Life Sciences Commons^™

Role Of Alström Syndrome 1 (Alms1) In Nkcc2 Endocytosis, Thick Ascending Limb Function, Blood Pressure Regulation And Metabolic Function, Ankita Bachhawat Jaykumar

Wayne State University Dissertations

NaCl absorption by the Thick Ascending Limb (TAL) is mediated by the apical Na+/K+/2Cl- co-transporter, NKCC2. Increased NKCC2 activity and apical trafficking are associated to salt sensitive hypertension in rodents and humans. NKCC2 endocytosis is important for maintaining surface NKCC2 such that blocking NKCC2 endocytosis increased NKCC2 surface abundance and NKCC2-mediated NaCl reabsorption. Despite its importance, NKCC2 endocytosis has been poorly studied and a part of the reason may be attributed to the lack of availability of methods with good time resolution. Hence, we developed a method to image apical NKCC2 to monitor its endocytosis in real-time by Total Internal …

Axonal Transport, Parkin, And Α-Synuclein; Novel Therapeutic Targets To Treat Methamphetamine Neurotoxicity, Bryan Andrew Killinger

Wayne State University Dissertations

Methamphetamine (METH) is a commonly abuse psychostimulant. Exposure to chronic high doses of METH can result in neurotoxicity primarily characterized by damage to striatal dopaminergic (DAergic) axons. There are currently no therapeutic interventions for METH neurotoxicity. To some extent damage to striatal DAergic axons is reversible and DAergic axon function may return following abstinence from METH. The reversible nature of METH neurotoxicity suggests that normal striatal function could be restored following exposure to METH. However, potential targets to treat METH neurotoxicity are needed. Axonal transport is required for restoration of DAergic axon components damaged or lost following METH. Here we …

Biomechanics Of Concussion: The Importance Of Neck Tension, Ron Jadischke

Wayne State University Dissertations

Linear and angular velocity and acceleration of the head are typically correlated to concussion. Despite improvements in helmet performance to reduce accelerations, a corresponding reduction in the incidence of concussion has not occurred (National Football League [NFL] 1996 – present).

There is compelling research that forces on and deformation to the brain stem are related to concussion. The brain stem is the center of control for respiration, blood pressure and heart rate and is the root of most cranial nerves. Injury to the brain stem is consistent with most symptoms of concussion reported in the National Football League and the …

Novel Functions Of Cardiolipin Remodeling In Saccharomyces Cerevisiae And Mammalian Cells: Implications For Barth Syndrome, Wenjia Lou

Wayne State University Dissertations

Cardiolipin (CL) is a unique phospholipid that is primarily localized within the inner mitochondrial membrane. Newly synthesized CL undergoes acyl remodeling to produce CL species enriched with unsaturated acyl groups. The tafazzin gene (TAZ) encodes a transacylase that remodels CL. Deficiencies in CL remodeling cause Barth syndrome (BTHS), an X-linked genetic disorder resulting from TAZ mutations that lead to reduced total CL content and an accumulation of monolysocardiolipin (MLCL), an intermediate of the CL remodeling pathway. However, which of these biochemical outcomes contributes to the physiological defects is not fully understood.

Deletion of yeast CL phospholipase rescues the taz1growth phenotype. …

Human Kinome In Skeletal Muscle Insulin Resistance, Yue Qi

Wayne State University Dissertations

Protein kinases play fundamental roles in regulation of biological processes and functions, such as insulin signaling and glucose metabolism. Dysregulation of protein kinases may cause impaired cell signaling and human diseases, such as metabolic syndrome and type 2 diabetes (T2D). Skeletal muscle is the main site responsible for insulin-stimulated glucose disposal, and insulin resistance in skeletal muscle is one of the key features of the pathogenesis of T2D. Therefore, malfunction of protein kinases and their interaction proteins may contribute to the molecular mechanism of insulin resistance in human skeletal muscle. However, no large scale profiling study has been reported to …

Design, Synthesis And Biological Evaluation Of Histone Deacetylase (Hdac) Inhibitors: Saha (Vorinostat) Analogs And Biaryl Indolyl Benzamide Inhibitors Display Isoform Selectivity, Ahmed Negmeldin

