Narciclasine attenuates diet-induced obesity by promoting oxidative metabolism in skeletal muscle.

Obesity develops when caloric intake exceeds metabolic needs. Promoting energy expenditure represents an attractive approach in the prevention of this fast-spreading epidemic. Here, we report a novel pharmacological strategy in which a natural compound, narciclasine (ncls), attenuates diet-induced obesity (DIO) in mice by promoting energy expenditure. Moreover, ncls promotes fat clearance from peripheral metabolic tissues, improves blood metabolic parameters in DIO mice, and protects these mice from the loss of voluntary physical activity. Further investigation suggested that ncls achieves these beneficial effects by promoting a shift from glycolytic to oxidative muscle fibers in the DIO mice thereby enhancing mitochondrial respiration and fatty acid oxidation (FAO) in the skeletal muscle. Moreover, ncls strongly activates AMPK signaling specifically in the skeletal muscle. The beneficial effects of ncls treatment in fat clearance and AMPK activation were faithfully reproduced in vitro in cultured murine and human primary myotubes. Mechanistically, ncls increases cellular cAMP concentration and ADP/ATP ratio, which further lead to the activation of AMPK signaling. Blocking AMPK signaling through a specific inhibitor significantly reduces FAO in myotubes. Finally, ncls also enhances mitochondrial membrane potential and reduces the formation of reactive oxygen species in cultured myotubes.

Comparative Transcriptomic and Epigenomic Analyses Reveal New Regulators of Murine Brown Adipogenesis.

Increasing energy expenditure through brown adipocyte recruitment is a promising approach to combat obesity. We report here the comprehensive profiling of the epigenome and transcriptome throughout the lineage commitment and differentiation of C3H10T1/2 mesenchymal stem cell line into brown adipocytes. Through direct comparison to datasets from differentiating white adipocytes, we systematically identify stage- and lineage-specific coding genes, lncRNAs and microRNAs. Utilizing chromatin state maps, we also define stage- and lineage-specific enhancers, including super-enhancers, and their associated transcription factor binding motifs and genes. Through these analyses, we found that in brown adipocytes, brown lineage-specific genes are pre-marked by both H3K4me1 and H3K27me3, and the removal of H3K27me3 at the late stage is necessary but not sufficient to promote brown gene expression, while the pre-deposition of H3K4me1 plays an essential role in poising the brown genes for expression in mature brown cells. Moreover, we identify SOX13 as part of a p38 MAPK dependent transcriptional response mediating early brown cell lineage commitment. We also identify and subsequently validate PIM1, SIX1 and RREB1 as novel regulators promoting brown adipogenesis. Finally, we show that SIX1 binds to adipogenic and brown marker genes and interacts with C/EBPα, C/EBPß and EBF2, suggesting their functional cooperation during adipogenesis.

Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis.

We investigated the role of protein tyrosine phosphatase 1B (PTP1B) in mammary tumorigenesis using both genetic and pharmacological approaches. It has been previously shown that transgenic mice with a deletion mutation in the region of Erbb2 encoding its extracellular domain (referred to as NDL2 mice, for 'Neu deletion in extracellular domain 2') develop mammary tumors that progress to lung metastasis. However, deletion of PTP1B activity in the NDL2 transgenic mice either by breeding with Ptpn1-deficient mice or by treatment with a specific PTP1B inhibitor results in significant mammary tumor latency and resistance to lung metastasis. In contrast, specific overexpression of PTP1B in the mammary gland leads to spontaneous breast cancer development. The regulation of ErbB2-induced mammary tumorigenesis by PTB1B occurs through the attenuation of both the MAP kinase (MAPK) and Akt pathways. This report provides a rationale for the development of PTP1B as a new therapeutic target in breast cancer.

Protein Supplement Perceptions, Use, and Associated Performance in Young Lebanese Resistance-Training Athletes.

