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Messenger RNA (mRNA)-based therapeutics and vaccines have emerged as a disruptive new drug class for various applications, including regenerative medicine, cancer treatment, and prophylactic and therapeutic vaccinations.This review provides an update about the rational structure-based design of various formats of mRNA-based therapeutics. The authors discuss the recent advances in the mRNA modifications that have been used to enhance stability, promote translation efficiency and regulate immunogenicity for specific applications.Extensive research efforts have been made to optimize mRNA constructs and preparation procedures to unleash the full potential of mRNA-based therapeutics and vaccines. Sequence optimization (untranslated region and codon usage), chemical engineering of nucleotides and modified 5'cap, and optimization of

Background: Nucleic acid amplification tests (NAATs) based methods such as real-time reverse transcription polymerase-chain reaction (real-time RT-PCR) are the gold standard for diagnosis of current infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The cobas® Liat® and cepheid® GeneXpert® systems are two rapid real-time RT-PCR platforms offering rapid, specimen-to-answer detection of SARS-CoV-2. Research design and methods: In this study, we compared the performance of these two systems on SARS-CoV-2 detection in 9 nasopharyngeal swab (NPS) and 70 posterior oropharyngeal saliva specimens collected from 79 patients suspected of SARS-CoV-2 infection between August 2020 and March 2021. Results: The Positive Percent Agreement (PPA), Negative Percent Agreement (NPA) and overall Percent Agreement (OPA) between cepheid® Xpress SARS-CoV-2 assay and cobas® Liat® SARS-CoV-2 & Influenza A/B assay were found to be 100%. We demonstrated an excellent overall test concordance of the Liat® SARS-CoV-2 & Influenza A/B assay and Xpress SARS-CoV-2 assay. The small sample size of SARS-CoV-2 positive and weak-positive specimens is the inherent limitation of this study. Conclusions: The performance of the cobas® Liat® SARS-CoV-2 & Influenza A/B assay is equivalent to the cepheid® Xpress SARS-CoV-2 assay for SARS-CoV-2 detection using NPS and posterior oropharyngeal saliva.

The recent advancement in massively parallel sequencing technologies has empowered liquid biopsies, in particular circulating tumor DNA (ctDNA) analysis, to be the new paradigm in personalized cancer management. Plasma ctDNA detection overcomes the current limitations in tumor tissue procurement and serves as a convenient and non-invasive method to capture tumor heterogeneity and genetic evolution along patients' cancer journey. In breast cancer, the current clinical application of ctDNA includes real-time monitoring of tumor response, detection of drug-resistant clones, assessing dynamic variations in tumor mutational landscape, identifying actionable mutations, detecting minimal residual disease and screening of early tumor. This review aims to summarize the current clinical evidence of ctDNA application in the management of breast cancer.

Oncogenic viruses are associated with approximately 15% of human cancers. In viral infections, microRNAs play an important role in host-pathogen interactions. miR-21 is a highly conserved non-coding RNA that not only regulates the development of oncogenic viral diseases, but also responds to the regulation of intracellular signal pathways. Oncogenic viruses, including HBV, HCV, HPV, and EBV, co-evolve with their hosts and cause persistent infections. The upregulation of host miR-21 manipulates key cellular pathways to evade host immune responses and then promote viral replication. Thus, a better understanding of the role of miR-21 in viral infections may help us to develop effective genetically-engineered oncolytic virus-based therapies against cancer.

Posttranscriptional regulation is a mechanism for the cells to control gene regulation at the RNA level. In this process, RNA-binding proteins (RBPs) play central roles and orchestrate the function of RNA molecules in multiple steps. Accumulating evidence has shown that the aberrant regulation of RBPs makes contributions to the initiation and progression of tumorigenesis via numerous mechanisms such as genetic changes, epigenetic alterations, and noncoding RNA-mediated regulations. In this article, we review the effects caused by RBPs and their functional diversity in the malignant transformation of cancer cells that occurs through the involvement of these proteins in various stages of RNA regulation including alternative splicing, stability, polyadenylation, localization, and translation. Besides this, we review the various interactions between RBPs and other crucial posttranscriptional regulators such as microRNAs and long noncoding RNAs in the pathogenesis of cancer. Finally, we discuss the potential approaches for targeting RBPs in human cancers.

To date, the transmission of Coronavirus Disease-2019 (COVID-19) is still uncontrollable with the fact that the numbers of confirmed and death cases are still increasing. Up to 1st October 2020, 33,842,281 confirmed cases and 1,010,634 confirmed deaths have been reported to the World Health Organization from 216 different countries, areas and territories. Despite the urgent demand for effective treatment strategies, there is still no specific antiviral treatment for COVID-19 and the treatment guidelines for COVID-19 vary between countries.In this article, we summarized the current knowledge on COVID-19 and the pandemic worldwide. Moreover, the epidemiology, pathogenesis, prevention and different treatment options will be discussed so that we shall prepare ourselves better to fight with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).The situation of the COVID-19 pandemic is still unpredictable. There is no effective vaccine or specific anti-viral drug to treat serve COVID-19 patients. Combination therapies have shown promising clinical improvement. Repurposing FDA-approved drugs might be one of possible treatment options. Without specific treatment and vaccines for COVID-19, the most effective way to prevent from being infected is to generate an ecosystem with effective protection, precautions and preventive measures.

Aims A variety of tissue clearing techniques have been developed to render intact tissue transparent. For thicker samples, additional partial tissue delipidation is required before immersion into the final refractive index (RI)‐matching solution, which alone is often inadequate to achieve full tissue transparency. However, it is difficult to determine a sufficient degree of tissue delipidation, excess of which can result in tissue distortion and protein loss. Here, we aim to develop a clearing strategy that allows better monitoring and more precise determination of delipidation progress. Methods We combined the detergent sodium dodecyl sulphate (SDS) with OPTIClear, a RI‐matching solution, to form a strategy termed Accurate delipidation with Optimal Clearing (Accu‐OptiClearing). Accu‐OptiClearing allows for a better preview of the final tissue transparency achieved when immersed in OPTIClear alone just before imaging. We assessed for the changes in clearing rate, protein loss, degree of tissue distortion, and preservation of antigens. Results Partial delipidation using Accu‐OptiClearing accelerated tissue clearing and better preserved tissue structure and antigens than delipidation with SDS alone. Despite achieving similar transparency in the final OPTIClear solution, more lipids were retained in samples cleared with Accu‐OptiClearing compared to SDS. Conclusions Combining the RI‐matching solution OPTIClear with detergents, Accu‐OptiClearing, can avoid excessive delipidation, leading to accelerated tissue clearing, less tissue damage and better preserved antigens., Our new strategy of using Accurate dilapidation with Optimal Clearing combines SDS, OPTIClear and refractive index‐matching solution. The new strategy provides fast, non‐swell/shrink, and no protein loss protocol for making the brain to be semi‐transparent. This opens a new avenue of fast pathological analysis of the brain without many thin tissue sectioning.

