Publications by authors named "Massimo Federici"

169 Publications

Impact of environmental pollution and weather changes on the incidence of ST-elevation myocardial infarction.

Eur J Prev Cardiol 2021 Oct;28(13):1501-1507

Division of Cardiology, Santa Maria Goretti Hospital, Italy.

Background: Environmental pollution and weather changes unfavorably impact on cardiovascular disease. However, limited research has focused on ST-elevation myocardial infarction (STEMI), the most severe yet distinctive form of acute coronary syndrome.

Methods And Results: We appraised the impact of environmental and weather changes on the incidence of STEMI, analysing the bivariate and multivariable association between several environmental and atmospheric parameters and the daily incidence of STEMI in two large Italian urban areas. Specifically, we appraised: carbon monoxide (CO), nitrogen dioxide (NO2), nitric oxide (NOX), ozone, particulate matter smaller than 10 μm (PM10) and than 2.5 μm (PM2.5), temperature, atmospheric pressure, humidity and rainfall. A total of 4285 days at risk were appraised, with 3473 cases of STEMI. Specifically, no STEMI occurred in 1920 (44.8%) days, whereas one or more occurred in the remaining 2365 (55.2%) days. Multilevel modelling identified several pollution and weather predictors of STEMI. In particular, concentrations of CO (p = 0.024), NOX (p = 0.039), ozone (p = 0.003), PM10 (p = 0.033) and PM2.5 (p = 0.042) predicted STEMI as early as three days before the event, as well as subsequently, and NO predicted STEMI one day before (p = 0.010), as well as on the same day. A similar predictive role was evident for temperature and atmospheric pressure (all p < 0.05).

Conclusions: The risk of STEMI is strongly associated with pollution and weather features. While causation cannot yet be proven, environmental and weather changes could be exploited to predict STEMI risk in the following days.
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http://dx.doi.org/10.1177/2047487320928450DOI Listing
October 2021

Effect of deprescribing in elderly patients with type 2 diabetes: iDegLira might improve quality of life.

Biomed Pharmacother 2021 Oct 19;144:112341. Epub 2021 Oct 19.

Department of System Medicine, University of Rome Tor Vergata, Italy.

Older people with type 2 diabetes (T2D) often have several comorbidities and take multiple drugs. This study tested a deprescribing strategy in older T2D patients, replacing a hypoglycemic therapeutic scheme with a single drug combination (iDegLira). In this 6-month, real-world, single-arm, open interventional study, we enrolled patients ≥ 75 years with T2D taking ≥ 2 medications for diabetes. Patients on a basal-bolus insulin regimen (n = 13), on a basal-insulin regimen plus oral glucose-lowering drugs (n = 9), and those on oral glucose-lowering drugs (n = 18) were switched to daily iDegLira. The primary clinical endpoint of the study was an improvement in CASP-19 and/or DTSQ score after 6 months. We also evaluated changes in glucose metabolism, depression, cognitive function, level of independence, and markers of inflammation. Thirty-five patients (12 women, mean age=81.4 y) completed the protocol. Results shown here are given as estimated mean difference (95%CI). DTSQ score improved [11.08 (7.13/15.02); p = 0.0001], whereas CASP-19 did not after 6 months of iDegLira treatment. We observed reductions in BMI [- 0.81 (- 1.27/0.35); p < 0.001], fasting glucose [- 52.07 (- 77.26/26.88); p < 0.001], HbA1c [- 0.58 (- 1.08/0.08); p < 0.05], and TNF-α [- 1.83 (- 3.12/- 0.54); p = 0.007]. Activities of daily living and cognitive function score increased [p = 0.006 and p = 0.02], whereas depression score significantly decreased [p = 0.02]. Notably, no patient reported episodes of severe hypoglycemia after initiation of iDegLira treatment. Among older patients with T2D, deprescribing using a single dose of iDegLira resulted in a greater likelihood of improving health and quality of life. Although our data indicate the effectiveness and safety of this approach, it must be confirmed in larger studies.
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http://dx.doi.org/10.1016/j.biopha.2021.112341DOI Listing
October 2021

Metabolic characteristics in patients with COVID-19 and no-COVID-19 interstitial pneumonia with mild-to-moderate symptoms and similar radiological severity.

Nutr Metab Cardiovasc Dis 2021 Aug 18. Epub 2021 Aug 18.

Department of Systems Medicine, University of Rome Tor Vergata, Italy.

Background And Aims: It is known that the highest COVID-19 mortality rates are among patients who develop severe COVID-19 pneumonia. However, despite the high sensitivity of chest CT scans for diagnosing COVID-19 in a screening population, the appearance of a chest CT is thought to have low diagnostic specificity. The aim of this retrospective case-control study is based on evaluation of clinical and radiological characteristics in patients with COVID-19 (n = 41) and no-COVID-19 interstitial pneumonia (n = 48) with mild-to-moderate symptoms.

Methods And Results: To this purpose we compared radiological, clinical, biochemical, inflammatory, and metabolic characteristics, as well as clinical outcomes, between the two groups. Notably, we found similar radiological severity of pneumonia, which we quantified using a disease score based on a high-resolution computed tomography scan (COVID-19 = 18.6 ± 14.5 vs n-COVID-19 = 23.2 ± 15.2, p = 0.289), and comparable biochemical and inflammatory characteristics. However, among patients without diabetes, we observed that COVID-19 patients had significantly higher levels of HbA1c than n-COVID-19 patients (COVID-19 = 41.5 ± 2.6 vs n-COVID-19 = 38.4 ± 5.1, p = 0.012). After adjusting for age, sex, and BMI, we found that HbA1c levels were significantly associated with the risk of COVID-19 pneumonia (odds ratio = 1.234 [95%CI = 1.051-1.449], p = 0.010).

Conclusions: In this retrospective case-control study, we found similar radiological and clinical characteristics in patients with COVID-19 and n-COVID-19 pneumonia with mild-to-moderate symptoms. However, among patients without diabetes HbA1c levels were higher in COVID-19 patients than in no-COVID-19 individuals. Future studies should assess whether reducing transient hyperglycemia in individuals without overt diabetes may lower the risk of SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/j.numecd.2021.08.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372447PMC
August 2021

Sodium-glucose co-transporter2 expression and inflammatory activity in diabetic atherosclerotic plaques: Effects of sodium-glucose co-transporter2 inhibitor treatment.

