Spiro Scaffold Chiral Organocatalyst of 3,2'-Pyrrolidinyl Spiro-oxindole Amine and Its Catalytic Evaluation in the Enantioselective Aldol Condensation between 3-(3-Hydroxy-1H-pyrazol-1-yl)-Oxindole and Paraformaldehyde.

The spiro scaffold chiral organocatalyst of 3,2'-pyrrolidinyl spiro-oxindole amine was successfully prepared from racemic spiro-oxindole amine using l-menthol as a chiral pool in 4 steps in 28%-40% overall yields with at least 99% ee in scale-up preparation, and its catalytic activity was evaluated in the enantioselective aldol condensation between 3-(3-hydroxy-1H-pyrazol-1-yl)-oxindole and paraformaldehyde. The spiro organocatalyst showed superior catalytic activity and selectivity compared with its counterparts, and most substrates offered good to excellent results with up to 96% yield in 96% ee.

Efficacy and Safety of a Novel Helical Self-Expanding Nitinol Stent for Femoropopliteal Artery Obliterans Disease.

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of a novel self-expanding nitinol stent (Smartflex stent) in femoropopliteal artery obliterans disease. METHODS: From June 2016 to May 2019, patients with atherosclerotic occlusion disease of the superficial femoral and popliteal arteries using the Smartflex stents were retrospectively analyzed in our institution. Patients were monitored at 1, 3, 6, and 12 months and annually thereafter. The main characteristics of the diseased vessels, perioperative and follow-up outcome were evaluated. Kaplan-Meier method was used to assess patency rate and the rate of freedom from clinically driven target lesion revascularization (CD-TLR). RESULTS: A total of 50 limbs from 48 patients (mean age 69.4 ± 8.95 years; 38 men) were included. Eighty-eight Smartflex stents (1.76 stents per limb) were deployed successfully. Of the study patients, 82% had claudication (Rutherford III), 10% had rest pain (Rutherford IV), and 8% had tissue loss (Rutherford V). Trans-Atlantic Inter-Society Consensus II C and D lesions were 26% and 42%, respectively. The mean lesion length was 18.2 ± 8.5 cm and the mean stented length was 22.3 ± 9.9 cm. The average follow-up time was 16.4 ± 8.2 months. Of these lesions, 42 (94%) were chronic total occlusions and 16 (32%) were severely calcified. The primary patency rate at 1 year per Kaplan-Meier estimating, the rate of freedom from CD-TLR at 1 year, and the second patency rate was 83.3%, 88.1%, and 94%, respectively. Among them, 90% patients had improved ankle-brachial indexes (0.47 ± 0.13 before and 0.84 ± 0.16 after). No stent fractures and kinking were identified. CONCLUSIONS: Stenting of the femoropopliteal artery diseases using the Smartflex stent appeared to be safe and effective. It performed well in long-segment and above knee joint lesions.

[Quantitative Segmentation and Measurement of Tooth from Computed Tomography Image Based on Regional Adaptive Deformation Model].

For tooth segmentation problem on the three-dimensional computed tomography(CT)volume data,this paper proposes a regional adaptive deformable model for tooth structure measurement of CT images.The proposed method combines the automatic thresholding segmentation,CV active contour model,and graph-cut.Firstly,we achieved the segmentation and location of dental crowns by automatic thresholding segmentation.And then by using the above segmentation result as the initial contour,we utilized active contour method to slice gradually the segment of remaining tooth.By incorporating active contour and graph-cut then,we realized the accurate segmentation for tooth root,which is the most difficult to be segmented.The experimental results showed that the proposed tooth structure measurement accurately and automatically segmented dental crowns from CT data,and then rapidly and accurately segmented the tooth neck and tooth root.The structure of tooth could be effectively segmented from CT data by using the proposed method.Experimental results indicated that the proposed method was rather robust and accurate,and could effectively assist the doctor for diagnosis in clinical treatment.

Impacts of groundwater recharge from rubber dams on the hydrogeological environment in Luoyang Basin, China.

