Background: The clearance of nanomaterials (NMs) from the liver is essential for clinical safety, and their hepatic clearance is primarily determined by the co-disposition process of various types of ...hepatic cells. Studies of this process and the subsequent clearance routes are urgently needed for organic NMs, which are used as drug carriers more commonly than the inorganic ones. Materials and methods: In this study, the co-disposition of chitosan-based nanoparticles (CsNps) by macrophages and hepatocytes at both the cellular and animal levels as well as their subsequent biological elimination were investigated. RAW264.7 and Hepa1-6 cells were used as models of Kupffer cells and hepatocytes, respectively. Results: The cellular studies showed that CsNps released from RAW264.7 cells could enter Hepa1-6 cells through both clathrin- and caveolin-mediated endocytosis. The transport from Kupffer cells to hepatocytes was also studied in mice, and it was observed that most CsNps localized to the hepatocytes after intravenous injection. Following the distribution in hepatocytes, the hepatobiliary-fecal excretion route was shown to be the primary elimination route for CsNps, besides the kidney-urinary excretion route. The elimination of CsNps in mice was a lengthy process, with a half time of about 2 months. Conclusion: The demonstration in this study of the transport of CsNps from macrophages to hepatocytes and the subsequent hepatobiliary-fecal excretion provides basic information for the future development and clinical application of NMs. Keywords: chitosan nanoparticles, hepatocytes, macrophages, disposition, hepatobiliary-fecal elimination
A self-powered microRNA biosensor with triple signal amplification systems was assembled through the integration of three-dimensional DNA walkers, enzymatic biofuel cells and a capacitor. The DNA ...walker is designed from an enzyme-free target triggered catalytic hairpin assembly of modified gold nanoparticles. When triggered by the target microRNA, the DNA walker will move along the catalytic hairpin track, resulting in a payload release of glucose oxidase. The enzymatic biofuel cell contains the glucose oxidase bioanode and a bilirubin oxidase biocathode that bring a dramatic open circuit voltage to realize the self-powered bioassays of microRNA. A capacitor is further coupled with the enzymatic biofuel cell to further amplify the electrochemical signal, and the sensitivity increases 28.82 times through optimizing the matching capacitor. Based on this design, the present biosensor shows high performance, especially for detection limit and sensitivity. Furthermore, the present biosensor was successfully applied for serum samples, directly demonstrating its good application in clinical biomedicine and disease diagnosis.
To investigated the effects of sufentanil in combination with flurbiprofen axetil and dexmedetomidine for patient-controlled intravenous analgesia (PCIA) on patients after open gastrointestinal tumor ...surgery, and compared this combination with traditional PCIA with pure opioids or epidural analgesia (PCEA).
Patients (n = 640) who underwent open gastrointestinal tumor surgery and received patient-controlled analgesia (PCA) were included. According to the type of PCA, patients were assigned to three groups: MPCIA (PCIA with sufentanil, flurbiprofen axetil, dexmedetomidine and metoclopramide), OPCIA (PCIA with sufentanil, tramadol and metoclopramide) and PCEA group (PCEA with sufentanil and ropivacaine). The characteristics of patients, intraoperative use of analgesics, postoperative visual analogue scale (VAS), postoperative adverse reactions and postoperative recovery were collected. The primary outcome was postoperative VAS score. One-way ANOVA, Kruskal-Wallis H test, Fisher exact probability method, and binary logistic regression analysis were used for analysis.
There were no significant differences in the characteristics of patients, operation time, tumor site and the use of postoperative rescue analgesics among the groups. In the first two days after open gastrointestinal tumor surgery, the VAS (expressed by median and interquartile range) of MPCIA (24
h, resting: 1,1; movement: 3,2. 48
h, resting: 0,1; movement: 2,1.) and PCEA (24
h, resting: 0,1; movement: 2,1. 48
h, resting: 0,1; movement: 2,2.) groups were significantly lower than those of OPCIA group (24
h, resting: 2.5,2; movement: 4,2. 48
h, resting: 1.5,1.75; movement: 3,1.) (all p < 0.01). The incidence of postoperative nausea and vomiting in MPCIA group was 13.6% on the first day after surgery, which was significantly higher than that in PCEA group. There was no significant difference in the incidence of other postoperative adverse events. Higher intraoperative sufentanil dosage (OR (95%CI) = 1.017 (1.002-1.031), p = 0.021), lower body mass index (OR (95%CI) = 2.081 (1.059-4.089), p = 0.033), and tumor location above duodenum (OR (95%CI) = 2.280 (1.445-3.596), p < 0.001) were associated with poor postoperative analgesia.
