Incorporation of montmorillonite into microfluidics-generated chitosan microfibers enhances neuron-like PC12 cells for application in neural tissue engineering.

The complexity in structure and function of the nervous system, as well as its slow rate of regeneration, makes it more difficult to treat it compared to other tissues. Neural tissue engineering aims to create an appropriate environment for nerve cell proliferation and differentiation. Fibrous scaffolds with suitable morphology and topography and better mimicry of the extracellular matrix have been promising for the alignment and migration of neural cells. On this premise, to improve the properties of the scaffold, we combined montmorillonite (MMT) with chitosan (CS) polymer and created microfibers with variable diameters and varied concentrations of MMT using microfluidic technology and tested its suitability for the rat pheochromocytoma cell line (PC12). According to the findings, CS/MMT 0.1 % compared to CS/MMT 0 % microfibers showed a 201 MPa increase in Young's modulus, a 68 mS/m increase in conductivity, and a 1.4-fold increase in output voltage. Analysis of cell mitochondrial activity verified the non-toxicity, resulting in good cell morphology with orientation along the microfiber. Overall, the results of this project showed that with a low concentration of MMT, the properties of microfibers can be significantly improved and a suitable scaffold can be designed for neural tissue engineering.

A doxycycline-loaded microfiber of poly-metformin/PCL for eradicating melanoma stem cells.

Nowadays, electrospun fibrous mats are used as drug delivery systems for loading of potential drugs in order to kill cancer cells. In the study, a skin patch for treating melanoma cancer after surgery was made using polycaprolactone and polymetformin microfibers that were loaded with doxycycline (PolyMet/PCL@DOX), an anti-cancer stem cell agent. The morphology, structure, mechanical characteristics, swelling, and porosity of the electrospun microfibers were examined. Drug release andanticancereffectiveness of PolyMet/PCL@DOXwas evaluated against A375 melanoma cancer stem cells using the MTS, Flow cytometry, colony formation and CD44 expression assays. Scanning electron microscopy (SEM) verified the micro fibrous structure with a diameter of about 2.31 µm. The porosity and swelling percentages for microfibers was 73.5 % and 2.9 %, respectively. The tensile strength at the breaking point was equal to 3.84 MPa. The IC50 of PolyMet/PCL@DOX was 7.4 µg/mL. The survival rate of A375 cells after 72 h of PolyMet/PCL@DOX treatment was 43.9 %. The colony formation capacity of A375 cells decreased after PolyMet/PCL@DOX treatment. The level of CD44 expression in the PolyMet/PCL@DOX group decreased compared to the control group. Generally, PolyMet/PCL@DOX microfibers can be a promising candidate as a patch after surgery to eradicate cancer stem cells, effectively.

Metformin ameliorates cardiopulmonary toxicity induced by chlorpyrifos.

Chlorpyrifos (CPF) is a widely used pesticide that can impair body organs. Nonetheless, metformin is known for its protective role against dysfunction at cellular and molecular levels led by inflammatory and oxidative stress. This study aimed to investigate the modulatory impacts of metformin on CPF-induced heart and lung damage. Following the treatment of Wistar rats with different combinations of metformin and CPF, plasma, as well as heart and lung tissues, were isolated to examine the level of oxidative stress biomarkers like reactive oxygen species (ROS) and malondialdehyde (MDA), inflammatory cytokines such as tumor necrosis alpha (TNF-α), high mobility group box 1 (HMGB1) gene, deoxyribonucleic acid (DNA) damage, lactate, ADP/ATP ratio, expression of relevant genes (TRADD, TERT, KL), and along with histological analysis. Based on the findings, metformin significantly modulates the impairments in heart and lung tissues induced by CPF.

Trimetazidine Preconditioning Potentiates the Effect of Mesenchymal Stem Cells Secretome on the Preservation of Rat Pancreatic Islet Survival and Function In Vitro.

