Therapeutic Opportunities in Breast Cancer by Targeting Macrophage Migration Inhibitory Factor as a Pleiotropic Cytokine.

As a heterogeneous disease, breast cancer (BC) has been characterized by the uncontrolled proliferation of mammary epithelial cells. The tumor microenvironment (TME) also contains inflammatory cells, fibroblasts, the extracellular matrix (ECM), and soluble factors that all promote BC progression. In this sense, the macrophage migration inhibitory factor (MIF), a pleiotropic pro-inflammatory cytokine and an upstream regulator of the immune response, enhances breast tumorigenesis through escalating cancer cell proliferation, survival, angiogenesis, invasion, metastasis, and stemness, which then brings tumorigenic effects by activating key oncogenic signaling pathways and inducing immunosuppression. Against this background, this review was to summarize the current understanding of the MIF pathogenic mechanisms in cancer, particularly BC, and address the central role of this immunoregulatory cytokine in signaling pathways and breast tumorigenesis. Furthermore, different inhibitors, such as small molecules as well as antibodies (Abs) or small interfering RNA (siRNA) and their anti-tumor effects in BC studies were examined. Small molecules and other therapy target MIF. Considering MIF as a promising therapeutic target, further clinical evaluation of MIF-targeted agents in patients with BC was warranted.

Harnessing exosomes in theranostic applications: advancements and insights in gastrointestinal cancer research.

Exosomes are small extracellular vesicles (30-150 nm) that are formed by endocytosis containing complex RNA as well as protein structures and are vital in intercellular communication and can be used in gene therapy and drug delivery. According to the cell sources of origin and the environmental conditions they are exposed to, these nanovesicles are very heterogeneous and dynamic in terms of content (cargo), size and membrane composition. Exosomes are released under physiological and pathological conditions and influence the pathogenesis of cancers through various mechanisms, including angiogenesis, metastasis, immune dysregulation, drug resistance, and tumor growth/development. Gastrointestinal cancer is one of the deadliest types of cancer in humans and can involve organs e.g., the esophagus and stomach, or others such as the liver, pancreas, small intestine, and colon. Early diagnosis is very important in this field because the overall survival of patients is low due to diagnosis in late stages and recurrence. Also, various therapeutic strategies have failed and there is an unmet need for the new therapeutic agents. Exosomes can become promising candidates in gastrointestinal cancers as biomarkers and therapeutic agents due to their lower immunity and passing the main physiological barriers. In this work, we provide a general overview of exosomes, their biogenesis and biological functions. In addition, we discuss the potential of exosomes to serve as biomarkers, agents in cancer treatment, drug delivery systems, and effective vaccines in immunotherapy, with an emphasis on gastrointestinal cancers.

Investigating the effect of parasites (toxoplasma gondii RH strain, Leishmania major (MRHO/IR/75/ER), and hydatid cyst) antigens on Alzheimer's disease: An in vivo evaluation.

This study aimed to investigate the effects of parasite antigens on Alzheimer's symptoms in animal model. Alzheimer's model was induced in Wistar rats using Amyloid-beta peptide, and treated with parasite crude antigens from T. gondii RH strain, L. major (MRHO/IR/75/ER), and HC. Spectrophotometry and real-time PCR were used to evaluate the oxidative stress levels, antioxidant enzyme activity, and gene expression of NLRP3, IL-8, IL-1ß, and Caspase-1. Histological assays were performed to investigate structural changes in the hippocampus. Apoptosis was analyzed using an Annexin V Apoptosis by Flow cytometer. The levels of total oxidant, antioxidant, and SOD increased in the Alzheimer's group compared with the control group, but these factors were lower in the L. major group. The apoptosis in the treated groups was lower compared to the Alzheimer's group. IL-8 expression was significantly higher in all Alzheimer's groups, but decreased in the HC and L. major treated group compared to Alzheimer's. IL-1ß and Caspase-1 expression were similarly increased in all groups compared with the control group, but decreased in the antigen-treated groups compared with Alzheimer's. NLRP3 expression was increased in all groups compared with the control group, with lower expression in HC group, but significantly decreased in L. major group compared with Alzheimer's. In histological results, only L. major group could play a therapeutic role in pathological damage of the hippocampus. The results showed that parasite antigens, specifically L. major antigens, may have neuroprotective effects that reduce oxidative stress, apoptosis, and histopathological changes in response to AD in animal model.

