Glucose oxidase and ruthenium nanorods-embedded self-healing polyvinyl alcohol/polyethylene imine hydrogel for simultaneous photothermal/photodynamic/starvation therapy and skin reconstruction.

Tumor recurrence and wound healing represent significant burdens for tumor patients after the surgical removal of melanomas. Wound dressings with wound healing and anticancer therapeutic abilities could help to solve these issues. Thus, a hybrid hydrogel made of polyvinyl alcohol (PVA) and polyethylene imine (PEI) was prepared by cross-linking imine bond and boronic acid bond. This hydrogel was loaded with ruthenium nanorods (Ru NRs) and glucose oxidase (GOx) and named as nanocomposite hydrogel (Ru/GOx@Hydrogel), exhibiting remarkable photothermal/photodynamic/starvation antitumor therapy and wound repair abilities. Ru NRs are bifunctional phototherapeutic agents that simultaneously exhibit intrinsic photothermal and photodynamic functions. Three-dimensional composite hydrogel loaded with GOx can also consume glucose in the presence of O2 during tumor starvation therapy. Near-infrared (NIR) light-triggered hyperthermia can not only promote the consumption of glucose, but also facilitate the ablation of residual cancer cells. The antitumor effect of the Ru/GOx@Hydrogel resulted in significant improvements, compared to those observed with either phototherapy or starvation therapy alone. Additionally, the postoperative wound was substantially healed after treatment with Ru/GOx@Hydrogel and NIR irradiation. Therefore, the Ru/GOx@Hydrogel can be used as a multi-stimulus-responsive nanoplatform that could facilitate on-demand controlled drug release, and be used as a promising postoperative adjuvant in combination therapy.

Effect of Different Doses of Butorphanol on Postoperative Shivering in Elderly Patients: A Randomized, Double-Blind, Placebo-Controlled Trial.

Purpose: This study was designed to investigate the effects of different doses of butorphanol on postoperative shivering and quality of recovery in elderly patients. Patients and Methods: A total of 147 elderly patients (aged 60 or older) scheduled for elective transurethral resection of the prostate were enrolled in the current study. Patients were randomly and evenly assigned into four groups: Group C (0.9% normal saline), Group B1 (butorphanol 0.01 mg/kg), Group B2 (butorphanol 0.02 mg/kg) and Group B3 (butorphanol 0.03 mg/kg). All drugs were diluted to 5mL and injected intravenously slowly 5 min before induction of anesthesia. The primary outcome measure was the incidence of postoperative shivering in the post-anesthesia care unit. Quality of Recovery-40 (QoR-40) scores were assessed on postoperative day (POD) 1, 2 and 3. Perioperative core and skin temperature, extubation time and adverse events were also recorded. Results: Patients among the four groups had comparable baseline characteristics. Compared with Group C, the incidence of shivering was significantly lower in Group B2 and B3 (P = 0.006 and P = 0.005, respectively). The QoR-40 scores on POD1 were significantly higher in all butorphanol groups than that in Group C (P < 0.0083). In Group B2 and B3, patients experienced lower pain intensity (P < 0.001). In addition, the incidence of catheter-related bladder discomfort (CRBD) was lower in all butorphanol groups than in Group C (P < 0.0083). Conclusion: Butorphanol 0.02 or 0.03 mg/kg could effectively prevent the occurrence of postoperative shivering in elderly patients scheduled for transurethral resection of the prostate, provided effective postoperative recovery and postoperative analgesia.

Gut microbiota and transcriptome profiling revealed the protective effect of aqueous extract of Tetrastigma hemsleyanum leaves on ulcerative colitis in mice.

Tetrastigma hemsleyanum, a traditional Chinese medicinal plant, possesses various biological activities, including anti-inflammatory and immunomodulatory functions. The purpose of this study was to determine the alleviating effect of the water extract of Tetrastigma hemsleyanum leaves (THLW) on ulcerative colitis (UC) and its relationship with gut microbiota. The administration of THLW significantly decreased the severity of dextran sulfate sodium (DSS)-induced intestinal damage, as demonstrated by the stabilization of body weight and colon length, and decreased disease activity index (DAI) and histological scores. THLW also decreased NF-κB protein expression in colon tissues and reduced the serum levels of IL-6, IL-1ß, and TNF-α. Further co-housing experiment confirmed that the anti-UC effect of THLW was possibly by regulating the structure and composition of gut microbiota, including increasing the abundance of Oscillospiraceae, Prevotellaceae and Corynebacterium. Additionally, the expression of genes related to inflammation and immunity was also regulated by THLW treatment as evidenced by transcriptome analysis. These results suggested that the protective effect of THLW on DSS-induced colitis was mediated by alleviating inflammation and modulating the microbiota composition. This work proved the potent protective effects of THLW treatment on colitis and may have potential for UC relief.

