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Biomolecules Jun 2024New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous...
New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, is blocked by OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to a cholinergic crisis. The oximes in use have one or two pyridinium rings and cross the brain-blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper, we described the synthesis of 63 heterostilbene derivatives, of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents-sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in the micromolar range, we identified several oximes as BChE or AChE selective inhibitors with the potential for drug development. Furthermore, the oximes were poor reactivators of AChE; four heterocyclic derivatives reactivated cyclosarin-inhibited BChE up to 70%, and - [2-(()-2-(5-(()-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had a reactivation efficacy comparable to the standard oxime HI-6. analysis and molecular docking studies, including molecular dynamics simulation, connected kinetic data to the structural features of these oximes and confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases such as Alzheimer's and Parkinson's.
Topics: Oximes; Cholinesterase Inhibitors; Butyrylcholinesterase; Acetylcholinesterase; Humans; Triazoles; Molecular Docking Simulation; Stilbenes; Cholinesterase Reactivators; Organophosphorus Compounds; Central Nervous System
PubMed: 38927082
DOI: 10.3390/biom14060679 -
Biomolecules Jun 2024Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (formerly known as Familial Amyloid Polyneuropathy (FAP)) is an endemic amyloidosis involving the... (Review)
Review
Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (formerly known as Familial Amyloid Polyneuropathy (FAP)) is an endemic amyloidosis involving the harmful aggregation of proteins, most commonly transthyretin (TTR) but sometimes also apolipoprotein A-1 or gelsolin. hATTR appears to be transmitted as an autosomal dominant trait. Over 100 point mutations have been identified, with the Val30Met substitution being the most common. Yet, the mechanism of pathogenesis and the overall origin of hATTR remain unclear. Here, we argue that hATTR could be related to harmful metal exposure. hATTR incidence is unevenly distributed globally, and the three largest defined clusters exist in Japan, Portugal, and Sweden. All three disease regions are also ancient mining districts with associated metal contamination of the local environment. There are two main mechanisms for how harmful metals, after uptake into tissues and body fluids, could induce hATTR. First, the metals could directly influence the expression, function, and/or aggregation of the proteins involved in hATTR pathology. Such metal-protein interactions might constitute molecular targets for anti-hATTR drug design. Second, metal exposure could induce hATTR -associated genetic mutations, which may have happened several generations ago. These two mechanisms can occur in parallel. In conclusion, the possibility that hATTR could be related to metal exposure in geochemically defined regions deserves further attention.
Topics: Humans; Amyloid Neuropathies, Familial; Prealbumin; Mining; Polyneuropathies; Portugal
PubMed: 38927056
DOI: 10.3390/biom14060652 -
BMC Pediatrics Jun 2024Guillain‒Barre syndrome (GBS) is an acute inflammatory peripheral neuropathy caused by autoimmunity. Gangliosides and sulfatides are important components of peripheral...
BACKGROUND
Guillain‒Barre syndrome (GBS) is an acute inflammatory peripheral neuropathy caused by autoimmunity. Gangliosides and sulfatides are important components of peripheral nerves. Anti-sulfatide antibody-mediated complement is associated with acute sensorimotor peripheral neuropathy in GBS, which is characterized by pain and paresthesias.
CASE PRESENTATION
The child was a 7-year-old girl with headache and abdominal pain, followed by limb numbness and pain. Cranial imaging showed ventricular dilatation, peripheral nerve function conduction examination showed polyradiculopathy, and cerebrospinal fluid tests showed normal cell counts but elevated protein levels, all of which led to the diagnosis of GBS. After treatment with intravenous immunoglobulin (400 mg/kg × 5 days), the symptoms did not improve, and muscle strength progressively worsened, accompanied by paroxysmal complexion flushing, heart rate fluctuation, hyperhidrosis, and a progressive increase in cerebrospinal fluid protein (up to 3780.1 mg/L). On the basis of these findings combined with serum anti-sulfatide IgM positivity, anti-sulfatide antibody-related GBS was considered, and treatment with low-dose prednisolone (1 mg/kg/d) led to symptom improvement.
CONCLUSIONS
Anti-sulfatide antibody-associated GBS is associated with small fiber peripheral neuropathy. The main manifestations are pain, paresthesias and autonomic dysfunction. In addition to the dysfunction of spinal nerve root absorption caused by increased cerebrospinal fluid protein, autonomic dysfunction may be involved in pain. When the therapeutic effect of immunoglobulin is not satisfactory, a low dose and short course of corticosteroids can be considered, and the prognosis is good.
