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Azam Shamsian,1,2 Mohammad Reza Sepand,3 Marziye Javaheri Kachousangi,1,2 Tahereh Dara,4 Seyed Nasser Ostad,3 Fatemeh Atyabi,1,2 Mohammad Hossein Ghahremani1,3 1Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 2Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 3Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 4Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IranCorrespondence: Mohammad Hossein GhahremaniDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, New Building, Room 2-318, Tehran 1417614411, IranTel/Fax +982166959102Email mhghahremani@tums.ac.irBackground: Among various theories for the origin of cancer, the “stemness phenotype model” suggests a dynamic feature for tumor cells in which non-cancer stem cells (non-CSCs) can inter-convert to CSCs. Differentiation with histone-deacetylase inhibitor, vorinostat (SAHA), can induce stem cells to differentiate as well as enforces non-CSCs to reprogram to CSCs. To avoid this undesirable effect, one can block the Wnt-βcatenin pathway. Thus, a dual delivery system of SAHA and a Wnt-βcatenin blocker will be beneficial in the induction of differentiation of CSCs. Protein corona (PC) formation in nanoparticle has a biologic milieu, and despite all problematic properties, it can be employed as a medium for dual loading of the drugs.Materials and Methods: We prepared sphere gold nanoparticles (GNPs) with human plasma protein corona loaded with SAHA as differentiating agent and PKF118-310 (PKF) as a Wnt-βcatenin antagonist. The MCF7 breast cancer stem cells were treated with NPs and the viability and differentiation were evaluated by Western blotting and sphere formation assay.Results: We found that both drugs loaded onto corona-capped GNPs had significant cytotoxicity in comparison to bare GNP-corona. Data demonstrated an increase in stem cell population and upregulation of mesenchymal marker, Snail by SAHA-loaded GNPs treatment; however, the combination of PKF loaded GNPs along with SAHA-loaded GNPs resulted in a reduction of stem cell populations and Snail marker. We have shown that in MCF7 and its CSCs simultaneous treatment with SAHA and PKF118-310 induced differentiation and inhibition of Snail induction.Conclusion: Our study reveals the PC-coated GNPs as a biocompatible career for both hydrophilic (PKF) and hydrophobic (SAHA) agents which can decrease breast cancer stem cell populations along with reduced stemness state regression.Keywords: co-delivery, HDAC inhibitor, Wnt, cancer stem cell, protein corona

Faezeh Vakhshiteh,1 Fatemeh Atyabi,1,2 Seyed Nasser Ostad3 1Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 2Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 3Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran Abstract: Mesenchymal stem cells (MSCs) are multipotent stromal cells present in various adult tissues. Several studies suggest that MSCs secrete exosomes that perform as mediators in the tumor niche and play several roles in tumorigenesis, angiogenesis, and metastasis. In contrast, there are other studies supporting the tumor-suppressing effects of MSC-derived exosomes. Therefore, the exact association of MSC exosomes and tumor cells remains open to debate. This review aimed to demonstrate the present knowledge of MSC-derived exosomes in cancer research and to illustrate current approaches to make use of modified exosomes as a platform in therapeutic strategies in cancer. Keywords: mesenchymal stem cells, exosome, drug delivery, exosome engineering, cancer therapy

Hosniyeh Hosseinzadeh1, Fatemeh Atyabi1, Rassoul Dinarvand1, Seyed Naser Ostad21Nanotechnology Research Centre, 2Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IranAbstract: Nanoparticles have proven to be an effective delivery system with few side effects for anticancer drugs. In this study, gemcitabine-loaded nanoparticles have been prepared by an ionic gelation method using chitosan and Pluronic® F-127 as a carrier. Prepared nanoparticles were characterized using dynamic light scattering, Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), scanning electron microscopy, and transmission electron microscopy. Different parameters such as concentration of sodium tripolyphosphate, chitosan, Pluronic, and drug on the properties of the prepared nanoparticles were evaluated. In vitro drug release was studied in phosphate-buffered saline (PBS; pH = 7.4). The cytotoxicity of the nanoparticles was assayed in the HT-29 colon cancer cell line. The mucoadhesion behavior of the nanoparticles was also studied by mucus glycoprotein assay. The prepared nanoparticles had a spherical shape with positive charge and a mean diameter ranging between 80 to 170 nm. FT-IR and DSC studies found that the drug was dispersed in its amorphous form due to its potent interaction with nanoparticle matrix. Maximum drug encapsulation efficiency was achieved at 0.4 mg/mL gemcitabine while maximum drug loading was 6% obtained from 0.6 mg/mL gemcitabine. An in vitro drug release study at 37°C in PBS (pH = 7.4) exhibited a controlled release profile for chitosan–Pluronic® F-127 nanoparticles. A cytotoxicity assay of gemcitabine-loaded nanoparticles showed an increase in the cytotoxicity of gemcitabine embedded in the nanoparticles in comparison with drug alone. The mucoadhesion study results suggest that nanoparticles could be considered as an efficient oral formulation for colon cancer treatment.Keywords: chitosan, nanoparticles, ionic gelation, gemcitabine, mucoadhesion, oral drug delivery, anticancer

Mona Noori Koopaei1, Rassoul Dinarvand1,2, Mohsen Amini3, Hojatollah Rabbani4, Shaghayegh Emami4, Seyed Nasser Ostad5, Fatemeh Atyabi1,21Novel Drug Delivery Laboratory, Faculty of Pharmacy, 2Nanotechnology Research Center, 3Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 4Monoclonal Antibody Research Center, Avesina Research Institute, ACECR, Tehran, Iran; 5Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Science, Tehran, IranBackground: The objective of this study was to develop pegylated poly lactide-co-glycolide acid (PLGA) immunonanocarriers for targeting delivery of docetaxel to human breast cancer cells.Methods: The polyethylene glycol (PEG) groups on the surface of the PLGA nanoparticles were functionalized using maleimide groups. Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2) antigens of cancer cells, used as the targeting moiety, was attached to the maleimide groups on the surface of pegylated PLGA nanoparticles. Nanoparticles prepared by a nanoprecipitation method were characterized for their size, size distribution, surface charge, surface morphology, drug-loading, and in vitro drug release profile.Results: The average size of the trastuzumab-decorated nanoparticles was 254 ± 16.4 nm and their zeta potential was -11.5 ± 1.4 mV. The average size of the nontargeted PLGA nanoparticles was 183 ± 22 nm and their zeta potential was -2.6 ± 0.34 mV. The cellular uptake of nanoparticles was studied using both HER2-positive (SKBR3 and BT-474) and HER2-negative (Calu-6) cell lines.Conclusion: The cytotoxicity of the immunonanocarriers against HER2-positive cell lines was significantly higher than that of nontargeted PLGA nanoparticles and free docetaxel.Keywords: nanoparticles, drug targeting, immunonanocarriers, trastuzumab, docetaxel, PLGA, HER2 receptor

