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.

Oral quercetin nanoparticles in hydrogel microspheres alleviate high-altitude sleep disturbance based on the gut-brain axis.

High-altitude sleep disturbance is a common symptom of acute mountain sickness, which can be alleviated via modulation of the gut-brain axis. Quercetin (Que) is used to modulate gut microbiota and serves as a potential drug to regulate the gut-brain axis, but the poor solubility and bioavailability affect its biological functions. Here, Que nanoparticles (QNPs) were prepared with zein using an antisolvent method, and QNP-loaded calcium alginate hydrogel microspheres (QNP@HMs) were prepared using electrospinning technology to improve the gastrointestinal stability and intestinal adhesion of QNPs. In the mouse model of high-altitude sleep disturbance, oral administration of QNP@HMs before the mice entering high altitude prolonged sleep duration, improved blood cell recovery, spontaneous behavior and short-term memory, and reduced such inflammation factors as TNF-α and iNOS. Moreover, QNP@HMs enhanced the abundance of probiotics in the gut, including Lactobacillus and Lachnospira, and reduced intestinal inflammation. However, in the mice after gut sterilization by long-term oral antibiotics, QNP@HMs showed no therapeutic effect. QNP@HMs are a promising medication for the prevention of high-altitude sleep disturbance based on the gut-brain axis.

Oral Curcumin-Thioketal-Inulin Conjugate Micelles against Radiation-Induced Enteritis.

Radiation-induced enteritis is an unavoidable complication associated with pelvic tumor radiotherapy, significantly influencing the prognosis of cancer patients. The limited availability of commercial gastrointestinal radioprotectors in clinical settings poses a substantial challenge in preventing radiation enteritis. Despite the inherent radioprotective characteristics of Cur in vitro, its poor solubility in water, instability, and low bioavailability lead to inferior therapeutic effects in vivo. Herein, we developed novel ROS-responsive micelles (CTI) from inulin and curcumin, aimed at mitigating radiation enteritis. CTI micelles had excellent solubility and stability. Importantly, CTI improved the cytotoxicity and bioavailability of curcumin, thereby showing enhanced effectiveness in neutralizing ROS induced by radiation, safeguarding against DNA damage, and reducing radiation-induced cellular mortality. Moreover, in a radiation enteritis mice model, CTI not only alleviated severe radiation-induced intestinal injury but also improved redox-related indicators and reduced inflammatory cytokine expression. Furthermore, CTI effectively increased gut microbiota abundance and maintained gut homeostasis. In conclusion, CTI could be a promising candidate for the clinical management of radiation enteritis. Our study provides a new perspective for radioprotection using natural antioxidants.

Effect of ropivacaine combined with sufentanil epidural anesthesia in abdominal surgery.

To explore and analyze the effect of ropivacaine plus sufentanil for epidural anesthesia during abdominal surgery, a total of 120 patients who underwent abdominal surgery at our institution between May 2019 and November 2020 were recruited and randomly assigned at a 1:1 ratio to receive either ropivacaine alone for epidural anesthesia (control group) or ropivacaine plus sufentanil (observation group). The total anesthesia effect in the observation group was significantly higher than that in the control group (96.66% vs 78.33%) (P<0.05). The combined anesthesia resulted in significantly lower visual analogue scale (VAS) scores (1.51±0.84, 1.63±0.56, 1.69±0.63, 1.54±0.42) in patients at 4h, 8h, 16h and 24h postoperatively versus ropivacaine alone (2.35±0.88, 2.49±0. 69, 2.47±0.78, 2.39±0.58) (P<0.05). The Ramsay sedation score (RSS) scores (1.98±0.81, 2.44±0.62, 2.18±0.62, 2.51±0.37) of the observation group at 4h, 8h, 16h and 24h after operation were significantly lower than those of the control group (1.42±0.52, 1.73±0.71, 1.47±0.66, 1.68±0.62) (P<0.05). Patients receiving ropivacaine plus sufentanil were associated with a lower incidence of adverse reactions than those given ropivacaine only (5.00% vs 30.00%) (P<0.05). In abdominal surgery, ropivacaine plus sufentanil epidural anesthesia resulted in reduced postoperative pain, enhanced sedative effects and a lower risk of adverse reactions versus ropivacaine alone.

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.

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.

Analgesic effects of different concentrations of ropivacaine in transversalis fascia plane block during laparotomy.

