Normal or improved cardiovascular risk factors in IGF-I-deficient adults with growth hormone receptor deficiency.

BACKGROUND: Human subjects with generalized growth hormone (GH) insensitivity due to GH receptor deficiency (GHRD)/Laron syndrome display a very low incidence of insulin resistance, diabetes, and cancer, as well as delayed age-related cognitive decline. However, the risk of cardiovascular disease (CVD) in these subjects is poorly understood. Here, we have assessed cardiovascular function, damage, and risk factors in GHRD subjects and their relatives. METHODS: We measured markers of CVD in two phases: one in a cohort of 30 individuals (GHRD = 16, control relatives = 14) brought to USC (in Los Angeles, CA) and one in a cohort including additional individuals examined in Ecuador (where the subjects live) for a total of 44 individuals (GHRD = 21, control relatives = 23). Data were collected on GHRD and control groups living in similar geographical locations and sharing comparable environmental and socio-economic circumstances. RESULTS: Compared to controls, GHRD subjects displayed lower serum glucose, insulin, blood pressure, smaller cardiac dimensions, similar pulse wave velocity, lower carotid artery intima-media thickness, lower creatinine, and a non-significant but major reduction in the portion of subjects with carotid atherosclerotic plaques (7% GHRDs vs. 36%, Controls p = 0.1333) despite elevated low-density lipoprotein cholesterol levels. CONCLUSION: The current study indicates that individuals with GHRD have normal or improved levels of cardiovascular disease risk factors as compared to their relatives. FUNDING: This study was funded in part by NIH/NIA grant P01 AG034906 to V.D.L.

Nutrition and dietary restrictions in cancer prevention.

The composition and pattern of dietary intake have emerged as key factors influencing aging, regeneration, and consequently, healthspan and lifespan. Cancer is one of the major diseases more tightly linked with aging, and age-related mortality. Although the role of nutrition in cancer incidence is generally well established, we are far from a consensus on how diet influences tumour development in different tissues. In this review, we will discuss how diet and dietary restrictions affect cancer risk and the molecular mechanisms potentially responsible for their effects. We will cover calorie restriction, intermittent fasting, prolonged fasting, fasting-mimicking diet, time-restricted eating, ketogenic diet, high protein diet, Mediterranean diet, and the vegan and vegetarian diets.

Fasting and Fasting Mimicking Diets in Obesity and Cardiometabolic Disease Prevention and Treatment.

Worldwide obesity has risen to record levels generating a major risk factor for metabolic syndrome, diabetes, hypertension, and cardiovascular disease as well as cancer and neurodegenerative diseases. Here we discuss the impact of obesity on lifespan and cardiometabolic disease in mice and humans and how different types of fasting can help prevent and treat them. We argue that specific types of fasting regimens which are associated with low burden, high long-term compliance and safety, can reduce obesity and other disease risk factors, lower morbidity and extend healthspan.

Fasting-mimicking diet prevents high-fat diet effect on cardiometabolic risk and lifespan.

Diet-induced obesity is a major risk factor for metabolic syndrome, diabetes and cardiovascular disease. Here, we show that a 5-d fasting-mimicking diet (FMD), administered every 4 weeks for a period of 2 years, ameliorates the detrimental changes caused by consumption of a high-fat, high-calorie diet (HFCD) in female mice. We demonstrate that monthly FMD cycles inhibit HFCD-mediated obesity by reducing the accumulation of visceral and subcutaneous fat without causing loss of lean body mass. FMD cycles increase cardiac vascularity and function and resistance to cardiotoxins, prevent HFCD-dependent hyperglycaemia, hypercholesterolaemia and hyperleptinaemia and ameliorate impaired glucose and insulin tolerance. The effect of monthly FMD cycles on gene expression associated with mitochondrial metabolism and biogenesis in adipocytes and the sustained ketogenesis in HFCD-fed mice indicate a role for fat cell reprogramming in obesity prevention. These effects of an FMD on adiposity and cardiac ageing could explain the protection from HFCD-dependent early mortality.

Time-Restricted Eating, Intermittent Fasting, and Fasting-Mimicking Diets in Weight Loss.

PURPOSE OF REVIEW: This article reviews the current literature on dietary interventions, including time-restricted eating (TRE), intermittent fasting (IF), and fasting-mimicking diets (FMD) and their effects on weight loss. RECENT FINDINGS: Dietary interventions, primarily known for their potential health benefits, are attracting considerable interest also for their effects on weight loss. The literature suggests that many popular diets can induce weight loss but only a limited number of studies actually demonstrate long-term weight loss efficacy. Here we present an update on the latest studies on some of the most popular dietary interventions able to trigger the physiology of fasting and highlight their impact on weight loss in overweight or obese individuals.

Generation of focal mutations and large genomic deletions in the pancreas using inducible in vivo genome editing.

Beyond the nearly uniform presence of KRAS mutations, pancreatic cancer is increasingly recognized as a heterogeneous disease. Preclinical in vivo model systems exist, but with the advent of precision oncology, murine models with enhanced genetic flexibility are needed to functionally annotate genetic alterations found in the human malignancy. Here, we describe the generation of focal gene disruptions and large chromosomal deletions via inducible and pancreas-specific expression of Cas9 in adult mice. Experimental mice are derived on demand directly from genetically engineered embryonic stem cells, without the need for further intercrossing. To provide initial validation of our approach, we show that disruption of the E3 ubiquitin ligase Rnf43 accelerates KrasG12D-dependent tumourigenesis. Moreover, we demonstrate that this system can be used to rapidly interrogate the impact of complex cancer-associated alleles through the generation of a previously unstudied 1.2 megabase deletion surrounding the CDKN2A and CDKN2B tumour suppressors. Thus, our approach is capable of reproducibly generating biallelic and precise loss of large chromosomal fragments that, in conjunction with mutant Kras, leads to development of pancreatic ductal adenocarcinoma with full penetrance.

