Enhanced Stability and Solidification of Volatile Eugenol by Cyclodextrin-Metal Organic Framework for Nasal Powder Delivery.

Eugenol (Eug) holds potential as a treatment for bacterial rhinosinusitis by nasal powder drug delivery. To stabilization and solidification of volatile Eug, herein, nasal inhalable γ-cyclodextrin metal-organic framework (γ-CD-MOF) was investigated as a carrier by gas-solid adsorption method. The results showed that the particle size of Eug loaded by γ-CD-MOF (Eug@γ-CD-MOF) distributed in the range of 10-150 µm well. In comparison to γ-CD and ß-CD-MOF, γ-CD-MOF has higher thermal stability to Eug. And the intermolecular interactions between Eug and the carriers were verified by characterizations and molecular docking. Based on the bionic human nasal cavity model, Eug@γ-CD-MOF had a high deposition distribution (90.07 ± 1.58%). Compared with free Eug, the retention time Eug@γ-CD-MOF in the nasal cavity was prolonged from 5 min to 60 min. In addition, the cell viability showed that Eug@γ-CD-MOF (Eug content range 3.125-200 µg/mL) was non-cytotoxic. And the encapsulation of γ-CD-MOF could not reduce the bacteriostatic effect of Eug. Therefore, the biocompatible γ-CD-MOF could be a potential and valuable carrier for nasal drug delivery to realize solidification and nasal therapeutic effects of volatile oils.

Structure and ecological function of the soil microbiome associated with 'Sanghuang' mushrooms suffering from fungal diseases.

BACKGROUND: The most serious challenges in medicinal 'Sanghuang' mushroom production are the fungal diseases caused by various molds. Application of biological agents has been regarded as a potential crop disease management strategy. Here, the soil microbiome associated with 'Sanghuang' mushroom affected by fungal diseases grown under field cultivation (FC) and hanging cultivation (HC) was characterized using culture-dependent and culture-independent methods. RESULTS: A total of 12,525 operational taxonomic units (OTUs) and 168 pure cultures were obtained using high-throughput sequencing and a culture-dependent method, respectively. From high-throughput sequencing, we found that HC samples had more OTUs, higher α-diversity, and greater microbial community complexity than FC samples. Analysis of ß-diversity divided the soil microbes into two groups according to cultivation mode. Basidiomycota (48.6%) and Ascomycota (46.5%) were the two dominant fungal phyla in FC samples, with the representative genera Trichoderma (56.3%), Coprinellus (29.4%) and Discosia (4.8%), while only the phylum Ascomycota (84.5%) was predominant in HC samples, with the representative genera Discosia (34.0%), Trichoderma (30.2%), Penicillium (14.9%), and Aspergillus (7.8%). Notably, Trichoderma was predominant in both the culture-independent and culture-dependent analyses, with Trichoderma sp. FZ0005 showing high host pathogenicity. Among the 87 culturable bacteria, 15 exhibited varying extents of antifungal activity against Trichoderma sp. FZ0005, with three strains of Bacillus spp. (HX0037, HX0016, and HX0039) showing outstanding antifungal capacity. CONCLUSIONS: Overall, our results suggest that Trichoderma is the major causal agent of 'Sanghuang' fungal diseases and that Bacillus strains may be used as biocontrol agents in 'Sanghuang' cultivation.

Anticancer Activity of Methyl Protodioscin against Prostate Cancer by Modulation of Cholesterol-Associated MAPK Signaling Pathway via FOXO1 Induction.

Methyl protodioscin (MPD), a furostanol saponin found in the rhizomes of Dioscoreaceae, has lipid-lowering and broad anticancer properties. However, the efficacy of MPD in treating prostate cancer remains unexplored. Therefore, the present study aimed to evaluate the anticancer activity and action mechanism of MPD in prostate cancer. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wound healing, transwell, and flow cytometer assays revealed that MPD suppressed proliferation, migration, cell cycle, and invasion and induced apoptosis of DU145 cells. Mechanistically, MPD decreased cholesterol concentration in the cholesterol oxidase, peroxidase and 4-aminoantipyrine phenol (COD-PAP) assay, disrupting the lipid rafts as detected using immunofluorescence and immunoblot analyses after sucrose density gradient centrifugation. Further, it reduced the associated mitogen-activated protein kinase (MAPK) signaling pathway protein P-extracellular regulated protein kinase (ERK), detected using immunoblot analysis. Forkhead box O (FOXO)1, a tumor suppressor and critical factor controlling cholesterol metabolism, was predicted to be a direct target of MPD and induced by MPD. Notably, in vivo studies demonstrated that MPD significantly reduced tumor size, suppressed cholesterol concentration and the MAPK signaling pathway, and induced FOXO1 expression and apoptosis in tumor tissue in a subcutaneous mouse model. These results suggest that MPD displays anti-prostate cancer activity by inducing FOXO1 protein, reducing cholesterol concentration, and disrupting lipid rafts. Consequently, the reduced MAPK signaling pathway suppresses proliferation, migration, invasion, and cell cycle and induces apoptosis of prostate cancer cells.

