Metaproteomics Approach and Pathway Modulation in Obesity and Diabetes: A Narrative Review

Low-grade inflammatory diseases revealed metabolic perturbations that have been linked to various phenotypes, including gut microbiota dysbiosis. In the last decade, metaproteomics has been used to investigate protein composition profiles at specific steps and in specific healthy/pathologic conditions. We applied a rigorous protocol that relied on PRISMA guidelines and filtering criteria to obtain an exhaustive study selection that finally resulted in a group of 10 studies, based on metaproteomics and that aim at investigating obesity and diabetes. This batch of studies was used to discuss specific microbial and human metaproteome alterations and metabolic patterns in subjects affected by diabetes (T1D and T2D) and obesity. We provided the main up- and down-regulated protein patterns in the inspected pathologies. Despite the available results, the evident paucity of metaproteomic data is to be considered as a limiting factor in drawing objective considerations. To date, ad hoc prepared metaproteomic databases collecting pathologic data and related metadata, together with standardized analysis protocols, are required to increase our knowledge on these widespread pathologies.

Download Full-text

Obstructive Sleep Apnea and Inflammation: Proof of Concept Based on Two Illustrative Cytokines

International Journal of Molecular Sciences ◽

10.3390/ijms20030459 ◽

2019 ◽

Vol 20 (3) ◽

pp. 459 ◽

Cited By ~ 31

Author(s):

Leila Kheirandish-Gozal ◽

David Gozal

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Inflammatory Diseases ◽

Sleep Apnea Syndrome ◽

Special Focus ◽

Normal Body Mass Index ◽

Low Grade ◽

Obstructive Sleep ◽

Inflammatory Processes ◽

Factor Α

Obstructive sleep apnea syndrome (OSAS) is a markedly prevalent condition across the lifespan, particularly in overweight and obese individuals, which has been associated with an independent risk for neurocognitive, behavioral, and mood problems as well as cardiovascular and metabolic morbidities, ultimately fostering increases in overall mortality rates. In adult patients, excessive daytime sleepiness (EDS) is the most frequent symptom leading to clinical referral for evaluation and treatment, but classic EDS features are less likely to be reported in children, particularly among those with normal body-mass index. The cumulative evidence collected over the last two decades supports a conceptual framework, whereby sleep-disordered breathing in general and more particularly OSAS should be viewed as low-grade chronic inflammatory diseases. Accordingly, it is assumed that a proportion of the morbid phenotypic signature in OSAS is causally explained by underlying inflammatory processes inducing end-organ dysfunction. Here, the published links between OSAS and systemic inflammation will be critically reviewed, with special focus on the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), since these constitute classical prototypes of the large spectrum of inflammatory molecules that have been explored in OSAS patients.

Download Full-text

Meta-inflammation in monocytes of patients with Acute Coronary Syndrome

European Heart Journal ◽

10.1093/ehjci/ehaa946.1568 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

F Canonico ◽

R Vinci ◽

D Pedicino ◽

E Pisano ◽

P Ciampi ◽

...

Keyword(s):