In silico design of a novel multi-epitope vaccine against HCV infection through immunoinformatics approaches.

Infection with the hepatitis C virus (HCV) is one of the causes of liver cancer, which is the world's sixth most prevalent and third most lethal cancer. The current treatments do not prevent reinfection; because they are expensive, their usage is limited to developed nations. Therefore, a prophylactic vaccine is essential to control this virus. Hence, in this study, an immunoinformatics method was applied to design a multi-epitope vaccine against HCV. The best B- and T-cell epitopes from conserved regions of the E2 protein of seven HCV genotypes were joined with the appropriate linkers to design a multi-epitope vaccine. In addition, cholera enterotoxin subunit B (CtxB) was included as an adjuvant in the vaccine construct. This study is the first to present this epitopes-adjuvant combination. The vaccine had acceptable physicochemical characteristics. The vaccine's 3D structure was predicted and validated. The vaccine's binding stability with Toll-like receptor 2 (TLR2) and TLR4 was confirmed using molecular docking and molecular dynamics (MD) simulation. The immune simulation revealed the vaccine's efficacy by increasing the population of B and T cells in response to vaccination. In silico expression in Escherichia coli (E. coli) was also successful.

Oncoviruses: Induction of cancer development and metastasis by increasing anoikis resistance.

The phenomenon of cell death is a vital aspect in the regulation of aberrant cells such as cancer cells. Anoikis is a kind of cell death that occurs when cells get separated from the extracellular matrix. Some cancer cells can inhibit anoikis in order to progress metastasis. One of the key variables that might be implicated in anoikis resistance (AR) is viral infections. The most important viruses involved in this process are Epstein-Barr virus, human papillomavirus, hepatitis B virus, human herpes virus 8, human T-cell lymphotropic virus type 1, and hepatitis C virus. A better understanding of how carcinogenic viruses suppress anoikis might be helpful in developing an effective treatment for virus-associated cancers. In the current study, we review the role of the mentioned viruses and their gene products in anoikis inhibition.

Engineered small extracellular vesicles as a novel platform to suppress human oncovirus-associated cancers.

BACKGROUND: Cancer, as a complex, heterogeneous disease, is currently affecting millions of people worldwide. Even if the most common traditional treatments, namely, chemotherapy (CTx) and radiotherapy (RTx), have been so far effective in some conditions, there is still a dire need for novel, innovative approaches to treat types of cancer. In this context, oncoviruses are responsible for 12% of all malignancies, such as human papillomavirus (HPV), Merkel cell polyomavirus (MCPyV), Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), as well as hepatitis B virus (HBV) and hepatitis C virus (HCV), and the poorest in the world also account for 80% of all human cancer cases. Against this background, nanomedicine has developed nano-based drug delivery systems (DDS) to meet the demand for drug delivery vectors, e.g., extracellular vesicles (EVs). This review article aimed to explore the potential of engineered small EVs (sEVs) in suppressing human oncovirus-associated cancers. METHODS: Our search was conducted for published research between 2000 and 2022 using several international databases, including Scopus, PubMed, Web of Science, and Google Scholar. We also reviewed additional evidence from relevant published articles. RESULTS: In this line, the findings revealed that EV engineering as a new field is witnessing the development of novel sEV-based structures, and it is expected to be advanced in the future. EVs may be further exploited in specialized applications as therapeutic or diagnostic tools. The techniques of biotechnology have been additionally utilized to create synthetic bilayers based on the physical and chemical properties of parent molecules via a top-down strategy for downsizing complicated, big particles into nano-sized sEVs. CONCLUSION: As the final point, EV-mediated treatments are less toxic to the body than the most conventional ones, making them a safer and even more effective option. Although many in vitro studies have so far tested the efficacy of sEVs, further research is still needed to develop their potential in animal and clinical trials to reap the therapeutic benefits of this promising platform.

