Mfsd2a-based pharmacological strategies for drug delivery across the blood-brain barrier.

The blood-brain barrier (BBB) keeps the central nervous system (CNS) safe from various brain diseases, while the BBB makes it difficult for effective drugs to enter the CNS. Mfsd2a is specifically expressed on the cell membrane of brain-microvascular endothelial cell (BMEC) and is implicated in the delivery of some substances across the BBB. Mfsd2a is the first inhibitor of the transcytosis and the first transporter for lysophosphatidylcholine-docosahexaenoic acid (LPC-DHA) in BMECs. The crucial dual function of Mfsd2a puts forward two kinds of Mfsd2a-based strategies for carrying drugs from blood to the CNS. First, the reversible inhibition of Mfsd2a may temporarily induce a general disinhibition of the transcytosis in BMECs to transport macromolecular drugs across the BBB (Strategy One). Second, Mfsd2a could be used for the transport of some small-molecule drugs chemically coupled to LPC across the BBB (Strategy Two), which is quite similar to the carrier-mediated transport (CMT) via the glucose transporter (GluT1) and the L-type amino acid transporter 1 (LAT1). We here analyze and discuss the clinical significance of the two Mfsd2a-based strategies, including therapeutic potential, available pharmaceuticals, side effects, administration procedures, and disease types. In summary, the regulatory role of Mfsd2a deepens our knowledge of the function of the BBB, potentially contributing to the effective drug delivery in the treatments for neurodegenerative diseases, brain tumors, and life-threatening infections in the CNS.

Simple sequence repeats in bryophyte mitochondrial genomes.

Simple sequence repeats (SSRs) are thought to be common in plant mitochondrial (mt) genomes, but have yet to be fully described for bryophytes. We screened the mt genomes of two liverworts (Marchantia polymorpha and Pleurozia purpurea), two mosses (Physcomitrella patens and Anomodon rugelii) and two hornworts (Phaeoceros laevis and Nothoceros aenigmaticus), and detected 475 SSRs. Some SSRs are found conserved during the evolution, among which except one exists in both liverworts and mosses, all others are shared only by the two liverworts, mosses or hornworts. SSRs are known as DNA tracts having high mutation rates; however, according to our observations, they still can evolve slowly. The conservativeness of these SSRs suggests that they are under strong selection and could play critical roles in maintaining the gene functions.

[Relationship between the increase of hepatic D-bifunctional protein activity and bile acid biosynthesis in rats].

OBJECTIVE: To determine the physiological role of D-bifunctional protein (DBP) in bile acid biosynthesis through investigating the effect of increasing activity of DBP on bile acid biosynthesis. METHODS: Twenty male Wistar rats were divided into two groups: diethylhexyl phthalate (DEHP) group (n = 10) and control group (n = 10). Serum triglyceride, total cholesterol, hepatic DBP activity, and fecal bile acids were assayed. The mRNA levels of hepatic peroxisome proliferator-activated receptor alpha (PPARalpha), DBP, and cholesterol 7alpha-hydroxylase (CYP7A1) were detected by RT-PCR. RESULTS: Compared with control group, serum triglyceride level was decreased significantly and PPARalphamRNA level was increased significantly in DEHP group (P < 0.01). Together with a sharp induction of DBP mRNA expression and DBP activity in DEHP group (P < 0.01), the levels of CYP7A1 mRNA and fecal bile acids were significantly increased by 1.9 times and 1.6 times respectively compared to control group (P < 0.01). There was a significantly positive correlation between DBP mRNA level or DBP activity and CYP7A1 mRNA level (r = 0.89, P < 0.01; r = 0.95, P < 0.01). CONCLUSION: The up-regulation of DBP mRNA and activity in liver can result in the increase in CYP7A1 mRNA expression and bile acid biosynthesis, suggesting that DBP may be involved in bile acid biosynthesis together with CYP7A1.

Finasteride reduces microvessel density and expression of vascular endothelial growth factor in renal tissue of diabetic rats.

BACKGROUND: Vascular endothelial growth factor (VEGF) plays a critical role in the pathogenesis of diabetic microvascular complications. Finasteride has been confirmed to decrease VEGF expression in prostate and prostatic suburethral tissue resulting in limiting hematuria from human benign prostatic hyperplasia. The purpose of this study was to evaluate the effects of finasteride on microvessel density (MVD), VEGF protein and mRNA expressions in the renal tissue of diabetic rats. METHODS: Diabetic rats induced by streptozotocin were intragastrically given finasteride at 30 mg/kg body weight once a day for 4 weeks. Histomorphologic changes in kidney were observed under light microscope. Immunohistochemistry for CD34 and VEGF on kidney sections was performed to assess MVD and VEGF protein expression in glomeruli of rats, respectively. The VEGF mRNA expression in the renal tissue was examined using reverse transcription polymerase chain reaction analysis. RESULTS: The glomerular tuft area, glomerular volume, MVD, VEGF protein expression in glomeruli and VEGF mRNA expression in the renal cortex tissue were significantly increased in diabetic rats and finasteride-treated rats when compared with controls (P < 0.01, P < 0.05). When compared with diabetic rats, the glomerular tuft area, glomerular volume, MVD, VEGF protein expression in glomeruli and VEGF mRNA expression in the renal cortex tissue of finasteride-treated rats were significantly decreased (P < 0.05, P < 0.01). CONCLUSIONS: Finasteride reduces the VEGF expression and decreases the MVD in the renal tissue of diabetic rats, suggesting the therapeutic potential of finasteride on diabetic microvascular complications.

Could Pin1 help us conquer essential hypertension at an earlier stage? A promising early-diagnostic biomarker and its therapeutic implications for the disease.

Essential hypertension is a major risk factor for cardiovascular morbidity and mortality, and the early-diagnosis is very important for the prevention of essential hypertension. Previously, we found that Pin1, the only known enzyme isomerizing pSer/pThr-Pro motifs in proteins, may gradually become inactive under conditions of stress such as intracellular acidification and fever. Interestingly, essential hypertension and the dysfunction of Pin1 often synchronously occur with the increasing age. Recent evidence indicates that Pin1 primarily increases the activity of endothelial nitric oxide synthase (eNOS) and the production of nitric oxide (NO) in multiple ways, significantly promoting the relaxation response of blood vessels and preventing the elevation of blood pressure. Further, the inhibition of Pin1 results in significantly increased blood pressure in rats. So, we hypothesized and evaluated the potential of Pin1 to be a new early-diagnostic biomarker as well as a therapeutic drug for essential hypertension. The unique activity of Pin1 and some epidemiological and experimental data evidence that the decreased activity of Pin1 may be closely associated with the development of essential hypertension. The factors that may impact the activity of Pin1 and correlate with the risk of essential hypertension were also discussed. These findings indicate that Pin1 plays a key and permanent role in efficiently preventing the development of essential hypertension, and that Pin1 may be a promising early-diagnostic biomarker as well as an effective therapeutic drug for the early-diagnosis, prevention, and treatment of essential hypertension, potentially decreasing the risk of cardiovascular morbidity and mortality.