Furanone loaded aerogels are effective antibiofilm therapeutics in a model of chronic Pseudomonas aeruginosa wound infection.

Almost 80% of chronic wounds have a bacterial biofilm present. These wound biofilms are caused by a range of organisms and are often polymicrobial. Pseudomonas aeruginosa is one of the most common causative organisms in wound infections and readily forms biofilms in wounds. To coordinate this, P. aeruginosa uses a process known as quorum sensing. Structural homologues of the quorum sensing signalling molecules have been used to disrupt this communication and prevent biofilm formation by Pseudomonas. However, these compounds have not yet reached clinical use. Here, we report the production and characterisation of a lyophilised PVA aerogel for use in delivering furanones to wound biofilms. PVA aerogels successfully release a model antimicrobial and two naturally occurring furanones in an aqueous environment. Furanone loaded aerogels inhibited biofilm formation in P. aeruginosa by up to 98.80%. Further, furanone loaded aerogels successfully reduced total biomass of preformed biofilms. Treatment with a sotolon loaded aerogel yielded a 5.16 log reduction in viable biofilm bound cells in a novel model of chronic wound biofilm, equivalent to the current wound therapy Aquacel AG. These results highlight the potential utility of aerogels in drug delivery to infected wounds and supports the use of biofilm inhibitory compounds as wound therapeutics.

Gene Therapy for Neuropsychiatric Disorders: Potential Targets and Tools.

Neuropsychiatric disorders that affect the central nervous system cause considerable pressures on the health care system and have a substantial economic burden on modern societies. The present treatments based on available drugs are mostly ineffective and often costly. The molecular process of neuropsychiatric disorders is closely connected to modifying the genetic structures inherited or caused by damage, toxic chemicals, and some current diseases. Gene therapy is presently an experimental concept for neurological disorders. Clinical applications endeavor to alleviate the symptoms, reduce disease progression, and repair defective genes. Implementing gene therapy in inherited and acquired neurological illnesses entails the integration of several scientific disciplines, including virology, neurology, neurosurgery, molecular genetics, and immunology. Genetic manipulation has the power to minimize or cure illness by inducing genetic alterations at endogenous loci. Gene therapy that involves treating the disease by deleting, silencing, or editing defective genes and delivering genetic material to produce therapeutic molecules has excellent potential as a novel approach for treating neuropsychiatric disorders. With the recent advances in gene selection and vector design quality in targeted treatments, gene therapy could be an effective approach. This review article will investigate and report the newest and the most critical molecules and factors in neuropsychiatric disorder gene therapy. Different genome editing techniques available will be evaluated, and the review will highlight preclinical research of genome editing for neuropsychiatric disorders while also evaluating current limitations and potential strategies to overcome genome editing advancements.

Crocin Inhibits Angiogenesis and Metastasis in Colon Cancer via TNF-α/NF-kB/VEGF Pathways.

Angiogenesis and metastasis play pivotal roles in the progression of cancer. We recently discovered that crocin, a dietary carotenoid derived from the Himalayan crocus, inhibited the growth of colon cancer cells. However, the exact role of crocin on the angiogenesis and metastasis in colorectal cancer remains unclear. In the present study, we demonstrated that crocin significantly reduces the viability of colon cancer cells (HT-29, Caco-2) and human umbilical vein endothelial cells (HUVEC), but was not toxic to human colon epithelial (HCEC) cells. Furthermore, pre-treatment of human carcinoma cells (HT-29 and Caco-2) with crocin inhibited cell migration, invasion, and angiogenesis in concentration -dependent manner. Further studies demonstrated that crocin inhibited TNF-α, NF-κB and VEGF pathways in colon carcinoma cell angiogenesis and metastasis. Crocin also inhibited cell migration, invasion, and tube formation in human umbilical vein endothelial cells (HUVEC) in a concentration -dependent manner. We also observed that crocin significantly reduced the secretion of VEGF and TNF-α induced activation of NF-kB by human colon carcinoma cells. In the absence of TNF-α, a concentration-dependent reduction in NF-kB was observed. Many of these observations were confirmed by in vivo angiogenesis models, which showed that crocin significantly reduced the progression of tumour growth. Collectively, these finding suggest that crocin inhibits angiogenesis and colorectal cancer cell metastasis by targeting NF-kB and blocking TNF-α/NF-κB/VEGF pathways.

