Development of Curcumin and Turmerone Loaded Solid Lipid Nanoparticle for Topical Delivery: Optimization, Characterization and Skin Irritation Evaluation with 3D Tissue Model.

Background: Curcuma longa L., commonly known as turmeric, is renowned for its therapeutic benefits attributed to bioactive compounds, namely curcumin (Cur) and aromatic turmerone (Tur), present in its rhizome. These compounds exhibit diverse therapeutic properties, including anti-inflammatory, antioxidant, and anti-tumor effects. However, the topical application of these compounds has a significant potential for inducing skin irritation. This study focuses on formulating solid lipid nanoparticle (SLN) carriers encapsulating both Cur and Tur for reduced irritation and enhanced stability. Methods: SLN formulations were prepared by a method using homogenization followed by ultrasonication procedures and optimized by applying response surface methodology (RSM). Results: The optimized SLN formulation demonstrated entrapment efficiencies, with 77.21 ± 4.28% for Cur and 75.12 ± 2.51% for Tur. A size distribution of 292.11 ± 9.43 nm was obtained, which was confirmed to be a spherical and uniform shape via environmental scanning electron microscopy (ESEM) images. The in vitro release study indicated cumulative releases of 71.32 ± 3.73% for Cur and 67.23 ± 1.64% for Tur after 24 hours under sink conditions. Physical stability tests confirmed the stability of formulation, allowing storage at 4°C for a minimum of 60 days. Notably, in vitro skin irritation studies, utilizing the reconstructed human epidermal model (EPI-200-SIT), revealed a significant reduction in irritation with the SLN containing Cur and Tur compared to nonencapsulated Cur and Tur. Conclusion: These findings collectively endorse the optimized SLN formulation as a favorable delivery system for Cur and Tur in diverse topical uses, offering enhanced stability, controlled release and reduced irritation.

The effect of curcumin supplementation on circulating adiponectin and leptin concentration in adults: a GRADE-assessed systematic review and meta-analysis of randomised controlled trials.

Curcumin is a phytocompound found in the root of turmeric, a common herbal ingredient in many Asian cuisines. The compound contains anti-inflammatory activity, which is mediated through an upregulation of adiponectin and reduction of leptin. Results of randomised controlled trials (RCT) have shown that the effects of curcumin on adipokines are conflicting. Therefore, the current systematic review and meta-analysis of RCT were conducted with the aim of elucidating the role of curcumin supplementation on serum adiponectin and leptin. The search included PubMed, Embase, Cochrane Library, Scopus, Web of Science and Google Scholar from inception to August 2023. For net changes in adipokines, standardised mean differences (SMD) were calculated using random effects models. Thirteen RCT with fourteen treatment arms were eligible for inclusion in this meta-analysis. Curcumin supplementation was effective in increasing serum adiponectin (SMD = 0·86, 95 % CI (0·33, 1·39), P < 0·001; I2 = 93·1 %, P < 0·001) and reducing serum leptin (SMD = -1·42, 95 % CI (-2·29, -0·54), P < 0·001; I2 = 94·7 %, P < 0·001). In conclusion, curcumin supplementation significantly increased circulating adiponectin and decreased leptin levels in adults.

Simulation and multi-objective optimization of the dimethyl carbonate production process.

Greenhouse gases such as CO2 are considered effective materials in global warming due to their high absorptivity. So, lowering atmospheric CO2 is one of the most practical strategies. Utilizing carbon dioxide in chemical processes is an applicable method. In this study, Aspen HYSYS 10 was used to investigate how carbon dioxide can be added to the process of dimethyl carbonate production, and the affective parameters of the process, including temperature, residence time, feed ratio, and recycle ratio, were evaluated. It was observed that the production of DMC grew as temperature rose. The simulation results also revealed that a maximum conversion of roughly 8% was attained in the MeOH/EC. Additionally, boosting the recycle ratio is detrimental, and the impact of temperature and MeOH/EC has been enhanced by increasing the residence time. The interactions of the above parameters have been studied by Design Expert 12. The optimum value of effective parameters for the production of dimethyl carbonate has been obtained as follows: temperature of 164.7° C, recycle ratio of 0.2, residence time of 139.45 min, and feed ratio of 5.9%, leading to the conversion of 70%.