The outlook for new therapeutic approaches is pivotal to ameliorate the deterioration caused by the abrogated Wnt signaling. Long non-coding RNAs (lncRNAs) are tiny molecules that have begun emerging as vital molecular manager for the regulation of various cellular processes at transcription and translation levels in the colorectal cancer (CRC). Targeting Wnt pathway with lncRNA seems a promising approach to eradicate CRC. However, little is known of their active role in commencing both apoptosis and proliferation in CRC. This article reviews the importance of these molecules in the pathogenesis of CRC and also emphasizes on the development of new therapeutic strategies to cope with the Wnt mediated CRC.

Gastric cancer is among the most common malignant tumors of the digestive tract. Establishing a robust and reliable animal model is the foundation for studying the pathogenesis of cancer. The present study established a mouse model of gastric carcinoma by inoculating immunocompetent mice with MKN45 cells using microcarrier. Sixty male C57BL/6 mice were randomly divided into three groups: a 2D group, an empty carrier group, and a 3D group, according to the coculture system of MKN45 and the microcarrier. The mouse models were established by hypodermic injection. Time to develop tumor, rate of tumor formation, and pathological features were observed in each group. In the 3D group, the tumorigenesis time was short, while the rate of tumor formation was high (75%). There was no detectable tumor formation in either the 2D or the empty carrier group. Both H&E and immunohistochemical staining of the tumor xenograft showed characteristic evidence of human gastric neoplasms. The present study successfully established a human gastric carcinoma model in immunocompetent mice, which provides a novel and valuable animal model for the cancer research and development of anticancer drugs.

Graphical abstract, Argonaute proteins are highly conserved in almost all organisms. They not only involve in the biogenesis of small regulatory RNAs, but also regulate gene expression and defend against foreign pathogen invasion via small RNA-mediated gene silencing pathways. As a key player in these pathways, the abnormal expression and/or mis-modifications of Argonaute proteins lead to the disorder of small RNA biogenesis and functions, thus influencing multiply biological processes and disease development, especially cancer. In this review, we focus on the post-translational modifications and novel functions of Argonaute proteins in alternative splicing, host defense and genome editing.

RNA-based cancer gene therapy shows potential in cancer treatment. However, the safe and efficient transfer of therapeutic RNA to target cells has always been a challenge. The ideal drug delivery system should be effective with low immunogenicity and toxicity. Besides, a high specificity of drug delivery is necessary to improve efficacy and avoid the side effects associated with tumor heterogeneity. As endogenous RNA vehicles, extracellular vesicles (EVs) have shown their advantages and potential as drug delivery systems in gene therapy.We summarize the performance of EVs as a drug delivery system in RNA-based cancer gene therapy and discuss the advantages, limitations, and potentials of this translational medicine. In addition, we compare the characteristics and differences of current drug delivery systems and expound the principles of selecting a drug delivery system suitable for cancer gene therapy.EVs are highly biocompatible membrane structures with low cytotoxicity which provide a new choice for drug delivery in RNA-based cancer gene therapy. The specificity of engineered EVs and artificial EV-mimetics can be improved through peptide or polymer decoration. However, apart from therapeutic RNA, EVs naturally carry many molecules. This may lead to unpredictable effects and thus should be applied with caution.

Resistance to conventional chemotherapy remains a major cause of cancer relapse and cancer-related deaths. Therefore, there is an urgent need to overcome resistance barriers. To improve cancer treatment approaches, it is critical to elucidate the basic mechanisms underlying drug resistance. Increasingly, the mechanisms involving micro-RNAs (miRNAs) are studied because miRNAs are also considered practical therapeutic options due to high degrees of specificity, efficacy, and accuracy, as well as their ability to target multiple genes at the same time. Years of research have firmly established miR-34 as a key tumor suppressor miRNA whose target genes are involved in drug resistance mechanisms. Indeed, numerous articles show that low levels of circulating miR-34 or tumor-specific miR-34 expression are associated with poor response to chemotherapy. In addition, elevation of inherently low miR-34 levels in resistant cancer cells effectively restores sensitivity to chemotherapeutic agents. Here, we review this literature, also highlighting some contradictory observations. In addition, we discuss the potential utility of miR-34 expression as a predictive biomarker for chemotherapeutic drug response. Although caution needs to be exercised, miR-34 is emerging as a biomarker that could improve cancer precision medicine.

Objective: A microRNA (miRNA) that functionally downregulates the expression of tumor suppressors can be defined as an oncomir. Here, we interrogate the biological significance of miR-592 in colorectal cancer (CRC). Research design and methods: The expression of miR-592 in CRC tissues and cell lines was ascertained by qRT-PCR assay, and the expression of its target gene was determined by immunohistochemistry staining. The oncogenic role of miR-592 was assessed in terms of cell proliferation, migration, and clonogenicity in vitro, whereas the tumorigenicity was assessed by inhibiting endogenous miR-592 in CRC cells in vivo. Results: A striking upregulation of miR-592 was observed in CRC tissues and cell lines compared to the matched adjacent non-tumor tissues and normal colon cells. Importantly, Forkhead Box O3A (FoxO3A) was identified as a novel target of miR-592. miR-592 inhibitor exhibited a significant reduction of migration, proliferation, and clonogenicity in CRC cells. These cells also displayed a decreased tumorigenicity in SCID mice relative to the control cells. Conclusion: These data suggest that miR-592 may promote the progression and metastasis, in part, by targeting FoxO3A in CRC. miR-592 may be a novel target for CRC treatment and antagomir-592 may inhibit the proliferation and metastasis of CRC cells.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype B non-Hodgkin lymphoma in adults. After rituximab being introduced to treat DLBCL, the current first-line treatment is R-CHOP regimen. This regimen greatly improves patient's prognosis, however, relapsed or refractory cases are commonly seen, mainly due to the resistance to rituximab. Although a large number of experiments have been conducted to investigate rituximab resistance, the exac mechanisms and solutions are still unclear. This review mainly explores the possible mechanisms oft rituximab resistance and current new effective treatments for rituximab resistance in DLBCL.

