Dietary fat quality impacts metabolic impairments of type 2 diabetes risk differently in male and female CD-1® mice

Metabolic impairments associated with type 2 diabetes, including insulin resistance and loss of glycemic control, disproportionately impact the elderly. Lifestyle interventions, such as manipulation of dietary fat quality (i.e., fatty acid (FA) composition), have been shown to favorably modulate metabolic health. Yet, whether or not chronic consumption of beneficial FAs can protect against metabolic derangements and disease risk during aging is not well-defined. We sought to evaluate whether long-term dietary supplementation of fish-, dairy-, or echium-derived FAs to the average FA profile in a U.S. American diet may offset metabolic impairments in males and females during aging. One-month-old CD-1® mice were fed isoenergetic, high-fat (40%) diets with the fat content comprised of either 100% control fat blend (CO) or 70% CO with 30% fish oil, dairy fat, or echium oil for 13 months. Every three months, parameters of glucose homeostasis were evaluated via glucose and insulin tolerance tests. Glucose tolerance improved in males consuming a diet supplemented with fish oil or echium oil as aging progressed, but not in females. Yet, females were more metabolically protected than males regardless of age. Additionally, Spearman correlations were performed between indices of glucose homeostasis and previously reported measurements of diet-derived FA content in tissues and colonic bacterial composition, which also revealed sex-specific associations. This study provides evidence that long-term dietary fat quality influences risk factors of metabolic diseases during aging in a sex-dependent manner, thus, sex is a critical factor to be considered in future dietary strategies to mitigate type 2 diabetes risk.

NMR-Based Metabolomic Analysis on the Protective Effects of Apolipoprotein A-I Mimetic Peptide against Contrast Media-Induced Endothelial Dysfunction

Endothelial dysfunction plays key roles in the pathological process of contrast media (CM)-induced acute kidney injury (CI-AKI) in patients undergoing vascular angiography or intervention treatment. Previously, we have demonstrated that an apolipoprotein A-I (apoA-I) mimetic peptide, D-4F, inhibits oxidative stress and improves endothelial dysfunction caused by CM through the AMPK/PKC pathway. However, it is unclear whether CM induce metabolic impairments in endothelial cells and whether D-4F ameliorates these metabolic impairments. In this work, we evaluated vitalities of human umbilical vein endothelial cells (HUVECs) treated with iodixanol and D-4F and performed nuclear magnetic resonance (NMR)-based metabolomic analysis to assess iodixanol-induced metabolic impairments in HUVECs, and to address the metabolic mechanisms underlying the protective effects of D-4F for ameliorating these metabolic impairments. Our results showed that iodixanol treatment distinctly impaired the vitality of HUVECs, and greatly disordered the metabolic pathways related to energy production and oxidative stress. Iodixanol activated glucose metabolism and the TCA cycle but inhibited choline metabolism and glutathione metabolism. Significantly, D-4F pretreatment could improve the iodixanol-impaired vitality of HUVECs and ameliorate the iodixanol-induced impairments in several metabolic pathways including glycolysis, TCA cycle and choline metabolism in HUVECs. Moreover, D-4F upregulated the glutathione level and hence enhanced antioxidative capacity and increased the levels of tyrosine and nicotinamide adenine dinucleotide in HUVECs. These results provided the mechanistic understanding of CM-induced endothelial impairments and the protective effects of D-4F for improving endothelial cell dysfunction. This work is beneficial to further exploring D-4F as a potential pharmacological agent for preventing CM-induced endothelial impairment and acute kidney injury.

Comparison of Tolerability and Impact on Metabolic Profiles of Antiretroviral Regimens Containing Darunavir/Ritonavir or Darunavir/Cobicistat in Romanian HIV Infected Patients

The management of the side effects caused by the antiretroviral therapy is one of the main problems facing clinicians. The patient’s tolerability and safety influence the success of the therapy. This retrospective study assesses the tolerability and impact on metabolic profiles of antiretroviral regimens containing darunavir/ritonavir (DRV/r) versus those containing darunavir/cobicistat (DRV/c), in routine clinical practice. The database of Prof. Dr Matei Bals of the National Institute of Infectious Diseases (INBI MB) was studied for the period 2017–2020, allowing the inclusion in the study of 462 HIV-infected patients who received the current regimen at least three months before evaluation. The following parameters were collected and analyzed: significant medical history, associated diseases, serum levels for profile evaluation: carbohydrate, lipidic, serum level of liver and pancreatic enzymes, serum markers of cardiac function, coagulation, and renal function. DRV/c (800 mg/150 mg, once daily) administrated in combination with other antiretroviral (ARV) in HIV-1 infected subjects proved to be better tolerated and with a lower impact on metabolic profile than DRV/r (600 mg/100 mg, twice daily). Patients in DRV/r group are significantly more at risk of developing, over time, side effects and metabolic impairments than those in DRV/c group, in all body functions studied, with statistically significant differences (p < 0.05) between the two groups. Laboratory data were correlated with patient’s demographic and clinical characteristics and statistically significant outcomes have been found, proving that a personalized regimen is needed to minimize the ART side effects and to maximize the success of therapy. The results of the study showed that DRV/c, associated with other antiretroviral drugs in the regimens of Romanian HIV infected subjects, have a more favorable metabolic profile than those containing DRV/r.

