Hertzrivera0153

Function of mTORC1 and mTORC2 has emerged as a driver of mesangial cell pathologies in diabetic nephropathy. The mechanism of mTOR activation is poorly understood in this disease. Deptor is a constitutive subunit and a negative regulator of both mTOR complexes. Mechanistic investigation in mesangial cells revealed that high glucose decreased the expression of deptor concomitant with increased mTORC1 and mTORC2 activities, induction of hypertrophy and, expression of fibronectin and PAI-1. shRNAs against deptor mimicked these pathologic outcomes of high glucose. Conversely, overexpression of deptor significantly inhibited all effects of high glucose. To determine the mechanism of deptor suppression, we found that high glucose significantly increased the expression of EZH2, resulting in lysine-27 tri-methylation of histone H3 (H3K27Me3). Employing approaches including pharmacological inhibition, shRNA-mediated downregulation and overexpression of EZH2, we found that EZH2 regulates high glucose-induced deptor suppression along with activation of mTOR, mesangial cell hypertrophy and fibronectin/PAI-1 expression. Moreover, expression of hyperactive mTORC1 reversed shEZH2-mediated inhibition of hypertrophy and expression of fibronectin and PAI-1 by high glucose. Finally, in renal cortex of diabetic mice, we found that enhanced expression of EZH2 is associated with decreased deptor levels and increased mTOR activity and, expression of fibronectin and PAI-1. Together, our findings provide a novel mechanism for mTOR activation via EZH2 to induce mesangial cell hypertrophy and matrix expansion during early progression of diabetic nephropathy. These results suggest a strategy for leveraging the intrinsic effect of deptor to suppress mTOR activity via reducing EZH2 as a novel therapy for diabetic nephropathy.The Y Box binding protein 1 (YB-1) is a member of the highly conserved Cold Shock Domain protein family with multifunctional properties both in the cytoplasm and inside the nucleus. YB-1 is also involved in various cellular functions, including regulation of transcription, mRNA stability, and splicing. Recent studies have associated YB-1 with the regulation of the malignant phenotypes in several tumor types. In this review article, we provide an in-depth and expansive review of the literature pertaining to the multiple physiological functions of YB-1. We will also review the role of YB-1 in cancer development, progression, metastasis, and drug resistance in various malignancies, with more weight on literature published in the last decade. The methodology included querying databases PubMed, Embase, and Google Scholar for Y box binding protein 1, YB-1, YBX1, and Y-box-1.LWHTH (Leu-Trp-His-Thr-His) is an antioxidant pentapeptide isolated from Styela clava tissue. Based on LWHTH, we designed and synthesized a series of novel peptides using the alanine scanning technique and determined the pharmacological activities of these derivatives. Among the ten newly synthesized LWHTH analogs, peptide CWHTH was identified as the most potent compound with prominent antioxidant activity. CWHTH not only showed the ability to scavenge several biologically important radicals, protected cells from H2O2 or APAP-induced damage by activating the PI3K/Akt and suppressing the JNK/c-Jun pathways, but also exerted strong in vivo hepatoprotective effects in an APAP-induced liver injury model in mice. Moreover, it was demonstrated that CWHTH possesses potent angiotensin converting enzyme (ACE) inhibitory activity and high stability against gastrointestinal proteases. In summary, CWHTH is a promising antioxidant peptide worthy of further investigation as a potential hepatoprotective and antihypertensive agent.3D printed pharmaceuticals offers the potential to manufacture personalized medicines for patients. Such technology is of particular benefit to pediatric populations from the offer of increased patient compliance and dose flexibility. With a bench-to-patient approach, this study established and optimized the critical parameters of the semi-solid micro-extrusion 3D printing process to guarantee the quality attributes of the final dosage form. Pediatrics orodispersible printlets of hydrochlorothiazide were manufactured through the modification of printing parameters, as well as printing surfaces materials. The printlets were characterized and the dimensions were measured using a digital caliper and computer vision algorithm. This study identified that the printing surface material and the first printing layer are critical parameters for high-resolution printlets. Following the optimization of 3D printing parameters, high quality orodispersible printlets loaded with hydrochlorothiazide - specifically tailored for pediatric patient's dosage forms - were obtained (4.62 mm × 1.90 mm). Mass and content uniformity assays demonstrated that the printlets satisfied the requirements for orodispersible printlets set by the European Pharmacopoeia. check details As such, in order to transition from laboratory research towards the treatment of patients, distinguishing accurate 3D printing parameters is necessary for the manufacture of medicines with key quality attributes that follow Pharmacopoeia requirements.The purpose of this study was to develop a drug-coated floss to allow delivery of therapeutics into diseased gum pocket. Periodontal (gum) disease affects nearly 45% of adults over 30 years of age. Bacterial persistence makes treatment challenging. Drug-coated floss is expected to provide a self-administrable and targeted method for drug delivery into the diseased gum pockets. We investigated various types of floss and sutures as potential candidates to coat drug. An un-waxed nylon braided floss was selected and dip-coated with model hydrophilic and hydrophobic drugs either in free form or after encapsulation in poly(lactic-co-glycolic acid) particles. By tuning the drug concentration or the number of times a floss is dipped into the coating solution we were able to coat from as little as 0.4 μg to as high as 1.6 mg of drug. Coated floss was passed within the gum pocket of excised porcine mandibles to demonstrate delivery efficiency up to 91%. Utilizing the porcine jaw in an ex-vivo condition we illustrated the ability of the delivered drug to diffuse into the tissue.