Krebs cycle derivatives, dimethyl fumarate and itaconate, control metabolic reprogramming in inflammatory human microglia cell line.

Metabolic reprogramming drives inflammatory activity in macrophages, including microglia, with Krebs cycle (KC) intermediates playing a crucial role as signaling molecules. Here, we show that the bioenergetic profile of LPS-activated human microglialclone 3 cell line (HMC3) is characterized by high levels of glycolysis and mitochondrial (mt) respiration, and the treatment with KC derivatives, namely dimethyl-fumarate (DMF) and itaconate (ITA), almost restores normal metabolism. However, despite comparable bioenergetic and anti-inflammatory effects, the mt hyper-activity was differentially modulated by DMF and ITA. DMF normalized complex I activity, while ITA dampened both complex I and II hyper-activity counteracting oxidative stress more efficiently.

Adherence to the Mediterranean Diet Mitigates Inflammation and Hospital Stay in Frail Elderly Patients: A Moderation Analysis.

Understanding the interaction between dietary patterns and nutritional status in influencing health outcomes is crucial, especially in vulnerable populations. Our study investigates the impact of adherence to the Mediterranean diet (MD) and nutritional status on inflammatory markers (CRP) and the length of stay (LOS) in hospitalized frail elderly patients. METHODS: We conducted two-way ANOVA and multiple regression analysis to evaluate the effects of nutritional status and MD adherence on the CRP levels and LOS in a cohort of 117 frail elderly patients aged 65 years or older. Patients with cancer or acute infection were excluded. Adherence to the MD was assessed using the 14-item PREDIMED questionnaire. RESULTS: Significant interactions were found between nutritional status and MD adherence for both the CRP and LOS. The patients with low-level MD adherence and a poor nutritional status exhibited higher CRP levels and longer hospital stays compared to those with high MD adherence. Specifically, a statistically significant interaction was observed for the CRP (F (1, 113) = 7.36, p = 0.008) and LOS (F (1, 113) = 15.4, p < 0.001), indicating the protective effect of high-level MD adherence. Moderation analysis confirmed that high-level MD adherence mitigates the adverse effects of malnutrition on both the inflammatory response and LOS. CONCLUSIONS: These findings highlight the importance of promoting the MD, particularly in malnourished elderly patients, to improve health outcomes and reduce hospitalization duration. Further longitudinal studies are warranted to establish causality and explore the underlying mechanisms.

Limits of pre-endoscopic scoring systems in geriatric patients with upper gastrointestinal bleeding.

Upper gastrointestinal bleeding (UGIB) is a common cause of hospital admission worldwide and several risk scores have been developed to predict clinically relevant outcomes. Despite the geriatric population being a high-risk group, age is often overlooked in the assessment of many risk scores. In this study we aimed to compare the predictive accuracy of six pre-endoscopic risk scoring systems in a geriatric population hospitalised with UGIB. We conducted a multi-center cross-sectional study and recruited 136 patients, 67 of these were 65-81.9 years old ("< 82 years"), 69 were 82-100 years old ("≥ 82 years"). We performed six pre-endoscopic risk scores very commonly used in clinical practice (i.e. Glasgow-Blatchford Bleeding and its modified version, T-score, MAP(ASH), Canada-United Kingdom-Adelaide, AIMS65) in both age cohorts and compared their accuracy in relevant outcomes predictions: 30-days mortality since hospitalization, a composite outcome (need of red blood transfusions, endoscopic treatment, rebleeding) and length of hospital stay. T-score showed a significantly worse performance in mortality prediction in the "≥ 82 years" group (AUROC 0.53, 95% CI 0.27-0.75) compared to "< 82 years" group (AUROC 0.88, 95% CI 0.77-0.99). In the composite outcome prediction, except for T-score, younger participants had higher sensitivities than those in the "≥ 82 years" group. All risk scores showed low performances in the prediction of length of stay (AUROCs ≤ 0.70), and, except for CANUKA score, there was a significant difference in terms of accuracy among age cohorts. Most used UGIB risk scores have a low accuracy in the prediction of clinically relevant outcomes in the geriatric population; hence novel scores should account for age or advanced age in their assessment.

Diagnostic Yield of Endoscopic Ultrasound-Guided Liver Biopsy in Comparison to Percutaneous Liver Biopsy: A Meta-Analysis of Randomized Controlled Trials and Trial Sequential Analysis.

