Nuclear Her2 contributes to paclitaxel resistance in breast cancer cells.

Translocation of full-length Her2 receptor into nucleus was reported by some studies. Here, we tested whether nuclear Her2 contributes to paclitaxel resistance in Her2-overexpressing breast cancer cells. Breast cancer cell was transfected with plasmids containing cDNA of wild-type Her2 or mutant-type Her2 lacking the nuclear localization signal (NLS) sequence which is required for Her2 nuclear transport. Cell resistance to paclitaxel was analyzed. Paclitaxel-resistant breast cancer cell was also developed and nuclear Her2 expression was tested. Then, correlation between nuclear Her2 and resistance to paclitaxel were analyzed. Expression of importin ß1 was decreased to downregulate nuclear Her2 level and cell resistance to paclitaxel was tested. We found that Her2 overexpression increases Her2 nuclear expression and cells resistance to paclitaxel in MCF-7 cells. In the paclitaxel resistant cell (SK-BR-3/R), nuclear Her2 expression is upregulated compared with parental SK-BR-3 cells. Increased expression of nuclear Her2 after short-time (48 h) treatment of paclitaxel was also observed in SK-BR-3 cells. Further downregulation of Her2 nuclear expression through blocking expression of importin ß1 sensitizes the cells to paclitaxel. The analysis showed that the Her2 nuclear expression increases the survivin expression which leads to resistance to paclitaxel. Her2 nuclear expression decreases paclitaxel-induced apoptosis. However, co-immunoprecipitation was applied, and the physical interaction of nuclear Her2 and survivin was not detected. We show for the first time that nuclear Her2 contributes to paclitaxel resistance in breast cancer cells which suggests that nuclear Her2 as a potential target to sensitize breast cancers to paclitaxel treatment.

MiR-221/SIRT1/Nrf2 signal axis regulates high glucose induced apoptosis in human retinal microvascular endothelial cells.

BACKGROUND: Diabetic retinopathy (DR) is a serious symptom associated with diabetes and could cause much suffer to patients. MiR-221, SIRT1 and Nrf2 were associated with apoptosis and proliferation and their expression were altered in DR patients. However, their roles and regulatory mechanisms in human retinal microvascular endothelial cells (hRMEC) were not clear. METHODS: Expression of mRNA was detected by qRT-PCR. Protein expression was detected by Western blot. Interaction between miR-221 and SIRT1 was predicted by bioinformatics analysis and validated by dual-luciferase reporter assay. We analyzed the viability and apoptosis of hRMEC by MTT assay and FACS assay, respectively. RESULTS: High glucose (HG) treatment enhanced expression of miR-221 and inhibited expression of SIRT1 and Nrf2. MiR-221 overexpression promoted apoptosis under HG condition. Moreover, miR-221 directly interacted with mRNA of SIRT1 and inhibited SIRT1 expression in hRMEC, through which miR-221 inhibited Nrf2 pathway and induced apoptosis of hRMEC. CONCLUSION: Our data demonstrated that miR-221/SIRT1/Nrf2 signal axis could promote apoptosis in hRMEC under HG conditions. This finding could provide theoretical support for future studies and may contribute to development of new treatment options to retard the process of DR development.

Quantum dot-based in situ simultaneous molecular imaging and quantitative analysis of EGFR and collagen IV and identification of their prognostic value in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a unique breast cancer subtype with high heterogeneity and poor prognosis. Currently, the treatment effect of TNBC has reached a bottleneck, rendering new breakthroughs difficult. Cancer invasion is not an entirely cell-autonomous process, requiring the cells to transmigrate across the surrounding extracellular matrix (ECM) barriers. Developing a new system that integrates key constituents in the tumor microenvironment with pivotal cancer cell molecules is essential for the in-depth investigation of the mechanism of invasion in TNBC. We describe a computer-aided algorithm developed using quantum dot (QD)-based multiplex molecular imaging of TNBC tissues. We performed in situ simultaneous imaging and quantitative detection of epidermal growth factor receptor (EGFR), expressed in the TNBC cell membrane, and collagen IV, the major ECM constituent; calculated the EGFR/collagen IV ratio; and investigated the prognostic value of the EGFR/collagen IV ratio in TNBC. We simultaneously imaged and quantitatively detected EGFR and collagen IV in the TNBC samples. In all patients, quantitative determination showed a statistically significant negative correlation between EGFR and collagen IV. The 5-year disease-free survival (5-DFS) of the high and low EGFR/collagen IV ratio subgroups was significantly different. The EGFR/collagen IV ratio was predictive and was an independent prognostic indicator in TNBC. Compared with EGFR expression, the EGFR/collagen IV ratio had a greater prognostic value for 5-DFS. Our findings open up a new avenue for predicting the clinical outcome in TNBC from the perspective of integrating molecules expressed in both cancer cells and the ECM.

