Effect and Mechanism of Pharmaceutical Excipients on Berberine to Alleviate Ulcerative Colitis via Regulating Gut Microbiota.

BACKGROUND: Various potential effect of drugs on alleviating diseases by regulating intestinal microbiome as well as the pharmaceutical excipients on gut microbiota has been revealed. However, the interaction between them is rarely investigated. METHODS: Histological analysis, immunohistochemistry analysis, enzyme-linked immunosorbent assay (ELISA) analysis, RT-qPCR, and 16S rRNA analysis were utilized to explore the effect mechanism of the five excipients including hydroxypropyl methylcellulose (HPMC) F4M, Eudragit (EU) S100, chitosan (CT), pectin (PT), and rheum officinale polysaccharide (DHP) on berberine (BBR) to cure UC. RESULTS: The combined BBR with PT and DHP group exhibited better therapeutic efficacy of UC with significantly increased colon length, and decreased hematoxylin-eosin (H&E) scores than other groups. Furthermore, the expression of tight junction ZO-1 and occludin in colon tissue were upregulated, and claudin-2 was downregulated. Ultimately, the serum content of tumor necrosis (TNF)-α, interleukin (IL)-1ß, and IL-6 was decreased. Moreover, the combined BBR with PT significantly promoted the restoration of gut microbiota. The relative abundance of Firmicutes and Lactobacillus was significantly increased by the supplement of PT and DHP, and the relative abundance of Proteobacteria was downregulated. CONCLUSIONS: Our study may provide a new perspective that the selection of pharmaceutical excipients could be a crucial factor affecting the drugs' therapeutic efficiency outcome.

Graphene Oxide and Gadolinium-Chelate Functionalized Poly(lactic acid) Nanocapsules Encapsulating Perfluorooctylbromide for Ultrasound/Magnetic Resonance Bimodal Imaging Guided Photothermal Ablation of Cancer.

This paper successfully fabricated a novel multifunctional theranostic agent (PFOB@PLA/GO/Gd-DTPA NCs) by loading perfluorooctylbromide (PFOB) into poly(lactic acid) (PLA) nanocapsules (NCs) followed by surface functionalization with graphene oxide (GO) and gadolinium-chelate (Gd-DTPA). It was found that the resulting nanoagent could serve as a contrast agent simultaneously to enhance ultrasound (US) and magnetic resonance imaging (MRI). Benefiting from the strong absorption in the near infrared (NIR) region, the nanocapsules could efficiently kill cancer cells under NIR laser irradiation. Thus, such a single theranostic agent with the combination of realtime US imaging and high-resolution MR imaging could achieve great therapeutic effectiveness without systemic damage to the body. In addition, the cytotoxicity assay on HUVEC cells revealed a good biocompatibility of PFOB@PLA/GO/Gd-DTPA NCs, showing that the versatile nanocapsule system may hold great potential as an effective nanoplatform for contrast enhanced imaging guided photothermal therapy.

Prussian Blue Modified PLA Microcapsules Containing R6G for Ultrasonic/Fluorescent Bimodal Imaging Guided Photothermal Tumor Therapy.

A theranostic agent has been successfully constructed for fluorescence/ultrasound dual-modal imaging guided photothermal therapy by loading the fluorescent dye R6G into polylactide microcapsules (PLA MCs) followed by deposition of Prussian blue nanoparticles (PB NPs) into the surface of PLA MCs. It was proved that the obtained microcapsules of R6G@PLA/PB MCs could serve as an efficient probe to simultaneously enhance fluorescence imaging and ultrasound imaging greatly in vivo. R6G@PLA/PB MCs exhibited significant photothermal cytotoxicity. Cancer cells could be killed efficiently through photothermal effects of R6G@PLA/PB MCs due to the strong absorption of PB NPs in the near infrared region under laser irradiation. In a word, R6G@PLA/PB MCs integrate multiple capabilities for effective tumor imaging and therapy. Such a single agent provides us a possibility to interpret accurately the obtained images, identify the size and location of the tumor, as well as guide and monitor the photothermal therapy.

Gold nanoshelled liquid perfluorocarbon nanocapsules for combined dual modal ultrasound/CT imaging and photothermal therapy of cancer.

The integration of multimodal contrast-enhanced diagnostic imaging and therapeutic capabilities could utilize imaging guided therapy to plan the treatment strategy based on the diagnostic results and to guide/monitor the therapeutic procedures. Herein, gold nanoshelled perfluorooctylbromide (PFOB) nanocapsules with PEGylation (PGsP NCs) are constructed by oil-in-water emulsion method to form polymeric PFOB nanocapsules, followed by the formation of PEGylated gold nanoshell on the surface. PGsP NCs could not only provide excellent contrast enhancement for dual modal ultrasound and CT imaging in vitro and in vivo, but also serve as efficient photoabsorbers for photothermal ablation of tumors on xenografted nude mouse model. To our best knowledge, this is the first report of gold nanoshell serving as both CT contrast agents and photoabsorbers for photothermal therapy. The novel multifunctional nanomedicine would be of great value to offer more comprehensive diagnostic information to guide more accurate and effective cancer therapy.