Wayne State University Dissertations

HDAC proteins have emerged as interesting targets for anti-cancer drugs due to their involvement in cancers, as well as several other diseases. Several HDAC inhibitors have been approved by the FDA as anti-cancer drugs, including SAHA (suberoylanilide hydroxamic acid, Vorinostat). Unfortunately, SAHA inhibits most HDAC isoforms, which limit its use as a pharmacological tool and may lead to side effects in the clinic. In this work we were interested in developing isoform selective HDAC inhibitors, which may decrease or eliminate the side effects associated with non-selective inhibitors treatment. In addition, isoform selective HDAC inhibitors can be used as biological tools …

Effects Of Dietary Intake Of Antioxidants And Omega-3 Fatty Acids On Free Radical Production In Children At Various Stages Of Chronic Kidney Disease, Linda Marie Sawyer

Wayne State University Dissertations

The purpose of this study was to understand the relationship between dietary intake of antioxidants and omega-3 fatty acids on free radical injury and free radical scavenging in children with chronic kidney disease (CKD) so that complications of kidney failure, especially cardiovascular disease, may be avoided or delayed. Children with CKD on dialysis and post-renal transplantation are at an extremely high risk for cardiovascular morbidity and mortality. We hypothesized that children with CKD who have higher dietary intake of antioxidants and omega-3 FAs, would have lower free radical injury, as measured by 8-Isoprostanes (8-ISOP) and Thiobarbituric Acid Reactive Substances (TBARS) …

Development Of Chemical Tools To Investigate Protein S-Glutathionylation In Response To Metabolic Alteration, Kusal Theekshana Gayan Samarasinghe

Wayne State University Dissertations

Oxidative stress is a common characteristic of age-related diseases such as vascular diseases, diabetes and cancer. Many diseases are known to be regulated by glutathionylation. Glutathionylation is referred to as the formation of disulfide bond between a protein cysteine and a glutathione. To understand the molecular mechanisms behind the disease initiation and progression, identification of such glutathionylated proteins is important. Even though existing methods have been widely used, several limitations of these methods hinder the identification of such proteins in disease conditions. Therefore, we developed a versatile chemical method that generates clickable glutathione inside the cells. In this method, we …

Development Of A Finite Element Pelvis And Lower Extremity Model With Growth Plates For Pediatric Pedestrian Protection, Ming Shen

Wayne State University Dissertations

Finite element (FE) model is a useful tool frequently used for investigating the injury mechanisms and designing protection countermeasures. At present, no 10 years old (YO) pedestrian FE model has been developed from appropriate anthropometries and validated against limitedly available impact response data. A 10 YO child FE pelvis and lower extremities (PLEX) model was established to fill the gap of lacking such models in this age group. The baseline model was validated against available pediatric postmortem human subjects (PMHS) test data and additional scaled adult data, then the PLEX model was integrated to build a whole-body FE model representing …

Biofidelity Assessment Of 6-Year-Old Anthropometric Test Devices (Atds) And Scaling Laws In Lateral Impact, Jennifer Yaek

Wayne State University Dissertations

There is a clear need to further develop the design and biofidelity of the 6-Year-Old ATDs for future child safety research and child occupant protection in side impacts. Due to the scarcity of pediatric PMHS impact testing, specifically in the lateral direction, alternative means of obtaining relevant data for pediatric models need to be considered.

In this first portion of this study, assessment of the mechanical behavior and biofidelity of existing 6-Year-Old ATDs in lateral impact were performed. None of the three 6-year-old ATDs (HIII, Q6, and Q6s) tested were found to be considered good tools for assessing side impact …

The In Vivo Effect Of Oil Palm Phenolics (Opp) In Atherogenic Diet Induced Rats Model Of Alzheimer’S Disease (Ad), Yan Wu

Wayne State University Dissertations

Alzheimer’s disease (AD) is the most common cause of dementia in the aging population. It is characterized by cognitive decline and deposition of ß-amyloid plaques in the hippocampus. It has been shown that hypercholesterolemia induced by high cholesterol diet is associated with AD development. Increased level of oxidative stress has also been observed in AD patients. An important strategy to treat or delay the impairment is based on dietary modification, using food supplements. OPP, a water soluble fraction from oil palm fruit, rich in phenolics has been found to possess significant antioxidant activities. Its beneficial effects on cardiovascular diseases, diabetes …

Optimization Of Growth Conditions And Characterization Of Properties On Christensenella Minuta, Qing Ai

