Integration of metabolomics and transcriptomics analyses reveals sphingosine-1-phosphate-mediated S1PR2/PI3K/Akt pathway involved in Talaromyces marneffei infection of macrophages.

Talaromycosis is a fatal mycosis caused by the thermally dimorphic fungus Talaromyces marneffei (T. marneffei). The pathogenic mechanisms of talaromycosis are still poorly understood. This work combined metabolomics, transcriptomics, and verification experiments in vivo and in vitro to detect metabolic profiles and differentially expressed genes (DEGs) in T. marneffei infected and uninfected macrophages to explore possible pathogenesis and underlying mechanisms. A total of 256 differential metabolites (117 up-regulated and 148 down-regulated) and 1320 DEGs (1286 up-regulated and 34 down-regulated) were identified between the two groups. Integrative metabolomics and transcriptomics analysis showed sphingolipid signaling pathway is the most influential. Verification experiments showed that compared with the control group, the production of sphingosine-1-phosphate (S1P) and the expression of the S1PR1, S1PR2, phosphor-PI3K, and phosphor-Akt genes involved in the sphingolipid signaling pathway have significantly increased in the T. marneffei infection group (p < 0.05). T. marneffei activates the S1PR2/PI3K/Akt pathways in J774A.1 macrophage, regulation of the S1P singling might serve as a promising therapeutic strategy for talaromycosis.

Thalidomide promotes NLRP3/caspase-1-mediated pyroptosis of macrophages in Talaromyces marneffei infection.

Macrophage-derived inflammatory cytokines are critical for host defense against Talaromyces marneffei (T. marneffei) infection among HIV/AIDS patients, and excessive inflammatory cytokines are associated with poor outcomes of AIDS-associated talaromycosis. However, the underlying mechanisms of macrophage-caused pyroptosis and cytokine storm are poorly understood. Here, in the T. marneffei-infected mice and macrophages, we show that T. marneffei induced pyroptosis in macrophages through the NLRP3/caspase-1 pathway. The immunomodulatory drug thalidomide could promote the pyroptosis of macrophages infected T. marneffei. In T. marneffei-infected mice, the splenic macrophages underwent increasing pyroptosis as talaromycosis deteriorated. Thalidomide ameliorated inflammation of mice, while amphotericin B (AmB) in combination with thalidomide did not improve overall survival compared with AmB alone. Taken together, our findings suggest that thalidomide promotes NLRP3/caspase-1-mediated pyroptosis of macrophages in T. marneffei infection.

Regulatory effect of isovitexin on MAPK/NF-κB signal in mice with acute ulcerative colitis.

The aim of this study was to investigate the anti-inflammatory effects and mechanism of isovitexin on ulcerative colitis mice and RAW264.7 cells. The results showed that isovitexin had strong antioxidant and anti-inflammatory effects, and could restore intestinal barrier integrity (p < 0.01). In addition, isovitexin inhibited the expression of MyD88, TLR4 and NF-κB p65 proteins. At the same time, isovitexin can inhibit the activation of MAPK/NF-κB signaling pathway in RAW264.7 cells. In conclusion, isovitexin has a protective effect on UC mice, and its improvement mechanism of UC might be related to MAPK/NF-κB signaling pathway.

Glutamine Maintains Satellite Glial Cells Growth and Survival in Culture.

Satellite glial cells (SGCs) tightly surround neurons and modulate sensory transmission in dorsal root ganglion (DRG). At present, the biological property of primary SGCs in culture deserves further investigation. To reveal the key factor for SGCs growth and survival, we examined the effects of different culture supplementations containing Dulbecco's Modified Eagle Medium (DMEM)/F12, DMEM high glucose (HG) or Neurobasal-A (NB). CCK-8 proliferation assay showed an increased proliferation of SGCs in DMEM/F12 and DMEM/HG, but not in NB medium. Bax, AnnexinV, and propidium iodide (PI) staining results showed that NB medium caused cell death and apoptosis. We showed that glutamine was over 2.5 mM in DMEM/F12 and DMEM/HG, whereas it was absence in NB medium. Interestingly, exogenous glutamine application significantly reversed the poor proliferation and cell death of SGCs in NB medium. These findings demonstrated that DMEM/F12 medium was optimal to get high-purity SGCs. Glutamine was the key molecule to maintain SGCs growth and survival in culture. Here, we provided a novel approach to get high-purity SGCs by changing the key component of culture medium. Our study shed a new light on understanding the biological property and modulation of glial cells of primary sensory ganglia.

