The Association Between Health-Related Behaviors and Traditional Chinese Medicine Syndromes in Type 2 Diabetes Mellitus Patients.

Background: Traditional Chinese medicine (TCM) has certain advantages in treating diabetes via TCM syndromes differentiation, and health-related behaviors can regulate TCM syndromes. This study aimed to identify the clusters of TCM syndromes in type 2 diabetes mellitus (T2DM) patients and to explore the association between health-related behaviors and those TCM syndromes clusters. Methods: This was a cross-sectional study of 1761 T2DM patients from the Ningxia Province. The TCM syndromes (11 TCM syndromes in total) scale was used to collect the syndrome information. Health-related behaviors, including smoking, alcohol use, tea drinking, the intensity of physical activity, sleep quality, and sleep duration, were collected via a face-to-face interview questionnaire. Latent profile analysis was employed to identify clusters of 11 TCM syndromes. Multinomial logistic regression was employed to examine the relationships between health-related behaviors and clusters of TCM syndromes. Results: TCM syndromes in T2DM patients were classified into three profiles using latent profile analysis: light, moderate, and heavy. Participants with poor health-related behaviors were more likely to have heavy 1.49 (95% CI: 1.12, 1.99) or moderate 1.75 (95% CI: 1.10, 2.79) profiles than those with good health-related habits. Smokers, tea drinkers, and those with poor sleep quality were more likely to have a moderate profile and heavy profile than a light profile. Compared with heavy physical activity, moderate activity 0.24 (95% CI: 0.07, 0.88) was negatively associated with a heavy profile. Conclusion: Results showed that most participants had light or moderate levels of TCM syndromes, and those with poor health-related behaviors were more likely to have heavy or moderate profiles. In the context of precision medicine, these results have important implications for understanding the prevention and treatment of diabetes via changing lifestyles and behaviors to regulate TCM syndromes.

Supplemental enzymes and probiotics on the gut health of broilers fed with a newly harvested corn diet.

Gut health is important for digestion and absorption of nutrient for animals. The purpose of this study was to investigate the therapeutic effect of enzymes and probiotics alone or in combination on the gut health of broilers fed with newly harvested corn diets. A total of 624 Arbor Acres Plus male broiler chickens were randomly divided into 8 treatment groups (PC: normal corn diet, NC: newly harvested corn diet, DE: NC + glucoamylase, PT: NC + protease, XL: NC + xylanase, BCC: NC + Pediococcus acidilactici BCC-1, DE + PT: NC + glucoamylase + protease, XL+BCC: NC + xylanase + Pediococcus acidilactici BCC-1). Each group was divided into 6 replicates, with 13 birds each. On d 21, intestinal morphological, intestinal tight junction and aquaporins gene expression, cecal short-chain fatty acid concentrations, and microflora were measured. Compared with the newly harvested corn diets (NC), supplemental glucoamylase (DE) significantly increased the relative abundance of Lachnospiraceae (P < 0.05) and decreased the relative abundance of Moraxellaceae (P < 0.05). Supplemental protease (PT) significantly increased the relative abundance of Barnesiella (P < 0.05), but the relative abundance of Campylobacter decreased by 44.4%. Supplemental xylanase (XL) significantly increased the jejunal mRNA expressions of MUC2, Claudin-1, and Occludin (P < 0.01), as well as the cecal digesta contents of acetic acid, butyric acid, and valeric acid (P < 0.01). Supplemental DE combined with PT increased the ileal mRNA expressions of aquaporins (AQP) 2, AQP5, and AQP7 (P < 0.01). Supplemental BCC significantly increased the jejunal villus height and crypt depth (P < 0.01), the jejunal mRNA expressions of MUC2, Claudin-1 and Occludin (P < 0.01), and the relative abundance of Bacteroides (P < 0.05). Supplemental xylanase in combination with BCC significantly increased jejunal villus height and crypt depth (P < 0.01), the ileal mRNA expressions of AQP2, AQP5 and AQP7 (P < 0.01), and the cecal digesta contents of acetic acid, butyric acid, and valeric acid (P < 0.01). This suggests that inclusions of supplemental protease (12,000 U/kg), glucoamylase (60,000 U/kg), or Pediococcus acidilactici BCC-1 (109 cfu/kg) individually or in combination with xylanase (4,800 U/kg) in the newly harvested corn diets can alleviate diarrhea in broilers, and be beneficial for the gut health.

