Browsing by Author "Siraj, Sohail"
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Item Analyzing the Sex-Dependent Effects of Intranasal Insulin on Memory Impairment Secondary to High-Fat Diet(2019-03-05) Siraj, Sohail; dos Santos, Natalia; Thompson, Lucien PhD; Ahmed, NadiaPurpose: Insulin can improve memory by enhancing the intrinsic excitability of hippocampal CA1 pyramidal neurons during memory consolidation. Chronic high-fat diet (HFD), however, can significantly impair spatial memory via reduction in excitability of these same neurons in both male and female rodent models. Interestingly, sex-dependent experimentation in these models has also shown that CA1 neurons from HFD females retain insulin-sensitivity while those from HFD males do not. Combining these findings from previous studies, it can be hypothesized that insulin therapy would improve memory deficits in females but not males fed a HFD. The following study aims to explore these sex-dependent responses to insulin therapy, as well as the use of intranasal insulin as an alternative and novel method of insulin administration that could potentially eliminate the harmful peripheral side effects of insulin via injection. Methods: Spatial memory of male and female Long-Evans rats fed control vs high-fat diet (HFD) was assessed in a spontaneous alternation task (SAT) using a four-arm radial maze (plus maze). Normally, rats will remember which arm of the maze they last visited and will attempt to sequentially explore new arms. The ability of the rats to do this is scored, with a low score indicating hippocampal impairment. Following behavioral experimentation, insulin tolerance testing was performed in order to rule-out peripheral presence of elevated insulin. Results: Intranasal delivery of insulin reversed memory impairments secondary to high-fat diet in both male and female rats. This was demonstrated by improvement in SAT scores of HFD rats treated with intranasal insulin therapy vs saline. These results were not as expected, but may be explained by the lack of a significant difference in fasting blood glucose levels of control vs high-fat diet animals. This indicates that high-fat diet animals were not showing symptoms of diabetes. It is possible then, that the animals in this experiment were in a pre-disease state where impairments were more readily reversible in both sexes and not just females. Additionally, lack of a decrease in peripheral glucose levels following intranasal insulin administration indicates that intranasal insulin did not have peripheral effects. Conclusions: This study highlights the possibility of the intranasal route as a novel method of insulin administration. Further studies should be conducted to explore the viability of this option compared to the current method of injecting insulin. For example, CSF extraction could be performed to confirm the presence of elevated insulin levels in the brain following intranasal insulin administration, as well as studies that provide further evidence that intranasal delivery bypasses the harmful peripheral side-effects of injected insulin. Lastly, although this study failed to reproduce diabetic responses, future experimentation in aged animals that have been on a HFD for [greater than] 12 weeks could better elucidate whether sex-dependent responses to chronic HFD would have an effect on insulin therapy and reversal of memory impairment.Item Anti-proliferative activity of clotam and copper-clotam against T-cell Acute lymphoblastic leukemia cell line CCRF-CEM(2020) Basha, Riyaz; Siraj, Sohail; Sankpal, Umesh; Polu, Rujula; Patel, KrishnaPurpose: Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children younger than 5 years. Patients with ALL have bone marrow that produces immature white blood cells, which are unable to effectively fight infections. NSAIDs are common pain reliving agents that act through COX inhibition, which stops the production of prostaglandins. Clotam (Tolfenamic Acid/TA) is an NSAID that has anti-tumor proliferative effects. It works through targeting specificity protein (Sp) transcription factors that assist cancer cells in inhibiting apoptosis. Our objective is to test TA and copper-TA (Cu-TA), a derivative of TA, to induce an anti-leukemic response. Methods: The T-cell ALL cell line CCRF-CEM was obtained from the American Type Culture Collection (Manassas, VA) and cells were cultured as per the supplier's instructions. A cell viability assay was performed in which cells were plated in a 96-well plate and treated with increasing concentrations of TA and Cu-TA. After 48-hours, the cells were lysed, and the amount of ATP in the cells was measured using luminescence. Using this data, IC50 values were calculated. Results: The IC50 values showed both TA and Cu-TA had anti-cancer proliferative effects. Cu-TA was 15 times more potent than TA in its ability to kill CCRF-CEM cells. Conclusion: Our results demonstrate that Cu-TA is more effective than TA for killing CCRF-CEM cells. This study suggests better implications of Cu-TA in ALL therapy, if further tested using pre-clinical models.Item Assessing the cytotoxicity of investigational agent for cancer therapy against non-malignant cells(2020) Patel, Krishna; Mukka, Lasya; Sankpal, Umesh; Basha, Riyaz; Siraj, SohailBackground: The treatment of cancer requires chemotherapy (ChT). Most of ChT agents exhibit unwanted side-effect and cause damage to healthy cells. Side effects from commonly used ChT agents are leaving pediatric cancer survivors with lasting damage to organ systems, specifically the heart. Studies conducted by our group demonstrated the anti-cancer activity of clotam (tolfenamic acid-TA) and copper-clotam (Cu-TA). Cu-TA is showing higher cytotoxicity against cancer cells even at much lower dose than TA in pancreatic cancer cells. Our long term objective is to test these agents to sensitize cancer cells to ChT. Methods: Cardiomyocytes H9c2 (cell line derived from rat heart tissue) originally obtained from the American Type Culture Collection (Manassas, VA) were cultured as per the supplier's instructions. H9c2 cells were treated with TA or Cu-TA or Doxorubicin and combinations (for example, TA and