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The hypoxic environment of melanoma results in CD73 upregulation on the surface of various tumor microenvironment (TME) cells including tumor cells, stromal cells and infiltrated immune cells. Consequently, CD73 through both enzymatic and none enzymatic functions affect melanoma progression. Overaccumulation of CD73-derived adenosine through interaction with its four G coupled receptors (A1AR, A2AAR, A2BAR, and A3AR) mediate tumor growth, immune suppression, angiogenesis, and metastasis. This paper aims to comprehensively review the therapeutic potential of CD73 ectonucleotidase targeting in melanoma. To reach this goal, firstly, we summarize the structure, function, regulation, and clinical outcome of CD73 ectonucleotidase. Then, we depict the metabolism and signaling of CD73-derived adenosine along with its progressive role in development of melanoma. Furthermore, the therapeutic potentials of CD73 -adenosine axis targeting is assessed in both preclinical and clinical studies. Targeting CD73-derived adenosine via small molecule inhibitor or monoclonal antibodies studies especially in combination with immune checkpoint blockers including PD-1 and CTLA-4 have shown desirable results for management of melanoma in preclinical studies and several clinical trials have recently been started to evaluate the therapeutic potential of CD73-derived adenosine targeting in solid tumors. Indeed, targeting of CD73-derived adenosine signaling could be considered as a new therapeutic target in melanoma.

Nonalcoholic fatty liver disease (NAFLD) significantly impacts global health. Despite considerable research, its pathophysiology remains partially unclear. In addition, selective serum biomarkers of disease diagnosis and progression are missing. Long noncoding RNAs (lncRNAs) are a heterogeneous group of ncRNAs with crucial roles in biological processes underlying the pathophysiology of different human diseases. Recent studies have shown that lncRNA could be associated with the genesis and progression of NAFLD towards the most severe forms. Although the field is still in its infancy, it is tempting to speculate that these transcripts could be used as both diagnostic and therapeutic targets. In this review, we summarize recent findings on lncRNAs in the complex research field of NAFLD.

The main goal of peptide-based cancer vaccines is to induce the immune system and activation of effective T cell responses against cancerous cells. Nevertheless, the potency of peptide vaccines is insufficient in most of cases and had limited clinical success. Therefore, the optimization of peptide-based cancer vaccine is essential to achieve powerful therapeutic outcomes. One strategy to enhanced potency of peptide vaccines and induce strong immune responses is the preparation of multi-epitope peptide formulation containing both Th- and cytotoxic T lymphocyte-induced responses epitope using suitable delivery system. For this reason, we studied the effect of Dioleoylphosphatidylethanolamine-containing liposomal vaccine composed of a mixture of short peptides AE36 and E75 (HER2/neu-derived peptides) and long multi-epitope peptide E75-AE36 (linkage of short peptides) in combination with a Pan HLA-DR epitope (PADRE) peptide. These formulations were examined using a series of subcutaneously injection to HER-2+ TUBO-tumoured mice in prophylactic and therapeutic model. We observed that mice vaccinated with liposomal long peptide in combination with PADRE resulted in the superior induction of CD4+ and CD8+ T cells responses and significantly enhanced production of IFN-γ compared with liposomal short peptides and non-liposomal peptides formulations. Moreover, liposome-long peptide with PADRE led to the considerable reduction of tumour growth and lifespan induction in mouse model. In conclusion, our study indicated that liposomal formulation containing long multi-epitope peptide E75-AE36 with PADRE could be used as an effective multi-epitope prophylactic/therapeutic vaccine to generate potent antigen-specific CD8+ T-cell immune response and may be introduced as a possible candidate peptide vaccine for breast cancer.

Inflammasomes are a group of cytosolic multi-protein signaling complexes that regulate maturation of the interleukin (IL)-1 family cytokines IL-1β and IL-18 through activation of inflammatory caspase-1. The NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome is the best characterized and consists of several key components that are assembled and activated in response to different endogenous and exogenous signals. The NLRP3 inflammasome is common to a number of human inflammatory diseases and its targeting may lead to novel anti-inflammatory therapy. NLRP3 inflammasome activation is tightly regulated by different mechanisms especially post-transcriptional modulation via microRNAs (miRNA). MicroRNAs are small endogenous noncoding RNAs that are 21-23 nucleotides in length and control the expression of various genes through binding to the 3'-untranslated regions of the respective mRNA and subsequent post-transcriptional regulation. MicroRNAs have recently been recognized as crucial regulators of the NLRP3 inflammasome. In this review, we summarize the current understanding of the role of miRNAs in the regulation of NLRP3 inflammasome complexes and their impact on the pathogenesis of inflammatory disease processes.

