Innovative tumor interstitial fluid-triggered carbon dot-docetaxel nanoassemblies for targeted drug delivery and imaging of HER2-positive breast cancer.

In this study, we have developed an innovative pH-triggered nanomedicine delivery system, targeting HER2-positive breast cancer cells for effective low-cost, imaging-guided drug delivery and precise therapy. The key feature of this system lies in its unique tumor interstitial fluid microenvironment-responsive drug release behavior which achieved tumor site-specific drug delivery. Our in vitro experiments demonstrated that the carbon dot-integrated material achieves more efficient DTX release (96.13 % at 72 h) in the tumor interstitial fluid microenvironment (pH 6.5), thereby boosting drug concentration at the tumor site and enhancing therapeutic efficacy. Further cell experiments confirmed the system's significant inhibitory effect on HER2-positive tumor cells SKBR3 in a pH 6.5 environment, and apoptosis assays indicating a notable increase in early cell apoptosis (from 8.39 % to 24.61 % compared with pH 7.4). Furthermore, the integration of HER2 aptamer within the carbon dot-based system enables targeted recognition and binding to tumor cells, ensuring more precise delivery of DTX while minimizing potential side effects. Crucially, the carbon dots in this system emit superior red fluorescence (the QY = 47.64 % excited at 535 nm compared with Rodamine 6G), enabling real-time visualization of the drug delivery process. This feature provides valuable feedback on treatment effectiveness, facilitating necessary adjustments. The small size (1.88 ±â€¯0.48 nm) of carbon dots significantly improved their ability to penetrate biological barriers, while their low toxicity (no significant cell toxicity under 350 µg/mL) contributed to the formulation's outstanding biocompatibility. Overall, this carbon dot-enhanced drug delivery system offers immense potential for enhancing drug efficacy, minimizing side effects, and providing real-time treatment monitoring, thus proposing a innovate strategy for breast cancer therapy.

Diterpenoid honatisine overcomes temozolomide resistance in glioblastoma by inducing mitonuclear protein imbalance through disruption of TFAM-mediated mtDNA transcription.

BACKGROUND: Glioblastoma (GBM) represents as the most formidable intracranial malignancy. The systematic exploration of natural compounds for their potential applications in GBM therapy has emerged as a pivotal and fruitful avenue of research. PURPOSE: In the present study, a panel of 96 diterpenoids was systematically evaluated as a repository of potential antitumour agents. The primary objective was to discern their potency in overcoming resistance to temozolomide (TMZ). Through an extensive screening process, honatisine, a heptacyclic diterpenoid alkaloid, emerged as the most robust candidate. Notably, honatisine exhibited remarkable efficacy in patient-derived primary and recurrent GBM strains. Subsequently, we subjected this compound to comprehensive scrutiny, encompassing GBM cultured spheres, GBM organoids (GBOs), TMZ-resistant GBM cell lines, and orthotopic xenograft mouse models of GBM cells. RESULTS: Our investigative efforts delved into the mechanistic underpinnings of honatisine's impact. It was discerned that honatisine prompted mitonuclear protein imbalance and elicited the mitochondrial unfolded protein response (UPRmt). This effect was mediated through the selective depletion of mitochondrial DNA (mtDNA)-encoded subunits, with a particular emphasis on the diminution of mitochondrial transcription factor A (TFAM). The ultimate outcome was the instigation of deleterious mitochondrial dysfunction, culminating in apoptosis. Molecular docking and surface plasmon resonance (SPR) experiments validated honatisine's binding affinity to TFAM within its HMG-box B domain. This binding may promote phosphorylation of TFAM and obstruct the interaction of TFAM bound to heavy strand promoter 1 (HSP1), thereby enhancing Lon-mediated TFAM degradation. Finally, in vivo experiments confirmed honatisine's antiglioma properties. Our comprehensive toxicological assessments underscored its mild toxicity profile, emphasizing the necessity for a thorough evaluation of honatisine as a novel antiglioma agent. CONCLUSION: In summary, our data provide new insights into the therapeutic mechanisms underlying honatisine's selective inducetion of apoptosis and its ability to overcome chemotherapy resistance in GBM. These actions are mediated through the disruption of mitochondrial proteostasis and function, achieved by the inhibition of TFAM-mediated mtDNA transcription. This study highlights honatisine's potential as a promising agent for glioblastoma therapy, underscoring the need for further exploration and investigation.