Novel co-crystal of 3-methylcinnamic acid with berberine (1:1): synthesis, characterization, and intestinal absorption property.

OBJECTIVE: To synthesis a novel 'Pharmaceutical Cocrystal' of berberine (BBR) with coformer 3-methylcinnamic acid (3MCA) for increasing its solubility and intestinal absorption property. SIGNIFICANCE: BBR-HCl has poor liposolubility, difficulty in penetrating the cell membrane and absorption in the gastrointestinal tract, low bioavailability, and limited clinical application. A new cocrystal is formed by the interaction between 3-MCA and BBR through molecular interaction, which improves the physicochemical properties, intestinal absorption property, and hygroscopicity. METHODS: The solvent evaporation method was used to synthesize BCR-3MCA cocrystal. The physicochemical properties of the crystals were confirmed by different spectral techniques, i.e. by X-ray diffraction (PXRD, SXRD), thermogravimetry and differential thermal analysis (DSC, TGA), and scanning electron microscopy (SEM). Hygroscopicity of the cocrystal was evaluated by dynamic water vapor sorption (DVS). The intestinal absorption property was evaluated by the Ussing chamber system. RESULTS: BBR and 3MCA can be directly self-assembled into uniform co-crystal by hydrogen bonds and π-π stacking interactions. Compared with BBR-HCl, the solubility of BBR-3MCA cocrystal in polar solvents of water, methanol, ethanol, and isopropanol increased by 13.9, 1.5, 4.7, and 15.8 times, respectively. The apparent absorption and the absorption rate constants were increased by 7.7 and 5.6 times, respectively. Surprisingly, BBR-3MCA co-crystal almost had no hygroscopicity. CONCLUSION: The absolute molecular structure of the co-crystal was further confirmed by single crystal X-ray diffraction. The hydrogen bonds drove the formation of X-like one-dimensional unit. Compared to the BBR-HCl, BBR-3MCA cocrystal displayed superior dissolution and solubility performance, improved physical-chemical properties and significantly improved intestinal absorption.

[Optimization of ethanol precipitation process of Nauclea officinalis extract based on concept of quality by design(QbD)].

The ethanol precipitation process of Nauclea officinalis extract was optimized based on the concept of quality by design(QbD). Single factor tests were carried out to determine the levels of test factors. The ethanol volume fraction, pre-ethanol precipitation drug concentration, and ethanol precipitation time were taken as critical process parameters(CPPs). With the comprehensive scores of strictosamide transfer rate and solid removal rate as the critical quality attributes(CQAs), Box-Behnken design was employed to establish the mathematical models and space design between CPPs and CQAs, and the obtained optimal operating space was validated. The optimal operating space included ethanol volume fraction of 65%-70%, pre-ethanol precipitation drug concentration of 22-27 mg·mL~(-1), and ethanol precipitation time of 12 h. Based on the concept of QbD, this study adopted the design space to optimize the ethanol precipitation process of N. officinalis extract, which provided a reliable theoretical basis for the quality control in the production process of N. officinalis preparations. Moroever, this study provided a reference value for guiding the research and industrial production of traditional Chinese medicines.

Fenpropathrin increases gliquidone absorption via causing damage to the integrity of intestinal barrier.

