Med Hypotheses
· 2021 Nov · PMID 34627046
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Corneal disease remains to be one of the leading causes of blindness in the world and limbal stem cell (LSC) therapy is a promising therapy for LSC deficiency, which is associated with the diseased corneal epithelium rep...Corneal disease remains to be one of the leading causes of blindness in the world and limbal stem cell (LSC) therapy is a promising therapy for LSC deficiency, which is associated with the diseased corneal epithelium repair. Soft substrate could effectively promote the stemness maintenance of LSC and thus modification of cell culture substrate would help in the potential LSC deficiency therapy. Both Hippo-Yes-associated protein (YAP) and Notch pathway have been reported to affect the LSC function, however, the detailed mechanisms remain unclear. Instead of some soft but biologically toxic substrates, we present a hypothesis on the application of soft substrate generated by HA/PTX3, an FDA approved nontoxic drug, on the LSC culture in this current study. Soft substrate could help in the stemness maintenance and thus promote the LSC deficiency treatment. In more detailed mechanism detection, we hypothesize that soft substrate would block the activation of Hippo-YAP pathway and thus decrease the activity of Notch pathway. This proposed hypothesis should be evaluated by both a series of in-vitro experiments based on soft and stiff substrates and in-vivo treatment with LSC cultured in different conditions. Advanced experiments on related cellular behaviors and detailed molecular mechanisms would provide us more knowledge on the molecular mechanism detection as well as cell transplantation therapy.
Sood A, Raghavan S, Batra P
… +2 more, Sharma K, Talwar A
Med Hypotheses
· 2021 Nov · PMID 34601231
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Oral Lichen Planus (OLP) is a chronic inflammatory disorder whose exact etiology remains unknown. Inflammatory mediators, cytotoxic CD8+ T cells and mast cells have been hypothesized to mediate the pathogenesis of OLP. C...Oral Lichen Planus (OLP) is a chronic inflammatory disorder whose exact etiology remains unknown. Inflammatory mediators, cytotoxic CD8+ T cells and mast cells have been hypothesized to mediate the pathogenesis of OLP. COVID-19 pandemic caused by SARS-CoV-2 is marked by cytokine storms in the affected patients. Altered T-cell responses marked by exhaustion of T-cell count with hyperaggressive remaining T-cells and presence of cross-reactive antibodies render infected humans as fertile grounds for development of multisystem disorders. In addition, Vitamin D deficiency in COVID-19 patients can further modify the T cell mediated immunity. Increased circulating cytokines and hyperactive CD8+ T cells can alter the oral immune barriers rendering them susceptible to oral disorders. Due to the widespread immune dysregulation, it is possible that patients of COVID-19 may develop OLP in the aftermath or during recovery. The paper explores the pathogenic mechanism behind development OLP as post-COVID condition on account of their target receptor, T-cell responses, cytokine profile, mucosal immune barriers and nutrition deficiency.
Med Hypotheses
· 2021 Nov · PMID 34598097
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Recognition of low grade or asymptomatic systemic diseases suggests prevention of the worst, yet has been proven challenging ever since. Biomarker-based liquid biopsy has emerged in recent years as a practical platform f...Recognition of low grade or asymptomatic systemic diseases suggests prevention of the worst, yet has been proven challenging ever since. Biomarker-based liquid biopsy has emerged in recent years as a practical platform for the assessment of systemic diseases yet, technical realizations were mainly focused on cancer, faced challenges in accuracy at early stage and are lacking provision of sufficient evidence of disease. In particular in cell-based cancer liquid biopsy, obstacles are rarity and heterogeneity of circulating tumor and tumor-associated rare cells. Evidence is mounting about an entire spectrum of distinct circulating rare cell types that denotes the systemic component of a certain physiological state. Therefore, circulating rare cells in combination may arise from yet, also account for systemic diseases, which we denote as multi-rare cell association and involves foremost bone marrow-derived progenitor and stem cells yet, also matured somatic cell types. One would expect immense diagnostic value in the read-out of the so called rare cell population which represents cytological evidence of abnormality. We hypothesize that comprehensive rare cell population profiling as contrasted to the biomarker screening approach may realize the premise of a biopsy as to confirm, characterize, grade, stage or predict a systemic disease. This novel approach represents the "missing link" in diagnostic care of in particular early or residual systemic disease and presumes a steady gain in knowledge about the clinical interpretation of rare cell population profiles thus, expecting the knowledge-driven transformation of cell-based liquid biopsy from suggestion to confirmation. We support our hypothesis by past findings made by others and us and provide insights how to interpret a certain rare cell population profile.
