Papers by Pramod Sukumaran
The Endocrine Society's 93rd Annual Meeting & Expo, June 4–7, 2011 - Boston, 2011
Cellular and Molecular Neurobiology, 2020
Regulation of Ca 2+ homeostasis is essential for neuronal function and its survival. Recent data ... more Regulation of Ca 2+ homeostasis is essential for neuronal function and its survival. Recent data suggest that TRPC1 function as the endogenous store-mediated Ca 2+ entry channel in dopaminergic cells, and loss of TRPC1 function leads to neurodegeneration; however, its regulation is not fully identified. Here we provide evidence that the sigma 1 receptor contributes to the loss of dopaminergic cells by blocking TRPC1-mediated Ca 2+ entry. Importantly, downregulation of sigma 1 receptor expression significantly decreased neurotoxin-induced loss of dopaminergic cells as measured by MTT assays and caspase activity was also inhibited. Importantly, sigma 1 receptor inhibited TRPC1-mediated Ca 2+ entry and silencing of sigma 1 receptor significantly restored store-dependent Ca 2+ influx. Although co-immunoprecipitation failed to show an interaction between the TRPC1 and sigma 1 receptor, store depletion promoted a decrease in the sigma 1 receptor-STIM1 association. Neurotoxin-induced loss of Ca 2+ entry was significantly restored in cells that had decreased sigma 1 receptor expression. Furthermore, TRPC1 or STIM1 silencing inhibited store-mediated Ca 2+ entry, which was further increased upon the downregulation of the sigma 1 receptor expression. TRPC1 silencing prevented the increased neuroprotection and caspase activity observed upon the downregulation of sigma 1 receptor. Finally, sigma 1 receptor activation also significantly decreased TRPC1-mediated Ca 2+ entry and lead to an increase in neurodegeneration. In contrast, addition of sigma 1 receptor antagonist prevented neurotoxin-induced neurodegeneration and facilitated TRPC1-mediated Ca 2+ influx. Together these results suggest that the sigma 1 receptor is involved in the inhibition of TRPC1-mediated Ca 2+ entry, which leads to the degeneration in the dopaminergic cells, and prevention of sigma 1 receptor function could protect neuronal cell death as observed in Parkinson's disease.
Cancer Research
Background: The successful use of hormone therapy (HT) has contributed to improved 5-year cause-s... more Background: The successful use of hormone therapy (HT) has contributed to improved 5-year cause-specific breast cancer survival rates and evidence shows that long-term use produces a larger reduction in recurrence and mortality, with nearly 50% reduction in breast cancer mortality during the second decade after diagnosis. Despite the proven benefits, hormone therapy adherence is suboptimal (less than 80% of daily doses taken) and about 33% of women who are prescribed HT do not take their medication as prescribed and are at increased risk of disease recurrence and increased mortality. Smartphone ownership has increased substantially over the past decade, providing an extraordinary opportunity for innovation in the delivery of tailored interventions to improve patients’ adherence to hormonal therapy. Purpose: We present the design and development process of a theory-based, culturally tailored, interactive mobile app to improve adherence to HT among breast cancer patients to be used in...
Cancer Epidemiology, Biomarkers & Prevention
Background: Adjuvant hormonal therapy (HT) is highly effective and appropriate for nearly all wom... more Background: Adjuvant hormonal therapy (HT) is highly effective and appropriate for nearly all women with hormone receptor-positive tumors, making such treatment the most widely prescribed therapy for patients with this type of breast cancer. Despite its proven benefits in reducing cancer recurrence and improving survival, HT adherence is suboptimal (less than 80%). About 33% of patients do not take their medication as prescribed and are at increased risk of disease recurrence and lower survival. Purpose: We will present the development and betatesting of HT Helper, a theory-based, bilingual, interactive mHealth app in combination with patient navigation to improve adherence to HT among patients attending the breast clinic at the Mays Cancer Center, as part of the initial phase of a two-group randomized clinical trial study. Methods: As part of the formative research phase, we conducted 4 focus groups (n=21) with breast cancer patients receiving HT, and personal interviews (n=8) with...
