serum, and NF-κB p65, p38 MAPK, and HMGB-1 were significantly increased in different tissues of LPS-challenged rats. SBH prevented tissue injury, ameliorated pro-inflammatory cytokines, and suppressed NF-κB p65, p38 MAPK, and HMGB-1 in rats that had received LPS. In addition, SBH diminished reactive oxygen species (ROS) production, lipid peroxidation, and oxidative DNA damage, and enhanced glutathione and Nrf2 in LPS-treated rats. CONCLUSION: SBH prevents systemic acute inflammation by suppressing NF-κB, p38 MAPK, HMGB-1, oxidative stress, and tissue injury in rats. Thus, SBH may represent an effective anti-inflammatory nutraceutical, pending further mechanistic studies.

Policy, toxicology and physicochemical considerations on the inhalation of high concentrations of food flavour.

Food flavour ingredients are required by law to obtain prior approval from regulatory bodies, such as the U.S. Food and Drug Administration (FDA) or the European Food Safety Authority (EFSA) in terms of toxicological data and intended use levels. However, there are no regulations for labelling the type and concentration of flavour additives on the product, primarily due to their low concentration in food and generally recognised as safe (GRAS) status determined by the flavour and extract manufacturers' association (FEMA). Their status for use in e-cigarettes and other vaping products challenges these fundamental assumptions, because their concentration can be over ten-thousand times higher than in food, and the method of administration is through inhalation, which is currently not evaluated by the FEMA expert panel. This work provides a review of some common flavour ingredients used in food and vaping products, their product concentrations, inhalation toxicity and aroma interactions reported with different biological substrates. We have identified several studies, which suggest that the high concentrations of flavour through inhalation may pose a serious health threat, especially in terms of their cytotoxicity. As a result of the wide range of possible protein-aroma interactions reported in our diet and metabolism, including links to several non-communicable diseases, we suggest that it is instrumental to update current flavour- labelling regulations, and support new strategies of understanding the effects of flavour uptake on the digestive and respiratory systems, in order to prevent the onset of future non-communicable diseases.

Induction of Chronic Subclinical Systemic Inflammation in Sprague-Dawley Rats Stimulated by Intermittent Bolus Injection of Lipopolysaccharide.

Chronic subclinical systemic inflammation has a key role in stimulating several chronic conditions associated with cardiovascular diseases, cancer, rheumatoid arthritis, diabetes, and neurodegenerative diseases. Hence, developing in vivo models of chronic subclinical systemic inflammation are essential to the study of the pathophysiology and to measure the immunomodulatory agents involved. Male Sprague-Dawley rats were subjected to intraperitoneal, intermittent injection with saline, or lipopolysaccharide (LPS) (0.5, 1, 2 mg/kg) thrice a week for 30 days. Hematological, biochemical, and inflammatory mediators were measured at different timepoints and at the end of the study. The hearts, lungs, kidneys, and livers were harvested for histological evaluation. Significant elevation in peripheral blood leukocyte includes neutrophils, monocytes, and lymphocytes, as well as the neutrophils-to-lymphocyte ratio. The pro-inflammatory mediator levels [C-reactive protein, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1ß, and IL-8] along with the biochemical profile (alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, creatine kinase, creatinine, and urea) were increased significantly (P < 0.05) and increased the expression of monocyte chemoattractant protein-1 and TNF-ß. The histopathological changes of heart, lung, kidney, and liver tissues revealed degeneration, cellular infiltration of leukocyte in the inflammatory foci and interstitial space, edema, early signs of fibrosis, apoptosis, and necrosis. In conclusion, these results indicate that intermittent exposure to LPS produces chronic subclinical systemic inflammation in multiple organs leading to chronic conditions and supports this model to be a useful preclinical tool for developing immunotherapeutic agents that could prevent, or reduce, chronic inflammatory diseases associated with, or without, bacterial translocation.

Stingless bee honey protects against lipopolysaccharide induced-chronic subclinical systemic inflammation and oxidative stress by modulating Nrf2, NF-κB and p38 MAPK.