Optimization of PLGA-DSPE hybrid nano-micelles with enhanced hydrophobic capacity for curcumin delivery.

Poly (D, L Lactic-co-Glycolic acid) (PLGA) is an FDA-approved polymer. It is distinguished from other biocompatible polymers by its feasibility of production and safety for intravenous cancer tumor targeting. Curcumin (CUR) is a natural molecule with versatile bioactivities including inhibiting the nuclear Factor kappa B (Nf-kB) levels in cancer cells, increased by chemotherapy agents. Our group previously reported a successful decrease in the p65 (RelA) subunit of Nf-kB using 125 µg/ml CUR loaded into PLGA nano-micelles. However, this amount was insufficient to reduce all Nf-kB subunits. This study aimed to increase the hydrophobic capacity of PLGA toward CUR using 1,2-Distearoyl-sn-glycerol-3-phosphoethanolamine (DSPE), an FDA-approved phospholipid. PLGA-DSPE hybrid nano-micelles (HNM) were prepared using two different methods, oil-in-water (OiWa) and film preparation-rehydration (FiRe). The encapsulated CUR was successfully increased to 250 µg/ml using the FiRe method. Physicochemical characterization of CUR-loaded HNM was performed using DLS FT-IR, DSC, and HPLC. In HNM with a size of 156.6 nm, DSPE, incorporated with all functional groups of PLGA, and CUR was trapped in the core of this structure. The release profile of CUR was suitable for targeted cancer therapy and the Encapsulation Efficacy was 92%.

Investigation of optimal operating conditions in dimethyl ether carbonylation to methyl acetate production process.

Ethanol production methods are expanding due to the importance of ethanol as a fuel or additive to fuels. One of these methods is converting methanol to ethanol in a three-step process. All of these steps need to deeply study and investigate to develop the process. In this research, the carbonylation of dimethyl ether to produce methyl acetate, which is the intermediate reaction of the three-step process of methanol to ethanol, has been simulated and optimized. The parameters of temperature, pressure, residence time, and feed ratio have been investigated as effective operational parameters of the process. It has been shown that the temperature and pressure of the process are more effective in the ranges of 220-280 °C and 30-50 bar, respectively. The simulation results showed a maximum point in dimethyl ether conversion in the feed ratio of 0.4-0.6, i.e., in temperature of 260 °C, residence time of 5 h, pressure of 45 bar, DME/CO/Ar = 30/67/3, and DME conversion about 22%. Also, it has been shown that increasing the residence time increases the effect of each of the above parameters. Optimization of the dimethyl ether carbonylation process has demonstrated that the combination of different ranges of the above parameters achieves the desired conversion, i.e., in pressure of 48.23 bar, temperature of 259.06 °C, residence time of 3.68 h, and dimethyl ether/feed of 0.461 vol%; conversion of dimethyl ether will be equal to 85.50%.

BuOH fraction of Salix Babylonica L. extract increases pancreatic beta-cell tumor death at lower doses without harming their function.

Salix babylonica L. is a species of the willow tree. Insulinoma is a tumor originating from pancreatic beta cells. This study aims to research the effect of different fractions of Salix babylonica L. leaf extract on INS-1 cells for treating pancreatic tumors. Cell death occurred at lower doses in the EtOAc fraction. The cells are functional in the BuOH fraction but not in EtOAc and H2O fractions. The EtOAc fraction has a higher percentage of necrosis and ROS. INS1, INS2, and AKT gene expressions in the H2O fraction, GLUT2, IR, HSP70 gene expressions, and WNT4 protein levels increased in the BuOH fraction. HSP90 gene expression, Beta-actin, GAPDH, insulin, HSP70, HSP90, HSF1, Beta-Catenin, and WNT7A protein levels were decreased, while IR immunolabelling intensity increased in both fractions. Ca+2, K+, Na+, and CA-19-9 in the cell, Ca+2 and K+ in secretion increased. The secondary metabolites in the EtOAc fraction cause more damage in INS-1 cells. Since the water fraction also causes the cells to die in high doses, cell function is damaged. The secondary metabolites in the BuOH fraction kill INS-1 cells with less damage. This makes the BuOH fraction of Salix babylonica L. more valuable.