Association study of selenium-related gene polymorphisms with geriatric depression in China.

Depression is a common mental health problem in older adults, but its cause remains unclear. Selenium is an essential micronutrient and a powerful antioxidant in the brain and nervous system. Several recent studies have reported a relationship between selenium levels and depression. This study aimed to investigate the relationship between 4 genes co-associated with selenium and geriatric depression. 1486 participants were included in this study from 5 communities in Ningxia Hui Autonomous Region during 2013 to 2016 in a health examination program for urban and rural residents. Polymorphisms of 4 selenium-related genes were analyzed in 1266 healthy volunteers and 220 patients with depression. The genotyping of rs2830072, rs2030324, rs6265, rs11136000, rs7982, rs10510412, rs1801282, rs1151999, rs17793951, rs709149, rs709154, and rs4135263 were performed by Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS) technology. The analysis of selenium-related genes showed that there were significant differences between depression and controls for allele and genotype frequencies of peroxisome proliferator activated receptor gamma (PPARG) rs10510412, rs709149, and rs709154 (all P < .05). In this study, when adjusting for age, sex, marital status, education, and alcohol consumption, results showed that rs709149 and rs709154 were still significantly correlated with geriatric depression in the codominant, dominant, overdominant, and log-additive models. Logistic regression analysis showed that rs709149 AG or GG gene carriers were 1.630 and 1.746 times more susceptible to depression than AA gene carriers (95% CI = 1.042-2.549; 1.207-2.526). The results of this study suggest that the rs709149 polymorphism of the selenium-related gene PPARG is a genetic risk factor for depression in older adults.

Atomically precise Au nanocluster-embedded carrageenan for single near-infrared light-triggered photothermal and photodynamic antibacterial therapy.

In this study, we report atomically precise gold nanoclusters-embedded natural polysaccharide carrageenan as a novel hydrogel platform for single near-infrared light-triggered photothermal (PTT) and photodynamic (PDT) antibacterial therapy. Briefly, atomically precise captopril-capped Au nanoclusters (Au25Capt18) prepared by an alkaline NaBH4 reduction method and then embedded them into the biosafe carrageenan to achieve superior PTT and PDT dual-mode antibacterial effect. In this platform, the embedded Au25Capt18, as simple-component phototherapeutic agents, exhibit superior thermal effects and singlet oxygen generation under a single near-infrared (NIR, 808 nm) light irradiation, which enables rapid elimination of bacteria. Carrageenan endows the hydrogel platform with superior gelation characteristics and wound microenvironmental regulation. The Au25Capt18-embedded hydrogels exhibited good water retention, hemostasis, and breathability, providing a favorable niche environment for promoting wound healing. In vitro experiments confirmed the excellent antibacterial activity of the Au25Capt18 hydrogels against Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli. The antibacterial effect and promoting wound healing function were further validated in a S. aureus-infected wound model. Biosafety evaluation showed that the Au25Capt18 hydrogel has excellent biocompatibility. This PTT/PDT dual-mode therapy offers an alternative strategy for battling bacterial infections without antibiotics. More importantly, this hydrogel is facile to prepare which is helpful for expanding applications.

Statin-Induced Geranylgeranyl Pyrophosphate Depletion Promotes PCSK9-Dependent Adipose Insulin Resistance.