Introduction Multiple Sclerosis (MS), as an autoimmune disease, has complicated immunopathology, which makes its management relevant to various factors. Novel pharmaceutical vehicles, especially liposomes, can support efficacious handling of this disease both in early detection and prognosis and also in a therapeutic manner. The most well-known trigger of MS onset is the predominance of cellular to humoral immunity and enhancement of inflammatory cytokines level. The installation of liposomes as nanoparticles to control this disease holds great promise up to now. Areas covered Various types of liposomes with different properties and purposes have been formulated and targeted immune cells with their surface manipulations. They may be encapsulated with anti-inflammatory, MS-related therapeutics, or immunodominant myelin-specific peptides for attaining a higher therapeutic efficacy of the drugs or tolerance induction. Cationic liposomes are also highly applicable for gene delivery of the anti-inflammatory cytokines or silencing the inflammatory cytokines. Liposomes have also been used as biotools for comprehending MS pathomechanisms or as diagnostic agents. Expert opinion The efforts to manage MS through nanomedicine, especially liposomal therapeutics, pave a new avenue to a high-throughput medication of this autoimmune disease and their translation to the clinic in the future for overcoming the challenges that MS patients confront.

Angiogenesis has a significant role in metastasis and progression of melanoma. Even small tumors may be susceptible to metastasis and hence lead to a worse outcome in patients with melanoma. One of the anti-angiogenic treatment approaches that is undergoing comprehensive study is specific immunotherapy. While tumor cells are challenging targets for immunotherapy due to their genetic instability and heterogeneity, endothelial cells (ECs) are genetically stable. Therefore, vaccines targeting angiogenesis in melanoma are appropriate choices that target both tumor cells and ECs while capable of inducing strong, anti-tumor immune responses with limited toxicity. The main targets of angiogenesis are VEGFs and their receptors but other potential targets have also been investigated, especially in preclinical studies. Various types of vaccines that target angiogenesis in melanoma have been studied including DNA, peptide, protein, dendritic cell-based, and endothelial cell vaccines. This review outlines a number of target antigens that are important for potential progress in developing vaccines for targeting angiogenesis in melanoma. We also discuss different types of vaccines that have been investigated, delivery mechanisms and popular adjuvants, and suggest ways to improve future clinical outcomes.

Cardiovascular disease (CVD), one of the main mortality causes worldwide is considered to be affected by general oxidative stress and inadequacy antioxidant system. Superoxide dismutase 1 (SOD1), a cytosolic antioxidant enzyme has a key role in neutralizing the excessive prooxidant by scavenging the super oxide anions. SOD1 polymorphic variants exhibit the altered activity properties. In the current study, we are aimed to investigate the association between the SOD1 polymorphism and CVD prevalence. A 6-years case control follow up study was designed to genotype the 526 participants (311 controls and 215 cases) for studying the 50 bp INS/DEL polymorphism at SOD1 promoter gene and analyze their blood lipid profile and anthropometric characteristics. Among the two possible alleles of the SOD1 gene (Wild [W] and Mutant [M]) the meaningful association was detected between the Mutants' frequency and the prevalence of CVD patients (p-value

Liposomal peptide-based vaccines can potentially suppress cancer cells proliferation in the host. To enhance the effectiveness of vaccination against cancer, additional strategies should also be employed. One strategy to promote peptide-based vaccine efficacy and induce powerful immune responses, is simultaneous activation of CD4+ and CD8+ T cells. To address this problem, we tested the efficacy of a nano-liposomal vaccine containing P5 peptide, a cytotoxic T lymphocytes (CTL) specific peptide derivative of rat HER2/neu protein, Pan HLA-DR (PADRE) peptide, a universal CD4+ T helper cell epitope and monophosphoryl lipid A (MPL) a toll-like receptor 4 ligand. We observed potent CD8+ T cell immune responses in TUBO mice vaccinated with liposomal P5 peptide in combination with PADRE and MPL. Also, this formulation remarkably improved anti-tumor effects against cells overexpressing HER2 in BALB/c mice compared to liposomal vaccine containing P5 only. Furthermore, we found that vaccination with Lip-P5- Integrated PADRE-MPL formulation significantly induced IFN-γ production, increased CD8+ T cells numbers and enhanced survival compared to other groups of treated mice. In conclusion, our study indicated that Lip-P5-Integrated PADRE-MPL, after further confirmatory investigations, could be employed as a promising vaccine to generate potent CTL anti-tumor immune responses that could be beneficial to treatment of HER2+ breast cancer.

A number of antiangiogenic drugs have been approved by the Food and Drug Administration which are used in cancer therapy, and variety of other agents in several stages of clinical development or in preclinical assessment. Among these, combretastatin A4 (CA-4) is an under-researched inhibitor of angiogenesis that shows potential activity in the treatment of advanced tumors with migration capacity. However, its clinical application has been limited due to poor water solubility, low bioavailability, rapid metabolism, and systemic elimination. During the last decade, numerous investigations have been done to overcome these problems by using different CA-4 delivery systems or developing produgs of CA-4 or its structural analogs. Nevertheless, these strategies could not be efficient out of the undesired side effects on normal tissues. Nanoliposomal CA-4 not only benefits from the advantage of using liposomal drugs as opposed to free drugs but also can accumulate in the tumor site via specific targeting ligands, which leads to efficient targeting and enhancement of bioavailability. To the best of our knowledge, we consider an important attempt to understand different factors that might influence the CA-4 loading and release pattern of liposomes and the consequent results in tumor therapy. In this review, we shed light on various studied liposomal CA-4 formulations showing application thereof in cancer treatment.

