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Argon preconditioning protects neuronal cells with a Toll-like receptor-mediated effect.

The noble gas argon has the potential to protect neuronal cells from cell death. So far, this effect has been studied in treatment after acute damage. Preconditioning using argon has not yet been investigated. In this study, human neuroblastoma SH-SY5Y cells were treated with different concentrations of argon (25%, 50%, and 74%; 21% O, 5% CO, balance nitrogen) at different time intervals before inflicting damage with rotenone (20 µM, 4 hours). Apoptosis was determined by flow cytometry after annexin V and propidium iodide staining. Surface expressions of Toll-like receptors 2 and 4 were also examined. Cells were also processed for analysis by western blot and qPCR to determine the expression of apoptotic and inflammatory proteins, such as extracellular-signal regulated kinase (ERK1/2), nuclear transcription factor-κB (NF-κB), protein kinase B (Akt), caspase-3, Bax, Bcl-2, interleukin-8, and heat shock proteins. Immunohistochemical staining was performed for TLR2 and 4 and interleukin-8. Cells were also pretreated with OxPAPC, an antagonist of TLR2 and 4 to elucidate the molecular mechanism. Results showed that argon preconditioning before rotenone application caused a dose-dependent but not a time-dependent reduction in the number of apoptotic cells. Preconditioning with 74% argon for 2 hours was used for further experiments showing the most promising results. Argon decreased the surface expression of TLR2 and 4, whereas OxPAPC treatment partially abolished the protective effect of argon. Argon increased phosphorylation of ERK1/2 but decreased NF-κB and Akt. Preconditioning inhibited mitochondrial apoptosis and the heat shock response. Argon also suppressed the expression of the pro-inflammatory cytokine interleukin-8. Immunohistochemistry confirmed the alteration of TLRs and interleukin-8. OxPAPC reversed the argon effect on ERK1/2, Bax, Bcl-2, caspase-3, and interleukin-8 expression, but not on NF-κB and the heat shock proteins. Taken together, argon preconditioning protects against apoptosis of neuronal cells and mediates its action via Toll-like receptors. Argon may represent a promising therapeutic alternative in various clinical settings, such as the treatment of stroke.

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Glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor regulate the interaction between astrocytes and Schwann cells at the trigeminal root entry zone.

The trigeminal root entry zone is the zone at which the myelination switches from peripheral Schwann cells to central oligodendrocytes. Its special anatomical and physiological structure renders it susceptible to nerve injury. The etiology of most primary trigeminal neuralgia is closely related to microvascular compression of the trigeminal root entry zone. This study aimed to develop an efficient in vitro model mimicking the glial environment of trigeminal root entry zone as a tool to investigate the effects of glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor on the structural and functional integrity of trigeminal root entry zone and modulation of cellular interactions. Primary astrocytes and Schwann cells isolated from trigeminal root entry zone of postnatal rats were inoculated into a two-well silicon culture insert to mimic the trigeminal root entry zone microenvironment and treated with glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor. In monoculture, glial cell line-derived neurotrophic factor promoted the migration of Schwann cells, but it did not have effects on the migration of astrocytes. In the co-culture system, glial cell line-derived neurotrophic factor promoted the bidirectional migration of astrocytes and Schwann cells. Brain-derived neurotrophic factor markedly promoted the activation and migration of astrocytes. However, in the co-culture system, brain-derived neurotrophic factor inhibited the migration of astrocytes and Schwann cells to a certain degree. These findings suggest that glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor are involved in the regulation of the astrocyte-Schwann cell interaction in the co-culture system derived from the trigeminal root entry zone. This system can be used as a cell model to study the mechanism of glial dysregulation associated with trigeminal nerve injury and possible therapeutic interventions.

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Neuro faces of beneficial T cells: essential in brain, impaired in aging and neurological diseases, and activated functionally by neurotransmitters and neuropeptides.

