Direct neural inputs to immune organs have been observed for decades,with their functions in neuroimmune regulation being increasingly appreciated.However,the current knowledge of such neural structures,particularly t...Direct neural inputs to immune organs have been observed for decades,with their functions in neuroimmune regulation being increasingly appreciated.However,the current knowledge of such neural structures,particularly those in primate immune organs,remains incomplete.In this study,we comprehensively assessed the 3D anatomy of autonomic(i.e.,sympathetic and parasympathetic)innervations in the immune organs of the rhesus macaque monkey and the human for the first time.Aided with the advanced technique of whole-tissue immunolabeling and lightsheet fluorescence imaging,we revealed the densely organized sympathetic architecture in the parenchyma of the adult monkey and human spleens.On the other hand,only sparse,if any,sympathetic inputs were observed inside the lymph nodes,Peyer's patches,or thymus.In contrast,there were minimal parasympathetic innervations in the parenchyma of these examined immune organs.Together,this work has documented the unique patterns of autonomic innervations in different immune organs of a non-human primate and the human,serving as an essential reference for future research on neuroimmune regulation in the field.展开更多
Autologous nerve transplantation is currently recognized as the gold standard for treating seve re peripheral nerve injuries in clinical practice.Howeve r,challenges such as a limited supply of donors,complications in...Autologous nerve transplantation is currently recognized as the gold standard for treating seve re peripheral nerve injuries in clinical practice.Howeve r,challenges such as a limited supply of donors,complications in the donor area,and the formation of neuromas necessitate the optimization of existing transplantation strategies.Additionally,the development of new and promising repair methods is a critical issue in the field of peripheral nerve research.The purpose of this article is to compare the advantages and disadvantages of autologous,allogeneic,decellularized nerve grafts,and cell-composite graft,as well as to summarize the diffe rences in their prognostic factors and associated adve rse events.The length,diamete r,polarity,and sensory or motor origin of autografts all influence axonal regeneration.While pre-denaturation treatment can accele rate early regeneration,long-term functional outcomes of autografts do not show significant differences compared with fresh autologous grafts.For decellularized nerve grafts,defect length is identified as an independent risk factor,and the internal microenvironment(delayed angiogenesis,Schwann cell senescence,and reduced T-cell infiltration)is considered a key factor limiting long-segment regeneration.Additionally,the decellula rization process(whether chemical,physical,or supercritical CO_(2))affects the integrity of the extracellular matrix and the presence of immune residuals,which directly impacts axonal guidance and host integration.Common adve rse events following autograft transplantation include donor site numbness,neuromas,and scarring.In contrast,adverse events associated with decellularized nerve graft transplantation may present as inflammatory reactions,excessive scar prolife ration,and misalignment or reconnection of regenerating axons,which can lead to sensory-m otor cross-innervation.To mitigate these issues,combining decellularized nerve grafts with autologous Schwann cells,mesenchymal stem cells,or induced pluripotent stem cellderived cells may help bridge the gap with autografts.However,the fact that structural recovery does not necessarily lead to functional recovery needs further clarification.Future research should establish la rge animal models to replicate the limits of human regenerative capacity,use gene editing to enhance the phenotype and microenvironment of transplanted cells,and develop a mild combined decellularization process that maximizes the preservation of natural nerve grafts.Through multidimensional optimization,decellularized nerve grafts have the potential to ultimately re place autograft transplantation,enabling precise repair of individualized,long-segment,and complex nerve defects.展开更多
Background:Donor nerve selection is a crucial factor in determining clinical outcomes of facial reanimation.Although dual innervation approaches using two neurotizers have shown promise,there is a lack of evidence-bas...Background:Donor nerve selection is a crucial factor in determining clinical outcomes of facial reanimation.Although dual innervation approaches using two neurotizers have shown promise,there is a lack of evidence-based comparison in the literature.Furthermore,no animal model of dual reinnervation has yet been published.This study aimed to establish such a model and verify its technical and anatomical feasibility by performing dual-innervated reanimation approaches in Wistar rats.Methods:Fifteen Wistar rats were divided into four experimental groups and one control group.The sural nerve was exposed and used as a cross-face nerve graft(CFNG),which was then anastomosed to the contralateral buccal branch of the facial nerve through a subcutaneous tunnel on the forehead.The CFNG,the masseteric nerve(MN),and the recipient nerve were coapted in one or two stages.The length and width of the utilized structures were measured under an operating microscope.Return of whisker motion was visually confirmed.Results:Nine out of the eleven rats that underwent surgery survived the procedure.Whisker motion was observed in all experimental animals,indicating successful reinnervation.The mean duration of the surgical procedures did not differ significantly between the experimental groups,ensuring similar conditions for all groups.Conclusions:Our experimental study confirmed that the proposed reanimation model in Wistar rats is anatomically and technically feasible,with a high success rate,and shows good prospects for future experiments.展开更多
Background and Objective:Neurotrophic keratitis(NK)is a neurodegenerative corneal disease characterized by decreased corneal sensitivity caused by damage to the trigeminal nerve,leading to reduced corneal sensitivity ...Background and Objective:Neurotrophic keratitis(NK)is a neurodegenerative corneal disease characterized by decreased corneal sensitivity caused by damage to the trigeminal nerve,leading to reduced corneal sensitivity and increased risk of trauma,infection,and ulceration.Although prior reviews on NK exist,most focus on traditional diagnostic and treatment modalities,with limited coverage of recent advances that target the underlying neuropathology.There remains a need for an updated synthesis of current literature that not only highlights emerging diagnostic technologies but also integrates key findings from recent clinical trials,retrospective studies,and prospective investigations.This review addresses that need by providing a comprehensive,data-driven framework to support informed clinical decision-making in the management of NK.Methods:A literature review was conducted using PubMed and Google Scholar,focusing on peer-reviewed articles,clinical guidelines,and meta-analyses from ophthalmic and neurological sources.Relevant literatures written in English were used.The timeframe included all papers up until August of 2024.Key Content and Findings:Corneal sensitivity testing remains the cornerstone of NK diagnosis,using both qualitative and quantitative methods.Recent innovations,such as the Brill Engines noncontact esthesiometer,offer a portable,noninvasive option for early detection.Although no single standard therapy exists,treatment spans from conservative approaches[artificial tears,bandage contact lenses(BCLs)]to biologics such as cenegermin[nerve growth factor(NGF)drops].Surgical strategies,including amniotic membrane transplantation,tarsorrhaphy,and conjunctival flaps,provide alternatives for refractory cases.Corneal neurotization is a novel technique showing promise in restoring innervation and reducing reliance on chronic therapy.Due to NK’s heterogeneous nature,treatment is individualized and often involves trial and error.Conclusions:NK is a relatively rare yet debilitating corneal disease.Clinicians should have a low threshold of suspicion for pursuing diagnostic tests in patients presenting classic and atypical symptoms.While recent advances in medical and surgical management have improved outlooks,continued research is essential to further optimize outcomes and prevent vision loss.展开更多