[Dynamic Analysis on Carbon Metabolism of the Northern Region of China Under the Background of Carbon Emission Trading Policy].

The launch of the national carbon emissions trading market in China is a policy to carry out the Beautiful China initiative and to establish a low-carbon economic development system that promotes carbon emission and waste reduction. In order to detect the carbon metabolic processes of the pilot and nonpilot municipalities or provinces in the northern region of China， the theory of urban carbon metabolism and the methods of input-output analysis and ecological network analysis were introduced and used. The results showed that the direct carbon emissions of Beijing and Tianjin had decreased， but their embodied carbon emissions had increased since 2012. The direct and embodied carbon emissions of the pilot sectors in Beijing and Tianjin had the same trend； specifically， the emissions of the sectors of mining and washing of coal， extraction of petroleum and natural gas， and manufacture of non-metallic mineral products decreased significantly， but the sectors of production and supply of electric power and steam with high carbon emission increased. The same trend of the embodied carbon emission intensities of sectors with that of their embodied carbon emissions verified that the embodied added values were not growing with the promotion of the carbon emission trading market. Subsequently， the embodied carbon emission of the pilot sectors in all the municipalities and provinces of the northern region were all contributed mainly by the emissions embodied by a path length less than 6； therefore， it showed that more attention should be paid to the trade among sectors with a path length less than 6 and reducing their carbon emissions. Furthermore， from 2007 to 2012， products or service trading among sectors mostly concentrated on sectors within one municipality or province， and these products or services had the characteristics of low carbon emission. Since 2012， the integration development of the Beijing-Tianjin-Hebei urban agglomeration and the new regional economic patterns established in the northern region both promoted the trading across provinces and across sectors. This research is based on the background of the carbon emission trading policy and aims to build a methodology to identify the key actors and paths in a metabolic system. This could provide a scientific basis for regional policy implementation and regional long-term sustainable development.

Photoreceptor changes in Leber hereditary optic neuropathy with m.G11778A mutation.

AIM: To evaluate the functional and structural changes of photoreceptors in patients and asymptomatic carriers with Leber hereditary optic neuropathy (LHON) using full-field electroretinography (FERG) and optical coherence tomography (OCT). METHODS: Individuals diagnosed with LHON at the Renmin Hospital of Wuhan University and their family members were included in this cross-sectional observational study. The FERG a-wave amplitude of affected patients and asymptomatic carriers was analyzed. The thickness of the outer nuclear layer (ONL), inner and outer segment (IS/OS) and total photoreceptors in the macular fovea and parafovea were measured. RESULTS: This study included 14 LHON patients (mean age: 20.00±9.37y), 12 asymptomatic carriers (mean age: 39.83±6.48y), and 14 normal subjects (mean age: 24.20±1.52y). The FERG results showed that the dark-adapted 3.0 electroretinography and light-adapted 3.0 electroretinography a-wave amplitudes of patients and carriers were significantly decreased (P<0.001). The ONL and photoreceptors layers were slightly thicker in patients than in normal subjects (P<0.05), whereas they were thinner in carriers (P<0.05). There were no differences in IS/OS thickness among the groups (P>0.05). CONCLUSION: Photoreceptors function is significantly impaired in LHON-affected patients and asymptomatic carriers. Meanwhile, photoreceptors morphology is slightly altered, mainly manifesting as a change in ONL thickness.

SB365 inhibits angiogenesis and induces apoptosis of hepatocellular carcinoma through modulation of PI3K/Akt/mTOR signaling pathway.