JMIR Formative Research, 2021
Background Cigarette smoking and alcohol use are well known to be concomitant behaviors, but ther... more Background Cigarette smoking and alcohol use are well known to be concomitant behaviors, but there is a lack of studies related to recruitment of smokers for mobile cessation services at places where alcohol is consumed, such as bars and clubs. Adapting recruitment strategies to expand the reach of cessation programs to where tobacco users are located may help decrease the health-equity gap in tobacco control by improving reach and enrollment of underserved smokers residing in low-income and rural areas who are not reached by traditional cessation services. Objective The purpose of this exploratory study was to assess the feasibility of direct outreach in bars, clubs, and restaurants to recruit smokers to Quitxt, our mobile smoking cessation service. Quitxt is delivered through SMS text messaging or Facebook Messenger. Methods We collaborated with an advertising agency to conduct in-person recruitment of young adult smokers aged 18-29 years, focusing on urban and rural Spanish-speak...
Advancing the Science of Cancer in Latinos, 2019
Cells, 2021
Calcium (Ca2+) functions as a second messenger that is critical in regulating fundamental physiol... more Calcium (Ca2+) functions as a second messenger that is critical in regulating fundamental physiological functions such as cell growth/development, cell survival, neuronal development and/or the maintenance of cellular functions. The coordination among various proteins/pumps/Ca2+ channels and Ca2+ storage in various organelles is critical in maintaining cytosolic Ca2+ levels that provide the spatial resolution needed for cellular homeostasis. An important regulatory aspect of Ca2+ homeostasis is a store operated Ca2+ entry (SOCE) mechanism that is activated by the depletion of Ca2+ from internal ER stores and has gained much attention for influencing functions in both excitable and non-excitable cells. Ca2+ has been shown to regulate opposing functions such as autophagy, that promote cell survival; on the other hand, Ca2+ also regulates programmed cell death processes such as apoptosis. The functional significance of the TRP/Orai channels has been elaborately studied; however, inform...
Cancer Epidemiology, Biomarkers & Prevention, 2022
Background: The successful use of hormone therapy (HT) has contributed to improved 5-year cause-s... more Background: The successful use of hormone therapy (HT) has contributed to improved 5-year cause-specific breast cancer survival rates, and evidence shows that long-term use produces a larger reduction in recurrence and mortality, with nearly 50% reduction in breast cancer mortality during the second decade after diagnosis. Despite the proven benefits, hormone therapy adherence is suboptimal (less than 80% of daily doses taken), and about 33% of women who are prescribed HT do not take their medication as prescribed and are at increased risk of disease recurrence and increased mortality. Smartphone ownership has increased substantially over the past decade, providing an extraordinary opportunity for innovation in the delivery of tailored interventions to improve patients' adherence to hormonal therapy. Purpose: We present preliminary results of a pilot study that involves a theory-based, culturally tailored, interactive mobile app + patient navigation to improve adherence to HT am...
FASEB BioAdvances, 2018
Calcium is a ubiquitous second messenger that modulates most of the cellular functions including ... more Calcium is a ubiquitous second messenger that modulates most of the cellular functions including gene expression and cellular homeostasis, 1,2 neurotransmitter release and neuronal function, 3,4 and modulation of metabolism and cell survival. 5 The known molecular regulators of cell calcium homeostasis, such as calcium release-activated calcium channel (ORAI), stromal interaction molecule 1 (STIM1) and TRPC channels are all implicated in modulating Ca 2+ entry in both excitable and nonexcitable cells. Importantly, TRPC and ORAI channels have been
Cell death & disease, Jan 5, 2015
Autophagy is a cellular catabolic process needed for the degradation and recycling of protein agg... more Autophagy is a cellular catabolic process needed for the degradation and recycling of protein aggregates and damaged organelles. Although Ca(2+) is suggested to have an important role in cell survival, the ion channel(s) involved in autophagy have not been identified. Here we demonstrate that increase in intracellular Ca(2+) via transient receptor potential canonical channel-1 (TRPC1) regulates autophagy, thereby preventing cell death in two morphologically distinct cells lines. The addition of DMOG or DFO, a cell permeable hypoxia-mimetic agents, or serum starvation, induces autophagy in both epithelial and neuronal cells. The induction of autophagy increases Ca(2+) entry via the TRPC1 channel, which was inhibited by the addition of 2APB and SKF96365. Importantly, TRPC1-mediated Ca(2+) entry resulted in increased expression of autophagic markers that prevented cell death. Furthermore, hypoxia-mediated autophagy also increased TRPC1, but not STIM1 or Orai1, expression. Silencing of ...
