Protective mechanism of quercetin in alleviating sepsis-related acute respiratory distress syndrome based on network pharmacology and in vitro experiments.

BACKGROUND: Sepsis-related acute respiratory distress syndrome (ARDS) has a high mortality rate, and no effective treatment is available currently. Quercetin is a natural plant product with many pharmacological activities, such as antioxidative, anti-apoptotic, and anti-inflammatory effects. This study aimed to elucidate the protective mechanism of quercetin against sepsis-related ARDS. METHODS: In this study, network pharmacology and in vitro experiments were used to investigate the underlying mechanisms of quercetin against sepsis-related ARDS. Core targets and signaling pathways of quercetin against sepsis-related ARDS were screened and were verified by in vitro experiments. RESULTS: A total of 4,230 targets of quercetin, 360 disease targets of sepsis-related ARDS, and 211 intersection targets were obtained via database screening. Among the 211 intersection targets, interleukin-6 (IL-6), tumor necrosis factor (TNF), albumin (ALB), AKT serine/threonine kinase 1 (AKT1), and interleukin-1ß (IL-1ß) were identified as the core targets. A Gene Ontology (GO) enrichment analysis revealed 894 genes involved in the inflammatory response, apoptosis regulation, and response to hypoxia. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis identified 106 pathways. After eliminating and generalizing, the hypoxia-inducible factor-1 (HIF-1), TNF, nuclear factor-κB (NF-κB), and nucleotide-binding and oligomerization domain (NOD)-like receptor signaling pathways were identified. Molecular docking revealed that quercetin had good binding activity with the core targets. Moreover, quercetin blocked the HIF-1, TNF, NF-κB, and NOD-like receptor signaling pathways in lipopolysaccharide (LPS)-induced murine alveolar macrophage (MH-S) cells. It also suppressed the inflammatory response, oxidative reactions, and cell apoptosis. CONCLUSION: Quercetin ameliorates sepsis-related ARDS by binding to its core targets and blocking the HIF-1, TNF, NF-κB, and NOD-like receptor signaling pathways to reduce inflammation, cell apoptosis, and oxidative stress.

Thermosensitive hydrogel with emodin-loaded triple-targeted nanoparticles for a rectal drug delivery system in the treatment of chronic non-bacterial prostatitis.

BACKGROUND: The complex etiology and pathogenesis underlying Chronic Non-Bacterial Prostatitis (CNP), coupled with the existence of a Blood Prostate Barrier (BPB), contribute to a lack of specificity and poor penetration of most drugs. Emodin (EMO), a potential natural compound for CNP treatment, exhibits commendable anti-inflammatory, anti-oxidant, and anti-fibrosis properties but suffers from the same problems as other drugs. METHODS: By exploiting the recognition properties of lactoferrin (LF) receptors that target intestinal epithelial cells (NCM-460) and prostate epithelial cells (RWPE-1), a pathway is established for the transrectal absorption of EMO to effectively reach the prostate. Additionally, hyaluronic acid (HA) is employed, recognizing CD44 receptors which target macrophages within the inflamed prostate. This interaction facilitates the intraprostatic delivery of EMO, leading to its pronounced anti-inflammatory effects. A thermosensitive hydrogel (CS-Gel) prepared from chitosan (CS) and ß-glycerophosphate disodium salt (ß-GP) was used for rectal drug delivery with strong adhesion to achieve effective drug retention and sustained slow release. Thus, we developed a triple-targeted nanoparticle (NPs)/thermosensitive hydrogel (Gel) rectal drug delivery system. In this process, LF, with its positive charge, was utilized to load EMO through dialysis, producing LF@EMO-NPs. Subsequently, HA was employed to encapsulate EMO-loaded LF nanoparticles via electrostatic adsorption, yielding HA/LF@EMO-NPs. Finally, HA/LF@EMO-NPs lyophilized powder was added to CS-Gel (HA/LF@EMO-NPs Gel). RESULTS: Cellular assays indicated that NCM-460 and RWPE-1 cells showed high uptake of both LF@EMO-NPs and HA/LF@EMO-NPs, while Raw 264.7 cells exhibited substantial uptake of HA/LF@EMO-NPs. For LPS-induced Raw 264.7 cells, HA/LF@EMO-NPs can reduce the inflammatory responses by modulating TLR4/NF-κB signaling pathways. Tissue imaging corroborated the capacity of HA/LF-modified formulations to breach the BPB, accumulating within the gland's lumen. Animal experiments showed that rectal administration of HA/LF@EMO-NPs Gel significantly reduced inflammatory cytokine expression, oxidative stress levels and fibrosis in the CNP rats, in addition to exerting anti-inflammatory effects by inhibiting the NF-κB signaling pathway without obvious toxicity. CONCLUSION: This triple-targeted NPs/Gel rectal delivery system with slow-release anti-inflammatory, anti-oxidant, and anti-fibrosis properties shows great potential for the effective treatment of CNP.