Bhandari R, Gupta R, Vashishth A
… +1 more, Kuhad A
Med Hypotheses
· 2021 Nov · PMID 34592564
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Zika virus was declared a national emergency by WHO (World Health Organization) in 2016 when its widespread outbreaks and life-threatening complications were reported, especially in newborns and adults. Numerous studies...Zika virus was declared a national emergency by WHO (World Health Organization) in 2016 when its widespread outbreaks and life-threatening complications were reported, especially in newborns and adults. Numerous studies reported that neuroinflammation is one of the significant root-causes behind its major neurological complications like microcephaly and Guillain-Barré syndrome (GBS). In this hypothesis, we propose Transient Receptor Potential Vanilloid 1 channel (TRPV1) as a major culprit in triggering positive inflammatory loop, ultimately leading to sustained neuroinflammation, one of the key clinical findings in Zika induced microcephalic and GBS patients. Opening of TRPV1 channel also leads to calcium influx and oxidative stress that ultimately results in cellular apoptosis (like Schwann cell in GBS and developing fetal nerve cells in microcephaly), ultimately leading to these complications. Currently, no specific cure exists for these complications. Most of the antiviral candidates are under clinical trials. Though there is no direct research on TRPV1 as a cause of Zika virus's neurological complications, but similarity in mechanisms is undeniable. Thus, exploring pathobiological involvement of TRPV1 channels and various TRPV1 modulators in these complications can possibly prove to be an effective futuristic therapeutic strategy for treatment and management of these life-threatening complications.
Med Hypotheses
· 2021 Nov · PMID 34592563
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COVID-19 (SARS-CoV-2) has emerged as one of the worst pandemics that have tormented the globe due to its highly contagious nature. Even if the disease manifests fever-like symptoms mostly, the disease may progress to the...COVID-19 (SARS-CoV-2) has emerged as one of the worst pandemics that have tormented the globe due to its highly contagious nature. Even if the disease manifests fever-like symptoms mostly, the disease may progress to the pulmonary-hyper inflammatory phase, with severe pneumonia, hypoxia and subsequent multiple organ infection. This subsequently creates a huge burden to the health care systems across the globe for an immediate arrangement of ventilator facilities, oxygen supply and advanced health care. We evaluated the pathological similarity of COVID-19 with other airway obstructive disorders such as COPD and asthma and found typical mucus hypersecretion and mucus plugging in COVID-19 subjects. From several bronchoscopy and clinical autopsy carried out in COVID-19 patients, the overexpression of mucin gene was evident which play a significant role in mucus hypersecretion and accumulation, leading to airway obstruction and further to respiratory distress. In the present work, we highlight the need for intense research inputs to elucidate the exact role the mucus plays in worsening COVID-19 symptoms. This will further help to find a proper approach to quantify the airway mucus plugging in each patient and to develop an appropriate therapy either to inhibit mucus secretion or to improve mucus clearance through well-designed clinical trials.
Med Hypotheses
· 2021 Nov · PMID 34583310
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Some of the COVID-19 patients present with ischemic lesions of their finger and toes. Standard anticoagulant therapy is usually unsuccessful for the treatment of this unique presentation of COVID-19. In this review curre...Some of the COVID-19 patients present with ischemic lesions of their finger and toes. Standard anticoagulant therapy is usually unsuccessful for the treatment of this unique presentation of COVID-19. In this review current evidence is presented, which supports the hypothesis that these necrotic lesions are primarily related to the formation of neutrophil extracellular traps is blood vessels. Also, currently available and potential pharmacological methods of the management of this unique thrombotic complication are discussed. Drugs that possibly could be used in COVID-19 patients suffering from acute ischemia of distal parts of the extremities particularly comprise DNase I and DNase1L3, which could directly dissolve these extracellular webs that are mostly composed of DNA. However, at the moment, none of these enzymes are registered for an intravascular administration in humans. Lactoferrin and dipyridamole are other pharmaceutical agents that could potentially be used for the treatment of neutrophil extracellular traps-evoked digital ischemia. These agents exhibit prophylactic activity against excessive formation of these extracellular structures. Such an experimental treatment should probably be accompanied by standard antithrombotic management with heparin. Open-label and then randomized trials are needed to confirm feasibility, safety and efficacy of the above-suggested management of critically ill COVID-19 patients.