Topics: Humans; Female; Child; Guillain-Barre Syndrome; Abdominal Pain; Headache; Sulfoglycosphingolipids; Autoantibodies; Prednisolone
PubMed: 38926645
DOI: 10.1186/s12887-023-04287-5 -
BMJ Case Reports Jun 2024A primigravida in mid 30s presented to hospital at 30+2 weeks gestation, due to progressive neurological symptoms including ascending limb weakness and paraesthesia...
A primigravida in mid 30s presented to hospital at 30+2 weeks gestation, due to progressive neurological symptoms including ascending limb weakness and paraesthesia bilaterally as well as dysphagia, facial weakness and dysphasia.The patient was diagnosed with Guillain-Barré syndrome after physical examination and electromyography, which showed a patchy demyelinating sensorimotor polyneuropathy. The patient underwent a 5-day course of intravenous immunoglobulin, beginning the day after admission. Markers of severity including forced vital capacity improved thereafter until delivery.With limited evidence favouring one particular anaesthetic technique in parturients with Guillain-Barré syndrome, combined spinal epidural anaesthesia was preferred over general anaesthesia in order to avoid the potential for prolonged intubation postoperatively and to allow careful titration of neuraxial blockade. Delivery by caesarean section at 34+1 weeks due to pre-eclampsia was uncomplicated. Thereafter the patient's condition deteriorated, requiring a further 5-day course of intravenous immunoglobulin with symptoms gradually improving over a 6-month admission.
Topics: Humans; Female; Guillain-Barre Syndrome; Cesarean Section; Pregnancy; Anesthesia, Epidural; Adult; Anesthesia, Spinal; Immunoglobulins, Intravenous; Anesthesia, Obstetrical; Pregnancy Complications
PubMed: 38926128
DOI: 10.1136/bcr-2024-260285 -
Canadian Journal of Surgery. Journal... 2024Understanding patterns of peripheral nerve injuries (PNIs) and brachial plexus injuries (BPIs) is essential to preventing and appropriately managing nerve injuries. We...
BACKGROUND
Understanding patterns of peripheral nerve injuries (PNIs) and brachial plexus injuries (BPIs) is essential to preventing and appropriately managing nerve injuries. We sought to assess the incidence, cause, and severity of PNIs and BPIs sustained by patients with trauma.
METHODS
We conducted a retrospective review of the Trauma Registry Database (January 2002 to December 2020) to identify patients with PNIs or BPIs.
RESULTS
We evaluated data from 24 905 patients with trauma; 335 (1.3%) sustained PNIs (81% male; mean age 36 yr, standard deviation [SD] 16 yr) and 64 (0.3%) sustained BPIs (84% male; mean age 35, SD 15 yr). Nerves in the upper extremities were more commonly affected than those in the lower extremities. Sharp injuries (39.4%) and motorcycle accidents (32.8%) were the most frequent causes of PNIs and BPIs, respectively. Other common causes of PNI were motor vehicle collisions (16.7%) and gunshot wounds (12.8%). Many patients with PNIs (69.0%) and BPIs (53%) underwent operative management. The most frequent reconstruction for PNI was primary nerve repair (66%), while nerve transfers (48%) were more frequently used for BPI.
CONCLUSION
Nerve injuries in the trauma population have decreased over the last 3 decades with shifts in mechanisms of injury and use of imaging, electrodiagnostic tests, and surgery. Nerve injuries are often complex and time-sensitive to treat; understanding changes in trends is important to ensure optimal patient management.
Topics: Humans; Male; Adult; Peripheral Nerve Injuries; Female; Retrospective Studies; Brachial Plexus; Middle Aged; Incidence; Young Adult; Registries; Accidents, Traffic; Adolescent
PubMed: 38925857
DOI: 10.1503/cjs.002424 -
Anticancer Research Jul 2024Chemotherapy-induced peripheral neuropathy (CIPN) continues to be a major source of chronic morbidity in patients with cancer. Current treatment options and efficacy are... (Review)
Review
BACKGROUND/AIM
Chemotherapy-induced peripheral neuropathy (CIPN) continues to be a major source of chronic morbidity in patients with cancer. Current treatment options and efficacy are limited; thus, there is a need to investigate more effective therapeutic options. Spinal neuromodulation including dorsal column spinal cord stimulation (SCS) and dorsal root ganglion stimulation (DRG-S) are being explored for these patients. The purpose of this narrative review was to critically summarize and evaluate the advancements that have been made in utilizing SCS and DRG-S for CIPN.
MATERIALS AND METHODS
A thorough literature search was conducted using PubMed for any research on patients with CIPN who underwent DRG-S or SCS. Studies involving patients with general cancer-related pain were not included. Only articles that were published in English, had original, extractable data, and were available on or before August 1, 2023, were included.