In the rubber dam's impact area, the groundwater total hardness (TH) has declined since 2000, ultimately dropping to 100-300 mg/L in 2012. pH levels have shown no obvious changes. NH4-N concentration in the groundwater remained stable from 2000 to 2006, but it increased from 2007 to 2012, with the largest increase up to 0.2 mg/L. NO3-N concentration in the groundwater generally declined in 2000-2006 and then increased from 2007; the largest increase was to 10 mg/L in 2012. Total dissolved solids (TDS) of the groundwater showed a general trend of decline from 2000 to 2009, but levels increased after 2010, especially along the south bank of the Luohe River where the largest increase recorded was approximately 100 mg/L. This study has shown that the increases in the concentrations of NH4-N and NO3-N were probably caused by changes in groundwater levels. Nitrates adsorbed by the silt clay of aeration zone appear to have entered the groundwater through physical and chemical reactions. TDS increased because of groundwater evaporation and some soluble ions entered the groundwater in the unsaturated zone. The distance of the contaminant to the surface of the aquifer became shorter due to the shallow depth of groundwater, resulting in the observed rise in pollutant concentrations more pronounced.

Female zebrafish (Danio rerio) exposure to polystyrene nanoplastics induces reproductive toxicity in mother and their offspring.

Nanoplastics (NPs) have been commonly detected in aquatic ecosystems, and their negative effects on aquatic organisms have raised concerns in the scientific community and general public. The acute toxicity, neurotoxicity, and metabolic toxicity induced by NPs on fishes have been reported by many studies, although less attention has been focused on how mother exposed to NPs affected their offspring in aquatic organisms. Here, female zebrafish (F0) were exposed to 0, 200 and 2000 µg/L polystyrene nanoplastics (PS-NPs) for 42 d, with their offspring (F1) reared in clear water until sexual maturity. The results showed that PS-NPs were detected in various organs of F0 and F1. PS-NPs exposure significantly decreased gonadal 17-estradiol (E2), while increasing testosterone (T) contents. Lower levels of cyp19a1a, lhr and erα expressions in the 2000 µg/L group were consistent with a reduced number of mature oocytes (MO), but an increase in perinucleolar oocytes (PO). Interestingly, the expression of vtg was only up-regulated by 200 µg/L PS-NPs. After exposure, the egg production was dramatically reduced, but the hatching rate and heartbeat of F1 embryos from treated females were significantly higher than those observed in females from the control group. Maternal PS-NPs exposure significantly decreased the E2 and T levels in F1 adults, while PS-NPs exposure significantly up-regulated the sox9a but down-regulated the foxl2a in F1 larvae of 30 days post fertilization (dpf). This study showed that PS-NPs caused reproductive toxicity by changing the hypothalamic-pituitary-gonadal (HPG) axis-related genes, impairing the reproductive capacity of female zebrafish, affecting the development and disrupting the endocrine function of F1. These results suggested that PS-NPs had adverse effects on fish reproductive system both in the directly exposed generation and in their unexposed offspring.

Hydrogen bonding-mediated interaction underlies the enhanced membrane toxicity of chemically transformed polystyrene microplastics by cadmium.

The global attention on microplastic pollution and its implications for human health has grown in recent years. Additionally, the co-existence of heavy metals may significantly alter microplastics' physicochemical characteristics, potentially amplifying their overall toxicity-a facet that remains less understood. In this study, we focused the membrane toxicity of modified polystyrene microplastics (PS-MPs) following cadmium (Cd) pretreatment. Our findings revealed that Cd-pretreated PS-MPs exacerbated their toxic effects, including diminished membrane integrity and altered phase fluidity in simulated lipid membrane giant unilamellar vesicles (GUVs), as well as heightened membrane permeability, protein damage, and lipid peroxidation in red blood cells and macrophages. Mechanistically, these augmented membrane toxicities can be partially ascribed to modifications in the surface roughness and hydrophilicity of Cd-pretreated PS-MPs, as well as to interactions between PS-MPs and lipid bilayers. Notably, hydrogen bonds emerged as a crucial mechanism underlying the enhanced interaction of PS-MPs with lipid bilayers.

A Dual-Targeting, Multi-Faceted Biocompatible Nanodrug Optimizes the Microenvironment to Ameliorate Abdominal Aortic Aneurysm.

