Publications by authors named "Jacek M Witkowski"

101 Publications

Targeting Impaired Antimicrobial Immunity in the Brain for the Treatment of Alzheimer's Disease.

Neuropsychiatr Dis Treat 2021 4;17:1311-1339. Epub 2021 May 4.

Department of Pathophysiology, Medical University of Gdansk, Gdansk, Poland.

Alzheimer's disease (AD) is the most common form of dementia and aging is the most common risk factor for developing the disease. The etiology of AD is not known but AD may be considered as a clinical syndrome with multiple causal pathways contributing to it. The amyloid cascade hypothesis, claiming that excess production or reduced clearance of amyloid-beta (Aβ) and its aggregation into amyloid plaques, was accepted for a long time as the main cause of AD. However, many studies showed that Aβ is a frequent consequence of many challenges/pathologic processes occurring in the brain for decades. A key factor, sustained by experimental data, is that low-grade infection leading to production and deposition of Aβ, which has antimicrobial activity, precedes the development of clinically apparent AD. This infection is chronic, low grade, largely clinically silent for decades because of a nearly efficient antimicrobial immune response in the brain. A chronic inflammatory state is induced that results in neurodegeneration. Interventions that appear to prevent, retard or mitigate the development of AD also appear to modify the disease. In this review, we conceptualize further that the changes in the brain antimicrobial immune response during aging and especially in AD sufferers serve as a foundation that could lead to improved treatment strategies for preventing or decreasing the progression of AD in a disease-modifying treatment.
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http://dx.doi.org/10.2147/NDT.S264910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106529PMC
May 2021

Nigella sativa oil inhibits proliferation and stimulates apoptosis of human lymphocytes in vitro.

Hum Immunol 2021 May 8. Epub 2021 May 8.

Department of Pathophysiology, Faculty of Medicine, Medical University of Gdansk, Poland.

The study aimed to examine the in vitro influence of Nigella sativa oil on human lymphocytes. Cells were stimulated with a monoclonal anti-CD3 antibody in the presence of serial oil ethanol dilutions. Then their proliferation and apoptosis rates were assessed using flow cytometry. Our results demonstrate that the lowest dilutions (1:1 and 1:10) of Nigella sativa oil inhibited lymphocytes' proliferation. The number of cell divisions was 8, 1.25, 1.88 after stimulation with anti-CD3, or its combination with 1:1 and 1:10 oil dilution. The percentage of proliferating cells was 92.48%, 8.75%, 24.3% after stimulation with anti-CD3 antibody, or its combination with 1:1 and 1:10 oil dilution. The mean percentage of living cells was 81% after stimulation with anti-CD3, 13.6%, 19.9% in the presence of 1:1 and 1:10 oil dilution. The preliminary studies show that black seed oil has a potent antiproliferative and proapoptotic effect on human lymphocytes in vitro.
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http://dx.doi.org/10.1016/j.humimm.2021.04.010DOI Listing
May 2021

Associations between constipation symptoms and the sleep quality in non-dialysis chronic kidney disease patients: a cross-sectional study.

Pol Arch Intern Med 2021 Apr 27. Epub 2021 Apr 27.

Introduction: Sleep disturbances, similarly to constipation-related symptoms, are common problems in chronic kidney disease (CKD) patients and are associated with worse health-related quality of life.

Objectives: We aimed at detailing the sleep problems in conservatively-treated CKD patients, and at verifying the associations between the sleep quality and constipation in these patients.

Patients And Methods: In this cross-sectional study, 100 conservatively-treated CKD outpatients filled questionnaires that included questions addressing sleep quality (The Medical Outcomes Study 12-item Sleep Scale-Revised (MOS-Sleep-R)) and constipation-related symptoms (PAC-SYM, Rome III criteria).

Results: The T-scores of none of the assessed sleep domains differed significantly across the eGFR terciles (all P > 0.05). PAC-SYM abdominal and stool scales scores significantly correlated with all assessed sleep quality domains. In both univariable and multivariable regression models adjusted for key clinical data, functional constipation, having less than 7 bowel movements a week, abdominal discomfort and pain, as well as too small bowel movements, were independently associated with increased prevalence ratio of decreased sleep quality.

Conclusions: In non-dialysis CKD patients, sleep disorders can possess common etiological factors with constipation-related symptoms.
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http://dx.doi.org/10.20452/pamw.15974DOI Listing
April 2021

The dual role of the immune system in the course of COVID-19. The fatal impact of the aging immune system.

Cent Eur J Immunol 2021 18;46(1):1-9. Epub 2021 Apr 18.

Chair of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland.

COVID-19 is a highly contagious respiratory disease caused by the novel coronavirus SARS-CoV-2. Since October 2020 the second wave of the pandemic has been observed around the world, as pathogen specific herd immunity has not been built yet. Moreover, the current, more contagious pathogen carrying the D614G mutation has become the globally dominant form of SARS-CoV-2. In this article we present the current state of knowledge on the impact of ACE2 and the reninangiotensin system (RAS) and the innate immune system on different outcomes of COVID-19. Especially, we point out the dual role of the immune system and ACE2 in pathogenesis of the disease. Namely, at the initial stage of the infection anti-viral activity of innate immunity is responsible for inhibition of SARS-CoV-2 replication. On the other hand, a dysregulated immune response may cause the detrimental hyperinflammation ("cytokine storm") responsible for the severe course of the disease. Concomitantly, we analyse the roles of ACE2 in both facilitation of infection and abrogation of its effects, as the major cellular entry receptor for SARS-CoV-2 and an important enzyme responsible for tissue protection, respectively. Finally, we discuss the dominant impact of aging on the fatal outcome of COVID-19.
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http://dx.doi.org/10.5114/ceji.2021.105240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056340PMC
April 2021

The role of 299v in supporting treatment of selected diseases.