Prevalence of developmental odontogenic cysts in children and adolescents with emphasis on dentigerous cyst and odontogenic keratocyst (keratocystic odontogenic tumor).

OBJECTIVE: To investigate the incidence and prevalence of developmental odontogenic cysts in children and adolescents and compare the features of the two most common types, dentigerous cyst and keratocystic odontogenic tumor (KCOT). STUDY DESIGN: A retrospective review in a series of 369 patients with all histological diagnoses of developmental odontogenic cysts in children (≤12 years) and adolescents (13-18 years) was conducted. RESULTS: Among these, 361 (97.8%) patients were diagnosed as dentigerous cyst (n = 281) and KCOT (n = 80), with the male-to-female ratios of dentigerous cyst and KCOT both being 2:1. The average age of the patients with KCOT was older than that of those with dentigerous cyst (14.7 years vs 11.8 years, p < 0.001). Dentigerous cyst (59.1%) was more common in children, but KCOT (78.8%) was more common in adolescents (p < 0.001). Dentigerous cyst (57.6%) predominantly located on the maxilla, but KCOT (60.3%) predominantly located on the mandible (p = 0.010). CONCLUSIONS: Adolescent patients with lesions located on the mandible would favor KCOT over dentigerous cyst. This study aids in better knowledge of the prevalence of developmental odontogenic cysts in a large pediatric population, and shows that a well-supported early diagnosis is indispensable for a more adequate treatment.

Preparation of polyelectrolyte multilayer coated microbubbles for use as ultrasound contrast agent.

OBJECTIVE: To prepare and characterize polyelectrolyte multilayer film coated microbubbles for use as ultrasound contrast agent (UCA) and evaluate its effects in ultrasonic imaging on normal rabbit's liver parenchyma. METHODS: Perfluorocarbon (PFC)-containing microbubbles (ST68-PFC) were prepared by sonication based on surfactant (Span 60 and Tween 80). Subsequently, the resulting ST68-PFC microbubbles were coated using oppositely charged polyelectrolytes by microbubble-templated layer-by-layer self-assembly technique via electrostatic interaction. The enhancement effects in ultrasonic imaging on normal rabbit's liver parenchyma were assessed. RESULTS: The obtained microbubbles exhibited a narrow size distribution. The polyelectrolytes were successfully assembled onto the surface of ST68-PFC microbubbles. In vivo experiment showed that polyelectrolyte multilayer film coated UCA effectively enhanced the imaging of rabbit's liver parenchyma. CONCLUSIONS: The novel microbubbles UCA coated with polyelectrolyte multilayer, when enabled more function, has no obvious difference in enhancement effects compared with the pre-modified microbubbles. The polymers with chemically active groups (such as amino group and carboxyl group) can be used as the outermost layer for attachment of targeting ligands onto microbubbles, allowing selective targeting of the microbubbles to combine with desired sites.

Differential diagnosis of gastric cancer and gastritis: the role of contrast-enhanced ultrasound (CEUS).

OBJECTIVES: To evaluate the diagnostic performance of contrast-enhanced ultrasound (CEUS) in differential diagnosis of gastric cancer and gastritis, with histological results as reference standard. METHODS: From September 2011 to August 2014, 82 patients (50 males and 32 females; mean age ± SD, 59.5 ± 15.0 years; range 19-91 years) with gastric cancer or gastritis were included in this Ethics Committee-approved prospective study. Conventional ultrasonography (US) and CEUS were applied to distinguish the two lesions, and both qualitative and quantitative features were evaluated. RESULTS: Of the 82 histopathologic-proven lesions, 58 were cancer and 24 were gastritis. For US, the gastric wall stratification was not preserved in about one-third of cancer (21/58, 36.2%) compared with gastritis (0/24, 0%) (p < 0.001). Blurred, angular, or spiculated serosa margin and increased echogenicity in perigastric fat appeared only in cancer (10/58, 17.2%), and all of them proved to be pathologic T3 or T4 stage. On CEUS, gastric cancer usually manifested as diffused enhancement without comb-teeth-like vessels (parallel curvilinear structures representing arterial branching within the gastric wall) (56/58, 96.6%), while these vessels presented in most gastritis (19/24, 79.2%, p < 0.001). For quantitative analysis, the malignant lesions showed later and lower enhancement (p < 0.001), and they also had slower speed to reach the peak intensity (p < 0.001). On CEUS, the absence of comb-teeth-like vessel is most reliable for diagnosing malignancy, and the sensitivity, specificity, and accuracy were 96.5%, 79.2%, and 91.5%, respectively. CONCLUSIONS: Our results demonstrated the usefulness and accuracy of US and CEUS in differential diagnosis of gastric cancer and gastritis. CEUS has the potential to make the diagnosis more accurate.