Islet transplantation offers improved glycemic control in individuals with type 1 diabetes mellitus. However, in vitro islet culture is associated with islet apoptosis and eventually will lose their functionality prior to transplantation. In this study, we examined the effects of mesenchymal stem cells (MSCs) secretome preconditioned with diazoxide (DZ) and trimetazidine (TMZ) on rat islet cells during pre-transplant culture. With and without preconditioned hAD-MSCs' concentrated conditioned media (CCM) were added to the culture medium containing rat islets every 12 h for 24 and 48 h, after testing for selected cytokine concentrations (interleukin (IL)-4, IL-6, IL-13). Insulin content, glucose-stimulated insulin secretion, islet cell apoptosis, and mRNA expression of pro-apoptotic (BAX, BAK-1, and PUMA) and anti-apoptotic factors (BCL-2, BCL-xL, and XIAP) in rat islets were assessed after 24 and 48 h of culture. The protein level of IL-6 and IL-4 was significantly higher in TMZ-MSC-CM compared to MSC-non-CM. In rat isolated islets, normalized secreted insulin in the presence of 16.7 mM glucose was significantly higher in treated islet groups compared to control islets at both 24 and 48 h cultivation. Also, the percentage of apoptotic islet cells TMZ-MSC-CCM-treated islets was significantly lower compared to MSC-CM and MSC-CCM-treated islets in both 24 and 48 h cultivation. Consistent with the number of apoptotic cells, after 24 h culture, the expression of BCL-2 and BCL-xL genes in the control islets was lower than all treatment islet groups and in 48 h was lower than only TMZ-MSC-CM-treated islets. Also, the expression of the XIAP gene in control islets was significantly lower compared to the TMZ-MSC-CCM-treated islets at both at 24 and 48 h. In addition, mRNA level of the BAX gene in TMZ-MSC-CCM-treated islets was significantly lower compared to other groups at 48 h. Our findings revealed that TMZ proved to be more effective than DZ and could enhance the potential of hAD-MSCs-CM to improve the function and viability of islets prior to transplantation.

Assessment of synthesized chitosan/halloysite nanocarrier modified by carbon nanotube for pH-sensitive delivery of curcumin to cancerous media.

Constructing a system to carry medicine for more effective remedy of cancer has been a leading challenge, as the number of cancer cases continues to increase. In this present research, a curcumin-loaded chitosan/halloysite/carbon nanotube nanomixture was fabricated by means of water/oil/water emulsification method. The drug loading efficiency (DL) and entrapment efficiency (EE), as a result, reached 42 % and 88 %, respectively and FTIR and XRD analysis confirmed the bonding between the drug and nanocarrier. Morphological observation through FE-SEM and characterization through DLS analysis demonstrated that the average size of nanoparticles is 267.37 nm. Assessment of release within 96 h in pH 7.4 and 5.4 showed sustained release. For more investigation, release data was analyzed by diverse kinetic models to understand the mechanism in the release procedure. An MTT assay was also carried out, and the results illustrated apoptosis induction on MCF-7 cells and exhibited ameliorated cytotoxicity of the drug-loaded nanocomposite compared to the free curcumin. These findings suggest that the unique pH-responsive chitosan/halloysite/carbon nanotube nanocomposite might make a good option for drug delivery systems, particularly for the cancer treatment.

Nanoemulsion carriers of porous γ-alumina modified by polyvinylpyrrolidone and carboxymethyl cellulose for pH-sensitive delivery of 5-fluorouracil.