Tigliane Diterpenoids with Larvicidal, Antifungal, and α-Glucosidase Inhibitory Activities from Croton damayeshu.

Thirty-five tigliane diterpenoids and two ent-kaurane diterpenoids were isolated from the leaves of Croton damayeshu, and, among them, compounds 1-10 were characterized as new tigliane diterpenoids. The structures of compounds 1-10 were determined by analysis of their HRESIMS, NMR, and ECD data and by chemical methods. The isolates were assayed for their larvicidal, antifungal, and α-glucosidase inhibitory activities, and compounds 8-10 were found to possess larvicidal activities against Plutella xylostella with LC50 values of 0.19, 0.16, and 0.26 µM, respectively, comparable to the LC50 of 0.14 µM for the positive control, flubendiamide.

A Reliable Murine Model of Disseminated Infection Induced by Talaromyces Marneffei.

Talaromycosis (penicilliosis) caused by Talaromyces marneffei is one of the most important opportunistic infection diseases in tropical countries of South and Southeast Asia. Most infections occurred in individuals with human immunodeficiency virus (HIV) and the primarily reason for the increase in the number of the cases is HIV pandemic. The pathogenesis of T. marneffei infection is unclear. There is still no ideal animal model for studying talaromycosis. In this study, we developed a stable, safe and maneuverable murine model that mimics human T. marneffei disseminated infection using T. marneffei yeast intraperitoneal injected to BALB/c nude mice. We successfully observed symptoms similar to those seen in clinical patients in this murine model, including skin lesions, hepatosplenomegaly, pulmonary infection and mesenteric lesions. We further studied the pathological changes of various tissues and organs in the infected animals to help better understand the severity of the infection. This model may provide a good tool for studying disseminated infection induced by T. marneffei.

Mendelian Randomization Analysis Reveals Causal Effects of the Human Gut Microbiota on Abdominal Obesity.

BACKGROUND: Although recent studies have revealed an association between the composition of the gut microbiota and obesity, whether specific gut microbiota cause obesity has not been determined. OBJECTIVES: The aim of this study is to determine the causal relationship between specific gut microbiota and abdominal obesity. Based on genome-wide association study (GWAS) summary statistics, we performed a 2-sample Mendelian randomization (MR) analysis to evaluate whether the gut microbiota affects abdominal obesity. METHODS: Gut microbiota GWAS in 1126 twin pairs (age range, 18-89 years; 89% were females) from the TwinsUK study were used as exposure data. The primary outcome tested was trunk fat mass (TFM) GWAS in 492,805 participants (age range, 40-69 years; 54% were females) from the UK Biobank. The gut microbiota were classified at family, genus, and species levels. A feature was defined as a distinct family, genus, or species. MR analysis was mainly performed by an inverse variance-weighted test or Wald ratio test, depending on the number of instrumental variables (IVs) involved. A sensitivity analysis was performed on significant results by a weighted median test and a weighted genetic risk score (GRS) analysis. RESULTS: Results of MR analyses provided evidence of a causal association between 3 microbiota features and TFM, including 1 family [Lachnosiraceae; P = 0.02; ß = 0.001 (SEE, 4.28 × 10-4)], 1 genus [Bifidobacterium; P = 5.0 × 10-9; ß = -0.08 (SEE, 0.14)], and 1 species [Prausnitzii; P = 0.03; ß = -0.007 (SEE, 0.003)]. Both the weighted median test and GRS analysis successfully validated the association of the genetically predicted family, Lachnosiraceae (Pweighted median = 0.03; PGRS = 0.004). CONCLUSIONS: Our findings provided evidence of a causal association between gut microbiota and TFM in UK adults and identified specific bacteria taxa that may regulate the fat metabolism, thus offering new direction for the treatment of obesity.

Habitual tea consumption and 5-year incident metabolic syndrome among older adults: a community-based cohort study.

