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Scientific Reports Jun 2024Diabetic peripheral neuropathy (DPN) is a common complication of type 2 diabetes mellitus (T2DM) that causes peripheral and autonomic nervous system dysfunction....
Diabetic peripheral neuropathy (DPN) is a common complication of type 2 diabetes mellitus (T2DM) that causes peripheral and autonomic nervous system dysfunction. Dysregulation of miRNAs plays a crucial role in DPN development. However, the role of miR-503-5p in DPN remains unknown. Herein, T2DM mice (db/db) were used as a DPN model in vivo, and astrocytes isolated from db/db mice were induced with high glucose levels as a DPN model in vitro. MiR-503-5p expression was analyzed using qRT-PCR. GFAP, MCP-1, and SEPT9 protein levels were analyzed using western blotting and immunofluorescence. Luciferase assays were performed to investigate the interaction between miR-503-5p and SEPT9. We found that miR-503-5p expression decreased in the spinal cord of DPN model mice and astrocytes treated with high glucose (HG). The db/db mice displayed higher body weight and blood glucose, lower mechanical withdrawal threshold and thermal withdrawal latency, and higher GFAP and MCP-1 protein levels than db/m mice. However, tail vein injection of agomiR-503-5p remarkably reversed these parameters, whereas antigomiR-503-5p enhanced them. HG markedly facilitated GFAP and MCP-1 protein expression in astrocytes, whereas miR-503-5p mimic or inhibitor transfection markedly blocked or elevated GFAP and MCP-1 protein expression, respectively, in astrocytes with HG. SEPT9 was a target of miR-503-5p. In addition, SEPT9 protein levels were found to be elevated in db/db mice and astrocytes treated with HG. Treatment with agomiR-503-5p and miR-503-5p mimic was able to reduce SEPT9 protein levels, whereas treatment with antigomiR-503-5p and miR-503-5p inhibitor led to inhibition of the protein. Furthermore, SEPT9 overexpression suppressed the depressing effect of miR-503-5p overexpression in astrocytes subjected to HG doses. In conclusion, miR-503-5p was found to alleviate peripheral neuropathy-induced neuropathic pain in T2DM mice by regulating SEPT9 expression.
Topics: Animals; MicroRNAs; Astrocytes; Mice; Septins; Diabetic Neuropathies; Diabetes Mellitus, Type 2; Male; Neuralgia; Disease Models, Animal
PubMed: 38906977
DOI: 10.1038/s41598-024-65096-z -
Reviews in the Neurosciences Jun 2024Small fiber neuropathy (SFN) is a peripheral nerve condition affecting thin myelinated Aδ and unmyelinated C-fibers, characterized by severe neuropathic pain and other... (Review)
Review
Small fiber neuropathy (SFN) is a peripheral nerve condition affecting thin myelinated Aδ and unmyelinated C-fibers, characterized by severe neuropathic pain and other sensory and autonomic symptoms. A variety of medical disorders can cause SFN; however, more than 50% of cases are idiopathic (iSFN). Some investigations suggest an autoimmune etiology, backed by evidence of the efficacy of IVIG and plasma exchange. Several studies suggest that autoantibodies directed against nervous system antigens may play a role in the development of neuropathic pain. For instance, patients with CASPR2 and LGI1 antibodies often complain of pain, and and studies support their pathogenicity. Other antibodies have been associated with SFN, including those against TS-HDS, FGFR3, and Plexin-D1, and new potential targets have been proposed. Finally, a few studies reported the onset of SFN after COVID-19 infection and vaccination, investigating the presence of potential antibody targets. Despite these overall findings, the pathogenic role has been demonstrated only for some autoantibodies, and the association with specific clinical phenotypes or response to immunotherapy remains to be clarified. The purpose of this review is to summarise known autoantibody targets involved in neuropathic pain, putative attractive autoantibody targets in iSFN patients, their potential as biomarkers of response to immunotherapy and their role in the development of iSFN.
PubMed: 38865989
DOI: 10.1515/revneuro-2024-0027 -
Cureus May 2024Guillain-Barre Syndrome (GBS) is an autoimmune condition that causes muscular weakness and can be potentially life-threatening if not identified early. GBS is diagnosed...
