Structure characterization of a highly branched galactan from the slug Vaginulus alte and its utilization by human gut microbiota.

The slug Vaginulus alte is used as folk medicine in China, but the structure and activities of its galactan components remain to be clarified. Here, the galactan from V. alte (VAG) was purified. The Mw of VAG was determined as ~28.8 kDa. Chemical composition analysis showed that VAG was composed of d-galactose (75 %) and l-galactose (25 %). To elucidate its precise structure, a series of disaccharides and trisaccharides were purified from mild acid hydrolyzed VAG and their structures were characterized by 1D/2D NMR spectroscopy. Based on methylation analysis and structural analysis of oligosaccharides, VAG was elucidated as a highly branched polysaccharide and mainly composed of (1 â†’ 6)- or (1 â†’ 3)-linked ß-d-galactose, and distinct (1 â†’ 2)-linked α-l-galactose. The investigation of probiotic effects in vitro revealed that VAG could promote the growth of B. thetaiotaomicron and B. ovatus, while had no effect on the growth of L. acidophilus, L. rhamnosus, B. longum subsp. infantis and B. animalis subsp. lactis, but dVAG-3 with Mw ~1.0 kDa could promote the growth of L. acidophilus. These results will provide insights into specific structures and functions of polysaccharides from the V. alte.

Anaemia can be improved by controlling the disease activity of Takayasu's arteritis without iron administration.

BACKGROUND: Anaemia is a common clinical manifestation observed in Takayasu's arteritis (TAK), but few studies have been conducted. This study investigated whether improvement of inflammatory indicators was associated with improvement of anaemia in TAK. We also investigated whether iron supplement treatment could benefit in addition to immunosuppressant therapy in the anaemia patients with TAK. METHODS: This was a retrospective cohort study of 160 patients diagnosed with TAK. All patients were further assigned into anaemia group (67 cases) or non-anaemia group (93 cases) according to their haemoglobin levels. Fifty two anaemia patients completed follow-up (median 5.2 months). RESULTS: There were 67 (41.88%) anaemia patients among all 160 TAK patients. Compared to TAK patients without anaemia, the average age [32 (24, 45) vs. 40 (31, 48), p = 0.002], disease duration [36 (7, 120) vs. 72 (14, 162), p = 0.017] and BMI [21.43 (18.96, 23.81) vs. 22.86 (20.09, 25.81), p = 0.008] were significantly lower in TAK patients with anaemia. The levels of ESR [23 (15, 51) vs. 11 (5.5, 22), p = 0.0001] and CRP [9.33 (1.99, 27.8) vs. 1.99 (0.45, 6.68), p = 0.0001] were significantly increased in TAK patients who complicated with anaemia. After follow-up, decrease of ESR, CRP and disease activity score (NIH and ITAS) were significantly associated with improvement of anaemia. One unit decrease of ESR and CRP, the hazard ratio of the improvement rate of anaemia was 1.02 [95% CI (1.00, 1.03); p = 0.027] and 1.04 [95% CI (1.02, 1.07); p < 0.001] respectively. One point decrease of NIH and ITAS-A was associated with a higher probability of anaemia improvement [HR 95% CI: 1.25 (1.02, 1.41), p = 0.022, HR 95% CI: 1.62 (1.21, 2.17), p = 0.001]. These relationships were consistent between iron supplement treatment group and without iron supplement treatment group. We found no significant difference in cumulative hazard between the two groups (p = 0.692). CONCLUSION: Anaemia was a common complication in TAK. Decrease of ESR, CRP and disease activity score (NIH and ITAS) were significantly associated with improvement of anaemia, even after adjusting for various covariates. Moreover, these relationships were consistent between iron supplement treatment group and without iron supplement treatment group. There was no significant difference in the improvement of anaemia in patients receiving immunosuppressant therapy with or without iron supplement treatment.

Akkermansia muciniphila ameliorates depressive disorders in a murine alcohol-LPS (mALPS) model.

