Non-cell autonomous mechanisms control mitochondrial gene dysregulation in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with insulin resistance and impaired energy metabolism in skeletal muscle, the aetiology of which is currently unclear. Here, we mapped the gene expression profile of skeletal muscle from women with PCOS and determined if cultured primary myotubes retain the gene expression signature of PCOS in vivo. Transcriptomic analysis of vastus lateralis biopsies collected from PCOS women showed lower expression of genes associated with mitochondrial function while the expression of genes associated with the extracellular matrix was higher compared to controls. Altered skeletal muscle mRNA expression of mitochondrial-associated genes in PCOS was associated with lower protein expression of mitochondrial complex II to V, but not complex I, with no difference in mitochondrial DNA content. Transcriptomic analysis of primary myotube cultures established from biopsies did not display any differentially expressed genes between controls and PCOS. Comparison of gene expression profiles in skeletal muscle biopsies and primary myotube cultures showed lower expression of mitochondrial and energy metabolism-related genes in vitro, irrespective of the group. Together, our results show that the altered mitochondrial-associated gene expression in skeletal muscle in PCOS is not preserved in cultured myotubes, indicating that the in vivo extracellular milieu, rather than genetic or epigenetic factors, may drive this alteration. Dysregulation of mitochondrial-associated genes in skeletal muscle by extracellular factors may contribute to the impaired energy metabolism associated with PCOS.

Inflammatory mediators and their clinical repercussions on anorexia nervosa

Anorexia Nervosa (AN) is an eating disorder that affects adults, young people and children, has a multifactorial etiology, characterized by a distortion of body image associated with fear of gaining weight, leading the individual to commit severe food restriction, causing extreme weight loss and malnutrition. This, clinical and metabolic manifestations associated with inflammatory biomarkers are triggered, based on evidence on the dysregulation of the immune system and an inflammatory immunomodudulation during AN. The present study aims to present evidence that demonstrates how inflammatory mediators are systematically related to the most common clinical manifestations more in AN. This is an integrative review, based on consultation of the databases: MEDLINE and LILACS. Sixteen studies were selected from 2014 to 2020 with 56, 25% NE3, followed by 31, 25% NE 5 and 12, 5% NE 2. Studies have shown that inflammatory biomarkers such as interleukins, and chemokines, leptin, ghrelin, omentine-1, adinonectin, BDNF, VEGF, VCAM, PCR, OC, CTX, OPG, RANK, RANKL, IFN -γ, NO, IGF and some classes of TNF are related to clinical manifestations in AN contributing to prolonged and difficult to reverse symptoms, such as depression, sleep disorders, memory and learning, altered behavior , tissue damage, decreased appetite, risk for cardiovascular disease, changes in the intestinal microbiome, osteoporosis, amenorrhea, inflammation of the hypothalamus, impaired energy metabolism and unregulated inflammatory state. However, further clarification is needed on this topic, as there are still few studies in this line of research.

Atrial fibrillation in diabetic patients.

The article summarizes the main clinical and theoretical data on features of atrial fibrillation (AF) course in combination with diabetes mellitus (DM). The potential relationship between these comorbid conditions is analyzed on the basis of the results of epidemiological and randomized studies, the gender features of the course of AF in this category of patients are assessed. Particular attention is paid to pathogenetic bases of AF development in DM (fibrosis, neurohumoral regulation, impaired energy metabolism of cardiomyocytes, oxidative stress, genetic factors, electrolyte metabolism disorders).