The transcription factor high mobility group protein A2 (HMGA2) plays an important role in the pathogenesis of some cancers including breast cancer. Polyamidoamine dendrimer generation 4 is a kind of highly branched polymeric nanoparticle with surface charge and highest density peripheral groups that allow ligands or therapeutic agents to attach it, thereby facilitating target delivery. Here, methotrexate (MTX)- modified polyamidoamine dendrimer generation 4 (G4) (G4/MTX) was generated to deliver specific small interface RNA (siRNA) for suppressing HMGA2 expression and the consequent effects on folate receptor (FR) expressing human breast cancer cell lines (MCF-7, MDA-MB-231). We observed that HMGA2 siRNA was electrostatically adsorbed on the surface of the G4/MTX nanocarrier for constructing a G4/MTX-siRNA nano-complex which was verified by changing the final particle size and zeta potential. The release of MTX and siRNA from synthesized nanocomplexes was found in a time- and pH-dependent manner. We know that MTX targets FR. Interestingly, G4/MTX-siRNA demonstrates significant cellular internalization and gene silencing efficacy when compared to the control. Besides, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay demonstrated selective cell cytotoxicity depending on the folate receptor expressing in a dose-dependent manner. The gene silencing and protein downregulation of HMGA2 by G4/MTX-siRNA was observed and could significantly induce cell apoptosis in MCF-7 and MDA-MB-231 cancer cells compared to the control group. Based on the findings, we suggest that the newly developed G4/MTX-siRNA nano-complex may be a promising strategy to increase apoptosis induction through HMGA2 suppression as a therapeutic target in human breast cancer. The transcription factor high mobility group protein A2 (HMGA2) plays an important role in the pathogenesis of some cancers including breast cancer. Polyamidoamine dendrimer generation 4 is a kind of highly branched polymeric nanoparticle with surface charge and highest density peripheral groups that allow ligands or therapeutic agents to attach it, thereby facilitating target deliv-ery. Here, methotrexate (MTX)-modified polyamidoamine dendrimer generation 4 (G4) (G4/MTX) was generated to deliver specific small interface RNA (siRNA) for suppressing HMGA2 expression and the consequent effects on folate receptor (FR) expressing human breast cancer cell lines (MCF-7, MDA-MB-231). We observed that HMGA2 siRNA was electrostatically adsorbed on the surface of the G4/MTX nanocarrier for constructing a G4/MTX-siRNA nano-complex which was verified by changing the final particle size and zeta potential. The release of MTX and siRNA from synthesized nanocomplexes was found in a time-and pH-dependent manner. We know that MTX targets FR. Interestingly, G4/MTX-siRNA demonstrates significant cellular internalization and gene silencing efficacy when compared to the control. Besides, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay demonstrated selective cell cytotoxicity depending on the folate receptor expressing in a dose-dependent manner. The gene silencing and protein downregulation of HMGA2 by G4/MTX-siRNA was observed and could significantly induce cell apoptosis in MCF-7 and MDA-MB-231 cancer cells compared to the control group. Based on the findings, we suggest that the newly developed G4/MTX-siRNA nano-complex may be a promising strategy to increase apoptosis induction through HMGA2 suppression as a therapeutic target in human breast cancer.

Wogonin is a flavonoid found in different plants such as roots of Scutellaria baicalensis Georgi distributed mainly in Asia and Europe. Dried root extracts of S. baicalensis with high content of wogonin, popularly known as "Huang-Qin" or Chinese or baical skullcap, have been used for long time in traditional Chinese medicine. Several health benefits are attributed to wogonin and derivatives showing anti-inflammatory, antiviral, anticancer, and antioxidant effects and more recently antineurodegenerative properties. Preclinical pharmacological activities of wogonin against diverse types of cancer such as breast, colorectal, and human gastric cancer will be presented in this review. In addition, studies on oxidative stress and bioavailability of wogonin will be discussed together with antineurodegenerative potential with special focus on Alzheimer's disease. Outcomes extracted from the last preclinical studies related to therapeutic applications of wogonin will be commented and updated in this review. The scientific evidence collected in this review aims to encourage transfer of the preclinical evidence of wogonin to new clinical studies. CONICYT PIA/APOYO CCTE: AFB170007 info:eu-repo/semantics/publishedVersion

Rapidly evolving and ever-increasing knowledge of the molecular pathophysiology of pancreatic cancer has leveraged our understanding altogether to a next level. Compared to the exciting ground-breaking discoveries related to underlying mechanisms of pancreatic cancer onset and progression, however, there had been relatively few advances in the therapeutic options available for the treatment. Since the discovery of the DNA structure as a helix which replicates semi-conservatively to pass the genetic material to the progeny, there has been conceptual refinement and continuous addition of missing pieces to complete the landscape of central dogma. Starting from transcription to translation, modern era has witnessed non-coding RNA discovery and central role of these versatile regulators in onset and progression of pancreatic cancer. Long non-coding RNAs (lncRNAs) have been shown to act as competitive endogenous RNAs through sequestration and competitive binding to myriad of microRNAs in different cancers. In this article, we set spotlight on emerging evidence of regulation of different signaling pathways (Hippo, TGFβ/SMAD, Wnt/β-Catenin, JAK/STAT and NOTCH) by lncRNAs. Conceptual refinements have enabled us to understand how lncRNAs play central role in post-translational modifications of various proteins and how lncRNAs work with epigenetic-associated machinery to transcriptionally regulate gene network in pancreatic cancer.

For many years, high-affinity subunit of IL-2 receptor (CD25) has been considered as a promising therapeutic target for different pathologic conditions like allograft rejection, autoimmunity, and cancers. Although CD25 is transiently expressed by newly-activated T cells, it is the hallmark of regulatory T (Treg) cells which are the most important immunosuppressive elements in tumor microenvironment. Thus, Tregs can be considered as a potential target for chimeric antigen receptor (CAR)-based therapeutic approaches. On the other hand, due to some profound adverse effects pertaining to the use of CAR T cells, CAR NK cells have caught researchers’ attention as a safer choice. Based on these, the aim of this study was to design and develop a CAR NK cell against CD25 as the most prominent biomarker of Tregs with the prospect of overcoming immune escape mechanism in solid and liquid cancers. In the current study, an anti-CD25 CAR was designed and evaluated by comprehensive in silico analyses. Then, using lentiviral transduction system, NK-92 cell line was engineered to express this anti-CD25 CAR construct. In vitro functional analyses of anti-CD25 CAR for its reactivity against CD25 antigen as well as for cytotoxicity and cytokine production assays against CD25 bearing Jurkat cell line were done. In silico analyses demonstrated that the anti-CD25 CAR transcript and scFv protein structures were stable and had proper interaction with the target. Also, in vitro analyses showed that the anti-CD25 CAR-engineered NK-92 cells were able to specifically detect and lyse target cells with an appropriate cytokine production and cytotoxic activity. To conclude, the results showed that this novel CAR NK cell is functional and warrant further investigations.

