Characterization of Acellular Cartilage Matrix-Sodium Alginate Scaffolds in Various Proportions.

The development of three-dimensional (3D) bioprinting technology has provided a new solution to address the shortage of donors, multiple surgeries, and aesthetic concerns in microtia reconstruction surgery. The production of bioinks is the most critical aspect of 3D bioprinting. Acellular cartilage matrix (ACM) and sodium alginate (SA) are commonly used 3D bioprinting materials, and there have been reports of their combined use. However, there is a lack of comprehensive evaluations on ACM-SA scaffolds with different proportions. In this study, bioinks were prepared by mixing different proportions of decellularized rabbit ear cartilage powder and SA and then printed using 3D bioprinting technology and crosslinked with calcium ions to fabricate scaffolds. The physical properties, biocompatibility, and toxicity of ACM-SA scaffolds with different proportions were compared. The adhesion and proliferation of rabbit adipose-derived stem cells on ACM-SA scaffolds of different proportions, as well as the secretion of Collagen Type II, were evaluated under an adipose-derived stem cell chondrogenic induction medium. The following conclusions were drawn: when the proportion of SA in the ACM-SA scaffolds was <30%, the printed structure failed to form. The ACM-SA scaffolds in proportions from 1:9 to 6:4 showed no significant cytotoxicity, among which the 5:5 proportion of ACM-SA scaffold was superior in terms of adhesiveness and promoting cell proliferation and differentiation. Although a higher proportion of SA can provide greater mechanical strength, it also significantly increases the swelling ratio and reduces cell proliferation capabilities. Overall, the 5:5 proportion of ACM-SA scaffold demonstrated a more desirable biological and physical performance.

Microneedle-mediated nose-to-brain drug delivery for improved Alzheimer's disease treatment.

Conventional transnasal brain-targeted drug delivery strategies are limited by nasal cilia clearance and the nasal mucosal barrier. To address this challenge, we designed dissolving microneedles combined with nanocarriers for enhanced nose-to-brain drug delivery. To facilitate transnasal administration, a toothbrush-like microneedle patch was fabricated with hyaluronic acid-formed microneedles and tannic acid-crosslinked gelatin as the base, which completely dissolved in the nasal mucosa within seconds leaving only the base, thereby releasing the loaded cyclodextrin-based metal-organic frameworks (CD-MOFs) without affecting the nasal cilia and nasal microbial communities. As nanocarriers for high loading of huperzine A, these potassium-structured CD-MOFs, reinforced with stigmasterol and functionalized with lactoferrin, possessed improved physical stability and excellent biocompatibility, enabling efficient brain-targeted drug delivery. This delivery system substantially attenuated H2O2- and scopolamine-induced neurocyte damage. The efficacy of huperzine A on scopolamine- and D-galactose & AlCl3-induced memory deficits in rats was significantly improved, as evidenced by inhibiting acetylcholinesterase activity, alleviating oxidative stress damage in the brain, and improving learning function, meanwhile activating extracellular regulated protein kinases-cyclic AMP responsive element binding protein-brain derived neurotrophic factor pathway. Moreover, postsynaptic density protein PSD-95, which interacts with two important therapeutic targets Tau and ß-amyloid in Alzheimer's disease, was upregulated. This fruitful treatment was further shown to significantly ameliorate Tau hyperphosphorylation and decrease ß-amyloid by ways including modulating beta-site amyloid precursor protein cleaving enzyme 1 and a disintegrin and metalloproteinase 10. Collectively, such a newly developed strategy breaks the impasse for efficient drug delivery to the brain, and the potential therapeutic role of huperzine A for Alzheimer's disease is further illustrated.

Correlation Between N-Demethyl Imatinib Trough Concentration and Serious Adverse Reactions in Patients with Gastrointestinal Stromal Tumors: A Retrospective Cohort Study.