Fenpropathrin is a commonly used pesticide, which was ingested by humans through diet and water. Gliquidone is a common hypoglycemic drug that diabetic patients need for long-term use. This study aimed to investigate the effects of long-term exposure to fenpropathrin on the intestinal barrier and intestinal absorption of the model drug gliquidone. The Ussing Chamber study had shown that fenpropathrin can increase the transport of gliquidone in an isolated intestinal model. In addition, the intestinal absorption of fluorescein was significantly increased in fenpropathrin-exposed rats administered by gavage. Further research suggested that fenpropathrin exposure caused a series of pathological effects: the structure of the intestine was damaged, the expression of tight junction proteins in the intestinal tissue was decreased, the intestinal MDA was increased, the SOD was decreased, and the expression of inflammatory factors was increased. In the Caco-2 cell model, it was found that fenpropathrin can increase the transport of gliquidone in the Caco-2 cell monolayer, reduce the expression of tight junction proteins and increase reactive oxygen species in Caco-2 cells. Fenpropathrin exposure also resulted in decreasing expression of PPAR-γ and UCP-2 in intestinal tissue and Caco-2 cell model, while causing increased expression of p-P38. The above results indicated that fenpropathrin exposure could induce oxidative stress and destroy the intestinal barrier by affecting the expression of p-P38/P38/PPAR-γ/UCP-2 protein, thereby increasing the intestinal absorption of gliquidone. This study provides new insights into the hazards of fenpropathrin residues in the environment.

Unique Double Intramolecular and Intermolecular Exciton Coupling in Ethene-Bridged aza-BODIPY Dimers for High-Efficiency Near-Infrared Photothermal Conversion and Therapy.

Spatial electronic communications of chromophores are both theoretically and practically fascinating. Despite intramolecular or intermolecular exciton coupling was observed in multichromophoric oligomers and J-aggregates, respectively, it is unusual that they both occur in the same molecule. Herein, ethene-bridged aza-BODIPY dimers with intramolecular exciton splitting have been developed. By encapsulating the dimer into F-127 polymer, J-type aggregated nanoparticles were produced, which showed obvious intermolecular exciton coupling and dramatically redshifted absorption and emission peaks at 936 and 1003 nm, respectively. The fabricated nanoagents have high photothermal conversion ability (η=60.3 %) and are ultra-photostable, leading to complete tumor ablation with 915 nm laser irradiation. This phototherapeutic nanoplatform through modulating both intra- and intermolecular exciton couplings is a valuable paradigm for developing photothermal agents for tumor treatment.

Enhancing the Antitumor Effect of Doxorubicin with Photosensitive Metal-Organic Framework Nanoparticles against Breast Cancer.

Breast cancer is one of the most common malignant tumors in women. The existence of multiple breast cancer subtypes often leads to chemotherapy failure or the development of drug resistance. In recent years, photodynamic therapy has been proven to enhance the sensitivity of tumors to chemotherapeutic drugs. Porphyrin-based metal-organic framework (MOF) materials could simultaneously be used as carriers for chemotherapy and photosensitizers in photodynamic therapy. In this paper, doxorubicin hydrochloride (DOX) was loaded in porphyrin MOFs, and the mechanism of the synergistic effect of the DOX carriers and photodynamic therapy on breast cancer was investigated. In vitro and in vivo experiments have shown that MOFs could prolong the residence time of DOX in tumor tissues and promote the endocytosis of DOX by tumor cells. In addition, adjuvant treatment with photodynamic therapy can promote breast cancer tumors to resensitize to DOX and synergistically enhance the chemotherapy effect of DOX. Therefore, this study can provide effective development ideas for reversing drug resistance during breast cancer chemotherapy and improving the therapeutic effect of chemotherapy on breast cancer.

Lactonic sophorolipid-induced apoptosis in human HepG2 cells through the Caspase-3 pathway.