Background:Cancer is the second leading cause of death before the age of 70. Improved cancer survival has put increasing demands on cancer care. Palliative care is the specialized multi-disciplinary care providing relief from the pain, symptoms, and stress of serious illness. The study aims to evaluate the adjunctive effect of acupuncture for advanced cancer patients in a collaborative model of palliative care.Methods/Design:This is a single-blinded, randomized, sham-controlled trial. One hundred twenty advanced cancer patients undergoing palliative care will be randomized in a ratio of 2:1:1 to manual acupuncture plus standard care group (ASC), sham acupuncture plus standard care group (SSC), and standard care group (SC). Patients in ASC and SSC will receive 9 sessions of acupuncture or sham acupuncture for 3 weeks, and will be followed up for 2 months. The primary measure is the change from baseline score of the Edmonton Symptom Assessment System at 3 weeks. The secondary measures include the Brief Fatigue Inventory, Hospital Anxiety and Depression Scale, Insomnia Severity Index, Numeric Rating Scale, and European Organization for Research and Treatment of Cancer Quality of Life 15 items Questionnaire for Palliative Care.Discussion:The finding of this trial will provide high-quality evidence on the adjunctive effect of acupuncture to standard care on advanced cancer patients undergoing palliative care.Trial Registration:Clinicaltrials.gov, NCT04398875 ( https://www.clinicaltrials.gov/ct2/show/NCT04398875 ), Registered on 21 May 2020.

Introduction: Metabolomics, the study of metabolites, is a promising research field for cancers. The metabolic pathway in a tumor cell is different from a normal tissue cell. There are two approaches to study the metabolism, targeted and untargeted. The general approach is that metabolomic data are interpreted by bioinformatics tools correlating with metabolomic databases to obtain significant findings. With the use of specific analysis tools, such as nuclear magnetic resonance (NMR) and mass spectrometer (MS) combined with chromatography, metabolic profile or metabolic fingerprint of various biological specimens could be obtained. The applications of metabolomics are used to discover potential cancer biomarkers and monitor the metastatic state, therapeutic and drug response for better patient management. Areas covered: In this review, the author introduce metabolomics and discuss the use of metabolomics approaches in different cancers, including the study of colorectal cancer, prostate cancer, liver cancer, pancreatic cancer and breast cancer using NMR and MS. Expert opinion: Knowledge on the molecular basis of cancer metabolism and its potential clinical applications has been improving recently. However, there are still many challenges for the technological development and integration of metabolomics with other omics spaces such as genomics. In the near future, it is expected that metabolomics will play an important role in cancer molecular diagnostics.

Introduction: NanoString nCounter technology, a novel molecular assay, is gaining prevalent use in clinical settings as it can overcome some common constraints that are associated with the use of polymerase chain reaction (PCR). Compared to PCR, NanoString technology does not involve any amplification steps, which significantly minimizes the chance of contamination. NanoString measures the number of mRNA transcripts directly by 'molecular counting', as up to 800 colored probes can be run simultaneously in a single reaction. Areas covered: This manuscript reviews the principle of NanoString and covers the main applications of NanoString in companion diagnostics with a focus on cancer immunotherapy and disease prognosis estimation. This review has also taken a step in the direction of personalized medicine, with the application of NanoString on the realm of companion diagnostics. Expert opinion: NanoString is going to take a vital role in companion diagnostics and personalized medicine, owing to its simple and easy to use characteristics. Yet, the use of NanoString requires normalization of expression level, which is represented by the copy number of respective mRNA, with a reference gene. Furthermore, difficulty in probe design, which demands prior knowledge of known sequence, has also been a limitation of NanoString.

MicroRNAs (miRNAs) exert a critical influence on physiological and pathological processes through post-transcriptional modification of their mRNA targets. They play important roles in tumorigenesis and are considered to be potential diagnostic and prognostic biomarkers with various cancers. MiR-200c and miR-9 are regulatory elements that can have dual impacts as oncogenes and/or tumor suppressor genes. MiR-200c regulates two transcription factors, ZEB1 and ZEB2, while miR-9 is a regulatory factor for the E-cadherin protein which has a critical function in cell-cell junctions and is inhibited by two transcription factors ZEB1 and ZEB2. In this study, expression levels of miR-200c and miR-9, ZEB-1, ZEB-2 and E-cadherin were assessed in 30 non-small cell lung cancers (NSCLCs) by real-time qPCR. MiR-9 was down-regulated significantly in tumor tissues compared to normal adjacent tissues, while there was no significant change in expression level of miR-200c. On the other hand, ZEB1 demonstrated significant increase and ZEB2a decrease at the mRNA level. These results indicate roles for miR-9 and ZEB1 in genesis of lung cancer, although clinico-pathological associations were not evident. Further studies are necessary to assess implications for treatment of lung cancer.

Emerging evidence demonstrates that long non-coding RNAs (lncRNAs) are deeply involved in the development of various cancers. This study identified that SBF2-AS1, an early-stage-specific lncRNA, is critical for the tumorigenesis of lung adenocarcinoma (LUAD). We first analyzed LUAD transcriptome data from The Cancer Genome Atlas and the GEO database by weighted gene co-expression network analysis (WGCNA). Five early LUAD-specific lncRNAs were filtered out, and only SBF2-AS1 was upregulated in LUAD. High expression of SBF2-AS1 indicates poor survival of LUAD, especially the early-stage LUAD, but not lung squamous cell carcinoma. SBF2-AS1 promotes LUAD cells proliferation in vitro, and RNA-sequencing data shows that many cell-cycle-related genes were downregulated after SBF2-AS1 knockdown. Mechanically, SBF2-AS1 could competitively bind with miR-338-3p and miR-362-3p to increase E2F1 expression. Finally, we show that the SBF2-AS1-miR-338-3p/362-3p-E2F1 axis could promote LUAD tumorigenesis in vitro and in vivo. Our study demonstrates that SBF2-AS1, an early-stage-specific lncRNA, promotes LUAD tumorigenesis by sponging miR-338-3p and miR-362-3p and increasing E2F1 expression. The SBF2-AS1-miR-338-3p/362-3p-E2F1 regulatory axis may serve as a prognostic marker and potential therapeutic target for LUAD. Keywords: WGCNA, lung adenocarcinoma, tumorigenesis, ceRNA, SBF2-AS1, lncRNA

Cancer is a serious health issue, which is one of the leading causes of death in this century. Cancer at the early stage is more likely to be curable, therefore early detection is an effective way ...

The purpose of this account is to review the compounds capable of eliciting mitochondria-mediated apoptosis in cancer cells produced by medicinal fungi and plants. The medicinal fungi discussed encompass Cordyceps, Ganoderma species, Coriolus versicolor and Hypsizygus marmoreus. The medicinal plants discussed comprise Astragalus complanatus, Dendrobium spp, Dioscorea spp, Glycyrrhiza spp, Panax notoginseng, Panax ginseng, and Momordica charantia. These compounds have the potential of development into anticancer drugs.