"Dual sensitive supramolecular curcumin nanoparticles" in "advanced yeast particles" mediate macrophage reprogramming, ROS scavenging and inflammation resolution for ulcerative colitis treatment.

Ulcerative colitis (UC) faces some barriers in oral therapy, such as how to safely deliver drugs to the colon and accumulate in the colon lesions. Hence, we report an advanced yeast particles system loaded with supramolecular nanoparticles with ROS scavenger (curcumin) to treat UC by reducing oxidative stress state and inflammatory response and accelerating the reprogramming of macrophages. In this study, the dual-sensitive materials are bonded on ß-cyclodextrin (ß-CD), the D-mannose (Man) is modified to adamantane (ADA), and then loaded with curcumin (CUR), to form a functional supramolecular nano-delivery system (Man-CUR NPs) through the host-guest interaction. To improve gastrointestinal stability and colonic accumulation of Man-CUR NPs, yeast cell wall microparticles (YPs) encapsulated Man-CUR NPs to form Man-CUR NYPs via electrostatic adsorption and vacuum extrusion technologies. As expected, the YPs showed the strong stability in complex gastrointestinal environment. In addition, the Man modified supramolecular nanoparticles demonstrated excellent targeting ability to macrophages in the in vitro cellular uptake study and the pH/ROS sensitive effect of Man-CUR NPs was confirmed by the pH/ROS-dual stimulation evaluation. They also enhanced lipopolysaccharide (LPS)-induced inflammatory model in macrophages through downregulation of pro-inflammatory factors, upregulation of anti-inflammatory factors, M2 macrophage polarization, and scavenging the excess ROS. Notably, in DSS-induced mice colitis model, Man-CUR NYPs can reduce the inflammatory responses by modulating TLR4/NF-κB signaling pathways, alleviate oxidative stress by Nrf2/HO-1 signaling pathway, promote macrophages reprogramming and improve the favorable recovery of the damaged colonic tissue. Taken together, this study not only provides strategy for "supramolecular curcumin nanoparticles with pH/ROS sensitive and multistage therapeutic effects" in "advanced yeast particles", but also provided strong theoretical support multi-effect therapy for UC.

MiR-526b-3p enhances sensitivity of head and neck squamous cell carcinoma cells to radiotherapy via suppressing exosomal LAMP3-mediated autophagy.

Lysosomal associated membrane protein 3 (LAMP3) has been reported to be a tumour promoter in multiple cancer types by modulating tumour cell autophagy. However, the potential mechanism of LAMP3 in radio-resistance of head and neck squamous cell carcinoma (HNSCC) remains unknown. Therefore, our current study aims to detect the impacts of LAMP3 on the resistance of HNSCC cells to radiotherapy and meanwhile explore its functional mechanism. Through RT-Qpcr examination, LAMP3 expression was identified to be expressed at a significantly high level in irradiation-resistant HNSCC cell lines compared with irradiation-sensitive HNSCC cell lines. Functional assays including CCK-8, colony formation and Transwell assays demonstrated that LAMP3 enhanced the radio-resistance through inducing autophagy to promote HNSCC cell growth. Furthermore, irradiation-resistant HNSCC cells could transfer exosomal LAMP3 to elevate LAMP3 expression in irradiation-sensitive HNSCC cells. Mechanistically, microRNA (miRNA) miR-526b-3p could inhibit LAMP3 expression so as to strengthen sensitivity of HNSCC cells to radiotherapy. In a word, exosomal LAMP3 expression promoted radioresistance of HNSCC cells via inducing autophagy, while this effect could be suppressed by miR-526b-3p in a targeted manner.

pH/ROS Dual-Sensitive Natural Polysaccharide Nanoparticles Enhance "One Stone Four Birds" Effect of Rhein on Ulcerative Colitis.