Do hypokyphotic adolescent idiopathic scoliosis patients treated with Ponte osteotomy obtain a better clinical efficacy? A preliminary retrospective study.

STUDY DESIGN: A retrospective case-control study. OBJECTIVE: To evaluate whether Ponte osteotomy improves thoracic kyphosis and to determine its clinical efficacy in hypokyphotic adolescent idiopathic scoliosis (AIS). METHODS: Eighty consecutive Lenke type 1 AIS patients with hypokyphotic curves who underwent posterior spinal fusion by one spine surgeon at a single institution were recruited. According to whether Ponte osteotomy was performed, the patients were divided into two groups. The preoperative, immediate, one-year postoperative, and two-year postoperative radiographs were analyzed. The demographic characteristics, surgical information, radiographic parameters, Scoliosis Research Societye-22 (SRS-22) questionnaire, and complications were compared. RESULTS: The sagittal alignment and coronal alignment were both improved in the Ponte group and the control group postoperatively. There was no significant difference in the preoperative parameters between the two groups, except the TL/L, CB, and LL. Significant differences were found in the MT (15.18° ± 2.84° vs. 20.33° ± 3.75°, P < 0.001) and TK (24.23° ± 2.71° vs. 19.93° ± 2.38°, P < 0.001) at the two-year follow-up. The Ponte group had a longer operation time and more intraoperative blood loss. No significant difference was observed between the groups in the SRS-22 scores at the final follow-up. CONCLUSIONS: Ponte osteotomy could obtain better coronal correction and sagittal contour restoration in AIS patients with hypokyphosis. However, Ponte osteotomies might lead to more intraoperative blood loss and longer operation time. Moreover, no discrepancy was found in the postoperative health-related quality of life of the included patients. Therefore, we considered that the Ponte osteotomy may be an alternative method to restore the desired thoracic kyphosis, which needs further study.

Copper-catalyzed direct decarboxylative fluorosulfonylation of aliphatic carboxylic acids.

Sulfonyl fluorides are emerging as key structural motifs in organic synthesis, medicinal chemistry, and materials science. Herein we report two efficient and complementary methods for direct decarboxylative fluorosulfonylation of carboxylic acids by the merging of copper catalysis with different N-centered HAT regents. A wide range of structurally diverse sulfonyl fluorides was readily accessed from primary, secondary, and tertiary carboxylic acids in a single step under mild conditions.

Properties of selenium nanoparticles stabilized by Lycium barbarum polysaccharide-protein conjugates obtained with subcritical water.

Selenium nanoparticles (SeNPs) in an aqueous solution have poor stability and tend to aggregate when stored for a long time. In the present study, SeNPs were stabilized by using Lycium barbarum polysaccharide (LBP) and Lycium barbarum protein (LBPr) conjugates (LBPP) as a stabilizer and dispersing agent. Particularly, the LBPP1 was obtained with subcritical water treatment. In addition, the physical stability, re-dispersity and antitumor activity of LBPP1-SeNPs were investigated. The results showed the particle size of LBPP1-SeNPs was maintained at 111.5-117 nm, which was stable at PH 6, 4 °C and darkness for at least 40 days. Besides, the result of TEM showed that the dispersion of LBPP1-SeNPs had more clear layers and smoother surfaces. Moreover, LBPP1-SeNPs had excellent re-dispersibility and exhibited a significant inhibitory effect on HepG-2 cells and Caco-2 cells, respectively (p < 0.05). Therefore, LBPP1-SeNPs can be used as potential selenium nutritional supplements for food and medical applications.