Identification of small molecules that safely inhibit cancer progression is critical for cancer therapeutics. Saponins exhibit cytostatic and cytotoxic activity against various cancer cells, but the mechanism is not well understood. Here, we investigated whether saponin D (designated SB365), an active component isolated from Pulsatilla koreana, could inhibit the progression of hepatocellular carcinoma (HCC) and considered its mechanism. SB365 strongly suppressed the growth of HCC cells in a dose-dependent manner and induced apoptosis by increasing the proportion of sub G1 apoptotic cells from 8% to 21% through induction of expression of Bax and cleaved caspase-3. In addition, SB365 exhibited potent anti-angiogenic activity and decreased the expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor, a key molecule for angiogenesis. Furthermore, SB365 suppressed the tube formation and migration of HUVEC, as well as in vivo neovascularization in a mouse Matrigel plug assay. In vivo study showed that SB365 significantly inhibited tumor growth in an HCC xenograft model, inducing apoptosis by increasing the expression of the cleaved caspase-3 and DNA fragmentation. The expressions of vascular endothelial growth factor and CD34 in the tumor tissue were decreased by SB365 treatment. In examining its mechanism, SB365 was found to effectively suppress the phosphorylation of PI3K downstream factors, such as Akt, mTOR and p70S6K both in vitro and in vivo. Our study demonstrates that SB365 not only induces apoptosis but also inhibits cell growth and angiogenesis through modulation of the PI3K/Akt/mTOR pathway in human HCC. We suggest that SB365 may be a new chemotherapeutic candidate against HCC.

Human bone marrow-derived clonal mesenchymal stem cells inhibit inflammation and reduce acute pancreatitis in rats.

BACKGROUND & AIMS: Acute pancreatitis (AP) has a high mortality rate; repetitive AP induces chronic AP and pancreatic adenocarcinoma. Mesenchymal stem cells (MSCs) have immunoregulatory effects and reduce inflammation. We developed a protocol to isolate human bone marrow-derived clonal MSCs (hcMSCs) from bone marrow aspirate and investigated the effects of these cells in rat models of mild and severe AP. METHODS: Mild AP was induced in Sprague-Dawley rats by 3 intraperitoneal injections of cerulein (100 µg/kg), given at 2-hour intervals; severe AP was induced by intraparenchymal injection of 3% sodium taurocholate solution. hcMSCs were labeled with CM-1,1'-dioctadecyl-3,3,3'-tetramethylindo-carbocyanine perchloride and administered to rats through the tail vein. RESULTS: hcMSCs underwent self-renewal and had multipotent differentiation capacities and immunoregulatory functions. Greater numbers of infused hcMSCs were detected in pancreas of rats with mild and severe AP than of control rats. Infused hcMSCs reduced acinar-cell degeneration, pancreatic edema, and inflammatory cell infiltration in each model of pancreatitis. The hcMSCs reduced expression of inflammation mediators and cytokines in rats with mild and severe AP. hcMSCs suppressed the mixed lymphocyte reaction and increased expression of Foxp3(+) (a marker of regulatory T cells) in cultured rat lymph node cells. Rats with mild or severe AP that were given infusions of hcMSCs had reduced numbers of CD3(+) T cells and increased expression of Foxp3(+) in pancreas tissues. CONCLUSIONS: hcMSCs reduced inflammation and damage to pancreatic tissue in a rat model of AP; they reduced levels of cytokines and induced numbers of Foxp3(+) regulatory T cells. hcMSCs might be developed as a cell therapy for pancreatitis.

[The efficacy of antihypertensive treatment on diabetes mellitus or impaired glucose tolerance patients with blood pressure below 140/90 mm Hg: a meta-analysis].

