Display omitted
•Nanostructured lipid carriers (NLC) are modified solid lipid nanoparticles consisting of a blend of solid and liquid lipids.•Overview of fabrication methods and characterization ...techniques.•Explores potential as a delivery system through various routes of administration.
Nanostructured lipid carriers (NLC), comprises of a blend of solid and liquid lipids which results in a partially crystallized lipid system and imparts many advantages over solid lipid nanoparticles such as enhanced drug loading capacity, drug release modulation flexibility and improved stability. NLC have found numerous applications in both pharmaceutical and cosmetic industry due to ease of preparation, the feasibility of scale-up, biocompatibility, non-toxicity, enhanced targeting efficiency and the possibility of site-specific delivery via various routes of administration. This review highlights the NLC with focus on the structure, the various fabrication techniques used and the characterization techniques which are critical in the development of a suitable and stable formulation. The review also provides an insight into the potential of NLC as site-specific delivery systems and the therapeutic applications explored via various routes of administration.
Ocular diseases have a significant effect on vision and quality of life. Drug delivery to ocular tissues is a challenge to formulation scientists. The major barriers to delivering drugs to the ...anterior and posterior segments include physiological barriers (nasolacrimal drainage, blinking), anatomical barriers (static and dynamic), efflux pumps and metabolic barriers. The static barriers comprise the different layers of the cornea, sclera, and blood-aqueous barriers whereas dynamic barriers involve conjunctival blood flow, lymphatic clearance and tear drainage. The tight junctions of the blood-retinal barrier (BRB) restrict systemically administered drugs from entering the retina. Nanocarriers have been found to be effective at overcoming the issues associated with conventional ophthalmic dosage forms. Various nanocarriers, including nanodispersion systems, nanomicelles, lipidic nanocarriers, polymeric nanoparticles, liposomes, niosomes, and dendrimers, have been investigated for improved permeation and effective targeted drug delivery to various ophthalmic sites. In this review, various nanomedicines and their application for ophthalmic delivery of therapeutics are discussed. Additionally, scale-up and clinical status are also addressed to understand the current scenario for ophthalmic drug delivery.
Ocular diseases have a significant effect on vision and quality of life.
Elevated levels of NO produced within the central nervous system (CNS) are associated with the pathogenesis of neuroinflammatory and neurodegenerative human diseases such as multiple sclerosis, HIV ...dementia, brain ischemia, trauma, Parkinson's disease, and Alzheimer's disease. Resident glial cells in the CNS (astroglia and microglia) express inducible nitric oxide synthase (iNOS) and produce high levels of NO in response to a wide variety of proinflammatory and degenerative stimuli. Although pathways resulting in the expression of iNOS may vary in two different glial cells of different species, the intracellular signaling events required for the expression of iNOS in these cells are slowly becoming clear. Various signaling cascades converge to activate several transcription factors that control the transcription of iNOS in glial cells. The present review summarizes different results and discusses current understandings about signaling mechanisms for the induction of iNOS expression in activated glial cells. A complete understanding of the regulation of iNOS expression in glial cells is expected to identify novel targets for therapeutic intervention in NO-mediated neurological disorders.
Thin film composite polyamide reverse osmosis membrane prepared in laboratory was used for filtration of two phenyl urea pesticides (diuron and isoproturon) dissolved in deionized water, tap water ...and agriculture field water. Membrane performance in removing pesticides from water was evaluated and compared with commercial membrane data. Membrane fouling was less for diuron and the value was restricted within 11%. Membrane fouling and permeate flux decline depends on water type. For field water flux decline was maximum. The presence of mono- (Na+) and bi-valent (Ca2+) ions in feed water influences membrane performance. Isoproturon rejection for the membranes was always higher than diuron. Pesticide rejection from field water was more than 95%. The presence of humic acid in water has no significant effect on diuron and isoproturon rejection. Post filtration behavior of membranes reflects hydrophilicity change irrespective of water type. Depending upon the pesticide, membrane property influences permeate flux and water permeability.
•Polyamide membrane was prepared and used for pesticide separation from water.•Significantly high separation could be achieved for diuron and isoproturon.•Ion type, concentration and pesticide nature influence membrane rejection property.•Isoproturon rejection was always higher than that of diuron.•Diuron and isoproturon modify membrane property which influences membrane flux.
The present study involves bacterial cellulose (BC) production using freshly prepared apple juice medium (AJM) and the bacterial strain
Gluconobacter xylinum
CCM 3611T. The AJM was modified with ...ammonium sulfate, dipotassium phosphate, sucrose, acetic acid, with and without ethanol. BC sheets (in the dry state) were analyzed on the basis of morphological, rheological and structural properties, thermal stability, water holding capacity (WHC) and water absorption capacity (WAC). Comparative X-ray diffractograms of BC using cobalt radiation is observed for the first time. The WAC analysis revealed that lyophilized BC samples had the higher WAC than the oven air-dried samples. There is an evidential structural difference observed in BC prepared from different AJM. Moreover, the AJM modified with only ethanol, exhibited quite a significant yield of BC. BC produced from the medium without ethanol had the highest thermal stability, viscoelasticity, and WHC.