BACKGROUND: The efficacy of endoscopic ultrasound-guided liver biopsy (EUS-LB) compared to percutaneous liver biopsy (PC-LB) remains uncertain. METHODS: Our data consist of randomized controlled trials (RCTs) comparing EUS-LB to PC-LB, found through a literature search via PubMed/Medline and Embase. The primary outcome was sample adequacy, whereas secondary outcomes were longest and total lengths of tissue specimens, diagnostic accuracy, and number of complete portal tracts (CPTs). RESULTS: Sample adequacy did not significantly differ between EUS-LB and PC-LB (risk ratio [RR] 1.18; 95% confidence interval [CI] 0.58-2.38; p = 0.65), with very low evidence quality and inadequate sample size as per trial sequential analysis (TSA). The two techniques were equivalent with respect to diagnostic accuracy (RR: 1; CI: 0.95-1.05; p = 0.88), mean number of complete portal tracts (mean difference: 2.29, -4.08 to 8.66; p = 0.48), and total specimen length (mean difference: -0.51, -20.92 to 19.9; p = 0.96). The mean maximum specimen length was significantly longer in the PC-LB group (mean difference: -3.11, -5.51 to -0.71; p = 0.01), and TSA showed that the required information size was reached. CONCLUSION: EUS-LB and PC-LB are comparable in terms of diagnostic performance although PC-LB provides longer non-fragmented specimens.

Circadian patterns of growth factor receptor-dependent signaling and implications for carcinogenesis.

Several different signaling pathways that regulate cell proliferation and differentiation are initiated by binding of ligands to cell-surface and membrane-bound enzyme-linked receptors, such as receptor tyrosine kinases and serine-threonine kinases. They prompt phosphorylation of tyrosine and serine-threonine residues and initiate downstream signaling pathways and priming of intracellular molecules that convey the signal in the cytoplasm and nucleus, with transcriptional activation of specific genes enriching cell growth and survival-related cascades. These cell processes are rhythmically driven by molecular clockworks endowed in every cell type and when deregulated play a crucial role in cancer onset and progression. Growth factors and their matching receptor-dependent signaling are frequently overexpressed and/or dysregulated in many cancer types. In this review we focus on the interplay between biological clocks and Growth Factor Receptor-dependent signaling in the context of carcinogenesis.

Monocyte bioenergetics: An immunometabolic perspective in metabolic dysfunction-associated steatohepatitis.

Monocytes (Mos) are crucial in the evolution of metabolic dysfunction-associated steatotic liver disease (MASLD) to metabolic dysfunction-associated steatohepatitis (MASH), and immunometabolism studies have recently suggested targeting leukocyte bioenergetics in inflammatory diseases. Here, we reveal a peculiar bioenergetic phenotype in circulating Mos of patients with MASH, characterized by high levels of glycolysis and mitochondrial (mt) respiration. The enhancement of mt respiratory chain activity, especially complex II (succinate dehydrogenase [SDH]), is unbalanced toward the production of reactive oxygen species (ROS) and is sustained at the transcriptional level with the involvement of the AMPK-mTOR-PGC-1α axis. The modulation of mt activity with dimethyl malonate (DMM), an SDH inhibitor, restores the metabolic profile and almost abrogates cytokine production. Analysis of a public single-cell RNA sequencing (scRNA-seq) dataset confirms that in murine models of MASH, liver Mo-derived macrophages exhibit an upregulation of mt and glycolytic energy pathways. Accordingly, the DMM injection in MASH mice contrasts Mo infiltration and macrophagic enrichment, suggesting immunometabolism as a potential target in MASH.

The Role of TLR-2 in Lethal COVID-19 Disease Involving Medullary and Resident Lung Megakaryocyte Up-Regulation in the Microthrombosis Mechanism.