T cells are essential for a healthy life, performing continuously: immune surveillance, recognition, protection, activation, suppression, assistance, eradication, secretion, adhesion, migration, homing, communications, and additional tasks. This paper describes five aspects of normal beneficial T cells in the healthy or diseased brain. First, normal beneficial T cells are essential for normal healthy brain functions: cognition, spatial learning, memory, adult neurogenesis, and neuroprotection. T cells decrease secondary neuronal degeneration, increase neuronal survival after central nervous system (CNS) injury, and limit CNS inflammation and damage upon injury and infection. Second, while pathogenic T cells contribute to CNS disorders, recent studies, mostly in animal models, show that specific subpopulations of normal beneficial T cells have protective and regenerative effects in several neuroinflammatory and neurodegenerative diseases. These include Multiple Sclerosis (MS), Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), stroke, CNS trauma, chronic pain, and others. Both T cell-secreted molecules and direct cell-cell contacts deliver T cell neuroprotective, neuroregenerative and immunomodulatory effects. Third, normal beneficial T cells are abnormal, impaired, and dysfunctional in aging and multiple neurological diseases. Different T cell impairments are evident in aging, brain tumors (mainly Glioblastoma), severe viral infections (including COVID-19), chronic stress, major depression, schizophrenia, Parkinson's disease, Alzheimer's disease, ALS, MS, stroke, and other neuro-pathologies. The main detrimental mechanisms that impair T cell function are activation-induced cell death, exhaustion, senescence, and impaired T cell stemness. Fourth, several physiological neurotransmitters and neuropeptides induce by themselves multiple direct, potent, beneficial, and therapeutically-relevant effects on normal human T cells, via their receptors in T cells. This scientific field is called "Nerve-Driven Immunity". The main neurotransmitters and neuropeptides that induce directly activating and beneficial effects on naïve normal human T cells are: dopamine, glutamate, GnRH-II, neuropeptide Y, calcitonin gene-related peptide, and somatostatin. Fifth, "Personalized Adoptive Neuro-Immunotherapy". This is a novel unique cellular immunotherapy, based on the "Nerve-Driven Immunity" findings, which was recently designed and patented for safe and repeated rejuvenation, activation, and improvement of impaired and dysfunctional T cells of any person in need, by ex vivo exposure of the person's T cells to neurotransmitters and neuropeptides. Personalized adoptive neuro-immunotherapy includes an early ex vivo personalized diagnosis, and subsequent ex vivo → in vivo personalized adoptive therapy, tailored according to the diagnosis. The Personalized Adoptive Neuro-Immunotherapy has not yet been tested in humans, pending validation of safety and efficacy in clinical trials, especially in brain tumors, chronic infectious diseases, and aging, in which T cells are exhausted and/or senescent and dysfunctional.

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Targeting the nitric oxide/cGMP signaling pathway to treat chronic pain.

Nitric oxide (NO)/cyclic guanosine 3',5'-monophosphate (cGMP) signaling has been shown to act as a mediator involved in pain transmission and processing. In this review, we summarize and discuss the mechanisms of the NO/cGMP signaling pathway involved in chronic pain, including neuropathic pain, bone cancer pain, inflammatory pain, and morphine tolerance. The main process in the NO/cGMP signaling pathway in cells involves NO activating soluble guanylate cyclase, which leads to subsequent production of cGMP. cGMP then activates cGMP-dependent protein kinase (PKG), resulting in the activation of multiple targets such as the opening of ATP-sensitive K channels. The activation of NO/cGMP signaling in the spinal cord evidently induces upregulation of downstream molecules, as well as reactive astrogliosis and microglial polarization which participate in the process of chronic pain. In dorsal root ganglion neurons, natriuretic peptide binds to particulate guanylyl cyclase, generating and further activating the cGMP/PKG pathway, and it also contributes to the development of chronic pain. Upregulation of multiple receptors is involved in activation of the NO/cGMP signaling pathway in various pain models. Notably the NO/cGMP signaling pathway induces expression of downstream effectors, exerting both algesic and analgesic effects in neuropathic pain and inflammatory pain. These findings suggest that activation of NO/cGMP signaling plays a constituent role in the development of chronic pain, and this signaling pathway with dual effects is an interesting and promising target for chronic pain therapy.

