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Background Heat induced by thermogenesis is an essential therapeutic intervention in medical practice. Moreover, thermogenesis improves the innate immune response. This study focuses on hand-clasping with a raised thumb (HCRT) as a thermogenic source and its effect on heart rate variability (HRV). Methods The study analyzed the ECG, thermal images of the upper body, axillary temperature, and breath exergy of 15 participants. The metabolic effect of thermogenesis is an important factor in type II diabetes mellitus (type II DM). Therefore, the clinical application included recording capillary blood glucose of 12 type-II DM subjects before and after the HCRT intervention. Results The mean axillary temperature slope increased by 11.5 %. The spatial change in temperature gradient (∇2T) at hot and cold spots also slightly increased by 3.42 % and 2.53 %, respectively. HRV improved as the VLFHF ratio decreased significantly (p < 0.05) by 52.62 %. The very low frequency (VLF) component of HRV has a relationship to thermoregulation, which is reflected through a significant increase (p < 0.05) of 41.7 % for the power under sub-VLF at 0.0327-0.04 Hz during HCRT. The spot width (SW), range, and norm of ∇2T reduces insignificantly during HCRT. There was a significant (p < 0.001) increase in the exhaled temperature by 0.5 ° C in both nostrils during 1st phase of HCRT. The standard deviation of exergy in the right nostril showed a significant increase (p < 0.05) of 72.72 % during HCRT. The Clinical tests showed a significant reduction (p < 0.001) of 24.14 % in capillary blood glucose (CBG) after HCRT. Conclusions HCRT aids in thermogenesis with higher exergy and HRV owing to a significant reduction in the VLFHF ratio.

The tolerability of different cannabinoids given orally to dogs was evaluated in a randomized, non-blinded, negative controlled, parallel design 90-day repeat dose study with a 14-day recovery period. Healthy beagles (16 males and 16 females) were randomized into four treatment groups and treated with either medium chain triglyceride oil as the control or one of the following: broad spectrum cannabidiol, broad spectrum cannabidiol with cannabigerol, or broad spectrum cannabidiol with cannabidiolic acid at 5 mg total cannabinoids/kg body weight/day. Animals were observed daily with detailed clinical examinations conducted weekly. Animals were monitored for an additional 2 weeks after dosing. Body weights, food consumption and clinical pathology evaluations were included in the study. Cannabinoids were well tolerated when healthy male and female beagles were dosed for 90 consecutive days. Annual post-market surveillance data for hemp-derived supplement products sold for use in dogs from 2010 to 2023 (partial year) shows that the rate per 1 million administrations sold is 2.10 for adverse events and 0.01 for serious adverse events. Based on the results of this study, other published studies, and data from extensive postmarket surveillance, hemp-derived cannabinoids are well tolerated in healthy dogs at a dose of 5 mg/kg body weight/day. [ABSTRACT FROM AUTHOR]

Cannabinoids have been shown to induce anti‐tumor activity in a variety of carcinoma cells such as breast, prostate, and brain. The aim of the present study is to investigate the anti‐tumor activity of cannabinoids, CBD (cannbidiol), and CBG (cannabigerol) in ovarian carcinoma cells sensitive and resistant to chemotherapeutic drugs. Sensitive A2780 cells and resistant A2780/CP70 carcinoma cells and non‐carcinoma cells were exposed to varying concentrations of CBD, CBG, carboplatin or CB1 and CB2 receptor antagonists, AM251 and AM630, respectively, alone or in combination, at different exposure times and cytotoxicity was measured by MTT assay. The mechanism of action of CBD and CB in inducing cytotoxicity was investigated involving a variety of apoptotic and cell cycle assays. Treatment with CBD and CBG selectively, dose and time dependently reduced cell viability and induced apoptosis. The effect of CBD was stronger than CBG in all cell lines tested. Both CBD and CBG induced stronger cytotoxicity than afforded by carboplatin in resistant cells. The cytotoxicity induced by CBD was not CB1 or CB2 receptor dependent in both carcinoma cells, however, CBG‐induced cytotoxicity may involve CB1 receptor activity in cisplatin‐resistant carcinoma cells. A synergistic effect was observed when cannabinoids at sublethal doses were combined with carboplatin in both carcinoma cells. The apoptotic event may involve loss of mitochondrial membrane potential, Annexin V, caspase 3/7, ROS activities, and cell cycle arrest. Further studies are required to investigate whether these results are translatable in the clinic. Combination therapies with conventional cancer treatments using cannabinoids are suggested. [ABSTRACT FROM AUTHOR]

The tolerability of different cannabinoids given orally to dogs was evaluated in a randomized, non-blinded, negative controlled, parallel design 90-day repeat dose study with a 14-day recovery period. Healthy beagles (16 males and 16 females) were randomized into four treatment groups and treated with either medium chain triglyceride oil as the control or one of the following: broad spectrum cannabidiol, broad spectrum cannabidiol with cannabigerol, or broad spectrum cannabidiol with cannabidiolic acid at 5 mg total cannabinoids/kg body weight/day. Animals were observed daily with detailed clinical examinations conducted weekly. Animals were monitored for an additional 2 weeks after dosing. Body weights, food consumption and clinical pathology evaluations were included in the study. Cannabinoids were well tolerated when healthy male and female beagles were dosed for 90 consecutive days. Annual post-market surveillance data for hemp-derived supplement products sold for use in dogs from 2010 to 2023 (partial year) shows that the rate per 1 million administrations sold is 2.10 for adverse events and 0.01 for serious adverse events. Based on the results of this study, other published studies, and data from extensive post-market surveillance, hemp-derived cannabinoids are well tolerated in healthy dogs at a dose of 5 mg/kg body weight/day.