Patients with COVID-19 have coagulation and platelet disorders, with platelet alterations and thrombocytopenia representing negative prognostic parameters associated with severe forms of the disease and increased lethality. METHODS: The aim of this study was to study the expression of platelet glycoprotein IIIa (CD61), playing a critical role in platelet aggregation, together with TRL-2 as a marker of innate immune activation. RESULTS: A total of 25 patients were investigated, with the majority (24/25, 96%) having co-morbidities and dying from a fatal form of SARS-CoV-2(+) infection (COVID-19+), with 13 men and 12 females ranging in age from 45 to 80 years. When compared to a control group of SARS-CoV-2 (-) negative lungs (COVID-19-), TLR-2 expression was up-regulated in a subset of patients with deadly COVID-19 fatal lung illness. The proportion of Spike-1 (+) patients found by PCR and ISH correlates to the proportion of Spike-S1-positive cases as detected by digital pathology examination. Furthermore, CD61 expression was considerably higher in the lungs of deceased patients. In conclusion, we demonstrate that innate immune prolonged hyperactivation is related to platelet/megakaryocyte over-expression in the lung. CONCLUSIONS: Microthrombosis in deadly COVID-19+ lung disease is associated with an increase in the number of CD61+ platelets and megakaryocytes in the pulmonary interstitium, as well as their functional activation; this phenomenon is associated with increased expression of innate immunity TLR2+ cells, which binds the SARS-CoV-2 E protein, and significantly with the persistence of the Spike-S1 viral sequence.

The influence of acute lifestyle changes on NAFLD evolution in a multicentre cohort: a matter of body composition.

BACKGROUND: Unhealthy lifestyles represent a key element fueling Non-alcoholic fatty liver disease (NAFLD) onset and worsening. We aimed to evaluate the effects of forced acute lifestyle changes on NAFLD evolution. METHODS: 187 NAFLD patients were followed two years pre- and two years during the lockdown social restrictions in three Italian medical centers. For each patient, biochemical, clinical, non-invasive liver fibrosis, nutritional, and body composition data were collected. RESULTS: An increase in fats and carbohydrate intake associated with impaired weekly physical activity during the lockdown was demonstrated as well as an increase in body mass index and waist-hip-ratio (p < 0.0001 for all). Total cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, glucose, insulin, homeostatic model assessment for insulin resistance, and transaminases worsened during the lockdown (glucose: p = 0.0007; p < 0.0001 for the others). Moreover, NAFLD fibrosis score, liver stiffness, and controlled attenuation parameter were also impaired during the same period (p < 0.0001 for all). The bioelectrical impedance analysis (BIA) evidenced an increase of fat mass (FM), and a reduction of free fat mass (FFM) and body cell mass (BCM) (p < 0.0001 for all). The lockdown overall hepatocellular carcinoma (HCC) and Milan-out HCC occurrence revealed Hazard Ratio (HR): 2.398, 95% Confidence Interval (CI):1.16-5, p = 0.02, and HR:5.931, CI:2-17.6, p = 0.008 respectively. A liver disease stage and comorbidities independent association between both the assessed outcomes and body composition analysis in terms of mean values and variation (T1-T2 Δ) was demonstrated. CONCLUSIONS: The acute lifestyle changes impacted NAFLD evolution via body composition modifications negatively influencing the HCC occurrence.

Potential Therapeutic Targets to Modulate the Endocannabinoid System in Alzheimer's Disease.

Alzheimer's disease (AD), the most common neurodegenerative disease (NDD), is characterized by chronic neuronal cell death through progressive loss of cognitive function. Amyloid beta (Aß) deposition, neuroinflammation, oxidative stress, and hyperphosphorylated tau proteins are considered the hallmarks of AD pathology. Different therapeutic approaches approved by the Food and Drug Administration can only target a single altered pathway instead of various mechanisms that are involved in AD pathology, resulting in limited symptomatic relief and almost no effect in slowing down the disease progression. Growing evidence on modulating the components of the endocannabinoid system (ECS) proclaimed their neuroprotective effects by reducing neurochemical alterations and preventing cellular dysfunction. Recent studies on AD mouse models have reported that the inhibitors of the fatty acid amide hydrolase (FAAH) and monoacylglycerol (MAGL), hydrolytic enzymes for N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), respectively, might be promising candidates as therapeutical intervention. The FAAH and MAGL inhibitors alone or in combination seem to produce neuroprotection by reversing cognitive deficits along with Aß-induced neuroinflammation, oxidative responses, and neuronal death, delaying AD progression. Their exact signaling mechanisms need to be elucidated for understanding the brain intrinsic repair mechanism. The aim of this review was to shed light on physiology and pathophysiology of AD and to summarize the experimental data on neuroprotective roles of FAAH and MAGL inhibitors. In this review, we have also included CB1R and CB2R modulators with their diverse roles to modulate ECS mediated responses such as anti-nociceptive, anxiolytic, and anti-inflammatory actions in AD. Future research would provide the directions in understanding the molecular mechanisms and development of new therapeutic interventions for the treatment of AD.

Association between Controlling Nutritional Status (CONUT) Score and Body Composition, Inflammation and Frailty in Hospitalized Elderly Patients.