BACKGROUND: The effect of tea consumption on metabolic syndrome (MetS) remains controversial. The objective of this study is to examine the prospective association of tea consumption with 5-year incident MetS among aged population in China. METHODS: This analysis included 3005 Chinese adults aged 60 years or older who were free of MetS at baseline examination. MetS was defined according to the National Cholesterol Education Program-Adult Treatment Panel III. Information regarding tea consumption was collected via an interviewer-administrated questionnaire. The prospective associations between tea consumption at baseline and 5-year incident MetS, as well as its individual components, were assessed by multiple logistic regression models. RESULTS: Of the 3005 participants free of MetS at baseline, 406 participants (cumulative incidence: 13.5%) developed MetS at the 5-year follow-up examination. In multiple logistic regressions, 5-year cumulative incidence of MetS was found to be higher in those who drank tea more than 5 times per week as compared with non-habitual drinkers (OR = 1.38, 95% CI: 1.05-1.82; P = 0.02). This relationship still existed in men (OR = 1.43, 95%CI: 1.00-2.01; P = 0.05) when stratified by gender. Among the five major components of MetS, low high-density lipoprotein cholesterol was observed in men, while high body mass index, elevated blood pressure and the presence of diabetes mellitus were significant in women. CONCLUSIONS: High-frequent tea consumption increased the risk of MetS among older Chinese adults. These findings may add novel knowledge to the current studies regarding the controversial effect of tea consumption on cardiovascular and metabolic health among the aged population.

Design, synthesis and biological evaluation of pyridine derivatives as selective SHP2 inhibitors.

SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, which affects the transduction of multiple signaling pathways, including RAS-ERK, PI3K-AKT and JAK-STAT. SHP2 also plays an important role in the programmed cell death pathway (PD-1/PD-L1). Studies have shown that SHP2 is associated with a variety of cancers, including breast, liver and gastric cancers. Therefore, the development of SHP2 inhibitors has attracted extensive attention. In this study, based on the known inhibitor 1 (SHP099), novel SHP2 inhibitors were designed by means of scaffold hopping, and 35 pyridine derivatives as SHP2 inhibitors were found. The in vitro enzyme activity assay was performed on these compounds, and multiple selective SHP2 inhibitors with activity potency similar to that of SHP099 were obtained. Among them, compound (2-(4-(aminomethyl)piperidin-1-yl)-5-(2,3-dichlorophenyl)pyridin-3-yl)methanol (11a) was the most potent and highly selective SHP2 inhibitor with an in vitro enzyme activity IC50 value of 1.36 µM. Fluorescence titration assay verified that 11a bound directly to SHP2 protein. Subsequently, cell assay of representative compounds showed that these compounds could effectively inhibit the proliferation of Ba/F3 cells. In addition, the pharmacokinetic characteristics of the designed compounds were analyzed by the in silico ADMET prediction. Molecular docking study provided more detailed information on the binding mode of compounds and SHP2 protein. In brief, this study reported for the first time that pyridine derivatives as novel SHP2 inhibitors had good inhibitory activity and selectivity, providing new clues for the development of small molecule SHP2 inhibitors.

HIV infection confers distinct mechanisms in severe drug eruption: Endogenous virus activation with aberrant Th2/Th1 and CD8+ T cells function.

Severe drug eruption (SDE), a common skin disease, becomes dangerous when it occurs in patients with human immunodeficiency virus (HIV). However, the molecular mechanisms are poorly understood. Forty patients including HIV+ SDE+ (n = 15), HIV- SDE+ (n = 15) and HIV+ SDE- (n = 10) subjects were enrolled in our study. All HIV+ patients were at acquired immune deficiency syndrome (AIDS) stage. Serum levels of TNF-α, IFN-γ, IL-4, IL-13, IL-6, CXCL9, and CCL17 were quantified by ELISA. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) loads were quantified by RT-qPCR. CD4, CD8, Th1, Th2, TNF-α-CD8, and IFN-γ-CD8 T cell populations were measured by flow cytometry. Levels of biochemical indexes in HIV+ SDE+ patients were significantly different from in HIV- SDE+ patients (P < .05). EBV and CMV viral loads were significantly higher in HIV+ SDE+ patients, but not in HIV- SDE+ patients (P < .05). Inflammatory cytokines TNF-α and IFN-γ were significantly elevated in HIV+ SDE+ patients (P < .05). Th2/Th1 populations and TNF-α secreting or IFN-γ secreting CD8+ T cells, were significantly up-regulated in HIV+ SDE+ patients compared to HIV- SDE+ patients (P < .05). Conversely, the CD4/CD8 ratio was significantly down-regulated in HIV+ SDE+ patients compared to HIV- SDE+ patients (P < .05). HIV infection confers distinct clinical phenotypes and immune inflammatory mechanisms in SDE. Sustained EBV and CMV activation, unbalanced Th2/Th1 and overactive CD8+ T cells mediating a pro-inflammatory response could act as distinct mechanisms in the aggravation of SDE in HIV+ SDE+ patients.