Doxorubicin) and cell viability assay was measured using CellTiter-Glo (Promega) kit at 48 hours post-treatment following manufacturer's instructions. Results & Conclusion: We found that TA or Cu-TA are not inducing toxicity in H9c2 cells at tested doses. TA kept more cells alive in conjunction with Doxorubicin than did the control. Our studies also show that H9c2 cells are not toxic to IC50 values of TA or Cu-TA determined with cancer cells. These results provide evidence that the tested investigational gents are not inducing toxicity in cardiomyocytes at tested doses and supports use of these agents in combination therapy with ChT.Item Determining the cytotoxicity of Clotam and Copper-Clotam against Cardiomyocytes(2021) Siraj, Sohail; Patel, Krishna; Mukka, Lasya; Sankpal, Umesh; Basha, RiyazBackground: Chemotherapy (ChT) is required in the treatment of many cancers. Most ChT agents exhibit unwanted side-effects by causing damage to healthy cells. Side effects from many common ChT agents are leaving pediatric cancer survivors with lasting organ system damage, specifically damage to the heart. Past studies conducted by our group demonstrated the anti-cancer activity of clotam (tolfenamic acid-TA) and copper-clotam (CuTA). Our laboratory demonstrated the anti-cancer activity of CuTA against several cancer cell lines. CuTa is showing higher cytotoxicity against cancer cells even at much lower dose than TA. Our long term objective is to test CuTA to sensitize cancer cells to ChT. Methods: Cardiomyocytes H9c2 (cell line derived from rat heart tissue) originally obtained from the American Type Culture Collection (Manassas, VA) were cultured as per the supplier's instructions. H9c2 cells were treated with TA or Cu-TA or Doxorubicin and combinations (for example, TA and Doxorubicin) and cell viability assay was measured using CellTiterGlo (Promega) kit at 48 hours post-treatment following manufacturer's instructions. Results & Conclusion: We found that TA or CuTA were not cytotoxic in H9c2 cells at tested doses. TA kept more cells alive in conjunction with Doxorubicin than did the control. Our results also demonstrate that the IC50 values of TA and CuTA, determined with cancer cell lines, are not toxic to H9c2 cells. These results provide evidence that CuTA does not induce toxicity in cardiomyocytes and supports further testing for translational application in combination therapy with ChT.Item Diabetes in Tarrant County: Populations Most at Risk, Barriers to Acquiring Care, and Resources Available for Disease Management(2019-03-05) Ahmed, Nadia; Mitchell, Michael; Panturu, Stefan; Patel, Vishal; Siraj, SohailAbstract PurposeDiabetes mellitus is quickly becoming a public health crisis in the United States. As of 2015, 23.1 million adults in the U.S. are diagnosed with diabetes, with an estimated 1.5 million new cases diagnosed each year. The purpose of this research is to provide background information on diabetes in Tarrant county. We identified which populations are most at risk for being diagnosed with Diabetes Mellitus (DM) Type II, determined potential barriers to acquiring care, and searched for regional programs available for disease management. Materials and MethodsEpidemiological information regarding DM in Texas was acquired through searching the Texas Department of State Health Services for current census information, as well as the CDC for national data in order to compare regional statistics to the rest of the U.S. population. A web search for local resources was conducted and relevant information for five available organizations providing care for DM patients of Tarrant County is presented here. ResultsDiabetes is the 6th leading cause of death in Tarrant County. Diabetes prevalence is highest among Non-Hispanic African Americans (16%), followed by Hispanics (12%). Prevalence of diabetes in Tarrant county is also higher among adults who did not graduate from high school. In Tarrant county, 21.9% of the population is uninsured, compared to 12.2% nationally. Resources available in Tarrant county for disease management include; Tarrant County Diabetes Collaboration, HealthForMe Self Management Classes, United Way of Tarrant County, Texas Healthy Lifestyles Workshop, and JPS Diabetes Education program. ConclusionsIn Tarrant county diabetes prevalence is highest in African American and Hispanic populations. Barriers to acquiring care include lack of health insurance and lack of knowledge regarding proper nutrition. Various community resources are available to aide in management of diabetes.Item Evaluating the anti-leukemic effect of clotam and copper-clotam using CCRF-CEM cell lines(2021) Patel, Krishna; Siraj, Sohail; Basha, Riyaz; Sankpal, UmeshPurpose: Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children younger than 5 years. Patients with ALL have bone marrow that produces immature white blood cells, which are unable to effectively fight infections. NSAIDs are common pain reliving agents that act through COX inhibition, which stops the production of prostaglandins. Clotam (Tolfenamic Acid/TA) is an NSAID that has anti-tumor proliferative effects. It works through targeting specificity protein (Sp) transcription factors that assist cancer cells in inhibiting apoptosis. Our objective is to test TA and copper-TA (Cu-TA), a derivative of TA, to induce an anti-leukemic response. Methods: The T-cell ALL cell line CCRF-CEM was obtained from the American Type Culture Collection (Manassas, VA) and cells were cultured as per the supplier's instructions. A cell viability assay was performed in which cells were plated in a 96-well plate and treated with increasing concentrations of TA and Cu-TA. After 48-hours, the cells were lysed, and the amount of ATP in the cells was measured using luminescence. Using this data, IC50 values were calculated. Results: The IC50 values showed both TA and Cu-TA had anti-cancer proliferative effects. Cu-TA was 15 times more potent than TA in its ability to kill CCRF-CEM cells. Conclusion: Our results demonstrate that Cu-TA is more effective than TA for killing CCRF-CEM cells. This study suggests better implications of Cu-TA in ALL therapy, if further tested using pre-clinical models.