Publications by authors named "Lerner Aaron"

105 Publications

Nutraceutical Aid for Allergies - Strategies for Down-Regulating Mast Cell Degranulation.

J Asthma Allergy 2021 27;14:1257-1266. Epub 2021 Oct 27.

Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Tel Hashomer, Israel.

Interactions of antigens with the mast cell FcεRI-IgE receptor complex induce degranulation and boost synthesis of pro-inflammatory lipid mediators and cytokines. Activation of spleen tyrosine kinase (Syk) functions as a central hub in this signaling. The tyrosine phosphatase SHP-1 opposes Syk activity; stimulation of NADPH oxidase by FcεRI activation results in the production of oxidants that reversibly inhibit SHP-1, up-regulating the signal from Syk. Activated AMPK can suppress Syk activation by the FcεRI receptor, possibly reflecting its ability to phosphorylate the FcεRI beta subunit. Cyclic GMP, via protein kinase G II, enhances the activity of SHP-1 by phosphorylating its C-terminal region; this may explain its inhibitory impact on mast cell activation. Hydrogen sulfide (HS) likewise opposes mast cell activation; HS can boost AMPK activity, up-regulate cGMP production, and trigger Nrf2-mediated induction of Phase 2 enzymes - including heme oxygenase-1, whose generation of bilirubin suppresses NADPH oxidase activity. Phycocyanobilin (PCB), a chemical relative of bilirubin, shares its inhibitory impact on NADPH oxidase, rationalizing reported anti-allergic effects of PCB-rich spirulina ingestion. Phase 2 inducer nutraceuticals can likewise oppose the up-regulatory impact of NADPH oxidase on FcεRI signaling. AMPK can be activated with the nutraceutical berberine. High-dose biotin can boost cGMP levels in mast cells via direct stimulation of soluble guanylate cyclase. Endogenous generation of HS in mast cells can be promoted by administering N-acetylcysteine and likely by taurine, which increases the expression of HS-producing enzymes in the vascular system. Mast cell stabilization by benifuuki green tea catechins may reflect the decreased surface expression of FcεRI.
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http://dx.doi.org/10.2147/JAA.S332307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558634PMC
October 2021

Microbial Transglutaminase Is a Very Frequently Used Food Additive and Is a Potential Inducer of Autoimmune/Neurodegenerative Diseases.

Toxics 2021 Sep 25;9(10). Epub 2021 Sep 25.

Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Tel Hashomer 5262000, Israel.

Microbial transglutaminase (mTG) is a heavily used food additive and its industrial transamidated complexes usage is rising rapidly. It was classified as a processing aid and was granted the GRAS (generally recognized as safe) definition, thus escaping full and thorough toxic and safety evaluations. Despite the manufacturers claims, mTG or its cross-linked compounds are immunogenic, pathogenic, proinflammatory, allergenic and toxic, and pose a risk to public health. The enzyme is a member of the transglutaminase family and imitates the posttranslational modification of gluten, by the tissue transglutaminase, which is the autoantigen of celiac disease. The deamidated and transamidated gliadin peptides lose their tolerance and induce the gluten enteropathy. Microbial transglutaminase and its complexes increase intestinal permeability, suppresses enteric protective pathways, enhances microbial growth and gliadin peptide's epithelial uptake and can transcytose intra-enterocytically to face the sub-epithelial immune cells. The present review updates on the potentially detrimental side effects of mTG, aiming to interest the scientific community, induce food regulatory authorities' debates on its safety, and protect the public from the mTG unwanted effects.
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http://dx.doi.org/10.3390/toxics9100233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537092PMC
September 2021

Plummer-Vinson syndrome in primary Sjögren syndrome: a case-based review.

Immunol Res 2021 Oct 14. Epub 2021 Oct 14.

Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Tel Hashomer, Israel.

This study aimed to describe a patient with Sjögren syndrome who developed Plummer-Vinson syndrome, and to review the literature and describe shared aspects of this rare association. A systematic screening of articles was conducted in PubMed/MEDLINE, LILACS, SciELO, Scopus, Web of Science, and Cochrane, dating 1940 to 2020. All the articles included the association between Sjögren syndrome and Plummer-Vinson syndrome. No language restriction was applied. The following terms were used: "Sjögren syndrome" or "sicca syndrome" and "Plummer-Vinson syndrome" or "Paterson-Kelly syndrome." We performed our analysis by adding our present case, with a total of 4 cases. Three out of four were female (75%), age varied from 56 to 58 years old. In 2 cases, Sjögren syndrome preceded Plummer-Vinson syndrome diagnosis, and in 1 report, Plummer-Vinson syndrome appeared before Sjögren syndrome. Disease duration varied from 7 to 20 years. In two cases, autoantibodies were available, and antinuclear antibodies and anti-Ro/SS-A were positive in both, and anti-La/SS-B in one of them was associated with anti-dsDNA; however, no data regarding lupus was available in the article. Treatment involved iron supplementation in 3/3. Two out of three received parenteral iron supplementation, and in these two cases, mechanical esophageal dilatation was needless. In the other case, an additional endoscopic esophageal dilatation was necessary to receive the oral iron supplement. All 3 cases had a good outcome. This case illustrates a patient with Sjögren syndrome who developed the rare Plummer-Vinson syndrome. In Sjögren syndrome, the presence of iron-deficiency anemia, dysphagia, and weight loss should alert the physician to search for associated Plummer-Vinson syndrome.
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http://dx.doi.org/10.1007/s12026-021-09243-yDOI Listing
October 2021

Celiac disease in the COVID-19 pandemic.