The aims of this study were first to evaluate the nutritional knowledge, perception, and source of nutrition information among resistance-trained individuals consuming protein supplements (PS), to determine whether a correlation exists between nutrition-related knowledge and the use of PS, and finally to compare the impact of PS use among participants classified as nonprotein supplement users (NPSUs) and protein supplement users (PSUs). A cross-sectional study was conducted among a highly selected group of resistance-specialized trainees (RSTs). Among the 100 RST participants recruited, the Internet and coaches were the most common source of nutritional information. About one-third of participants believed that there were no health risks after consuming PS. Both NPSU and PSU exhibit performance improvement that was significantly lessened in PSU compared to NPSU. This study demonstrated that RST may have misconceptions regarding the benefits of PS usage to increase strength. Our data also suggest a shortage of knowledge about PS and confirm that PSUs lack proper professional guidance. These findings highlight the need for proper monitoring to ensure adequate perception, awareness, and safety in the Lebanese sports sector.

Inverse Association Between the Mediterranean Diet and COVID-19 Risk in Lebanon: A Case-Control Study.

Background: Since 2019, the world is confronting the COVID-19 public health crisis that deeply impacted all aspects of life, from the health sector to economy. Despite the advancement of research targeting pandemic containment measures, more strategies are still needed to alleviate the burden caused by this novel disease. In particular, optimal nutrition was proposed as a possible mitigating factor in the context of COVID-19. Indeed, the light is shed on balanced diets, such as the Mediterranean diet, which present the finest nutritional quality to support the immune system and other physiologic functions. In contrast, less varied diets that lack the needed nutrients and favor inflammation have been correlated with adverse health effects, including a hindered immune response, such as the western diet. Methods: This observational case control study aimed at exploring the possible associations between the different dietary patterns present among a sample of the Lebanese population and the COVID-19 occurrence and outcomes. An online survey collected information about the sociodemographic characteristics, health status, lifestyle, and dietary habits through the Mediterranean diet questionnaire and a semi-quantitative fod frequency questionnaire, and the COVID-19 infection and its burden. The sample consisted of 399 respondents divided into the case and control groups (37.6 and 62.4%, respectively) on the basis of the presence or absence of a COVID-19 infection history. Results: The participants in the case and control groups had average adherence to the Mediterranean diet and their dietary intake was closer to the western diet. However, the cases had a lower mean of the MedDiet score (p = 0.009). Food groups consumption analysis showed that this significant difference within the overall similar dietary patterns was due to a higher consumption of poultry and a trend toward decreased consumption of olive oil and increased read meat and alcohol intake among the cases. Additionally, gender influenced the levels of different foods' consumption. Nonetheless, the dietary intake did not impact the COVID-19 burden. Conclusion: It is recommended to adopt healthy food choices within the different dietary patterns for a better protection against COVID-19. These findings should be validated in larger-scale studies.

Factors Associated with Adherence to the Mediterranean Diet and Dietary Habits among University Students in Lebanon.

Although the Mediterranean Diet has been acknowledged as the best overall diet for the year 2020, it has seen a decrease in its adherence over the past years. This is due to several reasons, one of which is the gradual shift to a more westernized diet with all the influences that occur especially on university students whose dietary choices set a path for future dietary habits. The aim of this study is to check the level of adherence to the Mediterranean Diet and frequency of breakfast consumption among university students in Lebanon and check whether they are influenced by sociodemographic, anthropometric, dietary knowledge, or academic data. A cross-sectional questionnaire was electronically sent to randomly selected students (210 females and 93 males) from different universities across Lebanon, aged between 18 and 25 years old. The questionnaire was filled online, and all data were self-reported. The Mediterranean Diet Quality Index (KIDMED) was used as a tool to evaluate adherence to the Mediterranean Diet. The results showed that 18.8% of respondents had high adherence to the Mediterranean Diet. Students who reported always consuming breakfast and not skipping meals had significantly higher adherence to the MD. Furthermore, students with lower BMI and higher KIDMED scores had significantly more correct answers on the nutritional knowledge questions. In addition, there was a significant difference in the average KIDMED scores between different GPA categories, most notably when comparing high and poor MD adherence; students with excellent GPA scores had higher adherence to the MD than those with poor GPA scores. In conclusion, nutrition awareness in a university setting is very important since it may positively affect academic outcomes and may be the last chance to teach and engrave healthy eating patterns to a large scale of students.

ACSL1 Is Associated With Fetal Programming of Insulin Sensitivity and Cellular Lipid Content.

