Oral submucous fibrosis (OSF) is considered as a pre‐cancerous condition of the oral mucosa and is highly associated with habitual areca quid chewing. Arecoline is the major alkaloid in areca quid ...and is thought to be involved in the pathogenesis of OSF. Our previous studies have demonstrated that arecoline could induce epithelial–mesenchymal transition (EMT)‐related factors in primary human buccal mucosal fibroblasts (BMFs). Therefore, we investigated the expression of zinc finger E‐box binding homeobox 1 (ZEB1), which is a well‐known transcriptional factor in EMT, in OSF tissues and its role in arecoline‐induced myofibroblast transdifferentiation from BMFs. The expression of ZEB1, as well as the myofibroblast marker α‐smooth muscle actin (α‐SMA), was significantly increased in OSF tissues, respectively. With immunofluorescence analysis, arecoline induced the formation of α‐SMA‐positive stress fibres in BMFs expressing nuclear ZEB1. Arecoline also induced collagen contraction of BMFs in vitro. By chromatin immunoprecipitation, the binding of ZEB1 to the α‐SMA promoter in BMFs was increased by arecoline. The promoter activity of α‐SMA in BMFs was also induced by arecoline, while knockdown of ZEB1 abolished arecoline‐induced α‐SMA promoter activity and collagen contraction of BMFs. Long‐term exposure of BMFs to arecoline induced the expression of fibrogenic genes and ZEB1. Silencing of ZEB1 in fibrotic BMFs from an OSF patient also suppressed the expression of α‐SMA and myofibroblast activity. Inhibition of insulin‐like growth factor receptor‐1 could suppress arecoline‐induced ZEB1 activation in BMFs. Our data suggest that ZEB1 may participate in the pathogenesis of areca quid–associated OSF by activating the α‐SMA promoter and inducing myofibroblast transdifferentiation from BMFs.
Pancreatic cancer is one of the most lethal types of cancer with a 5-year survival rate of ~5%. Histone deacetylases (HDACs) participate in many cellular processes, including carcinogenesis, and ...pharmacological inhibition of HDACs has emerged as a potential therapeutic strategy. In this study, we explored antitumor activity of the novel HDAC inhibitor AR-42 in pancreatic cancer.
Human pancreatic cancer cell lines BxPC-3 and PANC-1 were used in this study. Real-time PCR, RT-PCR, and western blotting were employed to investigate expression of specific genes and proteins, respectively. Translocation of apoptosis-inducing factor was investigated by immunofluorescence and subcellular fractionation. The number of apoptotic cells, cell cycle stages, and reactive oxygen species (ROS) generation levels were determined by flow cytometry. Cell invasiveness was examined by the Matrigel invasion assay. Efficacy of AR-42 in vivo was evaluated by utilizing BxPC-3 xenograft mouse model.
AR-42 inhibited pancreatic cancer cell proliferation by causing G2/M cell cycle arrest via regulating expression levels of genes and proteins involved in cell cycle. AR-42 also induced ROS generation and DNA damage, triggering apoptosis of pancreatic cancer cells via both caspase-3-dependent and caspase-3-independent pathways. In addition, AR-42 increased expression levels of negative regulators of p53 (miR-125b, miR-30d, and miR33), which could contribute to lower expression level of mutant p53 in pancreatic cancer cells. Cell invasion assay showed that AR-42 reduced cancer cell aggressiveness and significantly diminished BxPC-3 xenograft tumor growth in vivo.
AR-42, a novel HDAC inhibitor, inhibited pancreatic cancer cells by regulating p53 expression, inducing cell cycle arrest, particularly at the G2/M stage, and activating multiple apoptosis pathways. Additionally, AR-42 inhibited cell invasiveness and potently suppressed pancreatic cancer tumors in vivo. We conclude that by virtue of its multiple mechanisms of action, AR-42 possesses a considerable potential as an antitumor agent in pancreatic cancer.
Radiation is an integral part of cancer therapy. With the emergence of oncolytic vaccinia virus immunotherapy, it is important to study the combination of radiation and vaccinia virus in cancer ...therapy. In this study, we investigated the anti-tumor effect of and immune mechanisms underlying the combination of high-dose hypofractionated stereotactic body radiotherapy (SBRT) and oncolytic vaccinia virus in preclinical murine models. The combination enhanced the in vivo anti-tumor effect and increased the numbers of splenic CD4+Ki-67+ helper T lymphocytes and CD8+Ki-67+ cytotoxic T lymphocytes. Combinational therapy also increased tumor-infiltrating CD3+CD4+ helper T lymphocytes and CD3+CD8+ cytotoxic T lymphocytes, but decreased tumor-infiltrating regulatory T cells. In addition, SBRT combined with oncolytic vaccinia virus enhanced in vitro cell death, partly through necroptosis, and subsequent release of damage-associated molecular patterns (DAMPs), and shifted the macrophage M1/M2 ratio. We concluded that SBRT combined with oncolytic vaccinia virus can trigger tumor cell necroptosis and modify macrophages through the release of DAMPs, and then generate potent anti-tumor immunity and effects. Thus, combined therapy is potentially an important strategy for clinical cancer therapy.
