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1.
PLoS One ; 17(8): e0267990, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35913953

RESUMO

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of motor neurons and skeletal muscle atrophy which is caused by ubiquitous deficiency in the survival motor neuron (SMN) protein. Several cellular defects contribute to sensory-motor circuit pathology in SMA mice, but the underlying mechanisms have often been studied in one mouse model without validation in other available models. Here, we used Smn2B/- mice to investigate specific behavioral, morphological, and functional aspects of SMA pathology that we previously characterized in the SMNΔ7 model. Smn2B/- SMA mice on a pure FVB/N background display deficits in body weight gain and muscle strength with onset in the second postnatal week and median survival of 19 days. Morphological analysis revealed severe loss of proprioceptive synapses on the soma of motor neurons and prominent denervation of neuromuscular junctions (NMJs) in axial but not distal muscles. In contrast, no evidence of cell death emerged from analysis of several distinct pools of lumbar motor neurons known to be lost in the disease. Moreover, SMA motor neurons from Smn2B/- mice showed robust nuclear accumulation of p53 but lack of phosphorylation of serine 18 at its amino-terminal, which selectively marks degenerating motor neurons in the SMNΔ7 mouse model. These results indicate that NMJ denervation and deafferentation, but not motor neuron death, are conserved features of SMA pathology in Smn2B/- mice.


Assuntos
Atrofia Muscular Espinal , Doenças Neurodegenerativas , Animais , Morte Celular , Denervação , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos , Neurônios Motores/metabolismo , Atrofia Muscular Espinal/patologia , Doenças Neurodegenerativas/patologia , Proteína 2 de Sobrevivência do Neurônio Motor
5.
Bull Exp Biol Med ; 173(3): 306-311, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35844022

RESUMO

In experiments on narcotized male rats (n=85), the mean electroimpedance Z and peak-to-peak magnitudes (the swing ranges) of passive (ΔZp) and active (ΔZa) pulsatile electroimpedance oscillations of isolated segment of femoral arteries were determined in situ. These rheographic parameters (RP) were measured in intact animals and in those with modeled chronic myocardial infarction, chronic denervation of the right hind leg, as well as in rats subjected to sham operations to mimic denervation or infarction (with thoracic trauma). The rats with modeled myocardial infarction demonstrated decreasing trends of all RP. In sham-operated rats with thoracic trauma, ΔZp increased significantly on postsurgery months 2-4 by 4.3 times in comparison with the control. No essential correlation was found in denervated rats between RP of any femoral artery and severity of neuropathic pain syndrome assessed by autotomy of the operated leg. In these rats, the mean electroimpedance Z of any femoral artery was significantly greater than the control level. They demonstrated especially high values of ΔZp with significant difference between ΔZp of innervated and denervated hind leg. In denervated rats, ΔZa was significantly greater than the control value without significant difference between ΔZa of both femoral arteries. The paradoxically great increase of ΔZp (100- and 50-fold for innervated and denervated legs, respectively) and a significant 3-fold increment of ΔZa in both hind legs provoked by denervation of one of them are discussed in relation to searching for the ways of systemic influences on vascular network in clinics and experiments.


Assuntos
Artéria Femoral , Infarto do Miocárdio , Animais , Denervação , Artéria Femoral/cirurgia , Membro Posterior , Extremidade Inferior , Masculino , Ratos
6.
Basic Res Cardiol ; 117(1): 36, 2022 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-35834066

RESUMO

Atrial fibrillation (AF) is highly prevalent in hypertensive patients with metabolic syndrome and is related to inflammation and activation of the sympathoadrenergic system. The multi-ligand Receptor-for-Advanced-Glycation-End-products (RAGE) activates inflammation-associated tissue remodeling and is regulated by the sympathetic nervous system. Its counterpart, soluble RAGE (sRAGE), serves as anti-inflammatory decoy receptor with protective properties. We investigated the effect of sympathetic modulation by renal denervation (RDN) on atrial remodeling, RAGE/sRAGE and RAGE ligands in metabolic syndrome. RDN was performed in spontaneously hypertensive obese rats (SHRob) with metabolic syndrome compared with lean spontaneously hypertensive rats (SHR) and with normotensive non-obese control rats. Blood pressure and heart rate were measured by telemetry. The animals were killed 12 weeks after RDN. Left atrial (LA) and right atrial (RA) remodeling was assessed by histological analysis and collagen types. Sympathetic innervation was measured by tyrosine hydroxylase staining of atrial nerve fibers, RAGE/sRAGE, RAGE ligands, cytokine expressions and inflammatory infiltrates were analyzed by Western blot and immunofluorescence staining. LA sympathetic nerve fiber density was higher in SHRob (+44%) versus controls and reduced after RDN (-64% versus SHRob). RAGE was increased (+718%) and sRAGE decreased (- 62%) in SHRob as compared with controls. RDN reduced RAGE expression (- 61% versus SHRob), significantly increased sRAGE levels (+162%) and induced a significant decrease in RAGE ligand levels in SHRob (- 57% CML and - 51% HMGB1) with reduced pro-inflammatory NFkB activation (- 96%), IL-6 production (- 55%) and reduced inflammatory infiltrates. This led to a reduction in atrial fibrosis (- 33%), collagen type I content (- 72%), accompanied by reduced LA myocyte hypertrophy (- 21%). Transfection experiments on H9C2 cardiomyoblasts demonstrated that RAGE is directly involved in fibrosis formation by influencing cellular production of collagen type I. In conclusion, suppression of renal sympathetic nerve activity by RDN prevents atrial remodeling in metabolic syndrome by reducing atrial sympathetic innervation and by modulating RAGE/sRAGE balance and reducing pro-inflammatory and pro-fibrotic RAGE ligands, which provides a potential therapeutic mechanism to reduce the development of AF.


