Reduced endogenous estrogen delays epididymal development but has no effect on efferent duct morphology in boars

The study presented herein was designed to test the hypothesis that reduced endogenous estrogen in the boar alters efferent duct morphology, epididymal morphology, and steroid receptor expression. Twenty-eight littermate pairs of boars were treated with Letrozole, an aromatase inhibitor, or with vehicle from 1 week of age until castration at 2 through 8 months. Efferent ducts and epididymides were examined for morphological development and steroid receptor expression. Efferent duct morphology was not different between control and Letrozole-treated animals at any examined age. Androgen receptor (AR), estrogen receptor alpha (ERalpha), and beta (ERbeta) were expressed in the epithelial cells of the efferent ducts at all ages; expression was similar in control and treated animals. Morphological development of the caput and corpus was delayed in Letrozole-treated animals, but this delay was transient since morphology was similar between control and treated animals at 8 months. The cauda did not show a delay in development, but was more developed in treated animals at 2 months. AR, ERalpha, and ERbeta were expressed in all three epididymal regions; no difference was observed between control and treated animals. In summary, estrogen appears to be important for development of the epididymis; however, the cauda may be regulated differently than the caput and corpus. Results for the efferent ducts suggest that the normally high endogenous estrogens are not required for regulation of fluid reabsorption in the boar. It also suggests that any ER activation required for maintenance of efferent duct morphology and function is normal in Letrozole-treated boars.     

Broadband Omnidirectional Diversion of Light in Hybrid Plasmonic‐Photonic Heterocrystals

Broadband, omnidirectional, and polarization‐independent diversion has been achieved of more than 90% of the light flow intensity off its incidence direction using hybrid metal–dielectric plasmonic‐photonic heterocrystals. These architectures were prepared by depositing metal film on the interface between two photonic crystals of different parameters. The magnitude of light losses was extracted from angle‐resolved measurements of transmission and reflectance spectra. Comparing these data for different stages of constructing the complex architecture, the diffraction in colloidal crystals, the excitation and radiative decay of short‐living surface plasmon polaritons in a corrugated metal film and the eigenmode mismatch at the interface between two different photonic crystals were identified as corroborating physical mechanisms behind the light diversion.     

Design and Synthesis of a MAO‐B‐Selectively Activated Prodrug Based on MPTP: A Mitochondria‐Targeting Chemotherapeutic Agent for Treatment of Human Malignant Gliomas

Malignant gliomas, including glioblastomas, are extremely difficult to treat. The median survival for glioblastoma patients with optimal therapeutic intervention is 15 months. We developed a novel MAO‐B‐selectively activated prodrug, N,N‐bis(2‐chloroethyl)‐2‐(1‐methyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)propanamide (MP‐MUS), for the treatment of gliomas based on 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). The design of neutral MP‐MUS involved the use of a seeker molecule capable of binding to mitochondrial MAO‐B, which is up‐regulated ≥fourfold in glioma cells. Once the binding occurs, MP‐MUS is converted into a positively charged moiety, P⁺‐MUS, which accumulates inside mitochondria at a theoretical maximal value of 1000:1 gradient. The LD₅₀ of MP‐MUS against glioma cells is 75 μM , which is two‐ to threefold more potent than temozolomide, a primary drug for gliomas. Importantly, MP‐MUS was found to be selectively toxic toward glioma cells. In the concentration range of 150–180 μM MP‐MUS killed 90–95 % of glioma cells, but stimulated the growth of normal human astrocytes. Moreover, maturation of MP‐MUS is highly dependent on MAO‐B, and inhibition of MAO‐B activity with selegiline protected human glioma cells from apoptosis.     

Expression of fatty acyl-CoA binding proteins in colon cells: response to butyrate and transformation

Fatty acyl-CoA affect many cellular functions as well as serving as cellular building blocks. Several families of cytosolic fatty acyl-CoA binding proteins may modulate the activities of fatty acyl-CoA. Intestinal enterocytes contain at least three unique families of cytosolic proteins that bind fatty acyl-CoA: acyl-CoA binding protein (ACBP), fatty acid binding proteins (including the liver, L-FABP and intestinal, I-FABP), and sterol carrier protein-2 (SCP-2). Immortalized rat colon epithelial cell lines expressed only ACBP and SCP-2 at levels of 0.75±0.13 and 0.42±0.02 ng/μg protein. Ras and src transformation increased colon cell density and differentially altered ACBP and SCP-2 expression without affecting I-FABP or L-FABP levels. ACBP levels were 1.8-fold and 1.5-fold increased in ras- and src-transformed cells, respectively. In contrast, SCP-2 expression was significantly decreased 55 and 67% in ras- and src-transformed cells, respectively. Butyrate treatment of ras- and src-transformed cells decreased cell proliferation up to 60–85% as compared to 25–30% in control cells. Butyrate treatment decreased ACBP expression in all cell lines but had no effect on the levels of SCP-2, I-FABP, or L-FABP. These studies suggest that the differential expression of ACBP and SCP-2 in rat colonic cell lines, as well as their modulation by butyrate, may be altered by cell transformation.     

Selective and Brain‐Permeable Polo‐like Kinase‐2 (Plk‐2) Inhibitors That Reduce α‐Synuclein Phosphorylation in Rat Brain

Polo‐like kinase‐2 (Plk‐2) has been implicated as the dominant kinase involved in the phosphorylation of α‐synuclein in Lewy bodies, which are one of the hallmarks of Parkinson’s disease neuropathology. Potent, selective, brain‐penetrant inhibitors of Plk‐2 were obtained from a structure‐guided drug discovery approach driven by the first reported Plk‐2–inhibitor complexes. The best of these compounds showed excellent isoform and kinome‐wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk‐2 inhibition in vivo. One such compound significantly decreased phosphorylation of α‐synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson’s disease.