Objective: The aim of this study is to summarize preclinical studies on herbal medicines used to treat cancer cachexia and its underlying mechanisms. Methods: We searched four representing databases, including PubMed, EMBASE, the Allied and Complementary Medicine Database, and the Web of Science up to December 2016. Randomized animal studies were included if the effects of any herbal medicine were tested on cancer cachexia. The methodological quality was evaluated by the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADE) checklist. Results: A total of fourteen herbal medicines and their compounds were identified, including Coptidis Rhizoma, berberine, Bing De Ling, curcumin, Qing-Shu-Yi-Qi-Tang, Scutellaria baicalensis, Hochuekkito, Rikkunshito, hesperidin, atractylodin, Sipjeondaebo-tang, Sosiho-tang, Anemarrhena Rhizoma, and Phellodendri Cortex. All the herbal medicines, except curcumin, have been shown to ameliorate the symptoms of cancer cachexia through anti-inflammation, regulation of the neuroendocrine pathway, and modulation of the ubiquitin proteasome system or protein synthesis. Conclusions: This study showed that herbal medicines might be a useful approach for treating cancer cachexia. However, more detailed experimental studies on the molecular mechanisms and active compounds are needed.

Bacterial and viral infection is a common cause of pneumonia, respiratory failure, and even acute respiratory distress syndrome. Increasing evidence indicates that red blood cells (RBCs) may contribute to immune response and inflammation. However, the precise molecular mechanisms that link RBC and hemolysis to the development and progression of inflammatory pathologies are not entirely understood. In this study, we used bacterial endotoxin, lipopolysaccharide (LPS), to mimic an infectious hemolysis and found that RBCs dynamically regulated cell aggregation between immune cells and human lung microvascular endothelial cells (HLMVEC). When RBCs were treated with LPS, integrin α4β1 was increased and was accompanied by cytokines and chemokines release (TNF-α, IL-1β, IL-6, IL-8, IFN-γ, CXCL12, CCL5, CCL7 and CCL4). Upon α4β1 elevation, RBCs not only facilitated mature monocyte derived dendritic cell (mo-DCs) adhesion but also promoted HLMVEC aggregation. Furthermore, co-culture of the supernatant of LPS pre-treated RBCs with mo-DCs could promote naïve CD4 T cell proliferation. Notably, the filtered culture from LPS-lysed RBCs further promoted mo-DCs migration in a concentration dependent manner. From a therapeutic perspective, cyclic peptide inhibitor of integrin α4β1 combined with methylprednisolone (α4β1/Methrol) remarkably blocked RBCs aggregation to mo-DCs, HLMVEC, or mo-DCs and HLMVEC mixture. Moreover, α4β1/Methrol dramatically reduced mo-DCs migration up-regulated glucocorticoid-induced leucine zipper in mo-DCs, and ultimately reversed immune cell dysfunction induced by hemolysis. Taken together, these results indicate that integrin α4β1 on RBCs could mediate cell-cell interaction for adaptive immunity through influencing cell adhesion, migration, and T cell proliferation.

Breast cancer is a heterogeneous disease, affecting over 3.5 million women worldwide, yet the functional role of cis-regulatory elements including super-enhancers in different breast cancer subtypes remains poorly characterized. Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis. Here we apply integrated epigenomic and transcriptomic profiling to uncover super-enhancer heterogeneity between breast cancer subtypes, and provide clinically relevant biological insights towards TNBC. Using CRISPR/Cas9-mediated gene editing, we identify genes that are specifically regulated by TNBC-specific super-enhancers, including FOXC1 and MET, thereby unveiling a mechanism for specific overexpression of the key oncogenes in TNBC. We also identify ANLN as a TNBC-specific gene regulated by super-enhancer. Our studies reveal a TNBC-specific epigenomic landscape, contributing to the dysregulated oncogene expression in breast tumorigenesis., Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor prognostic outcomes. Here the authors characterize super-enhancer heterogeneity and they identify genes that are specifically regulated by TNBC-specific super-enhancers, including FOXC1, MET and ANLN.

Echinococcosis, mainly caused by Echinococcus granulosus, is one of the 17 neglected tropical diseases. Extracellular vesicles (EVs) play an essential role in the host–parasite interplay. However, the EVs in the hydatid fluid (HF) of E. granulosus are not fully characterized. Herein, three different types of HF EVs, designated as 2 K, 10 K, and 110 K EVs based on the centrifugal force used, were morphologically identified. A total of 97, 80, and 581 proteins were identified in 2 K, 10 K, and 110 K EVs, respectively, 39 of which were commonly shared. Moreover, 11, 8, and 25 miRNAs were detected, respectively, and all of the 7 selected miRNAs were validated by qPCR to be significantly lower abundant than that in protoscoleces. It was further deemed that 110 K EVs were internalized by sheep peripheral blood mononuclear cells (PBMCs) in a time-dependent manner and thus induced interleukin (IL)-10, tumor necrosis factor-α (TNF-α), and IRF5 were significantly upregulated and IL-1β, IL-17, and CD14 were significantly downregulated (p < 0.05). These data demonstrate the physical discrepancy of three HF EVs and an immunomodulatory effect of 110 K EVs on sheep PMBCs, suggesting a role in immune responses during E. granulosus infection.

The power of the small has been realized time and again in human history. The recent global fiasco, COVID-19, interlaced with unprecedented biomedical consequences and human loss, modifications in ...

Background Lithium is especially taken as a maintenance medication for Bipolar Disorder. In women with bipolar disorder, lithium is often effective during postpartum period, but breast-feeding for medicated mothers is controversial because of harmful effects for her child. At present, the biological mechanisms of lithium are not well-understood, affecting its usage and overall health implications. Procedure We developed a rat lithium and breast-feeding model at human therapeutic levels to study the effects of lithium exposure through breast-milk on pups' thyroid function. Novel laser analytical spectroscopy, along with traditional blood and immunohistochemical tests, were applied to further investigate the mechanisms behind the thyroid dysfunction. Maternal iodine supplementation was evaluated as a therapeutic method to address the pups' thyroid dysfunction. Results Pups exposed to lithium via breastmilk, even with the dam on a sub-therapeutic level, experienced weight gain, reduced blood thyroxine (T4 ), and elevated blood urea nitrogen, indicating effects on thyroid and kidney function. We show that lithium inhibited iodine uptake by thyroid follicles, initiating a mechanism that reduced iodination of tyrosine, thyroglobulin cleavage, and thyroid hormone production. Importantly, infant thyroid function can be significantly improved by administering supplementary iodine to the medicated dam's diet during breast-feeding. Conclusion These results elucidate the mechanisms of lithium in thyroid function, provide valuable information on use postpartum, and suggest a clinically applicable remedy to side-effects. The results are particularly important for patients (and their infants) who respond well to lithium and need, or choose, to breast-feed.

The gut microbiota plays an important role in human health. In modern life, with the improvement of living conditions, the intake of high-sugar and high-fat diets as well as the large-scale use of antibacterial drugs have an extensive impact on the gut microbiota, even leading to gut microbiota-orchestrating disorders. This review discusses the effects of various factors, including geographic location, age, diet, antibacterial drugs, psychological situation and exercise on gut bacteria, which helps us profoundly to understand the significance of gut bacteria to human health and to find effective solutions to prevent or treat related diseases.