Assuntos
Remodelamento Atrial , Denervação , Hipertensão , Rim , Síndrome Metabólica , Receptor para Produtos Finais de Glicação Avançada , Animais , Fibrilação Atrial/metabolismo , Colágeno Tipo I , Denervação/métodos , Fibrose , Hipertensão/complicações , Hipertensão/metabolismo , Inflamação/metabolismo , Rim/inervação , Rim/cirurgia , Ligantes , Síndrome Metabólica/complicações , Síndrome Metabólica/metabolismo , Síndrome Metabólica/terapia , Obesidade/metabolismo , Ratos , Ratos Endogâmicos SHR , Receptor para Produtos Finais de Glicação Avançada/metabolismo
7.
Biomed Res Int ; 2022: 2620876, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35865669

RESUMO

Background: Previous studies showed that a decline in BP can reverse pressure-overloaded left ventricular hypertrophy in the long term. Whether this structural remodeling and improved cardiac function were due to reduced BP levels or sympathetic tone is unclear. The aim of this study was to evaluate the efficacy of renal denervation (RDN) on cardiac function and left ventricular hypertrophy in patients diagnosed with resistant hypertension with systolic and diastolic dysfunction. Methods: Thirteen patients diagnosed with resistant hypertension underwent bilateral RDN (RDN group), and 13 patients were selected as the control group (drug group) who received regular antihypertensive drugs for the first time. Demographic analysis and hematologic tests were performed to determine renal function as well as BNP levels. Echocardiogram was performed at baseline and 12 months after RDN. Results: All the baseline characteristics are comparable in two groups. Both RDN and drug regiments resulted in significant reduction from baseline in SBP/DBP at 12-month follow-up (all P values < 0.01), and the decline due to two interventions showed no statistically significant difference (F = 1.64, P = 0.213 and F = 0.124, P = 0.853 for SBP and DBP, respectively). RDN significantly reduced mean LV mass index (LVMI) from 151.43 ± 46.91 g/m2 to 136.02 ± 37.76 g/m2 (P = 0.038) and ejection fraction (LVEF) increased from 57.15 ± 5.49% at baseline to 59.54 ± 4.18% at 12 months (P = 0.039). No similar changes were detected in the drug group (P values, 0.90 for EF and 0.38 for LVMI). Renal parameters including BUN, Cr, UA, and eGFR at baseline, 3 months, and 12 months showed no marked difference (P = 0.497, 0.223, 0.862, 0.075, respectively). Conclusions: Our findings show that in addition to hypertension and its progression, elevated sympathetic hyperactivity is related to left ventricular hypertrophy and cardiac function.


Assuntos
Hipertensão , Hipertrofia Ventricular Esquerda , Rim , Simpatectomia , Função Ventricular Esquerda , Pressão Sanguínea/fisiologia , Denervação/métodos , Humanos , Hipertensão/fisiopatologia , Hipertensão/cirurgia , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/cirurgia , Rim/inervação , Rim/fisiologia , Rim/cirurgia , Simpatectomia/métodos , Resultado do Tratamento , Função Ventricular Esquerda/fisiologia
9.
Urology ; 166: 159-163, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35644304