Combination of mulberry leaf active components possessed synergetic effect on SD rats with diabetic nephropathy by mediating metabolism, Wnt/ß-catenin and TGF-ß/Smads signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Mulberry leaf has attracted much attention due to its excellent curative effect on diabetes and its complications, whether the combination of its effective components have protective and synergistic effect on diabetic nephropathy (DN) in vivo remain unclear. AIM OF THE STUDY: The aim of this study was to investigate the protective and synergistic effect of the combination (MAF1:1 and MAF1:5) of mulberry leaf alkaloids (MA) and flavonoids extract (MF) on DN. MATERIALS AND METHODS: A step by step method consisted of network pharmacological prediction, animal in vivo validation and metabolic mechanism research was used to construct the multi-component-target-pathway network of mulberry leaf against DN. Firstly, the potential components and mechanism of mulberry leaf against DN was explored by network pharmacology analysis. Secondly, DN animal model was established to validate the anti-DN activity of these potential compounds. Thirdly, the metabolomics of serum and urine samples from animal experiments was analyzed to explore the anti-DN mechanism of these potential compounds. RESULTS: The results of network pharmacology demonstrated that a total of 7 compounds detected in MA and MF exhibited anti-DN activity, their mechanism were strongly in connection with metabolic pathways, arachidonic acid metabolism, sphingolipid signaling pathway, etc. The results of animal experiment indicated that MAF1:1 and MAF1:5 significantly relieved metabolic disorders through regulating Wnt/ß-catenin and TGF-ß/Smads signaling pathway, just like MF or MA alone. Metabolomics suggested they could regulate 16 serum and 7 urine endogenous metabolites through arachidonic acid metabolism, phenylalanine metabolism and sphingolipid metabolism, thus alleviated DN. Significantly, MAF1:1 and MAF1:5 might possess synergistic effect considering their therapeutic effects on DN rats were superior to the single use of MA or MF. CONCLUSIONS: MAF1:1 and MAF1:5 possessed protective and synergistic effect on DN rats through multi-target and multi-pathways. These findings were of great scientific significance and application value to reveal the advantage of mulberry leaf in preventing and treating DN.

Mulberry leaves ameliorate diabetes via regulating metabolic profiling and AGEs/RAGE and p38 MAPK/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Mulberry leaves have been used as traditional hypoglycemic medicine-food plant for thousand years in China. According to traditional Chinese medicine theory, type 2 diabetes mellitus (T2DM) belongs to the category of XiaoKe. Presently, the research of mulberry leaf hypoglycemic and lipid-lowering direction is mature, but the curative effects of alkaloids, flavonoids, polysaccharides, and other bioactive ingredients and the related mechanism is still unclear. AIM OF THE STUDY: This paper aims to study the efficacy and mechanism of alkaloids, flavonoids, polysaccharides, and other bioactive components in mulberry leaves in the treatment of T2DM individually. MATERIALS AND METHODS: The determination of levels of fasting blood glucose (FBG), triglyceride (TG) and total cholesterol (T-Cho), and pyruvate kinase (PK), hexokinase (HK), and alanine aminotransferase (ALT/GPT) of in plasma of diabetic mice. Urine metabolomics was analyzed by UPLC-QTOF/MS to evaluate differential metabolites from multiple metabolic pathways. The glucose uptake of HepG2 cells and 3T3-L1 cells. Expression of Caspase-3 and caspase-9, inflammatory injury and p38MAPK/NF-κB signaling pathway in GLUTag cells. RESULTS: Our study revealed alkaloids, flavonoids, and polysaccharides in mulberry leaf could increase the levels of PK, HK, and ALT/GPT, and decrease the levels of TG and T-Cho significantly, and regulate glucose, amino acid, and lipid metabolism. Furthermore, 1-deoxynojirimycin (DNJ) and isoquercitrin (QG) both could increase glucose uptake and promote differentiation of HepG2 cells, increase PPARγ, C/EBPα and SREBP-l expression in 3T3-L1 cells, and inhibit AGEs-induced injury and apoptosis in GLUTag cells, reduce the expression of proteins related to AGEs/RAGE and p38MAPK/NF-κB pathway. Notably, isoquercitrin exhibited more pronounced anti-diabetic efficacy. CONCLUSIONS: The alkaloids, flavonoids, and polysaccharides from mulberry leaf exhibited hypoglycemic activity through the regulation of glucose, amino acid, and lipid metabolism. 1-DNJ and QG increased glucose uptake and promoted differentiation of HepG2 cells, increased PPARγ, C/EBPα and SREBP-l expression in 3T3-L1 cells, and inhibited AGEs-induced injury and apoptosis in GLUTag cells via the AGEs/RAGE and p38 MAPK/NF-κB pathway.

