B Cell Subsets and Immune Checkpoint Expression in Patients with Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by dysfunctional B cells. Immune checkpoint molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1 (PD-1) are upregulated in patients with CLL and may correlate with prognostic markers such as beta-2 microglobulin (B2M). The aim of this study was to evaluate the levels of immune checkpoints on B cell subsets and to further correlate them with B2M levels in patients with CLL. We recruited 21 patients with CLL and 12 controls. B cell subsets and the levels of immune checkpoint expression were determined using conventional multi-color flow cytometry. Basal levels of B2M in patients with CLL were measured using an enzyme-linked immunosorbent assay. Patients with CLL had increased levels of activated B cells when compared to the control group, p < 0.001. The expression of PD-1 and CTLA-4 were increased on activated B cells and memory B cells, p < 0.05. There were no associations between B2M levels and the measured immune checkpoints on B cell subsets, after adjusting for sex and age. In our cohort, the patients with CLL expressed elevated levels of PD-1 and CTLA-4 immune checkpoints on activated and memory B cell subsets. However, there was no correlation between these immune checkpoint expressions and B2M levels.

The mean platelet volume and atherosclerotic cardiovascular-risk factors in adults with obesity: a systematic review and meta-analysis of observational studies.

BACKGROUND: Obesity is a major risk factor for atherosclerotic cardiovascular disease (ASCVD) and is associated with altered platelet function. The mean platelet volume (MPV) is a rapid measure of platelet activation and a prognostic marker in patients with cardiovascular disease. However, no meta-analysis on the association between MPV and obesity has been conducted, and the value of monitoring the MPV in patients with obesity remains unclear. OBJECTIVE: To provide cumulative evidence on whether the mean platelet volume (MPV) is increased in individuals with obesity and to describe associations between the ASCVD-risk factors and the MPV in individuals with obesity. METHODS: This meta-analysis was prepared following the Meta-analysis Of Observational Studies (MOOSE) guidelines. We searched the PubMed and Embase database from inception until the 31st of March 2021. Studies were included when they reported the mean platelet volume in individuals with obesity and provided a suitable non-obese comparator group. The risk of bias was independently assessed by two reviewers using the Newcastle-Ottawa scale. The primary outcome of the meta-analysis was the MPV, while we considered the atherosclerotic risk profiles as a secondary outcome. RESULTS: We identified 178 citations through the PUBMED and 255 citations through EMBASE database search. In all, 13 studies met the inclusion criteria. Firstly, we report an increased mean platelet volume in individuals with obesity compared to non-obese individuals (MD 0.79; [95%CI: 0.42 to 1.16], I2 = 93.4%). Moreover, the reported increase in the MPV was inversely associated with the body mass index (Coefficient: -0.57, standard error (SE): 0.18, p < 0.001) and directly related to changes in triglyceride levels (Coefficient: 4.99, standard error (SE): 1.14, p < 0.001). CONCLUSION: This meta-analysis and meta-regression showed an increased MPV in nondiabetic individuals living with obesity. Moreover, the MPV was associated with hypertriglyceridemia, an independent predictor of atherosclerotic cardiovascular disease. Overall, the findings suggest that MPV may be a valuable rapid marker for the monitoring and risk-stratification of individuals with obesity who may be at risk of developing cardiovascular disease.

The pleotropic effects of fluvastatin on complement-mediated T-cell activation in hypercholesterolemia.

T-cells orchestrate the inflammatory responses in atherosclerosis, and their function is modified by the lipoprotein milieu and complement activity. We investigated the effects of fluvastatin on the expression of complement decay-accelerating factor (DAF/CD55) antigen, and the levels of transcription factors in circulating T-cells in hypercholesterolemia. The hypercholesterolemic state was associated with the upregulation of DAF expression on circulating T-cells and increased levels nuclear factor kappa B (NF-kB) and interferon regulatory factor 4 (IRF4). Notably, the elevated levels of DAF and NF-kB expression persisted following treatment with fluvastatin. Therefore, the pleiotropic effects of fluvastatin are partially ascribed to its ability to mediate T-cell activation and regulate complement activity. Consequently, enhanced therapeutic interventions that targets complement-induced T-cell activation may be important in mitigating the development of atherosclerosis and major cardiovascular events in individuals with hypercholesterolemia.

