Potential Therapeutic Effects of Melatonin Mediate via miRNAs in Cancer.

miRNAs are evolutionarily conserved non-coding ribonucleic acids with a length of between 19 and 25 nucleotides. Because of their ability to regulate gene expression, miRNAs have an important function in the controlling of various biological processes, such as cell cycle, differentiation, proliferation, and apoptosis. Owing to the long-standing regulative potential of miRNAs in tumor-suppressive pathways, scholars have recently paid closer attention to the expression profile of miRNAs in various types of cancer. Melatonin, an indolic compound secreted from pineal gland and some peripheral tissues, has been considered as an effective anti-tumor hormone in a wide spectrum of cancers. Furthermore, it induces apoptosis, inhibits tumor metastasis and invasion, and also angiogenesis. A growing body of evidence indicates the effects of melatonin on miRNAs expression in broad spectrum of diseases, including cancer. Due to the long-term effects of the regulation of miRNAs expression, melatonin could be a promising therapeutic factor in the treatment of cancers via the regulation of miRNAs. Therefore, in this review, we will discuss the effects of melatonin on miRNAs expression in various types of cancers.

Resistance mechanisms to immune checkpoints blockade by monoclonal antibody drugs in cancer immunotherapy: Focus on myeloma.

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by the accumulation of neoplastic proliferation of a plasma cell in the bone marrow that produces a monoclonal immunoglobulin. The immune checkpoint inhibitors against programmed death-1/programmed death-1 ligand and cytotoxic T-lymphocyte antigen 4 axis have demonstrated appropriate anticancer activity in several solid tumors and liquid cancers, and are rapidly transforming the practice of medical oncology. However, in a high percentage of patients, the efficacy of immune checkpoints blockade remains limited due to innate or primary resistance. Moreover, the malignancies progress in many patients due to acquired or secondary resistance, even after the clinical response to immune checkpoints' blockade. The evidence shows that multiple tumor-intrinsic and tumor-extrinsic factors and alterations in signaling pathways are involved in primary and secondary resistance to immune checkpoints blockade. Improved identification of intrinsic and extrinsic factors and mechanisms of resistance or response to immune checkpoints blockade may not only provide novel prognostic or predictive biomarkers but also guide the optimal combination/sequencing of immune checkpoint blockade therapy in the clinic. Here, we review the underlying biology and role of immune checkpoints blockade in patients with MM. Furthermore, we review the host and tumor-related factor effects on immune checkpoints blockade in MM immunotherapy.

Identification of a compound heterozygous missense mutation in LAMA2 gene from a patient with merosin-deficient congenital muscular dystrophy type 1A.

BACKGROUND: Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is occurred by mutations in LAMA2 gene that encodes the laminin α2 chain (merosin). MDC1A is a predominant subtype of congenital muscular dystrophy. Herein, we identified two missense mutations in LAMA2 gene in compound heterozygous status in an Iranian patient with MDC1A using whole-exome sequencing (WES). METHODS: In the present study, we evaluated genetic alterations in an Iranian 35-month-old boy with MDC1A and his healthy family using WES method. The identified mutations further confirmed by Sanger sequencing method. Finally, in silico analysis was conducted to further evaluation of molecular function of the identified genetic variants. RESULTS: We identified two potentially pathogenic missense mutations in compound heterozygous state (c.7681G>A p.Gly2561Ser and c.4840A>G p.Asn1614Asp) in LAMA2 gene as contributing to the MDC1A phenotype. The healthy parents of our proband are single heterozygous for identified mutations. These variants were found to be pathogenic by in silico analysis. CONCLUSIONS: In general, we successfully identified LAMA2 gene mutations in an Iranian patient with MDC1A using WES. The identified mutations in LAMA2 gene can be useful in genetic counseling, prenatal diagnosis, and predicting prognosis of MDC1A.

Melatonin increases the anticancer potential of doxorubicin in Caco-2 colorectal cancer cells.

