Structural features of coronavirus SARS-CoV-2 spike protein: Targets for vaccination.

Various human pathogenic viruses employ envelope glycoproteins for host cell receptor recognition and binding, membrane fusion and viral entry. The spike (S) glycoprotein of betacoronavirus SARS-CoV-2 is a homotrimeric class I fusion protein that exists in a metastable conformation for cleavage by host cell proteases furin and TMPRSS2, thereby undergoing substantial structural rearrangement for ACE2 host cell receptor binding and subsequent viral entry by membrane fusion. The S protein is densely decorated with N-linked glycans protruding from the trimer surface that affect S protein folding, processing by host cell proteases and the elicitation of humoral immune response.

Novel Drugs Targeting the SARS-CoV-2/COVID-19 Machinery.

Like other human pathogenic viruses, coronavirus SARS-CoV-2 employs sophisticated macromolecular machines for viral host cell entry, genome replication and protein processing. Such machinery encompasses SARS-CoV-2 envelope spike (S) glycoprotein required for host cell entry by binding to the ACE2 receptor, viral RNA-dependent RNA polymerase (RdRp) and 3-chymotrypsin-like main protease (3Clpro/Mpro). Under the pressure of the accelerating COVID-19 pandemic caused by the outbreak of SARS-CoV-2 in Wuhan, China in December 2019, novel and repurposed drugs were recently designed and identified for targeting the SARS-CoV-2 reproduction machinery, with the aim to limit the spread of SARS-CoV-2 and morbidity and mortality due to the COVID-19 pandemic.

Candidate drugs against SARS-CoV-2 and COVID-19.

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.

The "Big Five" Phytochemicals Targeting Cancer Stem Cells: Curcumin, EGCG, Sulforaphane, Resveratrol and Genistein.

Cancer stem cells (CSCs) constitute a subpopulation of tumor cells that possess self-renewal and tumor initiation capacity, and the ability to give rise to the heterogeneous lineages of cancer cells that comprise the tumor. CSCs exhibit intrinsic mechanisms of resistance to virtually all conventional cancer therapeutics, allowing them to survive current cancer therapies and to initiate tumor recurrence and metastasis. Different pathways and mechanisms that confer resistance and survival of CSCs, including activation of the Wnt/β- catenin, Sonic Hedgehog, Notch, PI3K/Akt/mTOR and STAT3 signaling pathways, expression of aldehyde dehydrogenase 1 (ALDH1) and oncogenic microRNAs, and acquisition of epithelial-mesenchymal transition (EMT), have been identified recently.

Monoclonal antibodies against human cancer stem cells.

Cancer stem cells (CSCs) are a subpopulation of tumor cells that display self-renewal and tumor initiation capacity and the ability to give rise to the heterogenous lineages of cancer cells that comprise the tumor. CSCs exhibit intrinsic mechanisms of resistance to modern cancer therapeutics, allowing them to survive current cancer therapies and to initiate tumor recurrence and metastasis. Various cell surface and transmembrane proteins expressed by CSCs, including CD44, CD47, CD123, EpCAM (CD326), CD133, IGF receptor I, and proteins of the Notch and Wnt signaling pathways have been identified.

Salinomycin as a drug for targeting human cancer stem cells.

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 in cancer: A new mission for an old agent.

Salinomycin is a monocarboxylic polyether ionophore isolated from Streptomyces albus that has been used for more than 30 years as an agricultural antibiotic to prevent coccidiosis in poultry and to improve nutrient absorption and feed efficiency in ruminants and swine. As a inonophore with strict selectivety for alkali ions and a strong preference for potassium, salinomycin interferes with transmembrane potassium potential and promotes the efflux of K+ ions from mitochondria and cytoplasm. Salinomycin has recently been shown to kill human cancer stem cells and to inhibit breast cancer growth and metastasis in mice.

Salinomycin overcomes ABC transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like KG-1a cells.

Leukemia stem cells are known to exhibit multidrug resistance by expression of ATP-binding cassette (ABC) transporters which constitute transmembrane proteins capable of exporting a wide variety of chemotherapeutic drugs from the cytosol. We show here that human promyeloblastic leukemia KG-1a cells exposed to the histone deacetylase inhibitor phenylbutyrate resemble many characteristics of leukemia stem cells, including expression of functional ABC transporters such as P-glycoprotein, BCRP and MRP8. Consequently, KG-1a cells display resistance to the induction of apoptosis by various chemotherapeutic drugs.

Increased peripheral blood leukocyte subsets with regulatory phenotype in clinically stable long-term HIV-infected hemophilia patients on HAART may be beneficial and contribute to a decrease in autoimmunity.