Abstract Cannabinoids have been shown to induce anti‐tumor activity in a variety of carcinoma cells such as breast, prostate, and brain. The aim of the present study is to investigate the anti‐tumor activity of cannabinoids, CBD (cannbidiol), and CBG (cannabigerol) in ovarian carcinoma cells sensitive and resistant to chemotherapeutic drugs. Sensitive A2780 cells and resistant A2780/CP70 carcinoma cells and non‐carcinoma cells were exposed to varying concentrations of CBD, CBG, carboplatin or CB1 and CB2 receptor antagonists, AM251 and AM630, respectively, alone or in combination, at different exposure times and cytotoxicity was measured by MTT assay. The mechanism of action of CBD and CB in inducing cytotoxicity was investigated involving a variety of apoptotic and cell cycle assays. Treatment with CBD and CBG selectively, dose and time dependently reduced cell viability and induced apoptosis. The effect of CBD was stronger than CBG in all cell lines tested. Both CBD and CBG induced stronger cytotoxicity than afforded by carboplatin in resistant cells. The cytotoxicity induced by CBD was not CB1 or CB2 receptor dependent in both carcinoma cells, however, CBG‐induced cytotoxicity may involve CB1 receptor activity in cisplatin‐resistant carcinoma cells. A synergistic effect was observed when cannabinoids at sublethal doses were combined with carboplatin in both carcinoma cells. The apoptotic event may involve loss of mitochondrial membrane potential, Annexin V, caspase 3/7, ROS activities, and cell cycle arrest. Further studies are required to investigate whether these results are translatable in the clinic. Combination therapies with conventional cancer treatments using cannabinoids are suggested.

Availability and consumer use of hemp products is rapidly increasing, but little work has been done to assess aerosol emissions of hemp pre-rolls. The objective of this research was to characterize the aerosol of pre-rolled joints from hemp material enriched for production of cannabigerol (CBG) that were smoked on a test system mimicking human use patterns. Aerosol emissions were collected and analyzed using glass microfiber filters and charcoal cartridges. The aerosol was screened for nine phytocannabinoids and 19 terpenes. Three phytocannabinoids (CBG, cannabichromene (CBC), and delta-9-tetrahydrocannabinol (THC)) were detected and quantified at a mean (SD) concentration of 19.4 (4.7), 0.48 (0.01), and 0.40 (0.04) mg per pre-roll, respectively. Five terpenes ((–)-α-bisabolol, (–)-guaiol, β-caryophyllene, nerolidol, and α-humulene) were detected and quantified at an average concentration of 352.7 (112.0), 194.3 (66.4), 106.0 (50.4), 28.3 (9.3), and 27.7 (11.2) µg per pre-roll, respectively. Particle size distribution testing via aerodynamic particle sizer and inertial impactor showed that average size of emitted aerosols was 0.77 (0.0) and 0.54 (0.1) µm, respectively. This study describes methodology for characterization of cannabinoid and terpene dose in emitted aerosols and aerosolization efficiency from hemp pre-rolls. It also presents these data for one of the marketed products. [ABSTRACT FROM AUTHOR]

The determination of recent cannabis use is of forensic interest in the investigation of automotive crashes, workplace incidents and other mishaps. Because Δ9-tetrahydrocannabinol may persist in blood after psychoactive effects of intoxication resolve, particularly in regular users, short-lived minor cannabinoids such as cannabigerol have merited examination as adjunct indicators of recent cannabis inhalation. As part of an observational cohort study, whole blood cannabinoids including cannabigerol were measured in whole blood by liquid chromatography with tandem mass spectrometry at baseline, and 30 minutes after initiation of a 15-minute supervised interval of ad libitum cannabis smoking in occasional (1–2 days/week over the past 30 days) (n = 24) and daily cannabis smokers (n = 32). Per protocol, subjects self-reported abstention from inhaling cannabis (>8 h) or ingesting cannabis (>12 h) prior to baseline measurement. At baseline, none of the occasional users had detectable cannabigerol (limit of detection = 0.2 µg/L), whereas cannabigerol was detectable post-smoking in 7 of 24 (29%). Among daily cannabis users, 2 of 32 (6%) had detectable cannabigerol at baseline, increasing to 21 of 32 (66%) post-smoking. The odds ratio for recent cannabis smoking associated with a detectable cannabigerol was 27 (95% confidence interval: 6.6, 110.3). In this mixed cohort of occasional and daily cannabis users, receiver operator characteristic curve analysis indicated that whole blood cannabigerol concentration of ≥ 0.2 µg/L had 96% specificity, 50% sensitivity, and 73% accuracy for identifying a 15-minute interval of ad libitum cannabis smoking initiated 30 minutes earlier. Post smoking blood Δ9-tetrahydrocannabinol (median = 5.6 µg/L in occasional users, 21.3 µg/L in daily users) was significantly correlated with post-smoking cannabigerol (P < 0.0001). Whole blood cannabigerol may have forensic utility as a highly specific albeit insensitive biomarker of recent cannabis smoking. [ABSTRACT FROM AUTHOR]

Cannabigerol (CBG) is one of the compounds derived from Cannabis sativa L. that has drawn researchers' attention in recent years. In the process of biosynthesis, CBG acts as a precursor to various phytocannabinoids, including cannabidiol (CBD) and Δ9-tetrahydrocannabinol. After administration into the human body, however, it does not result in the formation of other cannabinoids due to the lack of necessary conversion pathways. Cannabigerol acts on serotonergic, a2 adrenergic receptors, peroxisome proliferator-activated receptors, and the cannabinoid receptor family. In addition, it presents an inhibitory effect on several anti-inflammatory mediators. Despite its weak interaction with CB1 and CB2 cannabinoid receptors, among phytocannabinoids it is the most potent ligand of the transient receptor vanilloid potential 1. When the endocannabinoid system becomes disrupted in various disease states, CBG, through its potential effects, can have an impact on maintaining homeostasis in the body. The range of its biological activity includes anti-inflammatory, antibacterial, antifungal, and neuromodulatory properties, as well as the regulation of redox balance. Applications for CBG have already been found in gastrointestinal, metabolic, and neurological disorders, as well as numerous inflammatory diseases. We are currently witnessing a widespread increase in the use of CBG in medicine due to its beneficial effects on health while lacking psychoactivity. Despite the growing interest, caution should be exercised in the use of CBG and CBD due to possible interactions with other medications. [ABSTRACT FROM AUTHOR]

