Medical hypotheses最新文献

{"title":"Activation of resident immune cells induces enteric neuronal death","authors":"João Janilson da Silva Sousa ,&nbsp;Vanessa de Sousa do Vale ,&nbsp;Rafael da Silva Prudêncio ,&nbsp;Diva de Aguiar Magalhães ,&nbsp;Viviane Pinheiro Alves de Almeida ,&nbsp;Antônio Kleiton de Sousa ,&nbsp;Tino Marcos Lino da Silva ,&nbsp;Kaique Aguiar Souza ,&nbsp;Vanderlene Oliveira Rodrigues ,&nbsp;André Luiz dos Reis Barbosa","doi":"10.1016/j.mehy.2024.111555","DOIUrl":"10.1016/j.mehy.2024.111555","url":null,"abstract":"<div><div>Resident immune cells are involved in the pathogenesis of inflammatory bowel diseases (IBDs). Studies have already demonstrated that these cells, mainly mast cells and macrophages, are close to and in communication with neurons of the enteric nervous system (ENS). Enteric neurons organized in ganglions participate in processes such as control of motility, secretory functions, absorption and blood flow. Morphological and functional changes in these neurons can cause intestinal damage, such as changes in intestinal motility and diarrhea, common features of IBD. Uncontrolled or unregulated activation of mast cells can also interfere with intestinal homeostasis and generate tissue dysfunction and promote inflammation in various gastrointestinal diseases. These cells can also act by releasing mediators that activate enteric glial cells (EGC), leading to reactive gliosis. Despite being recognized as essential regulators of neuronal function in the ENS, when activated by injuries and inflammatory processes, these cells can proliferate and undergo broad activation that, in association with other cells of the external muscular layer of the intestine (neutrophils, monocytes, resident macrophages and smooth muscles) produces and releases pro-inflammatory mediators. This pro-inflammatory action also involves the participation of the beta fraction of the calcium-binding protein S100 (S100β), which despite being found in other cells, in the intestine its expression is limited to EGC. The increase in the expression of this protein may be responsible for the death of neurons, through the activation of receptors for advanced glycation end products (RAGE) and consequent activation of the nuclear transcription factor-κB (NFκB). RAGE-type receptors are expressed in several cells, including their presence in macrophages. It is known that interactions between macrophages and the ENS interfere with intestinal motility, serve as a protective mechanism during injuries and infections, but can also contribute to tissue damage and other gastrointestinal disorders. Therefore, our hypothesis suggests that mast cells and macrophages, resident immune cells, are involved in enteric neuronal death, through the activation of EGCs and the release of pro-inflammatory factors.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"195 ","pages":"Article 111555"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143148417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heart rate variability may serve as an intermediate indicator for limiting atrial fibrillation in hypertensive patients","authors":"Hao Yang ,&nbsp;Mi He ,&nbsp;Yi He ,&nbsp;Tao Liu ,&nbsp;Houyuan Hu","doi":"10.1016/j.mehy.2024.111553","DOIUrl":"10.1016/j.mehy.2024.111553","url":null,"abstract":"<div><div>Hypertension（HT） is a common disease and, if uncontrolled, may lead to atrial fibrillation (AF). Current research has revealed that the autonomic nervous system dysfunction (ANSD) and body fluid imbalance are important factors in the progression of HT. Hence, we hypothesize that by improving ANSD via intermittent monitoring of heart rate variability (HRV) in conjunction with effective blood-pressure control, anti-HT treatment may reduce AF events more successfully. This hypothesis presents a novel direction and perspective for further research into early interventions and ambulatory management for HT patients to limit the risk of AF.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"195 ","pages":"Article 111553"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143148418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep cervical lymphovenous bypass for Parkinson’s disease: A hypothesis","authors":"Guanyu Yang ,&nbsp;Gaiqing Yang ,&nbsp;Feiyun Wang ,&nbsp;Qinjun Chu","doi":"10.1016/j.mehy.2024.111559","DOIUrl":"10.1016/j.mehy.2024.111559","url":null,"abstract":"<div><div>As the population ages, the incidence of Parkinson’s disease has been progressively increasing, becoming a significant global public health concern. This disease is closely associated with the abnormal accumulation of α-synuclein, which adversely affects neuronal function and exacerbates symptoms. Recent studies have indicated that the lymphatic system plays a crucial role in clearing metabolic waste from the brain. However, patients with Parkinson’s