Metastasis is a multistep biological process regulated by multiple signaling pathways. The integrity of the Golgi apparatus plays an important role in these signaling pathways. Inspired by the ...mechanism and our previous finding about accumulation of chondroitin sulfate in Golgi apparatus in hepatic stellate cells, we developed a Golgi apparatus-targeting prodrug nanoparticle system by synthesizing retinoic acid (RA)-conjugated chondroitin sulfate (CS) (CS–RA). The prodrug nanoparticles appeared to accumulate in the Golgi apparatus in cancer cells and realized RA release under an acidic environment. We confirmed that CS–RA exhibited successful inhibition of multiple metastasis-associated proteins expression in vitro and in vivo by disruption of the Golgi apparatus structure. Following loading with paclitaxel (PTX), the CS–RA based nanoformulation (PTX–CS–RA) inhibited migration, invasion, and angiogenesis in vitro and suppressed tumor growth and metastasis in 4T1-Luc bearing mice. This multistep targeted nanoparticle system potentially enhanced the effect of antimetastasis combined with chemotherapy.
Angiosperms are by far the most species-rich clade of land plants, but their origin and early evolutionary history remain poorly understood. We reconstructed angiosperm phylogeny based on 80 genes ...from 2,881 plastid genomes representing 85% of extant families and all orders. With a well-resolved plastid tree and 62 fossil calibrations, we dated the origin of the crown angiosperms to the Upper Triassic, with major angiosperm radiations occurring in the Jurassic and Lower Cretaceous. This estimated crown age is substantially earlier than that of unequivocal angiosperm fossils, and the difference is here termed the 'Jurassic angiosperm gap'. Our time-calibrated plastid phylogenomic tree provides a highly relevant framework for future comparative studies of flowering plant evolution.
In this study, the correlation between chip surface chromaticity and wear of cutting tools is established through experiments, and a system for judging and predicting tool wear by observing chip ...color is proposed. At present, the life prediction of cutting tools is indirectly measured and predicted by using vibration and current. In this study, chip color change is used to predict tool wear, and back-propagation Artificial Neural Networks (ANN) is used to predict and verify. The average error percentage between the predicted value and the actual value of tool wear is only 1.73% and 1.66%, respectively, which was confirmed by cutting test and verification experiments. This study uses Taylor’s tool life model and chip color to analyze, and after repeated tests and experimental analysis, the average error of repeatability is 4.5%. In the verification of stainless steel cutting hard-cutting materials, the equipment accuracy is between 0.5 and 3.0 color difference values of grade 2 to 3. Therefore, the measurement and model establishment of the system can accurately and quickly predict tool wear. In prediction experiment and analysis, the back neural network is used for test, the maximum error ranges are 0.0012 mm and 0.0097 mm, the mean error percentages are only 1.73% and 1.66%.
Since December 2019, the outbreak of infection caused by 2019 novel coronavirus (2019-nCoV) has become a major public health emergency worldwide. ...the chest CT scan of patient B revealed lesions of ...ground-glass opacity in the lower right lung suggesting viral infection. On admission, her vital signs were normal, with body temperature at 36.6°C, the pulse rate at 88 beats/min, respiratory rate at 20 breaths/min, blood pressure of 136/90 mmHg, and subcutaneous oxygen saturation (SpO2) of 99%. 3 In addition, from the epidemiological information, it can be deduced that her husband, patient B transmitted the viral infection to patient A. Although his CT scan had mild abnormality, he did not present with any symptoms until February 7, after his infection was confirmed.
