Dendrites undergo extensive growth and remodeling during their lifetime. Specification of neurites into dendrites is followed by their arborization, maturation, and functional integration into synaptic networks. Each of these distinct developmental processes is spatially and temporally controlled in an exquisite fashion. Protein kinases through their highly specific substrate phosphorylation regulate dendritic growth and plasticity. Perturbation of kinase function results in aberrant dendritic growth and synaptic function. Not surprisingly, kinase dysfunction is strongly associated with neurodevelopmental and psychiatric disorders. Herein, we review, (a) key kinase pathways that regulate dendrite structure, function and plasticity, (b) how aberrant kinase signaling contributes to dendritic dysfunction in neurological disorders and (c) emergent technologies that can be applied to dissect the role of protein kinases in dendritic structure and function.

Synaptic Vesicle Protein 2 (SV2) comprises a recently evolved family of proteins unique to secretory vesicles that undergo calcium-regulated exocytosis. In this review we consider SV2s' structural features, evolution, and function and discuss its therapeutic potential as the receptors for an expanding class of drugs used to treat epilepsy and cognitive decline.

Cytochrome P450 2J2 (CYP2J2) is a known arachidonic acid (AA) epoxygenase that mediates the formation of four bioactive regioisomers of cis-epoxyeicosatrienoic acids (EETs). Although its expression in the liver is low, CYP2J2 is mainly observed in extrahepatic tissues, including the small intestine, pancreas, lung, and heart. Changes in CYP2J2 levels or activity by xenobiotics, disease states, or polymorphisms are proposed to lead to various organ dysfunctions. Several studies have investigated the regulation of CYP2J2 and EET formation in various cell lines and have demonstrated that such regulation is tissue-dependent. In addition, studies linking CYP2J2 polymorphisms to the risk of developing cardiovascular disease (CVD) yielded contradictory results. This review will focus on the mechanisms of regulation of CYP2J2 by inducers, inhibitors, and oxidative stress modeling certain disease states in various cell lines and tissues. The implication of CYP2J2 expression, polymorphisms, activity and, as a result, EET levels in the pathophysiology of diabetes and CVD will also be discussed.

The concept of nanomedicine is not new. For instance, some nanocrystals and colloidal drug molecules are marketed that improve pharmacokinetic characteristics of single-agent therapeutics. For the past two decades, the number of research publications on single-agent nanoformulations has grown exponentially. However, formulations advancing to pre-clinical and clinical evaluations that lead to therapeutic products has been limited. Chronic diseases such as cancer and HIV/AIDS require drug combinations, not single agents, for durable therapeutic responses. Therefore, development and clinical translation of drug combination nanoformulations could play a significant role in improving human health. Successful translation of promising concepts into pre-clinical and clinical studies requires early considerations of the physical compatibility, pharmacological synergy, as well as pharmaceutical characteristics (e.g. stability, scalability and pharmacokinetics). With this approach and robust manufacturing processes in place, some drug-combination nanoparticles have progressed to non-human primate and human studies. In this article, we discuss the rationale and role of drug-combination nanoparticles, the pre-clinical and clinical research progress made to date and the key challenges for successful clinical translation. Finally, we offer insight to accelerate clinical translation through leveraging robust nanoplatform technologies to enable implementation of personalised and precision medicine.

Combination antiretroviral therapy (cART) given orally has transformed HIV from a terminal illness to a manageable chronic disease. Yet despite the recent development of newer and more potent drugs for cART and suppression of virus in blood to undetectable levels, residual virus remains in tissues. Upon stopping cART, virus rebounds and progresses to AIDS. Current oral cART regimens have several drawbacks including (1) challenges in patient adherence due to pill fatigue or side-effects, (2) the requirement of life-long daily drug intake, and (3) limited penetration and retention in cells within lymph nodes. Appropriately designed injectable nano-drug combinations that are long-acting and retained in HIV susceptible cells within lymph nodes may address these challenges. While a number of nanomaterials have been investigated for delivery of HIV drugs and drug combinations, key challenges involve developing and scaling delivery systems that provide a drug combination targeted to HIV host cells and tissues where residual virus persists. With validation of the drug-insufficiency hypothesis in lymph nodes, progress has been made in the development of drug combination nanoparticles that are long-acting and targeted to lymph nodes and cells. Unique drug combination nanoparticles (DcNPs) composed of three HIV drugs-lopinavir, ritonavir, and tenofovir-have been shown to provide enhanced drug levels in lymph nodes; and elevated drug-combination levels in HIV-host cells in the blood and plasma for two weeks. This review summarizes the progress in the development of nanoparticle-based drug delivery systems for HIV therapy. It discusses how injectable nanocarriers may be designed to enable delivery of drug combinations that are long-lasting and target-selective in physiological contexts (in vivo) to provide safe and effective use. Consistent drug combination exposure in the sites of residual HIV in tissues and cells may overcome drug insufficiency observed in patients on oral cART.

Cytochrome P450 2J2 (CYP2J2) is a known arachidonic acid (AA) epoxygenase that mediates the formation of four bioactive regioisomers of cis-epoxyeicosatrienoic acids (EETs). Although its expression in the liver is low, CYP2J2 is mainly observed in extrahepatic tissues, including the small intestine, pancreas, lung, and heart. Changes in CYP2J2 levels or activity by xenobiotics, disease states, or polymorphisms are proposed to lead to various organ dysfunctions. Several studies have investigated the regulation of CYP2J2 and EET formation in various cell lines and have demonstrated that such regulation is tissue-dependent. In addition, studies linking CYP2J2 polymorphisms to the risk of developing cardiovascular disease (CVD) yielded contradictory results. This review will focus on the mechanisms of regulation of CYP2J2 by inducers, inhibitors, and oxidative stress modeling certain disease states in various cell lines and tissues. The implication of CYP2J2 expression, polymorphisms, activity and, as a result, EET levels in the pathophysiology of diabetes and CVD will also be discussed.