Role of Coenzyme Q10 in Health and Disease: An Update on the Last 10 Years (2010-2020).

The present review focuses on preclinical and clinical studies conducted in the last decade that contribute to increasing knowledge on Coenzyme Q10's role in health and disease. Classical antioxidant and bioenergetic functions of the coenzyme have been taken into consideration, as well as novel mechanisms of action involving the redox-regulated activation of molecular pathways associated with anti-inflammatory activities. Cardiovascular research and fertility remain major fields of application of Coenzyme Q10, although novel applications, in particular in relation to topical application, are gaining considerable interest. In this respect, bioavailability represents a major challenge and the innovation in formulation aspects is gaining critical importance.

Diet-Induced Obesity Promotes the Upregulation of Fas Expression on T-cells.

This study was conducted to assess the expression of Fas (CD95) and programmed cell death-1 (PD-1) on circulating T-cells in obesity using a diet-induced obesity mouse model. Furthermore, we aimed to determine if there are any associations between metabolic disorders and the expression of T-cell regulatory markers. A total of 12 male C57BL/6 mice were randomized into either a high-fat diet (HFD) or low-fat diet (LFD) group for 8 weeks (n = 6/group). Changes in body weights were monitored on a weekly basis. The lipid, glucose, and hematological profiles, as well as Fas and PD1 expression on the T-cell immunophenotype, were measured after 8 weeks of feeding. The HFD-fed group had a higher percentage weight gain (29.17%) in comparison with the LFD-fed group (21.74%) after the 8-week period. In addition, the HFD group had increased fasting glucose and glucose excursion following a 2-h postprandial period. The levels of total cholesterol were elevated in the HFD group when compared with the LFD group (p < 0.05). Notably, the absolute white cell count (p = 0.0096), neutrophil count (p = 0.0022, lymphocytes (p = 0.0155), and monocyte count (p = 0.0015) were elevated in the HFD group when compared with the LFD-fed group. However, the platelets (0.0680), red cell counts (0.3575), and their indices (p > 0.05) were comparable between the two groups. Interestingly, HFD feeding was associated with elevated expression of Fas on T-cells (p < 0.0001), which positively correlated with body weights (r = 0.93, p = 0.0333). No associations were found between Fas expression and dyslipidemia or fasting blood glucose levels (p > 0.05). The multivariant regression analysis showed that the association between the levels of Fas on T-cells and body weights (coefficient: -1.00, t-value: 19.27, p = 0.0330) was independent of fasting blood glucose, total cholesterol, and lymphocyte count. Lastly, the expression of PD-1 on T-cells was comparable between the two diet groups (p = 0.1822). In all, immune activation, dyslipidemia, and poor glucose control in the early stages of obesity may drive the pathogenesis of metabolic T-cell disorders. Importantly, T-cell dysfunction in obesity is partially mediated by an upregulation of Fas which is independent of dyslipidemia and hyperglycemia.

A systematic review and meta-analysis on the regulation of programmed cell death-1 on T-cells in type 2 diabetes.

BACKGROUND: To assess T-cell exhaustion mediated by programmed cell death 1 (PD-1) pathway in patients living with type 2 diabetes (T2D). METHODS: MEDLINE and ProQuest electronic databases were searched for eligible studies from inception up to February 2020. The risk of bias and the quality of evidence were independently assessed by two reviewers using the modified Newcastle-Ottawa Scale adapted for cross-sectional studies and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool, respectively. The random effects model was used to calculate effect estimates. RESULTS: We identified 5 studies involving 380 participants which met the inclusion criteria. The pooled estimates showed elevated T helper cell exhaustion in patients with T2D in comparison to controls (mean difference [MD]: 2.57% [95% confidence interval [CI]: -3.84, 8.97]; I2 = 100%, P < .00001). Likewise, T2D patients had increased levels of cytotoxic T-cells exhaustion (MD: 3.09% [95% CI: -12.96, 19.14]; I2 = 100%, P < .00001). Although the upregulation of PD-1 on T-cells did not affect glucose metabolism-related profiles, it was associated with inflammation and the development of cardiovascular disease. CONCLUSION: In patients living with T2D, immune dysfunction is at least in part due to T-cell exhaustion mediated by the upregulation of PD-1 expression. Therefore, the use of immune checkpoint inhibitors as a therapeutic strategy may be beneficial in restoring immune function in patients with T2D.