disease often exhibit dysfunction of the brain’s lymphatic system, resulting in impaired clearance of α-synuclein. Therefore, reducing the accumulation of α-synuclein in the brain has emerged as a therapeutic target for Parkinson’s disease. In this context, a hypothesis is proposed regarding the use of deep cervical lymphovenous bypass surgery. This procedure aims to create a pathway for the drainage of cerebrospinal lymph by anastomosing the deep cervical lymphatic vessels with the cervical veins, thereby accelerating lymphatic drainage and improving the drainage function of the brain’s lymphatic system. If this hypothesis is validated, it could provide new solution into the treatment of Parkinson’s disease, potentially halting disease progression and possibly being applicable to other neurodegenerative disorders.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"195 ","pages":"Article 111559"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143148414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physical exercises can alleviate harmine toxicity in the case of oncological treatments","authors":"Bogdan-Alexandru Hagiu","doi":"10.1016/j.mehy.2025.111579","DOIUrl":"10.1016/j.mehy.2025.111579","url":null,"abstract":"<div><div>Research conducted on experimental animals has shown remarkable antitumor effects of harmine. However, the doses at which therapeutic effects are observed show toxic effects on hepatic and neuronal mitochondria. A possible way to mitigate these adverse effects is to practice physical exercises that stimulate the functionality, regeneration, and even biogenesis of mitochondria in the liver and nervous system. Drugs that stimulate mitochondrial biogenesis are also being researched, but they are either not effective enough, have long-term effects that can worsen cancer, or interfere pharmacologically with harmine.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"196 ","pages":"Article 111579"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143158748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential role of bacterial extracellular vesicles in the pathophysiology of systemic lupus erythematosus","authors":"Khianne Ed Miguel P. Orteza ,&nbsp;Marc Erickson G. Mosqueda ,&nbsp;Jericho V. Carena ,&nbsp;Ourlad Alzeus G. Tantengco","doi":"10.1016/j.mehy.2024.111545","DOIUrl":"10.1016/j.mehy.2024.111545","url":null,"abstract":"<div><div>Systemic Lupus Erythematosus (SLE) is a rare autoimmune disorder influenced by various factors, including infections. Following bacterial or viral infections, there is an increase in IFN-I production, primarily by plasmacytoid dendritic cells (pDCs). Overproduction of IFN-I has been shown to drive the progression of SLE. Recent findings indicate that the gene expression signature of IFN-I in lupus nephritis patients does not co-occur with pDCs as expected; instead, it is localized in glomerular regions with anastomosing capillaries, suggesting a potential source from the blood. T cells, natural killer cells, and myeloid lineage cells may also secrete IFN in the bloodstream. Bacterial presence in the bloodstream challenges the concept of blood sterility, raising the possibility that cell-free microbial components, such as bacterial extracellular vesicles (BEVs), could trigger excessive IFN production through systemic circulation. While existing studies suggest a role for BEVs in human SLE, experimental evidence has yet to establish a direct association between the entire BEV nanoparticle and the disease. Research has primarily focused on (1) mammalian EVs and (2) purified eDNA and other specific cargoes as contributors to SLE progression. It remains unproven whether these bacterial molecules exert their effects while associated with vesicular membranes, i.e., BEVs. We hypothesize that BEVs, which carry diverse cargoes including nucleic acids, may enter systemic circulation, induce cellular responses leading to IFN overproduction, and exacerbate SLE severity. Clinical studies could investigate the association of BEVs with SLE progression by monitoring their presence and quantity in blood samples and correlating these factors with disease outcomes. Furthermore, understanding the involvement of BEVs may aid in identifying SLE biomarkers, inform infection prevention strategies, and inspire the development of BEV-neutralizing agents.