Lymphopenia associated with survivin and its downstream pathway in COVID-19 serving as a potential route in COVID-19 pathogenesis.

PURPOSE: Starting in 2019, coronavirus disease 2019 (COVID-19) caused an epidemic that was growing rapidly and has harmed millions of people globally. It has been demonstrated that survivin regulates lymphocyte survival, a main route involved in COVID-19 pathogenesis. Survivin belongs to the inhibitor of apoptosis protein (IAP) family, and its primary functions comprise regulating mitosis and inhibiting apoptosis. Since lower survivin expression has been shown to increase the sensitivity of lymphocytes to apoptotic induction, we looked into the function of survivin and its corresponding pathways in COVID-19 pathogenesis. MATERIALS AND METHODS: The expression of survivin, X-linked inhibitor of apoptosis protein (XIAP), caspases 3, 7, 9, and poly (ADP-ribose) polymerase (PARP) was evaluated at both mRNA and protein levels in peripheral blood mononuclear cells (PBMCs) derived from healthy donors and patients with severe and moderate COVID-19 by qRT-PCR and Western blotting, respectively. Then, we enforced apoptosis to COVID-19 patient-derived lymphocytes, and the percent was assessed by flow cytometry. RESULTS: Survivin and XIAP were less expressed in PBMCs derived from COVID-19 patients as apoptosis inhibitors than PARP, cleaved-PARP, caspase 9, and cleaved caspases 3 and 7, according to the results of real-time PCR and Western blot analysis. Additionally, according to the flow cytometry results, the down-regulation of survivin served as a potential factor in the lymphocyte depletion observed in patients with COVID-19. CONCLUSION: The role of survivin and its related pathway was first discovered in the development of COVID-19 and may serve as a potential prognostic and therapeutic target.

A comprehensive insight into the correlation between ncRNAs and the Wnt/ß-catenin signalling pathway in gastric cancer pathogenesis.

During the past decades, gastric cancer (GC) has emerged as one of the most frequent malignancies with a growing rate of prevalence around the world. Despite considerable advances in therapeutic methods, the prognosis and management of patients with gastric cancer (GC) continue to be poor. As one of the candidate molecular targets in the treatment of many types of cancer, the Wnt/ß-catenin pathway includes a family of proteins that have important functions in adult tissue homeostasis and embryonic development. The aberrant regulation of Wnt/ß-catenin signaling is strongly correlated with the initiation and development of numerous cancers, including GC. Therefore, Wnt/ß-catenin signaling has been identified as one of the main targets for extending therapeutic approaches for GC patients. Non-coding RNAs (ncRNAs), including microRNAs and long ncRNAs, are important components of epigenetic mechanisms in gene regulation. They play vital roles in various molecular and cellular processes and regulate many signaling pathways, such as Wnt/ß-catenin pathways. Insights into these regulatory molecules involved in GC development may lead to the identification of potential targets for overcoming the limitations of current therapeutic approaches. Consequently, this review aimed to provide a comprehensive overview of ncRNAs interactions involved in Wnt/ß-catenin pathway function in GC with diagnostic and therapeutic perspectives. Video Abstract.

An updated overview of the application of CAR-T cell therapy in neurological diseases.

Genetically modified immune cells, especially CAR-T cells, have captured the attention of scientists over the past 10 years. In the fight against cancer, these cells have a special place. Treatment for hematological cancers, autoimmune disorders, and cancers must include CAR-T cell therapy. Determining the therapeutic targets, side effects, and use of CAR-T cells in neurological disorders, including cancer and neurodegenerative diseases, is the goal of this study. Due to advancements in genetic engineering, CAR-T cells have become crucial in treating some neurological disorders. CAR-T cells have demonstrated a positive role in treating neurological cancers like Glioblastoma and Neuroblastoma due to their ability to cross the blood-brain barrier and use diverse targets. However, CAR-T cell therapy for MS diseases is being researched and could be a potential treatment option. This study aimed to access the most recent studies and scientific articles in the field of CAR-T cells in neurological diseases and/or disorders.

A comprehensive survey into the role of exosomes in pancreatic cancer; from the origin of cancer to the progress and possibility of diagnosis and treatment.

