Search Results (59)

Anxiety symptomatology and excess weight are associated with chronic low-grade inflammation. Olive leaf extract (OLE) contains polyphenols with antioxidant and anti-inflammatory properties that have shown anxiolytic-like effects in experimental models; however, evidence in humans remains limited. This randomized double-blind placebo-controlled pilot trial evaluated the effects of OLE supplementation on anxiety symptomatology, inflammatory markers, and metabolic parameters in women with excess weight and mild to moderate anxiety symptoms. Participants received OLE (750 mg/day) or placebo for 12 weeks. Anxiety symptomatology was assessed using HAM-A, BAI, and STAI, while inflammatory and metabolic parameters were evaluated at baseline and post-intervention. Since the expected sample size was not achieved, our results are preliminary. No effect was observed from OLE supplementation. However, some differences within groups can direct future researchers interested in evaluating these parameters. OLE supplementation correlated with a particular reduction phenotype in anxious symptomatology (HAM-A, BAI and STAI-Trait) with inflammatory (hs-CRP) and metabolic parameters (c-HDL) that may open the possibility of an anti-inflammatory effect. In contrast, the observations in the Pb group seemed more associated with a pro-inflammatory state and a placebo effect related to somatic symptoms of anxiety. These preliminary observations need to be confirmed with larger randomized clinical trials that may help clarify these results and the possible underlying mechanisms. Full article

Background/Objectives: Metainflammation is a chronic low-grade inflammatory state driven by excessive nutrition and obesity. It is associated with adipocyte dysfunction, altered adipokine secretion, and the development of insulin resistance, which contributes to dysglycemia and hyperglycemia. Recent initiatives emphasize earlier recognition of pathological processes to enable timely detection and primary prevention of adverse cardiovascular outcomes. Metainflammation has traditionally been assessed using serum C-reactive protein (CRP) levels and several proposed indices, with inconsistent performance due to chronic inflammation-related changes in blood cell counts. This study aimed to evaluate a newly proposed MetaLGI score as a laboratory-based tool for identifying pronounced metainflammation in patients with metabolic syndrome. Methods: Patients with metabolic syndrome were assessed for metainflammation using the newly proposed MetaLGI score and compared with previously suggested indices and CRP-based definitions. The ability of these approaches to identify pronounced metainflammation and associated hematological and metabolic alterations was evaluated. Results: The MetaLGI score demonstrated superiority in recognizing pronounced metainflammation in patients with metabolic syndrome compared to previous indices. Additionally, the proposed laboratory definition of metainflammation showed better performance in identifying patients with increased platelet counts, highlighting its relevance for inflammation-related cardiovascular thrombosis. MetaLGI also outperformed earlier proposals in identifying patients with increased β-cell burden. Conclusions: The newly proposed MetaLGI score represents a superior and widely available laboratory-based method for detecting pronounced metainflammation in patients with metabolic syndrome. Its improved ability to identify increased platelet counts and β-cell burden suggests potential value for early risk stratification and primary prevention of cardiometabolic complications. Full article

Background: Metabolic and bariatric surgery is an established therapeutic option for severe obesity and obesity-related medical problems. Although minimally invasive techniques and enhanced recovery pathways have reduced postoperative morbidity, infectious complications remain clinically relevant because they may lead to readmission, reoperation, prolonged antimicrobial therapy, and mortality. Methods: We conducted a narrative review of the literature on infectious complications after metabolic and bariatric surgery. Evidence was synthesized across five clinically relevant domains: host-related pathophysiology, microbial epidemiology, preoperative optimization, antimicrobial prophylaxis and pharmacokinetic considerations, and diagnosis and management of postoperative infectious complications. Results: Patients with obesity present specific infection-related vulnerabilities, including chronic low-grade inflammation, altered immune responses, impaired tissue oxygenation, obesity-related medical problems, and procedure-specific risks. Contemporary prevention relies on multidisciplinary preoperative optimization, appropriate skin antisepsis, weight-based antimicrobial prophylaxis, intraoperative redosing when indicated, and adherence to enhanced recovery principles. Anastomotic leaks and intra-abdominal abscesses represent the most severe organ/space infections and require early recognition, source control, antimicrobial therapy, nutritional support, and coordinated surgical, radiological, and endoscopic management. Conclusions: Infectious complications after metabolic and bariatric surgery result from the interaction between host physiology, microbial factors, pharmacological considerations, and surgical technique. A structured approach integrating prevention, early diagnosis, and multidisciplinary management may improve outcomes. Further bariatric-specific studies are needed to strengthen the evidence base for several preventive and therapeutic strategies. Full article

