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Recent data suggests that (pre)diabetes onset is preceded by a period of hyperinsulinemia. Consumption of the "modern" Western diet, over-nutrition, genetic background, decreased hepatic insulin clearance, and fetal/metabolic programming may increase insulin secretion, thereby causing chronic hyperinsulinemia. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, polycystic ovarian syndrome, and Alzheimer's disease. Recent data suggests that the onset of prediabetes and diabetes are preceded by a variable period of hyperinsulinemia. Emerging data suggest that chromic hyperinsulinemia is also a driving force for increased activation of the hypothalamic-adrenal-pituitary (HPA) axis in subjects with the metabolic syndrome, leading to a state of "functional hypercortisolism". This "functional hypercortisolism" by antagonizing insulin actions may prevent hypoglycemia. It also disturbs energy balance by shifting energy fluxes away from muscles toward abdominal fat stores. Synergistic effects of hyperinsulinemia and "functional hypercortisolism" promote abdominal visceral obesity and insulin resistance which are core pathophysiological components of the metabolic syndrome. It is hypothesized that hyperinsulinemia-induced increased activation of the HPA axis plays an important etiological role in the development of the metabolic syndrome and its consequences. Numerous studies have demonstrated reversibility of hyperinsulinemia with lifestyle, surgical, and pharmaceutical-based therapies. Longitudinal studies should be performed to investigate whether strategies that reduce hyperinsulinemia at an early stage are successfully in preventing increased activation of the HPA axis and the metabolic syndrome. [ABSTRACT FROM AUTHOR]

Background: Patients with adrenal insufficiency are treated with oral hydrocortisone (HC) to compensate for the loss of endogenous cortisol production. Intrinsic imperfections of cortisol replacement strategies in mimicking normal cortisol secretion are the underlying cause of the increased morbidity and mortality of patients suffering from secondary adrenal insufficiency (SAI). To improve oral hydrocortisone substitution therapy, a better understanding of its pharmacokinetics (PK) is necessary. The previous PK model did not include protein binding. It is known that protein binding can impact hydrocortisone pharmacokinetics. The aim of this study is to describe HC pharmacokinetics including the protein-binding state using Edsim++ (Mediware, Prague) pharmacokinetic modeling software, paving the way for an in-silico tool suitable for drug delivery design. Methods: A total of 46 patients with SAI participated in a randomized double-blind crossover study Patients randomly received a low dose of HC (0.2–0.3 mg/kg body weight/day) for 10 weeks, followed by a high dose (0.4–0.6 mg/kg body weight/day) for another 10 weeks, or vice versa. Plasma samples were obtained and analyzed for free and total hydrocortisone. Single compartment population pharmacokinetic analysis was performed using an extended Werumeus-Buning model built in Edsim++. This model includes a mathematical approach for estimating free cortisol by Nguyen et al., taking the protein binding of HC to albumin and hydrocortisone-binding globulin (CBG, transcortin) into consideration, as well as different states of CBG which affect binding kinetics to HC. The goodness of fit for observed versus predicted values was calculated. Results and conclusions: Nguyen's formula for free cortisol estimation was successfully implemented in a pharmacokinetic model. The model shows high Spearman's correlation for observed versus predicted hydrocortisone concentrations. Significantly higher correlations (Spearman's r, 0.901 vs. 0.836) between total and free hydrocortisone AUC24 (area-under the curve over 24 h) are found when comparing new and old models. This new model was used to simulate the plasma concentration–time behavior of a more suitable hydrocortisone formulation. [ABSTRACT FROM AUTHOR]

Spinal cord injury affects the lives of millions of people around the world, often causing disability and, in unfortunate circumstances, death. Rehabilitation can partly improve outcomes and only a small percentage of patients, typically the least injured, can hope to return to normal living conditions. Cannabis sativa is gaining more and more interest in recent years, even though its beneficial properties have been known for thousands of years. Cannabigerol (CBG), extracted from C. sativa, is defined as the "mother of all cannabinoids" and its properties range from anti-inflammatory to antioxidant and neuroprotection. Using NSC-34 cells to model spinal cord injury in vitro, our work evaluated the properties of CBG treatments in motor neuron regeneration. While pre-treatment can modulate oxidative stress and increase antioxidant enzyme genes, such as Tnx1, decreasing Nos1 post-treatment seems to induce regeneration genes by triggering different pathways, such as Gap43 via p53 acetylation by Ep300 and Ddit3 and Xbp1 via Bdnf signaling, along with cytoskeletal remodeling signaling genes Nrp1 and Map1b. Our results indicate CBG as a phytocompound worth further investigation in the field of neuronal regeneration. [ABSTRACT FROM AUTHOR]

Since plant organs sense their environment locally, gradients of micro-climates in the plant shoot may induce spatial variability in the physiological state of the plant tissue and hence secondary metabolism. Therefore, plant architecture, which affects micro-climate in the shoot, may considerably affect the uniformity of cannabinoids in the Cannabis sativa plant, which has significant pharmaceutical and economic importance. Variability of micro-climates in plant shoots intensifies with the increase in plant size, largely due to an increase in inter-shoot shading. In this study, we therefore focused on the interplay between shoot architecture and the cannabinoid profile in large cannabis plants, ~2.5 m in height, with the goal to harness architecture modulation for the standardization of cannabinoid concentrations in large plants. We hypothesized that (i) a gradient of light intensity along the plants is accompanied by changes to the cannabinoid profile, and (ii) manipulations of plant architecture that increase light penetration to the plant increase cannabinoid uniformity and yield biomass. To test these hypotheses, we investigated effects of eight plant architecture manipulation treatments involving branch removals, defoliation, and pruning on plant morpho-physiology, inflorescence yield, cannabinoid profile, and uniformity. The results revealed that low cannabinoid concentrations in inflorescences at the bottom of the plants correlate with low light penetration, and that increasing light penetration by defoliation or removal of bottom branches and leaves increases cannabinoid concentrations locally and thereby through spatial uniformity, thus supporting the hypotheses. Taken together, the results reveal that shoot architectural modulation can be utilized to increase cannabinoid standardization in large cannabis plants, and that the cannabinoid profile in an inflorescence is an outcome of exogenous and endogenous factors. [ABSTRACT FROM AUTHOR]