Depression is the most common mental disorder in the world. Recently, an increasing number of studies have reported alcohol-related depression. However, there is no simple, efficient, and time-saving alcohol-related depression animal model yet. Based on the fact that people with alcohol addiction often have impaired gastrointestinal (GI) tract health like dysbiosis, which serves as a primary factor to augment lipopolysaccharides (LPS), we first developed a murine alcohol-LPS model (mALPS), with oral gavage of LPS in acute alcohol treated mice, and successfully observed depression-like symptoms. We found that acute alcohol treatment damaged the intestinal barrier and caused dysbiosis, which further increased the translocation of LPS and neuroinflammatory responses (TNF-α and IL-1ß) and led to abnormal expression of the depression-related genes, i.e. BDND and IDO, reduced the levels of 5-HT and caused depressive behaviors in mice. Probiotic intervention could improve depressive symptoms without notable adverse effects. Akkermansia muciniphila (AKK), one of the next-generation probiotics, has been widely used for the restoration of the intestinal barrier and reduction of inflammation. Here, we found that AKK significantly ameliorated alcohol-related depressive behaviors in a mALPS model, through enhancing the intestinal barrier and maintaining the homeostasis of the gut microbiota. Furthermore, AKK reduced serum LPS, ameliorated neuroinflammation (TNF-α and IL-1ß), normalized the expression of depression-related genes and increased the 5-HT levels in the hippocampus. Our study suggests that AKK supplements will be a promising therapeutic regime for alcohol-associated depression in the future.

Bacterial community composition and indicators of water quality in Caizi Lake, a typical Yangtze-connected freshwater lake.

Caizi Lake is an important lake connected to the Yangtze River in Anhui Province and a crucial connection for the Yangtze-to-Huaihe Water Diversion Project. There were marked differences in trophic status of the six sampling sites based on the physicochemical characterization. The Bacterial Eutrophic Index (BEI), used to quantify water quality, was well related to Carlson's trophic state index (TSI) (Spearman's ρ = 0.829, P < 0.05). Mean TSI and BEI were 54 and 0.58, respectively, indicating that Caizi Lake was slightly eutrophic. Actinobacteriota were the predominant bacterial phylum in the water and Acidobacteriota in sediments. The diversity and composition of the bacterial community was markedly different between sites for water but not sediment samples. Unlike other Yangtze-connected freshwater lakes, the distance-based redundancy analysis revealed that dissolved oxygen affected the composition of the planktonic bacterial community (P < 0.001), while total phosphorus was the major factor in the sediments (P < 0.05). The water quality of Caizi Lake has significantly improved since a few years ago. These results contribute to the long-term monitoring of the ecological quality of the water environment along the Yangtze River to the Huaihe River.

Acupuncture for retinitis pigmentosa: study protocol for a randomised, sham-controlled trial.

INTRODUCTION: Primary retinitis pigmentosa (RP) is a common hereditary retinal disease in ophthalmology that has a considerable impact on quality of life, but there are few effective therapeutic strategies. This trial aims to determine the efficacy and safety of acupuncture versus sham acupuncture (SA) for RP. METHODS AND ANALYSIS: This is a study protocol for a randomised, participant-blind, sham-controlled trial. 64 eligible patients with RP will randomly be divided into acupuncture group and SA group. All groups will receive 48 sessions over 3 months. Participants will complete the trial by visiting the research centre in month 6/9 for a follow-up assessment. The primary outcome is visual field mean sensitivity and visual field mean deviation at month 3/6/9 compared with baseline. Secondary outcomes include the best-corrected visual acuity, central macular thickness, subfoveal choroidal thicknes, traditional Chinese medicine syndrome score and the scale of life quality for diseases with visual impairment at month 3/6/9 compared with baseline. Adverse events and safety indexes will be recorded throughout the study. SPSS V.25.0 statistical software was used for analysis, and measurement data were expressed as mean±SD. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee of the Chinese Clinical Trial Registry (approval no: ChiECRCT20200460). The results of this study will be published in a peer-reviewed journal, and trial participants will be informed via email and/or phone calls. TRIAL REGISTRATION NUMBER: ChiCTR2000041090.

Divanillyl sulfone suppresses NLRP3 inflammasome activation via inducing mitophagy to ameliorate chronic neuropathic pain in mice.