Coating with cationic inulin enhances the drug release profile and in vitro anticancer activity of lecithin-based nano drug delivery systems.

Core-shell structured lipidic nanoparticles (LNPs) were developed using lecithin sodium acetate (Lec-OAc) ionic complex as a core unit and quaternized inulin (QIn) as the shell part. Inulin (In) was modified using glycidyl trimethyl ammonium chloride (GTMAC) as a positively charged shell part and used for coating the negatively surface charged Lec-OAc. The critical micelle concentration (CMC) of the core was determined as 1.047 × 10-4 M, which is expected to provide high stability in blood circulation as a drug-carrying compartment. The amounts of curcumin (Cur) and paclitaxel (Ptx) loaded to LNPs (CurPtx-LNPs), and quaternized inulin-coated LNPs (Cur-Ptx-QIn-LNPs) were optimized to obtain mono-dispersed particles with maximum payload. The total amount of 2.0 mg of the drug mixture (1 mg Cur and 1 mg Ptx) was the optimized quantity for QIn-LNPs and CurPtx-QIn-LNPs due to the favorable physicochemical properties determined by dynamic light scattering (DLS) studies. This inference was confirmed by differential scanning calorimeter (DSC), and Fourier-transform infrared (FT-IR). SEM and TEM images clearly revealed the spherical shapes of LNPs and QIn-LNPs, and QIn covered the LNPs completely. The cumulative release measurements of Cur and Ptx from CurPtx-QIn-LNPs, along with the kinetic studies, showed a significant decrease in the release period of drug molecules with the effect of the coating. At the same time, Korsmeyer-Peppas was the best diffusion-controlled release model. Coating of the LNPs with QIn increased the cell-internalization of NPs to the MDA-MB-231 breast cancer cell lines, resulting in a better toxicity profile than the empty LNPs.

Sexuality and psychological well-being in different polycystic ovary syndrome phenotypes compared with healthy controls: a cross-sectional study.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. The present study aimed to compare the women with different PCOS phenotypes with the healty group in terms of sexual function, depression, anxiety and quality of life scale. MATERIALS AND METHODS: The present cross-sectional study was carried out on 192 women with PCOS (classified on the basis of Rotterdam criteria into four categories) and 50 healthy controls. All participants were asked to fill out the valid and reliable questionnaires of FSFI (Female Sexual Function Index), HADS (Hospital Depression and Anxiety Scale) and SF-12. RESULTS: In the HADS questionnaire, phenotype B achieved the highest mean score in anxiety and depression domains, whereas, phenotype B had the lowest mean score in the FSFI and SF-12 quassionnaires. Furthermore, there was a significant difference between the women with PCOS phenotypes and the control grroup in arousal, lubrication, pain, and mean total score of FSFI (P < 0.05). In regression logistic analysis, age, infertility and depression were predictors of sexual dysfunction (P < 0.05). CONCLUSION: The results indicated significant differences in terms of sexual dysfunction, depression, anxiety and quality of life in the women suffering from different phenotypes of PCOS compared with the healthy group. These results provide evidence that care and recommendations for improving women's QoL and sexual function should be considered according to the relevant PCOS phenotypes.

Quantifying water stress of safflower (Carthamus tinctorius L.) cultivars by crop water stress index under different irrigation regimes.

