ABSTRACT
PURPOSE OF REVIEW: Myeloproliferative neoplasm (MPN) burdens the lives of those affected. MPN patients endure significant impacts on their physical, psychological, and social well-being. While pharmacological interventions offer some disease and symptom control, they often have unfavorable side effects. This review explores the potential of Integrative Oncology (IO) therapies in managing MPNs and their associated symptoms. RECENT FINDINGS: IO is dedicated to augmenting conventional treatments through integrating interventions targeting the mind, body, nutrition, supplements, and other supportive care therapies. Several small studies suggest the benefit of an IO approach in MPN patients. These benefits are postulated to be modulated through enhanced physical capacity, reduced disease-related inflammation, subconscious mind training, and gut microbiome modulation. By combining IO with evidence-based pharmacological treatments, the potential exists to enhance the quality of life and clinical outcomes for individuals with MPNs. Future research should prioritize well-powered studies, including diverse demographics and symptom profiles, with appropriate study duration, to draw definite conclusions regarding the observed effects.
ABSTRACT
Autophagy phenomenon in the cell maintains proteostasis balance by eliminating damaged organelles and protein aggregates. Imbalance in autophagic flux may cause accumulation of protein aggregates in various neurodegenerative disorders. Regulation of autophagy by either calcium or chaperone play a key role in the removal of protein aggregates from the cell. The neuromuscular rare genetic disorder, GNE Myopathy, is characterized by accumulation of rimmed vacuoles having protein aggregates of ß-amyloid and tau that may result from altered autophagic flux. In the present study, the autophagic flux was deciphered in HEK cell-based model for GNE Myopathy harbouring GNE mutations of Indian origin. The refolding activity of HSP70 chaperone was found to be reduced in GNE mutant cells compared to wild type controls. The autophagic markers LC3II/I ratio was altered with increased number of autophagosome formation in GNE mutant cells compared to wild type cells. The cytosolic calcium levels were also increased in GNE mutant cells of Indian origin. Interestingly, treatment of GNE mutant cells with HSP70 activator, BGP-15, restored the expression and refolding activity of HSP70 along with autophagosome formation. Treatment with calcium chelator, BAPTA-AM restored the cytoplasmic calcium levels and autophagosome formation but not LC3II/I ratio significantly. Our study provides insights towards GNE mutation specific response for autophagy regulation and opens up a therapeutic advancement area in calcium signalling and HSP70 function for GNE related Myopathy.
Subject(s)
Autophagy , Calcium , Distal Myopathies , HSP70 Heat-Shock Proteins , Multienzyme Complexes , Mutation , Humans , Autophagy/genetics , Autophagy/drug effects , Mutation/genetics , Calcium/metabolism , Distal Myopathies/genetics , Distal Myopathies/metabolism , Distal Myopathies/pathology , HSP70 Heat-Shock Proteins/genetics , HSP70 Heat-Shock Proteins/metabolism , Multienzyme Complexes/genetics , Multienzyme Complexes/metabolism , HEK293 Cells , Autophagosomes/metabolism , Autophagosomes/drug effects , IndiaABSTRACT
Introduction: In the context of Indian combat scenario, maxillofacial injuries from gunshots are uncommon. Methods: The first section of this study is a case report of a rare instance of metal foreign bodies that were lodged in the parapharyngeal space, deeper to the deep lobe of the parotid right next to the carotid space in the neck. The second section focusses on the unique treatment for blast injuries as well as the variety of imaging procedures that are readily available to assist with surgery, such as plain film, CT, angiography, and occasionally MR imaging. Result and Conclusion: According to the study, understanding the pertinent anatomy, precise imaging of the penetrating object in relation to vital structures, meticulously planned and conducted surgical removal of the foreign body, and repair of damaged structures are the key elements of a successful treatment.