J Transl Autoimmun 2021 31;4:100120. Epub 2021 Aug 31.

Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Tel Hashomer, 5262000, Israel.

Background: The COVID-19 pandemic has had an impact on global health.

Design: The impact of the COVID-19 pandemic on patients with coeliac disease was assessed in the present review.

Results: The incidence of coeliac disease and the problems associated with coeliac disease increased during the COVID-19 pandemic. Adherence to the diet is crucial for the patient's health and quality of life since the only approved therapy for coeliac disease is a gluten withdrawal.

Conclusions: A gluten-free diet should be promoted by the therapeutic team and implemented among these categories of patients.
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http://dx.doi.org/10.1016/j.jtauto.2021.100120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406545PMC
August 2021

Sex Disparities and Neutralizing-Antibody Durability to SARS-CoV-2 Infection in Convalescent Individuals.

mSphere 2021 08 25;6(4):e0027521. Epub 2021 Aug 25.

Department of Medicine, Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has now caused over 2 million deaths worldwide and continues to expand. Currently, much is unknown about functionally neutralizing human antibody responses and durability to SARS-CoV-2 months after infection or the reason for the discrepancy in COVID-19 disease and sex. Using convalescent-phase sera collected from 101 COVID-19-recovered individuals 21 to 212 days after symptom onset with 48 additional longitudinal samples, we measured functionality and durability of serum antibodies. We also evaluated associations of individual demographic and clinical parameters with functional neutralizing antibody responses to COVID-19. We found robust antibody durability out to 6 months, as well as significant positive associations with the magnitude of the neutralizing antibody response and male sex and in individuals with cardiometabolic comorbidities. In this study, we found that neutralizing antibody responses in COVID-19-convalescent individuals vary in magnitude but are durable and correlate well with receptor binding domain (RBD) Ig binding antibody levels compared to other SARS-CoV-2 antigen responses. In our cohort, higher neutralizing antibody titers are independently and significantly associated with male sex compared to female sex. We also show for the first time that higher convalescent antibody titers in male donors are associated with increased age and symptom grade. Furthermore, cardiometabolic comorbidities are associated with higher antibody titers independently of sex. Here, we present an in-depth evaluation of serologic, demographic, and clinical correlates of functional antibody responses and durability to SARS-CoV-2 which supports the growing literature on sex discrepancies regarding COVID-19 disease morbidity and mortality, as well as functional neutralizing antibody responses to SARS-CoV-2.
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http://dx.doi.org/10.1128/mSphere.00275-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386415PMC
August 2021

High Intakes of Bioavailable Phosphate May Promote Systemic Oxidative Stress and Vascular Calcification by Boosting Mitochondrial Membrane Potential-Is Good Magnesium Status an Antidote?

Cells 2021 07 9;10(7). Epub 2021 Jul 9.

Department of Research and Postgraduate in Food Science, Universidad de Sonora, Hermosillo 83000, Mexico.

Chronic kidney disease is characterized by markedly increased risk for cardiovascular mortality, vascular calcification, and ventricular hypertrophy, and is associated with increased systemic oxidative stress. Hyperphosphatemia, reflecting diminished glomerular phosphate (Pi) clearance, coupled with a compensatory increase in fibroblast growth factor 23 (FGF23) secretion are thought to be key mediators of this risk. Elevated serum and dietary Pi and elevated plasma FGF23 are associated with increased cardiovascular and total mortality in people with normal baseline renal function. FGF23 may mediate some of this risk by promoting cardiac hypertrophy via activation of fibroblast growth factor receptor 4 on cardiomyocytes. Elevated serum Pi can also cause a profound increase in systemic oxidative stress, and this may reflect the ability of Pi to act directly on mitochondria to boost membrane potential and thereby increase respiratory chain superoxide production. Moreover, elevated FGF23 likewise induces oxidative stress in vascular endothelium via activation of NADPH oxidase complexes. In vitro exposure of vascular smooth muscle cells to elevated Pi provokes an osteoblastic phenotypic transition that is mediated by increased mitochondrial oxidant production; this is offset dose-dependently by increased exposure to magnesium (Mg). In vivo, dietary Mg is protective in rodent models of vascular calcification. It is proposed that increased intracellular Mg opposes Pi's ability to increase mitochondrial membrane potential; this model could explain its utility for prevention of vascular calcification and predicts that Mg may have a more global protective impact with regard to the direct pathogenic effects of hyperphosphatemia.
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http://dx.doi.org/10.3390/cells10071744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303439PMC
July 2021

Gluten-free diet can ameliorate the symptoms of non-celiac autoimmune diseases.

Nutr Rev 2021 Aug 2. Epub 2021 Aug 2.

A. Lerner and Y. Shoenfeld are with the The Zabludowicz Research Center for Autoimmune Diseases, Chaim Sheba Medical Center, Tel Hashomer, Israel. J. Freire de Carvalho is with the Department of Rheumatology, Institute for Health Sciences of the Federal University of Bahia, Salvador, Bahia, Brazil. A. Kotrova and Y. Shoenfeld are with the Department of Autoimmune research, Saint Petersburg State University, St. Petersburg, Russia. Y. Shoenfeld is with the Department of Administration, Ariel University, Israel. Y. Shoenfeld is with the Department of Autoimmune research, I.M Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia.