BACKGROUND: Imatinib is the first-line treatment for gastrointestinal stromal tumors; however, the clinical prognosis and adverse reactions of patients vary owing to individualized discrepancies in plasma exposure. METHODS: To determine the safe interval for steady-state plasma trough concentrations (C min ) of imatinib and its active metabolite, N-demethyl imatinib (NDI), 328 plasma samples from 273 patients treated with imatinib were retrospectively analyzed. Imatinib C min and NDI C min were tested, and adverse reactions were recorded. The association between imatinib C min , NDI C min , and serious adverse reactions was evaluated. RESULTS: The C min range of imatinib was 209.5-4950.0 ng/mL, with the mean value and SD of 1491.8 ± 731.4 ng/mL. The C min range of NDI was 80.0-2390.0 ng/mL with the mean value and SD of 610.8 ± 281.5 ng/mL. NDI C min was positively correlated with imatinib C min , whereas the ratio of NDI C min to imatinib C min (NDI C min /imatinib C min ) was negatively correlated with imatinib C min . Univariate logistic regression analysis demonstrated that the treatment objective, daily dose, imatinib C min , NDI C min , and imatinib C min + NDI C min were significantly associated with serious adverse reactions. Multivariate logistic regression analysis showed that NDI C min was an independent risk factor for serious adverse reactions, with a threshold of 665 ng/mL. CONCLUSIONS: NDI C min was an independent risk factor for serious adverse reactions, with a threshold of 665 ng/mL. Monitoring NDI C min was beneficial for the rational application of imatinib and individualized treatment of patients with gastrointestinal stromal tumors.

A Compound Essential Oil Alters Stratum Corneum Structure, Potentially Promoting the Transdermal Permeation of Hydrophobic and Hydrophilic Ingredients.

BACKGROUND: The stratum corneum (SC) is the main barrier of the skin, and cosmeceuticals are different from ordinary cosmetics in that they need to deliver active ingredients targeting specific skin problems through the SC into the deeper layers of the skin. Thus, we designed a compound essential oil (CEO) extracted from Salvia miltiorrhiza Bge and Cinnamomum cassia Presl, supplemented with borneol to deliver active ingredients through the SC. METHODS: The CEO was prepared by flash extraction combined with the microwave method. Moreover, the main components of the CEO were determined using gas chromatography-mass spectrometry (GCMS). Visualization techniques, such as scanning electron microscopy (SEM), haematoxylin-eosin (HE) staining, and confocal laser scanning microscopy (CLSM), were used to study the permeationpromoting mechanism of the CEO on the skin. Furthermore, the permeation-promoting effects of the CEO on both hydrophobic and hydrophilic ingredients were tested via in vitro skin penetration experiments and in vivo microdialysis experiments. RESULTS: The results indicated the ability of the CEO to alter the structure of the SC, leading to enhanced transdermal permeation of hydrophobic and hydrophilic ingredients. The 1.5% CEO group demonstrated the best permeation-promoting effect compared to the other CEO groups and blank groups (P<0.05). Furthermore, the CEO displayed an expedited permeability-promoting effect on hydrophobic ingredients compared to hydrophilic ingredients. CONCLUSION: It is concluded that the prepared CEO can promote the transdermal permeation of hydrophobic and hydrophilic ingredients. This study will provide a reference for the application of the prepared CEO in the development of cosmeceuticals with natural efficacy.

Pharmacokinetic Interaction Between Imatinib and Metformin in Rats.