Protein Identification ◽

Mononuclear Cells ◽

Inflammatory Diseases ◽

Glycolytic Enzyme ◽

Potential Interaction ◽

Limiting Factor ◽

Funding Source ◽

Peripheral Blood Mononuclear ◽

Coronary Syndrome ◽

Key Enzyme

Abstract Background Several studies suggest that an alteration of monocyte metabolism might be implicated in inflammatory diseases. Enhanced glycolysis might be a hallmark of pro-inflammatory monocyte subsets. Improved glycolysis enables the immune cells to generate sufficient ATP and biosynthetic intermediates to carry out its particular effector functions. For macrophages this includes phagocytosis and inflammatory cytokine production. Pyruvate Kinase isozyme M2 (PKM-2) catalyzes the final step of glycolysis producing pyruvate and ATP. Latest studies have shown that a member of Jumonji family (JMJD8) acts as a positive regulator in TNF-induced NF-kB signaling leading to pro-inflammatory pathways in macrophages and is involved in angiogenesis and cellular metabolism through interacting with PKM-2 in endothelial cells. Purpose The aims of the study are to assess the expression of the glycolytic key enzyme PKM-2 in CD14+ monocytes obtained from patients with non-ST-elevation myocardial infarction (NSTEMI) or with stable angina (SA). Furthermore, the expression of JMJD8 was evaluated. Methods 30 patients with NSTEMI and 30 patients with SA were enrolled. Peripheral blood mononuclear cells were obtained from whole blood samples. For cytoplasmatic protein identification, cells were fixed and permeabilized and then incubated with fluorochrome-conjugated mAbs anti-CD14, anti-PKM-2 and anti-JMJD8. For analysis we used Two-tailed Mann-Whitney non parametric Comparison test. Results CD14+ monocytes from NSTEMI patients showed reduced expression of the key glycolytic enzyme PKM-2 as compared to CD14+ monocytes from SA patients (p=0.02) (Figure 1). JMJD8 expression in NSTEMI patients is increased compared with SA patients (p=0.02) (Figure 2). Conclusion This study introduces a role for immune-metabolism in the immunity dysregulation described in ACS patients and provides novel insights into the mechanisms responsible for coronary instability. Taking their potential interaction into account, our data suggest that in acute setting glycolysis key enzyme PKM2 expression is downregulated. Besides, JMJD8 protein levels increase in NSTEMI patients acting as potential limiting factor of PKM2 function. Moreover, our data propose the potential roles of immune-metabolism to detect novel therapeutic targets, associated with an accurate patient stratification based on immune-metabolic profiles, for prevention and treatment of atherosclerosis, in the perspective of a personalized medicine approach. Funding Acknowledgement Type of funding source: Private hospital(s). Main funding source(s): Fondazione Policlinico A. Gemelli

Download Full-text

G Protein-Coupled Estrogen Receptor in Cancer and Stromal Cells: Functions and Novel Therapeutic Perspectives

Cells ◽

10.3390/cells10030672 ◽

2021 ◽

Vol 10 (3) ◽

pp. 672

Author(s):

Richard A. Pepermans ◽

Geetanjali Sharma ◽

Eric R. Prossnitz

Keyword(s):

Estrogen Receptor ◽

G Protein ◽

Inflammatory Diseases ◽

Therapy Resistance ◽

Breast Cancers ◽

Obesity And Diabetes ◽

Therapeutic Value ◽

Health And Disease ◽

Multiple Cells ◽

G Protein Coupled

Estrogen is involved in numerous physiological and pathophysiological systems. Its role in driving estrogen receptor-expressing breast cancers is well established, but it also has important roles in a number of other cancers, acting both on tumor cells directly as well as in the function of multiple cells of the tumor microenvironment, including fibroblasts, immune cells, and adipocytes, which can greatly impact carcinogenesis. One of its receptors, the G protein-coupled estrogen receptor (GPER), has gained much interest over the last decade in both health and disease. Increasing evidence shows that GPER contributes to clinically observed endocrine therapy resistance in breast cancer while also playing a complex role in a number of other cancers. Recent discoveries regarding the targeting of GPER in combination with immune checkpoint inhibition, particularly in melanoma, have led to the initiation of the first Phase I clinical trial for the GPER-selective agonist G-1. Furthermore, its functions in metabolism and corresponding pathophysiological states, such as obesity and diabetes, are becoming more evident and suggest additional therapeutic value in targeting GPER for both cancer and other diseases. Here, we highlight the roles of GPER in several cancers, as well as in metabolism and immune regulation, and discuss the therapeutic value of targeting this estrogen receptor as a potential treatment for cancer as well as contributing metabolic and inflammatory diseases and conditions.

