Further Thymol Derivatives from Ageratina cylindrica

From the leaves of Ageratina cylindrica, in addition to the described [(2S)‐2‐{4‐formyl‐5‐hydroxy‐2‐[(2‐methylpropanoyl)oxy]phenyl}oxiran‐2‐yl]methyl benzoate (cylindrinol A, 8 ), seven new thymol derivatives were isolated and named cylindrinols B – H ( 1 – 7 ). The structures of these compounds were established as (2‐{4‐(hydroxymethyl)‐2‐[(2‐methylpropanoyl)oxy]phenyl}oxiran‐2‐yl)methyl benzoate ( 1 ), (2‐{4‐formyl‐2‐[(2‐methylpropanoyl)oxy]phenyl}oxiran‐2‐yl)methyl benzoate ( 2 ), (2‐{4‐[(acetyloxy)methyl]‐2‐[(2‐methylpropanoyl)oxy]phenyl}oxiran‐2‐yl)methyl benzoate ( 3 ), [2‐(2‐[(2‐methylpropanoyl)oxy]‐4‐{[(2‐methylpropanoyl)oxy]methyl}phenyl)oxiran‐2‐yl]methyl benzoate ( 4 ), [2‐(5‐hydroxy‐2‐[(2‐methylpropanoyl)oxy]‐4‐{[(2‐methylpropanoyl)oxy]methyl}phenyl)oxiran‐2‐yl]methyl benzoate ( 5 ), 2‐{4‐(hydroxymethyl)‐2‐[(2‐methylpropanoyl)oxy]phenyl}prop‐2‐en‐1‐yl benzoate ( 6 ), and 2‐hydroxy‐2‐[2‐hydroxy‐4‐(hydroxymethyl)‐phenyl]‐3‐[(2‐methylpropanoyl)oxy]propyl benzoate ( 7 ), by spectroscopic means. Compounds 1 showed moderate antiprotozoal activity on both protozoa. Compounds 4 and 5 showed selectivity on Giardia lamblia trophozoites. All isolated compounds were less active than two antiprotozoal drugs, metronidazole and emetine, used as positive controls. Compound 5 exhibited a high inhibitory effect on hyperpropulsive movement of the small intestine in rats; its effect was best than loperamide, antidiarrheal drug used as a positive control.     

一种费氏丙酸杆菌细胞离位转化生产维生素B_(12)的方法

为建立费氏丙酸杆菌的半连续耦合发酵工艺,克服DMB对维生素B_(12)连续发酵的不利影响,考察了费氏丙酸杆菌菌体细胞离位转化合成维生素B_(12)的可行性,优化了其离位转化工艺,确定了最佳的转化时机、转化体系及DMB添加方式,具体如下:当发酵进行至84 h时,将发酵液离心,收集菌体,然后用离心上清液重悬菌体,配成5倍浓度的菌液,加入终浓度为4.5 mg/L的DMB,于30℃条件下转化48 h,维生素B_(12)的产量达到108.06 mg/L,转化效率为2.26 mg/(Lh)。     

Elevated plasma vitamin B12 levels and cancer prognosis: A population-based cohort study

BackgroundElevated plasma vitamin B12 levels (cobalamin, Cbl) are associated with increased short-term cancer risk among patients referred for this laboratory measurement. We aimed to assess prognosis in cancer patients with elevated plasma Cbl.MethodsWe conducted a population-based cohort study using data from Danish medical registries during 1998–2014. The study included 25,017 patients with a cancer diagnosis and Cbl levels of 200–600 pmol/L (reference/normal range), 601–800 pmol/L and >800 pmol/L measured up to one year prior to diagnosis, and a comparison cohort of 61,988 cancer patients without a plasma Cbl measurement. Patients treated with Cbl were excluded. Survival probability was assessed using Kaplan–Meier curves. Mortality risk ratios (MRR) were computed using Cox proportional hazard regression, adjusted for age, sex, calendar year, cancer stage and comorbidity, scored using the Charlson comorbidity index.ResultsSurvival probabilities were lower among patients with elevated Cbl levels than among patients with normal levels and among members of the comparison cohort [(1-year survival,%) Cbl: 200–600 pmol/L: 69.3%; 601–800 pmol/L: 49.6%; >800 pmol/L: 35.8%; comparison cohort: 72.6%]. Thirty-day mortality was elevated for patients with Cbl levels of 601–800 pmol/L or >800 pmol/L, compared to patients with levels of 200–600 pmol/L [(MRR (95% confidence interval): 601–800 pmol/L vs. 200–600 pmol/L: 1.9 (1.6–2.2); >800 pmol/L vs. 200–600 pmol/L: 2.7 (2.4–3.1)]. This association remained robust for 31–90-day and 91–365-day mortality, showing similar dose-response patterns.ConclusionCancer patients with elevated Cbl levels had higher mortality than those with normal Cbl levels. These findings may have clinical significance for assessing the prognosis of cancer patients.     

Sesquiterpenoids from the Chinese endangered plant Manglietia aromatica

One new bourbonane-type (1) and one new cadinane-type (2) sesquiterpenoids, along with one known aromodendrane-type (3) and five known megastigmane-type (4–8) compounds, were isolated from the leaves and twigs of Manglietia aromatica, a Chinese endangered plant that has not been previously phytochemically investigated. The structures and absolute configurations of the new isolates, (1R,4S,5S,6S,7S,10S)-4-hydroxy-bourbon-8-one (1) and (1R,6S,7S)-1-hydroxy- cadin-4,9-dien-8-one (2), were established by means of spectroscopic methods and a combination of experimental and calculated electronic circular dichroism (ECD). Among the isolates, compound 2 was found to show a moderate inhibitory effect against the human protein tyrosine phosphatase 1 B (PTP1B) enzyme, a target for the treatment of type-II diabetes and obesity, with an IC₅₀ value of 83.5 μM.     

