Benzylidene Acylhydrazides Inhibit Chlamydial Growth in a Type III Secretion- and Iron Chelation-Independent Manner

Chlamydiae are widespread Gram-negative pathogens of humans and animals. Salicylidene acylhydrazides, developed as inhibitors of type III secretion system (T3SS) in Yersinia spp., have an inhibitory effect on chlamydial infection. However, these inhibitors also have the capacity to chelate iron, and it is possible that their antichlamydial effects are caused by iron starvation. Therefore, we have explored the modification of salicylidene acylhydrazides with the goal to uncouple the antichlamydial effect from iron starvation. We discovered that benzylidene acylhydrazides, which cannot chelate iron, inhibit chlamydial growth. Biochemical and genetic analyses suggest that the derivative compounds inhibit chlamydiae through a T3SS-independent mechanism. Four single nucleotide polymorphisms were identified in a Chlamydia muridarum variant resistant to benzylidene acylhydrazides, but it may be necessary to segregate the mutations to differentiate their roles in the resistance phenotype. Benzylidene acylhydrazides are well tolerated by host cells and probiotic vaginal Lactobacillus species and are therefore of potential therapeutic value.     

Comprehensive Multiple Molecular Profile of Epithelial Mesenchymal Transition in Intrahepatic Cholangiocarcinoma Patients

Background

The aim of this study is to investigate the expression profile of multiple epithelial mesenchymal transition (EMT)-related molecules in intrahepatic cholangiocarcinoma (ICC) and the related prognostic significance.

Methods

Immunohistochemistry was performed to determine the expression of E-cadherin, Vimentin, Snail, slug and β-catenin in a tissue microarray consisting of tumor tissues of 140 ICC patients undergoing curative resection. The correlation between the expression of these molecules and the clinicopathological characteristics of ICC patients was analyzed, and their prognostic implication was evaluated.

Results

Reduced E-cadherin and increased Vimentin expression, the characteristic changes of EMT, identified in 55.0% and 55.7% of primary ICCs, respectively, were correlated with lymphatic metastasis and poorer overall survival (OS) and disease-free survival (DFS) of ICCs. The overexpression of snail and nonmembranous β-catenin, which are the major regulators of the EMT, were identified in 49.2% and 45.7% of primary ICCs, while little slug expression was detected in ICCs. Cytoplasmic/nuclear β-catenin did not significantly predict worse DFS and was not related with E-cadherin loss. The overexpression of snail predicted worse OS and DFS. Snail overexpression correlated with the down-regulation of E-cadherin and the up-regulation of Vimentin. Inhibition of snail in an ICC cell line decreased the expression of E-cadherin, enhanced the expression of Vimentin and impaired the invasion and migration ability of ICC cells.

Conclusions

These data support the hypothesis that EMT plays vital roles in ICC progression and suggest that snail but not slug and β-catenin plays a crucial role in the EMT induction of ICC.     

Effects of R219K polymorphism of ATP-binding cassette transporter 1 gene on serum lipids ratios induced by a high-carbohydrate and low-fat diet in healthy youth

Background

Diets are the important players in regulating plasma lipid profiles. And the R219K polymorphism at the gene of ATP-binding cassette transporter 1(ABCA1) was reported to be associated with the profiles. However, no efforts have been made to investigate the changes of lipid profiles after a high-carbohydrate and low-fat diet in different subjects with different genotypes of this polymorphism. This study was to evaluate the effects of ABCA1 R219K polymorphism on serum lipid and apolipoprotein (apo) ratios induced by a high-carbohydrate/low-fat (high-CHO) diet. After a washout diet of 54.1% carbohydrate for 7 days, 56 healthy young subjects (22.89 ± 1.80 years old) were given a high-CHO diet of 70.1% carbohydrate for 6 days. Height, weight, waist circumference, hip circumference, glucose (Glu), triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apoA-1 and apoB-100 were measured on the 1^st, 8^th and 14^th days of this study. Body mass index (BMI), waist-to-hip ratios (WHR), log(TG/HDL-C), TC/HDL-C, LDL-C/HDL-C and apoA-1/apoB-100 were calculated. ABCA1 R219K was analyzed by a PCR-RFLP method.