BACKGROUND: Chronic neuropathic pain is a frequent sequel to peripheral nerve injury and maladaptive nervous system function. Divanillyl sulfone (DS), a novel structural derivative of 4,4'-dihydroxydibenzyl sulfoxide from a traditional Chinese medicine Gastrodia elata with anti-nociceptive effects, significantly alleviated neuropathic pain following intrathecal injection. Here, we aimed to investigate the underlying mechanisms of DS against neuropathic pain. METHODS: A chronic constrictive injury (CCI) mouse model of neuropathic pain induced by sciatic nerve ligation was performed to evaluate the effect of DS by measuring the limb withdrawal using Von Frey filament test. Immunofluorescence staining was used to assess the cell localizations and expressions of Iba-1, ASC, NLRP3, and ROS, the formation of autolysosome. The levels of NLRP3-related proteins (caspase-1, NLRP3, and IL-1ß), mitophagy-related proteins (LC3, Beclin-1, and p62), and apoptosis-related proteins (Bcl-XL and Bax) were detected by Western blotting. The apoptosis of BV-2 cell and caspase activity were evaluated by flow cytometry. RESULTS: DS significantly alleviated the neuropathic pain by increasing the mechanical withdrawal threshold and inhibiting the activation of NLRP3 in CCI-induced model mice. Our findings indicated that DS promoted the mitophagy by increasing the LC3II and Beclin 1 and decreasing the levels of p62 protein in BV-2 cell. This is accompanied by the inhibition of NLRP3 activation, which was shown as inhibited the expression of NLRP3 in lysates as well as the secretion of mature caspase-1 p10 and IL-1ß p17 in supernatants in cultured BV-2 microglia. In addition, DS could promote mitophagy-induced improvement of dysfunctional mitochondria by clearing intracellular ROS and restoring mitochondrial membrane potential. CONCLUSION: Together, our findings demonstrated that DS ameliorate chronic neuropathic pain in mice by suppressing NLRP3 inflammasome activation induced by mitophagy in microglia. DS may be a promising therapeutic agent for chronic neuropathic pain.

Clinical features and prognostic factors of pediatric idiopathic sudden hearing loss from moderate to profound degree.

BACKGROUND: The pediatric idiopathic sudden sensorineural hearing loss (PISSNHL) is not rare in the clinics, however, the prognostic factors of PISSNHL are still unclear. OBJECTIVES: To investigate the clinical and audiologic characteristics associated with prognosis in PISSNHL. MATERIAL AND METHODS: Clinical and audiological characteristics and possible prognostic factors were retrospectively evaluated in 76 PISSNHL patients aged less than 19 years. RESULTS: Hearing loss was moderate in nine patients, severe in 21 patients, profound in 46 patients. Among five types of audiogram, 3.9% were classified as ascending, 11.8% as descending, 25.0% as flat, 55.3% as profound, and 3.9% as concave. The recovery rate according to Siegel's criteria was 55.3%. There was no significant difference between the recovery group and the poor recovery group in terms of age, sex, laterality of hearing loss, the onset of treatment, and accompanying symptoms (p > 0.05). The initial hearing levels and the audiogram type were significantly different in the two groups (p < 0.001) according to univariate analysis, while only the initial hearing level was significantly different (p = 0.046) according to multivariate analysis. CONCLUSIONS AND SIGNIFICANCE: Prognosis of PISSNHL was mainly related to initial hearing at onset. An initial hearing level greater than 80 dB was a poor prognostic factor.

Hirudo (Leech) for proliferative vitreous retinopathy: A protocol for systemic review and meta-analysis.

INTRODUCTION: Proliferative vitreous retinopathy (PVR) is characterized by proliferation of cells and contraction of membranes on either the retinal surface or in the vitreous cavity, which leads to retinal detachment and visual impairment. PVR is commonly seen in patients with rhegmatogenous retinal detachment and diabetic retinopathy, which seriously affects the patient's work and life. Previous studies indicated that Hirudo (Leech) or compound prescription containing Hirudo (Leech) for treatment of PVR would be effective. However, due to the lack of evidence, there are no specific methods or suggestions, so it is necessary to carry out systematic evaluations on Hirudo (Leech) for PVR and provide effective evidence for further research. METHODS AND ANALYSIS: The following 8 databases will be searched: Cochrane Central Register of Controlled Trials, PubMed, MEDLINE, EMBASE, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, VIP Database, and Wanfang Database. All randomized controlled trials in English or Chinese related to Hirudo (Leech) for PVR will be included. Outcomes will include change in Vitreous opacity, Vision changes, production of the anterior macular membrane, and retinal detachment again. The incidence of adverse events will be assessed for safety evaluation. Study inclusion, data extraction and quality assessment will be performed independently by 2 reviewers. Assessment of risk of bias and data synthesis will be performed using Review Manager V.5.3. RESULTS: In this systematic review and meta-analysis, we will synthesize the studies to assess the safety and efficacy of Hirudo (Leech) for PVR. CONCLUSION: The summary of our study will clarify whether Hirudo (Leech) therapy could be an efficient and safe method for PVR, which can further guide the promotion and application of it. OPEN SCIENCE FRAMEWORK OSF REGISTRATION NUMBER: 10.17605/OSF.IO/FP7VG (https://osf.io/fp7vg).