BACKGROUND AND OBJECTIVE: Imatinib is primarily transported into the liver by organic cation transporter 1 (OCT1), organic anion transporting polypeptide 1B3 (OATP1B3), and novel organic cation transporter 2 (OCTN2), which is the first step in the metabolic and elimination of imatinib. Patients taking imatinib may concurrently take metformin, a substrate for OCT1. Drug-drug interactions (DDI) may occur between imatinib and metformin, affecting the clinical efficacy of imatinib. This experiment aimed to investigate the pharmacokinetic effects of metformin on imatinib and its active metabolism of N-desmethyl imatinib in rats. METHODS: Twenty healthy Sprague-Dawley rats were selected and randomly divided into control and experimental groups (10 rats per group). The control group was orally administered imatinib (30 mg/kg) for 14 days, and the experimental group was orally co-administered imatinib (30 mg/kg) and metformin (200 mg/kg) for 14 days. The plasma concentrations of imatinib and N-desmethyl imatinib in rats were determined by ultra-performance liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by DAS2.0 software. RESULTS: After single-dose co-administration of imatinib and metformin on day 1, the AUC0-24 (area under the plasma concentration-time curve) and Cmax (maximum concentration) of imatinib and the MRT (mean residence time) and Cmax of N-desmethyl imatinib in the experimental group were significantly decreased compared with the control group (P < 0.05). After multiple-dose co-administration of imatinib and metformin for 14 days, the AUC0-24 and Cmax of both imatinib and N-desmethyl imatinib were significantly decreased in the experimental group (P < 0.05). CONCLUSION: With both single and multiple co-administration doses, metformin significantly changed the pharmacokinetic parameters of imatinib and N-desmethyl imatinib. The results suggest that care should be taken when metformin and imatinib are co-administered.

A dynamic study of the postoperative management of thyroid cancer from 2003 to 2022: a bibliometric analysis.

Background: Over the past 20 years, the global incidence of thyroid cancer has continued to increase. The volume of literature on the postoperative management of thyroid cancer comprises 1,040 articles, from 64 countries, with 1,400 journals publishing the relevant literature, and several guidelines on the treatment of thyroid cancer. This study used bibliometric methods to identify research hotspots and explore future directions in this field. Methods: We comprehensively searched the Science Citation Index Expanded (SCI-E) database of the Web of Science Core Collection (WOSCC) for articles published from 2003 to 2022 on the postoperative management of thyroid cancer. Using CiteSpace 6.1.R6 and Microsoft Office Excel 2010, we evaluated and visualized the search results. Using R Studio, we generated a network of spatial geographic distribution maps and cooperative network. Results: A total of 1,040 publications were included in the study. The results revealed an overall upward trend in the number of publications and citations over the past 20 years. The United States of America (USA) had the largest number of publications and the highest centrality (n=282, centrality =0.28). Johns Hopkins University had highest centrality (centrality =0.15) and was the academic center of the field. Thyroid was the journal with the highest number of citations (n=826), and the American Journal of Surgical Pathology was the journal with the highest centrality (centrality =0.08). The top 10 citations in the literature were mainly guidelines and consensus statements on the management of thyroid cancer. A keyword-based clustering analysis revealed the prominence of clusters of keywords, such as follow-up, recurrent laryngeal nerve, and medullary thyroid carcinoma (MTC). A keyword burst detection analysis showed that the term papillary had the highest burst intensity (strength =8.02), while management guidelines, association guidelines, active surveillance (AS), microcarcinoma, and differentiated thyroid cancer were the current burst words. Conclusions: Over the past two decades, the number of relevant publications in the postoperative management of thyroid cancer field has continued to grow. Among the many research directions, follow-up, recurrent laryngeal nerve, and MTC are research hotspots. Future research is likely to revolve around guidelines and consensus statements on the management of thyroid cancer, AS, and microcarcinoma in differentiated thyroid cancer.

Phytosterol-mediated glycerosomes combined with peppermint oil enhance transdermal delivery of lappaconitine by modulating the lipid composition of the stratum corneum.