After initiation of highly-active antiretroviral therapy (HAART), long-term HIV-infected hemophilia patients have been shown to lose autoantibodies against CD4(+) peripheral blood leukocytes (PBL), suggesting that HAART induces autoimmunity-blocking mechanisms. We compared cytokine levels and subpopulations of lymphocytes and dendritic cells (DC) in the blood of 40 long-term HIV(+) patients with those of 13 long-term HIV(-) hemophilia patients; 23 HIV(+) patients had a detectable retroviral load. Cell subsets were determined using flow cytometry and cytokine levels were measured using ELISA.

Decreasing plasma soluble IL-1 receptor antagonist and increasing monocyte activation early post-transplant may be involved in pathogenesis of delayed graft function in renal transplant recipients.

Delayed graft function (DGF) increases the risk of acute allograft rejection and may affect long-term graft survival. We compared pre-transplant, early post-transplant, and late post-transplant serum creatinine (Cr) and plasma levels of neopterin, cytokines, and cytokine receptors/antagonists in patients with DGF (n = 39), slow graft function (SGF) (n = 43), or immediate graft function (IGF) (n = 30). Three and eight days post-transplant, plasma neopterin (p < 0.

Urinary proinflammatory cytokine response in renal transplant recipients with polyomavirus BK viruria.

Background: Polyomavirus BK (BKV) has emerged as an important complication after kidney transplantation. BKV-associated nephropathy develops in approximately 5% to 8% of renal transplant recipients, and its prognosis is poor. The relationship between urine cytokines and BK viruria in kidney recipients has not been defined.

Epidemiology of pretransplant EBV and CMV serostatus in relation to posttransplant non-Hodgkin lymphoma.

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.

Salinomycin induces apoptosis and overcomes apoptosis resistance in human cancer cells.

Salinomycin is a polyether antibiotic isolated from Streptomyces albus that acts in different biological membranes as a ionophore with a preference for potassium. It is widely used as an anticoccidial drug in poultry and is fed to ruminants to improve nutrient absorption and feed efficiency. Salinomycin has recently been shown to selectively deplete human breast cancer stem cells from tumorspheres and to inhibit breast cancer growth and metastasis in mice.

Proteasome inhibition activates the mitochondrial pathway of apoptosis in human CD4+ T cells.

We have previously shown that inhibition of the proteolytic activity of the proteasome induces apoptosis and suppresses essential functions of activated human CD4(+) T cells, and we report now the detailed mechanisms of apoptosis following proteasome inhibition in these cells. Here we show that proteasome inhibition by bortezomib activates the mitochondrial pathway of apoptosis in activated CD4(+) T cells by disrupting the equilibrium of pro-apoptotic and anti-apoptotic proteins at the outer mitochondrial membrane (OMM) and by inducing the generation of reactive oxygen species (ROS). Proteasome inhibition leads to accumulation of pro-apoptotic proteins PUMA, Noxa, Bim and p53 at the OMM.

Association of high IFN-gamma plasma levels with low B-cell counts in renal transplant recipients with stable long-term graft function.

Recently, we reported that patients with long-term stable good graft function had higher interferon-gamma (IFN-gamma) and lower IL-4 plasma levels late as compared with early post-transplant. These patients had more often detectable CD3(+)CD4(+)CD25(+)IFN-gamma(+)Foxp3(+) peripheral blood lymphocytes (PBL) late post-transplant than patients with impaired graft function. We therefore speculated that high plasma IFN-gamma late post-transplant might contribute to the maintenance of graft acceptance.

Helenalin suppresses essential immune functions of activated CD4+ T cells by multiple mechanisms.

Helenalin is a naturally occuring sesquiterpene lactone extracted from Arnica montana and Arnica chamissonis ssp. foliosa. Helenalin and its derivatives are known for anti-cancer and anti-inflammatory effects via inhibiting NF-kappaB and telomerase activity and impairing protein and DNA synthesis, suggesting that helenalin is a potential candidate for the treatment of deregulated and unwanted T cell-mediated immune responses.

Association of pretransplant soluble glycoprotein 130 (sgp130) plasma levels and posttransplant acute tubular necrosis in renal transplant recipients.

Objective: Previously, we reported that high pretransplant sIL-6R plasma levels are associated with posttransplant acute tubular necrosis (ATN). In this study, we examined associations of pretransplant plasma levels of sgp130 with ATN.

Patients And Methods: Pretransplant serum creatinine (Cr), plasma neopterin, and sgp130 levels were studied in 105 first renal transplant recipients who received grafts from deceased donors.

Role of ubiquitin ligases in neural stem and progenitor cells.