5-Fluorouracil (5-FU) is a cytotoxic drug with a low half-life. These features can cause some problems such as burst drug release and numerous side effects. In the present study, a pH-sensitive nanocomposite of polyvinylpyrrolidone (PVP)/carboxymethyl cellulose (CMC)/γ-alumina developed by using water in oil in water (W/O/W) double emulsion method. The fabricated emulsion has been employed as the 5-FU carrier to investigate its effects on drug half-life, side effects, drug loading efficiency (DLE), and drug entrapment efficiency (DEE). Analyzing the FTIR and XRD indicated the successful loading of 5-FU into the nanocarrier and affirmed the synthesized nanocomposite's chemical bonding and crystalline features. Furthermore, by using DLS and Zeta potential assessment, size and undersize distribution, as well as the stability of the drug-loaded nanocomposite were determined, which demonstrated the monodisperse and stable nanoparticles. Moreover, the nanocomposites with spherical shapes and homogeneous surfaces were shown in FE-SEM, which indicated good compatibility for the constituents of the nanocomposites. Moreover, by employing BET analysis the porosity has been investigated. Drug release pattern was studied, which indicated a controlled drug release behavior with above 96 h drug retention. Besides, the loading and entrapment efficiencies were obtained 44 % and 86 %, respectively. Furthermore, the curve fitting technique has been employed and the predominant release mechanism has been determined to evaluate the best-fitted kinetic models. MTT assay and flow cytometry assessment has been carried out to investigate the cytotoxic effects of the fabricated drug-loaded nanocomposite on MCF-7 and normal cells. The results showed enhanced cytotoxicity and late apoptosis for the PVP/CMC/γ-alumina/5-FU. Based on the MTT assay outcomes on normal cell lines (L929), which indicated above 90 % cell viability, the biocompatibility and biosafety of the synthesized nanocarrier have been confirmed. Moreover, due to the porosity of the PVP/CMC/γ-alumina, this nanocarrier can exploit from high specific surface area and be more sensitive to environmental conditions such as pH. These outcomes propose that the novel pH-sensitive PVP/CMC/γ-alumina nanocomposite can be a potential candidate for drug delivery applications, especially for cancer therapy.

Novel carboxymethyl cellulose-halloysite-polyethylene glycol nanocomposite for improved 5-FU delivery.

Drug nano-carriers are crucial for achieving targeted treatment against cancer disorders with minimal side effects. In this study, a pH-responsive nanocomposite based on halloysite nanotube (HNT) coated with carboxymethyl cellulose (CMC)/polyethylene glycol (PEG) hydrogel for controlled delivery of 5-Fluorouracil (5-FU), a hydrophobic chemotherapy drug prescribed for different types of cancers was synthesized for the first time using the water-in-oil-in-water (W/O/W) technique. The developed CMC/PEG/HNT/5-FU nanocomposite was characterized by dynamic light scattering (DLS), zeta potential, Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and Field emission scanning electron microscope (FE-SEM) to get information about the particle size, surface charge, interactions between functional groups, crystalline structure and morphology, respectively. High efficiencies in terms of drug entrapment and loading (46 % and 87 %, respectively) were attained. In-vitro drug release results revealed an improved and sustained 5-FU delivery in an acid environment compared to the physiological medium, corroborating the pH-sensitivity of the developed nano-carrier. Flow cytometry and MTT assays demonstrated that the 5-FU loaded nanocomposite had considerable cytotoxicity on MCF-7 breast cancer cells while it is not toxic against L929 fibroblast cells. The nanocomposite synthesized herein could serve as a platform for the pH-sensitive release of anti-cancer drugs.

Microfluidically fabricated fibers containing pancreatic islets and mesenchymal stromal cells improve longevity and sustained normoglycemia in diabetic rats.