•Stereotactic body radiation with oncolytic vaccinia generates potent anti-tumor immunity and effects.•Radiation combined with oncolytic vaccinia increases the immune responses of both helper and cytotoxic T lymphocytes.•Radiation combined with oncolytic vaccinia triggers tumor cell necroptosis.•Radiation combined with oncolytic vaccinia modifies macrophages through the release of DAMPs.
With the continuous emergence of new SARS-CoV-2 variants that feature increased transmission and immune escape, there is an urgent demand for a better vaccine design that will provide broader ...neutralizing efficacy.
We report an mRNA-based vaccine using an engineered "hybrid" receptor binding domain (RBD) that contains all 16 point-mutations shown in the currently prevailing Omicron and Delta variants.
A booster dose of hybrid vaccine in mice previously immunized with wild-type RBD vaccine induced high titers of broadly neutralizing antibodies against all tested SARS-CoV-2 variants of concern (VOCs). In naïve mice, hybrid vaccine generated strong Omicron-specific neutralizing antibodies as well as low but significant titers against other VOCs. Hybrid vaccine also elicited CD8+/IFN-γ+ T cell responses against a conserved T cell epitope present in wild type and all VOCs.
These results demonstrate that inclusion of different antigenic mutations from various SARS-CoV-2 variants is a feasible approach to develop cross-protective vaccines.
Sequential infections with SARS-CoV-2 variants such as Alpha, Delta, Omicron and its sublineages may cause high morbidity, so it is necessary to develop vaccines that can protect against both ...wild-type (WT) virus and its variants. Mutations in SARS-CoV-2's spike protein can easily alter viral transmission and vaccination effectiveness.
In this study, we designed full-length spike mRNAs for WT, Alpha, Delta, and BA.5 variants and integrated each into monovalent or bivalent mRNA-lipid nanoparticle vaccines. A pseudovirus neutralization assay was conducted on immunized mouse sera in order to examine the neutralizing potential of each vaccine.
Monovalent mRNA vaccines were only effective against the same type of virus. Interestingly, monovalent BA.5 vaccination could neutralize BF.7 and BQ.1.1. Moreover, WT, Alpha, Delta, BA.5, and BF.7 pseudoviruses were broadly neutralized by bivalent mRNA vaccinations, such as BA.5 + WT, BA.5 + Alpha, and BA.5 + Delta. In particular, BA.5 + WT exhibited high neutralization against most variants of concern (VOCs) in a pseudovirus neutralization assay.
Our results show that combining two mRNA sequences may be an effective way to develop a broadly protective SARS-CoV-2 vaccine against a wide range of variant types. Importantly, we provide the optimal combination regimen and propose a strategy that may prove useful in combating future VOCs.
Two new phenol derivatives, namely insphenol A (1) and acetylpeniciphenol (2), along with seven known analogs (3–9), were isolated from the deep‐sea cold seep‐derived fungus, Aspergillus insuetus ...SD‐512. The structures of 1 and 2 were established by extensive interpretation of NMR and mass spectroscopic data. The absolute configuration of 1 was determined by the combination of coupling constant analysis and acid hydrolysis. Among the isolated compounds, insphenol A (1) represents the first example of isopentenyl phenol derivative with a unique 1‐glycosylation from the species Aspergillus insuetus. The isolated new compounds were evaluated for antibacterial activities against six human or aquatic pathogens, while compound 2 exhibited inhibitory effect against Edwardsiella tarda, Vibrio alginolyticus, and V. vulnificus, with MIC values of 4, 8, and 8 μg/mL, respectively.
