SACM - United States of America
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Item Restricted UNRAVELING THE LINK BETWEEN ANTI-INFLAMMATORY DIET, ZINC, AND CADMIUM TOXICITY IN INFLAMMATION REGULATION AMONG CHILDREN AND ADOLESCENTS(Florida International University, 2024) Mobarki, Huda; Liuzzi, JuanZinc (Zn) is known for its antioxidant and anti-inflammatory properties and is important in regulating the body’s inflammatory response. However, there is limited evidence on how factors such as diet and heavy metal toxicity contribute to inflammation in children, and whether these effects are influenced by Zn status. This study aimed to investigate the links between diet, Zn, and cadmium (Cd) toxicity with inflammation, using high-sensitivity C-reactive protein (hsCRP) and white blood cell count (WBCs) as biomarkers. Using data from the 2015-2016 National Health and Nutrition Examination Survey (NHANES), which included 3,507 children in the U.S. aged 2-19 years, we explored the associations between the main exposure variables (Zn, Anti-inflammatory Diet Score (ADS), and Cd) and inflammatory biomarkers. Statistical analysis was conducted using a linear regression model. Of the participants, 49.4% were male and 50.6% female. We observed an inverse relationship between serum Zn and inflammation (β = -.236, p = .008 for WBCs, and β = -.223, p = .035 for hsCRP) after adjusting covariates. Although ADS was inversely associated with inflammation, the relationship was not significant (β = -.006, p = .186 for WBCs, and β = -.003, p = .210 for hsCRP). Significant associations were found between blood Cd and WBCs (β = .436, p = .008), but not for hsCRP. After adjusting for Zn, the relationship between Cd and inflammation became inversely associated (β = -.083 for WBCs, β = -.099 for hsCRP), although these results were not significant, suggesting that Zn may mitigate Cd’s inflammatory effects. To further support the epidemiological findings, we conducted studies using young C. elegans. The experiment consisted of two studies analyzing the effects of Zn and Cd on the survival of the worms using two-way ANOVA and Tukey tests. The results showed that Cd treatment significantly decreased the survival of worms; however, co-incubation with Zn attenuated this effect when the concentration of Cd and Zn were equal (100 µM). In conclusion, the epidemiological data indicate that serum Zn is a more reliable indicator of inflammation in children than Zn intake. The study also suggests zinc status neutralizes Cd's pro-inflammatory effects on inflammatory biomarkers. Additionally, C. elegans model demonstrated that Zn supplementation mitigated Cd-induced toxicity. These findings highlight the importance of maintaining adequate Zn status to mitigate the harmful effects of Cd exposure in children. Therefore, dietary interventions that improve Zn status could potentially reduce inflammation and counteract the adverse impact of Cd exposure on a population level.15 0Item Restricted NOVEL IN SILICO-DESIGNED SMYD3 INHIBITORS ELIMINATE UNRESTRAINED PROLIFERATION OF BREAST CARCINOMA CELLS(Saudi Digital Library, 2023-10-03) Alshiraihi, Ilham Mohammed; Brown, MarkSMYD3 is a lysine methyltransferase that regulates the expression of over 80 genes and is required for the uncontrolled proliferation of most breast, colorectal, and hepatocellular carcinomas. Elimination of SMYD3 restores normal expression patterns of these genes and halts aberrant cell proliferation. In this study, we used in silico screening to identify potential small molecule inhibitors of SMYD3 and tested the ability of these inhibitors to reduce its methyltransferase activity in vitro. Using breast cancer cell lines that overexpress SMYD3 and normal breast epithelial cell lines, we have confirmed the ability of one of these inhibitors, Inhibitor-4, to reduce cell proliferation, arrest the cell cycle, and induce apoptosis in breast cancer cells without affecting normal cell behavior. Our results provide a proof of concept for the in silico design of small molecule enzyme inhibitors and for the use of such an inhibitor to target SMYD3 for the treatment of cancer.14 0Item Restricted THE ANTIPROLIFERA TIVE AND APOPTOTIC EFFECTS OF ANNONA MURICATA EXTRACT ON PROSTATE CANCER CELLS(Saudi Digital Library, 2016-03-15) Bogis, Ahlam Mukhtar; Pino-Figueroa, AlejandroAnnona muricata (AM), a tropical evergreen tree, also known as graviola, guanabana or soursop, belongs to the custard apple tree family known as the Annonaceae. It has become known as a "cancer killer" due to its ability to reduce the proliferation of 12 different types of tumors, including breast, prostate, lung, colon and pancreatic cancers. The major phytochemical compounds that have been identified in AM are cyclic hexapeptides and annonaceous acetogenins (AAGs). The AAGs have been reported to have promising anticancer activities in multidrug resistant cancers (MOR). 10• 11 The structures of AA Gs are comprised of adjacent tetrahydrofuranic rings flanked by hydroxyl groups and tetrahydropyranic rings or epoxides. In previous studies AA Gs have been demonstrated to inhibit the ubiquinone-linked NADH oxidase that is constitutively overexpressed in the membranes of cancer cells, but which is only transiently expressed in normal cells. This event could potentially activate the apoptotic cascade. The purpose of this study was to evaluate the antiproliferative and apoptotic effects of the AM extracts on prostate cancer cells (PC3). The PC3 cells were treated with methanol extract (ME), aqueous fraction (WF), and ethyl acetate fraction (EAF) of AM (l-100 μg/mL). A cell viability assay utilizing 3-( 4, 5-dimethylthiazol-2-yl)-5- (3-carboxymethoxyphenyl)-2-( 4-sulfophenyl)-2H-tetrazolium (MTS) was performed to evaluate the antiproliferative effects. The results demonstrated that EAF results in a significant reduction in cell viability after 24 h (ICso 14.02 ± 1.14 