"nBackground: There is a growing interest in understanding the biological effects of time-tested folk medicinal plants including the green leafy vegetables, which supply minerals and vitamins to the diet. Trigonella foenum-graecum L (fenugreek) is a dietary vegetable and there are reports concerning its antinociceptive effects in Iranian traditional medicine. Its seeds are also known for their carminative, tonic, antidiabetic, antineoplastic and restorative properties. These reports and the hypoglycemic effect of fenugreek leaf extract encouraged us to assay fenugreek aqueous extract for cytotoxicity on NIH3T3 mouse fibroblast cells. "nMethods: The NIH3T3cell line was purchased from National Research Center for Genetic Engineering and Biotechnology of Iran. The cells were plated in 24-well microtiter plates with DMEM+F12 medium containing 10% fetal calf serum supplemented with 445 mg/L L-glutamine and maintained at 37oC with 5% CO2/95% air. Following a 24-hr incubation period, various concentrations (0.01-20 mg) of the extract to the culture wells. Cell viability was assessed using trypan blue and MTT assays after five days of incubation. "nResults: The results show that the IC50 of the fenugreek extract as calculated from the trypan blue and MTT assays were 1.25 and 2.5 mg/mL, respectively. "nConclusions: Our findings, therefore, suggest that the aqueous extract of fenugreek is classified as nontoxic. This observed cytotoxicity is not specific and could be due to membrane disturbances.

Background and Aim: Root filling materials are usually in close contact with living tissues. So their biological properties like mutagenicity and cytotoxicity are important. These properties help us determine the potential damage to periapical tissues, or potential DNA mutations, and malignant transformation of the cells. The aim of this study was to evaluate the mutagenicity and cytotoxicity of four root canal sealers: AH Plus (Dentsply, DeTrey), Ketac-Endo Aplicap (3M ESPE), Sankin Apatite III (Sankin K.K), and Tubli-Seal EWT (Kerr).Materials and Methods: In this experimental in vitro study fresh and set specimens from AH Plus, Ketac-Endo Aplicap, Sankin Apatite III, and Tubli-Seal EWT were immersed in culture medium for 1, 2 and 7 days. Cytotoxicity was assessed using tetrazolium bromide reduction assay (MTT) after 1, 2 and 7 days exposure of diluted extracts to L929 cells. Extracts of sealers in phosphate buffer saline (PBS) were used to examine the mutagenic effects by sos-umu test according to standard procedures. Data were analyzed using one way ANOVA, Kruskall Wallis, Mann Whitney and Post hoc tests with P

Background and Aim: An important requirement for a dentin bonding agent is biological compatibility. Since dentin bonding agents are placed in cavity preparations with subgingival extensions, with direct contact to gingival and mucosal tissues, tissue response to these materials must be investigated. The aim of this study was to examine the cytotoxicity of AdheSE, a self etching adhesive, on human gingival fibroblasts."nMaterials and Methods: In this experimental in vitro study, primary human gingival fibroblasts were exposed to different dilutions of primer & bond of AdheSE (Vivadent, Liechtenstein). The toxicity of the primer was tested in 30 seconds, 300 seconds and 24 hours. The cytotoxicity of the bond was analyzed in uncured mode after 20 seconds, 5 minutes and 24 hours. In cured mode, tested materials were analyzed after 24 and 48 hours. Cytotoxic effects were evaluated using MTT, cell counting and DNA condensation assays. Data were analyzed by two way repeated measure ANOVA with p

The mechanism by which lead may cause a perturbotion in the nevous system is through the nitric oxide synthase. In this study the effect of lead acetate on the hippocampal constitutive nitric oxide production was studied. The variation in the nitric oxide production may contribute to physiological lead neurotoxicity in vivo. Different concentrations of lead acetate (10-9 to 10-6 M), wre added to cultures of hippocampal pyramidal cell obtained from one-day newborn rats. Sodium acetate was used as control. In this range of stuy viability of cells did not alter when it was compared to control (P

Background: Mesenchymal stem cells (MSCs)-based treatment strategy has shown promise in bolstering the healing process of chronic wounds in diabetic patients, who are at risk of amputation and mortality. To overcome the drawbacks of suboptimal cell retention and diminished cell viability at the injury site, a novel nanofibrous biomaterial-based scaffold was developed by using a controlled extrusion of a polymeric solution to deliver the cells (human adipose-derived MSCs (ADMSCs) and placenta-derived MSCs (PLMSCs)) locally to the animal model of diabetic ulcers., Methods: The physicochemical and biological properties of the nano-bioscaffold were characterized in terms of microscopic images, FTIR spectroscopy, tensile testing, degradation and swelling tests, contact angle measurements, MTT assay, and cell attachment evaluation. To evaluate the therapeutic efficacy, a study using an excisional wound model was conducted on diabetic rats., Results: The SEM and AFM images of scaffolds revealed a network of uniform nanofibers with narrow diameters between 100-130 nm and surface roughness less than 5 nm, respectively. ADMSCs and PLMSCs had a typical spindle-shaped or fibroblast-like morphology when attached to the scaffold. Desired characteristics in terms of swelling, hydrophilicity, biodegradation rate, and biocompatibility were achieved with the CS70 formulation. The wound healing process was accelerated according to wound closure rate assay upon treatment with MSCs loaded scaffold resulting in increased re-epithelialization, neovascularization, and less inflammatory reaction. Our findings unequivocally demonstrated that the cell-loaded nano-bioscaffold exhibited more efficacy compared with its acellular counterpart. In summation, our study underscores the potential of this innovative cellular scaffold as a viable solution for enhancing the healing of diabetic ulcers., Conclusion: The utilization of MSCs in a nanofibrous biomaterial framework demonstrates significant promise, providing a novel avenue for advancing wound care and diabetic ulcer management., (© 2024. The Author(s).)

Over the past decades, opium derivatives have been discovered as new anticancer agents. In our study, Fe 3 O 4 superparamagnetic nanoparticles (SPIONs) decorated with chitosan were loaded with papaverine or noscapine to surmount drug delivery-related obstacles. Modifying the magnetic nanoparticles (MNP) surface with polymeric materials such as chitosan prevents oxidation and provides a site for drug linkage, which renders them a great drug carrier. The obtained systems were characterized by DLS (20-40 nm were achieved for MNPs and drug- loaded MNPs), TEM (spherical with average size of 11-20 nm) FTIR, XRD, and VSM (71.3 - 42.8 emu/g). Contrary to noscapine, papaverine-MNPs attenuated 4T1 murine breast cancer cell proliferation (11.50 ± 1.74 µg/mL) effectively compared to the free drug (62.35 ± 2.88 µg/mL) while sparing L-929 fibroblast cells (138.14 ± 4.38 µg/mL). Furthermore, SPION and SPION-chitosan displayed no cytotoxic activity. Colony-formation assay confirmed the long-term cytotoxicity of nanostructures. Both developed formulations promoted ROS production accompanied by late apoptotic cell death. The biocompatible nanoparticle exerted an augmenting effect to deliver papaverine to metastatic breast cancer cells.