Digestion and absorption properties of Lycium barbarum polysaccharides stabilized selenium nanoparticles.

In the present study, the digestion and absorption properties of Lycium barbarum polysaccharides stabilized selenium nanoparticles (LBP-SeNPs) were investigated. The results showed that selenium nanoparticles (SeNPs) exhibited a higher selenium release rate than LBP-SeNPs (p＜0.05) after being digested in the stages of oral cavity, stomach and intestine. During the digestion process, the particle size of the LBP-SeNPs and SeNPs were both significantly increased, but the particle size of LBP-SeNPs was significantly smaller than that of SeNPs. The results of TEM further indicated that LBP-SeNPs can better maintain the morphology and properties of nanoparticles. Besides, the experiments of the intestinal sac model showed that LBP-SeNPs can better promote the absorption of selenium in various parts (duodenum, jejunum and ileum) of the intestine. Therefore, the LBP can help to improve the structural stability of SeNPs in the digestion process and improve the bioavailability of selenium.

Synthesis, stability and anti-fatigue activity of selenium nanoparticles stabilized by Lycium barbarum polysaccharides.

Lycium barbarum polysaccharides (LBP) with different molecular weights (LBP1, LBP2 and LBP3) of 92,441 Da, 7714 Da, and 3188 Da were used as stabilizers and capping agents to prepare uniformly dispersed selenium nanoparticles (SeNPs), and determined the storage stability. In addition, the anti-fatigue activity of LBP-decorated SeNPs with the best stability (LBP1-SeNPs) was estimated by using forced swimming test. The results showed that LBP1-SeNPs exhibited smaller particle size and more excellent stability than those of LBP2-SeNPs and LBP3-SeNPs when the storage time was extended to 30 days, and the average particle size was maintained at about 105.4 nm. The exhaustion swimming time of all tested dose groups of LBP1-SeNPs was significantly longer than the control group (p < 0.05), and the high-dose group among them was even obviously longer than the positive group (p < 0.05). The results of glycogen, blood urea nitrogen (BUN), blood lactic acid (BLA), superoxide dismutase (SOD), and malondialdehyde (MDA) levels were further confirmed that LBP1-SeNPs could relieve fatigue by increasing the reserve of glycogen, enhancing antioxidant enzyme levels and regulating metabolic mechanism. These results demonstrated that LBP1-SeNPs could be developed as a potential anti-fatigue nutritional supplement.

A comprehensive review on traditional uses, chemical compositions, pharmacology properties and toxicology of Tetrastigma hemsleyanum.

ETHNOPHARMACOLOGICAL RELEVANCE: Tetrastigma hemsleyanum Diels et Gilg (T.hemsleyanum), a rare herbal plant distributed in subtropical areas of mainland China, has become a focus of scientific attention in recent years because of its high traditional value, including uses for treatment of children with fever, pneumonia, asthma, rheumatism, hepatitis, menstrual disorders, scrofula, and pharynx pain. AIM: This systematic review aims to provide an insightful understanding of traditional uses, chemical composition, pharmacological effect and clinical application of T. hemsleyanum, and lay a foundation for the further study and for the utilization of T. hemsleyanum resource. MATERIALS AND METHODS: A domestic and overseas literature search in known databases was conducted for published articles using the relevant keywords. RESULTS: One hundred and forty-two chemical constituents identified from T. hemsleyanum have been reported, including flavonoids, phenolic acids, polysaccharide, organic acids, fatty acids, terpenoids, steroids, amino acid and others. Among these components, flavonoids and polysaccharides were the representative active ingredients of T. hemsleyanum, which have been widely investigated. Modern pharmacological studies have shown that these components exhibited various pharmacological activities, such as anti-inflammatory, antioxidant, antivirus, antitumor, antipyretic, anti-hepatic injury, immunomodulatory, antibacterial etc. Moreover, different toxicological studies indicated that the clinical dosage of T. hemsleyanum was safe and reliable. CONCLUSIONS: Modern pharmacological studies have well supported and clarified some traditional uses, and T. hemsleyanum has a good prospect for the development of new drugs due to these outstanding properties. However, the present findings did not provide an in-depth evaluation of bioactivity of the extracts, the composition of its active extracts was not clear. Moreover, they were insufficient to satisfactorily explain some mechanisms of action. Data regarding many aspects of T. hemsleyanum, such as links between the traditional uses and bioactivities, pharmacokinetics, quality control standard and the clinical value of active compositions is still limited which need more attention.