Exploring the effect of N308D mutation on protein tyrosine phosphatase-2 cause gain-of-function activity by a molecular dynamics study.

One of the most common protein tyrosine phosphatase-2 (SHP2) mutations in Noonan syndrome is the N308D mutation, and it increases the activity of the protein. However, the molecular basis of the activation of N308D mutation on SHP2 conformations is poorly understood. Here, molecular dynamic simulations were performed on SHP2 and SHP2-N308D to explore the effect of N308D mutation on SHP2 cause gain of function activity, respectively. The principal component analysis, dynamic cross-correlation map, secondary structure analysis, residue interaction networks, and solvent accessible surface area analysis suggested that the N308D mutation distorted the residues interactions network between the allosteric site (residue Gly244-Gly246) and C-SH2 domain, including the hydrogen bond formation and the binding energy. Meanwhile, the activity of catalytic site (residue Gly503-Val505) located in the Q-loop in mutant increased due to this region's high fluctuations. Therefore, the substrate had more chances to access to the catalytic activity site of the precision time protocol domain of SHP2-N308D, which was easy to be exposed. In addition, we had speculated that the Lys244 located in the allosteric site was the key residue which lead to the protein conformation changes. Consequently, overall calculations presented in this study ultimately provide a useful understanding of the increased activity of SHP2 caused by the N308D mutation.

Exploring the effect of inhibitor AKB-9778 on VE-PTP by molecular docking and molecular dynamics simulation.

Diabetic macular edema, also known as diabetic eye disease, is mainly caused by the overexpression of vascular endothelial protein tyrosine phosphatase (VE-PTP) at hypoxia/ischemic. AKB-9778 is a known VE-PTP inhibitor that can effectively interact with the active site of VE-PTP to inhibit the activity of VE-PTP. However, the binding pattern of VE-PTP with AKB-9778 and the dynamic implications of AKB-9778 on VE-PTP system at the molecular level are poorly understood. Through molecular docking, it was found that the AKB-9778 was docked well in the binding pocket of VE-PTP by the interactions of hydrogen bond and Van der Waals. Furthermore, after molecular dynamic simulations on VE-PTP system and VE-PTP AKB-9778 system, a series of postdynamic analyses found that the flexibility and conformation of the active site undergone an obvious transition after VE-PTP binding with AKB-9778. Moreover, by constructing the RIN, it was found that the different interactions in the active site were the detailed reasons for the conformational differences between these two systems. Thus, the finding here might provide a deeper understanding of AKB-9778 as VE-PTP Inhibitor.

The TORC1-Sch9-Rim15 signaling pathway represses yeast-to-hypha transition in response to glycerol availability in the oleaginous yeast Yarrowia lipolytica.

The yeast-to-hypha dimorphic transition is important for survival under nutrient starvation in fungi. The oleaginous yeast Yarrowia lipolytica grows in the oval-shaped yeast form in glycerol media whereas it adopts a filamentous form in glucose media. It is not clear why this yeast responds differently to glycerol and glucose. Here, we show that glycerol blocks dimorphic transition even in the presence of glucose whereas glycerol depletion induces filamentous growth, suggesting that dimorphic transition is repressed in response to glycerol availability. We show that the repression of dimorphic transition in glycerol media is mediated by the TORC1-Sch9 signaling pathway as both TORC1 inhibition and the loss of YlSch9 cause hyperfilamentation. TORC1-Sch9 signaling inhibits the nuclear translocation of YlRim15, a protein kinase that positively regulates filamentous growth, preventing it from entering the nucleus to activate the transcription of genes implicated in filamentous growth. Interestingly, TORC1-Sch9 signaling appears not to inhibit YlRim15 in glucose media, which could explain why Y. lipolytica responds differently to glycerol and glucose. We identified MHY1, a transcription factor-encoding gene known to be critical for filamentous growth, as one target regulated by the TORC1-Sch9-Rim15 signaling pathway. Our results provide new insights in the regulation of dimorphic transition in yeast.

Roles of an N-terminal coiled-coil-containing domain in the localization and function of Bem3, a Rho GTPase-activating protein in budding yeast.