Abdominal aortic aneurysm (AAA) is a highly lethal cardiovascular disease that currently lacks effective pharmacological treatment given the complex pathophysiology of the disease. Here, single-cell RNA-sequencing data from patients with AAA and a mouse model are analyzed, which reveals pivotal pathological changes, including the M1-like polarization of macrophages and the loss of contractile function in smooth muscle cells (SMCs). Both cell types express the integrin αvß3, allowing for their dual targeting with a single rationally designed molecule. To this end, a biocompatible nanodrug, which is termed EVMS@R-HNC, that consists of the multifunctional drug everolimus (EVMS) encapsulated by the hepatitis B virus core protein modifies to contain the RGD sequence to specifically bind to integrin αvß3 is designed. Both in vitro and in vivo results show that EVMS@R-HNC can target macrophages as well as SMCs. Upon binding of the nanodrug, the EVMS is released intracellularly where it exhibits multiple functions, including inhibiting M1 macrophage polarization, thereby suppressing the self-propagating inflammatory cascade and immune microenvironment imbalance, while preserving the normal contractile function of SMCs. Collectively, these results suggest that EVMS@R-HNC presents a highly promising therapeutic approach for the management of AAA.

Implication of ferroptosis in hepatic toxicity upon single or combined exposure to polystyrene microplastics and cadmium.

Microplastics (MPs) are a newly emerging type of pollutants. To date, MPs have been found in the atmosphere, soil, water, and even in human samples, posing a non-negligible threat to humans. Furthermore, multiple heavy metals have been found to co-exist with MPs or be absorbed by MPs. This leads to a widespread concern about their combined toxicity, which is currently elusive. Herein, we investigated the single or combined toxic effects of polystyrene MPs (PS-MPs) and cadmium chloride (CdCl2) on the liver and hepatocytes. After co-incubation, cadmium (Cd) can be absorbed by PS-MPs, resulting in physiochemical alterations of PS-MPs. In vivo and in vitro experiments revealed that PS-MPs solely or together with CdCl2 induced ferroptosis in hepatocytes, a newly defined programmed cell death characterized by lipid oxidation and iron accumulation. PS-MPs exerted more ferroptotic effect on hepatocytes than CdCl2, and combined exposure to PS-MPs and CdCl2 enhanced their ferroptotic effect, mainly by stimulating reactive oxygen species (ROS) production and inhibiting antioxidant activity. Upon single or combined exposure to PS-MPs and CdCl2, the induction of ferroptosis in hepatocytes can be inhibited by N-acetyl-cysteine (NAC, an ROS scavenger), deferoxamine (DFO, an iron chelator), and particularly ferrostatin-1 (Fer-1, a specific ferroptosis inhibitor). Fer-1 efficiently rescued the cell viability of hepatocytes upon exposure to PS-MPs and CdCl2 through enhancing the antioxidant system via upregulating GPX4 and SLC7A11. These findings would contribute to an in-depth understanding of the single and combined toxicity of microplastics and cadmium.

Effects of microplastics and tetracycline on intestinal injury in mice.

Microplastics (MPs) and tetracycline are both emerging environmental pollutants that threaten human health. The toxic impacts of their single and coexposure on the intestine and gut microbiota have not been well studied in mammals. Given the spatial functional characteristics of the intestine, it is important to know whether the toxicities of MPs and tetracycline in different intestinal segments are distinct. This study investigated the pathological and functional injuries of different intestinal segments and the microbial disorder upon exposure to polystyrene microplastics (PS-MPs) and/or tetracycline hydrochloride (TCH). Both PS-MPs and TCH altered the intestinal morphology and induced functional impairment. However, the PS-MPs primarily damaged the colon, while TCH mainly damaged the small intestine, especially the jejunum. Combined treatment evoked ameliorative adverse effects on the intestinal segments except for the ileum. Gut microbiota analysis revealed that PS-MPs and/or TCH decreased gut microbiota diversity, especially PS-MPs. In addition, PS-MPs and TCH affected the microflora metabolic processes, especially protein absorption and digestion. Gut microbiota dysbiosis could partly lead to the physical and functional damage induced by PS-MPs and TCH. These findings enhance our knowledge regarding the hazards of coexisting microplastics and antibiotics for mammalian intestinal health.

