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

Ranneh Y, Akim AM, Hamid HA, Khazaai H, Mokhtarrudin N, Fadel A, et al.

Arch Immunol Ther Exp (Warsz), 2019 Dec;67(6):385-400.
PMID: 31278602 DOI: 10.1007/s00005-019-00553-6

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-1β, 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
Fulltext Stingless bee honey protects against lipopolysaccharide induced-chronic subclinical systemic inflammation and oxidative stress by modulating Nrf2, NF-κB and p38 MAPK

Ranneh Y, Akim AM, Hamid HA, Khazaai H, Fadel A, Mahmoud AM

Nutr Metab (Lond), 2019;16:15.
PMID: 30858869 DOI: 10.1186/s12986-019-0341-z

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-1β, 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.
Acute Inflammation and Oxidative Stress Induced by Lipopolysaccharide and the Ameliorative Effect of Stingless Bee Honey

Ranneh Y, Mahmoud AM, Fadel A, Albujja M, Akim AM, Hamid HA, et al.

Comb Chem High Throughput Screen, 2021;24(6):744-757.
PMID: 32957878 DOI: 10.2174/1386207323999200918152111

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

Fadel A, Plunkett A, Ashworth J, Mahmoud AM, Ranneh Y, El Mohtadi M, et al.

J Food Sci Technol, 2018 Mar;55(3):1201-1206.
PMID: 29487463 DOI: 10.1007/s13197-017-3010-0

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

Ranneh Y, Abu Bakar MF, Md Akim A, Bin Baharum Z, S Ellulu M, Fadel A

Asian Pac J Cancer Prev, 2023 Jul 01;24(7):2473-2483.
PMID: 37505782 DOI: 10.31557/APJCP.2023.24.7.2473

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.
Fulltext Comments on "Probiotic Bifidobacterium strains and galactooligosaccharides improve intestinal barrier function in obese adults but show no synergism when used together as synbiotics"

Ranneh Y, Mahmoud AM, Fadel A, Abu Bakar MF, Md Akim A

Front Pharmacol, 2023;14:1228359.
PMID: 37663246 DOI: 10.3389/fphar.2023.1228359
Fulltext Honey and its nutritional and anti-inflammatory value

Ranneh Y, Akim AM, Hamid HA, Khazaai H, Fadel A, Zakaria ZA, et al.

BMC Complement Med Ther, 2021 Jan 14;21(1):30.
PMID: 33441127 DOI: 10.1186/s12906-020-03170-5

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.
Fulltext The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity

Colombo M, Lòpez-Perolio I, Meeks HD, Caleca L, Parsons MT, Li H, et al.

Hum Mutat, 2018 May;39(5):729-741.
PMID: 29460995 DOI: 10.1002/humu.23411

Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10-115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.