Lymphoma is a name for malignant diseases of the lymphatic system including Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. Although several approaches are used for the treatment of these diseases, some of them are not successful and have serious adverse effects. Therefore, other effective treatment methods might be interesting. Studies have indicated that plant ingredients play a key role in treating several diseases. Some plants have already shown a potential therapeutic effect on many malignant diseases. Quercetin is a flavonoid found in different plants and could be useful in the treatment of different malignant diseases. Quercetin has its antimalignant effects through targeting main survival pathways activated in tumor cells. In vitro/in vivo experimental studies have demonstrated that quercetin possesses a cytotoxic effect on lymphoid cancer cells. Regardless of the optimum results that have been obtained from both in vitro/in vivo studies, few clinical studies have analyzed the antitumor effects of quercetin in lymphoid cancers. Thus, it seems that more clinical studies should introduce quercetin as a therapeutic, alone or in combination with other chemotherapy agents. Here, in this study, we reviewed the anticancer effects of quercetin and highlighted the potential therapeutic effects of quercetin in various types of lymphoma.

Introduction Tyrosine kinase inhibitors (TKIs) therapy targets at epidermal growth factor receptor (EGFR) gene mutations in non-small-cell lung cancer (NSCLC). We aimed to compare the EGFR mutation-guided target therapy versus empirical chemotherapy for first-line treatment of advanced NSCLC in the public healthcare setting of Hong Kong. Methods A Markov model was designed to simulate outcomes of a hypothetical cohort of advanced (stage IIIB/IV) NSCLC adult patients with un-tested EGFR-sensitizing mutation status. Four treatment strategies were evaluated: Empirical first-line chemotherapy with cisplatin-pemetrexed (empirical chemotherapy group), and EGFR mutation-guided use of a TKI (afatinib, erlotinib, and gefitinib). Model outcome measures were direct medical cost, progression-free survival, overall survival, and quality-adjusted life-years (QALYs). Incremental cost per QALY gained (ICER) was estimated. Sensitivity analyses were performed to examine robustness of model results. Results Empirical chemotherapy and EGFR mutation-guided gefitinib gained lower QALYs at higher costs than the erlotinib group. Comparing with EGFR mutation-guided erlotinib, the afatinib strategy gained additional QALYs with ICER (540,633 USD/QALY). In 10,000 Monte Carlo simulations for probabilistic sensitivity analysis, EGFR mutation-guided afatinib, erlotinib, gefitinib and empirical chemotherapy were preferred strategy in 0%, 98%, 0% and 2% of time at willingness-to-pay (WTP) 47,812 USD/QALY (1x gross domestic product (GDP) per capita), and in 30%, 68%, 2% and 0% of time at WTP 143,436 USD/QALY (3x GDP per capita), respectively. Conclusions EGFR mutation-guided erlotinib appears to be the cost-effective strategy from the perspective of Hong Kong public healthcare provider over a broad range of WTP.

Tumor mutational burden (TMB), the total number of somatic mutations per coding area of a tumor genome[1], has emerged as a biomarker predictive of response to immune checkpoint inhibition. Convent...

Breast cancer (BC) is the most diagnosed carcinoma and the leading cause of cancer death in female over 100 countries. Thanks to the advance in therapeutic strategies, patients' survival has improved. However, the lack of response to treatments and drug resistance are still a main concern, demanding for new therapeutic approaches, in particular for the advanced stages of the disease. Androgen receptor (AR) is gaining increasing interest as a fourth targetable receptor in BC, however, its regulation in BC cells is still poorly understood. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally. Here, we identified miR-9-5p as an inhibitor of AR expression, we validated the inverse correlation between miR-9-5p and AR in primary BC samples and we further identified a feedback loop in which androgen agonists of AR up-regulate miR-9-5p. We also provided evidence that miR-9-5p elicits anti-proliferative effects in BC cell lines regardless of their estrogen receptor status. Finally, we showed that miR-9-5p can revert AR-downstream signaling even in presence of AR-agonists, highlighting the role of this miR in the hormonal response of BC. In conclusion, this study supports the role of miR-9-5p as an anti-proliferative miR in BC and as a central modulator of AR-signaling response to circulating androgens in BC.

Although the majority of nasopharyngeal carcinoma (NPC) patients demonstrate favorable outcomes after radiotherapy and/or chemotherapy, about 8-10% of patients will develop recurrent disease, and genomic alterations (GAs) associated with the recurrence are unclear.This study investigated the GAs in the paired primary tumors and recurrent tumors of 7 NPC patients with relapse, as well as the primary tumors of 15 NPC patients without relapse by deep targeted next-generation sequencing on 440 cancer-related genes.The discovery of GAs associated with recurrence or survival in NPC may serve as potential prognostic gene signatures of high-risk patients. Targeted therapies are available in some of the clinically relevant GAs and may be considered in future clinical trials. Given the limitation of the sample size, validation by a larger cohort is warranted.

Lung cancer is a major public health burden and among the highest incidence and mortality rates of the cancers. MicroRNAs (miRNAs) play an important role in the development of lung cancer. The aim of this study was to investigate whether there was a potential causal relation between miRNAs and non-small-cell lung cancer (NSCLC). 1,026 patients with NSCLC from The Cancer Genome Atlas (TCGA) were analyzed. NSCLC associated SNPs’ allele scores were established, and candidate miRNAs were filtered from differential expression analysis. Mendelian randomization (MR) analysis was conducted for 5 candidate miRNA (hsa-miR-135b, hsa-miR-142, hsa-miR-182, hsa-miR-183 and hsa-miR-3607) and 76 candidate SNPs in lung adenocarcinoma (LUAD) group. According to the core assumptions of MR, there was no clear evidence of a causal relation between the 5 candidate miRNAs and LUAD. The reads per million miRNAs mapped (RPM) level of candidate miRNAs changed less than 3% per allele score. To our knowledge, this is the first study using the TCGA data set to investigate the causal relation between miRNAs and lung cancer using the MR approach, and also one of the first MR studies to use miRNA expression as an exposure factor, with the SNPs as instrumental variables.

Cancer recurrence presents a huge challenge in cancer patient management. Immune escape is a key mechanism of cancer progression and metastatic dissemination. CD25 is expressed in regulatory T (Treg) cells including tumor-infiltrating Treg cells (TI-Tregs). These cells specially activate and reinforce immune escape mechanism of cancers. The suppression of CD25/IL-2 interaction would be useful against Treg cells activation and ultimately immune escape of cancer. Here, software, web servers and databases were used, at which in silico designed small interfering RNAs (siRNAs), de novo designed peptides and virtual screened small molecules against CD25 were introduced for the prospect of eliminating cancer immune escape and obtaining successful treatment. We obtained siRNAs with low off-target effects. Further, small molecules based on the binding homology search in ligand and receptor similarity were introduced. Finally, the critical amino acids on CD25 were targeted by a de novo designed peptide with disulfide bond. Hence we introduced computational-based antagonists to lay a foundation for further in vitro and in vivo studies.

