teasing-out-interplay-between-natural-killer-cells-nociceptor

Teasing Out the Interplay Between Natural Killer Cells and Nociceptor Neurons

Somatosensory neurons have evolved to detect noxious stimuli and activate defensive reflexes. By sharing means of communication, nociceptor neurons also ...

Université de Montréal

Diabetes is a common condition characterized by persistent hyperglycemia. High blood sugar primarily affects cells that have a limited capacity to regulate their glucose intake. These cells include capillary endothelial cells in the retina, mesangial cells in the renal glomerulus, Schwann cells, and neurons of the peripheral and central nervous systems. As a result, hyperglycemia leads to largely intractable complications such as retinopathy, nephropathy, hypertension, and neuropathy. Diabetic pain neuropathy is a complex and multifactorial disease that has been associated with poor glycemic control, longer diabetes duration, hypertension, advanced age, smoking status, hypoinsulinemia, and dyslipidemia. While many of the driving factors involved in diabetic pain are still being investigated, they can be broadly classified as either neuron -intrinsic or -extrinsic. In neurons, hyperglycemia impairs the polyol pathway, leading to an overproduction of reactive oxygen species and reactive nitrogen species, an enhanced formation of advanced glycation end products, and a disruption in Na/K ATPase pump function. In terms of the extrinsic pathway, hyperglycemia leads to the generation of both overactive microglia and microangiopathy. The former incites a feed-forward inflammatory loop that hypersensitizes nociceptor neurons, as observed at the onset of diabetic pain neuropathy. The latter reduces neurons' access to oxygen, glucose and nutrients, prompting reductions in nociceptor terminal expression and losses in sensation, as observed in the later stages of diabetic pain neuropathy. Overall, microglia can be seen as potent and long-lasting amplifiers of nociceptor neuron activity, and may therefore constitute a potential therapeutic target in the treatment of diabetic pain neuropathy.

Neurons and Microglia; A Sickly-Sweet Duo in Diabetic Pain Neuropathy.

Vagal sensory neurons drive mucous cell metaplasia.

Phenotypic screening is an ideal strategy for the discovery of novel bioactive molecules. Using a customized high-throughput screening (HTS) assay employing primary T lymphocytes, we screened a small library of 4,398 compounds with unknown biological function/target to identify compounds eliciting immunomodulatory properties and discovered a sulfonyl-containing hit, we named InhiTinib. This compound inhibited interferon (IFN)-gamma production and proliferation of primary CD3 T cells without inducing cell death. In contrast, InhiTinib triggered apoptosis in several murine and human cancer cell lines. Besides, the compound was well tolerated by immunocompetent mice, triggered tumor regression in animals with pre-established EL4 T-cell lymphomas, and prolonged the overall survival of mice harboring advanced tumors. Altogether, our data demonstrate the anti-cancer properties of InhiTinib, which can henceforth bridge to wider-scale biochemical and clinical tests following further in-depth pharmacodynamic studies.

Article	Year
Neurons and Microglia; A Sickly-Sweet Duo in Diabetic Pain Neuropathy. Frontiers in neuroscience\| PubMed ID: 30766472	2019
Vagal sensory neurons drive mucous cell metaplasia. The Journal of allergy and clinical immunology\| PubMed ID: 31954778	2020
A Novel Sulfonyl-Based Small Molecule Exhibiting Anti-cancer Properties. Frontiers in pharmacology\| PubMed ID: 32231565	2020

Maryam Ahmadi

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