Corticosteroid-binding globulin (CBG) delivers cortisol through three discrete mechanisms, pyrexia, acidosis, and neutrophil elastase-mediated cleavage, acting in concert to deliver immunomodulatory cortisol directly to inflammatory sites. Inhibition of CBG synthesis also increases free cortisol fraction, in part obviating the reduced cortisol metabolism seen in sepsis. CBG deficiency occurs in one third of patients admitted to intensive care units (ICUs) with septic shock and predicts a threefold higher risk of mortality. CBG –/– mice have increased mortality after induced acute systemic inflammation as do mice also rendered CBG deficient through KLF 15 –/– status. Restoration of CBG in KLF15 –/– deficient mice improved survival after acute systemic inflammation. CBG may have other roles at the intracellular level via interaction with cell membrane-binding sites and effects on transmembrane signaling. Corticosteroid-binding globulin (CBG) is a 50–60 kDa circulating glycoprotein with high affinity for cortisol. CBG is adapted for sepsis; its cortisol binding is reduced reversibly by pyrexia and acidaemia, and reduced irreversibly by neutrophil elastase (NE) cleavage, converting high cortisol-binding affinity CBG to a low affinity form. These characteristics allow for the targeted delivery of immunomodulatory cortisol to tissues at the time and body site where cortisol is required in sepsis and septic shock. In addition, high titer inflammatory cytokines in sepsis suppress CBG hepatic synthesis, increasing the serum free cortisol fraction. Recent clinical studies have highlighted the importance of CBG in septic shock, with CBG deficiency independently associated with mortality. [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 hours 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.

During solid tumor progression, the tumor microenvironment (TME) evolves into a highly immunosuppressive milieu. Key players in the immunosuppressive environment are regulatory myeloid cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), which are recruited and activated via tumor-secreted cytokines such as colony-stimulating factor 1 (CSF-1). Therefore, the depletion of tumor-secreted cytokines is a leading anticancer strategy. Here, we found that CSF-1 secretion by melanoma cells is decreased following treatment with Cannabis extracts. Cannabigerol (CBG) was identified as the bioactive cannabinoid responsible for the effects. Conditioned media from cells treated with pure CBG or the high-CBG extract reduced the expansion and macrophage transition of the monocytic-MDSC subpopulation. Treated MO-MDSCs also expressed lower levels of iNOS, leading to restored CD8+ T-cell activation. Tumor-bearing mice treated with CBG presented reduced tumor progression, lower TAM frequencies and reduced TAM/M1 ratio. A combination of CBG and αPD-L1 was more effective in reducing tumor progression, enhancing survival and increasing the infiltration of activated cytotoxic T-cells than each treatment separately. We show a novel mechanism for CBG in modulating the TME and enhancing immune checkpoint blockade therapy, underlining its promising therapeutic potential for the treatment of a variety of tumors with elevated CSF-1 expression. [ABSTRACT FROM AUTHOR]

Uma Anand,1 Christian Oldfield,1 Barbara Pacchetti,2 Praveen Anand,1 Mikael H Sodergren1,2 1Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, W12 ONN, UK; 2EMMAC Life Sciences Ltd, London, UKCorrespondence: Uma AnandFaculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 ONN, UKEmail u.anand@imperial.ac.ukBackground: The analgesic effects of Cannabis sativa are mediated by ∆9 tetrahydrocannabinol (THC), but the contributions of other bioactive complex components, including cannabigerol (CBG) and cannabidiol (CBD), are unclear. We describe the individual and combined effects of CBG, CBD and THC, on blocking capsaicin responses in dorsal root ganglion (DRG) neurons, in an in vitro model of nociceptor hypersensitivity.Materials and Methods: Adult rat DRG were dissected and enzyme digested to obtain a neuronal suspension in BSF2 medium containing 2% fetal calf serum, and the neurotrophic factors NGF and GDNF. After 48 h, cultured neurons were loaded with Fura-2 AM, to determine the effects of cannabinoids on capsaicin responses using calcium imaging. In control experiments, neurons were treated with vehicle, followed by 1 μM capsaicin. In cannabinoid treated cultures, CBG, CBD or THC were applied individually, or combined (1:1:1 ratio), followed by 1 μM capsaicin. Data from n = 6 experiments were analysed with Student’s t-test and Pearson’s correlation coefficient.Results: CBG, CBD and THC, applied individually, elicited dose-related calcium influx in a subset of DRG neurons, and a corresponding dose-related reduction of subsequent responses to capsaicin. Maximum inhibition of capsaicin responses was observed at 30 μM CBG, 100 μM CBD, and 100 μM THC individually, and with combined CBD+CBG+THC (1:1:1) at 90 μM. THC+CBD+CBG combined in a 1:1:1 proportion has the potential to enhance the potency of these compounds applied individually. There was a high correlation between cannabinoid-mediated calcium influx and reduction of capsaicin responses: CBG = − 0.88, THC = − 0.97, CBD = − 0.99 and combined CBG + THC + CBD = − 1.00.Conclusion: CBG, CBD and THC demonstrated potent dose-related inhibition of capsaicin responses in DRG neurons when applied individually in vitro, and enhanced when applied in combination, being most effective at 90 μM. Thus, efficacy and tolerability of THC could be improved in combination with CBG and CBD at optimal concentrations, which deserve further studies in vivo.Keywords: cannabinoid, CBG, CBD, THC, TRPV1, DRG neurons, pain

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]