Statin treatment is accepted to prevent adverse cardiovascular events. However, statin therapy has been reported to be dose-dependently associated with increased risk for new-onset type 2 diabetes mellitus (T2DM). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is expressed in adipose tissue and is positively correlated with lipid metabolism. It is, however, unknown if PCSK9 participates in adipocyte insulin resistance occurring as a result of statin use. Our goal was to use an in vitro adipose tissue explant approach to support the hypothesis that PCSK9 regulates statin-induced new-onset T2DM. Studies were performed using Pcsk-/- and C57Bl/6J control mice. Pcsk9-/- and control mice were fed a high-fat diet to affect a state of chronically altered lipid metabolism and increased PCSK9. Epididymal fat was excised and incubated with atorvastatin (1 µmol/L) in the absence and presence of insulin or geranylgeranyl pyrophosphate (GGPP). PCSK9 mRNA was evaluated using quantitative rtPCR. We further examined the effects of atorvastatin on insulin-mediated AKT signaling in adipose tissue explants by immunoblotting. Atorvastatin was found to upregulate PCSK9 gene expression in adipose tissue. The metabolic intermediate GGPP is required to downregulate PCSK9 expression. PCSK9 deficiency protects against statin-induced impairments in insulin signaling. Moreover, supplementation with GGPP reversed atorvastatin-induced suppression of insulin signaling. Furthermore, the basal and atorvastatin-stimulated release of free fatty acids was observed in adipose tissue from wild-type mice but not PCSK9 deficient mice. Collectively, we describe a novel mechanism for PCSK9 expression in adipose tissue that could mediate statin-impaired adipose insulin resistance.

Component analysis and anti-pulmonary fibrosis effects of Rosa sterilis juice.

Rosa sterilis is a new variety of Rosa roxburghii Tratt, and is rich in bioactive substances, but its role in pulmonary fibrosis has not been elucidated. The purpose of this study was to investigate the potential components of Rosa sterili juice (RSJ) and its anti-pulmonary fibrosis effects. We employed HPLC-Q-Exactive Orbitrap-MS, HPLC, and ICP-MS to analyze the composition of RSJ, and carried out free radical scavenging assays to determine its antioxidant activity. Then, the anti-pulmonary fibrosis effect of RSJ was evaluated using the bleomycin-induced mice model and the TGF-ß1-induced cell model. A total of 49 components were identified in RSJ, and the vitamin C content was 11.29 ± 0.05 mg mL-1. Catechin was the most abundant phenol, and potassium was the highest mineral element in RSJ. Attractively, we found that RSJ alleviated bleomycin-induced inflammation infiltration and tissue injury, and inhibited TGF-ß1-induced epithelial-mesenchymal transition and fibroblast differentiation through the Smad2/3 signaling pathway. In conclusion, we discovered a new health-protective activity of Rosa sterilis, and the high levels of polyphenols, flavonoids, and vitamin C may be the basic anti-fibrosis substances.

Statin-Induced Geranylgeranyl Pyrophosphate Depletion Promotes Ferroptosis-Related Senescence in Adipose Tissue.

Statin treatment is accepted to prevent adverse cardiovascular events. However, atorvastatin, an HMG-CoA reductase inhibitor, has been reported to exhibit distinct effects on senescent phenotypes. Whether atorvastatin can induce adipose tissue senescence and the mechanisms involved are unknown. The effects of atorvastatin-induced senescence were examined in mouse adipose tissue explants. Here, we showed that statin initiated higher levels of mRNA related to cellular senescence markers and senescence-associated secretory phenotype (SASP), as well as increased accumulation of the senescence-associated ß-galactosidase (SA-ß-gal) stain in adipose tissues. Furthermore, we found that the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and Fe2+ were elevated in adipose tissues treated with atorvastatin, accompanied by a decrease in the expression of glutathione (GSH), and glutathione peroxidase 4 (GPX4), indicating an iron-dependent ferroptosis. Atorvastatin-induced was prevented by a selective ferroptosis inhibitor (Fer-1). Moreover, supplementation with geranylgeranyl pyrophosphate (GGPP), a metabolic intermediate, reversed atorvastatin-induced senescence, SASP, and lipid peroxidation in adipose tissue explants. Atorvastatin depleted GGPP production, but not Fer-1. Atorvastatin was able to induce ferroptosis in adipose tissue, which was due to increased ROS and an increase in cellular senescence. Moreover, this effect could be reversed by the supplement of GGPP. Taken together, our results suggest that the induction of ferroptosis contributed to statin-induced cell senescence in adipose tissue.

