Search

Although single treatment with sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) or vitamin D3 (VD3) inhibited metabolic dysfunction‐associated steatohepatitis (MASH) development in diabetic patients, their combination has not been explored previously. Hence, this study investigated the hepatoprotective effects of SGLT2i (empagliflozin) and/or VD3 against MASH in type 2 diabetic mice. Forty Mice were assigned into negative (NC) and positive (PC) controls, SGLT2i, VD3, and SGLT2i + VD3 groups. All animals, except the NC group, received high‐fructose/high‐fat diet (8 weeks) followed by diabetes induction. Diabetic mice then received another cycle of high‐fructose/high‐fat diet (4 weeks) followed by 8 weeks of treatment (five times/week) with SGLT2i (5.1 mg/kg/day) and/or VD3 (410 IU/Kg/day). The PC group demonstrated hyperglycaemia, dyslipidaemia, elevated liver enzymes, and increased non‐alcoholic fatty liver disease activity score (NAS) with fibrosis. Hepatic glucose transporting molecule (SGLT2) with lipogenesis (SREBP‐1/PPARγ), oxidative stress (MDA/H2O2), inflammation (IL1β/IL6/TNF‐α), fibrosis (TGF‐β1/α‐SMA), and apoptosis (TUNEL/Caspase‐3) markers alongside the PI3K/AKT/mTOR pathway increased in the PC group. Conversely, hepatic insulin‐dependent glucose transporter (GLUT4), lipolytic (PPARα/INSIG1), antioxidant (GSH/GPx1/SOD1/CAT), and anti‐inflammatory (IL‐10) molecules with the inhibitor of PI3K/AKT/mTOR pathway (PTEN) decreased in the PC group. Whilst SGLT2i monotherapy outperformed VD3, their combination showed the best attenuation of hyperglycaemia, dyslipidaemia, and fibrosis with the strongest modulation of hepatic glucose‐transporting and lipid‐regulatory molecules, PI3K/AKT/mTOR pathway, and markers of oxidative stress, inflammation, fibrosis, and apoptosis. This study is the first to reveal boosted hepatoprotection for SGLT2i and VD3 co‐therapy against diabetes‐induced MASH, possibly via enhanced metabolic control and modulation of hepatic PI3K/AKT/mTOR, anti‐inflammatory, anti‐oxidative, and anti‐fibrotic pathways. [ABSTRACT FROM AUTHOR]

This study investigated the chemotherapeutic effects of 5‐fluorouracil (5‐FU), metformin (Met), and/or thymoquinone (TQ) single/dual/triple therapies in the HT29, SW480 and SW620 colon cancer (CRC) cell lines. Cell cycle/apoptosis were measured by flow cytometry. The gene and protein expression of apoptosis (PCNA/survivin/BAX/Cytochrome‐C/Caspase‐3) and cell cycle (CCND1/CCND3/p21/p27) molecules, the PI3K/mTOR/HIF1α oncogenic pathway, and glycolysis regulatory enzymes were measured by quantitative‐PCR and Western blot. Markers of oxidative stress were also measured by colorimetric assays. Although all treatments induced anti‐cancer effects related to cell cycle arrest and apoptosis, the triple therapy showed the highest pro‐apoptotic actions that coincided with the lowest expression of CCND1/CCND3/PCNA/survivin and the maximal increases in p21/p27/BAX/Cytochrome‐C/Caspase‐3 in all cell lines. The triple therapy also revealed the best suppression of the PI3K/mTOR/HIF1α pathway by increasing its endogenous inhibitors (PTEN/AMPKα) in all cell lines. Moreover, the lowest expression of lactate dehydrogenase and pyruvate dehydrogenase kinase‐1 with the highest expression of pyruvate dehydrogenase were seen with the triple therapy, which also showed the highest increases in oxidative stress markers (ROS/RNS/MDA/protein carbonyl groups) alongside the lowest antioxidant levels (GSH/CAT) in all cell lines. In conclusion, this is the first study to reveal enhanced anti‐cancer effects for metformin/thymoquinone in CRC that were superior to all monotherapies and the other dual therapies. However, the triple therapy approach showed the best tumoricidal actions related to cell cycle arrest and apoptosis in all cell lines, possibly by enhancing oxidative glycolysis and augmenting oxidative stress through stronger modulation of the PI3K/mTOR/HIF1α oncogenic network. [ABSTRACT FROM AUTHOR]

