Current Molecular Pharmacology - Volume 9, Issue 4, 2016

With their capability to undergo unlimited self-renew and to differentiate into various functional cells, human pluripotent stem cells, including embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), hold great promise in regenerative medicine to treat currently incurable diseases. Significant progress has been achieved in differentiating pluripotent stem cells into various functional cells, such as pancreatic β cells, neural cells, hepatocytes, and cardiomyocytes. In addition, three hESC-based therapies to treat spinal cord injury, macular degeneration and type 1 diabetes have entered clinical trial. However, there remain several major bottlenecks that hinder the clinical trial of stem cell based therapy. One such key challenge is the immune rejection of cells derived from allogeneic hESCs. The challenge of immune rejection is mitigated by recent discovery of iPSCs, raising the hope that patient-specific hiPSCs can be differentiated into autologous cells for transplantation into the same patient without the concern of immune rejection. However, due to the oncogenic potential of the reprogramming factors and the reprogramming- induced DNA damage, there remain safety concerns about the cancer risk and immunogenicity of hiPSC-derived cells. This review discusses recent progress in our understanding of the immunogenicity of pluripotent stem cells and the development of new strategies to resolve this challenge.

Mesenchymal stem cells (MSCs) represent a new therapeutic paradigm for a number of diseases because they possess unique biological characteristics such as multipotency, immunomodulation and production of cytokines. Currently, 425 MSC based clinical trials have been conducted for at least 12 kinds of pathological conditions, with many completed trials demonstrating the safety and efficacy of MSCs. Here, we provide an overview of the clinical status of MSCs by searching the public clinical trials database http://clinicaltrials.gov. Particularly, the role of MSCs in clinical trials to treat bone defects and injuries is highlighted.

Microcephaly is a clinical condition defined as a reduction in head circumference and brain volume. The abnormal brain size may result from pathological neural stem cell (NSC) proliferation, survival, differentiation and migration during the development of the cerebral cortex. This process is controlled by many factors, including microRNAs that normally silence target genes at the posttranscriptional level. In this review, we will discuss the roles of microRNAs involved in different stages of the cortical development to shed light on the pathogenesis of microcephaly. Understanding the molecular mechanisms of microRNA-mediated cortical development may help develop a means of microRNA-based diagnosis and treatment for microcephaly in humans.

Stem cells are unique cell types with the ability of self-renewal and differentiation, which mainly include embryonic stem cells, induced pluripotent stem cells, and adult stem cells. Recently, several research groups have reported that stem cells can differentiate into germ cells under appropriate conditions in vitro. Advances in this field have revealed new perspectives for reproductive and regenerative medicine. Here, we review the progress of in vitro gamete production from stem cells.

The androgen receptor plays a pivotal role in the sebaceous glands. Its primary function is to stimulate cell proliferation and differentiation in the sebaceous and its associate with acne. Previous studies have demonstrated expression of AR and steroidogenic enzymes in normal sebaceous glands and in all sebaceous disorders present evidence that androgen receptor may be a sensitive marker of sebaceous differentiation. It has been previously suggested that AR and steroidogenic enzymes immunohistochemistry may be useful particularly in identifying poorly sebaceous carcinoma. This review will provide an overview of the AR functions in the sebaceous glands and discussion of the therapeutic targets in acne and carcinoma.

Several neurological diseases such as bipolar disorders and schizophrenia are linked to impaired brain energy metabolism. A key feature of brain bioenergetics is hexokinase (HK) binding to the outer mitochondrial membrane through the voltage dependent anion channel (VDAC). This has metabolic consequences, with phosphorylation of glucose by mitochondrially bound hexokinase being closely coupled to production of substrate ATP by intramitochondrial oxidative phosphorylation. Additionally, binding of HK to mitochondria inhibits Bax-induced cytochrome c release and apoptosis. Moreover VDAC1 expression level is elevated in cerebellum of patients with Down ´s syndrome, while in Alzheimer ´s disease, VDAC1 levels are decreased in frontal cortex and VDAC2 elevated in temporal cortex. Thus, understanding the roles of VDAC and HK, either separate or interacting in brain, provides new opportunities and challenges to elucidate pathophysiological mechanisms for future therapeutic strategies.

Background and Objective: Epilepsy is one of the most prevalent neurological disorders worldwide, but its underlying mechanisms have not yet been clarified. Among the possible molecular mechanisms that underlie its occurrence are those that are responsible for the neuronal ionic gradient, including the transmembrane enzyme Na+,K+-adenosine triphosphatase (ATPase). Na+,K+-ATPase plays an important role in controlling neuronal excitability, and it is believed to be related to the pathophysiology of epilepsy. However, the specific isozymes that may be related to this neurological disorder remain to be determined. The α3 subunit-containing Na+,K+-ATPase isozyme has high affinity for ouabain and appears to play a major role in the pathogenesis of epilepsies. However, more studies are needed to evaluate the possible participation of Na+,K+- ATPase isozymes with lower affinity for ouabain (i.e., those that contain the α1 and α2 subunits). Methods: The present study investigated whether rats with high (HTR) and low (LTR) thresholds for clonic convulsions that are induced by a benzodiazepine inverse agonist differ in the binding of [3H]- ouabain to Na+,K+-ATPase isozymes with lower affinity to ouabain in discrete brain regions. Results: Compared with the HTR group, the LTR group exhibited lower binding of [3H]-ouabain in the brainstem and frontal cortex. Conclusion: This finding supports the hypothesis that epilepsy is associated with impairments in Na+,K+- ATPase activity. The results also suggest that Na+,K+-ATPase isozymes that contain the α1/α2 subunits in these brain regions may underlie the susceptibility to methyl 6,7-dimethoxy-4-ethyl-β-carboline-3- carboxylate-induced convulsions.

Introduction: Addiction to drugs of abuse is a devastating condition which results in deterioration of brain function. On the other hand, social isolation also produces cognitive deficits such as learning and memory impairment. This study was designed to evaluate the potential negative synergistic effects of social isolation and morphine addiction on brain functions. Methods and Material: One hundred and two Sprague-Dawley rats were randomly divided into four groups for assessing neurogenesis and behaviour: group-housed, isolated, morphine-treated group-housed and morphine-treated isolated groups. Morphine- treated animals received BrdU (50 mg/kg; i.p.) and Morphine (0.75 mg/rat; i.p.) for 14 consecutive days, whereas, control rats received BrdU (50 mg/kg; i.p.) only. At the end of the study, Morris water maze and elevated plus maze tasks were performed to assess spatial working memory and anxiety levels, respectively. Furthermore, neurogenesis and BDNF levels were studied. Results: Reference and working memory was markedly impaired in isolated and morphine-treated isolated rats as compared to group-housed rats and morphine-treated group-housed rats, respectively. Neurogenesis and BDNF levels were reduced in isolated and morphine-treated isolated rats as compared to group-housed rats and morphine-treated group-housed rats, respectively. Furthermore, rats in both isolated groups demonstrated low anxiety levels when compared to group housed groups. Conclusion: Isolation during addiction imparts devastating effects on brain. Thus, socialization of addicts can minimize addiction - induce cognitive deficits and improve neurogenesis.