62 research outputs found
Reverse the Resistance to PARP Inhibitors
One of the DNA repair machineries is activated by Poly (ADP-ribose) Polymerase (PARP) enzyme. Particularly, this enzyme is involved in repair of damages to single-strand DNA, thus decreasing the chances of generating double-strand breaks in the genome. Therefore, the concept to block PARP enzymes by PARP inhibitor (PARPi) was appreciated in cancer treatment. PARPi has been designed and tested for many years and became a potential supplement for the conventional chemotherapy. However, increasing evidence indicates the appearance of the resistance to this treatment.
Specifically, cancer cells may acquire new mutations or events that overcome the positive effect of these drugs. This paper describes several molecular mechanisms of PARPi resistance which were reported most recently, and summarizes some strategies to reverse this type of drug resistance
A Scorpion Defensin BmKDfsin4 Inhibits Hepatitis B Virus Replication in Vitro
Hepatitis B virus (HBV) infection is a major worldwide health problem which can cause
acute and chronic hepatitis and can significantly increase the risk of liver cirrhosis and primary
hepatocellular carcinoma (HCC). Nowadays, clinical therapies of HBV infection still mainly rely on
nucleotide analogs and interferons, the usage of which is limited by drug-resistant mutation or side
effects. Defensins had been reported to effectively inhibit the proliferation of bacteria, fungi, parasites
and viruses. Here, we screened the anti-HBV activity of 25 scorpion-derived peptides most recently
characterized by our group. Through evaluating anti-HBV activity and cytotoxicity, we found that
BmKDfsin4, a scorpion defensin with antibacterial and Kv1.3-blocking activities, has a comparable
high inhibitory rate of both HBeAg and HBsAg in HepG2.2.15 culture medium and low cytotoxicity
to HepG2.2.15. Then, our experimental results further showed that BmKDfsin4 can dose-dependently
decrease the production of HBV DNA and HBV viral proteins in both culture medium and cell lysate.
Interestingly, BmKDfsin4 exerted high serum stability. Together, this study indicates that the scorpion
defensin BmKDfsin4 also has inhibitory activity against HBV replication along with its antibacterial
and potassium ion channel Kv1.3-blocking activities, which shows that BmKDfsin4 is a uniquely
multifunctional defensin molecule. Our work also provides a good molecule material which will be
used to investigate the link or relationship of its antiviral, antibacterial and ion channel–modulating
activities in the future
OMICRON N501Y MUTATION AMONG SARS-COV-2 LINEAGES: IN SILICO ANALYSIS OF POTENT BINDING TO TYROSINE KINASE AND HYPOTHETICAL REPURPOSED MEDICINE
Variants of SARS-CoV-2 lineages including the most recently circulated Omicron, and previous pandemic
B.1.351, B.1.1.7, which have been public concerns, contain a N501Y mutation located in the spike receptor
binding domain. However, the potential interactions with host cells linking N501Y mutation to pathogenic
relevance remain elusive. Recently, we and others report that kinases such as PI3K/AKT signaling are essential in
SARS-CoV-2 entry. Here we analyzed the predicted potential kinases interacting with the mutation. Bioinformatics
tools including structure-prediction based molecular docking analysis were applied. We found kinases
such as EGFR might potentially act as new factors involving the N501Y mutation binding through possible
phosphorylation at Y501 and enhanced affinity in certain variants. To our surprise, the Omicron receptor binding
domain harboring N501Y mutation did not enhance binding to EGFR which might be due to the mutations of
charged polar to uncharged polar side chains located on the interaction interfaces. Similarly, potent gains of
phosphorylation in B.1.351 and B.1.1.7 by mutations were predicted and interaction networks were analyzed
with enrichment of pathways. Given kinases might be elevated in cancer patients, the N501Y mutation containing
lineages may be possibly much more infectious and additional care for cancer management might be
taken into consideration by precision prevention, therapy or recovery
HONGHUA EXTRACT MEDIATED POTENT INHIBITION OF COVID‑19 HOST CELL PATHWAYS
Honghua (Carthami flos) and Xihonghua (Croci stigma) have been used in anti-COVID-19 as Traditional
Chinese Medicine, but the mechanism is unclear. In this study, we applied network pharmacology
by analysis of active compounds and compound-targets networks, enzyme kinetics assay, signaling
pathway analysis and investigated the potential mechanisms of anti-COVID-19. We found that both
herbs act on signaling including kinases, response to inflammation and virus. Moreover, crocin likely
has an antiviral effect due to its high affinity towards the human ACE2 receptor by simulation. The
extract of Honghua and Xihonghua exhibited nanozyme/herbzyme activity of alkaline phosphatase,
with distinct fluorescence. Thus, our data suggest the great potential of Honghua in the development
of anti-COVID-19 agents
LUCIDENIC ACID A INHIBITS THE BINDING OF HACE2 RECEPTOR WITH SPIKE PROTEIN TO PREVENT SARS-COV-2 INVASION
High infection caused by mutations of SARS-CoV-2 calls for new prevention strategy. Ganoderma lucidum known
as a superior immunoenhancer exhibits various antiviral effects, whether it can resist SARS-CoV-2 remains unclear.