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"195 ","pages":"Article 111545"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143148410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysfunction of the Gut-Brain-Axis in delayed encephalopathy after carbon monoxide poisoning","authors":"Kexin Xiong ,&nbsp;Yuehong Ma ,&nbsp;Wenying Lv ,&nbsp;Dazhi Guo","doi":"10.1016/j.mehy.2024.111550","DOIUrl":"10.1016/j.mehy.2024.111550","url":null,"abstract":"<div><div>Carbon monoxide (CO) poisoning usually causes brain lesions and delayed encephalopathy, also known as delayed neurological sequelae (DNS). The mechanism of direct brain damage caused by CO poisoning is extremely complicated which is mainly focused on the hypoxia, disorder of energy metabolism, failure of the cellular mitochondrial respiration, oxidative stress, inflammation, auto-immunological attack, excitatory amino acid toxicity, etc. However, the etiology for neurological deficits that arise from days to weeks after poisoning remains unclear. In recent years, more and more studies have shown that the intestinal flora and their gene expression products communicate directly with the brain and transmit information to each other through the complex enteric nervous system, also called Gut-Brain-Axis (GBA), and the<!--> <!-->mismatch<!--> <!-->between<!--> <!-->the<!--> <!-->metabolism and<!--> <!-->the<!--> <!-->gut microbiota<!--> <!-->is thought to be important<!--> <!-->for many neurological disorders, such as multiple sclerosis, mood and anxiety disorders, Alzheimer disease, etc. Therefore, we propose a hypothesis that CO poisoning leads to dysbiosis of the gut microbiota, affects neuroendocrine system, neuroimmnue system, autonomic system and enternic nervous system, causes disruption of symbiotic microbial populations in the gut and increases intestinal permeability, leading to “leaky out” of intestinal microorganisms and metabolites from the gut into the bloodstream, disrupts the homeostatic state of brain tissues and induces neuroinflammation, thus contributing to “persistent and worsening” brain damage and leading to the development of DNS. We believe that the combination therapies to remodel gut microbiota and regulate host metabolism may be important for the prevention and treatment of DNS after CO poisoning.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"195 ","pages":"Article 111550"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143148411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcitonin gene-related peptide-induced central sensitization: A hypothesis for long COVID symptoms","authors":"Ella J. Lee ,&nbsp;Cynthia Tsang ,&nbsp;Martha Lucía Gutiérrez Pérez ,&nbsp;Mehdi Abouzari ,&nbsp;Hamid R. Djalilian","doi":"10.1016/j.mehy.2025.111570","DOIUrl":"10.1016/j.mehy.2025.111570","url":null,"abstract":"<div><div>Central sensitization (CS) denotes aberrant processing of sensory stimuli within the central nervous system, wherein innocuous inputs activate pain pathways, leading to pain hypersensitivity. Features observed in CS conditions are often present in patients with long COVID, suggesting a potentially shared pathophysiological mechanism. We hypothesize that elevated levels of calcitonin gene-related peptide (CGRP), a neuropeptide known to play an integral role in the development of CS, may contribute to the persistent symptoms observed in long COVID. This article explores the role of CGRP within the context of CS and proposes its potential relationship to long COVID.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"195 ","pages":"Article 111570"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143148430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the hypothalamic MC4 receptor: A novel approach to senolytic therapy?","authors":"Youn Ju Kim,&nbsp;Joo Hyun Lim,&nbsp;Eun Ran Kim","doi":"10.1016/j.mehy.2024.111551","DOIUrl":"10.1016/j.mehy.2024.111551","url":null,"abstract":"<div><div>The hypothalamus is a center of whole-body energy metabolism. With aging, its function decreases, leading to a higher chance of metabolic disorders. Conversely, overnutrition, such as in cases of type 2 diabetes and obesity, can also cause cellular senescence independent of age. Elevated glucose levels accelerate neuronal senescence by inducing oxidative stress and inflammatory responses, leading to cellular aging and neurodegeneration. Melanocortin receptor 4 (MC4R) neurons in the hypothalamus play a crucial role in energy homeostasis, and MC4R expression levels tend to decrease with aging. In our study, we exposed a mouse hypothalamic cell line (mHypoE-N46) to high glucose (50 mM) and observed an increase in the levels of the cellular senescence marker <em>p21</em>, along with a reduction in <em>Mc4r</em> levels. Additionally, we found an increase in Basic helix-loop-helix ARNT-like protein 1(<em>Bmal1</em>) expression, indicating a disruption of circadian rhythm in energy homeostasis regulated by the hypothalamus. Therefore, we hypothesize that: i) High glucose elevates <em>Bmal1</em> in hypothalamic neurons, triggering senescence, which then downregulates MC4R. This leads to metabolic dysfunction and aging-independent metabolic abnormalities. ii) To ameliorate the senescence, agonizing MC4R signaling could be an option, potentially reducing <em>p21</em> expression and normalizing <em>Bmal1</em> expression rhythms in the