Ubiquitin ligases are central components of the ubiquitin-proteasome system (UPS), the major machinery for regulated proteolysis in eukaryotic cells. Proteins essential for regulating development, differentiation, proliferation, cell cycling, apoptosis, gene transcription, and signal transduction undergo posttranslational processing via selection by ubiquitin ligases and subsequent controlled proteolysis by the 26S proteasome, the proteolytic unit of the UPS. Neural stem cells (NSCs) are self-renewing multipotent cells of the embryonic and adult mammalian central nervous system.

Dysregulated cytokine responses during cytomegalovirus infection in renal transplant recipients.

Objective: Pre- and posttransplant predisposing factors for cytomegalovirus (CMV) activation and disease are not well defined. The aim of this study was to examine whether there are differences in plasma cytokine levels pretransplant, before and during CMV replication in renal transplant recipients.

Material And Methods: We studied 76 renal transplant recipients in whom CMV-DNA was studied at regular intervals posttransplant.

HMG-CoA reductase inhibitor simvastatin overcomes bortezomib-induced apoptosis resistance by disrupting a geranylgeranyl pyrophosphate-dependent survival pathway.

Simvastatin is a competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway required for the biosynthesis of cholesterol and higher isoprenoids such as geranylgeranyl pyrophosphate (GGPP). Apart from its capacity to lower cholesterol plasma levels and to protect against cardiovascular disease, simvastatin induces apoptosis in various cancer cells. We have generated human Namalwa Burkitt lymphoma cells that display general apoptosis resistance and hyperproliferation due to increased expression and proteolytic activity of 26S proteasomes in response to continuous treatment of the cells with the proteasome inhibitor bortezomib.

Observational support for an immunoregulatory role of CD3+CD4+CD25+IFN-gamma+ blood lymphocytes in kidney transplant recipients with good long-term graft outcome.

There is evidence that interferon-gamma (IFN-gamma)-dependent interactions of dendritic cell (DC), T regulatory (Treg), and T suppressor (Ts) subpopulations contribute to allograft acceptance. We measured DC subsets, CD3+CD4+CD25+ (Treg phenotype) and CD3+CD8+CD28(-) (Ts phenotype) peripheral blood lymphocytes (PBL) expressing Foxp3, Th1 or Th2 cytokines, peripheral T- and B-cell counts, and plasma cytokines in 33 kidney transplant recipients with a serum creatinine of < or =1.8 mg/dl and 32 recipients with a serum creatinine of > or =2.

Proteasome inhibition suppresses essential immune functions of human CD4+ T cells.

The proteasome constitutes the central proteolytic component of the highly conserved ubiquitin-proteasome system, which is required for the maintenance and regulation of basic cellular processes, including differentiation, proliferation, cell cycling, gene transcription and apoptosis. Here we show that inhibition of proteasomal proteolytic activity by the proteasome inhibitors bortezomib and lactacystin suppresses essential immune functions of human CD4(+) T cells activated by allogeneic dendritic cells (DCs). In activated CD4(+) T cells, proteasome inhibition induces apoptosis accompanied by rapid accumulation and stabilization of the tumour suppressor protein p53.

Normal or even increased dendritic cell and peripheral blood lymphocyte subsets with regulatory phenotype in clinically stable long-term HIV-infected patients with hemophilia on highly active antiretroviral therapy.

Defective regulatory components of the immune system seem to contribute to HIV disease progression. Highly active antiretroviral therapy (HAART) was reported to restore malfunctioning immunologic regulatory components. To corroborate this hypothesis, we studied different dendritic-cell (DC) and T-cell subsets with regulatory phenotype in 41 clinically stable patients with hemophilia more than 25 years after infection with HIV and 10 years after initiation of HAART.

Association of IL-12+ DC with High CD3+CD4-DR+ lymphocyte counts in long-term HIV-infected hemophilia patients with clinically stable disease.

We investigated dendritic cell (DC) subsets as well as cellular and humoral immune parameters in long-term HIV-infected hemophilia patients with clinically stable disease. DC subsets were determined by their function to produce either IL-10 or IL-12. CD11c(+)CD83(+)CD40(+)IL-10(+) and CD11c(+)CD83(+)CD40(+)IL-12(+) DC were studied in freshly obtained blood samples of 28 HIV(+) and 15 HIV(-) patients and 39 healthy controls using four-color flow cytometry, and were analyzed in relation to blood lymphocyte subpopulation counts, proportions of IgG-coated CD4(+) blood lymphocytes, neopterin, and HIV-1 viral load in the plasma, and in vitro responses of patient lymphocytes to mitogens.