Distribution of heavy metals in coastal sediments under the influence of multiple factors: A case study from the south coast of an industrialized harbor city (Tangshan, China).

This research investigated the spatial distribution of heavy metals, including mercury (Hg), cadmium (Cd), copper (Cu), arsenic (As), nickel (Ni), lead (Pb), chromium (Cr), and zinc (Zn), in surface sediments from a coastal area near to an industrial harbor (Tangshan Harbor, China) using 161 sediment samples. According to the geo-accumulation index (Igeo), 11 samples were classified as unpolluted (Igeo≤0). Notably, 41.0 % of the research samples were moderately or strongly polluted (2 < Igeo≤3) with Hg and 60.2 % of the samples were moderately polluted (1 < Igeo≤2) in Cd. The ecological effect evaluation showed that the metals Zn, Cd, and Pb were at the effect range low level, and 51.6 % of the samples for Cu, 60.9 % for Cr, 90.7 % for As, 41.0 % for Hg, and 64.0 % for Ni fell in the range between the effect range-low and the effect range-mean levels, respectively. The correlation analysis showed that the distribution patterns of Cr, Cu, Zn, Ni, and Pb were similar to each other, high in the northwest, southeast, and southwest regions of the study area and low in the northeast region, which corresponded well with sediment size components. Based on principal component analysis (PCA) and positive matrix factorization (PMF), four distinct sources of pollution were quantitatively attributed, including agricultural activities (22.08 %), fossil fuel consumption (24.14 %), steel production (29.78 %), and natural sources (24.00 %). Hg (80.29 %), Cd (82.31 %) and As (65.33 %) in the region's coastal sediments were predominantly contributed by fossil fuel, steel production and agricultural sources, respectively. Cr (40.00 %), Cu (43.63 %), Ni (47.54 %), and Zn (38.98 %) were primarily of natural lithogenic origin, while Pb mainly came from the mixed sources of agricultural activities (36.63 %), fossil fuel (36.86 %), and steel production (34.35 %). Multiple factors played important roles in the selective transportation of sedimentary heavy metals, particularly sediment properties, and hydrodynamic sorting processes in the study area.

Phthalates in Glass Window Films of Chinese University Dormitories and Their Associations with Indoor Decorating Materials and Personal Care Products.

Phthalates are widely used as plasticizers in the production of various consumer products used daily. We analyzed phthalate concentrations in window film samples from 144 dormitories in 13 universities and combined them with the results of questionnaires to explore the associations of phthalate concentrations with indoor decorating materials and personal care products. The phthalate pollution levels discovered in this study were much higher than those in previous studies of baby rooms and university buildings. Moreover, it was found that phthalate concentrations in glass window films were associated with laminated wood or polyvinyl chloride (PVC) flooring, iron furniture, medium density fiberboard (MDF) furniture, and the usage frequency of bottled skincare products. Laminated wood or PVC flooring, wallpaper, and iron furniture are very likely sources of specific phthalates, and the large surface areas of MDF furniture can act as sinks of phthalates. Transport of phthalates from the packaging of bottled skincare products into cosmetics should be given more attention. Our results provide a deep understanding of the sources of phthalates in glass window films.

Flexure-resistant and additive-free poly (L-lactic acid) hydrophobic membranes fabricated by slow phase separation.

PLLA membranes with excellent ductility were successfully prepared by a simple solvent evaporation-induced precipitation method, without any additive. The excellent mechanical properties are mainly attributed to the interconnecting pore morphology and the plastic deformation of the pore wall during the stretching process. The interconnecting pore morphology is determined by delaying non-solvent diffusion and molecular chain pre-nucleation. It was found that the average pore size gradually decreased from 19.25 µm to 6.71 µm as the concentration of the polymer solution increased from 0.03 g/ml to 0.10 g/ml, and the elongation at break of the membrane can reach 130.8%. The crystallinity is between 33.4% and 44.5%, and the crystal form is a perfect α crystal. Membrane with interconnecting pore structure contributes to the formation of 91.2% porosity. Furthermore, the solvent evaporation-induced precipitation method can also form surfaces containing micro-nano structures which significantly improves surface hydrophobicity. The combination of high porosity and hydrophobicity makes the membrane potentially applicable to the field of oil-water separation.

