Current Issue : October-December
Volume : 2022
Issue Number : 4
Articles : 5 Articles
Some viruses contain mimics of host chemokine receptors that influence host immunity;
however, such viral mimics have not yet been reported for severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2). In this study, I focused on C-X-C motif chemokine receptor 2 (CXCR2) as
a candidate chemokine receptor exploited by SARS-CoV-2. Similarities between the extracellular
domain (ECD) of human CXCR2 and the SARS-CoV-2 spike glycoprotein S1 (CoV2S1) were investigated.
Flow cytometric analysis of healthy donor-derived peripheral leukocytes was performed
to examine the cross-reactivity between specific monoclonal antibodies against these two proteins.
The results showed that CR3022, a monoclonal antibody to the receptor binding domain of CoV2S1,
recognized the CXCR2 ECD, and a murine monoclonal antibody to human CXCR2 recognized recombinant
CoV2S1. This reciprocal cross-reactivity suggests that CoV2S1 harbors a mimic of the
Cisplatin has been widely used in cancer treatments. Recent evidence indicates that
adenine has potential anticancer activities against various types of cancers. However, the effects of
the combination of adenine and cisplatin on hepatocellular carcinoma (HCC) cells remain sketchy.
Here, our objective was to elucidate the anticancer activity of adenine in combination with cisplatin
in HCC cells and its mechanistic pathways. Cell viability and cell cycle progression were assessed
by the SRB assay and flow cytometry, respectively. Apoptosis was demonstrated by PI/annexin V
staining and flow cytometric analysis. Protein expression, signaling cascade, and mRNA expression
were analyzed byWestern blotting and quantitative RT-PCR, respectively. Our results showed that
adenine jointly potentiated the inhibitory effects of cisplatin on the cell viability of SK-Hep1 and
Huh7 cells. Further investigation showed that adenine combined with cisplatin induced higher S
phase arrest and apoptosis in HCC cells. Mechanically, adenine induced AMPK activation, reduced
mTOR phosphorylation, and increased p53 and p21 levels. The combination of adenine and cisplatin
synergistically reduced Bcl-2 and increased PUMA, cleaved caspase-3, and PARP in HCC cells.
Adenine also upregulated the mRNA expression of p53, p21, PUMA, and PARP, while knockdown
of AMPK reduced the increased expression of these genes. Furthermore, adenine also induced the
activation of p38 MAPK through AMPK signaling, and the inhibition of p38 MAPK reduced the
apoptosis of HCC cells with exposure to adenine combined with cisplatin. Collectively, these findings
reveal that the combination of adenine and cisplatin synergistically enhances apoptosis of HCC cells,
which may be attributed to the AMPK-mediated p53/p21 and p38 MAPK cascades. It suggests that
adenine may be a potential adjuvant for the treatment of HCC in combination with cisplatin....
Purpose: To assess the expression levels of YAP and TAZ in patient-derived HCC tissue
and identify the effects of YAP/TAZ inhibition depending on the baseline YAP/TAZ expression
when combined with sorafenib using a patient-derived multicellular tumor spheroid (MCTS) model.
Methods: Primary HCC cell lines were established from patient-derived tissue. Six patient-derived
HCC cell lines were selected according to YAP/TAZ expression on Western blot: high, medium, low.
Then, MCTS was generated by mixing patient-derived HCC cells and stroma cells (LX2, WI38, and
HUVECs) and YAP/TAZ expression was assessed usingWestern blot. Cell viability of MCTS upon
48 h of drug treatment (sorafenib, sorafenib with CA3 0.1 μM, and CA3 (novel YAP1 inhibitor)) was
analyzed. Results: Out of six patient-derived HCC cell lines, cell lines with high YAP/TAZ expression
at the MCTS level responded more sensitively to the combination therapy (Sorafenib + CA3 0.1 μM)
despite the potent cytotoxic effect of CA3 exhibited in all of the patient-derived HCCs. Conclusion:
Targeting YAP/TAZ inhibition using the novel YAP1 inhibitor CA3 could be a promising therapeutic
strategy to enhance sensitivity to sorafenib especially in HCCs with high YAP/TAZ expression
Extramammary Paget’s disease (EMPD) is an adenocarcinoma that develops mainly in the
genital region of older adults. The prognosis for advanced EMPD is almost always poor; thus, novel
therapeutic strategies need to be developed. HER2-targeted antibody–drug conjugates (ADCs) such
as trastuzumab emtansine and trastuzumab deruxtecan have proven effective against HER2-positive
breast cancers; however, no studies have addressed HER2-targeted ADCs as treatments for EMPD.
We examine the efficacy of ADCs against an EMPD patient-derived xenograft (PDX) model harboring
pathogenic ERBB2 mutations and investigate the expression levels of HER2 using EMPD clinical
samples. Trastuzumab emtansine or trastuzumab deruxtecan was administered intravenously to
tumor-bearing NOD/Scid mice. Treatment with trastuzumab emtansine or trastuzumab deruxtecan
was found to significantly regress EMPD-PDX tumors in only seven days, with no recurrence observed
for 10 weeks. EMPD tumors extracted 48 h after drug administration revealed the TUNEL-positive
ratio to be significantly higher for the HER2-targeted ADC-treated tumors than for the control tumors.
EMPD patients’ clinical samples revealed a significant correlation between HER2 positivity and
invasion, suggesting that HER2 status is associated with tumor progression. Our results suggest
that HER2-targeted ADCs could be novel and promising treatment options for patients with EMPD,
especially in ERBB2-mutant or ERBB2-overexpressed cases....
It has been shown that citrus flavanone naringenin and its prenyl derivative 8-prenylnaringenin
(8-PN) possess various pharmacological activities in in vitro and in vivo models. Interestingly, it
has been proposed that prenylation can enhance biological potentials, including the estrogen-like
activities of flavonoids. The objective of this study was to investigate the anti-diabetic potential and
molecular mechanism of 8-PN in streptozotocin (STZ)-induced insulin-deficient diabetic mice in
comparison with naringenin reported to exhibit hypoglycemic effects. The oral administration of
naringenin and 8-PN ameliorated impaired glucose homeostasis and islet dysfunction induced by
STZ treatment. These protective effects were associated with the suppression of pancreatic β-cell
apoptosis and inflammatory responses in mice. Moreover, both naringenin and 8-PN normalized
STZ-induced insulin-signaling defects in skeletal muscles and apoptotic protein expression in the
liver. Importantly, 8-PN increased the protein expression levels of estrogen receptor-α (ERα) in the
pancreas and liver and of fibroblast growth factor 21 in the liver, suggesting that 8-PN could act as an
ERα agonist in the regulation of glucose homeostasis. This study provides novel insights into the
mechanisms underlying preventive effects of naringenin and 8-PN on the impairment of glucose
homeostasis in insulin-deficient diabetic mice....
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