Context: A gluten-free diet (GFD) is the recommended treatment for gluten-dependent disease. In addition, gluten withdrawal is popular and occasionally is suggested as a treatment for other autoimmune diseases (ADs).

Objective: The current systematic review summarizes those entities and discusses the logic behind using a GFD in classical non-gluten-dependentADs.

Data Sources: A search for medical articles in PubMed/MEDLINE, Web of Sciences, LILACS, and Scielo published between 1960 and 2020 was conducted, using the key words for various ADs and GFDs.

Data Exxtraction: Eight-three articles were included in the systematic review (using PRISMA guidelines).

Data Analysis: Reduction in symptoms of ADs after observance of a GFD was observed in 911 out of 1408 patients (64.7%) and in 66 out of the 83 selected studies (79.5%). The age of the patients ranged from 9 months to 69 years. The duration of the GFD varied from 1 month to 9 years. A GFD can suppress several harmful intraluminal intestinal events. Potential mechanisms and pathways for the action of GFD in the gut - remote organs' axis have been suggested.

Conclusion: A GFD might represent a novel nutritional therapeutic strategy for classical non-gluten-dependent autoimmune conditions.
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http://dx.doi.org/10.1093/nutrit/nuab039DOI Listing
August 2021

Alpha-enolase involvement in intestinal and extraintestinal manifestations of celiac disease.

J Transl Autoimmun 2021 16;4:100109. Epub 2021 Jun 16.

Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Tel Hashomer, Israel.

Celiac disease is a life-long intestinal autoimmune disease, characterized by the gluten intolerance and chronic enteric inflammation. Traditionally presented by intestinal manifestations, however, a shift toward extra intestinal presentation is taking place. One of the affected organs is the nervous systems presented by neuropsychiatric manifestations, hence the mechanism and pathways are not clear. The presence of neuronal and alpha-enolases and their corresponding antibodies were noticed in the mucosa and serum of celiac disease patients, as well as in other various autoimmune diseases with psycho-neurological manifestations. The aims of the present review are to screen the literature on different isoforms of enolase, mainly alpha enolase, and their specific antibodies and to suggest their potential pathophysiological mechanisms relaying the enolases to intestinal or extraintestinal celiac disease manifestations. The shared aspects between the enolases and celiac disease and the cross-talks between alpha-enolase and tissue transglutaminase suggest new potential pathophysiological mechanisms that might drive celiac disease evolvement.
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http://dx.doi.org/10.1016/j.jtauto.2021.100109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219987PMC
June 2021

Review - Nutraceuticals Can Target Asthmatic Bronchoconstriction: NADPH Oxidase-Dependent Oxidative Stress, RhoA and Calcium Dynamics.

J Asthma Allergy 2021 15;14:685-701. Epub 2021 Jun 15.

Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Tel Hashomer, 5262000, Israel.

Activation of various isoforms of NADPH oxidase contributes to the pathogenesis of asthma at multiple levels: promoting hypercontractility, hypertrophy, and proliferation of airway smooth muscle; enabling lung influx of eosinophils via VCAM-1; and mediating allergen-induced mast cell activation. Free bilirubin, which functions physiologically within cells as a feedback inhibitor of NADPH oxidase complexes, has been shown to have a favorable impact on each of these phases of asthma pathogenesis. The spirulina chromophore phycocyanobilin (PhyCB), a homolog of bilirubin's precursor biliverdin, can mimic the inhibitory impact of biliverdin/bilirubin on NADPH oxidase activity, and spirulina's versatile and profound anti-inflammatory activity in rodent studies suggests that PhyCB may have potential as a clinical inhibitor of NADPH oxidase. Hence, spirulina or PhyCB-enriched spirulina extracts merit clinical evaluation in asthma. Promoting biosynthesis of glutathione and increasing the expression and activity of various antioxidant enzymes - as by supplementing with N-acetylcysteine, Phase 2 inducers (eg, lipoic acid), selenium, and zinc - may also blunt the contribution of oxidative stress to asthma pathogenesis. Nitric oxide (NO) and hydrogen sulfide (HS) work in various ways to oppose pathogenic mechanisms in asthma; supplemental citrulline and high-dose folate may aid NO synthesis, high-dose biotin may mimic and possibly potentiate NO's activating impact on soluble guanylate cyclase, and NAC and taurine may boost HS synthesis. The amino acid glycine has a hyperpolarizing effect on airway smooth muscle that is bronchodilatory. Insuring optimal intracellular levels of magnesium may modestly blunt the stimulatory impact of intracellular free calcium on bronchoconstriction. Nutraceutical regimens or functional foods incorporating at least several of these agents may have utility as nutraceutical adjuvants to standard clinical management of asthma.
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http://dx.doi.org/10.2147/JAA.S307549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214517PMC
June 2021

Cross-Reactivity and Sequence Homology Between Alpha-Synuclein and Food Products: A Step Further for Parkinson's Disease Synucleinopathy.

Cells 2021 05 5;10(5). Epub 2021 May 5.

Regenera Medical,11620 Wilshire Blvd., Ste. 470, Los Angeles, CA 90025, USA.

Introduction: Parkinson's disease is characterized by non-motor/motor dysfunction midbrain neuronal death and α-synuclein deposits. The accepted hypothesis is that unknown environmental factors induce α-synuclein accumulation in the brain via the enteric nervous system.

Material And Methods: Monoclonal antibodies made against recombinant α-synuclein protein or α-synuclein epitope 118-123 were applied to the antigens of 180 frequently consumed food products. The specificity of those antibody-antigen reactions was confirmed by serial dilution and inhibition studies. The Basic Local Alignment Search Tool sequence matching program was used for sequence homologies.