Rhein (RH), a natural anthraquinone compound, is considered an effective treatment candidate for ulcerative colitis (UC), whose multiple biological activities contribute to UC, including anti-inflammation, antioxidation, intestinal barrier repair, and microflora regulation. However, the application of RH is severely limited by its low water solubility, low bioavailability, and poor colonic targeting. Although some nanoparticles have been developed for the oral delivery of RH, most of them mainly highlighted only one effect of some drug delivery strategies but the above multiple biological activities. Therefore, a multiple polysaccharide-based nanodelivery system, comprising chitosan (CS) and fucoidan (FU), with pH/reactive oxygen species (ROS) sensitivity and mucosal adhesion, was developed and first used to load RH as a comprehensive treatment for UC. Briefly, RH-F/C-NPs were prepared using the polyelectrolyte self-assembly method; the average size of RH-F/C-NPs was 233.1 ± 5.7 nm, and the encapsulation rate of RH was 93.67 ± 1.60%. And it could maintain gastric stability and release RH in the colon with the designed pH/ROS sensitivity contributed by the polysaccharide-based structures. Cellular uptake experiments showed that both NCM 460 cells and RAW 264.7 cells had a good uptake of RH-F/C-NPs. Importantly, the effects of RH were highlighted in in vivo experiments, the results of which showed that RH-F/C-NPs could significantly reduce DSS-induced inflammation by inhibiting the TLR4/NF-κB-mediated anti-inflammatory pathway, the Nrf2/HO-1-mediated antioxidant pathway, colonic mucosal barrier repair, and intestinal microflora regulation. In addition, pharmacokinetic studies have shown that F/C-NPs contribute to the increase in the plasma concentration and the accumulation of RH in the colon to some extent. In short, this study is the first to develop an oral multiple polysaccharide-based nanosystem with pH/ROS dual sensitivity to study the "one stone four birds" therapeutic effect of RH on UC.

Research progress on natural ß-glucan in intestinal diseases.

ß-Glucan, an essential natural polysaccharide widely distributed in cereals and microorganisms, exhibits extensive biological activities, including immunoregulation, anti-inflammatory, antioxidant, antitumor properties, and flora regulation. Recently, increasing evidence has shown that ß-glucan has activities that may be useful for treating intestinal diseases, such as inflammatory bowel disease (IBD), and colorectal cancer. The advantages of ß-glucan, which include its multiple roles, safety, abundant sources, good encapsulation capacity, economic development costs, and clinical evidence, indicate that ß-glucan is a promising polysaccharide that could be developed as a health product or medicine for the treatment of intestinal disease. Unfortunately, few reports have summarized the progress of studies investigating natural ß-glucan in intestinal diseases. This review comprehensively summarizes the structure-activity relationship of ß-glucan, its pharmacological mechanism in IBD and colorectal cancer, its absorption and transportation mechanisms, and its application in food, medicine, and drug delivery, which will be beneficial to further understand the role of ß-glucan in intestinal diseases.

Arctigenin attenuates paraquat-induced human lung epithelial A549 cell injury by suppressing ROS/p38 mitogen-activated protein kinases-mediated apoptosis.

