Outbreak and pandemic of coronavirus SARS-CoV-2 in 2019/2020 will challenge global health for the future. Because a vaccine against the virus will not be available in the near future, we herein try to offer a pharmacological strategy to combat the virus. There exists a number of candidate drugs that may inhibit infection with and replication of SARS-CoV-2. Such drugs comprise inhibitors of TMPRSS2 serine protease and inhibitors of angiotensin-converting enzyme 2 (ACE2). Blockade of ACE2, the host cell receptor for the S protein of SARS-CoV-2 and inhibition of TMPRSS2, which is required for S protein priming may prevent cell entry of SARS-CoV-2. Further, chloroquine and hydroxychloroquine, and off-label antiviral drugs, such as the nucleotide analogue remdesivir, HIV protease inhibitors lopinavir and ritonavir, broad-spectrum antiviral drugs arbidol and favipiravir as well as antiviral phytochemicals available to date may limit spread of SARS-CoV-2 and morbidity and mortality of COVID-19 pandemic. 1. Introduction The outbreak of coronavirus SARS-CoV-2 in Wuhan, China in December 2019, the cause of Corona Virus Disease of 2019 (COVID-19), represents a pandemic threat to global health [1,2]. The WHO declared COVID-19 as a pandemic on March 11th 2020. The outbreak has spread to more than 185 countries with more than 3,200,000 confirmed cases, more than 230,000 confirmed deaths and more than 1,000,000 total recoveries worldwide as of May 1st 2 2020 [3]. Hundreds of millions of lives have been affected as a result of mandatory isolations/quarantines. This pandemic has the potential to overwhelm national healthcare systems, and have major consequences on global economy if SARS-CoV-2 spread and virulence is not contained, or effective treatments are not developed.Coronaviruses are grouped into alpha, beta, gamma, and delta classes. Coronaviruses can infect both humans and animals. The source of the beta coronavirus SARS-CoV-2 is believed to be bats, which carry the virus with no signs of disease [4]. Beta coronaviruses caused earlier outbreaks of severe acute respiratory syndromes (SARS), including SARS-CoV (2002/2003 in Guangdong, China) and Middle East Respiratory Syndrome virus MERS-CoV (2012 in Saudi Arabia) [5]. Beta coronaviruses are pathogenic for humans and have a single stranded RNA genome, encapsulated by a membrane envelope [6]. The coronavirus crown-like ("corona") morphology is created by transmembrane spike glycoproteins (S proteins) that form homotrimers protruding from the viral surface [7]. The S proteins of SARS-CoV and SARS-CoV-2 display structural homology and conserved ectodomains, so earlier strategies employed to prevent binding of SARS-CoV to its host cell receptor angiotensin-converting enzyme 2 (ACE2) may be relevant, since SARS-CoV-2 also employs ACE2 for cell entry [8,9]. ACE2, an exopeptidase expressed on epithelial cells of the respiratory tract, may constitute a pharmacological target to limit cell entry of SARS-CoV-2. The established antimalarial drugs chloroquine and hydroxychloroquine ha...
Cancer stem cells (CSCs) represent a subpopulation of tumor cells that possess self-renewal and tumor initiation capacity and the ability to give rise to the heterogenous lineages of malignant cells that comprise a tumor. CSCs possess multiple intrinsic mechanisms of resistance to chemotherapeutic drugs, novel tumor-targeted drugs, and radiation therapy, allowing them to survive standard cancer therapies and to initiate tumor recurrence and metastasis. Various molecular complexes and pathways that confer resistance and survival of CSCs, including expression of ATP-binding cassette (ABC) drug transporters, activation of the Wnt/β-catenin, Hedgehog, Notch and PI3K/Akt/mTOR signaling pathways, and acquisition of epithelial-mesenchymal transition (EMT), have been identified recently. Salinomycin, a polyether ionophore antibiotic isolated from Streptomyces albus, has been shown to kill CSCs in different types of human cancers, most likely by interfering with ABC drug transporters, the Wnt/β-catenin signaling pathway, and other CSC pathways. Promising results from preclinical trials in human xenograft mice and a few clinical pilote studies reveal that salinomycin is able to effectively eliminate CSCs and to induce partial clinical regression of heavily pretreated and therapy-resistant cancers. The ability of salinomycin to kill both CSCs and therapy-resistant cancer cells may define the compound as a novel and an effective anticancer drug.
SUMMARY:The 26S proteasome constitutes the central proteolytic machinery of the highly conserved ubiquitin/proteasome system, the cell's major tool for extralysosomal protein degradation. Recently, a plethora of cell proteins implicated in the regulation of basic cellular processes, such as proliferation, differentiation, cell cycling, and apoptosis have been discovered to undergo processing and functional limitation by entering the ubiquitin/proteasome pathway with the final destination to be proteolytically degraded by the 26S proteasome. Because both negative and positive regulators of proliferation and apoptosis undergo proteasomal degradation in a tightly regulated and temporally controlled fashion, the 26S proteasome can play opposite roles in the regulation of proliferation and apoptosis. These roles are apparently defined by the cell's environment and proliferative state. Finally, proteasomal protein degradation is deregulated in a number of human diseases, including cancer and neurodegenerative and myodegenerative diseases, which all exhibit an imbalance of proliferation and apoptosis. An improved understanding of the modes of proteasomal action should lead to the development of beneficial therapeutic and diagnostic strategies in the future. (Lab Invest 2002, 82:965-980).
BACKGROUND.: Despite the importance of non-Hodgkin lymphoma (NHL) as a posttransplant complication, the relationship between NHL and recipient seropositivity for Epstein-Barr virus (EBV) or cytomegalovirus (CMV) is incompletely understood. METHODS.: Kidney, heart, and liver transplant recipients reported to the Collaborative Transplant Study with known pretransplant EBV and CMV serostatus were analyzed in terms of clinically manifest NHL. Cox multivariate regression analysis was performed to account for a wide range of possible confounders. RESULTS.: In total, 18,682 kidney, 2042 heart, and 2616 liver transplant recipients were analyzed. Regardless of age, pretransplant EBV serostatus was significantly associated with risk of NHL in kidney transplant recipients (P<0.001). There was no significant difference in lymphoma rates according to CMV and CMV serostatus among EBV and EBV recipients (log-rank P=0.55 and P=0.57, respectively), but hospitalization for CMV disease during year 1 posttransplant was associated with subsequent NHL (hazard ratio [HR] 6.1; 95% confidence interval [CI] 2.0-18.4; P=0.001). EBV serostatus was also associated with increased risk of NHL in heart transplant patients (HR 3.6; 95% CI 1.1-11.3; P=0.031) but, contrary to expectation, not in liver recipients (HR 0.6; 95% CI 0.1-1.7; P=0.32). CONCLUSIONS.: In view of the striking increase in risk of NHL in EBV kidney transplant recipients of all ages, EBV serostatus should be determined pretransplant in all age groups. CMV serostatus was not independently associated with risk of NHL after kidney transplantation. Surprisingly, in liver transplantation, the risk of NHL was virtually unaffected by EBV serostatus.
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