Type 1 diabetes mellitus is an autoimmune disease characterized by the loss of pancreatic isletßcells. Insulin injections and pancreas transplants are currently available therapies. The former requires daily insulin injections, while the latter is constrained by donor organ availability. Islet transplantation is a promising alternative treatment for type 1 diabetes mellitus that may overcome the limitations of previous techniques. Two challenges, however, must be addressed: limited cell retention as a result of the immune response and limited function of the transplanted cells that survive. To address these problems, we developed a microfluidic technology for a one-step generation of islet-laden fibers to protect them from the immune response. This approach enables continuous generation of microfibers with a diameter suitable for islet encapsulation (275µm). We, then, transplanted islet-laden fibers into diabetic Wistar rats. While islet-laden fibers alone were unable to restore normoglycemia in diabetic rats, adding mesenchymal stromal cells (MSCs) restored normoglycemia for an extended time. It increased the animals' lifespan by up to 75 d. Additionally, it improved the glucose-stimulated response of islets to the point where there was no significant difference between the treatment group and the healthy animals. Additionally, the presence of MSCs suppressed the immune response, as seen by decreased levels of pro-inflammatory cytokines such as tumor necrosis factor-α. Taken together, these fibers including islet and MSCs provide a versatile platform for concurrently improving cell preservation and functioning followingin vivotransplantation.

Chitosan/Gamma-Alumina/Fe3O4@5-FU Nanostructures as Promising Nanocarriers: Physiochemical Characterization and Toxicity Activity.

Today, cancer treatment is an important issue in the medical world due to the challenges and side effects of ongoing treatment procedures. Current methods can be replaced with targeted nano-drug delivery systems to overcome such side effects. In the present work, an intelligent nano-system consisting of Chitosan (Ch)/Gamma alumina (γAl)/Fe3O4 and 5-Fluorouracil (5-FU) was synthesized and designed for the first time in order to influence the Michigan Cancer Foundation-7 (MCF-7) cell line in the treatment of breast cancer. Physico-chemical characterization of the nanocarriers was carried out using X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), vibrating sample magnetometry (VSM), dynamic light scattering (DLS), and scanning electron microscopy (SEM). SEM analysis revealed smooth and homogeneous spherical nanoparticles. The high stability of the nanoparticles and their narrow size distribution was confirmed by DLS. The results of the loading study demonstrated that these nano-systems cause controlled, stable, and pH-sensitive release in cancerous environments with an inactive targeting mechanism. Finally, the results of MTT and flow cytometry tests indicated that this nano-system increased the rate of apoptosis induction on cancerous masses and could be an effective alternative to current treatments.

Epigenetic effects of graphene oxide and its derivatives: A mini-review.

Graphene oxide (GO), an engineered nanomaterial, has a two-dimensional structure with carbon atoms arranged in a hexagonal array. While it has been widely used in many industries, such as biomedicine, electronics, and biosensors, there are still concerns over its safety. Recently, many studies have focused on the potential toxicity of GO. Epigenetic toxicity is an important aspect of a material's toxicological profile, since changes in gene expression have been associated with carcinogenicity and disease progression. In this review, we focus on the epigenetic alterations caused by GO, including DNA methylation, histone modification, and altered expression of non-coding RNAs. GO can affect DNA methyltransferase activity and disrupt the methylation of cytosine bases in DNA strands, leading to alteration of genome expression. Modulation of histones by GO, targeting histone deacetylase and demethylase, as well as dysregulation of miRNA and lncRNA expression have been reported. Further studies are required to determine the mechanisms of GO-induced epigenetic alterations.

A novel pH-responsive nanoniosomal emulsion for sustained release of curcumin from a chitosan-based nanocarrier: Emphasis on the concurrent improvement of loading, sustained release, and apoptosis induction.

