Notes

Things of sophistication: transitional phase of class III and also Intravenous lanthipeptides.
The sleep-wake cycle is a complex process that includes wake (W), non-rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep. Each phase is regulated by specialized brain structures that, by means of different neurotransmitters, maintain the constant expression of the sleep-wake cycle. Molecules like orexin, serotonin, noradrenaline, histamine, for waking; GABA, adenosine, prostaglandins, for NREM sleep and acetylcholine and glutamate for REM sleep, among other molecules are responsible for the expression and maintenance of each phase. When the endocannabinoid system was being described for the first time, almost three decades ago, oleamide's sleep promoting properties were highlighted. Nowadays, enough evidence has been cumulated to support the endocannabinoid system role in the sleep-wake cycle regulation. The endocannabinoids oleamide anandamide, and 2-arachidonylglycerol promote NREM and/or REM sleep via the CB1R, thereby making this system a target to treat sleep disorders, such as insomnia.Sleep and wakefulness are complex, tightly regulated behaviors that occur in virtually all animals. With recent exciting developments in neuroscience methodologies such as optogenetics, chemogenetics, and cell-specific calcium imaging technology, researchers can advance our understanding of how discrete neuronal groups precisely modulate states of sleep and wakefulness. In this chapter, we provide an overview of key neurotransmitter systems, neurons, and circuits that regulate states of sleep and wakefulness. We also describe long-standing models for the regulation of sleep/wake and non-rapid eye movement/rapid eye movement cycling. We contrast previous knowledge derived from classic approaches such as brain stimulation, lesions, cFos expression, and single-unit recordings, with emerging data using the newest technologies. Our understanding of neural circuits underlying the regulation of sleep and wakefulness is rapidly evolving, and this knowledge is critical for our field to elucidate the enigmatic function(s) of sleep.The potential use of cannabinoids for therapeutic purposes is at the forefront of cannabinoid research which aims to develop innovative strategies to prevent, manage and treat a broad spectrum of human diseases. This chapter briefly reviews the pivotal role of the endocannabinoid system in modulating the central nervous system and its roles on neurodegenerative diseases and brain disorders. Ligand-induced modulation of cannabinoid 1 and 2 receptors to modulate immune response, decrease neurodegeneration and pain are aspects that are also discussed.Over the past few years, considerable attention has focused on cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), the two major constituents of Cannabis sativa, mainly due to the promising potential medical uses they have shown. RKI-1447 ic50 However, more information on the fate of these cannabinoids in human subjects is still needed and there is limited research on the pharmacokinetic drug-drug interactions that can occur in the clinical setting and their prevalence. As the use of cannabinoids is substantially increasing for many indications and they are not the first-line therapy in any treatment, health care professionals must be aware of drug-drug interactions during their use as serious adverse events can happen related with toxic or ineffective outcomes. The present chapter overview summarizes our current knowledge on the pharmacokinetics and metabolic fate of CBD and THC in humans and discusses relevant drug-drug interactions, giving a plausible explanation to facilitate further research in the area.The non-psychoactive component of Cannabis Sativa, cannabidiol (CBD), has centered the attention of a large body of research in the last years. Recent clinical trials have led to the FDA approval of CBD for the treatment of children with drug-resistant epilepsy. Even though it is not yet in clinical phases, its use in sleep-wake pathological alterations has been widely demonstrated.Despite the outstanding current knowledge on CBD therapeutic effects in numerous in vitro and in vivo disease models, diverse questions still arise from its molecular pharmacology. CBD has been shown to modulate a wide variety of targets including the cannabinoid receptors, orphan GPCRs such as GPR55 and GPR18, serotonin, adenosine, and opioid receptors as well as ligand-gated ion channels among others. Its pharmacology is rather puzzling and needs to be further explored in the disease context.Also, the metabolism and interactions of this phytocannabinoid with other commercialized drugs need to be further considered to elucidate its clinical potential for the treatment of specific pathologies.Besides CBD, natural and synthetic derivatives of this chemotype have also been reported exhibiting diverse functional profiles and providing a deeper understanding of the potential of this scaffold.In this chapter, we analyze the knowledge gained so far on CBD and its analogs specially focusing on its molecular targets and metabolic implications. Phytogenic and synthetic CBD derivatives may provide novel approaches to improve the therapeutic prospects offered by this promising chemotype.Cannabis sativa L. is a psychoactive plant that contains more than 500 chemical components. Even though the consumption (in the form of marijuana, hashish, or hashish oil) for recreational purposes, is the most popular way of using the plant, the knowledge of its components has also led to classify Cannabis sativa L. is a plant with medicinal or therapeutical use. Several comprehensive reviews have already been published focused on the chemical composition of Cannabis sativa. In this chapter, we will summarize relevant information about those components, which may help to understand its biological actions that will be described in the following chapters.
Many patients with hand osteoarthritis (HOA) experience reduced health-related quality of life. This study sought to better understand the disease and treatment experience of individuals with HOA, explore any differences in experiences between erosive and non-erosive HOA sub-types, and evaluate content validity of the Michigan Hand Outcomes Questionnaire (MHQ) in HOA.