Guillain-Barre Syndrome (GBS) is an autoimmune condition that causes muscular weakness and can be potentially life-threatening if not identified early. GBS is diagnosed definitively by cerebrospinal fluid (CSF) analysis and electromyographic (EMG) studies. Identifying illnesses that may have triggered GBS is crucial, as they could affect the course of the disease. Our patient was a 27-year-old woman who developed lower extremity weakness a few days after being treated for a dental abscess. Laboratory and imaging studies ruled out central nervous system (CNS) lesions, myelopathies, and metabolic causes. Diagnosis was difficult due to inconclusive initial investigations, refusal of lumbar puncture, and delayed availability of EMG studies. Additionally, there were no identifiable triggers to support GBS as a diagnosis. During the hospital course, the patient developed tachycardia with new electrocardiogram (EKG) changes. A transthoracic echocardiogram (TTE) showed suspicious vegetation, and a transesophageal echocardiogram (TEE) confirmed severe mitral regurgitation. The new valvular lesions and autonomic dysfunction with worsening lower extremity weakness increased our suspicion of GBS. Intravenous immunoglobulin (IVIG) was administered empirically, but she developed bulbar symptoms, prompting admission to the intensive care unit (ICU). A lumbar puncture performed at this time was negative for albumino-cytological dissociation and CNS infections. Signs of sepsis with valvular lesions raised concerns for infective endocarditis (IE). Due to recent treatment with antibiotics for dental abscess, a negative blood culture was a confounding factor in Duke's criteria, delaying the diagnosis of IE. Infectious disease experts suggested empirical treatment for suspected blood culture-negative infective endocarditis (BCNE) and valvular abscess. She was transferred to a cardiothoracic care facility for valvular surgery evaluation. EMG studies identified the patient's condition as the acute motor sensory axonal neuropathy (AMSAN) variant of GBS. The patient's antibodies tested positive for immunoglobulin G (IgG). Since this indicates a past infection, it is uncertain whether triggered the patient's GBS. However, new valvular vegetation and acute-onset lower extremity weakness make us hypothesize that BCNE may have triggered GBS.
PubMed: 38827011
DOI: 10.7759/cureus.59479 -
Biomedicine & Pharmacotherapy =... Jul 2024Diabetes and derived complications, especially diabetic nephropathy and neuropathy annually cause great morbimortality worldwide. 5-hydroxytryptamine (5-HT) acts as a...
Diabetes and derived complications, especially diabetic nephropathy and neuropathy annually cause great morbimortality worldwide. 5-hydroxytryptamine (5-HT) acts as a modulator of renal sympathetic input and vascular tone. In this line, 5-HT receptor blockade has been linked with reduced incidence and progression of diabetic microvascular alterations. In this work, we aimed to determine, in diabetic rats, whether 5-HT blockade ameliorates renal function and to characterize the serotonergic modulatory action on renal sympathetic neurotransmission. Diabetes was induced in male Wistar rats by alloxan administration (150 mg/kg, s.c.), and sarpogrelate (30 mg/kg·day, p.o.; 5-HT antagonist) was administered for 14 days (DM-S). Normoglycemic and diabetic (DM) animals were maintained as aged-matched controls. At 28th day, DM-S animals were anesthetized and prepared for the in situ autoperfusion of the kidney. Renal vasoconstrictor responses were induced electrically or by i.a. noradrenaline (NA) administration. The role of 5-HT and selective 5-HT agonist/antagonist were studied on these renal vasopressor responses. Sarpogrelate treatment decreased renal sympathetic-induced vasopressor responses, reduced renal hypertrophy and kidney damage markers increased in DM. Intraarterial 5-HT inhibited the sympathetic-induced renal vasoconstrictions, effect reproduced by 5-CT, AS-19, L-694,247 and LY 344864 (5-HT, 5-HT, 5-HT and 5-HT receptor agonists, respectively). Blocking 5-HT receptors completely abolished the 5-CT sympatho-inhibition. NA vasoconstrictions were not altered by any of the 5-HT agonists tested. Thus, in experimental diabetes, chronic sarpogrelate treatment reduces renal damage markers, kidney hypertrophy and renal sympathetic hyperactivity and modifies serotonergic modulation of renal sympathetic neurotransmission, causing a sympatho-inhibition by prejunctional 5-HT and 5-HT activation.
Topics: Animals; Succinates; Male; Diabetes Mellitus, Experimental; Rats, Wistar; Kidney; Sympathetic Nervous System; Rats; Serotonin 5-HT2 Receptor Antagonists; Serotonin; Diabetic Nephropathies; Vasoconstriction
PubMed: 38820974
DOI: 10.1016/j.biopha.2024.116814 -
Scientific Reports May 2024Despite treatment with levothyroxine, hypothyroidism and autoimmune thyroiditis (AIT) may be associated with reduced quality of life (QoL), an enigmatic condition...