Background: Many cancer studies have intensely focused on the role of diet, among other factors involved in cancer establishment. The positive effect of green tea polyphenols (GTP) on controlling breast cancer cells has been reported in several studies. Cancer stem cell-like cells (CSC-LCs) possessing self-renewal, metastatic, and drug-resistant capacities are considered prominent therapeutic targets. In many tumors, inducible nitric oxide synthase (iNOS) expression levels are high; however, they have a dual effect on breast cancer pathogenesis., Objective: This study aimed to investigate the cytotoxicity of the iNOS agonist (Sildenafil) and antagonist (LNAME), both alone and in combination with GTP, on MDA-MB-231, CD44+/CD24- CSC-LCs, and their parental cells (MCF-7)., Methods: The cell viability assay has been studied using the MTT assay. To analyze drug-drug combinations, CompuSyn and Combenefit software were used. The cytotoxicity mechanism was determined using flow cytometric analysis., Results: L-NAME and GTP showed a synergistic effect on MDA-MB-231 and CSC-LCs. Such an effect was not observed on MCF-7. Sildenafil and GTP, on the other hand, showed synergistic cytotoxicity in all the cells mentioned above. Flow cytometric tests resulted in more than 70% apoptosis in MDA-MB-231 and MCF-7. Also, sub-G1 arrest among MCF-7 cells and a considerable decrease in ROS production by MDA-MB-231 cells following treatment with Sildenafil and GTP were observed., Conclusion: Sildenafil, in combination with flavonoids, may be considered a novel strategy for cancer treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: The primary objective of this study was to optimize formulation variables and investigate the in vitro characteristics of fluticasone propionate (FP)-loaded mixed polymeric micelles, which were composed of depolymerized chitosan-stearic acid copolymer (DC-SA) in combination with either tocopheryl polyethylene glycol succinate or dipalmitoylphosphatidylcholine for pulmonary drug delivery., Methods: A D-optimal design was employed for the optimization procedure, considering lipid/ polymer ratio, polymer concentration, drug/ polymer ratio, and lipid type as independent variables. Dependent variables included particle size, polydispersion index, zeta potential, drug encapsulation efficiency, and loading efficiency of the polymeric micelles. Additionally, the nebulization efficacy and cell viability of the optimal FP-loaded DC-SA micellar formulations were evaluated., Results: The mixed polymeric micelles were successfully prepared with properties falling within the desired ranges, resulting in four optimized formulations. The release of FP from the optimal systems exhibited a sustained release profile over 72 hours, with 70% of the drug still retained within the core of the micelles. The nebulization efficiency of these optimal formulations reached up to 63%, and the fine particle fraction (FPF) ranged from 41% to 48%. Cellular viability assays demonstrated that FP-loaded DC-SA polymeric micelles exhibited lower cytotoxicity than the free drug but were slightly more cytotoxic than empty mixed micelles., Conclusion: In conclusion, this study suggests that DC-SA/ lipid mixed micelles have the potential to serve as effective carriers for nebulizing poorly soluble FP., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This study comparatively evaluated the possible effects of recurrent and non-recurrent patient-derived Cancer-Associated Fibroblasts (CAFs-R and -NR) on the bladder cancer cell line, EJ138. Both groups of CAFs increased cisplatin resistance and altered cell cycle distribution alongside induced resistance to apoptosis. Later, the scratch assay confirmed the cell migration-inducing effects of CAFs on cells. Nonetheless, only CAFs-R managed to increase sphere-formation and clonogenic levels in EJ138 cells, which were later validated by upregulating pluripotency transcription factors. Besides, CAFs-R also affected the expression levels of some of the EMT markers. Our study suggests that CAFs-R had stronger pro-tumorigenic effects on EJ138 cells.

Backgrounds: Targeting breast cancer stem cells with the CD44+/CD24- phenotype is critical for complete eradication of cancer cells due to its Self-renewal, differentiation, and therapeutic resistance ability. Quercetin is a popular flavonoid with lower adverse effects and has anti-tumor properties. Therefore, we assessed the anticancer activity of Quercetin and Doxorubicin alone and in combination in the T47D cells of human breast cancer and their isolated Cancer stem cells (CSCs)., Materials and Methods: The human breast cancer cell line T47D was used for this experiment. T47D CSCs were isolated by magnetic bead sorting using the MACS system. The anticancer activity of Quercetin and Doxorubicin alone and in combination were evaluated using MTT cytotoxicity assay and cell cycle distribution and apoptosis induction by flow cytometry analysis., Results: We have shown that almost 1% of T47D cell populations are made up of CD44+/CD24- cells, which considered as cancer stem cells. Quercetin and Doxorubicin alone or in combination inhibited cell proliferation and induced apoptosis in breast cancer T47D cells and in lower extent in CD44+/CD24- cells. Quercetin significantly strengthened Doxorubicin's cytotoxicity and apoptosis induction in both cell populations. Quercetin and Doxorubicin and their combination induced G2/M arrest in the T47D cells and to a lesser extent in isolated CSCs. A value of p < 0.05 was considered as indicating a statistically significant difference., Conclusion: These outcomes suggested that CSCs are a minor population of cancer cells, which play a significant role in drug resistance by being quiescent, slow cycling and resistance to apoptosis. Furthermore, our data showed that adding Quercetin to Doxorubicin is an effective approach for the treatment of both CSCs and bulk tumor cells.

Titanium dioxide (nano-TiO 2 ) is used abundantly in various industrial products and novel medical therapies. In addition, the impact of climate change on the health and safety will undoubtedly increase in the future. However, the effects of exposure to these nanoparticles and heat stress on hippocampal DNA damage and apoptosis remain unclear. This study was conducted to evaluate the DNA damage and apoptosis in the hippocampal tissue and the physiological responses in mice induced by intraperitoneal (i.p.) administration of TiO 2 nanoparticles (NPs) and heat stress for 14 consecutive days. The results showed that heat stress and TiO 2 -NPs were induced in the mouse hippocampus that led to hippocampal reactive oxygen species generation, oxidative damage of DNA, and apoptosis in a partly dose-dependent manner, especially at very hot temperature. High doses of nanosized TiO 2 and severe heat stress significantly damaged the function of the hippocampus, as shown in the comet assay and apoptosis tests. The results of this study may provide data for appropriate measures to control and assess the risk of nano-TiO 2 and thermal stress hazards to human health, especially workers. Safety guidelines and policies should be considered when handling nanomaterials in a hot environment., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Thermal stress has a direct effect on various types of DNA damage, which depends on the stage of the cell cycle when the cell is exposed to different climate conditions. A literature review was conducted to systematically investigate and assess the overall effect of heat stress and DNA damage following heat exposure. In this study, electronic databases including PubMed, Scopus, and Web of Science were searched to find relevant literature on DNA damage in different ambient temperatures. Outcomes included (1) measurement of DNA damage in heat exposure, (2) three different quantification methods (comet assay, 8-hydroxy-2-deoxyguanosine (8-OHdG), and γ-H2AX), and (3) protocols used for moderate (31) and high temperatures (42). The evidence shows that long exposure and very high temperature can induce an increase in DNA damage through aggregate in natural proteins, ROS generation, cell death, and reproductive damage in hot-humid and hot-dry climate conditions. A substantial increase in DNA damage occurs following acute heat stress exposure, especially in tropical and subtropical climate conditions. The results of this systematic literature review showed a positive association between thermal stress exposure and inhibition of repair of DNA damage., (© 2022. The Author(s) under exclusive licence to International Society of Biometeorology.)