The analgesic effects of PCIA with sufentanil in combination with flurbiprofen axetil and dexmedetomidine on postoperative analgesia was better than that of traditional pure opioids PCIA, and similar with that of PCEA.
Abstract
The development of fast-response sensors for detecting NH
3
at room temperature remains a formidable challenge. Here, to address this challenge, two highly robust Hoffmann-type metal-organic ...frameworks are rationally applied as the NH
3
sensing materials which possess ultra-high static adsorption capacity for NH
3
, only lower than the current benchmark material. The adsorption mechanism is in-depth unveiled by dynamic adsorption and simulation studies. The assembled interdigital electrode device exhibits low detection limit (25 ppb) and short response time (5 s) at room temperature, which set a record among all electrical signal sensors. Moreover, the sensor exhibits excellent selectivity towards NH
3
in the presence of 13 other potential interfering gases. Prominently, the sensor can stably output signals for more than two months at room temperature and can be recovered by simply purging nitrogen at room temperature without heating. This study opens up a way for reasonably designing gas sensing materials for toxic gases.
Consider a mobile client who travels over roads and wishes to receive location-based services (LBS) from untrusted service providers. How might the user obtain such services without exposing her ...private position information? Meanwhile, how could the privacy protection mechanism incur no disincentive, e.g., excessive computation or communication cost, for any service provider or mobile user to participate in such a scheme? We detail this problem and present a general model for privacy-aware mobile services. A series of key features distinguish our solution from existing ones: a) it adopts the
network-constrained
mobility model (instead of the conventional
random-waypoint
model) to capture the privacy vulnerability of mobile users; b) it regards the attack resilience (for mobile users) and the query-processing cost (for service providers) as two critical measures for designing location privatization solutions, and provides corresponding analytical models; c) it proposes a robust and scalable location anonymization model, XStar, which best leverages the two measures; d) it introduces multi-folded optimizations in implementing XStar, which lead to further performance improvement. A comprehensive experimental evaluation is conducted to validate the analytical models and the efficacy of XStar.
Long non-coding RNAs (lncRNAs) are a growing focus in cancer research. Deciphering pathways influenced by lncRNAs is important to understand their role in cancer. Although knock-down or ...overexpression of lncRNAs followed by gene expression profiling in cancer cell lines are established approaches to address this problem, these experimental data are not available for a majority of the annotated lncRNAs.
As a surrogate, we present lncGSEA, a convenient tool to predict the lncRNA associated pathways through Gene Set Enrichment Analysis of gene expression profiles from large-scale cancer patient samples. We demonstrate that lncGSEA is able to recapitulate lncRNA associated pathways supported by literature and experimental validations in multiple cancer types.
LncGSEA allows researchers to infer lncRNA regulatory pathways directly from clinical samples in oncology. LncGSEA is written in R, and is freely accessible at https://github.com/ylab-hi/lncGSEA .
Increased fat mass and fat redistribution are commonly observed in aging populations worldwide. Although decreased circulating levels of sex hormones, androgens and oestrogens have been observed, the ...exact mechanism of fat accumulation and redistribution during aging remains obscure. In this study, the receptor of follicle-stimulating hormone (FSH), a gonadotropin that increases sharply and persistently with aging in both males and females, is functionally expressed in human and mouse fat tissues and adipocytes. Follicle-stimulating hormone was found to promote lipid biosynthesis and lipid droplet formation; FSH could also alter the secretion of leptin and adiponectin, but not hyperplasia, in vitro and in vivo. The effects of FSH are mediated by FSH receptors coupled to the Gαi protein; as a result, Ca(2+) influx is stimulated, cAMP-response-element-binding protein is phosphorylated, and an array of genes involved in lipid biosynthesis is activated. The present findings depict the potential of FSH receptor-mediated lipodystrophy of adipose tissues in aging. Our results also reveal the mechanism of fat accumulation and redistribution during aging of males and females.
