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Elovanoid-N34 Modulates Txnrd1 Key In Protection Against Oxidative Stress-Related Diseases, Jorgelina M. Calandria, Surjyadipta Bhattacharjee, Sayantani Kala-Bhattacharjee, Pranab K. Mukherjee, Yuehan Feng, Jakob Vowinckel, Tobias Treiber, Nicolas G. Bazan Dec 2023

Elovanoid-N34 Modulates Txnrd1 Key In Protection Against Oxidative Stress-Related Diseases, Jorgelina M. Calandria, Surjyadipta Bhattacharjee, Sayantani Kala-Bhattacharjee, Pranab K. Mukherjee, Yuehan Feng, Jakob Vowinckel, Tobias Treiber, Nicolas G. Bazan

School of Graduate Studies Faculty Publications

The thioredoxin (TXN) system is an NADPH + H+/FAD redox-triggered effector that sustains homeostasis, bioenergetics, detoxifying drug networks, and cell survival in oxidative stress-related diseases. Elovanoid (ELV)-N34 is an endogenously formed lipid mediator in neural cells from omega-3 fatty acid precursors that modulate neuroinflammation and senescence gene programming when reduction-oxidation (redox) homeostasis is disrupted, enhancing cell survival. Limited proteolysis (LiP) screening of human retinal pigment epithelial (RPE) cells identified TXNRD1 isoforms 2, 3, or 5, the reductase of the TXN system, as an intracellular target of ELV-N34. TXNRD1 silencing confirmed that the ELV-N34 target was isoform 2 or 3. This …


Association Of Chlamydia Trachomatis Burden With The Vaginal Microbiota, Bacterial Vaginosis, And Metronidazole Treatment, Caleb M. Ardizzone, Christopher M. Taylor, Evelyn Toh, Rebecca A. Lillis, Jacob H. Elnaggar, John W. Lammons, Patricia Dehon Mott, Emily L. Duffy, Li Shen, Alison J. Quayle Dec 2023

Association Of Chlamydia Trachomatis Burden With The Vaginal Microbiota, Bacterial Vaginosis, And Metronidazole Treatment, Caleb M. Ardizzone, Christopher M. Taylor, Evelyn Toh, Rebecca A. Lillis, Jacob H. Elnaggar, John W. Lammons, Patricia Dehon Mott, Emily L. Duffy, Li Shen, Alison J. Quayle

School of Graduate Studies Faculty Publications

Bacterial vaginosis (BV), a dysbiosis of the vaginal microbiota, is a common coinfection with Chlamydia trachomatis (Ct), and BV-associated bacteria (BVAB) and their products have been implicated in aiding Ct evade natural immunity. Here, we determined if a non-optimal vaginal microbiota was associated with a higher genital Ct burden and if metronidazole, a standard treatment for BV, would reduce Ct burden or aid in natural clearance of Ct infection. Cervicovaginal samples were collected from women at enrollment and, if testing positive for Ct infection, at a follow-up visit approximately one week later. Cervical Ct burden was assessed by inclusion forming …


Prefrontal Cortex Glutamatergic Adaptations In A Mouse Model Of Alcohol Use Disorder, Mahum T. Siddiqi, Dhruba Podder, Amanda R. Pahng, Alexandria C. Athanason, Tali Nadav, Chelsea Cates-Gatto, Max Kreifeldt, Candice Contet, Amanda J. Roberts, Scott Edwards, Marisa Roberto, Florence P. Varodayan Nov 2023

Prefrontal Cortex Glutamatergic Adaptations In A Mouse Model Of Alcohol Use Disorder, Mahum T. Siddiqi, Dhruba Podder, Amanda R. Pahng, Alexandria C. Athanason, Tali Nadav, Chelsea Cates-Gatto, Max Kreifeldt, Candice Contet, Amanda J. Roberts, Scott Edwards, Marisa Roberto, Florence P. Varodayan

School of Graduate Studies Faculty Publications

Alcohol use disorder (AUD) produces cognitive deficits, indicating a shift in prefrontal cortex (PFC) function. PFC glutamate neurotransmission is mostly mediated by α-amino-3‑hydroxy-5-methyl-4-isoxazolepropionic acid-type ionotropic receptors (AMPARs); however preclinical studies have mostly focused on other receptor subtypes. Here we examined the impact of early withdrawal from chronic ethanol on AMPAR function in the mouse medial PFC (mPFC). Dependent male C57BL/6J mice were generated using the chronic intermittent ethanol vapor-two bottle choice (CIE-2BC) paradigm. Non-dependent mice had access to water and ethanol bottles but did not receive ethanol vapor. Naïve mice had no ethanol exposure. We used patch-clamp electrophysiology to measure …


Integrated Inflammatory Signaling Landscape Response After Delivering Elovanoid Free-Fatty-Acid Precursors Leading To Experimental Stroke Neuroprotection, Madigan M. Reid, Ludmila Belayev, Larissa Khoutorova, Pranab K. Mukherjee, Andre Obenaus, Kierany Shelvin, Stacey Knowles, Sung Ha Hong, Nicolas G. Bazan Sep 2023