Introduction: Cancer cell resistance to chemotherapy agents is a challenging issue in treating patients with cancer. Findings suggest that a combination of drugs may have synergistic or additive effects. in the present study, we systematically reviewed the combined regimens of metformin with cisplatin in various treating cancers., Methods: A comprehensive systematic search was performed in PubMed, Scopus, Embase, and other relevant databases with the following keyword "metformin", "cisplatin", "combination", "using all their equivalents and similar terms. Pooled odds ratio (OR) and 95% confidence intervals of cell viability and tumor volume as primary outcomes were calculated using Der-Simonian and Laird method while random effects meta-analysis was used, taking into account clinical and statistical heterogeneity., Results: Overall, 44 studies were retrieved, Findings of the present meta-analysis showed that combined regimens of metformin plus cisplatin was significantly associated with decreased odds of tumor volume and cell viability for all cancers compared with cisplatin alone (pooled OR: 0.40; 95% CI: 0.27, 0.58) and (pooled OR: 0.49; 95% CI: 0.42, 0.58) respectively. The result was same for cell viability in lung cancer (pooled OR: 0.59; 95% CI: 0.49, 0.70). The tumor size reduction and the response rate were evident in the animal xenografts model., Conclusion: Findings indicated that combining metformin with cisplatin is a practical therapeutic approach to increase treatment efficacy in the case of cell viability and tumor volume and minimize side effects. A combination of metformin with cisplatin could enhance treatment efficacy through synergistic inhibitory effects on the growth of cancer cells., (Copyright © 2022. Published by Elsevier Inc.)

Aluminum phosphide (AlP) poisoning is common in many countries responsible for high mortality. The heart is the main target organ in AlP poisoning. Several studies have reported the beneficial effects of cannabidiol (CBD) in reducing heart injuries. This study aimed to investigate the possible protective effect of CBD on cardiac toxicity caused by AlP poisoning. Study groups included almond oil, normal saline, sole CBD (100 µg/kg), AlP (11.5 mg/kg), and four groups of AlP + CBD (following AlP gavage, CBD administrated at doses of 5, 25, 50, and 100 μg/kg via intravenous ( iv ) injection). Thirty minutes after AlP treatment, an electronic cardiovascular device (PowerLab) was used to record electrocardiographic (ECG) changes, heart rate (HR), and blood pressure (BP) for three hours. Cardiac tissue was examined for the activities of mitochondrial complexes, ADP/ATP ratio, the release of cytochrome C, mitochondrial membrane potential (MMP), apoptosis, oxidative stress parameter, and cardiac biomarkers at 12 and 24 hours time points. AlP administration caused abnormal ECG, decreased HR, and BP. AlP also significantly reduced mitochondrial complex I and IV activity and ADP/ATP ratio. The level of cytochrome C release, apoptosis, oxidative stress, and cardiac biomarkers was considerably increased by AlP, which was compensated following CBD administration. CBD was able to improve hemodynamic function to some extent in AlP poisoned rats. CBD restored ATP levels and mitochondrial function and decreased oxidative damage and thus, prevented the heart cells from entering the apoptotic stage. Further clinical trials are needed to explore any possible benefits of CBD in AlP-poisoned patients.

The last generation of Coronavirus named COVID-19 is responsible for the recent worldwide outbreak. Concerning the widespread and quick predominance, there is a critical requirement for designing appropriate vaccines to surmount this grave problem. Correspondingly, in this revision, COVID-19 vaccines (which are being developed until March 29th, 2021) are classified into specific and non-specific categories. Specific vaccines comprise genetic-based vaccines ( mRNA , DNA ), vector-based, protein/recombinant protein vaccines, inactivated viruses, live-attenuated vaccines, and novel strategies including microneedle arrays ( MNAs ), and nanoparticles vaccines. Moreover, specific vaccines such as BCG , MRR , and a few other vaccines are considered Non-specific. What is more, according to the significance of Bioinformatic sciences in the cutting-edge vaccine design and rapid outbreak of COVID-19, herein, Bioinformatic principles including reverse vaccinology, epitopes prediction/selection and, their further applications in the design of vaccines are discussed. Last but not least, safety, challenges, advantages, and future prospects of COVID-19 vaccines are highlighted., Competing Interests: Conflict of Interests: There is no conflict of interests in this paper., (Copyright © 2022, Author(s).)

Aluminum phosphide (AlP) poisoning can be deadly in most cases targeting the heart. To overcome AlP toxicity, exenatide has been studied in the present study due to its pleiotropic effects on cardiac damages. In this study, the rats were exposed to LD 50 of AlP (10 mg/kg) by gavage, and exenatide at doses (0.05, 0.1, and 0.2 mg/kg) injected intraperitoneally 30 min after poisoning. The cardiac parameters including heart rate (HR), blood pressure (BP), QRS, corrected QT (QT c ), and ST were monitored for 180 min. Blood glucose level was measured in the study groups 30 min after exenatide injection. Evaluation of biochemical parameters including mitochondrial complexes I, II, and IV activities, adenosine diphosphate (ADP)/adenosine triphosphate (ATP) ratio, malondialdehyde (MDA), apoptosis, lactate, troponin I, and brain natriuretic peptide (BNP) was done on heart tissues after 12 and 24 h. Additionally, the tissues were analyzed for any pathological damages including necrosis, hemorrhage, or hyperemia 24 h post-treatment. Our results showed that AlP-induced HR, BP, and electrocardiographic changes were improved by exenatide at all doses. The blood glucose levels of poisoned animals reached control levels after exenatide treatment. Besides, treatment with exenatide at all doses improved complexes I and IV activity, ADP/ATP ratio, and apoptosis. Malondialdehyde, lactate, troponin I, and BNP levels were also diminished after exenatide co-treatment in poisoned animals. On the other hand, administration of exenatide doses improved the histopathology of AlP-induced tissues. Based on our findings, exenatide has a protective effect against phosphine-induced cardiotoxicity in an almost dose-dependent way. However, further investigations are needed on the potential clinical use of exenatide in this poisoning.

Endocrine disrupting chemicals (EDCs) are organic compounds that have estrogenic activity and can interfere with the endocrine system. Bisphenol-A (BPA) is one of these compounds which possess a potential risk for breast cancer. The aim of this research was to evaluate BPA concentration in both the urine and breast adipose tissue samples of breast cancer mastectomy and mammoplasty patients and study correlations of BPA levels in breast adipose tissue with urine samples in the both groups. Urine and breast adipose tissue samples from 41 breast cancer mastectomy and 11 mammoplasty patients were taken. BPA concentrations were detected using an ELISA assay. Urinary BPA concentrations were significantly higher in cancerous patients (2.12 ± 1.48 ng/ml; P < 0.01) compared to non-cancerous (0.91 ± 0.42 ng/ml). Likewise, tissue BPA concentrations in cancerous patients (4.20 ± 2.40 ng/g tissue; P < 0.01) were significantly higher than non- cancerous (1.80 ± 1.05 ng/g tissue). Urinary BPA concentrations were positively correlated with breast adipose tissue BPA in the case group (P < 0.001, R = 0.896). We showed that BPA was present in urine and breast adipose tissue samples of the studied populations. With regard to higher BPA mean concentration in cancerous patients than non-cancerous individuals in this study, BPA might increase the risk of breast cancer incidence., (© 2021. The Author(s).)