BACKGROUND: Paraquat (PQ)-induced acute lung injury (ALI) and pulmonary fibrosis are common diseases with high mortality but without effective antidotes in emergency medicine. Our previous study has proved that arctigenin suppressed pulmonary fibrosis induced by PQ. We wondered whether arctigenin could also have a protective effect on PQ-induced ALI. METHODS: A PQ-induced A549 cell injury model was used, and the effect of arctigenin was determined by a cell counting kit-8 (CCK-8) cell viability assay. In addition, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labelling (TUNEL) staining assays and mitochondrial membrane potential assays were performed to evaluate the level of cell apoptosis. The generation of reactive oxygen species (ROS) was reflected by dihydroethidium (DHE) staining and a 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay. Moreover, immunoblotting studies were used to assess the expression of mitogen-activated protein kinases (MAPKs) and p38 MAPK. RESULTS: Arctigenin attenuated PQ-induced inhibition of A549 cell viability in a dose-dependent manner. Arctigenin also significantly reduced PQ-induced A549 cell apoptosis, as reflected by the TUNEL assay and mitochondrial membrane potential assay, which may result from suppressed ROS/p38 MAPK signaling because we found that arctigenin dramatically suppressed ROS generation and p38 MAPK phosphorylation. CONCLUSION: Arctigenin could attenuate PQ-induced lung epithelial A549 cell injury in vitro by suppressing ROS/p38 MAPK-mediated cell apoptosis, and arctigenin might be considered a potential candidate drug for PQ-induced ALI.

Phosphatidylserine-Specific Phospholipase A1 Alleviates Lipopolysaccharide-Induced Macrophage Inflammation by Inhibiting MAPKs Activation.

Macrophages are a key in innate immune responses and play vital roles in homeostasis and inflammatory diseases. Phosphatidylserine-specific phospholipase A1 (PS-PLA1) is a specific phospholipase which hydrolyzes fatty acid from the sn-1 position of phosphatidylserine (PS) to produce lysophosphatidylserine (lysoPS). Both PS and lysoPS are associated with activation of immune cells including macrophages. However, the effect of PS-PLA1 on macrophage inflammation remains unclear. The purpose of this study is to evaluate the role of PS-PLA1 in lipopolysaccharide (LPS)-induced macrophage inflammation. Alterations of PS-PLA1 expression in LPS-stimulated RAW264.7 macrophages were investigated via Western blot. PS-PLA1 stable knockdown and overexpression RAW264.7 cell lines were generated by infecting cells with appropriate lentiviral vectors, respectively. PS-PLA1 expression was found to be dramatically upregulated in RAW264.7 macrophages after LPS stimulation. PS-PLA1 knockdown promotes while PS-PLA1 overexpression ameliorates the release of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and nitric oxide from RAW264.7 cells and M1 macrophage polarization. Additionally, PS-PLA1 knockdown facilitates phosphorylation of p38, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), while PS-PLA1 overexpression attenuates their phosphorylation. Moreover, mitogen-activated protein kinase (MAPK) inhibitors block the release of TNF-α and IL-1ß in PS-PLA1 knockdown RAW264.7 cells after LPS stimulation. These findings suggest PS-PLA1 ameliorates LPS-induced macrophage inflammation by inhibiting MAPKs activation, and PS-PLA1 might be considered as a target for modulating macrophage inflammation.

Mitoquinone mitigates paraquat-induced A549 lung epithelial cell injury by promoting MFN1/MFN2-mediated mitochondrial fusion.

Paraquat (PQ) poisoning often leads to severe lung injuries, in which the mitochondria damage plays a critical role. Mitoquinone (MitoQ), a newly designed mitochondria-targeted antioxidant, has been proved for its benefit in mitochondria protection. However, the role of MitoQ in PQ-induced lung injury remains unclear. Thus, this study was performed to investigate the effect of MitoQ on PQ-induced lung injury and its underlying mechanisms. Our work showed that PQ caused the inhibition of A549 lung epithelial cell viability in a dose-dependent manner, while MitoQ remarkably mitigated the PQ-induced cell viability suppression. Besides this, PQ-mediated apoptosis of A549 cells was significantly attenuated by MitoQ, as indicated by the TUNEL assay and mitochondria membrane potential assay. Moreover, the intracellular reactive oxygen species (ROS) production was also dramatically suppressed when cotreated MitoQ with PQ. This could be ascribed to enhanced mitochondrial fusion mediated by Mitofusin 1 (MFN1)/Mitofusin 2 (MFN2), because MitoQ preserved mitochondrial network integrity, as reflected by MitoTracker staining, and MitoQ also increased the expression of MFN1/MFN2 in A549 cells after PQ treatment. Our data suggested MitoQ mitigated PQ-induced lung epithelial cell injury by promoting MFN1/MFN2-mediated mitochondrial fusion, and MitoQ might be a potential candidate drug for the treatment of PQ-induced lung injury.

