Effects of a Long-Acting Formulation of Octreotide on Patients with Portal Hypertension

Objective. This study aimed to determine whether the treatment of a long-acting formulation of octreotide (OCT-LAR) exerted a similar effect on improving the prognosis of patients with portal hypertension compared with placement of transjugular intrahepatic portosystemic shunts (TIPSs). Methods. A total of 24 patients with portal hypertension who underwent TIPS placement or OCT-LAR treatment from January 2010 to January 2015 were reviewed. Hemodynamic studies, biological values, live functions, and treatment complications before and during the treatment were evaluated. Results. Baseline clinical characteristics were similar between two groups. Hepatic venous pressure gradient (HVPG) was improved in OCT-LAR groups (15.9 ± 2.4 to 12.8 ± 1.6 mmHg). Both groups showed a slight decrease in endothelin-1 (ET-1) and urotensin II and a slight increase in oxide metabolite (NOx) concentrations with no significant difference. Aspartate aminotransferase and alanine aminotransferase increased one week after TIPS placement when they improved in the OCT-LAR treatment group. The complications of OCT-LAR treatment were minor and transient. However, one patient who received TIPS placement presented procedure-related complications and required rehospitalization, and 2 patients had developed hepatic encephalopathy during the follow-up period. Conclusion. Prolonged administration of OCT-LAR exerted a virtually similar effect on improving hemodynamic parameters and liver function in patients with portal hypertension compared with placement of TIPS, with no apparent serious adverse effects

Resistin induces multidrug resistance in myeloma by inhibiting cell death and upregulating ABC transporter expression

Despite advances in therapy, multiple myeloma remains incurable, with a high frequency of relapse. This suggests the need to identify additional factors that contribute to drug resistance. Our previous studies revealed that bone marrow adipocytes promote resistance to chemotherapy in myeloma through adipocyte-secreted adipokines, but the mechanism underlying this effect and the specific adipokines involved are not well understood. We proposed to determine the role of resistin, an adipokine that is secreted by adipocytes, in chemotherapy resistance in myeloma. We found that resistin abrogated chemotherapy-induced apoptosis in established myeloma cell lines and primary myeloma samples. Resistin inhibited chemotherapy-induced caspase cleavage through the NF-κB and PI3K/Akt pathways. Resistin also increased the expression and drug efflux function of ATP-binding cassette (ABC) transporters in myeloma cells through decreasing the expression of both DNA methyltransferases DNMT1 and DNMT3a and the methylation levels of ABC gene promoters. In vivo studies further demonstrated the protective effect of resistin in chemotherapy-induced apoptosis. Our study thus reveals a new biological function of resistin in the pathogenesis of myeloma, with the implication that targeting resistin could be a potential strategy to prevent or overcome multidrug resistance in myeloma

Sirtuin1 Over-Expression Does Not Impact Retinal Vascular and Neuronal Degeneration in a Mouse Model of Oxygen-Induced Retinopathy

Proliferative retinopathy is a leading cause of blindness, including retinopathy of prematurity (ROP) in children and diabetic retinopathy in adults. Retinopathy is characterized by an initial phase of vessel loss, leading to tissue ischemia and hypoxia, followed by sight threatening pathologic neovascularization in the second phase. Previously we found that Sirtuin1 (Sirt1), a metabolically dependent protein deacetylase, regulates vascular regeneration in a mouse model of oxygen-induced proliferative retinopathy (OIR), as neuronal depletion of Sirt1 in retina worsens retinopathy. In this study we assessed whether over-expression of Sirtuin1 in retinal neurons and vessels achieved by crossing Sirt1 over-expressing flox mice with Nestin-Cre mice or Tie2-Cre mice, respectively, may protect against retinopathy. We found that over-expression of Sirt1 in Nestin expressing retinal neurons does not impact vaso-obliteration or pathologic neovascularization in OIR, nor does it influence neuronal degeneration in OIR. Similarly, increased expression of Sirt1 in Tie2 expressing vascular endothelial cells and monocytes/macrophages does not protect retinal vessels in OIR. In addition to the genetic approaches, dietary supplement with Sirt1 activators, resveratrol or SRT1720, were fed to wild type mice with OIR. Neither treatment showed significant vaso-protective effects in retinopathy. Together these results indicate that although endogenous Sirt1 is important as a stress-induced protector in retinopathy, over-expression of Sirt1 or treatment with small molecule activators at the examined doses do not provide additional protection against retinopathy in mice. Further studies are needed to examine in depth whether increasing levels of Sirt1 may serve as a potential therapeutic approach to treat or prevent retinopathy

Associations between trajectories of cardiovascular risk factor change and cognitive impairment in Chinese elderly: A nationwide cohort study