Current treatment of chronic wounds has been critically limited by various factors, including bacterial infection, biofilm formation, impaired angiogenesis, and prolonged inflammation. Addressing these challenges, we developed a multifunctional wound dressing-based three-pronged approach for accelerating wound healing. The multifunctional wound dressing, composed of nanofibers, functional nanoparticles, natural biopolymers, and selected protein and peptide, can target multiple endogenous repair mechanisms and represents a promising alternative to current wound healing products.

Type 1 diabetes is a metabolic disorder caused by the loss or dysfunction of β-cells in the pancreas. Organ shortage is a critical concern of diabetic patients in need of beta islet transplantation. Tissue engineered islets are promising alternatives to traditional organ transplantation. Recent progress in stem cell biology and gene cloning techniques has raised hopes for the generation of insulin producing cells (IPCs) without the need of immunosuppression. The purpose of this study was to produce IPCs using human adipose-derived stem cells (hADSCs) and human endometrial-derived stem cells (hEnSCs) and also to compare the level of insulin secretion by these cells in 2D and 3D culture systems on fibrin scaffolding. Stem cells differentiation was carried out through transduction with an insulin over expression lentiviral vector. Real-time PCR and immunocytochemistry confirmed the successful transduction of both cell types. Both cell types showed comparable insulin secretion by ELISA.3D culture resulted in higher amounts of insulin secretion of the two cell types versus 2D as control. This study showed that insulin gene delivery to the stem cells could be an efficient method for producing IPCs and fibrin encapsulation enhances the functionality of these cells., (© 2020 Wiley Periodicals LLC.)

Objectives: The microtubule is composed of αβ tubulin heterodimers and is an attractive target for the design of anticancer drugs. Over the years, various compounds have been developed and their effect on tubulin polymerization has been studied. Despite a great efforts to make an effective drug, no drug has been introduced which inhibit Colchicine binding site., Methods: In the current work a series of pyrimidine derivatives were designed and synthesized. Furthermore their cytotoxic activities were evaluated and molecular docking studies were performed. Twelve compounds of pyrimidine were synthesized in 3 different groups. In the first group, 4,6-diaryl pyrimidine was connected to the third aryl group via thio-methylene spacer. In the second group, this linker was substituted by sulfoxide-methylene moiety and in the third group sulfone-methylene group was used as spacer., Results: The cytotoxic activity of these compounds were evaluated against 3 different cancerous cell lines (HT-29, MCF-7, T47D) as well as normal cell line (NIH3T3). Compounds in group 2 showed the best cytotoxicity and compound 7D: showed the most potent cytotoxic activity against all cell lines. Molecular modelling studies revealed that compound 7D: could strongly bind to the colchicine binding site of tubulin., Conclusion: Altogether, with respect to obtained results, it is attractive and beneficial to further investigation on pyrimidine scaffold as antimitotic agents., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Aims: Exosomes hold great promise as bio-inspired delivery vehicles. Mesenchymal stem cells (MSCs) are recognized for their potential to yield huge quantities of exosomes. We aimed to investigate the potential use of modified exosomes derived from genetically modified dental pulp MSCs (DPSCs) as a carrier to deliver tumor suppressor miR-34a to repress proliferation of breast carcinoma cells., Materials and Methods: miR-34a-overexpressing DPSCs were prepared using XMIRXpress-34a lentivectors. The anticancer effects of the miR-34a-loaded exosomes were evaluated on breast carcinoma cells through apoptosis, migration, and invasion assays. Given the structural similarity between exosomes and liposomes, we compared the exosome-mediated miRNA delivery efficiency with that of liposomes., Key Findings: Our data demonstrated that genetically modified DPSCs were capable of secretion of exosomes enriched with therapeutic miRNAs and presented the feasibility of application of exosome-based vehicle for gene delivery., Significance: We showed the potential of MSC-derived exosomes as a tool for delivery of miRNAs in vitro. Nevertheless, optimizing gene-loading approaches is required before exosomes can be intended as a miRNA carrier for therapeutic applications., (Copyright © 2020 Elsevier Inc. All rights reserved.)

One of the main genotoxic drugs used in bladder cancer chemotherapy is cisplatin. While it is applied in most types of cancers, resistance to cisplatin is wildly common. In order to overcome drug resistance, it is necessary to determine a predictive marker. This study was conducted to provide basic data for selecting and designing a gene profile for further cohort and RCT studies in the future to improve response to treatment in bladder cancer. The expression levels of ERCC1, MLH1, MSH2, and CTR1 mRNA were determined in the tumor tissue using real-time q-PCR. Progression-free survival (PFS) was analyzed in term of the level of genes expression. The results revealed that the level of ERCC1 mRNA expression was higher in the recurrence (R) group compared to the no recurrence (NR) group. Moreover, the PFS time was increased in the patients with an ERCC1 expression level of below 1.57. The level of MLH1 and MSH2 mRNA expression was lower in the R group compared to the NR group; therefore, PFS time was increased in the patients with MLH1 and MSH2 gene expression levels above the cutoff point. While the level of CTR1 mRNA expression was higher in the R group versus the NR group, the PFS time was longer in the patients with CTR1 expression levels of below 1.265 compared to the patients with high levels of CTR1 expression. It can be concluded that the level of ERCC1, MLH1, MSH2, and CTR1 mRNA expression may be associated with PFS time as possible therapeutic targets for decreasing cisplatin resistance.

Pt-based drugs such as cisplatin are frontline drugs used for the treatment of different solid malignancies. However, they represent major problems, such as severe side effects and drug resistance. To find out the structure-activity relationship; in this study, Pt(II) and Pt(IV) complexes with similar ligands, namely tetrachloro(2,2'-dipyridylamine)platinum(IV) (1) and dichloro(2,2'-dipyridylamine)platinum(II) (2) were synthesized, tested for their in vitro activity over different tumor cell lines and compared with cisplatin. Despite nontoxicity against nonmalignant cells, both titled compounds depict considerable killing activity over HT-29 cells. So, this cell line is served for further investigation. Cell cycle test revealed that the mechanism of cell cycle arrest induced by complexes 1 and 2 over HT-29 cells was relatively similar and obviously different from cisplatin. Moreover, apoptosis analysis showed that late apoptosis/necrosis is the primary disease for the death of cell by three complexes. Comet assay and colony-forming test were also performed on HT-29 cells whose results were thoroughly discussed.