Context: Hydrocortisone administration in septic shock remains controversial. Corticosteroid-binding globulin (CBG) transports cortisol to inflammatory sites and is depleted in septic shock. Objective: To determine whether severely deficient serum CBG < 200 nmol/L (reference range 269-641 nmol/L) independently predicts septic shock mortality. Methods: A prospective observational study in patients with septic shock. Patients were categorized into 2 groups: mean plasma CBG concentrations <200 nmol/L and ≥200 nmol/L (day 1/2), with additional categorization by nadir CBG. Primary outcome was intensive care unit (ICU) mortality. Secondary outcomes were 28- and 90-day mortality, norepinephrine requirements, renal replacement therapy, and clinician-instituted hydrocortisone. Results: 135 patients were included. Mortality rates in ICU were higher in the CBG < 200 nmol/L vs the CBG ≥ 200 nmol/L group: 32.4% vs 13.9% [odds ratio (OR) 2.97 (95% CI 1.19, 7.41); P = 0.02] with 28-day mortality OR 2.25 (95% CI 0.99, 5.11) and 90-day mortality OR 2.21 (95% CI 0.99, 4.91). Multivariate analysis revealed 4 factors independently associated with ICU mortality: CBG < 200 nmol/L (adjusted OR 3.23, 95% CI 1.06, 9.88), Acute Physiology and Chronic Health Evaluation II > 25 (adjusted OR 3.58, 95% CI 1.20, 10.68), Sequential Organ Failure Assessment (SOFA) liver score (adjusted OR 1.98, 95% CI 1.04, 3.72), and renal replacement therapy (adjusted OR 6.59, 95% CI 2.17, 20.01). Nadir CBG levels were associated with higher SOFA cardiovascular scores and norepinephrine total dose (μg; P < 0.01) and duration (days; P < 0.01). Plasma cortisol concentrations and hydrocortisone administration did not relate to ICU mortality. Conclusion: Septic shock patients with CBG < 200 nmol/L had higher norepinephrine requirements and 3.2-fold higher ICU mortality. CBG concentration was the only directly reversible independent mortality risk factor. [ABSTRACT FROM AUTHOR]

• Melanoma is responsible for the majority of deaths related to skin cancer. • The effects of LE-127/2, a new CBG derivative was studied on melanoma cells (WM35, A2058, WM3000). • LE-127/2 effectively inhibited cell growth and clonogenic cell survival of melanoma cells. • LE-127/2 showed very low cytotoxicity on non-malignant HaCaT cells compared to parent CBG. • Analysis of protein expression revealed the induction of autophagy and apoptosis by LE-127/2. Despite the targeted- and immunotherapies used in the past decade, survival rate among patients with metastatic melanoma remains low, therefore, melanoma is responsible for the majority of skin cancer-related deaths. The ongoing investigation of natural antitumor agents, the nonpsychoactive cannabinoid, cannabigerol (CBG) found in Cannabis sativa is emerging as a promising candidate. CBG offers a potential therapeutic role in the treatment of melanoma demonstrating cell growth inhibition in some tumors. Its low water solubility and bioavailability hinder the potential effectiveness. To address these challenges, a modified CBG, namely LE-127/2 was synthesized by Mannich-type reaction. The aim was to investigate the effect of this novel compound on cell proliferation as well as the mechanism of cell death with a particular focus on autophagy and apoptosis. Human cutan melanoma cell lines, WM35, A2058 and WM3000 were utilized for the present study. Cell proliferation of the cells after the treatment with LE-127/2, parent CBG or vemurafenib was assessed by Cell Titer Blue Assay. Cells were treated with a 1.25–80 µM of the above-mentioned compounds, and it was found that at 20 μM of all drugs showed a comparable effective inhibition of cell proliferation, however, vemurafenib and CBG proved to be more effective than LE-127/2. In addition, clonogenic cell survival assays were performed to examine the inhibitory effect of LE-127/2 on the colony formation ability of melanoma cell lines. Cells treated with 20 µM of LE-127/2 for 14 days showed about a 50% suppression of clonogenic cell survival. LE-127/2 exerted the most intensive inhibition on A2058 cell colonies. Furthermore, notably, LDH cytotoxicity assay performed on HaCaT cell line, proved LE-127/2 to be cytotoxic only at higher concentration, such as 80 μM, while the parent CBG was cytotoxic at concentration as low as 5 μM, suggesting that the new CBG derivative as a drug candidate may be applied in human pharmacotherapy without causing a substantial damage in intact epidermal cells. Analysis of protein expression revealed the impact of LE-127/2 on the expression of basic proteins (LC-3, Beclin-1 and p62) involved in the process of autophagy in the three different melanoma cell lines studied. Elevated expression of these proteins was detected as a result of LE-127/2 (20 µM) treatment. LE-127/2 also induced the expression of some proteins involved in apoptosis, and it is particularly noteworthy the increased level of cleaved PARP. Based on the results obtained, it can be concluded that LE-127/2 induced autophagy could lead to the inhibition of cell proliferation and death in melanoma cells. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Background Dental plaque is a global health problem affecting people of various age groups. Cannabinoids are gaining enormous research attention due to its beneficial properties for various applications. A preliminary observation on antimicrobial property of cannabinoids against dental plaque bacteria has been reported recently. As a follow-up research, here we report the in vitro evaluation of cannabinoids infused mouthwash products against total culturable (aerobic) bacterial content from dental plaque samples. Methods We tested two cannabinoid-infused mouthwash products containing cannabidiol (CBD) and cannabigerol (CBG) respectively (each mouthwash containing

Abstract Background Serum protein glycosylation is an area of investigation in inflammatory arthritic disorders such as rheumatoid arthritis (RA). Indeed, some studies highlighted abnormalities of protein glycosylation in RA. Considering the numerous types of enzymes, monosaccharides and glycosidic linkages, glycosylation is one of the most complex post translational modifications. By this work, we started with a preliminary screening of glycoproteins in serum from RA patients and controls. Methods In order to isolate glycoproteins from serum, lectin wheat germ agglutinin was used and quantitative differences between patients and controls were investigated by LC–MS/MS. Consequently, we focused our attention on two glycoproteins found in this explorative phase: corticosteroid-binding globulin (CBG) and lipopolysaccharide-binding protein (LBP). The subsequent validation with immunoassays was widened to a larger number of early RA (ERA) patients (n = 90) and well-matched healthy controls (n = 90). Results We observed a significant reduction of CBG and LBP glycosylation in ERA patients compared with healthy controls. Further, after 12 months of treatment, glycosylated CBG and LBP levels increased both to values comparable to those of controls. In addition, these changes were correlated with clinical parameters. Conclusions This study enables to observe that glycosylation changes of CBG and LBP are related to RA disease activity and its response to treatment.