RESUMO

OBJECTIVE: To identify differences in neuroinflammatory gene expression in individuals with chronic orchialgia (CO) compared to asymptomatic controls. METHODS: Vas deferens, spermatic cord fascia, blood, and urine were collected from 9 men with CO at time of microscopic spermatic cord denervation and 7 asymptomatic controls at time of vasectomy. RNA was isolated and analyzed with the NanoString Human Neuroinflammation panel. Data were normalized, gene expression fold changes and enriched pathways relative to asymptomatic controls were determined. Gene expression was considered significantly different if there was a >2-fold change and P-value <.05 relative to controls. RESULTS: Mean patient age was 51 years and median symptom duration 12 months. There were 26 genes with significantly differential expression in vas deferens. cFos, a marker of nociceptive pain, had the greatest difference (30.2-fold change, P <.000001). Enriched pathways in vas deferens included nerve function, matrix remodeling, and innate immune responses. In fascia, cFos also had the greatest differential expression (38-fold, P = .000002), followed by S100A12 (11-fold, inducer of innate immune response). Enriched pathways in fascia included nerve function and inflammation. In blood, there were no differentially expressed genes, and in urine there were 95 differentially expressed genes. CONCLUSION: Men with CO have a diverse set of neuroinflammatory genes with differential expression in tissue and urine relative to healthy controls. These findings confirm pathologic changes in tissue targeted by denervation surgery, and suggest molecular changes in neuropathic pain that could lead to biomarker identification and novel treatment.


Assuntos
Cordão Espermático , Doenças Testiculares , Denervação , Expressão Gênica , Humanos , Masculino , Microcirurgia , Pessoa de Meia-Idade , Dor/cirurgia , Cordão Espermático/cirurgia , Doenças Testiculares/genética , Doenças Testiculares/cirurgia
13.
J Neurol Sci ; 439: 120317, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35709642

RESUMO

INTRODUCTION: Sporadic inclusion body myositis (sIBM) is often accompanied by signs suggestive of denervation on electromyography (EMG), which mimics neurogenic disorders. Hence, the current study aimed to assess reinnervation after denervation in sIBM and its clinical impllcation. METHODS: We retrospectively examined consecutive muscle biopsy specimens collected from 109 sIBM patients who were referred to our institution for diagnostic muscle biopsy from 2001 to 2018. Reinnervation after denervation in sIBM patients was assessed via muscle biopsy and EMG. The levels of acetylcholine receptor subunit γ (Chrng) and muscle-specific kinase (MuSK) mRNA, which are markers of denervation, were examined using real-time polymerase chain reaction. Response to treatment was defined as an increase of grade 1 or higher in two or more muscle groups as assessed using the Medical Research Council scale. RESULTS: In total, 93 (85.3%) of 109 sIBM patients had reinnervation after denervation on histological examination and/or EMG. The mean disease duration before biopsy was significantly longer in patients with reinnervation after denervation than in those without (p < 0.00001). Patients with denervation had significantly higher levels of Chrng and MuSK mRNA than those without. The proportion of patients who responded to immunosuppressive therapies was smaller in the patients with denervation than those without (p < 0.05). However, there was no significant difference regarding time from onset to using a walking aid between the two groups. DISCUSSION: Reinnervation after denervation is associated with disease duration and short-term response to therapy in individuals with sIBM.


Assuntos
Miosite de Corpos de Inclusão , Denervação , Eletromiografia , Humanos , Miosite de Corpos de Inclusão/diagnóstico , RNA Mensageiro , Estudos Retrospectivos
16.
J Vis Exp ; (183)2022 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-35695519

RESUMO

Chronic orchialgia is a common disease in department of urology and andrology. The etiology is complex, and the treatment is difficult. In severe cases, orchiectomy is even necessary. In recent years, microsurgical denervation of the spermatic cord (MDSC) is a minimally invasive and effective surgical method for the treatment of chronic orchialgia. Its greatest advantage is to preserve the testis and epididymis, avoid the possible organ resection. The key of the operation is to dissect all the fibrous tissues in the spermatic cord, while protecting the arteries (especially the testicular arteries) and several lymphatic vessels. Combined with the use of microvascular doppler in the operation, when separating the structure of spermatic cord under the microscope, the testicular arteries can be objectively and accurately protected (pulse "whistle" sound can be heard when the microvascular doppler probes the arterial surface), while artery injury and venous missed ligation can be avoided. The postoperative blood supply of the testis is also maximumly safeguarded. At the same time, we can be more fearless to cut the cremaster muscle, fatty and connective tissues surrounding the spermatic cord blood vessels and vas deferens after the arteries and lymphatic vessels being accurately protected under the microscope, finally achieve the spermatic cord completely "skeletonized" (only the testicular arteries, lymphatic vessels and vas deferens remained after the surgery). Thus we can better ensure the clinical curative effect (denervation thoroughly), avoid serious complications (testicular atrophy), and achieve better surgical results.


