Both biofilm cytotoxicity and monocytes' adhesion may be used as estimators of enterococcal virulence.

Our study aimed to identify markers of enterococci's virulence potential by evaluating the properties of strains of different sites of isolation. Enterococcal strains were isolated as commensals from faeces and as invasive strains from the urine and blood of patients from the University Clinical Centre, Gdansk, Poland. Changes in monocytes' susceptibility to the cytotoxic activity of isolates of different origins and their adherence to biofilm were evaluated using a flow cytometer. The bacterial protein profile was estimated by matrix assisted laser desorption ionization-time of flight mass spectrometer. The cytotoxicity of biofilm and monocytes' adherence to it were the most accurate factors in predicting the prevalence of the strain in the specific niche. Additionally, a bacterial protein with mass-to-charge ratio (m/z) 5000 was found to be responsible for the increased bacterial cytotoxicity, while monocytes' decreased adherence to biofilm was linked with the presence of proteins either with m/z 3330 or 2435. The results illustrate that monocytes' reaction when exposed to the bacterial biofilm can be used as an estimator of pathogens' virulence potential. The observed differences in monocytes' response are explainable by the bacterial proteins' profile. Additionally, the results indicate that the features of both bacteria and monocytes impact the outcome of the infection.

Viruses - a major cause of amyloid deposition in the brain.

INTRODUCTION: Clinically, Alzheimer's disease (AD) is a syndrome with a spectrum of various cognitive disorders. There is a complete dissociation between the pathology and the clinical presentation. Therefore, we need a disruptive new approach to be able to prevent and treat AD. AREAS COVERED: In this review, the authors extensively discuss the evidence why the amyloid beta is not the pathological cause of AD which makes therefore the amyloid hypothesis not sustainable anymore. They review the experimental evidence underlying the role of microbes, especially that of viruses, as a trigger/cause for the production of amyloid beta leading to the establishment of a chronic neuroinflammation as the mediator manifesting decades later by AD as a clinical spectrum. In this context, the emergence and consequences of the infection/antimicrobial protection hypothesis are described. The epidemiological and clinical data supporting this hypothesis are also analyzed. EXPERT OPINION: For decades, we have known that viruses are involved in the pathogenesis of AD. This discovery was ignored and discarded for a long time. Now we should accept this fact, which is not a hypothesis anymore, and stimulate the research community to come up with new ideas, new treatments, and new concepts.

Longevity, Centenarians and Modified Cellular Proteodynamics.

We have shown before that at least one intracellular proteolytic system seems to be at least as abundant in the peripheral blood lymphocytes of centenarians as in the same cells of young individuals (with the cells of the elderly population showing a significant dip compared to both young and centenarian cohorts). Despite scarce published data, in this review, we tried to answer the question how do different types of cells of longevous people-nonagenarians to (semi)supercentenarians-maintain the quality and quantity of their structural and functional proteins? Specifically, we asked if more robust proteodynamics participate in longevity. We hypothesized that at least some factors controlling the maintenance of cellular proteomes in centenarians will remain at the "young" level (just performing better than in the average elderly). In our quest, we considered multiple aspects of cellular protein maintenance (proteodynamics), including the quality of transcribed DNA, its epigenetic changes, fidelity and quantitative features of transcription of both mRNA and noncoding RNAs, the process of translation, posttranslational modifications leading to maturation and functionalization of nascent proteins, and, finally, multiple facets of the process of elimination of misfolded, aggregated, and otherwise dysfunctional proteins (autophagy). We also included the status of mitochondria, especially production of ATP necessary for protein synthesis and maintenance. We found that with the exception of the latter and of chaperone function, practically all of the considered aspects did show better performance in centenarians than in the average elderly, and most of them approached the levels/activities seen in the cells of young individuals.

Ageing-resembling phenotype of long-term allogeneic hematopoietic cells recipients compared to their donors.