Importance of STAT3 signalling in cancer, metastasis and therapeutic interventions.

The Signal Transducer and Activator of Transcription 3 (STAT3) protein is encoded on chromosome 17q21. The SH2 and the DNA binding domains are critical structural components of the protein, together with tyrosine and serine residues that initiate phosphorylation. STAT3 interacts with DNA directly and functions in cells as both a signal transducer and a transcription factor. Its cytoplasmic activation results in dimerisation and nuclear translocation, where it is involved in the transcription of a large number of target genes. STAT3 is hyperactive in cancer cells as a result of upstream STAT3 mutations or enhanced cytokine production in the tumour environment. The STAT3 signalling pathway promotes many hallmarks of carcinogenesis and metastasis, including enhanced cell proliferation and survival, as well as migration and invasion into the extracellular matrix. Recent investigations into novel STAT3-based therapies describe a range of innovative approaches, such as the use of novel oligonucleotide drugs. These limit STAT3 binding to its target genes by attaching to SH2 and DNA-binding domains. Yet, despite these significant steps in understanding the underpinning mechanisms, there are currently no therapeutic agents that addresses STAT3 signalling in a clinically relevant manner.

Dietary Crocin is Protective in Pancreatic Cancer while Reducing Radiation-Induced Hepatic Oxidative Damage.

Pancreatic cancer is one of the fatal causes of global cancer-related deaths. Although surgery and chemotherapy are standard treatment options, post-treatment outcomes often end in a poor prognosis. In the present study, we investigated anti-pancreatic cancer and amelioration of radiation-induced oxidative damage by crocin. Crocin is a carotenoid isolated from the dietary herb saffron, a prospect for novel leads as an anti-cancer agent. Crocin significantly reduced cell viability of BXPC3 and Capan-2 by triggering caspase signaling via the downregulation of Bcl-2. It modulated the expression of cell cycle signaling proteins P53, P21, P27, CDK2, c-MYC, Cyt-c and P38. Concomitantly, crocin treatment-induced apoptosis by inducing the release of cytochrome c from mitochondria to cytosol. Microarray analysis of the expression signature of genes induced by crocin showed a substantial number of genes involved in cell signaling pathways and checkpoints (723) are significantly affected by crocin. In mice bearing pancreatic tumors, crocin significantly reduced tumor burden without a change in body weight. Additionally, it showed significant protection against radiation-induced hepatic oxidative damage, reduced the levels of hepatic toxicity and preserved liver morphology. These findings indicate that crocin has a potential role in the treatment, prevention and management of pancreatic cancer.

Correction: Frankincense essential oil suppresses melanoma cancer through down regulation of Bcl-2/Bax cascade signaling and ameliorates heptotoxicity via phase I and II drug metabolizing enzymes.

[This corrects the article DOI: 10.18632/oncotarget.26930.].

Anti-bacterial activity of inorganic nanomaterials and their antimicrobial peptide conjugates against resistant and non-resistant pathogens.

This review details the antimicrobial applications of inorganic nanomaterials of mostly metallic form, and the augmentation of activity by surface conjugation of peptide ligands. The review is subdivided into three main sections, of which the first describes the antimicrobial activity of inorganic nanomaterials against gram-positive, gram-negative and multidrug-resistant bacterial strains. The second section highlights the range of antimicrobial peptides and the drug resistance strategies employed by bacterial species to counter lethality. The final part discusses the role of antimicrobial peptide-decorated inorganic nanomaterials in the fight against bacterial strains that show resistance. General strategies for the preparation of antimicrobial peptides and their conjugation to nanomaterials are discussed, emphasizing the use of elemental and metallic oxide nanomaterials. Importantly, the permeation of antimicrobial peptides through the bacterial membrane is shown to aid the delivery of nanomaterials into bacterial cells. By judicious use of targeting ligands, the nanomaterial becomes able to differentiate between bacterial and mammalian cells and, thus, reduce side effects. Moreover, peptide conjugation to the surface of a nanomaterial will alter surface chemistry in ways that lead to reduction in toxicity and improvements in biocompatibility.