μg/mL). Caspase 3/7 activities were also tested to verify activation of caspases. The activities of caspase 3/7 were significantly elevated 3 h after treatment with IO μg/mL of EAF. Furthermore, PC3 cells exposed to EAF were tested for Bcl-2 and Bax, the regulatory proteins involved in apoptosis, by Western Blot. EAF caused a significant reduction in the expression of the antiapoptotic protein Bcl-2 but had no effect on the expression of the proapoptotic protein Bax. Moreover, the Bax/Bcl-2 ratio was significantly increased after PC3 cells were treated with 30 μg/mL of EAF. These results suggested that the EAF reduces cell proliferation and/or causes cell death in PC3 cells by the induction of apoptosis. Further studies will confirm the application of these plant constituents in cancer therapy.19 0Item Restricted TSLP as a Potential Therapy for CRLF2 B-Cell Acute Lymphoblastic Leukemia(2023) Alkashgari, Hossam; Casiano, Carlos A; Figueroa, Johnny; Francis-Boyle, Olivia; Sun, Richard; Dovat, SinisaCytokine receptor-like factor 2 B-cell acute lymphoblastic leukemia (CRLF2 B- ALL) is a high-risk subtype characterized by CRLF2 overexpression with poor survival rates in children and adults. CRLF2 and interleukin-7 receptor alpha (IL-7Rα) form a receptor for the cytokine thymic stromal lymphopoietin (TSLP), which induces JAK/STAT and PI3K/AKT/mTOR pathway signals. Previous studies from our group showed that low TSLP doses increased STAT5, AKT, and S6 phosphorylation and contributed to CRLF2 B-ALL cell survival. Here we investigated the role of TSLP in the survival and proliferation of CRLF2 B-ALL cells in vitro and in vivo. We hypothesized that high doses of TSLP increase CRLF2 signals and contribute to increased proliferation of CRLF2 B-ALL cells in vitro and in vivo. Interestingly, we observed the opposite effect. Specifically, high doses of TSLP induced apoptosis in human CRLF2 B-ALL cell lines in vitro, prevented engraftment of CRLF2 B-ALL cells, and prolonged the survival of +TSLP patient-derived-xenograft mice. Mechanistically, we showed that continuous and one hour pulse high dose of TSLP induced loss of its receptor and loss of CRLF2 signals in vitro. These results suggest that high doses of TSLP could be further investigated as a potential therapy for the treatment of CRLF2 B-ALL.21 0Item Restricted Modulation of Autistic-Related Factors in Hippocampal Neurons: Role of Oxytocin(2023-04-24) Alfaifi, Hassan; Castejon, AnaBackground: Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with dysregulation of several cellular processes. Accumulating evidence links ASD to the abnormality of cellular growth and programmed cell death (apoptosis). According to many postmortem and animal studies, abnormalities of several apoptotic signaling pathways have been linked to the induction of ASD, such as the ERK and p53 signaling pathways. Besides, the participation of neuroinflammation and oxidative stress in ASD induction and perpetuation has been identified. It has been reported that the levels of ROS and interleukin-1β are abnormally increased in neuronal brain cells in individuals with ASD. Therefore, agents that can improve cellular growth, regulate apoptosis, and reduce oxidative stress and neuroinflammation, like the neuropeptide oxytocin (OXT), may be effective in managing ASD. Objective: Our main goal was to investigate the effects of OXT on autistic-related factors, including cellular growth, oxidative stress, and neuroinflammation, as well as the intracellular signaling pathways involved in these effects. Methodology: We evaluated the effect of OXT on cell growth and death by performing cell counting (hemocytometer), MTT assay, and Bresto blue assay in hippocampal neurons (mHippoE-2). The proliferative effect mechanisms were evaluated using western blotting and MTT assay. In the survival experiments, viability was assessed by MTT assay in cells incubated in the presence or absence of OXT 1000 nM and/or 1000nM OXTA with oxidative stress inducers (H2O2, DMNQ, and CPT) and neuroinflammatory inducer (LPS). The mechanisms of the protective effect were evaluated using western blotting, ELISA. Also, we used the DCFDA kit to evaluate the antioxidant effect of OXT. Moreover, we employed the immunocytochemistry technique to assess the effect of 1000 nM OXT and/or 1000 nM OXTA against the induced morphological alterations. v Results: This study revealed that OXT significantly induced cell growth in hippocampal neurons (mHippoE-2). The OXTA (L-371,257) significantly reduced cell growth. The proliferative effect of OXT is mediated through MEK/ERK signaling pathway. In addition, treatment with 1000 nM OXT significantly reduced the reduction in cell viability induced by oxidative stress inducers (H2O2, CPT, and DMNQ) but not inflammatory inducer (LPS). In addition, OXT significantly reduced ROS generation when the cells were exposed to H2O2 and DMNQ but not CPT. The western blotting technique demonstrated that OXT significantly reduced the protein levels of p53-caspase 3 and increased the levels of Mdm2 induced by H2O2 and DMNQ, but not CPT. Our morphological studies showed that OXT countered the reduction in cellular projection length induced by H2O2, CPT, and DMNQ. Furthermore, OXT significantly reduced the protein levels of PI3K and p-AKT but not the NLRP3-caspase 1 signaling pathway. Conclusion: Our results indicate that OXT has a proliferative effect by activating the ERK signaling pathway. Furthermore, we revealed that the protective effect of OXT was mediated through the modulation of oxidative stress and mitochondrial apoptosis pathway. Moreover, OXT decreased the levels of some inflammatory-mediated proteins. On the other hand, these effects were lacking in the presence of OXTA. These results will contribute to a better understanding of OXT’s potential role in autistic-related factors associated with cell loss, oxidative stress, and neuroinflammation.5 0