Wayne State University Theses

Currently, increasing numbers of people are suffering from obesity. The gut microbiome becomes a useful approach to control the mechanisms associated with obesity. A novel bacterium, Christensenella minuta, which was discovered in 2012, triggers body weight loss. Our purpose in this study is to further realize characteristics of C. Minuta as a potential probiotic supplement for future obesity studies. This study determines the following characteristics of C. Minuta: DNA identification, turbidity verification, generation time, as well as optimization of pH and temperature. To test the tolerance of C. Minuta as a gastrointestinal treatment, the pH and bile salts concentration in …

An Evaluation Of Endocrine Disrupting Effects Of Emerging Contaminants Using Daphnia Pulex And Danio Rerio, Lakshmi Neha Reddy Alla

Wayne State University Theses

The limit of the availability of water is based on two factors, scarcity and quality. Conserving and protecting our water resources one of the most critical issues facing humanity as we struggle to deal with contaminated lakes and rivers and climate change. The main aim of this study is to examine toxicity of known water contaminants on aquatic model organisms and be able to develop methodology that will enable the characterization of endocrine disrupting potential of water samples with unknown contaminants. Both the category of water contaminants known as pharmaceuticals, personal care products that are known as PPCPs and other …

Metformin, Glucotoxicity And Islet Dysfunction, Sartaj S. Baidwan

Wayne State University Theses

METFROMIN, GLUCOTOXICITY AND ISLET DYSFUNCTION

by

SARTAJ BAIDWAN

MAY 2017

Advisor: Dr. Anjaneyulu Kowluru

Major: Pharmaceutical Sciences

Degree: Master of Science

Glucotoxicity is the leading cause for β-cell dysfunction [e.g., defective glucose-stimulated insulin secretion] in Type 2 Diabetes [T2DM]. Recent studies from our lab have shown sustained Rac1 activation leading to the activation of downstream signaling steps including stress kinase [p53, p38MAPK] activation and mitochondrial dysregulation [caspase-3 activation] in pancreatic islet beta-cells exposed to glucotoxic [HG] conditions [20 mM; 24 hrs]. Metformin [MF] is an oral anti-diabetic drug that is being widely prescribed to T2DM. MF works by suppressing hepatic …

The Effect Of Acetylation Of Cytochrome C On Its Functions In Prostate Cancer, Viktoriia Bazylianska

Wayne State University Theses

Prostate cancer is the second leading cause of cancer death among men in America. The progression of cancer goes along with the Warburg effect, a metabolic switch from depending primarily on mitochondrial respiration to glycolysis. In addition, cancer cells manage to evade apoptosis. Cell signaling, via posttranslational modifications (PTMs), is one of the most important means of regulation, and most commonly dysregulated in cancer. In prostate cancer, androgen signaling plays a crucial role in driving cell proliferation.

Mammalian Cytochrome c (Cytc) is a multifunctional protein involved in cellular life and death decision. It is an essential component of the electron …

Development Of Gi Sustainable Probiotic Beads Using Microencapsulation, Jiarun Cui

Wayne State University Theses

Scientists tend to pay a lot attention to probiotics in recent years, due to its health related benefits for humans. Encapsulation is a necessary way to protect probiotics from being killed by harsh conditions of the gastrointestinal tract, and to help probiotics to release in the intestinal environment. This study is mainly focusing on the encapsulation technique of Christensenella minuta, and the food product development of C. minuta beads. The extrusion technique was applied as the encapsulation method, with alginate as the encapsulation material. The effect of single encapsulation and double encapsulation of C. minuta was compared to determine the …

Optimization Of Growth Conditions Of "Eubacterium Hallii" As A Potential Probiotics, Sampurna Guhathakurta

Wayne State University Theses

ABSTRACT

OPTIMIZATION OF GROWTH CONDITIONS OF “Eubacterium hallii” AS A POTENTIAL PROBIOTICS

by

SAMPURNA GUHATHAKURTA

May 2017

Advisor: Dr. Kequan Zhou

Major: Nutrition and Food Science

Degree: Master of Science

Probiotics are becoming popular to a greater extent over the past two decades for their potential benefits on human health. Therefore, they are widely used in the food industry by incorporation into food products. Nowadays, there are a lot of probiotics which are famous in the market. In this study, the strain of Eubacterium hallii was used because it has a significant importance in the pharmaceutical or food industry especially …

Investigation Into Roseburia Intesinalis For Optimal Growth And Survivability Conditions For Potential Probiotic Use, Lisa Rana Felczak