Nicotinamide Mononucleotide Ameliorates Silica-Induced Lung Injury through the Nrf2-Regulated Glutathione Metabolism Pathway in Mice.

Nicotinamide mononucleotide (NMN) is a natural antioxidant approved as a nutritional supplement and food ingredient, but its protective role in silicosis characterized by oxidative damage remains unknown. In this study, we generated a silicosis model by intratracheal instillation of silica, and then performed histopathological, biochemical, and transcriptomic analysis to evaluate the role of NMN in silicosis. We found that NMN mitigated lung damage at 7 and 28 days, manifested as a decreasing coefficient of lung weight and histological changes, and alleviated oxidative damage by reducing levels of reactive oxygen species and increasing glutathione. Meanwhile, NMN treatment also reduced the recruitment of inflammatory cells and inflammatory infiltration in lung tissue. Transcriptomic analysis showed that NMN treatment mainly regulated immune response and glutathione metabolism pathways. Additionally, NMN upregulated the expression of antioxidant genes Gstm1, Gstm2, and Mgst1 by promoting the expression and nuclear translocation of nuclear factor-erythroid 2 related factor 2 (Nrf2). Gene interaction analysis showed that Nrf2 interacted with Gstm1 and Mgst1 through Gtsm2. Promisingly, oxidative damage mediated by these genes occurred mainly in fibroblasts. In summary, NMN alleviates silica-induced oxidative stress and lung injury by regulating the endogenous glutathione metabolism pathways. This study reveals that NMN supplementation might be a promising strategy for mitigating oxidative stress and inflammation in silicosis.

Flavonoid-rich extracts from okra flowers exert antitumor activity in colorectal cancer through induction of mitochondrial dysfunction-associated apoptosis, senescence and autophagy.

Okra flowers contain a higher content of total flavonoids than most other flowers; however little research has been conducted on their potential benefits, including antitumor activity. In this study, we extracted and purified flavonoids from okra flower (AFE), and aimed to evaluate the effect of AFE and its underlying mechanism on colorectal cancer (CRC) cell growth in vitro and in vivo. Here, we identify that AFE is a safe, natural antioxidant and exerts significant antitumor efficacy on the inhibition of CRC cell proliferation and metastasis as well as tumour growth in vivo. We further reveal that AFE inhibits CRC cell proliferation by inducing mitochondrial dysfunction, which results from the activation of p53 and induction of apoptosis and senescence, and inhibits autophagic degradation. Furthermore, AFE inhibited migration and invasion of CRC cells by regulating the balance of MMP2/TIMP2 and MMP9 expression levels. Of note, administration of AFE as a preventive agent achieves a more effective antitumor effect than the therapeutic agent in a xenograft mouse model. Our results reveal, for the first time, that AFE is a safe, natural antioxidant with significant antitumor efficacy, which has great potential in the application for CRC prevention and treatment.

Phosphodiesterase 2 inhibitor Hcyb1 reverses corticosterone-induced neurotoxicity and depression-like behavior.