Dental pulp-dentin complex defects remain a major unresolved problem in oral medicines.Clinical therapeutic methods including root canal therapy and vital pulp therapy are both considered as conservative strategies,wh...Dental pulp-dentin complex defects remain a major unresolved problem in oral medicines.Clinical therapeutic methods including root canal therapy and vital pulp therapy are both considered as conservative strategies,which are incapable of repairing the pulpdentin complex defects.Although biomaterial-based strategies show remarkable progress in antibacterial,anti-inflammatory,and pulp regeneration,the important modulatory effects of nerves within pulp cavity have been greatly overlooked,making it challenging to achieve functional pulp-dentin complex regeneration.In this study,we propose an injectable bioceramicscontaining composite hydrogel in combination of Li-Ca-Si(LCS)bioceramics and gelatin methacrylate matrix with photocrosslinking properties.Due to the sustained release of bioactive Li,Ca and Si ions from LCS,the composite hydrogels possess multiple functions of promoting the neurogenic differentiation of Schwann cells,odontogenic differentiation of dental pulp stem cells,and neurogenesis-odontogenesis couples in vitro.In addition,the in vivo results showed that LCS-containing composite hydrogel can significantly promote the pulp-dentin complex repair.More importantly,LCS bioceramics-containing composite hydrogel can induce the growth of nerve fibers,leading to the re-innervation of pulp tissues.Taken together,the study suggests that LCS bioceramics can induce the innervation of pulp-dentin complex repair,offering a referable strategy of designing multifunctional filling materials for functional periodontal tissue regeneration.展开更多
Peripheral neuropathy is a common complication in diabetes,affecting around 50%of the diabetic population.Co-occurrence of diabetic peripheral neuropathy(DPN)and diabetic bone disease has led to the hypothesis that DP...Peripheral neuropathy is a common complication in diabetes,affecting around 50%of the diabetic population.Co-occurrence of diabetic peripheral neuropathy(DPN)and diabetic bone disease has led to the hypothesis that DPN influences bone metabolism,although little experimental evidence has yet supported this premise.To investigate,mice were fed a high-fat diet(HFD)followed by phenotyping of skeletal-innervating neurons and bone architectural parameters.Results showed that HFD feeding resulted in a marked decrease in skeletal innervation(69%–41%reduction in Beta-III-Tubulin-stained nerves,38%reduction in CGRP-stained nerves in long bone periosteum).展开更多
Liver innervation comprises sympathetic,parasympathetic and peptidergic nerve fibers,organized as either afferent or efferent nerves with different origins and roles.Their anatomy and physiology have been studied in t...Liver innervation comprises sympathetic,parasympathetic and peptidergic nerve fibers,organized as either afferent or efferent nerves with different origins and roles.Their anatomy and physiology have been studied in the past 30 years,with different results published over time.Hepatocytes are the main cell population of the liver,making up almost 80%of the total liver volume.The interaction between hepatocytes and nerve fibers is accomplished through a wealth of neurotransmitters and signaling pathways.In this short review,we have taken the task of condensing the most important data related to how the nervous system interacts with the liver and especially with the hepatocyte population,how it influences their metabolism and functions,and how different receptors and transmitters are involved in this complex process.展开更多
Objective To establish an artificial somatic-autonomic reflex arc in rats and observe the following distributive changes of neural fibers in the bladder. Methods Adult Sprague-Dawley rats were randomly divided into th...Objective To establish an artificial somatic-autonomic reflex arc in rats and observe the following distributive changes of neural fibers in the bladder. Methods Adult Sprague-Dawley rats were randomly divided into three groups： control group, spinal cord injury （SCI） group, and reinnervation group. DiI retrograde tracing was used to verify establishment of the model and to investigate the transport function of the regenerated efferent axons in the new reflex arc. Choline acetyltransferase （CHAT） in the DiI-labeled neurons was detected by immunohistochemistry. Distribution of neural fibers in the bladder was observed by acetylcholine esterase staining. Results DR-labeled neurons distributed mainly in the left ventral horn from L3 to L5, and some of them were also CHAT-positive. The neural fibers in the bladder detrusor reduced remarkably in the SCI group compared with the control （P 〈 0.05）. After establishment of the somatic-autonomic reflex arc in the reinnervation group, the number of ipsilateral fibers in the bladder increased markedly compared with the SCI group （P 〈 0.05）, though still much less than that in the control （P 〈 0.05）. Conclusion The efferent branches of the somatic nerves may grow and replace the parasympathetic preganglionic axons through axonal regeneration. Acetylcholine is still the major neurotransmitter of the new reflex arc. The controllability of detrusor may be promoted when it is reinnervated by the pelvic ganglia efferent somatic motor fibers from the postganglionic axons.展开更多
Thermomineral water from the Atomic Spa Gornja Trepca has been used for a century in the treatment of neurologic disease. The thermomineral water contains microelements, including lithium and magnesium, which show neu...Thermomineral water from the Atomic Spa Gornja Trepca has been used for a century in the treatment of neurologic disease. The thermomineral water contains microelements, including lithium and magnesium, which show neural regeneration-promoting effects after central nervous system injury. In this study, we investigated the effects of oral intake of thermomineral water from the Atomic Spa Gornja Trepca on nerve regeneration in a 3-month-old mouse model of spinal cord injury. The mice receiving oral intake of thermomineral water showed better locomotor recovery than those without administration of thermomineral water at 8 and 12 weeks after lower thoracic spinal cord compression. At 12 weeks after injury, sprouting of catecholaminergic axons was better in mice that drank thermomineral water than in those without administration of thermomineral water, but there was no difference in glial reaction to injury between mice with and without administration of thermomineral water. These findings suggest that thermomineral water can promote the nerve regeneration but cannot reduce glial scar formation in a mouse model of spinal cord injury.展开更多
In the present study, the oculomotor nerves were sectioned at the proximal （subtentorial） and distal （superior orbital fissure） ends and repaired. After 24 weeks, vestibulo-ocular reflex evaluation confirmed that ...In the present study, the oculomotor nerves were sectioned at the proximal （subtentorial） and distal （superior orbital fissure） ends and repaired. After 24 weeks, vestibulo-ocular reflex evaluation confirmed that the regenerating nerve fibers following oculomotor nerve injury in the superior orbital fissure had a high level of specificity for innervating extraocular muscles. The level of functional recovery of extraocular muscles in rats in the superior orbital fissure injury group was remarkably superior over that in rats undergoing oculomotor nerve injuries at the proximal end （subtentorium）. Horseradish peroxidase retrograde tracing through the right superior rectus muscle showed that the distribution of neurons in the nucleus of the oculomotor nerve was directly associated with the injury site, and that crude fibers were badly damaged. The closer the site of injury of the oculomotor nerve was to the extraocular muscle, the better the recovery of neurological function was. The mechanism may be associated with the aberrant number of regenerated nerve fibers passing through the injury site.展开更多
AIM： To clarify the innervation of human gallbladder,with special reference to morphological understanding of gallstone formation after gastrectomy.METHODS： The liver, gallbladder and surrounding structures were imm...AIM： To clarify the innervation of human gallbladder,with special reference to morphological understanding of gallstone formation after gastrectomy.METHODS： The liver, gallbladder and surrounding structures were immersed in a 10 mg/L solution of alizarin red S in ethanol to stain the peripheral nerves in cadavers （n = 10）. Innervation in the areas was completely dissected under a binocular microscope. Similarly,innervation in the same areas of 10 Suncus murinus （S. murinus） was examined employing whole mount immunohistochemistry.RESULTS： Innervation of the gallbladder occurred predominantly through two routes. One was from the anterior hepatic plexus, the innervation occurred along the cystic arteries and duct. Invariably this route passed through the hepatoduodenal ligament. The other route was from the posterior hepatic plexus, the innervation occurred along the cystic duct ventrally. This route also passed through the hepatoduodenal ligament dorsally.Similar results were obtained in S. murinus.CONCLUSION： The route from the anterior hepatic plexus via the cystic artery and/or duct is crucial for preserving gallbladder innervation. Lymph node dissection specifically in the hepatoduodenal ligament may affect the incidence of gallstones after gastrectomy.Furthermore, the route from the posterior hepatic plexus via the common bile duct and the cystic duct to the gallbladder should not be disregarded. Preservation of the plexus may attenuate the incidence of gallstone formation after gastrectomy.展开更多