Obesity is characterized by chronic low-grade inflammation (meta-inflammation) and metabolic dysregulation. Adipose tissue acts as an immunometabolic organ, with macrophages playing a central role. This review examines inflammatory memory in adipose tissue, focusing on CD68+ macrophages and their role in cardiometabolic and cancer risk during weight cycling. (2) Narrative synthesis of evidence from immunology, obesitology, and oncology, with emphasis on macrophage polarization and signaling pathways. (3) Weight cycling induces persistent immune memory in adipose tissue, characterized by exaggerated macrophage responses upon weight regain. CD68+ macrophages contribute to extracellular matrix remodeling, tumor signaling, and metabolic dysfunction. Key mechanisms include PI3K/AKT/mTOR dysregulation, FOXO1/KLF10 axis impairment, and CREB-mediated transcription. This inflammatory memory promotes atherosclerosis progression, insulin resistance, and increased cancer risk, despite prior weight loss. (4) Macrophage-driven inflammatory memory represents a key mechanistic link between obesity, cardiometabolic disease, and cancer. Targeting meta-inflammation independent of body weight should be integral to future therapies. Full article

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. During the last few years, remarkable advances have been made in the treatment of DN. Sodium–glucose cotransporter type 2 inhibitors (SGLT2i) consistently prevent or delay albuminuria and renal failure in patients with DN. Prior research from our group highlights the Janus kinase/signal transducers and activators of transcription axis as a critical target in DN. Specifically, the administration of suppression of cytokine signaling 1 (SOCS1) mimetic peptides (MiS1) modulates aberrant signaling, resulting in profound beneficial effects on renal function and structural integrity in experimental DN. The aim of this study was to evaluate the effect of empagliflozin and MiS1 on kidney damage and its associated inflammatory, oxidative stress and lipotoxic mechanisms in an advanced type 2 DN mouse model BTBR ob/ob. Mice were treated for 7 weeks with empagliflozin and MiS1, alone or in combination, and monitored for glycemia, body weight, albuminuria, histopathological damage, podocyte loss, and gene expression related to inflammation, redox balance, and lipid metabolism. Empagliflozin or MiS1 monotherapies significantly reduced albuminuria and structural renal injury, preserved podocyte number, and downregulated genes involved in inflammatory, oxidative, and mitochondrial–lipid metabolic dysregulation, with empagliflozin additionally improving metabolic parameters. Notably, the combined therapy achieved the greatest reduction in albuminuria and histological damage with enhanced suppression of pathogenic inflammatory and metabolic pathways, resulting in superior renoprotection compared with monotherapy. These findings suggested that add-on therapy with SOCS1 peptidomimetics and SGLT2i may help mitigate residual albuminuria and renal damage in type 2 DN. Full article

Insulin resistance (IR) is a central driver of cardiometabolic disease and an increasingly recognized modifier of inflammatory and vascular pathology. Beyond impaired glucose homeostasis, IR emerges from chronic, metabolically induced inflammation (“meta-inflammation”) and convergent cellular stress programs that propagate across tissues and organ systems, ultimately shaping endothelial dysfunction, atherogenesis, and cardiometabolic complications. Here, we synthesize multilevel links between insulin receptor signaling, intracellular stress modules (oxidative, endoplasmic reticulum, inflammatory, and fibrotic pathways), tissue-level dysfunction, and systemic inflammatory amplification. This work is a conceptual narrative review informed by targeted database searches and citation tracking, with explicit separation of mechanistic/experimental evidence from human observational and interventional data; causal inferences are framed primarily on mechanistic and interventional findings, whereas associative statements are reserved for observational evidence. We propose an integrative framework in which stress-response pathways are context-dependent and become maladaptive when chronically activated under nutrient excess and persistent inflammatory cues, generating self-reinforcing loops between IR and inflammation that accelerate vascular injury. This framework highlights points of convergence that can guide mechanistic prioritization and translational hypothesis testing. Full article

Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of the cases of HF worldwide. Among the different phenotypes, cardiometabolic HFpEF has the highest prevalence. Cumulative insults related to cardiometabolic comorbidities—obesity, hypertension and type 2 diabetes—create a milieu of metabolic derangements, low-grade systemic inflammation (i.e., metainflammation), endothelial dysfunction, and coronary microvascular disease. Emerging data indicate that the gut–heart axis is a potential amplifier of this process. Cardiometabolic comorbidities promote gut dysbiosis, loss of short-chain fatty acid (SCFA)-producing taxa, and disruption of the intestinal barrier, leading to endotoxemia and upregulation of pro-inflammatory pathways such as TLR4- and NLRP3-mediated signaling. Concomitantly, beneficial gut-derived metabolites (acetate, propionate, butyrate) decrease, while detrimental metabolites increase (e.g., TMAO), potentially fostering myocardial fibrosis, diastolic dysfunction, and adverse remodeling. SCFAs—acetate, propionate, and butyrate—may exert pleiotropic actions that directly target HFpEF pathophysiology: they may provide a CPT1-independent energy substrate to the failing myocardium, may improve lipid and glucose homeostasis via G protein-coupled receptors and AMPK activation, and may contribute to lower blood pressure and sympathetic tone, reinforce gut barrier integrity, and act as anti-inflammatory and epigenetic modulators through the inhibition of NF-κB, NLRP3, and histone deacetylases. This review summarizes current evidence linking gut microbiota dysfunction to cardiometabolic HFpEF, elucidates the mechanistic role of SCFAs, and discusses nutritional approaches aimed at enhancing their production and activity. Targeting gut–heart axis and SCFAs pathways may represent a biologically plausible and low-risk approach that could help attenuate inflammation and metabolic dysfunctions in patients with cardiometabolic HFpEF, offering novel potential therapeutic targets for their management. Full article

Fatty acid-binding proteins (FABPs) represent a superfamily of intracellular lipid chaperones essential for the transport of lipids and homeostatic lipid metabolism. Although well-known for their role in systemic metabolic diseases, emerging evidence has identified brain-expressed FABPs as core players in neurodegeneration. This review focuses on brain-expressed FABPs, synthesizing recent advancements that link their role in metabolic dysregulation to neurotoxicity. We present a system that integrates these proteins within a multi-tiered complex pathobiological system that involves: an advanced glial “meta-inflammation” paradigm; a novel view on proteotoxicity via liquid–liquid phase separation (LLPS); changes in the gut–brain axis; and an involvement in the regulation of ferroptosis. Additionally, we also discuss the emerging pharmacological pipeline, highlighting notable preclinical ligands and drawing important lessons from systemic disease first-in-class-targeted FABPs. These first-in-class therapies have successfully validated this target family in systemic diseases. Finally, we explore future therapeutic strategies, where we emphasize the challenges and the precision cell-type-specific delivery approaches to harness the full therapeutic potential of these pivotal proteins. Full article

During diabetic retinopathy (DR), cell death has been characterized in all of the major retinal cell types, but was observed initially in the microvasculature, particularly the mural cells: pericytes and vascular smooth muscle cells (VSMCs). Indeed, our ability to identify the mural cell corpses called “ghost cells” within the vascular basement membranes (BMs) in eyes of diabetic patients and animal models is indicative that removal of dead cells, or efferocytosis (EF), is dysfunctional during this disease. EF is the process whereby apoptotic cells are eliminated through phagocytic engulfment and digestion and is essential to maintain tissue integrity and immune homeostasis. The process occurs in three distinct phases: finding and recognition, engulfment, and digestion, under the direction of “find me” and “eat me” signals and a large array of their cognate receptors and bridging molecules. Efferocytosis can be performed by many cell types, but most efficiently by professional phagocytes, and with such rapidity that the process is extremely difficult to detect in healthy tissues. As delayed EF is a recognized cause of autoimmune and inflammatory disease, mural cell death in DR may create inflammatory foci in the neurovascular unit (NVU). Here we discuss the basic mechanisms of EF in the context of DR and the impact of diabetic metainflammation on EF effector cell dysfunction. Full article