Pancreatic cancer is the fourth most common malignant tumor in the world, which has a high mortality rate due to high invasiveness, early metastases, lack of specific symptoms, and high invasiveness. Recent studies have shown that exosomes can be essential sources of biomarkers in pancreatic cancer. Over the past ten years, exosomes have been implicated in multiple trials to prevent the growth and metastasis of many cancers, including pancreatic cancer. Exosomes also play essential roles in immune evasion, invasion, metastasis, proliferation, apoptosis, drug resistance, and cancer stemness. Exosomes help cells communicate by carrying proteins and genetic material, such as non-coding RNAs, including mRNAs and microRNAs. This review examines the biological significance of exosomes in pancreatic cancer and their functions in tumor invasion, metastasis, treatment resistance, proliferation, stemness, and immune evasion. We also emphasize recent advances in our understanding of the main functions of exosomes in diagnosing and treating pancreatic cancer.

A comprehensive review of the role of lncRNAs in gastric cancer (GC) pathogenesis, immune regulation, and their clinical applications.

Gastric cancer (GC) is the fifth most common malignant tumor and the third leading cause of cancer-related deaths worldwide. Although numerous studies have been conducted on advanced GC, the molecular mechanisms behind it remain obscure. Long non-coding RNAs (lncRNAs) are a family of RNA transcripts capable of regulating target genes at transcriptional, post-transcriptional, and translational stages. They do this by modifying mRNAs, miRNAs, and proteins. These RNAs are critical regulators of many biological processes, including gene epigenetics, transcription, and post-transcriptional levels. This article highlights recent results on lncRNAs involved in drug resistance, proliferation, migration, angiogenesis, apoptosis, autophagy, and immune response in GC. The potential clinical implications of lncRNAs as biomarkers and therapeutic targets in GC are also discussed.

Restoration of miR-648 overcomes 5-FU-resistance through targeting ET-1 in gastric cancer cells in-vitro.

BACKGROUND: Endothelin-1 (ET-1) is a peptide overexpressed in gastric cancer (GC) and linked to carcinogenesis and resistance to chemotherapy. Applying microRNAs (miRNAs/miRs) to downregulate ET-1 and reverse resistance to commonly used chemotherapy drugs such as 5-fluorouracil (5-FU) is practical. METHODS: The current study sought to evaluate the miR-648 expression in GC and any plausibility of its replacement, either with or without the combination of chemo agents to downregulate ET-1 expression through interaction with its target gene. To this end, miR-648 and ET-1 expression levels were assessed in GC tissues and adjacent non-tumor tissues driven from 65 patients who had already undergone surgery, fifteen of which had received 5-FU before surgery. The impact of miR-648 and chemo agents on ET-1 expression was measured using qPCR and Western blotting. Further, an MTT assay was conducted to assess its association with cell viability. Ultimately, the association of miR-648 and ET-1 with clinicopathological characteristics was evaluated. RESULTS: The current study revealed that miR-648 was considerably down-regulated, while ET-1 was substantially up-regulated in patients with GC. The 5-FU caused a significant increase in miR-648 and reduced ET-1 expression. It was also determined that overexpression of miR-648 suppressed ET-1 production, notably when combined with 5-FU, leading to survival reduction. These results further showed that miR-648 replacement could sensitize chemoresistant GC cells. Besides, a significant association between ET-1 and miR-648 with clinicopathological features was discovered CONCLUSIONS: miR-648 replacement may serve as a potential oncosuppressive therapeutic approach that warrants further investigation to translate into an effective GC treatment.

SARS-CoV-2-associated gut microbiome alteration; A new contributor to colorectal cancer pathogenesis.

The emergence of a novel coronavirus, COVID-19, in December 2019 led to a global pandemic with more than 170 million confirmed infections and more than 6 million deaths (by July 2022). Studies have shown that infection with SARS-CoV-2 in cancer patients has a higher mortality rate than in people without cancer. Here, we have reviewed the evidence showing that gut microbiota plays an important role in health and is linked to colorectal cancer development. Studies have shown that SARS-CoV-2 infection leads to a change in gut microbiota, which modify intestinal inflammation and barrier permeability and affects tumor-suppressor or oncogene genes, proposing SARS-CoV-2 as a potential contributor to CRC pathogenesis.

Regulation of Nrf2 and Nrf2-related proteins by ganoderma lucidum in hepatocellular carcinoma.