We performed a Bayesian network meta-analysis to indirectly compare the relative efficacy and safety of the latest JAK inhibitors for moderate-to-severe alopecia areata (AA). 13 trials totaling 3,613 ...patients were included. Two low-dose groups of oral formulations (ritlecitinib 10mg and ivarmacitinib 2mg) and two topical formulations (delgocitinib ointment and ruxolitinib cream) appeared to be relatively ineffective against moderate-to-severe AA. Ranking analysis suggested that brepocitinib 30mg has the best relative effect in reducing the SALT score (sucra = 0.9831), and demonstrated comparable efficacy to deuruxolitinib 12mg (sucra = 0.9245), followed by deuruxolitinib 8mg (sucra = 0.7736). Regarding the SALT
response, brepocitinib 30mg ranked highest (sucra = 0.9567), followed by ritlecitinib 50mg (sucra = 0.8689) and deuruxolitinib 12mg (sucra = 0.7690). For achieving the SALT
response, deuruxolitinib 12mg had the highest probability (sucra = 0.9761), followed by deuruxolitinib 8mg (sucra = 0.8678) and brepocitinib 30mg (sucra = 0.8448). Deuruxolitinib 12mg might be the most effective therapy for patients with severe AA (sucra = 0.9395), followed by ritlecitinib 50mg (sucra = 0.8753) and deuruxolitinib 8mg (sucra = 0.8070). Deuruxolitinib 12mg/8mg demonstrated notable efficacy for moderate-to-severe AA, and is expected to be a new treatment option for AA. It was worth noting that deuruxolitinib exhibit a greater likelihood of causing adverse events in comparison to other JAK inhibitors. Ritlecitinib 50mg seemed to exhibit fewer adverse effects in the high-dose groups of oral JAK inhibitors and might be an optimal choice to balance safety and efficacy. The majority of JAK inhibitors exhibited acceptable short-term safety profiles. To enhance the applicability and accuracy of our research, further head-to-head trials with longer follow-up periods are needed.
identifier CRD42022368012.
Epigenetic regulation is important for cancer progression; however, the underlying mechanisms, particularly those involving protein acetylation, remain to be fully understood. Here, we show that ...p300/CBP‐associated factor (PCAF)‐dependent acetylation of the transcription factor intestine‐specific homeobox (ISX) regulates epithelial–mesenchymal transition (EMT) and promotes cancer metastasis. Mechanistically, PCAF acetylation of ISX at lysine 69 promotes the interaction with acetylated bromodomain‐containing protein 4 (BRD4) at lysine 332 in tumor cells, and the translocation of the resulting complex into the nucleus. There, it binds to promoters of EMT genes, where acetylation of histone 3 at lysines 9, 14, and 18 initiates chromatin remodeling and subsequent transcriptional activation. Ectopic ISX expression enhances EMT marker expression, including TWIST1, Snail1, and VEGF, induces cancer metastasis, but suppresses E‐cadherin expression. In lung cancer, ectopic expression of PCAF–ISX–BRD4 axis components correlates with clinical metastatic features and poor prognosis. These results suggest that the PCAF–ISX–BRD4 axis mediates EMT signaling and regulates tumor initiation and metastasis.
Synopsis
The PCAF–ISX–BRD4 axis is an important regulator of tumor metastasis and cell plasticity. PCAF‐mediated acetylation of the transcription factor ISX promotes translocation of ISX‐BRD4 to the nucleus to activate EMT genes and to induce metastasis.
ISX transactivates genes encoding EMT regulators and promotes EMT.
PCAF acetylation of ISX is essential for ISX–BRD4 complex formation, and induces EMT and cancer cell metastasis.
PCA, ISX and BRD4 show high expression correlation with clinical outcomes and prognosis in patients with NSCLC.
The PCAF–ISX–BRD4 axis is an important regulator of tumor metastasis and cell plasticity. PCAF‐mediated acetylation of the transcription factor ISX promotes translocation of ISX‐BRD4 to the nucleus to activate EMT genes and to induce metastasis.
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Berberine (BBR) is a non-prescription drug to treat various bacteria-associated diarrheas. However, BBR has also been reported to cause diarrhea in clinic, with underlying mechanisms ...poorly understood. Because altered gut microbial ecology is a potential basis for diarrhea, this study was conducted to investigate the impact of BBR on gut microbiota of treatment-emergent diarrhea. BBR treatment (200 mg/kg, i.g.) in normal rats exhibited no significant changes in serum biochemical parameters but mild diarrhea occurred, accompanied with the decreased gastrointestinal transit time and increased fecal moisture, suggestive of the local effects of BBR in the intestine. Colon histology revealed the decreased abundance of mucus-filled goblet cells in BBR group. Although BBR-treated rats had the enlarged cecum with watery caecal digesta, short-chain fatty acids concentration was significantly lower than control group. Additionally, BBR caused gut microbiota dysbiosis by evaluating the decreased observed species number and Shannon index. BBR increased the relative abundances of families Porphyromonadaceae and Prevotellaceae as well as genera Parabacteroides, Prevotellaceae_UCG-001 and Prevotellaceae_NK3B31_group. Spearman’s correlation analysis revealed family Prevotellaceae and genus Prevotellaceae_UCG-001 as the most prominent drivers of the BBR treatment-emergent diarrhea, correlating positively with fecal moisture but negatively with gastrointestinal transit time. This study therefore demonstrated that the treatment-emergent mild diarrhea of BBR was most likely due to the dysbiosis of the gut microbiota.
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