RESULTS
This study evaluated twelve studies with a total of 13 patients that reported using SCS for CIPN and four studies with a total of 12 patients that reported using DRG-S for CIPN. Many of the studies demonstrated that DRG-S or SCS can assist in reducing opioid consumption, lowering pain scores, and improving sensory deficits.
CONCLUSION
DRG-S and SCS have the potential to improve symptoms and lower medication usage in patients suffering from CIPN. Spinal neuromodulation could be considered as an alternative therapy for patients with persistent symptoms.
Topics: Humans; Peripheral Nervous System Diseases; Spinal Cord Stimulation; Antineoplastic Agents; Ganglia, Spinal; Neoplasms; Pain Management
PubMed: 38925845
DOI: 10.21873/anticanres.17088 -
British Journal of Pharmacology Jun 2024Mitochondrial dysfunction contributes to the pathogenesis and maintenance of chemotherapy-induced peripheral neuropathy (CIPN), a significant limitation of cancer...
BACKGROUND AND PURPOSE
Mitochondrial dysfunction contributes to the pathogenesis and maintenance of chemotherapy-induced peripheral neuropathy (CIPN), a significant limitation of cancer chemotherapy. Recently, the stimulation of mitophagy, a pivotal process for mitochondrial homeostasis, has emerged as a promising treatment strategy for neurodegenerative diseases, but its therapeutic effect on CIPN has not been explored. Here, we assessed the mitophagy-inducing activity of 3,5-dibromo-2-(2',4'-dibromophenoxy)-phenol (PDE701), a diphenyl ether derivative isolated from the marine sponge Dysidea sp., and investigated its therapeutic effect on a CIPN model.
EXPERIMENTAL APPROACH
Mitophagy activity was determined by a previously established mitophagy assay using mitochondrial Keima (mt-Keima). Mitophagy induction was further verified by western blotting, immunofluorescence, and electron microscopy. Mitochondrial dysfunction was analysed by measuring mitochondrial superoxide levels in SH-SY5Y cells and Drosophila larvae. A thermal nociception assay was used to evaluate the therapeutic effect of PDE701 on the paclitaxel-induced thermal hyperalgesia phenotype in Drosophila larvae.
KEY RESULTS
PDE701 specifically induced mitophagy but was not toxic to mitochondria. PDE701 ameliorated paclitaxel-induced mitochondrial dysfunction in both SH-SY5Y cells and Drosophila larvae. Importantly, PDE701 also significantly ameliorated paclitaxel-induced thermal hyperalgesia in Drosophila larvae. Knockdown of ATG5 or ATG7 abolished the effect of PDE701 on thermal hyperalgesia, suggesting that PDE701 exerts its therapeutic effect through mitophagy induction.
CONCLUSION AND IMPLICATIONS
This study identified PDE701 as a novel mitophagy inducer and a potential therapeutic compound for CIPN. Our results suggest that mitophagy stimulation is a promising strategy for the treatment of CIPN and that marine organisms are a potential source of mitophagy-inducing compounds.
PubMed: 38925168
DOI: 10.1111/bph.16476 -
Human Vaccines & Immunotherapeutics Dec 2024The recombinant zoster vaccine (RZV) is included in the Spanish National Immunisation Programme for adults 65 years of age (years), with a potential progressive...
The recombinant zoster vaccine (RZV) is included in the Spanish National Immunisation Programme for adults 65 years of age (years), with a potential progressive catch-up program for adults 66-80 years, starting with 80 years. However, the risk of herpes zoster (HZ) increases significantly from 50 years. We estimated the public health impact (PHI) of vaccinating adults ≥50 years in Spain versus no vaccination, using a Markov model adapted to the Spanish setting. The model simulated a hypothetical ≥50 years cohort over a lifetime, with inputs from Spanish publications, databases, or publications from other countries where Spanish data were unavailable. Base case inputs included 67.7% RZV coverage and 61.1% second dose compliance. Outputs included clinical outcomes avoided, healthcare resource use avoided, and number-needed-to-vaccinate (NNV) to prevent one HZ case. Deterministic (DSA) and probabilistic sensitivity analyses (PSA) were also conducted. The model estimated that, compared with no vaccination, vaccinating adults ≥50 years in Spain ( = 19,850,213) with RZV could prevent 1,533,353 HZ cases, 261,610 postherpetic neuralgia episodes, 274,159 other complications, and 138 deaths through the cohorts' remaining lifetime, mostly in the 50-59 years cohort. Furthermore, 3,500,492 primary care visits and 71,156 hospitalizations could be avoided, with NNV = 9 to prevent one HZ case. DSA predicted NNV = 7 to prevent one HZ case when second dose compliance was increased to 100%. PSA demonstrated ≥200,000 and ≥1,400,000 cases could be prevented in 86.9% and 18.4% of simulations, respectively. Starting RZV from 50 years could therefore prevent a substantial number of HZ cases and complications. Increasing RZV coverage and second dose compliance could further alleviate PHI of HZ.