Results: While the antibody made against recombinant α-synuclein reacted significantly with 86/180 specific food antigens, the antibody made against α-synuclein epitope 118-123 reacted with only 32/180 tested food antigens. The food proteins with the greatest number of peptides that matched with α-synuclein were yeast, soybean, latex hevein, wheat germ agglutinin, potato, peanut, bean agglutinin, pea lectin, shrimp, bromelain, and lentil lectin. The cross-reactivity and sequence homology between α-synuclein and frequently consumed foods, reinforces the autoimmune aspect of Parkinson's disease. It is hypothesized that luminal food peptides that share cross-reactive epitopes with human α-synuclein and have molecular similarity with brain antigens are involved in the synucleinopathy. The findings deserve further confirmation by extensive research.
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http://dx.doi.org/10.3390/cells10051111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147930PMC
May 2021

[The influence of gluten on the sharpness of vision].

Harefuah 2021 May;160(5):336-337

Clalit Health Services, Sharon- Shomron District, Hadera, Israel.

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May 2021

The intestinal luminal sources of α-synuclein: a gastroenterologist perspective.

Authors:
Aaron Lerner

Nutr Rev 2021 May 3. Epub 2021 May 3.

A. Lerner is with the Zabludowicz Center for Autoimmune Diseases, Chaim Sheba Medical Center, Tel-Hashomer, Israel.

Parkinson's disease is characterized by nonmotor/motor dysfunction, midbrain dopaminergic neuronal death, and α-synuclein (aSN) deposits. The current hypothesis is that aSN accumulates in the enteric nervous system to reach the brain. However, invertebrate, vertebrate, and nutritional sources of aSN reach the luminal compartment. Submitted to local amyloidogenic forces, the oligomerized proteins' cargo can be sensed and sampled by a specialized mucosal cell to be transmitted to the adjacent enteric nervous system, starting their upward journey to the brain. The present narrative review extends the current mucosal origin of Parkinson's disease, presenting the possibility that the disease starts in the intestinal lumen. If substantiated, eliminating the nutritional sources of aSN (eg, applying a vegetarian diet) might revolutionize the currently used dopaminergic pharmacologic therapy.
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http://dx.doi.org/10.1093/nutrit/nuab024DOI Listing
May 2021

"Let Food Be Thy Medicine": Gluten and Potential Role in Neurodegeneration.

Cells 2021 03 30;10(4). Epub 2021 Mar 30.

Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Tel Hashomer 5262000, Israel.

Wheat is a most favored staple food worldwide and its major protein is gluten. It is involved in several gluten dependent diseases and lately was suggested to play a role in non-celiac autoimmune diseases. Its involvement in neurodegenerative conditions was recently suggested but no cause-and-effect relationship were established. The present narrative review expands on various aspects of the gluten-gut-brain axes events, mechanisms and pathways that connect wheat and gluten consumption to neurodegenerative disease. Gluten induced dysbiosis, increased intestinal permeabillity, enteric and systemic side effects, cross-reactive antibodies, and the sequence of homologies between brain antigens and gluten are highlighted. This combination may suggest molecular mimicry, alluding to some autoimmune aspects between gluten and neurodegenerative disease. The proverb of Hippocrates coined in 400 BC, "let food be thy medicine," is critically discussed in the frame of gluten and potential neurodegeneration evolvement.
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http://dx.doi.org/10.3390/cells10040756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065505PMC
March 2021

The second phase of brain trauma can be controlled by nutraceuticals that suppress DAMP-mediated microglial activation.

Expert Rev Neurother 2021 May 5;21(5):559-570. Epub 2021 Apr 5.

Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Tel Hashomer, Israel.

Introduction: A delayed second wave of brain trauma is mediated in large part by microglia that are activated to a pro-inflammatory M1 phenotype by DAMP proteins released by dying neurons. These microglia can promote apoptosis or necrosis in neighboring neurons by producing a range of pro-inflammatory cytokines and the deadly oxidant peroxynitrite. This second wave could therefore be mitigated with agents that blunt the post-traumatic M1 activation of microglia and that preferentially promote a pro-healing M2 phenotype.

Areas Covered: The literature on nutraceuticals that might have clinical potential in this regard.

Expert Opinion: The chief signaling pathway whereby DAMPs promote M1 microglial activation involves activation of toll-like receptor 4 (TLR4), NADPH oxidase, NF-kappaB, and the stress activated kinases JNK and p38. The green tea catechin EGCG can suppress TLR4 expression. Phycocyanobilin can inhibit NOX2-dependent NADPH oxidase, ferulate and melatonin can oppose pro-inflammatory signal modulation by NADPH oxidase-derived oxidants. Long-chain omega-3 fatty acids, the soy isoflavone genistein, the AMPK activator berberine, glucosamine, and ketone bodies can down-regulate NF-kappaB activation. Vitamin D activity can oppose JNK/p38 activation. A sophisticated program of nutraceutical supplementation may have important potential for mitigating the second phase of neuronal death and aiding subsequent healing.
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http://dx.doi.org/10.1080/14737175.2021.1907182DOI Listing
May 2021

Fibromyalgia associated with Chagas' disease treated with nutraceuticals.

Clin Nutr ESPEN 2021 04 6;42:212-214. Epub 2021 Feb 6.

