Virus against virus: strategies for using adenovirus vectors in the treatment of HPV-induced cervical cancer.

Although most human papillomavirus (HPV) infections are harmless, persistent infection with high-risk types of HPV is known to be the leading cause of cervical cancer. Following the infection of the epithelium and integration into the host genome, the oncogenic proteins E6 and E7 disrupt cell cycle control by inducing p53 and retinoblastoma (Rb) degradation. Despite the FDA approval of prophylactic vaccines, there are still issues with cervical cancer treatment; thus, many therapeutic approaches have been developed to date. Due to strong immunogenicity, a high capacity for packaging foreign DNA, safety, and the ability to infect a myriad of cells, adenoviruses have drawn attention of researchers. Adenovirus vectors have been used for different purposes, including as oncolytic agents to kill cancer cells, carrier for RNA interference to block oncoproteins expression, vaccines for eliciting immune responses, especially in cytotoxic T lymphocytes (CTLs), and gene therapy vehicles for restoring p53 and Rb function.

Oncolytic virotherapy: Challenges and solutions.

Viruses as cancer therapies have attracted attention since the 19th century. Scientists observation that viruses can preferentially lyse cancer cells rather than healthy cells, created the field of oncolytic virology. Like other therapeutic strategies, oncolytic virotherapy has challenges, such as penetration into tumor bulk, anti-viral immune responses, off-target infection, adverse conditions in the tumor microenvironment, and the lack of specific predictive and therapeutic biomarkers. Whilst much progress has been made, as highlighted by the first Food and Drug Administration approval of an oncolytic virus talimogene laherparepvec (T-VEC) in 2015, addressing these issues remains a significant hurdle. Here we discuss different types of oncolytic viruses, their application in clinical trials, and finally challenges faced by the field of oncolytic virotherapy and strategies to overcome them.

Strategies for enhancing intratumoral spread of oncolytic adenoviruses.

Oncolytic viruses, effectively replicate viruses within malignant cells to lyse them without affecting normal ones, have recently shown great promise in developing therapeutic options for cancer. Adenoviruses (Ads) are one of the candidates in oncolytic virotheraoy due to its easily manipulated genomic DNA and expression of wide rane of its receptors on the various cancers. Although systematic delivery of oncolytic adenoviruses can target both primary and metastatic tumors, there are some drawbacks in the effective systematic delivery of oncolytic adenoviruses, including pre-existing antibodies and liver tropism. To overcome these limitations, intratumural (IT) administration of oncolytic viruses have been proposed. However, IT injection of Ads leaves much of the tumor mass unaffected and Ads are not able to disperse more in the tumor microenvironment (TME). To this end, various strategies have been developed to enhance the IT spread of oncolytic adenoviruses, such as using extracellular matrix degradation enzymes, junction opening peptides, and fusogenic proteins. In the present paper, we reviewed different oncolytic adenoviruses, their application in the clinical trials, and strategies for enhancing their IT spread.

Targeting autophagy in cardiac ischemia/reperfusion injury: A novel therapeutic strategy.

Acute myocardial infarction (AMI) is one of the leading causes of morbidity worldwide. Myocardial reperfusion is known as an effective therapeutic choice against AMI. However, reperfusion of blood flow induces ischemia/reperfusion (I/R) injury through different complex processes including ion accumulation, disruption of mitochondrial membrane potential, the formation of reactive oxygen species, and so forth. One of the processes that gets activated in response to I/R injury is autophagy. Indeed, autophagy acts as a "double-edged sword" in the pathology of myocardial I/R injury and there is a controversy about autophagy being beneficial or detrimental. On the basis of the autophagy effect and regulation on myocardial I/R injury, many studies targeted it as a therapeutic strategy. In this review, we discuss the role of autophagy in I/R injury and its targeting as a therapeutic strategy.

Myeloid-derived suppressor cells and tumor: Current knowledge and future perspectives.