The present study investigated the prognostic values for office brachial (OB), office central (OC), and ambulatory daytime brachial (AmDB) hypertension, as defined by a unifying threshold of ...130/80 mmHg, and the incremental value of either OC or AmDB hypertension to OB hypertension. A total of 1219 community residents without receiving anti‐hypertensive treatment (671 men and 548 women, aged ≥ 30 years old) from central Taiwan and Kinmen islands had OB, OC, and AmDB blood pressure measurements during a cardiovascular survey conducted in 1992–1993. OB hypertension, OC hypertension, and AmDB hypertension were all defined in retrospect at the threshold of 130/80 mmHg. They were followed up for nonfatal and fatal cardiovascular events until December 31, 2017, by linking the baseline database to the National Health Insurance Research dataset and the National Death Registry. During a follow‐up of 25 612.5 person‐years (Average event‐free time: 21.0 years), there were 368 fatal and nonfatal cardiovascular events. In multivariable analyses, OB hypertension, OC hypertension, and AmDB hypertension had similar hazard ratios for cardiovascular events 2.03, 95% confidence interval: 1.47‐2.80; 1.92 (1.47‐2.51); and 1.79 (1.41‐2.29), respectively. Using OB normotension as the reference, either the concordant OB and OC hypertension 2.24 (1.61‐3.12), or the concordant OB and AmDB hypertension 2.52 (1.80‐3.54) was significantly associated with cardiovascular events. Moreover, OB hypertension plus AmDB normotension was also significantly associated with increased risk for cardiovascular events. We concluded that OB hypertension, OC hypertension, and AmDB hypertension defined by a unifying threshold of 130/80 mmHg may provide similar estimates of long‐term risk for cardiovascular events. Cross‐classification analyses suggest that addition of OC hypertension or AmDB hypertension may improve the prognostic value of OB hypertension.
Three new ophiobolin sesterterpenoids, (6R)-16,17,21,21-O-tetrahydroophiobolin G (1), (6R)-16,17-dihydroophiobolin H (2), and (5S,6S)-16,17-dihydroophiobolin H (3), and three new farnesylated ...phthalide derivatives farnesylemefuranones D–F (9–11), along with five known ophiobolin analogues (4–8), were isolated and identified from the culture extract of Aspergillus insuetus SD-512, a deep-sea-derived fungus obtained from cold seep sediments collected at a depth of 1331 m. Among them, compounds 9–11 are rare examples of phthalide derivatives linked with farnesyl moieties via ether bonds. Their structures were established on the basis of detailed interpretation of the NMR spectroscopic and mass spectrometric data. X-ray crystallographic analysis, ECD calculations, and DP4+ probability analysis were performed to confirm the structures and establish the relative and absolute configurations of compounds 1–4. Compounds 3 and 9–11 showed broad-spectrum antibacterial activities, and differences in potencies could be assigned to structural modifications. This is the first report of secondary metabolites obtained from a deep sea cold-seep-derived fungus.
Climate change leads to a variety of extreme weather conditions such as heat waves, unusual cold weather, and heavy rain, which always ends up with serious disasters. It could have a tremendous ...impact on a lot of industries in the world. The tourist industry, that plays a vital role in the global economy, has faced serious impacts from climate change in many tourist attractions, e.g., national parks, mountain areas, and beaches. The travel behavior of visitors has been changed under various climate change conditions. To understand the influence degrees of tourists on climate change factors, this study aimed to analyze whether there is difference in the influence of climate change on socio-demographic background, travel activities, travel intention, and the revisit intention attitude of tourists with different degrees of place attachment to Wuling National Forest Recreation Area. This study further investigated whether the climate change adaptation strategies offered by the park manager would have a positive influence on travel intention of tourists. The results of this study showed that except for heat waves, events related to climate change such as stronger typhoon, heavy rain, unusual cold weather condition, mud sliding, forest fire, and the appearance of mosquitos would have a negative influence on travel intention, especially for the tourists with a low degree of place attachment. In addition, if the park manager offers strategies to adapt to climate change conditions, these strategies would have a positive influence on travel intention.
Cardiovascular diseases (CVDs) are the leading cause of deaths globally. Mortality and incidence of CVDs are significantly higher in people with mood disorders. About 81.1% of CVD patients were ...reported with comorbidities in 2019, where the second most common comorbidity was due to major depressive disorder (MDD). This study, therefore, aimed to evaluate the genetic correlation between CVDs and mood disorders by using data from the UK Biobank towards understanding the influence of genetic factors on the comorbidity due to CVDs and mood disorders.
The UK Biobank database provides genetic and health information from half a million adults, aged 40-69 years, recruited between 2006 and 2010. A total of 117,925 participants and 6,128,294 variants were included for analysis after applying exclusion criteria and quality control steps. This study focused on two CVD phenotypes, two mood disorders and 12 cardiometabolic-related traits to conduct association studies.
The results indicated a significant positive genetic correlation between CVDs and overall mood disorders and MDD specifically, showing substantial genetic overlap. Genetic correlation between CVDs and bipolar disorder was not significant. Furthermore, significant genetic correlation between mood disorders and cardiometabolic traits was also reported.
The results of this study can be used to understand that CVDs and mood disorders share a great deal of genetic liability in individuals of European ancestry.
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