Louisiana Research Day Program Book 2025

Biomedical Research: Section 1

Biomedical Research: Section 1

Mohammed Almosa, OMS-II; Hamza Mehmood, OMS-II; Ishrar Shaid, OMS-II; John Woeste, OMS-II; Christian Caper, OMS-II; Dalal Dawud, Pharm D; Zakaria Abd Elmageed, PhD; Hassan Ebrahim, PhD VCOM-Louisiana 10 THE SHRUBBY SOPHORA SUPPRESSES THE ONCOGENESIS OF HUMAN BREAST CANCER CELLS

Hunter Santogrossi, DO 2 ; Ryan Vergara, DO 2 ; Keith Jackson, PhD 2 ; Dinesh Aryal, PhD 2 1 VCOM-Louisiana; 2 ULM, College of Pharmacy 11 EFFECT OF RENAL HEME OXYGENASE ON RENAL VASCULAR BLOOD FLOW DURING CHRONIC ACIDOSIS CONDITIONS IN RATS

Context: wNatural products (NPs), also known as secondary metabolites, constitute a unique resource for the discovery of validated hits, lead compounds and drug candidates. NPs are characterized by enormous scaffold diversity and structure complexity when compared to synthetic molecules making them ideals templates for early drug discovery. Furthermore, their structural three dimensionality, rigidity, and chirality empower NPs to interrogate the complex biological systems in a selective and efficient manner. Shrubby Sophora is a flowering plant belonging to family Fabaceae and is native to China. It harbors NPs of diverse chemical classes including alkaloids, flavonoids, isoflavonoids, and prenylated phenolics. Breast cancer (BC) is the most common diagnosed cancer and the second leading cause of death among women worldwide. In the US, statistics approximate that 1 in 8 American women will be diagnosed with BC during lifetime, and 1 in 43 will die from the advanced BC, highlighting the significant impact of the disease. Objectives and/or Hypothesis: Previous studies demonstrated the significant role of Sophora-derived phytochemicals in modulating

various human diseases, including cancer. Herein we aimed at identifying bioactive phytochemicals in the shrubby Sophora extract that are most likely mediating the anti BC activity and investigating their potential macromolecular targets. Polarity-based fractionation of the shrubby Sophora extract was executed by partition extraction technique. Fractions were tested against multiple human BC cells and to guide the efforts towards identifying biomolecules that most likely mediating the anticancer effect of Sophora. Cell proliferation, apoptosis, and cell cycle analysis were used to characterize the anticancer effect of the purified compounds. Computational molecular modeling and enzymatic assays were utilized to uncover the mechanistic target. Results: Shrubby Sophora extract significantly suppressed the proliferation of MDA-MB-468, MDA-MB-231, MCF-7, and BT-474 human BC cells in a concentration-dependent manner at low µg/mL concentration range. Additionally, the bioassay-guided fractionation of Sophora extract have led to the discovery of a pterocarpan flavonoid with potent anticancer activity at low µM level (IC50 values of 17.6,

19.1, 14.7 and 16.5 µM against the BC cell panel, respectively). Furthermore, it induced cell apoptosis and cell cycle arrest at G2/M phase. Computational molecular modeling suggested DNA topoisomerases as potential macromolecular targets, which was validated by DNA relaxation assays. Conclusion: NPs will stand as innovative resources for the discovery of anticancer hits. The bioassay-guided fractionation of shrubby Sophora extract have led to the discovery of a pterocarpan flavonoid as a DNA topoisomerases inhibitor with potential anticancer activity against human BC cells. Future preclinical studies are encouraged to validate the bioactivity of this novel herb.

Background: Chronic metabolic acidosis (CMA) characterized by prolonged systemic acidemia have been associated with various pathological conditions. Hypertension, as an outcome of prolonged acidosis, has been recently observed in experimental animals. It is documented that heme oxygenase-1 (HO-1), influences renal hemodynamics by affecting vascular tone and blood flow, potentially contributing to the regulation of blood pressure. We recently reported the renal HO-1 levels rise during chronic acidosis. The cellular and molecular events mediating the effects of acidosis on vascular homeostasis are incompletely understood. In the present study, we investigated the effect of HO-1 on renal vascular blood flow as well as the role of renal HO-1 on renal oxidative stress during chronically acidotic conditions. Objectives: (i) To examine renal blood flow during chronic acidosis condition to determine the potential renovascular hypertension, (ii) To measure the renal oxidative stress mediated by renal HO-1 during chronic acidosis conditions.

(I. Control, II. CMA, III. CMA+DALA, IV. CMA+Fasudil, V. CMA+ZnPP). 0.28M ammonium chloride induced chronic acidosis model is implemented for the latter 4 groups along with respective inducer/inhibitor treatments (once a week), for the period of 8 weeks. At the end of the experiment, renal arteries of all animals were examined for renal blood flow using Laser Doppler Flowmeter. Arterial walls were observed and quantified via imaging. ELISA was performed to measure the eNOS levels in the whole blood samples collected from each animal. The microdialysis samples taken from kidney interstitium of each animal were analyzed for their superoxide dismutase (SOD) levels and HO-1 levels. All animals used in this work were approved by IACUC at University of Louisiana at Monroe (Protocol # 23 SEPT DA_KEJ 01). Results: HO-1 levels in the renal interstitium of Group II were significantly elevated vs control group. The man arterial pressure (MAP) rises significantly in the CMA group though, as expected. The renal blood flow in all five groups weren’t significantly changed. Furthermore, there was no sign of stenosis in all the animals examined. Interestingly, the eNOS levels in CMA

was reduced significantly vs control group. This suggested that the elevated renal HO-1 in CMA group might have reduced the nitric oxide (NO) release in the vasculature which perhaps led to rise in MAP. No changes were seen in eNOS levels in groups: III & V, compared to group II. However, group IV showed a significant increase in eNOS levels vs group II. SOD levels in group II were reduced significantly vs the control group. Surprisingly, ROCK inhibitor (Fasudil) treated group had significantly increased levels of SOD compared to the CMA group. Conclusions: No renal blood flow was impaired in the experimented animals subjected to chronic metabolic acidosis. This suggested, no renovascular hypertension is contributing to the increase in MAP in the CMA group. Renal HO-1 may inhibit the release of eNOS leading to declining nitric oxide to promote the observed hypertension. Rho Kinase (ROCK) played a significant role compared to HO-1 to reduce the renal oxidative stress during chronic metabolic acidosis. Future studies are likely to further define the importance of HO-1 and ROCK synergism if any existed to clarify their independent role in chronic acidosis.

Methods: Male Sprague Dawley rats weighing 150-320g were grouped into 5 groups (n=5).

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2025 Research Recognition Day