Chaim Sheba Medical Center, The Zabludowicz Center, for Autoimmune Diseases Tel-Hashomer, Israel.

Objective: To describe a patient with Chagas' disease diagnosed with concomitant fibromyalgia and treated by an alternative approach and review the fibromyalgia-infections relationship.

Methods: The literature was reviewed for fibromyalgia association with infectious agents, using PubMed, spanning 2000-2020. The keywords were: fibromyalgia, infections, bacteria, microbe, and parasite. A case report is described.

Case Report: A 61-year-old female patient with a past medical history of Chagas' disease, presented with megaesophagus and dolichomegacolon for 30 years. Untreated anxiety accompanied her gastrointestinal manifestations. For the last ten years, she felt diffuse pain on both sides of the body, and in the upper and lower parts associated with sleep difficulties. On examination, she had 18 tender points, thus fulfilled the diagnostic criteria of fibromyalgia. 25-OH vitamin D was 26 ng/mL (>30 ng/mL). Serology for Chagas' disease was positive by two techniques (ELISA and indirect immunofluorescence), and the routine laboratory was within normal ranges. Psychotherapy, vitamin D 50,000 IU/week, and physical exercise (Pilates exercise twice a week and distance walking 3 times per week) were initiated. No antidepressant was prescribed due to the risk of detrimental gastrointestinal motility effects. After six months, the patient experienced a marked improvement in her clinical condition, the pain was almost absent, and anxiety was under control, and vitamin D levels were normal. Her quality of life improved substantially. Reviewing the literature on associated infections in myalgia/fibromyalgia disclosed multiple viral, bacterial, and parasitic agents. None mentioned Trypanosoma cruzi.

Conclusion: The present case illustrates the first patient with Chagas-related dolichomegacolon who evolved with fibromyalgia and was successfully treated by psychotherapy, Pilates exercise, and vitamin D. It appears that myalgia and/or fibromyalgia are associated with numerous infectious agents, including parasites, but the association of fibromyalgia and T. cruzi, was not found.
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http://dx.doi.org/10.1016/j.clnesp.2021.01.037DOI Listing
April 2021

A Fundamental Role for Oxidants and Intracellular Calcium Signals in Alzheimer's Pathogenesis-And How a Comprehensive Antioxidant Strategy May Aid Prevention of This Disorder.

Int J Mol Sci 2021 Feb 21;22(4). Epub 2021 Feb 21.

Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Tel Hashomer 5262000, Israel.

Oxidative stress and increased cytoplasmic calcium are key mediators of the detrimental effects on neuronal function and survival in Alzheimer's disease (AD). Pathways whereby these perturbations arise, and then prevent dendritic spine formation, promote tau hyperphosphorylation, further amplify amyloid β generation, and induce neuronal apoptosis, are described. A comprehensive program of nutraceutical supplementation, comprised of the NADPH oxidase inhibitor phycocyanobilin, phase two inducers, the mitochondrial antioxidant astaxanthin, and the glutathione precursor N-acetylcysteine, may have important potential for antagonizing the toxic effects of amyloid β on neurons and thereby aiding prevention of AD. Moreover, nutraceutical antioxidant strategies may oppose the adverse impact of amyloid β oligomers on astrocyte clearance of glutamate, and on the ability of brain capillaries to export amyloid β monomers/oligomers from the brain. Antioxidants, docosahexaenoic acid (DHA), and vitamin D, have potential for suppressing microglial production of interleukin-1β, which potentiates the neurotoxicity of amyloid β. Epidemiology suggests that a health-promoting lifestyle, incorporating a prudent diet, regular vigorous exercise, and other feasible measures, can cut the high risk for AD among the elderly by up to 60%. Conceivably, complementing such lifestyle measures with long-term adherence to the sort of nutraceutical regimen outlined here may drive down risk for AD even further.
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http://dx.doi.org/10.3390/ijms22042140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926325PMC
February 2021

Sex disparities and neutralizing antibody durability to SARS-CoV-2 infection in convalescent individuals.

medRxiv 2021 Feb 3. Epub 2021 Feb 3.

Department of Medicine, Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill NC 27599, USA.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) has now caused over 2 million deaths worldwide and continues to expand. Currently, much is unknown about functionally neutralizing human antibody responses and durability to SARS-CoV-2. Using convalescent sera collected from 101 COVID-19 recovered individuals 21-212 days after symptom onset with forty-eight additional longitudinal samples, we measured functionality and durability of serum antibodies. We also evaluated associations between individual demographic and clinical parameters with functional neutralizing antibody responses to COVID-19. We found robust antibody durability out to six months, as well as significant positive associations with the magnitude of the neutralizing antibody response and male sex. We also show that SARS-CoV-2 convalescent neutralizing antibodies are higher in individuals with cardio-metabolic comorbidities.

Significance: In this study we found that neutralizing antibody responses in COVID-19 convalescent individuals vary in magnitude but are durable and correlate well with RBD Ig binding antibody levels compared to other SARS-CoV-2 antigen responses. In our cohort, higher neutralizing antibody titers are independently and significantly associated with male sex compared to female sex. We also show for the first time, that higher convalescent antibody titers in male donors are associated with increased age and symptom grade. Furthermore, cardio-metabolic co-morbidities are associated with higher antibody titers independently of sex. Here, we present an in-depth evaluation of serologic, demographic, and clinical correlates of functional antibody responses and durability to SARS-CoV-2.
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http://dx.doi.org/10.1101/2021.02.01.21250493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872367PMC
February 2021

The Aging Bowel Dysfunction and Elderly Vulnerability towards COVID-19 Infection.