The secondary bile acids, ursodeoxycholic acid and lithocholic acid, protect against intestinal inflammation by inhibition of epithelial apoptosis.

Increased epithelial permeability is a key feature of IBD pathogenesis and it has been proposed that agents which promote barrier function may be of therapeutic benefit. We have previously reported the secondary bile acid, ursodeoxycholic acid (UDCA), to be protective in a mouse model of colonic inflammation and that its bacterial metabolism is required for its beneficial effects. The current study aimed to compare the effects of UDCA, LCA, and a non-metabolizable analog of UDCA, 6-methyl-UDCA (6-MUDCA), on colonic barrier function and mucosal inflammation in a mouse model of colonic inflammation. Bile acids were administered daily to C57Bl6 mice by intraperitoneal injection. Colonic inflammation, induced by addition of DSS (2.5%) to the drinking water, was measured as disease activity index (DAI) and histological score. Epithelial permeability and apoptosis were assessed by measuring FITC-dextran uptake and caspase-3 cleavage, respectively. Cecal bile acids were measured by HPLC-MS/MS. UDCA and LCA, but not 6-MUDCA, were protective against DSS-induced increases in epithelial permeability and colonic inflammation. Furthermore, UDCA and LCA inhibited colonic epithelial caspase-3 cleavage both in DSS-treated mice and in an in vitro model of cytokine-induced epithelial injury. HPLC-MS/MS analysis revealed UDCA administration to increase colonic LCA levels, whereas LCA administration did not alter UDCA levels. UDCA, and its primary metabolite, LCA, protect against intestinal inflammation in vivo, at least in part, by inhibition of epithelial apoptosis and promotion of barrier function. These data suggest that clinical trials of UDCA in IBD patients are warranted.

Furanone quorum-sensing inhibitors with potential as novel therapeutics against Pseudomonas aeruginosa.

Micro-organisms use quorum sensing (QS), a cell density-dependent process, to communicate. This QS mode of interchange leads to the production of a variety of virulence factors, co-ordination of complex bacterial behaviours, such as swarming motility, degradation of host tissue and biofilm formation. QS is implicated in numerous human infections and consequently researchers have sought ways of effectively inhibiting the process in pathogenic bacteria. Two decades ago, furanones were the first class of chemical compounds identified as Pseudomonas aeruginosa QS inhibitors (QSIs). P. aeruginosa is a ubiquitous organism, capable of causing a wide range of infections in humans, including eye and ear infections, wound infections and potentially fatal bacteraemia and thus novel treatments against this organism are greatly needed. This review provides a brief background on QS and the use of furanones as QSIs. Based on the effectiveness of action, both in vivo and in vitro, we will explore the use of furanones as potential antimicrobial therapeutics and conclude with open questions.

Frankincense essential oil suppresses melanoma cancer through down regulation of Bcl-2/Bax cascade signaling and ameliorates heptotoxicity via phase I and II drug metabolizing enzymes.

Melanoma is a deadly form of malignancy and according to the World Health Organization 132,000 new cases of melanoma are diagnosed worldwide each year. Surgical resection and chemo/drug treatments opted for early and late stage of melanoma respectively, however detrimental post surgical and chemotherapy consequences are inevitable. Noticeably melanoma drug treatments are associated with liver injuries such as hepatitis and cholestasis which are very common. Alleviation of these clinical manifestations with better treatment options would enhance prognosis status and patients survival. Natural products which induce cytotoxicity with minimum side effects are of interest to achieve high therapeutic efficiency. In this study we investigated anti-melanoma and hepatoprotective activities of frankincense essential oil (FEO) in both in vitro and in vivo models. Pretreatment with FEO induce a significant (p < 0.05) dose-dependent reduction in the cell viability of mouse (B16-F10) and human melanoma (FM94) but not in the normal human epithelial melanocytes (HNEM). Immunoblot analysis showed that FEO induces down regulation of Bcl-2 and up regulation of BAX in B16-F10 cells whereas in FM94 cells FEO induced dose-dependent cleavage of caspase 3, caspase 9 and PARP. Furthermore, FEO (10 µg/ml) treatment down regulated MCL1 in a time-dependent manner in FM94 cells. In vivo toxicity analysis reveals that weekly single dose of FEO (1200 mg/kg body weight) did not elicit detrimental effect on body weight during four weeks of experimental period. Histology of tissue sections also indicated that there were no observable histopathologic differences in the brain, heart, liver, and kidney compare to control groups. FEO (300 and 600 mg/kg body weight) treatments significantly reduced the tumor burden in C57BL/6 mice melanoma model. Acetaminophen (750 mg/kg body weight) was used to induce hepatic injury in Swiss albino mice. Pre treatment with FEO (250 and 500 mg/kg body weight) for seven days retained hematology (complete blood count), biochemical parameters (AST, ALT, ALK, total bilirubin, total protein, glucose, albumin/globulin ratio, cholesterol and triglyceride), and the level of phase I and II drug metabolizing enzymes (cytochrome P450, cytochromeb5, glutathione-S-transferase) which were obstructed by the administration of acetaminophen. Further liver histology showed that FEO treatments reversed the damages (central vein dilation, hemorrhage, and nuclei condensation) caused by acetaminophen. In conclusion, FEO elicited marked anti-melanoma in both in vitro and in vivo with a significant heptoprotection.

