Chronic hepatitis C virus (HCV) infection ultimately leads to chronic hepatitis, hepatic cirrhosis and hepatocellular carcinoma (HCC). As the standard treatment is not completely efficacious, a safer ...and more effective agent against HCV infection needs to be developed. In this report, we demonstrated that 3‐hydroxy caruilignan C (3‐HCL‐C) isolated from Swietenia macrophylla stems exhibited high anti‐HCV activity at both protein and RNA levels at nontoxic concentrations, with an EC50 value of 10.5 ± 1.2 μm. Combinations of 3‐HCL‐C and interferon‐α (IFN‐α), an HCV NS5B polymerase inhibitor (2′‐C‐methylcytidine; NM‐107) or an HCV NS3/4A protease inhibitor (Telaprevir; VX‐950) increased the suppression of HCV RNA replication. The results suggested that 3‐HCL‐C may be a potential anti‐viral agent. We then demonstrated that 3‐HCL‐C interfered with HCV replication by inducing IFN‐stimulated response element transcription and IFN‐dependent anti‐viral gene expression.
Chronic hepatitis C virus (HCV) infection is associated with chronic inflammation of liver, which leads to the development of cirrhosis and hepatocellular carcinoma (HCC). Because of severe side ...effects and only a 50–70% cure rate in genotype 1 HCV‐infected patients upon current standard treatment with pegylated interferon‐α plus ribavirin, new therapeutic regimens are still needed. San‐Huang‐Xie‐Xin‐Tang (SHXT) is a transitional Chinese herbal formula, composed of Rhei rhizoma, Scutellaria radix and Coptidis rhizome, and possesses anti‐inflammatory effect. Here, we describe a (+)‐catechin‐containing fraction extracted from SHXT, referred as SHXT‐frC, exhibited effective inhibition of HCV replication, with selectivity index value (SI; CC50/EC50) of 84, and displayed synergistic anti‐HCV effects when combined with interferon‐α, HCV protease inhibitor telaprevir or polymerase inhibitor 2′‐C‐methylcytidine. The activation of factor‐κB (NF‐κB) and cyclooxygenase‐2 (COX‐2) signalling pathway has particular relevance to HCV‐associated HCC. SHXT‐frC treatment also caused a concentration‐dependent decrease in the induction of COX‐2 and NF‐κB expression caused by either HCV replication or HCV NS5A protein. Collectively, SHXT‐frC could be an adjuvant treatment for patients with HCV‐induced liver diseases.
•Aflatoxin B1-lysine albumin biomarkers were measured in rural South Asian women during pregnancy and across the first 1000 days of life.
Aflatoxin B1 is a potent carcinogen, occurring from mold ...growth that contaminates staple grains in hot, humid environments. In this investigation, aflatoxin B1-lysine albumin biomarkers were measured by mass spectrometry in rural South Asian women, during the first and third trimester of pregnancy, and their children at birth and at two years of age. These subjects participated in randomized community trials of antenatal micronutrient supplementation in Sarlahi District, southern Nepal and Gaibandha District in northwestern Bangladesh. Findings from the Nepal samples demonstrated exposure to aflatoxin, with 94% detectable samples ranging from 0.45 to 2939.30 pg aflatoxin B1-lysine/mg albumin during pregnancy. In the Bangladesh samples the range was 1.56 to 63.22 pg aflatoxin B1-lysine/mg albumin in the first trimester, 3.37 to 72.8 pg aflatoxin B1-lysine/mg albumin in the third trimester, 4.62 to 76.69 pg aflatoxin B1-lysine/mg albumin at birth and 3.88 to 81.44 pg aflatoxin B1-lysine/mg albumin at age two years. Aflatoxin B1-lysine adducts in cord blood samples demonstrated that the fetus had the capacity to convert aflatoxin into toxicologically active compounds and the detection in the same 2-year-old children illustrates exposure over the first 1000 days of life.