Life (Basel) 2021 Jan 28;11(2). Epub 2021 Jan 28.

Catalytic Longevity, San Diego, CA 92109, USA.

Severe acute respiratory syndrome coronavirus 2, primarily a respiratory tract virus, also affects the enteric organs. The most affected sector of the community are the retirement and nursing home elderly residents. Along their life the senescent gastrointestinal functions are deteriorating and failing to fully execute their digestive, absorptive, mucosal barriers, and immune protective duties. Adding the decreased motility, increased intestinal permeability, dysbiosis, morbid chronic disease background, the consumed polypharmacy enteric adverse effects to the presence of the SARS-CoV-2 host receptor along the intestinal tracts put the basis for the current hypothesis. It is hypothesized that the disadvantages and failures of the aging enteric tract contribute to the elderly morbidity and mortality during the current new coronavirus pandemic. In a more optimistic look, several nutraceuticals can prevent or restore the dysfunctional intestinal barrier functions, mainly in the elderly and potentially in those who are SARS-CoV-2 infected.
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http://dx.doi.org/10.3390/life11020097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912227PMC
January 2021

Nutraceutical induction and mimicry of heme oxygenase activity as a strategy for controlling excitotoxicity in brain trauma and ischemic stroke: focus on oxidative stress.

Expert Rev Neurother 2021 02 28;21(2):157-168. Epub 2020 Dec 28.

Technion Israel Institute of Technology Ruth and Bruce Rappaport Faculty of Medicine- Research, Haifa, Israel (Retired).

: Ischemic stroke and traumatic brain injury are leading causes of acute mortality, and in the longer run, major causes of significant mental and physical impairment. Most of the brain neuronal cell death in the minutes and hours following an ischemic stroke or brain trauma is mediated by the process of excitotoxicity, in which sustained elevations of extracellular glutamate, reflecting a failure of ATP-dependent mechanism which sequester glutamate in neurons and astrocytes, drive excessive activation of NMDA receptors. : A literature search was undertaken to clarify the molecular mechanisms whereby excessive NMDA activation leads to excitotoxic neuronal death, and to determine what safe nutraceutical agents might have practical potential for rescuing at-risk neurons by intervening in these mechanisms. : Activation of both NADPH oxidase and neuronal nitric oxide synthase in the microenvironment of activated NMDA receptors drives production of superoxide and highly toxic peroxynitrite. This leads to excessive activation of PARP and p38 MAP kinase, mitochondrial dysfunction, and subsequent neuronal death. Heme oxygenase-1 (HO-1) induction offers protection via inhibition of NADPH oxidase and promotion of cGMP generation. Phase 2-inductive nutraceuticals can induce HO-1, and other nutraceuticals can mimic the effects of its products biliverdin and carbon monoxide.
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http://dx.doi.org/10.1080/14737175.2021.1861940DOI Listing
February 2021

Sjögren syndrome associated with protein-losing enteropathy: case-based review.

Clin Rheumatol 2021 Jun 3;40(6):2491-2497. Epub 2020 Nov 3.

Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Tel Hashomer, Israel.

The association between Sjögren's syndrome (SS) and protein-losing enteropathy (PLE) was scarcly reported. To analyze the clinical, therapeutic, and outcome characteristics of patients with SS and PLE and also to delineate the potential mechanisms and pathways connecting the gut to SS targeted organ's pathology. Systematic screening was conducted using PubMed/MEDLINE, LILACS, SciELO, Web of Science, and Cochrane, dating 1980 to 2020. SS and PLE were the key words. Eighteen patients with SS and PLE were summarized. The patient's ages ranged between 20 and 88 years, and only 4 were males. Primary SS was observed in most cases. Anti-Ro was detected in 100% of the cases while anti-La was reported in 64% of them. The clinical manifestations were protein loss, edema of the lower limbs, pleural effusion, ascites, facial edema, anasarca, diarrhea, and weight loss. Among these clinical manifestations, edema of the lower limbs was the most severe. Albumin concentration was 0.9-3.4 g/dL which increased to 2.8-4.3 g/dL after treatment. Small bowel biopsy was performed in all of the cases. Concerning the therapy, all the patients received systemic glucocorticoids. All of them improved. The period of onset of improvement ranged from 3 weeks to 36 months (an average of 3 months). The early diagnosis and appropriate therapy of PLE in patients with anti-Ro positive SS and who present edema, anasarca, or hypoalbuminemia is vital for a beneficial outcome. An excellent clinical improvement in all the cases was observed when treated early enough by cortico-therapy, thus preventing patient's deterioration, complications, and reducing morbidity and potential mortality.
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http://dx.doi.org/10.1007/s10067-020-05487-5DOI Listing
June 2021

Perspective: Prospects for Nutraceutical Support of Intestinal Barrier Function.

Adv Nutr 2021 03;12(2):316-324

Chaim Sheba Medical Center, Zabludowicz Center for Autoimmune Diseases, Tel-Hashomer, Israel.

