Med Hypotheses
· 2021 Oct · PMID 34753010
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As bacteriophage therapy is being investigated more as an alternative to antibiotics, laboratories are isolating and characterizing the functions of bacteriophages. Additionally, with large variations between gut microbi...As bacteriophage therapy is being investigated more as an alternative to antibiotics, laboratories are isolating and characterizing the functions of bacteriophages. Additionally, with large variations between gut microbiome studies and inconsistencies in results, there is a need for discrete characterization of specific gut microbes in situ. This hypothesis paper describes a method to utilize bacteriophages in order to outline the functions of specific gut bacteria in existing biological systems with minimal disturbance. Further, the effects of specific microbe depletion on gut bacterial composition and host health can theoretically also be measured.
Med Hypotheses
· 2021 Oct · PMID 34753009
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The adaptive and therapeutic nature of fever has been recognized for centuries and both local and systemic thermotherapy are now used to enhance the effectiveness of both chemotherapy and radiation therapy for cancer. We...The adaptive and therapeutic nature of fever has been recognized for centuries and both local and systemic thermotherapy are now used to enhance the effectiveness of both chemotherapy and radiation therapy for cancer. We propose that the success of antiseptic, antibiotic, antipyretic and antimalarial strategies and medications over the past century and a half may have had the unintended effect of releasing precancerous growths and neoplastic foci from the inhibitory effects of intermittent fever. This may be a previously unrecognized factor in the overall rise in cancer rates in the late 19th and early 20th centuries.
Med Hypotheses
· 2021 Oct · PMID 34753008
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In addition to uncontrolled diabetes and the excess use of corticosteroids, it is believed that other factors may be responsible for the recent spurt of COVID-19 associated mucormycosis (CAM). In the present paper it is...In addition to uncontrolled diabetes and the excess use of corticosteroids, it is believed that other factors may be responsible for the recent spurt of COVID-19 associated mucormycosis (CAM). In the present paper it is argued that COVID-19 increases the susceptibility of the patients to mucormycosis by augmenting the virulence factors of the mucor species, where deficient synthesis of melatonin plays a key role. Melatonin is synthesized from tryptophan via the serotonin pathway and melatonin deficiency in COVID-19 arises from the faulty absorption of tryptophan from the food because SARS-CoV-2 downregulates angiotensin-converting enzyme-2, the chaperone of the transporter of tryptophan. The enhanced fungal virulence in COVID-19 can be mitigated by correcting the melatonin deficiency as melatonin can prevent iron acquisition of the mucor species and inhibit their morphological transition from the yeast to the virulent hyphal form, given the fact that melatonin is an iron chelator, calmodulin blocker and inhibitor of myeloperoxidase as well as inhibitor of ferroptosis and pyroptosis. Also, by lowering the expression of glucose-regulated protein 78 and by inhibiting the suppression of T-cell immunity, melatonin can further increase the resistance of the patients to mucormycosis. Accordingly, clinical trials should be carried out on tryptophan supplementation, administration of selective serotonin reuptake inhibitors (to increase serotonin, the precursor of melatonin), and exogenous melatonin to find out how they perform in eliminating or reducing the propensity of the coronavirus patients to CAM.
Lee TW, Liu HW, Lin YF
… +3 more, Lee TI, Kao YH, Chen YJ
Med Hypotheses
· 2021 Oct · PMID 34753007
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Sarcopenia, the age-associated-fragility with loss of skeletal muscle mass and function, often coexists with type 2 diabetes (T2D) in older individuals. Derangement of muscle metabolism and mitochondrial dynamics is crit...Sarcopenia, the age-associated-fragility with loss of skeletal muscle mass and function, often coexists with type 2 diabetes (T2D) in older individuals. Derangement of muscle metabolism and mitochondrial dynamics is critical, particularly in high-energy-demand organs in patients with metabolic disorder. However, targeted therapies to halt or reverse the pathological progression of sarcopenia coexisting with T2D are unavailable. Studies have identified the pathological roles of class I histone deacetylases (HDACs) in both T2D and sarcopenia. In addition to their proinflammatory properties, HDACs are known to modify muscle metabolism and mitochondrial dynamics in both the development of sarcopenia and pathogenesis of diabetes. Proper quality control of mitochondrial dynamics through protein degradation and the synthesis of new proteins may improve skeletal muscle function in sarcopenia. Class I HDAC inhibitors improve energy metabolism and modulate autophagy-related genes in skeletal muscle. However, class IIa HDAC4 plays a protective role in preserving skeletal muscle structure following long-term denervation, and selective inhibition of class IIa HDAC activity had no impact on oxidative metabolism of muscle mitochondria. These findings suggest the vital role of class I HDAC modulation in bioenergetics and mitochondria quality control, and may lead to a novel therapeutic strategy targeting sarcopenia that coexists with T2D. HDAC inhibitors have been approved for clinical applications, and interventions targeting on HDACs may be promising for the treatment of sarcopenia.