AIM： To investigate whether manual acupuncture at representative acupoints in different parts of the body can modulate responses of gastric motility in rats and regular effects in different acupoint stimulation. METH...AIM： To investigate whether manual acupuncture at representative acupoints in different parts of the body can modulate responses of gastric motility in rats and regular effects in different acupoint stimulation. METHODS： The gastric motor activity of rats was recorded by the intrapyloric balloon. The changes of gastric motility induced by the stimulation were compared with the background activity in intragastric pressure and/or waves of gastric contraction recorded before any stimulation. Morphological study was also conducted by observing the Evans dye extravasation in the skin after mustard oil injection into the intragastric mucous membrane to certify cutaneous innervations of blue dots related to gastric segmental innervations. RESULTS： In all six rats that received mustard oil injections into intragastric mucosa, small blue dots appeared in the skin over the whole abdomen, but mainly in peri-midline upper- and middle- abdomen and middle-back, a few in thigh and groin. It may speculate that cutaneous innervations of blue dots have the same distribution as gastric segmental innervations. Acustimulation in acupoints of head-neck, four limbs, upper chest-dorsum and Iower-dorsum induced markedly augmentation of gastric motility （acupoints on headneck such as St-2： n = 16, 105.19 ± 1.36 vs 112.25 ± 2.02 and St-3： n = 14, 101.5 ± 1.75 vs 109.36 ± 1.8; acupoints on limbs such as Sp-6： n = 19, 100.74 ± 1.54 vs 110.26 ± 3.88; St-32： n = 17, 103.59 ± 1.64 vs 108.24 ± 2.41; St-36： n = 16, 104.81 ± 1.72 vs 110.81 ± 2.74 and U-11： n = 17, 106.47 ± 2.61 vs 114.77 ± 3.77, P 〈 0.05-0.001）. Vigorous inhibitory regulations of gastric motility induced by acu-stimulation applied in acupoints on whole abdomen and middle-dorsum were significantly different as compared with the controls before acu-stimulation （abdomen acupoints such as Cv-12： n = 11, 109.36 ± 2.09 vs 101 ± 2.21; Cv-6： n = 18, 104.39 ± 1.42 vs 91.83 ± 3.22 and St-21： n = 12, 107 ± 2.97 vs 98.58 ± 2.81; acupoints on middledorsum such as BI-17： n = 19, 100.63 ± 1.4 vs 92.21 ± 2.07 and BI-21： n = 19, 103.84 ± 1.48 vs 97.58 ± 2.16, P 〈 0.05-0.001）. CONCLUSION： Regular regulatory effects of facilitation and inhibition on gastric motility appear to be somatotopically organized in the acupoints of whole body, and the effective regularity of site-special acupoints on gastric motility is involved in segmental innervations between stomach and acupoints.展开更多
BACKGROUND： Studies have shown that abnormal innervation is an important factor impacting occurrence and development of pathological pain in endometriosis. OBJECTIVE： To observe uterine innervation of adenomyosis mi...BACKGROUND： Studies have shown that abnormal innervation is an important factor impacting occurrence and development of pathological pain in endometriosis. OBJECTIVE： To observe uterine innervation of adenomyosis mice and to analyze the cause of innervation changes due to nerve growth factor （NGF） expression, inflammation, and vascularization. DESIGN, TIME AND SETTING： This randomized, controlled, animal experiment was performed at the Research Institute of Obstetrics and Gynecology Hospital, and Central Laboratory of Zhongshan Hospital, Fudan University from March to December 2008. MATERIALS： Tamoxifen was provided by Fudan Forward, China. Rabbit anti-mouse NGF was purchased from Santa Cruz Corporation, USA; rabbit anti-protein gene product 9.5 （PGP9.5） and rabbit anti-substance P （SP） were purchased from Chemicon, USA. METHODS： A total of 40 newborn ICR mice were randomly assigned to adenomyosis model and control groups, with 20 animals in each group. Mice in the adenomyosis model group were orally administrated 2.7 μmol/kg tamoxifen on days 2-5 after birth, while the controls were not treated. MAIN OUTCOME MEASURES： Both uteri from all mice were harvested at days 135-145 after birth Expressions of polyclonal PGP9.5 and SP were immunohistochemically detected to demonstrate pan- and sensory nerve fibers. Microvessel density was quantified in the endometrium and myometrium using immunochemical staining for polyclonal rabbit anti-CD31, which stained vessels. Gene expression for NGF, high-affinity tyrosine kinase receptor （trkA）, p75 neuretrophin receptor （p75NTR）, bradykinin receptor-1 （BKR-1）, and 2 （BKR-2）, as well as substance P receptor （neurokininl receptor, NK1-R）, were detected by reverse transcription-polymerase chain reaction. NGF-13 protein expression was detected by Western blot analysis. RESULTS： More nerve fibers were stained with PGP9.5 in the endometrium and myometrium, and with SP in the endometrium, in adenomyosis mice compared with controls （P 〈 0.01 and P 〈 0.05）. Microvessel density in the myometrium of adenomyosis mice was significantly greater than the controls （P 〈 0.01）. In the uterus of adenomyosis mice, mRNA expression of NGF and its two receptors （trkA and p75 NTR）, BKR-1, and NK1-R, as well as protein expression of NGF-β, were greater than the control mice （P 〈 0.01 or P 〈 0.05）. CONCLUSION： Uterine innervation in the adenomyosis mice was increased compared with the controls. Moreover, NGF expression, inflammation, and vascularization, which have been shown to be impact factors of innervation, were abnormal in the uteri of adenomyosis mice.展开更多
Tissue innervation is a complex process controlled by the expression profile of signaling molecules secreted by tissue-resident cells that dictate the growth and guidance of axons.Sensory innervation is part of the ne...Tissue innervation is a complex process controlled by the expression profile of signaling molecules secreted by tissue-resident cells that dictate the growth and guidance of axons.Sensory innervation is part of the neuronal network of the bone tissue with a defined spatiotemporal occurrence during bone development.Yet,the current understanding of the mechanisms regulating the map of sensory innervation in the bone tissue is still limited.Here,we demonstrated that differentiation of human mesenchymal stem cells to osteoblasts leads to a marked impairment of their ability to promote axonal growth,evidenced under sensory neurons and osteoblastic-lineage cells crosstalk.The mechanisms by which osteoblast lineage cells provide this nonpermissive environment for axons include paracrine-induced repulsion and loss of neurotrophic factors expression.We identified a drastic reduction of NGF and BDNF production and stimulation of Sema3A,Wnt4;and Shh expression culminating at late stage of OB differentiation.We noted a correlation between Shh expression profile,OB differentiation stages,and OB-mediated axonal repulsion.Blockade of Shh activity and signaling reversed the repulsive action of osteoblasts on sensory axons.Finally,to strengthen our model,we localized the expression of Shh by osteoblasts in bone tissue.Overall,our findings provide evidence that the signaling profile associated with osteoblast phenotype differentiating program can regulate the patterning of sensory innervation,and highlight osteoblast-derived Shh as an essential player in this cue-induced regulation.展开更多
BACKGROUND： Numerous studies use fluorescent microscopy to obtain two-dimensional optical images of the morphology of nerve fibers in hypertrophic scars. In addition, current confocal microscopy studies have focused ...BACKGROUND： Numerous studies use fluorescent microscopy to obtain two-dimensional optical images of the morphology of nerve fibers in hypertrophic scars. In addition, current confocal microscopy studies have focused on normal, not pathological, cutaneous nerves. However, laser scanning confocal microscopy results in a three-dimensional structure of the nerve fibers. OBJECTIVE： To observe quantitative and morphological differences in nerve fibers from the proliferative and mature stage in hypertrophic scars using fluorescent and confocal microscopy. DESIGN, TIME AND SETTING： Neuropathological, comparison study was conducted at the Provincial Hospital Affiliated to Shandong University, China from June 2006 to July 2007. PARTICIPANTS： Specimens were selected from 30 patients undergoing scar restoration at the Provincial Hospital Affiliated to Shandong University of China at 1 month to 23 years following wound healing. The study comprised 20 males and 10 females. The scars were fibrous lesions, erythematous, tough, confined to skin lesions, did not exhibit ulceration or infection, exhibited telangiectasia, with or without itching and pain, and were not locally treated. Samples were equally assigned to two groups according to course of disease： proliferative group （〈 6 months） and mature group （6-24 months）. Control samples were collected from full-thickness skin from donor sites （n = 10）. METHODS： Nerve fiber morphology was observed using fluorescent and confocal microscopy following immunofluorescence of the skin specimens. The microscopic images were semi-quantitatively analyzed to acquire a positive area ratio of neurofilament protein-positive nerve fibers. MAIN OUTCOME MEASURES： Morphology and positive area ratio of neurofilament protein/positive nerve fibers was measured. RESULTS： The positive area ratio of neurofilament protein-positive nerve fibers was significantly greater in the proliferative group compared to the normal control group （P 〈 0.05）. Nerve fibers were irregularly distributed and exhibited local swelling, twisting, and disconnection. However, the positive area ratio of neurofilament protein-positive nerve fibers was significantly less in the mature group compared with the normal control group （P 〈 0.05）. The nerve fibers were arranged in an orderly manner, with intact inner and stereoscopic structures similar to normal skin. CONCLUSION： Compared with mature scars, hypertrophic scars exhibited a greater number of nerve fibers, with more serious pathologies.展开更多