"All-in-One" Theranostic Agent with Seven Functions Based on Bi-Doped Metal Chalcogenide Nanoflowers.

Most of the existing single-component nanostructures cannot provide comprehensive diagnostic information, and their treatment strategies always have to combine other therapeutics as a complementary for effective biomedical application. Here, we adopted a facile approach to design a theranostic nanoflower (NF) with robust efficacy for comprehensive tumor diagnosis and quadruple synergistic cancer therapy. The NF is equipped with a metallic hybrid of several functional elements and flower-like superstructures and thus shows excellent in vitro and in vivo theranostic performance. It shows high X-ray attenuation coefficiency for the Bi element, strong near-infrared (NIR) plasmon absorbance and singlet oxygen (1O2) generation ability for the Mo element, and great photothermal conversion efficiency (54.7%) because of enhanced photoabsorption of the petal structure. Moreover, the NF realizes a very high doxorubicin-loading efficiency (90.0%) and bimodal pH/NIR-responsive drug release, posing a promise as a controlled drug carrier. The NF also shows excellent performance at trimodal magnetic resonance/X-ray computed tomography/photoacoustic imaging for comprehensive tumor diagnosis. To our best knowledge, it is the first time that integrating at least seven functions into one biomedical nanomaterial for well-rounded tumor theranostics has been reported. This "all-in-one" NF opens a new perspective in developing novel and efficient multifunctional nanotheranostics.

The mechanism of mulberry leaves against renal tubular interstitial fibrosis through ERK1/2 signaling pathway was predicted by network pharmacology and validated in human tubular epithelial cells.

Mulberry leaf was reported that it has antidiabetic activity, although the mechanisms underlying the function have not been fully elucidated. In the present study, the results of network pharmacology suggested that mulberry leaves could regulate key biological process in development of diabetes, and the process implicates multiple signaling pathways, such as JAK-STAT, MAPK, VEGF, PPAR, and Wnt. Then, the research in vitro indicated that mulberry leaves remarkably ameliorated high glucose-induced epithelial to mesenchymal transition, which was characterized with significant reduction of intracellular reactive oxygen species (ROS) levels as well as downregulation of NADPH oxidase subunits NOX1, NOX2, and NOX4, and it was found to be connected with the ERK1/2 signaling pathway in human tubular epithelial cells (HK-2). Moreover, the results of bioinformatics and the dual luciferase report showed that ZEB1 might be a target gene of miR-302a; decreased miR-302a and increased ZEB1 expressions could significantly promote epithelial to mesenchymal transition. However, mulberry leaves could reverse these modulations. Our results demonstrated that network pharmacology could provide a guidance role for traditional Chinese medicine research, and mulberry leaves could be of benefit in preventing high glucose-induced EMT in HK-2 cells, which proved that it was related to the upregulation of miR-302a by targeting ZEB1 and the inhibition of NADPH oxidase/ROS/ERK1/2 pathway.

Matrix Solid-Phase Dispersion Combined with HPLC-DAD for Simultaneous Determination of Nine Lignans in Saururus chinensis.