The Controlling Nutritional Status (CONUT) score has demonstrated its ability to identify patients with poor nutritional status and predict various clinical outcomes. Our objective was to assess the association between the CONUT score, inflammatory status, and body composition, as well as its ability to identify patients at risk of frailty in hospitalized elderly patients. METHODS: a total of 361 patients were retrospectively recruited and divided into three groups based on the CONUT score. RESULTS: patients with a score ≥5 exhibited significantly higher levels of inflammatory markers, such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Neutrophil/Lymphocytes ratio (NLR), main platelet volume (MPV), and ferritin, compared to those with a lower score. Furthermore, these patients showed unfavorable changes in body composition, including a lower percentage of skeletal muscle mass (MM) and fat-free mass (FFM) and a higher percentage of fatty mass (FM). A positive correlation was found between the CONUT score and inflammatory markers, Geriatric Depression Scale Short Form (GDS-SF), and FM. Conversely, the Mini Nutritional Assessment (MNA), Mini-Mental Status Examination, activity daily living (ADL), instrumental activity daily living (IADL), Barthel index, FFM, and MM showed a negative correlation. Frailty was highly prevalent among patients with a higher CONUT score. The receiver operating characteristic (ROC) curve demonstrated high accuracy in identifying frail patients (sensitivity). CONCLUSIONS: a high CONUT score is associated with a pro-inflammatory status as well as with unfavorable body composition. Additionally, it is a good tool to identify frailty among hospitalized elderly patients.

Current Approaches for Monitoring of Patients with Inflammatory Bowel Diseases: A Narrative Review.

BACKGROUND: Patients with inflammatory bowel diseases (IBD) require proactive monitoring both during the active phase to evaluate therapeutic response and during the remission phase to evaluate relapse or colorectal cancer surveillance. However, monitoring may vary between patients with ulcerative colitis (UC) and Crohn's disease (CD), with distinct tools and intervals. METHODS: This narrative review aims to focus on modern approaches to IBD monitoring, considering international guidelines and expert consensus. RESULTS: The most recent European diagnostic guidelines advocate a combination of clinical, laboratory, endoscopic, and radiological parameters to evaluate the disease course of patients with IBD. Unfortunately, the conventional symptom-based therapeutic approach does not improve long-term outcomes and there is no single ideal biomarker available. Endoscopy plays a key role in evaluating response to therapy as well as monitoring disease activity. Recently, bedside intestinal ultrasound (IUS) has gained increasing interest and diffusion as it appears to offer several advantages including the monitoring of therapeutic response. CONCLUSION: In light of growing clinical advances, we present a schematic evidence-based monitoring algorithm that can be easily applied in clinical practice which combines all major monitoring modalities, including noninvasive tools such as IUS and video-capsule endoscopy.

Evolution of liver fibrosis in diabetic patients with NAFLD in a follow-up study: Hepatoprotective effects of sodium-glucose co-transporter-2 inhibitors.

BACKGROUND AND AIMS: Patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are at high risk of hepatic fibrosis. To prospectively evaluate changes in fibrosis in diabetic patients with NAFLD, predisposing factors and sodium glucose cotransporter 2 inhibitors (SGLT2i) influence. METHODS: 237 T2DM outpatients (mean age 67 ± 9 years, 54% male) were enrolled and re-evaluated after 52 ± 10 months. At baseline and follow-up NAFLD and liver fibrosis (LSM) were detected by ultrasonography and Fibroscan®. RESULTS: During follow-up an increase in LSM (6.0 ± 2.8 vs 5.8 ± 2.7 kPa, p = 0.02) and in the prescription of SGLT2i (20% vs 6%, p<0.001) was registered, despite stability of diabetic control. LSM worsened in 133(56%) subjects, 92 (39%) with worsening >10% from baseline. Patients with worsening versus non worsening of LSM had higher prevalence of increase in BMI during follow-up (45% vs 32%, p = 0.06) and lower SGLT2i prescription (15% vs 27%, p = 0.034). In multivariate analysis use of SGLT2-inhibitors at follow-up reduced the risk of LSM worsening (HR 0.34, 95% CI 0.13-0.88), even when considered>10% from baseline. CONCLUSIONS: A high prevalence of fibrosis progression was observed in diabetic subjects with NAFLD over a nearly 5-years follow up and SGLT2-inhibitors seem to reduce the risk of worsening of liver stiffness.