ABSTRACT
Sexual dimorphism has been revealed for many neurological disorders including chronic pain. Prelicinal studies and post-mortem analyses from male and female human donors reveal sexual dimorphism of nociceptors at transcript, protein and functional levels suggesting different mechanisms that may promote pain in men and women. Migraine is a common female-prevalent neurological disorder that is characterized by painful and debilitating headache. Prolactin is a neurohormone that circulates at higher levels in females and that has been implicated clinically in migraine. Prolactin sensitizes sensory neurons from female mice, non-human primates and humans revealing a female-selective pain mechanism that is conserved evolutionarily and likely translationally relevant. Prolactin produces female-selective migraine-like pain behaviors in rodents and enhances the release of calcitonin gene-related peptide (CGRP), a neurotransmitter that is causal in promoting migraine in many patients. CGRP, like prolactin, produces female-selective migraine-like pain behaviors. Consistent with these observations, publicly available clinical data indicate that small molecule CGRP-receptor antagonists are preferentially effective in treatment of acute migraine therapy in women. Collectively, these observations support the conclusion of qualitative sex differences promoting migraine pain providing the opportunity to tailor therapies based on patient sex for improved outcomes. Additionally, patient sex should be considered in design of clinical trials for migraine as well as for pain and reassessment of past trials may be warranted.
Subject(s)
Calcitonin Gene-Related Peptide , Migraine Disorders , Prolactin , Sex Characteristics , Migraine Disorders/physiopathology , Migraine Disorders/drug therapy , Migraine Disorders/metabolism , Humans , Female , Animals , Calcitonin Gene-Related Peptide/metabolism , Prolactin/metabolism , MaleABSTRACT
GNEM (GNE Myopathy) is a rare neuromuscular disease caused due to biallelic mutations in sialic acid biosynthetic GNE enzyme (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine Kinase). Recently direct or indirect role of GNE in other cellular functions have been elucidated. Hyposialylation of IGF-1R leads to apoptosis due to mitochondrial dysfunction while hyposialylation of ß1 integrin receptor leads to altered F-actin assembly, disrupted cytoskeletal organization and slow cell migration. Other cellular defects in presence of GNE mutation include altered ER redox state and chaperone expression such as HSP70 or PrdxIV. Currently, there is no cure to treat GNEM. Possible therapeutic trials focus on supplementation with sialic acid, ManNAc, sialyllactose and gene therapy that slows the disease progression. In the present study, we analyzed the effect of small molecules like BGP-15 (HSP70 modulator), IGF-1 (IGF-1R ligand) and CGA (cofilin activator) on cellular phenotypes of GNE heterozygous knock out L6 rat skeletal muscle cell line (SKMGNEHz). Treatment with BGP-15 improved GNE epimerase activity by 40 % and reduced ER stress by 45 % for SKMGNEHz. Treatment with IGF-1 improved epimerase activity by 37.5 %, F-actin assembly by 100 %, cell migration upto 36 % (36 h) and atrophy by 0.44-fold for SKMGNEHz. Treatment with CGA recovered epimerase activity by 49 %, F-actin assembly by 132 % and cell migration upto 41 % (24 h) in SKMGNEHz. Our study shows that treatment with these small effector molecules reduces the detrimental phenotype observed in SKMGNEHz, thereby, providing insights into potential therapeutic targets for GNEM.