Colorectal cancer (CC) is an important human malignancy with high cancer related death worldwide. The chemotherapy using doxorubicin hydrochloride is one of the most common cancer therapeutic methods. However, drug resistance lowers the treatment efficacy in CC patients. The combination therapies seem to be more promising by taking the advantage of synergistic effects. The present study aimed to evaluate a new strategy to enhance the anticancer activity of doxorubicin in Caco-2 CC cell line by co-administration of melatonin. The effects of doxorubicin, melatonin, and their combinations (Dox-Mel) were investigated on the proliferation and viability, morphological alterations, and tumor spheroid formation. Flow cytometry was employed to compare the apoptotic situation of the cells in study groups. Changes in metastatic potential of the cells were assessed by wound healing assay and trans-well migration assays. Moreover, expression of BAX, SMAC, BCL-2, SURVIVIN, MMP-2, and MMP-9 genes were evaluated by quantitative real time PCR and western blotting. Our study showed that doxorubicin, melatonin, and Dox-Mel significantly decreased the proliferation and viability, tumor spheroid formation, invasion, and migration. Furthermore, the changes were in a concentration and time dependent manner. There was an increase in apoptosis rate in the treatment groups. Expression of genes involved in apoptosis and cell motility were altered significantly. It was observed that anticancer activity of Dox-Mel combination was significantly more than doxorubicin and melatonin treatments alone. We showed an enhanced apoptotic and anticancer activity of doxorubicin and melatonin combination chemotherapy on CC cell line than doxorubicin or melatonin treatments alone. This combination could promote the treatment efficiency and alleviate the un-intended side effects by lowering the dose of doxorubicin prescription.

Enhanced anticancer potency of hydroxytyrosol and curcumin by PLGA-PAA nano-encapsulation on PANC-1 pancreatic cancer cell line.

Many chemotherapeutic regimens have been investigated for advanced unresectable and metastatic pancreatic cancer (PC), but with only minimal improvement in survival and prognosis. Here, we investigated anti-cancer function of free and nano-encapsulated hydroxytyrosol (Hyd) and curcumin (Cur), and its combinations (Hyd-Cur) on PANC-1 cell line. The poly lactide-co-glycolide-co-polyacrylic acid (PLGA-co-PAA) nano-encapsulated Hyd and Cur were synthesized, and MTT assay was performed to evaluate cytotoxic effects of free and nano-encapsulated Hyd, Cur, and Hyd-Cur. Effects of free and nano-encapsulated Hyd, Cur, and Hyd-Cur were evaluated on viability, migration, morphological alterations, colony formation, and apoptosis on PANC-1 cells. We observed that free and nano-encapsulated Hyd, Cur, and Hyd-Cur significantly increased apoptosis rates as well as significantly decreased viability, migration, and colony formation in PANC-1 cells. According to our results, Hyd-Cur combination and nano-encapsulation therapy exerts more profound apoptotic and anti-proliferative effects on PANC-1 cells than free Hyd or Hyd monotherapy.

Human Wharton's jelly stem cells inhibit endometriosis through apoptosis induction.

Endometriosis is a relatively benign disease characterized by endometrial tumors and uterus stroma. Apoptosis suppression is one of the most important pathological processes of endometriosis. Recently, several studies reported that human Wharton's jelly stem cells (hWJSCs) can inhibit growth and proliferation of various cancer cells through induction of apoptosis. Therefore, the aim of the present study was to investigate the effects of hWJSCs conditioned medium (hWJSC-CM) and cell-free lysate (hWJSC-CL) on endometriosis cells in vitro. In the present study, effects of different concentrations of hWJSC-CM and hWJSC-CL on viability and proliferation, morphological alterations, colony formation, migration, invasion, and apoptosis of endometriosis cells were evaluated. Our results showed that hWJSC-CM and hWJSC-CL decrease viability and proliferation, colony formation, migration, and invasion, as well as increase morphological alterations and apoptosis of endometriosis cells, in a concentration- and time-dependent manner. Decreased migration and invasion of treated endometriosis cells with hWJSC-CM and hWJSC-CL may be due to decrease of MMP-2 and MMP-9 gene expression. Moreover, induction of apoptosis in treated endometriosis cells can be due to regulation of apoptosis-related genes expression, including BAX, BCL-2, SMAC, and SURVIVIN. The results of the present study suggest that hWJSC-CM and hWJSC-CL can inhibit endometriosis cells at a mild-to-moderate level through various physiological mechanisms. However, further studies on animal models are necessary to achieve more accurate results.

