Therapeutic Potential of TAAR1 Agonists in Schizophrenia: Evidence from Preclinical Models and Clinical Studies

Trace amine-associated receptor 1 (TAAR1) has emerged as a promising therapeutic target for neuropsychiatric disorders due to its ability to modulate monoaminergic and glutamatergic neurotransmission. In particular, agonist compounds have generated interest as potential treatments for schizophrenia and other psychoses due to TAAR1-mediated regulation of dopaminergic tone. Here, we review unmet needs in schizophrenia, the current state of knowledge in TAAR1 circuit biology and neuropharmacology, including preclinical behavioral, imaging, and cellular evidence in glutamatergic, dopaminergic and genetic models linked to the pathophysiology of psychotic, negative and cognitive symptoms. Clinical trial data for TAAR1 drug candidates are reviewed and contrasted with antipsychotics. The identification of endogenous TAAR1 ligands and subsequent development of small-molecule agonists has revealed antipsychotic-, anxiolytic-, and antidepressant-like properties, as well as pro-cognitive and REM-sleep suppressing effects of TAAR1 activation in rodents and non-human primates. Ulotaront, the first TAAR1 agonist to progress to randomized controlled clinical trials, has demonstrated efficacy in the treatment of schizophrenia, while another, ralmitaront, is currently being evaluated in clinical trials in schizophrenia. Coupled with the preclinical findings, this provides a rationale for further investigation and development of this new pharmacological class for the treatment of schizophrenia and other psychiatric disorders.     

The Melatonergic System in Mood and Anxiety Disorders and the Role of Agomelatine: Implications for Clinical Practice

Melatonin exerts its actions through membrane MT1/MT2 melatonin receptors, which belong to the super family of G-protein-coupled receptors consisting of the typical seven transmembrane domains. MT1 and MT2 receptors are expressed in various tissues of the body either as single ones or together. A growing literature suggests that the melatonergic system may be involved in the pathophysiology of mood and anxiety disorders. In fact, some core symptoms of depression show disturbance of the circadian rhythm in their clinical expression, such as diurnal mood and other symptomatic variation, or are closely linked to circadian system functioning, such as sleep-wake cycle alterations. In addition, alterations have been described in the circadian rhythms of several biological markers in depressed patients. Therefore, there is interest in developing antidepressants that have a chronobiotic effect (i.e., treatment of circadian rhythm disorders). As melatonin produces chronobiotic effects, efforts have been aimed at developing agomelatine, an antidepressant with melatonin agonist activity. The present paper reviews the role of the melatonergic system in the pathophysiology of mood and anxiety disorders and the clinical characteristics of agomelatine. Implications of agomelatine in “real world” clinical practice will be also discussed.     

二芳甲酰基肼类(DAH)昆虫生长调节剂的构效关系及作用机理研究概述

介绍了二芳甲酰基肼类昆虫生长调节剂的构效关系和作用机理。     

石灰石粉在复合胶凝材料水化中的作用机理

将石灰石粉用作水工混凝土矿物掺合料,不仅能改善混凝土的性能,而且能降低工程造价,是绿色混凝土的重要发展方向之一。文章介绍了当前国内外在石灰石粉应用方面的研究概况及存在的不足;通过微观研究,得出石灰石粉在复合胶凝材料水化中的三大作用机理:填充效应、活性效应和加速效应;最后,提出石灰石粉应用研究中丞待解决的问题,指出还需继续开展的研究工作重点。     

双酰基肼类昆虫生长调节剂的作用机理及抗药性研究进展

双酰基肼类杀虫剂是近几年陆续开发的一类高效、选择性强、对环境友好的昆虫生长调节剂,其作用靶标与昆虫蜕皮激素(20E)一样,结合于蜕皮激素受体(EcR)——过剩气门蛋白(USP)的异源二聚体,诱导昆虫早期基因的转录,但由于双酰肼类化合物在昆虫体内的持续存在,使20E不存在情况下发生的事件不能进行,如多巴脱羧酶(DDC)等基因的表达受阻,不合成几丁质,羽化激素不能释放,最后使幼虫早熟脱皮而死亡。随着这类杀虫剂使用时间和范围的不断扩大,对其抗药性的研究也逐渐引起了重视。本文主要综述了这类新型杀虫剂作用机理及抗药性等方面的研究进展。     