Previous studies demonstrate an accumulation of transferrin and transferrin receptor 1(TfR1) in regenerating peripheral nerves.However, the expression and function of transferrin and TfR1 in the denervated skeletal mu...Previous studies demonstrate an accumulation of transferrin and transferrin receptor 1(TfR1) in regenerating peripheral nerves.However, the expression and function of transferrin and TfR1 in the denervated skeletal muscle remain poorly understood.In this study, a mouse model of denervation was produced by complete tear of the left brachial plexus nerve.RNA-sequencing revealed that transferrin expression in the denervated skeletal muscle was upregulated, while TfR1 expression was downregulated.We also investigated the function of TfR1 during development and in adult skeletal muscles in mice with inducible deletion or loss of TfR1.The ablation of TfR1 in skeletal muscle in early development caused severe muscular atrophy and early death.In comparison, deletion of TfR1 in adult skeletal muscles did not affect survival or glucose metabolism, but caused skeletal muscle atrophy and motor functional impairment, similar to the muscular atrophy phenotype observed after denervation.These findings suggest that TfR1 plays an important role in muscle development and denervation-induced muscular atrophy.This study was approved by the Institutional Animal Care and Use Committee of Beijing Institute of Basic Medical Sciences, China(approval No.SYXK 2017-C023) on June 1, 2018.展开更多
AIM: To characterize changes in the cornea nerve and pain responses in fungal keratitis(FK).METHODS: A retrospective analysis of in vivo confocal microscopy images of 11 FK corneas was performed, and the results were ...AIM: To characterize changes in the cornea nerve and pain responses in fungal keratitis(FK).METHODS: A retrospective analysis of in vivo confocal microscopy images of 11 FK corneas was performed, and the results were compared with those for 11 normal corneas. Subbasal corneal nerves were analyzed for total nerve number, main nerve trunk number, branching patterns and tortuosity. C57 BL/6 mice were infected with Aspergillus fumigatus. Disease severity was determined through clinical scoring and slit lamp photography. Corneas were harvested at 1, 3, 5, and 7 d post infection(p.i.) and assessed for β III tubulin. Corneal mechanical sensitivity thresholds were detected by von Frey test. β-endorphin(β-EP) and μ receptor protein expression was detected through Western blotting.RESULTS: Total nerve number, main nerve trunk number, and nerve branching were significantly lower in FK patients than in controls, but tortuosity was not significantly different. In infected mice, subbasal nerve density decreased from 1 d p.i., reaching a minimum at 5 d p.i. Clinical scores rose at 1 d p.i., peaked at 3 d p.i., and decreased at 5 d p.i. Mechanical sensitivity thresholds showed the same trends. β-EP and μ receptor protein expression increased after infection.CONCLUSION: Corneal nerve density is lower in FK patients and Aspergillus fumigatus-infected mice than in controls. Pain sensitivity decreases with postinfection corneal ulcer aggravation. β-EP and μ receptor proteins are both upregulated in infected mouse corneas.展开更多
Pancreatic ductal adenocarcinoma(PDAC)is a highly aggressive lethal malignancy,characterized by late diagnosis,aggressive growth,and therapy resistance,leading to a poor overall prognosis.Emerging evidence shows that ...Pancreatic ductal adenocarcinoma(PDAC)is a highly aggressive lethal malignancy,characterized by late diagnosis,aggressive growth,and therapy resistance,leading to a poor overall prognosis.Emerging evidence shows that the peripheral nerve is an important non-tumor component in the tumor microenvironment that regulates tumor growth and immune escape.The crosstalk between the neuronal system and PDAC has become a hot research topic that may provide novel mechanisms underlying tumor progression and further uncover promising therapeutic targets.In this review,we highlight the mechanisms of perineural invasion and the role of various types of tumor innervation in the progression of PDAC,summarize the potential signaling pathways modulating the neuronal-cancer interaction,and discuss the current and future therapeutic possibilities for this condition.展开更多
Astrocytes are implicated in the pathological changes of Alzheimer's disease.Our previous studies have demonstrated that estrogen deprivation and oxidative stress act synergistically to accelerate the progress of ...Astrocytes are implicated in the pathological changes of Alzheimer's disease.Our previous studies have demonstrated that estrogen deprivation and oxidative stress act synergistically to accelerate the progress of Alzheimer's disease.Long-term D-galactose injection combined with ovariectomy may serve as a rodent model for Alzheimer's disease.To address the potential contribution of astroglia to the Alzheimer's disease pathogenesis,we investigated pathological and biochemical alterations of astrocytes under this animal model.Ovadectomized rats injected with D-galactose for 2 weeks showed extensive localization of glial fibrillary acidic protein immunoreactive astrocytes and slightly elevated glutathione levels in the hippocampus without significant impairments in the water maze test and deficits of the cholinergic analyses,compared to the saline-injected rats.Ovariectomized rats injected with D-galactose for 6 weeks,however,exhibited degeneration of astrocytes and decreased glutathione levels in the hippocampus,accompanied with severe dysfunction of behavioral test and deficiency of cholinergic terminals.Electron microscopy further confirmed the pathological changes of astrocytes,especially in the aggregated area of synapse and brain microvessels.Consistent with degeneration of perivascular astrocytic endfeet,analysis of the horseradish peroxidase demonstrated an impairment of the blood-brain barrier permeability.These findings indicate that biochemical and pathological alterations of astrocytes may partially contribute to exacerbating neuronal deficits in the course of Alzheimer's disease.Restoring neuroprotective potential of astrocytes may be a useful therapeutic target for Alzheimer's disease and other neurodegenerative diseases.展开更多
Burn wounds were produced on two sides on the backs of Wistar rats, in addition to denervation on one side. The skin neural regeneration at the injury site and burn wound healing were evaluated following spinal nerve ...Burn wounds were produced on two sides on the backs of Wistar rats, in addition to denervation on one side. The skin neural regeneration at the injury site and burn wound healing were evaluated following spinal nerve root incision. No nerve regeneration was observed in the burn wound region post-denervation, and the degree of epithelization was significantly less than the control group. With increasing time, expression of type I collagen, which plays a supporting role, and collagen III, which exhibits elastJc propertJes, were sJgnificantly increased Jn the two groups, but the expression was less in the denervation group compared with the control group, and the wound healing was faster in the control group. The ratio of type I collagen to type III collagen was significantly lower in the denervation group compared with the control group. The ratio gradually decreased with prolonged time in the denervation group, but remained unchanged in the control group. However, the elasticity of the tissues in the denervation group was better than the control group. During burn wound healing, innervations can promote wound healing, but denervation can improve the quality of wound remodeling.展开更多
基金funded by the National Natural Science Foundation of China (To J.Y.,31771111,31970974,32061143007,32125017 and 32150008).
