Role of P-Glycoprotein at the Blood-Testis Barrier on Adjudin Distribution in the Testis: A Revisit of Recent Data.

Role of P-glycoprotein at the blood-testis barrier on adjudin distribution in the testis: a revisit of recent data.

Filed under: Drug and Alcohol Rehabilitation

Adv Exp Med Biol. 2012; 763: 318-33
Su L, Jenardhanan P, Mruk DD, Mathur PP, Cheng YH, Mok KW, Bonanomi M, Silvestrini B, Cheng CY

The blood-testis barrier (BTB) is one of the tightest blood-tissue barriers in mammals including rodents and humans. It is used to sequester meiosis I and II, postmeiotic spermatid development via spermiogenesis and the release of sperm at spermiation from the systemic circulation, such that these events take place in an immune-privileged site in the adluminal (apical) compartment behind the BTB, segregated from the host immune system. Additionally, drug transporters, namely efflux (e.g., P-glycoprotein) and influx (e.g., Oatp3) pumps, many of which are integral membrane proteins in Sertoli cells at the BTB also work cooperatively to restrict the entry of drugs, toxicants, chemicals, steroids and other xenobiotics into the adluminal compartment. As such, the BTB that serves as an important physiological and selective barrier to protect germ cell development also poses a “hurdle” in male contraceptive development. For instance, adjudin, 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide, a potential nonhormonal male contraceptive that exerts its effects on germ cell adhesion, most notably at the Sertoli cell-spermatid interface, to induce “premature” germ cell loss from the seminiferous epithelium mimicking spermiation, has a relatively poor bioavailability largely because of the BTB. Since male contraceptives (e.g., adjudin) will be used by healthy men for an extended period of his life span after puberty, a better understanding on the BTB is necessary in order to effectively deliver drugs across this blood-tissue barrier in particular if these compounds exert their effects on developing germ cells in the adluminal compartment. This can also reduce long-term toxicity and health risk if the effective dosing can be lowered in order to widen the margin between its safety and efficacy. Herein, we summarize latest findings in this area of research, we also provide a critical evaluation on research areas that deserve attention in future studies.
HubMed – drug


Drug transporters at brain barriers: expression and regulation by neurological disorders.

Filed under: Drug and Alcohol Rehabilitation

Adv Exp Med Biol. 2012; 763: 20-69
Ashraf T, Kis O, Banerjee N, Bendayan R

Drug transport in the central nervous system can be highly regulated by the expression of numerous influx and efflux transport proteins not only at the blood-brain barrier and blood-cerebrospinal fluid barrier but also in brain parenchymal cellular compartments (i.e., astrocytes, microglia, neurons). In particular, members of the ATP-Binding Cassette membrane-associated transporter superfamily and Solute Carrier family are known to be involved in the traffic of several endobiotics and xenobiotics (including drugs) into and out ofthe brain. These transport proteins have also been implicated in a number of neurological disorders including HIV-encephalitis, Alzheimer’s disease, Parkinson’s disease and neoplasia. This chapter summarizes recent knowledge on the role of drug transporters in the brain.
HubMed – drug


20-Hydroxyecdysone-induced bone morphogenetic protein-2-dependent osteogenic differentiation through the ERK pathway in human periodontal ligament stem cells.

Filed under: Drug and Alcohol Rehabilitation

Eur J Pharmacol. 2013 Jan 5; 698(1-3): 48-56
Jian CX, Liu XF, Hu J, Li CJ, Zhang G, Li Y, Zhu JW, Tan YH

20-Hydroxyecdysone, an ecdysteroid hormone, can induce osteogenic differentiation in mesenchymal stem cells. Periodontal ligament stem cells (PDLS cells) have mesenchymal-stem-cell-like qualities and are considered as one of the candidates of future clinical application in periodontitis treatment. However, there are no studies describing the effect of 20-Hydroxyecdysone on PDLS cells. In this paper, we report a detailed study on the effect of 20-Hydroxyecdysone on PDLS cell proliferation in vitro. PDLS cells were developed from human PDL cells and were treated with 20-Hydroxyecdysone to understand different aspects of its effects. 20-Hydroxyecdysone promoted PDLS cell proliferation; significantly increased the gene expression levels of runt-related transcription factor 2, alkaline phosphatase (ALP), type I collagen, and osteocalcin. Moreover, 20-Hydroxyecdysone enhanced bone formation by PDLS cells and significantly increased bone morphogenetic protein-2 (BMP-2) mRNA and protein expression. However, 20-Hydroxyecdysonemediated increase in ALP activity was blocked with a BMP-2-specific neutralizing antibody or with the antagonist noggin; and20-Hydroxyecdysone mediated induction of BMP-2 expression and increase of ALP activity were abolished by the extracellular regulated protein kinase (ERK) MAPK pathway inhibitor PD98059. 20-Hydroxyecdysone also increased the phosphorylation of ERK. These findings provide evidence to state that 20-Hydroxyecdysone stimulates cell proliferation and induces osteogenic differentiation through the induction of BMP-2 expression in PDLS cells. It also shows that the ERK pathway is involved in 20-Hydroxyecdysone induced BMP-2 expression and osteogenic differentiation. These results are suggesting its potential as a drug for periodontal regenerative therapy.
HubMed – drug


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