The Peripheral Cannabinoid Receptor Type 1 (CB1) as a Molecular Target for Modulating Body Weight in Man.

The cannabinoid 1 (CB1) receptor regulates appetite and body weight; however, unwanted central side effects of both agonists (in wasting disorders) or antagonists (in obesity and diabetes) have limited their therapeutic utility. At the peripheral level, CB1 receptor activation impacts the energy balance of mammals in a number of different ways: inhibiting satiety and emesis, increasing food intake, altering adipokine and satiety hormone levels, altering taste sensation, decreasing lipolysis (fat break down), and increasing lipogenesis (fat generation). The CB1 receptor also plays an important role in the gut-brain axis control of appetite and satiety. The combined effect of peripheral CB1 activation is to promote appetite, energy storage, and energy preservation (and the opposite is true for CB1 antagonists). Therefore, the next generation of CB1 receptor medicines (agonists and antagonists, and indirect modulators of the endocannabinoid system) have been peripherally restricted to mitigate these issues, and some of these are already in clinical stage development. These compounds also have demonstrated potential in other conditions such as alcoholic steatohepatitis and diabetic nephropathy (peripherally restricted CB1 antagonists) and pain conditions (peripherally restricted CB1 agonists and FAAH inhibitors). This review will discuss the mechanisms by which peripheral CB1 receptors regulate body weight, and the therapeutic utility of peripherally restricted drugs in the management of body weight and beyond.

Lead Drug Discover Strategies from Natural Medicines Based on Network Pharmacology.

The need for therapeutics to overcome development of existing diseases research to discover new lead agents. In the face of public health challenges worldwide, natural medicines play a pivotal role in innovative lead drug discovery. Network pharmacology can easily construct complicated poly-pharmacology network based on lead compound, biological function, and bioactive target proteins, which meets the overall feature of natural medicines, and enable to elucidate the action mechanism at molecule-protein level with systematic view. In this work, we first summarized the recent progress delineating lead drug development and its interaction with natural medicines. Second, we focused on the relationship between natural medicines and network pharmacology. Additionally, we discussed current issues and potential prospects for the lead drug discover from natural medicines by network pharmacology. Further investigations should be focus on relevant structural analysis for biological experiment, also the dynamic and quantitative network development. In summary, it is a rational approach for innovative lead drug discovery, and with the development of structure and biology research, this approach makes it a very powerful method for the lead molecules in a high-throughput manner from a comprehensive and powerful special multi-compound to target protein/disease poly pharmacology network.

Pharmaceutical applications of a nanospectroscopic technique: Surface-enhanced Raman spectroscopy.

Surface-enhanced Raman spectroscopy (SERS) is a very sensitive technique offering unique opportunities for detection and identification of molecules and molecular structures at extremely low concentrations even in complex sample matrixes. Since a nanostructured noble metal surface is required for the enhancement of Raman scattering, the acquired spectral information naturally originates from nanometer size domains making it a nanospectroscopic technique by breaking the diffraction limit of light. In this review, first Raman spectroscopy, its comparison to other related techniques, its modes and instrumentation are briefly introduced. Then, the SERS mechanism, substrates and the parameters influencing a SERS experiment are discussed. Finally, its applications in pharmaceuticals including drug discovery, drug metabolism, multifunctional chemo-photothermal-therapy-delivery-release-imaging, drug stability and drug/metabolite detection in complex biological samples are summarized and elaborated.

[A novel cell tool for α2δ-1-NMDAR target-based analgesic drug discovery].