文摘Direct neural inputs to immune organs have been observed for decades,with their functions in neuroimmune regulation being increasingly appreciated.However,the current knowledge of such neural structures,particularly those in primate immune organs,remains incomplete.In this study,we comprehensively assessed the 3D anatomy of autonomic(i.e.,sympathetic and parasympathetic)innervations in the immune organs of the rhesus macaque monkey and the human for the first time.Aided with the advanced technique of whole-tissue immunolabeling and lightsheet fluorescence imaging,we revealed the densely organized sympathetic architecture in the parenchyma of the adult monkey and human spleens.On the other hand,only sparse,if any,sympathetic inputs were observed inside the lymph nodes,Peyer's patches,or thymus.In contrast,there were minimal parasympathetic innervations in the parenchyma of these examined immune organs.Together,this work has documented the unique patterns of autonomic innervations in different immune organs of a non-human primate and the human,serving as an essential reference for future research on neuroimmune regulation in the field.
基金National Natural Science Foundation of China,No.82471412Science&Technology Innovation Talents Project of Henan Educational Committee,No.25HASTIT059+2 种基金Henan Academy of Medical Sciences Clinical Scientist Program,No.S20240069Young and Middle-aged Health Science and Technology Innovation Talent of Henan Province,No.JQRC2024014Henan Provincial Science&Technology Research and Development Program Joint Fund,No.232301420063(all to NZ)。
文摘Autologous nerve transplantation is currently recognized as the gold standard for treating seve re peripheral nerve injuries in clinical practice.Howeve r,challenges such as a limited supply of donors,complications in the donor area,and the formation of neuromas necessitate the optimization of existing transplantation strategies.Additionally,the development of new and promising repair methods is a critical issue in the field of peripheral nerve research.The purpose of this article is to compare the advantages and disadvantages of autologous,allogeneic,decellularized nerve grafts,and cell-composite graft,as well as to summarize the diffe rences in their prognostic factors and associated adve rse events.The length,diamete r,polarity,and sensory or motor origin of autografts all influence axonal regeneration.While pre-denaturation treatment can accele rate early regeneration,long-term functional outcomes of autografts do not show significant differences compared with fresh autologous grafts.For decellularized nerve grafts,defect length is identified as an independent risk factor,and the internal microenvironment(delayed angiogenesis,Schwann cell senescence,and reduced T-cell infiltration)is considered a key factor limiting long-segment regeneration.Additionally,the decellula rization process(whether chemical,physical,or supercritical CO_(2))affects the integrity of the extracellular matrix and the presence of immune residuals,which directly impacts axonal guidance and host integration.Common adve rse events following autograft transplantation include donor site numbness,neuromas,and scarring.In contrast,adverse events associated with decellularized nerve graft transplantation may present as inflammatory reactions,excessive scar prolife ration,and misalignment or reconnection of regenerating axons,which can lead to sensory-m otor cross-innervation.To mitigate these issues,combining decellularized nerve grafts with autologous Schwann cells,mesenchymal stem cells,or induced pluripotent stem cellderived cells may help bridge the gap with autografts.However,the fact that structural recovery does not necessarily lead to functional recovery needs further clarification.Future research should establish la rge animal models to replicate the limits of human regenerative capacity,use gene editing to enhance the phenotype and microenvironment of transplanted cells,and develop a mild combined decellularization process that maximizes the preservation of natural nerve grafts.Through multidimensional optimization,decellularized nerve grafts have the potential to ultimately re place autograft transplantation,enabling precise repair of individualized,long-segment,and complex nerve defects.
基金Grant Agency of Masaryk University,Grant/Award Number:MUNI/11/SUP/01/2020 and MUNI/A/1457/2021。
文摘Background:Donor nerve selection is a crucial factor in determining clinical outcomes of facial reanimation.Although dual innervation approaches using two neurotizers have shown promise,there is a lack of evidence-based comparison in the literature.Furthermore,no animal model of dual reinnervation has yet been published.This study aimed to establish such a model and verify its technical and anatomical feasibility by performing dual-innervated reanimation approaches in Wistar rats.Methods:Fifteen Wistar rats were divided into four experimental groups and one control group.The sural nerve was exposed and used as a cross-face nerve graft(CFNG),which was then anastomosed to the contralateral buccal branch of the facial nerve through a subcutaneous tunnel on the forehead.The CFNG,the masseteric nerve(MN),and the recipient nerve were coapted in one or two stages.The length and width of the utilized structures were measured under an operating microscope.Return of whisker motion was visually confirmed.Results:Nine out of the eleven rats that underwent surgery survived the procedure.Whisker motion was observed in all experimental animals,indicating successful reinnervation.The mean duration of the surgical procedures did not differ significantly between the experimental groups,ensuring similar conditions for all groups.Conclusions:Our experimental study confirmed that the proposed reanimation model in Wistar rats is anatomically and technically feasible,with a high success rate,and shows good prospects for future experiments.
基金supported by the Walter G.Ross Foundation(to R.K.L.)partly supported by the Camiener Foundation Glaucoma Research Fund and the Gutierrez Family Research Fund.
文摘Background and Objective:Neurotrophic keratitis(NK)is a neurodegenerative corneal disease characterized by decreased corneal sensitivity caused by damage to the trigeminal nerve,leading to reduced corneal sensitivity and increased risk of trauma,infection,and ulceration.Although prior reviews on NK exist,most focus on traditional diagnostic and treatment modalities,with limited coverage of recent advances that target the underlying neuropathology.There remains a need for an updated synthesis of current literature that not only highlights emerging diagnostic technologies but also integrates key findings from recent clinical trials,retrospective studies,and prospective investigations.This review addresses that need by providing a comprehensive,data-driven framework to support informed clinical decision-making in the management of NK.Methods:A literature review was conducted using PubMed and Google Scholar,focusing on peer-reviewed articles,clinical guidelines,and meta-analyses from ophthalmic and neurological sources.Relevant literatures written in English were used.The timeframe included all papers up until August of 2024.Key Content and Findings:Corneal sensitivity testing remains the cornerstone of NK diagnosis,using both qualitative and quantitative methods.Recent innovations,such as the Brill Engines noncontact esthesiometer,offer a portable,noninvasive option for early detection.Although no single standard therapy exists,treatment spans from conservative approaches[artificial tears,bandage contact lenses(BCLs)]to biologics such as cenegermin[nerve growth factor(NGF)drops].Surgical strategies,including amniotic membrane transplantation,tarsorrhaphy,and conjunctival flaps,provide alternatives for refractory cases.Corneal neurotization is a novel technique showing promise in restoring innervation and reducing reliance on chronic therapy.Due to NK’s heterogeneous nature,treatment is individualized and often involves trial and error.Conclusions:NK is a relatively rare yet debilitating corneal disease.Clinicians should have a low threshold of suspicion for pursuing diagnostic tests in patients presenting classic and atypical symptoms.While recent advances in medical and surgical management have improved outlooks,continued research is essential to further optimize outcomes and prevent vision loss.