OBJECTIVE: To investigate whether antihypertensive treatment is beneficial to patients with diabetes mellitus when their blood pressure (BP) is below 140/90 mm Hg (1 mm Hg = 0.133 kPa). METHODS: MEDLINE, EMBASE, IPA database and secondary resources were searched with terms including blood pressure, hypertension and anti-hypertension drug. INCLUSION CRITERIA: random control study; subjects were patients with diabetes mellitus or impaired glucose tolerance; endpoint BP ≤ 140/90 mm Hg; endpoint BP between two groups had significant differences. There were 16 studies meet inclusive criteria with a total of 51 470 patients. RR and 95%CI were used as index to judge the difference of clinical outcomes between aggressive antihypertensive treatment group and standard antihypertensive treatment group. RevMan5.0 software was used for statistical analysis. RESULTS: When BP of patients with diabetes mellitus were below 140/90 mm Hg, anti-hypertensive treatment could reduce incidence rate of cardiovascular event (RR 0.91, 95%CI 0.87 - 0.96, P = 0.0004) and stroke (RR 0.75, 95%CI 0.63 - 0.88, P = 0.0005), and increased incidence rate of symptomatic hypotension (RR 3.57, 95%CI 1.41 - 11.20, P = 0.03) and hyperpotassemia (RR 1.57, 95%CI 1.05 - 2.33, P = 0.03). There were no significant differences in all-cause mortality (RR 0.94, 95%CI 0.87 - 1.01, P = 0.08), cardiovascular mortality (RR 0.95, 95%CI 0.85 - 1.08, P = 0.05), myocardial infarction (RR 0.93, 95%CI 0.82 - 1.05, P = 0.26), heart failure (RR 0.90, 95%CI 0.76 - 1.06, P = 0.21) between the aggressive antihypertensive treatment group and standard antihypertensive treatment group. CONCLUSIONS: When blood pressure of patients with diabetes mellitus was below 140 mm Hg, there was little benefit from aggressive antihypertensive treatment, and the risk of serious adverse events even increased.

Single-cell and spatially resolved analysis uncovers cell heterogeneity of breast cancer.

The heterogeneity and the complex cellular architecture have a crucial effect on breast cancer progression and response to treatment. However, deciphering the neoplastic subtypes and their spatial organization is still challenging. Here, we combine single-nucleus RNA sequencing (snRNA-seq) with a microarray-based spatial transcriptomics (ST) to identify cell populations and their spatial distribution in breast cancer tissues. Malignant cells are clustered into distinct subpopulations. These cell clusters not only have diverse features, origins and functions, but also emerge to the crosstalk within subtypes. Furthermore, we find that these subclusters are mapped in distinct tissue regions, where discrepant enrichment of stromal cell types are observed. We also inferred the abundance of these tumorous subpopulations by deconvolution of large breast cancer RNA-seq cohorts, revealing differential association with patient survival and therapeutic response. Our study provides a novel insight for the cellular architecture of breast cancer and potential therapeutic strategies.

Suppression by fucoidan of liver fibrogenesis via the TGF-ß/Smad pathway in protecting against oxidative stress.

Fucoidan, a sulfated polysaccharide extracted from various types of brown seaweed, possesses a wide range of pharmacological properties. We investigated the protective effect of fucoidan on dimethylnitrosamine-induced liver fibrogenesis in rats and its mechanism. Liver fibrosis was induced by injecting DMN (10 mg/kg, 3 times per week, I.P.) for 4 weeks, and fucoidan was simultaneously administered (100 mg/kg, 3 times per week, P.O.). The anti-oxidative and anti-inflammatory effects of fucoidan were observed by relative mediators. Fucoidan improved liver fibrosis by inhibiting the expression of transforming growth factor beta 1 (TGF-ß(1))/Smad3 and the tissue inhibitor of metalloproteinase 1 (TIMP-1), and increasing the expression of metalloproteinase-9 (MMP-9). Fucoidan also significantly decreased the accumulation of the extracellular matrix (ECM) and collagen. These results suggest that fucoidan had an anti-fibrotic effect, which was exerted by inhibiting the TGF-ß/Smad pathway, as well as anti-oxidative and anti-inflammatory effects.

Sweep pattern visual evoked potential acuity in children during their periods of visual development.