Emergence of Three Dimensional Printed Cardiac Tissue: Opportunities and Challenges in Cardiovascular Diseases.

Three-dimensional (3D) printing, also known as additive manufacturing, was developed originally for engineering applications. Since its early advancements, there has been a relentless development in enthusiasm for this innovation in biomedical research. It allows for the fabrication of structures with both complex geometries and heterogeneous material properties. Tissue engineering using 3D bio-printers can overcome the limitations of traditional tissue engineering methods. It can match the complexity and cellular microenvironment of human organs and tissues, which drives much of the interest in this technique. However, most of the preliminary evaluations of 3Dprinted tissues and organ engineering, including cardiac tissue, relies extensively on the lessons learned from traditional tissue engineering. In many early examples, the final printed structures were found to be no better than tissues developed using traditional tissue engineering methods. This highlights the fact that 3D bio-printing of human tissue is still very much in its infancy and more work needs to be done to realise its full potential. This can be achieved through interdisciplinary collaboration between engineers, biomaterial scientists and molecular cell biologists. This review highlights current advancements and future prospects for 3D bio-printing in engineering ex vivo cardiac tissue and associated vasculature, such as coronary arteries. In this context, the role of biomaterials for hydrogel matrices and choice of cells are discussed. 3D bio-printing has the potential to advance current research significantly and support the development of novel therapeutics which can improve the therapeutic outcomes of patients suffering fatal cardiovascular pathologies.

Albumin nano-encapsulation of caffeic acid phenethyl ester and piceatannol potentiated its ability to modulate HIF and NF-kB pathways and improves therapeutic outcome in experimental colitis.

Hypoxia inducible factor and nuclear factor-kappa beta pathways have been proposed as therapeutic targets for several inflammatory diseases. Caffeic acid phenethyl ester (CAPE) and piceatannol (PIC) are natural anti-inflammatory compounds; however, poor bioavailability and limited understanding of biomolecular mechanistic limits its clinical use. The aims of this study are to enhance bioavailability and investigate their impact on nuclear p65 and HIF-1α for the first time in experimental colitis.Dextran sulphate sodium was used to induce colitis in mice and effect of either free CAPE/PIC or CAPE/PIC loaded albumin nanoparticles treatment was observed on disease development and levels of cellular p65 and HIF-1α.Our results indicate that albumin nano-encapsulation of CAPE/PIC not only enhances its anti-inflammatory potential but also potentiates its ability to effectively modulate inflammation related biomolecular pathways. Hence, combining nanotechnology with natural compounds could result in development of new therapeutic options for IBD.

Caffeic acid phenethyl ester (CAPE) reverses fibrosis caused by chronic colon inflammation in murine model of colitis.