Although the introduction of glycerosomes has enriched strategies for efficient transdermal drug delivery, the inclusion of cholesterol as a membrane stabilizer has limited their clinical application. The current study describes the development and optimization of a new type of glycerosome (S-glycerosome) that is formed in glycerol solution with ß-sitosterol as the stabilizer. Moreover, the transdermal permeation properties of lappaconitine (LA)-loaded S-glycerosomes and peppermint oil (PO)-mediated S-glycerosomes (PO-S-glycerosomes) are evaluated, and the lipid alterations in the stratum corneum are analyzed via lipidomics. The LA-loaded S-glycerosomes prepared by the preferred formulation from the uniform design have a mean size of 145.3 ± 7.81 nm and an encapsulation efficiency of 73.14 ± 0.35%. Moreover, the addition of PO positively impacts transdermal flux, peaking at 0.4% (w/v) PO. Tracing of the fluorescent probe P4 further revealed that PO-S-glycerosomes penetrate deeper into the skin than S-glycerosomes and conventional liposomes. Additionally, treatment with PO-S-glycerosomes alters the isoform type, number, and composition of sphingolipids, glycerophospholipids, glycerolipids, and fatty acids in the stratum corneum, with the most notable effect observed for ceramides, the main component of sphingolipids. Furthermore, the transdermal administration of LA-loaded PO-S-glycerosomes improved the treatment efficacy of xylene-induced inflammation in mice without skin irritation. Collectively, these findings demonstrate the feasibility of ß-sitosterol as a stabilizer in glycerosomes. Additionally, the inclusion of PO improves the transdermal permeation of S-glycerosomes, potentially by altering the stratum corneum lipids.

Bufalin reverses ABCB1-mediated resistance to docetaxel in breast cancer.

Background: Docetaxel (DCT) is widely used in clinical practice, but the drug resistance of breast cancer patients has become an important reason to limit its clinical efficacy. Chan'su is a commonly used traditional Chinese medicine for the treatment of breast cancer. Bufalin (BUF) is a bioactive polyhydroxy steroid extracted from chan'su and has strong antitumor activity, but there are few studies on reversing drug resistance in breast cancer. The aim of this study is to determine whether BUF can reverse the drug resistance to DCT and restore efficacy in breast cancer. Methodology: The reversal index of BUF was detected by Cell Counting Kit-8 (CCK-8) assays. The effects of BUF on enhancing the apoptosis of DCT were detected by flow cytometry and Western Blot (WB), and the main differential expression levels of sensitive and resistant strains were detected by high-throughput sequencing. Rhodamine 123 assay, WB and ATP Binding Cassette Subfamily B Member 1 (ABCB1) ATPase activity experiments were used to detect the effect of BUF on ABCB1. The nude mouse orthotopic model was constructed to investigate the reversal effect of BUF on DCT resistance in vivo. Results: With BUF intervention, the sensitivity of drug-resistant cell lines to DCT was increased. BUF can inhibit the expression of ABCB1 protein, increase the drug accumulation of DCT in drug-resistant strains, and reduce the ATPase activity of ABCB1. Animal experiments show that BUF can inhibit the growth of drug-resistant tumors in an orthotopic model of breast cancer and decrease the expression of ABCB1. Conclusion: BUF can reverse ABCB1-mediated docetaxel resistance in breast cancer.

ICG-ER: a new probe for photoimaging and photothermal therapy for breast cancer.

Breast cancer is common cancer type with high mortality. There are still inperfections in the traditional diagnosis and treatment methods for cancer. Photoacoustic imaging combines the advantages of high specificity and deep tissue penetration and is especially suitable for early cancer detection and treatment monitoring. With its specificity and noninvasiveness; photothermal therapy has become one of the best representative treatment methods. Indocyanine green (ICG) is a near-infrared imaging reagent approved by the FDA for clinical application, with a potential application for photothermal therapy. ICG has low targeting specificity. Through the combination of EB and ICG, the timeliness of ICG circulation in vivo is improved, and the tumor targeting of ICG-E is improved by using RGD. ICG-ER, an integrated optical probe for diagnosis and treatment, was constructed, and high uptake of ICG-ER by 4T1 cells was observed by flow cytometry and confocal laser scanning microscopy (CLSM). ICG-ER photoacoustic signal intensity is concentration-dependent. In vivo photoacoustic imaging showed that the ICG-ER concentration time in the tumor site was long and reached a peak at 42 hours. Under laser irradiation, the temperature of the tumor site in mice that were injected with ICG-ER reached 56°C. After photothermal treatment, the tumor tissue in the mice showed obvious necrosis and no tumor recurrence, proving that ICG-ER has a good photothermal effect. Based on the above results, ICG-ER can be used in breast cancer optical imaging and photothermal therapy, which is expected to provide new ideas for breast cancer clinical diagnosis and treatment.