Background: Obesity, mainly visceral obesity, causes a low-grade of chronic inflammation (meta-inflammation), associated with comorbidities such as type 2 diabetes, cardiovascular diseases, and certain cancers. Precision Nutrition aims to understand the bidirectional crosstalk between the genome and diet to improve human health. Additionally, by leveraging individual data, Precision Nutrition seeks to predict how people will respond to specific foods or dietary patterns, with the ultimate goal of providing personalized nutritional recommendations tailored to their unique needs and lifestyle factors, including poor dietary habits (e.g., high intake of sugar or saturated fatty acids, alcohol consumption, etc.) and sedentary habits, exacerbate obesity in genetically predisposed individuals. Genetic, metabolic, and environmental factors can play a crucial role during obesity. Objective: To investigate the effects of genetic variability in sweet taste receptors and their downstream signaling pathways in the gut–brain axis on anthropometry, biochemistry, and lifestyle variables. Methods: A sample of 676 volunteers (mean age of 42.22 ± 12 years, ranging from 18 to 73 years) from the database of the GENYAL platform for nutritional trials at the IMDEA Food Institute were included in this study. We present a first-in-class genetic chip, Glucosensing, designed to interrogate 25 single-nucleotide polymorphisms (SNPs) located in genes encoding sweet taste receptors and components of downstream signaling pathways. These include elements of the gut–brain axis and its associated metabolic networks, enabling a comprehensive analysis of individual variability in sweet taste perception and metabolic responses. Results: Several significant associations were found after correction for multiple comparisons, representing potential targets for personalized interventions. Full article

Background: Meta-inflammation is a hallmark of hidradenitis suppurativa (HS). Research on meta-inflammation in HS is growing, but there is still no research on haptoglobin as an inflammatory protein in lesional HS skin. This study examines the relationship between haptoglobin expression in HS skin lesions and clinical parameters. Methods: An examination was performed on 44 skin samples from HS patients and 10 healthy skin samples. Clinical parameters were then compared with haptoglobin expression. Results: Median haptoglobin expression was significantly higher in the Hurley stage III lesions compared with milder stages (H-score: 37.6 versus 17.1, p = 0.028). High haptoglobin expression (≥30.8% positive cells) was associated with advanced disease (Hurley stage III: 80% versus 41.7%, p = 0.01), active smoking (80% versus 50%, p = 0.039), increased pain (visual analogue scale: 5 versus 1.5, p = 0.03), and a higher prevalence of diabetes (35% versus 8.3%, p = 0.029) and hypertension (55% versus 25%, p = 0.042). No significant associations were found with the BMI, disease duration, or CRP levels. Conclusions: High haptoglobin expression (positive cells ≥ 30.8%) in a skin lesion is associated with higher HS severity, active smoking, more pain and the comorbidities of diabetes mellitus and arterial hypertension in HS patients. Full article

In obesity, recent research revealed that increased expression of the growth hormone secretagogue receptor (GHSR) in macrophages plays a pivotal role in the development of meta-inflammation, promoting macrophage infiltration and pro-inflammatory polarization. This study aimed to examine the association between GHSR-1a expression in atherosclerotic plaques and adjacent perivascular adipose tissue (PVAT) from 11 patients with obesity and peripheral artery disease (PAD) who underwent revascularization procedures. Immunohistochemistry was used to assess the expression of CD68, CD80, and CD14, while tissue homogenate levels of adiponectin, leptin, IL-6, and CRP were quantified via ELISA. Serum markers of inflammation were also measured. Among patients with GHSR-1a-positive (+) macrophages in atherosclerotic plaques, we observed significantly higher white blood cell counts and platelet-to-lymphocyte ratios in serum, a lower adiponectin-to-leptin ratio, and elevated IL-6 levels in both arterial and PVAT homogenates. Our findings suggest a link between GHSR-1a and macrophage/monocyte infiltration, macrophage polarization, and adipocytokine secretion in atherosclerotic plaques associated with obesity-induced PVAT dysfunction. Full article

