MicroRNA-33/33* inhibit the activation of MAVS through AMPK in antiviral innate immunity

Innate immunity plays a prominent role in the host defense against pathogens and must be precisely regulated. As vital orchestrators in cholesterol homeostasis, microRNA-33/33* have been widely investigated in cellular metabolism. However, their role in antiviral innate immunity is largely unknown. Here, we report that VSV stimulation decreased the expression of miR-33/33* through an IFNAR-dependent manner in macrophages. Overexpression of miR-33/33* resulted in impaired RIG-I signaling, enhancing viral load and lethality whereas attenuating type I interferon production both in vitro and in vivo. In addition, miR-33/33* specifically prevented the mitochondrial adaptor mitochondrial antiviral-signaling protein (MAVS) from forming activated aggregates by targeting adenosine monophosphate activated protein kinase (AMPK), subsequently impeding the mitophagy-mediated elimination of damaged mitochondria and disturbing mitochondrial homeostasis which is indispensable for efficient MAVS activation. Our findings establish miR-33/33* as negative modulators of the RNA virus-triggered innate immune response and identify a previously unknown regulatory mechanism linking mitochondrial homeostasis with antiviral signaling pathways.     

以案例为先导的比较形态学实验教学体系的构建和实践

在融合性形态学实验课程的基础上,以案例为先导,把人体的正常结构与病理变化有机地结合起来,通过比较学习人体解剖学、组织学和病理学知识,学生的学习效果得到了提升.     

A Brain-Spleen Axis Regulates Humoral Immunity

A happy mood helps to build a flourishing immune system.Interactions between the nervous and immune systems have attracted the interest of researchers for decades.It is well known that external stressors can activate the hypothalamus to regulate immune responses via the hypothalamic-pituitary-adrenal cortex(HPA)axis[1].As well,inflammatory stimuli can activate a rapid antiinflammatory reflex via the cholinergic vagus nerve pathway.     

Visible-light promoted three-component tandem reaction to synthesize difluoromethylated oxazolidin-2-imine

An effective synthetic method to achieve difluoromethylated oxazolidin-2-imine has been developed via visible-light promoted three-component tandem reaction of aryl allylamines, 2-BTSO2CF2H (BT = Benzothiazole) and isocyanates. This method features mild reaction conditions and good functional group tolerance, and the reaction mechanism was confirmed by experiments and interpreted by quantum chemical calculations.

Visible-light promoted three-component tandem reaction.

Difluoromethyl containing compounds have been widely used in the fields of pharmaceutics and agrochemistry because of their unique physical, chemical, and biological properties.¹ Generally, the –CF₂ moiety can act as a bioisostere of the –CH₂ or –CO group and the CF₂H is isopolar to the –OH and –SH group, which can be used as a lipophilic hydrogen bond donor.^2,3 In recent years, much attention has been focused on the synthesis of difluoromethylated molecules.⁴ FDA approved medicine Gemcitabine and Lubiprostone both contain difluoromethyl group (Fig. 1a).Open in a separate windowFig. 1(a) Structure of Gemcitabine and Lubiprostone (b) selected bioactive oxazolidin-2-imine derivatives.The oxazolidin-2-imine skeleton exists in many biologically active compounds. For example, compound I is a novel nitric oxide synthase inhibitor with an EC₅₀ value of 41 nM,⁵ and compound II acts as a very potent selective androgen receptor modulator (SARM) with a sub-nanomolar EC₅₀ value (Fig. 1b).⁶ In addition, substituted oxazolidin-2-imines are critical synthetic intermediates that can be transformed into a variety of other structures, and represent a useful chiral auxiliary for the asymmetric alkylations.⁷ The high value of oxazolidin-2-imine in medicinal chemistry and organic chemistry has driven successive efforts to develop effective synthetic methods. Shinichi Saito''s group reported the cycloaddition of aziridines with isocyanates catalyzed by NiI₂ to furnish oxazolidin-2-imines in good yields (Scheme 1a).⁸ Beifuss''s group revealed intermolecular 1,2-addition/intramolecular N-vinylation of 2-bromo-2-propen-1-ols and dicyclohexyl carbodiimide for the synthesis of oxazolidin-2-imines (Scheme 1b).⁹ Recently, Bu₂SnI₂–InCl₃ catalysed cycloaddition of propylene oxide with diphenyl carbodiimide was reported by Ikuya Shibata''s group¹⁰ (Scheme 1c).Open in a separate windowScheme 1Different protocols for the synthesis of oxazolidin-2-imine.Radical-triggered cascade multi-component reactions serve as an ideal strategy in the synthesis of heterocyclic scaffolds, owing to forming multiple bonds under a single set of reaction conditions.¹¹ Particularly, the visible-light promoted radical addition–cyclization has demonstrated its synthetic utility in the construction of compounds with various scaffold,¹² including 2-oxazolidinones,¹³ coumarin,¹⁴ phenanthridines,¹⁵ and so on. We envisioned that the combination of difluoromethyl moiety with oxazolidin-2-imine scaffold may exert potential use in medicinal chemistry and other related fields. As part of our work on the visible-light mediated radical difluoromethylation,¹⁵ we try to explore a novel and convenient method to construct HCF₂-containing oxazolidin-2-imines via visible-light promoted three-component tandem reaction (Scheme 1d).We began our investigation by using N-benzyl-2-phenylprop-2-en-1-amine 1a, 1-isocyanato-4-methylbenzene 3a as the model substrate and 2-BTSO₂CF₂H (Hu''s reagent) 2 as the difluoromethylation reagent. Initially, DABCO was used as base and target compound 4aa can be produced in 29% yield using Ru(bpy)₃Cl₂·6H₂O as photocatalyst (

