3D printing of multi-unit gastro-retentive tablets for the pulsatile release of artesunate.

Pulsatile drug delivery is hardly achieved by conventional gastro-retentive dosage forms. Artesunate as a typical anti-malaria medicine needs oral pulsatile release. Here, artesunate-loaded pulsatile-release multi-unit gastro-retentive tablets (APGTs) were prepared with a semi-solid extrusion three-dimensional (3D) printing method. An APGT was composed of three units: artesunate-loaded immediate and delayed release units and a block unit. The matrix of the immediate/delayed release units consisted of polyvinylpyrrolidone (PVP) K30 and croscarmellose sodium, which improved the rapid release of artesunate when contacting water. The block unit consisted of octadecanol, hydroxypropyl methyl cellulose K15M, PVP K30, and poloxamer F68. APGTs showed multi-phase release in simulated gastric liquids (SGLs). The first immediate release phase continued for 1 h followed by a long block phase for 7 h. The second rapid release phase was initiated when the eroded holes in the block unit extended to the inner delayed release unit, and this phase continued for about 14 h. Low-density APGTs could ensure their long-term floating in the stomach. Oral APGTs remained in the rabbit stomach for about 20 h. 3D printing provides a new strategy for the preparation of oral pulsatile-release tablets.

Chromium Picolinate Regulates Bone Metabolism and Prevents Bone Loss in Diabetic Rats.

Diabetic osteoporosis (DOP) is an abnormal metabolic disease caused by long-term hyperglycemia. In this study, a model rat of streptozotocin (STZ)-induced diabetes was established, and chromium picolinate (5 mg·kg-1) was given; the changes in blood glucose and body weight were detected before and after administration; and bone mineral density (BMD), bone morphology, bone turnover markers, inflammatory cytokines, and oxidative stress indicators were observed in each group. We found that after chromium picolinate (CP) intervention for 8 weeks, the blood glucose level was decreased; the BMD, the bone histomorphology parameters, and the pathological structure were improved; the expression of bone resorption-related proteins was downregulated; and the expression of bone formation-related proteins was upregulated. Meanwhile, serum antioxidant activity was increased, and inflammatory cytokine levels were decreased. In conclusion, CP could alleviate DOP by anti-oxidation, inhibition of bone turnover, anti-inflammation, and regulation of the OPG/RANKL/RANK signaling pathway. Therefore, CP has important application values for further development as a functional food or active medicine in DOP treatment.

Injectable multifunctional chitosan/dextran-based hydrogel accelerates wound healing in combined radiation and burn injury.

Clinical wound management of combined radiation and burn injury (CRBI) remains a huge challenge due to serious injuries induced by redundant reactive oxygen species (ROS), the accompanying hematopoietic, immunologic suppression and stem cell reduction. Herein, the injectable multifunctional Schiff base cross-linked with gallic acid modified chitosan (CSGA)/oxidized dextran (ODex) hydrogels were rationally designed to accelerate wound healing through elimination of ROS in CRBI. CSGA/ODex hydrogels, fabricated by mixing solutions of CSGA and Odex, displayed good self-healing ability, excellent injectability, strong antioxidant activity, and favorable biocompatibility. More importantly, CSGA/ODex hydrogels exhibited excellent antibacterial properties, which is facilitated for wound healing. Furthermore, CSGA/ODex hydrogels significantly suppressed the oxidative damage of L929 cells in an H2O2-induced ROS microenvironment. The recovery of mice with CRBI in mice demonstrated that CSGA/ODex hydrogels significantly reduced the hyperplasia of epithelial cells and the expression of proinflammatory cytokine, and accelerated wound healing which was superior to the treatment with commercial triethanolamine ointment. In conclusion, the CSGA/ODex hydrogels as a wound dressing could accelerate the wound healing and tissue regeneration of CRBI, which provides great potential in clinical treatment of CRBI.

Preparation of informative wafers (info-wafers) by combination of 3D printing, code design and photopolymerization.

3D printing is used in manufacturing of personalized and customized medications. Moreover, information technology has been integrated with 3D printing, which builds the basis of informative medications. Here, clonidine hydrochloride (CH) was formulated in informative wafers (info-wafers) by combination of 3D printing, code design and photopolymerization. Braille code (recognized by blind persons), bar code, and quick response (QR) code were used for the design of info-wafers. A code positive mold was 3D-printed with rigid resins by stereolithography, which was transformed to the silicone negative mold by thermal polymerization. A homogeneous CH suspension in N-vinyl pyrrolidone was casted into the negative mold followed by photopolymerization to form CH info-wafers. The bulgy parts of info-wafers were painted with edible ink except for Braille code info-wafers. The CH in info-wafers maintained the amorphous state, which was demonstrated by X-ray diffraction. The amorphous CH had rapid dissolution. Bar code info-wafers were scanned by smartphone though only simple information was obtained. QR code info-wafers were smartphone-scanned to link a website that contained sufficient information such as the instruction of CH application and the collection of patient information. Info-wafers provide online drug information and use instructions for patients to make the treatment standardization and normalization.

Potential applications of drug delivery technologies against radiation enteritis.

