α1 receptor blockade

Picrotoxin (PTX), a convulsant of plant origin, has been used in many studies as research tool. PTX is the open channel blocker of the GABAA receptor (GABAA R). Being in the pore, PTX initiates transfer of the channel to the closed state and thus it falls into the "trap". The consequence of this PTX trapping is so-called aftereffect, i.e. continuation of the blockade of the GABA-induced chloride current (IGABA ) after removal of PTX from the external solution. The present work shows that the positive allosteric modulators (PAMs) of the GABAA receptor, allopregnanolone (Allo) and zolpidem (Zolp) as well as a high concentration of GABA shortened the PTX aftereffect...

INTRODUCTION: Chemotherapy-induced neuropathic pain (CINP) is one of the main adverse effects of chemotherapy treatment. At the spinal level, CINP modulation involves glial cells that upregulate Toll-like receptor 4 (TLR4) and signaling pathways, which can be activated by pro-inflammatory mediators as the high mobility group box-1 (HMGB1). OBJECTIVE: To evaluate the spinal role of HMGB1 in the paclitaxel-induced neuropathic pain via receptor for advanced glycation end products (RAGE) and TLR4 activation expressed in glial cells...

Injection of polyinosinic:polycytidylic acid (poly(I:C)) into experimental animals induces neuroimmunological responses and thus has been used for the study of neurological disorders such as anxiety, depression, and chronic fatigue. Here, we investigated the effects of vagus nerve stimulation (VNS) on poly(I:C)-induced neuroinflammation and associated behavioral consequences in rats. The microglia in the prefrontal cortex (PFC) displayed the activated form of morphology in poly(I:C)-injected rats and changed to a normal shape after acute VNS (aVNS)...

Combinatorial strategies, such as targeting different immune checkpoint receptors, hold promise to increase the breadth and duration of the response to cancer therapy. Here we describe the preclinical evaluation of CTX-8371, a protein construct which combines PD-1 and PD-L1 targeting in one bispecific, tetravalent antibody. CTX-8371 matched or surpassed the activity of anti-PD-1 and PD-L1 benchmark antibodies in several in vitro T cell activation assays and outperformed clinically approved benchmarks in the subcutaneous MC38 colon and the B16F10 lung metastasis mouse tumor models...

Checkpoint inhibition (CPI) is a standard therapeutic approach in metastatic renal cell carcinoma (RCC). However, not all patients respond to CPI, and the immune suppressive characteristics of the RCC tumor microenvironment may contribute to treatment failure. Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) is a transmembrane protein expressed on a subset of myeloid cells with M2-like anti-inflammatory properties that has previously been associated with disease recurrence after nephrectomy and poor outcomes when expressed at high levels...

This works defines for the first time a molecular circuit connecting NAMPT activity to the B cell receptor (BCR) pathway. Using four distinct Richter's syndrome patient-derived xenograft models (RS-PDX), we show that B cell receptor cross-linking results in transcriptional activation of the NAD-biosynthetic enzyme nicotinamide mononucleoside phosphoribosyl transferase (NAMPT), with increased protein expression, in turn positively affecting global cellular NAD levels and sirtuins activity. NAMPT blockade, by using the novel OT-82 inhibitor in combination with either BTK or PI3K inhibitors (BTKi or PI3Ki), induces rapid and potent apoptotic responses in all four models, independently of their mutational profile and of the expression of the other NAD biosynthetic enzymes, including nicotinate phosphoribosyltransferase (NAPRT)...

Understanding cancer immunobiology has been hampered by difficulty identifying cancer-specific T cells. Merkel cell polyomavirus (MCPyV) causes most Merkel cell carcinomas (MCCs). All patients with virus-driven MCC express MCPyV oncoproteins, facilitating identification of virus (cancer)-specific T cells. We studied MCPyV-specific T cells from 27 patients with MCC using MCPyV peptide-HLA-I multimers, 26-color flow cytometry, single-cell transcriptomics, and T cell receptor (TCR) sequencing...

A major limitation to developing chimeric antigen receptor (CAR)-T cell therapies for solid tumors is identifying surface proteins highly expressed in tumors but not in normal tissues. Here, we identify Tyrosinase Related Protein 1 (TYRP1) as a CAR-T cell therapy target to treat patients with cutaneous and rare melanoma subtypes unresponsive to immune checkpoint blockade. TYRP1 is primarily located intracellularly in the melanosomes, with a small fraction being trafficked to the cell surface via vesicular transport...

Developmental neurogenesis is a tightly regulated spatiotemporal process with its dysregulation implicated in neurodevelopmental disorders. NMDA receptors are glutamate-gated ion channels that are widely expressed in the early nervous system, yet their contribution to neurogenesis is poorly understood. Notably, a variety of mutations in genes encoding NMDA receptor subunits are associated with neurodevelopmental disorders. To rigorously define the role of NMDA receptors in developmental neurogenesis, we used a mutant zebrafish line (grin1-/- ) that lacks all NMDA receptors yet survives to 10 days post-fertilization, offering the opportunity to study post-embryonic neurodevelopment in the absence of NMDA receptors...

Immune checkpoint blockades have been prized in circumventing and ablating the impediments posed by immunosuppressive receptors, reaching an exciting juncture to be an innovator in anticancer therapy beyond traditional therapeutics. Thus far, approved immune checkpoint blockades have principally targeted PD-1/PD-L1 and CTLA-4 with exciting success in a plethora of tumors and yet are still trapped in dilemmas of limited response rates and adverse effects. Hence, unveiling new immunotherapeutic targets has aroused immense scientific interest in the hope of expanding the clinical application of immune checkpoint blockades to scale new heights...