Liver cancer, one of the most common types of cancer in the world, is the second leading cause of death for cancer patients. For liver cancer, there is an urgent need for an effective treatment with no or less toxic side effects. Lactonic sophorolipids (LSL), as a potential anticancer drug, has attracted wide attention of pharmaceutical researchers with its good biological activities. The effects of LSL and cell death inhibitors were measured by MTT test on HepG2 cells. Meanwhile, the morphology of the cells was observed under a microscope. The apoptosis rate was detected by flow cytometry, and the expression levels of enzyme activity of Caspase-3 and Caspase-9 were measured by detection kits. Meanwhile, mRNA levels of Apaf-1, Caspase-3, Bax, and Bcl-2 were measured by quantitative real-time RT-PCR; protein levels of Caspase-3, Cleaved Caspase-3, Bax, and Bcl-2 were measured by western blot. LSL can inhibit the proliferation of cells, and it is possible to induce apoptosis in cells. The HepG2 cells with LSL co-culture exhibited typical apoptotic morphology, and the expression levels of enzyme activity of Caspase-3 and Caspase-9 increased (P< 0.05). We also found that LSL increases cell apoptosis rate and regulates the expression of genes and proteins associated with apoptosis through the Caspase-3 pathway. These results indicate that LSL may be one of the potential drug candidates to inhibit the proliferation and induce apoptosis in HepG2 cells.Key points• LSL, which is of good biological activities such as anti-bacterium, virus elimination, and inflammatory response elimination, has been firstly used to intervene in vitro to investigate its effect on HepG2 cell proliferation.• LSL can inhibit the proliferation of cells, and it is possible to induce apoptosis in HepG2 cells through the Caspase-3 pathway.• The mechanism of LSL action on HepG2 cell proliferation was firstly also discussed, which provides a certain experimental reference for the clinical treatment of liver cancer.

Multiboosting of Cancer Immunotherapy by a Core-Shell Delivery System.

The synergy of chemotherapy and antiangiogenesis therapy is a new strategy for cancer treatment. In this paper, a well-developed core-shell nanoparticle loaded with gambogic acid (GA), heparin (HP), and the immunoadjuvant cytosine-phosphate-guanine oligonucleotide (CpG ODN), called GHC NP, was constructed to treat hepatocellular carcinoma. GHC NPs with liver targeting activity can effectively inhibit tumor cell proliferation and angiogenesis. With the delivery of nanocarriers and the assistance of GA and HP, the GHC NPs can more effectively upregulate cytotoxic T cell (CTL) levels, promote helper T cell (Th cell) differentiation, and induce Th1 immune responses in long-term treatment compared with single CpG ODN. This synergistically enhanced immunotherapy might have universal application in cancer treatments.

Antifungal evaluation of traditional herbal monomers and their potential for inducing cell wall remodeling in Candida albicans and Candida auris.

Traditional herbal monomers (THMs) are widely distributed in many traditional Chinese formulas (TCFs) and decoctions (TCDs) and are frequently used for the prevention and treatment of fungal infections. The antifungal activities of five common THMs, including sodium houttuyfonate (SH), berberine (BER), palmatine (PAL), jatrorrhizine (JAT) and cinnamaldehyde (CIN), and their potential for inducing cell wall remodeling (CWR), were evaluated against Candida albicans SC5314 and Candida auris 12372. SH/CIN plus BER/PAL/JAT showed synergistic antifungal activity against both Candida isolates. Furthermore, SH-associated combinations (SH plus BER/PAL/JAT) induced stronger exposure of ß-glucan and chitin than their counterparts, while CIN triggered more marked exposure compared with CIN-associated combinations (CIN plus BER/PAL/JAT). Collectively, this study demonstrated the anti-Candida effect and the CWR induction potential of the five THMs and their associated combinations, providing a possibility of their in vivo application against fungal-associated infections.

Rosmarinic acid, the active component of Salvia miltiorrhizae, improves gliquidone transport by regulating the expression and function of P-gp and BCRP in Caco-2 cells.

Salvia miltiorrhiza (Danshen) is typically used in the treatment of diabetic complications and is often co-prescribed with gliquidone in China. However, whether danshen affects the absorption of gliquidone has not been elucidated. In this study, the effects of an aqueous extract of danshen (danshen injection, DSI) and its primary compounds (danshensu, protocatechuic aldehyde, rosmarinic acid and salvianolic acid B) on gliquidone transport across Caco-2 monolayer cells was investigated. DSI enhanced the transport of gliquidone in Caco-2 cell monolayers from the apical (AP) to basolateral (BL) sides and from the BL to AP sides. Rosmarinic acid (RA) also significantly increased the Papp (AP-BL) value for gliquidone transport. Verapamil (a P-gp inhibitor) and Ko143 (a BCRP inhibitor) inhibited the BL-AP transport of gliquidone and promoted the AP-BL transport of gliquidone, whereas MK571 (an MRP1 inhibitor), probenecid (an MRP2 inhibitor), and benzbromarone (an MRP3 inhibitor) had no effect on gliquidone transport. RA also enhanced the intracellular accumulation of Rho123 and Hoechst 33342. The expression of P-gp and BCRP was significantly downregulated, and P-gp ATPase activity was promoted by RA in a dose-dependent manner. These results indicate that an aqueous extract of danshen can increase the transport of gliquidone in Caco-2 cell monolayers and that RA may be the primary compound associated with this activity, which is in agreement with RA simultaneously suppressing the function and expression of P-gp and BCRP.