Subclinical micronutrient deficiencies remain a hidden aspect of malnutrition for which comprehensive data are lacking in school-aged children. We assessed the micronutrient status of Nepalese ...children, aged 6 to 8 y, born to mothers who participated in a community-based antenatal micronutrient supplementation trial from 1999 to 2001. Of 3305 participants, plasma indicators were assessed in a random sample of 1000 children. Results revealed deficiencies of vitamins A (retinol <0.70 μ mol/L, 8.5%), D (25-hydroxyvitamin D <50 nmol/L, 17.2%), E (α-tocopherol <9.3 μ mol/L, 17.9%), K (decarboxy prothombin >2 μ g/L, 20%), B-12 (cobalamin <150 pmol/L, 18.1%), B-6 pyridoxal-5′-phosphate (PLP) <20 nmol/L, 43.1%, and β-carotene (41.5% <0.09 μ mol/L), with little folate deficiency (6.2% <13.6 nmol/L). Deficiencies of iron ferritin <15 μ g/L, 10.7%; transferrin receptor (TfR) >8.3 mg/L, 40.1%; TfR:ferritin >500 μ g/μ g, 14.3%, iodine (thyroglobulin >40 μ g/L, 11.4%), and selenium (plasma selenium <0.89 μ mol/L, 59.0%) were observed, whereas copper deficiency was nearly absent (plasma copper <11.8 μ mol/L, 0.7%). Hemoglobin was not assessed. Among all children, 91.7% experienced at least 1 micronutrient deficiency, and 64.7% experienced multiple deficiencies. Inflammation (α-1 acid glycoprotein >1 g/L, C-reactive protein >5 mg/L, or both) was present in 31.6% of children, affecting the prevalence of deficiency as assessed by retinol, β-carotene, PLP, ferritin, TfR, selenium, copper, or having any or multiple deficiencies. For any nutrient, population deficiency prevalence estimates were altered by ≤5.4% by the presence of inflammation, suggesting that the majority of deficiencies exist regardless of inflammation. Multiple micronutrient deficiencies coexist in school-aged children in rural Nepal, meriting more comprehensive strategies for their assessment and prevention.
This study aimed to describe the timing and patterns of pubertal maturation of girls living in rural Bangladesh. Starting in September 2015, a total of 15,320 girls from a birth cohort, aged 9 to 15 ...years at initial encounter, were visited twice at about a one year interval, typically in their birth month. Participants were asked to self-report extent of pubertal maturation, including breast development, pubic hair growth and age at menarche, if applicable. Pubertal stage (abbreviated as B2 and B3-4 for breast development and PH2 and PH3-4 for pubic hair growth) was assigned. Data from both visits were pooled, yielding a total of 29,377 age-related observations per pubertal characteristic. Probit regression models were used to estimate distributions of age at which each stage of pubertal development was attained. Before age 8, <3% of the study population initiated pubertal maturation as indicated by onset of breast development (B2). The median (95% confidence interval) age of B2 and B3-4 was 11.02 (11.00-11.04) and 12.82 (12.80-12.83) years, respectively; and 12.93 (12.91-12.94) and 14.29 (14.27-14.31) years for the onset (PH2) and advanced stage (PH3-4) of pubic hair growth, respectively. Median age at menarche was 13.17 (13.15-13.19) years, with 2.15 years of timespan from B2 to menarche. Girls in rural Bangladesh progressed through puberty following a well-documented sequence of sexual maturation stages. The age at which each pubertal milestone took place was somewhat later, but the tempo from breast development to menarche was comparable to that observed elsewhere. Our findings present a current norm of pubertal maturation in a typical, rural adolescent population in South Asia, which could help inform future studies and interventions to preserve or improve early adolescent health and development.