LAG3-Ig as an immune adjuvant has elicited potent anti-tumor immune responses in several preclinical and clinical studies, but the full potential immunostimulatory of LAG3-Ig has yet to be achieved. We hypothesized that by anchoring LAG3-Ig to the surface of liposomes, the adjuvant activity of LAG3-Ig could be improved. We also investigated the immunotherapy by co-delivery of liposome-coupled LAG3-Ig and P5 tumor antigen in mice model of TUBO breast cancer. We prepared and characterized novel PEGylated liposomes bearing surface conjugated LAG3-Ig and P5. Consistent with our hypothesis, liposomes-conjugated LAG3-Ig via multivalent binding to MHC class II molecules exerted immunostimulatory of LAG3-Ig and markedly induced maturation of dendritic cells more efficiently than free LAG3-Ig. LAG3-Ig-P5-immunoliposomes effectively elicited protective anti-tumor responses more than locally injected soluble LAG3-Ig + P5. The higher percentage of CD4+ and CD8+ T cells in the spleen and more rapid and pronounced infiltration of these effector cells into the site of the tumor were seen following immunoliposome therapy. Finally, anti-tumor immunity induced by LAG3-Ig-P5-immunoliposomes translated into the more tumor regression and prolonged survival of treated mice, compared to soluble immunotherapy. Taken together, our findings suggest that LAG3-Ig-P5-immunoliposomes can be considered as a valuable candidate for developing a liposome-based therapeutic cancer vaccine in treating HER2/ neu+ breast cancer patients.

Disorders of the central nervous system (CNS) and tumors of the brain are challenging to treat, and they rank amongst the most common causes of death worldwide. The delivery of drugs to the brain is problematic because the blood-brain barrier (BBB) effectively arrests the transport of large molecules (including drugs) from the blood to the CNS. Nanoparticle (NP)-mediated drug delivery has received much interest as a technique to overcome this difficulty. In particular, liposome NPs are promising candidates to carry and deliver drugs across the BBB and into the CNS. Liposomes are easy to prepare, highly biodegradable and biocompatible. Liposomes can be easily modified with various ligands to enable efficient and targeted drug delivery. Liposomes can promote increased cellular uptake of drugs and can reduce the extent to which efflux transporters can remove drugs. Liposomes can be loaded with a wide range of drugs and biologically active substances. In this review, we will summarize recent advances in research relating to liposome-based strategies to enable drug delivery across the BBB.

Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells causing resistance to immunotherapies in cancer tumors. In the current study, various immunogenic and therapeutic features of the combination therapies with non-liposomal Doxorubicin (Dox) and the E75 immunogenic peptide (Pep), derived from the human epidermal receptor-2 (HER-2), are investigated in parallel with their liposomal formulations (Lip-Dox (Doxil®) and Lip-Pep). Therefore, triple injection doses of Lip-Pep were preceded with Dox and Lip-Dox injections in TUBO/breast tumor-bearing BALB/c mice. Chemotherapy with either Dox or Lip-Dox reduced the frequency of MDSCs, the level of reactive oxygen species (ROS), and MDSCs-associated genes of Arg1, iNOS, S100A8, S100A9. Whereas Lip-Pep + Dox and Lip-Pep + Lip-Dox treatments synergistically potentiated the immunized splenocytes to produce INF-γ and enhanced the frequency of the anti-tumor CD8+ and CD4+ T cells as opposed to both chemotherapy and immunotherapy regimens. Chemo-immunotherapy increased the number of tumor-infiltrating lymphocytes (TILs) and reduced the level of CD25+ FoxP3+ T regulatory cells. Taken together, chemo-immunotherapy was the optimum treatment for the limitation of tumor progression as they targeted more cancer-related immune players.

Liposomal formulations were made using Solvent-assisted active loading technology (SALT). Two formulations composed of HSPC:DPPG:Chol:DSPE-mPEG2000 (PG-LipCUR) and HSPC:Chol:DSPE-mPEG2000 (LipCUR) demonstrated good colloidal properties and the CUR-encapsulation of 82% and 89% for PG-LipCUR and LipCUR, respectively. The results showed that both formulations were stable during 6 months storage at 4 °C. The release study showed that the PG-LipCUR and LipCUR formulations are relatively stable at pH 7.4. Both formulations had higher cytotoxicity on TUBO and 4T1 cell lines in compassion with normal cells. PG-LipCUR had the higher amounts of CUR cellular uptake than LipCUR. Biodistribution studies showed that both formulations could enhance the half-life of the CUR 2–3 times compared to free CUR. The tumor accumulation of PG-LipCUR was significantly higher than LipCUR. The antitumor activities of liposomes on 4T1 tumor model demonstrated the efficacy of both formulations compared to PBS and free CUR. PG-LipCUR also was more potent in tumor growth delay in comparison with LipCUR. However, combination of the Caelyx® and PG-LipCUR had the most antitumor properties among other treatments. Based on the results, PG-LipCUR could be a promising formulation for the delivery of CUR which also significantly increased the efficacy of Caelyx® and merits further investigation.