Download Full-text

Current State of (Dis)Integration: Public Health and Fusion Centers

Journal of Homeland Security and Emergency Management ◽

10.1515/jhsem-2018-0076 ◽

2020 ◽

Vol 17 (2) ◽

Author(s):

Cody Minks ◽

Anke Richter

Keyword(s):

Public Health ◽

Law Enforcement ◽

Information Sharing ◽

Homeland Security ◽

Large Scale ◽

Ad Hoc ◽

Limiting Factor ◽

Fusion Centers ◽

Public Health Emergencies ◽

Public Health Information

AbstractObjectiveResponding to large-scale public health emergencies relies heavily on planning and collaboration between law enforcement and public health officials. This study examines the current level of information sharing and integration between these domains by measuring the inclusion of public health in the law enforcement functions of fusion centers.MethodsSurvey of all fusion centers, with a 29.9% response rate.ResultsOnly one of the 23 responding fusion centers had true public health inclusion, a decrease from research conducted in 2007. Information sharing is primarily limited to information flowing out of the fusion center, with little public health information coming in. Most of the collaboration is done on a personal, informal, ad-hoc basis. There remains a large misunderstanding of roles, capabilities, and regulations by all parties (fusion centers and public health). The majority of the parties appear to be willing to work together, but there but there is no forward momentum to make these desires a reality. Funding and staffing issues seem to be the limiting factor for integration.ConclusionThese problems need to be urgently addressed to increase public health preparedness and enable a decisive and beneficial response to public health emergencies involving a homeland security response.

Download Full-text

Regulation of Metabolism: A Cross Talk Between Gut Microbiota and Its Human Host

Physiology ◽

10.1152/physiol.00023.2012 ◽

2012 ◽

Vol 27 (5) ◽

pp. 300-307 ◽

Cited By ~ 33

Author(s):

Rémy Burcelin

Keyword(s):

Immune System ◽

Gut Microbiota ◽

Low Grade ◽

Gene Products ◽

Individual Level ◽

Obesity And Diabetes ◽

Regulation Of Metabolism ◽

Molecular Origin ◽

The Individual ◽

Low Grade Inflammation

The recent epidemic of obesity and diabetes and the diversity at the individual level could be explained by the intestinal microbiota-to-host relationship. More than four million gene products from the microbiome could interact with the immune system to induce a tissue metabolic infection, which is the molecular origin of the low-grade inflammation that characterizes the onset of obesity and diabetes.

Download Full-text

The Fatty Acid and Protein Profiles of Circulating CD81-Positive Small Extracellular Vesicles Are Associated with Disease Stage in Melanoma Patients

Cancers ◽

10.3390/cancers13164157 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4157

Author(s):

Giovanni Paolino ◽

Veronica Huber ◽

Serena Camerini ◽

Marialuisa Casella ◽

Alberto Macone ◽

...

Keyword(s):

Fatty Acid ◽

Extracellular Vesicles ◽

Ad Hoc ◽

Early Stage ◽

Disease Onset ◽

Protein Composition ◽

Disease Stage ◽

Biological Macromolecules ◽

Healthy Donors ◽

Melanoma Patients

The early detection of cutaneous melanoma, a potentially lethal cancer with rising incidence, is fundamental to increasing survival and therapeutic adjustment. In stages II–IV especially, additional indications for adjuvant therapy purposes after resection and for treatment of metastatic patients are urgently needed. We investigated whether the fatty acid (FA) and protein compositions of small extracellular vesicles (sEV) derived from the plasma of stage 0–I, II and III–IV melanoma patients (n = 38) could reflect disease stage. The subpopulation of sEV expressing CD81 EV marker (CD81sEV) was captured by an ad hoc immune affinity technique from plasma depleted of large EV. Biological macromolecules were investigated by gas chromatography and mass spectrometry in CD81sEV. A higher content of FA was detectable in patients with respect to healthy donors (HD). Moreover, a higher C18:0/C18:1 ratio, as a marker of cell membrane fluidity, distinguished early (stage 0–I) from late (III–IV) stages’ CD81sEV. Proteomics detected increases in CD14, PON1, PON3 and APOA5 exclusively in stage II CD81sEV, and RAP1B was decreased in stage III–IV CD81sEV, in comparison to HD. Our results suggest that stage dependent alterations in CD81sEV’ FA and protein composition may occur early after disease onset, strengthening the potential of circulating sEV as a source of discriminatory information for early diagnosis, prediction of metastatic behavior and following up of melanoma patients.