Metformin Reduces Renal Uptake of Radiotracers and Protects Kidneys from Radiation-Induced Damage.

Metformin is the most widely prescribed drug for type 2 diabetes. Chemically, metformin is a hydrophilic base that functions as an organic cation, suggesting that it may have the capacity to inhibit the tubular reabsorption of peptide radiotracers. The purpose of this study was to investigate whether metformin could reduce renal uptake of peptidyl radiotracers and serve as a radioprotective agent for peptide receptor radionuclide therapy (PRRT). METHODS: We used two radiolabeled peptides: a 68Ga-labeled cyclic (TNYL-RAW) peptide (68Ga-NOTA-c(TNYL-RAW) (NOTA: 1,4,7 triazacyclononane-1,4,7-trisacetic acid) targeting EphB4 receptors and an 111In- or 64Cu-labeled octreotide (111In/64Cu-DOTA-octreotide) (DOTA: 1,4,7,10 triazacyclododecane-1,4,7,10-tetraacetic acid) targeting somatostatin receptors. Each radiotracer was injected intravenously into normal Swiss mice or tumor-bearing nude mice in the presence or absence of metformin administered intravenously or orally. Micropositron emission tomography or microsingle-photon emission computed tomography images were acquired at different times after radiotracer injection, and biodistribution studies were performed at the end of the imaging session. To assess the radioprotective effect of metformin on the kidneys, normal Swiss mice received two doses of 111In-DOTA-octreotidein the presence or absence of metformin, and renal function was analyzed via blood chemistry and histology. RESULTS: Intravenous injection of metformin with 68Ga-NOTA-c(TNYL-RAW) or 111In-DOTA-octreotide reduced the renal uptake of the radiotracer by 60% and 35%, respectively, compared to uptake without metformin. These reductions were accompanied by greater uptake in the tumors for both radiolabeled peptides. Moreover, the renal uptake of 111In-DOTA-octreotide was significantly reduced when metformin was administered via oral gavage. Significantly more radioactivity was recovered in the urine collected over a period of 24 h after intravenous injection of 64Cu-DOTA-octreotide in mice that received oral metformin than in mice that received vehicle. Finally, coadministration of 111In-DOTA-octreotide with metformin mitigated radio-nephrotoxicity. CONCLUSION: Metformin inhibits kidney uptake of peptidyl radiotracers, protecting the kidney from nephrotoxicity. Further studies are needed to elucidate the mechanisms of these finding and to optimize mitigation of radiation-induced damage to kidney in PRRT.

Efficient Targeting Drug Delivery System for Lewis Lung Carcinoma, Leading to Histomorphological Abnormalities Restoration, Physiological and Psychological Statuses Improvement, and Metastasis Inhibition.

Lung cancer is a kind of malignant tumor with high morbidity and metastasis tendency. Gambogic acid (GA) has demonstrated significant antitumor activity in vitro, but its poor water-solubility and adverse effects restrict its application in vivo and in clinic. In this study, a passive-targeting GA delivery system was prepared for orthotopic Lewis lung carcinoma model mice. Besides the ∼7 µm size distribution, slow and steady in vitro drug release in a week, high targeting effect to lung, effective restoration of histomorphological abnormalities in lung, maintaining on bodyweight, and prolongation on survival time, excellent improvements of the GA-loaded particles on physiological and psychological statuses and obvious inhibition on tumor metastasis to liver have also been observed, through the measurements of Porsolt forced swim, hypoxic tolerance time, ultrastructure of pulmonary capillary, pulmonary vascular permeability, and hepatic histological change. These results suggest that this GA-loaded particle may be an ideal approach to achieve satisfactory therapeutic function on lung cancer.

The difference between blood-associated and water-associated herbs of Danggui-Shaoyao San in theory of TCM, based on serum pharmacochemistry.

