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Neurological Sciences : Official... May 2024Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited multisystemic disorder caused by mutations in...
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited multisystemic disorder caused by mutations in mitochondrial DNA that result in cellular energy deficiency. MELAS affects the most metabolically active organs, including the brain, skeletal muscles, cochlea, retina, heart, kidneys, and pancreas. As a result, about 85% of carriers of m.3243A > G, the most common mutation in MELAS, develop diabetes by the age of 70. Although metformin is the most widely prescribed drug for diabetes, its usefulness in mitochondrial dysfunction remains controversial. Here, we present the case of a 32-year-old Korean patient diagnosed with MELAS who presented with exacerbated stroke-like episodes and lactic acidosis triggered by metformin.
Topics: Adult; Humans; Acidosis, Lactic; Diabetes Mellitus; DNA, Mitochondrial; MELAS Syndrome; Metformin; Mutation; Stroke; Republic of Korea
PubMed: 38265537
DOI: 10.1007/s10072-024-07343-9 -
Bone Reports Mar 2024X-linked hypophosphatemia (XLH) is a rare X-linked dominant inherited disorder caused by loss-of-function variants in the PHEX gene and characterized by renal phosphate...
X-linked hypophosphatemia (XLH) is a rare X-linked dominant inherited disorder caused by loss-of-function variants in the PHEX gene and characterized by renal phosphate wasting, hypophosphatemia, abnormal vitamin D metabolism, growth retardation and lower limb deformities. We describe a case of XLH-rickets in a 7-year-old girl with scaphocephaly, Chiari syndrome type I and syringomyelia, with a de novo non-canonical splice variant (c.1080-3C > G) in intron 9 of the PHEX gene, that has not been previously described.
PubMed: 38226334
DOI: 10.1016/j.bonr.2023.101731 -
Neuroradiology Apr 2024
Topics: Humans; MELAS Syndrome; Glutamine; Phenotype
PubMed: 38194084
DOI: 10.1007/s00234-024-03284-4 -
Acta Parasitologica Mar 2024Skeeter syndrome is a severe local allergic response to mosquito bites that is accompanied by considerable inflammation and, in some cases, a systemic response like...
BACKGROUND
Skeeter syndrome is a severe local allergic response to mosquito bites that is accompanied by considerable inflammation and, in some cases, a systemic response like fever. People with the syndrome develop serious allergies, ranging from rashes to anaphylaxis or shock. The few available studies on mosquito venom immunotherapy have utilized whole-body preparations and small sample sizes. Still, owing to their little success, vaccination remains a promising alternative as well as a permanent solution for infections like Skeeter's.
METHODS
This study, therefore, illustrated the construction of an epitope-based vaccine candidate against Skeeter Syndrome using established immunoinformatic techniques. We selected three species of mosquitoes, Anopheles melas, Anopheles funestus, and Aedes aegypti, to derive salivary antigens usually found in mosquito bites. Our construct was also supplemented with bacterial epitopes known to elicit a strong TH1 response and suppress TH2 stimulation that is predicted to reduce hypersensitivity against the bites.
RESULTS
A quality factor of 98.9496, instability index of 38.55, aliphatic index of 79.42, solubility of 0.934747, and GRAVY score of -0.02 indicated the structural (tertiary and secondary) stability, thermostability, solubility, and hydrophilicity of the construct, respectively. The designed Aedes-Anopheles vaccine (AAV) candidate was predicted to be flexible and less prone to deformability with an eigenvalue of 1.5911e-9 and perfected the human immune response against Skeeter (hypersensitivity) and many mosquito-associated diseases as we noted the production of 30,000 Th1 cells per mm with little (insignificant production of Th2 cells. The designed vaccine also revealed stable interactions with the pattern recognition receptors of the host. The TLR2/vaccine complex interacted with a free energy of - 1069.2 kcal/mol with 26 interactions, whereas the NLRP3/vaccine complex interacted with a free energy of - 1081.2 kcal/mol with 16 molecular interactions.
CONCLUSION
Although being a pure in-silico study, the in-depth analysis performed herein speaks volumes of the potency of the designed vaccine candidate predicting that the proposition can withstand rigorous in-vitro and in-vivo clinical trials and may proceed to become the first preventative immunotherapy against mosquito bite allergy.