The Role of Progranulin (PGRN) in the Pathogenesis of Ischemic Stroke.

Stroke is a life-threatening medical condition and is a leading cause of disability. Cerebral ischemia is characterized by a distinct inflammatory response starting with the production of various cytokines and other inflammation-related agents. Progranulin (PGRN), a multifunctional protein, is critical in diverse physiological reactions, such as cell proliferation, inflammation, wound healing, and nervous system development. A mature PGRN is anti-inflammatory, while granulin, its derivative, conversely induces pro-inflammatory cytokine expression. PGRN is significantly involved in the brain tissue and its damage, for example, improving mood and cognitive disorders caused by cerebral ischemia. It may also have protective effects against nerve and spinal cord injuries by inhibiting neuroinflammatory response and apoptosis or it may be related to the proliferation, accumulation, differentiation, and activation of microglia. PGRN is a neurotrophic factor in the central nervous system. It may increase post-stroke neurogenesis of the subventricular zone (SVZ), which is particularly important in improving long-term brain function following cerebral ischemia. The neurogenesis enhanced via PGRN in the ischemic brain SVZ may be attributed to the induction of PI3K/AKT and MAPK/ERK signaling routes. PGRN can also promote the proliferation of neural stem/progenitor cells through PI3K/AKT signaling pathway. PGRN increases hippocampal neurogenesis, reducing anxiety and impaired spatial learning post-cerebral ischemia. PGRN alleviates cerebral ischemia/reperfusion injury by reducing endoplasmic reticulum stress and suppressing the NF-κB signaling pathway. PGRN can be introduced as a potent neuroprotective agent capable of improving post-ischemia neuronal actions, mainly by reducing and elevating the inflammatory and anti-inflammatory cytokines. Expression, storage, cleavage, and function of progranulin (PGRN) in the pathogenesis of ischemic stroke.

Small extracellular vesicles as key players in cancer development caused by human oncogenic viruses.

BACKGROUND: Exosomes are the smallest group of extracellular vesicles in size from 30 to 150 nm, surrounded by a lipid bilayer membrane, and originate from multivesicular bodies secreted by different types of cells, such as virus-infected cells. The critical role of exosomes is information transfer among cells, representing a unique way for intercellular communication via a load of many kinds of molecules, including various signaling proteins and nucleic acids. In this review, we aimed to comprehensively investigate the role of exosomes in promoting human oncogenic viruses-associated cancers. METHODS: Our search was conducted for published researches between 2000 and 2022 by using several international databases includeing Scopus, PubMed, and Web of Science as well as Google scholar. We also reviewed additional evidence from relevant published articles. RESULTS: It has been shown that exosomes can create the conditions for viral spread in viral infections. Exosome secretion in a human tumor virus can switch on the cell signaling pathways by transferring exosome-encapsulated molecules, including viral oncoproteins, signal transduction molecules, and virus-encoded miRNAs, into various cells. CONCLUSION: Given the role of exosomes in viruses-associated cancers, they can also be considered as molecular targets in diagnosis and treatment.

Differentially Expressed miRNAs in Ulcerative Colitis and Crohn's Disease.

Differential microRNA (miRNA or miR) regulation is linked to the development and progress of many diseases, including inflammatory bowel disease (IBD). It is well-established that miRNAs are involved in the differentiation, maturation, and functional control of immune cells. miRNAs modulate inflammatory cascades and affect the extracellular matrix, tight junctions, cellular hemostasis, and microbiota. This review summarizes current knowledge of differentially expressed miRNAs in mucosal tissues and peripheral blood of patients with ulcerative colitis and Crohn's disease. We combined comprehensive literature curation with computational meta-analysis of publicly available high-throughput datasets to obtain a consensus set of miRNAs consistently differentially expressed in mucosal tissues. We further describe the role of the most relevant differentially expressed miRNAs in IBD, extract their potential targets involved in IBD, and highlight their diagnostic and therapeutic potential for future investigations.