Hydroxychavicol, a primary active phenolic compound of betel leaves, previously inhibited bone loss in vivo by stimulating osteogenesis. However, the effect of hydroxychavicol on bone remodeling induced by osteoclasts is unknown. In this study, the anti-osteoclastogenic effects of hydroxychavicol and its mechanism were investigated in receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclasts. Hydroxychavicol reduced the number of tartrate resistance acid phosphatase (TRAP)- positive multinucleated, F-actin ring formation and bone-resorbing activity of osteoclasts differentiated from RAW264...

Circadian arrhythmia has been linked to increased susceptibility to multiple inflammatory diseases, such as sepsis. However, it remains unclear how disruption of the circadian clock modulates molecular aspects of innate immune responses, including inflammasome signaling. Here, we examined the potential role of the circadian clock in inflammasome-mediated responses through myeloid-specific deletion of BMAL1, a master circadian clock regulator. Intriguingly, Bmal1 deficiency significantly enhanced pyroptosis of macrophages and lethality of mice under noncanonical inflammasome-activating conditions but did not alter canonical inflammasome responses...

The endocannabinoid system interacts with the reward system to modulate responsiveness to natural reinforcers, as well as drugs of abuse. Previous preclinical studies suggested that direct blockade of CB1 cannabinoid receptors (CB1R) could be leveraged as a potential pharmacological approach to treat substance use disorder, but this strategy failed during clinical trials due to severe psychiatric side effects. Alternative strategies have emerged to circumvent the side effects of direct CB1 binding through the development of allosteric modulators...

The development and progression of breast cancer (BC) depend heavily on the tumor microenvironment (TME), especially tumor infiltration leukocytes (TILs). TME-based classifications in BC remain largely unknown and need to be clarified. Using the bioinformatic analysis, we attempted to construct a prognostic nomogram based on clinical features and TME-related differentially expressed genes (DEGs). We also tried to investigate the association between the prognostic nomogram and clinical characteristics, TILs, possible signaling pathways, and response to immunotherapy in BC patients...

BACKGROUND: Peripheral blood oxygen monitoring via chemoreceptors in the carotid body (CB) is an integral function of the autonomic cardiorespiratory regulation. The presence of the purinergic P2Y12 receptor (P2Y12R) has been implicated in CB; however, the exact role of the receptor in O2 sensing and signal transduction is unknown. METHODS: The presence of P2Y12R was established by immunoblotting, RT qPCR and immunohistochemistry. Primary glomus cells were used to assess P2Y12R function during hypoxia and hypercapnia, where monoamines were measured by HPLC; calcium signal was recorded utilizing OGB-1 and N-STORM Super-Resolution System...

BACKGROUND: Cryoablation is a minimally invasive option for patients with medically inoperable non-small cell lung cancer (NSCLC) and can trigger abscopal immune-regulatory effects. However, it remains unclear how cryoablation affects the host-level immune response in NSCLC. In this study, we investigated the local and systemic immunological effects of cryoablation and the potential of combining cryoablation with programmed cell death protein 1 (PD-1) blockade to boost immunotherapy efficacy in NSCLC...

Arsenic (As) is a prevalent and hazardous environmental toxicant associated with cancer and various health problems, which has been shown suppressive effects on dendritic cells (DCs). Autophagy is essential for the innate and adaptive immune responses of DCs, and the transcription factors TFEB and TFE3 are key regulators of autophagic and lysosomal target genes. However, the detrimental alterations of the autophagy-lysosome pathway in As-exposed DCs and the possible coordinating roles of TFEB and TFE3 in the immune dysfunction of this cell are less understood...

We studied whether the function of presynaptic inhibitory cannabinoid CB1 receptors on the sympathetic nerve fibres innervating resistance vessels is increased in spontaneously hypertensive rats (SHR) like in deoxycorticosterone (DOCA)-salt hypertension. An increase in diastolic blood pressure (DBP) was induced by electrical stimulation of the preganglionic sympathetic neurons or by phenylephrine injection in pithed SHR and normotensive Wistar-Kyoto rats (WKY). The electrically (but not the phenylephrine) induced increase in DBP was inhibited by the cannabinoid receptor agonist CP55940, similarly in both groups, and by the endocannabinoid reuptake inhibitor AM404 in SHR only...

BACKGROUND & PURPOSE: Radium-223 (Ra223) improves survival in metastatic prostate cancer (mPC), but its impact on systemic immunity is unclear, and biomarkers of response are lacking. We examined markers of immunomodulatory activity during standard clinical Ra223 and studied the impact of Ra223 on response to immune checkpoint inhibition (ICI) in preclinical models. MATERIALS & METHODS: We conducted a single-arm biomarker study of Ra223 in 22 bone mPC patients...

BACKGROUND: Programmed cell death protein 1(PD-1) axis blockade has become the mainstay in the treatment of recurrent and/or metastatic (R/M) head and neck squamous cell cancer (HNSCC). PD-L1 is the only approved biomarker for patient selection; however, response rate is limited even among high expressors. Our primary objective was to investigate the association of immune-cell-related biomarkers in the tumor and tumor microenvironment with PD-1 checkpoint inhibitors' outcomes in patients with R/M HNSCC...