Claudin1 plays a critical role in maintaining the epithelial barrier, and mucus hypersecretion induced by epidermal growth factor receptor (EGFR) activation is a pivotal pathological feature of ...asthma. The relationship between claudin1 expression and mucus hypersecretion and EGFR activation is still poorly understood. In this report, we showed that claudin1 expression correlated with asthma stage, in both patients with asthma and in the house dust mite (HDM)-induced mouse asthma model. Claudin1 knockdown induced MUC5AC overexpression both in 16HBE cells and in mouse airways. In addition, claudin1 expression negatively correlated with asthma severity as demonstrated by significantly higher MUC5AC expression, more severe airway inflammation, and increased airway hyperreactivity in mouse lungs with claudin1 knockdown following HDM challenge. EGFR activation reduced claudin1 expression and increased MUC5AC expression, both in vitro and in vivo. Erlotinib alleviated murine allergic airway inflammation, restored claudin1 expression and decreased MUC5AC expression. These results suggest that EGFR activation-induced decreases in claudin1 promote goblet-cell metaplasia, and restoring claudin1 to maintain barrier integrity by EGFR antagonism may provide a novel therapeutic strategy for asthma.
NCAPD3 is one of the three non-SMC subunits of condensin II complex, which plays an important role in the chromosome condensation and segregation during mitosis. Notably, elevated levels of NCAPD3 ...are found in many somatic cancers. However, the clinical role, biological functions of NCAPD3 in cancers especially in colorectal cancer (CRC) and the underlying molecular mechanisms remain poorly elucidated.
Clinical CRC and adjacent normal tissues were used to confirm the expression of NCAPD3. The association of NCAPD3 expression with clinicopathological characteristics and patient outcomes were analyzed by using online database. In vivo subcutaneous tumor xenograft model, NCAPD3 gene knockout following azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced tumor mouse model, Co-IP, western blot, qRT-PCR, IHC, ChIP assays and cell functional assays were used to investigate the biological functions of NCAPD3 in CRC and the underlying molecular mechanisms.
NCAPD3 was overexpressed in CRC tissues and positively correlated with poor prognosis of CRC patients. NCAPD3 knockout suppressed CRC development in AOM/DSS induced and xenograft mice models. Moreover, we found that NCAPD3 promoted aerobic glycolysis in CRC. Mechanistically, NCAPD3 up-regulated the level of c-Myc and interacted with c-Myc to recruit more c-Myc to the gene promoter of its downstream glycolytic regulators GLUT1, HK2, ENO1, PKM2 and LDHA, and finally enhanced cellular aerobic glycolysis. Also, NCAPD3 increased the level of E2F1 and interacted with E2F1 to recruit more E2F1 to the promoter regions of PDK1 and PDK3 genes, which resulted in the inhibition of PDH activity and TCA cycle.
Our data demonstrated that NCAPD3 promoted glucose metabolism reprogramming and enhanced Warburg effect in colorectal tumorigenesis and CRC progression. These findings reveal a novel mechanism underlying NCAPD3 mediated CRC cell growth and provide new targets for CRC treatment.
The use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) brings remarkable benefits for the survival of patients with advanced NSCLC harboring EGFR mutations. Unfortunately, ...acquired resistance seems to be inevitable and limits the application of EGFR-TKIs in clinical practice. This study reported a common molecular mechanism sustaining resistance and potential treatment options to overcome EGFR-TKIs resistance.
EGFR-TKIs resistant NSCLC cells were established and confirmed by MTT assay. Cholesterol content was detected and the promotional function of cholesterol on NSCLC growth was determined in vivo. Then, we identified ERRα expression as the downstream factor of cholesterol-mediated drug resistance. To dissect the regulatory mechanism, we conducted experiments, including immunofluorescence, co-immunoprecipitation, luciferase reporter assay and chromatin immunoprecipitation assay.
Long-term exposure to EGFR-TKIs generate drug resistance with the characteristic of cholesterol accumulation in lipid rafts, which promotes EGFR and Src to interact and lead EGFR/Src/Erk signaling reactivation-mediated SP1 nuclear translocation and ERRα re-expression. Further investigation identifies ERRα as a target gene of SP1. Functionally, re-expression of ERRα sustains cell proliferation by regulating ROS detoxification process. Lovastatin, a drug used to decrease cholesterol level, and XCT790, an inverse agonist of ERRα, overcome gefitinib and osimertinib resistance both in vitro and in vivo.
Our study indicates that cholesterol/EGFR/Src/Erk/SP1 axis-induced ERRα re-expression promotes survival of gefitinib and osimertinib-resistant cancer cells. Besides, we demonstrate the potential of lowing cholesterol and downregulation of ERRα as effective adjuvant treatment of NSCLC.