Integrated Inflammatory Signaling Landscape Response After Delivering Elovanoid Free-Fatty-Acid Precursors Leading To Experimental Stroke Neuroprotection, Madigan M. Reid, Ludmila Belayev, Larissa Khoutorova, Pranab K. Mukherjee, Andre Obenaus, Kierany Shelvin, Stacey Knowles, Sung Ha Hong, Nicolas G. Bazan

School of Graduate Studies Faculty Publications

Despite efforts to identify modulatory neuroprotective mechanisms of damaging ischemic stroke cascade signaling, a void remains on an effective potential therapeutic. The present study defines neuroprotection by very long-chain polyunsaturated fatty acid (VLC-PUFA) Elovanoid (ELV) precursors C-32:6 and C-34:6 delivered intranasally following experimental ischemic stroke. We demonstrate that these precursors improved neurological deficit, decreased T2WI lesion volume, and increased SMI-71 positive blood vessels and NeuN positive neurons, indicating blood–brain barrier (BBB) protection and neurogenesis modulated by the free fatty acids (FFAs) C-32:6 and C-34:6. Gene expression revealed increased anti-inflammatory and pro-homeostatic genes and decreases in expression of pro-inflammatory genes in …


Targeting Mcl-1 By A Small Molecule Nsc260594 For Triple-Negative Breast Cancer Therapy, Shengli Dong, Margarite D. Matossian, Hassan Yousefi, Maninder Khosla, Bridgette M. Collins-Burow, Matthew E. Burow, Suresh K. Alahari Jul 2023

Targeting Mcl-1 By A Small Molecule Nsc260594 For Triple-Negative Breast Cancer Therapy, Shengli Dong, Margarite D. Matossian, Hassan Yousefi, Maninder Khosla, Bridgette M. Collins-Burow, Matthew E. Burow, Suresh K. Alahari

School of Graduate Studies Faculty Publications

Triple-negative breast cancers (TNBCs) are aggressive forms of breast cancer and tend to grow and spread more quickly than most other types of breast cancer. TNBCs can neither be targeted by hormonal therapies nor the antibody trastuzumab that targets the HER2 protein. There are urgent unmet medical needs to develop targeted drugs for TNBCs. We identified a small molecule NSC260594 from the NCI diversity set IV compound library. NSC260594 exhibited dramatic cytotoxicity in multiple TNBCs in a dose-and time-dependent manner. NSC260594 inhibited the Myeloid cell leukemia-1 (Mcl-1) expression through downregulation of Wnt signaling proteins. Consistent with this, NSC260594 treatment increased …


High Glucose-Upregulated Pd-L1 Expression Through Ras Signaling-Driven Downregulation Of Ptrh1 Leads To Suppression Of T Cell Cytotoxic Function In Tumor Environment, Chenggang Gao, Jiaoshun Chen, Jianwei Bai, Haoxiang Zhang, Yanyi Tao, Shihong Wu, Hehe Li, Heshui Wu, Qiang Shen, Tao Yin Jul 2023

High Glucose-Upregulated Pd-L1 Expression Through Ras Signaling-Driven Downregulation Of Ptrh1 Leads To Suppression Of T Cell Cytotoxic Function In Tumor Environment, Chenggang Gao, Jiaoshun Chen, Jianwei Bai, Haoxiang Zhang, Yanyi Tao, Shihong Wu, Hehe Li, Heshui Wu, Qiang Shen, Tao Yin

School of Graduate Studies Faculty Publications

Background: Nearly 80% of patients with pancreatic cancer suffer from glucose intolerance or diabetes. Pancreatic cancer complicated by diabetes has a more immunosuppressive tumor microenvironment (TME) and is associated with a worse prognosis. The relationship between glucose metabolism and programmed cell death-Ligand 1 (PD-L1) is close and complex. It is important to explore the regulation of high glucose on PD-L1 expression in pancreatic cancer and its effect on infiltrating immune effectors in the tumor microenvironment. Methods: Diabetic murine models (C57BL/6) were used to reveal different immune landscape in euglycemic and hyperglycemic pancreatic tumor microenvironment. Bioinformatics, WB, iRIP [Improved RNA Binding …


Cancer Cell-Specific Cgas/Sting Signaling Pathway In The Era Of Advancing Cancer Cell Biology, Vijay Kumar, Caitlin Bauer, John H. Stewart Jul 2023

Cancer Cell-Specific Cgas/Sting Signaling Pathway In The Era Of Advancing Cancer Cell Biology, Vijay Kumar, Caitlin Bauer, John H. Stewart

School of Graduate Studies Faculty Publications

Pattern-recognition receptors (PRRs) are critical to recognizing endogenous and exogenous threats to mount a protective proinflammatory innate immune response. PRRs may be located on the outer cell membrane, cytosol, and nucleus. The cGAS/STING signaling pathway is a cytosolic PRR system. Notably, cGAS is also present in the nucleus. The cGAS-mediated recognition of cytosolic dsDNA and its cleavage into cGAMP activates STING. Furthermore, STING activation through its downstream signaling triggers different interferon-stimulating genes (ISGs), initiating the release of type 1 interferons (IFNs) and NF-κB-mediated release of proinflammatory cytokines and molecules. Activating cGAS/STING generates type 1 IFN, which may prevent cellular transformation …