Med Hypotheses
· 2021 Nov · PMID 34583309
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TP53 (tumor protein 53)-induced glycolysis and apoptosis regulator (TIGAR) belongs to the phosphatases family of proteins that modulates the level of reactive oxygen species in tumor cells. This protein plays a vital rol...TP53 (tumor protein 53)-induced glycolysis and apoptosis regulator (TIGAR) belongs to the phosphatases family of proteins that modulates the level of reactive oxygen species in tumor cells. This protein plays a vital role as a negative regulator of glycolysis, thus lowering ROS levels in the cells, which helps the cancerous cells to resist programmed cell death. Besides, TIGAR also mediates the DNA damage repair in cancer cells by increasing tumor cell survival. In the current study, we have screened natural products that compete with the substrate to bind to the active site of TIGAR. Extra precision and MMGBSA scoring function were used to screen the lead molecules. Five compounds were considered as lead molecules with 2-(2-(3,4-dihydroxy phenyl)-3,5-dihydroxy-8-(4-hydroxyphenyl)-4-oxo-4H-furo[2,3-h]chromen-9-yl) acetic acid(DDFA) as a top lead with a docking score of -9.428, and -53.16 MMGBSA, bind to the positively charged amino acids present in the active site. Further, the molecular dynamics simulation studies indicated the structural stability attained by TIGAR protein upon the binding of DDFA, suggesting it to be a potent inhibitor of TIGAR, and could be employed as an anticancer drug during combinational therapy.
Med Hypotheses
· 2021 Nov · PMID 34583308
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Schizophrenia is a severe mental disease involving both neurological and psychiatric abnormalities. Previous studies mainly focus on damage to high-order cognitive dysfunction, which is related to high-level cortical reg...Schizophrenia is a severe mental disease involving both neurological and psychiatric abnormalities. Previous studies mainly focus on damage to high-order cognitive dysfunction, which is related to high-level cortical regions such as the prefrontal and temporal lobes. Recent research reveals that impairment of low-level sensory processing occurs in the early stage of schizophrenia, which may be due to impairment of the subcortical magnocellular visual pathway. Moreover, the structure and function of some important nuclei in a subcortical visual pathway are reported to be abnormal in patients with schizophrenia. Inspired by the above evidence, we propose a hypothesis that impairment of the Superior Colliculus-Pulvinar-Amygdala subcortical visual pathway may be involved in the pathological mechanisms of early stages of schizophrenia. And we propose a possible method to detect dysfunction of this subcortical pathway through examining topological processing, which may help early diagnosis of schizophrenia.
Med Hypotheses
· 2021 Oct · PMID 34560443
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The body's innate and acquiredimmunesystems are critical in responses to a wide spectrum of assaults, including SARS-CoV-2 infection. We identify studies of autoimmunity to support our hypothesis that a high intelligence...The body's innate and acquiredimmunesystems are critical in responses to a wide spectrum of assaults, including SARS-CoV-2 infection. We identify studies of autoimmunity to support our hypothesis that a high intelligence quotient (IQ) may put children at increased risk for severe COVID-19 sequelae; especially those whose viral load is high and/or who develop multisystem inflammatory syndrome in children (MIS-C). MIS-C is associated with a higher risk of COVID-19 morbidity and death, even in otherwise healthy children. As information and evidence about SARS-CoV-2 infection continue to expand, our hypothesis suggests adding a potentially intriguing piece to the pandemic puzzle for further investigation. Drawing on a select review of published research and case reports, we discuss immune dysregulation in paediatric patients with a high IQ, including post-infection cytokine expression in the myocardium. Further, we provide a review of 27 paediatric (≤19 years; median age 16) cases of severe COVID-19 outcomes, drawn from media sources published between March and September 2020, in which we identify possible evidence of a 'hyper brain, hyper body' response to infection. We aver these cases are noteworthy given that paediatric death with COVID-19 disease is remarkably rare, and the estimated prevalence of a high IQ (or giftedness) is only 2% in the general population. These observations warrant prospective and retrospective studies of autoinflammatory markers and mechanisms to elucidate any special psychoneuroimmunological vulnerability in children with a high IQ, as such studies may raise implications for how and when prophylactic medical care is provided to children.