Simultaneous determination of 14 analgesics in postoperative analgesic solution by HPLC-DAD and LC-MS/MS.

A green, efficient, sensitive and accurate detection method by HPLC-DAD and LC-MS/MS was developed and validated for the quantification of morphine, hydromorphone, oxycodone, ketamine tramadol, dezocine, ropivacaine, remifentanil, butorphanol, bupivacaine, droperidol, fentanyl, lornoxicam and sufentanil. The 14 mixtures were chromatographed via HPLC-DAD method which employed 0.05 mol/L potassium dihydrogen phosphate solution-acetonitrile as the mobile phase, the analytes were gradient elution on a SinoChrom ODS-BP C18 column with a total separation time of 35 min, and 14 mixtures showed a good linear relationship in the linear range. The Limit of Quantitation (LOQ) ranged from 0.10 to 20.0 µg/mL, the inter-day and intra-day precision of each analyte is within 1.1-2.0% and 0.4-1.3%, and the average absolute recovery of all compounds was above 98%. The LC-MS/MS method was used to successfully separate the 14 mixtures within 10 min which employed 0.1% formic acid-acetonitrile as the mobile phase, the analytes were gradient elution on a ACQUITY UPLC-BEH C18 column with a total separation time of 13 min, and 14 mixtures showed a good linear relationship in the linear range. The LOQ ranged from 0.005 to 0.2 ng/mL, the inter-day and intra-day precision of each analyte is within 1.2-4.1% and 0.6-3.3%, and the average absolute recovery of all compounds was above 93%. The proposed method has been successfully applied in the clinic and provides a strong technical basis for the quantitative detection of these 14 mixtures for detecting drug abuse, and for studying the stability and compatibility of analgesic solutions. The proposed methods were validated against ICH guidelines.

Genetically Engineered Cell Membrane-Coated Nanoparticles with High-Density Customized Membrane Receptor for High-Performance Drug Lead Discovery.

Cell membrane coating strategies have been increasingly researched due to their unique capabilities of biomimicry and biointerfacing, which can mimic the functionality of the original source cells in vivo but fail to provide customized nanoparticle surfaces with new or enhanced capabilities beyond natural cells. However, the field of drug lead discovery necessitates the acquisition of sufficient surface density of specific target membrane receptors, presenting a heightened demand for this technology. In this study, we developed a novel approach to fabricate high density of fibroblast growth factor receptor 4 (FGFR4) cell membrane-coated nanoparticles through covalent site-specific immobilization between genetically engineered FGFR4 with HaloTag anchor on cell membrane and chloroalkane-functionalized magnetic nanoparticles. This technique enables efficient screening of tyrosine kinase inhibitors from natural products. And the enhanced density of FGFR4 on the surface of nanoparticles were successfully confirmed by Western blot assay and confocal laser scanning microscopy. Further, the customized nanoparticles demonstrated exceptional sensitivity (limit of detection = 0.3 × 10-3 µg mL-1). Overall, the proposed design of a high density of membrane receptors, achieved through covalent site-specific immobilization with a HaloTag anchor, demonstrates a promising strategy for the development of cell membrane surface engineering. This approach highlights the potential of cell membrane coating technology for facilitating the advanced extraction of small molecules for drug discovery.

Affinity character analysis of magnolol and honokiol based on stepwise frontal analysis coupled with cell membrane chromatography.