Cent Eur J Immunol 2020 25;45(4):488-493. Epub 2021 Jan 25.

Department of Surgical Oncology, Medical University of Gdansk, Gdansk, Poland.

Alterations in composition of human gut microbiome can lead to its dysbiosis. It is associated with gastrointestinal side effects during anti-cancer treatment, antibiotics administration, or infectious agents. There are studies confirming positive effect of consuming Lactobacillus plantarum 299v on intestinal microflora. This review summarizes the current knowledge about the role of L. plantarum 299v in supporting treatment of selected diseases, such as cancer, irritable bowel syndrome (IBS), and Clostridium difficile infection. The immunomodulating properties of L. plantarum 299v include an increase in the level of anti-inflammatory cytokines, which reduce the risk of cancer and improve the efficacy of regimens. The intake of L. plantarum 299v provides benefits for IBS patients, mainly due to normalization of stool and relief of abdominal pain, which significantly improves the quality of life of IBS patients. In addition, the intake of L. plantarum 299v prevents C. difficile-associated diarrhea among patients receiving antibiotic treatment. Due to the limited possibilities of treating these diseases and numerous complications of cancer treatment, there is a need for new therapeutic strategies. The administration of L. plantarum 299v seems to be useful in these cases.
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http://dx.doi.org/10.5114/ceji.2020.101515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882405PMC
January 2021

Proteodynamics and aging of eukaryotic cells.

Mech Ageing Dev 2021 03 6;194:111430. Epub 2021 Jan 6.

Research Center on Aging, Graduate Program in Immunology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Quebec, Canada.

All aspects of each protein existence in the eukaryotic cells, starting from the pre-translation events, through translation, multiple different post-translational modifications, functional life and eventual proteostatic removal after loss of functionality and changes in physico-chemical properties, can be collectively called the proteodynamics. With aging, passing of time as well as accumulating effects of exposures, interactions and wearing-off lead to problems at each of the above mentioned stages, eventually leading to general malfunction of the proteome. This work briefly reviews and summarizes current knowledge concerning this important topic.
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http://dx.doi.org/10.1016/j.mad.2021.111430DOI Listing
March 2021

Enhancement of Circulating and Intestinal T Regulatory Cells and Their Expression of Helios and Neuropilin-1 in Children with Inflammatory Bowel Disease.

J Inflamm Res 2020 26;13:995-1005. Epub 2020 Nov 26.

Department of Pediatrics, Pediatric Gastroenterology, Allergology and Nutrition, Medical University of Gdańsk, Gdańsk, Poland.

Background/aims: The proportions of intestinal and peripheral regulatory T cells (Tregs) in pediatric inflammatory bowel disease (IBD) were poorly investigated, as well as different subsets of these cells. Helios and Neuropilin-1 were proposed as markers differentiating between thymic and peripheral Tregs. Therefore, the aim of current work was to investigate the proportions of Tregs and expression of Helios and Neuropilin-1 in Tregs in peripheral blood and intestinal mucosa of children with inflammatory bowel disease.

Materials And Methods: Fifteen patients newly diagnosed with inflammatory bowel disease: ulcerative colitis (n=7) and Crohn's disease (n=8) were included in the study. Nine children who presented with no abnormalities in colonoscopy served as a control group. Quantification of regulatory T cells of the CD4CD25FOXP3 phenotype, as well as Helios and Neuropilin-1 in peripheral blood and bowel mucosa was based on multicolor flow cytometry.

Results: The rates of circulating and intestinal Tregs were significantly higher in the studied group than in the control group. The rate of intestinal T regulatory lymphocytes was significantly higher than circulating Tregs in patients with IBD, but not in the control group. The median proportion of circulating FOXP3Helios cells amounted to 24.83% in IBD patients and 15.93% in the controls. The median proportion of circulating FOXP3Nrp-1 cells was 34.23% in IBD and 21.01% in the control group. No statistically significant differences were noted for the circulating FOXP3Helios cells and FOXP3Nrp-1 cells between the studied and the control group.

Conclusion: The rates of circulating and intestinal T regulatory cells are increased in naïve pediatric patients with IBD. The rate of Tregs is higher in intestinal mucosa than in peripheral blood in patients with IBD. Flow cytometry is a valuable method assessing the composition of infiltrates in inflamed tissue. Helios and Neuropilin-1 likely cannot serve as markers to differentiate between natural and adaptive Tregs.
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http://dx.doi.org/10.2147/JIR.S268484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705274PMC
November 2020

Constipation and the Quality of Life in Conservatively Treated Chronic Kidney Disease Patients: A Cross-sectional Study.

Int J Med Sci 2020 18;17(18):2954-2963. Epub 2020 Oct 18.

Department of Nephrology, Transplantology and Internal Medicine, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.