Inhibitory Effects of Bilirubin on Colonization and Migration of A431 and SK-MEL-3 Skin Cancer Cells Compared with Human Dermal Fibroblasts (HDF).

This study evaluated the inhibitory effects of bilirubin on colony formation and cell migration of melanoma and non-melanoma skin cancer cell lines SK-MEL-3 and A431, compared with normal human dermal fibroblasts (HDF). The IC50 obtained from the MTT assay was 125, 100, and 75 µM bilirubin for HDF, A431, and SK-MEL-3 cells, respectively. The colony formation and cell migration of cancer cells, treated with 100 µM bilirubin, were reduced significantly (p < 0.05). Bilirubin decreased cell adhesion and inhibited cell colonization via inducing apoptosis and cell death. Also by interaction with migration main factors, bilirubin caused inhibition the cell migration.

Effects of Xenogen Mesenchymal Stem Cells and Cryo-Platelet Gel on Intractable Wound Healing in Animal Model (Rat).

BACKGROUND: Today, the effects of growth factors and mesenchymal stem cells (MSCs) in promoting wound healing has been confirmed. OBJECTIVE: This study aimed to investigate the effect of MSCs and platelet cryogel on wound healing. METHODS: 40 male wistar rats were randomly divided into five groups (n=8). The control group was just dressed, the second group received platelet cryogel, the third group received platelet cryogel containing MSCs, the fourth group received plasma, and the fifth group received plasma plus MSCs. The biopsy was obtained from the wounds in the 2, 4, 6, and 8 days of the treatment. Then, pathological evaluation was conducted. Finally, qRT-PCR was performed to determine angiogenesis. RESULTS: The intervention groups had faster wound healing and lower wound area than the control group (p<0.05). The highest wound healing rate and the smallest wound area was observed in the group receiving platelet cryogel plus MSCs. Angiogenesis, fibrosis, myoepithelial and epithelialization in the pathologic examination using H & E staining were not significantly different between the groups. The expression of Ang-1 in the intervention groups was higher than the control group and the highest expression was observed in the platelet cryogel plus MSCs, followed by the platelet cryogel group. The expression of VEGF in the plasma plus MSCs was higher than in the other groups. CONCLUSION: Further studies require to determine the effects of combined use of platelet cryogel plus MSCs on other types of wound and evaluate mechanisms involved in wound healing like collagenesis and inflammatory factors.

Identifying genotype profile of chronic hepatitis C infection in Southwest Iran.

BACKGROUND: Hepatitis C virus (HCV) infection is one of the most important risk factors for liver failure which can lead to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Approximately 170-200 million (almost 3% of the world's population) people have been reported to have HCV infection worldwide. HCV has six genotypes and multiple subtypes. HCV genotyping and identification of subtypes are critical steps for HCV vaccine development. MATERIALS AND METHODS: In this community-based study, we aimed to investigate the HCV genotypes in infected patients referring to the laboratory of Hajar Hospital of Shahrekord city (the capital of Chaharmahal and Bakhtiari Province) in Iran from November 21, 2016, to October 21, 2017. During 2016-2017, the sera were obtained from 2377 individuals referring to the laboratory of Hajar Hospital of Shahrekord, Iran. The anti-HCV antibody was tested for all sera by enzyme-linked immunosorbent assay test. Following HCV RNA isolation and cDNA synthesis, HCV genotype detection was performed by quantitative reverse transcription-polymerase chain reaction. RESULTS: Genotypes 3, 1a, and 1b were found in 28.6% (95% confidence interval [CI]: 17.0%-40.0%), 9.5% (95% CI: 2.1%-17.0%), and 3.2% (95% CI: 0.0%-7.6%) of the patients, respectively. In 5 patients (7.9%, 95% CI: 1.1%-14.8%), however, we did not observe any genotypes. We could not find any significant difference between the plasma viral load of infected patients and different genotypes. There was no significant difference either between age groups and genotypes (P > 0.05). CONCLUSION: The findings of the present study determined that HCV genotype 3 was the predominant genotype followed by the genotypes 1a and 1b in Chaharmahal and Bakhtiari Province.