Liver fibrosis is a serious liver disease associated with high morbidity and mortality. The activation of hepatic stellate cells (HSCs) and the overproduction of extracellular matrix proteins are key ...features during disease progression. In this work, chondroitin sulfate nanomicelles (CSmicelles) were developed as a delivery system targeting HSCs for the treatment of liver fibrosis. CS-deoxycholic acid conjugates (CS–DOCA) were synthesized via amide bond formation. Next, retinoic acid (RA) and doxorubicin (DOX) were encapsulated into CSmicells to afford a DOX+RA-CSmicelles codelivery system. CSmicelles were selectively taken up in activated HSCs and hepatoma (HepG2) cells other than in normal hepatocytes (LO2), the internalization of which was proven to be mediated by CD44 receptors. Interestingly, DOX+RA-CSmicelles preferentially accumulated in the Golgi apparatus, destroyed the Golgi structure, and ultimately downregulated collagen I production. Following tail-vein injection, DOX+RA-CSmicelles were delivered to the cirrhotic liver and showed synergistic antifibrosis effects in the CCl4-induced fibrotic rat model. Further, immunofluorescence staining of dissected liver tissues revealed CD44-specific delivery of CS derivatives to activated HSCs. Together, our results demonstrate the great potential of CS based carrier systems for the targeted treatment of chronic liver diseases.
Sequential transformations of unactivated C–O and C–H bonds under chromium catalysis are described. The use of a N-benzyl-substituted imino group as an auxiliary combined with chromium(II) chloride ...as a precatalyst and 2,3-dichlorobutane as an oxidant allows the arene C–O and C–H bonds to sequentially couple to arylmagnesium reagents to incorporate two identical or different aryl groups into the ortho positions of benzaldehydes.
Abstract
Background
The expression of the Bcl‐2 protein is frequently observed in basal cell carcinomas (BCCs), making it a significant biological marker and potential therapeutic target. Skin ...ultrasonography offers a noninvasive means of obtaining anatomical information about cutaneous tumors.
Objectives
The purpose of this study was to investigate the correlation between ultrasound features and Bcl‐2 expression in BCCs, to provide a reference for developing pharmacological treatment plans.
Methods
According to the Bcl‐2 protein expression, 74 BCCs confirmed by surgical pathology were divided into high Bcl‐2 expression BCCs (HB‐BCCs) and low Bcl‐2 expression BCCs (LB‐BCCs). Preoperative lesion ultrasound features were analyzed retrospectively based on Liang's criteria, which included the following features: shape, surface, keratinization, base, infiltration level, internal echogenicity, distribution of hyperechoic spots, posterior echogenic changes, internal Doppler signal, and lesion size (maximum diameter and infiltration depth). The differences of two groups were compared using a chi‐square test or a paired t‐test.
Results
Based on ultrasound features, cystic areas were more frequent in LB‐BCCs (
χ
2
= 7.015,
P
= .008). Furthermore, LB‐BCCs exhibited greater infiltration depth than HB‐BCCs (4.86 ± 2.12 mm vs. 2.72 ± 1.40 mm,
P
= .000), had a higher propensity to infiltrate the subcutaneous tissue (
χ
2
= 12.422,
P
= .002), and displayed a more abundant internal Doppler signal within the lesions (
χ
2
= 24.696,
P
= .000). Conversely, maximum diameter of the lesions, shape, surface, keratinization, base, hyperechoic spots distribution, and posterior echogenic changes of the lesions did not differ significantly between the two groups.
Conclusions
Ultrasound features are correlated with Bcl‐2 protein expression level in BCCs. LB‐BCCs show greater infiltration depth, subcutaneous infiltration, more cystic changes and more abundant internal Doppler signal than HB‐BCCs, which may suggest a potential basis for drug selection in BCC chemotherapy.