Thirty subjects from the United States (n = 15 erosive HOA; n = 15 non-erosive HOA) participated in semi-structured interviews concept elicitation explored symptoms/impacts important to patients; cognitive interviews assessed understanding and relevance of the MHQ. A sub-sample participated in real-time data capture (RTDC) activities via a smartphone/tablet app over 7 days. Verbatim transcripts were coded using Atlas.ti software and thematically analyzed. Concept saturation and MHQ content validity were evaluated.

Most participants reported experiencing pain, swelling and stiffness, symptoms that most commonly had a direct impact on physicur findings suggest that disease experience is similar for patients with erosive and non-erosive HOA. Evaluation of stiffness and swelling items in conjunction with the MHQ may enhance relevance and improve measurement precision to assess important domains of HQRoL in an HOA population.
This study characterizes key symptoms of HOA which are burdensome for patients and not well controlled by current therapies, highlighting an unmet treatment need. Although the study is limited by a small sample size that may not be representative of the broader erosive and non-erosive HOA population, concept saturation was achieved, and our findings suggest that disease experience is similar for patients with erosive and non-erosive HOA. Evaluation of stiffness and swelling items in conjunction with the MHQ may enhance relevance and improve measurement precision to assess important domains of HQRoL in an HOA population.Chronic non-infectious diseases are important to research as they are the main causes of death in Brazil and worldwide. One very important chronic non-infectious disease is cardiovascular disease, whose risk factors (diabetes, dyslipidemia, and renal failure) can be detected through assessments of serum biochemical components. The objective of this study was to evaluate the analytical performance of Raman spectroscopy for analysis of lipid profile (total cholesterol, triglycerides, and HDL cholesterol), non-protein nitrogenous compounds (urea and creatinine), and glucose in 242 human serum samples. Models to discriminate and quantify the samples were developed using the predicted concentration by quantitative regression model based on partial least squares (PLS). The analytical error for the "leave-one-out" cross-validation based on the predicted PLS concentration was 10.5 mg/dL for total cholesterol, 21.4 mg/dL for triglyceride, 13.0 mg/dL for HDL cholesterol, 4.9 mg/dL for urea, 0.21 mg/dL for creatinine, and 15.4 mg/dL for glucose. The Kappa coefficient indicate very good agreement for cholesterol (0.83), good for triglyceride (0.77), urea (0.70) and creatinine (0.66), and fair for HDL cholesterol (0.38) and glucose (0.30). The results of the analytical performance demonstrated that Raman spectroscopy can be considered an important methodology to screen the population, especially for serum triglycerides and cholesterol.Cancer metastasis and recurrence are potentially lethal. A small number of cancer cell groups called cancer stem cells (CSCs) have both stem cell capacity and cancer-forming ability and are reported to play important roles in cancer metastasis and recurrence. These CSCs are considered to be radiation-resistant (RR). Therefore, understanding the biological effects of radiation on squamous cell carcinoma (SCC) cell lines in vitro and in vivo might be worthwhile to circumvent radiation resistance. Currently, there are no reports on the establishment of RR-SCC cells in serum-free defined culture, which mimics biological mechanisms and prevents instability of using serum in the culture medium. We isolated radiation-resistant strains, designated A431-LDR and A431-HDR, from A431 cells derived from vulval SCC and irradiated them with a total dose of 60 Gy at a low-dose rate (2.2 Gy/d) (RM1000) and a high-dose rate (5 Gy/5.75min) in serum-free defined culture. These cells exhibited high sphere-forming and migration ability in vitro and high tumor-forming ability in nude mice xenografts. Overexpression of KRT13 in A431-RR cells might play a role in its radiation-resistant characteristics. These cells might be useful not only to study cancer stem cells but also to study the circumvention of radiation resistance by novel cancer treatment modalities.Hormesis describes a biphasic dose-response relationship generally characterized by a low-dose excitement and a high-dose inhibition. This phenomenon has been observed in the regulation of cell, organ, and organismic level. However, hormesis has not reported in oocytes. In this study, we observed, for the first time, hormetic responses of PIPP levels in oocytes by inhibitor of Akt1 or PKCδ. The expression of PIPP was detected by qPCR, immunofluorescent (IF), and Western Blot (WB). To observe the changes of PIPP levels, we used the inhibitors against pAkt1 (Ser473) or PKCδ, SH-6 or sotrastaurin with low and/or high-dose, treated GV oocytes and cultured for 4 h, respectively. The results showed that PIPP expression was significantly enhanced when oocytes were treated with SH-6 or sotrastaurin 10 μM, but decreased with SH-6 or sotrastaurin 100 μM. We also examined the changes of PIPP levels when GV oocytes were treated with exogenous PtdIns(3,4,5)P3 or LY294002 for 4 h. Our results showed that PIPP level was enhanced much higher under the treatment of 0.
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