Infrared thermometry allows evaluating water status of the crop by measuring crop water stress index (CWSI), without the need of physical contact to leaves. In order to quantify water stress by CWSI and finding the best irrigation regime a two-year field experiment was conducted in safflower during 2017 and 2018 growing seasons at Darab, Fars province, Iran. Two safflower cultivars (Goldasht and Local Isfahan) and four irrigation regimes consisted of well-watered [Irrigation based on 100% field capacity (FC)], mild (75% FC), severe (50% FC), and most severe (25% FC) water stress were arranged as split plot according to randomized completely block design with four replicates. The relationship between vapor pressure deficit (VPD) and canopy-air temperature differences (Tc-Ta) was plotted under upper (fully stressed) and lower baselines (non-stressed) equations. In two cultivars, by VPD increment, the distance between upper and lower base lines increased. In Goldasht, the upper baseline (Tc-Ta)ul, was 7.8 °C in 2017 and 8.9 °C in 2018. From April to July when air warmed, Tc-Ta differential was increased up to July and the highest seasonal CWSI (0.72-0.77) were obtained in Local Isfahan under most severe water stress. In 2017, under water stress, the highest relative water content (RWC; 55%), color quality (6-7) and water use efficiency (WUE; 2.69 g m-2 mm-1) was observed in Goldasht under mild water stress which was more than 2018 and Local Isfahan. It might be attributed the more tolerance of Goldasht to water stress and lower air temperature and evaporation in the first year. CWSI with total water consumed (R2 = 0.88∗∗), RWC (R2 = 0.87∗∗), color quality (R2 = 0.75∗) and seed yield (R2 = 0.83∗∗) related, negatively. Overall, a mild water stress (75% FC) with 0.28-0.33 seasonal CWSI had higher RWC, color quality, WUE, with an acceptable yield, which could be the best irrigation regime under water deficit conditions for safflower.

Enhancing the Kinetic Stability of Polymeric Nanomicelles (PLGA) Using Nano-Montmorillonite for Effective Targeting of Cancer Tumors.

The toxic profile of chemical cross-linkers used in enhancing the stability of self-assembled nanomicelles made of amphiphilic polymeric materials hinders their use in clinical applications. This study was aimed to use the layered structure of Na-montmorillonite (MMT) as a stabilizer for nanomicelles made of poly(d,l-lactide-co-glycolide) (PLGA) amphiphilic polymer. The size of Na-MMT was reduced below 40 nm (nano-MMT) by processing in an attritor prior to its incorporation with PLGA. Hybrid PLGA nano-MMT (PM) nanoparticles (NPs) were prepared using dialysis nanoprecipitation. The size distribution was measured using dynamic light scattering (DLS). Loading 1250 µg of the model drug molecule curcumin to PM (PMC) resulted in obtaining 88 nm-sized particles, suitable for passive targeting of cancer tumors. The structure of nano-MMT and its position in PMC were investigated using FT-IR, differential scanning chalorimetry (DSC), XRF, XRD, ESEM, and EDAX assays, all of which showed the exfoliated structure of nano-MMT incorporated with both hydrophilic and hydrophobic blocks of PLGA. Curcumin was mutually loaded to PLGA and nano-MMT. This firm incorporation caused a serious extension in the release of curcumin from PMC compared to PLGA (PC). Fitting the release profile to different mathematical models showed the remarkable role of nano-MMT in surface modification of PLGA NPs. The ex vivo dynamic model showed the enhanced stability of PMC in simulated blood flow, while cytotoxicity assays showed that nano-MMT does not aggravate the good toxic profile of PLGA but improves the anticancer effect of payload. Nano-MMT could be used as an effective nontoxic stabilizer agent for self-assembled NPs.

Levan enhanced the NF-κB suppression activity of an oral nano PLGA-curcumin formulation in breast cancer treatment.

Chemoresistance (CR) is one of the reasons why chemotherapy agents like Gemcitabine (GMC) remain insufficient in healing breast cancer. Activation of Nuclear Factor-kappa B (NF-κB) during chemotherapy is known as an important factor in the development of CR. The hydrophobic polyphenol curcumin is shown to inhibit NF-κB and hence CR. The aim of this work was to increase the poor bioavailability of curcumin by loading it into the nano-micelles made of Poly (Lactide-co-Glycolide) (PLGA) and levan, where levan as a natural fructose homopolymer makes the nano-micelle more stable and increases its uptake using the fructose moieties. In this study, a PLGA-levan-curcumin formulation (PLC) was designed and characterized. The size was measured as 154.16 ± 1.45 nm with a 67.68% encapsulation efficiency (EE%). The incorporation between the components was approved. Levan made the nano-micelles stable for at least three months, increased their uptake, and led to a 10,000-fold increase in the solubility of curcumin. The enhanced bioavailability of curcumin reduced the NF-κB levels elevated by GMC, both in vitro and in vivo. The PLC showed a complete tumor treatment, while GMC only showed a rate of 52%. These point to the great potential of the PLC to be used simultaneously with chemotherapy.