BACKGROUND: Ageing is a complex phenomenon that leads to decreased proliferative activity, loss of function of the cells, and cellular senescence. Senescence of the immune system exacerbates individual's immune response, both humoral and cellular but increases the frequency of infections. We hypothesized that physiological ageing of adaptive immune system occurs in recipients of allogeneic hematopoietic cells transplant (allo-HCT) at faster rate when compared to their respective donors since the small number of donor cells undergo immense proliferative stress restoring recipients hematopoiesis. We compared molecular characterizations of ageing between recipients and donors of allo-HCT: telomeric length and immunophenotypic changes in main lymphocyte subsets - CD4+, CD8+, CD19+, CD56+. RESULTS: Median telomeric length (TL) of CD8+ lymphocytes was significantly longer in donors compared to recipients (on average 2,1 kb and 1,7 kb respectively, p = 0,02). Similar trends were observed for CD4+ and CD19+ although the results did not reach statistical significance. We have also found trends in the immunophenotype between recipients and donors in the subpopulations of CD4+ (naïve and effector memory), CD8+ Eomes+ and B-lymphocytes (B1 and B2). Lower infection risk recipients had also a significantly greater percentage of NK cells (22,3%) than high-risk patients (9,3%) p = 0,04. CONCLUSION: Our data do not support the initial hypothesis of accelerated aging in the long term all-HCT recipients with the exception of the recipients lymphocytes (mainly CD8+) which present some molecular features, characteristic for physiological ageing (telomeric shortening, immunophenotype) when compared to their respective donors. However, a history of lower infection numbers in HCT recipients seems to be associated with increased percentage of NK cells. The history of GVHD seems not to affect the rate of ageing. Therefore, it is safe to conclude that the observed subtle differences between recipients' and donors' cells result mainly from the proliferative stress in the early period after allo-HCT and the difference between hosts' and recipients' microenvironments.

Prevalence and Severity of Lower Gastrointestinal Symptoms amongst Non-Dialysis Chronic Kidney Disease Patients: A Systematic Review and Meta-Analysis.

Chronic kidney disease (CKD) patients experience a wide range of symptoms that deteriorate their health-related quality of life (HRQoL). We aimed to estimate the prevalence and severity of lower gastrointestinal (GI) symptoms in non-dialysis CKD adult outpatients, and to summarize the relationships between these symptoms and HRQoL, laboratory test results, and clinical data. The protocol of the study was preregistered (PROSPERO CRD42021255122). We searched MEDLINE, Scopus, Web of Science, and grey literature sources from the databases' inception up until 27 November 2021. Wide citation chasing was conducted. Single proportions (prevalence of functional constipation, self-reported constipation, diarrhea, abdominal bloating, fecal incontinence, and abdominal/rectal pain) were pooled using generalized linear mixed models. A total of 37 studies with 12,074 patients were included. We found that lower GI symptoms, especially self-reported abdominal bloating [CKD G1-2: 48.45% (95% CI: 43.5-53.4%; 2 studies); G3: 46.95% (95% CI: 45.0-48.9%; 2 studies), G4-5: 36.1% (95% CI: 25.4-48.5%; 8 studies)] and constipation [CKD G1-2: 31.8% (95% CI: 13.9-54.9%); G3: 29.8% (95% CI: 21.2-40.1%; 4 studies); G4-5: 38.8% (95% CI: 30.9-47.4%); 22 studies)], were common in non-dialysis CKD patients. The severity of the symptoms was limited. Self-reported constipation was most consistently associated with worse HRQoL, whereas hard stool consistency was associated with higher uremic toxins levels. To conclude, since lower GI symptoms are common in CKD, using symptom questionnaires that do not take them into account cannot provide full insight into the patient's experience. Further studies are needed to cover identified knowledge gaps, including the exploration of the pathophysiology of GI symptoms in CKD with multi-omics data.

Emerging cellular senescence-centric understanding of immunological aging and its potential modulation through dietary bioactive components.

Immunological aging is strongly associated with the observable deleterious effects of human aging. Our understanding of the causes, effects, and therapeutics of aging immune cells has long been considered within the sole purview of immunosenescence. However, it is being progressively realized that immunosenescence may not be the only determinant of immunological aging. The cellular senescence-centric theory of aging proposes a more fundamental and specific role of immune cells in regulating senescent cell (SC) burden in aging tissues that has augmented the notion of senescence immunotherapy. Now, in addition, several emerging studies are suggesting that cellular senescence itself may be prevalent in aging immune cells, and that senescent immune cells exhibiting characteristic markers of cellular senescence, similar to non-leucocyte cells, could be among the key drivers of various facets of physiological aging. The present review integrates the current knowledge related to immunosenescence and cellular senescence in immune cells per se, and aims at providing a cohesive overview of these two phenomena and their significance in immunity and aging. We present evidence and rationalize that understanding the extent and impact of cellular senescence in immune cells vis-à-vis immunosenescence is necessary for truly comprehending the notion of an 'aged immune cell'. In addition, we also discuss the emerging significance of dietary factors such as phytochemicals, probiotic bacteria, fatty acids, and micronutrients as possible modulators of immunosenescence and cellular senescence. Evidence and opportunities related to nutritional bioactive components and immunological aging have been deliberated to augment potential nutrition-oriented immunotherapy during aging.

