Cisplatin and other DNA-damaging chemotherapeutics are widely used to treat a broad spectrum of malignancies. However, their application is limited by both intrinsic and acquired chemoresistance. ...Most mutations that result from DNA damage are the consequence of error-prone translesion DNA synthesis, which could be responsible for the acquired resistance against DNA-damaging agents. Recent studies have shown that the suppression of crucial gene products (e.g., REV1 , REV3L) involved in the error-prone translesion DNA synthesis pathway can sensitize intrinsically resistant tumors to chemotherapy and reduce the frequency of acquired drug resistance of relapsed tumors. In this context, combining conventional DNA-damaging chemotherapy with siRNA-based therapeutics represents a promising strategy for treating patients with malignancies. To this end, we developed a versatile nanoparticle (NP) platform to deliver a cisplatin prodrug and REV1 / REV3L -specific siRNAs simultaneously to the same tumor cells. NPs are formulated through self-assembly of a biodegradable poly(lactide- co glycolide)- b -poly(ethylene glycol) diblock copolymer and a self-synthesized cationic lipid. We demonstrated the potency of the siRNA-containing NPs to knock down target genes efficiently both in vitro and in vivo. The therapeutic efficacy of NPs containing both cisplatin prodrug and REV1 / REV3L -specific siRNAs was further investigated in vitro and in vivo. Quantitative real-time PCR results showed that the NPs exhibited a significant and sustained suppression of both genes in tumors for up to 3 d after a single dose. Administering these NPs revealed a synergistic effect on tumor inhibition in a human Lymph Node Carcinoma of the Prostate xenograft mouse model that was strikingly more effective than platinum monotherapy.
Oil spill accidents and oily wastewater discharged by petrochemical industries have severely wasted water resources and damaged the environment. The use of special wetting materials to separate oil ...and water is efficient and environment-friendly. Cellulose is the most abundant renewable resource and has natural advantages in removing pollutants from oily wastewater. The application and modification of cellulose as special wetting materials have attracted considerable research attention. Therefore, we summarized cellulose-based superlipophilic/superhydrophobic and superhydrophilic/superoleophobic materials exhibiting special wetting properties for oil/water separation. The treatment mechanism, preparation technology, treatment effect, and representative projects of oil-bearing wastewater are discussed. Moreover, cellulose-based intelligent-responsive materials for application to oil/water separation and the removal of other pollutants from oily wastewater have also been summarized. The prospects and potential challenges of all the materials have been highlighted.
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•Fabrication of BC-based multifunctional membrane for wastewater treatment.•Blending of BC nanofibers with TiO2 NPs and further modified with ZnO NPs.•Membrane exhibited oil/water ...mixture and oil-in-water emulsion separations.•Membrane showed photocatalytic activity under visible light.•It showed antibacterial activity against tested bacterial species.
Superhydrophilic/underwater superoleophobic (SUS) membrane technology has attracted extensive attention for water purification. However, the fabrication of multifunctional membranes to satisfy the complex wastewater treatment is still a big challenge. In this work, bacterial cellulose (BC) based multifunctional SUS membranes were designed for water purification. Membranes were prepared by blending BC nanofibers with TiO2 nanoparticles (NPs), and further modified by the in situ growth of ZnO-NPs. The composite membranes showed oil/water (o/w) separation under a small driving pressure (0.2–0.3 bar) with a flux rate of 8232.81 ± 212 L m−2h−1 and with a high separation efficiency (>99.9%). Membranes could also separate oil-in-water emulsion with a separation flux of 1498 ± 74 L m−2h−1 and with high efficiency (99.25%). Moreover, the composite membrane exhibited photocatalytic activity under visible light with a high efficiency (>92%). The composite membranes were also investigated for antibacterial activity against Gram-positive and Gram-negative bacterial strains. This work may inspire the fabrication of next-generation multifunctional membranes for wastewater treatment, particularly oily wastewater, dyes and microbial contaminated water.