Despite treatment with levothyroxine, hypothyroidism and autoimmune thyroiditis (AIT) may be associated with reduced quality of life (QoL), an enigmatic condition referred to as "syndrome T". Peripheral neuropathy, described in untreated thyroid disease, could be a contributing mechanism. We analysed autonomic and somatosensory function in 29 patients with AIT and treated hypothyroidism and 27 healthy volunteers. They underwent heart rate variability (HRV) analysis and quantitative sensory testing (n = 28), comprising 13 parameters of small and large nerve fibre function and pain thresholds. Autonomic cardiovascular function was assessed in rest, deep respiration and orthostasis. Additionally, biomarkers for autoimmunity and thyroid function were measured. Anxiety, depression and QoL were assessed using validated questionnaires. 36% of the patients showed at least one sign of somatosensory small or large fibre dysfunction. 57% presented with mild hyperalgesia to at least one stimulus. Several markers of autonomic function and some detection thresholds were related to the antibody titres. Anxiety, depression scores and QoL correlated to antibody titres and HRV measures. Autonomic and somatosensory dysfunction indicate that in treated hypothyroidism and AIT a subgroup of patients suffers from neuropathic symptoms leading to impaired QoL. Additionally, mild hyperalgesia as a possible sensitisation phenomenon should be considered a target for symptomatic treatment.
Topics: Humans; Female; Male; Middle Aged; Adult; Autonomic Nervous System; Quality of Life; Thyroiditis, Autoimmune; Heart Rate; Hypothyroidism; Thyroxine; Aged; Somatosensory Disorders; Anxiety
PubMed: 38811750
DOI: 10.1038/s41598-024-63158-w -
Frontiers in Genetics 2024Congenital insensitivity to pain with anhidrosis (CIPA, OMIM #256800), also known as hereditary sensory and autonomic neuropathy type Ⅳ (HSAN-IV), is a rare autosomal...
BACKGROUND
Congenital insensitivity to pain with anhidrosis (CIPA, OMIM #256800), also known as hereditary sensory and autonomic neuropathy type Ⅳ (HSAN-IV), is a rare autosomal recessive disorder characterized by recurrent episodic fevers, anhidrosis, insensitivity to noxious stimuli, self-mutilating behavior and intellectual disability. CIPA can be caused by the variants in gene, which encodes a high-affinity tyrosine kinase receptor for nerve growth factor. To ascertain the hereditary cause of a patient with CIPA accompanied by the additional symptoms of mild growth retardation, prone to fracture, underdeveloped nails of fingers and toes, irregular tooth alignment, enamel hypoplasia, postoperative wound healing difficulty, hand and limb deformity, and dislocation of hip joint, whole exome sequencing was used and revealed a compound heterozygous variant in .
METHODS
DNA was extracted from peripheral blood samples of pediatric patients and their parents, and subjected to comprehensive analysis using whole-exome sequencing (WES), followed by verification of variant sites in the gene through Sanger sequencing. To elucidate the functional impact of the newly discovered variants, an experimental system was established. Splicing analysis was conducted using PCR and Sanger sequencing, while expression levels were assessed through qPCR and Western blot techniques.
RESULTS
One hotspot variant c.851-33T>A(ClinVar ID: 21308) and a novel variant c.850 + 5G>A(ClinVar ID:3069176) was inherited from her father and mother, respectively, identified in the affected individuals. The c.850 + 5G>A variant in resulted in two forms of aberrant mRNA splicing: 13bp deletion (c.838_850del13, p. Val280Ser fs180) and 25bp deletion (826_850del25, p. Val276Ser fs180) in exon 7, both leading to a translational termination at a premature stop codon and forming a C-terminal truncated protein. The expression of two abnormal splicing isoforms was decreased both in the level of mRNA and protein.
CONCLUSION
In conclusion, this study elucidated the genetic cause of a patient with CIPA and identified a novel variant c.850 + 5G>A in , which broadened the and enriched the mutation spectrum.
PubMed: 38798698
DOI: 10.3389/fgene.2024.1345081 -
Journal of Personalized Medicine May 2024This study aimed to investigate whether baroreflex sensitivity (BRS) could serve as a reliable metric for assessing cardiovascular autonomic neuropathy (CAN) and...
Baroreflex Sensitivity as a Surrogate Biomarker for Concurrently Assessing the Severity of Arterial Stiffness and Cardiovascular Autonomic Neuropathy in Individuals with Type 2 Diabetes.