Obesity is an important feature of the metabolic syndrome and is associated with an increased risk of type 2 diabetes mellitus, cardiovascular disease, and some cancers. The aim of this study was to determine the relationship between body fat percentage and an imbalance of the prooxidant/antioxidant balance (PAB), serum superoxide dismutase (SOD1) and inflammation (serum hs-CRP) and increase risk of metabolic syndrome and diabetes mellitus. In this study, 9154 individuals were recruited as part of the Mashhad Stroke and Heart Association Disorder (MASHAD) study. Subjects were categorized into two groups according to body fat percentage as defined >25% in male and > 30% in female, according to gender. Biochemical factors, including serum PAB, SOD1, and hs-CRP were measured in all subjects. SPSS version 18 was used for statistical analyses for all. GraphPad Prism 6 for figures was used. Of total number of subjects (9154), 6748 (73.7%) were found to have a high body fat (BF) percentage. Serum hs-CRP and PAB were significantly higher in individuals with a high BF percentage (P 0.05). BF percentage, serum PAB and serum hs-CRP were significantly higher in individuals with metabolic syndrome and diabetes versus those without metabolic syndrome and diabetes mellitus (P < 0.05), however serum SOD1 was significantly lower in individuals with metabolic syndrome (P < 0.005). Oxidative stress and inflammation are two factors that may link the presence of high BF percentage with the development of metabolic syndrome, diabetes, and cardiovascular disease. © 2018 BioFactors, 45(1):35-42, 2019.

The main obstacles that lead to clinical failure in cancer treatment are the development of resistant to chemotherapy and a rise in invasive characteristics in cancer tumor cells due to prolonged chemotherapeutic processes. Recent studies have revealed some evidence about the existence of a direct relationship between development of drug resistance and triggering of invasive capability in tumor cells. Therefore, devising and application of chemotherapeutic procedures that are not prone to the development of chemotherapy resistance are necessary. Here, we focus on CD147, CD44, ANAX2, P-gp, MMPs, and UCH-L1 proteins involved in the crosstalk between metastasis and cancer treatment. We think that further structural and functional analysis of these proteins may direct scientists towards designing highly effective chemotherapy procedures.

Curcumin, the bioactive pigment of turmeric which has polyphenolic-hydrophobic components, has been used for the treatment of a variety of diseases. However, due to its insignificant intestinal-liver metabolism, low stability, quick systemic elimination and its hydrophobic property with low solubility, curcumin has limited bioavailability. Exosomes are nanovesicles (30-100 nm) released from diverse cell types into extracellular and, ultimately, into bio-fluids in a tightly regulated manner. Exosomes are capable of transferring lipids, proteins, RNAs and DNAs, both with and without direct cell-to-cell contact. Curcumin-encapsulated exosomes are highly bioavailable, soluble and safe, and can reach high concentrations in the blood; they, therefore, have therapeutic potential without toxic effects and immune stimulation. Thus, curcumin-encapsulated exosomes could be superior to other synthetic nanoparticles as a carrier of curcumin. The aim of the current review is to offer an overview of the in vitro, in vivo and clinical studies pertaining to the role of curcumin-primed and curcumin-encapsulated exosomes in the treatment of cancer, oxidative stress, brain disorders, cholesterol, and endothelial dysfunction.

An effective Leishmania vaccine must induce strong Th1 immune responses and generate long-term effectiveness in the host. To date, most designated anti-Leishmania vaccines have shown poor efficacy in clinical studies. One of the most effective approaches in enhancing the efficacy of vaccines to generate protective immunity is the use of multiple distinct antigens in a single vaccination regimen. For this reason, we investigated the immunogenicity and protective efficacy of liposomal formulation composed of DOTAP:Cholesterol, protamine and CpG ODNs (LPD NPs) containing rLmaC1N and rgp63 recombinant proteins (LPD-rLmaC1N/rgp63) as an effective vaccine. Then, we have investigated the immunogenicity and protective efficacy of LPD-rLmaC1N/rgp63 in experimental animal model of cutaneous leishmaniasis compared to free antigens. Our study showed that mice immunization with LPD-rLmaC1N/rgp63 significantly activates Th1 immune response and enhances IFN-γ production and IgG2a levels. Notably, LPD-rLmaC1N/rgp63 immunization greatly reduced the number of live parasites in the spleen and footpads of immunized mice compared to other vaccinated groups. As well, the thickness of footpad was remarkably smaller in mice immunized with LPD-rLmaC1N/rgp63. In conclusion, our study indicated that LPD-rLmaC1N/rgp63 could be regarded as a promising multiple-antigen candidate vaccine compared to single antigen counterparts to generate protective immunity against leishmaniasis. The potential advantages of this formulation may warrant further investigation.