INTRODUCTION: The incidence of abdominal tumors, such as colorectal and prostate cancers, continually increases. Radiation therapy is widely applied in the clinical treatment of patients with abdominal/pelvic cancers, but it often unfortunately causes radiation enteritis (RE) involving the intestine, colon, and rectum. However, there is a lack of suitable treatment options for effective prevention and treatment of RE. AREAS COVERED: Conventional clinical drugs for preventing and treating RE are usually applied by enemas and oral administration. Innovative gut-targeted drug delivery systems including hydrogels, microspheres, and nanoparticles are proposed to improve the prevention and curation of RE. EXPERT OPINION: The prevention and treatment of RE have not attracted sufficient attention in the clinical practice, especially compared to the treatment of tumors, although RE takes patients great pains. Drug delivery to the pathological sites of RE is a huge challenge. The short retention and weak targeting of conventional drug delivery systems affect the therapeutic efficiency of anti-RE drugs. Novel drug delivery systems including hydrogels, microspheres, and nanoparticles can allow drugs long-term retention in the gut and targeting the inflammation sites to alleviate radiation-induced injury.

Phillygenin from Forsythia suspensa leaves exhibits analgesic potential and anti-inflammatory activity in carrageenan-induced paw edema in mice.

Forsythia suspensa (Thunb.) Vahl (Oleaceae) leaves are valuable sources of phillygenin. This study aimed to isolate phillygenin from F. suspensa leaves and examine its analgesic and anti-inflammatory effects. Phillygenin was successfully extracted and isolated from F. suspensa leaves after fermentation. Phillygenin significantly reduced the number of writhing induced by acetic acid, prolonged the latency period in the hot plate test, and inhibited the xylene-induced ear edema and carrageenan-induced paw edema in mice. IL-6, TNF-α, IL-1ß, NO, and PGE2 levels in the carrageenan-induced paw edema were notably reduced after pretreatment with phillygenin. Phillygenin significantly decreased the iNOS and COX-2 protein expressions and the IκB-α and NF-κB p65 phosphorylation. This study demonstrated that phillygenin is a potential therapeutic candidate for managing pain and inflammation-mediated disorders. The study contributes to the comprehensive development and utilization of F. suspensa leaves for economic and health care. PRACTICAL APPLICATIONS: Phillygenin is one of the major active ingredients in Forsythia suspensa. But the content of phillygenin in F. suspensa is very low which limits its application. Phillygenin has potential pharmacological activity and anti-inflammatory properties. However, the potential effects of phillygenin on analgesic activity have not been clarified. Furthermore, the data on its anti-inflammatory activity in vivo are relatively limited. This study evaluated the analgesic activity for the first time and the acute anti-inflammatory effect of phillygenin from F. suspensa leaves by fermentation, which indicated phillygenin is a potential therapeutic candidate for managing pain and inflammation-mediated disorders.

Light-triggered on-site rapid formation of antibacterial hydrogel dressings for accelerated healing of infected wounds.

An optimal wound dressing can seal variously shaped wounds and provide a complete barrier to resist bacterial invasion; more importantly, the dressing can be stretched or compressed when the wounds are subjected to external forces and quickly return to its original state after the forces are withdrawn. Here, we designed dressings with light-triggered on-site rapid formation of antibacterial hydrogel for the accelerated healing of infected wounds. The pro-hydrogel, composed of acrylamide (AM) and dopamine-hyaluronic acid-ε-poly-l-lysine (DA-HA-EPL), was filled into the Vibrio vulnificus-infected wound. A 405-nm blue light was exerted on the wound to rapidly photopolymerize AM to its polymer, i.e., polyacrylamide (PAM). A hydrogel network of PAM/DA-HA-EPL immediately formed on site within several seconds to insulate the wound. PAM/DA-HA-EPL possessed adhesion performance to adapt to changes in wound morphologies due to external forces. Moreover, it presented high antibacterial ability due to the presence of EPL, in vitro biocompatibility and the ability to promote cell migration. Vibrio vulnificus-infected wounds were established on full-thickness mouse skin, and the hydrogel dressing exhibited high healing efficiency in terms of skin tissue regeneration, collagen deposition, and angiogenesis. PAM/DA-HA-EPL is a promising hydrogel dressing for the accelerated healing of infected wounds.

Dietary phillygenin supplementation ameliorates aflatoxin B1-induced oxidative stress, inflammation, and apoptosis in chicken liver.

Aflatoxin B1 (AFB1), a mycotoxin contaminating food and feed, can trigger liver immune toxicity and threaten the poultry industry. Phillygenin (PHI) is a natural lignan derived primarily from Forsythia suspensa with hepatoprotective pharmacological and medicinal properties. This research aimed to investigate the preventive effects of PHI on the toxicity of AFB1 in the liver of chickens. Chickens were administered with AFB1 (2.8 mg/kg) and/or treated with PHI (24 mg/kg) for 33 days. The histopathological changes, serum biochemical indices, oxidative damage, inflammatory mediators, apoptosis, and activation of the NF-κB and Nrf2 signaling pathways were measured. Results revealed that dietary PHI ameliorated liver function indicators, reduced the malondialdehyde and inflammatory mediator production and the apoptotic cell number, and increased the antioxidant enzyme contents and Bcl-2 level. The quantitative realtime PCR and Western blot results revealed that PHI reduced p53, cytochrome c, Bax, caspase-9, and caspase-3 levels, normalized the NF-κB p65 phosphorylation, and upregulated the Nrf2 and its downstream genes expression in chicken liver. These results indicated that PHI has beneficial effects on AFB1-induced liver damage, oxidative damage, inflammatory response, apoptosis, and immunotoxicity by inhibiting NF-κB and activating the Nrf2 signaling pathway in chickens. This study provides new insight into the therapeutic uses of PHI.