Yes-Associated Protein-1 Overexpression In Ocular Surface Squamous Neoplasia; A Potential Diagnostic Marker And Therapeutic Target, Peter Julius, Stepfanie N. Siyumbwa, Fred Maate, Phyllis Moonga, Guobin Kang, Trevor Kaile, John T. West, Charles Wood, Peter C. Angeletti Jul 2023

Yes-Associated Protein-1 Overexpression In Ocular Surface Squamous Neoplasia; A Potential Diagnostic Marker And Therapeutic Target, Peter Julius, Stepfanie N. Siyumbwa, Fred Maate, Phyllis Moonga, Guobin Kang, Trevor Kaile, John T. West, Charles Wood, Peter C. Angeletti

School of Graduate Studies Faculty Publications

Yes-associated protein-1 (YAP-1) is a Hippo system transcription factor, which serves as an oncogene in squamous cell carcinoma, and several solid tumors when the Hippo pathway is dysregulated. Yet, the activity of YAP-1 in ocular surface squamous neoplasia (OSSN) has not been determined. Here, we investigate the relationship between YAP-1 overexpression and OSSN. Using a cross-sectional study design, we recruited 227 OSSN patients from the University Teaching Hospitals in Lusaka, Zambia. Immunohistochemistry was used to assess YAP-1 protein overexpression in tumor tissue relative to surrounding benign squamous epithelium. OSSN patient samples (preinvasive, n = 62, 27% and invasive, n = …


Targeting Cgas/Sting Signaling-Mediated Myeloid Immune Cell Dysfunction In Time, Vijay Kumar, Caitlin Bauer, John H. Stewart Jun 2023

Targeting Cgas/Sting Signaling-Mediated Myeloid Immune Cell Dysfunction In Time, Vijay Kumar, Caitlin Bauer, John H. Stewart

School of Graduate Studies Faculty Publications

Myeloid immune cells (MICs) are potent innate immune cells serving as first responders to invading pathogens and internal changes to cellular homeostasis. Cancer is a stage of altered cellular homeostasis that can originate in response to different pathogens, chemical carcinogens, and internal genetic/epigenetic changes. MICs express several pattern recognition receptors (PRRs) on their membranes, cytosol, and organelles, recognizing systemic, tissue, and organ-specific altered homeostasis. cGAS/STING signaling is a cytosolic PRR system for identifying cytosolic double-stranded DNA (dsDNA) in a sequence-independent but size-dependent manner. The longer the cytosolic dsDNA size, the stronger the cGAS/STING signaling activation with increased type 1 interferon …


Systemic Review Of Clot Retraction Modulators, Alaina Guilbeau, Rinku Majumder Jun 2023

Systemic Review Of Clot Retraction Modulators, Alaina Guilbeau, Rinku Majumder

School of Graduate Studies Faculty Publications

Through a process termed clot retraction, platelets cause thrombi to shrink and become more stable. After platelets are activated via inside-out signaling, glycoprotein αIIbβIII binds to fibrinogen and initiates a cascade of intracellular signaling that ends in actin remodeling, which causes the platelet to change its shape. Clot retraction is also important for wound healing. Although the detailed molecular biology of clot retraction is only partially understood, various substances and physiological conditions modulate clot retraction. In this review, we describe some of the current literature pertaining to clot retraction modulators. In addition, we discuss compounds from Cudrania trucuspidata, Arctium lappa, …


Study Of The Potential Toxicity Of Adrenaline To Neurons, Using The Sh-Sy5y Human Cellular Model, Vera Marisa Costa, João Paulo Capela, Maria Lourdes Bastos, Fernando Remião, Kurt James Varner, José Alberto Duarte, Félix Carvalho May 2023

Study Of The Potential Toxicity Of Adrenaline To Neurons, Using The Sh-Sy5y Human Cellular Model, Vera Marisa Costa, João Paulo Capela, Maria Lourdes Bastos, Fernando Remião, Kurt James Varner, José Alberto Duarte, Félix Carvalho

School of Graduate Studies Faculty Publications

Prolonged overexposure to catecholamines causes toxicity, usually credited to continuous adrenoceptor stimulation, autoxidation, and the formation of reactive pro-oxidant species. Non-differentiated SH-SY5Y cells were used to study the possible contribution of oxidative stress in adrenaline (ADR)-induced neurotoxicity, as a model to predict the toxicity of this catecholamine to peripheral nerves. Cells were exposed to several concentrations of ADR (0.1, 0.25, 0.5 and 1mM) and two cytotoxicity assays [lactate dehydrogenase (LDH) release and 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) reduction] were performed at several time-points (24, 48, and 96h). The cytotoxicity of ADR was concentration-and time-dependent in both assays, since the lowest concentration …