Magnolol and honokiol have been reported to exhibit anti-cancer activity. However, few studies are in relation to the interaction of magnolol/honokiol with vascular endothelial growth factor 2 (VEGFR2). In this study, a membrane chromatography method based on VEGFR2 was established for the interaction characteristic analysis between drug and receptor. The selectivity, repeatability and stability of the chromatographic model were evaluated using drugs acting on different receptors. The affinity between VEGFR2 and magnolol/honokiol was verified by cell membrane chromatography. The binding sites of magnolol/honokiol and VEGFR2 were analyzed by zonal elution. Especially, the dissociation equilibrium constants (Kd) of magnolol/honokiol and VEGFR2 were measured by zonal elution and stepwise frontal analysis respectively. In addition, the actions of magnolol/honokiol on VEGFR2 were analyzed by stepwise frontal analysis at different temperatures. The results showed that the binding sites of magnolol and honokiol on VEGFR2 were different from sorafenib, indicating that magnolol and honokiol could be used as competitive agents for self-competitive displacement experiment. The Kd values (order of magnitude) of magnolol/honokiol with VEGFR2 measured by stepwise frontal analysis were consistent with the zonal elution results. Honokiol binds VEGFR2 with higher affinity than magnolol. The main forces that stabilize the interactions of honokiol with VEGFR2 are hydrogen bonds and van der Waal's forces, and the main force of magnolol is electrostatic forces. These discoveries could assist in the prediction of drug activity and understanding for the underlying mechanism.

A mannitol-modified emodin nano-drug restores the intestinal barrier function and alleviates inflammation in a mouse model of DSS-induced ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is an inflammatory disease of the colon that is characterized by mucosal ulcers. Given its increasing prevalence worldwide, it is imperative to develop safe and effective drugs for treating UC. Emodin, a natural anthraquinone derivative present in various medicinal herbs, has demonstrated therapeutic effects against UC. However, low bioavailability due to poor water solubility limits its clinical applications. METHODS: Emodin-borate nanoparticles (EmB) were synthesized to improve drug solubility, and they modified with oligomeric mannitol into microgels (EmB-MO) for targeted delivery to intestinal macrophages that express mannose receptors. UC was induced in a mouse model using dextran sulfate sodium (DSS), and different drug formulations were administered to the mice via drinking water. The levels of inflammation-related factors in the colon tissues and fecal matter were measured using enzyme-linked immunosorbent assay. Intestinal permeability was evaluated using fluorescein isothiocyanate dextran. HE staining, in vivo imaging, real-time PCR, and western blotting were performed to assess intestinal barrier dysfunction. RESULTS: Both EmB and EmB-MO markedly alleviated the symptoms of UC, including body weight loss, stool inconsistency, and bloody stools and restored the levels of pro- and anti-inflammatory cytokines. However, the therapeutic effects of EmB-MO on the macroscopic and immunological indices were stronger than those of EmB and similar to those of 5-aminosalicylic acid. Furthermore, EmB-MO selectively accumulated in the inflamed colon epithelium and restored the levels of the gut barrier proteins such as ZO-1 and Occludin. CONCLUSIONS: EmB-MO encapsulation significantly improved water solubility, which translated to greater therapeutic effects on the immune balance and gut barrier function in mice with DSS-induced UC. Our findings provide novel insights into developing emodin-derived drugs for the management of UC.

MXene-sensitized electrochemiluminescence sensor for thrombin activity detection and inhibitor screening.

