Synthesis, structural, molecular docking and spectroscopic studies of (E)-N'-(4-methoxybenzylidene)-5-methyl-1H-pyrazole-3-carbohydrazide

In early childhood, individuals with Prader-Willi syndrome (PWS) experience excess weight gain and severe hyperphagia with food compulsivity, which often leads to early onset morbid obesity. Effective treatments for appetite suppression and weight control are currently unavailable for PWS. Our aim to further understand the pathogenesis of PWS led us to carry out a comprehensive search of the current and emerging therapies for managing hyperphagia and extreme weight gain in PWS. A literature search was performed using PubMed and the following keywords: "PWS" AND "therapy" OR "[drug name]"; reference lists, pharmaceutical websites, and the ClinicalTrials.gov registry were also reviewed. Articles presenting data from current standard treatments in PWS and also clinical trials of pharmacological agents in the pipeline were selected. Current standard treatments include dietary restriction/modifications, exercise, and growth hormone replacement, which appear to have limited efficacy for appetite and weight control in patients with PWS. The long-term safety and effectiveness of bariatric surgery in PWS remains unknown. However, many promising pharmacotherapies are in development and, if approved, will bring much needed choices into the PWS pharmacological armamentarium. With the progress that is currently being made in our understanding of PWS, an effective treatment may not be far off.

Current and emerging therapies for managing hyperphagia and obesity in Prader-Willi syndrome: A narrative review.

Cannabidiol (CBD), a phytocannabinoid compound, presents antidepressant and anxiolytic-like effects in the type-1 diabetes mellitus(DM1) animal model. Although the underlying mechanism remains unknown, the type-1A serotonin receptor (5-HT1A) and cannabinoids type-1 (CB1) and type-2 (CB2) receptors seem to play a central role in mediating the beneficial effects on emotional responses. We aimed to study the involvement of these receptors on an antidepressant- and anxiolytic-like effects of CBD and on some parameters of the diabetic condition itself. After 2 weeks of the DM1 induction in male Wistar rats by streptozotocin (60 mg/kg; i.p.), animals were treated continuously for 2-weeks with the 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg, i.p.), CB1 antagonist AM251 (1 mg/kg i.p.) or CB2 antagonist AM630 (1 mg/kg i.p.) before the injection of CBD (30 mg/kg, i.p.) or vehicle (VEH, i.p.) and then, they were submitted to the elevated plus-maze and forced swimming tests. Our findings show the continuous treatment with CBD improved all parameters evaluated in these diabetic animals. The previous treatment with the antagonists − 5-HT1A, CB1, or CB2 - blocked the CBD-induced antidepressant-like effect whereas only the blockade of 5-HT1A or CB1 receptors was able to inhibit the CBD-induced anxiolytic-like effect. Regarding glycemic control, only the blockade of CB2 was able to inhibit the beneficial effect of CBD in reducing the glycemia of diabetic animals. These findings indicated a therapeutic potential for CBD in the treatment of depression/anxiety associated with diabetes pointing out a complex intrinsic mechanism in which 5-HT1A, CB1, and/or CB2 receptors are differently recruited.

Cannabidiol induces antidepressant and anxiolytic‐like effects in experimental type-1 diabetic animals by multiple sites of action

Hydrogen peroxide appears to be the key reactive oxygen species involved in redox signalling, but comparisons of the low concentrations of hydrogen peroxide that are calculated to exist within cells with those previously shown to activate common signalling events in vitro indicate that direct oxidation of key thiol groups on "redox-sensitive" signalling proteins is unlikely to occur. A number of potential mechanisms have been proposed to explain how cells overcome this block to hydrogen peroxide-stimulated redox signalling and these will be discussed in the context of the redox-stimulation of specific adaptations of skeletal muscle to contractile activity and exercise. It is argued that current data implicate a role for currently unidentified effector molecules (likely to be highly reactive peroxidases) in propagation of the redox signal from sites of hydrogen peroxide generation to common adaptive signalling pathways.

Hydrogen peroxide as a signal for skeletal muscle adaptations to exercise: What do concentrations tell us about potential mechanisms?