Hepatocellular carcinoma (HCC) is known as fifth common malignancies and third common cause of cancer-related death worldwide. The identification of various mechanisms which are involved in hepatocarcinogenesis contributes in finding a variety of cellular and molecular targets for HCC diagnosis, prevention and therapy. Among various identified targets in HCC pathogenesis, Gankyrin is a crucial oncoprotein that is up-regulated in HCC and plays a pivotal role in the initiation and progression of the HCC. Oncogenic role of Gankyrin has been found to stem from inhibition of two ubiquitous tumour suppressor proteins, retinoblastoma protein (pRb) and P53, and also modulation of several vital cellular signalling pathways including Wnt/β-Catenin, NF-κB, STAT3/Akt, IL-1β/IRAK-1 and RhoA/ROCK. As a result, Gankyrin can be considered as a potential candidate for diagnosis and treatment of HCC. In this review, we summarized the physiological function and the significant role of Gankyrin as an important therapeutic target in HCC.

Peritoneal adhesion between abdominal organs is a complication of surgery. It causes major complications like pain, bowel obstruction, infertility and increases risk of death. Honey is known to have anti-inflammatory and antioxidant properties potentially relevant for adhesive protection.Thirty rats were divided into five groups: negative control without any surgical procedure (normal group), control group treated with normal saline, experimental group I treated with 1ml of 10% honey, experimental group II treated with honey at half concentration of group I (honey0.5), and positive control group receiving 1ml of dextrose 5%. Inflammatory, growth and angiogenesis factors (TNF-α, Il-6, IL-1β, TGF-β1 and VEGF) of the adhesion tissue were assessed using ELISA. Antioxidant factors (NO, GSH and MDA) were also assessed using biochemical procedures.The difference between peritoneal adhesion scores, TNF-α, IL-1β, IL-6, TGF-β1, VEGF, NO, GSH and MDA value of all groups was strongly significant (p0.001). We showed that honey can decrease peritoneal adhesion (p0.001), TNF-α (p0.001), IL-1β (p0.001), IL-6 (p0.001), TGF-β1 (p0.001), VEGF (p0.001), NO (p0.001), MDA (p0.001) and increase GSH (p0.001) compared with control group. Honey 0.5 also significantly decreased peritoneal adhesion (p0.001), TNF-α (p0.001), IL-1β (p0.01), IL-6 (p0.001), VEGF (p0.001), NO (p0.001), MDA (p0.01) and increase GSH (p0.001) compared with control group.We find that honey can decrease inflammatory, growth and angiogenesis factors which can advance peritoneal adhesion and increase antioxidant factors. Honey could serve as a protective agent for peritoneal adhesion.

In this study, we have surface-functionalized PEGylated-nanoliposomal doxorubicin (DOX) with anti-EpCAM (epithelial cell adhesion molecule) aptamer via post-insertion of anti-EpCAM aptamer-conjugated DSPE-mPEG2000 into Caelyx® (ED-lip). The size, charge, release profile, and cytotoxicity and cellular uptake of formulation were determined. The characterization of the ED-lip demonstrated the slightly increase in size and PDI along with the decrease in zeta potential which indicated that post-insertion efficiently done. The results of flow cytometry and fluorescent microscopy have shown that ED-lip enhanced the rate of cell uptake on C26 cell line compared to Caelyx®. The ED-lip also had more cytotoxic effects than Caelyx® which indicated the efficacy of anti-EpCAM aptamer as targeting ligand. The pharmacokinetic and tissue biodistribution of formulations in mice bearing C26 tumors demonstrated that ED-lip did not affect the distribution profile of DOX compared to Caelyx® in animal model. In addition, ED-lip effectively improved the tumor accumulation of DOX and promoted survival of animals compared to Caelyx®. These results suggest that the functionalization of Caelyx® with anti-EpCAM aptamer is promising in cancer treatment and merits further investigation.

Introduction: Pyrene and phenanthrene are polycyclic aromatic hydrocarbons (PAHs) are priority pollutants. The aim of this study was to investigate the ability of isolated bacteria from stabilized compost‌ for biodegradation of pyrene and phenanthrene from soil contaminated with municipal solid waste leachate. Materials and Methods: In this study, phenanthrene and pyrene were selected as priority PAHs pollutants. The degrading bacteria of these compounds were isolated from the stabilized compost and their ability to remove different concentrations of pyrene and phenanthrene investigated. The remaining concentrations of pyrene and phenanthrene were measured by GC-MS. The growth kinetics of bacteria were also studied using a spectrophotometer at 595-nm wavelength. One-way ANOVA was used to determine the statistical significance and plot the related curves, and the Excel software and SPSS version 24 to do statistical analysis. Results: The most potent bacteria in removing pyrene and phenanthrene were Paenibacillus and Bacillus, respectively. The concentrations to be studied were determined as 10, 25, 40 and 55 μg/kg according to the concentrations of PAHs in the soil contaminated with municipal solid waste leachate. At constant temperature of 30 °C after 30 days at these concentrations, the removal efficiency was, respectively, 96.3%, 83%, 77.8%, and 72.4% for pyrene and 100%, 99.6%, 95.9%, and 94.6% for phenanthrene. The growth kinetics of phenanthrene-exposed bacteria were better than those of pyrene-exposed bacteria. Conclusion: The results show that bacteria in stabilized compost are able to remove pyrene and phenanthrene. The bacteria of the highest efficiency for removal of pyrene and phenanthrene are Paenibacillus and Bacillus, respectively.