Mol Metab 2021 Sep 7;54:101337. Epub 2021 Sep 7.

Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli,", Italy; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy. Electronic address:

Objective: We evaluated sodium-glucose co-transporter2 (SGLT2) expression and the effect of SGLT2 inhibitor (SGLT2i) therapies on carotid plaques of asymptomatic diabetic and non-diabetic patients.

Methods: Plaques were obtained from 296 non-diabetic patients and 227 patients with type 2 diabetes undergoing carotid endarterectomy. 97 patients with type 2 diabetes were treated with SGLT2 inhibitors for 16 ± 4 months before endarterectomy. After propensity score matching analysis, patients with type 2 diabetes were categorized without (n = 87) and with SGLT2i therapy (n = 87). To investigate SGLT2 expression levels' effects on major adverse endpoints (MACE = stroke, transient ischemic attack, myocardial infarction, and death), we evaluated MACE outcomes at a 2-year follow-up.

Results: Compared to plaques from patients without diabetes, plaques from patients with diabetes had higher SGLT2 expression, inflammation, and oxidative stress, along with lower SIRT6 expression and collagen content. Compared with plaques from patients with diabetes, SGLT2i-treated patients with type 2 diabetes presented increased SIRT6 expression and collagen content and lowered inflammation and ion and oxidative stress, thus indicating a more stable plaque phenotype. These results supported in vitro observations on human aorta endothelial cells (EC) (TeloHAEC-cells). Indeed, EC treated with high glucose (25 mM) in the presence of SGLT2i (100 nM canagliflozin) presented higher SIRT6 expression and decreased mRNA and protein SGLT2 levels, nuclear factor-kappa B (NF-B(NF-κB), and matrix metallopeptidase 9 (MMP-9) expression compared to cells treated only with high glucose. After two years following endarterectomy, a multivariable Cox regression analysis showed significantly higher 2-year overall survival from MACE in patients without diabetes (P < 0.01). Among patient with diabetes, the current SGLT2i users presented a significantly lower rate of MACE through 2 years compared to non-SGLT2i users (P < 0.05).

Conclusions: These findings unveil a critical involvement of the SGLT2/SIRT6 pathway in the inflammatory process of diabetic atherosclerotic lesions and suggest its possible favorable modulation by SGLT2i.
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http://dx.doi.org/10.1016/j.molmet.2021.101337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473552PMC
September 2021

The feeding behaviour of Amyotrophic Lateral Sclerosis mouse models is modulated by the Ca -activated K 3.1 channels.

Br J Pharmacol 2021 Aug 19. Epub 2021 Aug 19.

Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, Italy.

Background And Purpose: Amyotrophic lateral sclerosis (ALS) patients exhibit dysfunctional energy metabolism and weight loss, which is negatively correlated with survival, together with neuroinflammation. However, the possible contribution of neuroinflammation to deregulations of feeding behaviour in ALS has not been studied in detail. We here investigated if microglial K 3.1 is linked to hypothalamic neuroinflammation and affects feeding behaviours in ALS mouse models.

Experimental Approach: hSOD1 and TDP43 mice were treated daily with 120 mg·kg of TRAM-34 or vehicle by intraperitoneal injection from the presymptomatic until the disease onset phase. Body weight and food intake were measured weekly. The later by weighing food provided minus that left in the cage. RT-PCR and immunofluorescence analysis were used to characterize microglia phenotype and the main populations of melanocortin neurons in the hypothalamus of hSOD1 and age-matched non-tg mice. The cannabinoid-opioid interactions in feeding behaviour of hSOD1 mice were studied using an inverse agonist and an antagonist of the cannabinoid receptor CB (rimonabant) and μ-opioid receptors (naloxone), respectively.

Key Results: We found that treatment of hSOD1 mice with the K 3.1 inhibitor TRAM-34 (i), attenuates the pro-inflammatory phenotype of hypothalamic microglia, (ii) increases food intake and promotes weight gain, (iii) increases the number of healthy pro-opiomelanocortin (POMC) neurons and (iv), changes the expression of cannabinoid receptors involved in energy homeostasis.

Conclusion And Implications: Using ALS mouse models, we describe defects in the hypothalamic melanocortin system that affect appetite control. These results reveal a new regulatory role for K 3.1 to counteract weight loss in ALS.
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http://dx.doi.org/10.1111/bph.15665DOI Listing
August 2021

A Serum Resistin and Multicytokine Inflammatory Pathway Is Linked With and Helps Predict All-cause Death in Diabetes.

J Clin Endocrinol Metab 2021 Oct;106(11):e4350-e4359

Research Unit of Diabetes and Endocrine Diseases, Fondazione IRCCS "Casa Sollievo della Sofferenza," 71013 San Giovanni Rotondo, Italy.

Context: Type 2 diabetes (T2D) shows a high mortality rate, partly mediated by atherosclerotic plaque instability. Discovering novel biomarkers may help identify high-risk patients who would benefit from more aggressive and specific managements. We recently described a serum resistin and multicytokine inflammatory pathway (REMAP), including resistin, interleukin (IL)-1β, IL-6, IL-8, and TNF-α, that is associated with cardiovascular disease.

Objective: We investigated whether REMAP is associated with and improves the prediction of mortality in T2D.

Methods: A REMAP score was investigated in 3 cohorts comprising 1528 patients with T2D (409 incident deaths) and in 59 patients who underwent carotid endarterectomy (CEA; 24 deaths). Plaques were classified as unstable/stable according to the modified American Heart Association atherosclerosis classification.

Results: REMAP was associated with all-cause mortality in each cohort and in all 1528 individuals (fully adjusted hazard ratio [HR] for 1 SD increase = 1.34, P < .001). In CEA patients, REMAP was associated with mortality (HR = 1.64, P = .04) and a modest change was observed when plaque stability was taken into account (HR = 1.58; P = .07). REMAP improved discrimination and reclassification measures of both Estimation of Mortality Risk in Type 2 Diabetic Patients and Risk Equations for Complications of Type 2 Diabetes, well-established prediction models of mortality in T2D (P < .05-< .001).