Targeting breast cancer using pirarubicin-loaded vasoactive intestinal peptide grafted sterically stabilized micelles.

In this study the chemotherapeutic agent Pirarubicin (PRB) which is known for its serious side effects was actively targeted to the breast cancer cells by uploading it to the biocompatible and biodegradable Sterically Stabilized Micelles (SSMs) made of 1,2- Distearoyl- sn- glycero­3- phosphoethanolamine- N- methoxy­ polyethylene glycol 2000 (DSPE-PEG2000) to enhance efficacy and reduce toxicity. Vasoactive intestinal peptide (VIP), the receptors of which are overexpressed on the breast cancer cells, was grafted on the surface of the micelles. To the best of our knowledge this is the first report on active targeting of PRB to tumor site. For this purpose, PRB loaded VIP grafted SSMs (PRB-SSM-VIP) were synthesized and characterized. The in vitro efficiency of PRB-SSM-VIP along with SSM and free PRB was investigated on the MCF-7 breast cancer cells and the in vivo effects were studied on the 4T1 breast cancer bearing nude mice. Solubilizing 300 µg of PRB using 2.81 mg of DSPE-PEG2000 resulted in obtaining monodispersed particles of 12.16 ± 2.7 nm with slow drug release profile. Incorporation of PRB within the hydrophobic DSPE core of SSM was confirmed using differential scanning calorimetry (DSC) and the spherical shape of the synthesized particles was demonstrated using atomic force microscope (AFM). Both in vitro and in vivo studies showed significantly higher activity of PRB-SSM-VIP compared to free PRB. In vivo imaging showed successful accumulation of PRB-SSM-VIP at the tumor site and 98.8% tumor eradication was obtained with no signs of side effects. Current study suggests that SSM-VIP could be used as new drug delivery system for targeting PRB to the breast cancer cells.

A Preliminary Research Study on the Cytotoxicity of Expired and Non-expired Composite Resins: In Vitro Study / Estudio preliminar in vitro de la citotoxicidad de resinas compuestas caducadas y no caducadas

Astracts Objective: Studies have focused on use of non-expired composites. Unfortunately some clinicians still use expired composite resins without considering their effects. The objective of this in vitro preliminary research was to investigate cytotoxicity of expired(6-months) and non-expired composite resins. Materials and methods: Expired (E) and non-expired (NE) samples of one bulk-fill (Tetric N-Ceram Bulk-fill (TNB), Ivoclar Vivadent), two nano-hybrid (Tetric N-Ceram (TN), Ivoclar Vivadent; Clearfil Majesty ES-2 (CM), Kuraray) composite resins were tested on L929 fibroblast cells. Medium covering cells was removed then plastic rings (2-mm height) were filled with non-polymerized composite resins, placed in direct contact with cells and polymerized with LED light curing unit (LCU). Three samples were prepared for each group. After polymerization, removed medium was added to the cells. Cells that were left without medium (WOM) and cells that were exposed to LCU were used as positive control groups. Cells without any treatment were used as negative control group (C). Cells were incubated with tested materials for 7-days to evaluate cytotoxicity. Cell viability was calculated by sulforhodamine B test as a percentage (%). One-way ANOVA and post-hoc Tukey tests were used for statistical analyses (p0.05), except between TN NE and TN E (p0.05). All experimental groups compared with C group showed statistically significant cytotoxicity (p<0.05). A statistically significant difference existed between LCU and C groups (p<0.05). Conclusions: In clinical practice, expired composite resins should never be used. Although a correlation was found between expiration dates of nano-hybrid composite resins and cell viability, opposite data were obtained for bulk- fill composite resin. Researches are still required to evaluate biocompatibility of bulk- fill composite resins at various thicknesses with current LCUs.