Med Hypotheses
· 2021 Oct · PMID 34753006
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We hypothesized that neural EGFL like 1 (NELL1) promoter hypermethylation might be associated with the prognosis of gastric cancer. Some studies considered NELL1 as a tumor suppressor gene and our research confirmed for...We hypothesized that neural EGFL like 1 (NELL1) promoter hypermethylation might be associated with the prognosis of gastric cancer. Some studies considered NELL1 as a tumor suppressor gene and our research confirmed for the first time the hypermethylation in the promoter region of NELL1 by the application of mass spectrometry. Promoter hypermethylation can cause the silencing of tumor suppressor genes and promote tumor progression. Based on present studies and research results, we proposed that NELL1 promoter hypermethylation might be associated with cancer staging and the survival of gastric cancer patients and had prognostic value. We hoped that NELL1 promoter hypermethylation would be applied not only for early detection but also prognosis prediction of gastric cancer and would become a new prognostic biomarker.
Med Hypotheses
· 2021 Dec · PMID 34731681
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Triple negative breast cancer (TNBC) is an aggressive form of breast cancer with high rates of tumor relapse and metastasis. The existing drugs for treatment of TNBC are unable to target the cells of origin (breast cance...Triple negative breast cancer (TNBC) is an aggressive form of breast cancer with high rates of tumor relapse and metastasis. The existing drugs for treatment of TNBC are unable to target the cells of origin (breast cancer stem cells) of TNBC. TNF-α related apoptosis inducing ligand (TRAIL) has propensity to target TNBC cells including cancer stem cells. However, resistance to TRAIL due to activation of anti-apoptotic mechanisms is a limitation for TRAIL based anticancer therapy for TNBC. In the present study we propose an hypothesis for effective targeting of triple negative breast cancer by overcoming TRAIL resistance.
Orešković D, Kaštelančić A, Raguž M
… +7 more, Almahariq F, Romić D, Dlaka D, Janeš A, Milotić V, Novaković S, Chudy D
Med Hypotheses
· 2021 Dec · PMID 34717073
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Venous thromboembolism (VTE) is a significant public health issue causing severe morbidity and mortality. One of the most vulnerable populations for VTE development are cancer patients. And among them, patients with brai...Venous thromboembolism (VTE) is a significant public health issue causing severe morbidity and mortality. One of the most vulnerable populations for VTE development are cancer patients. And among them, patients with brain tumors have arguably the highest risk of developing this often fatal complication. Hyperglycemia is a well-known factor which leads to a wide variety of pro-thrombotic changes. In this article, we review the current literature on the topic of VTE in brain tumor patients. We also discuss the known correlation between VTE and glycemia, as well as the importance and frequency of glycemia dysregulation in brain tumor patients. Based on the already well-known importance of glucose metabolism in cancer patients, as well as the previous research of our group, we hypothesize that there is a significant number of brain tumor patients who have chronically elevated glycemia, a fact that so-far hasn't been reported. We argue that these patients carry a significantly higher risk of VTE development and would benefit greatly from strict glycemic control. We present our hypothesis, the ways in which to test it, as well as the possible counter-arguments against it. Our hope is that other investigators will be inspired by our article to continue this type of research, since we consider the topic of VTE in brain tumor patients highly important and urgent, primarily due to its prevalence and severity.