基金funded by the National Key R&D Program of China(2022YFC2405904)the National Natural Science Foundation of China(52272284,32225028)+1 种基金Joint Research Unit Plan of the Chinese Academy of Sciences(121631ZYLH20240014)the Science and Technology Commission of Shanghai Municipality(24520750100)。
文摘Dental pulp-dentin complex defects remain a major unresolved problem in oral medicines.Clinical therapeutic methods including root canal therapy and vital pulp therapy are both considered as conservative strategies,which are incapable of repairing the pulpdentin complex defects.Although biomaterial-based strategies show remarkable progress in antibacterial,anti-inflammatory,and pulp regeneration,the important modulatory effects of nerves within pulp cavity have been greatly overlooked,making it challenging to achieve functional pulp-dentin complex regeneration.In this study,we propose an injectable bioceramicscontaining composite hydrogel in combination of Li-Ca-Si(LCS)bioceramics and gelatin methacrylate matrix with photocrosslinking properties.Due to the sustained release of bioactive Li,Ca and Si ions from LCS,the composite hydrogels possess multiple functions of promoting the neurogenic differentiation of Schwann cells,odontogenic differentiation of dental pulp stem cells,and neurogenesis-odontogenesis couples in vitro.In addition,the in vivo results showed that LCS-containing composite hydrogel can significantly promote the pulp-dentin complex repair.More importantly,LCS bioceramics-containing composite hydrogel can induce the growth of nerve fibers,leading to the re-innervation of pulp tissues.Taken together,the study suggests that LCS bioceramics can induce the innervation of pulp-dentin complex repair,offering a referable strategy of designing multifunctional filling materials for functional periodontal tissue regeneration.
基金supported by NIH/NIAMS(P01 AG066603,R01 AR079171,R21 AR078919)NIH/NIDCR(R01 DE031488,R01 DE031028)+4 种基金Alex’s Lemonade Stand Foundation(22-26743)American Cancer Society(DBG-23-1155131-01-IBCD)the Maryland Stem Cell Research Foundation(2021-MSCRFD-5641),and Department of Defense(USAMRAA HT9425-24-1-0051)MC is supported by Merkin Peripheral Neuropathy and Nerve Regeneration Center(23-DF/C2/260)M.K.is supported by NIH(T32HD044355).
文摘Peripheral neuropathy is a common complication in diabetes,affecting around 50%of the diabetic population.Co-occurrence of diabetic peripheral neuropathy(DPN)and diabetic bone disease has led to the hypothesis that DPN influences bone metabolism,although little experimental evidence has yet supported this premise.To investigate,mice were fed a high-fat diet(HFD)followed by phenotyping of skeletal-innervating neurons and bone architectural parameters.Results showed that HFD feeding resulted in a marked decrease in skeletal innervation(69%–41%reduction in Beta-III-Tubulin-stained nerves,38%reduction in CGRP-stained nerves in long bone periosteum).
文摘Liver innervation comprises sympathetic,parasympathetic and peptidergic nerve fibers,organized as either afferent or efferent nerves with different origins and roles.Their anatomy and physiology have been studied in the past 30 years,with different results published over time.Hepatocytes are the main cell population of the liver,making up almost 80%of the total liver volume.The interaction between hepatocytes and nerve fibers is accomplished through a wealth of neurotransmitters and signaling pathways.In this short review,we have taken the task of condensing the most important data related to how the nervous system interacts with the liver and especially with the hepatocyte population,how it influences their metabolism and functions,and how different receptors and transmitters are involved in this complex process.
文摘Objective To establish an artificial somatic-autonomic reflex arc in rats and observe the following distributive changes of neural fibers in the bladder. Methods Adult Sprague-Dawley rats were randomly divided into three groups： control group, spinal cord injury （SCI） group, and reinnervation group. DiI retrograde tracing was used to verify establishment of the model and to investigate the transport function of the regenerated efferent axons in the new reflex arc. Choline acetyltransferase （CHAT） in the DiI-labeled neurons was detected by immunohistochemistry. Distribution of neural fibers in the bladder was observed by acetylcholine esterase staining. Results DR-labeled neurons distributed mainly in the left ventral horn from L3 to L5, and some of them were also CHAT-positive. The neural fibers in the bladder detrusor reduced remarkably in the SCI group compared with the control （P 〈 0.05）. After establishment of the somatic-autonomic reflex arc in the reinnervation group, the number of ipsilateral fibers in the bladder increased markedly compared with the SCI group （P 〈 0.05）, though still much less than that in the control （P 〈 0.05）. Conclusion The efferent branches of the somatic nerves may grow and replace the parasympathetic preganglionic axons through axonal regeneration. Acetylcholine is still the major neurotransmitter of the new reflex arc. The controllability of detrusor may be promoted when it is reinnervated by the pelvic ganglia efferent somatic motor fibers from the postganglionic axons.
基金supported by the Southeast Europe Cooperation, Hamburg, Germany
文摘Thermomineral water from the Atomic Spa Gornja Trepca has been used for a century in the treatment of neurologic disease. The thermomineral water contains microelements, including lithium and magnesium, which show neural regeneration-promoting effects after central nervous system injury. In this study, we investigated the effects of oral intake of thermomineral water from the Atomic Spa Gornja Trepca on nerve regeneration in a 3-month-old mouse model of spinal cord injury. The mice receiving oral intake of thermomineral water showed better locomotor recovery than those without administration of thermomineral water at 8 and 12 weeks after lower thoracic spinal cord compression. At 12 weeks after injury, sprouting of catecholaminergic axons was better in mice that drank thermomineral water than in those without administration of thermomineral water, but there was no difference in glial reaction to injury between mice with and without administration of thermomineral water. These findings suggest that thermomineral water can promote the nerve regeneration but cannot reduce glial scar formation in a mouse model of spinal cord injury.
基金the National Natural Science Foundation of China, No. 30571907the Grant from the Science and Technology Commission of Shanghai, No. 05QMH1409
文摘In the present study, the oculomotor nerves were sectioned at the proximal （subtentorial） and distal （superior orbital fissure） ends and repaired. After 24 weeks, vestibulo-ocular reflex evaluation confirmed that the regenerating nerve fibers following oculomotor nerve injury in the superior orbital fissure had a high level of specificity for innervating extraocular muscles. The level of functional recovery of extraocular muscles in rats in the superior orbital fissure injury group was remarkably superior over that in rats undergoing oculomotor nerve injuries at the proximal end （subtentorium）. Horseradish peroxidase retrograde tracing through the right superior rectus muscle showed that the distribution of neurons in the nucleus of the oculomotor nerve was directly associated with the injury site, and that crude fibers were badly damaged. The closer the site of injury of the oculomotor nerve was to the extraocular muscle, the better the recovery of neurological function was. The mechanism may be associated with the aberrant number of regenerated nerve fibers passing through the injury site.
基金Supported by Ministry of Education, Culture, Sports, Science and Technology of Japan, Grant No. 16590139
文摘AIM： To clarify the innervation of human gallbladder,with special reference to morphological understanding of gallstone formation after gastrectomy.METHODS： The liver, gallbladder and surrounding structures were immersed in a 10 mg/L solution of alizarin red S in ethanol to stain the peripheral nerves in cadavers （n = 10）. Innervation in the areas was completely dissected under a binocular microscope. Similarly,innervation in the same areas of 10 Suncus murinus （S. murinus） was examined employing whole mount immunohistochemistry.RESULTS： Innervation of the gallbladder occurred predominantly through two routes. One was from the anterior hepatic plexus, the innervation occurred along the cystic arteries and duct. Invariably this route passed through the hepatoduodenal ligament. The other route was from the posterior hepatic plexus, the innervation occurred along the cystic duct ventrally. This route also passed through the hepatoduodenal ligament dorsally.Similar results were obtained in S. murinus.CONCLUSION： The route from the anterior hepatic plexus via the cystic artery and/or duct is crucial for preserving gallbladder innervation. Lymph node dissection specifically in the hepatoduodenal ligament may affect the incidence of gallstones after gastrectomy.Furthermore, the route from the posterior hepatic plexus via the common bile duct and the cystic duct to the gallbladder should not be disregarded. Preservation of the plexus may attenuate the incidence of gallstone formation after gastrectomy.
