The development of colorectal cancer (CRC) is accompanied by extensive epigenetic changes, including frequent regional hypermethylation particularly of gene promoter regions. Specific genes, ...including SEPT9, VIM1 and TMEFF2 become methylated in a high fraction of cancers and diagnostic assays for detection of cancer-derived methylated DNA sequences in blood and/or fecal samples are being developed. There is considerable potential for the development of new DNA methylation biomarkers or panels to improve the sensitivity and specificity of current cancer detection tests.
Combined epigenomic methods - activation of gene expression in CRC cell lines following DNA demethylating treatment, and two novel methods of genome-wide methylation assessment - were used to identify candidate genes methylated in a high fraction of CRCs. Multiplexed amplicon sequencing of PCR products from bisulfite-treated DNA of matched CRC and non-neoplastic tissue as well as healthy donor peripheral blood was performed using Roche 454 sequencing. Levels of DNA methylation in colorectal tissues and blood were determined by quantitative methylation specific PCR (qMSP).
Combined analyses identified 42 candidate genes for evaluation as DNA methylation biomarkers. DNA methylation profiles of 24 of these genes were characterised by multiplexed bisulfite-sequencing in ten matched tumor/normal tissue samples; differential methylation in CRC was confirmed for 23 of these genes. qMSP assays were developed for 32 genes, including 15 of the sequenced genes, and used to quantify methylation in tumor, adenoma and non-neoplastic colorectal tissue and from healthy donor peripheral blood. 24 of the 32 genes were methylated in >50% of neoplastic samples, including 11 genes that were methylated in 80% or more CRCs and a similar fraction of adenomas.
This study has characterised a panel of 23 genes that show elevated DNA methylation in >50% of CRC tissue relative to non-neoplastic tissue. Six of these genes (SOX21, SLC6A15, NPY, GRASP, ST8SIA1 and ZSCAN18) show very low methylation in non-neoplastic colorectal tissue and are candidate biomarkers for stool-based assays, while 11 genes (BCAT1, COL4A2, DLX5, FGF5, FOXF1, FOXI2, GRASP, IKZF1, IRF4, SDC2 and SOX21) have very low methylation in peripheral blood DNA and are suitable for further evaluation as blood-based diagnostic markers.
In a clinical study, tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1RA), provided superior glycemic control vs the GLP-1RA semaglutide. ...The physiologic mechanisms are incompletely understood.
To evaluate treatment effects by model-based analyses of mixed-meal tolerance test (MMTT) data.
A 28-week double-blind, randomized, placebo-controlled trial.
Two clinical research centers in Germany.
Patients with type 2 diabetes treated with metformin.
Tirzepatide 15 mg, semaglutide 1 mg, placebo.
Glycemic control, model-derived β-cell function indices including insulin secretion rate (ISR) at 7.2-mmol/L glucose (ISR7.2), β-cell glucose (β-CG) sensitivity, insulin sensitivity, and estimated hepatic insulin-to-glucagon ratio.
Tirzepatide significantly reduced fasting glucose and MMTT total glucose area under the curve (AUC) vs semaglutide (P < 0.01). Incremental glucose AUC did not differ significantly between treatments; therefore, greater total glucose AUC reduction with tirzepatide was mainly attributable to greater suppression of fasting glucose. A greater reduction in total ISR AUC was achieved with tirzepatide vs semaglutide (P < 0.01), in the context of greater improvement in insulin sensitivity with tirzepatide (P < 0.01). ISR7.2 was significantly increased with tirzepatide vs semaglutide (P < 0.05), showing improved β-CG responsiveness. MMTT-derived β-CG sensitivity was increased but not significantly different between treatments. Both treatments reduced fasting glucagon and total glucagon AUC, with glucagon AUC significantly reduced with tirzepatide vs semaglutide (P < 0.01). The estimated hepatic insulin-to-glucagon ratio did not change substantially with either treatment.
These results suggest that the greater glycemic control observed for tirzepatide manifests as improved fasting glucose and glucose excursion control, due to improvements in ISR, insulin sensitivity, and glucagon suppression.
Homologous recombination (HR), an evolutionary conserved pathway, plays a paramount role(s) in genome plasticity. The pivotal HR step is the strand invasion/exchange of double-stranded DNA by a ...homologous single-stranded DNA (ssDNA) covered by RAD51. Thus, RAD51 plays a prime role in HR through this canonical catalytic strand invasion/exchange activity. The mutations in many HR genes cause oncogenesis. Surprisingly, despite its central role in HR, the invalidation of RAD51 is not classified as being cancer prone, constituting the "RAD51 paradox". This suggests that RAD51 exercises other noncanonical roles that are independent of its catalytic strand invasion/exchange function. For example, the binding of RAD51 on ssDNA prevents nonconservative mutagenic DNA repair, which is independent of its strand exchange activity but relies on its ssDNA occupancy. At the arrested replication forks, RAD51 plays several noncanonical roles in the formation, protection, and management of fork reversal, allowing for the resumption of replication. RAD51 also exhibits noncanonical roles in RNA-mediated processes. Finally, RAD51 pathogenic variants have been described in the congenital mirror movement syndrome, revealing an unexpected role in brain development. In this review, we present and discuss the different noncanonical roles of RAD51, whose presence does not automatically result in an HR event, revealing the multiple faces of this prominent actor in genomic plasticity.
Tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist, has, in clinical trials, demonstrated greater reductions in glucose, body weight, ...and triglyceride levels compared with selective GLP-1R agonists in people with type 2 diabetes (T2D). However, cellular mechanisms by which GIPR agonism may contribute to these improved efficacy outcomes have not been fully defined. Using human adipocyte and mouse models, we investigated how long-acting GIPR agonists regulate fasted and fed adipocyte functions. In functional assays, GIPR agonism enhanced insulin signaling, augmented glucose uptake, and increased the conversion of glucose to glycerol in a cooperative manner with insulin; however, in the absence of insulin, GIPR agonists increased lipolysis. In diet-induced obese mice treated with a long-acting GIPR agonist, circulating triglyceride levels were reduced during oral lipid challenge, and lipoprotein-derived fatty acid uptake into adipose tissue was increased. Our findings support a model for long-acting GIPR agonists to modulate both fasted and fed adipose tissue function differentially by cooperating with insulin to augment glucose and lipid clearance in the fed state while enhancing lipid release when insulin levels are reduced in the fasted state.
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•GIPR is expressed and functionally signals in both human and mouse adipocytes•Tirzepatide signals to adipocytes via long-acting GIPR agonism•Tirzepatide regulates adipocyte lipid and glucose storage as well as lipid efflux•Tirzepatide regulation of adipocyte function likely contributes to overall efficacy
Tirzepatide, a novel long-acting GIPR/GLP-1R agonist, has recently demonstrated clinical efficacy in reducing HbA1c and body weight compared with placebo or selective GLP-1R agonists. Here, Regmi et al. identify mechanisms by which the long-acting GIPR agonism of tirzepatide may uniquely contribute to these clinical benefits by regulating adipocyte nutrient metabolism.
Purpose of Review
Food insecurity (FI) is a serious public health issue affecting 2 billion people worldwide. FI is associated with increased risk for multiple chronic diseases, including obesity, ...type 2 diabetes, cardiovascular disease, and mental health. We selected these four chronic diseases given their global prevalence and comorbid associations with each other. We evaluated the most recent literature published over the past 5 years and offer strategies for the screening of FI.
Recent Findings
Recent systematic reviews and meta-analyses report an association between FI and obesity in adult women as well as adult men and women living in low- and middle-income countries. Gender differences also were observed between FI and type 2 diabetes, such that adult women showed an increased risk for type 2 diabetes. This association was influenced by social determinants of health. Very low food security (i.e., high FI) was associated with increased risk for cardiovascular disease and a higher risk for cardiovascular disease mortality. Finally, several studies showed an association between FI and adverse mental health outcomes, including increased risk for stress, depression, anxiety, sleep disorders, and suicidal ideation.
Summary
FI and its negative association with body weight, type 2 diabetes, cardiovascular disease, and mental health provide a compelling rationale for identification of FI in clinical settings. Brief, well-validated screening measures are available in multiple languages. Despite the need for FI screening, many guidelines do not address its implementation. For this reason, more research and targeted interventions are needed to increase FI screening rates and close the loop in the coordination of resources.
Female sexual promiscuity can have significant effects on male mating decisions because it increases the intensity of competition between ejaculates for fertilization. Because sperm production is ...costly, males that can detect multiple matings by females and allocate sperm strategically will have an obvious fitness advantage. The presence of rival males is widely recognized as a cue used by males to assess sperm competition. However, for species in which males neither congregate around nor guard females, other more cryptic cues might be involved. Here, we demonstrate unprecedented levels of sperm competition assessment by males, which is mediated via the use of chemical cues. Using the cricket Teleogryllus oceanicus, we manipulated male perception of sperm competition by experimentally coating live unmated females with cuticular compounds extracted from males. We found that males adjusted their ejaculate allocation in response to these compounds: the viability of sperm contained within a male's ejaculate decreased as the number of male extracts applied to his virgin female partner was increased. We further show that males do not respond to the relative concentration of male compounds present on females, but rather to the number of distinct signature odours of individual males. Our results conform to sperm competition theory, and show for the first time, to our knowledge, that males can detect different intensities of sperm competition by using distinct chemical cues of individual males present on females.
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