[Improvement in compatibility of hot melt pressure-sensitive adhesive with cinnamon volatile oil and in vitro transdermal property by physical blending].

Hot melt pressure-sensitive adhesive(HMPSA) has broad application potential in the field of traditional Chinese medicine(TCM) plasters due to its high drug loading, weak skin irritation, satisfactory adhesion, etc. compared with rubber plasters.However, the structure of HMPSA is prone to suffer from the damage caused by volatile oils in TCM plasters. In view of this, a kind of HMPSA with a stable structure was prepared by physical blending of DINCH, polypropylene wax and liquid rubber(LIR) in the present study, which is denoted as DPL. The dosage of cinnamon volatile oil(CVO), the model drug, was selected with viscosity, softening point and cohesion as evaluation indexes. The interaction between DPL and HMPSA was investigated by Fourier transform infrared spectroscopy(FT-IR) and differential scanning calorimetry(DSC). The compatibility of HMPSA with CVO and its transdermal ability were studied by in vitro transdermal test, adhesion, scanning electron microscopy( SEM) and rheological evaluation. The results showed that 5% CVO began to damage the structure of HMPSA. The initial adhesion and holding adhesion of DPL-modified HMPSA(DPL-HMPSA) were not significantly changed compared with those of HMPSA, whereas the 180° peel strength was decreased. FI-IR unraveled that DPL formed the n-π conjugated system with styrene-isoprene-styrene block copolymer(SIS), and there was no significant difference in the glass transition temperature according to DSC results, which indicated the good compatibility of DPL with HMPSA. With 5% CVO loaded, the drug content of DPL-HMPSA was 1. 14 times higher than that of HMPSA, and the decrease rate of drug content in DPL-HMPSA was 16% lower than that in HMPSA after 3 months. SEM demonstrated that CVO did not cause obvious structural damage to DPL-HMPSA. Rheological evaluation revealed that the storage modulus and loss factor of DPL-HMPSA were higher than those of HMPSA, and the cohesion was also stronger. The percutaneous penetration rate of cinnamaldehyde in DPL-HMPSA was 2. 25 times that of HMPSA. In conclusion, DPL-HMPSA had more stable structure, better compatibility with CVO, and higher in vitro transdermal efficiency of cinnamaldehyde than before the modification. This study can provide reference for the mitigation of the matrix structure damage caused by volatile oil components in TCM plasters and the enhancement of the content and in vitro transdermal rate of drug.

Development of a new atmospheric pressure plasmaspray ionization for ambient mass spectrometry.

A new atmospheric pressure ionization method, plasmaspray ionization, termed as PSI, was developed to be an alternative ambient ion source for mass spectrometry. It comprises a plasma jet device and a sample spray part. While the nonthermal plasma jet strikes the surface of stainless steel tube out of the spray capillary, the sprayed sample will be ionized with the assistant of auxiliary gas. Although PSI is a little bit more complex than electrospray ionization (ESI) in instrument, it shows both better linearity and higher sensitivity for organic compounds. For protein samples, it presents wider distributions of multiply charged ions and higher mass resolution without sacrificing any sensitivity. For the mechanism of PSI, the charge build-up process on the tip of capillary should play a key role for the ion formation, and the stimulated pulsed voltage on the flow tube will promote the ion aggregation speed until the charge density is high enough. PSI source contains the features of plasma ionization and ESI and can be considered as a novel combo bridging these techniques. These results reflect that this method of PSI can be applied and further developed as a versatile new ion source for a wild range of organic and biological samples.

