Urolithin A affects cellular migration and modulates matrix metalloproteinase expression in colorectal cancer cells.

Colorectal cancer (CRC) is the world's second most common gastrointestinal malignancy. Preventing tumor cell proliferation and dissemination is critical for patient survival. Polyphenols have a variety of health advantages and can help prevent cancer. The current study examined different cellular activities of the gut-microbiota metabolite urolithin A (UA) on several colon cancer cell lines. The results revealed that UA suppressed cell growth in a dose- and time-dependent manner. In the current investigation, UA substantially affected cell migration in the wound-healing experiment and greatly decreased the number of colonies generated in each CRC cell culture. UA decreased cellular migration in CRC cells 48 h after treatment, which was significant (p < .001) compared to the migration rate in untreated cells. When compared to untreated cells, UA slowed the process of colony formation by reducing the number of colonies or altering their morphological shape. The western blot analysis investigation revealed that UA inhibits cellular metastasis by lowering the expression levels of matrix metalloproteinases 1 and 2 (MMP1 and MMP2) by more than 43% and 41% (p < .001) in HT29, 28% and 149% (p < .001) in SW480, and 90% and 74% (p < .001) in SW620, respectively, at a 100 µM dosage of UA compared to the control. Surprisingly, at a 100 µM dosage of UA, the expression levels of the tissue inhibitor of metalloproteinases 1 (TIMP1) were elevated in HT29, SW480, and SW620 cells treated with 100 µM of UA by more than 89%, 57%, and 29%, respectively. Our findings imply that UA has anticancer properties and might be used therapeutically to treat CRC. The findings provided the first indication of the influence of UA on cellular migration and metastasis in colon cancer cells. All of these data showed that UA might be used as an adjuvant therapy in the treatment of various forms of CRC.

Regulation of miRNA-155-5p ameliorates NETosis in pulmonary fibrosis rat model via inhibiting its target cytokines IL-1ß, TNF-α and TGF-ß1.

Idiopathic pulmonary fibrosis (IPF) is an age-related inflammatory disease with no cure up till now.It is accompanied by neutrophils infiltration as the main responders to inflammation and fibrosis. Importantly, neutrophils release neutrophil extracellular traps (NETs) through NETosis process. The function of microRNAs during inflammation became of great biological attention. Owing to microRNAs' central role in immune system, microRNA-155-5p (miR-155-5p) is intensely involved in the inflammatory response. Capsaicin (Cap) is a bioactive compound that exhibits antioxidative and anti-inflammatory functions. Recent studies have shown its role in regulation of certain microRNAs' expressions. Accordingly, the present study aims to investigate the effect of miR-155-5p regulation in suppressing NETs production via ameliorating its target inflammatory cytokines, IL-1ß, TNF-α and TGF-ß1, in bleomycin (BLM)-induced pulmonary fibrosis rat model treated by Cap. The obtained results demonstrated that miR-155-5p downregulation was associated with significant decrease in IL-1ß, TNF-α, TGF-ß1, which consequently, reduced hydroxyproline (HYP), NETs activity markers as NE and PAD-4, and alleviated CTGF levels in lung tissues of animals treated by Cap. Furthermore, NETosis ultrastructure examination by transmission electron microscope (TEM), MPO immunohistochemical staining and histopathological studies confirmed an abolishment in NETs formation and an improvement in lung tissue architecture in Cap-treated rats. This study concluded that Cap quenched the inflammatory response through interrupting IL-1ß, TNF-α and TGF-ß1 pathway via modulating miR-155-5p expression. In addition, Cap was able to alleviate pulmonary NETosis markers by restraining NETs activity markers. These findings provide novel insight into the application of Cap-based treatment in ameliorating pulmonary damage in IPF.

Withania somnifera Alter BCL2/Bax signaling and trigger apoptosis of MCF-7 and MDA-MB231 breast cancer cells exposed to γ-radiation.