Topics: Humans; Herpes Zoster Vaccine; Spain; Herpes Zoster; Aged; Middle Aged; Aged, 80 and over; Male; Female; Public Health; Vaccination; Vaccines, Synthetic; Markov Chains; Neuralgia, Postherpetic; Immunization Programs
PubMed: 38925145
DOI: 10.1080/21645515.2024.2366353 -
Science Translational Medicine Jun 2024Congenital pseudarthrosis of the tibia (CPT) is a severe pathology marked by spontaneous bone fractures that fail to heal, leading to fibrous nonunion. Half of patients...
Congenital pseudarthrosis of the tibia (CPT) is a severe pathology marked by spontaneous bone fractures that fail to heal, leading to fibrous nonunion. Half of patients with CPT are affected by the multisystemic genetic disorder neurofibromatosis type 1 (NF1) caused by mutations in the tumor suppressor gene, a negative regulator of RAS-mitogen-activated protein kinase (MAPK) signaling pathway. Here, we analyzed patients with CPT and knockout mice to elucidate the pathogenic mechanisms of CPT-related fibrous nonunion and explored a pharmacological approach to treat CPT. We identified -deficient Schwann cells and skeletal stem/progenitor cells (SSPCs) in pathological periosteum as affected cell types driving fibrosis. Whereas -deficient SSPCs adopted a fibrotic fate, -deficient Schwann cells produced critical paracrine factors including transforming growth factor-β and induced fibrotic differentiation of wild-type SSPCs. To counteract the elevated RAS-MAPK signaling in both -deficient Schwann cells and SSPCs, we used MAPK kinase (MEK) and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibitors. Combined MEK-SHP2 inhibition in vivo prevented fibrous nonunion in the knockout mouse model, providing a promising therapeutic strategy for the treatment of fibrous nonunion in CPT.
Topics: Animals; Schwann Cells; Pseudarthrosis; Neurofibromin 1; Humans; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Mice, Knockout; Stem Cells; Tibia; Mice; Cell Differentiation; Male; Neurofibromatosis 1; Fibrosis; Female; Mitogen-Activated Protein Kinase Kinases
PubMed: 38924432
DOI: 10.1126/scitranslmed.adj1597 -
Diabetic Medicine : a Journal of the... Jun 2024AIMSWERNER SYNDROME IS A RARE PREMATURE AGEING AUTOSOMAL RECESSIVE DISORDER CAUSED BY PATHOGENIC VARIANTS IN THE WRN GENE. PEOPLE WITH WERNER SYNDROME MAY DEVELOP... (Review)
Review
UNLABELLED
AIMSWERNER SYNDROME IS A RARE PREMATURE AGEING AUTOSOMAL RECESSIVE DISORDER CAUSED BY PATHOGENIC VARIANTS IN THE WRN GENE. PEOPLE WITH WERNER SYNDROME MAY DEVELOP DIABETES MELLITUS. CHRONIC FOOT ULCERATION IS SEEN, WITH SOME CHARACTERISTICS OVERLAPPING WITH DIABETIC FOOT DISEASE. HOWEVER, THE CLINICAL COURSE OF THE ULCERATION IS ATYPICAL OF DIABETIC FOOT DISEASE. WE PRESENT FOUR SIBLINGS FROM AN IRISH TRAVELLER FAMILY WITH WERNER SYNDROME TO HIGHLIGHT THE COMPLEXITY OF THIS CONDITION. THE IRISH TRAVELLER POPULATION ARE AN INDIGENOUS, ENDOGAMOUS POPULATION IN WHICH CONSANGUINITY IS COMMON. AS A RESULT, RARE AUTOSOMAL RECESSIVE DISORDERS ARE PREVALENT AMONG THIS POPULATION: .
METHODS
We describe our experience managing the complex foot disease seen in all four siblings. Foot complications present in the siblings include painful peripheral neuropathy, chronic foor ulceration, underlying osteomyelitis and acral melanoma.
RESULTS
The cases are described individually, with a particular focus on the complex foot disease associated with the condition.
CONCLUSIONS
Although the siblings attend a diabetic foot clinic, we suggest that the combination of clinical features seen in these cases is unique to Werner syndrome and warrants the title 'Werner Syndrome' (rather than 'Diabetic') foot.
PubMed: 38924167
DOI: 10.1111/dme.15390