Curcumin application as an anti-cancer drug is faced with several impediments. This study has developed a platform that facilitates the sustained release of curcumin, improves loading efficiency, and anti-cancer activity. Montmorillonite (MMT) nanoparticles were added to chitosan (CS)-agarose (Aga) hydrogel and then loaded with curcumin (Cur) to prepare a curcumin-loaded nanocomposite hydrogel. The loading capacity increased from 63% to 76% by adding MMT nanoparticles to a chitosan-agarose hydrogel. Loading the fabricated nanocomposite in the nanoniosomal emulsion resulted in sustained release of curcumin under acidic conditions. Release kinetics analysis showed diffusion and erosion are the dominant release mechanisms, indicating non-fickian (or anomalous) transport based on the Korsmeyer-Peppas model. FTIR spectra confirmed that all nanocomposite components were present in the fabricated nanocomposite. Besides, XRD results corroborated the amorphous structure of the prepared nanocomposite. Zeta potential results corroborated the stability of the fabricated nanocarrier. Cytotoxicity of the prepared CS-Aga-MMT-Cur on MCF-7 cells was comparable with that of curcumin-treated cells (p < 0.001). Moreover, the percentage of apoptotic cells increased due to the enhanced release profile resulting from the addition of MMT to the hydrogel and the incorporation of the fabricated nanocomposite into the nanoniosomal emulsion. To recapitulate, the current delivery platform improved loading, sustained release, and curcumin anti-cancer effect. Hence, this platform could be a potential candidate to mitigate cancer therapy restrictions with curcumin.

Molecular Evidence on the Inhibitory Potential of Metformin against Chlorpyrifos-Induced Neurotoxicity.

Chlorpyrifos (CPF) is an organophosphorus (OP) pesticide, resulting in various health complications as the result of ingestion, inhalation, or skin absorption, and leads to DNA damage and increased oxidative stress. Metformin, derived from Galega officinalis, is reported to have anti-inflammatory and anti-apoptotic properties; thus, this study aimed to investigate the beneficial role of metformin in neurotoxicity induced by sub-acute exposure to CPF in Wistar rats. In this study, animals were divided into nine groups and were treated with different combinations of metformin and CPF. Following the 28 days of CPF and metformin administration, brain tissues were separated. The levels of inflammatory biomarkers such as tumor necrosis factor alpha (TNFα) and interleukin 1ß (IL-1ß), as well as the expression of 5HT1 and 5HT2 genes, were analyzed. Moreover, the levels of malondialdehyde (MDA), reactive oxygen species (ROS), and the ADP/ATP ratio, in addition to the activity of acetylcholinesterase (AChE) and superoxide dismutase (SOD), were tested through in vitro experiments. This study demonstrated the potential role of metformin in alleviating the mentioned biomarkers, which can be altered negatively as a result of CPF toxicity. Moreover, metformin showed protective potential in modulating inflammation, as well as oxidative stress, the expression of genes, and histological analysis, in a concentration-dependent manner.

Ameliorating quercetin constraints in cancer therapy with pH-responsive agarose-polyvinylpyrrolidone -hydroxyapatite nanocomposite encapsulated in double nanoemulsion.

Despite quercetin (QC) promising features for cancer therapy, low solubility, poor permeability, and short biological half-life time significantly confine its application in cancer therapy. In this study, a novel approach is developed to improve loading efficiency and attain quercetin sustained-release concurrently. In this direction, hydrogel nanocomposite of agarose (AG)-polyvinylpyrrolidone (PVP)-hydroxyapatite (HAp) was loaded with QC. Incorporating HAp nanoparticles in the AG-PVP hydrogel improved the loading efficiency up to 61%. Also, the interactions between nanoparticle, drug, and hydrogel polymers rendered the nanocomposite pH-responsive at acidic conditions and controlled the burst release at neutral conditions. Then, QC-loaded hydrogel was encapsulated into the water in oil in water nanoemulsions to further sustain the drug release. As a result, the pH-responsive release of QC with prolonged-release over 96 h was observed. In more detail, according to the Korsmeyer-Peppas mathematical model, the mechanism of release was anomalous (diffusion-controlled) at pH 7.4 and anomalous transport (dissolution-controlled) at pH 5.4. The presence of all nanocomposite components was confirmed with FTIR analysis, and XRD results approved the incorporation of QC in the fabricated nanocomposite. The homogeneous surface of the nanocomposite in FESEM images showed good compatibility between components. The zeta potential analysis confirmed the good stability of the nanocarriers. Besides, the fabricated AG-PVP-HAp-QC platform showed significant cytotoxicity on MCF-7 cells compared to QC as a free drug (p < 0.001) and to quercetin-loaded AG-PVP (AG-PVP-QC) (p < 0.001) with enhanced apoptosis induction after the addition of HAp. Accordingly, this delivery platform ameliorated loading and sustained-release of QC, as well as its anticancer activity by releasing the drug at an effective therapeutic level over a long period to induce apoptosis. Thus, turning this drug delivery system into a potential candidate for further biomedical applications.