hypothalamus. Besides, these agonists could also serve as senolytic therapeutics for correcting neuronal dysfunction in age-related metabolic regulation. Given the decreased levels of MC4R during aging, these agonists could be useful not only for senescence caused by overnutrition but also in natural aging processes. These hypotheses can be demonstrated using an animal model with high glucose or high-fat diet and hypothalamic-specific MC4R knockout mice. Understanding the mechanisms underlying biological age-independent senescence is crucial for identifying novel therapeutic targets and interventions to mitigate age-related diseases and promote healthy aging. The exploration of MC4R agonism as a senolytic approach could provide valuable insights into novel therapeutic avenues for combating age-related disorders and extending healthspan.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"195 ","pages":"Article 111551"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143148412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypothesized molecular mechanism of formation of membrano-cystic lesions","authors":"Toshitsugu Nakamura","doi":"10.1016/j.mehy.2024.111561","DOIUrl":"10.1016/j.mehy.2024.111561","url":null,"abstract":"<div><div>Membrano-cystic lesions (MCLs) are characterized by undulating lipomembranous changes of lipid droplets and usually found in atherosclerotic lesions of aorta/arteries or in adipose tissues associated with panniculitis. MCLs are composed of lipid-carbohydrate-protein complexes (LCPCs), stable even in paraffin-embedded tissue sections, and are histochemically similar, but not identical, to lipofuscin and ceroid. Lipid peroxides damage carbohydrates and proteins, generating advanced glycation end products and advanced oxidative protein products that may play an important role in the formation of MCLs and lipofuscin/ceroid; MCLs are formed by deposition of oxidative LCPCs into lipid droplet membranes. The author proposes a speculative hypothesis that these deposits may change membrane stiffness/fluidity and impair lipid efflux/influx in various kinds of degree by a part, resulting in deformation of lipid droplets and MCL formation. As membrane stiffness/fluidity in unaffected cells varies according to cholesterol concentration or saturated/unsaturated form of lipids, qualitive/quantitative variety of molecular components of the droplets may contribute to the deformability to lipid droplets.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"195 ","pages":"Article 111561"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143148428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vitamin D mitigates soluble endoglin levels in preeclampsia by regulating sphingomyelin/ ceramide content of the placental exosome","authors":"Juhi Nema,&nbsp;Sadhana Joshi","doi":"10.1016/j.mehy.2024.111556","DOIUrl":"10.1016/j.mehy.2024.111556","url":null,"abstract":"<div><div>Vitamin D deficiency is associated with increased risk of preeclampsia. Vitamin D influences angiogenesis in preeclampsia, however the underlying mechanism remains unclear. Placental exosomes are released in the maternal circulation as early as the 6th week of gestation and its levels are reported to be increased in preeclampsia. Similarly, changes in the placental exosome cargo (increased sphingomyelin (SM) content) has also been reported in women with preeclampsia. Endoglin, an anti-angiogenic marker, has an affinity for SM-18:0 enriched microdomains which when released into the maternal circulation may lead to endothelial dysfunction. Our earlier studies in preeclampsia reports that alterations in the levels of angiogenic markers predate clinical diagnosis of preeclampsia. We have also reported that maternal vitamin D status influence fatty acid levels and their metabolism. It has been reported that vitamin D influences sphingolipid metabolism pathway and increases ceramide levels in the exosome bilayer. It is likely that vitamin D levels influence sphingomyelinase activity thereby affecting composition of sphingolipids and ceramides in exosomes and their release into the maternal circulation. Since, SM-18:0-enriched exosomes are associated with increased endoglin levels (in the exosomal cargo); it is possible that vitamin D influences angiogenesis by regulating the content of lipids in exosomes. We hypothesize that lower maternal vitamin D levels will increase sphingomyelin content in the exosomal bilayer resulting in increased endoglin cargo in the placental exosome which will be released into the maternal circulation. This will subsequently lead to impaired angiogenesis and endothelial dysfunction in preeclampsia.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"195 ","pages":"Article 111556"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143148429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}