Interaction Mechanism Between the HSV-1 Glycoprotein B and the Antimicrobial Peptide Amyloid-ß.

Background: Unravelling the mystery of Alzheimer's disease (AD) requires urgent resolution given the worldwide increase of the aging population. There is a growing concern that the current leading AD hypothesis, the amyloid cascade hypothesis, does not stand up to validation with respect to emerging new data. Indeed, several paradoxes are being discussed in the literature, for instance, both the deposition of the amyloid-ß peptide (Aß) and the intracellular neurofibrillary tangles could occur within the brain without any cognitive pathology. Thus, these paradoxes suggest that something more fundamental is at play in the onset of the disease and other key and related pathomechanisms must be investigated. Objective: The present study follows our previous investigations on the infectious hypothesis, which posits that some pathogens are linked to late onset AD. Our studies also build upon the finding that Aß is a powerful antimicrobial agent, produced by neurons in response to viral infection, capable of inhibiting pathogens as observed in in vitro experiments. Herein, we ask what are the molecular mechanisms in play when Aß neutralizes infectious pathogens? Methods: To answer this question, we probed at nanoscale lengths with FRET (Förster Resonance Energy Transfer), the interaction between Aß peptides and glycoprotein B (responsible of virus-cell binding) within the HSV-1 virion. Results: The experiments show an energy transfer between Aß peptides and glycoprotein B when membrane is intact. No energy transfer occurs after membrane disruption or treatment with blocking antibody. Conclusion: We concluded that Aß insert into viral membrane, close to glycoprotein B, and participate in virus neutralization.

Proteolysis dysfunction in the process of aging and age-related diseases.

In this review, we discuss in detail the most relevant proteolytic systems that together with chaperones contribute to creating the proteostasis network that is kept in dynamic balance to maintain overall functionality of cellular proteomes. Data accumulated over decades demonstrate that the effectiveness of elements of the proteostasis network declines with age. In this scenario, failure to degrade misfolded or faulty proteins increases the risk of protein aggregation, chronic inflammation, and the development of age-related diseases. This is especially important in the context of aging-related modification of functions of the immune system.

The influence of Nigella sativa essential oil on proliferation, activation, and apoptosis of human T lymphocytes in vitro.

In previous work, we tested the immunomodulatory effect of Nigella sativa (NS) fatty oil. Our results demonstrated that unrefined, obtained by cold pressing black cumin seed oil inhibited lymphocytes' proliferation and induced their apoptosis in a dose-dependent manner. In this study, we examined the immunomodulatory properties of essential oil (EO) obtained from the NS seeds by hydrodistillation and its two main constituents: thymoquinone (TQ) and p-cymene. We analyzed the proliferation, activation phenotype, and apoptosis rates of human T lymphocytes stimulated with an immobilized monoclonal anti-CD3 antibody in the presence of serial ethanol dilutions of tested oil or serial distilled water dilutions of tested compounds with flow cytometry. Our results showed that NSEO significantly inhibited the proliferation of CD4+ and CD8+ T lymphocytes, induced cell death in a dose-dependent manner, and reduced the expression of CD28 and CD25 antigens essential for lymphocyte activation. TQ inhibited the proliferation of T lymphocytes and induced cell death, particularly in high concentrations. Meanwhile, p-cymene did not influence lymphocyte proliferation. However, its high concentration induced cell necrosis. These results show that the essential oil from Nigella sativa has powerful immunomodulatory properties, which, at least partially, are related to the TQ component.

Immunosenescence and Altered Vaccine Efficiency in Older Subjects: A Myth Difficult to Change.