Constipation is a common gastrointestinal disorder that in general population is associated with worse health-related quality of life (HRQoL). The epidemiology of constipation has not been reliably determined in conservatively-treated CKD patients. We aimed to determine the prevalence of constipation and constipation-related symptoms in conservatively-treated CKD patients, to find factors associated with their altered prevalence ratio (PR), and to verify the associations between constipation and HRQoL. In this cross-sectional study, 111 conservatively-treated CKD outpatients fulfilled questionnaires that included questions addressing HRQoL (SF-36v2®), constipation-related symptoms (The Patient Assessment of Constipation-Symptoms questionnaire), the Bristol stool form scale (BSFS), Rome III criteria of functional constipation (FC), and frequency of bowel movement (BM). Depending on the used definition, the prevalence of constipation was 6.6-28.9%. Diuretics and paracetamol were independently associated with increased PR of BSFS-diagnosed constipation (PR 2.86, 95% CI 1.28-6.37, = 0.01) and FC (PR 2.67, 95% CI 1.07-6.64, = 0.035), respectively. The most commonly reported symptoms were bloating (50.9%) and straining to pass a BM (42.7%). Abdominal discomfort (37.3%) was independently associated with worse scores in all analyzed HRQoL domains. In multiple regressions, FC and having <7 BM/week, but not BSFS-diagnosed constipation, were associated with lower scores in several HRQoL domains. Constipation and related symptoms are prevalent in CKD patients. FC and decreased frequency of defecation, but not BSFS-diagnosed constipation, are associated with worse assessment of HRQoL in conservatively-treated CKD patients.
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http://dx.doi.org/10.7150/ijms.49648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646105PMC
October 2020

Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework.

Mech Ageing Dev 2020 10 18;191:111316. Epub 2020 Jul 18.

Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, QC, H3A 2B4, Canada; Metabolic Disorders and Complications Program, and Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, H4A 3J1, Canada. Electronic address:

At a recent symposium on aging biology, a debate was held as to whether or not we know what biological aging is. Most of the participants were struck not only by the lack of consensus on this core question, but also on many basic tenets of the field. Accordingly, we undertook a systematic survey of our 71 participants on key questions that were raised during the debate and symposium, eliciting 37 responses. The results confirmed the impression from the symposium: there is marked disagreement on the most fundamental questions in the field, and little consensus on anything other than the heterogeneous nature of aging processes. Areas of major disagreement included what participants viewed as the essence of aging, when it begins, whether aging is programmed or not, whether we currently have a good understanding of aging mechanisms, whether aging is or will be quantifiable, whether aging will be treatable, and whether many non-aging species exist. These disagreements lay bare the urgent need for a more unified and cross-disciplinary paradigm in the biology of aging that will clarify both areas of agreement and disagreement, allowing research to proceed more efficiently. We suggest directions to encourage the emergence of such a paradigm.
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http://dx.doi.org/10.1016/j.mad.2020.111316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603428PMC
October 2020

Excessive amount and activity of μ-calpain affects apoptotic machinery in chronic B-cell leukemia cells and influences the course of the disease.

Acta Biochim Pol 2020 Jun;67(2):247-257

Gdańsk Medical University, Gdańsk, Poland.

B-cell Chronic Lymphocytic Leukemia (B-CLL) is the most common hematological disorder among middle-aged/elderly people in the Western countries. We have shown earlier that B-CLL cells exhibit elevated total amount and available activity of µ-calpain, belonging to a family of ubiquitous, strongly Ca-dependent proteases, involved in the control of proliferation and apoptosis. In this study we attempted to estimate a potential clinical value of μ-calpain in relation to B-CLL clinical staging in patients with extremely high lymphocytosis and studied the molecular mechanisms associating calpain activity with clinical progress of the disease. We observed significant correlations between the amounts of intracellular μ-calpain and clinical staging of the disease, with RAI stage 1 corresponding to the highest calpain amounts in the leukemic cells. There was also a positive, statistically significant correlation between the amount of μ-calpain and phosphorylated (p)ZAP-70 in B-CLL lymphocytes. Calpain activity in the B-CLL cells is associated with decreased activities of pro-apoptotic caspases -3 and -9, and reciprocally with an increased amount of anti-apoptotic Bcl-2. Together, all of these findings make calpain activity in B-CLL cells a promising target modifying the properties of these cells and facilitating therapy. Finally, the proportion of CD19+ B cells with elevated μ-calpain and pZap-70 was markedly reduced in patients after successful therapy.
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http://dx.doi.org/10.18388/abp.2020_5226DOI Listing
June 2020

Targeting Infectious Agents as a Therapeutic Strategy in Alzheimer's Disease.

CNS Drugs 2020 07;34(7):673-695

Department of Microbiology and Infectious diseases, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC, Canada.

Alzheimer's disease (AD) is the most prevalent dementia in the world. Its cause(s) are presently largely unknown. The most common explanation for AD, now, is the amyloid cascade hypothesis, which states that the cause of AD is senile plaque formation by the amyloid β peptide, and the formation of neurofibrillary tangles by hyperphosphorylated tau. A second, burgeoning theory by which to explain AD is based on the infection hypothesis. Much experimental and epidemiological data support the involvement of infections in the development of dementia. According to this mechanism, the infection either directly or via microbial virulence factors precedes the formation of amyloid β plaques. The amyloid β peptide, possessing antimicrobial properties, may be beneficial at an early stage of AD, but becomes detrimental with the progression of the disease, concomitantly with alterations to the innate immune system at both the peripheral and central levels. Infection results in neuroinflammation, leading to, and sustained by, systemic inflammation, causing eventual neurodegeneration, and the senescence of the immune cells. The sources of AD-involved microbes are various body microbiome communities from the gut, mouth, nose, and skin. The infection hypothesis of AD opens a vista to new therapeutic approaches, either by treating the infection itself or modulating the immune system, its senescence, or the body's metabolism, either separately, in parallel, or in a multi-step way.
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http://dx.doi.org/10.1007/s40263-020-00737-1DOI Listing
July 2020

Natural Killer Cells, Aging, and Vaccination.