Impact of Acrylamide on Cellular Senescence Response and Cell Cycle Distribution via an In-vitro Study.

Exposure to certain environmental toxins has been shown to be associated with cellular senescence mainly through induction of oxidative stress and impact on cellular systems. Acrylamide (ACR) has raised worldwide concerns regarding the high risk of human dietary exposure to its hazardous effect. Although there is ample evidence about the carcinogenicity of ACR, limited studies have focused on its impact on cellular aging. The levels of ß-galactosidase (SA-ß-gal) activity, cell cycle distribution, and the expression of the senescence-associated gene and inflammatory markers were evaluated following exposure of embryonic fibroblast cells to ACR. A significant elevation in SA-ß-gal activity after exposure to different concentrations of ACR was accompanied by a considerably increased level of reactive oxygen species and lipid peroxidation. ACR-treated cells showed a noticeable decline in the total antioxidant capacity and thiol molecules. Moreover, the expression of cellular senescence-related genes including p38, p53, and p21 significantly upregulated at the high concentration of 5 mM ACR. ACR also induced G0/G1 phase arrest in embryonic fibroblast cells. The current study results revealed that exposure to ACR could enhance senescence response, contributing to increased oxidative stress and cellular damage.

Estrogens counteract tributyltin-induced toxicity in the rat islets of Langerhans.

BACKGROUND: Tributyltin (TBT) is known as an endocrine disruptor able to interfere with estrogen receptors (ERs) leading to toxic effects on the related endocrine pathways. TBT is an obesogen, reported to disrupt glucose homeostasis leading to diabetes. The aim of this study was to assess the influence of TBT and ß-estradiol on the pancreatic islets of Langerhans in simultaneous exposures. EXPERIMENTAL: Pancreatic islets of 15 male rat were isolated and exposed to TBT (10 µM), ß-estradiol, and TBT plus ß-estradiol for 24 h. Therewith, cellular viability, oxidative stress, apoptosis, and insulin secretion markers were investigated. RESULTS: TBT decreased the viability and increased the apoptosis, reactive oxygen species, and insulin secretion TBT led to increased amounts of apaptosis, reactive oxygen species (ROS), and insulin secretion in pancreatic islets; however, cellular viability was reduced. Co-exposure with ß-estradiol ameliorated the entire mentioned variables near to the control level. CONCLUSION: These results showed that ß-estradiol protect pancreatic islets of Langerhans against TBT-induced toxicity by counteracting oxidative stress and apoptosis as well as insulin secretion. In this way, it is postulated that pancreatic ER pathways particularly in ß-cells might be the determinant target of toxic effects of xenoestrogens like TBT. Hence, evaluation of xenoestrogens-induced ER dysfunction in the endocrine pancreas can be helpful in diabetic risk assessment of these contaminants. Pharmacological modifications of ER pathway in the ß-cells seems promising for better management of diabetes.

Molecular and Biochemical Evidences for Beneficial Effects of Zinc Oxide Nanoparticles in Modulation of Chlorpyrifos Toxicity in Human Lymphocytes.