There is currently a steep rise in the global prevalence of obesity. Pharmaceutical therapy is a valuable component of conservative obesity therapy. Herein, medications currently in the phase of preclinical or clinical testing are reviewed, along with an overview of the mechanisms that regulate energy intake and expenditure. In addition, the current and potential future directions of obesity drug therapy are discussed. Although the current arsenal of obesity pharmacotherapy is limited, a considerable number of agents that exert their actions through a variety of pharmacodynamic targets and mechanisms are in the pipeline. This expansion shapes a potential near future of obesity conservative management, characterized by tailored combined therapeutic regimens, targeting not only weight loss but also improved overall health outcomes. The progress regarding the elucidation of the mechanisms which regulate the bodily energy equilibrium has led to medications which mimic hormonal adaptations that follow bariatric surgery, in the quest for a “Medical bypass.” These, combined with agents which could increase energy expenditure, point to a brilliant future in the conservative treatment of obesity.

The Fight Against Obesity Escalates: New Drugs on the Horizon and Metabolic Implications.

Endogenous cannabinoids (ECs) are lipid-signaling molecules that specifically bind to cannabinoid receptor types 1 and 2 (CB1R and CB2R) and are highly expressed in central and many peripheral tissues under pathological conditions. Activation of hepatic CB1R is associated with obesity, insulin resistance, and impaired metabolic function, owing to increased energy intake and storage, impaired glucose and lipid metabolism, and enhanced oxidative stress and inflammatory responses. Additionally, blocking peripheral CB1R improves insulin sensitivity and glucose metabolism and also reduces hepatic steatosis and body weight in obese mice. Thus, targeting EC receptors, especially CB1R, may provide a potential therapeutic strategy against obesity and insulin resistance. There are many CB1R antagonists, including inverse agonists and natural compounds that target CB1R and can reduce body weight, adiposity, and hepatic steatosis, and those that improve insulin sensitivity and reverse leptin resistance. Recently, the use of CB1R antagonists was suspended due to adverse central effects, and this caused a major setback in the development of CB1R antagonists. Recent studies, however, have focused on development of antagonists lacking adverse effects. In this review, we detail the important role of CB1R in hepatic insulin resistance and the possible underlying mechanisms, and the therapeutic potential of CB1R targeting is also discussed.

https://www.mdpi.com/1422-0067/20/9/2109/pdf

Role of Cannabinoid Receptor Type 1 in Insulin Resistance and Its Biological Implications

본 연구는 죽음불안이 주관적 안녕감에 미치는 영향에서 삶의 의미의 조절효과와 사회적 지지의 삼원조절효과를 알아봄으로써 어떠한 조건에서 조절효과가 나타나는지를 확인하고자 하였다. 이를 위해 20대 이상의 성인 총 227명을 대상으로 죽음불안, 삶의 의미, 사회적지지 그리고 주관적 안녕감 척도를 사용하여 설문을 실시하였다. 설문을 통해 수합된 자료는 SPSS 22.0으로 분석하였으며 조절효과는 PROCESS Macro 3.0의 Model 1을 사용하여 분석하였다. 그 결과 죽음불안이 주관적 안녕감에 영향을 미칠 때 삶의 의미는 유의미한 조절효과를 갖는 것으로 나타났다. 그러나 이러한 결과는 사회적 지지가 높은 집단에서는 동일하게 유의미하였으나, 사회적 지지가 낮은 집단에서는 삶의 의미가 높더라도 죽음에 대한 높은 불안이 주관적 안녕감을 낮추지 못하는 것으로 나타났다. 따라서 본 연구는 높은 죽음불안으로 인해 주관적 안녕감이 낮아지는 것을 완화시키기 위해서는 삶의 의미 뿐 아니라 사회적 지지에 대한 지각을 높이는 노력이 요구된다는 점을 젊을 밝혀냈다는 데 의의가 있다. 이러한 연구결과는 죽음불안에 대한 개입시 삶의 의미와 사회적 지지가 포함되어야 함을 시사한다. 

Jooyeon Shin

Papers

Role of Cannabinoid Receptor Type 1 in Insulin Resistance and Its Biological Implications

The Relationship between Death Anxiety and Subjective Well-being: The Three-way Moderating Effect of the Life Meaning and Social Support