Kaur J, Gulati M, Gowthamarajan K
… +7 more, Vishwas S, Kumar Chellappan D, Gupta G, Dua K, Pandey NK, Kumar B, Singh SK
Med Hypotheses
· 2021 Nov · PMID 34555619
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Colon cancer is characterised by the persistent change in bowel habits due to the formation of polyps (cancerous) in the inner lining of the colon. Clinically, there are several anticancer drugs available to treat colon...Colon cancer is characterised by the persistent change in bowel habits due to the formation of polyps (cancerous) in the inner lining of the colon. Clinically, there are several anticancer drugs available to treat colon cancer. Oxaliplatin (third generation platinum drug) is widely prescribed anticancer drug due to its broad range anticancer properties and low toxicities over cisplatin and carboplatin. Currently, use of oxaliplatin as adjuvant chemotherapy represents a standard care for the treatment of advanced colon cancer. Despite this, its rapid degradation in systemic circulations upon administration, lack of tumor specificity, and low bioavailability limits its anticancer potential. On the other hand, vanillic acid (VA) has shown anticancer potential in colon cancer by targeting mTOR/Ras pathway, HIF-1α inhibition, NF-ĸB, and Nrf2 that regulate cell growth, cell survival, proliferation and adaptation to cancer microenvironment. Normal oral delivery of these two drugs offers non-specific drug release in gastrointestinal tract that leads to unwanted toxicity and very less amount of drug become available for colonic site. Therefore, loading of these two drugs in polysaccharide based functionalized polymeric micelles (FPMs) can offer selective targeting at colonic site and could offer better therapeutic efficacy at much lesser doses of drugs. Therefore, a new hypothesis has been proposed that the combination of vanillic acid with oxaliplatin co-loaded in FPMs could provide colon targeting ability with enhanced potency and safety profile by targeting multiple pathways than current adjuvant chemotherapies available in the market for the treatment of colon cancer.
Med Hypotheses
· 2021 Oct · PMID 34467856
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The human immunity has a pivotal role in nutrition acquisition from the pathogens and damaged body tissue during the SARS-CoV-2 virus infection, which may lead to transient overnutrition in the patients, lead to lipotoxi...The human immunity has a pivotal role in nutrition acquisition from the pathogens and damaged body tissue during the SARS-CoV-2 virus infection, which may lead to transient overnutrition in the patients, lead to lipotoxicity and further damage in non-adipose tissues, and cause hyperinflammation and cytokine storm in severe cases of COVID-19. In view of this, high-quality clinical trials on restrictive eating should be designed to investigate the possible benefits of food intake restriction on patients' recovery from COVID-19 disease.