The aberrant expression of CD69 on peripheral T-helper cells in diet-induced inflammation is ameliorated by low-dose aspirin and metformin treatment.

Chronic inflammation in patients with type 2 diabetes (T2D) is associated with T-cell dysfunction. Using a rodent model, we evaluated changes in metabolic profiles, inflammation status and the expression of T-cell function markers following high-fat diet (HFD)-feeding. In addition, we assessed the modulatory effects of treatment with low-dose aspirin (LDA) and its combination with metformin (LDA + Met) on these parameters. Notably, HFD-feeding induced metabolic disorders and aggravated inflammation. Most importantly, it was associated with decreased expression of CD69 on T-helper cells but had no effect on the expression of programmed cell death 1 (PD-1). Treatment with LDA monotherapy had no effect on metabolic profiles. However, its combination with metformin ameliorated the levels of inflammation and up-regulated the expression of CD69 although it had no therapeutic effect on the levels of PD-1 expression. Therefore, alleviating inflammation and lowering glucose levels in T2D may be an effective strategy to improve T-cell function in these patients.

Ubiquinol supplementation in elderly patients undergoing aortic valve replacement: biochemical and clinical aspects.

Epidemiological data show a rise in the mean age of patients affected by heart disease undergoing cardiac surgery. Senescent myocardium reduces the tolerance to ischemic stress and there are indications about age-associated deficit in post-operative cardiac performance. Coenzyme Q10 (CoQ10), and more specifically its reduced form ubiquinol (QH), improve several conditions related to bioenergetic deficit or increased exposure to oxidative stress. This trial (Eudra-CT 2009-015826-13) evaluated the clinical and biochemical effects of ubiquinol in 50 elderly patients affected by severe aortic stenosis undergoing aortic valve replacement and randomized to either placebo or 400 mg/day ubiquinol from 7 days before to 5 days after surgery. Plasma and cardiac tissue CoQ10 levels and oxidative status, circulating troponin I, CK-MB (primary endpoints), IL-6 and S100B were assessed. Moreover, main cardiac adverse effects, NYHA class, contractility and myocardial hypertrophy (secondary endpoints) were evaluated during a 6-month follow-up visit. Ubiquinol treatment counteracted the post-operative plasma CoQ10 decline (p<0.0001) and oxidation (p=0.038) and curbed the post-operative increase in troponin I (QH, 1.90 [1.47-2.48] ng/dL; placebo, 4.03 [2.45-6.63] ng/dL; p=0.007) related to cardiac surgery. Moreover, ubiquinol prevented the adverse outcomes that might have been associated with defective left ventricular ejection fraction recovery in elderly patients.

The impact of immune checkpoint inhibitors in patients with chronic lymphocytic leukemia (CLL): A protocol for a systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: The global burden of chronic lymphocytic leukemia (CLL) has constantly increased over the years, with a current incidence of 3.5 cases per 100,000 people. Although the conventional drugs used to treat CLL patients have been effective treatment failure rate in some of the patients is alarming. Therefore, as a result, novel treatment strategies with improved outcomes such as the blockade of immune checkpoints have emerged. However, consensus on the risk-benefit effects of the using these drugs in patients with CLL is controversial and has not been comprehensively evaluated. This systemic review and meta-analysis provide a comprehensive synthesis of available data assessing adverse events associated with the use of immune checkpoint inhibitors in patients with CLL as well as their influence on the overall survival rate. METHODS: This protocol for a systematic review and meta-analysis has been prepared in accordance with Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 guidelines. A search strategy will be developed using medical subject headings words in PubMed search engine with MEDLINE database. The search terms will also be adapted for gray literature, Embase, and Cochrane Central Register of Controlled Trials electronic databases. Two reviewers (AN and SRN) will independently screen studies, with a third reviewer consulted in cases of disagreements using a defined inclusion and exclusion criteria. Data items will be extracted using a predefined data extraction sheet. Moreover, the risk of bias and quality of the included studies will be appraised using the Downs and Black checklist and the quality and strengths of evidence across selected studies will be assessed using the Grading of Recommendations Assessment Development and Evaluation approach. The Cochran's Q statistic and the I statistics will be used to analyze statistical heterogeneity across studies. If the included studies show substantial level of statistical heterogeneity (I > 50%), a random-effects meta-analysis will be performed using R statistical software. ETHICS AND DISSEMINATION: The review and meta-analysis will not require ethical approval and the findings will be published in peer-reviewed journals and presented at local and international conferences. This review may help provide clarity on the risk-benefit effects of using immune checkpoint inhibitors in patients with CLL. SYSTEMATIC REVIEW REGISTRATION: International prospective Register of Systematic Reviews (PROSERO) number: CRD42020156926.