Organismal ageing is associated with many physiological changes, including differences in the immune system of most animals. These differences are often considered to be a key cause of age-associated diseases as well as decreased vaccine responses in humans. The most often cited vaccine failure is seasonal influenza, but, while it is usually the case that the efficiency of this vaccine is lower in older than younger adults, this is not always true, and the reasons for the differential responses are manifold. Undoubtedly, changes in the innate and adaptive immune response with ageing are associated with failure to respond to the influenza vaccine, but the cause is unclear. Moreover, recent advances in vaccine formulations and adjuvants, as well as in our understanding of immune changes with ageing, have contributed to the development of vaccines, such as those against herpes zoster and SARS-CoV-2, that can protect against serious disease in older adults just as well as in younger people. In the present article, we discuss the reasons why it is a myth that vaccines inevitably protect less well in older individuals, and that vaccines represent one of the most powerful means to protect the health and ensure the quality of life of older adults.

Immunosenescence and COVID-19.

Ageing is associated with modified function of both innate and adaptive immunity. It is believed that changes occurring in ageing immune system are responsible for increased severity and deadliness of COVID-19 in the elderly. Although supported by statistics and epidemiology, these finding do not compute at the mechanistic level as depending solely on chronological and biological ageing. The phenomena describing changes in the aging immune system are immunosenescence and inflammageing, which develop in time depending on challenges to the individual immune system (immunobiography). Thus, "richer" immunobiography (in addition to other factors, including genetic, epigenetics or metabolic) may adversely affect the reactivity to the SARS-CoV-2 not only at later decades of life, but also earlier, in young and middle-aged individuals. On the other hand, infection with SARS-CoV-2 is affecting the function of both innate and adaptive branches of the immune system, adding to the individual immunobiography. Summarizing, immunosenescence and inflammaging may aggravate, but also may be aggravated by SARS-CoV-2 infection.

Immune system aging and the aging-related diseases in the COVID-19 era.

The interest in the process of aging, and specifically in how aging affects the working of our immune system, has recently enormously grown among both specialists (immunologists and gerontologists) and representatives of other disciplines of health sciences. An obvious reason for this interest is the current pandemics of COVID-19, known to affect the elderly more than younger people. In this paper current knowledge about mechanisms and complex facets of human immune system aging is presented, stemming from the knowledge about the working of various parts of the immune system, and leading to understanding of immunological mechanisms of chronic, inflammatory, aging-related diseases and of COVID-19.

The methodological quality and clinical applicability of meta-analyses on probiotics in 2020: A cross-sectional study.

Systematic reviews with meta-analyses (SR/MA) are frequently conducted to investigate clinical efficacy of probiotics. However, only rigorously prepared analyses can serve as the highest level of evidence for a specified research question. We have aimed to determine (1) what is the methodological quality of recent SR/MA conducted to assess the efficacy of probiotics; (2) whether the results of SR/MA have a clinical application; and (3) what are factors associated with better quality and applicability of the SR/MA. We systematically searched 4 databases for SR/MA on the probiotics efficacy published in 2020 (PROSPERO CRD42020222716). The AMSTAR 2 tool and pre-defined authors' criteria were used to evaluate methodological quality and clinical applicability, respectively. A total of 114 SR/MA were appraised. In the case of 88 papers (77%), the overall confidence in the results was rated as "critically low". The most prevalent flaws were lack of list of excluded studies with justification (79.8%), lack of study protocol (60.5%), and problems with appropriate results combination(54.4%). A declaration of conduction a probiotic efficacy SR/MA could have been misleading in case of 18 studies that included also synbiotics, paraprobiotics, and prebiotics trials in analyses. Only 14 SR/MA provided results that can be apply in clinical practice. Higher journal impact factor and European affiliation of the 1st and corresponding authors were most consistently associated with higher odds of AMSTAR 2 items fulfillments. Based on our findings, SR/MA of probiotics trials cannot be treated as the highest level of evidence without a careful evaluation of their methodological validity.

The influence of biologics on the microbiome in immune-mediated inflammatory diseases: A systematic review.

