Family caregiver’s loneliness and related health factors: what can be changed?

Background Loneliness is a public health issue which may affect the entire population. Loneliness is associated with depression, sleep disorders, fatigue and increase the risk of obesity and diabetes. Risk factors for loneliness include poor social network and poor physical and mental health. The main objective was to study factors related to loneliness of family caregivers caring for independent older people. Methods We performed a non-interventional observational cross-sectional study in south-eastern France. Family Caregivers caring for people aged 70 and over living at home were included. These older people were independent, without long-term conditions and who applied for professional social assistance for daily living. Data were collected through a questionnaire, administered face-to-face or by telephone. Loneliness and perceived health status were measured through a single-question. Burden was assessed through the Mini-Zarit Scale, frailty was measured through the Gerontopole Frailty Screening Tool. Results Of the 876 caregivers included, 10% felt lonely often or always. They reported more physical and mental health issues than those who did not feel loneliness (p<0.001). Family caregivers with loneliness were more likely to be looking after a parent and were twice as likely to have a moderate to severe burden (OR=2.6). They were more likely to feel anxious (OR=5.6), to have sleep disorders (OR=2.4), to be frail (OR=2) and to feel their health as poor or bad (OR=2). Conclusions Loneliness has a negative impact on health, frailty and burden of family caregivers. Means must be implemented to anticipate the consequences of the loneliness felt by family caregivers, notably by orienting them towards the relevant services.

Iron chelation increases beige fat differentiation and metabolic activity, preventing and treating obesity

Beige and brown fat consume glucose and lipids to produce heat, using uncoupling protein 1 (UCP1). It is thought that full activation of brown adipose tissue (BAT) may increase total daily energy expenditure by 20%. Humans normally have more beige and potentially beige-able fat than brown fat. Strategies to increase beige fat differentiation and activation may be useful for the treatment of obesity and diabetes. Mice were fed chow or high-fat diet (HFD) with or without the iron chelator deferasirox. Animals fed HFD + deferasirox were markedly lighter than their HFD controls with increased energy expenditure (12% increase over 24 h, p < 0.001). Inguinal fat from HFD + deferasirox mice showed increased beige fat quantity with greater Ucp1 and Prdm16 expression. Inguinal adipose tissue explants were studied in a Seahorse bioanalyser and energy expenditure was significantly increased. Deferasirox was also effective in established obesity and in ob/ob mice, indicating that intact leptin signalling is not needed for efficacy. These studies identify iron chelation as a strategy to preferentially activate beige fat. Whether activating brown/beige fat is effective in humans is unproven. However, depleting iron to low-normal levels is a potential therapeutic strategy to improve obesity and related metabolic disorders, and human studies may be warranted.

Decreased Iron Ion Concentrations in the Peripheral Blood Correlate with Coronary Atherosclerosis

(1) Background: Obesity and diabetes continue to reach epidemic levels in the population with major health impacts that include a significantly increased risk of coronary atherosclerosis. The imbalance of trace elements in the body caused by nutritional factors can lead to the progression of coronary atherosclerosis. (2) Methods: We measured the concentrations of sodium (Na), potassium (K), magnesium (Mg), calcium (Ca), Zinc (Zn), and iron (Fe) in peripheral blood samples from 4243 patients and performed baseline analysis and propensity matching of the patient datasets. The patients were grouped into acute myocardial infarction (AMI, 702 patients) and stable coronary heart disease (SCAD1, 253 patients) groups. Both of these groups were included in the AS that had a total of 1955 patients. The control group consisted of 2288 patients. The plasma concentrations of calcium, magnesium, and iron were measured using a colorimetric method. For comparison, 15 external quality assessment (EQA) samples were selected from the Clinical Laboratory Center of the Ministry of Health of China. SPSS software was used for statistical analysis. The average values and deviations of all of the indicators in each group were calculated, and a p-value threshold of <0.05 was used to indicate statistical significance. (3) Results: The iron ion concentrations of the acute myocardial infarction (AMI) group were significantly lower than the control group (p < 0.05, AUC = 0.724, AUC = 0.702), irrespective of tendency matching. Compared to the data from the stable coronary artery disease (SCAD) group, the concentration of iron ions in the acute myocardial infarction group was significantly lower (p < 0.05, AUC = 0.710, AUC = 0.682). Furthermore, the iron ion concentrations in the (AMI + SCAD) group were significantly lower (p < 0.05) than in the control group. (4) Conclusions: The data presented in this study strongly indicate that the concentration of iron ions in the peripheral blood is related to coronary atherosclerosis. Decreases in the levels of iron ions in the peripheral blood can be used as a predictive biomarker of coronary atherosclerosis.