Obesity-related asthma in children is characterized by T-helper 1 rather than T-helper 2 immune response: A meta-analysis.

BACKGROUND: Asthma is a chronic inflammatory condition characterized by T-helper (TH) 2 polarization. In children, the prevalence of obesity is associated with an increased incidence of asthma. Notably, obesity is linked with TH1-mediated inflammation and has been identified as a major risk factor for asthma. OBJECTIVE: To investigate the impact of obesity on TH1 (tumor necrosis factor α, interferon gamma, interleukin (IL)-6, IL-8) and TH2 (IL-4, IL-5, IL-10, IL-13) immune responses in children with asthma. METHODS: We searched the MEDLINE and gray literature electronic databases for eligible studies from inception up until April 2020. The quality of included studies and evidence was independently assessed by 2 reviewers. The random-effects model was used in this meta-analysis, and outcomes were reported as standardized mean difference (SMD) and 95% confidence interval (CI). RESULTS: Overall, 5 studies comprising 482 participants met the inclusion criteria. The meta-analysis revealed an increased TH2-mediated immune response in lean people with asthma compared with controls without asthma (SMD: -1.15 [95% CI: -1.93, 0.36]; I2 = 93%; pH < .001). However, in obese people with asthma, there was polarization toward TH1 immune response compared with lean people with asthma (SMD: -0.43 [95% CI: -0.79, -0.08]; I2 = 88%, pH < .001). CONCLUSION: This meta-analysis reveals that there are differences in immune responses mediated by T-helper cells in lean and obese children with asthma. Moreover, and not unique to asthma, obesity polarizes the immune response toward TH1 rather than the classical TH2. This could be an important aspect to understand to establish effective therapeutic targets for obese children with asthma.

The impact of metformin and aspirin on T-cell mediated inflammation: A systematic review of in vitro and in vivo findings.

Chronic inflammation and hyperglycaemia are well-established aspects in the pathogenesis of type 2 diabetes mellitus (T2D), including the progression of its associated complications such as cardiovascular diseases (CVDs). In fact, emerging evidence shows that dysfunctional immune responses due to dysregulated T-cell function aggravates CVD-related complications in T2D. However, there is a lack of specific therapeutic interventions that protect patients with diabetes who are at risk of heart failure. Metformin and aspirin are among the leading therapies being used to protect or at the very least slow the progression of CVD-related complications. The current review made use of major electronic databases to identify and systematically synthesise emerging experimental data on the impact of these pharmacological drugs on T-cell responses. The quality and risk of bias of include evidence were independently assessed by two reviewers. Overwhelming evidence showed that both metformin and aspirin can ameliorate T-cell mediated inflammation by inducing regulatory T-cells (Tregs) polarisation, inhibiting T-cell trafficking and activation as well as signal transducer and activator of transcription (STAT)3 signalling. As a plausible mechanism to mediate T-cell function, metformin showed enhanced potential to regulate mechanistic targets of rapamycin (mTOR), STAT5 and adenosine-monophosphate-activated protein kinase (AMPK) signalling pathways. Whilst aspirin modulated nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-kB) and co-stimulatory signalling pathways and induced T-cell anergy. Overall, synthesised data prompt further investigation into the combinational effect of metformin and aspirin for the management of T2D-related cardiovascular complications.