[Effect of injecting mouse nerve growth factor in different ways on motor development, cerebral hemodynamics and biochemical metabolism in children with cerebral palsy].

OBJECTIVE: To compare the effect of acupoint injection and intramuscular injection with mouse nerve growth factor (mNGF) on gross motor function development of children with cerebral palsy (CP), and explore the treatment mechanism. METHODS: A total of 63 children with CP were randomly divided into an observation group (32 cases, 4 cases dropped off ) and a control group (31 cases, 3 cases dropped off). Based on the routine rehabilitation therapy, the control group received intramuscular injection of mNGF(18 µg/2 mL), and the observation group received acupoint injection of mNGF at Xinshu (BL 15), Ganshu (BL 18), Pishu (BL 20), Shenshu (BL 23), Sanjiaoshu (BL 22), Shenting (GV 24), Baihui (GV 20), Fengfu (GV 16), Dazhui (GV 14), etc. Of them, 5-6 acupoints alternately were selected each time, and each acupoint was given 0.3-0.5 mL, totally 18 µg/2 mL. Both treatment were carried out once every other day for six months. Before and after treatment, the children's development of brain function was assessed using gross motor function classification system (GMFCS). Before treatment (T0), after 2 (T2), 4 (T4) and 6 (T6) months of treatment, the motor function was evaluated by gross motor function measure (GMFM-88). The systolic peak velocity (Vs), mean velocity (Vm) and vascular resistance index (RI) of anterior cerebral artery (ACA) and middle cerebral artery (MCA) were measured, and the level of N-acetyl aspartate acid (NAA), choline (Cho), lactate (Lac) and creatine (Cr) from the basal ganglia, thalamus and periventricular white mater were detected by magnetic resonance spectroscopy (MRS) technology with MAGNETOM Skyra3.0T magnetic resonance imaging system before and after treatment. RESULTS: Compared with before treatment, the GMFCS classification of the observation group after treatment was significantly improved (P<0.05); after treatment, the difference of GMFCS classification between the two groups was not significant (P>0.05), however, the observation group had a 3.142 times of feasibility for good gross motor function development by more than level 1 compared to the control group (P<0.05). After 2, 4, and 6 months of treatment, the GMFM-88 scores of the two groups showed an upward trend (P<0.01), and the increase of the observation group was greater than that of the control group (P<0.05). Compared with before treatment, in the ACA and MCA, the Vs and Vm increased, RI decreased in both groups after treatment (P<0.01), and in the brain, NAA/Cr increased, Cho/Cr and Lac/Cr decreased (P<0.01), and after treatment, the Vs, Vm of ACA and MCA and NAA/Cr of brain in the observation group were higher than those in the control group (P<0.05), and the RI of ACA and MCA and Cho/Cr and Lac/Cr of brain in the observation group were lower than those in the control group (P<0.05). CONCLUSION: The mNGF acupoint injection has a better effect on the gross motor function in the children with cerebral palsy compared with the intramuscular injection, and the mechanism may be associated with exhibiting the double effects of acupoint effect and the targeting therapy of drug, which can effectively improve the cerebral hemodynamics and the metabolism of cerebral nervous substances.

Tumor Microenvironment-Responsive Theranostic Nanoplatform for in Situ Self-Boosting Combined Phototherapy through Intracellular Reassembly.

Through rational design, in vivo supramolecular construction of nanodrugs could precisely proceed in the lesion areas, which may apparently improve the theranostic performance of nanomaterials. Herein, a tumor microenvironment-responsive theranostic nanoplatform (Ce6-GA@MnO2-HA-PEG) has been constructed to achieve in vivo supramolecular construction and enhance the therapeutic efficacy of combined phototherapy through intracellular reassembly. Under the tumor microenvironment, such nanoplatform could undergo the process of decomposition-reassembly and form in situ photothermal assemblies. The generation of assemblies would endow this nanoplatform with the capacity of photothermal therapy. Meanwhile, this nanoplatform could alleviate hypoxia and improve the therapeutic efficacy of photodynamic therapy. The results of in vitro and in vivo experiments reveal that tumors can be ablated efficiently by the designed nanoplatform under laser irradiation. In addition, fluorescence imaging and magnetic resonance imaging can be activated by the decomposition of MnO2 to realize tumor imaging in vivo. Therefore, this multifunctional nanoplatform exhibits the capacity for boosting dual-modal imaging-guided combined phototherapy through intracellular reassembly, which may propose a new thought in cancer theranostics.