Self-Microemulsifying Drug Delivery System of Phillygenin: Formulation Development, Characterization and Pharmacokinetic Evaluation.

Phillygenin, as an active ingredient of Forsythia suspensa, possesses a wide range of biological and pharmacological activity. However, its development and application are restricted due to its poor bioavailability and low solubility. Our work aimed to develop a self-microemulsifying drug delivery system to improve the oral bioavailability of phillygenin. The composition of the self-microemulsifying drug delivery system was preliminary screened by the pseudo-ternary phase diagram. Subsequently, the central composite design method was employed to optimize the prescription of the self-microemulsifying drug delivery system loaded with phillygenin. The prepared self-microemulsifying drug delivery system of phillygenin was characterized in terms of morphology, droplet size distribution, polydispersity index and stability. Then, the in vitro dissolution and the oral bioavailability were analyzed. The optimized self-microemulsifying drug delivery system of phillygenin consisted of 27.8% Labrafil M1944CS, 33.6% Cremophor EL, 38.6% polyethylene glycol 400 (PEG-400) and 10.2 mg/g phillygenin loading. The prepared self-microemulsifying drug delivery system of phillygenin exhibited spherical and uniform droplets with small size (40.11 ± 0.74 nm) and satisfactory stability. The in vitro dissolution experiment indicated that the cumulative dissolution rate of the self-microemulsifying drug delivery system of phillygenin was significantly better than that of free phillygenin. Furthermore, after oral administration in rats, the bioavailability of phillygenin was significantly enhanced by the self-microemulsifying drug delivery system. The relative bioavailability of the self-microemulsifying drug delivery system of phillygenin was 588.7% compared to the phillygenin suspension. These findings suggest that the self-microemulsifying drug delivery system of phillygenin can be a promising oral drug delivery system to improve the absorption of phillygenin.

Transcriptome analysis of mud crab (Scylla paramamosain) gills in response to Mud crab reovirus (MCRV).

Mud crab (Scylla paramamosain) is an economically important marine cultured species in China's coastal area. Mud crab reovirus (MCRV) is the most important pathogen of mud crab, resulting in large economic losses in crab farming. In this paper, next-generation sequencing technology and bioinformatics analysis are used to study transcriptome differences between MCRV-infected mud crab and normal control. A total of 104.3 million clean reads were obtained, including 52.7 million and 51.6 million clean reads from MCRV-infected (CA) and controlled (HA) mud crabs respectively. 81,901, 70,059 and 67,279 unigenes were gained respectively from HA reads, CA reads and HA&CA reads. A total of 32,547 unigenes from HA&CA reads called All-Unigenes were matched to at least one database among Nr, Nt, Swiss-prot, COG, GO and KEGG databases. Among these, 13,039, 20,260 and 11,866 unigenes belonged to the 3, 258 and 25 categories of GO, KEGG pathway, and COG databases, respectively. Solexa/Illumina's DGE platform was also used, and about 13,856 differentially expressed genes (DEGs), including 4444 significantly upregulated and 9412 downregulated DEGs were detected in diseased crabs compared with the control. KEGG pathway analysis revealed that DEGs were obviously enriched in the pathways related to different diseases or infections. This transcriptome analysis provided valuable information on gene functions associated with the response to MCRV in mud crab, as well as detail information for identifying novel genes in the absence of the mud crab genome database.

Identification of mud crab reovirus VP12 and its interaction with the voltage-dependent anion-selective channel protein of mud crab Scylla paramamosain.

Mud crab reovirus (MCRV) is the causative agent of a severe disease in cultured mud crab (Scylla paramamosain), which has caused huge economic losses in China. MCRV is a double-stranded RNA virus with 12 genomic segments. In this paper, SDS-PAGE, mass spectrometry and Western blot analyses revealed that the VP12 protein encoded by S12 gene is a structural protein of MCRV. Immune electron microscopy assay indicated that MCRV VP12 is a component of MCRV outer shell capsid. Yeast two hybrid cDNA library of mud crab was constructed and mud crab voltage-dependent anion-selective channel (mcVDAC) was obtained by MCRV VP12 screening. The full length of mcVDAC was 1180 bp with an open reading frame (ORF) of 849 bp encoding a 282 amino acid protein. The mcVDAC had a constitutive expression pattern in different tissues of mud crab. The interaction between MCRV VP12 and mcVDAC was determined by co-immunoprecipitation assay. The results of this study have provided an insight on the mechanisms of MCRV infection and the interactions between the virus and mud crab.