Resumen Objetivo: Los estudios se han concentrado en el uso de resinas compuestas no vencidos. Desafortunadamente, algunos clínicos aún usan resinas caducadas sin considerar sus efectos. El objetivo de este estudio preliminar in vitro fue investigar la citotoxicidad de resinas compuestas caducadas (6 meses) y no caducadas. Materiales y métodos: muestras caducadas (E) y no caducadas (NE) de una resina bulk-fill (Tetric N-Ceram Bulk-fill (TNB), Ivoclar Vivadent) y dos resinas nanohíbridas (Tetric N-Ceram (TN) Ivoclar Vivadent) (Clearfil Majesty ES-2 (CM), Kuraray), se probaron en células de fibroblastos L929. Se retiraron las células que cubrían el medio, luego se llenaron anillos de plástico (2 mm de altura) con resinas no polimerizadas, se colocaron en contacto directo con las células y se polimerizaron con una unidad de fotocurado LED (LCU). Se prepararon tres muestras para cada grupo. Después de la polimerización, se añadió el medio eliminado a las células. Las células que quedaron sin medio (WOM) y las células que se expusieron a LCU se usaron como grupos de control positivo. Las células sin ningún tratamiento se utilizaron como grupo de control negativo (C). Las células se incubaron con las resinas durante 7 días para evaluar la citotoxicidad. La viabilidad celular se calculó mediante la prueba de sulforodamina B como un porcentaje (%). ANOVA unidireccional y pruebas post-hoc de Tukey se utilizaron para los análisis estadísticos (p 0.05), excepto entre TN NE y TN E (p 0.05). Todos los grupos experimentales en comparación con el grupo C mostraron citotoxicidad estadísticamente significativa (p <0,05). Existió una diferencia estadísticamente significativa entre LCU y grupos C (p <0.05). Conclusiones: En la práctica clínica, las resinas compuestas caducadas nunca deben usarse. Aunque se encontró una correlación entre las fechas de vencimiento de las resinas compuestas nano-híbridas y la viabilidad celular, se obtuvieron datos opuestos para la resina bulk-fill. Se requieren nuevas investigaciones para evaluar la biocompatibilidad de las resinas bulk-fill en distintos espesores con las LCU actuales.

Targeted Nanomedicines for Cancer Therapy, From Basics to Clinical Trials.

Traditional systemic chemotherapy involves the wide distribution of drug molecules in the body, causing toxic side effects in the healthy tissues and limiting the therapeutic dose required at the site of drug action. In order to decrease side effects and increase the drug efficacy, recent research on chemotherapy focuses on drug targeting. Targeted therapy can be achieved by several mechanisms including; 1) using an antibody as a drug that is specific to a disease biomarker, 2) using an antibody (or peptide) as a targeting agent conjugated to the drug molecule, 3) delivering the drug molecules to the target tissue in a nano-carrier with or without the targeting agent attached on its surface. The third approach involves the nanomedicines that can be targeted to diseased tissues by both passive (extravasating at diseased sites due to leaky vasculature) and active (specific interaction of the targeting agent with disease biomarker) targeting mechanisms. In this review we will cover the passively targeted nanomedicines prepared using nano drug carriers. Ideally the carrier particle should be in the right size (1-100nm), stable enough to prevent drug leakage during circulation, and safe not to cause any damage to healthy tissues. Competition for all these properties generated many different types of materials to be used as nanodrug delivery systems. After a brief review of most commonly used drug carriers, we discuss the clinical use of the targeted nanomedicines with regard to their pharmacokinetic and pharmacodynamics properties, and how these properties vary from conventional formulations providing free drugs in the circulation after administration.

Anticholinesterase and Antioxidant Activities of Natural Abietane Diterpenoids with Molecular Docking Studies.

