15 research outputs found
Fatty Acids Derived from Royal Jelly Are Modulators of Estrogen Receptor Functions
Royal jelly (RJ) excreted by honeybees and used as a nutritional and medicinal agent has estrogen-like effects, yet the compounds mediating these effects remain unidentified. The possible effects of three RJ fatty acids (FAs) (10-hydroxy-2-decenoic-10H2DA, 3,10-dihydroxydecanoic-3,10DDA, sebacic acid-SA) on estrogen signaling was investigated in various cellular systems. In MCF-7 cells, FAs, in absence of estradiol (E2), modulated the estrogen receptor (ER) recruitment to the pS2 promoter and pS2 mRNA levels via only ERβ but not ERα, while in presence of E2 FAs modulated both ERβ and ERα. Moreover, in presence of FAs, the E2-induced recruitment of the EAB1 co-activator peptide to ERα is masked and the E2-induced estrogen response element (ERE)-mediated transactivation is inhibited. In HeLa cells, in absence of E2, FAs inhibited the ERE-mediated transactivation by ERβ but not ERα, while in presence of E2, FAs inhibited ERE-activity by both ERβ and ERα. Molecular modeling revealed favorable binding of FAs to ERα at the co-activator-binding site, while binding assays showed that FAs did not bind to the ligand-binding pocket of ERα or ERβ. In KS483 osteoblasts, FAs, like E2, induced mineralization via an ER-dependent way. Our data propose a possible molecular mechanism for the estrogenic activities of RJ's components which, although structurally entirely different from E2, mediate estrogen signaling, at least in part, by modulating the recruitment of ERα, ERβ and co-activators to target genes
Immunomodulators for immunocompromised patients hospitalized for COVID-19: a meta-analysis of randomized controlled trials
BACKGROUND: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19.METHODS: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care).FINDINGS: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61-1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64-1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09-0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality.INTERPRETATION: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19.FUNDING: Hellenic Foundation for Research and Innovation.</p
Plitidepsin: Mechanisms and Clinical Profile of a Promising Antiviral Agent against COVID-19
Current standard treatment of COVID-19 lacks in effective antiviral options. Plitidepsin, a cyclic depsipeptide authorized in Australia for patients with refractory multiple myeloma, has recently emerged as a candidate anti-SARS-CoV-2 agent. The aim of this review was to summarize current knowledge on plitidepsin’s clinical profile, anti-tumour and anti-SARS-CoV-2 mechanisms and correlate this with available or anticipated, preclinical or clinical evidence on the drug’s potential for COVID-19 treatment.PubMed, Scopus, CENTRAL, clinicaltrials.gov, medRxiv and bioRxiv databases were searched.Plitidepsinexerts its anti-tumour and antiviral properties primarily through acting on isoforms of the host cell’s eukaryotic-translation-elongation-factor-1-alpha (eEF1A). Through inhibiting eEF1A and therefore translation of necessary viral proteins, it behaves as a “host-directed” anti-SARS-CoV-2 agent. In respect to its potent anti-SARS-CoV-2 properties, the drug has demonstrated superior ex vivo efficacy compared to other host-directed agents and remdesivir, and it might retain its antiviral effect against the more transmittable B.1.1.7 variant. Its well-studied safety profile, also in combination with dexamethasone, may accelerate its repurposing chances for COVID-19 treatment. Preliminary findings in hospitalized COVID-19 patients, have suggested potential safety and efficacy of plitidepsin, in terms of viral load reduction and clinical resolution. However, the still incomplete understanding of its exact integration into host cell–SARS-CoV-2 interactions, its intravenous administration exclusively purposing it for hospital settings the and precocity of clinical data are currently considered its chief deficits. A phase III trial is being planned to compare the plitidepsin–dexamethasone regimen to the current standard of care only in moderately affected hospitalized patients. Despite plitidepsin’s preclinical efficacy, current clinical evidence is inadequate for its registration in COVID-19 patients.Therefore, multicentre trials on the drug’s efficacy, potentially also studying populations of emerging SARS-CoV-2 lineages, are warranted
Plitidepsin: Mechanisms and Clinical Profile of a Promising Antiviral Agent against COVID-19
