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Weight loss inside Postmenopausal Japanese Patients along with Osteo-arthritis.
Furthermore, early proof-of-concept clinical trials have found a degree of success in combating ischemic retinal disease through intravitreal delivery of an siRNA targeting the REDD1 mRNA. Overall, REDD1-associated signaling represents an intriguing target for novel clinical therapies that go beyond addressing the symptoms of diabetes by targeting the underlying molecular mechanisms that contribute to DR.Previous reports revealed that mutation of mitochondrial inner-membrane located protein SFXN1 led to pleiotropic hematological and skeletal defects in mice, associated with the presence of hypochromic erythroid cell, iron overload in mitochondrion of erythroblast and the development of sideroblastic anemia (SA). However, the potential role of sfxn1 during erythrocyte differentiation and the development of anemia, especially the pathological molecular mechanism still remains elusive. In this study, the correlation between sfxn1 and erythroid cell development is explored through zebrafish in vivo coupled with human hematopoietic cells assay ex vivo. Both knockdown and knockout of sfxn1 result in hypochromic anemia phenotype in zebrafish. Further analyses demonstrate that the development of anemia attributes to the biosynthetic deficiency of hemoglobin, which is caused by the biosynthetic disorder of heme that associates with one‑carbon (1C) metabolism process of mitochondrial branch in erythrocyte. Sfxn1 is also involved in the differentiation and maturation of erythrocyte in inducible human umbilical cord blood stem cells. In addition, we found that functional disruption of sfxn1 causes hypochromic anemia that is distinct from SA. These findings reveal that sfxn1 is genetically conserved and essential for the maturation of erythrocyte via facilitating the production of hemoglobin, which may provide a possible guidance for the future clinical treatment of sfxn1 mutation associated hematological disorders.Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and transcriptional modulators with crucial functions in hepatic and whole-body energy homeostasis. Besides their well-documented roles in lipid and glucose metabolism, emerging evidence also implicate PPARs in the control of other processes such as inflammatory responses. Recent technological advances, such as single-cell RNA sequencing, have allowed to unravel an unexpected complexity in the regulation of PPAR expression, activity and downstream signaling. Here we provide an overview of the latest advances in the study of PPARs in liver physiology, with a specific focus on formerly neglected aspects of PPAR regulation, such as tissular zonation, cellular heterogeneity, circadian rhythms, sexual dimorphism and species-specific features.Dysregulation of transcription factors is one of the common problems in the pathogenesis of human cancer. Among them, SOX9 is one of the critical transcription factors involved in various diseases, including cancer. The expression of SOX9 is regulated by microRNAs (miRNAs), methylation, phosphorylation, and acetylation. Interestingly, SOX9 acts as a proto-oncogene or tumor suppressor gene, relying upon kinds of cancer. Recent studies have reported the critical role of SOX9 in the regulation of the tumor microenvironment (TME). Additionally, activation of SOX9 signaling or SOX9 regulated signaling pathways play a crucial role in cancer development and progression. Accumulating evidence also suggests that SOX9 acquires stem cell features to induce epithelial-mesenchymal transition (EMT). Moreover, SOX9 has been broadly studied in the field of cancer stem cell (CSC) and EMT in the last decades. However, the link between SOX9 and cancer drug resistance has only recently been discovered. Furthermore, its differential expression could be a potential biomarker for tumor prognosis and progression. This review outlined the various biological implications of SOX9 in cancer progression and cancer drug resistance and elucidated its signaling network, which could be a potential target for designing novel anticancer drugs.Lack of selectivity together with severe side effects in conventional cancer treatment have afforded the development of new strategies based on gene therapy. Nowadays, gene therapy is employed through both viral and non-viral vectors. In spite of the high transfection activity of viral vectors, some drawbacks have pointed out to non-viral vectors as a safer alternative. To overcome low efficiency as well as other issues associated with the use of non-viral vectors, complexes formed by lipids and polymers with DNA, named lipoplexes and polyplexes respectively, have been modified in order to improve its features. Suitability of cancer gene therapy also requires the capacity to distinguish between normal and tumoral cells. This requirement has been solved by the addition of specific ligands that enable receptor binding and subsequent endocytosis. In this article we review the most recent approaches in structure modification of non-viral vectors through different methods comprising conjugation, addition of helper lipids or changes in design and synthesis as well as the strategy based on exploiting receptors that are usually overexpressed in malignancies. Such improvements confer specificity, efficient gene delivery, condensation, protection of DNA and low levels of toxicity avoiding off-target effects which turn into a potential tool to treat cancer.Skin regeneration is one of the most important issues in tissue engineering. Research on more effective biomaterials that will enhance regeneration while enabling requirements of a healing skin site is an important challenge in skin tissue engineering. In this study, heparin was encapsulated in Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) which were then incorporated into Sericin/Gelatin (Ser/Gel) nanofibers during the electrospinning process in order to develop a combined system that has controlled release approach, besides