Interdiscip Top Gerontol Geriatr 2020 9;43:18-35. Epub 2020 Apr 9.

Research Center on Aging, Graduate Program in Immunology, Faculty of Medicine and Health Sciences, Department of Medicine, University of Sherbrooke, Sherbrooke, Québec, Canada,

Aging is associated with changes in the immune system. Both (innate and adaptive) arms of the immune system are involved. Natural killer (NK) cells are part of the innate immune system. They participate in host defense by eliminating cells that are virally infected, transformed, or senescent. They are also able to modulate the adaptive part of the immune system. As all cells, NK cells are subjected to changes with aging, which affects both their phenotype and functions. Aging is associated with various latent chronic viral infections, and the most significant among them is CMV. It is difficult to distinguish between the influence of CMV infection and that of aging itself on the NK cell properties. Recently, NK cells have been shown to be an important player in vaccine efficacy, which is also decreased with aging. In this chapter, we describe age-related changes in NK cells and their possible influence on the efficacy of vaccination in old age.
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http://dx.doi.org/10.1159/000504493DOI Listing
June 2020

Characterization of three-dimensional rat central nervous system culture maturation, with applications to monitor cholinergic integrity.

Biotechnol Prog 2020 07 13;36(4):e2976. Epub 2020 Feb 13.

Department of Medicine, Faculté de médecine et des sciences de la santé, Centre de recherche sur le vieillissement, Université de Sherbrooke, Sherbrooke, Québec, Canada.

Studying age-related neuropathologies in vitro requires a three-dimensional (3D) culture system presenting mature phenotypes. In this study, we aimed to determine whether aged reaggregate cultures physiologically represent mature brain tissue. Results support that embryo-derived rat central nervous system (CNS) reaggregate cultures develop into mature-like tissues, comparable to in vivo maturation, including the following characteristics: (a) progressive reduction in cell proliferation (reduced anti-Ki-67 immunoreactivity), (b) progressive restriction of long neurite growth potential (as explant cultures), and (c) increased and sustained synaptic enzyme (acetylcholine esterase, AChE) activity. The acquisition of mature-like reaggregate cultures has allowed us to pursue the hypothesis that the physiological integrity of 3D CNS cultures may be monitored by synaptic enzyme activity. To assess this hypothesis, mature-like reaggregates were exposed to H O , glutamate, or amyloid β(1-42); each resulted in diminished AChE activity. H O exposure resulted in nuclear fragmentation. Glutamate and amyloid β(1-42) exposure resulted in acetylcholine content reduction. Simultaneous reduction of AChE activity and acetylcholine content verified diminished cholinergic integrity. This scheme exploiting synapse enzyme activity of mature-like 3D CNS tissue is therefore applicable to age-related neuropathology research including in vitro screening of conditions potentially affecting synapse integrity, including the promotion of dementia.
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http://dx.doi.org/10.1002/btpr.2976DOI Listing
July 2020

Are We Ill Because We Age?

Front Physiol 2019 18;10:1508. Epub 2019 Dec 18.

Department of Pathophysiology, Medical University of Gdansk, Gdansk, Poland.

Growing elderly populations, sometimes referred to as gray (or silver) tsunami, are an increasingly serious health and socioeconomic concern for modern societies. Science has made tremendous progress in the understanding of aging itself, which has helped medicine to extend life expectancies. With the increase of the life expectancy, the incidence of chronic age-related diseases (ARDs) has also increased. A new approach trying to solve this problem is the concept of geroscience. This concept implies that the aging process itself is the common cause of all ARDs. The corollary and consequence of such thinking is that we can and should treat aging itself as a disease. How to translate this into the medical practice is a big challenge, but if we consider aging as a disease the problem is solved. However, as there is no common definition of what aging is, what its causes are, why it occurs, and what should be the target(s) for interventions, it is impossible to conclude that aging is a disease. On the contrary, aging should be strongly considered not to be a disease and as such should not be treated; nonetheless, aging is likely amenable to optimization of changes/adaptations at an individual level to achieve a better functional healthspan.
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http://dx.doi.org/10.3389/fphys.2019.01508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951428PMC
December 2019

Should we Try to Alleviate Immunosenescence and Inflammaging - Why, How and to What Extent?

Curr Pharm Des 2019 ;25(39):4154-4162

Research Center on Aging, Faculty of Medicine and Health Sciences, Department of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada.

With advancing age, immune responses of human beings to external pathogens, i.e., bacteria, viruses, fungi and parasites, and to internal pathogens - malignant neoplasm cells - become less effective. Two major features in the process of aging of the human immune system are immunosenescence and inflammaging. The immune systems of our predecessors co-evolved with pathogens, which led to the occurrence of effective immunity. However, the otherwise beneficial activity may pose problems to the organism of the host and so it has builtin brakes (regulatory immune cells) and - with age - it undergoes adaptations and modifications, examples of which are the mentioned inflammaging and immunosenescence. Here we describe the mechanisms that first created our immune systems, then the consequences of their changes associated with aging, and the mechanisms of inflammaging and immunosenescence. Finally, we discuss to what extent both processes are detrimental and to what extent they might be beneficial and propose some therapeutic approaches for their wise control.
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http://dx.doi.org/10.2174/1381612825666191111153016DOI Listing
July 2020

Chemical variability of Rhododendron tomentosum (Ledum palustre) essential oils and their pro-apoptotic effect on lymphocytes and rheumatoid arthritis synoviocytes.