Chlorpyrifos (CP), an acetylcholinesterase (AChE) inhibitor, is used throughout the world as an insecticide in agriculture and an eradicating agent for termites around homes. In the present study, we examined the protective role of zinc oxide nanoparticles (ZnO NPs) in human CP-treated lymphocytes. Lymphocytes isolated by Ficoll and exposed to 75 µg/mL CP either alone or in combination with logarithmic doses of ZnO NPs (0/1, 1, 10, 100 µg/mL). After a 3-day incubation period, the viability and oxidative stress markers were determined. Then, the levels of tumor necrosis factor-α (TNF-α), as an inflammatory index along with AChE activity and cell death were evaluated. Our results showed that incubation with CP significantly increases the percent of cell death, activities of caspase-3 and -9, level of TNF-α and also promotes the levels of biomarkers which play important role in oxidative stress. On the other hand, the activity of AChE and levels of the total antioxidant power (TAP) decreased in CP-treated lymphocytes. In contrast, lymphocytes treated with different concentrations of ZnO NPs showed a significant decrease in the percent of mortality as well as the levels of TNF-α, as compared with CP-treated lymphocytes. Besides, ZnO NPs increased the levels of AChE and TAP at 1 µg/mL. In conclusion, the results indicate the protective effects of ZnO NPs in the prevention of cytotoxic activity of CP in the lymphocytes.

Reduction of marginal mass required for successful islet transplantation in a diabetic rat model using adipose tissue-derived mesenchymal stromal cells.

BACKGROUND AIMS: Adipose tissue-derived mesenchymal stromal cells (AT-MSCs), widely known as multipotent progenitors, release several cytokines that support cell survival and repair. There are in vitro and in vivo studies reporting the regenerative role of AT-MSCs possibly mediated by their protective effects on functional islet cells as well as their capacity to differentiate into insulin-producing cells (IPCs). METHODS: On such a basis, our goal in the present study was to use three different models including direct and indirect co-cultures and islet-derived conditioned medium (CM) to differentiate AT-MSCs into IPCs and to illuminate the molecular mechanisms of the beneficial impact of AT-MSCs on pancreatic islet functionality. Furthermore, we combined in vitro co-culture of islets and AT-MSCs with in vivo assessment of islet graft function to assess whether co-transplantation of islets with AT-MSCs can reduce marginal mass required for successful islet transplantation and prolong graft function in a diabetic rat model. RESULTS: Our findings demonstrated that AT-MSCs are suitable for creating a microenvironment favorable for the repair and longevity of the pancreas ß cells through the improvement of islet survival and maintenance of cell morphology and insulin secretion due to their potent properties in differentiation. Most importantly, hybrid transplantation of islets with AT-MSCs significantly promoted survival, engraftment and insulin-producing function of the graft and reduced the islet mass required for reversal of diabetes. CONCLUSIONS: This strategy might be of therapeutic potential solving the problem of donor islet material loss that currently limits the application of allogeneic islet transplantation as a more widespread therapy for type 1 diabetes.

Molecular and biochemical evidence on the role of zearalenone in rat polycystic ovary.

Globally, food and animal feed contamination with mycotoxins is one of the most important challenges affecting human health. Zearalenone is a non-steroidal mycotoxin with estrogen-like activity that has been reported to induce reproductive dysfunctions including polycystic ovary in women. The aim of this study was to assess the possible impact of prolonged low dose zearalenone (0.1 mg/kg b.w.) exposure to increase the risk of developing polycystic ovary in rats. We found that zearalenone increases the plasma insulin, glucose, testosterone, progesterone and luteinizing hormone levels, while the plasma estradiol level was reduced. Zearalenone also incited tumor necrosis factor-α and the secreted frizzled-related protein-4 expressions. Histological examination showed atresia of follicles in the treated group. It is concluded that zearalenone intoxication intensely manipulates the plasma hormonal factors and the level of gene expressions related to the polycystic ovary in rats, thus increases the risk of its progression.

Peptide functionalized poly ethylene glycol-poly caprolactone nanomicelles for specific cabazitaxel delivery to metastatic breast cancer cells.