Thrombin, a crucial enzyme involved in blood coagulation and associated diseases, requires accurate detection of its activity and screening of inhibitors for clinical diagnosis and drug discovery. To address this, an electrochemiluminescence (ECL) method was developed to detect thrombin activity based on the sensitization of Ti3C2Tx MXene, which could sensitize the Ru(bpy)32+ ECL system greatly. The thrombin-cleavable substrate bio-S-G-R-P-V-L-G-C was used as recognizer to evaluate the activity of thrombin. Under the optimal conditions, the limit of detection for thrombin in serum was 83 pU/mL (S/N = 3) with a linear range from 0.1 nU/mL to 1 µU/mL. Moreover, the developed ECL biosensor was employed to screen for thrombin inhibitors from Artemisiae argyi Folium. Four potential thrombin inhibitors (isoquercitrin, nepetin, L-camphor, L-borneol) were screened out with inhibition rates beyond 50%, among which isoquercitrin had the best inhibition rate of 90.26%. Isoquercitrin and nepetin were found to be competitive inhibitors of thrombin, with [Formula: see text] values of 0.91 µM and 2.18 µM, respectively. Molecular docking results showed that these compounds could interact with the active sites of thrombin through hydrogen bonds including ASP189, SER195, GLY216, and GLY219. The electrochemical biosensor constructed provides a new idea for the detection of thrombin activity and screening of its inhibitors.

Hybrid biointerface engineering nanoplatform for dual-targeted tumor hypoxia relief and enhanced photodynamic therapy.

The clinical application of photodynamic therapy (PDT) is limited by the lack of tumor selectivity of photosensitizer (PS) and the hypoxic tumor microenvironment (TME). To address these limitations of PDT, we developed a hybrid engineered biointerface nanoplatform that integrated anti-epidermal growth factor receptor (EGFR)-aptamer (EApt)-modified liposomes with tumor cell membranes (TMs) to create M/L-EApt. M/L-EApt exhibited enhanced stability and significant dual-targeting ability, enabling selectively accumulate in hypoxic tumor regions after systemic infusion. PHI@M/L-EApt, formed by M/L-EApt loaded with an oxygen carrier perfluorotributylamine (PFTBA) and IR780 (a PS), effectively promoted the therapeutic performance of PDT by reversing the hypoxic TME and increasing the accumulation of IR780 at the tumor sites, resulting in a robust anti-tumor efficacy. In vivo results showed that PHI@M/L-EApt treatment effectively suppressed the growth of triple-negative breast tumors in mice. Our findings demonstrated the synergistic effect of oxygen supply and PDT on tumor treatment using PHI@M/L-EApt. This study presented a biomimetic interface engineering strategy and dual-targeted hybrid nanoplatform for relieving hypoxic TME and potentially facilitating the clinical application of PDT.

Engineering Biomimetic Biosensor Using Dual-Targeting Multivalent Aptamer Regulated 3D DNA Walker Enables High-Performance Detection of Heterogeneous Circulating Tumor Cells.

The phenotypic heterogeneity of circulating tumor cells (CTCs) and the nonspecific adsorption of background cells impede the effective and sensitive detection of rare CTCs. Although leukocyte membrane coating approach has a good antileukocyte adhesion ability and holds great promise for addressing the challenge of capture purity, its limited specificity and sensitivity prevent its use in the detection of heterogeneous CTCs. To overcome these obstacles, a biomimetic biosensor that integrated dual-targeting multivalent aptamer/walker duplex functionalized biomimetic magnetic beads and an enzyme-powered DNA walker signal amplification strategy is designed. As compared to conventional leukocyte membrane coating, the biomimetic biosensor achieves efficient and high purity enrichment of heterogeneous CTCs with different epithelial cell adhesion molecule (EpCAM) expression while minimizing the interference of leukocytes. Meanwhile, the capture of target cells can trigger the release of walker strands to activate an enzyme-powered DNA walker, resulting in cascade signal amplification and the ultrasensitive and accurate detection of rare heterogeneous CTCs. Importantly, the captured CTCs remained viable and can be recultured in vitro with success. Overall, this work provides a new perspective for the efficient detection of heterogeneous CTCs by biomimetic membrane coating and paves the way for early cancer diagnosis.

Evaluating the association between dietary salt intake and the risk of atrial fibrillation using Mendelian randomization.