Danggui-Shaoyao San (DSS) is a famous Chinese formula for activating blood circulation and promoting urination. This study was to investigate the difference of material basis between a blood-associated herbs group and a water-associated herbs group. According to the theory of traditional Chinese medicine, the formula can be divided into a blood-associated herbs group (Angelica sinensis, Paeonia lactiflora and Ligusticum chuanxiong) and a water-associated herbs group (Atractylodes macrocephala, Alisma orientale and Poria cocos). The HPLC fingerprint of the formula was established for quality control. Serum samples from rats, orally administrated DSS, and the decomposed recipes of DSS, were analyzed by HPLC-DAD and the transitional blood components of DSS were identified. Twenty-one common peaks were identified in the fingerprint of DSS. Contents of paeoniflorin, albiflorin, ferulic acid and alisol B 23-acetate in co-decoction were significantly higher than those in individual decoction. Eleven peaks belonged to the blood-associated herbs group (four metabolites and seven prototype components; paeoniflorin and ferulic acid appeared in prototype components), whereas six peaks belonged to the water-associated herbs group (three metabolites and three prototype components). It was concluded that the serum pharmacochemistry is a meaningful approach for clarifying the difference between blood-associated and water-associated herbs in chemical composition.

Sinomenine hydrochloride-loaded dissolving microneedles enhanced its absorption in rabbits.

Sinomenine hydrochloride-loaded dissolving microneedles (SH-DM) were fabricated by maltose and poly-lactic-co-glycolic acid using a casting method. The mechanical strength of SH-DM was investigated by an insertion test. In vivo transdermal absorption experiment was performed to evaluate the percutaneous absorption of SH-DM, sinomenine hydrochloride gel (SH-G) was used as a control. The results demonstrated that prepared SH-DM was morphologically intact with sufficient mechanical strength after inserting into aluminum foil and rat skin. The value of area under curve obtained after administration of SH-DM through transdermal in rabbits showed a significantly rise and was 1.99 times higher than that of SH-G, and the relative bioavailability value was 199.21%. These results showed that SH-DM enhanced bioavailability and permeability of SH.

Gambogic acid-loaded electrosprayed particles for site-specific treatment of hepatocellular carcinoma.

This study aims to assess the targeted effect and antitumor efficacy of Gambogic-acid-loaded particles (GA-Ps). GA-Ps with uniform particle sizes of 69.8 ± 17.8 nm (GA-P1), 185.6 ± 33.8 nm (GA-P2), 357.8 ± 81.5 nm (GA-P3), and 7.56 ± 0.95 µm (GA-P4) were prepared using an electrospray technique and exhibited extremely high entrapment efficiency. As the particle size increased from the nano- to microscale, the in vitro GA release rate sharply decreased. After tail-vein injection in mice, GA-P samples GA-P1, GA-P2, GA-P3, and GA-P4 improved the uptake of GA 1.67-times in the liver, 1.78-times in the liver, 2.18-times in the spleen, and 2.35-times in the lung, respectively, compared with GA solution (GA-S). The antitumor efficacy of GA-P2, with an 82.51% targeting efficiency (Te) for the liver, was examined in hepatocellular carcinoma (HCC) model mice. After 2 weeks of administration, HCC mice in the GA-P2 group exhibited a lower degree of tumor invasion and cell lesions in hepatic tissue, recovered liver function, and significantly prolonged survival time, compared with mice in the model, GA-S, and normal saline (NS) groups. Pharmacokinetic studies indicated that the superior antitumor efficacy of GA-P2 was attributed not only to tissue targeting but also to low clearance, extended retention, high bioavailability in plasma, and increased GA stability.

[Effect of supplementing Qi and activating blood circulation method on protein uptake in NRK-52E cells injured by high glucose].

OBJECTIVE: To study the effect of supplementing Qi and activating blood circulation method with danshen and huangqi on protein uptake in NRK-52E cells injured by high glucose. METHODS: The influence of combined use of huangqi and danshen on NRK-52E cells proliferation were determined by MTT method, FITC-BSA uptake were observed by fluorescence microscope and analyzed by fluorescence spectrophotometer, and megalin expression were detected by the method of immunohistochemistry. RESULTS: Combined use of huangqi and danshen could strengthen its protection effect. The FITC-BSA uptake and expression of megalin in NRK-52E cells were decreased in high glucose environment. Combined use of huangqi and danshen could increase FITC-BSA uptake and megalin expression in high glucose-injured NRK-52E cells. CONCLUSION: The method of supplementing Qi and activating blood circulation can protect high glucose injured NRK-52E cells and improve the function of protein uptake by increasing expression of megalin.