Temperature-sensitive gel-loaded composite nanomedicines for the treatment of cervical cancer by vaginal delivery.

In this study, toad venom (TV) and realgar were loaded into a poloxamer 188/407 (F127/F188)-based temperature-sensitive in situ gel (TISG) and encapsulated in solid lipid nanoparticles (TV-SLN) or ground nano-realgar (NR) to improve drug release and reduce local irritation after vaginal administration. The combination of TV-SLN and NR (TV-SLN/NR) greatly enhanced the inhibition of tumor cell proliferation and was most effective at a dose ratio of 2:3 (w/w). After TV-SLN/NR treatment, S and G0/G1 phase arrest were observed in HeLa and SKOV-3 cells and the inhibitory effects on proliferation were stronger than those in the conventional powder group. The gelation temperature of TV-SLN and NR-loaded TISG (TV-SLN/NR-TISG) using the selected formulation was 33 ± 0.91 °C. The cumulative release of the drug increased as the dissolution of gel progressed, showing a linear relationship (r > 0.99). TV-SLN/NR-TISG enabled the sustained release of cargo by adhesion to the vaginal mucosa and showed excellent biocompatibility during continuous administration for 7 days. We specifically demonstrated the effectiveness of the TISG for the vaginal delivery of TV-SLN and NR, supporting its important clinical implications for the treatment of cervical cancer.

Folic acid modified lipid-bilayer coated mesoporous silica nanoparticles co-loading paclitaxel and tanshinone IIA for the treatment of acute promyelocytic leukemia.

In this work, paclitaxel (Ptx) combined with tanshinone IIA (TanIIA) was found to show synergistic effect on inducing apoptosis of human acute promyelocytic leukemia (APL) cell line NB4, and the anti-tumor effect was strongest when its molar ratio was 1:1. To enhance the efficacy and reduce side effects, an active targeting drug delivery system with mesoporous silica nanoparticles (MSNs) coated with folic acid (FA) modified PEGylated lipid-bilayer (LB) membrane (FA-LB-MSNs) was established for co-loading drugs. The drug loadings of Ptx and TanIIA in FA-LB-MSNs were 5.5% and 1.8%, respectively. Compared with the uncoated MSNs, the FA-LB-MSNs showed a sustained drug release, and Ptx and TanIIA released synchronously from the carriers. By means of biological adhesion between FA and its receptors, the uptake of FA-LB-MSNs by NB4 cells was significantly higher than that of uncoated preparations, and Ptx combined with TanIIA had strong synergistic effect to enhance the apoptosis and differentiation of NB4 cells. The results of pharmacodynamics in vivo showed that the FA-LB-MSNs targeted tumor in nude mice more effectively than the compared formulations without FA modification. The Ptx and TanIIA-loaded FA-LB-MSNs group showed significantly better effects on inducing apoptosis and inhibiting tumor growth than the reference groups, which agreed with the results of anti-tumor experiments in vitro. Furthermore, no toxicity was observed to the heart, liver, spleen, lung and kidney of the tumor-bearing animals, indicating good biocompatibility of the prepared novel nanocarriers. This study confirmed the synergistic therapeutic effect of Ptx and TanIIA on APL, and the superior of FA-LB-MSNs as co-loaded nanocarriers for active targeted therapy of tumors.

Co-hybridized composite nanovesicles for enhanced transdermal eugenol and cinnamaldehyde delivery and their potential efficacy in ulcerative colitis.