Topics: Animals; Insect Bites and Stings; Anopheles; Aedes; Epitopes; Hypersensitivity; Vaccines; Humans
PubMed: 38194049
DOI: 10.1007/s11686-023-00771-1 -
Balkan Medical Journal Jan 2024Coronavirus disease 2019 (COVID-19) is caused by the novel severe acute respiratory coronavirus-2 (SARS-CoV-2). Several explanations for the development of... (Review)
Review
Coronavirus disease 2019 (COVID-19) is caused by the novel severe acute respiratory coronavirus-2 (SARS-CoV-2). Several explanations for the development of cardiovascular complications during and after acute COVID-19 infection have been hypothesized. The COVID-19 pandemic, caused by SARS-CoV-2, has emerged as one of the deadliest pandemics in modern history. The myocardial injury in COVID-19 patients has been associated with coronary spasm, microthrombi formation, plaque rupture, hypoxic injury, or cytokine storm, which have the same pathophysiology as the three clinical variants of Kounis syndrome. The angiotensin-converting enzyme 2 (ACE2), reninaldosterone system (RAAS), and kinin-kallikrein system are the main proposed mechanisms contributing to cardiovascular complications with the COVID-19 infection. ACE receptors can be found in the heart, blood vessels, endothelium, lungs, intestines, testes, neurons, and other human body parts. SARS-CoV-2 directly invades the endothelial cells with ACE2 receptors and constitutes the main pathway through which the virus enters the endothelial cells. This causes angiotensin II accumulation downregulation of the ACE2 receptors, resulting in prothrombotic effects, such as hemostatic imbalance via activation of the coagulation cascade, impaired fibrinolysis, thrombin generation, vasoconstriction, endothelial and platelet activation, and pro-inflammatory cytokine release. The KKS system typically causes vasodilation and regulates tissue repair, inflammation, cell proliferation, and platelet aggregation, but SARS-CoV-2 infection impairs such counterbalancing effects. This cascade results in cardiac arrhythmias, cardiac arrest, cardiomyopathy, cytokine storm, heart failure, ischemic myocardial injuries, microvascular disease, Kounis syndrome, prolonged COVID, myocardial fibrosis, myocarditis, new-onset hypertension, pericarditis, postural orthostatic tachycardia syndrome, pulmonary hypertension, stroke, Takotsubo syndrome, venous thromboembolism, and thrombocytopenia. In this narrative review, we describe and elucidate when, where, and how COVID-19 affects the human cardiovascular system in various parts of the human body that are vulnerable in every patient category, including children and athletes.
Topics: Child; Humans; COVID-19; SARS-CoV-2; Renin-Angiotensin System; Angiotensin-Converting Enzyme 2; Peptidyl-Dipeptidase A; Cytokine Release Syndrome; Endothelial Cells; Pandemics; Kounis Syndrome; Cardiovascular System
PubMed: 38173173
DOI: 10.4274/balkanmedj.galenos.2023.2023-10-25 -
International Journal of Molecular... Dec 2023Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome, caused by a single base substitution in mitochondrial DNA (m.3243A>G), is one...
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome, caused by a single base substitution in mitochondrial DNA (m.3243A>G), is one of the most common maternally inherited mitochondrial diseases accompanied by neuronal damage due to defects in the oxidative phosphorylation system. There is no established treatment. Our previous study reported a superior restoration of mitochondrial function and bioenergetics in mitochondria-deficient cells using highly purified mesenchymal stem cells (RECs). However, whether such exogenous mitochondrial donation occurs in mitochondrial disease models and whether it plays a role in the recovery of pathological neuronal functions is unknown. Here, utilizing induced pluripotent stem cells (iPSC), we differentiated neurons with impaired mitochondrial function from patients with MELAS. MELAS neurons and RECs/mesenchymal stem cells (MSCs) were cultured under contact or non-contact conditions. Both RECs and MSCs can donate mitochondria to MELAS neurons, but RECs are more excellent than MSCs for mitochondrial transfer in both systems. In addition, REC-mediated mitochondrial transfer significantly restored mitochondrial function, including mitochondrial membrane potential, ATP/ROS production, intracellular calcium storage, and oxygen consumption rate. Moreover, mitochondrial function was maintained for at least three weeks. Thus, REC-donated exogenous mitochondria might offer a potential therapeutic strategy for treating neurological dysfunction in MELAS.
Topics: Humans; MELAS Syndrome; Mitochondria; Acidosis, Lactic; DNA, Mitochondrial; Mitochondrial Diseases; Neurons; Mesenchymal Stem Cells
PubMed: 38139018
DOI: 10.3390/ijms242417186 -
Neuroradiology Mar 2024MELAS syndrome is a genetic disorder caused by mitochondrial DNA mutations. We previously described that MELAS patients had increased CSF glutamate and decreased CSF... (Observational Study)
Observational Study
PURPOSE
MELAS syndrome is a genetic disorder caused by mitochondrial DNA mutations. We previously described that MELAS patients had increased CSF glutamate and decreased CSF glutamine levels and that oral glutamine supplementation restores these values. Proton magnetic resonance spectroscopy (H-MRS) allows the in vivo evaluation of brain metabolism. We aimed to compare H-MRS of MELAS patients with controls, the H-MRS after glutamine supplementation in the MELAS group, and investigate the association between H-MRS and CSF lactate, glutamate, and glutamine levels.