This study aimed to investigate whether baroreflex sensitivity (BRS) could serve as a reliable metric for assessing cardiovascular autonomic neuropathy (CAN) and concurrently act as a surrogate biomarker for evaluating the severity of arterial stiffness and CAN in individuals diagnosed with type 2 diabetes mellitus (T2DM). Participants underwent brachial-ankle pulse wave velocity (baPWV) as well as autonomic function evaluations encompassing the Sudoscan-based modified composite autonomic scoring scale (CASS), baroreflex sensitivity, and heart rate variability in time domains and frequency domains. Linear regression analysis was performed to evaluate the influence of independent variables on baPWV and modified CASS. Participants with higher baPWV values were older, with longer diabetes duration, lower body weight, body mass index, waist circumference, elevated systolic and diastolic blood pressure, and mean arterial blood pressure. They also exhibited a higher prevalence of retinopathy as the underlying disease and reduced estimated glomerular filtration rate. Multiple linear regression analysis revealed that age and BRS were significantly associated with baPWV while diabetes duration, UACR, and BRS were significantly associated with modified CASS. Our study confirms the significant association of BRS with baPWV and modified CASS in T2DM, highlighting its pivotal role in linking microvascular and macrovascular complications. This supports BRS as a surrogate marker for assessing both the severity of arterial stiffness and cardiovascular autonomic neuropathy in T2DM, enabling the early identification of complications.
PubMed: 38793073
DOI: 10.3390/jpm14050491 -
Journal of Personalized Medicine Apr 2024Functional gastrointestinal disorders (FGIDs), including functional dyspepsia (FD) and irritable bowel syndrome (IBS), are characterized by chronic and recurrent...
BACKGROUND
Functional gastrointestinal disorders (FGIDs), including functional dyspepsia (FD) and irritable bowel syndrome (IBS), are characterized by chronic and recurrent gastrointestinal symptoms. Clinically, FD and IBS often resemble gastrointestinal dysmotility caused by autoimmune autonomic neuropathy. We examined the seropositive frequency of autoantibodies against ganglionic nicotinic acetylcholine receptors (gnAChRs) in patients presenting with FGIDs.
OBJECTIVE
To elucidate the seropositivity of gnAChR antibodies and the clinical features of seropositive FD and IBS.
MATERIALS AND METHODS
We measured autoantibodies against the gnAChR α3 and β4subunits using luciferase immunoprecipitation systems. Serum samples from patients with any autonomic symptoms were obtained from hospitals in Japan between January 2012 and August 2018 (1787 serum samples of 1381 patients). We selected FD and IBS patients and compared the clinical characteristics and prevalence of autonomic symptoms between those with seropositive and seronegative IBS and FD.
RESULTS
Nine IBS and two FD cases (one comorbid case with IBS) were found. We found four patients (36.4%) in whom gnAChR antibodies were positive in these eleven patients. Sicca symptoms were observed in three of four cases (75%) of seropositive FGID compared with zero of seven cases (0%) of seronegative FGID.
CONCLUSIONS
We found patients with gnAChR antibodies in FD and IBS patients. These data will be valuable for elucidating the pathophysiology of these FGIDs and developing new treatment strategies.
PubMed: 38793066
DOI: 10.3390/jpm14050485 -
Medicina (Kaunas, Lithuania) May 2024: Cardiac autonomic neuropathy (CAN) is a severe complication of diabetes mellitus (DM) strongly linked to a nearly five-fold higher risk of cardiovascular mortality....
: Cardiac autonomic neuropathy (CAN) is a severe complication of diabetes mellitus (DM) strongly linked to a nearly five-fold higher risk of cardiovascular mortality. Patients with Type 2 Diabetes Mellitus (T2DM) are a significant cohort in which these assessments have particular relevance to the increased cardiovascular risk inherent in the condition. : This study aimed to explore the subtle correlation between the Ewing test, Sudoscan-cardiovascular autonomic neuropathy score, and cardiovascular risk calculated using SCORE 2 Diabetes in individuals with T2DM. The methodology involved detailed assessments including Sudoscan tests to evaluate sudomotor function and various cardiovascular reflex tests (CART). The cohort consisted of 211 patients diagnosed with T2DM with overweight or obesity without established ASCVD, aged between 40 to 69 years. : The prevalence of CAN in our group was 67.2%. In the study group, according SCORE2-Diabetes, four patients (1.9%) were classified with moderate cardiovascular risk, thirty-five (16.6%) with high risk, and one hundred seventy-two (81.5%) with very high cardiovascular risk. : On multiple linear regression, the SCORE2-Diabetes algorithm remained significantly associated with Sudoscan CAN-score and Sudoscan Nephro-score and Ewing test score. Testing for the diagnosis of CAN in very high-risk patients should be performed because approximately 70% of them associate CAN. Increased cardiovascular risk is associated with sudomotor damage and that Sudoscan is an effective and non-invasive measure of identifying such risk.
Topics: Humans; Middle Aged; Male; Female; Diabetes Mellitus, Type 2; Adult; Aged; Cardiovascular Diseases; Diabetic Neuropathies; Cohort Studies; Risk Assessment; Autonomic Nervous System Diseases; Heart Disease Risk Factors; Risk Factors
PubMed: 38793011
DOI: 10.3390/medicina60050828