Distal sensory polyneuropathy (DSP) with associated neuropathic pain is the most common neurological disorder affecting patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Viral protein R (Vpr) is a neurotoxic protein encoded by HIV-1 and secreted by infected macrophages. Vpr reduces neuronal viability, increases cytosolic calcium and membrane excitability of cultured dorsal root ganglion (DRG) sensory neurons, and is associated with mechanical allodynia in vivo. A clinical trial with HIV/AIDS patients demonstrated that nerve growth factor (NGF) reduced the severity of DSP-associated neuropathic pain, a problem linked to damage to small diameter, potentially NGF responsive fibers. Herein, the actions of NGF were investigated in our Vpr model of DSP and we demonstrated that NGF significantly protected sensory neurons from the effects of Vpr. Footpads of immunodeficient Vpr transgenic (vpr/RAG1−/−) mice displayed allodynia (p<0.05), diminished epidermal innervation (p<0.01) and reduced NGF mRNA expression (p<0.001) compared to immunodeficient (wildtype/RAG1−/−) littermate control mice. Compartmented cultures confirmed recombinant Vpr exposure to the DRG neuronal perikarya decreased distal neurite extension (p<0.01), whereas NGF exposure at these distal axons protected the DRG neurons from the Vpr-induced effect on their cell bodies. NGF prevented Vpr-induced attenuation of the phosphorylated glycogen synthase-3 axon extension pathway and tropomyosin related kinase A (TrkA) receptor expression in DRG neurons (p<0.05) and it directly counteracted the cytosolic calcium burst caused by Vpr exposure to DRG neurons (p<0.01). TrkA receptor antagonists indicated that NGF acted through the TrkA receptor to block the Vpr-mediated decrease in axon outgrowth in neonatal and adult rat and fetal human DRG neurons (p<0.05). Similarly, inhibiting the lower affinity NGF receptor, p75, blocked Vpr’s effect on DRG neurons. Overall, NGF/TrkA signalling or p75 receptor inhibition protects somatic sensory neurons exposed to Vpr, thus laying the groundwork for potential therapeutic options for HIV/AIDS patients suffering from DSP.
This study deal with introducing a novel biocompatible porous nanomaterial for anticancer drug delivery. For this purpose, a porous covalent triazine framework (CTF) was prepared by a solvothermal reaction. The structure and morphology characterization of the synthesized CTF was done through different techniques. Imatinib (IMA) were loaded thoroughly into the CTF to form IMA-loaded CTF (IMA@CTF) in which drug loading and encapsulation efficiency was calculated to be 82% and 96%, respectively. The releases of 73% and 48%% after 72 h for the IMA@CTF were obtained in pH = 5.3 and pH = 7.4, respectively, which reflected pH-dependent behavior as well as sustained imatinib release. Biocompatibility and cytotoxicity effect of CTF and IMA@CTF assessed after 48 h incubation with normal cell line L929 as well as K562 cells. The biocompatibility study indicated reasonable biosafety of the synthesized CTF and MTT assay on chronic myeloma cancer cells showed no reduction effect in the anticancer activity of IMA after incorporating into CTF. The results demonstrated the synthesized CTF could be as a promise anti-cancer drug carrier.
Paternal metabolic status is an important factor in the health status of offspring. Cholestasis, as a metabolic disorder, significantly disrupts spermatogenesis. Spermatogonial stem cells (SSCs) are considered the dividing germ cells, which maintain spermatogenesis throughout the lifespan. Here, we investigated the in vivo and in vitro effect(s) of cholestasis on SSCs. Cholestasis was induced in rats by bile duct How to cite this article: Hasani Fard AH, Mohseni Kouchesfehani H, Jalali H. Investigation of cholestasis-related changes in characteristics of spermatogonial stem cells in testis tissue of male Wistar rats.
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