Background: Previous studies have suggested that dietary salt intake affects atrial fibrillation (AF); however, the causal association between them still remains unclear. Thus, we conducted this Mendelian randomization (MR) study to explore the correlation between them. Methods: Genetic instruments for dietary salt intake were from a genome-wide association study (GWAS), which included 462,630 European individuals. Summary-level data for AF were obtained from another published GWAS (22,068 cases and 116,926 controls). The inverse-variance weighting (IVW) method was performed as the primary MR analysis. Multiple MR methods, including Robust Adjusted Profile Score (MR-RAPS), maximum likelihood estimation, and Mendelian randomization pleiotropy residual sum and outlier test (MR-PRESSO) were conducted as complementary analyses. The MR-Egger regression intercept and MR-PRESSO global test were conducted to test potential horizontal pleiotropy. The IVW (Q) method and MR-Egger were performed to detect heterogeneity. Results: Our results suggested that high dietary salt intake was significantly correlated with increased risk of AF [IVW: odds ratio (OR), 1.36; 95% confidence interval (CI), 1.04-1.77; p = 2.25E-02]. The maximum likelihood estimation (OR, 1.37; 95% CI, 1.05-1.78; p = 2.09E-02), MR-RAPS (OR, 1.37; 95% CI, 1.03-1.81; p = 2.79E-02), and MR-PRESSO method (OR, 1.36; 95% CI, 1.05-1.76; p = 2.37E-02) also showed that dietary salt intake was significantly correlated with the risk of AF. Conclusion: The findings of this study provide robust evidence supporting the correlation between dietary salt intake and the risk of AF. Future studies are required to further clarify this relationship and translate the findings into clinical and public health practice.

Stir-bar sorptive extraction based on hydroxyl-functionalized zirconium-metal-organic framework for the detection of three quinolones in actual samples.

A novel analytical method based on stir-bar sorptive extraction was proposed for the determination of three trace quinolones in fish and shrimp samples. UiO-66-(OH)2 , a hydroxyl-functionalized zirconium metal-organic framework, has been coated on frosted glass rods by an in situ growth method. The product, UiO-66-(OH)2 modified frosted glass rods, has been characterized and key parameters have been optimized in combination with ultra-high-performance liquid chromatography. The detection limits of enoxacin, norfloxacin, and ciprofloxacin were 0.48-0.8 ng ml-1 , and the detection concentrations were in the range of 10-300 ng ml-1 , showing a good linear relationship. This method was used for the determination of three quinolones in aquatic organisms, and the recoveries in spiked fish and shrimp muscle tissue samples were 74.8%-105.4% and 82.5%-115.8%, respectively. The relative standard deviations were less than 6.9%. The established method combined stir-bar sorptive extraction based on UiO-66-(OH)2 modified frosted glass rods with ultra-high-performance liquid chromatography, has good application prospects for the detection of quinolone residues in fish and shrimp muscle samples.

Boosting the integration of cell membrane-nanomaterial hybrids via dextran-mediated dynamic dispersion system to capture bioactive compounds in natural products.

Efficient integration is a prerequisite for the application of cell membrane-nanomaterial hybrids (CN hybrids) in bioanalysis, however, the poor dispersity of nanomaterials limits the development of this technology. Although the traditional hydrophilic modification method could improve the dispersity of nanomaterials, it would hinder the coating of the cell membrane, thus making it unsuitable for the integration of CN hybrids. Herein, a method has been proposed to improve the integration efficiency of CN hybrids from a different perspective, that is, establishing a dynamic dispersion system to enhance the interfacial interaction between cell membranes and nanomaterials. Specifically, magnetic graphene oxide (MGO) nanosheets were used as the model carrier and HepG2 cells were used as the source for membrane coating. The addition of the macromolecular stabilizer dextran to the integration process enhanced the dispersity of MGO and avoided the resistance to membrane coating caused by surface modification. Intriguingly, MGO in the dynamic dispersion system showed superior membrane coating ability as compared to hydrophilic modification methods, resulting in the more efficient integration of CN hybrids and greater sensitivity in capturing bioactive compounds from natural products. The proposed design principle provides a brand-new perspective for optimizing the behavior of CN hybrids and can improve the effectiveness of CN hybrids in bioanalytical applications.