RATIONALE: Currently available PDE2 inhibitors have poor brain penetration that limits their therapeutic utility in the treatment of depression. Hcyb1 is a novel selective PDE2 inhibitor that was introduced more lipophilic groups with polar functionality to the scaffold pyrazolopyrimidinone to improve the blood-brain barrier (BBB) penetration. Our previous study suggested that Hcyb1 increased the neuronal cell viability and exhibited antidepressant-like effects, which were parallel to the currently available PDE2 inhibitor Bay 60-7550. OBJECTIVES: The present study investigated whether Hcyb1 protected HT-22 cells against corticosterone-induced neurotoxicity and produced antidepressant-like effects in behavioral tests in stressed mice. METHODS: The neuroprotective effects of Hcyb1 against corticosterone-induced cell lesion were examined by cell viability (MTS) assay. The enzyme-linked immunosorbent assay (ELISA) and immunoblot analysis were used to determine the levels of cAMP or cGMP and expression of pCREB or BDNF, respectively, in the corticosterone-treated HT-22 cells. The antidepressant-like effects of Hcyb1 were determined in the tail suspension and novelty suppressed feeding tests in stressed mice. RESULTS: In the cell-based assay, Hcyb1 significantly increased cell viability of HT-22 cells against corticosterone-induced neurotoxicity in a time- and dose-dependent manner. Hcyb1 also rescued corticosterone-induced decreases in both cGMP and cAMP levels, pCREB/CREB and BDNF expression. These protective effects of Hcyb1 were prevented by pretreatment with either the PKA inhibitor H89 or the PKG inhibitor KT5823. Moreover, Hcyb1 reversed acute stress-induced increases in immobility time and the latency to feed in the tail suspension and novelty suppressed feeding tests, respectively, which were prevented by pretreatment with H89 or KT5823. CONCLUSION: These findings provide evidence that the neuroprotective effects of Hcyb1 are mediated by PDE2-dependent cAMP/cGMP signaling.

Cryptotanshinone reverses the epithelial-mesenchymal transformation process and attenuates bleomycin-induced pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fibrotic interstitial pneumonia that causes pulmonary tissue damage and functional impairment. To investigate the effects of cryptotanshinone on pulmonary fibrosis, the expression of NIH/3T3, HPF, and rat primary pulmonary fibroblasts was measured and found to be inhibited by CPT in a time- and concentration-dependent manner, and the upregulation of α-SMA expression in NIH/3T3 and HPF cells, which had been stimulated by TGFß-1, was decreased after CPT administration. We observed that CPT could reverse the increase in α-SMA expression and vimentin and the decrease in E-cad expression in A549 cells, which had been induced by 5 ng/mL TGFß-1, indicating that CPT has inhibitory effects in the EMT process. A BLM-induced pulmonary fibrosis model was established in C57BL/6 mice. The lung coefficient and hydroxyproline content increased significantly in the BLM-induced group and were decreased in the CPT-treated group. The expression levels of collagen-I and α-SMA and the phosphorylation level of Stat3 were significantly increased, and CPT treatment decreased these levels. Furthermore, the results from the flow cytometry analysis indicated that, in lung tissues, the frequencies of MDSCs, macrophages, DCs and T cells were considerably increased in the BLM-induced group, while CPT treatment reduced these immunocyte populations.

Effects of Lycium barbarum polysaccharides on immunological parameters, apoptosis, and growth performance of Nile tilapia (Oreochromis niloticus).

In this study, the effect of Lycium barbarum polysaccharides (LBP) on immunological parameters, apoptosis, and growth performance of Nile tilapia (Oreochromis niloticus) was investigated. Dietary supplementation with LBP significantly increased complement 3 (C3) activity and promoted interleukin IL-1ß gene expression in spleen tissue, significantly reduced apoptosis in spleen tissue, increased the specific growth rate (SGR), relative length gain (LG), and relative weight gain (WG) of Nile tilapia. However, dietary supplementation with LBP did not have a significant effect on serum alkaline phosphatase (AKP), malondialdehyde (MDA), and superoxide dismutase (SOD), blood constituents, apoptosis, or gene expression of IL-1ß in liver tissue. Overall, the results showed that dietary supplementation with LBP increased the nonspecific immunity of Nile tilapia and reduced the apoptosis rate to promote growth and development. Thus, LBP has potential for use as a new immunostimulant in aquaculture.

Tiotropium added to low- to medium-dose inhaled corticosteroids (ICS) versus low- to medium-dose ICS alone for adults with mild to moderate uncontrolled persistent asthma: A systematic review and meta-analysis.