Epidermal growth factor receptor (EGFR) is a member of the ErbB family of proteins and are involved in downstream signal transduction, plays prominent roles in cell growth regulation, proliferation, and the differentiation of many cell types. They are correlated with the stage and severity of cancer. Therefore, EGFRs are targeted proteins for the design of new drugs to treat cancers that overexpress these proteins. Currently, several bioactive natural extracts are being studied for therapeutic purposes. Cannabis has been reported in many studies to have beneficial medicinal effects, such as anti-inflammatory, analgesic, antibacterial, and anti-inflammatory effects, and antitumor activity. However, it is unclear whether cannabinoids reduce intracellular signaling by inhibiting tyrosine kinase phosphorylation. In this study, cannabinoids (CBD, CBG, and CBN) were simulated for binding to the EGFR-intracellular domain to evaluate the binding energy and binding mode based on molecular docking simulation. The results showed that the binding site was almost always located at the kinase active site. In addition, the compounds were tested for binding affinity and demonstrated their ability to inhibit kinase enzymes. Furthermore, the compounds potently inhibited cellular survival and apoptosis induction in either of the EGFR-overexpressing cell lines.

Pathogenic fungi are a major cause of postharvest loss of fresh produce. While chemical fungicides effectively control postharvest diseases their use raises concerns and alternatives are required. Natural compounds with antifungal properties and natural defense response elicitors are explored. Among those compounds, phytocannabinoids are secondary metabolites generated from Cannabis sativa that are of particular interest. Among the non-psychotropic cannabinoids are cannabidiol (CBD) and cannabigerol (CBG). The current study investigates the effect of CBD and CBG's effect on postharvest fungal pathogens and the fruit defense response. CBD and CBG inhibit the growth of major postharvest pathogens such as Botrytis cinerea, Penicillium expansum , and Colletotrichum gloeosporioides. Moreover, CBD and CBG significantly decreased gray mold development caused by B. cinerea on grapes. Studying their mode of action indicated that both CBD and CBG affected B. cinerea fungal cell wall composition and cell-wall-related remodeling genes, as well as cell membrane fluidity and permeability. CBD treatment causes hyperpolarization of the fungal mitochondria membrane, which results in increased intracellular ROS levels. Evaluation of the effect of CBD and CBG on the fruit defense response displayed a priming effect by up-regulating pathogenic related proteins and induced salicylic acid and flavonols production resulting in inhibition of decay development. Overall, the results of the current study reveal the direct and indirect ability of natural phytocannabinoids to control fungal decay development and reduce food loss. This novel eco-friendly postharvest treatment has the potential to replace chemically hazardous fungicides. ● Non-psychotropic cannabinoids inhibit fungal growth and fruit colonization. ● Cannabinoids change fungal cell wall composition and membrane integrity. ● Cannabinoids prime the fruit defense response. ● Non-psychotropic cannabinoids could be a novel eco-friendly postharvest treatment. [ABSTRACT FROM AUTHOR]

Previous preclinical studies have demonstrated that cannabidiol (CBD) and cannabigerol (CBG), two non-psychotomimetic phytocannabinoids from Cannabis sativa, induce neuroprotective effects on toxic and neurodegenerative processes. However, a comparative study of both compounds has not been reported so far, and the targets involved in this effect remain unknown. The ability of CBD and CBG to attenuate the neurotoxicity induced by two insults involving oxidative stress (hydrogen peroxide, H2O2) and mitochondrial dysfunction (rotenone) was evaluated in neural cell cultures. The involvement of CB-1 and CB-2 or 5-HT1A receptors was investigated. The neuroprotective effect of their respective acids forms, cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA), was also analyzed. MTT and immunocytochemistry assays were used to evaluate cell viability. No significant variation on cell viability was per se induced by the lower concentrations tested of CBD and CBG or CBDA and CBGA; however, high concentrations of CBD, CBDA, or CBGA were toxic since a 40–50% reduction of cell viability was observed. CBD and CBG showed neuroprotective effects against H2O2 or rotenone; however, both compounds were more effective in attenuating the rotenone-induced neurotoxicity. A high concentration of CBDA reduced the rotenone-induced neurotoxicity. WAY100635 (5-HT1A receptor antagonist) but not AM251 and AM630 (CB1 or CB2 receptor antagonists, respectively) significantly diminished the neuroprotective effect induced by CBG only against rotenone. Our results contribute to the understanding of the neuroprotective effect of CBD and CBG, showing differences with their acid forms, and also highlight the role of 5-HT1A receptors in the mechanisms of action of CBG. [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.

Objective: Systemic amyloidosis may affect many organs, and may cause endocrinologic problems which may result in adrenal insufficiency. However, assessment of adrenocortical reserve is challenging in amyloidosis patients with renal involvement. We aimed to evaluate adrenocortical reserve with various methods of cortisol measurement to determine any occult clinical condition. Methods: Patients with renal amyloidosis and healthy subjects were evaluated in this crosssectional study. Basal cortisol, corticosteroid-binding globulin (CBG), and albumin levels were measured. Serum free cortisol (cFC) level was calculated. Cortisol response tests performed after ACTH stimulation test (250 µg, intravenously) were evaluated, and free cortisol index (FCI) was calculated. Results: Twenty renal amyloidosis patients, and 25 healthy control subjects were included in the study. Patients and control subjects had similar median serum baseline cortisol levels [258 (126-423) vs 350 (314-391) nmol/L, p=0.169)] whereas patients' stimulated cortisol levels at the 60th minute were lower [624 (497-685) vs 743 (674-781) nmol/L, p=0.011)]. The 60th-minute total cortisol levels of 8 of the 20 (40%) amyloidosis patients were <500 nmol/L, but only three of these 8 patients had stimulated FCI <12 nmol/mg suggesting an adrenal insufficiency (15%). Conclusion: ACTH stimulation test and cortisol measurements should be considered in renal amyloidosis patients with severe proteinuria to avoid false positive results if only ACTH stimulation test is used. It will be appropriate to evaluate this group of patients together with estimated measurements as FCI. [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.