Fibrosis is known to be the hallmarks of chronic inflammation of the bowel. Epithelial damage due to inflammation compromises the barrier function of the gastrointestinal tract. This barrier dysfunction leads to further spread of inflammation resulting in a chronic state of inflammation. This chronic inflammation leads to development of fibrosis, which has very limited therapeutic options and usually requires surgical removal of the affected tissue. Our previous work has shown that Caffeic acid phenethyl ester (CAPE) is a naturally occurring anti-inflammatory agent, found in propolis, has been found to be protective in experimental colitis via enhancement of epithelial barrier function. However, the impact of CAPE on resolution of fibrosis in the long-term is unknown. The aim of this follow up study was to investigate the effect of CAPE on colon fibrosis in a chronic model of Dextran sulphate sodium induced colitis in mice. Dextran sulphate sodium (DSS) 2.5% w/v was administered in drinking water to induce colitis in C57/BL6 mice for 5 days on the 6th day DSS was stopped and test group mice were treated with intraperitoneal administration of CAPE (30 mg kg-1 day-1) for a further 7 days. Disease activity index (DAI) score, colon length and tissue histology and level of tissue fibrosis was observed. CAPE-treated mice had significantly lower levels of DAI, tissue inflammation scores and fibrosis as compared with control group. Our results show that CAPE is effective in resolving colon fibrosis in chronic inflammation. Thus, we can conclude CAPE could be a potential therapeutic agent for further clinical investigations for treatment of fibrosis in inflammatory bowel diseases in humans.

Enhanced cutaneous wound healing in rats following topical delivery of insulin-loaded nanoparticles embedded in poly(vinyl alcohol)-borate hydrogels.

Insulin plays an important role in the wound healing process, but its method of delivery to the wound bed and subsequent effect on rate of healing is less well investigated. In this study, we evaluated the therapeutic effectiveness of topical human insulin delivery using a nanoparticulate delivery system suspended in a structured hydrogel vehicle. Poly(lactide-co-glycolide) (PLGA) nanoparticles (NP) of 202.6 nm diameter and loaded with 33.86 µg insulin per milligram of polymer were formulated using a modified double-emulsion solvent evaporation technique and dispersed in a dilatant hydrogel (poly(vinyl alcohol)-borate). Importantly, this hydrogel formulation was used to achieve ultimate contact with the wound bed. A comparison of wound healing rates following local administration of insulin in the free and nanoencapsulated forms was performed in diabetic and healthy rats. In non-diabetic rats, there was no significant difference between healing observed in control and wounds treated with free insulin (p > 0.05), whereas treatment with insulin encapsulated within PLGA NP showed a significant difference (p < 0.001). In diabetic cohorts, both free insulin and nanoencapsulated insulin induced significant improvement in wound healing when compared to controls, with better percentage wound injury indices observed with the colloidal formulation. At day 10 of the experiment, the difference between percentage wound injury indices of insulin-PLGA NP and free insulin comparing to their controls were 29.15 and 12.16%, respectively. These results support strongly the potential of insulin-loaded colloidal carriers for improved wound healing when delivered using dilatant hydrogel formulations.

Polymeric nano-encapsulation of 5-fluorouracil enhances anti-cancer activity and ameliorates side effects in solid Ehrlich Carcinoma-bearing mice.

Biodegradable PLGA nanoparticles, loaded with 5-fluorouracil (5FU), were prepared using a double emulsion method and characterised in terms of mean diameter, zeta potential, entrapment efficiency and in vitro release. Poly (vinyl alcohol) was used to modify both internal and external aqueous phases and shown have a significant effect on nanoparticulate size, encapsulation efficiency and the initial burst release. Addition of poly (ethylene glycol) to the particle matrix, as part of the polymeric backbone, improved significantly the encapsulation efficiency. 5FU-loaded NPs were spherical in shape and negatively charged with a size range of 185-350 nm. Biological evaluation was performed in vivo using a solid Ehrlich carcinoma (SEC) murine model. An optimised 5FU-loaded formulation containing PEG as part of a block copolymer induced a pronounced reduction in tumour volume and tumour weight, together with an improved percentage tumour growth inhibition. Drug-loaded nanoparticles showed no significant toxicity or associated changes on liver and kidney function in tested animals, whereas increased alanine aminotransferase, aspartate aminotransferase and serum creatinine were observed in animals treated with free 5FU. Histopathological examination demonstrated enhanced cytotoxic action of 5FU-loaded nanoparticles when compared to the free drug. Based on these findings, it was concluded that nano-encapsulation of 5FU using PEGylated PLGA improved encapsulation and sustained in vitro release. This leads to increased anti-tumour efficacy against SEC, with a reduction in adverse effects.