Impairment of intestinal barrier function is linked to certain pathologies and to aging, and can be a cause of bacterial infections, systemic and hepatic inflammation, food allergies, and autoimmune disorders. The formation and maintenance of intestinal tight junctions is supported by glucagon-like peptide-2 (GLP-2), which via insulin-like growth factor I activity boosts phosphoinositide 3-kinase/Akt/mammalian target of rapamycin complex 1 (PI3K/Akt/mTORC1) signaling in enterocytes. 5'-AMP-activated protein kinase (AMPK) activity as well as estrogen receptor-β (ERβ) activity are also protective in this regard. Conversely, activation of mitogen-activated protein kinases (MAPKs) and cellular Src (c-Src) under inflammatory conditions can induce dissociation of tight junctions. Hence, nutraceuticals that promote GLP-2 secretion from L cells-effective pre/probiotics, glycine, and glutamine-as well as diets rich in soluble fiber or resistant starch, can support intestinal barrier function. AMPK activators-notably berberine and the butyric acid produced by health-promoting microflora-are also beneficial in this regard, as are soy isoflavones, which function as selective agonists for ERβ. The adverse impact of MAPK and c-Src overactivation on the intestinal barrier can be combatted with various antioxidant measures, including phycocyanobilin, phase 2-inducer nutraceuticals, and N-acetylcysteine. These considerations suggest that rationally designed functional foods or complex supplementation programs could have clinical potential for supporting and restoring healthful intestinal barrier function.
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http://dx.doi.org/10.1093/advances/nmaa139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243597PMC
March 2021

Feed your microbiome and your heart: The gut-heart axis.

Front Biosci (Landmark Ed) 2021 01 1;26:468-477. Epub 2021 Jan 1.

AESKU.KIPP Institute, Mikroforum Ring 2, Wendelsheim, 55234, Germany.

Cardiovascular and metabolic diseases are the leading causes of disability, morbidity, and mortality worldwide. Genetics plays an important role, but environmental factors change the game and hold the potential for prevention, reversibility, and applied therapy. Nutrition, phenotype, and behavior of microorganisms, intestinal eco-events, and intestinal permeability play a crucial role in the induction of diseases. The present mini-review summarizes nutrients, diets, microbial manipulations, and tight junction function modifiers that might prevent, modulate, or treat certain diseases.
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http://dx.doi.org/10.2741/4902DOI Listing
January 2021

Perspective: Low Risk of Parkinson's Disease in Quasi-Vegan Cultures May Reflect GCN2-Mediated Upregulation of Parkin.

Adv Nutr 2021 03;12(2):355-362

Research Department, Rapaport School of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Mitochondrial dysfunction in dopaminergic neurons of the substantia nigra (SN) appears to be a key mediating feature of Parkinson's disease (PD), a complex neurodegenerative disorder of still unknown etiology. Parkin is an E3 ubiquitin ligase that promotes mitophagy of damaged depolarized mitochondria while also boosting mitochondrial biogenesis-thereby helping to maintain efficient mitochondrial function. Boosting Parkin expression in the SN with viral vectors is protective in multiple rodent models of PD. Conversely, homozygosity for inactivating mutations of Parkin results in early-onset PD. Moderate protein plant-based diets relatively low in certain essential amino acids have the potential to boost Parkin expression by activating the kinase GCN2, which in turn boosts the expression of ATF4, a factor that drives transcription of the Parkin gene. Protein-restricted diets also upregulate the expression of PINK1, a protein that binds to the outer membrane of depolarized mitochondria and then recruits and activates Parkin. This effect of protein restriction is mediated by the downregulation of the kinase activity of mammalian target of rapamycin complex 1; the latter suppresses PINK1 expression at the transcriptional level. During the 20th century, cultures in East Asia and sub-Sahara Africa consuming quasi-vegan diets were found to be at notably decreased risk of PD compared with the USA or Europe. It is proposed that such diets may provide protection from PD by boosting Parkin and PINK1 expression in the SN. Other measures that might be expected to upregulate protective mitophagy include supplemental N-acetylcysteine (precursor for hydrogen sulfide) and a diet rich in spermidine-a polyamine notably high in corn.
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http://dx.doi.org/10.1093/advances/nmaa112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009740PMC
March 2021

Candida albicans in celiac disease: A wolf in sheep's clothing.

Autoimmun Rev 2020 Sep 18;19(9):102621. Epub 2020 Jul 18.

AESKU, KIPP Institute, Wendelsheim, Germany.

Candida albicans is a commensal fungus with a potential pathogenicity and celiac disease is an autoimmune condition. Both share multiple pathophysiological junctions, including serological markers against cell-wall proteins of Candida, anti-gliadin antibodies are positive in both entities, gluten and a candidal virulence factor share sequence similarity and the autoantigen of celiac disease, the tissue transglutaminase, is pivotal in Candida albicans commensalism and hostile behavior and its covalently cross linked products are stable and resistant to breakdown in the two entities. Those autoimmune/infectious cross roads are the basis for the hypothesis that Candida albicans is an additional environmental factor for celiac disease autoimmunogenesis.
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http://dx.doi.org/10.1016/j.autrev.2020.102621DOI Listing
September 2020

[THE GUT FEELING OF THE EYES: GUT-EYE AXIS].

Harefuah 2020 Jun;159(6):455-457

Clalit Health Services, Sharon-Shomron district, Israel.

Introduction: In intestinal diseases there are ophthalmological abnormalities. In celiac disease, for example, the eyes' pathologies are expressed by motoric, neurological, inflammatory, autoimmune, vision sharpness, dryness, redness, conjunctivitis and cataract tendency etc. It appears that intestinal luminal components and processes can irradiate to peripheral organs, including to the eyes, inducing functional abnormalities in this target organ. The present review describes the luminal and mucosal constituents and processes, the sensing mechanisms of those generated signals and the routes to deliver those messages to remote organs, eyes included. The gut-eye axis is very challenging and its exploration might bring future therapeutic strategies to treat ophthalmological disease.
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June 2020

Nutraceuticals Targeting Generation and Oxidant Activity of Peroxynitrite May Aid Prevention and Control of Parkinson's Disease.