The α2δ-1 protein coded by Cacna2d1 is dramatically up-regulated in dorsal root ganglion (DRG) neurons and spinal dorsal horn following sensory nerve injury in various animal models of neuropathic pain. Cacna2d1 overexpression potentiates presynaptic and postsynaptic NMDAR activity of spinal dorsal horn neurons to cause pain hypersensitivity. The α2δ-1-NMDAR interaction promotes surface trafficking and synaptic targeting of NMDARs in neuropathic pain caused by chemotherapeutic agents and peripheral nerve injury, as well as in other pathological conditions such as in the paraventricular nucleus (PVN) with neurogenic hypertension and in the brain with ischemic stroke. The lentiviral transfection method was used to construct a human embryonic kidney HEK293T cell line that could stably express α2δ-1-NMDAR complex. A stably transfected cell line was observed by florescence microscope, and identified by RT-qPCR and Western blotting. The results showed that the HEK293T cell line was successfully transfected and the genes could be stably expressed. Subsequently, the transfected cell line was successfully developed into a target drug screening system using patch clamp techniques. It provides a promising cell model for further research on the interaction mechanism of α2δ-1-NMDAR complex and drug screening for chronic pain and related diseases with low side effects.

Small Molecule Wnt Pathway Modulators from Natural Sources: History, State of the Art and Perspectives.

The Wnt signaling is one of the major pathways known to regulate embryonic development, tissue renewal and regeneration in multicellular organisms. Dysregulations of the pathway are a common cause of several types of cancer and other diseases, such as osteoporosis and rheumatoid arthritis. This makes Wnt signaling an important therapeutic target. Small molecule activators and inhibitors of signaling pathways are important biomedical tools which allow one to harness signaling processes in the organism for therapeutic purposes in affordable and specific ways. Natural products are a well known source of biologically active small molecules with therapeutic potential. In this article, we provide an up-to-date overview of existing small molecule modulators of the Wnt pathway derived from natural products. In the first part of the review, we focus on Wnt pathway activators, which can be used for regenerative therapy in various tissues such as skin, bone, cartilage and the nervous system. The second part describes inhibitors of the pathway, which are desired agents for targeted therapies against different cancers. In each part, we pay specific attention to the mechanisms of action of the natural products, to the models on which they were investigated, and to the potential of different taxa to yield bioactive molecules capable of regulating the Wnt signaling.

Strategies against methicillin-resistant Staphylococcus aureus persisters.

Chronic Staphylococcus aureus infections are complicated by frequent relapses not only from the development of drug resistance to conventional antibiotics, but also through the formation of persister bacterial cells. Bacterial persisters are in a transient, metabolically inactive state, making conventional antibiotics that target essential cellular growth processes ineffective, resulting in high clinical failure rates of antibiotic chemotherapy. The development of new antibiotics against persistent S. aureus is an urgent issue. Over the last decade, new strategies to identify S. aureus persister-active compounds have been proposed. This review summarizes the proposed targets, antipersister compounds and innovative methods that may augment conventional antibiotics against S. aureus persisters. The reviewed antipersister strategies can be summarized as two broad categories; directly targeting growth-independent targets and potentiating existing, ineffective antibiotics by aiding uptake or accessibility.

Candidiasis and the impact of flow cytometry on antifungal drug discovery.

INTRODUCTION: Invasive candidiasis continues to be associated with significant morbidity and mortality as well as substantial health care costs nationally and globally. One of the contributing factors is the development of resistance to antifungal agents that are already in clinical use. Moreover, there are known treatment limitations with all of the available antifungal agents. Since traditional techniques in novel drug discovery are time consuming, high-throughput screening using flow cytometry presents as a potential tool to identify new antifungal agents that would be useful in the management of these patients. Areas covered: In this review, the authors discuss the use of automated high-throughput screening assays based upon flow cytometry to identify potential antifungals from a library comprised of a large number of bioactive compounds. They also review studies that employed the use of this research methodology that has identified compounds with antifungal activity. Expert opinion: High-throughput screening using flow cytometry has substantially decreased the processing time necessary for screening thousands of compounds, and has helped enhance our understanding of fungal pathogenesis. Indeed, the authors see this technology as a powerful tool to help scientists identify new antifungal agents that can be added to the clinician's arsenal in their fight against invasive candidiasis.