Subject(s)
Distal Myopathies , N-Acetylneuraminic Acid , Oximes , Piperidines , Animals , Rats , Actins/genetics , Distal Myopathies/drug therapy , Distal Myopathies/genetics , Insulin-Like Growth Factor I , Mutation , N-Acetylneuraminic Acid/genetics , N-Acetylneuraminic Acid/metabolism , Oximes/pharmacology , Piperidines/pharmacology , Racemases and Epimerases/geneticsABSTRACT
GNE myopathy is a rare genetic neuromuscular disease that is caused due to mutations in the GNE gene responsible for sialic acid biosynthesis. Foot drop is the most common initial symptom observed in GNE myopathy patients. There is slow progressive muscle weakness in the lower and upper extremities while the quadriceps muscles are usually spared. The exact pathophysiology of the disease is unknown. Besides sialic acid biosynthesis, recent studies suggest either direct or indirect involvement of GNE in other cellular functions such as protein aggregation, apoptosis, ER stress, cell migration, HSP70 chaperone activity, autophagy, muscle atrophy, and myogenesis. Both animal and in vitro cell-based model systems are generated to elucidate the mechanism of GNE myopathy and evaluate the efficacy of therapies. The many therapeutic avenues explored include supplementation with sialic acid derivatives or precursors and gene therapy. Recent studies suggest other therapeutic options such as modulators of HSP70 chaperone (BGP-15), cofilin activator (CGA), and ligands like IGF-1 that may help to rescue cellular defects due to GNE dysfunction. This review provides an overview of the pathophysiology associated with GNE function in the cell and promising therapeutic leads to be explored for future drug development.
Subject(s)
Distal Myopathies , N-Acetylneuraminic Acid , Animals , Humans , N-Acetylneuraminic Acid/metabolism , N-Acetylneuraminic Acid/therapeutic use , Distal Myopathies/drug therapy , Distal Myopathies/genetics , Distal Myopathies/diagnosis , Mutation , Muscle, Skeletal/metabolismSubject(s)
Paratyphoid Fever , Typhoid Fever , Humans , Typhoid Fever/complications , Typhoid Fever/diagnosis , Salmonella typhiSubject(s)
Brain Diseases , Dengue , Leukoencephalitis, Acute Hemorrhagic , Humans , Brain Diseases/etiology , Brain Diseases/therapy , Leukoencephalitis, Acute Hemorrhagic/diagnosis , Leukoencephalitis, Acute Hemorrhagic/etiology , Leukoencephalitis, Acute Hemorrhagic/therapy , Plasmapheresis , Dengue/complications , Dengue/therapy , Magnetic Resonance ImagingABSTRACT
The computational modeling of electrochemical interfaces and their applications in electrocatalysis has attracted great attention in recent years. While tremendous progress has been made in this area, however, the accurate atomistic descriptions at the electrode/electrolyte interfaces remain a great challenge. The Computational Hydrogen Electrode (CHE) method and continuum modeling of the solvent and electrolyte interactions form the basis for most of these methodological developments. Several posterior corrections have been added to the CHE method to improve its accuracy and widen its applications. The most recently developed grand canonical potential approaches with the embedded diffuse layer models have shown considerable improvement in defining interfacial interactions at electrode/electrolyte interfaces over the state-of-the-art computational models for electrocatalysis. In this Review, we present an overview of these different computational models developed over the years to quantitatively probe the thermodynamics and kinetics of electrochemical reactions in the presence of an electrified catalyst surface under various electrochemical environments. We begin our discussion by giving a brief picture of the different continuum solvation approaches, implemented within the ab initio method to effectively model the solvent and electrolyte interactions. Next, we present the thermodynamic and kinetic modeling approaches to determine the activity and stability of the electrocatalysts. A few applications to these approaches are also discussed. We conclude by giving an outlook on the different machine learning models that have been integrated with the thermodynamic approaches to improve their efficiency and widen their applicability.
ABSTRACT
Trehalose, a disaccharide molecule of natural origin, is known for its diverse biological applications, like in drug development, research application, natural scaffold, stem cell preservation, food, and various other industries. This review has discussed one such diverse molecule 'trehalose aka mycose', and its diverse biological applications with respect to therapeutics. Due to its inertness and higher stability at variable temperatures, it has been developed as a preservative to store stem cells, and later, it has been found to have anticancer properties. Trehalose has recently been associated with modulating cancer cell metabolism, diverse molecular processes, neuroprotective effect, and so on. This article describes the development of trehalose as a cryoprotectant and protein stabilizer as well as a dietary component and therapeutic agent against various diseases. The article discusses its role in diseases via modulation of autophagy, various anticancer pathways, metabolism, inflammation, aging and oxidative stress, cancer metastasis and apoptosis, thus highlighting its diverse biological potential.