Effects of light curing modes and ethanol-wet bonding on dentin bonding properties.

OBJECTIVE: This study explored the effects of different light curing modes and ethanol-wet bonding on dentin bonding strength and durability. METHODS: A total of 54 molars were randomly divided into three groups: Single Bond 2, Gluma Comfort Bond, and N-Bond. Based on the three light-curing modes and presence or absence of ethanol pretreatment, the samples were assigned to six subgroups: high-light mode, ethanol pretreatment+high-light mode, soft-start mode, ethanol pretreatment+soft-start mode, standard mode, and ethanol pretreatment+standard mode. All samples were bonded with resin based on the experimental groups. After 24 h and 6 months of water storage, a universal testing machine was used to measure microtensile bond strength. Scanning electron microscopy (SEM) was applied to observe mixed layer morphology. RESULTS: The 24-h and 6-month microtensile bond strengths of the ethanol pretreatment groups were significantly higher than those of the non-ethanol pretreatment groups at the same light modes (P<0.05). With or without ethanol pretreatment, the microtensile bond strengths of the high-light modes were significantly lower than those of the soft-start modes and standard modes (P<0.05). The microtensile bond strengths of samples from the 6-month water storage group significantly decreased compared with those of samples from the 24-h water storage group (P<0.05). The soft-start groups and standard groups formed better mixed layers than the high-light mode groups, whereas the ethanol pretreatment groups formed more uniform mixed layers than those without ethanol pretreatment. CONCLUSIONS: Ethanol-wet bonding technique, soft-start, and standard modes could improve dentin bonding properties.

Engineering of perfluorooctylbromide polypyrrole nano-/microcapsules for simultaneous contrast enhanced ultrasound imaging and photothermal treatment of cancer.

A versatile oil-in-water emulsion method has been explored for constructing water-dispersible polypyrrole (PPy) nano-/microcapsules with a soluble PPy complex as multifunctional photothermal agents for tumor ablation. In this work, both PPy nanocapsules (280.4 ± 79.0 nm) and microcapsules (1.31 ± 0.45 µm) with liquid perfluorooctylbromide (PFOB) core could be obtained by simply tuning the process energy for emulsion formation from ultrasonication to homogenization. Owing to the encapsulated liquid PFOB and strong near-infrared (NIR) absorption of PPy shell, the resulted PPy capsules showed great promise in ultrasound imaging guided photothermal ablation of tumor cells without inducing any significant side effect. Thus, it is anticipated that fine-tuning of the other encapsulated drugs or functional materials in PPy capsules would foster avenues for the development of multifunctional platforms for cancer treatments.

Graphene oxide modified PLA microcapsules containing gold nanoparticles for ultrasonic/CT bimodal imaging guided photothermal tumor therapy.

Theranostic microcapsules were successfully fabricated by introducing gold nanoparticles into poly(lactic acid) microcapsules through a double-microemulsion method, followed by depositing graphene oxide onto the microcapsule surface via electrostatic layer-by-layer self-assembly technique. It was proved that the obtained microcapsules could serve as a contrast agent to simultaneously enhance US imaging and X-ray CT imaging greatly both in vitro and in vivo. In addition, the in vivo therapeutic examinations showed that the microcapsule was an effective agent for photothermal therapy of cancer. The near-infrared laser light ablated the tumor completely within 9 days in the presence of the microcapsules and the tumor growth inhibition was 83.8%. The combination of real-time ultrasound with 3-D computed tomography through a single microcapsule agent is very helpful for accurately interpreting the obtained images, identifying the size and location of the tumor, as well as guiding and monitoring the photothermal therapy. Simultaneously, the effectiveness of photothermal therapy could be evaluated by the combined US and CT imaging enhanced by the microcapsule agent. Such a versatile microcapsule system might bring opportunities to the next generation of multimodal imaging guided cancer therapy.

Polypyrrole hollow microspheres as echogenic photothermal agent for ultrasound imaging guided tumor ablation.

Ultrasound (US) imaging provides a valuable opportunity to administer photothermal therapy (PTT) of cancer with real-time guidance to ensure proper targeting, but only a few theranostic agents were developed by physically grafting near infrared (NIR)-absorbing inorganic nanomaterials to ready-made ultrasound contrast agents (UCAs) for US imaging guided PTT. In this paper, NIR absorbing hollow microspheres were generated from polypyrrole merely using a facile one-step microemulsion method. It was found that the obtained polypyrrole hollow microspheres (PPyHMs) can act as an efficient theranostic agent not only to enhance US imaging greatly, but also exhibit excellent photohyperthermic effects. The contrast consistently sustained the echo signals for no less than 5 min and the NIR laser light ablated the tumor completely within two weeks in the presence of PPyHMs. More importantly, no use of additional NIR absorber substantially minimizes an onetime dose of the theranostic agent.