the ability to help the regeneration of skin tissue by the involvement of biopolymers; gelatin, and sericin. The loading capacity and heparin encapsulation efficiency in the nanoparticles were determined as 30.04 mg/g of polymer and 60%, respectively. Cumulative release of heparin from NPs for 1 week was faster than from NPs loaded gelatin scaffolds and from dual protein (Ser/Gel) scaffolds with ratios 1/7 and 1/2 (approximately 85%, 65%, 55%, and 40%, respectively). Sericin addition slowed down the degradation properties of the scaffold. The scaffold having a Ser/Gel ratio (1/2) was found as the most promising candidate because of its proper fiber morphology, high water retention, and low degradation degree.Due to the increasing inability of antibiotics to treat multidrug-resistant (MDR) bacteria, metal and metal oxide nanoparticles have been gaining interest as antimicrobial agents. Among those, silver nanoparticles have been used extensively as broad-spectrum antimicrobial agents. Here, we describe a newly-developed, 10-min (120 °C at 5 bar pressure) microwave-assisted synthesis of silver nanoparticles made from the wood biopolymer lignin as a reducing and capping agent. The resulting lignin-capped silver nanoparticles (AgLNPs) had an average particle diameter of 13.4 ± 2.8 nm. Antimicrobial susceptibility assays against a variety of MDR clinical Gram-positive and Gram-negative pathogens revealed a minimal inhibitory concentration (MIC) of AgLNPs ≤5 µg/mL. AgLNPs (10 µg/mL) showed ≤20% cytotoxicity towards monocytic THP-1 cells and were well tolerated when administered subcutaneously in mice at high concentrations (5 mg at a concentration of 100 mg/mL) with no obvious toxicity. AgLNPs showed efficacy in an in vivo infection (abscess) mouse model against MDR Pseudomonas aeruginosa LESB58 and methicillin-resistant Staphylococcus aureus USA300. WZB117 concentration A significant decrease in abscess sizes was observed for both strains as well as a reduction in bacterial loads of P. aeruginosa after three days. This demonstrates that microwave-assisted synthesis provides an optimized strategy for the production of AgLNPs while maintaining antimicrobial activity in vitro and in vivo.The neonatal and pediatric populations have long been neglected concerning the development of oral dosage forms. For close to two decades, caregivers have had to adjust the doses of the off-label medicines and drugs for adults to suit the neonatal and pediatric needs. This is due to the lack of rules and regulations regarding neonates and pediatrics clinical trials while pharmaceutical industries see this as a non-lucrative approach. Despite such limitations, the administration of solid and liquid dosage forms to neonates and pediatrics necessitates the development of new technologies and even new strategies to meet the needs. Current approaches have not only focused on the development of suitable dosage forms but also the advancement of devices to enhance drug administration to pediatrics and neonates. Though current approaches have significantly added to the number of pediatric and neonatal oral dosage formulations on the market, there is still more room for improvement(s). While novel dosage forms including multiparticulates, orodispersible tablets/films, and chewable tablets have extensively been researched, some administration devices (e.g., nipple shield, pill swallowing cup, and solid dosage pen) have also been explored. Although a few of these products are in the market, the concerted efforts of regulation administrative bodies, pharmaceutical industry settings, and scientists in academia have been oriented to address all issues and advance the neonatal and pediatric-centric pharmaceutical products.The aim was to produce PEG-coated nanoparticles (NP-PEG), with mucus-permeating properties, for oral drug delivery purposes by using simple procedures and regulatory-approved compounds in order to facilitate a potential clinical development. For this purpose, zein nanoparticles were prepared by desolvation and, then, coated by incubation with PEG 35,000. The resulting nanocarriers displayed a mean size of about 200 nm and a negative zeta potential. The presence of PEG on the surface of nanoparticles was evidenced by electron microscopy and confirmed by FTIR analysis. Likely, the hydrophobic surface of zein nanoparticles (NP) was significantly reduce by their coating with PEG. This increase of the hydrophilicity of PEG-coated nanoparticles was associated with an important increase of their mobility in pig intestinal mucus. In laboratory animals, NP-PEG (fluorescently labelled with Lumogen® Red 305) displayed a different behavior when compared with bare nanoparticles. After oral administration, NP appeared to be trapped in the mucus mesh, whereas NP-PEG were capable of crossing the protective mucus layer and reach the epithelium. Finally, PEG-coated zein nanoparticles, prepared by a simple and reproducible method without employing reactive reagents, may be adequate carriers for promoting the oral bioavailability of biomacromolecules and other biologically active compounds with low permeability properties.Uncontrolled cell proliferation is a hallmark of cancer as a result of rapid and deregulated progression through the cell cycle. The inhibition of cyclin-dependent kinases (CDKs) activities is a promising therapeutic strategy to block cell cycle of tumor cells. In this work we reported a new example of nanocomposites based on halloysite nanotubes (HNTs)/pyrazolo[3,4-d]pyrimidine derivatives (Si306 and Si113) as anticancer agents and CDK inhibitors. HNTs/Si306 and HNTs/Si113 nanocomposites were synthesized and characterized. The release kinetics were also investigated. Antitumoral activity was evaluated on three cancer cell lines (HeLa, MDA-MB-231 and HCT116) and the effects on cell cycle arrest in HCT116 cells were evaluated. Finally, molecular dynamics simulations were performed of the complexes between Si113 or Si306 and the active site of both CDK 1 and 2.
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