Toll like receptor 5 (TLR5) plays a crucial role in the innate immune response by recognizing bacterial flagellin proteins. In the present study, the genomic and 5′-flanking sequences of LcTLR5M ...(membrane) and LcTLR5S (soluble) were cloned from the large yellow croaker, Larimichthys crocea. Then, their promoter activities were determined in human embryonic kidney (HEK293T) cells. LcTLR5M contained 4 exons and 3 introns, and LcTLR5S contained 2 exons and 1 intron. Bioinformatic prediction of transcription factor binding sites (TFBSs) indicated that the promoter structures were different between LcTLR5M and LcTLR5S. A dual luciferase assay showed that the deletion mutant −471 to +189 of LcTLR5M promoter possessed the greatest activity with 36 times activity of the control (P < 0.05). For LcTLR5S, two deletion mutants, −1687 to +106 and − 720 to +106, showed high promoter activity. Furthermore, site-directed mutation demonstrated that a −392 to −391 AT/GG substitution in Oct-1 binding site, and a −104 to −103 GG/TT and a −98 to −97 CC/AA substitution in the NF-κB binding site of TLR5S caused a significant decline of luciferase activity (P < 0.05). Moreover, the co-transfection of an NF-κB/p65 over-expression plasmid with wild type TLR5S (−720 to +106) resulted in an extremely significant increase of promoter activity by more than 9 times compared with the NF-kB mutant (P < 0.01). Our findings suggest that the genomic organization and promoter structure may differ between LcTLR5M and LcTLR5S. Oct1 and NF-κB binding sites might be cis-regulatory elements in the LcTLR5S promoter. NF-κB/p65 plays an important role in LcTLR5S promoter activation through binding with the NF-κB binding site.
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•The genome organization and promoter activity of TLR5M and TLR5S were detected in large yellow croaker.•The crucial transcription factors binding sites (TFBSs) in LcTLR5M and LcTLR5S promoters were determined.•The cis-elements in LcTLR5S and LcTLR5S promoters were investigated.•NF-κB/p65 involves in LcTLR5S promoter activation through binding with cis-acting element NF-κB.
Azvudine is a novel nucleoside reverse transcriptase inhibitor with antiviral activity on human immunodeficiency virus, hepatitis B virus and hepatitis C virus. Here we reported the in vitro activity ...of azvudine against HIV-1 and HIV-2 when used alone or in combination with other antiretroviral drugs and its drug resistance features. Azvudine exerted highly potent inhibition on HIV-1 (EC(50)s ranging from 0.03 to 6.92 nM) and HIV-2 (EC(50)s ranging from 0.018 to 0.025 nM). It also showed synergism in combination with six approved anti-HIV drugs on both C8166 and PBMC. In combination assay, the concentrations of azvudine used were 1000 or 500 fold lower than other drugs. Azvudine also showed potent inhibition on NRTI-resistant strains (L74V and T69N). Although M184V caused 250 fold reduction in susceptibility, azvudine remained active at nanomolar range. In in vitro induced resistant assay, the frequency of M184I mutation increased with induction time which suggests M184I as the key mutation in azvudine treatment. As control, lamivudine treatment resulted in a higher frequency of M184I/V given the same induction time and higher occurrence of M184V was found. Molecular modeling analysis suggests that steric hindrance is more pronounced in mutant M184I than M184V due to the azido group of azvudine. The present data demonstrates the potential of azvudine as a complementary drug to current anti-HIV drugs. M184I should be the key mutation, however, azvudine still remains active on HIV-1LAI-M184V at nanomolar range.
Heart aging is characterized by structural and diastolic dysfunction of the heart. However, there is still no effective drug to prevent and treat the abnormal changes in cardiac function caused by ...aging. Here, we present the preventive effects of emodin and its derivative Kanglexin (KLX) against heart aging. We found that the diastolic dysfunction and cardiac remodeling in mice with D-galactose (D-gal)-induced aging were markedly mitigated by KLX and emodin. In addition, the senescence of neonatal mouse cardiomyocytes induced by D-gal was also reversed by KLX and emodin treatment. However, KLX exhibited better anti-heart aging effects than emodin at the same dose. Dysregulated mitophagy was observed in aging hearts and in senescent neonatal mouse cardiomyocytes, and KLX produced a greater increase in mitophagy than emodin. The mitophagy-promoting effects of KLX and emodin were ascribed to their abilities to enhance the protein stability of Parkin, a key modulator in mitophagy, with different potencies. Molecular docking and SPR analysis demonstrated that KLX has a higher affinity for the ubiquitin-like (UBL) domain of Parkin than emodin. The UBL domain might contribute to the stabilizing effects of KLX on Parkin. In conclusion, this study identifies KLX and emodin as effective anti-heart aging drugs that activate Parkin-mediated mitophagy and outlines their putative therapeutic importance.