Conclusion: REMAP is independently associated with and improves predict all-cause mortality in T2D; it can therefore be used to identify high-risk individuals to be targeted with more aggressive management. Whether REMAP can also identify patients who are more responsive to IL-6 and IL-1β monoclonal antibodies that reduce cardiovascular burden and total mortality is an intriguing possibility to be tested.
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http://dx.doi.org/10.1210/clinem/dgab472DOI Listing
October 2021

TIMP3 involvement and potentiality in the diagnosis, prognosis and treatment of diabetic nephropathy.

Acta Diabetol 2021 Dec 28;58(12):1587-1594. Epub 2021 Jun 28.

Departments of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.

Diabetic kidney disease, one of the most severe complications associated with diabetes, is characterized by albuminuria, glomerulosclerosis and progressive loss of renal function. Loss of TIMP3, an Extracellular matrix-bound protein, is a hallmark of diabetic nephropathy in human and mouse models, suggesting its pivotal role in renal diseases associated to diabetes. There is currently no specific therapy for diabetic nephropathy, and the ability to restore high TIMP3 activity specifically in the kidney may represent a potential therapeutic strategy for the amelioration of renal injury under conditions in which its reduction is directly related to the disease. Increasing evidence shows that diabetic nephropathy is also regulated by epigenetic mechanisms, including noncoding RNA. This review recapitulates the pathological, diagnostic and therapeutic potential roles of TIMP3 and the noncoding RNA (microRNA, long noncoding RNA) related to its expression, in the progression of diabetic nephropathy.
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http://dx.doi.org/10.1007/s00592-021-01766-yDOI Listing
December 2021

Inhibition of Lysine 63 Ubiquitination Prevents the Progression of Renal Fibrosis in Diabetic DBA/2J Mice.

Int J Mol Sci 2021 May 14;22(10). Epub 2021 May 14.

Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy.

Diabetic nephropathy (DN) is the most frequent cause of end-stage renal disease. Tubulointerstitial accumulation of lysine 63 (K63)-ubiquitinated (Ub) proteins is involved in the progression of DN fibrosis and correlates with urinary miR-27b-3p downregulation. We explored the renoprotective effect of an inhibitor of K63-Ub (NSC697923), alone or in combination with the ACE-inhibitor ramipril, in vitro and in vivo. Proximal tubular epithelial cells and diabetic DBA/2J mice were treated with NSC697923 and/or ramipril. K63-Ub protein accumulation along with α-SMA, collagen I and III, FSP-1, vimentin, p16 expression, SA-α Gal staining, Sirius Red, and PAS staining were measured. Finally, we measured the urinary albumin to creatinine ratio (uACR), and urinary miR-27b-3p expression in mice. NSC697923, both alone and in association with ramipril, in vitro and in vivo inhibited hyperglycemia-induced epithelial to mesenchymal transition by significantly reducing K63-Ub proteins, α-SMA, collagen I, vimentin, FSP-1 expression, and collagen III along with tubulointerstitial and glomerular fibrosis. Treated mice also showed recovery of urinary miR-27b-3p and restored expression of p16. Moreover, NSC697923 in combination with ramipril demonstrated a trend in the reduction of uACR. In conclusion, we suggest that selective inhibition of K63-Ub, when combined with the conventional treatment with ACE inhibitors, might represent a novel treatment strategy to prevent the progression of fibrosis and proteinuria in diabetic nephropathy and we propose miR-27b-3p as a biomarker of treatment efficacy.
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http://dx.doi.org/10.3390/ijms22105194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157080PMC
May 2021

Cardiovascular risk management in type 2 diabetes mellitus: A joint position paper of the Italian Cardiology (SIC) and Italian Diabetes (SID) Societies.

Nutr Metab Cardiovasc Dis 2021 06 6;31(6):1671-1690. Epub 2021 Mar 6.

Dipartimento di Medicina Clinica e Sperimentale, Università di Catania, Italy. Electronic address:

Aim: This review represents a joint effort of the Italian Societies of Cardiology (SIC) and Diabetes (SID) to define the state of the art in a field of great clinical and scientific interest which is experiencing a moment of major cultural advancements, the cardiovascular risk management in type 2 diabetes mellitus.

Data Synthesis: Consists of six chapters that examine various aspects of pathophysiology, diagnosis and therapy which in recent months have seen numerous scientific innovations and several clinical studies that require extensive sharing.

Conclusions: The continuous evolution of our knowledge in this field confirms the great cultural vitality of these two cultural spheres, which requires, under the leadership of the scientific Societies, an ever greater and effective collaboration.
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http://dx.doi.org/10.1016/j.numecd.2021.02.029DOI Listing
June 2021

Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome.

Microbiome 2021 05 7;9(1):104. Epub 2021 May 7.

Department of Endocrinology, Diabetes and Nutrition, Hospital of Girona "Dr Josep Trueta", Girona, Spain.

Background: The gut microbiome and iron status are known to play a role in the pathophysiology of non-alcoholic fatty liver disease (NAFLD), although their complex interaction remains unclear.

