Lessons learned from SARS-CoV and MERS-CoV : FDA-approved Abelson tyrosine-protein kinase 2 inhibitors may help us combat SARS-CoV-2

SARS-CoV-2 is a newly emerging infectious disease, which originated from Wuhan in the Hubei province of China in late December 2019 [1]. Since then, it has rapidly spread all over the world, and at the time of writing this letter, WHO statistics show more than 1,696,588 cases and 105,952 deaths confirmed across the world [2]. Although there is no specific therapy for SARS-CoV-2 infection [3], combination therapy with antiviral and anti-inflammatory drugs accompanied by supportive treatment have been used for SARS-CoV-2 patients [4]. The combination of well-known HIV protease inhibitors, such as ritonavir with lopinavir, has also been a common approach to treat SARS-CoV-2. Insufficient outcome in severe cases is, however, one of the main challenges associated with the current antiviral-based therapy for SARS-CoV-2 [5]. In view of the long period required for novel drug discovery and the desperate need for a prompt response to this pandemic infection, one must resort to repurposing FDA-approved drugs. In this direction, our experience with other close members of coronaviruses such as SARS and MERS has taught us that repurposing the current drugs is a reasonable strategy. Abelson tyrosine-protein kinase 2 (Abl2), the imatinib target, was required for efficient SARS-CoV and MERS-CoV replication in vitro [6]. Coleman et al. have shown that the imatinib target Abl2 is indispensable for efficient replication of SARS-CoV and MERS-CoV in vitro

Apple polyphenols in human and animal health*

Apples contain substantial amounts of polyphenols, and diverse phenolics mainly flavonoids and phenolic acids, have been identified in their flesh and skins. This work aimed to analyze the overall landscape of the research literature published to date on apple phenolic compounds in the context of human and animal health. The Web of Science Core Collection electronic database was queried with (apple* polyphenol*) AND (health* OR illness* OR disease* OR medic* OR pharma*) to identify relevant papers covering these words and their derivatives in the titles, abstracts, and keywords. The resulted 890 papers were bibliometrically analyzed. The VOSviewer software was utilized to produce term maps that illustrate how the frequent phrases fared in terms of publication and citation data. The apple polyphenol papers received global contributions, particularly from China, Italy, the United States, Spain, and Germany. Examples of frequently mentioned chemicals/chemical classes are quercetin, anthocyanin, catechin, epicatechin, and flavonol, while examples of frequently mentioned medical conditions are cardiovascular disease, atherosclerosis, diabetes, Alzheimers disease, and obesity. The potential health benefits of apple polyphenols on humans and animals are diverse and warrant further study.Authors acknowledge the support from The National Centre for Research and Development (NCBR) of Poland (project number POIR.01.01.01-00-0593/18).info:eu-repo/semantics/publishedVersio

Deregulated expression of TANK in glioblastomas triggers pro-tumorigenic ERK1/2 and AKT signaling pathways

Signal transmission by the noncanonical IkappaB kinases (IKKs), TANK-binding kinase 1 (TBK1) and IKKɛ, requires interaction with adapter proteins such as TRAF associated NF-κB activator (TANK). Although increased expression or dysregulation of both kinases has been described for a variety of human cancers, this study shows that deregulated expression of the TANK protein is frequently occurring in glioblastomas (GBMs). The functional relevance of TANK was analyzed in a panel of GBM-derived cell lines and revealed that knockdown of TANK arrests cells in the S-phase and prohibits tumor cell migration. Deregulated TANK expression affects several signaling pathways controlling cell proliferation and the inflammatory response. Interference with stoichiometrically assembled signaling complexes by overexpression or silencing of TANK prevented constitutive interferon-regulatory factor 3 (IRF3) phosphorylation. Knockdown of TANK frequently prevents constitutive activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). TANK-mediated ERK1/2 activation is independent from the canonical MAP kinase or ERK kinase (MEK) 1/2-mediated pathway and utilizes an alternative pathway that uses a TBK1/IKKɛ/Akt signaling axis, thus identifying a novel pathway suitable to block constitutive ERK1/2 activity.Peer reviewe

Natural products in drug discovery: advances and opportunities

Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer and infectious diseases. Nevertheless, natural products also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization, which contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s onwards. In recent years, several technological and scientific developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — are addressing such challenges and opening up new opportunities. Consequently, interest in natural products as drug leads is being revitalized, particularly for tackling antimicrobial resistance. Here, we summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities

CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer

The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk

Combining the chemotherapeutic effects of epigallocatechin 3-gallate with siRNA-mediated p53 knock-down results in synergic pro-apoptotic effects