Background: Serum protein glycosylation is an area of investigation in inflammatory arthritic disorders such as rheumatoid arthritis (RA). Indeed, some studies highlighted abnormalities of protein glycosylation in RA. Considering the numerous types of enzymes, monosaccharides and glycosidic linkages, glycosylation is one of the most complex post translational modifications. By this work, we started with a preliminary screening of glycoproteins in serum from RA patients and controls.Methods: In order to isolate glycoproteins from serum, lectin wheat germ agglutinin was used and quantitative differences between patients and controls were investigated by LC-MS/MS. Consequently, we focused our attention on two glycoproteins found in this explorative phase: corticosteroid-binding globulin (CBG) and lipopolysaccharide-binding protein (LBP). The subsequent validation with immunoassays was widened to a larger number of early RA (ERA) patients (n = 90) and well-matched healthy controls (n = 90).Results: We observed a significant reduction of CBG and LBP glycosylation in ERA patients compared with healthy controls. Further, after 12 months of treatment, glycosylated CBG and LBP levels increased both to values comparable to those of controls. In addition, these changes were correlated with clinical parameters.Conclusions: This study enables to observe that glycosylation changes of CBG and LBP are related to RA disease activity and its response to treatment. [ABSTRACT FROM AUTHOR]

Cannabis is a plant with more than 500 different phytochemicals. The most studied components are cannabinoids especially CBD and THC, but also researches on the cannabinoids CBC and CBG are becoming more common. Cannabinoids have two different biosynthetic pathways; polyketide pathway and plastidal 2-C-methyl-Derythritol- 4-phospate pathway which both lead to CBG-A formation, a precursor for the main cannabinoids. In 1987, chemotype IV with high content of CBG and low content of other cannabinoids was first time mentioned. CBG plants have B0B0 genotype. Allele B0 is in combination with BD allele completely recessive and therefore hard to detect with current molecular technics and also hard to differentiate chemotype IV from chemotype III (BDBD genotip). CBG can bind with different receptors in body and therefore have positive effects on human and animal health. CBG can have mild antifungal properties, antidepresive and antioxidant effects. It has anticancer properties on basic animal models, beneficial effects on murine colitis in mice, positive effects on inflammatory bowel disease and has antibacterial properties against MRSA. CBG is appetite stimulator and has inhibitory effects on aldose reductase activity which can cause diabetes. According to the known facts about CBG there is still a lot of potential for further research in this field. [ABSTRACT FROM AUTHOR]

Through the potency monitoring program at the University of Mississippi supported by National Institute on Drug Abuse (NIDA), a total of 18108 samples of cannabis preparations have been analyzed over the last decade, using a validated GC/FID method. The samples are classified as sinsemilla, marijuana, ditchweed, hashish, and hash oil (now referred to as cannabis concentrate). The number of samples received over the last 5 years has decreased dramatically due to the legalization of marijuana either for medical or for recreational purposes in many US states. The results showed that the mean Δ9-THC concentration has increased dramatically over the last 10 years, from 8.9% in 2008 to 17.1% in 2017. The mean Δ9-THC:CBD ratio also rose substantially from 23 in 2008 to 104 in 2017. There was also marked increase in the proportion of hash oil samples (concentrates) seized (0.5-4.7%) and their mean Δ9-THC concentration (6.7-55.7%) from 2008 to 2017. Other potency monitoring programs are also present in several European countries such as The Netherlands, United Kingdom, France, and Italy. These programs have also documented increases in Δ9-THC concentrations and Δ9-THC:CBD ratios in cannabis. These trends in the last decade suggest that cannabis is becoming an increasingly harmful product in the USA and Europe. [ABSTRACT FROM AUTHOR]

Summary: Context: Corticosteroid‐binding globulin (CBG) and albumin transport circulating cortisol. Cleavage of high‐affinity CBG (haCBG) by neutrophil elastase at inflammatory sites causes cortisol release into tissues, facilitating immunomodulatory effects. Objective: To determine whether depletion of haCBG is related to mortality in septic shock. Design: A single‐center prospective observational cohort study of patients recruited with critical illness or septic shock, using serum samples collected at 0, 8, 24, 48 and 72 hours. Serum total and haCBG, and total and free cortisol were assayed directly. Glucocorticoid treatment was an exclusion criterion. Mortality was assessed at 28 days from Intensive Care Unit admission. Results: Thirty septic shock (SS) and 42 nonseptic critical illness (CI) patients provided 195 serum samples. SS/CI patients had lower total CBG, haCBG and low‐affinity CBG (laCBG) than controls. Total CBG and haCBG were significantly lower in septic shock patients who died than in those that survived (P < 0.009, P = 0.021, respectively). Total and free cortisol were higher in septic than nonseptic individuals. Free/total cortisol fractions were higher in those with low haCBG as observed in septic shock. However, cortisol levels were not associated with mortality. Albumin levels fell in sepsis but were not related to mortality. Conclusions: Low circulating haCBG concentrations are associated with mortality in septic shock. These results are consistent with an important physiological role for haCBG in cortisol tissue delivery in septic shock. [ABSTRACT FROM AUTHOR]

The article focuses on the comparative analysis of tactics of the rational complete and incomplete revascularizations in patients with ST elevation myocardial infarction and angina, underwent multivessel stenting and coronary bypass grafting.Patients with diffuse atherosclerotic lesion of coronary arteries are one of the most strenuous kinds of patients. The demand for revascularization of high in this group and, by the data of several authors, is up to 70% among all surgeries. This origins from the changes in demographics (population ageing) as the manifest of ischemic disease in younger age that further presents with the worse morphological substrate. The problem of optimal tactics choice (coronary bypass, endovascular revascularization, conservative strategy) of diffuse coronary atherosclerosis is still of the main topics in discussion and controversy in science.