Two-in-one platform based on conjugated polymer for ultrasensitive ratiometric detection and efficient removal of perfluoroalkyl substances from environmental water.

Continuous emergence of persistent organic pollutants perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) in various water bodies around the world poses a serious threat to the global ecosystem. The exploration of advanced detection/removal techniques to monitor/treat such type of toxicants is urgently required. Herein, we unveiled a donor-acceptor type conjugated polymer PF-DBT-Im as a first-of-its-kind ratiometric fluorescent probe for visual, amplified, and specific monitoring of PFOA and PFOS with ultra-low detection limits of 6.12 nM (PFOA) and 14.3 nM (PFOS), respectively. PF-DBT-Im undergoes strong aggregation after binding with PFOA/PFOS as evident by transmission electron microscopy, zeta potential measurements, and dynamic light scattering studies. This promotes interchain Förster resonance energy transfer process to endorse an obvious emission color change from blue-to-magenta under ultraviolet lamp excitation. Consequently, a smartphone-integrated portable device is fabricated for realizing rapid and on-site detection of PFOA/PFOS. Besides, a new class of magnetic adsorbent Fe3O4@NH2&F13 is also prepared and used in combination with PF-DBT-Im to remove PFOA/PFOS from the environmental water effectively and rapidly as confirmed by liquid chromatography-mass spectrometry analysis. Thus, utilizing the excellent signal amplification property of PF-DBT-Im and the remarkable magnetic separation capability of Fe3O4@NH2&F13, a multifunctional system is developed for step-wise recognition and separation of PFOA/PFOS from the environmental water proficiently and rapidly.

Increasing brain glucose uptake by Gypenoside LXXV ameliorates cognitive deficits in a mouse model of diabetic Alzheimer's disease.

We have previously reported that Gypenoside LXXV (GP-75), a novel natural PPARγ agonist isolated from Gynostemma pentaphyllum, ameliorated cognitive deficits in db/db mice. In this study, we further investigated the beneficial effects on cognitive impairment in APP/PS1 mice and a mouse model of diabetic AD (APP/PS1xdb/db mice). Interestingly, intragastric administration of GP-75 (40 mg/kg/day) for 3 months significantly attenuated cognitive deficits in APP/PS1 and APP/PS1xdb/db mice. GP-75 treatment markedly reduced the levels of glucose, HbA1c and insulin in serum and improved glucose tolerance and insulin sensitivity in APP/PS1xdb/db mice. Notably, GP-75 treatment decreased the ß-amyloid (Aß) burden, as measured by 11 C-PIB PET imaging. Importantly, GP-75 treatment increased brain glucose uptake as measured by 18 F-FDG PET imaging. Moreover, GP-75 treatment upregulated PPARγ and increased phosphorylation of Akt (Ser473) and GLUT4 expression levels but decreased phosphorylation of IRS-1 (Ser616) in the hippocampi of both APP/PS1 and APP/PS1xdb/db mice. Furthermore, GP-75-induced increases in GLUT4 membrane translocation in primary hippocampal neurons from APP/PS1xdb/db mice was abolished by cotreatment with the selective PPARγ antagonist GW9662 or the PI3K inhibitor LY294002. In summary, GP-75 ameliorated cognitive deficits in APP/PS1 and APP/PS1xdb/db mice by enhancing glucose uptake via activation of the PPARγ/Akt/GLUT4 signaling pathways.

Bioinspired nano-plate-coral platform enabled efficient detection of circulating tumor cells via the synergistic capture of multivalent aptamer and tumor cell membrane.