Distinct adverse outcomes and lipid profiles of erythrocytes upon single and combined exposure to cadmium and microplastics.

The growing accumulation of environmental microplastics (MPs) has become a global concern. MPs are capable to interact with other environmental contaminants leading to altered toxicity. Red blood cells (RBCs), are the target with highest priority for most of toxic xenobiotics after entering blood stream. Whether co-existence of MPs changes the toxicity of cadmium, a typical hemolysis inducer, in RBCs is unknown. We investigated the adverse effects of CdCl2 and Polystyrene-MPs (PS-MPs) on RBCs in mice. We found that CdCl2 induced mild microcytic hypochromic anemia while PS-MPs induced polycythemia vera, indicating distinct outcomes between them. Moreover, co-treatment of PS-MPs with CdCl2 did not change the phenotype of microcytic hypochromic anemia, indicating an antagonistic relationship between CdCl2 and PS-MPs. However, the lipid profiles were also distinct between single exposure and combined exposure to CdCl2 and PS-MPs. The significant changed lipids were mainly involved in altering the physiochemical or biological properties of RBCs, including decreased membrane components, disrupted bilayer thickness and intrinsic lipid curvature. These results indicated impaired membrane functions of RBCs. The altered lipid profiles observed in the current study may represent new and previously unrecognized harmful characteristics of cadmium and MPs on erythrocytes at low dose without apparent induction of anemia.

Orally delivered thioketal nanoparticles loaded with TNF-α-siRNA target inflammation and inhibit gene expression in the intestines.

Small interfering RNAs (siRNAs) directed against proinflammatory cytokines have the potential to treat numerous diseases associated with intestinal inflammation; however, the side-effects caused by the systemic depletion of cytokines demands that the delivery of cytokine-targeted siRNAs be localized to diseased intestinal tissues. Although various delivery vehicles have been developed to orally deliver therapeutics to intestinal tissue, none of these strategies has demonstrated the ability to protect siRNA from the harsh environment of the gastrointestinal tract and target its delivery to inflamed intestinal tissue. Here, we present a delivery vehicle for siRNA, termed thioketal nanoparticles (TKNs), that can localize orally delivered siRNA to sites of intestinal inflammation, and thus inhibit gene expression in inflamed intestinal tissue. TKNs are formulated from a polymer, poly-(1,4-phenyleneacetone dimethylene thioketal), that degrades selectively in response to reactive oxygen species (ROS). Therefore, when delivered orally, TKNs release siRNA in response to the abnormally high levels of ROS specific to sites of intestinal inflammation. Using a murine model of ulcerative colitis, we demonstrate that orally administered TKNs loaded with siRNA against the proinflammatory cytokine tumour necrosis factor-alpha (TNF-α) diminish TNF-α messenger RNA levels in the colon and protect mice from ulcerative colitis.

Enhanced hepatic cytotoxicity of chemically transformed polystyrene microplastics by simulated gastric fluid.

Microplastics pollution has emerged as one of the top-ranked global environmental issues, receiving worldwide attention in recent years. However, knowledge about the detrimental effects of microplastics on human health is still limited. In real-world settings, the physicochemical characteristics of microplastics were modified by environmental and biological transformation, largely changing their ultimate toxicity. Nonetheless, the toxicity change related to transformation of microplastics has not been considered in most published studies thus far. In the current study, we investigated the cytotoxicity of transformed polystyrene microplastics in hepatocytes. Our results revealed that 500 nm polystyrene microplastics, which were chemically transformed by simulated gastricfluid, exacerbated their adverse effects on SMMC-7721 cells at 20 µg/mL for 24 h treatment, including morphological alteration, membrane damage and increased cell apoptosis via oxidative stress. This exacerbated cytotoxicity could be at least partially explained by the degradation, changed surface charge and altered surface chemistry of these polystyrene microplastics after transformation. In conclusion, our study demonstrates that the hepatic cytotoxicity of polystyrene microplastics is enhanced after transformation.