Association between attendance and overall academic performance on a module within a professional pharmacy degree.

BACKGROUND AND PURPOSE: As the higher education (HE) classroom begins to adopt newer internet-based technologies, the relationship between attendance and performance needs to be re-evaluated, particularly for professional degree courses such as pharmacy. In the present study, we aimed to establish if an association exists between attendance at all timetabled classes and academic performance, in a Clinical Pharmacology and Therapeutics (CPT) module, as part of the Master of Pharmacy (MPharm) degree course at Ulster University. EDUCATIONAL ACTIVITY AND SETTING: Data on attendance, final examination and coursework performance were collected over two academic years (2013-14 and 2014-15) of the CPT module at Ulster. In total 67 students were analysed. The MPharm degree at Ulster University implements an attendance policy, both as a pastoral support tool and to reinforce the need for professional conduct as a pharmacist. FINDINGS: Student (2013-14 and 2014-15, n = 35 and 32, respectively) attendance on the module across both year groups was approximately 80%. We observed positive, and statistically significant relationships between attendance and performance on the examination, and especially in the coursework elements of the module. Student failure (below 40%) in the final examination was linked to attendance below an 80% threshold in nine of 12 cases. Reasons for not attending class varied, but illness was unquestionably the most commonly cited extenuation. DISCUSSION: Taken together, these data confirm a convincing association between student attendance and academic achievement. SUMMARY: Our studies promote the use of attendance monitoring policies for professional degree courses such as pharmacy.

Effect of poly(ethylene glycol) content and formulation parameters on particulate properties and intraperitoneal delivery of insulin from PLGA nanoparticles prepared using the double-emulsion evaporation procedure.

CONTEXT: Size, encapsulation efficiency and stability affect the sustained release from nanoparticles containing protein-type drugs. OBJECTIVES: Insulin was used to evaluate effects of formulation parameters on minimizing diameter, maximizing encapsulation efficiency and preserving blood glucose control following intraperitoneal (IP) administration. METHODS: Homogenization or sonication was used to incorporate insulin into poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles with increasing poly(ethylene glycol) (PEG) content. Effects of polymer type, insulin/polymer loading ratio and stabilizer in the internal aqueous phase on physicochemical characteristics of NP, in vitro release and stability of encapsulated insulin were investigated. Entrapment efficiency and release were assessed by radioimmunoassay and bicinconnic acid protein assay, and stability was evaluated using SDS-PAGE. Bioactivity of insulin was assessed in streptozotocin-induced, insulin-deficient Type I diabetic mice. RESULTS: Increasing polymeric PEG increased encapsulation efficiency, while the absence of internal stabilizer improved encapsulation and minimized burst release kinetics. Homogenization was shown to be superior to sonication, with NP fabricated from 10% PEG-PLGA having higher insulin encapsulation, lower burst release and better stability. Insulin-loaded NP maintained normoglycaemia for 24 h in diabetic mice following a single bolus, with no evidence of hypoglycemia. CONCLUSIONS: Insulin-loaded NP prepared from 10% PEG-PLGA possessed therapeutically useful encapsulation and release kinetics when delivered by the IP route.

Polymeric Nano-Encapsulation of Curcumin Enhances its Anti-Cancer Activity in Breast (MDA-MB231) and Lung (A549) Cancer Cells Through Reduction in Expression of HIF-1α and Nuclear p65 (Rel A).