Cell Calcium, 2016
Intracellular calcium (Ca 2+) levels play a vital role in regulating cellular fate. The coordinat... more Intracellular calcium (Ca 2+) levels play a vital role in regulating cellular fate. The coordination and interrelation among the cellular organelles, mainly the intracellular Ca 2+ stores in endoplasmic reticulum (ER), are crucial in maintaining cytosolic Ca 2+ levels and in general cellular homeostasis. Moreover, maintaining Ca 2+ homeostasis is essential for regulating diverse and sometimes opposing processes such as cell survival and cell death in disease conditions such as, neurodegeneration, cancer and aging. Ca 2+ is able to regulate opposing functions by either regulating the cellular "self-eating" phenomenon of autophagy to promote cell survival or by regulating the programmed cell death process of apoptosis. Autophagy is also important for cell survival especially after induction of ER stress and association between ER stress and autophagy may have relevance to numerous diseases. Moreover, a multitude of evidence is emerging that the functional regulation of TRP channels, their unique localization, and their interaction with other Ca 2+-sensing elements define these diverse regulatory pathways. It is this unique function which allows individual TRP channels to contribute differently in the regulation of cell fate and, in turn, determines the precise effect of modulating Ca 2+ signaling via the particular channel. Thus, in this review we have focused on the aspects of TRP channel localization and function (Ca 2+ signaling) that affects the ER stress and autophagic process.
BACKGROUND Latinx people comprise 18% of the US adult population and a large share of youth and c... more BACKGROUND Latinx people comprise 18% of the US adult population and a large share of youth and continue to experience inequities that perpetuate health disparities. To engage Latinx people in advocacy for health equity based on this population’s heavy share of smartphone, social media, and Twitter users, Salud America! launched the #SaludTues Tweetchat series. In this paper, we explore the use of #SaludTues to promote advocacy for Latinx health equity. OBJECTIVE This study aims to understand how #SaludTues Tweetchats are used to promote dissemination of culturally relevant information on social determinants of health, to determine whether tweetchats serve to drive web traffic to the Salud America! website, and to understand who participates in #SaludTues Tweetchats and what we can learn about the participants. We also aim to share our own experiences and present a step-by-step guide of how tweetchats are planned, developed, promoted, and executed. METHODS We explored tweetchat data...
BASIC/TRANSLATIONAL/CLINICAL - Thyroid Gland Development & Function
Molecular Neurobiology
Mg 2+ homeostasis is essential for cell survival and the loss of this regulation has been associa... more Mg 2+ homeostasis is essential for cell survival and the loss of this regulation has been associated with many neurodegenerative diseases, including loss of dopaminergic neurons. Although the neurotoxin-mediated loss of dopaminergic neurons in Parkinson disease models is extensively studied, the ion channel(s) that regulate Mg 2+ homeostasis and thus could prevent neuronal cell death is not yet identified. Here, we show that TRPM7 (transient receptor potential melastatin 7) is involved in regulating Mg 2+ homeostasis in dopaminergic cells. Importantly, transient loss of TRPM7 decreased intracellular Mg 2+ levels and decreased dopaminergic cells/neurons survival. We provide further evidence that both increases in extracellular Mg 2+ or transiently increasing TRPM7 levels protected dopaminergic SH-SY5Y cells against neurotoxin-mediated cell death. Neurotoxin treatment significantly decreased TRPM7 levels in both SH-SY5Y cells and the substantia nigra pars compacta region of mice, along with a decrease in Mg 2+ influx. Moreover, Mg 2+ supplementation showed a concentration-dependent decrease in caspase-3 activity, an increase in cell survival, restored mitochondrial membrane potential, and increase TRPM7 levels in neurotoxin-treated cells. In contrast, transient silencing of TRPM7 inhibited the positive effect of Mg 2+ supplementation in protecting against neurotoxins. Whereas, TRPM7 overexpression not only maintained Mg 2+ homeostasis but also inhibited caspase 3 activity that induced cell survival. Overall, these results suggest a significant role of TRPM7 channels in Mg 2+ homeostasis and the survival of neurotoxininduced loss of dopaminergic cells.
