Decrease In Nerve Fiber Density Research Articles

Neuronatin Promotes the Progression of Non-Small Cell Lung Cancer by Activating the NF-κB Signaling.

Understanding the regulatory mechanisms involving neuronatin (NNAT) in non-small cell lung cancer (NSCLC) is an ongoing challenge. This study aimed to elucidate the impact of NNAT knockdown on NSCLC by employing both in vitro and in vivo approaches. To investigate the role of NNAT, its expression was silenced in NSCLC cell lines A549 and H226. Subsequently, various parameters, including cell proliferation, invasion, migration, and apoptosis, were assessed. Additionally, cell-derived xenograft models were established to evaluate the effect of NNAT knockdown on tumor growth. The expression of key molecules, including cyclin D1, B-cell leukemia/lymphoma 2 (Bcl-2), p65, matrix metalloproteinase (MMP) 2, and nerve growth factor (NGF) were examined both in vitro and in vivo. Nerve fiber density within tumor tissues was analyzed using silver staining. Upon NNAT knockdown, a remarkable reduction in NSCLC cell proliferation, invasion, and migration was observed, accompanied by elevated levels of apoptosis. Furthermore, the expression of cyclin D1, Bcl-2, MMP2, and phosphorylated p65 (p-p65) showed significant downregulation. In vivo, NNAT knockdown led to substantial inhibition of tumor growth and a concurrent decrease in cyclinD1, Bcl-2, MMP2, and p-p65 expression within tumor tissues. Importantly, NNAT knockdown also led to a decrease in nerve fiber density and downregulation of NGF expression within the xenograft tumor tissues. Collectively, these findings suggest that neuronatin plays a pivotal role in driving NSCLC progression, potentially through the activation of the nuclear factor-kappa B signaling cascade. Additionally, neuronatin may contribute to the modulation of tumor microenvironment innervation in NSCLC. Targeting neuronatin inhibition emerges as a promising strategy for potential anti-NSCLC therapeutic intervention.

Alterations in corneal nerves following crack cocaine use mimic diabetes-induced nerve damage.

SummaryThe use of in vivo confocal microscopy (IVCM) is rapidly emerging as an important clinical tool to evaluate changes in corneal sensory nerves as a surrogate measure for diabetic peripheral neuropathy. Commonly used metrics to document and grade the severity of diabetes and risk for diabetic peripheral neuropathy include nerve fiber length, density, branching and tortuosity. In addition to corneal nerves, thinning of the retinal fiber layer has been shown to correlate with the severity of diabetic disease. Here, we present a case report on a pre-diabetic 60-year-old native American woman with abnormal corneal nerve morphology and retinal nerve fiber layer thinning. Her past medical history was positive for illicit substance abuse. IVCM showed a decrease in nerve fiber density and length, in addition to abnormally high levels of tortuosity. OCT revealed focal areas of reduced retinal nerve fiber layer thickness that were asymmetric between eyes. This is the first report of abnormally high levels of tortuosity in the corneal sub-basal nerve plexus in a patient with a past history of cocaine abuse. It also demonstrates, for the first time, that illicit substance abuse can have long-term adverse effects on ocular nerves for years following discontinued use of the drug. Studies using IVCM to evaluate changes in corneal nerve morphology in patients with diabetes need to consider a past history of illicit drug use as an exclusionary measure.Learning points:Multiple ocular and systemic factors can impede accurate assessment of the corneal sub-basal nerve plexus by IVCM in diabetes.Although current history was negative for illicit substance abuse, past history can have longstanding effects on corneal nerves and the retinal nerve fiber layer.Illicit drug use must be considered an exclusionary measure when evaluating diabetes-induced changes in corneal nerve morphology and the retinal nerve fiber layer.