Results: Here, we applied an integrative systems medicine approach (faecal metagenomics, plasma and urine metabolomics, hepatic transcriptomics) in 2 well-characterised human cohorts of subjects with obesity (discovery n = 49 and validation n = 628) and an independent cohort formed by both individuals with and without obesity (n = 130), combined with in vitro and animal models. Serum ferritin levels, as a markers of liver iron stores, were positively associated with liver fat accumulation in parallel with lower gut microbial gene richness, composition and functionality. Specifically, ferritin had strong negative associations with the Pasteurellaceae, Leuconostocaceae and Micrococcaea families. It also had consistent negative associations with several Veillonella, Bifidobacterium and Lactobacillus species, but positive associations with Bacteroides and Prevotella spp. Notably, the ferritin-associated bacterial families had a strong correlation with iron-related liver genes. In addition, several bacterial functions related to iron metabolism (transport, chelation, heme and siderophore biosynthesis) and NAFLD (fatty acid and glutathione biosynthesis) were also associated with the host serum ferritin levels. This iron-related microbiome signature was linked to a transcriptomic and metabolomic signature associated to the degree of liver fat accumulation through hepatic glucose metabolism. In particular, we found a consistent association among serum ferritin, Pasteurellaceae and Micrococcacea families, bacterial functions involved in histidine transport, the host circulating histidine levels and the liver expression of GYS2 and SEC24B. Serum ferritin was also related to bacterial glycine transporters, the host glycine serum levels and the liver expression of glycine transporters. The transcriptomic findings were replicated in human primary hepatocytes, where iron supplementation also led to triglycerides accumulation and induced the expression of lipid and iron metabolism genes in synergy with palmitic acid. We further explored the direct impact of the microbiome on iron metabolism and liver fact accumulation through transplantation of faecal microbiota into recipient's mice. In line with the results in humans, transplantation from 'high ferritin donors' resulted in alterations in several genes related to iron metabolism and fatty acid accumulation in recipient's mice.

Conclusions: Altogether, a significant interplay among the gut microbiome, iron status and liver fat accumulation is revealed, with potential significance for target therapies. Video abstract.
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http://dx.doi.org/10.1186/s40168-021-01052-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106161PMC
May 2021

The risk of carotid plaque instability in patients with metabolic syndrome is higher in women with hypertriglyceridemia.

Cardiovasc Diabetol 2021 05 6;20(1):98. Epub 2021 May 6.

Anatomic Pathology, Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, Rome, RM, 00133, Italy.

Background: Metabolic syndrome certainly favors growth of carotid plaque; however, it is uncertain if it determines plaque destabilization. Furthermore, it is likely that only some components of metabolic syndrome are associated with increased risk of plaque destabilization. Therefore, we evaluated the effect of different elements of metabolic syndrome, individually and in association, on carotid plaques destabilization.

Methods: A total of 186 carotid endarterectomies from symptomatic and asymptomatic patients were histologically analysed and correlated with major cardiovascular risk factors.

Results: Metabolic syndrome, regardless of the cluster of its components, is not associated with a significant increase in risk of plaque destabilization, rather with the presence of stable plaques. The incidence of unstable plaques in patients with metabolic syndrome is quite low (43.9 %), when compared with that seen in the presence of some risk factors, but significantly increases in the subgroup of female patients with hypertriglyceridemia, showing an odds ratio of 3.01 (95% CI, 0.25-36.30).

Conclusions: Our data may help to identify patients with real increased risk of acute cerebrovascular diseases thus supporting the hypothesis that the control of hypertriglyceridemia should be a key point on prevention of carotid atherosclerotic plaque destabilization, especially in post-menopausal female patients.
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http://dx.doi.org/10.1186/s12933-021-01277-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103747PMC
May 2021

Association of Urinary and Plasma Levels of Trimethylamine N-Oxide (TMAO) with Foods.

Nutrients 2021 Apr 23;13(5). Epub 2021 Apr 23.

Section of Clinical Nutrition and Nutrigenomic, Department of Biomedicine and Prevention, University of Tor Vergata, via Montpellier 1, 00133 Rome, Italy.

Introduction: Trimethylamine N-oxide (TMAO) may play a key mediator role in the relationship between the diet, gut microbiota and cardiovascular diseases, particularly in people with kidney failure. The aim of this review is to evaluate which foods have a greater influence on blood or urinary trimethylamine N-oxide (TMAO) levels.

Methods: 391 language articles were screened, and 27 were analysed and summarized for this review, using the keywords "TMAO" AND "egg" OR "meat" OR "fish" OR "dairy" OR "vegetables" OR "fruit" OR "food" in December 2020.

Results: A strong correlation between TMAO and fish consumption, mainly saltwater fish and shellfish, but not freshwater fish, has been demonstrated. Associations of the consumption of eggs, dairy and meat with TMAO are less clear and may depend on other factors such as microbiota or cooking methods. Plant-based foods do not seem to influence TMAO but have been less investigated.

Discussion: Consumption of saltwater fish, dark meat fish and shellfish seems to be associated with an increase in urine or plasma TMAO values. Further studies are needed to understand the relationship between increased risk of cardiovascular disease and plasma levels of TMAO due to fish consumption. Interventions coupled with long-term dietary patterns targeting the gut microbiota seem promising.
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http://dx.doi.org/10.3390/nu13051426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145508PMC
April 2021

Gut Dysbiosis and Western Diet in the Pathogenesis of Essential Arterial Hypertension: A Narrative Review.

Nutrients 2021 Apr 1;13(4). Epub 2021 Apr 1.

UOC of Internal Medicine-Center of Hypertension and Nephrology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.

Metabolic syndrome is a cluster of the most dangerous cardiovascular (CV) risk factors including visceral obesity, insulin resistance, hyperglycemia, alterations in lipid metabolism and arterial hypertension (AH). In particular, AH plays a key role in the complications associated with metabolic syndrome. High salt intake is a well-known risk factor for AH and CV diseases. Vasoconstriction, impaired vasodilation, extracellular volume expansion, inflammation, and an increased sympathetic nervous system (SNS) activity are the mechanisms involved in the pathogenesis of AH, induced by Western diet. Gut dysbiosis in AH is associated with reduction of short chain fatty acid-producing bacteria: acetate, butyrate and propionate, which activate different pathways, causing vasoconstriction, impaired vasodilation, salt and water retention and a consequent high blood pressure. Moreover, increased trimethylamine N-oxide and lipopolysaccharides trigger chronic inflammation, which contributes to endothelial dysfunction and target organs damage. Additionally, a high salt-intake diet impacts negatively on gut microbiota composition. A bidirectional neuronal pathway determines the "brain-gut" axis, which, in turn, influences blood pressure levels. Then, we discuss the possible adjuvant novel treatments related to gut microbiota modulation for AH control.
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http://dx.doi.org/10.3390/nu13041162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066853PMC
April 2021

IL-6 Levels Influence 3-Month All-Cause Mortality in Frail Hospitalized Older Patients.