Biocompatible polypyrrole nanoparticles as a novel organic photoacoustic contrast agent for deep tissue imaging.

Photoacoustic tomography (PAT) has emerged as a hybrid, nonionizing imaging modality because of its satisfactory spatial resolution and high soft tissue contrast. Here, we demonstrate the application of a novel organic PAT contrast agent based on polypyrrole nanoparticles (PPy NPs). Monodisperse PPy NPs are ∼46 nm in diameter with strong absorption in the near-infrared (NIR) range, which allowed visualization of PPy NP-containing agar gel embedded in chicken breast muscle at a depth of ∼4.3 cm. Compared with PAT images based on the intrinsic optical contrast in mice, the PAT images acquired within 1 h after intravenous administration of PPy NPs showed the brain vasculature with greater clarity than hemoglobin in blood. Preliminary results showed no acute toxicity to the vital organs (heart, liver, spleen, lungs and kidneys) in mice following a single imaging dose of PPy NPs. Our results indicate that PPy NPs are promising contrast agents for PAT with good biocompatibility, high spatial resolution and enhanced sensitivity.

[Evaluation of mechanical properties of four kinds of composite resins for inlay].

PURPOSE: To evaluate the compressive strength, wear resistance, hardness, and soaking fatigue of four composite resins for inlay, which were Ceramage, Surefil, Solitaire 2, and Filtek(TM) Z350. Scanning electron microscope (SEM) was used to analyze the microstructures of the wear surface of the samples. METHODS: The samples for the compression test, hardness test and wear were prepared. The samples were respectively immersed in the artificial saliva for 2 months for immersed test. The electronic universal testing machine was used to test the compression strength. Hardness was quantified by micro-Vickers hardness test. The wear tester was used for the wear test. SEM was used to analyze the microstructures of the wear surface of samples. All the data was analyzed by using SPSS17.0 software package. RESULTS: The compressive strength of Surefil was the biggest which was significantly higher than the other three resins before soaking (P<0.05). After soaking, there was no significant difference between the composite resins (P>0.05). The hardness of Surefil was the best, and significant difference was found between the hardness of the materials before soaking (P<0.05). After soaking, no significant difference was obtained between the hardness of Surefil and Filtek(TM) Z350 (P>0.05).The compressive strength and hardness of 4 materials decreased after soaking in artificial saliva. But only the compressive strength of Filtek(TM) Z350 had no significant change after immersion (P>0.05). Except Filtek(TM) Z350, there was significant difference between the other three materials (P<0.05). Significant relationship was observed between wear and hardness of three materials (P<0.05). According to SEM observation, abrasive wear occurred in four materials. In addition to Ceramage, other composite resins had adhesive wear. CONCLUSIONS: The mechanical property of Surefil is the best, and it is suitable for fabrication of posterior inlay. Filtek(TM) Z350's ability to resist fatigue is the best.

Novel ultrasound contrast agent based on microbubbles generated from surfactant mixtures of Span 60 and polyoxyethylene 40 stearate.

In this study, novel perfluorocarbon-filled microbubbles as ultrasound contrast agent were fabricated using ultrasonication of a surfactant mixture of sorbitan monostearate (Span 60) and polyoxyethylene 40 stearate (PEG40S) in aqueous media. The microbubbles generated from a 1:9 mixture of PEG40S/Span 60 exhibited an average diameter of 2.08+/-1.27 microm. More than 99% of the microbubbles had a mean particle diameter less than 8 microm, indicating that they were appropriately sized for intravenous administration as ultrasound contrast agent. The stabilization mechanism of the microbubbles was investigated by the Langmuir-Blodgett technique including the measurements of surface pressure-area (pi-A) isotherms and compression-decompression cycles with a two-dimensional monolayer of Span 60 and PEG40S. The dependence on molar fraction of PEG40S in pi-A isotherms of mixed monolayers provided a strong evidence of interactions between the two microbubble-forming materials. It is suggested that the monolayer shell imparts good stability to the microbubbles by three means: (1) a low surface tension monolayer hinders dissolution through the reduction of surface tension, which introduces a mechanical surface pressure that counters the Laplace pressure; (2) the presence of a monolayer shell imparts a significant barrier to gas escaping from the core into the aqueous medium; and (3) encapsulation elasticity stabilizes microbubbles against diffusion-driven dissolution and explains the long shelf-life of microbubble contrast agent. The preliminary in vivo ultrasound imaging study showed that such stabilized microbubbles demonstrated excellent enhancement under grey-scale pulse inversion harmonic imaging and power Doppler imaging.