METHODS
We conducted an observational case-control study and an open-label, single-cohort study with single-voxel MRS (TE 144/35 ms). We assessed the brain metabolism changes in the prefrontal (PFC) and parieto-occipital) cortex (POC) after oral glutamine supplementation in MELAS patients. MR spectra were analyzed with jMRUI software.
RESULTS
Nine patients with MELAS syndrome (35.8 ± 3.2 years) and nine sex- and age-matched controls were recruited. Lactate/creatine levels were increased in MELAS patients in both PFC and POC (0.40 ± 0.05 vs. 0, p < 0.001; 0.32 ± 0.03 vs. 0, p < 0.001, respectively). No differences were observed between groups in glutamate and glutamine (Glx/creatine), either in PFC (p = 0.930) or POC (p = 0.310). No differences were observed after glutamine supplementation. A positive correlation was found between CSF lactate and lactate/creatine only in POC (0.85, p = 0.003).
CONCLUSION
No significant metabolite changes were observed in the brains of MELAS patients after glutamine supplementation. While we found a positive correlation between lactate levels in CSF and H-MRS in MELAS patients, we could not monitor treatment response over short periods with this tool.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04948138; initial release 24/06/2021; first patient enrolled on 1/07/2021. https://clinicaltrials.gov/ct2/show/NCT04948138.
Topics: Humans; Glutamine; MELAS Syndrome; Creatine; Case-Control Studies; Cohort Studies; Magnetic Resonance Spectroscopy; Glutamic Acid; Proton Magnetic Resonance Spectroscopy; Lactates; Dietary Supplements
PubMed: 38114794
DOI: 10.1007/s00234-023-03263-1 -
Cureus Nov 2023A patient with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, a rare mitochondrial disease characterized by myopathy,...
A patient with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, a rare mitochondrial disease characterized by myopathy, epilepsy, encephalopathy, acidosis, and recurrent cerebral ischemic episodes, underwent systemic hematogenous ozone therapy for 17 years. Despite advancements in the study of mitochondrial diseases, there are currently no available treatments for MELAS. The patient in this case has received over 280 sessions of systemic hematic ozone therapy since 2003 (from the age of 10 years) till the time of publication, without reporting any adverse effects, achieving a normal level of development considering the comorbidities. Possible mechanisms of action of systemic hematogenous ozone therapy include improved efficiency of the mitochondrial oxidative chain through the induction of antioxidant enzymes (catalase, superoxide dismutases {SOD}, peroxidase). More studies are needed to evaluate the actual safety of long-term systemic hematogenous ozone therapy in patients with mitochondrial diseases.
PubMed: 38054163
DOI: 10.7759/cureus.48261 -
Nature Metabolism Dec 2023Nuclease-mediated editing of heteroplasmic mitochondrial DNA (mtDNA) seeks to preferentially cleave and eliminate mutant mtDNA, leaving wild-type genomes to repopulate...
Nuclease-mediated editing of heteroplasmic mitochondrial DNA (mtDNA) seeks to preferentially cleave and eliminate mutant mtDNA, leaving wild-type genomes to repopulate the cell and shift mtDNA heteroplasmy. Various technologies are available, but many suffer from limitations based on size and/or specificity. The use of ARCUS nucleases, derived from naturally occurring I-CreI, avoids these pitfalls due to their small size, single-component protein structure and high specificity resulting from a robust protein-engineering process. Here we describe the development of a mitochondrial-targeted ARCUS (mitoARCUS) nuclease designed to target one of the most common pathogenic mtDNA mutations, m.3243A>G. mitoARCUS robustly eliminated mutant mtDNA without cutting wild-type mtDNA, allowing for shifts in heteroplasmy and concomitant improvements in mitochondrial protein steady-state levels and respiration. In vivo efficacy was demonstrated using a m.3243A>G xenograft mouse model with mitoARCUS delivered systemically by adeno-associated virus. Together, these data support the development of mitoARCUS as an in vivo gene-editing therapeutic for m.3243A>G-associated diseases.
Topics: Humans; Animals; Mice; DNA, Mitochondrial; MELAS Syndrome; Mitochondria; Mutation
PubMed: 38036771
DOI: 10.1038/s42255-023-00932-6