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Engineering human spinal microphysiological systems to model opioid-induced tolerance.

pioids are commonly used for treating chronic pain. However, with continued use, they may induce tolerance and/or hyperalgesia, which limits therapeutic efficacy. The human mechanisms of opioid-induced tolerance and hyperalgesia are significantly understudied, in part, because current models cannot fully recapitulate human pathology. Here, we engineered novel human spinal microphysiological systems (MPSs) integrated with plug-and-play neural activity sensing for modeling human nociception and opioid-induced tolerance. Each spinal MPS consists of a flattened human spinal cord organoid derived from human stem cells and a 3D printed organoid holder device for plug-and-play neural activity measurement. We found that the flattened organoid design of MPSs not only reduces hypoxia and necrosis in the organoids, but also promotes their neuron maturation, neural activity, and functional development. We further demonstrated that prolonged opioid exposure resulted in neurochemical correlates of opioid tolerance and hyperalgesia, as measured by altered neural activity, and downregulation of μ-opioid receptor expression of human spinal MPSs. The MPSs are scalable, cost-effective, easy-to-use, and compatible with commonly-used well-plates, thus allowing plug-and-play measurements of neural activity. We believe the MPSs hold a promising translational potential for studying human pain etiology, screening new treatments, and validating novel therapeutics for human pain medicine.

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Colonoscopy-assisted percutaneous sigmoidopexy for a complete rectal prolapse: A case report.

Colonoscopy-assisted percutaneous sigmoidopexy is a simple and swift procedure that does not require general anesthesia. While we first developed this procedure for treating sigmoid volvulus, we herein present the first case in which we used it to correct a complete rectal prolapse in an older patient. Existing treatment modalities for rectal prolapses are limited by high recurrence rates, greater invasiveness, and greater complications; thus, there is a need for minimally invasive techniques that are associated with lower recurrence rates and fewer complications. In this case, a woman in her 90s complained of persistent fecal incontinence, dysuria, anal pain, and difficulty in walking. She was diagnosed with a complete rectal prolapse of 15 cm and was treated with colonoscopy-assisted percutaneous sigmoidopexy. The sigmoid colon was tractioned colonoscopically and fixed to the abdominal wall to immobilize the prolapsed rectum. The patient developed no complications intraoperatively and postoperatively and experienced no recurrence during a 5-year postoperative period. This report documents the first case wherein colonoscopy-assisted percutaneous sigmoidopexy was used successfully to correct a complete rectal prolapse.

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White gastric mucosa during endoscopy as a new endoscopic feature of chronic ischemic gastritis: A case report.

Chronic ischemic gastritis (CIG) requires early diagnosis and treatment as complications of thromboembolism can be fatal. Although computed tomography (CT) is useful in the diagnosis of CIG, it is difficult to diagnose from a patient's history, endoscopic findings, and tissue biopsy. Identification of the key findings that motivate computed tomography is an important issue. We report a case of CIG diagnosed by endoscopic findings of white patches of mucosa over time. A 63-year-old man presented with epigastric pain. He had a history of repeated gastric ulcers of an undetermined cause. We performed upper endoscopy and observed the appearance of multiple white patches on the gastric mucosa. Central vessel stenosis was considered, and aortic computed tomography revealed complete occlusion of the superior mesenteric artery and stenosis of the celiac artery. We carried out a surgical bypass and found no postoperative endoscopic mucosal changes or abdominal pain. White patch changes in the gastric mucosa over time during endoscopy may indicate CIG. This finding may help in the future diagnosis of CIG.

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Acute idiopathic blind spot enlargement syndrome (AIBSES) with retinal vasculitis.

To report the clinical and anatomical features of an unusual case of acute idiopathic blind spot enlargement syndrome (AIBSES) with retinal vasculitis.

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Microscopic corneal epithelial changes and clinical outcomes in simple limbal epithelial transplantation surgery after treatment with amniotic membrane eye drops (AMED): A case report.

To describe the microscopic epithelial changes and the clinical outcomes of a patient treated with amniotic membrane eye drops (AMED) because of a persistent epithelial defect (PED) and a partial limbal stem cell deficiency (LSCD) after simple limbal epithelial transplantation (SLET) and deep anterior lamellar keratoplasty (DALK).

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Trigeminal Neuralgia: Diagnosis and Treatment.

Trigeminal neuralgia is characterized classically by recurrent, evocable, unilateral brief, electric, shocklike pains with an abrupt onset and cessation that affects one or more divisions of the trigeminal nerve. In recent years, the classification of trigeminal neuralgia has been updated based on further understanding. In this manuscript, the authors aim to explain the current understanding of the pathophysiology of trigeminal neuralgia, current diagnosis criteria, and the pharmacologic management and surgical treatments of options currently available.

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