For the treatment of many types of cancers, targeting drug delivery vehicles to the mitochondria is a major area of interest which provides a significant strategy. This study aimed to investigate whether modifying Doxil® with mitochondriotropic SS-02 peptide could improve the therapeutic efficacy of liposomal formulation in vitro and in vivo. To this purpose, the peptide conjugation was done through the covalent coupling of the cysteine thiol group of SS-02 peptide to the pyrrole group of maleimide. The novel formulations of SS-02-Doxil® (100 and 200 peptides on Doxil® surface) were prepared by post-insertion which were well characterized. In vitro study indicated that Doxil® modification with SS-02 peptides could effectively enhance the cytotoxicity, cellular binding, and uptake in TUBO tumor cells. Moreover, the increase in caspase-3, and caspase-9 activities was observed in TUBO cells following the treatment with SS-02-Doxil® formulations that confirm the mitochondria targeting. Following the administration of formulations at 10 mg/kg doxorubicin in mice model of breast cancer, SS-02-Doxil® formulations significantly reduced the growth of tumor which improved animals' survival compared to Doxil®. Furthermore, the findings of in vitro and in vivo studies indicate that Doxil® modification with SS-02 peptide could improve the therapeutic efficacy due to targeting the mitochondria of tumor cells.

Samaneh Abolbashari,1,* Susan Darroudi,1,* Maryam Tayefi,2,3 Zahra Khashyarmaneh,4 Parvin Zamani,5 Hamideh Moalemzadeh Haghighi,4 Amir Hooshang Mohammadpour,6,7 Shima Tavalaei,8 Mahsa Ahmadnezhad,9 Habibollah Esmaily,10 Gordon A Ferns,11 Zahra Meshkat,12 Majid Ghayour-Mobarhan8 1Student Research Committee, Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; 2Cardiovascular Research Center, Mashhad University of Medical Science, Mashhad, Iran; 3University International Accreditation, International Office, Clinical Research Unit, Mashhad University of Medical Sciences, Mashhad, Iran; 4Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; 5Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; 6Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; 7Clinical Pharmacy Department, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; 8Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; 9Nutrition Research Center, Department of Community Nutrition, Tabriz University of Medical Sciences, Tabriz, Iran; 10Department of Biostatistics, School of Health, Mashhad University of Medical Sciences, Mashhad, Iran; 11Brighton and Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex, UK; 12Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran *These authors contributed equally to this work Introduction: Copper (Cu) and zinc (Zn) are important trace elements that are also structural ions of superoxide dismutase (SOD), which reduce oxidative stress. Zinc deficiency and excess copper have been reported to be associated with inflammation. The human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus, which is believed to cause systemic inflammation. The aim of this study is to measure levels of Zn, Cu, SOD, and prooxidant–antioxidant balance (PAB) in HTLV-1-positive patients and investigate the association between serum Zn and Cu concentrations and levels of oxidative stress in them.Methods: The serum samples of 1,116 subjects who had participated in the “Mashhad Stroke and Heart Atherosclerotic Disorder” study, including 279 HTLV-1-positive and 837 HTLV-1-negative patients, were used. Levels of Zn, Cu, SOD, and PAB were measured.Results: Zinc and SOD levels were lower in the HTLV-1-positive group; however, the difference was statistically significant only for the level of SOD (P=0.003). On the other hand, levels of copper and PAB were significantly higher in HTLV-1 positive subjects; P=0.004 and P=0.002, respectively.Conclusion: In HTLV-infected patients, serum Zn concentration is lower and Cu concentration is higher than healthy controls. This altered situation might be either primary or secondary to HTLV-1 infection, which should be investigated in larger studies. We showed that SOD is significantly lower in HTLV-1-infected subjects. As in some other viruses that evolve different mechanisms to potentiate virus replication by changing the physiologic condition of host cells, HTLV-1 too probably decreases the activity of copper–zinc SOD1 by suppressing its gene.Keywords: HTLV-1, trace elements, superoxide dismutase, prooxidant-oxidant balance

Depression and Anxiety are two important public health problems that are known to be associated with viral infections. The association between the intake of nutrients such as zinc and copper with symptoms of depression has been studied previously. The aim of the current study was to investigate the association between depression with human T cell lymphotropic virus type 1 (HTLV-1) infection and serum content of zinc and copper in a large Iranian population cohort. The study population consisted of 279 HTLV-1-positive patients who were identified after recruitment as part of a large cohort study: the Mashhad Stroke and Heart Association Disorder (MASHAD) study. They were divided into two groups of diagnosed with or without depression based on their symptoms. Serum zinc and copper levels of all subjects were measured using the flame atomic absorption spectrometry. The population sample comprised of 279 individuals infected with HTLV-1 of whom 192 (68.8%) were women. The mean serum zinc in the group with and without depression was 78.69 ± 13.79 μg/dl and 86.87 ± 19.44 μg/dl, respectively (p