GTPase-activating proteins (GAPs) play critical roles in the spatial and temporal control of small GTPases. The budding yeast Bem3 is a GAP for Cdc42, a Rho GTPase crucial for actin and septin organization. Bem3 localizes to the sites of polarized growth. However, the amino acid sequence determinants mediating recruitment of Bem3 to its physiological sites of action and those important for Bem3 function are not clear. Here, we show that Bem3's localization is guided by two distinct targeting regions-the PX-PH-domain-containing TD1 and the coiled-coil-containing TD2. TD2 localization is largely mediated by its interaction with the polarisome component Epo1 via heterotypic coiled-coil interaction. This finding reveals a novel role for the polarisome in linking Bem3 to its functional target, Cdc42. We also show that the coiled-coil domain of Bem3 interacts homotypically and this interaction is important for the regulation of Cdc42 by Bem3. Moreover, we show that overexpression of a longer version of the TD2 domain disrupts septin-ring assembly in a RhoGAP-independent manner, suggesting that TD2 may be capable of interacting with proteins implicated in septin-ring assembly. Furthermore, we show that the longer version of TD2 interacts with Kss1, a MAPK involved in filamentous growth. Kss1 is reported to localize mainly in the nucleus. We find that Kss1 also localizes to the sites of polarized growth and Bem3 interacts with Kss1 at the septin-ring assembly site. Our study provides new insights in Bem3's localization and function.

Anti-HIV Activities and Mechanism of 12-O-Tricosanoylphorbol-20-acetate, a Novel Phorbol Ester from Ostodes katharinae.

APOBEC3G is a member of the human cytidine deaminase family that restricts Vif-deficient viruses by being packaged with progeny virions and inducing the G to A mutation during the synthesis of HIV-1 viral DNA when the progeny virus infects new cells. HIV-1 Vif protein resists the activity of A3G by mediating A3G degradation. Phorbol esters are plant-derived organic compounds belonging to the tigliane family of diterpenes and could activate the PKC pathway. In this study, we identified an inhibitor 12-O-tricosanoylphorbol-20-acetate (hop-8), a novel ester of phorbol which was isolated from Ostodes katharinae of the family Euphorbiaceae, that inhibited the replication of wild-type HIV-1 and HIV-2 strains and drug-resistant strains broadly both in C8166 cells and PBMCs with low cytotoxicity and the EC50 values ranged from 0.106 µM to 7.987 µM. One of the main mechanisms of hop-8 is to stimulate A3G expressing in HIV-1 producing cells and upregulate the A3G level in progeny virions, which results in reducing the infectivity of the progeny virus. This novel mechanism of hop-8 inhibition of HIV replication might represents a promising approach for developing new therapeutics for HIV infection.

A Silver(I)-Estrogen Nanocluster: GSH Sensitivity and Targeting Suppression on HepG2 Cell.

A structure-determined silver nanocluster of [Ag10 (Eth)4 (CF3 COO)6 (CH3 OH)3 ]·3C-H3 OH (Eth = ethisterone) (1), is firstly demonstrated by self-assembly of silver salt and ethisterone. Due to the thiophilicity of silver(I) ions, complex 1 shows reactivity with glutathione (GSH) molecules in solution and induces the fluorescence quenching behavior. Thus, complex 1 can be used as a fluorescent sensor for GSH. In consideration of the higher level of GSH in cancerous cells, complex 1 presents significant tumor suppression reactivity toward the human hepatocellular carcinoma (HepG2) cells with IC50 value of 165 × 10-9 m. Especially, complex 1 displays 3.4-fold higher in vitro cytotoxicity to HepG2 cells than that of the normal CCC-HEL-1 cells, which makes complex 1 a potential targeting suppression agent for cancerous cells. The molecular design of complex 1 not only generates a new medicine-silver(I) cluster family, but also opens a new avenue to the targeting anticancer organosilver(I) materials.

Design, synthesis and anti-HIV-1 evaluation of hydrazide-based peptidomimetics as selective gelatinase inhibitors.

As our ongoing work on research of gelatinase inhibitors, an array of hydrazide-containing peptidomimetic derivatives bearing quinoxalinone as well as spiro-heterocyclic backbones were designed, synthesized, and assayed for their in vitro enzymatic inhibitory effects. The results demonstrated that both the quinoxalinone (series I and II) and 1,4-dithia-7-azaspiro[4,4]nonane-based hydrazide peptidomimetics (series III) displayed remarkably selectivity towards gelatinase A as compared to APN, with IC50 values in the micromole range. Structure-activity relationships were herein briefly discussed. Given evidences have validated that gelatinase inhibition may be contributable to the therapy of HIV-1 infection, all the target compounds were also submitted to the preliminary in vitro anti-HIV-1 evaluation. It resulted that gelatinase inhibition really has positive correlation with anti-HIV-1 activity, especially compounds 4m and 7h, which gave enhanced gelatinase inhibition in comparison with the positive control LY52, and also decent anti-HIV-1 potencies. The FlexX docking results provided a straightforward insight into the binding pattern between inhibitors and gelatinase, as well as the selective inhibition towards gelatinase over APN. Collectively, our research encouraged potent gelatinase inhibitors might be used in the development of anti-HIV-1 agents. And else, compounds 4m and 7h might be promising candidates to be considered for further chemical optimization.