Circulating tumor cells (CTCs) offer rich information for early disease diagnosis and therapy evaluation. However, the limited sensitivity, binding affinity, and stability of current monovalent recognition-based CTCs detection techniques remain a challenge for extending their applications. Inspired by the highly efficient predation manner of plate corals, we firstly introduce an efficient and sensitive biomimetic CTCs recognition platform based on the conjugation of multivalent aptamer onto tumor cell membrane-coated magnetic graphene oxide to form a plate coral-like CTCs capture nanoprobe (MNPA-TCMMGO). In this method, the tumor cell membrane was employed to provide a biomimetic homologous fluidic interface for targeting homologous tumor cells. At the same time, multivalent aptamers were used as capture probes, which greatly enhanced the binding affinity and association probability between aptamer and target cells via cooperative multivalent effect. The unique features (robustness, high binding affinity and specificity, and biocompatibility) of MNPA-TCMMGO allow efficient, sensitive, and specific capture of rare tumor cells from biological samples. More importantly, the captured cells could maintain good viability, which is crucial for downstream analysis. Therefore, our developed biomimetic approach offers a new way to address the limitations of current CTCs detection methods and presents considerable potential for clinical cancer diagnostics.

Effective extraction of fluoroquinolones from water using facile modified plant fibers.

In this study, ecofriendly and economic carboxy-terminated plant fibers (PFs) were used as adsorbents for the effective in-syringe solid phase extraction (IS-SPE) of fluoroquinolone (FQ) residues from water. Based on the thermal esterification and etherification reaction of cellulose hydroxy with citric acid (CA) and sodium chloroacetate in aqueous solutions, carboxy groups grafted onto cotton, cattail, and corncob fibers were fabricated. Compared with carboxy-terminated corncob and cotton, CA-modified cattail with more carboxy groups showed excellent adsorption capacity for FQs. The modified cattail fibers were reproducible and reusable with relative standard deviations of 3.2%-4.2% within 10 cycles of adsorption-desorption. A good extraction efficiency of 71.3%-80.9% was achieved after optimizing the extraction condition. Based on carboxylated cattail, IS-SPE coupled with ultra-performance liquid chromatography with a photodiode array detector was conducted to analyze FQs in environmental water samples. High sensitivity with limit of detections of 0.08-0.25 µg/L and good accuracy with recoveries of 83.8%-111.7% were obtained. Overall, the simple and environment-friendly modified waste PFs have potential applications in the effective extraction and detection of FQs in natural waters.

Effect of Nanoparticles of DOX and miR-125b on DNA Damage Repair in Glioma U251 Cells and Underlying Mechanisms.

Glioma is the most common primary craniocerebral malignant tumor, arising from the canceration of glial cells in the brain and spinal cord. The quality of life and prognosis of patients with this disease are still poor. Doxorubicin (DOX) is one of the most traditional and economical chemotherapeutic drugs for the treatment of glioma, but its toxic effect on normal cells and the resistance of tumor cells to DOX make the application of DOX in the treatment of glioma gradually less effective. To solve this problem, we co-encapsulated DOX and endogenous tumor suppressor miR-125b into nanoparticles (NPs) by nanoprecipitation methods, and passively targeted them into glioma cells. In vitro experiments show that miR-125b and DOX can be effectively encapsulated into nanoparticles with different ratios, and by targeting YES proto-oncogene 1 (YES1), they can affect the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/p53 pathway and induce brain glioma cell apoptosis. They can also affect the DNA damage repair process and inhibit cell proliferation. The obtained data suggest that co-delivery of DOX and miR-125b could achieve synergistic effects on tumor suppression. Nanosystem-based co-delivery of tumor suppressive miRNAs and chemotherapeutic agents may be a promising combined therapeutic strategy for enhanced anti-tumor therapy.