BACKGROUND: Alzheimer's Disease (AD) is one of the most prevalent causes of dementia in the world, and no drugs available that can provide a complete cure. Cholinergic neurons of the cerebral cortex of AD patients are lost due to increased activity of cholinesterase enzymes. OBJECTIVE: Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE) are the two major classes of cholinesterases in the mammalian brain. The involvement of oxidative stress in the progression of AD is known. Thus, the objective of this study is to determine strong ChE inhibitors with anti-oxidant activity. METHODS: In this study, 41 abietane diterpenoids have been assayed for antioxidant and anticholinesterase (both for AChE and BuChE) properties in vitro, which were previously isolated from Salvia species, and structurally determined by spectroscopic methods, particularly intensive 1D- and 2DNMR and mass experiments. Molecular modeling studies were performed to rationalize the in vitro ChE inhibitory activity of several abietane diterpenoids compared with galantamine. RESULTS: Thirteen out of the tested 41 abietane diterpenoids exhibited at least 50% inhibition on either AChE or BuChE. The strongest inhibitory activity was obtained for Bractealine against BuChE (3.43 µM) and AChE (33.21 µM) while the most selective ligand was found to be Hypargenin E against BuChE enzyme (6.93 µM). A full correlation was not found between anticholinesterase and antioxidant activities. The results obtained from molecular modelling studies of Hypargenin E and Bractealine on AChE and BuChE were found to be in accordance with the in vitro anti-cholinesterase activity tests. CONCLUSION: Abietane diterpenoids are promising molecules for the treatment of mild-moderate AD.

Engineering of siRNA loaded PLGA Nano-Particles for highly efficient silencing of GPR87 gene as a target for pancreatic cancer treatment.

G protein-coupled receptor (GPCR) 87, is overexpressed in various cancer cells especially pancreatic cancer and plays a critical role in tumor cell survival. Nano-particles (NP) have become the essential vehicles for nucleotide internalization to the cell, due to the negative charge of nucleotides and their poor stability in blood circulation. In this study, the HEK293T cell linewas transfected with GPR87-plasmid after which the double-stranded RNA molecules targeting the GPR87 gene were prepared and purified. 1.1B4 cancer cell lines were used as model pancreatic cancer cells. Produced siRNA molecules were encapsulated in Poly(Lactic-Co-Glycolic Acid) (PLGA) nano-micelles using three different methods, two of which were according to literature with (siR-PLGA-S) or without (siR-PLGA-V) sonication. However, a new method was suggested to overcome problems such as poly-dispersity and large sizes of siR-PLGA-S and siR-PLGA-V. The new method consists of encapsulating siRNA using mild agitation to the pre-made PLGA NPs. The latter method provided mono-dispersed particles (siR-P-PLGA) with 92 nm size and desired Encapsulation Efficiency (EE%). siR-P-PLGA was able to silence the GPR-87 gene in a ratio of 83.9%, almost 41 times more effective than siR-PLGA-S and siR-PLGA-V in HEK 293 T cells. siR-P-PLGA was able to show a mild cytotoxic effect on 1.1B4 pancreatic cancer cells within 48 h.

Investigation of cell death mechanism and activity of esculetin-loaded PLGA nanoparticles on insulinoma cells in vitro.

AIM: The purpose of this study was to prepare targeted cancer therapy formulation against insulinoma INS-1 cells and to study its effect on cell death with related mechanisms in vitro. METHODS: Polylactide-co-glycolide (PLGA) nano-micelles were used for preparation of esculetin nano-formulation (nano-esculetin). The cells were treated with nano-esculetin and free esculetin. Apoptotic and necrotic cell death percentages, cell proliferation, ATP and GTP reductions and insulin levels were investigated on insulinoma INS-1 cells for both free and nano-esculetin formulations. RESULTS: About 50 mg of PLGA was able to carry 20 mg esculetin in 20 ml of formulation. The obtained optimized formulation was 150 nm, with 92% encapsulation efficiency and a slow-release behaviour was observed during release studies. Nano-esculetin bearing 25, 50 and 100 µg esculetin and free esculetin in equivalent doses successfully decreased cell viability. The prevailing cell death mechanism was necrosis. Along with cell proliferation, intracellular insulin and the ratio of ATP and GTP were decreased even with 12.5, 25 and 50 µg esculetin bearing nano-formulation and its equivalent free esculetin. CONCLUSIONS: The results revealed that esculetin is able to show its anti-tumor afficacy after loading to PLGA nano-micelles and nano-encapsulation intensifies its cytotoxic activity in vitro. Current study shows that esculetin and its nano formulations are promising agents in treatment of insulinoma.

Inhibition of Amyloid ß Aggregation Using Optimized Nano-Encapsulated Formulations of Plant Extracts with High Metal Chelator Activities.