Metastatic cancer is responsible for 90% of deaths in world. Usage of nano-carriers improve the delivery and efficacy of chemotherapeutic agents. Recent studies suggest that decoration of the surface of nano-carriers with various targeting agents may further improve their overall therapeutic efficacy. Using specified peptides in targeted drug delivery is a key point in recent researches. In this study, tumor metastasis targeting (TMT) homing peptide was applied as a targeting group to improve specific drug delivery to tumor cells. TMT peptide is conjugated to poly ethylene glycol-poly caprolactone (PEG-PCL) micellar nanoparticles as carriers for targeted delivery of cabazitaxel to metastatic breast cancer cells. Synthesis of PEG-PCL copolymer was performed by amidation reaction between carboxylic acid group of PEG and amine group of PCL. Nanomicelles were prepared via solvent evaporation method. TMT peptide was covalently conjugated onto nanomicelles through the amine group of PEG. TMT-PEG-PCL nanoparticles were analyzed by Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM), dynamic light scattering (DLS), gel permeation chromatography (GPC) and nuclear magnetic resonance (NMR). Toxicity and cellular uptake of nanomicelles were investigated by in vitro cytotoxicity assays and confocal scanning microscopy in MCF-7 (non-metastatic breast cancer cells) and MDA-MB-231 (metastatic breast cancer cells). The final nanomicelles had about 110nm mean size and encapsulation efficiency of 82.5%. Treatment of metastatic breast cancer cells with targeted nanomicelles significantly increased the necrosis rate to 65%, compared to 33% in non-targeted nanomicelles and 8% in control group. The MDA-MB-231 cells treated with targeted nanomicelles exhibited a strong increase in the fluorescence intensity of coumarin in comparison to the cells treated with non-targeted nanomicelles (p<0.001). It could be concluded that the present carrier has the potential to be considered in treatment of metastatic breast cancer cells.

Effect of styrene exposure on plasma parameters, molecular mechanisms and gene expression in rat model islet cells.

Styrene is an aromatic hydrocarbon compound present in the environment and have primary exposure through plastic industry. The current study was designed to evaluate styrene-induced toxicity parameters in rat plasma fasting blood glucose (FBG) level, oral glucose tolerance, insulin secretion, oxidative stress, and inflammatory cytokines in cellular and molecular levels. Styrene was dissolved in corn oil and administered at different doses (250, 500, 1000, 1500, 2000mg/kg/day and control) to each rat, for 42days. In treated groups, styrene significantly increased fasting blood glucose, plasma insulin (p<0.001) and glucose tolerance. Glucose tolerance, insulin resistance and hyperglycemia were found to be the main consequences correlating gene expression of islet cells. Styrene caused a significant enhancement of oxidative stress markers (p<0.001) and inflammatory cytokines in a dose and concentration-dependent manner in plasma (p<0.001). Moreover, the activities of caspase-3 and -9 of the islet cells were significantly up-regulated by this compound at 1500 and 2000mg/kg/day styrene administrated groups (p<0.001). The relative fold change of GLUD1 was downregulated (p<0.05) and upregulated at 1500 and 2000mg/kg, respectively (p<0.01). The relative fold changes of GLUT2 were down regulated at 250 and 1000mg/kg and up regulated in 500, 1500 and 2000mg/kg doses of styrene (p<0.01). The expression level of GCK indicated a significant upregulation at 250mg/kg and downregulation of relative fold changes in the remaining doses of styrene, except for no change at 2000mg/kg of styrene for GCK. Targeting genes (GLUD1, GLUT2 and GCK) of the pancreatic islet cells in styrene exposed groups, disrupted gluconeogenesis, glycogenolysis pathways and insulin secretory functions. The present study illustrated that fasting blood glucose, insulin pathway, oxidative balance, inflammatory cytokines, cell viability and responsible genes of glucose metabolism are susceptible to styrene, which consequently lead to other abnormalities in various organs.