Hypoxia in the microenvironment is related to chemotherapy resistance, tumor progression, and metastasis. Curcumin, as a phenolic compound extracted from the turmeric, has been used as an anti-cancer agent with low toxicity in recent years. Since curcumin has inhibitory activities against hypoxia-inducible factors (HIFs) in several cancers, this study was conducted to examine the effect of curcumin on MCF-7 cells and cancer stem-like cells (CS-LCs) under hypoxic and normoxic conditions. CS-LCs were isolated from MCF-7 cells using the magnet activated cell sorting (MACS) method based on CD 44 + / CD 24 - surface markers. The effects of curcumin on the viability of MCF-7 cells and CS-LCs were examined in hypoxic and normoxic conditions using the MTT test. The effects of curcumin on apoptosis and cell cycle of CS-LCs and MCF-7 cells were analyzed using flow cytometry. Moreover, the inhibitory effects of curcumin on the levels of HIF-1 and HIF-2α protein in CS-LCs were investigated using the western blot method. Early apoptosis occurred in CSC-LCs more than MCF-7 cells under hypoxic conditions. Flow cytometry assay showed that curcumin caused cell cycle arrest of CSC-LCs and MCF-7 at the G2/M phase under hypoxic conditions while under normoxic conditions, arrest occurred at the G0/G1 phase in MCF-7 cells and at S and G2/M phases in CS-LCs. Based on the results, the curcumin inhibited the expression of HIF-1 by degrading ARNT in CS-LCs.In conclusion, curcumin has inhibitory effects on MCF- 7 cells and CS- LCs and thus may be used as an antitumor agent., Competing Interests: The authors declare no potential conflicts of interest., (Thieme. All rights reserved.)

The main goal of this study was to explore the beneficial effect of nerve growth factor (NGF)-overexpressing of human adipose-derived mesenchymal stem cells (hADSCs) encapsulated in injectable chitosan/β-glycerophosphate/hydroxyethylcellulose (CS/β-GP/HEC) hydrogel for spinal cord regeneration. The CS/β-GP/HEC hydrogel and genetically transduced hADSCs using pseudo-lentiviruses-NGF were prepared. The mechanical properties, morphology and cytotoxicity of the hydrogel were investigated by rheometry, scanning electron microscope (SEM), and MTT assay, respectively. Rats animals were undergone spinal cord injury (SCI), then one-week post-injury, CS/β-GP/HEC hydrogel, transduced hADSCs and transduced hADSCs/CS/β-GP/HEC hydrogel injected into the site of the lesion. Animals with SCI and animals with laminectomy without SCI were considered as negative control and sham groups, respectively. Positive control group received no surgical intervention. At eight weeks post-injection, histological studies indicated a significant increase in cell proliferation, a smaller cavity in size at the SCI site as well as better locomotor functions for transduced hADSCs/CS/β-GP/HEC hydrogel group (P ≤ 0.05) compared to other experimental groups. Our results showed that CS/β-GP/HEC hydrogel in combination with transduced-hADSCs is able to successfully regenerate SCI. These results may be applicable in the selection of the best therapeutic strategy based on gene therapy and tissue engineering for SCI treatment., (Copyright © 2020 Tissue Viability Society. Published by Elsevier Ltd. All rights reserved.)

Liraglutide is a long-acting human glucagon-like peptide-1 (GLP-1) analogue and an effective treatment for patients with metabolic diseases including type 2 diabetes mellitus (T2DM) and obesity. This review focuses on the mechanism of action of liraglutide as a well-known glucagon-like peptide-1 receptor agonist (GLP-1 RA) in patients with T2DM and obesity. The lower and the higher doses of GLP-1 RAs are used for glycaemic control in T2DM and in obesity respectively. GLP-1 RAs such as liraglutide enhance insulin secretion and inhibit glucagon release via the stimulation of glucagon-like peptide-1 receptors (GLP-1Rs). Liraglutide decreases hemoglobin A1c (HbA1c) in type 2 diabetes (T2D) patients when prescribes as monotherapy or in combination with one or more antidiabetic drugs. Usually, it is well tolerated with minor hypoglycemia in combination therapy. Liraglutide reduces cardiovascular events and related risk factors including improvement of lipid profile and control of blood pressure. Accordingly, it can be cost-effective and may be a budget neutral medication option by considering its protective effect on the cardiovascular system in long-term use in the health care plan. In the near future, by pharmacogenomics approach, prediction of the highest patient's response with the lowest adverse drug reactions and also rationality of drug development will be possible. Liraglutide can be used as a desirable medicine for glycemic control and obesity. It shows extensive evidence based benefits in diabetes complications. In this narrative review, we have summarized and evaluated studies related to the role of liraglutide in clinical practice., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interests., (© Springer Nature Switzerland AG 2020.)

Background: Green tea ( Camellia sinensis ), which is the most common drink across the world after water, has many antioxidant properties. Epigallocatecin-3-gallate (EGCG) is a flavonoid which accounts for 33-50% of green tea solids. It functions as a powerful antioxidant, preventing oxidative damage in healthy cells, with antiangiogenic and antitumor activities and as a modulator of tumor cell response to chemotherapy. Malathion is an organophosphate pesticide which is widely used in agriculture, veterinary and industries. Oxidative stress has been identified as one of malathion's main molecular mechanisms. The purpose of this study was to evaluate protective role of EGCG against malathion induced genotoxicity using human lymphocyte model. Blood samples from 8 non-smoker healthy volunteers with no history of chemotherapy were collected and divided into six groups: Control, EGCG (50 µM), EGCG (20 µM), Malathion (24 µM), EGCG (50 µM)+Malathion (24 µM) and EGCG (20 µM)+Malathion (24 µM). For genotoxicity assay, we employed micronuclei test. For antioxidant capacity evaluation, GSH content and MDA levels were measured. Malathion showed significant genotoxic damage compared to the intact lymphocytes, however, treatment with EGCG at both concentrations were reduced the genotoxic effect of malathion. Malathion induced lipid peroxidation, while pre-treatment with EGCG at both concentrations, significantly protected the lymphocytes against malathion induced lipid peroxidation. Malathion significantly reduced GSH content, but pre-treatment with EGCG significantly recovered GSH content. Overall this study demonstrated that EGCG (at both concentrations) significantly prevents human lymphocytes against malathion induced genotoxicity and oxidative damage., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Hepatocellular carcinoma is the third cause of cancer-related mortality with the low 5-year survival in which more than 50 percent of patients have recurrent cancer within 2 years of treatment. The present study investigated the cytotoxicity and lethal dose of Ficus carica L. (Figure) latex and phytochemical composition of effective fraction. Figure latex was collected in summer and 4 fractions of Figure latex were prepared. The cytotoxic effect of each fraction was studied and the most effective fraction was selected for apoptosis assay, acute toxicity study, and phytochemical analysis using column chromatography. The isolated compounds were identified by 1 H-NMR, 13 C-NMR, and mass spectroscopy. Chloroform fraction was the most effective fraction with the IC 50 value of 0.219 and 0.748 mg/mL for HepG2 and NIH cell lines, respectively. Presence of cells in early apoptotic phase was documented by flow cytometry assay. Single dose administration of 2g/kg of fraction did not cause any death. Phytochemical analyses confirmed presence of lupeol acetate and lupeol palmitate in chloroform fraction . The present study revealed that the chloroform fraction is not only 3.4 times more toxic in HepG2 cell line but also has low in-vivo toxicity which could be considered as a good candidate for a chemo-preventive agent.