Med Hypotheses
· 2021 Oct · PMID 34455132
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Some organophosphorus compounds (OPs) can cause a type of delayed neurotoxicity in human being, which is known as organophosphorus-induced delayed neuropathy (OPIDN). Signs and symptoms of the patients include tingling a...Some organophosphorus compounds (OPs) can cause a type of delayed neurotoxicity in human being, which is known as organophosphorus-induced delayed neuropathy (OPIDN). Signs and symptoms of the patients include tingling and sensory loss of the hands and feet, followed by progressive muscle weakness in the lower and upper limbs, and ataxia. Pathologically, OPIDN are characterized by distal sensorimotor axonopathy due to the distal axonal degeneration of nerve tracts located in central and peripheral nervous systems. The morphological pattern of the distal axonopathy is similar to Wallerian degeneration that occurs after nerve injury in vitro. It is generally acknowledged that inhibition and subsequent aging of neuropathy target esterase (NTE) is required for the occurrence of OPIDN. However, the underlying mechanisms through which NTE triggers axonal degeneration in OPIDN is still largely unclear. Recently, sterile alpha and toll/interleukin receptor motif-containing protein 1（SARM1) has been identified as a key player in Wallerian degeneration. In physical and chemical transection of axons, SARM1 was found to promotes axon degeneration by hydrolyzing NAD+. By contrast, SARM1 deficiency could prevent neuron degeneration in response to a wide range of insults. Furthermore, SARM1 can also translocate to mitochondria and cause mitochondrial damage, thus triggering axon degeneration and neuron death. These findings suggested the existence of a pathway in axonal degeneration that might be targeted therapeutically. Here, we hypothesize that SARM1 activation after NTE inhibition and aging might be an etiological factor in OPIDN that regulates Wallerian-like degeneration. Analysing SARM1 mediated NAD degeneration pathway and its upstream activators in OPIDN could contribute to the development of novel therapies to treat OPIDN.
Med Hypotheses
· 2021 Oct · PMID 34455131
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Blood pathogenic trypanosomatids as Trypanosoma cruzi, the causative agent of Chagas Disease, have specialized systems to export virulence factors into host cells. Extracellular vesicles shed by T. cruzi promote infectio...Blood pathogenic trypanosomatids as Trypanosoma cruzi, the causative agent of Chagas Disease, have specialized systems to export virulence factors into host cells. Extracellular vesicles shed by T. cruzi promote infection susceptibility of host cells. Sterile inflammation is part of the innate immune response to molecules released upon tissue injury and is collectively indicated as damage-associated molecular patterns. The complex regulatory pathways that modulate the generation and trafficking of damage-associated molecular patterns are being actively investigated, given their potential to provide a relevant understanding of the physiological and pathological conditions of various diseases that affect humans. However, the common biochemical pathway in the generation of damage-associated molecular patterns and extracellular vesicles shed by T. cruzi is unclear. I propose the following hypothesis: some contents of extracellular vesicles from T. cruzi-infected cells can act as damage-associated molecular patterns during T. cruzi infection. This hypothesis is based on two elements to support it: first, damage-associated molecular patterns can be secreted or exposed by living cells undergoing a life-threatening stress. The second is the composition of extracellular vesicles shed by T. cruzi and released by the host cells during T. cruzi infection. Additionally, we discuss the implications of extracellular vesicles shed by T. cruzi and damage-associated molecular patterns in Chagas disease.
Med Hypotheses
· 2021 Oct · PMID 34425452
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Alterations within consciousness in schizophrenia can be evidenced by impediments in self-awareness and loss of agency. Ned Block's definition of access consciousness is applied in order to further delineate cognitive de...Alterations within consciousness in schizophrenia can be evidenced by impediments in self-awareness and loss of agency. Ned Block's definition of access consciousness is applied in order to further delineate cognitive deficits involving reflective thought and autonoetic thinking in persons with schizophrenia. Current theories on the nature and functioning of consciousness are discussed, which include Global Workspace Theory and metarepresentational characterizations. These describe a recursive, integrative quality to consciousness, contributed to by the functions of access consciousness, that is relevant in examining cognitive deficits in schizophrenia. The integrative deficit that is described as operating in conscious process involves a failure to incorporate prior outputs from a separate cognitive task and integrate these into a novel working schema. The alterations in access consciousness in persons with schizophrenia appear to be a consequence of disrupted integrative cognitive functions. An anteceding problem with cortical circuits involving integrative functions related to access consciousness is therefore hypothesized to manifest as subsequent cognitive dysfunction that leads to symptoms of schizophrenia. Constitutive failures to integrate information in schizophrenia could lead to an inability to create experiential unity and manage content in autonoetic consciousness. Some of the aberrant reasoning manifested by persons with schizophrenia, including problems with hierarchical relational reasoning, model-based-learning, J-con, ipseity, and source monitoring, could also reflect alterations in access consciousness, and their investigation offers additional approaches for scientific inquiry.