BACKGROUND: Immune-mediated inflammatory diseases (IMIDs) are a group of several chronic disorders with elusive pathogenesis that results in dysregulation of the normal immune response and leads to organ-specific or systemic inflammation. There are many reports on gastrointestinal or skin dysbiosis in patients with IMIDs; however, it is not clear whether dysbiosis is a cause or a result of the observed inflammation. We aimed to determine whether treatment of IMIDs patients with biologics affects their microbiota in comparison with baseline or placebo. METHODS: We searched for studies in MEDLINE, Embase, Scopus, and Web of Science. Due to both high heterogeneity and lacking data, vote-counting and structured tables were used to summarize the data. RESULTS AND LIMITATIONS: A total of 25 longitudinal human studies with 816 IMIDs patients receiving biologics were included. Data on α-diversity change are inconclusive. Most evidence supports the increase in all α-diversity metrics in responding inflammatory bowel disease (IBD) patients; however, vote counting did not confirm the significance of the directional change. In case of ß-diversity, treatment with biologics made patients' microbiome more similar to the microbiome of healthy controls in 5 out of 7 studies. The changes in taxa abundance and predicted functionality of microbiome were systematically summarized. Limited number and quality of the included studies highly restricted the conclusions of the study. CONCLUSIONS: Local inflammation may play pivotal role in the gut microbiome disruption in IMIDs patients. The effect of the biologics on human microbiota should be evaluated in randomized controlled trials and transparently reported.

Hyperactivation of monocytes and macrophages in MCI patients contributes to the progression of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease ultimately manifesting as clinical dementia. Despite considerable effort and ample experimental data, the role of neuroinflammation related to systemic inflammation is still unsettled. While the implication of microglia is well recognized, the exact contribution of peripheral monocytes/macrophages is still largely unknown, especially concerning their role in the various stages of AD. OBJECTIVES: AD develops over decades and its clinical manifestation is preceded by subjective memory complaints (SMC) and mild cognitive impairment (MCI); thus, the question arises how the peripheral innate immune response changes with the progression of the disease. Therefore, to further investigate the roles of monocytes/macrophages in the progression of AD we assessed their phenotypes and functions in patients at SMC, MCI and AD stages and compared them with cognitively healthy controls. We also conceptualised an idealised mathematical model to explain the functionality of monocytes/macrophages along the progression of the disease. RESULTS: We show that there are distinct phenotypic and functional changes in monocyte and macrophage populations as the disease progresses. Higher free radical production upon stimulation could already be observed for the monocytes of SMC patients. The most striking results show that activation of peripheral monocytes (hyperactivation) is the strongest in the MCI group, at the prodromal stage of the disease. Monocytes exhibit significantly increased chemotaxis, free radical production, and cytokine production in response to TLR2 and TLR4 stimulation. CONCLUSION: Our data suggest that the peripheral innate immune system is activated during the progression from SMC through MCI to AD, with the highest levels of activation being in MCI subjects and the lowest in AD patients. Some of these parameters may be used as biomarkers, but more holistic immune studies are needed to find the best period of the disease for clinical intervention.

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

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 (Aß) and its aggregation into amyloid plaques, was accepted for a long time as the main cause of AD. However, many studies showed that Aß 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 Aß, 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.

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

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.

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

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.

Associations between symptoms of constipation and sleep quality in patients with nondialysis chronic kidney disease: a cross-sectional study.

INTRODUCTION Sleep disturbances, similarly to constipation­related symptoms, are common problems in patients with chronic kidney disease (CKD) and are associated with worse health-related quality of life. OBJECTIVES The aim of the study was to investigate sleep problems in conservatively treated patients with CKD and to assess association between sleep quality and constipation in that population. PATIENTS AND METHODS In this cross­sectional study, 100 conservatively treated outpatients with CKD filled questionnaires addressing sleep quality (The Medical Outcomes Study 12­item Sleep Scale-Revised [MOS­Sleep­R]) and constipation­related symptoms (PAC­SYM, Rome III criteria). RESULTS The T scores of none of the assessed sleep domains differed across the estimated glomerular filtration rate terciles (all P >0.05). The scores from the PAC-SYM abdominal and stool subscales correlated with all assessed sleep quality domains. In both univariable and multivariable regression models adjusted for key clinical data, functional constipation, 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 patients with nondialysis CKD, sleep disorders might have common etiological factors with constipation-related symptoms.

Proteodynamics and aging of eukaryotic cells.

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.