iScience, Jan 26, 2018
Macrophage plasticity is essential for innate immunity, but in-depth signaling mechanism(s) regul... more Macrophage plasticity is essential for innate immunity, but in-depth signaling mechanism(s) regulating their functional phenotypes are ill-defined. Here we report that interferon (IFN) γ priming of naive macrophages induces store-mediated Ca entry and inhibition of Ca entry impairs polarization to M1 inflammatory phenotype. In vitro and in vivo functional analyses revealed ORAI1 to be a primary contributor to basal Ca influx in macrophages, whereas IFNγ-induced Ca influx was mediated by TRPC1. Deficiency of TRPC1 displayed abrogated IFNγ-induced M1 inflammatory mediators in macrophages. In a preclinical model of peritonitis by Klebsiella pneumoniae infection, macrophages showed increased Ca influx, which was TRPC1 dependent. Macrophages from infected TRPC1 mice showed inhibited expression of M1-associated signature molecules. Furthermore, in human patients with systemic inflammatory response syndrome, the level of TRPC1 expression in circulating macrophages directly correlated with ...
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Jan 15, 2018
Neutrophil extracellular trap (NET) formation constitutes an important extracellular antimicrobia... more Neutrophil extracellular trap (NET) formation constitutes an important extracellular antimicrobial function of neutrophils that plays a protective role in bacterial pneumonia. Formation of reactive oxygen species (ROS) such as highly diffusible hydrogen peroxide (HO) is a hallmark of oxidative stress during inflammatory lung conditions including pneumonia. However, the impact of exogenous ROS on NET formation and the signaling pathway involved in the process is not completely understood. Here we demonstrate that the ROS-sensing, nonselective, calcium-permeable channel transient receptor potential melastatin 2 (TRPM2) is required for NET formation in response to exogenous HO. This TRPM2-dependent HO-mediated NET formation involved components of autophagy and activation of AMPK and p38 MAPK, but not PI3K and AKT. Primary neutrophils from Trpm2 mice fail to activate this pathway with a block in NET release and a concomitant decrease in their antimicrobial capacity. Consequently, Trpm2 ...
Advances in experimental medicine and biology, 2017
Parkinson's disease (PD) is a common neurodegenerative disorder, which involves degeneration ... more Parkinson's disease (PD) is a common neurodegenerative disorder, which involves degeneration of dopaminergic neurons that are present in the substantia nigra pars compacta (SNpc) region. Many factors have been identified that could lead to Parkinson's disease; however, almost all of them are directly or indirectly dependent on Ca2+ signaling. Importantly, though disturbances in Ca2+ homeostasis have been implicated in Parkinson's disease and other neuronal diseases, the identity of the calcium channel remains elusive. Members of the transient receptor potential canonical (TRPC) channel family have been identified as a new class of Ca2+ channels, and it could be anticipated that these channels could play important roles in neurodegenerative diseases, especially in PD. Thus, in this chapter we have entirely focused on TRPC channels and elucidated its role in PD.
The Journal of biological chemistry, Dec 15, 2017
The transient receptor potential canonical channel-1 (TRPC1) is a Ca2+-permeable channel found in... more The transient receptor potential canonical channel-1 (TRPC1) is a Ca2+-permeable channel found in key metabolic organs and tissues, including the hypothalamus, adipose tissue, and skeletal muscle. Loss of TRPC1 may alter the regulation of cellular energy metabolism resulting in insulin resistance thereby leading to diabetes. Exercise reduces insulin resistance, but it is not known whether TRPC1 is involved in exercise-induced insulin sensitivity. The role of TRPC1 in adiposity and obesity-associated metabolic diseases has not yet been determined. Our results show that TRPC1 functions as a major Ca2+ entry channel in adipocytes. We have also shown that fat mass and fasting glucose concentrations were lower in TRPC1 KO mice that were fed a high-fat (HF) (45% fat) diet and exercised as compared with WT mice fed a HF diet and exercised. Adipocyte numbers were decreased in both subcutaneous and visceral adipose tissue of TRPC1 KO mice fed a HF diet and exercised. Finally, autophagy marke...
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Papers by Pramod Sukumaran