Publications by authors named "Bimal N Desai"

Pannexin 1 (PANX1) is a member of a topologically related and stoichiometrically diverse family of large pore membrane ion channels that support the flux of signaling metabolites (e.g., ATP) and fluorescent dyes.

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  • Most pandemic viruses have a protective covering and enter cells through a specific method that involves helper proteins.
  • Researchers found that a protein called TRPM7 is very important for these viruses to infect cells, as it helps create the right conditions inside the cell for the virus to fuse and enter.
  • The study suggests that targeting TRPM7 could lead to new medicines that could prevent many types of these viruses from infecting cells.
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TRPM7, a TRP channel with ion conductance and kinase activities, has emerged as an attractive drug target for immunomodulation. Reverse genetics and cell biological studies have already established a key role for TRPM7 in the inflammatory activation of macrophages. Advancing TRPM7 as a viable molecular target for immunomodulation requires selective TRPM7 inhibitors with in vivo tolerability and efficacy.

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  • TRPM7 is identified as a promising drug target for controlling immune responses, particularly in inflammatory activation of macrophages.
  • Researchers tested non-phosphorylatable analogs of FTY720, which do not activate S1P receptors and showed effectiveness in inhibiting TRPM7 and reducing inflammation in macrophages.
  • One of these analogs, VPC01091.4, demonstrated significant anti-inflammatory effects in a mouse model, highlighting its potential as a selective TRPM7 inhibitor with broad therapeutic applications.
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Mitochondrial dysfunction is linked to age-associated inflammation or inflammaging, but underlying mechanisms are not understood. Analyses of 700 human blood transcriptomes revealed clear signs of age-associated low-grade inflammation. Among changes in mitochondrial components, we found that the expression of mitochondrial calcium uniporter (MCU) and its regulatory subunit MICU1, genes central to mitochondrial Ca (mCa) signaling, correlated inversely with age.

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Acetyl-CoA carboxylase (ACC) regulates lipid synthesis; however, its role in inflammatory regulation in macrophages remains unclear. We generated mice that are deficient in both ACC isoforms in myeloid cells. ACC deficiency altered the lipidomic, transcriptomic, and bioenergetic profile of bone marrow-derived macrophages, resulting in a blunted response to proinflammatory stimulation.

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  • Activation of Pannexin 1 (PANX1) ion channels is linked to the release of intercellular signaling molecules and is triggered by G protein-coupled receptors (GPCRs), specifically α1-adrenergic receptors (α1-ARs).
  • The study reveals that α1-AR activation of PANX1 occurs through a deacetylation process involving the protein RhoA, mDia, and histone deacetylase 6 (HDAC6), rather than through traditional signaling pathways like phospholipase C or calcium influx.
  • Key experiments show that modifying acetylated lysine residues on PANX1 can either block or maintain its activation by HDAC6,
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Herpes simplex virus-1 (HSV-1) establishes a latent infection in neurons and periodically reactivates to cause disease. The stimuli that trigger HSV-1 reactivation have not been fully elucidated. We demonstrate HSV-1 reactivation from latently infected mouse neurons induced by forskolin requires neuronal excitation.

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The thymic development of regulatory T (T) cells, crucial suppressors of the responses of effector T (T) cells, is governed by the transcription factor FOXP3. Despite the clinical importance of T cells, there is a dearth of druggable molecular targets capable of increasing their numbers in vivo. We found that inhibiting the function of the TRPM7 chanzyme (ion channel and enzyme) potentiated the thymic development of T cells in mice and led to a substantially higher frequency of functional T cells in the periphery.

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Objective: Brown adipose tissue (BAT) is specialized in thermogenesis. The conversion of energy into heat in brown adipocytes proceeds via stimulation of β-adrenergic receptor (βAR)-dependent signaling and activation of mitochondrial uncoupling protein 1 (UCP1). We have previously demonstrated a functional role for pannexin-1 (Panx1) channels in white adipose tissue; however, it is not known whether Panx1 channels play a role in the regulation of brown adipocyte function.

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  • Macrophages quickly adjust their metabolism to kill pathogens by using a two-step process involving calcium signals.
  • When a fungal pathogen is detected, macrophages elevate their cytosolic Ca levels, then simultaneously increase calcium influx into their mitochondria to boost energy production.
  • Without proper mitochondrial calcium signaling, macrophages struggle to produce reactive oxygen species needed for killing fungi, making mice lacking this signaling more vulnerable to infections.
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Insulin secretion from β-cells is reduced at the onset of type-1 and during type-2 diabetes. Although inflammation and metabolic dysfunction of β-cells elicit secretory defects associated with type-1 or type-2 diabetes, accompanying changes to insulin granules have not been established. To address this, we performed detailed functional analyses of insulin granules purified from cells subjected to model treatments that mimic type-1 and type-2 diabetic conditions and discovered striking shifts in calcium affinities and fusion characteristics.