Cardiac dysfunction is a major side effect of trastuzumab therapy for patients with HER2-positive breast cancer. Beta blockers, such as carvedilol, have been used for protection of trastuzumab cardiotoxicity but there is no definitive conclusive clinical report on their efficacy. In the present study, the preservability effects of carvedilol on trastuzumab-induced left ventricular (LV) dysfunction and the reversibility of trastuzumab-induced cardiotoxicity were evaluated in Wistar rats by echocardiography method. We showed that trastuzumab treatment of rats could induce the LV dysfunction through increasing the LV internal systolic diameter (LVIDs), increasing the end-systolic volume (ESV), decreasing the ejection fraction (EF), and decreasing the fractional shortening (FS). These parameters were not reversed after 14 days of stopping trastuzumab administration. Interestingly, carvedilol improved LVIDs, ESV, EF, and FS. Collectively, the results of this study have verified clinical observations which simultaneously administration of carvedilol may be considered as a possible therapeutic strategy to prevent trastuzumab-mediated LV dysfunction., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

It is becoming increasingly accepted that various diseases have a capacity to alter the composition of plasma proteins. This alteration in protein composition may consequently change the targeting capacity of nanoparticles (NPs). In this study, the impact of a model targeting ligand's (i.e., Transferrin; Tf) concentration in human plasma on the targeting capacity of gold NPs (Au NPs), pre-conjugated with Tf, is investigated. Our findings demonstrate that the protein corona formation by both healthy and Tf depleted human plasma diminishes the targeting efficacy of Au NPs within human cancer cells despite a preservation of targeting ability by plasma with excess Tf (10-fold). Moreover, the plasma samples obtained from patients with various Tf levels (e.g., thalassemia major, sickle cell anemia, aplastic anemia, and iron deficiency anemia) have affected the accessibility of the targeting Tf in the corona layer and subsequently affected their targeting ability, which emphasizes the critical role of disease-specific protein corona on the efficacy of Au NPs. Ultimately, variations of protein concentration (e.g., due to disease occurrence and progress) in plasma affect its recruiting in corona formation, and in turn, affect the targeting and therapeutic efficacies of Au NPs.

Background: Placenta-specific 1 (PLAC1), as a new Cancer/Testis Antigen (CTA), is frequently expressed in a variety of cancers and localized to cytoplasm and plasma membrane. Surface expression of cancer target antigens is of great importance that enables antibody-mediated cancer immunotherapy. The aim of the current study was to express the intact human PLAC1 protein on plasma membrane of a eukaryotic cell as a model for future anti-PLAC1-based cancer immunotherapy., Methods: In the first approach, entire human PLAC1 gene including its own Signal Peptide (SP) was cloned into pIRES2-EGFP and LeGO-iG2 vectors and expressed in CHO-K1 cells. In the second approach, cytosolic and Signal-Anchor (SA) sequence of Transferrin Receptor Protein 1 (TFR1) were fused to extracellular portion of PLAC1 and expressed as above. Expression of PLAC1 was then assessed using Reverse Transcription Polymerase Chain Reaction (RT-PCR), Western Blot (WB), Immunocytochemistry (ICC), Immunofluorescence (IF) and Flow Cytometry (FC)., Results: The first approach resulted in the expression of PLAC1 in submembranous but not in the surface of transfected CHO-K1 cells. Using the chimeric human PLAC1 construct, the same intracellular expression pattern was observed., Conclusion: These results indicated that there are some yet unknown PLAC1 localization signals employed by cancer cells for surface expression of PLAC1., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright© 2020 Avicenna Research Institute.)

Introduction: This study aims to develop and characterize the regenerative potential of an atelopeptidized treated dentin matrix xenograft using in vitro and in vivo models., Methods: Freshly extracted bovine dentin was pulverized into 250- to 500-μm particles and demineralized with 17% EDTA for 1, 7, and 13 days. The samples were atelopeptidized with pepsin. The degree of demineralization and the effect of atelopeptidization were assessed using field emission scanning electron microscopy combined with energy-dispersive X-ray spectroscopy and Fourier transform infrared spectroscopy, respectively. The expression of dentin matrix acidic phosphoprotein 1, dentin sialophosphoprotein, and osteopontin was evaluated in dental pulp stem cells using quantitative real-time polymerase chain reaction. The samples were then implanted intramuscularly in rats for 30 days, and the inflammatory cells were quantified histologically., Results: Field emission scanning electron microscopy combined with energy-dispersive X-ray spectroscopy revealed an exposed tubular structure of dentin after 1 and 7 days of demineralization. Fourier transform infrared spectroscopy confirmed the absence of amide peaks at 1260 to 1640/cm after atelopeptidization. The dental pulp stem cell expression of dentin matrix acidic phosphoprotein 1 and dentin sialophosphoprotein increased in all compared with the untreated control group (P < .05). The maximum expression rates were observed for the 1-day demineralized and atelopeptidized group. The 1-day demineralized group elicited the highest inflammatory response compared with the 7- or 13-day demineralized groups (P < .001). Atelopeptidization significantly decreased the inflammatory response only in the 1-day demineralized dentin group (P < .05)., Conclusions: Atelopeptidization of 1-day demineralized dentin xenograft preserved the collagen structure, minimized the immune reaction, and provided sufficient regenerative potential., (Copyright © 2019 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Objective: Heart dysfunctions are the major complications of trastuzumab in patients with Human Epidermal growth factor Receptor-2 (HER2)-positive breast cancers., Methods: In this study, the cytotoxicity of trastuzumab on H9c2 cardiomyoblasts was demonstrated, and the proteome changes of cells were investigated by a tandem mass tagging quantitative approach. The Differentially Abundant Proteins (DAPs) were identified and functionally enriched., Results: We determined that carvedilol, a non-selective beta-blocker, could effectively inhibit trastuzumab toxicity when administrated in a proper dose and at the same time. The proteomics analysis of carvedilol co-treated cardiomyoblasts showed complete or partial reversion in expressional levels of trastuzumab-induced DAPs., Conclusion: Downregulation of proteins involved in the translation biological process is one of the most important changes induced by trastuzumab and reversed by carvedilol. These findings provide novel insights to develop new strategies for the cardiotoxicity of trastuzumab., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: Recent studies suggest xenogeneic extracellular matrices as potential regenerative tools in dental pulp regeneration. This study aimed to fabricate and characterize a novel three-dimensional macroporous pulp-derived scaffold that enables the attachment, penetration, proliferation and differentiation of mesenchymal stem cells., Method: Bovine pulp was decellularized and characterized with histological and DNA content methods. This scaffold was prepared using finely milled lyophilized decellularized pulp extracellular matrix (ECM) digested with pepsin. Three different concentrations of ECM (1.50, 2.25 and 3.00mg/ml) were freeze-dried and were tested with/without chemical crosslinking. The specimens were subjected to physicochemical characterization, cell viability and quantitative real time polymerase chain reaction assessments with human bone marrow mesenchymal stem cells (hBMMSCs). All scaffolds were subcutaneously implanted in rats for two weeks and histological and immunostaining analyses were performed., Results: Histological and DNA analysis confirmed complete decellularization. All samples demonstrated more than 97% porosity and 1.50mg/ml scaffold demonstrated highest water absorption. The highest cell viability and proliferation of hBMMSCs was observed on the 3.00mg/ml crosslinked scaffolds. The gene expression analysis showed a significant increase of dmp-1 and collagen-I on 3.00mg/ml crosslinked scaffolds compared to the other scaffolds. Histological examination of subcutaneous implanted scaffolds revealed low immunological response, and enhanced angiogenesis in cross-linked samples compared to non-crosslinked samples., Significance: The three-dimensional macroporous pulp-derived injectable scaffold developed and characterized in this study displayed potential for regenerative therapy. While the scaffold biodegradability was decreased by crosslinking, the biocompatibility of post-crosslinked scaffold was significantly improved., (Copyright © 2019 The Academy of Dental Materials. All rights reserved.)