Treatment strategies encompass synchronization of more than one therapy with specific dependence on zeroing side effects of natural products that might represent a niche in the continuous struggle against cancer. Thus, this study aimed at assessing the role of Withania somnifera; WS (Ashwagandha) in forcing MCF7 or MDA-MB 231 irradiated breast cancer cells to outweigh the route of programmed cell death. We check to what extent SIRT1-BCL2/Bax signaling pathway was interrelated to form apoptotic cancer cells. MDA or MCF7 cells are categorized into four groups: gp1, Control (C): MDA-MB-231 or MCF7 cells not treated with WS or exposed to γ-rays, gp2 (WS): cells challenged with WS for MDA-MB-231 or MCF7 cells respectively, gp3: irradiated (R) MDA-MB-231 or MCF7 cells exposed to γ-rays (4 Gy; one shot) and gp4 WS and irradiated (WS + R): cells challenged with WS as in gp2 and exposed to gamma rays as in gp3. The results revealed that, WS established IC50 equivalent to 4897.8 µg/ml in MDA-MB-231 cells or equivalent to 3801.9 µg/ml in MCF7 cells. The flowcytometric analysis (Annexin V and cell cycle) showed that WS induces apoptosis at pre-G phase and induces cell arrest at G2/M and preG1 phases for MDA-MB-231 and at the preG1 for MCF7 cells. Furthermore, the WS + R group of cells (MDA-MB-231 and MCF7) showed significant increases in the expression of SIRT1, and BCL2 and a decrease in BAX compared with WS or R group. It could be concluded that WS has an anti-proliferative action on MDA-MB-231 and MCF7 cells because of its capability to enhance apoptosis.

Nattokinase attenuates bisphenol A or gamma irradiation-mediated hepatic and neural toxicity by activation of Nrf2 and suppression of inflammatory mediators in rats.

Nattokinase (NK), a protease enzyme produced by Bacillus subtilis, has various biological effects such as lipid-lowering activity, antihypertensive, antiplatelet/anticoagulant, and neuroprotective effects. Exposure to environmental toxicants such as bisphenol A (BPA) or γ-radiation (IR) causes multi-organ toxicity through several mechanisms such as impairment of oxidative status, signaling pathways, and hepatic and neuronal functions as well as disruption of the inflammatory responses. Therefore, this study is designed to evaluate the ameliorative effect of NK against BPA- or IR-induced liver and brain damage in rats. Serum ammonia level and liver function tests were measured in addition to brain oxidative stress markers, amyloid-beta, tau protein, and neuroinflammatory mediators. Moreover, relative quantification of brain nuclear factor-erythroid 2-related factor-2 (Nrf2)/heme oxygenase-1 (HO-1) genes, as well as apoptotic markers in brain tissue, was carried out in addition to histopathological examination. The results showed that NK improved liver functions, impaired oxidative status, the cholinergic deficits, and minified the misfolded proteins aggregates. Furthermore, NK alleviated the neuroinflammation via modulating NF-κB/Nrf2/HO-1 pathway and glial cell activation in addition to their antiapoptotic effect. Collectively, the current results revealed the protective effect of NK against hepatic and neurotoxicity derived from BPA or IR.

Dual Hyaluronic Acid and Folic Acid Targeting pH-Sensitive Multifunctional 2DG@DCA@MgO-Nano-Core-Shell-Radiosensitizer for Breast Cancer Therapy.

Globally, breast cancer (BC) poses a serious public health risk. The disease exhibits a complex heterogeneous etiology and is associated with a glycolytic and oxidative phosphorylation (OXPHOS) metabolic reprogramming phenotype, which fuels proliferation and progression. Due to the late manifestation of symptoms, rigorous treatment regimens are required following diagnosis. Existing treatments are limited by a lack of specificity, systemic toxicity, temporary remission, and radio-resistance in BC. In this study, we have developed CD44 and folate receptor-targeting multi-functional dual drug-loaded nanoparticles. This composed of hyaluronic acid (HA) and folic acid (FA) conjugated to a 2-deoxy glucose (2DG) shell linked to a layer of dichloroacetate (DCA) and a magnesium oxide (MgO) core (2DG@DCA@MgO; DDM) to enhance the localized chemo-radiotherapy for effective BC treatment. The physicochemical properties of nanoparticles including stability, selectivity, responsive release to pH, cellular uptake, and anticancer efficacy were thoroughly examined. Mechanistically, we identified multiple component signaling pathways as important regulators of BC metabolism and mediators for the inhibitory effects elicited by DDM. Nanoparticles exhibited sustained DDM release properties in a bio-relevant media, which was responsive to the acidic pH enabling eligibility to the control of drug release from nanoparticles. DDM-loaded and HA-FA-functionalized nanoparticles exhibited increased selectivity and uptake by BC cells. Cell-based assays revealed that the functionalized DDM significantly suppressed cancer cell growth and improved radiotherapy (RT) through inducing cell cycle arrest, enhancing apoptosis, and modulating glycolytic and OXPHOS pathways. By highlighting DDM mechanisms as an antitumor and radio-sensitizing reagent, our data suggest that glycolytic and OXPHOS pathway modulation occurs via the PI3K/AKT/mTOR/NF-κB/VEGFlow and P53high signaling pathway. In conclusion, the multi-functionalized DDM opposed tumor-associated metabolic reprogramming via multiple signaling pathways in BC cells as a promising targeted metabolic approach.