ACE2 pathway regulates thermogenesis and energy metabolism

Identification of key regulators of energy homeostasis holds important therapeutic promise for metabolic disorders, such as obesity and diabetes. ACE2 cleaves angiotensin II (Ang II) to generate Ang-(1-7) which acts mainly through the Mas1 receptor. Here, we identify ACE2 pathway as a critical regulator in the maintenance of thermogenesis and energy expenditure. We found that ACE2 is highly expressed in brown adipose tissue (BAT) and that cold stimulation increases ACE2 and Ang-(1-7) levels in BAT and serum. Ace2 knockout mice (Ace2-/y) and Mas1 knockout mice (Mas1-/-) displayed impaired thermogenesis. Mice transplanted with brown adipose tissue from Mas1-/- display metabolic abnormalities consistent with those seen in the Ace2 and Mas1 knockout mice. In contrast, impaired thermogenesis of Leprdb/db obese diabetic mice and high-fat diet-induced obese mice were ameliorated by overexpression of Ace2 or continuous infusion of Ang-(1-7). Activation of ACE2 pathway was associated with improvement of metabolic parameters, including blood glucose, lipids and energy expenditure in multiple animal models. Consistently, ACE2 pathway remarkably enhanced the browning of white adipose tissue. Mechanistically, we showed that ACE2 pathway activated Akt/FoxO1 and PKA pathway, leading to induction of UCP1 and activation of mitochondrial function. Our data propose that adaptive thermogenesis requires regulation of ACE2 pathway and highlight novel potential therapeutic targets for the treatment of metabolic disorders.

Evaluation of NAFLD fibrosis, FIB-4 and APRI score in diabetic patients receiving exenatide treatment for non-alcoholic fatty liver disease

There is a closely relationship between the development and progression of nonalcoholic fatty liver disease (NAFLD) or metabolic associated fatty liver disease (MAFLD) and obesity and diabetes. NAFLD fibrosis scores should be routinely used to rule out patients with advanced fibrosis. High scores may help identify patients at higher risk of all causes andliverrelated morbidity and mortality. The aim of this study was to investigate the association between exenatide and fibrosis scores. The effect of exenatide treatment on fibrosis scores was evaluated in type 2 diabetes mellitus (DM) patients with MAFLD. Evaluation was made of 50 patients with type 2 DM and MAFLD. The NFS, FIB4 and APRI scores were calculated before and after 6 months of treatment. After 6 months of exenatide treatment, the NFS and APRI scores were determined to have decreased significantly. Exenatide was observed to control blood glucose, reduce body weight and improve fibrosis scores in MAFLD patients with type 2 diabetes.

Results of the non-interventional observational program: Influence of Novel COroNavirus on the condition of patients with liver and gastrointestinal Tract diseases and the effect of Ursodeoxycholic acid drugs and Rebamipide on the course of COVID-19 infection (CONTUR)