Synthetic biology in various cellular and molecular fields: applications, limitations, and perspective.

Synthetic biology breakthroughs have facilitated genetic circuit engineering to program cells through novel biological functions, dynamic gene expressions, as well as logic controls. SynBio can also participate in the rapid development of new treatments required for the human lifestyle. Moreover, these technologies are applied in the development of innovative therapeutic, diagnostic, as well as discovery-related methods within a wide range of cellular and molecular applications. In the present review study, SynBio applications in various cellular and molecular fields such as novel strategies for cancer therapy, biosensing, metabolic engineering, protein engineering, and tissue engineering were highlighted and summarized. The major safety and regulatory concerns about synthetic biology will be the environmental release, legal concerns, and risks of the engineered organisms. The final sections focused on limitations to SynBio.

Increased in vitro migration of human umbilical cord mesenchymal stem cells toward acellular foreskin treated with bacterial derivatives of monophosphoryl lipid A or supernatant of Lactobacillus acidophilus.

Migration and homing are known as critical steps toward regeneration of damaged tissues via cell therapies. Among various cellular sources of stem cells, the umbilical cord has been thus recognized as an interesting one endowed with high benefits. Accordingly, the main objective of the present study was to determine whether monophosphoryl lipid A (MPLA) or supernatant of Lactobacillus acidophilus (SLA) could increase migration of human umbilical cord mesenchymal stem cells (hUMSCs) toward acellular foreskin or not. In this study, the hUMSCs were isolated and cultured through acellular MPLA- or SLA-treated foreskin. Expression of some migration genes (i.e., VCAM-1, MMP-2, VLA-4, CXCR-4, and VEGF) was also investigated using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Moreover; vimentin, cytokeratin 5 (CK5), and matrix metalloproteinases-2 (MMP-2) were detected via immunohistochemistry (IHC) analysis. The hUMSCs in the presence of MPLA- or SLA-treated foreskin showed more tissue tropism compared with those in the control group. Besides, the scanning electron microscopy (SEM) results established that the hUMSCs had more migratory activity in the presence of MPLA- or SLA-treated foreskin than the untreated one. The IHC analysis results correspondingly indicated that expression of vimentin, CK5, and MMP-2 proteins had augmented in both treatments compared with those in the control group. It was concluded that MPLA had revealed more prominent results than SLA, even though both treatments could be regarded as inducing factors in migration. Ultimately, it was suggested to introduce the use of MPLA and probiotic components as a promising approach to improve therapies in regenerative medicine.

Long Non-Coding RNAs in Thyroid Cancer: Implications for Pathogenesis, Diagnosis, and Therapy.

Thyroid cancer is a rare malignancy and accounts for less than 1% of malignant neoplasms in humans; however, it is the most common cancer of the endocrine system and responsible for most deaths from endocrine cancer. Long non-coding (Lnc)RNAs are defined as non-coding transcripts that are more than 200 nucleotides in length. Their expression deregulation plays an important role in the progress of cancer. These molecules are involved in physiologic cellular processes, genomic imprinting, inactivation of chromosome X, maintenance of pluripotency, and the formation of different organs via changes in chromatin, transcription, and translation. LncRNAs can act as a tumor suppressor genes or oncogenes. Several studies have shown that these molecules can interact with microRNAs and prevent their binding to messenger RNAs. Research has shown that these molecules play an important role in tumorigenicity, angiogenesis, proliferation, migration, apoptosis, and differentiation. In thyroid cancer, several lncRNAs (MALAT1, H19, BANCR, HOTAIR) have been identified as contributing factors to cancer development, and can be used as novel biomarkers for early diagnosis or even treatment. In this article, we study the newest lncRNAs and their role in thyroid cancer.