Int J Mol Sci 2020 May 21;21(10). Epub 2020 May 21.

B. Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa 3525422, Israel.

Parkinson's disease (PD) is a chronic low-grade inflammatory process in which activated microglia generate cytotoxic factors-most prominently peroxynitrite-which induce the death and dysfunction of neighboring dopaminergic neurons. Dying neurons then release damage-associated molecular pattern proteins such as high mobility group box 1 which act on microglia via a range of receptors to amplify microglial activation. Since peroxynitrite is a key mediator in this process, it is proposed that nutraceutical measures which either suppress microglial production of peroxynitrite, or which promote the scavenging of peroxynitrite-derived oxidants, should have value for the prevention and control of PD. Peroxynitrite production can be quelled by suppressing activation of microglial NADPH oxidase-the source of its precursor superoxide-or by down-regulating the signaling pathways that promote microglial expression of inducible nitric oxide synthase (iNOS). Phycocyanobilin of spirulina, ferulic acid, long-chain omega-3 fatty acids, good vitamin D status, promotion of hydrogen sulfide production with taurine and N-acetylcysteine, caffeine, epigallocatechin-gallate, butyrogenic dietary fiber, and probiotics may have potential for blunting microglial iNOS induction. Scavenging of peroxynitrite-derived radicals may be amplified with supplemental zinc or inosine. Astaxanthin has potential for protecting the mitochondrial respiratory chain from peroxynitrite and environmental mitochondrial toxins. Healthful programs of nutraceutical supplementation may prove to be useful and feasible in the primary prevention or slow progression of pre-existing PD. Since damage to the mitochondria in dopaminergic neurons by environmental toxins is suspected to play a role in triggering the self-sustaining inflammation that drives PD pathogenesis, there is also reason to suspect that plant-based diets of modest protein content, and possibly a corn-rich diet high in spermidine, might provide protection from PD by boosting protective mitophagy and thereby aiding efficient mitochondrial function. Low-protein diets can also promote a more even response to levodopa therapy.
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http://dx.doi.org/10.3390/ijms21103624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279222PMC
May 2020

The temperature and pH repertoire of the transglutaminase family is expanding.

FEBS Open Bio 2020 04;10(4):492-494

AESKU.KIPP Institute, Wendelsheim, Germany.

Transglutaminases (TGs) play important roles in the food industry, pharmacology, and biotechnology, but as protein cross-linkers, their complexes are stable, resistant, immunogenic, and potentially pathogenic. Many TGs have been characterized, but they operate in narrow temperature and pH range limits. In a research article in this issue, Clemens Furnes and colleagues describe a novel cold-adapted TG from Atlantic cod, which expands the operating boundaries to a lower temperature and a wider pH. In this accompanying commentary, we discuss how this TG opens new applications in cold environments and can be deactivated by heating. New sources of TGs should be explored in hot environments like hot springs, in order to increase the temperature and widen the pH ranges for human and industrial benefits.
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http://dx.doi.org/10.1002/2211-5463.12839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137796PMC
April 2020

The Yin and Yang of dietary gluten transgressions in real-life scenarios of celiac patients.

BMC Med 2020 03 11;18(1):70. Epub 2020 Mar 11.

AESKU.KIPP Institute, Mikroforum Ring 2, 55234, Wendelsheim, Germany.

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http://dx.doi.org/10.1186/s12916-020-01535-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065308PMC
March 2020

Processed Food Additive Microbial Transglutaminase and Its Cross-Linked Gliadin Complexes Are Potential Public Health Concerns in Celiac Disease.

Int J Mol Sci 2020 Feb 8;21(3). Epub 2020 Feb 8.

AESKU.KIPP Institute, Mikroforum Ring 2, 55234 Wendelsheim, Germany.

Microbial transglutaminase (mTG) is a survival factor for microbes, but yeasts, fungi, and plants also produce transglutaminase. mTG is a cross-linker that is heavily consumed as a protein glue in multiple processed food industries. According to the manufacturers' claims, microbial transglutaminase and its cross-linked products are safe, i.e., nonallergenic, nonimmunogenic, and nonpathogenic. The regulatory authorities declare it as "generally recognized as safe" for public users. However, scientific observations are accumulating concerning its undesirable effects on human health. Functionally, mTG imitates its family member, tissue transglutaminase, which is the autoantigen of celiac disease. Both these transglutaminases mediate cross-linked complexes, which are immunogenic in celiac patients. The enzyme enhances intestinal permeability, suppresses mechanical (mucus) and immunological (anti phagocytic) enteric protective barriers, stimulates luminal bacterial growth, and augments the uptake of gliadin peptide. mTG and gliadin molecules are cotranscytosed through the enterocytes and deposited subepithelially. Moreover, mucosal dendritic cell surface transglutaminase induces gliadin endocytosis, and the enzyme-treated wheat products are immunoreactive in CD patients. The present review summarizes and updates the potentially detrimental effects of mTG, aiming to stimulate scientific and regulatory debates on its safety, to protect the public from the enzyme's unwanted effects.
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http://dx.doi.org/10.3390/ijms21031127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037116PMC
February 2020
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