Cold and hot water extracted polysaccharides (CW‐PNPs and HW‐PNPs) were isolated from Pholiota nameko. The rheological properties of PNPs were investigated by steady shear and oscillatory rheological ...measurements. The PNPs exhibited typical non‐Newtonian and shear‐thinning behavior, which are affected by PNP concentration, temperature, pH value, salt ion, and concentration. Specifically, the apparent viscosity of the two PNPs solutions at concentration of 1% (w/w) was shown as HW‐PNPs > CW‐PNPs. The apparent viscosity of PNPs decreases under acidic and alkaline conditions and when the temperature rises; K+ and Na+ cause the apparent viscosity of CW‐PNPs to decrease, while Ca2+ and Al3+ are opposite. The addition of four different salt ions all caused the apparent viscosity of the HW‐PNPs to decrease. The results of dynamic rheological experiments show that G′ and G″ showed slightly frequency dependency with G′ exceeding G″ throughout the accessible range of frequency for CW‐PNPs and HW‐PNPs.
Surgery is the preferred treatment for basal cell carcinoma (BCC), locally advanced or metastatic BCC, radiation therapy or systemic therapy can be considered. Programmed death receptor 1 (PD-1) ...inhibitors are rarely used to treat cutaneous BCC. In the present case, we found that tislelizumab, a PD-1 immunosuppressant, had a positive effect on BCC.
A 74-year-old male patient presented with a mass in the left back in October 2021, which was surgically removed and diagnosed as BCC. The patient was diagnosed with squamous lung cancer after presenting with a cough and coughing up a small amount of white, sticky sputum in December 2021.
BCC and squamous lung cancer.
Docetaxel + nedaplatin systemic chemotherapy combined with tislelizumab immunotherapy.
Both BCC and squamous lung cancer were significantly reduced in size.
After 2 cycles of immunotherapy with tislelizumab, the lung tumor shrank, the back mass disappeared, and the wound healed.
A facile photocatalytic radical 4+2 cyclization of N-aryl-α-amino acids with various alkenes to access structurally polysubstituted tetrahydroquinolines has been developed. Using a simple bipyridine ...as a catalyst, different N-aryl-α-amino acids could be utilized as the radical precursors to react with diverse electrophilic alkenes, including exocyclic terminal alkenes, acyclic terminal alkenes, and cycloalkenes, producing 10 types of nitrogen-containing heterocyclic compounds fused in multiple frameworks in generally moderate yields with good diastereoselectivities. Scale-up synthesis and transformations of the products further demonstrated the synthetic application of this protocol. Moreover, a decarboxylative radial pathway via a proton-coupled electron transfer process for illustration of this 4+2 cyclization was proposed on the basis of the control experiments. This process is highlighted by a simple bipyridine photocatalysis, mild reaction conditions, various N-aryl-α-amino acids and alkene materials, and application for the modification of natural products.
Abstract
Electric drilling tools have been developed in the field of drilling because of their high efficiency. As the core component of electric drilling tool, permanent magnet synchronous ...motor(PMSM) provides power for drilling tool. However, in the process of drilling, the permanent magnet of PMSM will appear demagnetization.The value of air-gap flux density affects the performance and efficiency of the motor directly. Demagnetization faults are divided into uniform demagnetization and local demagnetization.In order to study the influence of demagnetization of PMSM on the air-gap flux density, mechanism of permanent magnet is analyzed Firstly, and then establishing numerical model with analytical method. Finally, simulation motor demagnetization using finite element method(FEM) based on Maxwell. No-load and load operating state are analyzed under the two fault modes are considered in this paper, and compared with the healthy state of the motor. The analytical results show that when the demagnetization fault occurs in the motor permanent magnet, the air-gap flux density will decrease accordingly.The FEM method results show that with the increase of uniform demagnetization rate, the flux density of the air-gap almost decreases in proportion to the increase of demagnetization rate. The demagnetization of single pole permanent magnet has little effect on the magnetic density of the nearby permanent magnet, but it will lead to the imbalance of the whole electromagnetic field of the motor. The air-gap flux density can be used as a characteristic index to judge the fault of demagnetization.
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