基金Supported by the National Natural Science Foundation of China, No. C30100245 and National Basic Research 973 Program, No. 2005CB523308
文摘AIM： To investigate whether manual acupuncture at representative acupoints in different parts of the body can modulate responses of gastric motility in rats and regular effects in different acupoint stimulation. METHODS： The gastric motor activity of rats was recorded by the intrapyloric balloon. The changes of gastric motility induced by the stimulation were compared with the background activity in intragastric pressure and/or waves of gastric contraction recorded before any stimulation. Morphological study was also conducted by observing the Evans dye extravasation in the skin after mustard oil injection into the intragastric mucous membrane to certify cutaneous innervations of blue dots related to gastric segmental innervations. RESULTS： In all six rats that received mustard oil injections into intragastric mucosa, small blue dots appeared in the skin over the whole abdomen, but mainly in peri-midline upper- and middle- abdomen and middle-back, a few in thigh and groin. It may speculate that cutaneous innervations of blue dots have the same distribution as gastric segmental innervations. Acustimulation in acupoints of head-neck, four limbs, upper chest-dorsum and Iower-dorsum induced markedly augmentation of gastric motility （acupoints on headneck such as St-2： n = 16, 105.19 ± 1.36 vs 112.25 ± 2.02 and St-3： n = 14, 101.5 ± 1.75 vs 109.36 ± 1.8; acupoints on limbs such as Sp-6： n = 19, 100.74 ± 1.54 vs 110.26 ± 3.88; St-32： n = 17, 103.59 ± 1.64 vs 108.24 ± 2.41; St-36： n = 16, 104.81 ± 1.72 vs 110.81 ± 2.74 and U-11： n = 17, 106.47 ± 2.61 vs 114.77 ± 3.77, P 〈 0.05-0.001）. Vigorous inhibitory regulations of gastric motility induced by acu-stimulation applied in acupoints on whole abdomen and middle-dorsum were significantly different as compared with the controls before acu-stimulation （abdomen acupoints such as Cv-12： n = 11, 109.36 ± 2.09 vs 101 ± 2.21; Cv-6： n = 18, 104.39 ± 1.42 vs 91.83 ± 3.22 and St-21： n = 12, 107 ± 2.97 vs 98.58 ± 2.81; acupoints on middledorsum such as BI-17： n = 19, 100.63 ± 1.4 vs 92.21 ± 2.07 and BI-21： n = 19, 103.84 ± 1.48 vs 97.58 ± 2.16, P 〈 0.05-0.001）. CONCLUSION： Regular regulatory effects of facilitation and inhibition on gastric motility appear to be somatotopically organized in the acupoints of whole body, and the effective regularity of site-special acupoints on gastric motility is involved in segmental innervations between stomach and acupoints.
基金the Construction Program of Shanghai Medical Intensive Subject (Obstetrics and Gynaecology), No. 05-111-0165
文摘BACKGROUND： Studies have shown that abnormal innervation is an important factor impacting occurrence and development of pathological pain in endometriosis. OBJECTIVE： To observe uterine innervation of adenomyosis mice and to analyze the cause of innervation changes due to nerve growth factor （NGF） expression, inflammation, and vascularization. DESIGN, TIME AND SETTING： This randomized, controlled, animal experiment was performed at the Research Institute of Obstetrics and Gynecology Hospital, and Central Laboratory of Zhongshan Hospital, Fudan University from March to December 2008. MATERIALS： Tamoxifen was provided by Fudan Forward, China. Rabbit anti-mouse NGF was purchased from Santa Cruz Corporation, USA; rabbit anti-protein gene product 9.5 （PGP9.5） and rabbit anti-substance P （SP） were purchased from Chemicon, USA. METHODS： A total of 40 newborn ICR mice were randomly assigned to adenomyosis model and control groups, with 20 animals in each group. Mice in the adenomyosis model group were orally administrated 2.7 μmol/kg tamoxifen on days 2-5 after birth, while the controls were not treated. MAIN OUTCOME MEASURES： Both uteri from all mice were harvested at days 135-145 after birth Expressions of polyclonal PGP9.5 and SP were immunohistochemically detected to demonstrate pan- and sensory nerve fibers. Microvessel density was quantified in the endometrium and myometrium using immunochemical staining for polyclonal rabbit anti-CD31, which stained vessels. Gene expression for NGF, high-affinity tyrosine kinase receptor （trkA）, p75 neuretrophin receptor （p75NTR）, bradykinin receptor-1 （BKR-1）, and 2 （BKR-2）, as well as substance P receptor （neurokininl receptor, NK1-R）, were detected by reverse transcription-polymerase chain reaction. NGF-13 protein expression was detected by Western blot analysis. RESULTS： More nerve fibers were stained with PGP9.5 in the endometrium and myometrium, and with SP in the endometrium, in adenomyosis mice compared with controls （P 〈 0.01 and P 〈 0.05）. Microvessel density in the myometrium of adenomyosis mice was significantly greater than the controls （P 〈 0.01）. In the uterus of adenomyosis mice, mRNA expression of NGF and its two receptors （trkA and p75 NTR）, BKR-1, and NK1-R, as well as protein expression of NGF-β, were greater than the control mice （P 〈 0.01 or P 〈 0.05）. CONCLUSION： Uterine innervation in the adenomyosis mice was increased compared with the controls. Moreover, NGF expression, inflammation, and vascularization, which have been shown to be impact factors of innervation, were abnormal in the uteri of adenomyosis mice.
基金Claudia Machado(Instituto de Investigacao e Inovacao em Saude)for her help in preparing the bone slides for the immunohistochemistryThis work was financed by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalisation(POCI),Portugal 2020,and by Portuguese funds through FCT/MCTES in the framework of the project SproutcORE—Inervagao patologica em metastases osseas:OSTEOCLASTOS,o que estao a fazer?(PTDC/MED-PAT/30158/2017,POCI-01-0145-FEDER-030158)+1 种基金D.M.S.is a recipient of a Post-Doc fellowship(SFRH/BPD/115341/2016)L.L.and F.C.are recipients of Ph.D.fellowships(SFRH/BD/109686/2015 and SFRH/BD/128771/2017,respectively).
文摘Tissue innervation is a complex process controlled by the expression profile of signaling molecules secreted by tissue-resident cells that dictate the growth and guidance of axons.Sensory innervation is part of the neuronal network of the bone tissue with a defined spatiotemporal occurrence during bone development.Yet,the current understanding of the mechanisms regulating the map of sensory innervation in the bone tissue is still limited.Here,we demonstrated that differentiation of human mesenchymal stem cells to osteoblasts leads to a marked impairment of their ability to promote axonal growth,evidenced under sensory neurons and osteoblastic-lineage cells crosstalk.The mechanisms by which osteoblast lineage cells provide this nonpermissive environment for axons include paracrine-induced repulsion and loss of neurotrophic factors expression.We identified a drastic reduction of NGF and BDNF production and stimulation of Sema3A,Wnt4;and Shh expression culminating at late stage of OB differentiation.We noted a correlation between Shh expression profile,OB differentiation stages,and OB-mediated axonal repulsion.Blockade of Shh activity and signaling reversed the repulsive action of osteoblasts on sensory axons.Finally,to strengthen our model,we localized the expression of Shh by osteoblasts in bone tissue.Overall,our findings provide evidence that the signaling profile associated with osteoblast phenotype differentiating program can regulate the patterning of sensory innervation,and highlight osteoblast-derived Shh as an essential player in this cue-induced regulation.