Assuntos
Doença Enxerto-Hospedeiro , Cordão Espermático , Doenças Testiculares , Denervação/efeitos adversos , Denervação/métodos , Humanos , Masculino , Microcirurgia/métodos , Dor/complicações , Cordão Espermático/diagnóstico por imagem , Cordão Espermático/cirurgia , Doenças Testiculares/complicações , Doenças Testiculares/diagnóstico por imagem , Doenças Testiculares/cirurgia
17.
J Vis Exp ; (183)2022 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-35695539

RESUMO

The benefits of renal sympathetic denervation (RDN) on blood pressure have been proved in a large number of clinical trials in recent years. However, the regulatory mechanism of RDN on hypertension remains elusive. Thus, it's essential to establish a simpler RDN model in mice. In this study, osmotic mini pumps filled with Angiotensin II were implanted in 14-week-old C57BL/6 mice. One week after the implantation of the mini-osmotic pump, a modified RDN procedure was performed on bilateral renal arteries of the mice using phenol. Age-sex-matched mice were given saline and served as sham group. Blood pressure was measured at baseline and every week subsequently for 21 days. Then, renal artery, abdominal aorta and heart were collected for histological examination using H&E and Masson staining. In this study, we present a simple, practical, repeatable, and standardized RDN model, which can control hypertension and alleviate cardiac hypertrophy. The technique can denervate peripheral renal sympathetic nerves without renal artery damage. Compared to previous models, the modified RDN facilitates the study of the pathobiology and pathophysiology of hypertension.


Assuntos
Angiotensina II , Hipertensão , Animais , Pressão Sanguínea , Denervação , Rim , Camundongos , Camundongos Endogâmicos C57BL , Artéria Renal/cirurgia , Simpatectomia/métodos
18.
Hypertens Res ; 45(7): 1111-1122, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35650248

RESUMO

Hypertension is highly prevalent and a major contributor to cardiovascular mortality and morbidity. In spite of the availability of efficacious, safe and affordable anti-hypertensive drugs, hypertension remains poorly controlled in the majority of hypertensive patients. Various reasons including non-adherence to the anti-hypertensive drugs, account for the poor control. Resistant hypertension is also one of the reasons for poor control of blood pressure (BP). The sympathetic nervous system (SNS) has long been recognized as one of the determinants in the pathophysiology of a raised BP. Overactivity of the SNS is a contributor to sustained arterial hypertension. Renal denervation (RDN) is increasingly recognized as a safe and effective adjunctive therapy to control BP with or without pharmacotherapy. Hence for patients who remain uncontrolled despite all efforts, renal denervation (RDN) is a novel treatment that can potentially improve BP control, hence reducing the major adverse cardiovascular events (MACE). More recent randomized, sham control trials of RDN have shown that RDN produces a sustained lowering of BP. To date, this lowering of BP through RDN is maintained for at least 3 years. Furthermore, this procedure has been found to be safe. Hence this consensus summarises the science behind RDN and the available clinical data to support the use of this therapy. It is hoped that this consensus will offer guidance on the importance of identifying patients who will benefit most from this therapy. A multidisciplinary team approach in the management of the patient undergoing RDN is recommended.


Assuntos
Anti-Hipertensivos , Hipertensão , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Denervação/métodos , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/cirurgia , Rim , Simpatectomia/métodos , Resultado do Tratamento
20.
Neurochem Res ; 47(8): 2416-2430, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35716295

RESUMO

Myocardial infraction (MI) is the principal risk factor for the onset of heart failure (HF). Investigations regarding the physiopathology of MI progression to HF have revealed the concerted engagement of other tissues, such as the autonomic nervous system and the medulla oblongata (MO), giving rise to systemic effects, important in the regulation of heart function. Cardiac sympathetic afferent denervation following application of resiniferatoxin (RTX) attenuates cardiac remodelling and restores cardiac function following MI. While the physiological responses are well documented in numerous species, the underlying molecular responses during the initiation and progression from MI to HF remains unclear. We obtained multi-tissue time course proteomics with a murine model of HF induced by MI in conjunction with RTX application. We isolated tissue sections from the left ventricle (LV), MO, cervical spinal cord and cervical vagal nerves at four time points over a 12-week study. Bioinformatic analyses consistently revealed a high statistical enrichment for metabolic pathways in all tissues and treatments, implicating a central role of mitochondria in the tissue-cellular response to both MI and RTX. In fact, the additional functional pathways found to be enriched in these tissues, involving the cytoskeleton, vesicles and signal transduction, could be downstream of responses initiated by mitochondria due to changes in neuronal pulse frequency after a shock such as MI or the modification of such frequency communication from the heart to the brain after RTX application. Development of future experiments, based on our proteomic results, should enable the dissection of more precise mechanisms whereby metabolic changes in neuronal and cardiac tissues can effectively ameliorate the negative physiological effects of MI via RTX application.


Assuntos
Insuficiência Cardíaca , Infarto do Miocárdio , Animais , Denervação , Modelos Animais de Doenças , Redes e Vias Metabólicas , Camundongos , Infarto do Miocárdio/metabolismo , Proteômica , Transdução de Sinais
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