BACKGROUND: The anti-cancer potential of curcumin, a natural NFκß inhibitor, has been reported extensively in breast, lung and other cancers. In vitro and in vivo studies indicate that the therapeutic efficacy of curcumin is enhanced when formulated in a nanoparticulate carrier. However, the mechanism of action of curcumin at the molecular level in the hypoxic tumour micro-environment is not fully understood. Hence, the aim of our study was to investigate the mechanism of action of curcumin formulated as nanoparticles in in vitro models of breast and lung cancer under an hypoxic microenvironment. METHODS: Biodegradable poly(lactic-co-glycolic acid) PLGA nanoparticles (NP), loaded with curcumin (cur-PLGA-NP), were fabricated using a solvent evaporation technique to overcome solubility issues and to facilitate intracellular curcumin delivery. Cytotoxicity of free curcumin and cur-PLGA-NP was evaluated in MDA-MB-231 and A549 cell lines using migration, invasion and colony formation assays. All treatments were performed under an hypoxic micro-environment and whole cell lysates from controls and test groups were used to determine the expression of HIF-1α and p65 levels using ELISA assays. RESULTS: A ten-fold increase in solubility, three-fold increase in anti-cancer activity and a significant reduction in the levels of cellular HIF-1α and nuclear p65 (Rel A) were observed for cur-PLGA-NP, when compared to free curcumin. CONCLUSION: Our findings indicate that curcumin can effectively lower the elevated levels of HIF-1α and nuclear p65 (Rel A) in breast and lung cancer cells under an hypoxic tumour micro-environment when delivered in nanoparticulate form. This applied means of colloidal delivery could explain the improved anti-cancer efficacy of curcumin and has further potential applications in enhancing the activity of anti-cancer agents of low solubility.

Caffeic acid phenethyl ester is protective in experimental ulcerative colitis via reduction in levels of pro-inflammatory mediators and enhancement of epithelial barrier function.

BACKGROUND: Inhibition of the nuclear factor kappa beta (NF-κß) pathway has been proposed as a therapeutic target due to its key role in the expression of pro-inflammatory genes, including pro-inflammatory cytokines, chemokines, and adhesion molecules. Caffeic acid phenethyl ester (CAPE) is a naturally occurring anti-inflammatory agent, found in propolis, and has been reported as a specific inhibitor of NF-κß. However, the impact of CAPE on levels of myeloperoxidases (MPO) and pro-inflammatory cytokines during inflammation is not clear. The aims of this study were to investigate the protective efficacy of CAPE in the mouse model of colitis and determine its effect on MPO activity, pro-inflammatory cytokines levels, and intestinal permeability. METHOD: Dextran sulphate sodium was administered in drinking water to induce colitis in C57/BL6 mice before treatment with intraperitoneal administration of CAPE (30 mg kg-1 day-1). Disease activity index (DAI) score, colon length and tissue histology levels of MPO, pro-inflammatory cytokines, and intestinal permeability were observed. RESULTS: CAPE-treated mice had lower DAI and tissue inflammation scores, with improved epithelial barrier protection and significant reduction in the level of MPO and pro-inflammatory cytokines. CONCLUSION: Our results show that CAPE is effective in suppressing inflammation-triggered MPO activity and pro-inflammatory cytokines production while enhancing epithelial barrier function in experimental colitis. Thus, we conclude that CAPE could be a potential therapeutic agent for further clinical investigations for treatment of inflammatory bowel diseases in humans.

Effect of poly(ethylene glycol) on insulin stability and cutaneous cell proliferation in vitro following cytoplasmic delivery of insulin-loaded nanoparticulate carriers - A potential topical wound management approach.

We describe the development of a nanoparticulate system, with variation of poly(ethylene glycol) (PEG) content, capable of releasing therapeutic levels of bioactive insulin for extended periods of time. Recombinant human insulin was encapsulated in poly(d,l-lactide-co-glycolide) nanoparticles, manufactured with variation in poly(ethylene glycol) content, and shown to be stable for 6days using SDS-PAGE, western blot and MALDI MS. To determine if insulin released from this sustained release matrix could stimulate migration of cell types normally active in dermal repair, a model wound was simulated by scratching confluent cultures of human keratinocytes (HaCaT) and fibroblasts (Hs27). Although free insulin was shown to have proliferative effect, closure of in vitro scratch fissures was significantly faster following administration of nano-encapsulated insulin. This effect was more pronounced in HaCaT cells when compared to Hs27 cells. Variation in PEG content had the greatest effect on NP size, with a lesser influence on scratch closure times. Our work supports a particulate uptake mechanism that provides for intracellular insulin delivery, leading to enhanced cell proliferation. When placed into an appropriate topical delivery vehicle, such as a hydrogel, the extended and sustained topical administration of active insulin delivered from a nanoparticulate vehicle shows promise in promoting tissue healing.