Enhanced anticancer potency of doxorubicin in combination with curcumin in gastric adenocarcinoma.

Gastric cancer (GC) is one of the prevalent human malignancies and the third most common cause of cancer-related death worldwide. The doxorubicin hydrochloride is one of the important chemotherapeutic anticancer agents, with a limited therapeutic efficacy for treatment of GC. Therefore, taking advantage of synergistic effects by strategies like combination therapy seems appropriate and promising in treatment of GC. The aim of this study was to investigate a novel method to enhance the therapeutic efficacy of doxorubicin (as a chemotherapeutic agent) by co-administration of curcumin (as a bioactive herbal compound) in GC treatment. In the present study, the effects of curcumin, doxorubicin, and their combinations (Dox-Cur) were evaluated on the viability, morphological features, tumor spheroid formation, migration, invasion, and apoptosis of gastric adenocarcinoma cell line (AGS). Moreover, expression levels of BAX, BCL-2, and CASP9 genes were assessed among AGS cells treated with curcumin, doxorubicin, and Dox-Cur. The obtained results showed that all of curcumin, doxorubicin, and Dox-Cur treatments significantly decreased the viability, tumor spheroid formation, migration, and invasion in the GC model cells. Furthermore, apoptosis rates in AGS cells were increased in a concentration- and time-dependent manner in all of the treatment groups. Moreover, the anticancer activity of the Dox-Cur combination was significantly more than curcumin and doxorubicin treatments alone. According to the results, Dox-Cur combination therapy exerts more profound apoptotic and anticancer effects on the AGS cell line than curcumin or doxorubicin monotherapy.

Pattern-recognition receptors (PRRs) in SARS-CoV-2.

Pattern recognition receptors (PRRs) are specific sensors that directly recognize various molecules derived from viral or bacterial pathogens, senescent cells, damaged cells, and apoptotic cells. These sensors act as a bridge between nonspecific and specific immunity in humans. PRRs in human innate immunity were classified into six types: toll-like receptors (TLR), C-type lectin receptors (CLRs), nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs), absent in melanoma 2 (AIM2)-like receptors (ALRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), and cyclic GMP-AMP (cGAMP) synthase (cGAS). Numerous types of PRRs are responsible for recognizing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which is immensely effective in prompting interferon responses. Detection of SARS-CoV-2 infection by PRRs causes the initiation of an intracellular signaling cascade and subsequently the activation of various transcription factors that stimulate the production of cytokines, chemokines, and other immune-related factors. Therefore, it seems that PRRs are a promising potential therapeutic approach for combating SARS-CoV-2 infection and other microbial infections. In this review, we have introduced the current knowledge of various PRRs and related signaling pathways in response to SARS-CoV-2.

Chimeric antigen receptor T (CAR-T) cells: Novel cell therapy for hematological malignancies.

Over the last decade, the emergence of several novel therapeutic approaches has changed the therapeutic perspective of human malignancies. Adoptive immunotherapy through chimeric antigen receptor T cell (CAR-T), which includes the engineering of T cells to recognize tumor-specific membrane antigens and, as a result, death of cancer cells, has created various clinical benefits for the treatment of several human malignancies. In particular, CAR-T-cell-based immunotherapy is known as a critical approach for the treatment of patients with hematological malignancies such as acute lymphoblastic leukemia (ALL), multiple myeloma (MM), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), and non-Hodgkin's lymphoma (NHL). However, CAR-T-cell therapy of hematological malignancies is associated with various side effects. There are still extensive challenges in association with further progress of this therapeutic approach, from manufacturing and engineering issues to limitations of applications and serious toxicities. Therefore, further studies are required to enhance efficacy and minimize adverse events. In the current review, we summarize the development of CAR-T-cell-based immunotherapy and current clinical antitumor applications to treat hematological malignancies. Furthermore, we will mention the current advantages, disadvantages, challenges, and therapeutic limitations of CAR-T-cell therapy.

Prevalence of Chromosomal Abnormalities in Iranian Patients with Infertility.