Dysregulation of cell surface proteolysis has been strongly implicated in tumorigenicity and metastasis. In this study, we delineated the role of hepatocyte growth factor activator inhibitor-2 ...(HAI-2) in prostate cancer (PCa) cell migration, invasion, tumorigenicity and metastasis using a human PCa progression model (103E, N1, and N2 cells) and xenograft models. N1 and N2 cells were established through serial intraprostatic propagation of 103E human PCa cells and isolation of the metastatic cells from nearby lymph nodes. The invasion capability of these cells was revealed to gradually increase throughout the serial isolations (103E<N1<N2). In this series of cells, the expression of HAI-2 but not HAI-1 was significantly decreased throughout the progression and occurred in parallel with increased activation of matriptase. The expression level and activity of matriptase increased whereas the HAI-2 protein level decreased over the course of orthotopic tumor growth in mice, which was consistent with the immunohistochemical profiles of matriptase and HAI-2 in archival PCa specimens. Knockdown of matriptase reduced the PCa cell invasion induced by HAI-2 knockdown. HAI-2 overexpression or matriptase silencing in N2 cells downregulated matriptase activity and significantly decreased tumorigenicity and metastatic capability in orthotopically xenografted mice. These results suggest that during the progression of human PCa, matriptase activity is primarily controlled by HAI-2 expression. The imbalance between HAI-2 and matriptase expression led to matriptase activation, thereby increasing cell migration, invasion, tumorigenicity and metastasis.
Maternal vitamin A deficiency is a public health concern in the developing world. Its prevention may improve maternal and infant survival.
To assess efficacy of maternal vitamin A or beta carotene ...supplementation in reducing pregnancy-related and infant mortality.
Cluster randomized, double-masked, placebo-controlled trial among pregnant women 13 to 45 years of age and their live-born infants to 12 weeks (84 days) postpartum in rural northern Bangladesh between 2001 and 2007. Interventions Five hundred ninety-six community clusters (study sectors) were randomized for pregnant women to receive weekly, from the first trimester through 12 weeks postpartum, 7000 μg of retinol equivalents as retinyl palmitate, 42 mg of all-trans beta carotene, or placebo. Married women (n = 125,257) underwent 5-week surveillance for pregnancy, ascertained by a history of amenorrhea and confirmed by urine test. Blood samples were obtained from participants in 32 sectors (5%) for biochemical studies.
All-cause mortality of women related to pregnancy, stillbirth, and infant mortality to 12 weeks (84 days) following pregnancy outcome.
Groups were comparable across risk factors. For the mortality outcomes, neither of the supplement group outcomes was significantly different from the placebo group outcomes. The numbers of deaths and all-cause, pregnancy-related mortality rates (per 100,000 pregnancies) were 41 and 206 (95% confidence interval CI, 140-273) in the placebo group, 47 and 237 (95% CI, 166-309) in the vitamin A group, and 50 and 250 (95% CI, 177-323) in the beta carotene group. Relative risks for mortality in the vitamin A and beta carotene groups were 1.15 (95% CI, 0.75-1.76) and 1.21 (95% CI, 0.81-1.81), respectively. In the placebo, vitamin A, and beta carotene groups the rates of stillbirth and infant mortality were 47.9 (95% CI, 44.3-51.5), 45.6 (95% CI, 42.1-49.2), and 51.8 (95% CI, 48.0-55.6) per 1000 births and 68.1 (95% CI, 63.7-72.5), 65.0 (95% CI, 60.7-69.4), and 69.8 (95% CI, 65.4-72.3) per 1000 live births, respectively. Vitamin A compared with either placebo or beta carotene supplementation increased plasma retinol concentrations by end of study (1.46 95% CI, 1.42-1.50 μmol/L vs 1.13 95% CI, 1.09-1.17 μmol/L and 1.18 95% CI, 1.14-1.22 μmol/L, respectively; P < .001) and reduced, but did not eliminate, gestational night blindness (7.1% for vitamin A vs 9.2% for placebo and 8.9% for beta carotene P < .001 for both).
Use of weekly vitamin A or beta carotene in pregnant women in Bangladesh, compared with placebo, did not reduce all-cause maternal, fetal, or infant mortality.
clinicaltrials.gov Identifier: NCT00198822.