Objectives: This study aimed to investigate the relationship between long-term trajectories of changes in cardiovascular risk factors (CVRFs) and the risk of cognitive impairment among Chinese adults over 60 years old. Methods: Data were obtained from the Chinese Longitudinal Healthy Longevity Survey 2005–2018. Cognitive function was evaluated longitudinally through the Chinese version of the Mini-Mental State Examination (C-MMSE), and cognitive impairment (C-MMSE ≤23) was used as the main outcome variable. The cardiovascular risk factors, including systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), pulse pressure (PP), and body mass index (BMI), were continuously measured in the follow-up duration. The patterns of trajectories of changes in CVRFs were derived from the latent growth mixture model (LGMM). The Cox regression model was used to evaluate the cognitive impairment hazard ratio (HR) across different CVRF trajectories. Results: A total of 5,164 participants aged ≥60 years with normal cognitive function at baseline were included in the study. After a median follow-up of 8 years, 2,071 participants (40.1%) developed cognitive impairment (C-MMSE ≤ 23). The four-class trajectories of SBP and BMI were obtained by means of LGMM, and the trajectories of DBP, MAP, and PP were grouped into a three-class subgroup. In the final adjusted Cox model, the lowered SBP [adjusted HR (aHR): 1.59; 95% CI: 1.17–2.16], lowered PP (aHR: 2.64; 95% CI: 1.66–4.19), and progressively obese (aHR: 1.28; 95% CI: 1.02–1.62) and stable slim (aHR: 1.13; 95% CI: 1.02–1.25) were associated with the higher risk of cognitive impairment. Low stable DBP (aHR: 0.80; 95% CI: 0.66–0.96) and elevated PP (aHR: 0.76; 95% CI: 0.63–0.92) decreased the risk for cognitive impairment among participants. Conclusion: Lowered SBP, lowered PP, progressive obesity, and stable slim increased the risk for cognitive impairment in the Chinese elderly. Low stable DBP and elevated PP were protective against cognitive impairment, but more DBP lowering and ≥25 mmHg growth in PP contributed to a higher risk of cognitive impairment. The findings have important implications for preventing cognitive impairment in elder adults based on the long-term trajectories of changes in CVRFs

Protective immunity against Trichinella spiralis infection induced by TsNd vaccine in mice

BACKGROUND: We have previously reported that Trichinella spiralis Nudix hydrolase (TsNd) bound to intestinal epithelial cells (IECs), and vaccination of mice with recombinant TsNd protein (rTsNd) produced a partial protective immunity. The aim of this study was to investigate the immune protection induced by TsNd DNA vaccine. METHODS: The full-length cDNA sequence of TsNd gene was cloned into pcDNA3.1 and used to immunize BALB/c mice by intramuscular injection. Transcription and expression of TsNd were detected by RT-PCR and IFT. The levels of specific IgA, IgG, IgG1 and IgG2a, and cytokines were assayed by ELISA at weeks 0, 6 and 8 post-immunization. The immune protection of TsNd DNA vaccine against challenge infection was investigated. RESULTS: Immunization of mice with TsNd DNA elicited a systemic Th1/Th2 immune response and a local mucosal IgA response. The in vitro transcription and expression of TsNd gene was observed at all developmental stages of T. spiralis (ML, IIL, AW and NBL). Anti-rTsNd IgG levels were increased after immunization and levels of IgG1 were obviously higher than that of IgG2a. Intestinal specific IgA levels of immunized mice were significantly higher than those of vector and PBS control mice. Cytokine profiling also showed a significant increase in Th1 (IFN-γ, IL-2) and Th2 (IL-4, 10) responses in splenocytes of immunized mice on stimulation with rTsNd. Vaccination of mice with pcDNA3.1-TsNd displayed a 40.44% reduction in adult worms and a 53.9% reduction in larval burden. CONCLUSIONS: TsNd DNA induced a mixed Th1/Th2 immune response and partial protection against T. spiralis infection in mice

NMR Structure and Dynamics of a Designed Water-Soluble Transmembrane Domain of Nicotinic Acetylcholine Receptor

The nicotinic acetylcholine receptor (nAChR) is an important therapeutic target for a wide range of pathophysiological conditions, for which rational drug designs often require receptor structures at atomic resolution. Recent proof-of-concept studies demonstrated a water-solubilization approach to structure determination of membrane proteins by NMR (Slovic et al., PNAS, 101: 1828–1833, 2004; Ma et al., PNAS, 105: 16537–42, 2008). We report here the computational design and experimental characterization of WSA, a water-soluble protein with ~ 83% sequence identity to the transmembrane (TM) domain of the nAChR α1 subunit. Although the design was based on a low-resolution structural template, the resulting high-resolution NMR structure agrees remarkably well with the recent crystal structure of the TM domains of the bacterial Gloeobacter violaceuspentameric ligand-gated ion channel (GLIC), demonstrating the robustness and general applicability of the approach. NMR T2 dispersion measurements showed that the TM2 domain of the designed protein was dynamic, undergoing conformational exchange on the NMR timescale. Photoaffinity labeling with isoflurane and propofol photolabels identified a common binding site in the immediate proximity of the anesthetic binding site found in the crystal structure of the anesthetic-GLIC complex. Our results illustrate the usefulness of high-resolution NMR analyses of water-solubilized channel proteins for the discovery of potential drug binding sites