BACKGROUND: The numerical and structural abnormalities of chromosomes are the most common cause of infertility. Here, we evaluated the prevalence and types of chromosomal abnormalities in Iranian infertile patients. METHODS: We enrolled 1750 couples of reproductive age with infertility, who referred to infertility clinics in Tehran during 2014- 2019, in order to perform chromosomal analysis. Peripheral blood samples were obtained from all couples and chromosomal abnormalities were evaluated by G-banded metaphase karyotyping. In some cases, the detected abnormalities were confirmed using fluorescence in-situ hybridization (FISH). RESULTS: We detected various chromosomal abnormalities in 114/3500 (3.257%) patients with infertility. The prevalence of chromosomal abnormalities was 44/114 (38.596%) among infertile females and 70/114 (61.403%) among infertile males. Structural chromosomal abnormalities were found in 27/1750 infertile females and 35/1750 infertile males. Numerical chromosomal abnormalities were found in 17/1750 of females and 35/1750 of males. The 45, XY, rob (13;14) (p10q10) translocation and Klinefelter syndrome (47, XXY) were the most common structural and numerical chromosomal abnormalities in the Iranian infertile patients, respectively. CONCLUSION: In general, we found a high prevalence of chromosomal abnormalities in Iranian patients with reproductive problems. Our study highlights the importance of cytogenetic studies in infertile patients before starting infertility treatments approaches.

The Regulatory Role of Pivotal MicroRNAs in the AKT Signaling Pathway in Breast Cancer.

Breast cancer is the most prevalent type of cancer among women, and it remains the main challenge despite improved treatments. MicroRNAs (miRNAs) are a small non-coding family of RNAs that play an indispensable role in regulating major physiological processes, including differentiation, proliferation, invasion, migration, cell cycle regulation, stem cell maintenance apoptosis, and organ development. The dysregulation of these tiny molecules is associated with various human malignancies. More than 50% of these non-coding RNA sequences estimated have been placed on genomic regions or fragile sites linked to cancer. Following the discovery of the first signatures of specific miRNA in breast cancer, numerous researches focused on involving these tiny RNAs in breast cancer physiopathology as a new therapeutic approach or as reliable prognostic biomarkers. In the current review, we focus on recent findings related to the involvement of miRNAs in breast cancer via the AKT signaling pathway related to their clinical implications.

The pivotal role of MicroRNAs in glucose metabolism in cancer.

Cancer cells are able to undergo aerobic glycolysis and metabolize glucose to lactate instead of oxidative phosphorylation, which is known as Warburg effect. Accumulating evidence has revealed that microRNAs regulate cancer cell metabolism, which manifest a higher rate of glucose metabolism. Various signaling pathways along with glycolytic enzymes are responsible for the emergence of glycolytic dependence. MicroRNAs are a class of non-coding RNAs that are not translated into proteins but regulate target gene expression or in other words function pre-translationally and post-transcriptionally. MicroRNAs have been shown to be involved in various biological processes, including glucose metabolism via targeting major transcription factors, enzymes, oncogenes or tumor suppressors alongside the oncogenic signaling pathways. In this review, we describe the regulatory role of microRNAs of cancer cell glucose metabolism, including in the glucose uptake, glycolysis, tricarboxylic acid cycle and several signaling pathways and further suggest that microRNA-based therapeutics can be used to inhibit the process of glucose metabolism reprogramming in cancer cells and thus suppressing cancer progression.

CRISPR Technology in Gene-Editing-Based Detection and Treatment of SARS-CoV-2.

Outbreak and rapid spread of coronavirus disease (COVID-19) caused by coronavirus acute respiratory syndrome (SARS-CoV-2) caused severe acute respiratory syndrome (SARS-CoV-2) that started in Wuhan, and has become a global problem because of the high rate of human-to-human transmission and severe respiratory infections. Because of high prevalence of SARS-CoV-2, which threatens many people worldwide, rapid diagnosis and simple treatment are needed. Genome editing is a nucleic acid-based approach to altering the genome by artificially changes in genetic information and induce irreversible changes in the function of target gene. Clustered, regularly interspaced short palindromic repeats (CRISPR/Cas) could be a practical and straightforward approach to this disease. CRISPR/Cas system contains Cas protein, which is controlled by a small RNA molecule to create a double-stranded DNA gap. Evidence suggested that CRISPR/Cas was also usable for diagnosis and treatment of SARS-CoV-2 infection. In this review study, we discoursed on application of CRISPR technology in detection and treatment of SARS-CoV-2 infection. Another aspect of this study was to introduce potential future problems in use of CRISPR/Cas technology.