Fitoterapia 2019 Nov 28;139:104402. Epub 2019 Oct 28.

Department of Pharmacognosy, Medical University of Gdansk, Hallera 107, 80-416 Gdansk, Poland. Electronic address:

Rhododendron tomentosum (Ledum palustre) is an aromatic plant traditionally used for alleviating rheumatic complaints which makes it a potential candidate for a natural drug in rheumatoid arthritis (RA) treatment. However, the effects of plants' volatiles on apoptosis of synovial fibroblasts and infiltrating leucocytes of RA synovia, have not been reported. Volatile fraction of R. tomentosum is chemically variable and chemotypes of the plants need to be defined if the oil is to be used for therapeutic purposes. In the presented work, cluster analysis of literature data enabled to define 10 chemotypes of the plant. The volatile fractions of known composition were then tested for bioactivity using a RA-specific in vitro models. Essential oils of two wild types (γ-terpineol and palustrol/ledol type) and one in vitro chemotype (ledene oxide type) were obtained by hydrodistillation and their bioactivity was tested in two in vitro models: I - peripheral blood lymphocytes of healthy volunteers and II - synoviocytes and immune cells isolated from synovia of RA patients. The influence of oils on blood lymphocytes' proliferation and apoptosis rates of synovia-derived cells was determined by flow cytometry. Dose-dependent inhibitory effect of the serial dilutions of R. tomentosum oils on proliferation rates of blood lymphocytes was found. At 1:400 dilutions, all the tested oils increased the number of necrotic cells in synovial fibroblasts from RA synovia. Additionally, increased proportions of late apoptotic cells were observed in leucocyte populations subjected to oils at 1:400 dilution.
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http://dx.doi.org/10.1016/j.fitote.2019.104402DOI Listing
November 2019

The role of elastin-derived peptides in human physiology and diseases.

Matrix Biol 2019 11 8;84:81-96. Epub 2019 Jul 8.

Research Center on Aging, Faculty of Medicine and Health Sciences, Department of medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada(1). Electronic address:

Once considered as inert, the extracellular matrix recently revealed to be biologically active. Elastin is one of the most important components of the extracellular matrix. Many vital organs including arteries, lungs and skin contain high amounts of elastin to assure their correct function. Physiologically, the organism contains a determined quantity of elastin from the early development which may remain physiologically constant due to its very long half-life and very low turnover. Taking into consideration the continuously ongoing challenges during life, there is a physiological degradation of elastin into elastin-derived peptides which is accentuated in several disease states such as obstructive pulmonary diseases, atherosclerosis and aortic aneurysm. These elastin-derived peptides have been shown to have various biological effects mediated through their interaction with their cognate receptor called elastin receptor complex eliciting several signal transduction pathways. In this review, we will describe the production and the biological effects of elastin-derived peptides in physiology and pathology.
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http://dx.doi.org/10.1016/j.matbio.2019.07.004DOI Listing
November 2019

Lactulose: Patient- and dose-dependent prebiotic properties in humans.

Anaerobe 2019 Oct 5;59:100-106. Epub 2019 Jun 5.

Department of Pathophysiology, Faculty of Medicine, Medical University of Gdańsk, ul. Dębinki 7, 80-211, Gdańsk, Poland.

Lactulose is a disaccharide used in clinical practice since 1957 and has since been tested in the treatment of many human disorders, including chronic constipation, hepatic encephalopathy, and chronic kidney disease. Its mode of action is based on the lactulose fermentation by intestinal microbiota. Based on in silico, in vitro and in vivo studies we comprehensively review here the impact of lactulose on human gut/fecal and vaginal microbiota composition and both fecal and blood metabolomes. However, both in vitro and in vivo studies summarized in this review have revealed that the effects of lactulose on human microbiota composition are both patient- and dose-dependent. This highlights the need of heterogeneity indication in clinical trials.
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http://dx.doi.org/10.1016/j.anaerobe.2019.06.002DOI Listing
October 2019

Human Inflammaging.

Gerontology 2019 3;65(5):495-504. Epub 2019 May 3.

Department of Pathophysiology, Medical University of Gdansk, Gdansk, Poland.

Human aging is a very complex process that occurs in an intricate biological and physiological setting. Many changes occur with aging and among the most important are changes in immune reactivity associated with cell differentiation stages and the phenomenon of inflammaging, understood as subclinical inflammatory readiness, manifested by elevated levels of proinflammatory factors. It was stated for a long time that this tandem occurs in parallel or eventually sequentially. However, recent evidence points to the fact that, as both originate from chronic antigen stimulation, they mutually drive each other. In this context, inflammaging is considered the basis of most age-related diseases (ARD). In this review concerning human inflammaging, we argue that inflammatory diseases develop during whole life as a diverted (excessive) normal immune reaction to specific stressors. Thus, inflammaging may not be the cause of these diseases; however, it can be the trigger of clinical manifestation of ARD. In this context, the best intervention should aim to regulate the balance between pro- and anti-inflammatory signals and the more appropriate reaction to chronic stimulations to avoid/delay the appearance of associated diseases.
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http://dx.doi.org/10.1159/000497375DOI Listing
February 2020

Peripheral blood lymphocyte subpopulations in patients with bipolar disorder type II.

Sci Rep 2019 04 10;9(1):5869. Epub 2019 Apr 10.

Department of Pathophysiology, Medical University of Gdansk, Faculty of Medicine, Gdańsk, Poland.