The immunosuppressive features of tumor lesions participate not only as one of the major players inducing cancer progression but also a big challenge for effective immunotherapy. It has been found that immunosuppression associated with chronic inflammatory factors, such as growth factors, cytokines, and chemokines is generated by stroma and tumor cells. Chronic and exhaustive secretion of these mediators triggers the generation of myeloid-derived suppressor cells (MDSCs) demonstrating one of the key players engaged in tumor immunosuppression. In point of fact, direct cell-to-cell contact is a prerequisite for immunosuppressive functions of MDSCs. From the clinical perspective, the frequency of peripheral blood MDSCs is correlated with clinical stage and therapeutic response in various cancers. Furthermore, MDSCs are involved in chemoresistant settings. Altogether, it is a rational therapeutic approach to block the fierce cycle in which MDSCs are developed and infiltrated to favor cancer progression. In this review, we will summarize recent findings of MDSCs in tumor progression and discuss potential therapeutic strategies that could be evaluated in future clinical trials.

Cardioprotective and anti-apoptotic effects of Potentilla reptans L. root via Nrf2 pathway in an isolated rat heart ischemia/reperfusion model.

BACKGROUND: Previous studies have shown that proanthocyanidins have cardioprotective effects which are mediated via the release of nitric oxide (NO) ultimately resulting in increasing the antioxidant activity. We have investigated to show whether 1) the total extract and ethyl acetate fraction (Et) of Potentilla reptans root have an ischemic preconditioning (IPC) effect, 2) P. reptans has antioxidant and cardioprotective effects mediated by nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and scavenging of reactive oxygen species (ROS), 3) NO, caspase-3 and Bcl-2/Bax are involved in the IPC effect of P. reptans. METHODS: Male Wistar rats were divided into 10 groups. The isolated hearts were subjected to 30 min of ischemia and 100 min of reperfusion. The P. reptans was applied before the main ischemia. The infarct size was estimated by triphenyl-tetrazolium chloride staining. The hemodynamic parameters and ventricular arrhythmias were calculated during the reperfusion. Antioxidant markers and immunohistochemistry assays were determined at the end of the protocol. RESULTS: The Et significantly decreased the infarct size, arrhythmia scores, ventricular fibrillation incidence, and enhanced the hemodynamic parameters in a concentration-dependent manner against the ischemia/reperfusion group. SOD and CAT activity were increased and MDA level was decreased in response to the Et. Meanwhile, Et attenuated the suppression of Nrf2 expression and reduced the apoptotic indexes. The cardioprotective effect of P. reptans was abrogated by L-NAME. CONCLUSIONS: P. reptans demonstrated that the cardioprotective preconditioning effects via NO release, Nrf2 pathway, and antioxidant activity lead to a decrease in the apoptotic index.

Association of Promoter Polymorphisms of Interleukin-10 and Interferon-Gamma Genes with Tuberculosis in Azeri Population of Iran.

Promoter polymorphism of cytokine genes may lead to inter-individual differences in cytokine levels, therefore, polymorphisms may associate with susceptibility to infectious diseases. In this study, we investigated a possible association between interleukin-10 (IL-10) -1082A/G (rs1800896) and interferon (IFN)-gamma +874T/A (rs2430561) promoter polymorphisms and tuberculosis (TB) in the Azeri population of Iran. IL-10 -1082G/A and IFN-gamma +874T/A single nucleotide polymorphisms (SNPs) were genotyped by amplification refractory mutation system (ARMS)-PCR in 200 healthy controls and 124 tuberculosis patients. IL-10 -1082 A allele was more frequent in the control group than in the patient group (p=0.001, odds ratio [OR]=2.183). On the other hand, the AA genotype was significantly more frequent in the control group (p=0.0001). The frequency of IFN-gamma +874 T allele was significantly higher in the controls (p=0.013, OR=1.56). There was no significant association between IFN-gamma +874 T/A genotypes and susceptibility to tuberculosis (p=0.078), but TT genotype was more frequent in the control group. Our findings suggest that interleukin-10 -1082G/A polymorphism may play an important role in susceptibility to tuberculosis in our population. On the other hand, the +874T allele, which has been suggested to be associated with high IFN-gamma levels, was significantly higher in the controls and TT genotype was also more frequent in the control group. Thus, +874 T allele may be associated with resistance to tuberculosis in this Azeri population of Iran.