Wharton jelly stem cells inhibits AGS gastric cancer cells through induction of apoptosis and modification of MAPK and NF-κB signaling pathways.

BACKGROUND: Gastric cancer) GC) is one of the most common cancer with high mortality worldwide. The human Wharton's jelly stem cells (hWJSCs) can inhibit several cancer cells through several molecular pathways. Therefore, the present study aimed to investigate anticancer effects of hWJSCs conditioned medium (hWJSC-CM) and cell-free lysate (hWJSC-CL) against of GC cell line AGS and underlying signaling pathways. METHODS: In this study, we evaluated the effects of hWJSC-CM and hWJSC-CL on viability, proliferation, migration, invasion, apoptosis, and MAPK and NF-κB signaling pathways in AGS cells. Moreover, mRNA expression of genes involved in apoptosis (BAX, BCL2, SMAC, and SURVIVIN), as well as expression of proteins involved in NF-κB and MAPK signaling pathways were evaluated. RESULTS: The obtained results showed that the hWJSC-CM and hWJSC-CL decreased viability, migration, and invasion of GC cell line AGS in a concentration and time dependent manner. We observed that the hWJSC-CM and hWJSC-CL induced apoptosis pathway through regulation of apoptosis involved genes mRNA expression. In addition, the hWJSC-CM and hWJSC-CL suppressed NF-κB signaling pathways as well as promoted MAPK signaling pathways. CONCLUSION: In general, our study suggested that the hWJSC-CM and hWJSC-CL inhibits proliferation and viability of GC cell line AGS through induction of apoptosis, as well as modification of NF-κB and MAPK signaling pathways.

Anti-inflammatory activity of emu oil-based nanofibrous scaffold through downregulation of IL-1, IL-6, and TNF-α pro-inflammatory cytokines.

Background Inflammation is one of the most important responses of the body against infection or disease, and it protects tissues from injury; however, it causes redness, swelling, pain, fever and loss of function. The aim of this present study was to evaluate the anti-inflammatory activity of emu oil (Eu) formulated nanofibrous scaffold in HFFF2 fibroblast cells. Materials and methods Eu was formulated successfully in nanofibers through the electrospinning method. Besides, the morphological and structural properties of Eu nanofibres were evaluated using Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The MTT assay (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) was performed to evaluate the HFFF2 fibroblast cells' viability. Also, real-time polymerase chain reaction (PCR) was used to evaluate the anti-inflammatory signaling pathway in treated HFFF2 cells with Eu nanofiber. Results Our study showed that the Eu nanofiber increased the viability of fibroblast HFFF2 cells (p < 0.05). Also, the expression of interleukin1 (IL1), IL6 and tumor necrosis factor- alpha (TNF-α) pro-inflammatory cytokines genes were significantly decreased in treated HFFF2 cells with Eu nanofiber (p < 0.05). Conclusions In conclusion, Eu nanofiber scaffold potentially can reduce the inflammation process through downregulation of IL-1, IL-6 and TNF-α cytokines.

Regulatory role of microRNAs in cancer through Hippo signaling pathway.

Cancer is the major cause of death worldwide in countries of all income levels. The Hippo signaling pathway is a Drosophila kinase gene that was identified to regulate organ size, cell regeneration, and contribute to tumorigenesis. A huge variety of extrinsic and intrinsic signals regulate the Hippo signaling pathway. The Hippo signaling pathway consists of a wide array of components that merge numerous signals such as mechanical signals to address apoptosis resistance, cell proliferation, cellular outputs of growth, cell death and survival at cellular and tissue level. Recent studies have shed new light on the regulatory role of microRNAs in Hippo signaling and how they contribute to cancer progression. MicroRNAs influence various cancer-related processes such as, apoptosis, proliferation, migration, cell cycle and metabolism. Inhibition and overexpression of miRNAs via miRNA mimics and miRNA inhibitors, respectively, can uncover a hopeful and reliable insight for treatment and early diagnosis of cancer patients. In this review we will discuss our current understanding of regulatory role of miRNAs in Hippo signaling pathway.