Reappraisal of metabolic dysfunction in neurodegeneration: Focus on mitochondrial function and calcium signaling

The cellular and molecular mechanisms that drive neurodegeneration remain poorly defined. Recent clinical trial failures, difficult diagnosis, uncertain etiology, and lack of curative therapies prompted us to re-examine other hypotheses of neurodegenerative pathogenesis. Recent reports establish that mitochondrial and calcium dysregulation occur early in many neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson’s disease, Huntington's disease, and others. However, causal molecular evidence of mitochondrial and metabolic contributions to pathogenesis remains insufficient. Here we summarize the data supporting the hypothesis that mitochondrial and metabolic dysfunction result from diverse etiologies of neuropathology. We provide a current and comprehensive review of the literature and interpret that defective mitochondrial metabolism is upstream and primary to protein aggregation and other dogmatic hypotheses of NDDs. Finally, we identify gaps in knowledge and propose therapeutic modulation of mCa2+ exchange and mitochondrial function to alleviate metabolic impairments and treat NDDs.

Amiloride ameliorates muscle wasting in cancer cachexia through inhibiting tumor-derived exosome release

Background Cancer cachexia (CAC) reduces patient survival and quality of life. Developments of efficient therapeutic strategies are required for the CAC treatments. This long-term process could be shortened by the drug-repositioning approach which exploits old drugs approved for non-cachexia disease. Amiloride, a diuretic drug, is clinically used for treatments of hypertension and edema due to heart failure. Here, we explored the effects of the amiloride treatment for ameliorating muscle wasting in murine models of cancer cachexia. Methods The CT26 and LLC tumor cells were subcutaneously injected into mice to induce colon cancer cachexia and lung cancer cachexia, respectively. Amiloride was intraperitoneally injected daily once tumors were formed. Cachexia features of the CT26 model and the LLC model were separately characterized by phenotypic, histopathologic and biochemical analyses. Plasma exosomes and muscle atrophy-related proteins were quantitatively analyzed. Integrative NMR-based metabolomic and transcriptomic analyses were conducted to identify significantly altered metabolic pathways and distinctly changed metabolism-related biological processes in gastrocnemius. Results The CT26 and LLC cachexia models displayed prominent cachexia features including decreases in body weight, skeletal muscle, adipose tissue, and muscle strength. The amiloride treatment in tumor-bearing mice distinctly alleviated muscle atrophy and relieved cachexia-related features without affecting tumor growth. Both the CT26 and LLC cachexia mice showed increased plasma exosome densities which were largely derived from tumors. Significantly, the amiloride treatment inhibited tumor-derived exosome release, which did not obviously affect exosome secretion from non-neoplastic tissues or induce observable systemic toxicities in normal healthy mice. Integrative-omics revealed significant metabolic impairments in cachectic gastrocnemius, including promoted muscular catabolism, inhibited muscular protein synthesis, blocked glycolysis, and impeded ketone body oxidation. The amiloride treatment evidently improved the metabolic impairments in cachectic gastrocnemius. Conclusions Amiloride ameliorates cachectic muscle wasting and alleviates cancer cachexia progression through inhibiting tumor-derived exosome release. Our results are beneficial to understanding the underlying molecular mechanisms, shedding light on the potentials of amiloride in cachexia therapy.

Determination of irisin and nitric oxide levels in patients with metabolic impairments in intensive care unit

Objective: The newly discovered myokine irisin has been proposed to affect physical activity. However, clinical and functional studies on the association of irisin with muscle mass, and metabolic status remain controversial. The nitric oxide is a molecule produced by the endothelium and in a variety of additional cells, including skeletal muscle. The aim of the study was to determine irisin and nitric oxide (NO) levels in physically inactive patients with severe acute metabolic disorders in intensive care unit. Material and Method: Total of 80 subjects were divided into 3 groups: healthy control (n=20), cerebrovascular disease (including hemi and paraplegic patients) (n=40), pulmonary disease (PD) (n=20). Plasma irisin levels were analyzed using a commercial ELISA kits. The total serum nitrate and nitrite was measured using a Nitrate/Nitrite Colorimetric Assay Kit. Results: We have found significantly higher irisin levels (322.8±20.4 ng/ml) in patients with cerebrovascular disease (p=0.0001) and (302.6±40.2 ng/ml) in patients with PD (p=0.01) compared to (171.4±10.5 ng/ml) control subjects. In addition, higher NO levels were observed (42.42±1.9 μM) in patients with cerebrovascular disease (p<0.001) and (44.36±2.7 μM) in patients with PD (p<0.001), compared to (27.65±0.7 μM) control subjects. Discussion: Observation of higher levels of irisin and NO in critically ill intensive care unit patients may indicate the protective roles of these agents against serious metabolic impairments.