Engineering a switch-on peptide to ricin A chain for increasing its specificity towards HIV-infected cells.

BACKGROUND: Ricin is a type II ribosome-inactivating protein (RIP) that potently inactivates eukaryotic ribosomes by removing a specific adenine residue at the conserved α-sarcin/ricin loop of 28S ribosomal RNA (rRNA). Here, we try to increase the specificity of the enzymatically active ricin A chain (RTA) towards human immunodeficiency virus type 1 (HIV-1) by adding a loop with HIV protease recognition site to RTA. METHODS: HIV-specific RTA variants were constructed by inserting a peptide with HIV-protease recognition site either internally or at the C-terminal region of wild type RTA. Cleavability of variants by viral protease was tested in vitro and in HIV-infected cells. The production of viral p24 antigen and syncytium in the presence of C-terminal variants was measured to examine the anti-HIV activities of the variants. RESULTS: C-terminal RTA variants were specifically cleaved by HIV-1 protease both in vitro and in HIV-infected cells. Upon proteolysis, the processed variants showed enhanced antiviral effect with low cytotoxicity towards uninfected cells. CONCLUSIONS: RTA variants with HIV protease recognition sequence engineered at the C-terminus were cleaved and the products mediated specific inhibitory effect towards HIV replication. GENERAL SIGNIFICANCE: Current cocktail treatment of HIV infection fails to eradicate the virus from patients. Here we illustrate the feasibility of targeting an RIP towards HIV-infected cells by incorporation of HIV protease cleavage sequence. This approach may be generalized to other RIPs and is promising in drug design for combating HIV.

[Empathy for pain: A novel bio-psychosocial-behavioral laboratory animal model].

Empathy, a basic prosocial behavior, is referred to as an ability to understand and share others' emotional state. Generally, empathy is also a social-behavioral basis of altruism. In contrast, impairment of empathy development may be associated with autism, narcissism, alexithymia, personality disorder, schizophrenia and depression. Thus, study of the brain mechanisms of empathy has great importance to not only scientific and clinical advances but also social harmony. However, research on empathy has long been avoided due to the fact that it has been considered as a distinct feature of human beings from animals, leading to paucity of knowledge in the field. In 2006, a Canadian group from McGill University found that a mouse in pain could be shared by its paired cagemate, but not a paired stranger, showing decreased pain threshold and increased pain responses through emotional contagion while they were socially interacting. In 2014, we further found that a rat in pain could also be shared by its paired cagemate 30 min after social interaction, showing long-term decreased pain threshold and increased pain responses, suggesting persistence of empathy for pain (empathic memory). We also mapped out that the medial prefrontal cortex, including the anterior cingulate cortex, prelimbic cortex and infralimbic cortex, is involved in empathy for pain in rats, suggesting that a neural network may be associated with development of pain empathy in the CNS. In the present brief review, we give a brief outline of the advances and challenges in study of empathy for pain in humans and animals, and try to provide a novel bio-psychosocial-behavioral model for study of pain and its emotional comorbidity using laboratory animals.

Inhibition of macrophage MAPK/NF-κB pathway and Th2 axis by mangiferin ameliorates MC903-induced atopic dermatitis.

Available online Atopic dermatitis (AD) is a chronic, persistent inflammatory skin disease characterized by eczema-like lesions and itching. Although topical steroids have been reported for treating AD, they are associated with adverse effects. Thus, safer medications are needed for those who cannot tolerate these agents for long periods. Mangiferin (MAN) is a flavonoid widely found in many herbs, with significant anti-inflammatory and immunomodulatory activities. However, the potential modulatory effects and mechanisms of MAN in treating Th2 inflammation in AD are unknown. In the present study, we reported that MAN could reduce inflammatory cell infiltration and scratching at the lesion site by decreasing MC903-induced levels of Th2-type cytokines, Histamine, thymic stromal lymphopoietin, Leukotriene B4, and immunoglobulin E. The mechanism may be related to reductions in MAPK and NF-κB-associated protein phosphorylation by macrophages. The results suggested that MAN may be a promising therapeutic agent for AD.