In China, the prevention and control of Zika virus disease has been a public health threat since the first imported case was reported in February 2016. To determine the vector competence of potential ...vector mosquito species, we experimentally infected Aedes aegypti, Ae. albopictus, and Culex quinquefasciatus mosquitoes and determined infection rates, dissemination rates, and transmission rates. We found the highest vector competence for the imported Zika virus in Ae. aegypti mosquitoes, some susceptibility of Ae. albopictus mosquitoes, but no transmission ability for Cx. quinquefasciatus mosquitoes. Considering that, in China, Ae. albopictus mosquitoes are widely distributed but Ae. aegypti mosquito distribution is limited, Ae. albopictus mosquitoes are a potential primary vector for Zika virus and should be targeted in vector control strategies.
Saline soil in Western China contains high concentrations of chloride ions, sulfate ions, and other corrosive ions, and the performance of concrete will substantially deteriorate from exposure to ...this environment. Therefore, it is of great significance to study and predict the concrete compressive strength in saline soil environments. In this paper, the effects of corrosion on concrete were analyzed from the aspects of surface damage, damage depth, and X-ray diffraction (XRD) of the corrosion products. The effects of corrosion were quantified by damage depth and corrosion depth. Then, considering the corrosion effects combined with Fick’s diffusion law, a time-dependent model of concrete compressive strength and a time-dependent model of damage depth were established. The results show that the deterioration of concrete gradually developed from the surface to the interior, and that the interface of the concrete specimen was equivalent to three parts: a failure zone, a filling zone, and an undisturbed zone. The results also showed that the time-varying model of concrete compressive strength proposed by the author was fully applicable, with an error of less than five percent. The service life of concrete predicted by the damage depth was found to be about 253 months (21.1 years), and the service life predicted by the time-varying compressive strength model was about 187 months (15.6 years). Both prediction results were far less than the normal concrete service life of 50 years. In addition, the long-term compressive strength of the corroded concrete was about 90% of that of the noncorroded concrete, which did not deteriorate with the corrosion time.
Dengue is a mosquito-borne disease that has been an epidemic in China for many years.
is the dominant
mosquito species and the main vector of dengue in China. Epidemiologically, dengue mainly occurs ...in Guangdong Province; it does not occur or rarely occurs in other areas of mainland China. This distribution may be associated with climate, mosquito density, and other factors in different regions; however, the effect of temperature on the vector competence of
for dengue viruses (DENV) remains unclear. In this study,
was orally infected with dengue virus 2 (DENV-2) and reared at constant temperatures (18, 23, 28, and 32°C) and a fluctuating temperature (28-23-18°C). The infection status of the midguts, ovaries, and salivary glands of each mosquito was detected by polymerase chain reaction (PCR) at 0, 5, 10, and 15 days post-infection (dpi). DENV-2 RNA copies from positive tissues were quantified by quantitative real time PCR (qRT-PCR). At 18°C, DENV-2 proliferated slowly in the midgut of
, and the virus could not spread to the salivary glands. At 23 and 28°C, DENV-2 was detected in the ovaries and salivary glands at 10 dpi. The rates of infection, dissemination, population transmission, and DENV-2 copies at 28°C were higher than those at 23°C at any time point. At 32°C, the extrinsic incubation period (EIP) for DENV-2 in
was only 5 dpi, and the vector competence was the highest among all the temperatures. Compared with 28°C, at 28-23-18°C, the positive rate and the amount of DENV-2 in the salivary glands were significantly lower. Therefore, temperature is an important factor affecting the vector competence of
for DENV-2. Within the suitable temperature range, the replication of DENV-2 in
accelerated, and the EIP was shorter with a higher temperature. Our results provide a guide for vector control and an experimental basis for differences in the spatial distribution of dengue cases.
Tubulointerstitial fibrosis is one of the most common pathological features of diabetic nephropathy. Autophagy, an intracellular mechanism to remove damaged or dysfunctional cell parts and maintain ...metabolic homeostasis, is inhibited in diabetic neuropathy. Icariin is a traditional Chinese medicine extract known for nourishing the kidney and reinforcing Yang. In this study, we investigated the effects and mechanism of Icariin on renal function, autophagy, and fibrosis in type 2 diabetic nephropathic rats and in high-glucose-incubated human renal tubular epithelial cells and rat renal fibroblasts (
in vitro
). Icariin improved diabetes, renal function, restored autophagy, and alleviated fibrosis in type 2 diabetic neuropathic rats and
in vitro
. After we applied autophagy-related gene 5-small interfering RNA, we found that fibrosis improvement by Icariin was related to autophagy restoration. By detecting serum sex hormone levels, and using dihydrotestosterone, siRNA for androgen receptor, and the androgen receptor antagonist Apalutamide (ARN-509), we found that Icariin had an androgen-like effect and restored autophagy and reduced fibrosis by regulating the androgen receptor. In addition, miR-192-5p levels were increased under high glucose but reduced after dihydrotestosterone and Icariin treatment. Furthermore, dihydrotestosterone and Icariin inhibited miR-192-5p overexpression-induced fibrosis production and autophagy limitation. Glucagon-like peptide-1 receptor (GLP-1R) was downregulated by high glucose and overexpression of miR-192-5p and could be restored by dihydrotestosterone and Icariin. By using ARN-509, we found that Icariin increased GLP-1R expression by regulating the androgen receptor. GLP-1R-siRNA transfection weakened the effects of Icariin on autophagy and fibrosis. These findings indicate that Icariin alleviates tubulointerstitial fibrosis by restoring autophagy through the miR-192-5p/GLP-1R pathway and is a novel therapeutic option for diabetic fibrosis.