Herein, virtual screening combined with in vitro hACE2 inhibition assays were used to investigate its anti
SARS-CoV-2 effect. Potential 54 active components, 80 core targets and 20 crucial pathways were identified by
the component-target-pathway network. The binding characters of these components to hACE2 and its complexes
with spike protein including omicron variant was analyzed by molecular docking. Lucidenic acid A was
selected as the top molecule with high affinity to all receptors by forming hydrogen bonds. Molecular dynamics
simulation showed it had good binding stability with the receptor proteins. Finally, in vitro FRET test demonstrated
it inhibited the hACE2 activity with IC50 2 μmol/mL. Therefore, lucidenic acid A can prevent the virus
invasion by blocking hACE2 binding with SARS-CoV-2
T Cell Receptor (TCR)-Induced PLC-γ1 Sumoylation via PIASxβ and PIAS3 SUMO E3 Ligases Regulates the Microcluster Assembly and Physiological Function of PLC-γ1
The SUMO modification system plays an important role in T cell activation, yet how sumoylation regulates TCR-proximal signaling remains largely unknown. We show here that Phospholipase C-γ1 (PLC-γ1) is conjugated by SUMO1 at K54 and K987 upon TCR stimulation and that K54 sumoylation is pivotal for PLC-γ1-mediated T cell activation. We further demonstrate that TCR-induced K54 sumoylation of PLC-γ1 significantly promotes the formation of PLC-γ1 microclusters and the association of PLC-γ1 with the adaptor proteins SLP76 and Gads, but only slightly affects the phosphorylation of PLC-γ1 on Y783, which determines the enzyme catalytic activity. Moreover, upon TCR stimulation, the SUMO E3 ligases PIASxβ and PIAS3 both interact with PLC-γ1 and cooperate to sumoylate PLC-γ1, facilitating the assembly of PLC-γ1 microclusters. Together, our findings reveal a critical role of PLC-γ1 K54 sumoylation in PLC-γ1 microcluster assembly that controls PLC-γ1-mediated T cell activation, suggesting that sumoylation may have an important role in the microcluster assembly of TCR-proximal signaling proteins
NETWORK PHARMACOLOGY WITH EXPERIMENTAL INVESTIGATION OF THE MECHANISMS OF RHIZOMA POLYGONATI AGAINST PROSTATE CANCER WITH ADDITIONAL HERBZYMATIC ACTIVITY
A combination therapy of Rhizoma Polygonati (RP) with goji (Lycium chinense) has earned a long history in the prescriptions to promote male health. However, the mechanisms at both molecular and nanoscale quantum levels are unclear. Here, we found that processed RP extract induces apoptosis and cell cycle arrest in cancer cells, thereby inhibiting prostate cancer cell proliferation enhanced by processed goji extract associated with an augment of the nanoscale herbzyme of phosphatase. For network pharmacology analysis, RP-induced PI3K-AKT pathways are essential for both benign prostatic hyperplasia and prostate cancer, and the RP/goji combination induces potent pathways which include androgen and estrogen response, kinase regulation, apoptosis, and prostate cancer singling. In addition, the experimental investigation showed that the prostate cancer cells are sensitive to RP extract for inhibiting colony formation. Finally, the natural compound baicalein found in RP ingredients showed a linked activity of top-ranked signaling targets of kinases including MAPK, AKT, and EGFR by the database of cMAP and HERB. Thus, both the nanozyme and ingredients might contribute to the RP in anti-prostate cancer which can be enhanced by goji extract. The proposed nanoscale RP extract might be of significance in developing novel anti-prostate cancer agents by combining goji compositions and targeted therapy compounds
Nuclear MET requires ARF and is inhibited by carbon nanodots through binding to phospho-tyrosine in prostate cancer
Nuclear receptor tyrosine kinases (nRTKs) are aberrantly upregulated in many types of cancers, but the regulation of nRTK remains unclear. We previously showed androgen deprivation therapy (ADT) induces nMET in castration-resistant prostate cancer (CRPC) specimens. Through gene expression microarray profiles reanalysis, we identified that nMET signaling requires ARF for CRPC growth in Pten/Trp53 conditional knockout mouse model. Accordingly, aberrant MET/nMET elevation correlates with ARF in human prostate cancer (PCa) specimens. Mechanistically, ARF elevates nMET through binding to MET cytoplasmic domain to stabilize MET. Furthermore, carbon nanodots resensitize cancer cells to MET inhibitors through DNA damage response. The inhibition of phosphorylation by carbon nanodots was identified through binding to phosphate group of phospho-tyrosine via computational calculation and experimental assay. Thus, nMET is essential to precision therapy of MET inhibitor. Our findings reveal for the first time that targeting nMET axis by carbon nanodots can be a novel avenue for overcoming drug resistance in cancers especially prostate cancer
URGENCY OF COVID-19 VACCINATION IN ADOLESCENTS: ANDROGEN AND ESTROGEN RECEPTORS VIEW
Given that international and domestic flights now require only adults
to be vaccinated or have negative PCR test results, adolescents’ vacci nation of COVID-19 for safe travel needs urgent consideration. As adults
benefit from vaccination policies that give them priority, now children
may become a source of infection transmission leading to new COVID-19
wave outbreaks [1].
With the new cases surging, 12–17 years old adolescents are rec ommended for vaccination (https://www.cdc.gov/coronavirus/20
19-ncov/vaccines/recommendations/adolescents.html). However, the
hesitation and decreasing roll-out make further worrisome because ad olescents’ immune system development or the elevation of hormones
may let them become more vulnerable to the infection of SARS-CoV-2
and emerging variants
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