Fragile histidine triad (FHIT) serves a critical function as a tumor suppressor that inhibits p53 degradation by mouse double minute 2 (MDM2). The functional domains of FHIT involved in tumor inhibition was interpreted. In-silico screening data were employed to construct truncated forms of FHIT to assess their cytotoxic effects on the HT1080 cell line. Full FHIT expression was confirmed by western blotting and expression of two FHIT truncates were confirmed by RT-PCR. Transfection of these truncated forms into HT1080 cells showed that the N-terminal truncated form (amino acids 17-102) better inhibited proliferation than the full-length FHIT. The combined effects of these truncated forms augmented doxorubicin-induced cytotoxicity. Functional analysis demonstrated that these fragments and their combination with doxorubicin can arrest cells in the G2 phase of the cell cycle as specified by flow cytometry. The FHIT functional domains can be used as lead compounds for development of drug designs and gene transfer for cancer therapy.

Tissue engineering is one of the most promising areas for treatment of various ophthalmic diseases particularly for patients who suffer from limbal stem cell deficiency and this is due to the lack of existence of appropriate matrix for stem cell regeneration. The aim of this research project is to design and fabricate triple layered electrospun nanofibers as a suitable corneal tissue engineering scaffold and the objective is to investigate and perform various in vitro tests to find the most optimum and suitable scaffold for this purpose. Electrospun scaffolds were prepared in three layers. Poly(d, l-lactide-co-glycolide; PLGA, 50:50) nanofibers were electrospun as outer and inner layers of the scaffold and aligned type I collagen nanofibers were electrospun in the middle layer. Furthermore, the scaffolds were cross-linked by 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide hydrochloride and glutaraldehyde. Structural, physical, and mechanical properties of scaffolds were investigated by using N 2 adsorption/desorption isotherms, Fourier transform infrared spectroscopy, contact angle measurement, tensile test, degradation, shrinkage analysis, and scanning electron microscopy (SEM). In addition, capability to support cell attachment and viability were characterized by SEM, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, and 4',6-diamidino-2-phenylindole staining. According to the result of Brunauer-Emmett-Teller analysis, specific surface area of electrospun scaffold was about 23.7 m 2 g -1 . Tensile tests on cross-linked scaffolds represented more suitable hydrophilicity and tensile behavior. In addition, degradation rate analysis indicated that noncross-linked scaffolds degraded faster than cross-linked one and cross-linking led to controlled shrinkage in the scaffold. The SEM analysis depicted nano-sized fibers in good shape. Also, the in vitro study represented an improved cell attachment and proliferation in the presence of human endometrial stem cells for both cross-linked and noncross-linked samples. The current study suggests the possibility of producing an appropriate substrate for successful cornea tissue engineering with a novel design., (© 2019 Wiley Periodicals, Inc.)

Ethnopharmacological Relevance: Calligonum comosum is a desert plant that is applied in traditional folkloric medicine for the treatment of abnormally heavy or prolonged menstruation and menstrual cramps. Moreover, it has been suggested for the treatment of infertility-causing conditions. Its bioactive chemical constituents inhibit multiple processes, such as angiogenesis, inflammation and invasive tissue growth, which may be beneficial in the therapy of endometriosis., Aim of the Study: We investigated the effects of Calligonum comosum on the development of endometriotic lesions., Materials and Methods: We evaluated the anti-angiogenic activity of Calligonum comosum ethyl acetate fraction (CCEAF) in different in vitro angiogenesis assays. Moreover, we surgically induced endometriotic lesions in BALB/c mice, which received 50 mg/kg Calligonum comosum total extract (CCTE) or vehicle (control) over 4 weeks. The growth, cyst formation, vascularization and immune cell infiltration of the lesions were assessed with high-resolution ultrasound imaging, caliper measurements, histology and immunohistochemistry., Results: CCEAF doses of up to 10 μg/mL did not impair the viability of human dermal microvascular endothelial cells (HDMEC), but dose-dependently suppressed their migration, tube formation and sprouting, indicating a substantial anti-angiogenic effect of CCEAF. Furthermore, CCTE significantly inhibited the growth and cyst formation of developing murine endometriotic lesions when compared to vehicle-treated controls. This was associated with a reduced vascularization, cell proliferation and immune cell infiltration., Conclusions: Our findings show that Calligonum comosum targets multiple, fundamental processes in the pathogenesis of endometriosis, which may be beneficial for the treatment of this common gynecological disorder., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The emergence of immunotherapy has revolutionized medical oncology with unprecedented advances in cancer treatment over the past two decades. However, a major obstacle in cancer immunotherapy is identifying appropriate tumor-specific antigens to make targeted therapy achievable with fewer normal cells being impaired. The similarity between placentation and tumor development and growth has inspired many investigators to discover antigens for effective immunotherapy of cancers. Placenta-specific 1 (PLAC1) is one of the recently discovered placental antigens with limited normal tissue expression and fundamental roles in placental function and development. There is a growing body of evidence showing that PLAC1 is frequently activated in a wide variety of cancer types and promotes cancer progression. Based on the restricted expression of PLAC1 in testis, placenta and a wide variety of cancers, we have designated this molecule with new terminology, cancer-testis-placenta (CTP) antigen, a feature that PLAC1 shares with many other cancer testis antigens. Recent reports from our lab provide compelling evidence on the preferential expression of PLAC1 in prostate cancer and its potential utility in prostate cancer immunotherapy. PLAC1 may be regarded as a potential CTP antigen for targeted cancer immunotherapy based on the available data on its promoting function in cancer development and also its expression in cancers of different histological origin. In this review, we will summarize current data on PLAC1 with emphasis on its association with cancer development and immunotherapy.