Results

The results indicate that the male subjects of all the genotypes had higher WHR than their female counterparts on the 1^st, 8^th and 14^th days of this study. The male K carriers had higher log(TG/HDL-C) and TC/HDL-C than the female carriers on the 1^st and 14^th days, and higher LDL-C/HDL-C on the 14^th day. When compared with that on the 8^th day, TC/HDL-C was decreased regardless of the genotypes and genders on the 14^th day. Log(TG/HDL-C) was increased in the males with the RR genotype and the female K carriers. Lowered BMI, Glu and LDL-C/HDL-C were found in the male K carriers, but only lowered BMI in the female K carriers and only lowered LDL-C/HDL-C in the females with the RR genotype.

Conclusions

These results suggest that ABCA1 R219K polymorphism is associated differently in males and females with elevated log(TG/HDL-C) and decreased LDL-C/HDL-C induced by the high-CHO diet.     

Effects of Slag-Based Silicon Fertilizer on Rice Growth and Brown-Spot Resistance

It is well documented that slag-based silicon fertilizers have beneficial effects on the growth and disease resistance of rice. However, their effects vary greatly with sources of slag and are closely related to availability of silicon (Si) in these materials. To date, few researches have been done to compare the differences in plant performance and disease resistance between different slag-based silicon fertilizers applied at the same rate of plant-available Si. In the present study both steel and iron slags were chosen to investigate their effects on rice growth and disease resistance under greenhouse conditions. Both scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to examine the effects of slags on ultrastructural changes in leaves of rice naturally infected by Bipolaris oryaze, the causal agent of brown spot. The results showed that both slag-based Si fertilizers tested significantly increased rice growth and yield, but decreased brown spot incidence, with steel slag showing a stronger effect than iron slag. The results of SEM analysis showed that application of slags led to more pronounced cell silicification in rice leaves, more silica cells, and more pronounced and larger papilla as well. The results of TEM analysis showed that mesophyll cells of slag-untreated rice leaf were disorganized, with colonization of the fungus (Bipolaris oryzae), including chloroplast degradation and cell wall alterations. The application of slag maintained mesophyll cells relatively intact and increased the thickness of silicon layer. It can be concluded that applying slag-based fertilizer to Si-deficient paddy soil is necessary for improving both rice productivity and brown spot resistance. The immobile silicon deposited in host cell walls and papillae sites is the first physical barrier for fungal penetration, while the soluble Si in the cytoplasm enhances physiological or induced resistance to fungal colonization.     

Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice

Lipoprotein glomerulopathy (LPG) is a renal disease often accompanied by dyslipidemia and increased serum apoE levels. apoE_Sendai (Arg145Pro), a rare mutant based on the apoE3 sequence carrying an apoE2 charge, causes LPG in humans and transgenic mice, but its effects on the artery wall are unknown. Macrophage expression of apoE_Sendai may also directly influence renal and arterial homeostasis. We investigated the effects of macrophage-expressed apoE_Sendai in apoE^−/− mice with or without LDL receptor (LDLR). Murine bone marrow transduced to express apoE2, apoE3, or apoE_Sendai was transplanted into lethally irradiated mice. Macrophage apoE_Sendai expression reduced aortic lesion size and inflammation by 32 and 28%, respectively, compared with apoE2 in apoE^−/− recipients. No differences in lesion size or inflammation were found between apoE_Sendai and apoE3 in apoE^−/− recipients. Macrophage apoE_Sendai expression also reduced aortic lesion size by 18% and inflammation by 29% compared with apoE2 in apoE^−/−/LDLR^−/− recipients. Glomerular lesions compatible with LPG with increased mesangial matrix, extracellular lipid accumulation, and focal mesangiolysis were only observed in apoE^−/−/LDLR^−/− mice expressing apoE_Sendai. Thus, macrophage expression of apoE_Sendai protects against atherosclerosis while causing lipoprotein glomerulopathy. This is the first demonstration of an apoprotein variant having opposing effects on vascular and renal homeostasis.     