Urolithin A induces cell cycle arrest and apoptosis by inhibiting Bcl-2, increasing p53-p21 proteins and reactive oxygen species production in colorectal cancer cells.

Colorectal cancer (CRC) is the second most common gastrointestinal cancer globally. Prevention of tumor cell proliferation and metastasis is vital for prolonging patient survival. Polyphenols provide a wide range of health benefits and prevention from cancer. In the gut, urolithins are the major metabolites of polyphenols. The objective of our study was to elucidate the molecular mechanism of the anticancer effect of urolithin A (UA) on colorectal cancer cells. UA was found to inhibit the cell proliferation of CRC cell lines in a dose-dependent and time-dependent manner in HT29, SW480, and SW620 cells. Exposure to UA resulted in cell cycle arrest in a dose-dependent manner along with alteration in the expression of cell cycle-related protein. Treatment of CRC cell lines with UA resulted in the induction of apoptosis. Treatment of HT29, SW480, and SW620 with UA resulted in increased expression of the pro-apoptotic proteins, p53 and p21. Similarly, UA treatment inhibited the anti-apoptotic protein expression of Bcl-2. Moreover, exposure of UA induced cytochrome c release and caspase activation. Furthermore, UA was found to generate reactive oxygen species (ROS) production in CRC cells. These findings indicate that UA possesses anticancer potential and may be used therapeutically for the treatment of CRC.

Royal jelly modulates oxidative stress and tissue injury in gamma irradiated male Wister Albino rats.

BACKGROUND: Royal jelly is a nutritive secretion produced by the worker bees, rich in proteins, carbohydrates, vitamins and minerals. AIM: The present study was designed to determine the possible protective effects of royal jelly against radiation induced oxidative stress, hematological, biochemical and histological alterations in male Wister albino rats. MATERIALS AND METHODS: Male Wister albino rats were exposed to a fractionated dose of gamma radiation (2 Gy every 3 days up to 8 Gy total doses). Royal jelly was administrated (g/Kg/day) by gavages 14 days before exposure to the 1(st) radiation fraction and the treatment was continued for 15 days after the 1(st) irradiation fraction till the end of the experiment. The rats were sacrificed 3(rd), equivalent to 3rd post 2nd irradiation fraction, and equivalent to 3rd day post last irradiation fraction. RESULTS: In the present study, gamma- irradiation induced hematological, biochemical and histological effects in male Wister albino rats. In royal jelly treated irradiated group, there was a noticeable decrease recorded in thiobarbituric reactive substances concentration when compared to γ-irradiated group. Also, the serum nitric oxide concentration was significantly improved. The administration of royal jelly to irradiated rats according to the current experimental design significantly ameliorates the changes induced in serum lipid profile. Moreover, in royal jelly treated irradiated group, there was a noticeable amelioration recorded in all hematological parameters along the three experimental intervals. The microscopic examination of cardiac muscle of royal jelly treated irradiated rats demonstrated structural amelioration, improved nuclei and normal features of capillaries and veins in endomysium when compared to gamma-irradiated rats. CONCLUSION: It was suggested that the biochemical, hematological and histological amelioration observed in royal jelly (g/Kg/day) treated irradiated rats might be due to the antioxidant capacity of royal jelly active constituents.