Differential gene content and gene expression for bacterial evolution and speciation of Shewanella in terms of biosynthesis of heme and heme-requiring proteins.

BACKGROUND: Most species of Shewanella harbor two ferrochelatase paralogues for the biosynthesis of c-type cytochromes, which are crucial for their respiratory versatility. In our previous study of the Shewanella loihica PV-4 strain, we found that the disruption of hemH1 but not hemH2 resulted in a significant accumulation of extracellular protoporphyrin IX (PPIX), but it is different in Shewanella oneidensis MR-1. Hence, the function and transcriptional regulation of two ferrochelatase genes, hemH1 and hemH2, are investigated in S. oneidensis MR-1. RESULT: In the present study, deletion of either hemH1 or hemH2 in S. oneidensis MR-1 did not lead to overproduction of extracellular protoporphyrin IX (PPIX) as previously described in the hemH1 mutants of S. loihica PV-4. Moreover, supplement of exogenous hemins made it possible to generate the hemH1 and hemH2 double mutant in MR-1, but not in PV-4. Under aerobic condition, exogenous hemins were required for the growth of MR-1ΔhemH1ΔhemH2, which also overproduced extracellular PPIX. These results suggest that heme is essential for aerobic growth of Shewanella species and MR-1 could also uptake hemin for biosynthesis of essential cytochrome(s) and respiration. Besides, the exogenous hemin mediated CymA cytochrome maturation and the cellular KatB catalase activity. Both hemH paralogues were transcribed in wild-type MR-1, and the hemH2 transcription was remarkably up-regulated in MR-1ΔhemH1 mutant to compensate for the loss of hemH1. The periplasmic glutathione peroxidase gene pgpD, located in the same operon with hemH2, and a large gene cluster coding for iron, heme (hemin) uptake systems are absent in the PV-4 genome. CONCLUSION: Our results indicate that the genetic divergence in gene content and gene expression between these Shewanella species, accounting for the phenotypic difference described here, might be due to their speciation and adaptation to the specific habitats (iron-rich deep-sea vent versus iron-poor freshwater) in which they evolved and the generated mutants could potentially be utilized for commercial production of PPIX.

Inhibition of Rat CYP1A2 and CYP2C11 by Honokiol, a Component of Traditional Chinese Medicine.

BACKGROUND AND OBJECTIVES: Honokiol, a major constituent isolated from Magnolia officinalis, is regarded as a phytochemical marker and bioactive substance present in many traditional Chinese medicines. However, the effect of honokiol on cytochrome P450 (CYP) has not been thoroughly investigated. The aim of this study was to investigate the effect of honokiol on CYP1A2 and CYP2C11 in vitro and in vivo. METHODS: The effect of honokiol on CYP1A2 and CYP2C11 was investigated with rat liver microsomes (RLMs) by measuring phenacetin and tolbutamide metabolism (probe drugs for CYP1A2 and CYP2C11, respectively), and then explored in vivo by measuring the effect of honokiol (2.5 and 5 mg/kg, intravenous injection) on the pharmacokinetics of theophylline and tolbutamide (probe drugs for CYP1A2 and CYP2C11, respectively) in rats in vivo. RESULTS: Honokiol inhibited the formation of acetaminophen from phenacetin and 4-hydroxytolbutamide from tolbutamide in RLMs, with inhibition constant (Ki) values of 1.6 µM and 16.5 µM, respectively. In vivo, honokiol (2.5 or 5.0 mg/kg) increased the half-life (t1/2) of theophylline by 40.9% and 119.9%, decreased the clearance (CL) by 23.8% and 42.9%, and increased the area under the curve (AUC) by 41.3% and 83.4%, respectively. Similarly, the t1/2 of tolbutamide increased by 25.5% and 33.8%, the CL decreased by 14.3% and 19.1%, and the AUC increased by 19.2% and 25.7%, respectively. CONCLUSION: The inhibition of CYP1A2 by honokiol is greater than the inhibition of CYP2C11. The changes in the pharmacokinetics of theophylline and tolbutamide in rats treated with honokiol are due to the inhibition of CYP1A2 and CYP2C11 activity in a dose-dependent manner.

Specific effects of prenatal DEHP exposure on neuroendocrine gene expression in the developing hypothalamus of male rats.

