Targeted delivery of a phosphopeptide prodrug inhibits the proliferation of a human glioma cell line

Peptides are ideal candidates for developing therapeutics. Polo-like kinase 1 is an important regulatory protein in the cell cycle and contains a C-terminal polo-box domain, which is the hallmark of this protein family. We developed a peptide inhibitor of polo-like kinase 1 that targets its polo-box domain. This new phosphopeptide, cRGDyK-S-S-CPLHSpT, preferentially penetrates the cancer cell membrane mediated by the integrin receptor, which is expressed at high levels by cancer cells. In the present study, using high performance liquid chromatography and mass spectroscopy, we determined the stability of cRGDyK-S-S-CPLHSpT and its cleavage by glutathione under typical conditions for cell culture. We further assessed the ability of the peptide to inhibit the proliferation of the U87MG glioma cell line. The phosphorylated peptide was stable, and the disulfide bond of cRGDyK-S-S-CPLHSpT was cleaved in 50 mM glutathione. This peptide inhibited the growth of cancer cells and changed their morphology. Therefore, we conclude that the phosphopeptide shows promise as a prodrug and has a high potential to act as an anticancer agent by inhibiting polo-like kinase 1 by binding its polo-box domain. These findings indicate the therapeutic potential of PLHSpT and peptides similarly targeted to surface receptors of cancer cells and to the functional domains of regulatory proteins.     

Effect of sorghum ethyl-acetate extract on benign prostatic hyperplasia induced by testosterone in Sprague–Dawley rats

ABSTRACT

Benign prostatic hyperplasia (BPH) is commonly observed in men > 50 years worldwide. Phytotherapy is one of the many treatment options. Sorghum (Sorghum bicolor L.) contains various health-improving phytochemicals with antioxidant and inhibitory activities on cell proliferation, both in vitro and in vivo. To confirm the effects of Donganme sorghum ethyl-acetate extract (DSEE) on BPH, we induced BPH in Spragye–Dawley rats using exogenous testosterone. We measured prostate weight, examined prostrates histopathologically, and analyzed mRNAs associated with male hormones and proteins associated with cell proliferation in the prostate. DSEE inhibited weight gain of the prostate; decreased mRNA expressions of androgen receptor and 5α-reductase II; and improved histopathological symptoms, the protein-expressed ratio of Bax/Bcl-2, and the oxidative status of BPH induced by testosterone in SD rats. Therefore, DSEE may have potential as a preventive or therapeutic agent against BPH.     

HAWAIIAN SKIRT regulates the quiescent center‐independent meristem activity in Arabidopsis roots

Root apical meristem (RAM) drives post‐embryonic root growth by constantly supplying cells through mitosis. It is composed of stem cells and their derivatives, the transit‐amplifying (TA) cells. Stem cell organization and its maintenance in the RAM are well characterized, however, their relationships with TA cells remain unclear. SHORTROOT (SHR) is critical for root development. It patterns cell types and promotes the post‐embryonic root growth. Defective root growth in the shr has been ascribed to the lack of quiescent center (QC), which maintains the surrounding stem cells. However, our recent investigation indicated that SHR maintains TA cells independently of QC by modulating PHABULOSA (PHB) through miRNA165/6. PHB controls TA cell activity by modulating cytokinin levels and type B Arabidopsis Response Regulator activity, in a dosage‐dependent manner. To further understand TA cell regulation, we conducted a shr suppressor screen. With an extensive mutagenesis screen followed by genome sequencing of a pooled F₂ population, we discovered two suppressor alleles with mutations in HAWAIIAN SKIRT (HWS). HWS, encoding an F‐box protein with kelch domain, is expressed, partly depending on SHR, in the root cap and in the pericycle of the differentiation zone. Interestingly, root growth in the shr hws was more active than the wild‐type roots for the first 7 days after germination, without recovering QC. Contrary to shr phb, shr hws did not show a recovery of cytokinin signaling. These indicate that HWS affects QC‐independent TA cell activities through a pathway distinctive from PHB.     

Comparison of patient-specific intensity modulated radiation therapy quality assurance for the prostate across multiple institutions

AimTo evaluate the success of a patient-specific intensity modulated radiation therapy (IMRT) quality assurance (QA) practice for prostate cancer patients across multiple institutions using a questionnaire survey.BackgroundThe IMRT QA practice involves different methods of dose distribution verification and analysis at different institutions.Materials and MethodsTwo full-arc volumetric modulated arc therapy (VMAT) plan and 7 fixed-gantry IMRT plan with DMLC were used for patient specific QA across 22 institutions. The same computed tomography image and structure set were used for all plans. Each institution recalculated the dose distribution with fixed monitor units and without any modification. Single-point dose measurement with a cylindrical ionization chamber and dose distribution verification with a multi-detector or radiochromic film were performed, according to the QA process at each institution.ResultsTwenty-two institutions performed the patient-specific IMRT QA verifications. With a single-point dose measurement at the isocenter, the average difference between the calculated and measured doses was 0.5 ± 1.9%. For the comparison of dose distributions, 18 institutions used a two or three-dimensional array detector, while the others used Gafchromic film. In the γ test with dose difference/distance-to-agreement criteria of 3%?3 mm and 2%?2 mm with a 30% dose threshold, the median gamma pass rates were 99.3% (range: 41.7%–100.0%) and 96.4% (range: 29.4%–100.0%), respectively.ConclusionThis survey was an informative trial to understand the verification status of patient-specific IMRT QA measurements for prostate cancer. In most institutions, the point dose measurement and dose distribution differences met the desired criteria.     

Genome-Wide Association Study Reveals Two Nucleotide Variants Associated with Educational Attainment in Koreans

Russian Journal of Genetics - Genome-wide association studies for educational attainment have been limited to Europeans, but genetic factors might be largely related to cultural environments and...     

Implication of a pepper h-type thioredoxin in type I- and II-nonhost resistance to Xanthomonas axonopodis

Thioredoxins (TRXs) are distributed ubiquitously in prokaryotic and eukaryotic organisms. Plants have the most complex forms of TRXs. The functional roles of such TRXs have been studied in abiotic stress but their roles in plant defense responses against biotic stresses have been less well studied. Here, we identified an h-type TRX gene from pepper, CaTRXh1, and characterized its possible effect on Type II nonhost resistance, which entails localized programmed cell death in response to nonhost pathogens. Peptide sequences of CaTRXh1 showed a high degree of similarity with TRXhs from tobacco and Arabidopsis thaliana. Southern blot analyses revealed that CaTRXh1 was present as a single copy in the pepper genome. Intriguingly, leaf infiltration by Xanthomonas axonopodis pv. glycines 8ra, eliciting a visible type II nonhost hypersensitive response (HR), and its type III secretion-system null mutant 8–13, eliciting a type I nonhost non-HR, both induced CaTRXh1 at a level similar to that of pathogenesis-related protein 4, an HR marker gene in pepper. More surprisingly, expression of CaTRXh1 was significantly increased when X. axonopodis pv. vesicatoria race 3 infiltrated the leaf of a pepper cultivar containing a resistance gene, but not with infiltration of a susceptible pepper cultivar. Taken together, our study suggests that the expression of CaTRXh1 has a critical role in HR-mediated active defense responses in pepper. GenBank accession number: EF371503.