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After recognizing extracellular bacterial lipopolysaccharide (LPS), the toll-like receptor 4 (TLR4)-CD14 signaling complex initiates two distinct signaling pathways-one from the plasma membrane and the other from the signaling endosomes (Kagan 2008). Understanding the early stages of TLR4 signal transduction therefore requires a robust and quantitative method to measure LPS-triggered TLR4 and CD14 receptor endocytosis, one of the earliest events of LPS detection. Here, we describe a flow cytometry-based method that we used recently to study the role of the ion channel TRPM7 in TLR4 endocytosis (Schappe 2018).

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Adipose tissue macrophages (ATMs) adapt their metabolic phenotype either to maintain lean tissue homeostasis or drive inflammation and insulin resistance in obesity. However, the factors in the adipose tissue microenvironment that control ATM phenotypic polarization and bioenergetics remain unknown. We have recently shown that oxidized phospholipids (OxPL) uniquely regulate gene expression and cellular metabolism in macrophages, but the presence of the phenotype in adipose tissue has not been reported.

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  • Toll-like receptors (TLRs) detect harmful patterns from pathogens, triggering inflammation through the production of cytokines, particularly in response to lipopolysaccharide (LPS) via TLR4.
  • The ion channel TRPM7 plays a crucial role in elevating cytosolic calcium levels, which are necessary for the activation of macrophages and the signaling pathways involving IRF3 and NFκB.
  • Mice lacking TRPM7 in their macrophages showed significantly reduced inflammatory responses to LPS, indicating the importance of TRPM7 and calcium signaling in mediating TLR4 activities.
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Rationale: Resistant hypertension is a major health concern with unknown cause. Spironolactone is an effective antihypertensive drug, especially for patients with resistant hypertension, and is considered by the World Health Organization as an essential medication. Although spironolactone can act at the mineralocorticoid receptor (MR; NR3C2), there is increasing evidence of MR-independent effects of spironolactone.

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Pannexin 1 (Panx1) forms plasma membrane ion channels that are widely expressed throughout the body. Panx1 activation results in the release of nucleotides such as adenosine triphosphate and uridine triphosphate. Thus, these channels have been implicated in diverse physiological and pathological functions associated with purinergic signaling, such as apoptotic cell clearance, blood pressure regulation, neuropathic pain, and excitotoxicity.

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Optogenetics is a powerful research approach that allows localized optical modulation of selected cells within an animal via the expression of genetically encoded photo-excitable ion channels. Commonly used optogenetic techniques rely on the expression of microbial opsin variants, which have many excellent features but suffer from various degrees of blue spectral overlap and limited channel conductance. Here, we expand the optogenetics toolbox in the form of a tunable, high-conductance vertebrate cation channel, zTrpa1b, coupled with photo-activated channel ligands, such as optovin and 4g6.

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Neuropathic pain symptoms respond poorly to available therapeutics, with most treated patients reporting unrelieved pain and significant impairment in daily life. Here, we show that Pannexin 1 (Panx1) in hematopoietic cells is required for pain-like responses following nerve injury in mice, and a potential therapeutic target. Panx1 knockout mice (Panx1) were protected from hypersensitivity in two sciatic nerve injury models.

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In addition to a fundamental role in cellular bioenergetics, the purine nucleotide adenosine triphosphate (ATP) plays a crucial role in the extracellular space as a signaling molecule. ATP and its metabolites serve as ligands for a family of receptors that are collectively referred to as purinergic receptors. These receptors were first described and characterized in the nervous system but it soon became evident that they are expressed ubiquitously.

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Caspase-11 is a highly inducible caspase that controls both inflammatory responses and cell death. Caspase-11 controls interleukin 1β (IL-1β) secretion by potentiating caspase-1 activation and induces caspase-1-independent pyroptosis downstream of noncanonical NLRP3 inflammasome activators such as lipopolysaccharide (LPS) and Gram-negative bacteria. However, we still know very little about the downstream mechanism of caspase-11 in regulating inflammation because the known substrates of caspase-11 are only other caspases.

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