The emergence of anovel coronavirus identified in patients with unknown cause of acute respiratory disease in Wuhan, China at the end of 2019 has caused aglobal outbreak. The causative coronavirus was later named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease caused by SARS-CoV-2 was named as Coronavirus Disease-2019 (COVID-19). As of 10 August 2020, more than 19,718,030 confirmed cases and 728,013 deaths have been reported. COVID-19 is spread via respiratory droplets which are inhaled into the lungs.In this article, we summarized the knowledge about the causative pathogen of COVID-19 and various diagnostic methods in this pandemic for better understanding of the limitations and the nuances of virus testing for COVID-19.In this pandemic, rapid and accurate identification of COVID-19 patients are critical to break the chain of infection in the community. RT-PCR provides a rapid and reliable identification of SARS-CoV-2 infection. In the future, molecular diagnostics will still be the gold standard and next-generation sequencing can help us to understand more on the pathogenesis and detect novel mutations. It is believed that more sophisticated detection methods will be introduced to detect SARS-CoV-2 as earliest as possible.

Curcumin, a yellow polyphenolic pigment from the Curcuma longa L. (turmeric) rhizome, has been used for centuries for culinary and food coloring purposes, and as an ingredient for various medicinal preparations, widely used in Ayurveda and Chinese medicine. In recent decades, their biological activities have been extensively studied. Thus, this review aims to offer an in-depth discussion of curcumin applications for food and biotechnological industries, and on health promotion and disease prevention, with particular emphasis on its antioxidant, anti-inflammatory, neuroprotective, anticancer, hepatoprotective, and cardioprotective effects. Bioavailability, bioefficacy and safety features, side effects, and quality parameters of curcumin are also addressed. Finally, curcumin’s multidimensional applications, food attractiveness optimization, agro-industrial procedures to offset its instability and low bioavailability, health concerns, and upcoming strategies for clinical application are also covered. This work was supported by CONICYT PIA/APOYO CCTE AFB170007. N. Martins would like to thank the Portuguese Foundation for Science and Technology (FCT-Portugal) for the Strategic project ref. UID/BIM/04293/2013 and "NORTE2020 - Northern Regional Operational Program" (NORTE-01-0145-FEDER-000012).

Exploring the function of every gene is a challenging task. There is a paradigm shift of RNA interference with the introduction of clustered regularly interspaced short palindromic repeat (CRISPR)-based genome-wide screening. CRISPR-based screening can detect the loss-of-function and gain-of-function targets. Many DNA-binding proteins are engineered as effective tools for modulating gene expression and for investigating therapeutic targets for a spectrum of diseases. Among them, CRISPR-Cas9 has received extensive attention with its potential for screening cancer treatment targets.This article reviews CRISPR toolkit and its applications in screening cancer therapeutic targets, especially genome-wide screens using different CRISPR-Cas9 systems. We compare and summarize the characteristics of CRISPR systems, which would be helpful for understanding and optimizing current CRISPR toolkits, as well as reflecting on the potential future development and clinical applications of CRISPR screens.The application of CRISPR-based therapeutic target screening is broadly used in cancer drug development. Its application in cancer immunotherapy and precision oncology is blooming. Nevertheless, more effective methods of Cas protein delivery and the development of more accurate and efficient genome-editing tools are needed.

Our previous study revealed that Epimedii Folium (EF) and Codonopsis Radix (CNR) significantly promoted tumor growth on a subcutaneous mouse model of prostate cancer (PCa) via enhancing the mRNA and protein expressions of androgen receptor (AR), while Astragali Radix (AGR) inhibited tumor growth via suppressing the protein expression of AR. In the present study, we aimed to investigate the potential interactions between EF, CNR or AGR and AR antagonist (abiraterone acetate [ABI]) on the tumor growth using subcutaneous and orthotopic PCa mouse models. EF, CNR, AGR and ABI were intragastrically given to mice once every 2 days for 4 weeks. The pharmacokinetics of ABI were evaluated in the plasma of rats when combined with EF, CNR, or AGR. Our results demonstrated that EF or CNR could weaken the anti-tumor effects of ABI via increasing the AR expression involving activation of the PI3K/AKT and Rb/E2F pathways and decreasing the bioavailability of ABI, while AGR could enhance the anti-tumor effects of ABI through suppressing the AR expression via inhibiting the activations of PI3K/AKT and Rb/E2F pathways and increasing the bioavailability of ABI. These findings imply that cautions should be exercised when prescribing EF and CNR for PCa patients.

Oxygen sensing is inherent among most animal lifeforms and is critical for organism survival. Oxygen sensing mechanisms collectively trigger cellular and physiological responses that enable adaption to a reduction in ideal oxygen levels. The major mechanism by which oxygen-responsive changes in the transcriptome occur are mediated through the hypoxia-inducible factor (HIF) pathway. Upon reduced oxygen conditions, HIF activates hypoxia-responsive gene expression programs. However, under normal oxygen conditions, the activity of HIF is regularly suppressed by cellular oxygen sensors; prolyl-4 and asparaginyl hydroxylases. Recently, these oxygen sensors have also been found to suppress the function of two lysine methyltransferases, G9a and G9a-like protein (GLP). In this manner, the methyltransferase activity of G9a and GLP are hypoxia-inducible and thus present a new avenue of low-oxygen signaling. Furthermore, G9a and GLP elicit lysine methylation on a wide variety of non-histone proteins, many of which are known to be regulated by hypoxia. In this article we aim to review the effects of oxygen on G9a and GLP function, non-histone methylation events inflicted by these methyltransferases, and the clinical relevance of these enzymes in cancer.

Background Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved for first-line treatment of non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations. However, NSCLC patients bearing mutant KRAS are inherently unresponsive to gefitinib. Defective autophagy was proposed to mediate resistance to EGFR-TKIs. In this study, the reversal of primary resistance to gefitinib in NSCLC by putative autophagy inducers was investigated. Materials and methods A few putative autophagy inducers were investigated in NSCLC cells harboring KRAS or EGFR mutations. Quantitative real-time PCR and Western blot analysis were used to evaluate expression of autophagy-related genes and proteins. Sulforhodamine B assay was used to evaluate cytotoxicity of drug combinations. Flow cytometric asssays were used to study apoptotic and cell cycle effects. Results The antidiarrheal agent loperamide was identified as an autophagy inducer. Loperamide promoted the formation of autophagosomes and it potentiated the cytotoxic effect of gefitinib specifically in NSCLC cells bearing mutant KRAS and wild-type EGFR. Gefitinib-loperamide combination enhanced apoptosis and G1 cell cycle arrest, both of which could not be reversed by pharmacological autophagy inhibitor (3-methyladenine). Moreover, synergistic anticancer effect of gefitinib-loperamide combination was observed in both autophagy-proficient (Atg5-wild type) and -deficient (Atg5-knockout) mouse embryonic fibroblasts. Loperamide overcome gefitinib resistance in NSCLC harboring mutant KRAS and wild-type EGFR through increased apoptosis but independent of autophagy induction. Conclusion Loperamide could be repurposed to overcome primary resistance to gefitinib in KRAS-mutation bearing NSCLC as it also helps relieve the common side effect of diarrhea caused by EGFR-TKIs.