pH/ROS dual-sensitive and chondroitin sulfate wrapped poly (ß-amino ester)-SA-PAPE copolymer nanoparticles for macrophage-targeted oral therapy for ulcerative colitis.

An oral nanoparticle (NPs) encapsulated in chitosan/alginate hydrogel (CA-Gel) with dual-sensitive in pH and reactive oxygen species (ROS) was developed to load curcumin (CUR) based on the intracellular-specific characteristics of macrophages. Chondroitin sulfate (CS) wrapped PBAE-SA-PAPE with intracellular pH/ROS dual-sensitive characteristics and CUR via a simple nanoprecipitation method to form NPs (CS-CUR-NPs), and mixed CA-Gel to acquire the final preparation (CS-CUR-NPs-Gel). CS-CUR-NPs displayed an ideal average particle size (179.19±5.61nm) and high encapsulating efficiency (94.74±1.15%). CS showed a good targeting ability on macrophages and the CA-Gel contribution in protecting NPs from being destroyed in the upper gastrointestinal tract. As expected, CS-CUR-NPs-Gel could significantly alleviate inflammation in DSS-induced UC mice via TLR4-MAPK/NF-κB pathway. This study is the first to attempt to design a novel pH/ROS dual-stimulated release strategy in helping intracellular CUR delivery and anticipated for efficient anti-UC therapy.

ß-1,3-d-Glucan based yeast cell wall system loaded emodin with dual-targeting layers for ulcerative colitis treatment.

Herein, a ß-1,3-d-glucan based microcarrier, yeast cell wall microparticles (YPs), was used to develop a food-source-based nano-in-micro oral delivery system for ulcerative colitis (UC) treatment. Briefly, lactoferrin (Lf), which targets intestinal epithelial cells, was used to encapsulate emodin (EMO) to form nanoparticles (EMO-NPs), and then loaded into YPs with the natural macrophages targeting ability, forming a final formula with two outer-inner targeting layers (EMO-NYPs). These dual-targeting strategy could enhance the dual-effects of EMO in anti-inflammatory and mucosal repair effects respectively. As expected, cell uptake assessment confirmed that EMO-NPs and EMO-NYPs could target on the Lf and dection-1 receptors on the membranes of Caco-2 cells and macrophages, respectively. Importantly, EMO-NYPs showed the best anti-UC effects compared to EMO-NPs and free EMO, by inhibiting NF-κB pathway to anti-inflammation and promoting intestinal mucosa repair via MLCK/pMLC2 pathway. The results show that EMO-NYPs are a promising food-based oral delivery system in anti-UC.

Lentinan-Based Oral Nanoparticle Loaded Budesonide With Macrophage-Targeting Ability for Treatment of Ulcerative Colitis.

Ulcerative colitis (UC) is a global, chronic, and refractory disease. Corticosteroids are first-line drugs for the treatment of UC but also cause adverse side effects. Budesonide (BUD), a corticosteroid with relatively low side effects, has been approved by the Food and Drug Administration for use as enteric capsules (Entocort EC) for the treatment of inflammatory bowel disease (IBD). However, this formulation lacks specific targeting ability to UC lesions. Herein, we describe the development of an advanced macrophage-targeted oral lentinan (LNT)-based nanoparticles (NPs) loaded BUD for treatment of UC. Briefly, LNT was used as a food source and natural carrier to load BUD by a simple solvent evaporation method to form LNT/BUD-NPs. LNT showed good loading capacity with high encapsulation and loading efficiencies to BUD of approximately 92.19 and 9.58%, respectively. Evaluation of the gastric stability of LNT/BUD-NPs indicated that LNT could effectively protect BUD from gastric acid and digestive enzymes. The release behavior and transmission electron microscopy image of LNT/BUD-NPs in the intestinal content of mice confirmed that intestinal flora can promote BUD release from LNT. Moreover, evaluation of cellular uptake showed that LNT/BUD-NPs could specifically target macrophages and enhance their uptake rate via the Dectin-1 receptor. In biodistribution studies, LNT/BUD-NPs were able to efficiently accumulate in the inflamed colon of mice. As expected, LNT/BUD-NPs could significantly alleviate inflammation by inhibiting the TLR4/MyD88/NF-κB signaling pathway. Therefore, LNT/BUD-NPs have the advantages of good gastric stability, release mediated by mouse intestinal content, macrophage-targeting, and anti-UC effects. These advantages indicate LNT-based NPs are a promising oral drug delivery system for UC therapy.