OBJECTIVE: To explore the analgesic effects of different concentrations of ropivacaine in transversalis fascia plane (TFP) block during laparotomy. METHODS: Ninety patients who underwent laparotomy admitted to our hospital from March 2019 to March 2020 were selected as the study subjects and were divided equally into a low concentration group, a medium concentration group, and a high concentration group according to the randomized grouping method. The low concentration group adopted 0.4% ropivacaine 40 ml, the medium concentration group was given 0.5% ropivacaine 40 ml, and the high concentration group was given 0.6% ropivacaine 40 ml. The hemodynamic indexes and the incidence of adverse reactions in the two groups were compared. The Numerical Rating Scale (NRS) was used to assess the postoperative pain in the three groups, the Bruggrmann comfort scale (BCS) was used to assess the comfort level in the three groups, and the Mini-mental State Examination (MMSE) was used to evaluate the postoperative cognitive function of the three groups of patients. RESULTS: The mean artery pressure (MAP) and heart rate (HR) levels at T1 and T2 were significantly lower in the medium concentration group than in the other two groups (P < 0.05). The low concentration group had a significantly higher NRS score at T2 than the medium concentration group and the high concentration group (P < 0.05). A significantly higher BCS score was observed in the high concentration group than the other two groups (P < 0.05). There were significantly higher Ramsay scores and MMSE scores in the medium concentration group than in the low concentration and high concentration groups (P < 0.05). The overall incidence of adverse reactions of the high concentration group was significantly higher than that of the low concentration group (P < 0.05), but showed similar results with the medium concentration group. CONCLUSION: The medium concentration group exhibits a better analgesic effect than the low concentration group and higher safety than the high concentration group. Therefore, the use of medium concentration ropivacaine in TFP block may provide a referential basis for clinical treatment.

VersicanV1 promotes proliferation and metastasis of hepatocellular carcinoma through the activation of EGFR-PI3K-AKT pathway.

Versican has been reported to participate in carcinogenesis in several malignant tumors. However, the accurate role of VersicanV1, a predominant isoform of Versican in liver, remains an enigma in hepatocellular carcinoma (HCC). The expression of VersicanV1 in HCC tissues and adjacent tissues was detected by Reverse Transcription-Polymerase Chain Reaction (RT-PCR), Western Blot (WB) and inmumohistochemistry (IHC). Gain and loss of function assays were performed to examine the role of VersicanV1 in proliferation and metastasis of HCC. Measurement of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in vitro and PET-CT (positron emission tomography/computed tomography) analysis in vivo were applied to evaluate the effects of VersicanV1 on glycolysis. RNA sequencing, Co-IP (Co-immunoprecipitation) and MS (mass spectrometry) were utilized to investigate the molecular mechanisms. Our current study reveals that VersicanV1, regulated by direct interaction with Linc01225, is significantly upregulated in HCC tissues and correlates with poor prognosis. Both in vitro and in vivo experiments show that knockdown of VersicanV1 in HCC cells attenuates cancer cells malignancy. Further studies identify the positive role of VersicanV1 in aerobic glycolysis. Mechanistic investigation discovers the activation of EGFR-PI3K-AKT pathway in HCC cells expressing high VersicanV1. Moreover, EGF-like motif is indispensable for VersicanV1 to promote Warburg effect of HCC cells and subsequently, proliferation, invasion, and metastasis ability via activation of EGFR-PI3K-AKT axis. In sum, our research highlights a novel role of VersicanV1 in the progression of HCC, suggesting that VersicanV1 is an indicator for prognosis and a potential therapeutic target of HCC.

Correction: VersicanV1 promotes proliferation and metastasis of hepatocellular carcinoma through the activation of EGFR-PI3K-AKT pathway.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Targeting of N-Type Calcium Channels via GABAB-Receptor Activation by α-Conotoxin Vc1.1 Variants Displaying Improved Analgesic Activity.

α-Conotoxins exhibiting analgesic activity, such as Vc1.1, have been shown to inhibit α9α10 nicotinic acetylcholine receptors (nAChRs) and GABAB-receptor (GABABR) coupled N-type (CaV2.2) calcium channels. Here, we report two Vc1.1 variants, Vc1.1[N9R] and benzoyl-Vc1.1[N9R], that selectively inhibit CaV2.2 channels via GABABR activation but exhibit reduced inhibitory activity at α9α10 and other neuronal nAChR subtypes compared with Vc1.1. Surprisingly, the analgesic activity of Vc1.1[N9R] and benzoyl-Vc1.1[N9R] was more potent than that of Vc1.1 when tested in partial sciatic nerve ligation injury and chronic constriction injury models. Vc1.1[N9R] and benzoyl-Vc1.1[N9R] exhibited either similar or tenfold higher activity of GABABR-mediated CaV2.2 inhibition but no activity at CaV2.2 alone; however, the mechanism of increased analgesic activity is unknown. The effects on analgesic activity and α9α10 nAChR of other Vc1.1 variations at position 9 and the N-terminus were also determined. Our findings provide new insights for designing potent inhibitors for GABABR-coupled N-type (CaV2.2) calcium channels.