Zamzam is a Muslim holy water from a well in Al-Haram in the holy city of Makkah. It has alkaline pH and high levels of minerals such as calcium, sodium, and magnesium. A previous study found that alkaline water induces antioxidant activity during oxidative stress. This study aimed to evaluate Zamzam's antioxidant activity during oxidative stress induced by Nerium oleander in mice. Forty 6-to 8-week-old Blab/c mice were classified into four groups: control, Zamzam water, Nerium oleander, and Zamzam water-Nerium oleander. The weight of each mouse was measured at the beginning, after 3 and 6 weeks, and at the end of the experiment. At the end of the experiment, a blood sample was collected from each mouse in plain and EDTA tubes for estimation of hematological and chemical parameters, respectively. Furthermore, the mice were sacrificed, and the heart, liver, and kidney were immediately collected and washed with saline. These organs were used for histopathological and biochemical tests. The hematological parameters (RBCs count, hemoglobin, hematocrit, and MCV, besides serum ALT, AST, total CK, CK-MB, and ctroponin I were measured for each mouse. Moreover, lipid peroxidation (LPO), carbonyl carbon (CC), reduced glutathione (GSH), catalase, glutathione peroxidase (GSH Px), and superoxide dismutase (SOD) were estimated in cardiac, hepatic, and kidney homogenates. The mice in the Zamzam water group had significantly higher weight gain by the end of 3 and 6 weeks (p<0.05), and at the end of the experiment (p<0.01). The hematological parameters had no statistically significant differences between the four groups. Serum AST, ALT, total CK, CK-MB, and ctroponin I showed statistically significant differences among all groups (p<0.01). Both LPO and CC levels in cardiac homogenate were significantly reduced in the Zamzam water group (p<0.01 and p<0.05, respectively). Moreover, GSH level and catalase, GSH Px, and SOD activities were significantly elevated in the Zamzam water group in the same homogenate. In hepatic homogenate, GSH level and catalase activity were increased significantly in the Zamzam water group (p<0.05). Finally, the LPO level was significantly decreased (p<0.01), while catalase activity increased (p<0.05) in the Zamzam water group. Zamzam water has an antioxidant capacity during oxidative stress. This capacity may result from the induction of the antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase. Moreover, Zamzam's minerals and chemical elements have nutritional value that induces weight gain in mice. [ABSTRACT FROM AUTHOR]

Background: Metastatic secondary ocular tumors spread from systemic malignancies, including breast cancer. This study aimed to evaluate the cytotoxicity of extracts from 5 medicinal plants native to Saudi Arabia., Methods: For preliminary activity screening, cytotoxicity using the MTT assay and selectivity index determinations were made for medicinal plant extracts against various cancer cell-lines. The most promising extract was subjected to GC-MS analysis to determine the phytochemical composition. Clonogenic assays were performed using the most promising extract to confirm the initial results. Finally, western blot analysis was used to determine the modulation in expression of survivin and P27 suppressor genes in the human breast adenocarcinoma (MCF7) cell-line to understand the potential mechanistic properties of the active plant extract., Results: The 5 plant extracts showed various cytotoxic activity levels using IC 50 . The most active extract was found to be the leaves of Capparis spinosa L. ( BEP-07 extract) against the MCF7 breast cancer cell-line (IC 50  = 3.61 ± 0.99 μg/ml) and selectivity index of 1.17 compared to the normal human fetal lung fibroblast (MRC5) cells. BEP-07 extract showed a dose dependent clonogenic effect against the MCF7 colonies which was comparable with the effect of doxorubicin. BEP-07 extract caused a significant decrease of survivin and increase in P27 expression compared to control GAPDH at its highest dose (14 µg/ml). The GC-MS chromatogram of Capparis spinosa L. ( BEP-07 extract) revealed the existence of 145 compounds, belonging to the diverse classes of phytoconstituents. Fatty acids and their derivatives represent 15.4%, whilst octadecanoic acid, 2,3-dihydroxypropyl ester was the principal component (7.9%) detected., Conclusion: Leaves of Capparis spinosa L. ( BEP-07 extract) exhibited a significant cytotoxic effect particularly against breast cancer cells. It exhibited this effect through survivin inhibition and via P27 upregulation. The detected phytoconstituents in the plant extract might be involved in tested cytotoxic activity, while further investigations are required to complete the drug candidate profile., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.