Aging Dis 2021 Apr 1;12(2):353-359. Epub 2021 Apr 1.

1Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

The multidimensional prognostic index (MPI) is a sensitive and specific prognosis estimation tool that accurately predicts all-cause mortality in frail older patients. It has been validated to assess the risk of 1-month to 2-year mortality in frail older patients during hospitalization and after hospital discharge. However, whether the MPI is a valid prognostic tool for follow-up periods of different lengths remains to be validated. To this end, we followed up 80 hospitalized patients (female=37, male 43) at least 75 years of age (mean age=82.6±4.4, range=75-94 years) to assess the 3-month all-cause mortality (mean follow-up=61.0 ± 31.7 months [range 4-90 days]). Accordingly, patients were subdivided into low (MPI-1, score 0-0.33), moderate (MPI-2, score 0.34-0.66) and high (MPI-3, score 0.67-1) mortality risk classes. Moreover, baseline biochemical, inflammatory and metabolic parameters, as well as anamnestic and clinical characteristics, were obtained. Although the MPI-3 score was significantly associated with 3-month all-cause mortality in univariate analysis (HR=5.79, 95%CI=1.77-18.92, p=0.004), a multivariate model indicated that only low albumin (HR=0.33, 95%CI=0.16-0.68, p=0.003) and high IL6 (HR=1.01, 95%CI=1.00-1.02, p=0.010) levels were significantly associated with 3-month all-cause mortality. In conclusion, we suggest that measurement of IL6 as well as albumin, rather than the MPI score, may help in providing tailored therapeutic interventions to decrease short term mortality in older hospitalized individuals.
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http://dx.doi.org/10.14336/AD.2020.0713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990358PMC
April 2021

Alterations in Rev-ERBα/BMAL1 ratio and glycated hemoglobin in rotating shift workers: the EuRhythDia study.

Acta Diabetol 2021 Aug 31;58(8):1111-1117. Epub 2021 Mar 31.

Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier, 100133, Rome, Italy.

Objective: To detect premature gluco-metabolic defects among night shift workers with disturbances in circadian rhythms.

Design And Methods: We performed a hypothesis-generating, cross-sectional analysis of anthropometric, metabolic, lipid, and inflammation parameters, comparing active (a-NSW, n = 111) and former (f-NSW, n = 98) rotating night shift workers with diurnal workers (controls, n = 69). All participants were hospital nurses. We also evaluated the Pittsburgh Sleep Quality Index (PSQI) and assessed expression of transcription factors REV-ERBα and BMAL1 in peripheral blood mononuclear cells (PBMCs), as indicators of the molecular clock.

Results: Both a-NSW and f-NSW participants had significantly higher glycated hemoglobin (HbA1c) and white blood cell counts (WBC) (p < 0.001 for both), PSQI global score (p = 0.001) and diastolic blood pressure levels (p = 0.024) compared with controls. Expression of REV-ERBα/BMAL1 RNA in PBMC was significantly higher in a-NSW (p = 0.05) than in f-NSW or control participants. Multivariate regression analysis showed that working status and PSQI were independent determinants of higher HbA1c levels (p < 0.001).

Conclusions: We demonstrated that young, healthy night shift workers show subclinical abnormalities in HbA1c and changes in peripheral clock gene expression.
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http://dx.doi.org/10.1007/s00592-021-01676-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272695PMC
August 2021

Light therapy improves diurnal blood pressure control in night shift workers via reduction of catecholamines: the EuRhythDia study.

J Hypertens 2021 08;39(8):1678-1688

Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objectives: Night shift work is associated with high rates of hypertension and cardiometabolic disease, which are linked to disrupted circadian rhythms. We hypothesized that timed light therapy might improve disrupted circadian rhythms and stabilize diurnal control of blood pressure and glucose in night shift workers.

Methods: We randomized 24 rotating night shift workers (mean age, 36 ± 13 years, 7 men) who had spent a median of 6 years on rotating night shifts (median, six night shifts per month) to 12 weeks of light therapy or no intervention and compared them with 12 daytime workers (37 ± 11 years, 6 men). We measured oral glucose tolerance (OGTT), 24-h blood pressure and arterial stiffness, and the circadian profiles of melatonin, cortisol, metanephrine and nor-metanephrine at baseline, after 12 weeks of intervention, and 12 weeks after the end of intervention.

Results: At baseline, fewer night shift workers showed dipper status as compared with daytime workers (29 vs. 58%; P < 0.001). After 12 weeks of light therapy, there was a highly significant increase in the proportion of dippers (to 58%; P < 0.0001). We also observed a significant decrease in serum glucose during OGTT in the light therapy group (-22%; P < 0.05) with no change in serum insulin. Whilst circadian profiles of melatonin and cortisol were unchanged, plasma metanephrine and nor-metanephrine levels were significantly reduced in the light therapy group (P < 0.01).

Conclusion: Timed light therapy improves diurnal blood pressure control and glucose tolerance in rotating night shift workers. This effect is unrelated to melatonin and cortisol but is paralleled by reduced catecholamine levels.
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http://dx.doi.org/10.1097/HJH.0000000000002848DOI Listing
August 2021

Restoration of renal TIMP3 levels via genetics and pharmacological approach prevents experimental diabetic nephropathy.

Clin Transl Med 2021 02;11(2):e305

Departments of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.

Background: Diabetic nephropathy (DN), one of the major complications of diabetes, is characterized by albuminuria, glomerulosclerosis, and progressive loss of renal function. Loss of TIMP3, an Extracellular Matrix bound protein affecting both inflammation and fibrosis, is a hallmark of DN in human subjects and mouse models.

Methods: This study was designed to provide evidences that the modulation of the system involving TIMP3 and its target A Disintegrin And Metalloproteinase 17 (ADAM17), may rescue kidney pathology in diabetic mice. Mice with cell-targeted overexpression of TIMP3 in myeloid cells (MacT3), podocyte-specific ADAM17 knockout mice (∆PodA17), and DBA/2J mice, were rendered diabetic at 8 weeks of age with a low-dose streptozotocin protocol. DBA/2J mice were administered new peptides based on the human TIMP3 N-terminal domain, specifically conjugated with G3C12, a carrier peptide highly selective and efficient for transport to the kidney. Twelve weeks after Streptozotocin injections, 24-hour albuminuria was determined by ELISA, kidney morphometry was analyzed by periodic acid-shift staining, and Real Time-PCR and western blot analysis were performed on mRNA and protein extracted from kidney cortex.