Subject(s)
Oxidative Stress , Trehalose , Trehalose/pharmacology , Trehalose/metabolism , Stem Cells/metabolism , AutophagyABSTRACT
Muscular dystrophy is a well-known genetically heterogeneous group of rare muscle disorders. This progressive disease causes the breakdown of skeletal muscles over time and leads to grave weakness. This breakdown is caused by a diverse pattern of mutations in dystrophin and dystrophin associated protein complex. These mutations lead to the production of altered proteins in response to which, the body stimulates production of various cytokines and immune cells, particularly reactive oxygen species and NFκB. Immune cells display/exhibit a dual role by inducing muscle damage and muscle repair. Various anti-oxidants, anti-inflammatory and glucocorticoid drugs serve as potent therapeutics for muscular dystrophy. Along with the above mentioned therapeutics, induced pluripotent stem cells also serve as a novel approach paving a way for personalized treatment. These pluripotent stem cells allow regeneration of large numbers of regenerative myogenic progenitors that can be administered in muscular dystrophy patients which assist in the recovery of lost muscle fibers. In this review, we have summarized gene-editing, immunological and induced pluripotent stem cell based therapeutics for muscular dystrophy treatment.
Subject(s)
Gene Editing/methods , Induced Pluripotent Stem Cells , Muscular Dystrophies/genetics , Muscular Dystrophies/immunology , Animals , Dystrophin/genetics , Humans , Muscular Dystrophies/metabolism , Muscular Dystrophies/therapy , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolismABSTRACT
AIM: Recently, with the second wave of COVID-19, the Indian subcontinent has witnessed a dramatic rise in mucormycosis infection in patients recovered from COVID-19. This association has been documented in various case reports/case series and institutional experiences, and the mortality associated with this fungal infection is emerging as a cause of concern. The aim of the present paper is to provide a scientific overview on the pathogenesis of mucormycosis in COVID-19 beyond the conventional understanding of the disease process, which may not otherwise explain the increased incidence of mucormycosis in SARS-CoV-2. METHODOLOGY: This paper is structured as a narrative review of the published literature on the pathogenesis of COVID-19 which contributes to the development of mucormycosis. Apart from the acknowledged role of ketoacidosis, high blood sugar, and iron metabolism in the pathogenesis of mucormycosis, other factors involved in pathophysiology of COVID-19 which might alter or enhance the mucormycosis infection such as (1) the role of ferritin, (2) high serum iron, (3) free radical-induced endothelitis, (4) hepcidin activation, (5) upregulation of glucose receptor protein (GRP78) are discussed in the pathophysiology of COVID-19-associated mucormycosis. CONCLUSION: A new proposal for the pathogenesis based on the ferritin, viral mimicry of hepcidin and GRP78-CotH3 interaction, which clearly explains the surge in mucormycosis in SARS-CoV-2 infection, has been explained.
ABSTRACT
ABSTRACT: Facial nerve palsy is an exceedingly debilitating condition, incapacitating functional and aesthetic facets of the face. Orthodromic transfer of temporalis muscle is an easy and predictable technique which offers early animation of oral commissure and lower face. A retrospective chart review of 6 patients of facial palsy treated with orthodromic temporalis tendon transfer for facial reanimation is presented. The technique consisted of intra-oral coronoidectomy followed by attachment of fascia lata grafts from the coronoid to the commissure, the upper and lower lips via small cutaneous incisions. Contraction of the temporalis, pulls the fascia lata extensions thereby reanimating the lower face. 4 male and 2 female patients with an age range of 25 to 49 years were treated. Simultaneous fat grafting (2 patients), depressor labi inferioris muscle resection (2 patients) and wedge excision of nasolabial fold (2 patients) was done as ancillary procedures. Post-operative smile evaluation was carried out using the Terzis and Noah facial grading system. Patients were asked to smile with and without biting, and photographs and video were taken. The results were graded from 1 to 5 based on a 5-point scale (ie, poor, fair, moderate, good, and excellent) by an independent observer. The results were excellent in 1 patient (Terzis grading 5/5) and good in the remaining 5 patients (Terzis grading 4/5). Excursion of the oral commissure ranged from 6 to 10âmm. Our experience indicates that temporalis tendon transfer for facial reanimation has a short learning curve and provides early predictable outcome without significant complications. This single-stage, day-care procedure can be easily incorporated by maxillofacial surgeons to expand their surgical spectrum.