Download Full-text

The role of selected mechanisms of innate immunity in the pathogenesis of diabetes

Journal of Education, Health and Sport ◽

10.12775/jehs.2021.11.09.071 ◽

2021 ◽

Vol 11 (9) ◽

pp. 544-549

Author(s):

Paulina Trojanowska ◽

Magdalena Chrościńska-Krawczyk ◽

Alina Trojanowska ◽

Ewa Tywanek ◽

Jakub Wronecki ◽

...

Keyword(s):

Innate Immunity ◽

Metabolic Diseases ◽

Inflammatory Diseases ◽

The Body ◽

Low Grade ◽

Intracellular Space ◽

Cytoplasmic Proteins

Understanding the important role of the non-specific immune response in protecting the body against the development of numerous diseases has become partially possible after the discovery of several classes of pattern recognition receptors (PRR), such as Toll-like or NOD-like receptors. A group of cytoplasmic proteins called the inflammasome, which detect PAMP and DAMP through the PRR receptors, is able to activate pro-inflammatory cytokines and trigger an acute inflammatory reaction both in the extracellular and intracellular space. Low-grade systemic and local inflammation contributes to the development and progression of various conditions, including autoimmune and metabolic diseases, such as diabetes, metabolic syndrome and atherosclerosis, which until recently were not even considered inflammatory diseases. This review will discuss the role of innate immunity in the development of type 1 and type 2 diabetes, focusing on the role of specific innate immunity receptors and insulin resistance involved in these diseases pathogenesis.

Download Full-text

My D88-Dependent Interplay Between Myeloid and Endothelial Cells in the Initiation and Progression of Obesity-Associated Inflammatory Diseases

Blood ◽

10.1182/blood.v128.22.sci-44.sci-44 ◽

2016 ◽

Vol 128 (22) ◽

pp. SCI-44-SCI-44

Author(s):

Xiaoxia Li

Keyword(s):

Insulin Resistance ◽

Endothelial Cells ◽

Adipose Tissue ◽

Systemic Inflammation ◽

Conflicts Of Interest ◽

Ex Vivo ◽

Inflammatory Diseases ◽

Critical Role ◽

Low Grade

Abstract Low-grade systemic inflammation is often associated with metabolic syndrome, which plays a critical role in the development of the obesity-associated inflammatory diseases, including insulin resistance and atherosclerosis. Here, we investigate how Toll-like receptor-MyD88 signaling in myeloid and endothelial cells coordinately participates in the initiation and progression of high fat diet-induced systemic inflammation and metabolic inflammatory diseases. MyD88 deficiency in myeloid cells inhibits macrophage recruitment to adipose tissue and their switch to an M1-like phenotype. This is accompanied by substantially reduced diet-induced systemic inflammation, insulin resistance, and atherosclerosis. MyD88 deficiency in endothelial cells results in a moderate reduction in diet-induced adipose macrophage infiltration and M1 polarization, selective insulin sensitivity in adipose tissue, and amelioration of spontaneous atherosclerosis. Both in vivo and ex vivo studies suggest that MyD88-dependent GM-CSF production from the endothelial cells might play a critical role in the initiation of obesity-associated inflammation and development of atherosclerosis by priming the monocytes in the adipose and arterial tissues to differentiate into M1-like inflammatory macrophages. Collectively, these results implicate a critical MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Quantitative trait locus on chromosome 20q13 for plasma levels of C-reactive protein in healthy whites: the HERITAGE Family Study

Physiological Genomics ◽

10.1152/physiolgenomics.00054.2005 ◽

2006 ◽

Vol 27 (2) ◽

pp. 103-107 ◽

Cited By ~ 10

Author(s):

Timo A. Lakka ◽

Tuomo Rankinen ◽

Treva Rice ◽

Arthur S. Leon ◽

D. C. Rao ◽

...