稻壳灰对油井水泥性能的影响及作用机理初探

为了改善油井水泥石力学性能及孔隙结构,研究了稻壳灰对油井水泥浆及水泥石性能的影响.通过测试掺有稻壳灰的水泥浆和空白样的水泥浆体的性能,以及不同掺量下水泥石的力学性能及渗透率和孔隙度,研究其对油井水泥性能的影响;利用XRD和TG测试,对稻壳灰水泥石和空白样进行物性分析,同时通过SEM对水泥石的微观形貌进行对比分析,初步探索稻壳灰对油井水泥石性能的作用机理.实验结果表明:稻壳灰对油井水泥浆的基本性能影响甚微;但其对水泥石的力学性能影响较大,与空白样对比,稻壳灰掺量为15％时,水泥石24h抗压强度提高56％,抗拉强度提高46％,孔隙度降低42％;同时,研究表明稻壳灰中含有的高活性非晶SiO2通过与水化产生的Ca(OH)2反应生成硅酸钙凝胶,能提高水泥石中的胶凝相,降低水泥石的空隙,达到提高水泥石力学性能的目的.     

Alemtuzumab in Multiple Sclerosis: Mechanism of Action and Beyond

Alemtuzumab is a humanized monoclonal antibody against CD52 (cluster of differentiation 52) and is approved for the therapy of relapsing-remitting multiple sclerosis. The application of alemtuzumab leads to a rapid, but long-lasting depletion predominantly of CD52-bearing B and T cells with reprogramming effects on immune cell composition resulting in the restoration of tolerogenic networks. Alemtuzumab has proven high efficacy in clinical phase II and III trials, where interferon β-1a was used as active comparator. However, alemtuzumab is associated with frequent and considerable risks. Most importantly secondary autoimmune disease affects 30%–40% of patients, predominantly impairing thyroid function. Extensive monitoring and early intervention allow for an appropriate risk management. However, new and reliable biomarkers for individual risk stratification and treatment response to improve patient selection and therapy guidance are a significant unmet need. Only a deeper understanding of the underlying mechanisms of action (MOA) will reveal such markers, maximizing the best potential risk-benefit ratio for the individual patient. This review provides and analyses the current knowledge on the MOA of alemtuzumab. Most recent data on efficacy and safety of alemtuzumab are presented and future research opportunities are discussed.     

低品质粉煤灰在混凝土中的作用机理及激发机制

我国低品质粉煤灰排放量大,其处置利用问题一直备受关注。本文从粉煤灰的活性出发,分析和讨论了粉煤灰在混凝土中的作用机理,提出采用不同的方法来激发粉煤灰活性,可为低品质粉煤灰的广泛应用提供参考。     

Cannabidiol in Neurological and Neoplastic Diseases: Latest Developments on the Molecular Mechanism of Action

As the major nonpsychotropic constituent of Cannabis sativa, cannabidiol (CBD) is regarded as one of the most promising therapeutic agents due to its proven effectiveness in clinical trials for many human diseases. Due to the urgent need for more efficient pharmacological treatments for several chronic diseases, in this review, we discuss the potential beneficial effects of CBD for Alzheimer’s disease, epilepsy, multiple sclerosis, and neurological cancers. Due to its wide range of pharmacological activities (e.g., antioxidant, anti-inflammatory, and neuroprotective properties), CBD is considered a multimodal drug for the treatment of a range of neurodegenerative disorders, and various cancer types, including neoplasms of the neural system. The different mechanisms of action of CBD are here disclosed, together with recent progress in the use of this cannabis-derived constituent as a new therapeutic approach.     