MicroRNA-139-5p improves sepsis-induced lung injury by targeting Rho-kinase1.

Sepsis-induced acute lung injury (ALI) is an inflammatory process that involves inflammatory cytokine production and cell apoptosis. In the present study, the regulatory role of microRNA (miR)-139-5p in sepsis-induced ALI was investigated using a murine model of cecal ligation puncture (CLP) and an in vitro model using lipopolysaccharide (LPS)-induced normal human bronchial epithelial cells (NHBEs). Sepsis-induced pathological changes in the lungs of ALI mice were detected using hematoxylin and eosin staining. Lung water content was determined, and the expression of proinflammatory cytokines in the bronchoalveolar lavage fluid and serum of sepsis-induced ALI mice were quantified using ELISA. The levels of oxidative stress in lung tissues were determined using commercial kits. The degree of apoptosis was determined using a TUNEL assay. The expression levels of miR-139-5p and Rho-kinase 1 (ROCK1) were determined using reverse transcription-quantitative PCR and western blot analyses. A dual-luciferase reporter assay was used to confirm the direct targeting of ROCK1 by miR-139-5p. NHBEs were co-transfected with vectors expressing ROCK1 (or empty vector) and miR-139-5p mimics or control mimics prior to LPS treatment. The transcriptional activity of caspase-3, the ratio of apoptotic cells, the expression levels of mucin 5AC, mucin 1, TNF-α, IL-1ß, IL-6, NLR family pyrin domain containing 3, apoptosis-associated speck-like protein containing a CARD and caspase-1 were evaluated. Compared with the normal group, mice that underwent CLP exhibited abnormal lung morphology, enhanced production of TNF-α, IL-1ß and IL-6, increased reactive oxygen species (ROS), malondialdehyde and lactate dehydrogenase levels, an increased proportion of apoptotic cells and increased ROCK1 expression. Superoxide dismutase, glutathione peroxidase and miR-139-5p levels were decreased following CLP. In the NHBEs, stimulation with LPS caused a marked increase in inflammatory cytokine levels and apoptosis compared with the untreated cells. Overexpression of miR-139-5p attenuated cell apoptosis and inflammation. Overexpression of ROCK1 in NHBEs restored the ROS levels and proinflammatory cytokine production inhibited by miR-139-5p. In conclusion, miR-139-5p alleviated sepsis-induced ALI via suppression of its downstream target, ROCK1, suggesting that miR-139-5p may hold promise in the treatment of sepsis-induced ALI.

Xuebijing Protects Against Septic Acute Liver Injury Based on Regulation of GSK-3ß Pathway.