Med Hypotheses
· 2021 Dec · PMID 34717072
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Attention-deficit/hyperactivity disorder (ADHD) and pathological pain are two complex syndromes of multifactorial origin. Despite their prevalence and broad impacts, these conditions are seldom recognized and managed sim...Attention-deficit/hyperactivity disorder (ADHD) and pathological pain are two complex syndromes of multifactorial origin. Despite their prevalence and broad impacts, these conditions are seldom recognized and managed simultaneously. The co-existence of neuropsychiatric conditions (such as ADHD) and altered pain perception and chronic pain has been noted in children, and the comorbidity of ADHD and chronic pain is well documented in adults. Pathophysiological studies have suggested dysfunction of the dopaminergic system as a common neurochemical basis for comorbid ADHD and pain. Considerable evidence supports the role of neuroinflammation in the pathophysiology of both. We suggest that central neuroinflammation underlies altered pain perception and pain sensitization in persons with ADHD. Based on our hypothesis, targeting neuroinflammation may serve as a potential new therapeutic intervention to treat ADHD and comorbid pain in children and adolescents and a preventive strategy for the development of chronic pain in adults with ADHD.
Solanki P, Ansari MD, Anjali
… +7 more, Khan I, Jahan RN, Nikita, Pandit J, Aqil M, Ahmad FJ, Sultana Y
Med Hypotheses
· 2021 Dec · PMID 34710749
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Osteoarthritis is still a disease burden for pharmaceutical scientists and strategy makers. It is associated with the chronic inflammation of joints especially weight-bearing joints like knee, hip, backbone, and phalange...Osteoarthritis is still a disease burden for pharmaceutical scientists and strategy makers. It is associated with the chronic inflammation of joints especially weight-bearing joints like knee, hip, backbone, and phalanges. NSAIDs that are used for the management of inflammation associated with osteoarthritis have high side effects related to gastric upset, gastric ulcer, and long term treatment associated with liver and kidney damage. Nanotechnology has gained a huge scope for the management of arthritis as it can reach out to the deep inside the cell and alter cellular physiology as desired. The present study hypothesizes the use of polyion complex nanoparticles of hyaluronic acid linked Pentosan polysulfate sodium, a disease-modifying agent for the treatment of osteoarthritis administered through transdermal route. The hypothesis involves the use of drug repurposing as the drug was initially approved for interstitial cystitis, a condition of the urinary bladder associated with pain and swelling. Being very low oral bioavailability and gastric irritation profile, the transdermal route would be beneficial. To overcome the problem associated with the oral route, there is a need for the targeted approach that will particularly reach at inflammatory sites. Thereby transdermal delivery of hyaluronic acid linked Pentosan polysulfate sodium through polyion complex nanoparticle therapy will be a novel therapeutic approach to combat osteoarthritis.
Pandya R, Grace San Diego K, Shabbir T
… +4 more, Modi AP, Wang J, Dhahbi J, Barsky SH
Med Hypotheses
· 2021 Dec · PMID 34688214
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Cancers arise from single transformed cells from virtually every organ of the body, divide in a relatively uncontrolled manner, and metastasize widely. A search for a "magic bullet" to precisely diagnose, characterize, a...Cancers arise from single transformed cells from virtually every organ of the body, divide in a relatively uncontrolled manner, and metastasize widely. A search for a "magic bullet" to precisely diagnose, characterize, and ultimately treat cancer has largely failed because cancer cells do not differ significantly from their organ-specific cells of origin. Instead of searching for genomic, epigenetic, transcriptional, and translational differences between cancers and their cells of origin, we should paradoxically focus on what cancer cells have in common with their untransformed cells of origin. This redirected search will lead to improved diagnostic and therapeutic strategies where therapeutic index considerations and drug-limiting toxicities can largely be circumvented. We cite three cancer examples that illustrate this paradigm-shifting strategy: pseudomyxoma peritonei (PP), metastasis of unknown origin (cancers of unknown primary) (MUO), and cancers that arise from potentially dispensable organs (CAD). In each of these examples, the cell of cancer origin still provides the most reliable road map to its diagnosis, prognosis (biology), and therapy.