Potential Mechanism of Action of Current Point-of-Care Autologous Therapy Treatments for Osteoarthritis of the Knee—A Narrative Review

Osteoarthritis (OA) is a progressive degenerative disease that manifests as pain and inflammation and often results in total joint replacement. There is significant interest in understanding how intra-articular injections made from autologous blood or bone marrow could alleviate symptoms and potentially intervene in the progression of the disease. There is in vitro an in vivo evidence that suggests that these therapies, including platelet-rich plasma (PRP), autologous anti-inflammatories (AAIs), and concentrated bone marrow aspirate (cBMA), can interrupt cartilage matrix degradation driven by pro-inflammatory cytokines. This review analyzes the evidence for and against inclusion of white blood cells, the potential role of platelets, and the less studied potential role of blood plasma when combining these components to create an autologous point-of-care therapy to treat OA. There has been significant focus on the differences between the various autologous therapies. However, evidence suggests that there may be more in common between groups and perhaps we should be thinking of these therapies on a spectrum of the same technology, each providing significant levels of anti-inflammatory cytokines that can be antagonists against the inflammatory cytokines driving OA symptoms and progression. While clinical data have demonstrated symptom alleviation, more studies will need to be conducted to determine whether these preclinical disease-modifying findings translate into clinical practice.     

甲磺隆对水华鱼腥藻作用机理初探

以水华鱼腥藻的乙酰乳酸合成酶（ALS）比活力作为研究对象,通过在离体和活体条件下比较其对甲磺隆的敏感性,探讨了甲磺隆对水华鱼腥藻的作用机理.结果表明：离体条件下,甲磺隆对水华鱼腥藻ALS抑制强烈,且浓度越高抑制作用越强,其IC50=0.026mg/L;活体条件下,当甲磺隆的浓度为0.001mg/L时,甲磺隆对水华鱼腥藻ALS几乎没有抑制作用,这可能是甲磺隆在水华鱼腥藻体内被降解失活的缘故.当甲磺隆的浓度为0.01～10mg/L时,甲磺隆对水华鱼腥藻ALS抑制与离体条件下的抑制作用基本一样,其IC50=0.714mg/L.     

轻集料混凝土界面区形成与作用机理研究进展

轻集料混凝土中界面区的组成、结构与性能是决定其性能的关键.针对轻集料混凝土界面区的性能和特点,概括了轻集料混凝土界面区的微观结构特征和相关模型,分析了轻集料混凝土界面区的形成机理,综述了轻集料混凝土界面区对混凝土力学、耐久性能以及体积稳定性能的影响,总结了轻集料混凝土界面区研究中存在的不足和值得深入研究的方向,为轻集料混凝土界面区研究提供参考.     

Metformin’s Mechanism of Action Is Stimulation of the Biosynthesis of the Natural Cyclic AMP Antagonist Prostaglandylinositol Cyclic Phosphate (Cyclic PIP)

Metformin is the leading drug for treating type 2 diabetics, but the mechanism of action of metformin, despite some suggested mechanisms such as the activation of the AMP-kinase, is largely unknown. Among its many positive effects are the reduction of blood glucose levels, the inhibition of cyclic AMP synthesis, gluconeogenesis and an increase in sensitivity to insulin. Recent studies have described the natural antagonist of cyclic AMP, prostaglandylinositol cyclic phosphate. Synthesis of cyclic PIP is stimulated in all organs by hormones such as insulin and also by drugs such as metformin. Its primary action is to trigger the dephosphorylation of proteins/enzymes, phosphorylated on serine/threonine residues. Cyclic PIP triggers many of the regulations requested by insulin. The parallels between the beneficial effects of metformin and the regulations triggered by cyclic PIP suggest that the mechanism of action of this key drug may well be explained by its stimulation of the synthesis of cyclic PIP.