Xuebijing (XBJ), the only drug approved for the sepsis and multiple organ dysfunction, and its protective effects against acute liver injury (ALI) and its mechanism. The aim of this study was to evaluate the protective effect of XBJ on cecal ligation and perforation (CLP)-induced mouse ALI model and LPS-induced RAW264.7 cell ALI model. Mice were pretreated with XBJ before the CLP model was established, and serum and liver tissues were collected at the end of the experiment to assess the levels of inflammatory factors and liver injury. Results showed that XBJ pretreatment reduced liver/body weight, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities in serum, and inhibited levels of pro-inflammatory factors in serum. Cells were treatment with XBJ and modeled by LPS modeling increased cell viability in the XBJ-treated group compared to the model group and XBJ also decreased serum pro-inflammatory factors in a dose-dependent manner. Western blot detected that XBJ also up-regulated the phosphorylated levels of glycogen synthase kinase-3ß (p-GSK-3ß) and cAMP-response element-binding protein (p-CREB) and down-regulated the phosphorylated level of nuclear factor kappa-B (p-NF-κB) in liver and cell. After overexpression of GSK-3ß in cells, the mechanism was further investigated using CO-IP analysis. The binding of p-NF-κB and p-CREB to CREB-binding protein (CBP) was increased and decreased, respectively, indicating that GSK-3ß regulated inflammation by regulating the binding of p-NF-κB and p-CREB to CBP. The present studies suggested that the hepatoprotective effect of XBJ may be through up-regulation of GSK-3ß (Ser9) and increasing the binding of p-CREB to CBP, thereby alleviating the inflammatory response.

Entrapment of Macrophage-Target Nanoparticles by Yeast Microparticles for Rhein Delivery in Ulcerative Colitis Treatment.

In this study, we developed an advanced colitis-targeted nanoparticles (NPs)-into-yeast cell wall microparticles (YPs) drug delivery system for ulcerative colitis (UC) therapy. In brief, YPs entrap hyaluronic acid (HA), and polyethylenimine (PEI) modified rhein (RH)-loaded ovalbumin NPs (HA/PEI-RH NPs) to form HA/PEI-RH NYPs. YPs can make HA/PEI-RH NPs pass through gastric environment stably and be degraded by ß-glucanase to promote drug release from HA/PEI-RH NYPs in the colon. Cellular uptake evaluation confirmed that HA/PEI-RH NPs could specifically target and enhance the uptake rate via HA ligands. In biodistribution studies, HA/PEI-RH NYPs were able to efficiently accumulate in the inflammed colon in mice. In vivo experiments revealed that the HA/PEI-RH NYPs could significantly alleviate inflammation by inhibiting the TLR4/MyD88/NF-κB signaling pathway. Therefore, HA/PEI-RH NYPs have advantages of good gastric stability, ß-glucanase-sensitive release ability, macrophage-targeted ability, and anti-UC effects. These advantages indicate YPs-entrapped multifunctional NPs are a promising oral drug delivery system for UC therapy.

Arctigenin Suppressed Epithelial-Mesenchymal Transition Through Wnt3a/ß-Catenin Pathway in PQ-Induced Pulmonary Fibrosis.

Arctigenin (ATG), a major bioactive substance of Fructus Arctii, counters renal fibrosis; however, whether it protects against paraquat (PQ)-induced lung fibrosis remains unknown. The present study was to determine the effect of ATG on PQ-induced lung fibrosis in a mouse model and the underlying mechanism. Firstly, we found that ATG suppressed PQ-induced pulmonary fibrosis by blocking the epithelial-mesenchymal transition (EMT). ATG reduced the expressions of Vimentin and α-SMA (lung fibrosis markers) induced by PQ and restored the expressions of E-cadherin and Occludin (two epithelial markers) in vivo and in vitro. Besides, the Wnt3a/ß-catenin signaling pathway was significantly activated in PQ induced pulmonary fibrosis. Further analysis showed that pretreatment of ATG profoundly abrogated PQ-induced EMT-like phenotypes and behaviors in A549 cells. The Wnt3a/ß-catenin signaling pathway was repressed by ATG treatment. The overexpression of Wnt3a could weaken the therapeutic effect of ATG in A549 cells. These findings suggested that ATG could serve as a new therapeutic candidate to inhibit or even reverse EMT-like changes in alveolar type II cells during PQ-induced lung fibrosis, and unraveled that the Wnt3a/ß-catenin pathway might be a mechanistic tool for ATG to control pulmonary fibrosis.

Schizandrin B Mitigates Rifampicin-Induced Liver Injury by Inhibiting Endoplasmic Reticulum Stress.