We investigated the phenotype of peripheral blood lymphocytes of patients with bipolar disorder type II in different phases of the disease in order to check whether there are specific changes in the immune parameters. Lymphocytes subpopulations were analyzed ex vivo with flow cytometry in patients in euthymic, depression or hypomanic phase of the disease and compared with healthy controls. All BD patients were characterized by lower percentage of CD3CD4 and CD3CD8 cells compared with healthy people. But only patients in depression and remission had higher percentage of B cells (CD19 cells) compared with healthy people. The percentage of CD4CD25 and CD8CD25 cells was decreased in patients in hypomanic phase compared with healthy control. Patients in remission were characterized by increased concentrations of IL-6 and IL-10 and decreased level of TNF in blood serum. Significant correlations between immunologic parameters and the results of Hamilton or Young scale have also been found. Our results demonstrate that there are significant differences in lymphocyte subpopulations which depend on the phase of the disease the patient is currently in.
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http://dx.doi.org/10.1038/s41598-019-42482-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458153PMC
April 2019

The influence of a single hemodialysis procedure on human T lymphocytes.

Sci Rep 2019 03 25;9(1):5041. Epub 2019 Mar 25.

Department of Pathophysiology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.

At the moment it is unknown to what extent the impaired function of T lymphocytes in ESRD patients depends on uremia, and to what extent on hemodialysis (HD) procedure. Therefore, the purpose of the study was to evaluate percentages of T lymphocyte subpopulations ex vivo, plasma concentrations of IL12p70, TNF, IL-10, IL-6, IL-1β, IL-8 cytokines and selected proliferation parameters of in vitro activated T lymphocytes in HD patients before and after single HD procedure using flow cytometry. We demonstrated that the percentage of CD8 cells ex vivo was decreased while the CD4/CD8 ratio was increased after HD procedure. Also, there was significant decrease in the percentage of CD8HLA-DR, CD8CD69 and CD8CD95 cells after HD. At the same time, an increase in the percentage of CD4CD95 cells was observed after HD. From all analyzed cytokines, only the concentration of IL-8 was significantly decreased after HD procedure. A single HD session enhanced proliferation capacity of CD4 cells but not CD8 cells in vitro by increasing number of cell divisions and percentage of dividing cells. Our results show that a single hemodialysis can have immunomodulatory effect on HD patients and may contribute to the state of immune deficiency observed in patients with ESRD.
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http://dx.doi.org/10.1038/s41598-019-41619-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434050PMC
March 2019

Does HIV infection contribute to increased beta-amyloid synthesis and plaque formation leading to neurodegeneration and Alzheimer's disease?

J Neurovirol 2019 10 13;25(5):634-647. Epub 2019 Mar 13.

Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Quebec, Canada.

HIV infection in the combination antiretroviral therapy (cART) era has become a chronic disease with a life expectancy almost identical to those free from this infection. Concomitantly, chronic diseases such as neurodegenerative diseases have emerged as serious clinical problems. HIV-induced cognitive changes, although clinically very diverse are collectively called HIV-associated neurocognitive disorder (HAND). HAND, which until the introduction of cART manifested clinically as a subcortical disorder, is now considered primarily cognitive disorder, which makes it similar to diseases like Alzheimer's (AD) and Parkinson's disease (PD). The pathogenesis involves either the direct effects of the virus or the effect of viral proteins such as Tat, Ggp120, and Nef. These proteins are either capable of destroying neurons directly by inducing neurotoxic mediators or by initiating neuroinflammation by microglia and astrocytes. Recently, it has become recognized that HIV infection is associated with increased production of the beta-amyloid peptide (Aβ) which is a characteristic of AD. Moreover, amyloid plaques have also been demonstrated in the brains of patients suffering from HAND. Thus, the question arises whether this production of Aβ indicates that HAND may lead to AD or it is a form of AD or this increase in Aβ production is only a bystander effect. It has also been discovered that APP in HIV and its metabolic product Aβ in AD manifest antiviral innate immune peptide characteristics. This review attempts to bring together studies linking amyloid precursor protein (APP) and Aβ production in HIV infection and their possible impact on the course of HAND and AD. These data indicate that human defense mechanisms in HAND and AD are trying to contain microorganisms by antimicrobial peptides, however by employing different means. Future studies will, no doubt, uncover the relationship between HAND and AD and, hopefully, reveal novel treatment possibilities.
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http://dx.doi.org/10.1007/s13365-019-00732-3DOI Listing
October 2019

Immunological aspects of autoimmune thyroid disease - Complex interplay between cells and cytokines.

Cytokine 2019 04 1;116:128-133. Epub 2019 Feb 1.

Department of Pathology and Experimental Rheumatology, Medical University of Gdansk, Poland. Electronic address:

Autoimmune thyroid disease (ATD) is a chronic autoimmune thyroiditis with a complex pathogenesis including environmental factors, genetic background and immune system actions. Despite the large-scale research and discovery of new subpopulations of lymphocytes, cytokines, chemokines and their functions in the human body, the ethiology of ATD in many aspects remains a mystery. This article tries to summarize mostly the immunological aspects of this disease, including the roles of different cells types (dendritic cells, B cells, CD4 and CD8 T cells, NK cells and regulatory T cells) and of different cytokines (secreted by Th1/Th2/Th17/Th22 lymphocyte subpopulations and other, including the IL-23 and CXCL10). We describe the role of immunological abnormalities in the ATD pathogenesis and show that for some cells and cytokines their respective roles are not clear, and bi-directional action is possible. Finally, we propose a network of interactions between the immune cells and thyrocytes in the course of ATD.
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http://dx.doi.org/10.1016/j.cyto.2019.01.003DOI Listing
April 2019

T cells in IgA nephropathy: role in pathogenesis, clinical significance and potential therapeutic target.

