Proliferation-Attenuating and Apoptosis-Inducing Effects of Tryptanthrin on Human Chronic Myeloid Leukemia K562 Cell Line in Vitro

Tryptanthrin, a kind of indole quinazoline alkaloid, has been shown to exhibit anti-microbial, anti-inflammation and anti-tumor effects both in vivo and in vitro. However, its biological activity on human chronic myeloid leukemia cell line K562 is not fully understood. In the present study, we investigated the proliferation-attenuating and apoptosis-inducing effects of tryptanthrin on leukemia K562 cells in vitro and explored the underlying mechanisms. The results showed that tryptanthrin could significantly inhibit K562 cells proliferation in a time- and dose-dependent manner as evidenced by MTT assay and flow cytometry analysis. We also observed pyknosis, chromatin margination and the formation of apoptotic bodies in the presence of tryptanthrin under the electron microscope. Nuclei fragmentation and condensation by Hoechst 33258 staining were detected as well. The amount of apoptotic cells significantly increased whereas the mitochondrial membrane potential decreased dramatically after tryptanthrin exposure. K562 cells in the tryptanthrin treated group exhibited an increase in cytosol cyt-c, Bax and activated caspase-3 expression while a decrease in Bcl-2, mito cyt-c and pro-caspase-3 contents. However, the changes of pro-caspase-3 and activated caspase-3 could be abolished by a pan-caspase inhibitor ZVAD-FMK. These results suggest that tryptanthrin has proliferation-attenuating and apoptosis-inducing effects on K562 cells. The underlying mechanism is probably attributed to the reduction in mitochondria membrane potential, the release of mito cyt-c and pro-caspase-3 activation

Nrf2 Expression Is Regulated by Epigenetic Mechanisms in Prostate Cancer of TRAMP Mice

Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is a transcription factor which regulates the expression of many cytoprotective genes. In the present study, we found that the expression of Nrf2 was suppressed in prostate tumor of the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice. Similarly, the expression of Nrf2 and the induction of NQO1 were also substantially suppressed in tumorigenic TRAMP C1 cells but not in non-tumorigenic TRAMP C3 cells. Examination of the promoter region of the mouse Nrf2 gene identified a CpG island, which was methylated at specific CpG sites in prostate TRAMP tumor and in TRAMP C1 cells but not in normal prostate or TRAMP C3 cells, as shown by bisulfite genomic sequencing. Reporter assays indicated that methylation of these CpG sites dramatically inhibited the transcriptional activity of the Nrf2 promoter. Chromatin immunopreceipitation (ChIP) assays revealed increased binding of the methyl-CpG-binding protein 2 (MBD2) and trimethyl-histone H3 (Lys9) proteins to these CpG sites in the TRAMP C1 cells as compared to TRAMP C3 cells. In contrast, the binding of RNA Pol II and acetylated histone H3 to the Nrf2 promoter was decreased. Furthermore, treatment of TRAMP C1 cells with DNA methyltransferase (DNMT) inhibitor 5-aza-2′-deoxycytidine (5-aza) and histone deacetylase (HDAC) inhibitor trichostatin A (TSA) restored the expression of Nrf2 as well as the induction of NQO1 in TRAMP C1 cells. Taken together, these results indicate that the expression of Nrf2 is suppressed epigenetically by promoter methylation associated with MBD2 and histone modifications in the prostate tumor of TRAMP mice. Our present findings reveal a novel mechanism by which Nrf2 expression is suppressed in TRAMP prostate tumor, shed new light on the role of Nrf2 in carcinogenesis and provide potential new directions for the detection and prevention of prostate cancer

Amicoumacins from the marine-derived bacterium Bacillus sp. with the inhibition of NO production

Chemical examination of the fermentation broth of the marine-derived bacterium Bacillus sp. resulted in the isolation of seven new amicoumacin-type isocoumarin derivatives, namely bacillcoumacins A–G (1–7), together with four known analogues. Their structures were elucidated on the basis of extensive spectroscopic analysis, while the absolute configurations of the new compounds were determined by CD, Mosher’s method, and chemical conversion. Compounds 7 and 9 showed inhibitory effects against the NO production induced by lipopolysaccharide (LPS) in mouse macrophage RAW 264.7 cells

Association between Protein Intake and the Risk of Hypertension among Chinese Men and Women: A Longitudinal Study