PURPOSE: To study the clinical usage of sweep pattern visual evoked potential (SPVEP) acuity in children's visual development periods and compare the amplitude-spatial frequency (A-SP) function regression method with the amplitude-logarithm of the visual angle (A-logVA) function regression method in evaluating the SPVEP acuity of children, especially those who have poor visual acuities. METHODS: Twenty-six eyes of 26 amblyopic children (ages ranged from 3 to 12 years; mean age±standard deviation 6.69±1.74 years) and 31 eyes of normal children whose ages were matched with the amblyopic group were involved in this study. SPVEP acuity was recorded with GT-2000 NV (Guote Medical Apparatus Ltd., China) using sinusoidally modulated horizontal gratings with 10 different spatial frequencies from 0.99 to 12.89 cycles per degree to stimulate the retina. The averaging responses were displayed with the discrete Fourier transformation method. SPVEP acuity was assessed by both the A-SP function regression method and the A-logVA function regression method. The logarithm of minimal angle of resolution (logMAR) chart was used to obtain logMAR visual acuity. RESULTS: In the normal group, logMAR acuity calculated by both the A-SP and A-logVA function regression methods had a significant correlation with SPVEP acuity. The average value of SPVEP acuity (by A-logVA) was closer to logMAR acuity. The difference of mean values between logMAR acuity and SPVEP acuity was significant in both regression methods. In the amblyopic group, it was SPVEP acuity (by A-logVA) that had a significant correlation with logMAR acuity, whereas the result was not significant when calculated by the A-SP function regression method (p=0.515). The average value of SPVEP acuity (A-SP) was closer to logMAR acuity. The difference of mean values between logMAR acuity and SPVEP acuity (A-logVA) was significant; however, when compared with SPVEP acuity (A-SP), it was not significant (p=0.174). In addition, SPVEP acuity may be overestimated or underestimated when it is compared with different logMAR visual acuities. CONCLUSION: SPVEP could be used to evaluate the visual acuity for normal children or those with poor visual acuity. Moreover, the A-logVA function regression method was more accurate than the A-SP function regression method in evaluating SPVEP acuity.

Genome-wide CRISPR/Cas9 screening identifies CARHSP1 responsible for radiation resistance in glioblastoma.

Glioblastomas (GBM) is the most common primary malignant brain tumor, and radiotherapy plays a critical role in its therapeutic management. Unfortunately, the development of radioresistance is universal. Here, we identified calcium-regulated heat-stable protein 1 (CARHSP1) as a critical driver for radioresistance utilizing genome-wide CRISPR activation screening. This is a protein with a cold-shock domain (CSD)-containing that is highly similar to cold-shock proteins. CARHSP1 mRNA level was upregulated in irradiation-resistant GBM cells and knockdown of CARHSP1 sensitized GBM cells to radiotherapy. The high expression of CARHSP1 upon radiation might mediate radioresistance by activating the inflammatory signaling pathway. More importantly, patients with high levels of CARHSP1 had poorer survival when treated with radiotherapy. Collectively, our findings suggested that targeting the CARHSP1/TNF-α inflammatory signaling activation induced by radiotherapy might directly affect radioresistance and present an attractive therapeutic target for GBM, particularly for patients with high levels of CARHSP1.

Melatonin ameliorates cerulein-induced pancreatitis by the modulation of nuclear erythroid 2-related factor 2 and nuclear factor-kappaB in rats.

Melatonin exhibits a wide variety of biological effects, including antioxidant and anti-inflammatory functions. Its antioxidant role impedes the etiopathogenesis of pancreatitis, but little is known about the signaling pathway of melatonin in the induction of antioxidant enzymes in acute pancreatitis (AP). The aim of this study was to determine whether melatonin could prevent cerulein-induced AP through nuclear factor erythroid 2-related factor 2 (Nrf2) and curtail inflammation by inhibition of NF-kappaB. AP was induced by two intraperitoneal (i.p.) injections of cerulein at 2 h intervals (50 microg/kg) in Sprague-Dawley rats. Melatonin (10 or 50 mg/kg/daily, i.p.) was administered 24 h before each injection of cerulein. The rats were killed 12 h after the last injection. Acinar cell degeneration, pancreatic edema, and inflammatory infiltration were significantly different in cerulein- and melatonin-treated rats. Melatonin significantly reduced amylase, lipase, MPO, and MDA levels, and increased antioxidant enzyme activities including SOD and GPx, which were decreased in AP (P < 0.05). Melatonin increased the expression of NQO1, HO-1, and SOD2 when compared with the cerulein-induced AP group (P < 0.05). In addition, melatonin increased Nrf2 expression, and reduced expressions of tumor necrosis factor-alpha, IL-1beta, IL-6, IL-8, and iNOS. The elevated nuclear binding of NF-kappaB in the cerulein-induced pancreatitis group was inhibited by melatonin. These results show that melatonin increases antioxidant enzymes and Nrf2 expression, and limits inflammatory mediators in cerulein-induced AP. It is proposed that melatonin may play an important role in oxidative stress via the Nrf2 pathway in parallel with reduction of inflammation by NF-kappaB inhibition.