Skin-inspired cellulose conductive hydrogels with integrated self-healing, strain, and thermal sensitive performance.

In this study, a versatile cellulose conductive hydrogels with outstanding mechanical properties, rapid self-healing performance, and excellent thermal sensitivity were successfully fabricated. The tensile strength and toughness of the gels gradually increased to 249 kPa and 1.57 MJ/m3, respectively, and the healing efficiency of the hydrogels quickly reached 96.3% within 60 min. Importantly, the hydrogels exhibited a broad strain window (0-2066%) with a gauge factor ranging from 0.22 to 6.7, which could monitor of both obvious and subtle motion of the human body with high sensitivity and good repeatability. Moreover, the sensors also possessed good thermal sensitivity in the 0% and 400% state, and the response of the gel sensors increased from 8.3 to 87.9 when the temperature was increased from 35 to 85 °C. This study provides inspiration for the development of biocompatible and multifunctional cellulose-based wearable sensors with excellent mechanical, strain and temperature sensing and self-healing properties.

Application of Hydroxycholesterols for Alveolar Cleft Osteoplasty in a Rodent Model.

BACKGROUND: Bone morphogenetic proteins (BMPs) have played a central role in the regenerative therapies for bone reconstruction, including alveolar cleft and craniofacial surgery. However, the high cost and significant adverse effect of BMPs limit their broad application. Hydroxycholesterols, naturally occurring products of cholesterol oxidation, are a promising alternative to BMPs. The authors studied the osteogenic capability of hydroxycholesterols on human mesenchymal stem cells and the impact of hydroxycholesterols on a rodent alveolar cleft model. METHODS: Human mesenchymal stem cells were treated with control medium or osteogenic medium with or without hydroxycholesterols. Evaluation of cellular osteogenic activity was performed. A critical-size alveolar cleft was created and one of the following treatment options was assigned randomly to each defect: collagen sponge incorporated with hydroxycholesterols, BMP-2, or no treatment. Bone regeneration was assessed by means of radiologic and histologic analyses and local inflammation in the cleft evaluated. Moreover, the role of the hedgehog signaling pathway in hydroxycholesterol-mediated osteogenesis was examined. RESULTS: All cellular osteogenic activities were significantly increased on human mesenchymal stem cells treated with hydroxycholesterols relative to others. The alveolar cleft treated with collagen sponge with hydroxycholesterols and BMP-2 demonstrated robust bone regeneration. The hydroxycholesterol group revealed histologically complete bridging of the alveolar defect with architecturally mature new bone. The inflammatory responses were less in the hydroxycholesterol group compared with the BMP-2 group. Induction of hydroxycholesterol-mediated in vitro osteogenesis and in vivo bone regeneration were attenuated by hedgehog signaling inhibitor, implicating involvement of the hedgehog signaling pathway. CONCLUSION: Hydroxycholesterols may represent a viable alternative to BMP-2 in bone tissue engineering for alveolar cleft.

Triple-functional polyetheretherketone surface with enhanced bacteriostasis and anti-inflammatory and osseointegrative properties for implant application.

Polyetheretherketone (PEEK) is considered a potential orthopedic/dental material because of its excellent mechanical and chemical properties (e.g., similar elastic modulus to that of human bone). However, the poor bacteriostasis and anti-inflammatory and osseointegrative properties of bioinert PEEK impede its clinical application. We previously developed a facile and versatile surface modification method using dexamethasone plus minocycline-loaded liposomes (Dex/Mino liposomes) bonded by a mussel-inspired polydopamine coating, which effectively modulated cell inflammatory response and discouraged bacterial colonization in vitro. Herein, we report the application of this multifunctional surface modification method to improve bioinert PEEK, aimed at further studying the in vitro osteogenesis and in vivo properties of Dex/Mino liposome-modified PEEK to prevent bacterial contamination, attenuate the inflammatory response, and enhance ossification for physiologic osseointegration. Our study established that the Dex/Mino liposome-modified PEEK surface presented favorable stability and cytocompatibility. Compared with bare PEEK, improved osteogenic differentiation of human mesenchymal stem cells under both osteoinductive and osteoconductive conditions was found on the functionalized surface due to the liposomal Dex releasing. In vivo bacteriostasis assay confirmed that Mino released from the functionalized surface provided an effective antibacterial effect. Moreover, the subcutaneous foreign body reaction and beagle femur implantation models corroborated the enhanced anti-inflammatory and osteointegrative properties of the functionalized PEEK. Our findings indicate that the developed Dex/Mino liposome-modified PEEK with enhanced antibacterial, anti-inflammatory, and osseointegrative capacity has great potential as an orthopedic/dental implant material for clinical application.