Wayne State University Theses

Obesity and diabetes is an epidemic of increasing concern. Certain novel bacteria have been found to be an aid in reversing some of the mechanisms associated. This study focused on investigating the optimal stability conditions for R.intestinalis that can associate with an increase in growth. First, environmental conditions were tested to find the optimal conditions associated with each. Once growth conditions were found, generation time was calculated and various prebiotics were used to investigate a potential for additional growth. Next, common antibiotics were tested to see if the R.intestinalis could still show growth when exposed. Large batches of R.intestinalis were …

The Potential Stimulation Of C. Minuta Growth By Various Prebiotics, And Its Sensitivity To Various Antibiotics, Maria Elena Hakim

Wayne State University Theses

Gut microbiota play a crucial role in maintaining intestinal health and integrity; a feature that is both heritable, as well as affected by the environment and lifestyle. Probiotics are supplements containing live microorganisms that act in a similar manner to gut microflora, and maintain a balance in the latter. C. minuta is a novel bacterium in the gut that was found to be associated with reduction in body weight and adiposity. The aim of this study was to determine the possible effects of different prebiotics on C. minuta growth, and the survival of C. minuta in response to different antibiotics. …

Fam129b, A Novel Adherent Junction Protein, Forms A Complex With Keap1, Fatme Ali Hachem

Wayne State University Theses

FAM129B/Minerva, a protein implicated in melanoma cell invasion, has been shown to suppress TNFα induced apoptosis in cancer cells (Song, Evans & Evans (2010), JBC 286, 10201-09), thus contributing to the survival of metastatic cells. KEAP1, a substrate recognition molecule for the CUL3 E3 ubiquitin ligase, plays a central role in the activation of the TNFα pathway. We wish to test the hypothesis that the up-regulation of FAM129B in cancer cells suppresses apoptosis by sequestering KEAP1, thus preventing its participation in the apoptotic pathway. The first step is to demonstrate that FAM129B and KEAP1 form a complex. We have cloned …

Development Of Student Data Visualization Tool, Adaption Of Clostridium Difficile Toxin A Into Protein Delivery Vehicle, And Elucidation Of Tcdc Mechanism Of Toxin Control, Adam Boyden

Wayne State University Theses

Advancing student success in higher education is of paramount importance, and is in need for a tool that visualizes student data in a longitudinal manner. Student Circos plots achieve this by plotting student data in circular plots, depicting the timeline and grades for students selected by demographic or performance information. Cellular delivery of exogenous proteins is a bountiful area of research. However, most current systems have limited in vivo applications and most lack cellular specificity. By adapting Toxin A from Clostridium difficile, the goal was to create a cell specific protein delivery vehicle that would be robust in vivo. However, …

Effects Of Palm Oil Tocotrienols Rich Fraction On Cholesterol Efflux, Erandi Jayamini Jayawardana Arachchige

Wayne State University Theses

Tocotrienols are naturally occurring bioactive compounds which possess beneficial effects on multiple chronic diseases including atherosclerosis and cancer. It is believed to exert atheroprotective effects via promoting reverse cholesterol transport, a process that removes excess cholesterol from the body. Cholesterol efflux is an early step in reverse cholesterol transport and impaired cholesterol efflux is known to trigger foam cell formation, a hallmark of atherosclerosis. An increase in cholesterol efflux and decrease in cholesterol influx in macrophages has been suggested to reduce atherosclerosis risk by reducing foam cell formation. In addition, tocotrienols have shown anti-cancer effects on Non-small cell lung cancer …

Endocrine-Disrupting Properties Of Pharmaceuticals And Personal Care Products (Ppcps): An Evaluation Using Aquatic Model Organisms, Manahil Monshi

Wayne State University Theses

Thousands of chemicals have introduced into the environment as a result of human activity since the industrial revolution, and the U.S. Government Accountability Office has estimated that as many as 1,500 new chemical entities are synthesized each year ("Key Issues: Toxic Chemicals - High Risk Issue," 2017). Many of these chemicals are now found in surface water and ground water and can have detrimental effects on environmental health and on human health. This anthropogenic contamination has resulted in the labeling of the diverse array of chemicals found in water, which are not routinely monitored or regulated, as contaminants of emerging …

Determination Of The Direct Protein-Protein Interactions In The Drosophila Sin3a Complex, Ian Moore

Wayne State University Theses

The proteins that comprise the Drosophila SIN3 220 and SIN3 187 complexes are currently known. Limited information with regard to interacting complex member proteins has been described. Much of these data are results of high-throughput investigations, and there have been no studies done to reconstitute all direct interactions within the complex. The unique C-terminal region of the SIN3 220 isoform was used to test for interactions with other complex proteins using the bacterial expression system. Additionally, the region of Caf1-55 necessary for interaction with SIN3 in vivo was identified using a truncation mutant. The results of this work identified novel …