Results: Our results showed that both genetic modifications and peptides treatment positively affect renal function and structure in diabetic mice, as indicated by a significant and consistent decline in albuminuria along with reduction in glomerular lesions, as indicated by reduced mesangial expansion and glomerular hypertrophy, decreased deposition of extracellular matrix in the mesangium, diminished protein expression of the NADPH oxidases 4 (NOX4), and the improvement of podocyte structural markers such as WT1, nephrin, and podocin. Moreover, the positive effects were exerted through a mechanism independent from glycemic control.

Conclusions: In diabetic mice the targeting of TIMP3 system improved kidney structure and function, representing a valid approach to develop new avenues to treat this severe complication of diabetes.
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http://dx.doi.org/10.1002/ctm2.305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862169PMC
February 2021

Cutaneous and metabolic defects associated with nuclear abnormalities in a transgenic mouse model expressing R527H lamin A mutation causing mandibuloacral dysplasia type A (MADA) syndrome.

Acta Myol 2020 Dec 1;39(4):320-335. Epub 2020 Dec 1.

Laboratory of Medical Genetics, Tor Vergata Hospital, Rome, Italy.

LMNA gene encodes for lamin A/C, attractive proteins linked to nuclear structure and functions. When mutated, it causes different rare diseases called laminopathies. In particular, an Arginine change in Histidine in position 527 (p.Arg527His) falling in the C-terminal domain of lamin A precursor form (prelamin A) causes mandibuloacral dysplasia Type A (MADA), a segmental progeroid syndrome characterized by skin, bone and metabolic anomalies. The well-characterized cellular models made difficult to assess the tissue-specific functions of 527His prelamin A. Here, we describe the generation and characterization of a MADA transgenic mouse overexpressing 527His LMNA gene, encoding mutated prelamin A. Bodyweight is slightly affected, while no difference in lifespan was observed in transgenic animals. Mild metabolic anomalies and thinning and loss of hairs from the back were the other observed phenotypic MADA manifestations. Histological analysis of tissues relevant for MADA syndrome revealed slight increase in adipose tissue inflammatory cells and a reduction of hypodermis due to a loss of subcutaneous adipose tissue. At cellular levels, transgenic cutaneous fibroblasts displayed nuclear envelope aberrations, presence of prelamin A, proliferation, and senescence rate defects. Gene transcriptional pattern was found differentially modulated between transgenic and wildtype animals, too. In conclusion, the presence of 527His Prelamin A accumulation is further linked to the appearance of mild progeroid features and metabolic disorder without lifespan reduction.
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http://dx.doi.org/10.36185/2532-1900-036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783430PMC
December 2020

Sialic acid: an important contributor to cardiovascular risk.

Minerva Cardioangiol 2020 Nov 4. Epub 2020 Nov 4.

Division of Cardiology, S. Maria Goretti Hospital, Latina, Italy.

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http://dx.doi.org/10.23736/S0026-4725.20.05444-4DOI Listing
November 2020

Timed physical exercise does not influence circadian rhythms and glucose tolerance in rotating night shift workers: The EuRhythDia study.

Diab Vasc Dis Res 2020 May-Jun;17(5):1479164120950616

Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objectives: Night shift workers are at cardiometabolic risk due to circadian misalignment. We investigated whether infrequent exercise before each night shift that intentionally would not improve physical performance improves glucose tolerance and 24-h blood pressure profiles and synchronizes circadian rhythms of melatonin and cortisol in rotating night shift workers.

Methods: A total of 24 rotating night shift workers (mean age, 35.7 ± 11.8 years) were randomized to exercise or no intervention. Workers in the exercise group performed 15.2 ± 4.5 exercise sessions within 2 h before each night shift. Before and after 12 weeks of exercise intervention and 12 weeks after the intervention, spiroergometry, oral glucose tolerance testing and 24-h blood pressure profiles were performed. Plasma melatonin and cortisol levels were measured in 3-hourly intervals during one 24-h period on each study day.

Results: Exercise did not significantly change serum glucose nor insulin levels during oral glucose tolerance testing. Timed physical exercise had no effect on physical performance, nor did it change the circadian rhythms of melatonin and cortisol or influence 24-h blood pressure profiles.

Conclusion: Physical exercise before each night shift at a low intensity level that does not improve physical performance does not affect circadian timing, glucose tolerance or 24-h blood pressure profiles in rotating night shift workers.
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http://dx.doi.org/10.1177/1479164120950616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919228PMC
January 2021

Bariatric Surgery-Induced Changes in Intima-Media Thickness and Cardiovascular Risk Factors in Class 3 Obesity: A 3-Year Follow-Up Study.

Obesity (Silver Spring) 2020 09 9;28(9):1663-1670. Epub 2020 Aug 9.

Department of Radiology (IDI), Girona Biomedical Research Institute (IDIBGI), Hospital Universitari de Girona Dr Josep Trueta, Girona, Spain.

Objective: The impact of weight loss induced by bariatric surgery (BS) and nonsurgical approaches on cardiovascular risk factors (CVRFs) has not been fully elucidated. We assessed the effects of BS and a nonsurgical approach on carotid intima-media thickness (CIMT) and CVRFs in participants with class 3 obesity.

Methods: A total of 87 participants with obesity (59 women; 46 [37-52] years old; BMI, 43 [40-47]) and 75 controls were recruited; 21 (25%) participants with obesity underwent BS. BMI, blood pressure, cholesterol, triglycerides, fasting plasma glucose, C-reactive protein, CIMT, and Framingham Risk Score were measured at baseline and at 3-year follow-up. Independent factors for reduction in CIMT were analyzed. The literature on the effects of BS and CIMT was reviewed.