In the search for biological basis of robustness, this study aimed (i) at the determination of the heritability of the cortisol response to ACTH in juvenile pigs, using restricted maximum likelihood methodology applied to a multiple trait animal model, and (ii) at the study of the relationships between basal and stimulated cortisol levels with corticosteroid-binding globulin (CBG), IGF-I and haptoglobin, all important players in glucose metabolism and production traits. At 6 weeks of age, 298 intact male and female piglets from 30 litters (30 dams and 30 boars) were injected with 250 µg ACTH(1–24) (Synacthen). Blood was taken before ACTH injection to measure basal levels of cortisol, glucose, CBG, IGF-I and haptoglobin, and 60 min later to measure stimulated cortisol levels and glucose. Cortisol increased 2.8-fold after ACTH injection, with a high correlation between basal and stimulated levels (phenotypic correlation, rp=0.539; genetic correlation, rg=0.938). Post-ACTH cortisol levels were highly heritable (h2=0.684) and could therefore be used for genetic selection of animals with a more reactive hypothalamic–pituitary–adrenocortical axis. CBG binding capacity correlated with cortisol levels measured in basal conditions in males only. No correlation was found between CBG binding capacity and post-ACTH cortisol levels. Basal IGF-I concentration was positively correlated with BW at birth and weaning, and showed a high correlation with CBG binding capacity with a strong sexual dimorphism, the correlation being much higher in males than in females. Basal haptoglobin concentrations were negatively correlated with CBG binding capacity and IGF-I concentrations. Complex relationships were also found between circulating glucose levels and these different variables that have been shown to be related to glucose resistance in humans. These data are therefore valuable for the genetic selection of animals to explore the consequences on production and robustness traits, but also point at pigs as a relevant model to explore the underlying mechanisms of the metabolic syndrome including the contribution of genetic factors.

Glucocorticoid hormones play a pivotal role in the response to stressful challenges. The surge in glucocorticoid hormone secretion after stress needs to be tightly controlled with characteristics like peak height, curvature and duration depending on the nature and severity of the challenge. This is important as chronic hyper- or hypo-responses are detrimental to health due to increasing the risk for developing a stress-related mental disorder. Proper glucocorticoid responses to stress are critical for adaptation. Therefore, the tight control of baseline and stress-evoked glucocorticoid secretion are important constituents of an organism's resilience. Here, we address a number of mechanisms that illustrate the multitude and complexity of measures safeguarding the control of glucocorticoid function. These mechanisms include the control of mineralocorticoid (MR) and glucocorticoid receptor (GR) occupancy and concentration, the dynamic control of free glucocorticoid hormone availability by corticosteroid-binding globulin (CBG), and the control exerted by glucocorticoids at the signaling, epigenetic and genomic level on gene transcriptional responses to stress. We review the beneficial effects of regular exercise on HPA axis and sleep physiology, and cognitive and anxiety-related behavior. Furthermore, we describe that, possibly through changes in the GABAergic system, exercise reduces the impact of stress on a signaling pathway specifically in the dentate gyrus that is strongly implicated in the behavioral response to that stressor. These observations underline the impact of life style on stress resilience. Finally, we address how single nucleotide polymorphisms (SNPs) affecting glucocorticoid action can compromise stress resilience, which becomes most apparent under conditions of childhood abuse.

Industrial hemp cultivation in Europe is dual-purpose, with stalks providing fibers and hurds, and seeds being used for food, feed and pharmaceutical applications. Economic sustainability of hemp cultivation should encompass the possibility of recovering non-narcotic secondary metabolites from hemp by-products (leaves, leaflets and bracts) originating from seed harvest and seed cleaning procedures. Surprisingly, no information is currently available on the contents of high added value bioactive compounds (CBD, CBG, cannflavin A, Δ 9 -THC) in industrial hemp inflorescence and threshing residues. This observation provided a rationale for investigating the issue on three monoecious varieties grown in Northern Italy. The concentration of target compounds was monitored from full-flowering until plant senescence by LC–MS/MS analysis of methanolic extracts of the plant biomass. The anti-inflammatory prenylated flavonoid cannflavin A was present in all varieties at levels mainly affected by genotype and air temperature. Conversely, the concentration of CBD, currently the clinically most promising non-narcotic cannabinoid, correlated to the overall extent and distribution of precipitation during growing cycle. Our findings suggest that postponing harvest after seed maturity increases the CBD contents and increase the CBD/Δ 9 -THC ratio in harvest threshing. [ABSTRACT FROM AUTHOR]

Aim. To analyze structural chareacteristics and electroencephalographic (EEG) pattern of post-operation cognitive dysfunction (POCD) in patients after direct myocardial revascularization under artificial circulation (AI). Material and methods. Totally 114 male-patients included, underwent scheduled coronary bypass grafting (CBG) under the AI, with average age 55,9±5,3 y. In 3-5 days before operation and on 7-10 day after all patients underwent neurophysiological testing; of those 65 patients also underwent EEG. Results. The CBG operation with AI leads in 79% of cases to the early POCD. Cognitive impairment usually becomes prominent in the domains of neurodynamics and memory. It is shown that the early POCD is followed by EEG-signs of cortical dysfunction (increase of low-frequency theta-rhythm magnitude).Conclusion. According to the results of the study, in post-operative CBG with AI period the structure of POCD consists of injury of neurodynamics and memory, which might be a cause of decreased life quality of patients and efficacy of surgery itself.

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.

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.