BACKGROUND: The role of Fe+2, Cu+2 and Zn+2 in facilitating aggregation of Amyloid ß (Aß) and consequently, the progression of Alzheimer's disease (AD) is well established. OBJECTIVE: Development of non-toxic metal chelators is an emerging era in the treatment of AD, in which complete success has not been fully achieved. The purpose of this study was to determine plant extracts with high metal chelator and to encapsulate them in nano-micellar systems with the ability to pass through the Blood Brain Barrier (BBB). METHODS: Extracts of 36 different Anatolian plants were prepared, total phenolic and flavonoid contents were determined, and the extracts with high content were examined for their Fe+2, Cu+2 and Zn+2 chelating activities. Apolipoprotein E4 (Apo E) decorated nano-formulations of active extracts were prepared using Poly (Lactide-co-Glycolide) (PLGA) (final product ApoEPLGA) to provide BBB penetrating property. RESULTS: Verbascum flavidum aqueous extract was found as the most active sample, incubation of which, with Aß before and after metal-induced aggregation, resulted in successful inhibition of aggregate formation, while re-solubilization of pre-formed aggregates was not effectively achieved. The same results were obtained using ApoEPLGA. CONCLUSION: An optimized metal chelator nano-formulation with BBB penetrating ability was prepared and presented for further in-vivo studies.

Development and optimization of a novel PLGA-Levan based drug delivery system for curcumin, using a quality-by-design approach.

This study aimed to develop a PLGA, Levan-based drug delivery system (DDS) of Curcumin using a quality-by-design (QbD) approach to reveal how formulation parameters affect the critical quality attributes (CQAs) of this DDS and to present an optimal design. First, a risk assessment was conducted to determine the impact of various process parameters on the CQAs of the DDS (i.e., average particle size, ZP, encapsulation efficiency and polydispersity index). Plackett-Burman design revealed that potential risk factors were Levan molecular weight, PLGA amount and acetone amount. Then, the optimization of the DDS was achieved through a Box-Behnken Design. The optimum formulation was prepared using low molecular weight Levan (134 kDa), 51.51 mg PLGA and 10 ml acetone. The model was validated and the optimized formulation was further characterized using different physic-chemical methods. The study resulted in the most stable NP with a spherical and uniform shape and physical stability tests indicated its stability for at least 60 days at room temperature. In conclusion, this study was an effort for developing a DDS which solubilizes Curcumin in clinically applicable concentrations.

Association between quality and quantity of dietary carbohydrate and pregnancy-induced hypertension: A case-control study.

BACKGROUND & AIMS: Pregnancy-induced hypertension (PIH) is a pregnancy-specific disorder that increases maternal and infant mortality and morbidity. The quantity and quality of consumed carbohydrates are probably the main dietary factors affecting blood pressure. The present study aimed to evaluate the association of carbohydrate quality and quantity with PIH. METHODS: This case-control study was performed on 202 pregnant women with or without PIH. The dietary data were collected using 168-item semi-quantitative food frequency questionnaires. Daily glycemic index (GI) and glycemic load (GL), ratio of whole grains to total grains, ratio of solid carbohydrates to total carbohydrates, dietary fiber and carbohydrate intake, and carbohydrate quality index (CQI) were calculated and their associations with PIH were evaluated using logistic regression. We eliminated collinearity within independent variables using factor analysis and then with evaluating the relationship between extracted factors and PIH. RESULTS: In pregnant women in whom the daily carbohydrate intake and GL were higher than median increased frequency of PIH compared to whom had lower than median ones (OR = 3.23, 95% CI 1.46-7.17, and P = 0.004; OR = 2.60, 95% CI 1.21-5.56; and P = 0.035, respectively). Furthermore, we showed a significant inverse association between extracted factor that was mostly related to total fiber intake frequency of PIH (OR = 0.45; 95% CI 0.20-0.97, and P = 0.049 when higher than median values compared to lower than ones). The GI, ratio of whole grains to total grains, ratio of solid carbohydrates to total carbohydrates, and CQI did not associate with PIH. CONCLUSIONS: These findings suggest that carbohydrate intake and GL are related to higher and daily fiber intake to lower frequency of PIH.