BACKGROUND: HCC is among the most common cancer. Ganoderma lucidum (G.lucidum) has been essential in preventing and treating cancer. The Nrf2 signaling cascade is a cell protective mechanism against further damage, such as cancer development. This signaling pathway upregulates the cytoprotective genes and is vital in eliminating xenobiotics and reactive oxygen. This study aimed to show the potential cytotoxic activity of G. lucidum aqueous extract in HCC. METHODS AND RESULTS: MTT assay was used to detect cell viability. Nrf2-related proteins were measured by western blotting, and the flow cytometry method assayed cell population in different cycle phases. Cell viability was 49% and 47% following G. lucidum extract at 100 µg/ml at 24 and 48 h treatments, respectively. G. lucidum extract (aqueous, 100 or 50 µg/ml) treatments for 24, 48, or 72 h were able to significantly change the cytoplasmic/nuclear amount of Nrf2 and HO-1, NQO1 protein levels. Moreover, at both concentrations, arrest of the G0/G1 cell cycle was stimulated in HCC. CONCLUSIONS: The activation of the Nrf2 signaling pathways seems to be among the mechanisms underlining the protective and therapeutic action of G. lucidum against HCC.

A comprehensive review about the utilization of immune checkpoint inhibitors and combination therapy in hepatocellular carcinoma: an updated review.

A pharmacological class known as immune checkpoint inhibitors (ICIs) has been developed as a potential treatment option for various malignancies, including HCC. In HCC, ICIs have demonstrated clinically significant advantages as monotherapy or combination therapy. ICIs that target programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1), as well as cytotoxic T lymphocyte antigen 4 (CTLA-4), have made significant advances in cancer treatment. In hepatocellular carcinoma (HCC), several ICIs are being tested in clinical trials, and the area is quickly developing. As immunotherapy-related adverse events (irAEs) linked with ICI therapy expands and gain worldwide access, up-to-date management guidelines become crucial to the safety profile of ICIs. This review aims to describe the evidence for ICIs in treating HCC, emphasizing the use of combination ICIs.

Association between microRNAs and chemoresistance in pancreatic cancer: Current knowledge, new insights, and forthcoming perspectives.

Pancreatic duct adenocarcinoma, commonly known as pancreatic cancer (PC), is a cancer-related cause of death due to delayed diagnosis, metastasis, and drug resistance. Patients with PC suffer from incorrect responses to chemotherapy due to inherent and acquired chemical resistance. Numerous studies have shown the mechanism of the effect of chemoresistance on PC, such as genetic and epigenetic changes or the elucidation of signaling pathways. In this regard, microRNAs (miRNAs) have been identified as essential modulators of gene expression in various cellular functions, including chemoresistance. Thus, identifying the underlying link between microRNAs and PC chemoresistance helps determine the exact pathogenesis of PC. This study aims to classify miRNAs and signaling pathways related to PC chemoresistance, suggesting new therapeutic approaches to overcome PC chemoresistance.

A comprehensive survey into the role of microRNAs in ovarian cancer chemoresistance; an updated overview.

Ovarian cancer (OC), a frequent malignant tumor that affects women, is one of the leading causes of cancer-related death in this group of individuals. For the treatment of ovarian cancer, systemic chemotherapy with platinum-based drugs or taxanes is the first-line option. However, drug resistance developed over time during chemotherapy medications worsens the situation. Since uncertainty exists for the mechanism of chemotherapy resistance in ovarian cancer, there is a need to investigate and overcome this problem. miRNAs are engaged in various signaling pathways that contribute to the chemotherapeutic resistance of ovarian cancer. In the current study, we have tried to shed light on the mechanisms by which microRNAs contribute to the drug resistance of ovarian cancer and the use of some microRNAs to combat this chemoresistance, leading to the worse outcome of ovarian cancer patients treated with systemic chemotherapeutics.

Anastasis: cell recovery mechanisms and potential role in cancer.

Balanced cell death and survival are among the most important cell development and homeostasis pathways that can play a critical role in the onset or progress of malignancy steps. Anastasis is a natural cell recovery pathway that rescues cells after removing the apoptosis-inducing agent or brink of death. The cells recuperate and recover to an active and stable state. So far, minimal knowledge is available about the molecular mechanisms of anastasis. Still, several involved pathways have been explained: recovery through mitochondrial outer membrane permeabilization, caspase cascade arrest, repairing DNA damage, apoptotic bodies formation, and phosphatidylserine. Anastasis can facilitate the survival of damaged or tumor cells, promote malignancy, and increase drug resistance and metastasis. Here, we noted recently known mechanisms of the anastasis process and underlying molecular mechanisms. Additionally, we summarize the consequences of anastatic mechanisms in the initiation and progress of malignancy, cancer cell metastasis, and drug resistance. Video Abstract.

MicroRNAs and JAK/STAT3 signaling: A new promising therapeutic axis in blood cancers.