Targeting Lysosome for Enhanced Cancer Photodynamic/Photothermal Therapy in a "One Stone Two Birds" Pattern.

Highly immunogenic programmed death of tumor cells, such as immunogenic cell death (ICD) and pyroptosis, strengthens antitumor responses and thus represents a promising target for cancer immunotherapy. However, the development of ICD and pyroptosis inducers remains challenging, and their efficiency is typically compromised by self-protective autophagy. Here, we report a potent ICD and pyroptosis-inducing strategy by coupling combined photodynamic/photothermal therapy (PTT/PDT) to biological processes in cancer cells. For this purpose, we rationally synthesize a lysosomal-targeting boron-dipyrromethene dimer (BDPd) with intense NIR absorption/emission, high reactive oxygen species (ROS) yield, and photothermal abilities, which can be self-assembled with Pluronic F127, producing lysosomal-acting nanomicelles (BDPd NPs) to facilitate cancer cell internalization of BDPd and generation of intracellular ROS. Owing to the favorable lysosomal-targeting ability of the morpholine group on BDPd, the intracellular BDPd NPs can accumulate in the lysosome and induce robust lysosomal damage in cancer cells upon 660 nm laser irradiation, which results in the synergetic induction of pyroptosis and ICD via activating NLRP3/GSDMD and caspase-3/GSDME pathways simultaneously. More importantly, PTT/PDT-induced self-protective autophagic degradation was blocked due to the dysfunction of lysosomes. Either intratumorally or intravenously, the injected BDPd NPs could markedly inhibit the growth of established tumor tissues upon laser activation, provoke local and systemic antitumor immune responses, and prolong the survival time in the mouse triple-negative breast cancer model. Collectively, this work represents a promising strategy to boost the therapeutic potential of PTT/PDT by coupling phototherapeutic reagents with the subcellular organelles, creating a "one stone two birds" pattern.

Hyperoside Inhibits RNF8-mediated Nuclear Translocation of ß-catenin to Repress PD-L1 Expression and Prostate Cancer.

BACKGROUND: Hyperoside is a flavonol glycoside isolated from Hypericum perforatum L. that has inhibitory effects on cancer cells; however, its effects on prostate cancer (PCa) remain unclear. Therefore, we studied the anti-PCa effects of hyperoside and its underlying mechanisms in vitro and in vivo. AIM: This study aimed to explore the mechanism of hyperoside in anti-PCa. METHODS: 3-(4,5-Dimethyl-2-Thiazolyl)-2,5-Diphenyl Tetrazolium Bromide (MTT), transwell, and flow cytometry assays were used to detect PCa cell growth, invasion, and cell apoptosis. Immunoblot analysis, immunofluorescence, immunoprecipitation, and quantitative real-time PCR (qRT-PCR) were used to analyze the antitumor mechanism of hyperoside. RESULTS: Hyperoside inhibited PCa cell growth, invasion, and cell cycle and induced cell apoptosis. Furthermore, RING finger protein 8 (RNF8), an E3 ligase that assembles K63 polyubiquitination chains, was predicted to be a direct target of hyperoside and was downregulated by hyperoside. Downregulation of RNF8 by hyperoside impeded the nuclear translocation of ß-catenin and disrupted the Wnt/ß-catenin pathway, which reduced the expression of the target genes c-myc, cyclin D1, and programmed death ligand 1 (PD-L1). Decreased PD-L1 levels contributed to induced immunity in Jurkat cells in vitro. Finally, in vivo studies demonstrated that hyperoside significantly reduced tumor size, inhibited PD-L1 and RNF8 expression, and induced apoptosis in tumor tissues of a subcutaneous mouse model. CONCLUSION: Hyperoside exerts its anti-PCa effect by reducing RNF8 protein, inhibiting nuclear translocation of ß-catenin, and disrupting the Wnt/ß-catenin pathway, in turn reducing the expression of PD-L1 and improving Jurkat cell immunity.