The regulation of cannabinoid synthesis in Cannabis sativa is of increasing research interest as restrictions around the globe loosen to allow the plant's legal cultivation. Of the major cannabinoids, the regulation of cannabigerolic acid (CBGA) production is the least understood. The purpose of this study was to elucidate the inheritance of CBGA dominance in C. sativa and describe a marker related to this chemotype. We produced two crossing populations, one between a CBGA dominant cultivar and a tetrahydrocannabinolic acid (THCA) dominant cultivar, and one between a CBGA dominant cultivar and a cannabidiolic acid (CBDA) cultivar. Chemical and genotyping analyses confirmed that CBGA dominance is inherited as a single recessive gene, potentially governed by a non-functioning allelic variant of the THCA synthase. The "null" THCAS synthase contains a single nucleotide polymorphism (SNP) that may render the synthase unable to convert CBGA to THCA leading to the accumulation of CBGA. This SNP can be reliably used as a molecular marker for CBGA dominance in the selection and breeding of C. sativa. [ABSTRACT FROM AUTHOR]

Innovative breeds of sugar cane yield up to 2.5 times as much organic matter as conventional breeds, resulting in a great potential for biogas production. The use of biogas production as a complementary solution to conventional and second-generation ethanol production in Brazil may increase the energy produced per hectare in the sugarcane sector. Herein, it was demonstrated that through ensiling, energy cane can be conserved for six months; the stored cane can then be fed into a continuous biogas process. This approach is necessary to achieve year-round biogas production at an industrial scale. Batch tests revealed specific biogas potentials between 400 and 600 LN/kgVS for both the ensiled and non-ensiled energy cane, and the specific biogas potential of a continuous biogas process fed with ensiled energy cane was in the same range. Peak biogas losses through ensiling of up to 27% after six months were observed. Finally, compared with second-generation ethanol production using energy cane, the results indicated that biogas production from energy cane may lead to higher energy yields per hectare, with an average energy yield of up to 162 MWh/ha. Finally, the Farm2CBG concept is introduced, showing an approach for decentralized biogas production. [ABSTRACT FROM AUTHOR]

Simple Summary: Our understanding of the Endocannabinoid System of animals, and its ubiquitous presence in nearly all members of Animalia, has opened the door to novel approaches targeting pain management, cancer therapeutics, modulation of neurologic disorders, stress reduction, anxiety management, and inflammatory diseases. Both endogenous and exogenous endocannabinoid-related molecules are able to function as direct ligands or, otherwise, influence the EndoCannabinoid System (ECS). This review article introduces the reader to the ECS in animals, and documents its potential as a source for emerging therapeutics. The endocannabinoid system has been found to be pervasive in mammalian species. It has also been described in invertebrate species as primitive as the Hydra. Insects, apparently, are devoid of this, otherwise, ubiquitous system that provides homeostatic balance to the nervous and immune systems, as well as many other organ systems. The endocannabinoid system (ECS) has been defined to consist of three parts, which include (1) endogenous ligands, (2) G-protein coupled receptors (GPCRs), and (3) enzymes to degrade and recycle the ligands. Two endogenous molecules have been identified as ligands in the ECS to date. The endocannabinoids are anandamide (arachidonoyl ethanolamide) and 2-AG (2-arachidonoyl glycerol). Two G-coupled protein receptors (GPCR) have been described as part of this system, with other putative GPC being considered. Coincidentally, the phytochemicals produced in large quantities by the Cannabis sativa L plant, and in lesser amounts by other plants, can interact with this system as ligands. These plant-based cannabinoids are termed phytocannabinoids. The precise determination of the distribution of cannabinoid receptors in animal species is an ongoing project, with the canine cannabinoid receptor distribution currently receiving the most interest in non-human animals. [ABSTRACT FROM AUTHOR]

An acute traumatic event can lead to lifelong changes in stress susceptibility and result in psychiatric disease such as Post-Traumatic Stress Disorder (PTSD). We have previously shown that access to a concentrated glucose solution for 24 h beginning immediately after trauma decreased stress-related pathology in the learned helplessness model of PTSD and comorbid major depression. The current study sought to investigate the peripheral physiological effects of post-stress glucose consumption. We exposed 128 male Sprague-Dawley rats to inescapable and unpredictable 1-milliamp electric tail shocks or simple restraint in the learned helplessness procedure. Rats in each stress condition had access to a 40% glucose solution, 40% fructose solution, or water. Blood and liver tissue were extracted and processed for assay. We assessed corticosterone, corticosteroid-binding globulin (CBG), glucose, and liver glycogen concentrations at various time points following stress. We found that rats given access to glucose following exposure to traumatic shock showed a transient rise in blood glucose and an increase in liver glycogen repletion compared to those that received water or fructose following exposure to electric shock. We also found that animals given glucose following shock exhibited reduced free corticosterone and increased CBG compared to their water-drinking counterparts. However, this difference was not apparent when glucose was compared to fructose. These data suggest that post-stress glucose prophylaxis is likely not working via modulation of the HPA axis, but rather may provide its benefit by mitigating the metabolic challenges of trauma exposure. [ABSTRACT FROM AUTHOR]