Mechanistic And Inhibitory Analysis Of Clostridium Difficile Associated Diseases, Brianna Marie Jackman

Wayne State University Theses

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The Effect Of Oil Palm Phenolics (Opp) And Curcumin On Plasma Metabolomic Profile In Atherogenic Diet Induced Rat Model Of Alzheimer’S Disease (Ad), Soniya Katekar

Wayne State University Theses

Alzheimer's disease (AD) is the most widely recognized reason for dementia in the aging population. It is described by intellectual decay and deposition of ß-amyloid plaques in the hippocampus. It has been demonstrated that hypercholesterolemia incited by elevated cholesterol abstain from food is related with AD advancement. Expanded level of oxidative stress has additionally been seen in AD patients. An essential methodology to treat or postpone the disability depends on dietary change, utilizing nourishment supplements. OPP, a water-soluble fraction from oil palm fruit, rich in phenolics has been found to possess significant antioxidant activities. Curcumin, a polyphenol extricated from the …

Protein Phosphatase 2a Function And Regulation In Insulin Resistant Human Skeletal Muscle Cells, Shukurat Sulaiman

Wayne State University Theses

Protein Phosphatase 2A (PP2A), a major serine/threonine phosphatase involved in insulin signaling pathway, plays a critical role in the development of insulin resistance and type 2 diabetes (T2D), which is characterized with hyperinsulinemic hyperglycemic condition. Moreover, majority of the glucose disposal takes place in the skeletal muscle which is also the main tissue responsible for insulin resistance. The catalytic subunit of PP2A (PP2Ac) can interact with multiple regulatory subunits and other regulatory proteins as well as substrates. These interactions are important for maintain normal PP2A function and subsequent cell signaling. We hypothesized that hyperinsulinemic hyperglycemic condition and insulin stimulation would …

Synaptotagmin C2b Ca2+-Binding Loops Impose Distinct Exocytosis Phenotypes, Michael W. Schmidtke

Wayne State University Theses

Regulated exocytosis from chromaffin cells in the adrenal medulla plays a critical role in maintaining organismal homeostasis. In the absence of stress, these cells release physiologically relevant substances into the blood stream only in limited quantities, whereas stressful conditions result in a rapid deluge of signaling molecules used, for example, to increase heart rate and pain tolerance. Although the cellular mechanisms governing the switch from low-level to stress-induced secretion are not well understood, recent evidence has implicated the exocytotic Ca2+-sensing protein Synaptotagmin (Syt) in this role.

Two isoforms of Syt are expressed in chromaffin cells (Syt-1 and Syt-7), and each …

Elucidating Structure, Function, And Small Molecular Interactions Of Human Immunodeficiency Virus And Chikungunya Virus, Kristin Nicole Slater

Wayne State University Theses

Abstract HIV-1:

Human immunodeficiency virus-1 (HIV-1) is a widespread, incurable retrovirus known to cause

immunodeficiency and a shortened life span. Despite successful treatment methods, HIV-1

frequently mutates, resulting in antiviral resistance. Many therapies target the HIV-1 protease

(PR), which is responsible for cleaving the viral polyprotein essential for its life cycle. HIV-1 PR

often evades treatment by way of mutations and less commonly through residue insertions. We

have identified a clinical isolate with a five residue insertion between residues 28 and 29.

Through molecular dynamics simulations we analyzed the protease protein structure and

determined that the residue insertion created a …

Redox Responsive Cerium Oxide Nanoparticles And Cd44 Targeted Nanomicelles For Selective Cancer Therapy, Zhaoxian Wang

Wayne State University Theses

Redox-responsive cerium oxide nanoparticles (CNPs) can play a versatile role in cancer therapy due to their ability to induce oxidative stress under proper pH conditions. Hyaluronic acid micelles with a high affinity to CD44 receptor which achieved more cytotoxicity towards cancer cells. The polymer-coated CNPs and HA-SMA-TPGS-CDF nanomicelles were developed for cancer therapy. The results showed that the toxicity of CNPs in tumor cells was mediated by the pro-oxidant property of CNPs under relative low pH conditions (pH~6.5) of the tumor microenvironment whereas CNPs play a (cytoprotective) anti-oxidant role, scavenging reactive oxygen species and reducing oxidative stress under normal pH …