The setting time of alkali-activated slag (AAS) binders is extremely short, while traditional retarders of Portland cement may be invalid for AAS. To find an effective retarder with a less negative ...impact on strength, borax (B), sucrose (S), and citric acid (CA) were selected as potential retarders. The setting time of AAS with different admixtures dosages of 0%, 2%, 4%, 6%, and 8%, and the unconfined compressive strength and beam flexural strength of 3 d, 7 d, and 28 d AAS mortar specimens were tested. The microstructure of AAS with different additives was observed by scanning using an electron microscope (SEM), and the hydration products were analyzed by energy dispersive spectroscopy (EDS), X-ray diffraction analysis (XRD), and thermogravimetric analysis (DT-TGA) to explain the retarding mechanism of AAS with different additives. The results showed that the incorporation of borax and citric acid could effectively prolong the setting time of AAS more than that of sucrose, and the retarding effect is more and more obvious with the increase in borax and citric acid dosages. However, sucrose and citric acid negatively influence AAS's unconfined compressive strength and flexural stress. The negative effect becomes more evident with the increase in sucrose and citric acid dosages. Borax is the most suitable retarder for AAS among the three selected additives. SEM-EDS analysis showed that the incorporation of borax does three things: produces gels, covers the surface of the slag, and slows down the hydration reaction rate.
High mud content in the sand has a negative impact on cement mortar but there is little research on Alkali-activated slag (AAS) mortar. In order to explore the impacts of mud content in the sand on ...the performance of AAS mortar, this paper used sand that contains silt, clay, and a mixture of silt and clay; tested the setting time of AAS with different mud contents of 0%, 2%, 4%, 6%, 8%, and 10%; and measured the unconfined compressive strength and beam flexural strength of 3 d, 7 d, and 28 d AAS mortar specimens. The microstructure of AAS mortar with different kinds of mud was observed by scanning electron microscope (SEM), the elemental composition of the hydration product was tested by energy dispersive spectroscopy (EDS), and the AAS interaction mechanism with different kinds of mud was analyzed. The main conclusions are: the higher the mud content in the sand, the shorter the initial setting time and the longer the final setting time of AAS, mainly because the mud in the sand affects the hydration process; mud content above 4% causes a rapid decrease in the compressive and flexural strengths of AAS mortar, mainly because the mud affects the hydration process and hinders the bonding of the hydration product with the sand. When there is no mud in the sand, the main hydration product of AAS is dense calcium-alumina-silicate-hydrate (C-A-S-H) gel. When the sand contains silt, the hydration product of AAS is loose C-A-S-H gel. When the sand contains clay, the hydration products of AAS contain C-A-S-H gel and a small amount of sodium-aluminum-silicate-hydrate (N-A-S-H), and needle-like crystals. Loose gel and crystals have a negative effect on the AAS mortar strength.
Hydraulic fracturing (HF) is an important reason for inducing rock landslides. The impacts of the angle between the transverse pressure stress and the initial fracture, the transverse pressure ...stress, the length and aperture of the initial fracture on the critical water pressure stress of HF were analyzed based on the model tests of cement mortar specimens. The HF numerical simulations were carried out and the fracture aperture, pore pressure, strain and stiffness degradation index were analyzed, and the HF mechanism of rock was revealed. Taking a rock slope along G205 in China as an example, the landslide stability under high groundwater pressure was studied by numerical simulations, and the whole processes of the expansion, propagation, penetration and the rock slope failure were reproduced. The results showed that when HF occurred on the cement mortar specimens, a large amount of water seeped from the fracture and made a dull sound of failure, the water pressure on the fracture plane decreased rapidly, but not completely penetrated, and there was still a certain residual strength of the specimen. The HF of rock is a quasi-brittle failure, including static stage, micro fracture propagation stage and macro fracture formation stage. There are 3 dangerous rocks on the rock slope, among which WYT3 is in a stable state under the natural condition and in an unstable state under the rainstorm condition and seismic condition. The fracture propagation of WYT3 under the action of high groundwater pressure experienced slow development stage, rapid development stage and penetration stage, among which the slow development stage lasted the longest, and the slope failure occurred immediately after the fracture penetrated.
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