Oral Delivery of Nanoparticles Loaded With Ginger Active Compound, 6-Shogaol, Attenuates Ulcerative Colitis and Promotes Wound Healing in a Murine Model of Ulcerative Colitis.

BACKGROUND AND AIMS: Oral drug delivery is the most attractive pathway for ulcerative colitis [UC] therapy, since it has many advantages. However, this strategy has encountered many challenges, including the instability of drugs in the gastrointestinal tract [GT], low targeting of disease tissues, and severe adverse effects. Nanoparticles capable of colitis tissue-targeted delivery and site-specific drug release may offer a unique and therapeutically effective system that addresses these formidable challenges. METHODS: We used a versatile single-step surface-functionalising technique to prepare PLGA/PLA-PEG-FA nanoparticles loaded with the ginger active compound, 6-shogaol [NPs-PEG-FA/6-shogaol]. The therapeutic efficacy of NPs-PEG-FA/6-shogaol was evaluated in the well-established mouse model of dextran sulphate sodium [DSS]-induced colitis. RESULTS: NPs-PEG-FA exhibited very good biocompatibility both in vitro and in vivo. Subsequent cellular uptake experiments demonstrated that NPs-PEG-FA could undergo efficient receptor-mediated uptake by colon-26 cells and activated Raw 264.7 macrophage cells. In vivo, oral administration of NPs-PEG-FA/6-shogaol encapsulated in a hydrogel system [chitosan/alginate] significantly alleviated colitis symptoms and accelerated colitis wound repair in DSS-treated mice by regulating the expression levels of pro-inflammatory [TNF-α, IL-6, IL-1ß, and iNOS] and anti-inflammatory [Nrf-2 and HO-1] factors. CONCLUSIONS: Our study demonstrates a convenient, orally administered 6-shogaol drug delivery system that effectively targets colitis tissue, alleviates colitis symptoms, and accelerates colitis wound repair. This system may represent a promising therapeutic approach for treating inflammatory bowel disease [IBD].

TNFα gene silencing mediated by orally targeted nanoparticles combined with interleukin-22 for synergistic combination therapy of ulcerative colitis.

Pro-resolving factors that are critical for colonic epithelial restitution were down-regulated during the treatment with inhibitor of pro-inflammatory cytokines (e.g., anti-TNFα antibody) in ulcerative colitis (UC) therapy. We hypothesized that increased amounts of factors such as interleukin-22 (IL-22) during the therapeutic inhibition of TNFα could facilitate the resolution of intestinal inflammation. As combination therapy is an emerging strategy for UC treatment, we attempt to treat established UC based on the combination of TNFα siRNA (siTNF) and IL-22. Initially, we loaded siTNF into galactosylated polymeric nanoparticles (NPs). The resultant Gal-siTNF-NPs had a desirable average diameter (~261 nm), a narrow size distribution and a slightly negative surface charge (~-6 mV). These NPs successfully mediated the targeted delivery of siTNF to macrophages and efficiently inhibited the expression of TNFα. Meanwhile, IL-22 could obviously accelerate mucosal healing. More importantly, oral administration of Gal-siTNF-NPs plus IL-22 embedded in a hydrogel (chitosan/alginate) showed much stronger capacities to down-regulate the expression of pro-inflammatory factors and promote mucosal healing. This formulation also yielded a much better therapeutic efficacy against UC in a mouse model compared to hydrogel loaded with Gal-siTNF-NPs or IL-22 alone. Our results strongly demonstrate that Gal-siTNF-NP/IL-22-embedded hydrogel can target to inflamed colon, and co-deliver siTNF and IL-22 to boost the effects of either monotherapy, which may become a promising oral drug formulation and enable targeted combination therapy of UC.