Percutaneous absorption of drugs can be enhanced by ethosomes, which are nanocarriers with excellent deformability and drug-loading properties. However, the ethanol within ethosomes increases phospholipid membrane fluidity and permeability, leading to drug leakage during storage. Here, we developed and characterized a new phospholipid nanovesicles that is co-hybridized with hyaluronic acid (HA), ethanol and the encapsulated volatile oil medicines (eugenol and cinnamaldehyde [EUG/CAH]) for transdermal administration. In comparison with EUG/CAH-loaded ethosomes (ES), the formulation stability and percutaneous drug absorption of EUG/CAH-loaded HA-immobilized ethosomes (HA-ES) were significantly improved. After transdermal administration of HA-ES, the interstitial cells of Cajal in the colon of rats with trinitrobenzene sulfonate-induced ulcerative colitis (UC) were significantly increased, and the stem cell factor/c-kit signaling pathway was partly repaired. Overall, HA-ES possesses excellent deformability and showed improved efficacy against UC compared with ES, which is demonstrated as a promising transdermal delivery vehicle for volatile oil medicines.

Cortical Neural Stem Cell Lineage Progression Is Regulated by Extrinsic Signaling Molecule Sonic Hedgehog.

Neural stem cells (NSCs) in the prenatal neocortex progressively generate different subtypes of glutamatergic projection neurons. Following that, NSCs have a major switch in their progenitor properties and produce γ-aminobutyric acid (GABAergic) interneurons for the olfactory bulb (OB), cortical oligodendrocytes, and astrocytes. Herein, we provide evidence for the molecular mechanism that underlies this switch in the state of neocortical NSCs. We show that, at around E16.5, mouse neocortical NSCs start to generate GSX2-expressing (GSX2+) intermediate progenitor cells (IPCs). In vivo lineage-tracing study revealed that GSX2+ IPC population gives rise not only to OB interneurons but also to cortical oligodendrocytes and astrocytes, suggesting that they are a tri-potential population. We demonstrated that Sonic hedgehog signaling is both necessary and sufficient for the generation of GSX2+ IPCs by reducing GLI3R protein levels. Using single-cell RNA sequencing, we identify the transcriptional profile of GSX2+ IPCs and the process of the lineage switch of cortical NSCs.

Unexpected culprit of increased estrogenic effects: Oligomers in the photodegradation of preservative ethylparaben in water.

Widespread occurrence of emerging organic contaminants (EOCs) in water have been explicitly associated with adverse effects on human health, therefore representing a major risk to public health. Especially the increased toxicity is frequently observed during the photodegradation of EOCs in natural water, and even wastewater treatment plants. However, the culprit of increased toxicity and formation mechanism has yet to be recognized regarding the estrogenic activity. In this study, by combining laboratory experiments with quantum chemical calculations, the induction of human estrogenic activity was investigated using the yeast two-hybrid reporter assay during the photodegradation of preservatives ethylparaben (EP), along with identification of toxic products and formation mechanisms. Results showed that the increase in estrogenic effect was induced by photochemically generated oligomers, rather than the expected OH-adduct. The maximum estrogenic activity corresponded to the major formation of oligomers, while OH-adducts were less than 12%. Two photochemically generated oligomers were found to contribute to estrogenic activity, produced from the cleavage of excited triplet state molecules and subsequent radical-radical reactions. Computational toxicology results showed that the increased estrogenic activity was attributed to oligomer [4-Hydroxy-isophthalic acid 1-ethyl ester 3-(4-hydroxy-phenyl)] and its EC50 was lower than that of the parent EP. In contrast, OH-adducts exhibited higher EC50 values than the parent EP, while still possessing estrogenic activity. Therefore, more attention should be paid to these photodegradation products of EOCs, including OH-adducts.

Activation of a gamma-cyclodextrin-based metal-organic framework using supercritical carbon dioxide for high-efficient delivery of honokiol.