Current standard treatment of COVID-19 lacks in effective antiviral
options. Plitidepsin, a cyclic depsipeptide authorized in Australia for
patients with refractory multiple myeloma, has recently emerged as a
candidate anti-SARS-CoV-2 agent. The aim of this review was to summarize
current knowledge on plitidepsin’s clinical profile, anti-tumour and
anti-SARS-CoV-2 mechanisms and correlate this with available or
anticipated, preclinical or clinical evidence on the drug’s potential
for COVID-19 treatment.PubMed, Scopus, CENTRAL, clinicaltrials.gov,
medRxiv and bioRxiv databases were searched.Plitidepsinexerts its
anti-tumour and antiviral properties primarily through acting on
isoforms of the host cell’s
eukaryotic-translation-elongation-factor-1-alpha (eEF1A). Through
inhibiting eEF1A and therefore translation of necessary viral proteins,
it behaves as a “host-directed” anti-SARS-CoV-2 agent. In respect to
its potent anti-SARS-CoV-2 properties, the drug has demon-strated
superior ex vivo efficacy compared to other host-directed agents and
remdesivir, and it might retain its antiviral effect against the more
transmittable B.1.1.7 variant. Its well-studied safety profile, also in
combination with dexamethasone, may accelerate its repurposing chances
for COVID-19 treatment. Preliminary findings in hospitalized COVID-19
patients, have suggested potential safety and efficacy of plitidepsin,
in terms of viral load reduction and clinical resolution. However, the
still incomplete understanding of its exact integration into host
cell-SARS-CoV-2 interactions, its intravenous administration exclusively
purposing it for hospital settings the and precocity of clinical data
are currently considered its chief deficits. A phase III trial is being
planned to compare the plitidepsin-dexamethasone regimen to the current
standard of care only in moderately affected hospitalized patients.
Despite plitidepsin’s preclinical efficacy, current clinical evidence is
inadequate for its registration in COVID-19 patients.Therefore,
multicentre trials on the drug’s efficacy, potentially also studying
populations of emerging SARS-CoV-2 lineages, are warranted
Senescence in HBV-, HCV- and NAFLD- Mediated Hepatocellular Carcinoma and Senotherapeutics: Current Evidence and Future Perspective
Simple Summary Recent scientific discoveries identify cell senescence as
pivotal in hepatocellular cancer (HCC) biology. Specifically, hepatitis
B virus (HBV), hepatitis C virus (HCV) and non-alcoholic fatty liver
disease (NAFLD) are major risk factors for HCC occurrence and it seems
that cell senescence serves as a mediator. Furthermore, senescence is
also implicated in HCC therapy resistance. Therefore, understanding and
harnessing senescence (via senotherapeutics) seems highly important
towards the discovery of new preventative and treatment strategies.
Herein, we review the role of cell senescence in HBV-, HCV- and NAFLD-
mediated HCC, and also explore the possible place of senotherapeutics in
the management of HCC. By shining the spotlight on senescence-mediated
HCC, we aim to inspire future research towards this rapidly evolving and
highly promising field. Cell senescence constitutes a physiological
process that serves as protection from malignant transformation of
cells. However, recent scientific discoveries also identify cell
senescence as pivotal in hepatocellular cancer (HCC) biology. The review
herein aimed to accumulate evidence on senescence as a mediator of HCC
occurrence in hepatitis B (HBV), C (HCV) virus infections, and
non-alcoholic fatty liver disease (NAFLD). In HBV infection, the
carcinogenic HBV X protein frequently mutates during chronic infection,
and subsequently exhibits different effects on senescence. In HCV
infection, senescent non-functional T-cells do not effectively clear
pre-malignant hepatocytes. Furthermore, the HCV Core protein inhibits
the occurrence of normal stress-induced hepatocyte senescence, allowing
damaged cells to maintain their proliferative potential. In
NAFLD-mediated HCC, current data point towards the gut microbiome and
hepatic stellate cell senescence. Additionally, senescence contributes
in the development of resistance in targeted therapies, such as
sorafenib. Finally, the promising role of senotherapeutics in HCC was
also explored. Overall, although we may still be at a primitive stage in
fully unraveling the role of senescence in cancer, it seems that
understanding and harnessing senescence may have the potential to
revolutionize the way we treat hepatocellular cancer