Clin Exp Nephrol 2019 Mar 7;23(3):291-303. Epub 2018 Nov 7.

Department of Pathophysiology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 7, 80-211, Gdańsk, Poland.

Background: Immunoglobulin A nephropathy (IgAN), the most frequent cause of primary glomerulonephritis worldwide, is an autoimmune disease with complex pathogenesis. In this review, we focus on T cells and summarize knowledge about their involvement in pathophysiology and treatment of IgAN METHODS: We reviewed the literature for (1) alterations of T cell subpopulations in IgAN, (2) experimental and clinical proofs for T cells' participation in IgAN pathogenesis, (3) clinical correlations with T cell-associated alterations, and (4) influence of drugs used in IgAN therapy on T cell subpopulations.

Results: We found that IgAN is characterized by higher proportions of circulatory Th2, Tfh, Th17, Th22 and γδ T cells, but lower Th1 and Treg cells. We discuss genetic and epigenetic makeup that may contribute to this immunological phenotype. We found that Th2, Th17 and Tfh-type interleukins contribute to elevated synthesis of galactose-deficient IgA1 (Gd-IgA1) and that the production of anti-Gd-IgA1 autoantibodies may be stimulated by Tfh cells. We described the roles of Th2, Th17, Th22 and Treg cells in the renal injury and summarized correlations between T cell-associated alterations and clinical features of IgAN (proteinuria, reduced GFR, hematuria). We detailed the impact of immunosuppressive drugs on T cell subpopulations and found that the majority of drugs have nonoptimal influence on T cells in IgAN patients.

Conclusions: T cells play an important role in IgAN pathogenesis and are correlated with its clinical severity. Clinical trials with the drugs targeting the reported alterations of the T-cell compartment are highly desirable.
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http://dx.doi.org/10.1007/s10157-018-1665-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394565PMC
March 2019

The integration of inflammaging in age-related diseases.

Semin Immunol 2018 12 2;40:17-35. Epub 2018 Oct 2.

Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A⁎STAR), Immunos Building, Biopolis, Singapore, Singapore; Department of Biology, Faculty of Science, University Tunis El Manar, Tunis, Tunisia.

Aging is characterized by a morpho-functional adaptation, variably affecting major physiological systems, depending on a complex interaction between genetic, environmental and stochastic factors. This dynamic interaction drives an age-related remodelling of a number of pathways/systems, providing the chance to reach the extreme limit of human life in healthy state which is reflected in the ever-increasing number of centenarians. This conceptualization implies that aging process per se and the development of the most common age-related diseases (ARD) are somewhat separate but must share somehow common set of basic biological mechanisms. One of the features that characterize both processes is the development and progression of an inflammatory state named inflammaging. Notably, inflammaging is characterized by a peculiar presentation, being a chronic, systemic, low grade and therefore for a long time subclinical, inflammatory process. For these reasons, even if the rate of progression of inflammaging is currently recognized as the main force driving aging and one of the main risk factors for clinical morbidity and mortality in the elderly, current knowledge on the causal agents are still incomplete and the "clinical evaluation" of inflammaging has not yet been standardized. Even if a number of biomarkers of inflammaging have been identified, their analysis is not recommended as part of the routine evaluation of elderly patients. This review will aim to describe the concept of inflammaging within several other concepts such as the definition of aging per se and how we integrate it in the context of ARD.
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http://dx.doi.org/10.1016/j.smim.2018.09.003DOI Listing
December 2018

The Level of Cytokines in the Vitreous Body of Severe Proliferative Diabetic Retinopathy Patients Undergoing Posterior Vitrectomy.

Curr Pharm Des 2018 ;24(27):3276-3281

Department of Pathophysiology, Medical University of Gdansk, Gdansk, Poland.

Objective: The objective of the study was to compare cytokine levels in the vitreous body of patients with proliferative diabetic retinopathy (PDR) undergoing posterior vitrectomy.

Patients And Methods: The study included 39 patients (39 eyes) undergoing pars plana vitrectomy (PPV). Patients were divided into three groups: patients with proliferative diabetic retinopathy (PDR) without aflibercept injection prior to the surgery, PDR patients administered aflibercept injection prior to the surgery, and patients without diabetes mellitus (control group). All patients underwent a comprehensive eye examination one day before and 3 weeks after the surgery, including measurements of: best-corrected visual acuity (BVCA) and intraocular pressure (IOP), slit-lamp examination and spectral domain optical coherence tomography (SOCT). Concentrations of cytokines: IL-6, IL-8, IL-12p70, TNF, IL-10, IL-1β were measured in the vitreous body of patients with BD™ Cytometric Bead Array (CBA) Human Inflammatory Cytokines Kit.

Results: PDR patients who received pretreatment with aflibercept injection showed significantly lower concentrations of IL-12p70, TNF, IL-10 and IL-1β in the vitreous body compared to the control group. Meanwhile, patients without prior aflibercept injection had a significantly higher concentration of IL-8. There was also a significant positive correlation between IOP before PPV and IL-8 concentration in both PDR patients' groups.

Conclusion: Findings of our study suggest an important role of IL-8 in the development of severe PDR. Aflibercept administration on the day before elective vitrectomy facilitated the surgery.
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http://dx.doi.org/10.2174/1381612824666180926110704DOI Listing
November 2019

Can an Infection Hypothesis Explain the Beta Amyloid Hypothesis of Alzheimer's Disease?