Intriduction. The course and outcome of COVID-19 infection in patients with liver and gastrointestinal tract diseases remain poorly understood. The article presents a multicenter non-interventional observational program conducted by the Russian Society for the Study of the Liver.Aim. To study the relationship between COVID-19 and injuries of gastrointestinal tract and liver, to assess the effect of therapy with UDCA and Rebamipide on the course and outcome of COVID-19 infection. Materials and methods. 460 patients were enrolled in the study, of which 46% were patients with gastrointestinal and liver diseases. Some patients received Rebamipide and UDCA at a dose of 15 mg/kg body weight, followed by assessment of the clinical and laboratory parameters.Results. In the study group, more severe lung injury and the course of infection were observed. The investigators detected three phenotypes of gastrointestinal tract injury: dyspeptic, diarrheal and painful. The latter was more common in patients with gastrointestinal diseases. Liver injury occurred in 87% of patients with COVID-19 (of which 44% had a history of liver disease). Increased ALT and AST were more often recorded in patients with obesity and diabetes mellitus and correlated with the severity of the infection. An inverse relationship was found between the albumin level and death and transfer to mechanical ventilation. At least 5-day Rebamipide therapy leads to reduction of diarrhea and abdominal pain (p < 0.00001 and p = 0.002), decrease in the levels of systemic inflammatory markers (CRP and ferritin, p<0.00001). The use of UDCA leads to a decrease of the systemic inflammation markers: ferritin and is associated with a significant decrease/normalization of ALT levels (p < 0.00001).Conclusions. In patients with diseases of the gastrointestinal tract and liver, COVID-19 develops in a more severe form and symptoms of gastrointestinal tract injury may prevail in the clinical picture. The severity of liver injury correlates with the severity of COVID-19 and a poor prognosis. Rebamipide reduces diarrhea and abdominal pain. UDCA prevents or reduces liver injury in COVID-19 infection. Both drugs reduce the level of systemic inflammation markers.

Molecular mechanisms of liver carcinogenesis related to metabolic syndrome

Global prevalence of non-alcoholic fatty liver disease (NAFLD) and of NAFLD-hepatocellular carcinoma (HCC) is estimated to grow in the next years. The burden of NAFLD and the evidence that NAFLD-HCC arises also in non-cirrhotic patients, explain the urgent need of a better characterization of the molecular mechanisms involved in NAFLD progression. Obesity and diabetes cause a chronic inflammatory state which favors changes in serum cytokines and adipokines, an increase in oxidative stress, DNA damage, and the activation of multiple signaling pathways involved in cell proliferation. Moreover, a role in promoting NAFLD-HCC has been highlighted in the innate and adaptive immune system, dysbiosis, and alterations in bile acids metabolism. Several dietary, genetic, or combined mouse models have been used to study nonalcoholic steatohepatitis (NASH) development and its progression to HCC, but models that fully recapitulate the biological and prognostic features of human NASH are still lacking. In humans, four single nucleotide polymorphisms (PNPLA3, TM6SF2, GCKR, and MBOAT7) have been linked to the development of both NASH and HCC in cirrhotic and non-cirrhotic patients, whereas HSD17B13 polymorphism has a protective effect. In addition, higher rates of somatic ACVR2A mutations and a novel mutational signature have been recently discovered in NASH-HCC patients. The knowledge of the molecular pathogenesis of NAFLD-HCC will be helpful to personalized screening programs and allow for primary and secondary chemopreventive treatments for NAFLD patients who are more likely to progress to HCC.

Integrative system biology and mathematical modeling of genetic networks identifies shared biomarkers for obesity and diabetes

<abstract> <p>Obesity and type 2 and diabetes mellitus (T2D) are two dual epidemics whose shared genetic pathological mechanisms are still far from being fully understood. Therefore, this study is aimed at discovering key genes, molecular mechanisms, and new drug targets for obesity and T2D by analyzing the genome wide gene expression data with different computational biology approaches. In this study, the RNA-sequencing data of isolated primary human adipocytes from individuals who are lean, obese, and T2D was analyzed by an integrated framework consisting of gene expression, protein interaction network (PIN), tissue specificity, and druggability approaches. Our findings show a total of 1932 unique differentially expressed genes (DEGs) across the diabetes versus obese group comparison (p≤0.05). The PIN analysis of these 1932 DEGs identified 190 high centrality network (HCN) genes, which were annotated against 3367 GO terms and functional pathways, like response to insulin signaling, phosphorylation, lipid metabolism, glucose metabolism, etc. (p≤0.05). By applying additional PIN and topological parameters to 190 HCN genes, we further mapped 25 high confidence genes, functionally connected with diabetes and obesity traits. Interestingly, <italic>ERBB2, FN1, FYN, HSPA1A, HBA1</italic>, and <italic>ITGB1</italic> genes were found to be tractable by small chemicals, antibodies, and/or enzyme molecules. In conclusion, our study highlights the potential of computational biology methods in correlating expression data to topological parameters, functional relationships, and druggability characteristics of the candidate genes involved in complex metabolic disorders with a common etiological basis.</p> </abstract>