DNA methylation of loci within ABCG1 and PHOSPHO1 in blood DNA is associated with future type 2 diabetes risk

Identification of subjects with a high risk of developing type 2 diabetes (T2D) is fundamental for prevention of the disease. Consequently, it is essential to search for new biomarkers that can improve the prediction of T2D. The aim of this study was to examine whether 5 DNA methylation loci in blood DNA (ABCG1, PHOSPHO1, SOCS3, SREBF1, and TXNIP), recently reported to be associated with T2D, might predict future T2D in subjects from the Botnia prospective study. We also tested if these CpG sites exhibit altered DNA methylation in human pancreatic islets, liver, adipose tissue, and skeletal muscle from diabetic vs. non-diabetic subjects. DNA methylation at the ABCG1 locus cg06500161 in blood DNA was associated with an increased risk for future T2D (OR = 1.09, 95% CI = 1.02–1.16, P-value = 0.007, Q-value = 0.018), while DNA methylation at the PHOSPHO1 locus cg02650017 in blood DNA was associated with a decreased risk for future T2D (OR = 0.85, 95% CI = 0.75–0.95, P-value = 0.006, Q-value = 0.018) after adjustment for age, gender, fasting glucose, and family relation. Furthermore, the level of DNA methylation at the ABCG1 locus cg06500161 in blood DNA correlated positively with BMI, HbA1c, fasting insulin, and triglyceride levels, and was increased in adipose tissue and blood from the diabetic twin among monozygotic twin pairs discordant for T2D. DNA methylation at the PHOSPHO1 locus cg02650017 in blood correlated positively with HDL levels, and was decreased in skeletal muscle from diabetic vs. non-diabetic monozygotic twins. DNA methylation of cg18181703 (SOCS3), cg11024682 (SREBF1), and cg19693031 (TXNIP) was not associated with future T2D risk in subjects from the Botnia prospective study.     

BAG3 regulates total MAP1LC3B protein levels through a translational but not transcriptional mechanism

Autophagy is mainly regulated by post-translational and lipid modifications of ATG proteins. In some scenarios, the induction of autophagy is accompanied by increased levels of certain ATG mRNAs such as MAP1LC3B/LC3B, ATG5 or ATG12. However, little is known about the regulation of ATG protein synthesis at the translational level. The cochaperone of the HSP70 system BAG3 (BCL2-associated athanogene 3) has been associated to LC3B lipidation through an unknown mechanism. In the present work, we studied how BAG3 controls autophagy in HeLa and HEK293 cells. Our results showed that BAG3 regulates the basal amount of total cellular LC3B protein by controlling its mRNA translation. This effect was apparently specific to LC3B because other ATG protein levels were not affected. BAG3 knockdown did not affect LC3B lipidation induced by nutrient deprivation or proteasome inhibition. We concluded that BAG3 maintains the basal amount of LC3B protein by controlling the translation of its mRNA in HeLa and HEK293 cells.     

Efficacy of poly (ADP-ribose) polymerase inhibitor olaparib against head and neck cancer cells: Predictions of drug sensitivity based on PAR–p53–NF-κB interactions

Poly (ADP-ribose) polymerase (PARP) is a key molecule in the DNA damage response (DDR), which is a major target of both chemotherapies and radiotherapies. PARP inhibitors therefore comprise a promising class of anticancer therapeutics. In this study, we evaluated the efficacy of the PARP inhibitor olaparib, and also sought to identify the mechanism and predictive marker associated with olaparib sensitivity in head and neck cancer (HNC) cells. A total of 15 HNC cell lines, including AMC HNC cells, were tested. AMC-HN3 and HN4 exhibited stronger responses to olaparib. Among cisplatin-resistant cell lines, only AMC HN9-cisR cells were significantly suppressed by olaparib. We found that basal poly (ADP-ribose) (PAR) levels, but not PARP-1 levels, correlated with olaparib sensitivity. AMC-HN3 and HN4 cells exhibited higher basal levels of NF-κB that decreased significantly after olaparib treatment. In contrast, apoptotic proteins were intrinsically expressed in AMC-HN9-cisR cells. As interference with p53 expression led to NF-κB reactivation, we concluded that elevated basal PAR and NF-κB levels are predictive of olaparib responsiveness in HNC cells; in addition, olaparib inhibits HNC cells via PAR–p53–NF-κB interactions.     

Coronin 1B supports RhoA signaling at cell-cell junctions through Myosin II

Non-muscle myosin II (NMII) motor proteins are responsible for generating contractile forces inside eukaryotic cells. There is also a growing interest in the capacity for these motor proteins to influence cell signaling through scaffolding, especially in the context of RhoA GTPase signaling. We previously showed that NMIIA accumulation and stability within specific regions of the cell cortex, such as the zonula adherens (ZA), allows the formation of a stable RhoA signaling zone. Now we demonstrate a key role for Coronin 1B in maintaining this junctional pool of NMIIA, as depletion of Coronin 1B significantly compromised myosin accumulation and stability at junctions. The loss of junctional NMIIA, upon Coronin 1B knockdown, perturbed RhoA signaling due to enhanced junctional recruitment of the RhoA antagonist, p190B Rho GAP. This effect was blocked by the expression of phosphomimetic MRLC-DD, thus reinforcing the central role of NMII in regulating RhoA signaling.