OBJECTIVE: To assess the efficacy and safety profile of tiotropium when added to low- to medium-dose inhaled corticosteroid (ICS) regimen versus low- to medium-dose ICS alone for adults with mild to moderate uncontrolled persistent asthma. DATA SOURCES: The online databases Pubmed, Embase and the Cochrane Library were searched for relevant data published up to November 14, 2017; we also conducted a supplementary search using clinicaltrials.gov. STUDY SELECTIONS: Only randomized control trials were included in this review. RESULTS: Four studies met our inclusion criteria for this review. In our review, two crossover studies were rated as "high risk" in the domain of "other bias" because a washout was not performed between each intervention. Lung function was significantly improved in the patient group receiving low- to medium-dose ICS with tiotropium. Results were consistent between each of three subgroups (tiotropium dry powder inhaler 18 µg or Respimat Soft Mist inhaler 5 µg, Respimat Soft Mist inhaler 2.5 µg, and Respimat Soft Mist inhaler 1.25 µg). Although no significant difference in Asthma Control Questionnaire (ACQ) score was found between the two treatment groups, substantial heterogeneity was observed. The incidence of serious adverse events between the two treatment groups was not statistically significant. CONCLUSIONS: Tiotropium as a once daily add-on to low- to medium-dose ICS may be efficacious and well-tolerated treatment in adults with moderate uncontrolled asthma. However, as only a few studies were identified, more studies of better design and long-term trial duration are required in the future.

GZFLW Induces Apoptosis of Ectopic Endometrial Stromal Cells via Promoting VPS53 Protein Stability.

Endometriosis is still a major problem in obstetrics and gynecology. While GZFLW (Gui Zhi Fu Ling Wan) has been originally used for treating gynecological diseases, however, the molecular mechanism that GZFLW acts on endometriosis is not clear. To investigate the molecular mechanism that GZFLW plays role on endometriosis, iTRAQ (isobaric tags for relative and absolute quantification) proteomics and human endometrial stromal cells (Y14) obtained from a patient with endometriosis were used in in vitro study. Our results demonstrated that GZFLW decreased Y14 cells proliferation while increased cells apoptosis. The differential expression protein VPS53 (Vacuolar protein sorting 53 homolog) was predicted by iTRAQ coupled LC-MS/MS and further identified by western blot. Besides, GZFLW induced VPS53 protein level by promoting its stabilization. Our findings highlight a novel role for VPS53 in gynecology and provide a potent therapeutic strategy against endometriosis.

Polydatin Prevents Methylglyoxal-Induced Apoptosis through Reducing Oxidative Stress and Improving Mitochondrial Function in Human Umbilical Vein Endothelial Cells.

Methylglyoxal (MGO), an active metabolite of glucose, has been reported to induce vascular cell apoptosis in diabetic complication. Polydatin (PD), a small natural compound from Polygonum cuspidatum, has a number of biological functions, such as antioxidative, anti-inflammatory, and nephroprotective properties. However, the protective effects of PD on MGO-induced apoptosis in endothelial cells remain to be elucidated. In this study, human umbilical vein endothelial cells (HUVECs) were used to explore the effects of PD on MGO-induced cell apoptosis and the possible mechanism involved. HUVECs were pretreated with PD for 2 h, followed by stimulation with MGO. Then cell apoptosis, reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) impairment, mitochondrial morphology alterations, and Akt phosphorylation were assessed. The results demonstrated that PD significantly prevented MGO-induced HUVEC apoptosis. PD pretreatment also significantly inhibited MGO-induced ROS production, MMP impairment, mitochondrial morphology changes, and Akt dephosphorylation. These results and the experiments involving N-acetyl cysteine (antioxidant), Cyclosporin A (mitochondrial protector), and LY294002 (Akt inhibitor) suggest that PD prevents MGO-induced HUVEC apoptosis, at least in part, through inhibiting oxidative stress, maintaining mitochondrial function, and activating Akt pathway. All of these data indicate the potential application of PD for the treatment of diabetic vascular complication.

A randomized controlled trial of a mindfulness-based intervention program for people with schizophrenia: 6-month follow-up.