Med Hypotheses
· 2021 Dec · PMID 34673372
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SARS-COV-2 infection causes severe respiratory tract illness leading to asphyxia and death. The onset of infection is associated with loss of smell, blurred vision, headache with bronchopulmonary symptoms. The clinical o...SARS-COV-2 infection causes severe respiratory tract illness leading to asphyxia and death. The onset of infection is associated with loss of smell, blurred vision, headache with bronchopulmonary symptoms. The clinical observations of neurological abnormalities lead us to address the question, does the virus enter into brain and what is the underlying mechanism of brain infection? The working hypothesis is, SARS-COV-2 Spike epitopes modify blood brain barrier and infect glial cells to induce brain inflammation in genetically diverse human population. The hypothesis is tested by determining binding or interacting ability of virus Spike epitope peptides M1Lys60 and Ala240Glu300 with human toll-like receptor 8 (TLR 8), brain targeted Vascular Cell adhesion Molecules (VCAM1) proteins, Zonula Occludens (ZO), glial cell specific protein NDRG2 and Apo- S100B. The molecular dynamic experiments are performed, and root mean square deviation (RMSD) values are determined for interactions between the Spike peptides and selected proteins. The observations demonstrate formation of heterodimeric complex between the epitope peptides and selected protein structures. The viral epitopes have ability to bind with HLA-DRB1 15:01, 07:01 or 03.01 alleles thus found immunogenic in nature. The observations altogether suggest entry of these Spike protein epitopes into human brain causes inflammation.
Med Hypotheses
· 2021 Dec · PMID 34673371
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A subset of COVID-19 patients is experiencing secondary immune thrombocytopenia, also called immune thrombocytopenic purpura (ITP) or secondary hemophagocytic lymphohistiocytosis (HLH). The pathogenesis of SARS-CoV-2 ass...A subset of COVID-19 patients is experiencing secondary immune thrombocytopenia, also called immune thrombocytopenic purpura (ITP) or secondary hemophagocytic lymphohistiocytosis (HLH). The pathogenesis of SARS-CoV-2 associated thrombocytopenia is unknown. Very rare cases of vaccine induced prothrombotic immune thrombocytopenia (VIPIT) are occurring associated with COVID-19 vaccines. COVID-19 VIPIT is associated with autoantibodies targeting platelet factor 4 (PF4) for COVID-19 adenovirus vaccines. Herein, four models for hemophagocytic histocytes contributions to the etiology of thrombocytopenia associated with SARS-CoV-2 are proposed. One of the models proposes potential involvement of hemophagocytic histocytes targeting platelets bound by autoantibodies consistent with observed PF4 autoantibodies in COVID-19 VIPIT.
Med Hypotheses
· 2021 Dec · PMID 34670172
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Sedentary lifestyle increases the risk of hospitalization for COVID-19 independently of other factors. There is enough statistics to show that exercise prevents severe forms of COVID-19, but current recommendations do no...Sedentary lifestyle increases the risk of hospitalization for COVID-19 independently of other factors. There is enough statistics to show that exercise prevents severe forms of COVID-19, but current recommendations do not set an upper limit for exercise intensity. The hypothesis presented in the paper states that intense exercise, through blood hypoxia, increases the expression of transmembrane angiotensin-converting enzyme 2 (tACE2) in the vascular endothelium, increasing the risk of developing serious forms of disease, especially in the untrained. On the other hand, moderate-intensity exercise increases the blood concentration of soluble angiotensin-converting enzyme 2 (ACE2) which has a protective role for SARS-CoV-2 infection and may prevent complications. The importance of this hypothesis consists in the revision of COVID-19 prophylaxis programs through physical exercises, with the possibility of administration of antioxidants to speed up the adaptation of vascular endothelial cells to exertion.
Med Hypotheses
· 2021 Dec · PMID 34666261
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Multiple Sclerosis (MS) is a demyelinating autoimmune disease in which autoreactive T lymphocytes infiltrate the central nervous system (CNS) and react against antigens derived from proteins of the myelin sheath. The rea...Multiple Sclerosis (MS) is a demyelinating autoimmune disease in which autoreactive T lymphocytes infiltrate the central nervous system (CNS) and react against antigens derived from proteins of the myelin sheath. The reason why T lymphocytes recognize certain myelin antigens as exogenous, activating the autoimmune response, remains unknown and represents the key to understand the pathogenesis of MS. Neurons are characterized by an elevated glycolytic metabolism. Methylglyoxal (MG) is a highly reactive α-oxoaldehyde spontaneously formed as a by-product of glycolysis, and it reacts with proteins, nucleotides and phospholipids forming stable adducts called advanced glycation end-products (AGEs). Several studies demonstrate that MG-derived AGEs accumulate in the plasma and brain of MS patients. Furthermore, there are evidences that post-myelinated oligodendrocytes, the myelin-forming glial cells, increase their glycolytic metabolism to maintain their survival and functions, likely explaining the progressive accumulation of MG in MS lesions. The hypothesis proposed here is that the MG-derived AGEs, accumulated on the proteins composing the myelin sheath, are responsible for the altered antigen presentation process, mimicking exogenous antigens and triggering the autoimmune response. If this hypothesis will be experimentally confirmed a new pathogenic mechanism of MS will be identified.