Sargassum fusiforme polysaccharides (SFPs), including SFP-3-40, SFP-3-60, SFP-3-80, SFP-7-40, SFP-7-60, SFP-7-80, SFP-10-40, SFP-10-60, and SFP-10-80, were extracted at different pH (3, 7, and 10), ...and then precipitated with graded precipitation of 40%, 60% and 80% (v/v) ethanol solution, respectively. Their physicochemical properties and α-glucosidase inhibitory activity were determined. Results showed that SFPs significantly differed in the contents of total sugar, protein, uronic acid, sulfate, the zeta potential, and molecular weight distribution. SFPs, including SFP-10-40, SFP-10-60, and SFP-10-80, had bigger absolute zeta potential value and higher respective average molecular weight in the same ethanol concentration precipitate. All samples were mainly composed of fucose, glucuronic acid, and mannose with different molar ratios. The extraction pH and precipitation ethanol solution concentration caused little changes in functional groups, but significantly altered surface morphology of SFPs. Congo red test revealed that all polysaccharides were not helical polysaccharides. Rheological measurements indicated that SFPs were pseudoplastic fluids and showed elastic behavior of the gel. Except SFP-3-40 and SFP-3-60, all other samples had a stronger α-glucosidase inhibitory activity than that of acarbose. The inhibition type of SFPs against α-glucosidase varied owing to different extraction pH and precipitation ethyl concentration. This study shows that extraction pH can significantly affect the structure and hypoglycemic activity of SFPs and provide a data support for the scientific use of Sargassum fusiforme in industrial production.
Display omitted
•Nine polysaccharide fractions were obtained from Sargassum fusiforme (Harv.) Setch at different extraction pH.•The physicochemical properties of SFPs were significant different.•SFP-7-40 showed the strongest α-glucosidase inhibitory activity with IC50 values of 0.304 mg/mL.
Photodynamic therapy (PDT) is an emerging therapeutic approach that can inhibit tumor growth by destroying local tumors and activating systemic antitumor immune responses. However, PDT can be ...ineffective because of photosensitizer aggregation, tumor-induced dendritic cells (DCS) dysfunction and PDT-mediated immunosuppression. Therefore, we designed chondroitin sulfate-based prodrug nanoparticles for the co-delivery of the photosensitizer chlorin e6 (Ce6) and retinoic acid (RA), which can reduce PDT-mediated immunosuppression by disrupting the Golgi apparatus and blocking the production of immunosuppressive cytokines. Moreover, CpG oligodeoxynucleotide was combined as immunoadjuvant to promote the maturation of DCs. As expected, the strategy of Golgi apparatus targeting immunotherapy combined PDT was confirmed to relieve PDT-induced immunosuppression, showed excellent PDT antitumor efficacy in B16F10-subcutaneous bearing mice model. Thus, our finding offers a promising approach for photodynamic immunotherapy of advanced cancers.
Golgi apparatus has been shown to be a potential target of immunosuppression for producing several immunosuppressive cytokines. In this work, a Golgi apparatus-targeted prodrug nanoparticle was developed to enhance the immune response in photodynamic immunotherapy. The nanoparticle can target and disrupt the Golgi apparatus in tumor cells, which reduced PDT-mediated immunosuppression by blocking the production of immunosuppressive cytokines. This work provides an effective strategy of PDT in combination with the Golgi apparatus-targeted nanovesicle for enhanced cancer therapy.
Display omitted
Multidrug resistance has remained a major cause of treatment failure in chemotherapy due to the presence of P-glycoproteins (P-gp) that actively pump drugs from inside the cell to the outside. P-gp ...inhibitors were developed and coadministered with chemotherapeutic drugs to overcome the effect of efflux pumps thus enhancing the chemosensitivity of therapeutics. Our study aimed at developing a lipid nanoemulsion system for the coencapsulation of doxorubicin (DOX) and bromotetrandrine (W198) to reverse multidrug resistance (MDR) in breast cancer. W198 was a potent P-gp inhibitor, and DOX was selected as a model compound which is a common substrate for P-gp. Coencapsulated DOX and W198 lipid nanoemulsions (DOX/W198-LNs) displayed significantly enhanced cytotoxicity in DOX-resistant human breast cancer cells (MCF-7/ADR) compared with DOX loaded lipid nanoemulsions (DOX-LNs) (p < 0.05), which is due to the enhanced intracellular uptake of DOX in MCF-7/ADR cells. The biodistribution study was performed using a nude mice xenograft model, which demonstrates enhanced tumor uptake of DOX in the DOX/W198-LN treated group. Compared with DOX solution, DOX/W198-LNs showed reduced cardiac toxicity and gastrointestinal injury in rats. Taken together, DOX/W198-LNs represent a promising formulation for overcoming MDR in breast cancer.
PDF