Mindfulness-based interventions have been increasingly evidenced to be effective in different mental illnesses but limited in schizophrenia. This single-blind, multisite randomized controlled trial tested the effects of a mindfulness-based psychoeducation group program (MPGP in addition to usual care) versus a conventional psychoeducation group program (CPGP) versus treatment-as-usual (TAU) alone, in schizophrenia spectrum disorders over a 6-month follow-up. In each of the two study sites (outpatient clinics), 69 outpatients with schizophrenia or its subtypes (N=138) were randomly allocated to one of the three study groups (n=46) after baseline measurements and underwent 6 months of intervention. Primary outcomes including patients' mental state and rehospitalization rate and other secondary outcomes were assessed at entry and at 1 week and 6 months. One hundred and thirty-one (95%) participants completed the interventions assigned and one to two post-tests. Multivariate analyses of variance (followed by univariate contrast tests) indicated that the MPGP participants reported greater reductions in their psychotic symptoms (P=0.003) and length/duration of rehospitalizations (P=0.005) at 6-month follow-up. Patients in the MPGP group also reported greater improvements in their insight into illness/treatment (P=0.0008) and level of functioning (P=0.002) than the CPGP and TAU alone at the 1-week and 6-month follow-up. Overall, the findings suggest that MPGP can be useful in improving the short- to medium-term clinical outcomes of outpatients with schizophrenia spectrum disorders, not only in terms of their mental state and risk of relapse but also their insight into illness/treatment and psychosocial functioning.

Hydroxysafflor Yellow A Promotes Angiogenesis via the Angiopoietin 1/ Tie-2 Signaling Pathway.

BACKGROUND: The flowers of Carthamus tinctorius L. are widely used in traditional Chinese medicine to treat cerebrovascular and cardiovascular diseases. Hydroxysafflor yellow A (HSYA), the main constituent of C. tinctorius L. flowers, is known for its multiple biological activities. The present study investigated the effects of HSYA on angiogenesis in vitro and in a mouse hindlimb ischemia model. METHODS: Using human umbilical vein endothelial cells (HUVEC) in vitro and a mouse hindlimb ischemia model in vivo, the angiogenic role of HSYA was evaluated. RESULTS: HSYA significantly increased the capillary-like tube formation and migration of HUVEC. HSYA not only induced a rise in the expression of angiopoietin 1 and Tie-2 but it also increased phosphorylation of Tie-2, Akt, and extracellular signal-regulated kinase 1/2. Furthermore, an anti-Tie-2 neutralizing antibody significantly inhibited HSYA-induced HUVEC tube formation and migration. In vivo, the recovery of perfusion of ischemic hindlimb tissue after femoral artery interruption was significantly increased in HSYA-treated mice compared to vehicle controls. Consistent with these results, the arteriole and capillary densities in ischemic gastrocnemius muscles were significantly increased in HSYA-treated mice. CONCLUSIONS: These results indicate the potential utility of HSYA for the treatment of ischemic diseases.

An In Vivo Pharmacological Screen Identifies Cholinergic Signaling as a Therapeutic Target in Glial-Based Nervous System Disease.

The role that glia play in neurological disease is poorly understood but increasingly acknowledged to be critical in a diverse group of disorders. Here we use a simple genetic model of Alexander disease, a progressive and severe human degenerative nervous system disease caused by a primary astroglial abnormality, to perform an in vivo screen of 1987 compounds, including many FDA-approved drugs and natural products. We identify four compounds capable of dose-dependent inhibition of nervous system toxicity. Focusing on one of these hits, glycopyrrolate, we confirm the role for muscarinic cholinergic signaling in pathogenesis using additional pharmacologic reagents and genetic approaches. We further demonstrate that muscarinic cholinergic signaling works through downstream Gαq to control oxidative stress and death of neurons and glia. Importantly, we document increased muscarinic cholinergic receptor expression in Alexander disease model mice and in postmortem brain tissue from Alexander disease patients, and that blocking muscarinic receptors in Alexander disease model mice reduces oxidative stress, emphasizing the translational significance of our findings. We have therefore identified glial muscarinic signaling as a potential therapeutic target in Alexander disease, and possibly in other gliopathic disorders as well. SIGNIFICANCE STATEMENT: Despite the urgent need for better treatments for neurological diseases, drug development for these devastating disorders has been challenging. The effectiveness of traditional large-scale in vitro screens may be limited by the lack of the appropriate molecular, cellular, and structural environment. Using a simple Drosophila model of Alexander disease, we performed a moderate throughput chemical screen of FDA-approved drugs and natural compounds, and found that reducing muscarinic cholinergic signaling ameliorated clinical symptoms and oxidative stress in Alexander disease model flies and mice. Our work demonstrates that small animal models are valuable screening tools for therapeutic compound identification in complex human diseases and that existing drugs can be a valuable resource for drug discovery given their known pharmacological and safety profiles.