Endocrine disrupting chemicals may disrupt developing neuroendocrine systems, especially when the exposure occurs during a critical period. This study aimed to investigate whether prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a major component of plasticizers used worldwide, disrupted the development of a network of genes important for neuroendocrine function in male rats. Pregnant rats were treated with corn oil (vehicle control), 2, 10 or 50 mg/kg DEHP by gavage from gestational day 14 to 19. The neuroendocrine gene expressions were quantified using a 48-gene Taqman qPCR array in the whole hypothalamus of neonatal rats (postnatal day 1) and in the anteroventral periventricular nucleus (AVPV), medial preoptic nucleus (MPN) and arcuate nucleus (ARC) of adult rats (postnatal day 70). Immunofluorescent signals of ERα and CYP19 were detected using the confocal microscopy in adult AVPV, MPN and ARC. The results showed that prenatal DEHP exposure perturbed somatic and reproductive development of offspring. Eleven genes were down-regulated in neonatal hypothalamus and showed non-monotonic dose-response relationships, that the 10 mg/kg DEHP dosage was associated with the greatest number of gene expression changes. Different from this, 14 genes were altered in adult AVPV, MPN and ARC and most of alterations were found in the 50 mg/kg DEHP group. Also, 50 mg/kg DEHP reduced ERα expression in the ARC, but no alterations were observed in CYP19 expression. These results indicated that prenatal DEHP exposure may perturb hypothalamic gene programming and the influences are permanent. The effects showed dependence on developmental stages and nuclei region.

Effect of Tongxinluo on pulmonary hypertension and pulmonary vascular remodeling in rats exposed to a low pressure hypoxic environment.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongxinluo (TXL), which is a Chinese medicine rooted from traditional used herbs, has been used in clinic to treat cardiovascular and cerebrovascular diseases. However, it remains unknown whether TXL alleviates low pressure hypoxic pulmonary hypertension. AIM OF THE STUDY: Here, we aimed to observe the influence of TXL on pulmonary hypertension in a rat model that exposed to high altitude environment characterized by low pressure hypoxia. MATERIALS AND METHODS: A total of 32 male Sprague-Dawley rats were divided into four groups: control group (normal pressure and normoxia), pulmonary hypertension group (PAH, the parameter is equal to that in altitude 5000m), TXL group (rats living in environment equal to that at altitude of 5000m received TXL treatment), vardenafil group (VDNF, rats living in environment equal to that altitude of 5000m received vardenafil treatment). The high altitude environment was created in chamber by adjusting the inner pressure and oxygen content concomitantly. Before entering the chamber, the TXL group was given TXL (1.2gkg-1d-1) for 28 days, and the VDNF group was given VDNF (0.1gkg-1d-1) for 28 days. After 28 days, the mean pulmonary artery pressure (mPAP) and right ventricular pressure was measured using right heart catheterization. The weight of the right ventricle (RV), left ventricle (LV) and interventricular septum (IVS) was measured, and the right ventricular mass index was calculated. Lung tissue was subjected to hematoxylin and elastic fiber staining, and the medial wall thickness (MT), medial wall cross-sectional area (MA), MT%, and MA% were measured. Proliferative activity within the pulmonary arteries was quantified by Ki67staining. RESULTS: After 28 days, as compared with that in normal control group, animals living in the chamber (PAH group) showed a significant increase in mPAP( 47.5mmHg versus 18mmHg), RV/LV+IVS (0.45 versus 0.21) and MA% (78% versus 44%), respectively. Administration of TXL resulted in a significant decrease of 20mmHg in mPAP, returning of RV/LV+IVS to 0.27, and a 40% reduction in MT% compared with that in PAH group. In the VDNF group, RV/LV+IVS and MT% was 0.268 and 38.77, significantly lower than that in PAH group. While, mPAP increased by 12.5mmHg with treatment by VDNF. In contrast to the PAH group, alpha- Smooth Muscle Actin (α-SMA reduced by 19% in the TXL group (p=0.005) and 16% in the VDNF group (p=0.01). Ki67 expression in the VDNF group was significantly lower than the PAH group (P<0.01). Ki67 expression in the TXL group was significantly lower than the PAH group (P<0.01). Compared with the VDNF group, the indexes above reduced in the TXL group. Our results indicate that TXL significantly reduces pulmonary artery pressure, right ventricular hypertrophy, pulmonary small artery wall thickness, and luminal stenosis. In addition, smooth muscle proliferation markedly decreased and muscular artery decreased. However, TXL was unable to restore parameters to control levels. CONCLUSIONS: The automatic-adjusted low pressure hypoxic chamber was capable of establishing a pulmonary hypertension rat model at an altitude of 5000m. Compared with VDNF, TXL decreased mPAP and right ventricular hypertrophy index (RVHI) in the pulmonary hypertension rat model, and prevented vascular remodeling by reducing small pulmonary artery thickening, smooth muscle thickening and proliferation. Thus, TXL may be a potential treatment for pulmonary hypertension.