Development of animal model for vasculatic neuropathy: Induction by ischemic-reperfusion in the rat femoral artery

Ischemic-reperfusion (I/R) is common in various pathological conditions like diabetic complication, complex regional pain syndrome type II (CRPS II), necrotizing vascular occlusive disease and trauma. We have developed an animal model of ischemic-reperfusion injury induced nociceptive sensory neuropathy in rats. The model was validated after 2, 4 and 6 h of ischemia followed by prolonged reperfusion. The sensory behavioral assessment revealed thermal and mechanical hyperalgesia in paw and in tail which expressed the peripheral and central neuropathic pain respectively. We observed a decrease in the serum IL-10 and nerve conduction velocity and increase in the serum nitrate, malondialdehyde (MDA) and TNF-α levels in the 4 and 6 h I/R groups in biochemical and electrophysiological evaluations. Histopathological study had revealed the decrease in nerve fiber density in the moderate and severe I/R groups. We selected the moderate (4 h) ischemic-reperfusion injury as beneficial model because of the good correlation with clinical status for the development of neuropathy in human associated with severe pain disorders. This model can be used to explore pathophysiological mechanisms implied in the genesis of neuropathic pain and also to evaluate the new analgesic agents, peripheral neuro-vasoactive substances and neuroprotective drugs.

Decrease in nerve fibre density in human sigmoid colon circular muscle occurs with growth but not aging

Studies in animals suggest that enteric neurons decrease in density or number with increasing age. Neurons containing nitric oxide (NO), vasoactive intestinal peptide (VIP) and Substance P (SP) have been implicated. In human large intestine, NO-utilizing neurons decrease during childhood or early adulthood but it is not known if the innervation of the muscle changes. This study examined the density of nerve fibres containing these transmitters in sigmoid colon circular muscle from children and adults. Fluorescence immunohistochemistry using antibodies to neuronal NO synthase (nNOS), VIP and SP was performed on sigmoid colon from 18 adults with colorectal cancer, two children with familial adenomatous polyposis, and normal colon from nine children with Hirschsprung's disease. The percentage area of immunoreactive (IR) nerve fibres containing each transmitter in circular muscle was quantified in confocal images. In the adult sigmoid colon circular muscle, the percentage area of nerve fibres containing nNOS>VIP>SP (6 : 2 : 1). Paediatric groups had significantly higher percentage area of nerve fibres containing nNOS, VIP or SP-IR than adults, with the decrease in nerve fibre density occurring from birth to 30 years. Circular muscle thickness increased between 12 and 30 years. Total nerve fibre area remained constant, while the muscle increased in thickness. In human sigmoid colon circular muscle, there are reductions in nNOS-, VIP- and SP-IR nerve fibre density with growth from newborn to late adolescence but little further change with aging. The reduction in nerve density is due to an increase in circular muscle thickness rather than a loss of nerve fibres.

Investigation into the possible cause of subjective decreased sensory perception in the nipple-areola complex of women with macromastia.

Patients with macromastia often comment on a lack of sensation in their nipple-areola complex. A study was designed to investigate the cause of this decreased sensation. Two hypotheses were proposed. First, the decreased sensation could result from neuropraxia of the sensory nerve fibers secondary to traction caused by the heavy breast parenchyma. The second hypothesis proposed that tissue expansion of the nipple and areola by the voluminous breast parenchyma caused a decrease in nerve fibers per surface area and hence decreased sensory perception. Sixty-one patients were assessed in the study. All patients underwent surgery in which histological biopsy of either the areola alone (31 reduction mammaplasty patients) or the nipple and areola (30 mastectomy patients) was possible. Before surgery, each nipple-areola complex was tested with Weinstein Enhanced Sensory Test monofilaments as a quantitative test of tactile sensation. Breast cup size, ptosis, and weight of tissue excised were recorded to allow general assessment of the breast size. The nipple and areola biopsy specimens were assessed using immunohistochemistry (S-100 polyclonal antibody, Dako Z311) to measure nerve fiber count per unit area. Statistical analysis was undertaken to find any association among sensitivity, breast cup size, ptosis, weight of tissue resected, and nerve fiber density in the nipple and areola biopsy specimens. Sensitivity at the areola decreased with increasing breast cup size (r = 0.47, p < 0.001) and ptosis (r = 0.42, p = 0.002 for increasing distance between inframammary crease and nipple; r = 0.49, p < 0.001 for increasing manubrium to nipple distance). There was a weak correlation between nerve fiber density at the areola and breast cup size (r = -0.22, p = 0.1). Sensitivity at the nipple was higher than at the areola. Nerve fiber density count at the nipple was higher than at the areola, but there was no statistically significant correlation between nipple sensitivity and breast cup size, ptosis, or weight of tissue resected. The results suggest that the areola and nipple are different in their neuroanatomy. The areola is a thin, pliable structure that is predisposed to stretch as the breast enlarges and therefore experience a decrease in nerve fiber density. The nipple is a compact structure that is less likely to stretch with breast enlargement. In the nipple, neither sensory perception nor nerve fiber density varied with size or breast ptosis. The perceived lack of sensation in the nipple-areola complex is multifactorial. This study shows that neither traction injury to the sensory nerves nor decreased nerve density alone can explain the subjective numbness reported by patients with macromastia. Psychological factors, such as dissatisfaction with body form or interpretation of lack of sensation in the areola as also affecting the nipple, may influence the patient's assessment of the nipple-areola sensitivity.