Front Aging Neurosci 2018 24;10:224. Epub 2018 Jul 24.

Department of Microbiology and Infectious Diseases, University of Sherbrooke, Sherbrooke, QC, Canada.

Alzheimer's disease (AD) is the most frequent type of dementia. The pathological hallmarks of the disease are extracellular senile plaques composed of beta-amyloid peptide (Aβ) and intracellular neurofibrillary tangles composed of pTau. These findings led to the "beta-amyloid hypothesis" that proposes that Aβ is the major cause of AD. Clinical trials targeting Aβ in the brain have mostly failed, whether they attempted to decrease Aβ production by BACE inhibitors or by antibodies. These failures suggest a need to find new hypotheses to explain AD pathogenesis and generate new targets for intervention to prevent and treat the disease. Many years ago, the "infection hypothesis" was proposed, but received little attention. However, the recent discovery that Aβ is an antimicrobial peptide (AMP) acting against bacteria, fungi, and viruses gives increased credence to an infection hypothesis in the etiology of AD. We and others have shown that microbial infection increases the synthesis of this AMP. Here, we propose that the production of Aβ as an AMP will be beneficial on first microbial challenge but will become progressively detrimental as the infection becomes chronic and reactivates from time to time. Furthermore, we propose that host measures to remove excess Aβ decrease over time due to microglial senescence and microbial biofilm formation. We propose that this biofilm aggregates with Aβ to form the plaques in the brain of AD patients. In this review, we will develop this connection between Infection - Aβ - AD and discuss future possible treatments based on this paradigm.
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http://dx.doi.org/10.3389/fnagi.2018.00224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066504PMC
July 2018

Proliferation and apoptosis of T lymphocytes in patients with bipolar disorder.

Sci Rep 2018 02 20;8(1):3327. Epub 2018 Feb 20.

Department of Physiopathology, Medical University of Gdansk, Gdansk, Poland.

The aim of the study was to evaluate proliferation capacity and susceptibility to apoptosis of T lymphocytes of patients with bipolar disorder (BD) and to investigate in vitro influence of two standard mood stabilizers: lithium and valproic acid on these parameters using flow cytometry. Our results show that T lymphocytes of BD patients, especially those treated with lithium, have reduced proliferation capacity compared to healthy people. In vitro studies showed that valproic acid reduces the number of cell divisions and percentages of proliferating cells regardless of health status but mainly in very high dose, while lithium has no significant influence on proliferation capacity of patients' T lymphocytes. Lymphocytes of BD patients are also more prone to apoptosis compared with healthy individuals which is related to high expression of Bax, a pro-apoptotic protein. In vitro lithium protected patients' lymphocytes from apoptosis proportionally to dose used. Valproic acid protected lymphocytes of patients from apoptosis mainly in therapeutic concentration. Our results show that mood stabilizers used to prevent relapses of the disease have anti-apoptotic effect on T lymphocytes of BD patients but they are not able to improve their proliferation capacity.
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http://dx.doi.org/10.1038/s41598-018-21769-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820246PMC
February 2018

Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes?

Front Immunol 2017 10;8:1960. Epub 2018 Jan 10.

Italian National Research Center on Aging, Department of Experimental Pathology, University of Bologna, Bologna, Italy.

The immune system is the most important protective physiological system of the organism. It has many connections with other systems and is, in fact, often considered as part of the larger neuro-endocrine-immune axis. Most experimental data on immune changes with aging show a decline in many immune parameters when compared to young healthy subjects. The bulk of these changes is termed immunosenescence. Immunosenescence has been considered for some time as detrimental because it often leads to subclinical accumulation of pro-inflammatory factors and inflamm-aging. Together, immunosenescence and inflamm-aging are suggested to stand at the origin of most of the diseases of the elderly, such as infections, cancer, autoimmune disorders, and chronic inflammatory diseases. However, an increasing number of immune-gerontologists have challenged this negative interpretation of immunosenescence with respect to its significance in aging-related alterations of the immune system. If one considers these changes from an evolutionary perspective, they can be viewed preferably as adaptive or remodeling rather than solely detrimental. Whereas it is conceivable that global immune changes may lead to various diseases, it is also obvious that these changes may be needed for extended survival/longevity. Recent cumulative data suggest that, without the existence of the immunosenescence/inflamm-aging duo (representing two sides of the same phenomenon), human longevity would be greatly shortened. This review summarizes recent data on the dynamic reassessment of immune changes with aging. Accordingly, attempts to intervene on the aging immune system by targeting its rejuvenation, it may be more suitable to aim to maintain general homeostasis and function by appropriately improving immune-inflammatory-functions.
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http://dx.doi.org/10.3389/fimmu.2017.01960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767595PMC
January 2018

The significance of neonatal thymectomy for shaping the immune system in children with congenital heart defects.

Kardiochir Torakochirurgia Pol 2017 Dec 20;14(4):258-262. Epub 2017 Dec 20.

Department of Physiopathology, Medical University of Gdańsk, Poland.

The thymus plays an important role in the development of the immune cell pool; it serves as the primary location for T-lymphocyte maturation. Early cardiac surgical interventions for congenital heart defects are necessarily associated with thymectomy, i.e. the partial or complete removal of the thymus. A newborn infant already has a functioning thymus and developed cells of the immune system. However, thymectomy eliminates the primary location where T cells differentiate and mature. This study summarizes the current knowledge of the cellular disturbances and potential clinical consequences associated with performing thymectomy in children treated surgically for congenital heart defects.
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http://dx.doi.org/10.5114/kitp.2017.72231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767777PMC
December 2017