Individuals who are born small for gestational age (SGA) have a risk to develop various metabolic diseases during their life course. The biological memory of the prenatal state of growth restricted individuals may be reflected in epigenetic alterations in stem cell populations. Mesenchymal stem cells (MSCs) from the Wharton's jelly of umbilical cord tissue are multipotent, and we generated primary umbilical cord MSC isolates from SGA and normal neonates, which were subsequently differentiated into adipocytes. We established chromatin state maps for histone marks H3K27 acetylation and H3K27 trimethylation and tested whether enrichment of these marks was associated with gene expression changes. After validating gene expression levels for 10 significant chromatin immunoprecipitation sequencing candidate genes, we selected acyl-coenzyme A synthetase 1 (ACSL1) for further investigations due to its key roles in lipid metabolism. The ACSL1 gene was found to be highly associated with histone acetylation in adipocytes differentiated from MSCs with SGA background. In SGA-derived adipocytes, the ACSL1 expression level was also found to be associated with increased lipid loading as well as higher insulin sensitivity. ACSL1 depletion led to changes in expression of candidate genes such as proinflammatory chemokines and down-regulated both, the amount of cellular lipids and glucose uptake. Increased ACSL1, as well as modulated downstream candidate gene expression, may reflect the obese state, as detected in mice fed a high-fat diet. In summary, we believe that ACSL1 is a programmable mediator of insulin sensitivity and cellular lipid content and adipocytes differentiated from Wharton's jelly MSCs recapitulate important physiological characteristics of SGA individuals.

Impact of oncogenic protein tyrosine phosphatases in cancer.

Protein tyrosine phosphatases (PTPs) constitute a large family of enzymes that can exert both positive and negative effects on signaling pathways. They play dominant roles in setting the levels of intracellular phosphorylation downstream of many receptors including receptor tyrosine kinases and G protein-coupled receptors. As observed with kinases, deregulation of PTP activity can also contribute to cancer. This review will examine a broad array of PTP family members that positively affect oncogenesis in human cancer tissues. We will describe the PTP family, their biological significance in oncology, and how recent progress is being made to more effectively target specific PTPs. Finally, we will discuss the therapeutic implications of targeting these oncogenic PTPs in cancer.

Inside the human cancer tyrosine phosphatome.

Members of the protein tyrosine phosphatase (Ptp) family dephosphorylate target proteins and counter the activities of protein tyrosine kinases that are involved in cellular phosphorylation and signalling. As such, certain PTPs might be tumour suppressors. Indeed, PTPs play an important part in the inhibition or control of growth, but accumulating evidence indicates that some PTPs may exert oncogenic functions. Recent large-scale genetic analyses of various human tumours have highlighted the relevance of PTPs either as putative tumour suppressors or as candidate oncoproteins. Progress in understanding the regulation and function of PTPs has provided insights into which PTPs might be potential therapeutic targets in human cancer.

Insufficient milk supply and breast cancer risk: a systematic review.

BACKGROUND: An association between insufficient milk supply, the inability of a mother's breast milk to provide sufficiently for her infant, and breast cancer has been suggested by observations in animal models. To determine if an association has been reported in epidemiological studies of human breast cancer, a systematic review of the literature has been conducted. We also sought to identify the methodological limitations of existing studies to guide the design of any future prospective studies in this field. METHODOLOGY/PRINCIPAL FINDINGS: PubMed, EMBASE, Web of Science, BIOSIS, and CAB abstracts were searched. We selected any study that (1) assessed breast cancer in association with breastfeeding history and (2) examined the relationship between insufficient milk supply with breast cancer. Seven relevant studies were identified that met both criteria. There was statistically significant heterogeneity among the results which likely reflects clinically significant differences in definitions of insufficient milk supply and reference groups that were used. Among premenopausal women who had experienced insufficient milk supply, odds ratios (ORs) for breast cancer risk ranged from 0.9 to 16.3. Among postmenopausal women, ORs ranged from 0.6 to 6.7. Based on the range of odds ratios obtained in the studies reported in this review, it remains unclear if there is a true association between insufficient milk supply and breast cancer. CONCLUSIONS/SIGNIFICANCE: Although some studies have shown a strong positive association, there is no consistent evidence for an effect of insufficient milk supply on breast cancer risk. Exposure definitions are in need of improvement in order to focus on primary insufficient milk supply. Reference groups consisting of women who have successfully breastfed may also introduce positive bias (inflation of the odds ratio) into study results because of the protective effect of prolonged breastfeeding in the control group.