A conserved role for AMP-activated protein kinase in NGLY1 deficiency

Mutations in human N-glycanase 1 (NGLY1) cause the first known congenital disorder of deglycosylation (CDDG). Patients with this rare disease, which is also known as NGLY1 deficiency, exhibit global developmental delay and other phenotypes including neuropathy, movement disorder, and constipation. NGLY1 is known to regulate proteasomal and mitophagy gene expression through activation of a transcription factor called "nuclear factor erythroid 2-like 1" (NFE2L1). Loss of NGLY1 has also been shown to impair energy metabolism, but the molecular basis for this phenotype and its in vivo consequences are not well understood. Using a combination of genetic studies, imaging, and biochemical assays, here we report that loss of NGLY1 in the visceral muscle of the Drosophila larval intestine results in a severe reduction in the level of AMP-activated protein kinase α (AMPKα), leading to energy metabolism defects, impaired gut peristalsis, failure to empty the gut, and animal lethality. Ngly1–/– mouse embryonic fibroblasts and NGLY1 deficiency patient fibroblasts also show reduced AMPKα levels. Moreover, pharmacological activation of AMPK signaling significantly suppressed the energy metabolism defects in these cells. Importantly, the reduced AMPKα level and impaired energy metabolism observed in NGLY1 deficiency models are not caused by the loss of NFE2L1 activity. Taken together, these observations identify reduced AMPK signaling as a conserved mediator of energy metabolism defects in NGLY1 deficiency and suggest AMPK signaling as a therapeutic target in this disease.

Adaptogens: modern realities and prospects for the search of new effective and safe medicines (review of literature and authors’ research)

In present medical practice adaptogens and antihypoxants are a promising, but still insufficiently studied group of medicines. The largest evidence base among plant adaptogens was developed for ginseng, aralia, eleutherococcus, lemongrass, rhodiola, leuzea, sterculia. Antihypoxants, like trimetazidine, meldonium, succinic and -aminobutyric acid medications are included in the clinical guidelines. They have the most pronounced antihypoxic effects in a variety of diseases and pathological conditions, accompanied by impaired energy metabolism in the tissues. But their effect is not always high due to the variety of etiological factors causing hypoxia. Tetrahydropyrido[2,1-b][1,3,5]thiadiazine derivatives characterized by various pharmacodynamic effects with low toxicity which opens up prospects for a detailed further study. In animal experiments, the most pronounced adaptogenic and antidepressant effects is exerted by compounds TD-0348 and TD-0479, superior in strength to the antihypoxants used in modern clinical practice, the classic plant adaptogen ginseng.

Lean Body Mass and Endocrine Status But Not Age Are Determinants of Resting Energy Expenditure in Patients with Non-Small Cell Lung Cancer

Background: Cancer and aging are both frequently associated with malnutrition, a factor of poor prognosis. In adult cancer patients, this may be related in part to impaired energy metabolism, with higher than predicted resting energy expenditure (REE) in about 50% of patients. We hypothesized that frequently impaired energy metabolism in elderly patients could potentiate cancer-associated hypermetabolism, further promoting risk of malnutrition. Objective: To study the hypermetabolic response to cancer in a predominantly aged population and the potential underlying determinants. Methods: This was a cross-sectional exploratory study in patients with non-small-cell lung cancer. REE was measured by indirect calorimetry. Body composition was determined from a single CT scan imaging at L3 level. Endocrine, inflammatory, nutritional and metabolic status were evaluated. Results: Twenty-seven patients, of median age 68 years (range 32–81) completed the study. In this population, mean measured REE was 7.5% higher than calculated REE. Sex and weight accounted for about 51% of REE variations, whereas age accounted only for 4%. However, these parameters did not explain the REE-to-lean body mass (LBM) ratio variations, suggesting that they influenced REE only through their effect on LBM. Among the other parameters evaluated, only the thyroid-stimulating hormone and interleukin-6 plasma levels appeared to have an influence on REE. The study of the consequences of this increase in REE-to-LBM ratio showed a growing inability of patients to meet their energy needs but showed no effect on nutritional markers such as transthyretin. Conclusions: The results of this pilot study suggest that in our population, age was not an important factor of REE. The elevated energy metabolism was associated with patients’ failure to increase their energy intakes sufficiently, which can contribute to the development of cachexia. Clinical Trial: This trial is registered at clinicaltrials.gov under NCT0314.