Results: After BS, BMI decreased from 45.45 to 27.28 (P < 0.001), and mean CIMT decreased from 0.64 mm (0.56-0.75 mm) to 0.54 mm (0.46-0.65) mm (P < 0.012), equivalent to 0.005 mm/kg of weight lost. At 3-year follow-up, participants who had undergone BS had similar CIMT and CVRFs to the control group. No changes in CVRFs were seen related to the nonsurgical approach. BMI reduction after BS had the strongest independent association with decreased CIMT.

Conclusions: Weight loss after BS decreases CIMT and CVRFs in middle-aged participants with class 3 obesity, resulting in CIMT similar to that observed in lean participants.
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http://dx.doi.org/10.1002/oby.22905DOI Listing
September 2020

Carotid intimal medial thickness in rotating night shift is related to IL1β/IL6 axis.

Nutr Metab Cardiovasc Dis 2020 09 7;30(10):1826-1832. Epub 2020 Jun 7.

Department of Systems Medicine, University of Rome Tor Vergata, Italy.

Background And Aims: Sleep disturbances may promote glucose abnormalities and inflammatory burden among shift workers. Therefore, precocious subclinical atherosclerotic process might develop in healthy shift workers even without known metabolic and cardiovascular risk factors.

Methods And Results: We measured anthropometric parameters, glucose, lipids, inflammation and common carotid Intimal Medial Thickness (cIMT) in rotating-night shift workers (r-NSW, n = 88, age = 40.3 ± 7.8 y) in comparison with former-night shift workers (f-NSW, n = 35, age = 44.2 ± 6.4 y) and with day-only workers (DW, n = 64, age = 44.1 ± 8.9 y). R-NSW and f-NSW showed significantly higher cIMT and high sensitivity C-Reactive Protein (hs-CRP) respect to DW (p = 0.043 and p = 0.025, respectively). IL-1β levels were higher in r-NSW than in DW and f-NSW (p = 0.043) and significantly correlated with IL6 (r = 0.365, p < 0.001). In addition, r-NSW and f-NSW had higher HbA1c levels in comparison with DW (p = 0.047). Carotid-IMT was significantly related to night shift work (p = 0.023), with age (p < 0.001), with HOMA IR (p = 0.009), with insulin (p = 0.006) with HbA1c (p = 0.002), with LDL cholesterol (p < 0.001), with diastolic BP (p < 0.001), with WBC (p = 0.002) and with IL6 (p = 0.004). After performing a multivariate analysis night shift work remained statistically related to cIMT (B = 2.633, 95%CI = 0.489-4.776, p = 0.016).

Conclusions: Our result described a possible link bridging night shift work, inflammation and carotid Intimal Medial Thickness. Future studies are warranted to understand if carotid atherosclerosis process should be mainly driven by the IL1β/IL6 citokine axis connected to sleep disturbances.
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http://dx.doi.org/10.1016/j.numecd.2020.05.028DOI Listing
September 2020

Complete blood count might help to identify subjects with high probability of testing positive to SARS-CoV-2.

Clin Med (Lond) 2020 07 2;20(4):e114-e119. Epub 2020 Jul 2.

Emergency Department, Tor Vergata University Hospital, Rome, Italy.

The SARS-CoV-2 pandemic has dramatically increased the workload for health systems and a consequent need to optimise resources has arisen, including the selection of patients for swab tests. We retrospectively reviewed consecutive patients presenting to the emergency department with symptoms suggestive of COVID-19 and undergoing swab tests for SARS-CoV-2. Complete blood counts (CBCs) were analysed looking for predictors of test positivity. Eight significant predictors were identified and used to build a 'complete' CBC score with a discriminatory power for COVID-19 diagnosis of AUC 92% (p<0.0001). When looking at the weight of individual variables, mean corpuscular volume (MCV), age, platelets and eosinophils (MAPE: MCV ≤90 fL, 65 points; age ≥45 years, 100 points; platelets ≤180×103/μL, 73 points; eosinophils <0.01/μL, 94 points) gave the highest contribution and were used to build a 'simplified' MAPE score with a discriminatory power of AUC 88%. By setting the cut-off MAPE score at ≥173 points, sensitivity and specificity for COVID-19 diagnosis were 83% and 82%, respectively, and the actual test positivity rate was 60% as compared to 6% of patients with MAPE score <173 points (odds ratio 23.04, 95% confidence interval [CI] 9.1-58.3, p-value <0.0001). In conclusion, CBC-based scores have potential for optimising the SARS-CoV-2 testing process: if these findings are confirmed in the future, swab tests may be waived for subjects with low score and uncertain symptoms, while they may be considered for asymptomatic or oligosymptomatic patients with high scores.
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http://dx.doi.org/10.7861/clinmed.2020-0373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385801PMC
July 2020

Impact of environmental pollution and weather changes on the incidence of ST-elevation myocardial infarction.

Eur J Prev Cardiol 2020 Jun 2:2047487320928450. Epub 2020 Jun 2.

Division of Cardiology, Santa Maria Goretti Hospital, Italy.

Background: Environmental pollution and weather changes unfavorably impact on cardiovascular disease. However, limited research has focused on ST-elevation myocardial infarction (STEMI), the most severe yet distinctive form of acute coronary syndrome.

Methods And Results: We appraised the impact of environmental and weather changes on the incidence of STEMI, analysing the bivariate and multivariable association between several environmental and atmospheric parameters and the daily incidence of STEMI in two large Italian urban areas. Specifically, we appraised: carbon monoxide (CO), nitrogen dioxide (NO2), nitric oxide (NOX), ozone, particulate matter smaller than 10 μm (PM10) and than 2.5 μm (PM2.5), temperature, atmospheric pressure, humidity and rainfall. A total of 4285 days at risk were appraised, with 3473 cases of STEMI. Specifically, no STEMI occurred in 1920 (44.8%) days, whereas one or more occurred in the remaining 2365 (55.2%) days. Multilevel modelling identified several pollution and weather predictors of STEMI. In particular, concentrations of CO (=0.024), NOX (=0.039), ozone (=0.003), PM10 (=0.033) and PM2.5 (=0.042) predicted STEMI as early as three days before the event, as well as subsequently, and NO predicted STEMI one day before ( = 0.010), as well as on the same day. A similar predictive role was evident for temperature and atmospheric pressure (all  < 0.05).

