13 research outputs found
Genetically engineered cell membrane-coated nanoparticles for antibacterial and immunoregulatory dual-function treatment of ligature-induced periodontitis
Purpose: In order to overcome the problem that conventional pharmacological treatments of periodontitis cannot effectively synergizing antimicrobial and immunomodulation, inspired by the critical role of toll-like receptor 4 (TLR4) in bacterial recognition and immune activation, we demonstrated a combined antibacterial-immunoregulatory strategy based on biomimetic nanoparticles.Methods: Functioned cell membranes and silk fibroin nanoparticles (SNs) loaded with minocycline hydrochloride (Mino) were used to prepare a biomimetic nanoparticle (MSNCs). SNs and MSNCs were characterized by Scanning Electron Microscope, size, zeta potential, dispersion index. At the same time, SNs were characterized by cell counting kit-8 and real-time Polymerase Chain Reaction (RT-PCR). TLR4-expressing cell membranes were characterized by RT-PCR and western blot (WB). Cell membrane coating was characterized by Transmission Electron Microscope (TEM), the Bradford staining and WB. Then, Laser confocal, flow cytometry and agar plate coating were evaluated in vitro with antibacterial effects, RT-PCR was simultaneously evaluated with immunoregulatory effects. Finally, Anti-inflammatory treatment of MSNCs was evaluated in a ligature-induced periodontitis (LIP) mouse model.Results: Successfully prepared cell membranes overexpressing TLR4 and constructed MSNCs. In vitro studies had shown that MSNCs effectively targeted bacteria via TLR4 and acted as molecular decoys to competitively neutralize lipopolysaccharide (LPS) in the microenvironment as well as inhibit inflammatory activation of macrophages. In vivo, MSNCs effectively attenuated periodontal tissue inflammation and alveolar bone loss in a LIP mouse model.Conclusion: MSNCs have good targeted antibacterial and immunoregulatory effects, and provide a new and effective strategy for the treatment of periodontitis and have good potential for application in various types of pathogenic bacterial infections
Preparation and Characterization of 8YSZ Thermal Barrier Coatings on Rare Earth-Magnesium Alloy
Interactive Effects of Seawater Acidification and Elevated Temperature on the Transcriptome and Biomineralization in the Pearl Oyster <i>Pinctada fucata</i>
Interactive
effects of ocean acidification and ocean warming on
marine calcifiers vary among species, but little is known about the
underlying mechanisms. The present study investigated the combined
effects of seawater acidification and elevated temperature (ambient
condition: pH 8.1 × 23 °C, stress conditions: pH 7.8 ×
23 °C, pH 8.1 × 28 °C, and pH 7.8 × 28 °C,
exposure time: two months) on the transcriptome and biomineralization
of the pearl oyster <i>Pinctada fucata</i>, which is an
important marine calcifier. Transcriptome analyses indicated that <i>P. fucata</i> implemented a compensatory acid–base mechanism,
metabolic depression and positive physiological responses to mitigate
the effects of seawater acidification alone. These responses were
energy-expensive processes, leading to decreases in the net calcification
rate, shell surface calcium and carbon content, and changes in the
shell ultrastructure. Elevated temperature (28 °C) within the
thermal window of <i>P. fucata</i> did not induce significant
enrichment of the sequenced genes and conversely facilitated calcification,
which was detected to alleviate the negative effects of seawater acidification
on biomineralization and the shell ultrastructure. Overall, this study
will help elucidate the mechanisms by which pearl oysters respond
to changing seawater conditions and predict the effects of global
climate change on pearl aquaculture
Influence of the Extrapallial Fluid of <i>Pinctada fucata</i> on the Crystallization of Calcium Carbonate and Shell Biomineralization
Extrapallial
fluid (EPF) is located between the shell and the mantle,
and it is believed to play key roles in shell biomineralization in <i>Pinctada fucata</i>. However, few studies have been performed
on the biomineralization effect of EPF. In this work, CaCO<sub>3</sub> crystallization experiments showed that EPF proteins could not only
control the morphology but also regulate the phase transition of calcium
carbonate through the different proteins specific binding to calcite
or aragonite. In crystal growth inhibition experiments, when the final
concentration of CaCl<sub>2</sub> and NaHCO<sub>3</sub> reduced from
50 to 5 mM, the function of EPF proteins (50 μg/mL) transferred
from significantly improving over the number of CaCO<sub>3</sub> crystals
(448 ± 28) upon the control (128 ± 20) to inhibiting the
precipitation of CaCO<sub>3</sub>. The precipitation rate of CaCO<sub>3</sub> was also inhibited by EPF proteins. <i>In vivo</i>, once EPF was extracted daily for 20 days, the nacre platelet in
the nacreous layer was disturbed, and calcite deposited randomly due
to the reduction of EPF proteins. Furthermore, EPF also acted as an
external signal to induce the expression variation of shell-related
genes to regulate nacre and prism formation. In conclusion, our findings
demonstrate that EPF proteins not only take part in the nucleation,