[Association of interleukin-10 gene polymorphism with cachexia in patients with gastric cancer].

OBJECTIVE: To investigate whether the single nucleotide polymorphisms (SNPs) at -1082, -819 and -592 of interleukin-10 gene and its haplotype are associated with cachexia in patients with gastric cancer. METHODS: Radioimmunoassay was used to examine the serum levels of IL-10 in 223 patients with gastric cancer. The single nucleotide polymorphisms (SNPs) of IL-10 gene -1082G/A, -819T/C and -592A/C were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The serum levels of IL-10 were significantly higher in patients with cachexia than those without (P < 0.001). An increased frequency of -1082G allele was noted in patients with cachexia (P = 0.049). The frequencies of -1082AG and -819CC genotypes were elevated in patients with cachexia than those without (P = 0.036, 0.024). In a logistic regression analysis adjusted for actual weight, carcinoma location and stage, the -1082AG genotype was associated with an odds ratio of 1.989 (95%CI, 1.041 - 3.802, P = 0.037), and the -819CC genotype with an odds ratio of 3.393 (95%CI, 1.298 - 8.871, P = 0.013) for cachexia. Furthermore, haplotype analysis revealed that G1082C819C592 haplotype was associated with a significantly increased risk of cachexia (OR = 2.21; 95%CI, 1.14 - 4.30; P = 0.02). CONCLUSION: Our results suggest that the gene haplotype of IL-10 contributes to the occurrence of cachexia in patients with gastric cancer in Chinese population.

[Impact of application time of aspirin and clopidogrel on platelet aggregation in patients with acute coronary syndrome].

OBJECTIVE: To observe the impact of various application time of aspirin and clopidogrel on the circadian rhythm changes of platelet aggregation in patients with acute coronary syndrome. METHODS: Patients with acute coronary syndrome were divided into day-time (8:00) and night-time (20:00) medication group (n = 15 each). After plasma concentration reached steady state, platelet aggregation was assessed at 5 time points within 24 hours with a mobile four-channel whole blood impedance aggregometer. The platelet aggregation was induced by ADP and arachidonic acid. Thereafter, the two groups were exchanged and platelet aggregation was assessed in the same way post plasma steady state. RESULTS: Arachidonic acid-induced platelet aggregation was the highest at 10:00 Am [(7.96 +/- 3.64) ohm] and the lowest at 0:00 [(6.12 +/- 3.29) ohm, P > 0.05] in day-time group. Platelet aggregation was the highest at 20:00 [(9.40 +/- 5.39) ohm] and the lowest at 10:00 [(5.46 +/- 3.93) ohm], P < 0.05). ADP-induced platelet aggregation was the highest at 10:00 and the lowest at 16:00 in day-time group (P > 0.05) and was the highest at 20:00 and the lowest at 10:00 in night-time group (P > 0.05). Platelet aggregation induced by two inducers was significantly higher at 10:00 in day-time group compared to values in night-time group (all P < 0.05). CONCLUSION: Taking aspirin and clopidogrel at 20:00 was superior to taking the same medications at 8:00 for inhibiting peak platelet aggregation in the morning.

Development of an oral bentonite-based modified-release freeze-dried powder of vactosertib: Pharmacokinetics and anti-colitis activity in rodent models of ulcerative colitis.

Vactosertib is a novel inhibitor of transforming growth factor-ß signaling. Clinical applications of vactosertib have been challenging since conventional oral formulations such as immediate-release tablets demonstrate a rapid rise and fast decline in plasma concentrations. In this study, a novel bentonite-based, modified-release, freeze-dried powder of vactosertib was developed and evaluated to determine its potential in the treatment of ulcerative colitis. The formulation released vactosertib slowly and steadily in an in vitro drug release test. The extent of vactosertib released from the formulation was markedly low (18.0%) at pH 1.2 but considerably high (95.6%) at pH 7.4. Compared with vactosertib oral solution, the formulation demonstrated a 52.5% lower mean maximum concentration of vactosertib and three times longer median time to maximum concentration without a significant change in the extent of vactosertib absorption in a rodent colitis model. Furthermore, colitis mice administered with this formulation showed a significant reduction in the total histopathological score by 30% compared with those administered with the positive control, whereas the administration of vactosertib oral solution resulted in only a 10% reduction. Collectively, this novel formulation resolved the pharmacokinetic drawbacks of vactosertib and is expected to enhance its therapeutic effect by delivering vactosertib to the colitis lesions in the lower gastrointestinal tract.