文摘BACKGROUND： Numerous studies use fluorescent microscopy to obtain two-dimensional optical images of the morphology of nerve fibers in hypertrophic scars. In addition, current confocal microscopy studies have focused on normal, not pathological, cutaneous nerves. However, laser scanning confocal microscopy results in a three-dimensional structure of the nerve fibers. OBJECTIVE： To observe quantitative and morphological differences in nerve fibers from the proliferative and mature stage in hypertrophic scars using fluorescent and confocal microscopy. DESIGN, TIME AND SETTING： Neuropathological, comparison study was conducted at the Provincial Hospital Affiliated to Shandong University, China from June 2006 to July 2007. PARTICIPANTS： Specimens were selected from 30 patients undergoing scar restoration at the Provincial Hospital Affiliated to Shandong University of China at 1 month to 23 years following wound healing. The study comprised 20 males and 10 females. The scars were fibrous lesions, erythematous, tough, confined to skin lesions, did not exhibit ulceration or infection, exhibited telangiectasia, with or without itching and pain, and were not locally treated. Samples were equally assigned to two groups according to course of disease： proliferative group （〈 6 months） and mature group （6-24 months）. Control samples were collected from full-thickness skin from donor sites （n = 10）. METHODS： Nerve fiber morphology was observed using fluorescent and confocal microscopy following immunofluorescence of the skin specimens. The microscopic images were semi-quantitatively analyzed to acquire a positive area ratio of neurofilament protein-positive nerve fibers. MAIN OUTCOME MEASURES： Morphology and positive area ratio of neurofilament protein/positive nerve fibers was measured. RESULTS： The positive area ratio of neurofilament protein-positive nerve fibers was significantly greater in the proliferative group compared to the normal control group （P 〈 0.05）. Nerve fibers were irregularly distributed and exhibited local swelling, twisting, and disconnection. However, the positive area ratio of neurofilament protein-positive nerve fibers was significantly less in the mature group compared with the normal control group （P 〈 0.05）. The nerve fibers were arranged in an orderly manner, with intact inner and stereoscopic structures similar to normal skin. CONCLUSION： Compared with mature scars, hypertrophic scars exhibited a greater number of nerve fibers, with more serious pathologies.
基金supported by the National Natural Science Foundation of China, Nos.31770929(to HTW), 31522029(to HTW), 81902847(to HHY)the Beijing Municipal Science and Technology Commission of China, Nos.Z181100001518001(to HTW), Z161100000216154(to HTW)。
文摘Previous studies demonstrate an accumulation of transferrin and transferrin receptor 1(TfR1) in regenerating peripheral nerves.However, the expression and function of transferrin and TfR1 in the denervated skeletal muscle remain poorly understood.In this study, a mouse model of denervation was produced by complete tear of the left brachial plexus nerve.RNA-sequencing revealed that transferrin expression in the denervated skeletal muscle was upregulated, while TfR1 expression was downregulated.We also investigated the function of TfR1 during development and in adult skeletal muscles in mice with inducible deletion or loss of TfR1.The ablation of TfR1 in skeletal muscle in early development caused severe muscular atrophy and early death.In comparison, deletion of TfR1 in adult skeletal muscles did not affect survival or glucose metabolism, but caused skeletal muscle atrophy and motor functional impairment, similar to the muscular atrophy phenotype observed after denervation.These findings suggest that TfR1 plays an important role in muscle development and denervation-induced muscular atrophy.This study was approved by the Institutional Animal Care and Use Committee of Beijing Institute of Basic Medical Sciences, China(approval No.SYXK 2017-C023) on June 1, 2018.
基金Supported by the National Natural Science Foundation of China(No.81470609 No.81870632)+4 种基金the Youth National Natural Science Foundation of China(No.81700800 No.81800800 No.81500695)Natural Science Foundation of Shandong Province(No.ZR2017MH008 No.ZR2017BH025)
文摘AIM: To characterize changes in the cornea nerve and pain responses in fungal keratitis(FK).METHODS: A retrospective analysis of in vivo confocal microscopy images of 11 FK corneas was performed, and the results were compared with those for 11 normal corneas. Subbasal corneal nerves were analyzed for total nerve number, main nerve trunk number, branching patterns and tortuosity. C57 BL/6 mice were infected with Aspergillus fumigatus. Disease severity was determined through clinical scoring and slit lamp photography. Corneas were harvested at 1, 3, 5, and 7 d post infection(p.i.) and assessed for β III tubulin. Corneal mechanical sensitivity thresholds were detected by von Frey test. β-endorphin(β-EP) and μ receptor protein expression was detected through Western blotting.RESULTS: Total nerve number, main nerve trunk number, and nerve branching were significantly lower in FK patients than in controls, but tortuosity was not significantly different. In infected mice, subbasal nerve density decreased from 1 d p.i., reaching a minimum at 5 d p.i. Clinical scores rose at 1 d p.i., peaked at 3 d p.i., and decreased at 5 d p.i. Mechanical sensitivity thresholds showed the same trends. β-EP and μ receptor protein expression increased after infection.CONCLUSION: Corneal nerve density is lower in FK patients and Aspergillus fumigatus-infected mice than in controls. Pain sensitivity decreases with postinfection corneal ulcer aggravation. β-EP and μ receptor proteins are both upregulated in infected mouse corneas.
基金supported by a grant from the Tianjin“Project+Team”Key Cultivation Program(XC202034)a Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-009A).
文摘Pancreatic ductal adenocarcinoma(PDAC)is a highly aggressive lethal malignancy,characterized by late diagnosis,aggressive growth,and therapy resistance,leading to a poor overall prognosis.Emerging evidence shows that the peripheral nerve is an important non-tumor component in the tumor microenvironment that regulates tumor growth and immune escape.The crosstalk between the neuronal system and PDAC has become a hot research topic that may provide novel mechanisms underlying tumor progression and further uncover promising therapeutic targets.In this review,we highlight the mechanisms of perineural invasion and the role of various types of tumor innervation in the progression of PDAC,summarize the potential signaling pathways modulating the neuronal-cancer interaction,and discuss the current and future therapeutic possibilities for this condition.
文摘Astrocytes are implicated in the pathological changes of Alzheimer's disease.Our previous studies have demonstrated that estrogen deprivation and oxidative stress act synergistically to accelerate the progress of Alzheimer's disease.Long-term D-galactose injection combined with ovariectomy may serve as a rodent model for Alzheimer's disease.To address the potential contribution of astroglia to the Alzheimer's disease pathogenesis,we investigated pathological and biochemical alterations of astrocytes under this animal model.Ovadectomized rats injected with D-galactose for 2 weeks showed extensive localization of glial fibrillary acidic protein immunoreactive astrocytes and slightly elevated glutathione levels in the hippocampus without significant impairments in the water maze test and deficits of the cholinergic analyses,compared to the saline-injected rats.Ovariectomized rats injected with D-galactose for 6 weeks,however,exhibited degeneration of astrocytes and decreased glutathione levels in the hippocampus,accompanied with severe dysfunction of behavioral test and deficiency of cholinergic terminals.Electron microscopy further confirmed the pathological changes of astrocytes,especially in the aggregated area of synapse and brain microvessels.Consistent with degeneration of perivascular astrocytic endfeet,analysis of the horseradish peroxidase demonstrated an impairment of the blood-brain barrier permeability.These findings indicate that biochemical and pathological alterations of astrocytes may partially contribute to exacerbating neuronal deficits in the course of Alzheimer's disease.Restoring neuroprotective potential of astrocytes may be a useful therapeutic target for Alzheimer's disease and other neurodegenerative diseases.
基金the Natural Science Foundation of Shandong Province, No. Y2002C29
文摘Burn wounds were produced on two sides on the backs of Wistar rats, in addition to denervation on one side. The skin neural regeneration at the injury site and burn wound healing were evaluated following spinal nerve root incision. No nerve regeneration was observed in the burn wound region post-denervation, and the degree of epithelization was significantly less than the control group. With increasing time, expression of type I collagen, which plays a supporting role, and collagen III, which exhibits elastJc propertJes, were sJgnificantly increased Jn the two groups, but the expression was less in the denervation group compared with the control group, and the wound healing was faster in the control group. The ratio of type I collagen to type III collagen was significantly lower in the denervation group compared with the control group. The ratio gradually decreased with prolonged time in the denervation group, but remained unchanged in the control group. However, the elasticity of the tissues in the denervation group was better than the control group. During burn wound healing, innervations can promote wound healing, but denervation can improve the quality of wound remodeling.