Obesity is an important feature of the metabolic syndrome and is associated with an increased risk of type 2 diabetes mellitus, cardiovascular disease, and some cancers. The aim of this study was to determine the relationship between body fat percentage and an imbalance of the prooxidant/antioxidant balance (PAB), serum superoxide dismutase (SOD1) and inflammation (serum hs-CRP) and increase risk of metabolic syndrome and diabetes mellitus. In this study, 9154 individuals were recruited as part of the Mashhad Stroke and Heart Association Disorder (MASHAD) study. Subjects were categorized into two groups according to body fat percentage as defined25% in male and30% in female, according to gender. Biochemical factors, including serum PAB, SOD1, and hs-CRP were measured in all subjects. SPSS version 18 was used for statistical analyses for all. GraphPad Prism 6 for figures was used. Of total number of subjects (9154), 6748 (73.7%) were found to have a high body fat (BF) percentage. Serum hs-CRP and PAB were significantly higher in individuals with a high BF percentage (P0.05) but SOD1 was not significantly different between the two groups (P0.05). BF percentage, serum PAB and serum hs-CRP were significantly higher in individuals with metabolic syndrome and diabetes versus those without metabolic syndrome and diabetes mellitus (P0.05), however serum SOD1 was significantly lower in individuals with metabolic syndrome (P0.005). Oxidative stress and inflammation are two factors that may link the presence of high BF percentage with the development of metabolic syndrome, diabetes, and cardiovascular disease. © 2018 BioFactors, 45(1):35-42, 2019.

Peritoneal adhesion is a major complication of surgery that can lead to serious problems such as bowel obstruction, pain, infertility and even mortality. Propolis is a honey bee product with anti-inflammatory and anti-oxidant activities that could potentially protect against adhesive surgical complications.Forty 8-weeks-old rats (275 ± 25 g) were divided into five groups: normal group without any surgical procedure, and experimental groups treated with normal saline, 50 mg/kg, 100 mg/kg and 200 mg/kg of propolis. Peritoneal adhesions were examined macroscopically and also, the levels of inflammatory factors (IL-6, IL-1β and TNF-α), growth factors (TGF-β1 and VEGF) were evaluated in the study groups using ELISA. Biochemical indices of oxidative status including Nitric Oxide (NO), Malondialdehyde (MDA) and Glutathione (GSH) were also measured.Peritoneal adhesion scores, IL-1β, IL-6, TNF-α, TGF-β1, VEGF, NO, GSH and MDA levels were significantly different between the study groups (p 0.001). Propolis treatment reduced peritoneal adhesion (p 0.001), TNF-α (p 0.001), IL-1β (p 0.001), IL-6 (p 0.001), TGF-β1 (p 0.001), VEGF (p 0.001), NO (p 0.001) and MDA (p 0.001), while GSH levels were increased (p 0.001) compared with the vehicle group. Our results showed that higher dose of propolis was associated with significantly greater reductions in peritoneal adhesion (p 0.001), TNF-α (p 0.001), IL-1β (p 0.001), IL-6 (p 0.001), VEGF (p 0.001), NO (p 0.001) and MDA (p 0.001), a greater increase in GSH levels (p 0.001) compared with the lower dose.Propolis treatment can dose-dependently reduce peritoneal adhesion through its anti-inflammatory, anti-angiogenic and antioxidant properties. Therefore, propolis might serve as a protective agent against post-surgical adhesive complications.

Cancer immunotherapy is one of the commonly used methods in the treatment of cancer. The aim of this approach is to strengthen or restore immune function for effective diagnosis of aberrant cells antigens. For this reason, cancer specific peptides or proteins are used as antigens to induce an immune response capable of removing cancer cells. Liposomal formulations are an important carrier system frequently used for delivery of antigen because the specific properties of this component such as lipid composition, charge, size, encapsulation of antigens, or adjuvants can be changed. Among different types of liposomal formulations, the use of cationic and pH-sensitive nanoliposomes has been markedly increased for liposome-based vaccines. In this review, we describe the properties of nanoliposomes as delivery systems for cancer immunotherapy.