N-Acetylcysteine Attenuates Ischemia-Reperfusion-Induced Apoptosis and Autophagy in Mouse Liver via Regulation of the ROS/JNK/Bcl-2 Pathway

Background

Hepatic ischemia–reperfusion injury (HIRI) remains a pivotal clinical problem after hemorrhagic shock, transplantation, and some types of toxic hepatic injury. Apoptosis and autophagy play important roles in cell death during HIRI. It is also known that N-acetylcysteine (NAC) has significant pharmacologic effects on HIRI including elimination of reactive oxygen species (ROS) and attenuation of hepatic apoptosis. However, the effects of NAC on HIRI-induced autophagy have not been reported. In this study, we evaluated the effects of NAC on autophagy and apoptosis in HIRI, and explored the possible mechanism involved.

Methods

A mouse model of segmental (70%) hepatic warm ischemia was adopted to determine hepatic injury. NAC (150 mg/kg), a hepatoprotection agent, was administered before surgery. We hypothesized that the mechanism of NAC may involve the ROS/JNK/Bcl-2 pathway. We evaluated the expression of JNK, P-JNK, Bcl-2, Beclin 1 and LC3 by western blotting and immunohistochemical staining. Autophagosomes were evaluated by transmission electron microscopy (TEM).

Results

We found that ALT, AST and pathological changes were significantly improved in the NAC group. Western blotting analysis showed that the expression levels of Beclin 1 and LC3 were significantly decreased in NAC-treated mice. In addition, JNK, p-JNK, Bax, TNF-α, NF-κB, IL2, IL6 and levels were also decreased in NAC-treated mice.

Conclusion

NAC can prevent HIRI-induced autophagy and apoptosis by influencing the JNK signal pathway. The mechanism is likely to involve attenuation of JNK and p-JNK via scavenged ROS, an indirect increase in Bcl-2 level, and finally an alteration in the balance of Beclin 1 and Bcl-2.     

New insights into TRP channels: Interaction with pattern recognition receptors

An increasing number of studies have implicated that the activation of innate immune system and inflammatory mechanisms are of importance in the pathogenesis of numerous diseases. The innate immune system is present in almost all multicellular organisms in response to pathogens or tissue injury, which is performed via germ-line encoded pattern-recognition receptors (PRRs) to recognize pathogen-associated molecular patterns (PAMPs) or dangers-associated molecular patterns (DAMPs). Intracellular pathways linking immune and inflammatory response to ion channel expression and function have been recently identified. Among ion channels, transient receptor potential (TRP) channels are a major family of non-selective cation-permeable channels that function as polymodal cellular sensors involved in many physiological and pathological processes. In this review, we summarize current knowledge about classifications, functions, and interactions of TRP channels and PRRs, which may provide new insights into their roles in the pathogenesis of inflammatory diseases.     

Iodine Deficiency and Excess Coexist in China and Induce Thyroid Dysfunction and Disease: A Cross-Sectional Study

Background

In spite of the salt iodization, iodine deficiency disorders (IDD) have not been sustainably eliminated in China. There are coastal areas with low iodized salt coverage rates (iodine nutrition is inadequate) and other areas with excessive amounts of iodine in the drinking water.

Objective

This study aimed to clarify the association of iodine deficiencies resulting from a low coverage rate of iodized salt, excess iodine intake from drinking water with thyroid function and disease in adults.

Design

A cross-sectional study was conducted in adults in different iodine nutrition areas in three provinces in China.

Results

The prevalence of thyroid nodules was 15.52%, 8.66% and 22.17% in the iodine excess, sufficient and deficient groups, respectively. The prevalence of subclinical hypothyroidism was 20.09%, 10.41%, and 2.25% in the excess, sufficient and deficient iodine groups, respectively. The prevalence of subclinical hyperthyroidism and overt hyperthyroidism in the iodine deficient group was higher than that in the iodine excess group ( = 9.302, p = 0.002) and iodine sufficient group ( = 7.553, p = 0.006). Thyroid-stimulating hormone (TSH) was significantly correlated with excess iodine intake (β = 1.764,P = 0.001) and deficient iodine intake (β = −1.219, P = 0.028).

Conclusions

Thyroid nodules are more likely to be present in the iodine excess and deficient areas than in the iodine sufficient areas. Subclinical hyperthyroidism and overt hyperthyroidism are more likely to be prevalent in the iodine deficient areas than in the iodine excess or sufficient areas. Subclinical hypothyroidism is more likely to be prevalent in the high iodine intake areas than in the iodine deficient or sufficient areas. Median TSH may be deemed as an alternative indicator for monitoring the iodine nutrition status of the adult population in iodine excess and deficient areas.