Background: Metabolic syndrome (MetS) patients have impaired hypothalamic regulatory functions involved in food intake and energy expenditure and suffer from a state of meta-inflammation. Pre-clinical studies demonstrated that ultramicronized palmitoylethanolamide (PEA) acts both on the adipose tissue and the central nervous system, while hydroxytyrosol (HTyr) counteracts several types of dysmetabolism. Objectives: The aim of our randomized crossover double-blind placebo-controlled pilot study was to evaluate the potential effects of a food supplement (FS) containing a co-micronized formulation of PEA and rutin along with HTyr, combined with a tailored calorie-controlled Mediterranean diet, in patients with MetS. Methods: Nineteen patients were enrolled and block-randomized to an eight-week MD together with the FS or placebo. After a two-week washout period, the treatments were reversed. Data on laboratory parameters and those detected by capillary sampling, anthropometry, body composition analysis, ultrasound examination, blood pressure monitoring, the 36-Item Short-Form Health Survey questionnaire, handgrip strength test, and physical performance tests were collected at each time point (protocol code R.S. 262.22, registered on 20 December 2022). Results: At the end of the study, patients supplemented with the FS showed a significant reduction in body weight, body mass index, fat mass, and inflammation biomarkers (CRP and ESR), compared to placebo-supplemented patients. In contrast, the fat-free mass, phase angle, and body cell mass were increased in FS compared to placebo patients. Conclusions: Although preliminary, the results of our clinical study suggest that co-micronized PEA–rutin and HTyr may be of help against adiposopathy in patients with MetS. Full article

Background: Obesity and aging are associated with the progressive loss of brown adipose tissue (BAT), an increase in visceral white adipose tissue (vWAT), and a reduction in subcutaneous white adipose tissue (sWAT). The progressive expansion of visceral obesity promotes a low grade of systemic chronic inflammation (meta-inflammation), contributing to the onset of comorbidities such as type 2 diabetes mellitus (T2DM), metabolic syndrome, and even cancer. Thus, preserving the thermogenic activity of adipose tissue and improving the metabolic flexibility of sWAT could be an effective strategy to prevent the development of metabolic chronic diseases and promote healthy aging. Precision nutrition has emerged as a complementary approach to control the metabolic alterations associated with unhealthy obesity and aging. In a previous work, we described that a silymarin-enriched extract from milk thistle (Mthistle) increased markers of browning and thermogenesis in vitro in human differentiated adipocytes (SGBS). Objectives/Methods: Therefore, this study aims to evaluate the potential of Mthistle to activate thermogenesis in a preclinical model of high-fat diet (HFD)-induced obesity (DIO). Results: Our results demonstrate that Mthistle increases systemic energy expenditure (EE), preserves body temperature after cold exposure, improves insulin resistance, and reduces inflammatory markers in WAT. Conclusions: Based on these results, silymarin-enriched extract from Mthistle may be proposed as a nutraceutical for the management of metabolic chronic diseases and/or accelerated aging. Full article

White adipose tissue (WAT) and the gut are involved in the development of neuroinflammation when an organism detects any kind of injury, thereby triggering metainflammation. In fact, the autonomous nervous system innervates both tissues, although the complex role played by the integrated sympathetic, parasympathetic, and enteric nervous system functions have not been fully elucidated. Our aims were to investigate the participation of inflamed WAT and the gut in neuroinflammation. Firstly, we conducted an analysis into how inflamed peripheral WAT plays a key role in the triggering of metainflammation. Indeed, this included the impact of the development of local insulin resistance and its metabolic consequences, a serious hypothalamic dysfunction that promotes neurodegeneration. Then, we analyzed the gut–brain axis dysfunction involved in neuroinflammation by examining cell interactions, soluble factors, the sensing of microbes, and the role of dysbiosis-related mechanisms (intestinal microbiota and mucosal barriers) affecting brain functions. Finally, we targeted the physiological crosstalk between cells of the brain–WAT–gut axis that restores normal tissue homeostasis after injury. We concluded the following: because any injury can result not only in overall insulin resistance and dysbiosis, which in turn can impact upon the brain, but that a high-risk of the development of neuroinflammation-induced neurodegenerative disorder can also be triggered. Thus, it is imperative to avoid early metainflammation by applying appropriate preventive (e.g., lifestyle and diet) or pharmacological treatments to cope with allostasis and thus promote health homeostasis. Full article