T-cell activation and cardiovascular risk in adults with type 2 diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Chronic immune activation has been described in the development of cardiovascular diseases (CVDs) and in the pathogenesis of type 2 diabetes mellitus (T2D). However, the precise functional role of T-cells remains controversial. We therefore, assessed T-cell activation and cardiovascular risk in T2D. METHODS: The protocol was registered with PROSPERO [CRD42018099745]. We searched electronic databases and grey literature for eligible studies. The risk of bias and quality of evidence were assessed and the random-effects model was used in the meta-analysis. FINDINGS: Fifteen studies met the inclusion criteria. We report on increased T-cell activation in T2D and nondiabetics with CVD. Comorbidity of T2D and CVD (T2D + CVD) exacerbated T-cell activation. In addition, T2D + CVD comorbidity was associated with an increased CVD risk profile. CONCLUSION: This meta-analysis suggests increased T-cell activation in T2D and nondiabetics with CVD. Moreover, an increased cardiovascular risk in patients with T2D which is exacerbated in T2D and CVD comorbidity.

Obesity-induced inflammation and insulin resistance: A mini-review on T-cells.

Excessive lipid accumulation in an obese state is linked with activation and release of detrimental cytokines and chemokines that promote metabolic dysregulation. In fact, emerging experimental evidence shows that abnormal modulation of T-cells in an obese state correlates with the development and progression of insulin resistance. Importantly, the evolving concept linking insulin resistance with impaired immunological mechanisms such as T-cell responses provides new prospects for understanding the role of inflammation in moderating metabolic complications.

Platelet function and cardiovascular risk in adult HIV-infected patients on HAART: a protocol for a systematic review and meta-analysis.

INTRODUCTION: The incidence of cardiovascular disease (CVD) is now at least threefold higher in HIV-infected patients as compared with the general population. Although platelet activation and reactivity are implicated in the development of CVDs in HIV-infected patients, its precise role remains inconclusive. We aim to assess the association between platelet activation and selected cardiovascular risk factors in HIV-1-infected individuals on highly active antiretroviral treatment (HAART). METHODS: This will be a systematic review and meta-analysis of published studies evaluating the association between platelet activation and CVD risk factors in HAART-treated adults. The search strategy will include medical subject headings words for MEDLINE, and this will be adapted to Embase search headings (Emtree) terms for the EMBASE database. The search will cover literature published between 1 January 1996 to 30 April 2017. Studies will be independently screened by two reviewers using predefined criteria. Relevant eligible full texts will be screened; data will be extracted, and a qualitative synthesis will be conducted. Data extraction will be performed using Review Manager V.5.3. To assess the quality and strengths of evidence across selected studies, the Grading of Recommendations Assessment Development and Evaluation approach will be used. The Cochran's Q statistic and the I2 statistics will be used to analyse statistical heterogeneity between studies. If included studies show high levels of homogeneity, a random effects meta-analysis will be performed using R statistical software. ETHICS AND DISSEMINATION: This will be a review of existing studies and will not require ethical approval. The findings will be disseminated through peer-reviewed publication and presented at local and international conferences. An emerging patient management dilemma is that of the increased incidence of CVD in people living with HIV on HAART. This review may inform treatment and cardiovascular risk stratification of HIV-infected patients at increased risk of developing CVD. PROSPERO REGISTRATION NUMBER: CRD42017062393.

Phenylpyruvic Acid-2-O-ß-D-Glucoside Attenuates High Glucose-Induced Apoptosis in H9c2 Cardiomyocytes.

Chronic hyperglycemia is closely associated with impaired substrate metabolism, dysregulated mitochondrial membrane potential, and apoptosis in the diabetic heart. As adult cardiomyocytes display a limited capacity to regenerate following an insult, it is essential to protect the myocardium against the detrimental effects of chronic hyperglycemia. This study therefore investigated whether phenylpyruvic acid-2-O-ß-D-glucoside, present in Aspalathus linearis (rooibos), is able to attenuate hyperglycemia-induced damage in H9c2 cardiomyocytes. H9c2 cardiomyocytes were exposed to a high glucose concentration (33 mM) prior to treatment with phenylpyruvic acid-2-O-ß-D-glucoside (1 µM), metformin (1 µM), or a combination of phenylpyruvic acid-2-O-ß-D-glucoside and metformin (both at 1 µM). Our data revealed that high glucose exposure increased cardiac free fatty acid uptake and oxidation, mitochondrial membrane potential, and apoptosis (caspase 3/7 activity and TUNEL), and decreased the Bcl2/Bax protein expression ratio. Phenylpyruvic acid-2-O-ß-D-glucoside treatment, alone or in combination with metformin, attenuated these glucose-induced perturbations, confirming its protective effect in H9c2 cardiomyocytes exposed to chronic hyperglycemia.