The objective of this research was to study suitability of compressed bio-methane gas (CBG) to use in vehicles by considering it’s Wobbe Index (WI). Wobbe index can be used to increase burner efficiency. In this experiment, the average heating value of CBG was 32.43 MJ/Nm 3 and specific gravity of CBG at 0 °C 1-atmosphere pressure was 0.67 kg/m 3 . Therefore, the Wobbe index was 39.62 MJ/Nm 3 , It was classified in family 2 subordinate type with Wobbe index (2L) of 39 - 45 MJ/Nm 3 . The natural gas quality for vehicle standards by the Department of Energy Business, Ministry of Energy, Thailand required heating value is 37- 42 MJ/Nm 3 . The Wobbe index result show at that the CBG is suitable to use for the shuttle bus in Khon Kaen University (KKU), Thailand. [ABSTRACT FROM AUTHOR]

Selective serotonin reuptake inhibitor medications (SSRIs) are the first lines of treatment for maternal affective disorders, and are prescribed to up to 10% of pregnant women. Concern has been raised about how perinatal exposure to these medications affect offspring neurobehavioral outcomes, particularly those related to social interactions, as recent research has reported conflicting results related to autism spectrum disorder (ASD) risk in children prenatally exposed to SSRIs. Therefore, the aim of this work was to investigate the effects of perinatal exposure to the SSRI fluoxetine on social play behaviors and the hypothalamic pituitary adrenal system, using a model of pre-gestational maternal stress. We also investigated synaptic proteins in the CA2, CA3, and dentate gyrus of the hippocampus, as well as number of immature neurons in the granule cell layer, as both measures of plasticity in the hippocampus have been linked to social behaviors. In pre-adolescent male and female Sprague-Dawley rat offspring, main findings show that perinatal fluoxetine prevents the negative effect of maternal stress on sibling play behavior. However, perinatal fluoxetine increased social aggressive play with a novel conspecific in both sexes and decreased time grooming a novel conspecific in males only. Perinatal fluoxetine also increased serum corticosteroid binding globulin levels, 5-HT levels in the hippocampus, and pre-synaptic density assessed via synaptophysin in the dentate gyrus. Social interaction was significantly correlated with changes in plasticity in the CA2 region of the hippocampus. Pre-gestational maternal stress exposure resulted in significantly decreased rates of hippocampal neurogenesis and synaptophysin density in the dentate gyrus of pre-adolescent males, but not females. Together, these results further characterize the role of perinatal SSRIs, maternal stress prior to conception, and sex/gender on developing social behaviors and related plasticity in the hippocampus of pre-adolescent offspring. [ABSTRACT FROM AUTHOR]

Corticosteroid-binding globulin (CBG) binds most of the cortisol in circulation and is a non-functional member of the family of serine protease inhibitors (serpins) with an exposed elastase sensitive reactive centre loop (RCL). The RCL can be cleaved by human neutrophil elastase, released from activated neutrophils, and can also be cleaved at nearby site(s) by elastase released by Pseudomonas aeruginosa, and at two further sites, also within the RCL, by bovine chymotrypsin. Cleavage of the RCL results in a conformational change accompanied by a marked decrease in affinity for cortisol and hence its release at the site of proteolysis. These cleavages are irreversible and the similar half-lives of cleaved and intact CBG could mean that there may be some advantage in slowing the rate of CBG cleavage in acute inflammation thereby increasing the proportion of intact CBG in circulation. Here we show, for the first time, that pre-incubation of tethered human CBG with two monoclonal antibodies to the RCL of CBG protects against cleavage by all three enzymes. Furthermore, in plasma, pre-incubation with both RCL monoclonal antibodies delays neutrophil elastase cleavage of the RCL and one of these RCL monoclonal antibodies also delays bovine chymotrypsin cleavage of the RCL. These findings may provide a basis and rationale for the concept of the use of RCL antibodies as therapeutic agents to effectively increase the proportion of intact CBG in circulation which may be of benefit in acute inflammation. [ABSTRACT FROM AUTHOR]

Maize (Zea mays) has burgeoning demand as energy crop for biogas production and is considered to have the highest yield potential of field crops. In Bangladesh, about 27.5 lakh tons of maize is grown in 2015-2016 to meet the food demand and the needs of poultry feed sector. The maize stover is left over and has little economic value besides lying in the fields or some being used as fuel. Rotting of plants gives off methane which is a contributor to greenhouse gas. But if it is utilized in a process, it can be converted into useful feedstock to produce biogas and the solid content of the sludge can also be used as fertilizer. This research was aimed at compressed biogas (CBG) production from maize plant by anaerobic digestion process. Several experiments were performed in variable condition where anaerobic digestion of maize stover was observed with cow dung and without cow dung. Methane production was observed for 60~100 days in batch digester at 33°C. Startup and retention time of anaerobic digestion was longer and biogas yield was lower in normal condition. To increase specific biogas yield, two types of pretreatment processes were performed. One treatment was done with dirty water and the other with sodium hydroxide. These effects are briefly discussed with characteristic graphs. Maximum yield of biogas and approximate CBG was found 0.271m3/kg and 0.1195kg with cow dung. Methane content of produced biogas was (55~70) % which can be converted to CBG consisting =97% methane. It would be a successful attempt if maize waste is implemented for producing CBG as an alternative source of CNG in Bangladesh as a renewable source of energy to mitigate the emerging energy crisis. [ABSTRACT FROM AUTHOR]

The adaptation of the serpin framework and its mechanism to perform diverse functions is epitomised in the hormone carriers of the blood. Thyroxine and the corticosteroids are transported bound in a 1:1 ratio on almost identical sites in the two homologous binding-globulins, TBG and CBG. Recent structural findings show an equilibrated, rather than on-and-off, release of the hormones from the carriers, reflecting small reversible movements of the hinge region of the reactive loop that modify the conformational flexibility of the underlying hormone-binding site. Consequently, contrary to previous concepts, the binding affinities of TBG and CBG are not fixed but can be allosterically modified to allow differential hormone delivery. Notably, the two carriers function like protein thermocouples with a surge in hormone release as body temperatures rise in fevers, and conversely a large diminution in free hormone levels at hibernation temperatures. By comparison angiotensinogen, the source of the angiotensin peptides that control blood pressure, does not appear to utilise the serpin mechanism. It has instead evolved a 63 residue terminal extension containing the buried angiotensin cleavage site, which on interaction moves into the active cleft of the renin. The conformational shift involved is critically linked by a labile disulphide bridge. The observation of changes in the redox status of this S–S bridge, in the hypertensive complication of pregnancy, pre-eclampsia, has opened an unexpected level of regulation at what is the initial stage in the control of blood pressure. [ABSTRACT FROM AUTHOR]