Targeting cancer stem cells by melatonin: Effective therapy for cancer treatment.

Melatonin is a physiological hormone produced by the pineal gland. In recent decades, enormous investigations showed that melatonin can prompt apoptosis in cancer cells and inhibit tumor metastasis and angiogenesis in variety of malignancies such as ovarian, melanoma, colon, and breast cancer; therefore, its possible therapeutic usage in cancer treatment was confirmed. CSCs, which has received much attention from researchers in past decades, are major challenges in the treatment of cancer. Because CSCs are resistant to chemotherapeutic drugs and cause recurrence of cancer and also have the ability to be regenerated; they can cause serious problems in the treatment of various cancers. For these reasons, the researchers are trying to find a solution to destroy these cells within the tumor mass. In recent years, the effect of melatonin on CSCs has been investigated in some cancers. Given the importance of CSCs in the process of cancer treatment, this article reviewed the studies conducted on the effect of melatonin on CSCs as a solution to the problems caused by CSCs in the treatment of various cancers.

Association of rs1946518 C/A Polymorphism in Promoter Region of Interleukin 18 Gene and Breast Cancer Risk in Iranian Women: A Case-control Study.

Breast cancer (BC) is the most frequently diagnosed cancer among women in the world. Genetic polymorphisms in Interleukin (IL) genes are one of the most important risk factors in BC. The aim of this study was to investigate the association of rs1946518 C/A polymorphism in the promoter region of the IL-18 gene and BC risk in Iranian women. In this case-control study, we recruited 140 women with BC as a case group and 140 age and ethnically matched women as healthy controls from East Azerbaijan, Tabriz in Iran. The genomic DNA was extracted using a salting-out method from peripheral blood leukocytes. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The genotype distribution in BC patients was 37.86% CC, 47.14% CA, and 15.00% AA, whereas in healthy controls these were 40.72% CC, 42.85% CA, and 16.43% AA. Statistical analysis showed that the genotype and allele frequencies of IL-18 rs1946518 C/A polymorphism were not significantly different between BC patients and healthy controls (p>0.05). The only significant difference between cases and controls was related to family history (p=0.023). In conclusion, our study indicated that IL-18 rs1946518 C/A polymorphism was not associated with BC in the Iranian women population. However, more studies on different races and geographic areas are required to determine the exact role of rs1946518 C/A polymorphism in prognosis, diagnosis, and risk of BC.

Analysis of cervical lesions for presence of HSV-2 and HPV-16 and HPV-18 in Iranian patients by PCR.

Objective Cervical cancer (CC) is one of the leading causes of deaths from cancer among women worldwide. Viral infections is now one of the known risk factors for CC. The aim of this study was to investigate the presence of herpes simplex virus type 2 (HSV-2), human papilloma virus types 16 (HPV-16) and human papilloma virus types 18 (HPV-18) in Iranian patients with CC using the polymerase chain reaction (PCR). Materials and methods This case-control study was conducted on a total of 45 patients with CC from Khatam-Al-Anbiya Hospital, Hamadan, Iran during 2014, and 30 samples from healthy subjects as controls. The presence of HSV-2 and HPV-16/18 DNA sequences was detected by PCR. Results Eight of CC patients (17.77%) had HPV-16/18 DNA and only one patient (2.22%) with HSV-2 was identified. These viruses were not detected in control cases. Among HPV-16/18 positive patients, 62.5% and 37.5% biopsies were positive for HPV-16 and HPV-18, respectively. On the other hand, only one case (2.22%) was positive for HPV-16/18, but HSV-2 and this co-infection was not detected in the control group. Conclusion Our results demonstrate that there was no direct molecular evidence to support a cofactor relationship between HSV-2 and HPV-16/18 in cervical malignancies. However, the results about HPV-16/18 was in accordance with previous studies.