Melatonin downregulates nuclear erythroid 2-related factor 2 and nuclear factor-kappaB during prevention of oxidative liver injury in a dimethylnitrosamine model.

Melatonin has potent hepatoprotective effects as an antioxidant. However, the signaling pathway of melatonin in the induction of antioxidant enzymes against acute liver injury is not fully understood. The study aimed to determine whether melatonin could prevent dimethylnitrosamine (DMN)-induced liver injury through nuclear erythroid 2-related factor 2 (Nrf2) and inflammation. Liver injury was induced in rats by a single injection of DMN (30 mg/kg, i.p.). Melatonin treatment (50 mg/kg/daily, i.p.) was initiated 24 hr after DMN injection for 14 days, after which the rats were killed and samples were collected. Serum and antioxidant enzyme activities improved in melatonin-treated rats, compared with DMN-induced liver injury group (P < 0.01). Melatonin reduced the infiltration of inflammatory cells and necrosis in the liver, and increased the expression of NADPH: quinone oxidoreductase-1, heme oxygenase-1, and superoxide dismutase-2, which were decreased by DMN. Melatonin increased expression of novel transcription factor, Nrf2, and decreased expression of inflammatory mediators including tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and inducible nitric oxide synthase. The increased nuclear binding of nuclear factor-kappa B (NF-kappaB) in the DMN-induced liver injury group was inhibited by melatonin. Our results show that melatonin increases antioxidant enzymes and Nrf2 expression in parallel with the decrease of inflammatory mediators in DMN-induced liver injury, suggesting that melatonin may play a role of antioxidant defense via the Nrf2 pathway, by reducing inflammation by NF-kappaB inhibition.

One-pot synthesis of nickel-cobalt hydroxyfluorides nanowires with ultrahigh energy density for an asymmetric supercapacitor.

A novel and unique nickel-cobalt hydroxyfluorides (NiCo-HF) nanowires material is fabricated by one-pot solvothermal synthesis method for asymmetric supercapacitor. The synthesis mechanism and factors that influence the formation of the NiCo-HF nanowires have been further discussed. The as-prepared NiCo-HF electrode exhibits a high specific capacitance of 3,372.6 F g-1, and the capacitance retention of 94.3% can be achieved at a high current density of 20 A g-1 after 10,000 cycles. The outstanding electrochemical performance of the electrode can be attributed to the synergistic effect of the nanowires morphology and complicated redox process of active material. Furthermore, an asymmetric supercapacitor assembled with NiCo-HF nanowires as positive electrode and activated carbon as the negative electrode shows an ultrahigh energy density of 83.6 Wh kg-1 at a power density of 379.4 W kg-1 and an excellent cycling stability with 86.3% capacitance retention after 10,000 cycles, indicating that this novel material has great promise for potential application in energy storage device.

The Effect of Intragastric Administration of Botulinum Toxin Type A on Reducing Adiposity in a Rat Model of Obesity Using Micro-CT and Histological Examinations.

BACKGROUND/AIMS: Botulinum toxin type A (BTX), a long-acting inhibitor of muscular contraction in both striated and smooth muscles, is responsible for gastric motility. The aim of this study was to investigate the effects of an endoscopic intragastric BTX injection on weight loss, body fat accumulation, and gastric emptying time. METHODS: The BTX group consisted of 15 obese rats in which 20 U of BTX were injected into the gastric antrum. The saline group consisted of 15 obese rats injected with 20 U of saline, and the control group included 10 obese rats that did not receive a surgical intervention. The gastric emptying time, biochemical parameters, and body fat volume were evaluated using micro-computed tomography (micro-CT) and histologic evaluations. RESULTS: The postoperative body weight of the BTX group was significantly lower than those of the other groups (p<0.001) at 6 weeks after the operation. The gastric emptying time (156±54 minutes) was significantly delayed in the BTX group. The BTX group showed significantly lower lipid levels than the other groups. A reduction in body fat volume was observed in the BTX group using micro-CT and histological evaluations. CONCLUSIONS: BTX application to the gastric antrum represents a potentially effective treatment for obesity and may help improve the lipid profile by increasing the gastric emptying time.