The low frequency of p53 alterations e.g., mutations/deletions (∼10%) in multiple myeloma (MM) makes this tumor type an ideal candidate for p53-targeted therapies. RITA is a small molecule which can ...induce apoptosis in tumor cells by activating the p53 pathway. We previously showed that RITA strongly activates p53 while selectively inhibiting growth of MM cells without inducing genotoxicity, indicating its potential as a drug lead for p53-targeted therapy in MM. However, the molecular mechanisms underlying the pro-apoptotic effect of RITA are largely undefined. Gene expression analysis by microarray identified a significant number of differentially expressed genes associated with stress response including c-Jun N-terminal kinase (JNK) signaling pathway. By Western blot analysis we further confirmed that RITA induced activation of p53 in conjunction with up-regulation of phosphorylated ASK-1, MKK-4 and c-Jun. These results suggest that RITA induced the activation of JNK signaling. Chromatin immunoprecipitation (ChIP) analysis showed that activated c-Jun binds to the activator protein-1 (AP-1) binding site of the p53 promoter region. Disruption of the JNK signal pathway by small interfering RNA (siRNA) against JNK or JNK specific inhibitor, SP-600125 inhibited the activation of p53 and attenuated apoptosis induced by RITA in myeloma cells carrying wild type p53. On the other hand, p53 transcriptional inhibitor, PFT-α or p53 siRNA not only inhibited the activation of p53 transcriptional targets but also blocked the activation of c-Jun suggesting the presence of a positive feedback loop between p53 and JNK. In addition, RITA in combination with dexamethasone, known as a JNK activator, displays synergistic cytotoxic responses in MM cell lines and patient samples. Our study unveils a previously undescribed mechanism of RITA-induced p53-mediated apoptosis through JNK signaling pathway and provides the rationale for combination of p53 activating drugs with JNK activators in the treatment of MM.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
p53 is a powerful tumor suppressor and is an attractive cancer therapeutic target. A breakthrough in cancer research came from the discovery of the drugs which are capable of reactivating p53 ...function. Most anti-cancer agents, from traditional chemo- and radiation therapies to more recently developed non-peptide small molecules exert their effects by enhancing the anti-proliferative activities of p53. Small molecules such as nutlin, RITA, and PRIMA-1 that can activate p53 have shown their anti-tumor effects in different types of hematological malignancies. Importantly, nutlin and PRIMA-1 have successfully reached the stage of phase I/II clinical trials in at least one type of hematological cancer. Thus, the pharmacological activation of p53 by these small molecules has a major clinical impact on prognostic use and targeted drug design. In the current review, we present the recent achievements in p53 research using small molecules in hematological malignancies. Anticancer activity of different classes of compounds targeting the p53 signaling pathway and their mechanism of action are discussed. In addition, we discuss how p53 tumor suppressor protein holds promise as a drug target for recent and future novel therapies in these diseases.
Multiple myeloma (MM) is incurable in virtually all patients due to the presence of innate and emergent drug-resistance. To identify potential drug resistance mechanisms in MM we used iTRAQ (isobaric ...tags for relative and absolute quantitation) mass spectrometry to compare protein expression profiles of drug-resistant (RPMI 8226-R5) and sensitive (RPMI 8226-S) isogenic cell lines. We identified selective overexpression of myristoylated alanine-rich C-kinase substrate (MARCKS) in drug-resistant R5 cells. MARCKS overexpression was also observed in several drug-resistant human myeloma cell lines (HMCLs) and in drug-resistant primary MM samples. Functionally, inhibition of MARCKS phosphorylation by enzastaurin or knockdown of the gene by RNAi significantly enhanced the sensitivity of resistant HMCLs and primary MM samples to bortezomib and to other anti-myeloma drugs, providing evidence that MARCKS can modulate drug response. Mechanistically, pMARCKS (phosphorylated form of MARCKS) was found to function as an E2F-1 cofactor to regulate SKP2 transcription. pMARCKS promoted cell-cycle progression by facilitating SKP2 expression, suppressing p27(Kip1) and potentially counteracting drug-induced cell-cycle arrest by promoting Cyclin E/CDK2 activity. Importantly, MARCKS knockdown in combination with bortezomib treatment overcame bortezomib resistance, significantly inhibited tumor growth and prolonged host survival in a MM xenograft model. These data provide a rationale for therapeutic targeting of pMARCKS to improve the outcome of patients with refractory/relapsed MM.
We have developed and optimized a microfluidic device platform for the capture and analysis of circulating pancreatic cells (CPCs) and pancreatic circulating tumor cells (CTCs). Our platform uses ...parallel anti-EpCAM and cancer-specific mucin 1 (MUC1) immunocapture in a silicon microdevice. Using a combination of anti-EpCAM and anti-MUC1 capture in a single device, we are able to achieve efficient capture while extending immunocapture beyond single marker recognition. We also have detected a known oncogenic KRAS mutation in cells spiked in whole blood using immunocapture, RNA extraction, RT-PCR and Sanger sequencing. To allow for downstream single-cell genetic analysis, intact nuclei were released from captured cells by using targeted membrane lysis. We have developed a staining protocol for clinical samples, including standard CTC markers; DAPI, cytokeratin (CK) and CD45, and a novel marker of carcinogenesis in CPCs, mucin 4 (MUC4). We have also demonstrated a semi-automated approach to image analysis and CPC identification, suitable for clinical hypothesis generation. Initial results from immunocapture of a clinical pancreatic cancer patient sample show that parallel capture may capture more of the heterogeneity of the CPC population. With this platform, we aim to develop a diagnostic biomarker for early pancreatic carcinogenesis and patient risk stratification.
Optimization of pancreatic CTC immunocapture and phenotyping in a microfluidic device.
PDF