Keyword(s):

Plasma Levels ◽

Family Study ◽

Inflammatory Diseases ◽

Low Grade ◽

C Reactive Protein ◽

Lod Score ◽

Chronic Inflammatory Diseases ◽

Reactive Protein ◽

A Genome ◽

Chromosome 20Q13

C-reactive protein (CRP) is a sensitive marker of systemic low-grade inflammation. Increased plasma levels of CRP predict the risk of cardiovascular and metabolic diseases. Although genetic factors account for 30–40% of individual differences in plasma CRP levels, genomic regions contributing to CRP levels remain unknown. We performed a genome-wide linkage scan for plasma CRP levels in healthy whites from the HERITAGE Family Study. CRP was measured with a high-sensitivity assay. Multipoint linkage analyses were performed in 280 sibling pairs with 654 markers using regression and variance components-based methods. Data were adjusted for independent correlates of plasma CRP. We showed the strongest evidence of linkage for plasma CRP levels on chromosome 20q13. Markers which gave suggestive linkages in this region were D20S52 [logarithm of odds (LOD) score 3.18, P = 0.00006], D20S857 (LOD score 2.87, P = 0.00014), D20S869 (LOD score 2.75, P = 0.0002), D20S480 (LOD score 2.59, P = 0.0003), D20S501 (LOD score 2.55, P = 0.0003), D20S840 (LOD score 2.18, P = 0.0008), and D20S876 (LOD score 2.07, P = 0.001). We also detected suggestive linkage on chromosome 5p13 for marker D5S1470 (LOD score 2.23, P = 0.0007). Chromosome 20q13 may contribute to plasma CRP levels in healthy whites. This region contains genes that are important in the inflammatory process and may play a role in the development of chronic inflammatory diseases. The present findings may be useful in the ongoing effort to search for genes contributing to inflammation and to identify individuals at an increased risk of chronic inflammatory diseases.

Download Full-text

CHIP & HIPs: Clonal Hematopoiesis is Common in Hip Arthroplasty Patients and Associates with Autoimmune Disease

Blood ◽

10.1182/blood.2020010163 ◽

2021 ◽

Author(s):

Judith S. Hecker ◽

Luise Hartmann ◽

Jennifer Rivière ◽

Michèle Constanze Buck ◽

Mark van der Garde ◽

...

Keyword(s):

Hip Arthroplasty ◽

Inflammatory Diseases ◽

Low Grade ◽

Related Condition ◽

Clonal Hematopoiesis ◽

Mild Anemia ◽

Age Related ◽

Mutation Burden ◽

Clinical Associations ◽

Low Grade Inflammation

Clonal hematopoiesis (CH) is an age-related condition predisposing to blood cancer and cardiovascular disease (CVD). Murine models demonstrate CH-mediated altered immune function and proinflammation. Low-grade inflammation has been implicated in the pathogenesis of osteoarthritis (OA), the main indication for total hip arthroplasty (THA). THA-derived hip bones serve as a major source of 'healthy' hematopoietic cells in experimental hematology. We prospectively investigated frequency and clinical associations of CH in 200 patients without known hematologic disease undergoing THA. Prevalence of CH was 50%, including 77 patients with CH of indeterminate potential (CHIP, defined as somatic variants with allele frequencies [VAF] ≥2%), and 23 patients harboring CH with lower mutation burden (VAF 1-2%). Most commonly mutated genes were DNMT3A (29.5%), TET2 (15.0%) and ASXL1 (3.5%). CHIP significantly associated with lower hemoglobin, higher mean corpuscular volume, prior/present malignant disease, and CVD. Strikingly, we observed a previously unreported association of CHIP with autoimmune diseases (AID; multivariate adjusted odds ratio, 6.6; 95% confidence interval [1.7, 30]; p=0.0081). These findings underscore the association between CH and inflammatory diseases. Our results have considerable relevance for management of patients with OA and AID or mild anemia, and question use of hip bone-derived cells as 'healthy' experimental controls.

Download Full-text