Med Hypotheses
· 2021 Dec · PMID 34666260
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Keratoconus (KC) is a noninflammatory, bilateral, progressive corneal stromal thinning disorder that leads to corneal ectasia, central anterior corneal stromal scarring, irregular myopic astigmatism, and reduced visual a...Keratoconus (KC) is a noninflammatory, bilateral, progressive corneal stromal thinning disorder that leads to corneal ectasia, central anterior corneal stromal scarring, irregular myopic astigmatism, and reduced visual acuity. Fuchs endothelial corneal dystrophy (FECD) is bilateral, sporadic, or autosomal dominant, non-inflammatory, dystrophy involving the corneal endothelium. As the dystrophy evolves, the major complaints include glare, halos, and reduced visual acuity. Very rarely, both the pathologies can co-exist in the same patient. After the initial report of KC with FECD, there have been nearly 70 cases of coexistence reported in the literature till now. The reported number of cases varies from region to region and the majority of cases have no documented family history, hence it is difficult to approximate the incidence and prevalence based on the available literature. Hence, we hypothesize that both pathologies have probably the same genetic link. Available literature supporting the hypothesis has been discussed. We have also discussed various probable mechanisms of coexistence and proposed a management algorithm while assessing and attempting surgery in these patients. We also propose that all these patients must undergo genetic screening and counselling to prevent the spread of these pathologies in future generations.
Med Hypotheses
· 2021 Dec · PMID 34656854
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What neurons are connected and what neurons are disconnected? These are crucial questions since they determine the structural connectivity of the brain. We address this matter in question and propose a speculative hypoth...What neurons are connected and what neurons are disconnected? These are crucial questions since they determine the structural connectivity of the brain. We address this matter in question and propose a speculative hypothesis. We claim that the neuron selection for synapse formation and pruning process is an electrokinesis-based stochastic physical process. Propagating input signals generate a varying electromagnetic field in the interstitial fluid, which is filled with ions. Varying electromagnetic field exerts Lorentz force on the ions and causes local fluid flows. These fluid flows alter the position of presynaptic boutons and dendritic spines, and hence the likelihood of making contact. Above a certain level of field strength, the likelihood of pruning increases. If the proposed hypothesis is correct, in addition to explaining the natural process of neuron selection for synapse formation and pruning, it can also explain why and why not brain stimulation techniques work. Additionally, it will provide a controllable mechanism to alter brain connectivity as desired, which may have a profound impact on many connectivity-based psychiatric and neurological diseases.
Med Hypotheses
· 2021 Nov · PMID 34628112
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Depression is the second leading cause of disability in the world. Despite developing some efficacious treatments, many patients do not respond to the treatment well due to the complexity of depression and unknown mechan...Depression is the second leading cause of disability in the world. Despite developing some efficacious treatments, many patients do not respond to the treatment well due to the complexity of depression and unknown mechanisms involved in its pathogenesis. It has been reported that patients with major depressive disorder (MDD) experience autonomic dysfunctions in different aspects. Evidence suggests that modulation of the autonomic nervous system may improve depression. Von Economo neurons (VENs) are shown to be involved in the pathophysiology of some of the neurological and psychological diseases. VENs are also important for the "ego" formation, sense of empathy, intuition, and cognition. These neurons express a high level of adrenoreceptor alpha 1a, which confirms their role in the autonomic function. Here, based on some evidence, I propose the hypothesis that these neurons may play a role in depression, possibly through being involved in the autonomic function. More focused studies on VENs and their possible role in depression is suggested in future. This pathway may open a new window in the treatment of depression.