Betaine supplementation is less effective than methionine restriction in correcting phenotypes of CBS deficient mice.

Cystathionine beta synthase (CBS) deficiency is a recessive inborn error of metabolism characterized by elevated serum total homocysteine (tHcy). Betaine supplementation, which can lower tHcy by stimulating homocysteine remethylation to methionine, is often given to CBS deficient patients in combination with other treatments such as methionine restriction and supplemental B-vitamins. However, the effectiveness of betaine supplementation by itself in the treatment of CBS deficiency has not been well explored. Here, we have examined the effect of a betaine supplemented diet on the Tg-I278T Cbs (-/-) mouse model of CBS deficiency and compared its effectiveness to our previously published data using a methionine restricted diet. Tg-I278T Cbs (-/-) mice on betaine, from the time of weaning until for 240 days of age, had a 40 % decrease in mean tHcy level and a 137 % increase in serum methionine levels. Betaine-treated Tg-I278T Cbs (-/-) mice also exhibited increased levels of betaine-dependent homocysteine methyl transferase (BHMT), increased levels of the lipogenic enzyme stearoyl-coenzyme A desaturase (SCD-1), and increased lipid droplet accumulation in the liver. Betaine supplementation largely reversed the hair loss phenotype in Tg-I278T Cbs (-/-) animals, but was far less effective than methionine restriction in reversing the weight-loss, fat-loss, and osteoporosis phenotypes. Surprisingly, betaine supplementation had several negative effects in control Tg-I278T Cbs (+/-) mice including decreased weight gain, lean mass, and bone mineral density. Our findings indicate that while betaine supplementation does have some beneficial effects, it is not as effective as methionine restriction for reversing the phenotypes associated with severe CBS deficiency in mice.

Triggered disassembly of hierarchically assembled onion-like micelles into the pristine core-shell micelles via a small change in pH.

The size and surface property of nanomaterial-based delivery systems administered intravenously play important roles in their cell uptake and in vivo distribution. Both of them should be capable of self-evolution in order to achieve efficient targeting performance. A facile strategy was proposed to manipulate both the size and surface property of polymeric micelles. It was found that the hierarchical assembly between trimethylated chitosan-g-poly(ε-caprolactone) (TMC-PCL) micelles and carboxyethyl chitosan-g-poly(ethylene glycol) (CEC-PEG) could produce onion-like micelles with enlarged size and PEGylated surface. The onion-like micelles could withstand the ionic strength of plasma and competitive exchange with BSA, and abruptly disassemble into the pristine TMC-PCL micelles via a small change in pH. By varying the degree of carboxyethylation, the disassembly pH could be modulated to the range of the tumoral microclimate pH. In contrast with TMC-PCL micelles, which displayed high cytotoxicity and endocytic ability towards C6 glioma cells, the onion-like micelles were cell-friendly and internalized by the cells at a very low level. Doxorubicin was used as a model chemotherapeutic agent and incorporated within TMC-PCL micelles. Dox release from both TMC-PCL micelles and the onion-like micelles was very slow under normal physiological conditions and displayed excellent pH sensitivity. Cell viability of Dox-loaded micelles was also investigated.