Effect of Auricular Acupressure on Uremic Pruritus in Patients Receiving Hemodialysis Treatment: A Randomized Controlled Trial

Background. Uremic pruritus (UP) is a common symptom in patients undergoing maintenance hemodialysis for end-stage renal disease (ESRD). Objective. To determine the clinical efficacy of auricular acupressure therapy on pruritus in hemodialysis patients and to explore possible underlying mechanisms. Methods. Patients receiving maintenance hemodialysis at a referral medical center were recruited and assigned to intervention (n=32) and control (n=30) groups. The intervention group underwent auricular acupressure treatment three times a week for six weeks. Auricular acupressure was not applied to patients in the control group. However, tape without Vaccaria seeds was applied to the same six auricular acupoints as the intervention group. Pruritus scores were assessed using VAS scores, and enzyme-linked immunosorbent assays (ELISA) were used to measure levels of other possible contributory biochemical factors. Results. There was a significant difference in mean VAS scores between the postintervention and control groups during follow-up (3.844 ± 1.687 versus 5.567 ± 2.285, F=22.32, P<0.0001). Compared to the control group, serum histamine levels in the postintervention group at the six-week follow-up had decreased significantly (F=5.01, P=0.0290). Conclusion. Our findings suggest that auricular acupressure may be a useful treatment in the multidisciplinary management of UP in ESRD patients

Choroid Sprouting Assay: An Ex Vivo Model of Microvascular Angiogenesis

Angiogenesis of the microvasculature is central to the etiology of many diseases including proliferative retinopathy, age-related macular degeneration and cancer. A mouse model of microvascular angiogenesis would be very valuable and enable access to a wide range of genetically manipulated tissues that closely approximate small blood vessel growth in vivo. Vascular endothelial cells cultured in vitro are widely used, however, isolating pure vascular murine endothelial cells is technically challenging. A microvascular mouse explant model that is robust, quantitative and can be reproduced without difficulty would overcome these limitations. Here we characterized and optimized for reproducibility an organotypic microvascular angiogenesis mouse and rat model from the choroid, a microvascular bed in the posterior of eye. The choroidal tissues from C57BL/6J and 129S6/SvEvTac mice and Sprague Dawley rats were isolated and incubated in Matrigel. Vascular sprouting was comparable between choroid samples obtained from different animals of the same genetic background. The sprouting area, normalized to controls, was highly reproducible between independent experiments. We developed a semi-automated macro in ImageJ software to allow for more efficient quantification of sprouting area. Isolated choroid explants responded to manipulation of the external environment while maintaining the local interactions of endothelial cells with neighboring cells, including pericytes and macrophages as evidenced by immunohistochemistry and fluorescence-activated cell sorting (FACS) analysis. This reproducible ex vivo angiogenesis assay can be used to evaluate angiogenic potential of pharmacologic compounds on microvessels and can take advantage of genetically manipulated mouse tissue for microvascular disease research

Primary succession of nitrogen cycling microbial communities along the deglaciated forelands of Tianshan Mountain, China

Structural succession and its driving factors for nitrogen (N) cycling microbial communities during the early stages of soil development (0-44 years) were studied along a chronosequence in the glacial forelands of the Tianshan Mountain No.1 glacier in the arid and semi-arid region of central Asia. We assessed the abundance and population of functional genes affiliated with N-fixation (nifH), nitrification (bacterial and archaeal amoA), and denitrification (nirK/S and nosZ) in a glacier foreland using molecular methods. The abundance of functional genes significantly increased with soil development. N cycling community compositions were also significantly shifted within 44 years and were structured by successional age. Cyanobacterial nifH gene sequences were the most dominant N fixing bacteria and its relative abundance increased from 56.8-93.2% along the chronosequence. Ammonia-oxidizing communities shifted from the Nitrososphaera cluster (AOA-amoA) and the Nitrosospira cluster ME (AOB-aomA) in younger soils (0 and 5 years) to communities dominated by soil and sediment 1 (AOA-amoA) and Nitrosospira Cluster 2 Related (AOB-aomA) in older soils (=17 years). Most of the denitrifers closest relatives were potential aerobic denitrifying bacteria, and some other types of denitrifying bacteria (like autotrophic nitrate-reducing, sulfide-oxidizing bacteria and denitrifying phosphorus removing bacteria) were also detected in all soil samples. The regression analysis showed that N cycling microbial communities were dominant in younger soils (0-5 years) and significantly correlated with soil total carbon, while communities that were most abundant in older soils were significantly correlated with soil total nitrogen. These results suggested that the shift of soil C and N contents during the glacial retreat significantly influenced the abundance, composition and diversity of N cycling microbial communities. © 2016 Zeng, Lou, Zhang, Wang, Hu, Shen, Zhang, Han, Zhang, Lin, Chalk and He