Increasing brain glucose metabolism by ligustrazine piperazine ameliorates cognitive deficits through PPARγ-dependent enhancement of mitophagy in APP/PS1 mice.

PPARγ agonists have been proven to be neuroprotective in vitro and in vivo models of Alzheimer's disease (AD). In the present study, we identified ligustrazine piperazine derivative (LPD) as a novel PPARγ agonist, which was detected by a dual-luciferase reporter assay system. LPD treatment dose-dependently reduced Aß40 and Aß42 levels in PC12 cells stably transfected with APP695swe and PSEN1dE9. Intragastric administration of LPD for 3 months dose-dependently reversed cognitive deficits in APP/PS1 mice. LPD treatment substantially decreased hippocampal Aß plaques in APP/PS1 mice and decreased the levels of Aß40 and Aß42 in vivo and in vitro. Moreover, LPD treatment induced mitophagy in vivo and in vitro and increased brain 18F-FDG uptake in APP/PS1 mice. LPD treatment significantly increased OCR, ATP production, maximal respiration, spare respiratory capacity, and basal respiration in APP/PS1 cells. Mechanistically, LPD treatment upregulated PPARγ, PINK1, and the phosphorylation of Parkin (Ser65) and increased the LC3-II/LC3-I ratio but decreased SQSTM1/p62 in vivo and in vitro. Importantly, all these protective effects mediated by LPD were abolished by cotreatment with the selective PPARγ antagonist GW9662. In summary, LPD could increase brain glucose metabolism and ameliorate cognitive deficits through PPARγ-dependent enhancement of mitophagy in APP/PS1 mice.

Recent applications of organic molecule-based framework porous materials in solid-phase microextraction for pharmaceutical analysis.

Sample preparation is an indispensable part of detection of complex samples in pharmaceutical analysis. Solid-phase microextraction (SPME) has obtained a lot of attention due to its advantages of time saving, less solvent and easily automation. A variety of functional materials are used as sorbents in SPME to carry out selective and high extraction. This review centers around the recent applications of organic molecule-based framework porous materials, such as metal organic frameworks (MOFs) and covalent organic frameworks (COFs), as SPME coating materials mainly focus on pharmaceutical analysis in food, environment, and biological samples. Four representative extraction devices are introduced, including on-fiber SPME, in-tube SPME, thin film SPME, stir bar SPME. The application prospect of other organic porous materials as sorbents for pharmaceutical analysis are also discussed, such as hyper crosslinked polymers (HCPs) and conjugated microporous polymers (CMPs). The progresses and discusses are provided to offer references for further research focusing on application and development of organic molecule-based framework porous materials in the field of SPME.

Cucurbitane triterpenoid entities derived from Hemsleya penxianensis triggered glioma cell apoptosis via ER stress and MAPK signalling cross-talk.

In the present study, six new cucurbitane type compounds, including three triterpenoids hemsleyacins P-R (6-7, 13) and three cucurbitane-type triterpenoid glycosides hemsleyaosides L-N (15-17), along with seventeen known cucurbitacin analogues were separated from the root tuber of Hemsleya penxianensis and elucidated based on NMR and HRESIMS. Then, 23 analogues of three types, namely, polyhydroxy-type (I) (1-7), monohydroxy-type (II) (8-13), and glycosides-type (III) (14-23), were assessed for their antitumor activity and structure-activity relationship analysis (SAR). We determined temozolomide (TMZ)-resistant GBM cell was the most sensitive to the tested compounds, and found hemsleyaoside N (HDN) displayed the best antineoplastic potency. Furthermore, we confirmed the anti-glioma activity of HDN in patient-derived recurrent GBM strains, GBM organoid (GBO) and orthotopic nude mouse models. Investigations exploring the mechanism made clear that HDN induced synchronous activation of UPR and MAPK signaling, which triggered deadly ER stress and apoptosis. Taken together, the potent antitumor activity of HDN warrants further comprehensive evaluation as a novel anti-glioma agent.