Schisandra chinensis is widely used and effective in protecting liver. There are many mechanisms of drug-induced hepatocyte injury, among which endoplasmic reticulum (ER) stress-induced cell injury plays an important role. However, little is known about whether schisandra chinensis can inhibit rifampicin (RFP)-induced hepatocyte injury by affecting ER stress. In our study, firstly, L02 cells were treated with different concentrations of RFP for different time intervals, and the apoptosis, survival rate and endoplasmic reticulum stress gene and protein expressions of glucose-regulated protein 78 (GRP 78), PKR-like ER kinase (PERK), activating transcription factor (ATF)4, C/EBP-homologus protein (CHOP), ATF6, arginine-rich, mutated in early stage tumors (ARMET), p-inositol-requiring enzyme 1 (IRE1) and X-box binding protein 1 (XBP-1) were measured. We found that RFP increased apoptosis of L02 cells, decreased cell survival, and increased the gene and protein expression levels of GRP78, PERK, ATF4, CHOP, ATF6, ARMET, p-IRE1 and XBP-1, suggesting that RFP could induce hepatocyte injury, and the degree of injury was positively correlated with the dose and time of RFP. Next, we treated RFP-damaged hepatocytes with schizandrin B. We found that schizandrin B increased cell survival rate in dose-dependent and time-dependent manner, decreased cell apoptosis rate, and reduced protein and gene expression levels of GRP78, PERK, ATF4, CHOP, ATF6, ARMET and XBP-1. These results indicate that schizandrin B alleviates RFP-induced injury in L02 cells by inhibiting ER stress.

Evaluating grain size in polycrystals with rough surfaces by corrected ultrasonic attenuation.

Surface roughness of a sample has a great effect on the calculated grain size when measurements are based on ultrasonic attenuation. Combining modified transmission and reflection coefficients at the rough interface with a Multi-Gaussian beam model of the transducer, a comprehensive correction scheme for the attenuation coefficient is developed. An approximate inverse model of the calculated attenuation, based on Weaver's diffuse scattering theory, is established to evaluate grain size in polycrystals. The experimental results showed that for samples with varying surface roughness and matching microstructures, the fluctuation of evaluated average grain size was ±1.17µm. For polished samples with different microstructures, the relative errors to optical microscopy were no more than ±3.61%. The presented method provides an effective nondestructive tool for evaluating the grain size in metals with rough surfaces.

[A Meta analysis on the associations between air pollution and respiratory mortality in China].

OBJECTIVE: To analyze the associations between air pollution and adverse health outcomes on respiratory diseases and to estimate the short-term effects of air pollutions [Particulate matter with particle size below 10 microns (PM(10)), PM(10) particulate matter with particle size below 2.5 microns (PM(2.5)), nitrogen dioxide (NO2), sulphur dioxide (SO2) and ozone (O3)] on respiratory mortality in China. METHODS: Data related to the epidemiological studies on the associations between air pollution and adverse health outcomes of respiratory diseases that published from 1989 through 2014 in China, were collected by systematically searching databases of PubMed, SpringerLink, Embase, Medline, CNKI, CBM and VIP in different provinces of China. Short-term effects between (PM(10), PM(2.5), NO2, SO2, O3) and respiratory mortality were analyzed by Meta-analysis method, and estimations were pooled by random or fixed effect models, using the Stata 12.0 software. RESULTS: A total of 157 papers related to the associations between air pollution and adverse health outcomes of respiratory diseases in China were published, which covered 79.4% of all the provinces in China. Results from the Meta-analysis showed that a 10 µg/m³ increase in PM10, PM(2.5), NO2, SO2, and O3was associated with mortality rates as 0.50% (95% CI: 0-0.90%), 0.50% (95% CI: 0.30%-0.70%), 1.39% (95% CI: 0.90%-1.78%), 1.00% (95% CI: 0.40%-1.59%) and 0.10% (95% CI: -1.21%-1.39%) in respiratory tracts, respectively. No publication bias was found among these studies. CONCLUSION: There seemed positive associations existed between PM(10)/PM(2.5)/NO2/SO2and respiratory mortality in China that the relationship called for further attention on air pollution and adverse health outcomes of the respiratory diseases.