This study aimed to examine the relationship between hypertension risk and protein intake in Chinese individuals. Our analysis included 7007 men and 7752 women from 9 China Health and Nutrition Survey waves (1991–2015). The main outcome was incident hypertension. Dietary intake was recorded using a combination of 3 consecutive 24-h recalls and a household food inventory survey. Energy-adjusted cumulative average intakes were analyzed, and Cox proportional hazards regression models were built. After 143,035 person-years of follow-up, 2586 and 2376 new male and female hypertension cases were identified, respectively. In multivariate-adjusted models with dietary protein intakes included as categorical variables, higher animal protein intake was associated with lower hypertension risk in women (p-trend = 0.01), whereas non-significant in men. Plant protein intake showed a significant positive correlation with hypertension risk, while non-significant for total protein. On a continuous scale, restricted cubic spline curves visually revealed L-, J-, and U-shaped associations between hypertension risk and animal-, plant-, and total-protein intakes, respectively, in both sexes (all p-nonlinearity < 0.0001). Our results suggest a beneficial association between intakes of animal, plant, and total proteins and hypertension risk at lower intake levels, and excessive intake of plant or total protein may increase the hypertension risk in the Chinese population

Nrf2 Activation Enhances Muscular MCT1 Expression and Hypoxic Exercise Capacity

Introduction Skeletal muscle is the major producing and metabolizing site of lactic acid. A family of monocarboxylate transporter (MCT) proteins, especially MCT1 and MCT4, are involved in the lactate–pyruvate exchange and metabolism. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal coordinator of antioxidant response and energy metabolism, and has been reported to associate with the physiological functions of the skeletal muscle. Methods In this study, C57BL/6 J mice were administrated with an Nrf2 activator, sulforaphane (SFN) before taking incremental treadmill exercise to exhaustion under hypoxia; then the effects of SFN on exercise endurance and molecular/biochemical makers of the skeletal muscle were evaluated. Results The results indicated that SFN pretreatment enhanced the exercise endurance under hypoxia. SFN not only increased the expressions of antioxidant genes and activity of antioxidant enzymes, but also significantly increased the mRNA and protein levels of MCT1 and CD147, but not MCT4. Moreover, the expressions of LDH-B and LDH activity of converting lactate into pyruvate, as well as citrate synthase activity were significantly higher, whereas the LDH activity of converting pyruvate into lactate and blood lactate level were remarkably lower in the SFN-exercise mice than those of the phosphate-buffered saline–exercise group. Furthermore, Atf3Δzip2 (the alternatively spliced isoform of activating transcription factor-3) mRNA was increased by the exercise and further potentiated by SFN. Conclusion These results show, for the first time, that SFN increases MCT1 expression in the skeletal muscle under acute hypoxic exercise and suggest that Nrf2 activation is a promising strategy to enhance exercise performance under hypoxia

Synthesis and Cytotoxicity Evaluation of Naphthalimide Derived N-Mustards

A series of N-mustards, which was conjugated to mono- or bis-naphthalimides with a flexible amine link, were synthesized and evaluated for cytotoxicity against five cancer cell lines (HCT-116, PC-3, U87 MG, Hep G2 and SK-OV-3). Several compounds displayed better activities than the control compound amonafide. Further evaluations by fluorescence spectroscopy studies and DNA-interstrand cross-linking assays revealed that the derivatives showed both alkylating and intercalating properties. Among the derivatives, the bis-naphthalimide N-mustard derivative 11b was found to exhibit the highest cytotoxic activity and DNA cross-linking ability. Both 11b and 7b induce HCT-116 cell apoptosis by S phase arrest

Dietary restriction slightly affects glucose homeostasis and delays plasma cholesterol removal in rabbits with dietary lipid lowering

Dietary restriction (DR) has been reported to promote the beneficial effects on atherosclerotic progression, lipid and glucose metabolism, but little is known about these effects can be enhanced or weakened by dietary lipid lowering. After 12 weeks of the high-cholesterol diet (HCD) feeding, hypercholesterolemic rabbits were fed with either a chow diet ad libitum (AL) or a chow diet with DR for 16 weeks of dietary lipid lowering. Here, we found the DR group exhibited a loss in body weight, small internal organs and the reduced fat mass, but the AL group accumulated more subcutaneous fat than the baseline group. DR treatment slightly worsened glucose tolerance but enhanced insulin sensitivity, and a slight effect of DR on insulin secretion was also observed. After diet cholesterol withdrawal, rabbits showed persistently lowering of total cholesterol and triglyceride in plasma. The DR group had significantly higher plasma total cholesterol than the AL group at the most time points during 7 to 16 weeks of lipid lowering. Although both AL and DR groups developed more severe atherosclerosis than baseline group, DR did not improve atherosclerotic progression and the accumulation of macrophages and smooth muscle cells as well. We concluded that DR affected glucose and lipid metabolism but did not ameliorate atherosclerosis in rabbits when associated with lipid lowering by the dietary cholesterol withdrawal.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author