A facile method for the activation of γ-cyclodextrin metal-organic framework (CD-MOF) without channel blockage and framework collapse was first developed using supercritical carbon dioxide (scCO2), which enabled higher surface area and larger pore volume. The scCO2-assisted impregnation method was also applied to introduce the insoluble drug, honokiol (HNK), into the pores of CD-MOF with higher cargo loading compared to the conventional liquid phase incorporation in ethanol. Notably, the resulting HNK-loaded CD-MOF (HNK@CD-MOF) had improved apparent solubility and enhanced dissolution rate. The intestinal cellular uptake and transport experiments demonstrated that CD-MOF could enhance cellular uptake and increase drug transport across the intestinal epithelial cells compared to the cyclodextrin inclusion complex. Moreover, the in vivo pharmacokinetic studies further confirmed that CD-MOF could significantly improve the oral absorption and bioavailability of HNK. Overall, the scCO2 activation and scCO2-assisted impregnation approaches were demonstrated as promising strategies to maximize the potential capability of CD-MOF.

Repression of Death Receptor-Mediated Apoptosis of Hepatocytes by Hepatitis B Virus e Antigen.

Hepatitis B virus (HBV) e antigen (HBeAg) is associated with viral persistence and pathogenesis. Resistance of HBV-infected hepatocytes to apoptosis is seen as one of the primary promotors for HBV chronicity and malignancy. Fas receptor/ligand (Fas/FasL) and the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) system plays a key role in hepatic death during HBV infection. We found that HBeAg mediates resistance of hepatocytes to FasL or TRAIL-induced apoptosis. Introduction of HBeAg into human hepatocytes rendered resistance to FasL or TRAIL cytotoxicity in a p53-dependent manner. HBeAg further inhibited the expression of p53, total Fas, membrane-bound Fas, TNF receptor superfamily member 10a, and TNF receptor superfamily member 10b at both mRNA and protein levels. In contrast, HBeAg enhanced the expression of soluble forms of Fas through facilitation of Fas alternative mRNA splicing. In a mouse model, expression of HBeAg in mice injected with recombinant adenovirus-associated virus 8 inhibited agonistic anti-Fas antibody-induced hepatic apoptosis. Xenograft tumorigenicity assay also found that HBeAg-induced carcinogenesis was resistant to the proapoptotic effect of TRAIL and chemotherapeutic drugs. These results indicate that HBeAg may prevent hepatocytes from FasL and TRAIL-induced apoptosis by regulating the expression of the proapoptotic and antiapoptotic forms of death receptors, which may contribute to the survival and persistence of infected hepatocytes during HBV infection.

Management and outcomes of pregnant patients with central nervous system hemangioblastoma.

The study aims to assess the management and maternal and fetal outcomes of pregnancies complicated by central nervous system (CNS) hemangioblastoma. Twenty-four female patients with CNS hemangioblastoma, who were pregnant in a tumor-burden status, were identified. Their medical charts, treatments, and follow-up materials were carefully reviewed. Of the included 24 CNS patients with hemangioblastoma (14 intracranial and 10 spinal hemangioblastomas), 5 patients (20.8%) were diagnosed with Von Hippel-Lindau disease (VHL). The median age of these patients at admission was 27.5 years. Intracranial hypertension was a common presenting symptom for patients with intracranial hemangioblastoma and was observed in 85.7% (12/14) of cases; the other 10 patients with spinal hemangioblastomas all suffered from paresthesia. Overall, 66.7% (16/24) of patients with CNS hemangioblastoma went through the gestational course with conventional observation; 16.6% (4/24) of patients accepted a ventriculo-peritoneal shunt (VPS) to delay the tumor resection; and 16.7% (4/24) of patients needed urgent tumor resection even when symptomatic treatments were given. Variable symptom improvement was seen when patients had follow-up visits at a median of 32.5 months. No maternal death or tumor recurrence was identified. For the fetal prognoses, one (4.2%) pregnancy ended in a spontaneous miscarriage and for (16.7%) pregnancies were interrupted; the other 19 (79.2%) live births were in good status without any congenital malformations. Symptomatic treatment was the first choice for pregnant patients with CNS hemangioblastoma. When needed, urgent tumor resection could be safely achieved with careful maternal and fetal monitoring. Both maternal and fetal prognoses were favorable during follow-up.