A simple and rapid method, based on matrix solid-phase dispersion (MSPD) and high-performance liquid chromatography (HPLC) was developed for simultaneous determination of nine lignans, including (-)-(7R,8R)-machilin D (Wang, C., Wang, P., Chen, X., Wang, W., Jin, Y.; Saururus chinensis (Lour.) Baill blocks enterovirus 71 infection by hijacking MEK1-ERK signaling pathway; Antiviral Research, (2015); 119:47-56), dihydroguaiaretic acid (Quan, Z., Lee, Y.J., Yang, J.H., Lu,Y., Li,Y., Lee,Y.K., et al.; Ethanol extracts of Saururus chinensis suppress ovalbumin-sensitization airway inflammation; Journal of Ethnopharmacology, (2010); 132:143-149.), sauchinone (Zhuang, T., Liang, J.Y., Sun, J.B., Wu, Y., Huang, L.R., Qu, W.; Secondary metabolites from Saururus chinensis and their chemotaxonomic significance; Biochemical Systematics and Ecology, (2014); 56:95-98.), rel-(7S,8S,7'R,8'R)-3,3',4,4',5,5'-hexamethoxy-7.O.7',8.8'-lignan (Tsai, W.J., Shen, C.C., Tsai, T.H., Lin, L.C.; Lignans from the aerial parts of Saururus chinensis: isolation, structural characterization, and their effects on platelet aggregation; Journal of Natural Products, (2014); 77:125-131), licarin A (Cui, H., Xu, B., Wu, T., Xu, J., Yuan, Y., Gu, Q.; Potential antiviral lignans from the roots of Saururus chinensis with activity against Epstein-Barr virus lytic replication; Journal of Natural Products, (2014); 77:100-110.), manassantin A (Lu, Y., Piao, D., Zhang, H., Li, X., Chao, G.H., Park, S.J., et al.; Saucerneol F inhibits tumor necrosis factor-alpha and IL-6 production by suppressing Fyn-mediated pathways in FcepsilonRI-mediated mast cells; Food and Chemical Toxicology, (2013); 59:696-702.), saurucinol I (Kwon, O.E., Lee, H.S., Lee, S.W., Chung, M.Y., Bae, K.H., Rho, M.C., et al.; Manassantin A and B isolated from Saururus chinensis inhibit TNF-α-induced cell adhesion molecule expression of human umbilical vein endothelial cells; Archives of Pharmacal Research, (2005); 28:55-60.), manassantin B (Hwang, B.Y., Lee, J.H., Jung, H.S., Kim, K.S., Nam, J.B., Hong, Y.S., et al.; Sauchinone, a lignan from Saururus chinensis, suppresses iNOS expression through the inhibition of transactivation activity of RelA of NF-κB; Planta Medica, (2003); 69:1096-01.) and licarin B (Hwang, B.Y., Lee, J.H., Nam, J.B., Hong, Y.S., Lee, J.J.; Lignans from Saururus chinensis inhibiting the transcription factor NF-κB; Phytochemistry, (2003); 64:765-771.) in Saururus chinensis. The parameters of MSPD were optimized to be that 0.2 g of sample, blended with 0.4 g silica gel, and eluted with 5 mL of methanol. The separation was carried out on a C18 column with acidified aqueous acetonitrile gradients. The established method was fully validated in terms of linearity (r2 ≥ 0.9994), sensitivity, precision (RSD ≤ 3.18%), repeatability (RSD ≤ 3.02%) as well as recovery (93.49-103.52%), and subsequently applied to six samples of S. chinensis from different areas. The MSPD extraction promoted higher extraction yields of nine lignans, lower solvent sample and solvent consumption.

Xiao-Xu-Ming Decoction Reduced Mitophagy Activation and Improved Mitochondrial Function in Cerebral Ischemia and Reperfusion Injury.

We investigated whether Xiao-Xu-Ming decoction reduced mitophagy activation and kept mitochondrial function in cerebral ischemia-reperfusion injury. Rats were randomly divided into 5 groups: sham, ischemia and reperfusion (IR), IR plus XXMD (60 g/kg/day) (XXMD60), IR plus cyclosporin A (10 mg/kg/day) (CsA), and IR plus vehicle (Vehicle). Focal cerebral ischemia and reperfusion models were induced by middle cerebral artery occlusion (MCAO). Cerebral infarct areas were measured by triphenyl tetrazolium chloride staining. Cerebral ischemic injury was evaluated by hematoxylin and eosin staining (HE) and Nissl staining. Ultrastructural features of mitochondria and mitophagy in the penumbra of the ischemic cortex were observed by transmission electron microscopy. Mitophagy was detected by immunofluorescence labeled with LC3B and VDAC1. Autophagy lysosome formation was observed by immunofluorescence labeled with LC3B and Lamp1. The expression of LC3B, Beclin1, and Lamp1 was analyzed by Western blot. The rats subjected to MCAO showed worsened neurological score and cell ischemic damage. These were all significantly reversed by XXMD or CsA. Moreover, XXMD/CsA notably downregulated mitophagy and reduced the increase in LC3, Beclin1, and Lamp1 expression induced by cerebral ischemia and reperfusion. The findings demonstrated that XXMD exerted neuroprotective effect via downregulating LC3, Beclin1, Lamp1, and mitochondrial p62 expression level, thus leading to the inhibition of mitophagy.