Maternal micronutrient deficiencies may adversely affect fetal and infant health, yet there is insufficient evidence of effects on these outcomes to guide antenatal micronutrient supplementation in ...South Asia.
To assess effects of antenatal multiple micronutrient vs iron-folic acid supplementation on 6-month infant mortality and adverse birth outcomes.
Cluster randomized, double-masked trial in Bangladesh, with pregnancy surveillance starting December 4, 2007, and recruitment on January 11, 2008. Six-month infant follow-up ended August 30, 2012. Surveillance included 127,282 women; 44,567 became pregnant and were included in the analysis and delivered 28,516 live-born infants. Median gestation at enrollment was 9 weeks (interquartile range, 7-12).
Women were provided supplements containing 15 micronutrients or iron-folic acid alone, taken daily from early pregnancy to 12 weeks postpartum.
The primary outcome was all-cause infant mortality through 6 months (180 days). Prespecified secondary outcomes in this analysis included stillbirth, preterm birth (<37 weeks), and low birth weight (<2500 g). To maintain overall significance of α = .05, a Bonferroni-corrected α = .01 was calculated to evaluate statistical significance of primary and 4 secondary risk outcomes (.05/5).
Among the 22,405 pregnancies in the multiple micronutrient group and the 22,162 pregnancies in the iron-folic acid group, there were 14,374 and 14,142 live-born infants, respectively, included in the analysis. At 6 months, multiple micronutrients did not significantly reduce infant mortality; there were 764 deaths (54.0 per 1000 live births) in the iron-folic acid group and 741 deaths (51.6 per 1000 live births) in the multiple micronutrient group (relative risk RR, 0.95; 95% CI, 0.86-1.06). Multiple micronutrient supplementation resulted in a non-statistically significant reduction in stillbirths (43.1 vs 48.2 per 1000 births; RR, 0.89; 95% CI, 0.81-0.99; P = .02) and significant reductions in preterm births (18.6 vs 21.8 per 100 live births; RR, 0.85; 95% CI, 0.80-0.91; P < .001) and low birth weight (40.2 vs 45.7 per 100 live births; RR, 0.88; 95% CI, 0.85-0.91; P < .001).
In Bangladesh, antenatal multiple micronutrient compared with iron-folic acid supplementation did not reduce all-cause infant mortality to age 6 months but resulted in a non-statistically significant reduction in stillbirths and significant reductions in preterm births and low birth weight.
clinicaltrials.gov Identifier: NCT00860470.
Highlights • 2 kidneys 1 clip method (2K1C) constricts 1 renal artery and induces hypertension. • 2K1C-induced hypertension impairs long-term, but not short-term, memory in mice. • 2K1C reduces ...dendritic complexity of CA1 neurons and hippocampal neurogenesis. • 2K1C doesn’t alter vascular density or glial activation status in the hippocampus. • 2K1C-induced impairments in the hippocampus are related to downregulation of BDNF.
Abstract
Harnessing the spin–momentum locking of topological surface states in conjunction with magnetic materials is the first step to realize novel topological insulator-based devices. Here, we ...report strong interfacial coupling in Bi
2
Se
3
/yttrium iron garnet (YIG) bilayers manifested as large interfacial in-plane magnetic anisotropy (IMA) and enhancement of damping probed by ferromagnetic resonance. The interfacial IMA and damping enhancement reaches a maximum when the Bi
2
Se
3
film approaches its two-dimensional limit, indicating that topological surface states play an important role in the magnetization dynamics of YIG. Temperature-dependent ferromagnetic resonance of Bi
2
Se
3
/YIG reveals signatures of the magnetic proximity effect of
T
C
as high as 180 K, an emerging low-temperature perpendicular magnetic anisotropy competing the high-temperature IMA, and an increasing exchange effective field of YIG steadily increasing toward low temperature. Our study sheds light on the effects of topological insulators on magnetization dynamics, essential for the development of topological insulator-based spintronic devices.
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