morphology, inhibition, and phase transition of CaCO<sub>3</sub> but
also play a dual role in both shell biomineralization and prism–nacre
transition, which is mediated by different proteins and their secondary
structure and conformational changes
Metformin escape in prostate cancer by activating the PTGR1 transcriptional program through a novel super-enhancer
Abstract The therapeutic efficacy of metformin in prostate cancer (PCa) appears uncertain based on various clinical trials. Metformin treatment failure may be attributed to the high frequency of transcriptional dysregulation, which leads to drug resistance. However, the underlying mechanism is still unclear. In this study, we found evidences that metformin resistance in PCa cells may be linked to cell cycle reactivation. Super-enhancers (SEs), crucial regulatory elements, have been shown to be associated with drug resistance in various cancers. Our analysis of SEs in metformin-resistant (MetR) PCa cells revealed a correlation with Prostaglandin Reductase 1 (PTGR1) expression, which was identified as significantly increased in a cluster of cells with metformin resistance through single-cell transcriptome sequencing. Our functional experiments showed that PTGR1 overexpression accelerated cell cycle progression by promoting progression from the G0/G1 to the S and G2/M phases, resulting in reduced sensitivity to metformin. Additionally, we identified key transcription factors that significantly increase PTGR1 expression, such as SRF and RUNX3, providing potential new targets to address metformin resistance in PCa. In conclusion, our study sheds new light on the cellular mechanism underlying metformin resistance and the regulation of the SE-TFs-PTGR1 axis, offering potential avenues to enhance metformin’s therapeutic efficacy in PCa
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Metformin escape in prostate cancer by activating the PTGR1 transcriptional program through a novel super-enhancer.
The therapeutic efficacy of metformin in prostate cancer (PCa) appears uncertain based on various clinical trials. Metformin treatment failure may be attributed to the high frequency of transcriptional dysregulation, which leads to drug resistance. However, the underlying mechanism is still unclear. In this study, we found evidences that metformin resistance in PCa cells may be linked to cell cycle reactivation. Super-enhancers (SEs), crucial regulatory elements, have been shown to be associated with drug resistance in various cancers. Our analysis of SEs in metformin-resistant (MetR) PCa cells revealed a correlation with Prostaglandin Reductase 1 (PTGR1) expression, which was identified as significantly increased in a cluster of cells with metformin resistance through single-cell transcriptome sequencing. Our functional experiments showed that PTGR1 overexpression accelerated cell cycle progression by promoting progression from the G0/G1 to the S and G2/M phases, resulting in reduced sensitivity to metformin. Additionally, we identified key transcription factors that significantly increase PTGR1 expression, such as SRF and RUNX3, providing potential new targets to address metformin resistance in PCa. In conclusion, our study sheds new light on the cellular mechanism underlying metformin resistance and the regulation of the SE-TFs-PTGR1 axis, offering potential avenues to enhance metformins therapeutic efficacy in PCa
A HIF1α-GPD1 feedforward loop inhibits the progression of renal clear cell carcinoma via mitochondrial function and lipid metabolism
Abstract Background Hypoxia signaling, especially the hypoxia inducible factor (HIF) pathway, is a major player in clear cell renal cell carcinoma (ccRCC), which is characterized by disorders in lipid and glycogen metabolism. However, the interaction between hypoxia and lipid metabolism in ccRCC progression is still poorly understood. Methods We used bioinformatic analysis and discovered that glycerol-3-phosphate dehydrogenase 1 (GPD1) may play a key role in hypoxia and lipid metabolism pathways in ccRCC. Tissue microarray, IHC staining, and survival analysis were performed to evaluate clinical function. In vitro and in vivo assays showed the biological effects of GPD1 in ccRCC progression. Results We found that the expression of GPD1 was downregulated in ccRCC tissues, and overexpression of GPD1 inhibited the progression of ccRCC both in vivo and in vitro. Furthermore, we demonstrated that hypoxia inducible factor-1α (HIF1α) directly regulates GPD1 at the transcriptional level, which leads to the inhibition of mitochondrial function and lipid metabolism. Additionally, GPD1 was shown to inhibit prolyl hydroxylase 3 (PHD3), which blocks prolyl-hydroxylation of HIF1α and subsequent proteasomal degradation, and thus reinforces the inhibition of mitochondrial function and phosphorylation of AMPK via suppressing glycerol-3-phosphate dehydrogenase 2 (GPD2). Conclusions This study not only demonstrated that HIF1α-GPD1 forms a positive feedforward loop inhibiting mitochondrial function and lipid metabolism in ccRCC, but also discovered a new mechanism for the molecular basis of HIF1α to inhibit tumor activity, thus providing novel insights into hypoxia-lipid-mediated ccRCC therapy