Subject(s)
Facial Paralysis , Plastic Surgery Procedures , Adult , Esthetics, Dental , Facial Paralysis/surgery , Female , Humans , Male , Middle Aged , Retrospective Studies , Smiling , Temporal Muscle/surgery , Tendon TransferABSTRACT
INTRODUCTION: Homozygous familial hypercholesterolaemia (HoFH) carries a grave prognosis but is often underdiagnosed and undertreated. Confirmation of molecular diagnosis helps in planning effective management and determining prognosis accurately. Aim of the study: To determine the spectrum of mutations in the LDLR gene in a cohort of children with a clinical diagnosis of HoFH. MATERIAL AND METHODS: Genomic DNA was extracted from peripheral blood samples of 8 patients, who were children of either sex, aged under 16 years, and diagnosed clinically with HoFH using the Simon Broome criteria. The potential variants in the LDLR gene were analysed by Sanger sequencing. RESULTS: Fifty variations were found in the 8 patients; 39 (78%) were single nucleotide variations while 8 (16%) and 3 (6%) were deletions and insertions, respectively. The pathogenic variants in the LDLR gene were detected in four patients; three showed duplication in exon 17 (c.2416dupG) creating an amino acid change at position 806 (p.Val806GlyfsTer11) while one had a missense variant in the exon 9 at position c.1285G>A resulting in a change in amino acid at position 429 (p.Val429Met). The variants were found in heterozygous state in the parents or siblings of probands who showed pathogenic variants. CONCLUSIONS: The frequency of disease-causing variants in the LDLR gene in our patients with HoFH was 50%. Further studies to characterise mutations in genes for apolipoprotein B, proprotein convertase subtilisin/kexin type 9, or LDL adaptor protein are suggested in all children with a clinical diagnosis of HoFH.
Subject(s)
Hyperlipoproteinemia Type II , Receptors, LDL , Aged , Child , Homozygote , Humans , Hyperlipoproteinemia Type II/genetics , Mutation , Phenotype , Receptors, LDL/geneticsABSTRACT
The aim of the study was to evaluate the effectiveness of sublingual gland flap in the reconstruction of surgical defect following sequestrectomy in medication induced osteonecrosis of jaws (MRONJ), osteomyelitis (OML), and osteoradionecrosis (ORN) of mandible. A total of 6 patients with MRONJ (nâ=â4) osteomyelitis (nâ=â1) and ORN (nâ=â1) underwent sequestrectomy and reconstruction with sublingual gland flap. There were 03 males and 03 females. The age range was 45-71-70 years. All defects were present in the posterior mandible. All patients' undergone sequestrectomy, debridement, and reconstruction with sublingual gland flap under local anesthesia. Postoperatively patients were followed up at 1, 3, and 6 months. Patients were monitored for complete epithelization of defect, infection, pain, and recurrence of the lesion. Complete epithelization with closure of the defect was achieved in all cases. None of the patients had residual pain or inflammation at the surgical site. None of our patients experienced any donor site morbidities. There was no case of postoperative infection. Reconstruction of intraoral defects using sublingual gland flap is an effective treatment modality to reconstruct small to medium sized defect of oral cavity.