Therapeutic benefits of neoadjuvant and post-operative denosumab on sacral giant cell tumor: a retrospective cohort study of 30 cases.

PURPOSE: Denosumab, a new monoclonal antibody that inhibits receptor activator for nuclear factor Kß ligand (RANKL), has recently been approved by FDA for the treatment of aggressive giant cell tumor of bone (GCTB). So we initiated this study to evaluate the clinical benifits of denosumab used preoperatively or postoperatively. METHODS: Patients diagnosed with classic sacral GCT without metastasis were included in this study. Patients were assigned into 3 groups according to the use of denosumab: control group 1, post-operative group 2 and neoadjuvant group 3. The latter two groups were treated with 120 mg of subcutaneous denosumab every 4 weeks with loading doses on days 8 and 15 of the first cycle. The primary endpoints were event-free-survival (EFS) and objective response rate (OPR) based on RECIST criteria. A system (MUD system) proposed by our center was applied to score the sacral nerve deficit changes before surgery in group 3. RESULTS: A total 30 patients (13 men and 17 women, mean age 34.7 years, range 15-56) were enrolled from April 2014 to July 2016. Group 1 included 10 patients, group 2 9 and group 3 11. The study ended in March 01, 2017, and followup ranged from 3 to 36 months (mean 18.3). Two patients with PET-CT showed SUV max uptake down to muscle tissue level. In the neoadjuvant group 3 7 patients had partial responses and 4 stable disease (ORR 63.6%; 95% CI 35-92). Most (80%) patients achieved significant improvement in pain and great relief in the bladder and bowel functions. In 4 patients the urocatheter was removed after neoadjuvant denosumab. CONCLUSION: Neoadjuvant therapy with denosumab can significantly relieve the symptoms and neurologic deficits.

Aberrant intrinsic functional connectivity in thalamo-cortical networks in major depressive disorder.

OBJECTIVE: Growing evidence has implicated dysfunction of the thalamus and its projection cortical targets in depression. However, the anatomical specificity of thalamo-cortical connectivity in major depressive disorder (MDD) remains unknown due to the regional heterogeneity of the thalamus and limited methods to examine this. METHODS: Resting-state fMRI was collected on 70 MDD patients and 70 healthy controls. The thalamus was parcellated based on connectivity with six predefined cortical regions of interest (ROIs). The segmented thalamic nuclei were used as seeds to map connectivity with the rest of the whole brain. The cortical-to-thalamus connectivity values and thalamus-based connectivity maps were compared between groups. RESULTS: The cortical ROIs demonstrated correlations with spatially distinct zones within the thalamus. We found a trend toward reduced parietal ROI-to-thalamus connectivity in MDD. Importantly, MDD patients demonstrated reduced connectivity between prefrontal and parietal thalamus ROIs and bilateral middle frontal gyrus (MFG) and the right posterior default mode network (DMN) and between the prefrontal and motor thalamus ROIs and lateral temporal regions. Conversely, increased connectivity emerged between the motor thalamus ROI and right MFG and right medial frontal gyrus/anterior cingulate; between motor/somatosensory thalamus ROIs and right posterior DMN; between prefrontal/somatosensory thalamus ROIs and cerebellum; and between the parietal thalamus ROI and left insula. CONCLUSIONS: This study is the first to examine the anatomical specificity of thalamo-cortical connectivity disturbances in MDD. Subjects with MDD demonstrated altered thalamo-cortical connectivity characterized by a complex pattern of region-dependent hypo- or hyperconnectivity. We therefore speculate that selectively modulating the connectivity of thalamo-cortical circuitry may be a potential novel therapeutic mechanism for MDD.

Degradable rhenium trioxide nanocubes with high localized surface plasmon resonance absorbance like gold for photothermal theranostics.