Neuropeptide-containing C-fibres and wound healing in rat skin. Neither capsaicin nor peripheral neurotomy affect the rate of healing.

Wound healing in rat skin was studied in standardized wounds inflicted on both hind legs after unilateral sciatic nerve sectioning and/or capsaicin-induced depletion of sensory nerve (C-fibre) neuropeptide content. Daily visual inspection, histological examination and immunohistochemistry with antibodies against substance P, calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide, neuropeptide Y and a pan-neuronal marker, protein gene product 9.5 (PGP 9.5) were used to assess wound healing and determine the distribution of dermal nerve fibres. In controls, nerve fibre density in the wound tissue was low during the first few days after wound infliction, but started to increase on day 4, reaching a peak on day 7 when 25% of medial wounds and 70% of lateral wounds were healed. All wounds were healed on day 11, a scar appearing on day 14 followed by a decrease in nerve fibre density. Capsaicin treatment and/or sciatic nerve sectioning reduced the density of CGRP-immunoreactive nerve fibres by 70% and that of PGP 9.5-immunoreactive fibres by 50%. The capsaicin-induced reduction in PGP 9.5-immunoreactive nerve fibre density is attributable to partial destruction of peripheral nerve fibres. CGRP-immunoreactive and PGP 9.5-immunoreactive nerve fibre density was restored both in capsaicin-treated and denervated groups, reaching a maximum, corresponding to the original level, by days 4-10. Neither the reduction in nerve fibre density following sciatic nerve sectioning nor the impairment of sensory nerve functional capacity following capsaicin treatment affected the rate of wound healing, all wounds being closed on day 11. The study shows that it is difficult to knock out all cutaneous sensory innervation. Thirty per cent of C-fibre innervation seems enough to ensure a normal wound healing.

Ultrastructural morphometric analysis of peripheral nerves after intraoperative irradiation.

Intraoperative irradiation (IORT) is used to enhance local tumour control by using large, single doses while removing critical structures from the treatment field. Peripheral nerve remains a dose-limiting normal tissue that often cannot be removed from the field. To assess ultrastructural changes in canine sciatic nerve after IORT, computerized morphometric analysis of plastic sections and electron micrographs of nerve cross-sections was used. Surgically exposed sciatic nerves were irradiated with 6 MeV electrons to 12, 20 or 28 Gy. Twelve months after treatment dogs were killed humanely and the nerves from three dogs per dose group, including non-irradiated controls, were analyzed. Twelve months after 28-Gy IORT a significant decrease in nerve fiber density occurred. Nerve fiber loss was particularly prominent in the central portion of the nerve predominantly among large nerve fibers. Other nerve fiber parameters including fiber and axon area, diameter and perimeter, myelin thickness, form factor (measure of roundness), and G ratio (axon diameter/fiber diameter) did not show significant, dose-related changes. An increase in microtubule and neurofilament density in irradiated nerve axons was found. These changes are suggestive of radiation-induced hypoxia (damage to microvasculature) resulting in axon damage and subsequent nerve fiber loss as a possible mechanism of late radiation injury to peripheral nerve.