Cancer immunotherapy has been emerged as a promising strategy for treatment of a broad spectrum of malignancies ranging from hematological to solid tumors. One of the principal approaches of cancer immunotherapy is transfer of natural or engineered tumor-specific T-cells into patients, a so called “adoptive cell transfer”, or ACT, process. Construction of allogeneic T-cells is dependent on the employment of a gene-editing tool to modify donor-extracted T-cells and prepare them to specifically act against tumor cells with enhanced function and durability and least side-effects. In this context, CRISPR technology can be used to produce universal T-cells, equipped with recombinant T cell receptor (TCR) or chimeric antigen receptor (CAR), through multiplex genome engineering using Cas nucleases. The robust potential of CRISPR-Cas in preparing the building blocks of ACT immunotherapy has broaden the application of such therapies and some of them have gotten FDA approvals. Here, we have collected the last investigations in the field of immuno-oncology conducted in partnership with CRISPR technology. In addition, studies that have addressed the challenges in the path of CRISPR-mediated cancer immunotherapy, as well as pre-treatment applications of CRISPR-Cas have been mentioned in detail.

Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases and increases mortality in type 2 diabetic patients. HHcy induces endoplasmic reticulum (ER) stress and oxidative stress to impair endothelial function. The glucagon-like peptide 1 (GLP-1) analog exendin-4 attenuates endothelial ER stress, but the detailed vasoprotective mechanism remains elusive. The present study investigated the beneficial effects of exendin-4 against HHcy-induced endothelial dysfunction. Exendin-4 pretreatment reversed homocysteine-induced impairment of endothelium-dependent relaxations in C57BL/6 mouse aortae ex vivo. Four weeks subcutaneous injection of exendin-4 restored the impaired endothelial function in both aortae and mesenteric arteries isolated from mice with diet-induced HHcy. Exendin-4 treatment lowered superoxide anion accumulation in the mouse aortae both ex vivo and in vivo. Exendin-4 decreased the expression of ER stress markers (e.g., ATF4, spliced XBP1, and phosphorylated eIF2α) in human umbilical vein endothelial cells (HUVECs), and this change was reversed by cotreatment with compound C (CC) (AMPK inhibitor). Exendin-4 induced phosphorylation of AMPK and endothelial nitric oxide synthase in HUVECs and arteries. Exendin-4 increased the expression of endoplasmic reticulum oxidoreductase (ERO1α), an important ER chaperone in endothelial cells, and this effect was mediated by AMPK activation. Experiments using siRNA-mediated knockdown or adenoviral overexpression revealed that ERO1α mediated the inhibitory effects of exendin-4 on ER stress and superoxide anion production, thus ameliorating HHcy-induced endothelial dysfunction. The present results demonstrate that exendin-4 reduces HHcy-induced ER stress and improves endothelial function through AMPK-dependent ERO1α upregulation in endothelial cells and arteries. AMPK activation promotes the protein folding machinery in endothelial cells to suppress ER stress.

Cancer remains a major cause of morbidity and mortality irrespective of the type of conventional chemotherapy. Therefore, there is an urgent need for new and effective anticancer therapeutic agents. Bacterial proteins and their derivative peptides appear as a promising approach for cancer treatment. Several, including an amphipathic, α-helical, 28-amino acid peptide derived from azurin, a 128-amino acid copper-containing redox protein secreted from Pseudomonas aeruginosa, show clinical promise in the treatment of adult and pediatric solid tumors. The peptide, p28, is a post-translational, multi-target anticancer agent that preferentially enters a wide variety of solid tumor cells. Mechanistically, after entry, p28 has two major avenues of action. It binds to both wild-type and mutant p53 protein, inhibiting constitutional morphogenic protein 1 (Cop1)-mediated ubiquitination and proteasomal degradation of p53. This results in increased levels of p53, which induce cell-cycle arrest at G2/M and an eventual apoptosis that results in tumor cell shrinkage and death. In addition, p28 also preferentially enters nascent endothelial cells and decreases the phosphorylation of FAK and Akt inhibiting endothelial cell motility and migration. Here, we review the current basic and clinical evidence suggesting the potential of p28 as a cancer therapeutic peptide.

Breast cancer is a complex disease posing a serious threat to the female population worldwide. A complex molecular landscape and tumor heterogeneity render breast cancer cells resistant to drugs and able to promote metastasis and invasiveness. Despite the recent advancements in diagnostics and drug discovery, finding an effective cure for breast cancer is still a major challenge. Positive and negative regulation of apoptosis has been a subject of extensive study over the years. Numerous studies have shed light on the mechanisms that impede the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling cascade. Long non-coding RNAs (lncRNAs) have been implicated in the orchestration, development, proliferation, differentiation and metastasis of breast cancer. However, the roles of lncRNAs in fine-tuning apoptosis regulating machinery in breast cancer remain to be elucidated. The present review illuminates the roles of these molecules in the regulation of breast cancer and the interplay between lncRNA and TRAIL in breast cancer. The present review also attempts to reveal their role in the regulation of apoptosis in breast cancer appears a promising approach for the development of new diagnostic and therapeutic regimens.

Metastasis is the fundamental cause of cancer mortality, but there are still very few anti-metastatic drugs available. Endosomal trafficking has been implicated in tumor metastasis, and we have previously found that small chemical vacuolin-1 (V1) potently inhibits autophagosome-lysosome fusion and general endosomal-lysosomal degradation. Here, we assessed the anti-metastatic activity of V1 both in vitro and in vivo. V1 significantly inhibits colony formation, migration, and invasion of various cancer cells in vitro. It also compromises the assembly-disassembly dynamics of focal adhesions (FAs) by inhibiting the recycling and degradation of integrins. In various experimental or transgenic mouse models, V1 significantly suppresses the metastasis and/or tumor growth of breast cancer or melanoma. We further identified capping protein Zβ (CapZβ) as a V1 binding protein and showed that it is required for the V1-mediated inhibition of migration and metastasis of cancer cells. Collectively, our results indicate that V1 targets CapZβ to inhibit endosomal trafficking and metastasis.