The applications of inorganic theranostic agents in clinical trials are generally limited to their innate non-biodegradability and potential long-term biotoxicity. To address this problem, herein via a straightforward and tailored space-confined on-substrate route, we obtained rhenium trioxide (ReO3) nanocubes (NCs) that display a good biocompatibility and biosafety. Importantly, their aqueous dispersion has high localized surface plasmon resonance (LSPR) absorbance in near-infrared (NIR) region different from previous report, which possibly associates with the charge transfer and structural distortion in hydrogen rhenium bronze (HxReO3), as well as ReO3's cubic shape. Such a high LSPR absorbance in the NIR region endows them with photoacoustic (PA)/infrared (IR) thermal imaging, and high photothermal conversion efficiency (∼57.0%) for efficient ablation of cancer cells. Also, ReO3 NCs show X-ray computed tomography (CT) imaging derived from the high-Z element Re. More attractively, those ReO3 NCs, with pH-dependent oxidized degradation behaviors, are revealed to be relatively stable in hypoxic and weakly acidic microenvironment of tumor for imaging and treatment whilst degradable in normal physiological environments of organs to enable effective clearance. In spite of their degradability, ReO3 NCs still possess tumor targeting capabilities. We thus develop a simple but powerful, safe and biodegradable inorganic theranostic platform to achieve PA/CT/IR imaging-guided cancer photothermal therapy (PTT) for improved therapeutic efficacy and decreased toxic side effects.

[Pharmacokinetics of Mori Folium flavones and alkaloids in normal and diabetic rats].

To study the pharmacokinetic effect of Mori Folium flavones and alkaloids in normal and diabetic rats. An UPLC-TQ-MS method was developed for the simultaneous determination of rutin, isoquercitrin, astragalin, kaempferol, quercetin, chlorogenic acid, cryptochlorogenic acid, neochlorogenic acid, DNJ and fagomine in plasma of rats. The diabetic rat model was induced through intravenous injection with alloxan and high-fat diet. Samples of plasma of rats were obtained at different time points, after the rats were administrated with Mori Folium flavones and alkaloids. After the deproteinization with acetonitrile, the concentrations of Mori Foliam constituents in rats at different time points were detected by UPLC-TQ-MS method, and pharmacokinetic parameters were calculated by DAS 2.0 software. The results showed that quercetin and kaempferol reached peak at 0.333 h, indicating that Mori Folium flavonoid constituents were absorbed and distributed quickly. At about 4 h after administration, both of them reached the peak concentrations for the second time, suggesting that they stayed in intestine for a long time. DNJ and fagomine in gastrointestinal tract can be quickly absorbed into blood, and the concentration in plasma reached peak after 0.667 h, suggesting that both of them could be rapidly distributed in the systemic circulation of rats. Cryptochlorogenic acid, neochlorogenic acid, quercetin, kaempferol and rutin were found to have a higher Cmax and AUC0-t in normal rats than those in diabetic rats. The t1/2values of cryptochlorogenic acid and neochlorogenic acid were shorter in diabetic rats, while quercetin, kaempferol and rutin had a longer t1/2value in diabetic rats. Chlorogenic acid, astragalin, isoquercitrin, fagomine had a higher Cmax in diabetic rats, and the t1/2values of astragalin and fagomine were longer, which suggested differences in absorption of active ingredients under normal and diabetic conditions.

Evaluation of Drug-Drug Interaction Potential Between Sacubitril/Valsartan (LCZ696) and Statins Using a Physiologically Based Pharmacokinetic Model.

Sacubitril/valsartan (LCZ696) has been approved for the treatment of heart failure. Sacubitril is an in vitro inhibitor of organic anion-transporting polypeptides (OATPs). In clinical studies, LCZ696 increased atorvastatin Cmax by 1.7-fold and area under the plasma concentration-time curve by 1.3-fold, but had little or no effect on simvastatin or simvastatin acid exposure. A physiologically based pharmacokinetics modeling approach was applied to explore the underlying mechanisms behind the statin-specific LCZ696 drug interaction observations. The model incorporated OATP-mediated clearance (CLint,T) for simvastatin and simvastatin acid to successfully describe the pharmacokinetic profiles of either analyte in the absence or presence of LCZ696. Moreover, the model successfully described the clinically observed drug effect with atorvastatin. The simulations clarified the critical parameters responsible for the observation of a low, yet clinically relevant, drug-drug interaction DDI between sacubitril and atorvastatin and the lack of effect with simvastatin acid. Atorvastatin is administered in its active form and rapidly achieves Cmax that coincide with the low Cmax of sacubitril. In contrast, simvastatin requires a hydrolysis step to the acid form and therefore is not present at the site of interactions at sacubitril concentrations that are inhibitory. Similar models were used to evaluate the drug-drug interaction risk for additional OATP-transported statins which predicted to maximally result in a 1.5-fold exposure increase.