Correction to: Transcriptome-wide identification of genes involved in Ascorbate-Glutathione cycle (Halliwell-Asada pathway) and related pathway for elucidating its role in antioxidative potential in finger millet (Eleusine coracana (L.)).

[This corrects the article DOI: 10.1007/s13205-018-1511-9.].

Transcriptome-wide identification of genes involved in Ascorbate-Glutathione cycle (Halliwell-Asada pathway) and related pathway for elucidating its role in antioxidative potential in finger millet (Eleusine coracana (L.)).

Finger millet is being recognized as a potential future crop due to their nutrient contents and antioxidative properties, which are much higher compared to the other minor millets for providing health benefits. The synthesis of these nutritional components is governed by the expression of several gene(s). Therefore, it is necessary to characterize these genes for understanding the molecular mechanisms behind de novo synthesis of nutrient components. Apart from this, these important compounds could also serve as candidate genes for imparting stress tolerance in other crop plants also. In the present study, effort has been made to identify genes involved in Ascorbate-Glutathione cycle (Halliwell-Asada Pathway) and related pathway genes for elucidating its role in antioxidative potential mechanism through transcriptome data analysis. APX, DHAR, MDHAR, GR, and SOD have been identified as the key genes of the pathway in two genotypes GP-1 (low Ca2+) and GP-45 (high Ca2+) of finger millet with reference to rice as a model system, besides, 30 putatively expressed genes/proteins were also investigated. Furthermore, the sequences of identified genes were analyzed systematically; gene ontology (GO) annotation and enrichment analysis of assembled unitranscripts were also performed using Blast2GO. As a result, 49 GO terms, 5 Enzyme Commission (EC) numbers, and 2 KEGG pathway maps were generated. GO results revealed that these genes are mainly involved in two biological processes (BP), viz., oxidation-reduction process (GO:0055114) and cellular oxidant detoxification (GO:0098869), and showed oxidoreductase activity (GO:0016491). KEGG analysis showed that APX, DHAR, MDHAR, and GR are directly connected to biosynthetic pathways of secondary metabolites, mainly polyphenolic compounds (flavonoid, tannin, and lignin) involved in glutathione metabolism (KEGG:00480) and ascorbate and aldarate metabolism (KEGG:00053). While SOD, is indirectly connected and also has significant medicinal attributes and antioxidant properties. Moreover, Fragments Per Kilobase of transcript per Million mapped reads (FPKM) values were also calculated for expression analysis and found that the FPKM values of genes present in GP-1 are higher than that of GP-45. Thus, GP-1 genotype was found to have higher stress regulated gene expression in comparison to GP-45. Taken together, the present transcriptome-based investigation unlocks new avenues for systematic functional analysis of novel ROS scavenging candidate genes that could be effectively applied for improvising human health and nutrition.

Decreased expression of cell adhesion genes in cancer stem-like cells isolated from primary oral squamous cell carcinomas.

The goal of this study was to isolate cancer stem-like cells marked by high expression of CD44, a putative cancer stem cell marker, from primary oral squamous cell carcinomas and identify distinctive gene expression patterns in these cells. From 1 October 2013 to 4 September 2015, 76 stage III-IV primary oral squamous cell carcinoma of the gingivobuccal sulcus were resected. In all, 13 tumours were analysed by immunohistochemistry to visualise CD44-expressing cells. Expression of CD44 within The Cancer Genome Atlas-Head and Neck Squamous Cell Carcinoma RNA-sequencing data was also assessed. Seventy resected tumours were dissociated into single cells and stained with antibodies to CD44 as well as CD45 and CD31 (together referred as Lineage/Lin). From 45 of these, CD44+Lin- and CD44-Lin- subpopulations were successfully isolated using fluorescence-activated cell sorting, and good-quality RNA was obtained from 14 such sorted pairs. Libraries from five pairs were sequenced and the results analysed using bioinformatics tools. Reverse transcription quantitative polymerase chain reaction was performed to experimentally validate the differential expression of selected candidate genes identified from the transcriptome sequencing in the same 5 and an additional 9 tumours. CD44 was expressed on the surface of poorly differentiated tumour cells, and within the The Cancer Genome Atlas-Head and Neck Squamous Cell Carcinoma samples, its messenger RNA levels were higher in tumours compared to normal. Transcriptomics revealed that 102 genes were upregulated and 85 genes were downregulated in CD44+Lin- compared to CD44-Lin- cells in at least 3 of the 5 tumours sequenced. The upregulated genes included those involved in immune regulation, while the downregulated genes were enriched for genes involved in cell adhesion. Decreased expression of PCDH18, MGP, SPARCL1 and KRTDAP was confirmed by reverse transcription quantitative polymerase chain reaction. Lower expression of the cell-cell adhesion molecule PCDH18 correlated with poorer overall survival in the The Cancer Genome Atlas-Head and Neck Squamous Cell Carcinoma data highlighting it as a potential negative prognostic factor in this cancer.