Homology modeling and virtual screening for inhibitors of lipid kinase PI(4)K from Plasmodium.

Malaria parasite strains have emerged to tolerate the therapeutic effects of the prophylactics and drugs presently available. Recent studies have shown that KAI715 and its analogs inhibit malaria parasites growth by binding to lipid kinase PI(4)K (phosphatidylinositol-4-OH kinase) of the parasites. Therefore, targeting PI(4)K may open up new avenues of target-based drug discovery to identify novel anti-malaria drugs. In this investigation, we describe the discovery of novel potent PfPI(4)K (PI(4)K from P. falciparum) inhibitors by employing a proposed hybrid virtual screening (VS) method, including pharmacophore model, drug-likeness prediction and molecular docking approach. 3D structure of PfPI(4)K has been established by homology modeling. Pharmacophore model HypoA of PfPI(4)K inhibitors has been developed based on the ligand complexed with its corresponding receptor. 174 compounds with good ADMET properties were carefully selected by a hybrid virtual screening method. Finally, the 174 hits were further validated by using a new pharmacophore model HypoB built based on the docking pose of BQR685, and 95 compounds passed the last filter. These compounds would be further evaluated by biological activity assays. The molecular interactions of the top two potential inhibitors with the active site residues are discussed in detail. These identified hits can be further used for designing the more potent inhibitors against PfPI(4)K by scaffold hopping, and deserve consideration for further structure-activity relationship (SAR) studies.

Integrative functional transcriptomic analyses implicate specific molecular pathways in pulmonary toxicity from exposure to aluminum oxide nanoparticles.

Gene expression profiling has developed rapidly in recent years and it can predict and define mechanisms underlying chemical toxicity. Here, RNA microarray and computational technology were used to show that aluminum oxide nanoparticles (Al2O3 NPs) were capable of triggering up-regulation of genes related to the cell cycle and cell death in a human A549 lung adenocarcinoma cell line. Gene expression levels were validated in Al2O3 NPs exposed A549 cells and mice lung tissues, most of which showed consistent trends in regulation. Gene-transcription factor network analysis coupled with cell- and animal-based assays demonstrated that the genes encoding PTPN6, RTN4, BAX and IER play a role in the biological responses induced by the nanoparticle exposure, which caused cell death and cell cycle arrest in the G2/S phase. Further, down-regulated PTPN6 expression demonstrated a core role in the network, thus expression level of PTPN6 was rescued by plasmid transfection, which showed ameliorative effects of A549 cells against cell death and cell cycle arrest. These results demonstrate the feasibility of using gene expression profiling to predict cellular responses induced by nanomaterials, which could be used to develop a comprehensive knowledge of nanotoxicity.

Metabolic changes at the early stage of sepsis induced by cecal ligation and puncture in rats and the interventional effects of Huang-Lian-Jie-Du-Tang.

Sepsis is a disease with high mortality that requires rapid diagnosis and treatment. This study used a metabolomic approach to profile the metabolic changes at the early stage of sepsis induced by cecal ligation and puncture (CLP) in rats and investigated the interventional effects of Huang-Lian-Jie-Du-Tang (HLJDT). Male SD rats were intragastrically administered 270mg/kg HLJDT 2h prior to CLP, serum extracts were profiled by liquid chromatography/quadrupole time-of-flight mass spectrometer (LC-Q-TOF-MS) and multivariate analytical (MVA) methods were employed to evaluate the metabolic changes of extracts. A Partial Least-Squares Discriminant Analysis (PLS-DA) score plot indicated that septic rats undergo significant metabolic changes 2h after CLP, and HLJDT administration could reverse the metabolic changes induced by CLP. Sixteen biomarkers involved in amino acid metabolism, unsaturated fatty acid metabolism, purine metabolism, and lipid metabolism were identified after Orthogonal Partial Least-Squares Analysis (OPLS). Among the 16 metabolites, 10 were regulated by HLJDT. This study established the foundation for further research of the early diagnosis biomarkers and therapeutic evaluation biomarkers discovery of sepsis.

Feeding reduces waterborne Cu bioaccumulation in a marine rabbitfish Siganus oramin.