Prostate cancer is the second most commonly diagnosed cancer among men worldwide. Identifying new prognostic and predictive biomarkers will help stratification of prostate cancer patients for a better treatment. Gankyrin is a novel oncoprotein which regulates cell cycle and protein degradation. Gankyrin overexpression correlated with the malignant phenotypes and promotes the tumorigenicity and metastasis in many cancers. However, there are not any reports on the role of Gankyrin in prostate cancer. Therefore, this study was designed to investigate the expression of Gankyrin in prostate cancer and analyze its correlation with some clinicopathological characteristics. We characterized the expression of gankyrin in fifty five prostate cancer specimens and twenty non-cancerous tissues by immunohistochemical staining and the results were correlated with clinical characteristics and pathological parameters.Results showed that Gankyrin was expressed in 41 of 55 (74%) prostate cancer patients and its expression was significantly higher than corresponding adjacent normal tissues (p

Background Hypertension (HTN) is a risk factor for stroke, renal failure, and cardiovascular disease. The association between biochemical and hematological parameters with high blood pressure may provide a more precise approach to risk prediction conferred by HTN in these patients. Objective The aim of current study was to explore whether biochemical and hematological parameters are associated with HTN in a cohort study with a 7-year follow-up. Materials and Methods A total of 9808 individuals were enrolled and recruited as part of the Mashhad Stroke and Heart Atherosclerotic Disorders (MASHAD) cohort study, and biochemical and hematological factors were measured in all subjects. Univariate and multivariate logistic regression analysis were performed to determine the association of biochemical and hematological parameters with HTN. Results Several biochemical parameters including fasting plasma glucose (FBG), serum high-sensitivity C-reactive protein (hs-CRP), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and uric acid were increased in hypertensive participants. In contrast, serum high-density lipoprotein cholesterol (HDL-C) was lower in hypertensive individuals. Furthermore, we demonstrated that hematological parameters including white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin (HGB), hematocrit (HCT), and mean corpuscular hemoglobin (MCH) were higher in the hypertensive group compared to the control group. But mean corpuscular volume (MCV), and red cell distribution width (RDW), were decreased in the hypertensive group. Furthermore, our results strongly suggested that among these parameters, hematocrit was the independent risk factor for hypertension in the population. Conclusion We demonstrated the association of altered biochemical and hematological factors with hypertension supporting the value of emerging markers for early prediction of high blood pressure in prone individuals.

Aims The development of highly efficient and low toxic non-viral gene delivery vectors is the most challenging issues for successful application of gene therapy. A particular focus has been on understanding structure-activity relationships for transfection activity and toxicity of polyethylenimine (PEI). During the last decade, the use of cerium oxide nanoparticles (CeO2-NPs) in biomedicine has attracted much attention due to their pH-dependent antioxidant activity. CeO2-NPs provide protection normal cells from various forms of reactive oxygen species, but possess innate cytotoxicity and apoptosis to cancer cells. The purpose of this study was to design a new class of gene carriers by low molecular weight PEI (B-PEI 10 kDa) coordination onto CeO2-NPs. Main methods B-PEI 10 kDa was conjugated to CeO2-NPs by Epichlorohydrin linker. Transfection efficiency, cytotoxic and apoptotic effects of pDNA-PEI-CeO2 NPs were evaluated on WEHI 164 cancer cells and normal L929 cells lines. Key findings PEI-CeO2 NPs was able to condense the pDNA at carrier/plasmid (C/P) weight ratios of 0.5. The size and zeta potential of pDNA-PEI-CeO2 NPs were 124 ± 7 nm and 22 ± 2 mV, respectively. The transfection efficacy of synthesized pDNA-PEI-CeO2 NPs improved and the cytotoxicity was decreased compared to pDNA-PEI. Moreover, pDNA-PEI-CeO2 NPs induced more apoptosis than unmodified PEI and CeO2-NPs control groups. pDNA-PEI-CeO2 NPs displayed more transfection, cytotoxicity, and apoptosis in WEHI 164 cancer cells than normal L929 cells. Significance In conclusion, PEI-CeO2 nanocarriers could act as a potential candidate for gene and drug delivery to cancerous and tumor cells.

Liposome is one of the promising technologies for antigen delivery in cancer immunotherapies. It seems that the phospholipid content of liposomes can act as immunostimulatory molecules in cancer immunotherapy. In the present study, the immunological properties of different phospholipid content of liposomal antigen delivery platforms were investigated. To this aim, F1 to F4 naïve liposomes (without tumor-specific loaded antigens) of positively charged DOTAP/Cholesterol/DOPE (4/4/4 mol ratio), negatively charged DMPC/DMPG/Cholesterol/DOPE (15/2/3/5), negatively charged DSPC/DSPG/Cholesterol/DOPE (15/2/3/5) and PEGylated HSPC/mPEG2000-DSPE/Cholesterol (13/110) liposomal compositions were administered in mice bearing C26 colon carcinoma to assess tumor therapy. Moreover, In-vitro studies were conducted, including cytotoxicity assay, serum cytokines measurements, IFN-γ and IL-4 ELISpot assay, T cells subpopulation frequencies assay. The liposomes containing DOTAP and DOPE (F1 liposomes) were able to stimulate cytotoxic T lymphocytes signals such as IFN-γ secretions. In parallel, the aforementioned phospholipids stimulated secretion of IL-4 and IL-17 cytokines from T helper cells. However, these liposomes did not improve survival indices in mice. As conclusion, DOTAP and DOPE contained liposomes (F1 liposomes) stimulate a mixture of Th1 and Th2 immune responses in a tumor-specific antigens-free manner in mice bearing C26 colon carcinoma. Therefore, phospholipid composition of liposomes merits consideration in designing antigen-containing liposomes for cancer immunotherapy.