Blood disorders include a wide spectrum of blood-associated malignancies resulting from inherited or acquired defects. The ineffectiveness of existing therapies against blood disorders arises from different reasons, one of which is drug resistance, so different types of leukemia may show different responses to treatment. Leukemia occurs for a variety of genetic and acquired reasons, leading to uncontrolled proliferation in one or more cell lines. Regarding the genetic defects, oncogene signal transducer and activator of transcription (STAT) family transcription factor, especially STAT3, play an essential role in hematological disorders onset and progress upon mutations, dysfunction, or hyperactivity. Besides, microRNAs, as biological molecules, has been shown to play a dual role in either tumorigenesis and tumor suppression in various cancers. Besides, a strong association between STAT3 and miRNA has been reported. For example, miRNAs can regulate STAT3 via targeting its upstream mediators such as IL6, IL9, and JAKs or directly binding to the STAT3 gene. On the other hand, STAT3 can regulate miRNAs. In this review study, we aimed to determine the role of either microRNAs and STAT3 along with their effect on one another's activity and function in hematological malignancies.

Potential of chimeric antigen receptor (CAR)-redirected immune cells in breast cancer therapies: Recent advances.

Despite substantial developments in conventional treatments such as surgery, chemotherapy, radiotherapy, endocrine therapy, and molecular-targeted therapy, breast cancer remains the leading cause of cancer mortality in women. Currently, chimeric antigen receptor (CAR)-redirected immune cell therapy has emerged as an innovative immunotherapeutic approach to ameliorate survival rates of breast cancer patients by eliciting cytotoxic activity against cognate tumour-associated antigens expressing tumour cells. As a crucial component of adaptive immunity, T cells and NK cells, as the central innate immune cells, are two types of pivotal candidates for CAR engineering in treating solid malignancies. However, the biological distinctions between NK cells- and T cells lead to differences in cancer immunotherapy outcomes. Likewise, optimal breast cancer removal via CAR-redirected immune cells requires detecting safe target antigens, improving CAR structure for ideal immune cell functions, promoting CAR-redirected immune cells filtration to the tumour microenvironment (TME), and increasing the ability of these engineered cells to persist and retain within the immunosuppressive TME. This review provides a concise overview of breast cancer pathogenesis and its hostile TME. We focus on the CAR-T and CAR-NK cells and discuss their significant differences. Finally, we deliver a summary based on recent advancements in the therapeutic capability of CAR-T and CAR-NK cells in treating breast cancer.

A comprehensive review about immune responses and exhaustion during coronavirus disease (COVID-19).

Coronavirus disease (COVID-19) is a viral infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. The infection was reported in Wuhan, China, in late December 2019 and has become a major global concern due to severe respiratory infections and high transmission rates. Evidence suggests that the strong interaction between SARS-CoV-2 and patients' immune systems leads to various clinical symptoms of COVID-19. Although the adaptive immune responses are essential for eliminating SARS-CoV-2, the innate immune system may, in some cases, cause the infection to progress. The cytotoxic CD8+ T cells in adaptive immune responses demonstrated functional exhaustion through upregulation of exhaustion markers. In this regard, humoral immune responses play an essential role in combat SARS-CoV-2 because SARS-CoV-2 restricts antigen presentation through downregulation of MHC class I and II molecules that lead to the inhibition of T cell-mediated immune response responses. This review summarizes the exact pathogenesis of SARS-CoV-2 and the alteration of the immune response during SARS-CoV-2 infection. In addition, we've explained the exhaustion of the immune system during SARS-CoV-2 and the potential immunomodulation approach to overcome this phenomenon. Video Abstract.

Expression of proliferation-related genes in BM-MSC-treated ALL cells in hypoxia condition is regulated under the influence of epigenetic factors in-vitro.

Mesenchymal stem cells affect ALL cell biology under hypoxic conditions. We studied survival, proliferation, expression, and promoter methylation levels of essential genes involved in expanding MOLT-4 cells co-cultured with BM-MSC under the hypoxic condition. Here, MOLT-4 cells were co-cultured with BMMSCs under hypoxic conditions. First, the apoptosis rate was evaluated by Flow cytometry. Then, MOLT-4 cells' proliferation rate was assessed using MTT assay, and the expressions and methylation rates of genes were determined by qRT-PCR and MS-qPCR, respectively. The results showed that although MOLT-4 cells proliferation and survival rates were reduced under hypoxic conditions, this reduction was not statistically significant. Also, we showed that hypoxic conditions caused upregulation of candidate genes and affected their methylation status. Besides, it was revealed that Pontin was downregulated, while KDM3A, SKP2, and AURKA had an upward trend in the presence of MOLT-4 cells plus BM-MSC. The co-culture of leukemia cells with BMMSCs under hypoxic conditions may be a potential therapeutic approach for ALL.