Ioana Berindan-Neagoe,1,2 Cornelia Braicu,1 Alexandru Irimie3,41Department of Functional Genomics and Experimental Pathology, Cancer Institute, “Ion Chiricuta”, Cluj-Napoca, Romania; 2Department of Immunology, University of Medicine and Pharmacy, “I. Hatieganu”, Cluj-Napoca, Romania; 3Department of Surgical Oncology, University of Medicine and Pharmacy, “I. Hatieganu”, Cluj-Napoca, Romania; 4Department of Surgery, Cancer Institute, “Ion Chiricuta”, Cluj-Napoca, RomaniaAbstract: Plant extracts and compounds are applied to a wide variety of diseases in which traditional drugs have proven ineffective. A quickly developing trend in biomedicine is the therapeutic use of siRNA (short interfering RNA) structures. The focus of this study was on evaluating the gene expression involved in the modulation of apoptosis, in cases of combinatorial treatment (-)-epigallocatechin-3-gallate (EGCG) and/or p53siRNA. EGCG in combination with p53siRNA exerts synergic pro-apoptotic effects that are greater than those of each agent taken individually. There is a cumulative antiproliferative effect, induced by EGCG and p53siRNA treatment, and it is mediated through the activation of a large number of pro-apoptotic genes and the inhibition of anti-apoptotic protein expression levels. p53siRNA promotes the convergence of the extrinsic and intrinsic pathways in a synergic manner with EGCG. The chemotherapeutic effects of EGCG in combination with p53siRNA therapy induced a synergic pro-apoptotic effect, indicating the potential for development of promising new anticancer therapies.Keywords: p53siRNA, apoptosis, HeLa cell

Sorafenib for the treatment of solid malignancies: what about the cancer microenvironment?

Ciprian Tomuleasa, Andrei Cucuianu, Mihaela Aldea, Ioana Berindan-NeagoeResearch Center of Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, RomaniaWe have read with great interest the study of Kim et al, recently published in the International Journal of Nanomedicine.1 The physicians from South Korea describe the anti-tumor efficacy of sorafenib in cholangiocarcinoma, a malignancy with a dismal prognosis and refractory to most chemotherapy options. Surgery is the only curative option, but is limited to only a small number of cases due to the late diagnosis.2 This emphasizes the need to develop new approaches for such cases and the first potential new option is the tyrosine kinase inhibitor sorafenib, already proven to improve the therapeutic ratio of hepatocellular carcinoma, as according to Llovet et al.3 But unlike hepatocellular carcinoma, cholangiocarcinomas are epithelial cancers with a highly developed desmoplastic stroma due to the interaction between the cancer cell and the cancer associated fibroblasts (CAFs), as well as the macrophages, and the natural killer (NK) cells.4 This tumor microenvironment makes it difficult for a chemotherapy drug to reach the cancer cell and be efficient, which partially explains the reason why Kim et al1 developed a sorafenib-coated stent, that can be placed inside the biliary tree and deliver the drug continuously.View original paper by Kim and colleagues

Restoring the p53 'Guardian' Phenotype in p53-Deficient Tumor Cells with CRISPR/Cas9

With an increasing prevalence in the human population, cancer has become one of the most investigated fields of medicine. Among the potential targets for cancer therapy is the tumor suppressor gene TP53, which is found in a mutated state in approximately 50% of human cancers and is often associated with poor prognosis. We propose a novel, highly tumor-specific delivery system for TP53, based on the CRISPR/Cas9 genome editing technology. This system will restore the normal p53 phenotype in tumor cells by replacing the mutant TP53 gene with a functional copy, leading to sustained expression of p53 protein and tumor regression

CRISPR/Cas9: transcending the reality of genome editing

With the expansion of the microbiology field of research, a new genome editing tool arises from the biology of bacteria that holds the promise of achieving precise modifications in the genome with a simplicity and versatility that surpasses previous genome editing methods. This new technique, commonly named CRISPR/Cas9, led to a rapid expansion of the biomedical field; more specifically, cancer characterization and modeling have benefitted greatly from the genome editing capabilities of CRISPR/Cas9. In this paper, we briefly summarize recent improvements in CRISPR/Cas9 design meant to overcome the limitations that have arisen from the nuclease activity of Cas9 and the influence of this technology in cancer research. In addition, we present challenges that might impede the clinical applicability of CRISPR/Cas9 for cancer therapy and highlight future directions for designing CRISPR/Cas9 delivery systems that might prove useful for cancer therapeutics

The extensive role of miR-155 in malignant and non-malignant diseases

MicroRNAs (miRNAs) have rapidly emerged as key molecules in cancer initiation and development, showing the capability to regulate pivotal oncogenic pathways. MiR-155 has gathered an increased attention especially in oncology, but also in non-malignanat pathologies. Nowadays, this noncoding RNA is one of the most important miRNAs in cancer, due to the extensive signaling network associated with it, implication in immune system regulation and also deregulation in disease states. Therefore, numerous research protocols are focused on preclinical modulation of miR-155 for therapeutic purposes, or investigation of its dynamic expression for diagnostic/prognostic assessments, with the final intention of bringing this miRNA into the clinical setting. This review comprehensively presents the extended role of miR-155 in cancer and other pathologies, where its expression is dysregulated. Finally, we assess the future steps toward miR-155 based therapeutics