Conclusions: The risk of STEMI is strongly associated with pollution and weather features. While causation cannot yet be proven, environmental and weather changes could be exploited to predict STEMI risk in the following days.
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http://dx.doi.org/10.1177/2047487320928450DOI Listing
June 2020

Diet high in protein-rich foods with structured sport activity may be useless to lose fat mass and maintain fat-free mass.

Minerva Gastroenterol Dietol 2020 Dec 23;66(4):321-327. Epub 2020 Apr 23.

Department of Systems Medicine, Tor Vergata University, Rome, Italy.

Background: The aim of this study was to demonstrate that a normal protein diet along with minimal sports activity can be enough to lose fat mass and maintain muscle mass.

Methods: All participants were prescribed a hypocaloric nutritionally balanced Mediterranean-style diet tailored to the individual for 8 weeks. Body composition and energy expenditure were measured. Sedentary patients (G1) were only recommended to perform minimal aerobic training, while sport subjects (G2) were prescribed structured physical activity and higher calorie and protein contents in the diet.

Results: There were no significant differences between the two groups for any of the measured parameters.

Conclusions: The models of lifestyle changes that are currently circulating were for the most part ineffective. It does not appear to be necessary to increase the protein content of the diet above that recommended by guidelines in order to lose weight. Even prescribing specific physical activity is not necessary to maintain muscle mass.
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http://dx.doi.org/10.23736/S1121-421X.20.02704-XDOI Listing
December 2020

Cross-omics analysis revealed gut microbiome-related metabolic pathways underlying atherosclerosis development after antibiotics treatment.

Mol Metab 2020 06 13;36:100976. Epub 2020 Mar 13.

Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Center for Atherosclerosis, Policlinico Tor Vergata, Rome, Italy. Electronic address:

Objective: The metabolic influence of gut microbiota plays a pivotal role in the pathogenesis of cardiometabolic diseases. Antibiotics affect intestinal bacterial diversity, and long-term usage has been identified as an independent risk factor for atherosclerosis-driven events. The aim of this study was to explore the interaction between gut dysbiosis by antibiotics and metabolic pathways with the impact on atherosclerosis development.

Methods: We combined oral antibiotics with different diets in an Apolipoprotein E-knockout mouse model linking gut microbiota to atherosclerotic lesion development via an integrative cross-omics approach including serum metabolomics and cecal 16S rRNA targeted metagenomic sequencing. We further investigated patients with carotid atherosclerosis compared to control subjects with comparable cardiovascular risk.

Results: Here, we show that increased atherosclerosis by antibiotics was connected to a loss of intestinal diversity and alterations of microbial metabolic functional capacity with a major impact on the host serum metabolome. Pathways that were modulated by antibiotics and connected to atherosclerosis included diminished tryptophan and disturbed lipid metabolism. These pathways were related to the reduction of certain members of Bacteroidetes and Clostridia by antibiotics in the gut. Patients with atherosclerosis presented a similar metabolic signature as those induced by antibiotics in our mouse model.

Conclusion: Taken together, this work provides insights into the complex interaction between intestinal microbiota and host metabolism. Our data highlight that detrimental effects of antibiotics on the gut flora are connected to a pro-atherogenic metabolic phenotype beyond classical risk factors.
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http://dx.doi.org/10.1016/j.molmet.2020.100976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183232PMC
June 2020

Venous distal bypass should be considered as the gold standard to finally attempt limb salvage in patients with severe critical limb ischemia and diabetic foot, or under dialysis.

Acta Diabetol 2020 08 3;57(8):1019-1020. Epub 2020 Apr 3.

Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

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http://dx.doi.org/10.1007/s00592-020-01524-6DOI Listing
August 2020

The APOA1bp-SREBF-NOTCH axis is associated with reduced atherosclerosis risk in morbidly obese patients.

Clin Nutr 2020 11 8;39(11):3408-3418. Epub 2020 Mar 8.

Department of Endocrinology, Diabetes and Nutrition, Hospital of Girona "Dr Josep Trueta", Departament de Ciències Mèdiques, University of Girona, Girona Biomedical Research Institute (IdibGi), Girona, Spain; CIBERobn Pathophysiology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain. Electronic address:

Background & Aims: Atherosclerosis is characterized by an inflammatory disease linked to excessive lipid accumulation in the artery wall. The Notch signalling pathway has been shown to play a key regulatory role in the regulation of inflammation. Recently, in vitro and pre-clinical studies have shown that apolipoprotein A-I binding protein (AIBP) regulates cholesterol metabolism (SREBP) and NOTCH signalling (haematopoiesis) and may be protective against atherosclerosis, but the evidence in humans is scarce.

Methods: We evaluated the APOA1bp-SREBF-NOTCH axis in association with atherosclerosis in two well-characterized cohorts of morbidly obese patients (n = 78) within the FLORINASH study, including liver transcriptomics, H NMR plasma metabolomics, high-resolution ultrasonography evaluating carotid intima-media thickness (cIMT), and haematological parameters.

Results: The liver expression levels of APOA1bp were associated with lower cIMT and leukocyte counts, a better plasma lipid profile and higher circulating levels of metabolites associated with lower risk of atherosclerosis (glycine, histidine and asparagine). Conversely, liver SREBF and NOTCH mRNAs were positively associated with atherosclerosis, liver steatosis, an unfavourable lipid profile, higher leukocytes and increased levels of metabolites linked to inflammation and CVD such as branched-chain amino acids and glycoproteins. APOA1bp and NOTCH signalling also had a strong association, as revealed by the negative correlations among APOA1bp expression levels and those of all NOTCH receptors and jagged ligands.

Conclusions: We here provide the first evidence in human liver of the putative APOA1bp-SREBF-NOTCH axis signalling pathway and its association with atherosclerosis and inflammation.
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http://dx.doi.org/10.1016/j.clnu.2020.02.034DOI Listing
November 2020
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