Waterborne metal uptake has been extensively studied and dietary metal assimilation is increasingly recognized in fish, whilst the interaction between the two uptake routes is largely overlooked. This study compared the waterborne Cu bioaccumulation ((65)Cu as tracer) in a juvenile rabbitfish at different feeding regimes (starvation (SG), feeding normal diet (NDG) or diet supplemented with extra Cu (DCG)) to test the hypothesis that feeding can influence waterborne metal uptake in marine fish. NDG and DCG diet was fed as a single meal and then all fish were exposed to waterborne (65)Cu for 48 h, during which the time course sampling was conducted to determine (65)Cu bioaccumulation, chyme flow and dietary Cu assimilation. The results revealed that SG fish accumulated the highest (65)Cu, followed by NDG (61% of SG), whilst DCG fish accumulated the lowest (65)Cu (34% of SG). These results suggested a protective effect of feeding against waterborne Cu bioaccumulation. This effect was most notable between 10 min and 16 h when there was chyme in gastrointestinal tract (GT). Dietary Cu assimilation mainly occurred before 16 h after feeding. Waterborne (65)Cu influx rate in the GT was positively correlated with (65)Cu contents of chyme in NDG, whereas it was largely negatively correlated with (65)Cu contents of chyme in DCG. The waterborne Cu uptake in the GT was mainly influenced by the chyme flow and dietary Cu assimilation. Overall, our findings suggested that feeding has an important effect on waterborne metal uptake and that both the feeding status of the fish and the relative metal exposure through water and food should be considered in prediction of the metal bioaccumulation and biomonitoring programs.

Astragaloside IV Attenuates Glutamate-Induced Neurotoxicity in PC12 Cells through Raf-MEK-ERK Pathway.

Astragaloside IV (AGS-IV) is a main active ingredient of Astragalus membranaceus Bunge, a medicinal herb prescribed as an immunostimulant, hepatoprotective, antiperspirant, a diuretic or a tonic as documented in Chinese Materia Medica. In the present study, we employed a high-throughput comparative proteomic approach based on 2D-nano-LC-MS/MS to investigate the possible mechanism of action involved in the neuroprotective effect of AGS-IV against glutamate-induced neurotoxicity in PC12 cells. Differential proteins were identified, among which 13 proteins survived the stringent filter criteria and were further included for functional discussion. Two proteins (vimentin and Gap43) were randomly selected, and their expression levels were further confirmed by western blots analysis. The results matched well with those of proteomics. Furthermore, network analysis of protein-protein interactions (PPI) and pathways enrichment with AGS-IV associated proteins were carried out to illustrate its underlying molecular mechanism. Proteins associated with signal transduction, immune system, signaling molecules and interaction, and energy metabolism play important roles in neuroprotective effect of AGS-IV and Raf-MEK-ERK pathway was involved in the neuroprotective effect of AGS-IV against glutamate-induced neurotoxicity in PC12 cells. This study demonstrates that comparative proteomics based on shotgun approach is a valuable tool for molecular mechanism studies, since it allows the simultaneously evaluate the global proteins alterations.

Development and evaluation of the Nurotron 26-electrode cochlear implant system.

Although the cochlear implant has been widely acknowledged as the most successful neural prosthesis, only a fraction of hearing-impaired people who can potentially benefit from a cochlear implant have actually received one due to its limited awareness, accessibility, and affordability. To help overcome these limitations, a 26-electrode cochlear implant has been developed to receive China's Food and Drug Administration (CFDA) approval in 2011 and Conformité Européenne (CE) Marking in 2012. The present article describes design philosophy, system specification, and technical verification of the Nurotron device, which includes advanced digital signal processing and 4 current sources with multiple amplitude resolutions that not only are compatible with perceptual capability but also allow interleaved or simultaneous stimulation. The article also presents 3-year longitudinal evaluation data from 60 human subjects who have received the Nurotron device. The objective measures show that electrode impedance decreased within the first month of device use, but was stable until a slight increase at the end of two years. The subjective loudness measures show that electric stimulation threshold was stable while the maximal comfort level increased over the 3 years. Mandarin sentence recognition increased from the pre-surgical 0%-correct score to a plateau of about 80% correct with 6-month use of the device. Both indirect and direct comparisons indicate indistinguishable performance differences between the Nurotron system and other commercially available devices. The present 26-electrode cochlear implant has already helped to lower the price of cochlear implantation in China and will likely contribute to increased cochlear implant access and success in the rest of the world. This article is part of a Special Issue entitled .