BACKGROUND: Epidemiological and experimental studies have extensively indicated that chronic subclinical systemic inflammation (CSSI) and oxidative stress are risk factors for several chronic diseases, including cancer, arthritis, type 2 diabetes, and cardiovascular and neurodegenerative diseases. This study examined the protective effect of stingless bee honey (SBH) supplementation against lipopolysaccharide (LPS)-induced CSSI, pointing to the possible involvement of NF-κB, p38 MAPK and Nrf2 signaling. METHODS: CSSI was induced in male Sprague Dawley rats by intraperitoneal injection of LPS three times per week for 28 days, and SBH (4.6 and 9.3 g/kg/day) was supplemented for 30 days. RESULTS: LPS-induced rats showed significant leukocytosis, and elevated serum levels of CRP, TNF-α, IL-1ß, IL-6, IL-8, MCP-1, malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), accompanied with diminished antioxidants. Treatment with SBH significantly ameliorated inflammatory markers, MDA and 8-OHdG, and enhanced antioxidants in LPS-induced rats. In addition, SBH decreased NF-κB p65 and p38 MAPK, and increased Nrf2 expression in the liver, kidney, heart and lung of LPS-induced rats. Furthermore, SBH prevented LPS-induced histological and functional alterations in the liver, kidney, heart and lung of rats. CONCLUSION: SBH has a substantial protective role against LPS-induced CSSI in rats mediated via amelioration of inflammation, oxidative stress and NF-κB, p38 MAPK and Nrf2 signaling.

The effect of extrusion screw-speed on the water extractability and molecular weight distribution of arabinoxylans from defatted rice bran.

Arabinoxylans (AXs) are major dietary fibre in cereals. Recently, AXs have attracted a great deal of attention because of their biological activities. These activities have been suggested to be related to the content of low molecular weight (Mw) AXs, in particular those with Mw below 32 kDa. Rice bran is a rich source of AXs. However, water extraction of AXs is difficult and often gives low yield. Extrusion processing has been used to increase the solubility of cereal dietary fibre. The aim of this research was to study the effect of extrusion screw-speeds (80 and 160) rpm on the extraction yield and Mw of water extractable AXs from rice bran. It was found that the extraction of AXs increased significantly with an increase in screw speed and was accompanied by a significant decrease in the Mw of AXs from extruded rice bran. The percentage of very low molecular weight AXs (0.79-1.58 kDa) significantly increased with increasing screw speed.

Health-related effects and improving extractability of cereal arabinoxylans.

Arabinoxylans (AXs) are major dietary fibers. They are composed of backbone chains of ß-(1-4)-linked xylose residues to which α-l-arabinose are linked in the second and/or third carbon positions. Recently, AXs have attracted a great deal of attention because of their biological activities such as their immunomodulatory potential. Extraction of AXs has some difficulties; therefore, various methods have been used to increase the extractability of AXs with varying degrees of success, such as alkaline, enzymatic, mechanical extraction. However, some of these treatments have been reported to be either expensive, such as enzymatic treatments, or produce hazardous wastes and are non-environmentally friendly, such as alkaline treatments. On the other hand, mechanical assisted extraction, especially extrusion cooking, is an innovative pre-treatment that has been used to increase the solubility of AXs. The aim of the current review article is to point out the health-related effects and to discuss the current research on the extraction methods of AXs.

Commiphora molmol Modulates Glutamate-Nitric Oxide-cGMP and Nrf2/ARE/HO-1 Pathways and Attenuates Oxidative Stress and Hematological Alterations in Hyperammonemic Rats.

Hyperammonemia is a serious complication of liver disease and may lead to encephalopathy and death. This study investigated the effects of Commiphora molmol resin on oxidative stress, inflammation, and hematological alterations in ammonium chloride- (NH4Cl-) induced hyperammonemic rats, with an emphasis on the glutamate-NO-cGMP and Nrf2/ARE/HO-1 signaling pathways. Rats received NH4Cl and C. molmol for 8 weeks. NH4Cl-induced rats showed significant increase in blood ammonia, liver function markers, and tumor necrosis factor-alpha (TNF-α). Concurrent supplementation of C. molmol significantly decreased circulating ammonia, liver function markers, and TNF-α in hyperammonemic rats. C. molmol suppressed lipid peroxidation and nitric oxide and enhanced the antioxidant defenses in the liver, kidney, and cerebrum of hyperammonemic rats. C. molmol significantly upregulated Nrf2 and HO-1 and decreased glutamine and nitric oxide synthase, soluble guanylate cyclase, and Na+/K+-ATPase expression in the cerebrum of NH4Cl-induced hyperammonemic rats. Hyperammonemia was also associated with hematological and coagulation system alterations. These alterations were reversed by C. molmol. Our findings demonstrated that C. molmol attenuates ammonia-induced liver injury, oxidative stress, inflammation, and hematological alterations. This study points to the modulatory effect of C. molmol on glutamate-NO-cGMP and Nrf2/ARE/HO-1 pathways in hyperammonemia. Therefore, C. molmol might be a promising protective agent against hyperammonemia.