Autophagy in synaptic development,function, and pathology

Neuroscience Bulletin - In the nervous system, neurons contact each other to form neuronal circuits and drive behavior, relying heavily on synaptic connections. The proper development and growth of...     

CD36 palmitoylation disrupts free fatty acid metabolism and promotes tissue inflammation in non-alcoholic steatohepatitis

1. Download high-res image (151KB)
2. Download full-size image

     

Targeting eradication of chronic myeloid leukemia using chimeric oncolytic adenovirus to drive IL-24 expression

Chronic myeloid leukemia (CML) is a clonal disorder in which cells of the myeloid lineage undergo massive clonal expansion as well as resistance to conventional chemotherapy. Gene therapy hold a great promise for treatment of malignancies based on the transfer of genetic material to the tissues. In this study, we explore whether chimeric oncolytic adenovirus-mediated transfer of human interleukin-24 (IL-24) gene induce the enhanced antitumor potency. Our results showed that chimeric oncolytic adenovirus carrying hIL-24 (AdCN205-11-IL-24) could produce high levels of hIL-24 in CML cancer cells, as compared with constructed double-regulated oncolytic adenovirus expressing hIL-24 (AdCN205-IL-24). AdCN205-11-IL-24 could specifically induce cytotoxocity to CML cancer cells, but little or no effect on normal cell lines. AdCN205-11-IL-24 exhibited remarkable anti-tumor activities and induce higher antitumor activity to CML cancer cells by inducing apoptosis in vitro. Our study may provides a potent and safe tool for CML gene therapy.     

Genetic Diversity,Antimicrobial Resistance,and Virulence Genes of Aeromonas Isolates from Clinical Patients,Tap Water Systems,and Food

Objective This study aimed to evaluate the genetic diversity, virulence, and antimicrobial resistance of Aeromonas isolates from clinical patients, tap water systems, and food.Methods Ninety Aeromonas isolates were obtained from Ma'anshan, Anhui province, China, and subjected to multi-locus sequence typing(MLST) with six housekeeping genes. Their taxonomy was investigated using concatenated gyr B-cpn60 sequences, while their resistance to 12 antibiotics was evaluated. Ten putative virulence factors and several resistance genes were identified by PCR and sequencing.Results The 90 Aeromonas isolates were divided into 84 sequence types, 80 of which were novel,indicating high genetic diversity. The Aeromonas isolates were classified into eight different species. PCR assays identified virulence genes in the isolates, with the enterotoxin and hemolysin genes act, aer A, alt,and ast found in 47(52.2%), 13(14.4%), 22(24.4%), and 12(13.3%) of the isolates, respectively. The majority of the isolates(≥ 90%) were susceptible to aztreonam, imipenem, cefepime, chloramphenicol,gentamicin, tetracycline, and ciprofloxacin. However, several resistance genes were detected in the isolates, as well as a new mcr-3 variant.Conclusions Sequence type, virulence properties, and antibiotic resistance vary in Aeromonas isolates from clinical patients, tap water systems, and food.     

Different metabolic profiles of K1 serotype and non-serotype K1 and K2 Klebsiella pneumoniae isolates in oral infection mice model

K1 or K2 serotype Klebsiella pneumoniae isolate caused clinical pyogenic liver abscess (KLA) infection is prevalent in many areas. It has been identified that K1 or K2 serotype K. pneumoniae isolates caused KLA infection in mice by oral inoculation. In our study, K1 serotype K. pneumoniae isolate Kp1002 with hypermucoviscosity (HV)-positive phenotype caused KLA infection in C57BL/6 mice by oral inoculation. Simultaneously, non-serotype K1 and K2 isolate Kp1014 with HV-negative phenotype failed to cause KLA infection in the same manner. It seems that gastrointestinal tract translocation is the pathway by which K1 or K2 serotype K. pneumoniae caused KLA infection. Liquid chromatography-tandem mass spectrometry was used to further analyze metabolic profile changes in mice with KLA infection. Data showed that after Kp1002 or Kp1014 oral inoculation, serum Phosphatidylcholine (PC) and Lysophosphatidylcholine (LPC) levels significantly changed in mice. Some PC and LPC molecules showed changes both in the Kp1002 KLA group and the Kp1014 no-KLA group compared with the control group. The level of 18:1/18:2-PC significantly changed in the Kp1002 KLA group compared with the control group, but showed no change between the Kp1014 no-KLA group and the control group. The level of 18:1/18:2-PC might have been particularly affected by KLA infection caused by K1 serotype K. pneumoniae Kp1002. It may be a potential biomarker for KLA infection.