Mangiferin prevents hepatocyte epithelial-mesenchymal transition in liver fibrosis via targeting HSP27-mediated JAK2/STAT3 and TGF-ß1/Smad pathway.

Hepatocytes has been confirmed to undergo EMT and can be converted into myofibroblasts during hepatic fibrogenesis. However, the mechanism of hepatocyte EMT regulation in hepatic fibrosis, particularly through HSP27 (human homologue of rodent HSP25), remains unclear. Mangiferin (MAN), a compound extracted from Mangifera indica L, has been reported to attenuate liver injury. This study aimed to investigate the mechanisms underlying HSP27 inhibition and the anti-fibrotic effect of MAN in liver fibrosis. Our results revealed that the expression of HSP27 was remarkably increased in the liver tissues of patients with liver cirrhosis and CCl4 -induced fibrotic rats. However, HSP27 shRNA treatment significantly alleviated fibrosis. Furthermore, MAN was found to inhibit CCl4 - and TGF-ß1-induced liver fibrosis and reduced hepatocyte EMT. More importantly, MAN decreased HSP27 expression to suppress the JAK2/STAT3 pathway, and subsequently blocked TGF-ß1/Smad signaling, which were consistent with its protection against CCl4 -induced EMT and liver fibrosis. Together, these results suggest that HSP27 may play a crucial role in hepatocyte EMT and liver fibrosis by activating JAK2/STAT3 signaling and TGF-ß1/Smad pathway. The suppression of HSP27 expression by MAN may be a novel strategy for attenuating the hepatocyte EMT in liver fibrosis.

Anti-inflammatory and neuroprotective effects of natural cordycepin in rotenone-induced PD models through inhibiting Drp1-mediated mitochondrial fission.

Accumulating evidences suggest that inflammation-mediated neurons dysfunction participates in the initial and development of Parkinson's disease (PD), whereas mitochondria have been recently recognized as crucial regulators in NLRP3 inflammasome activation. Cordycepin, a major component of cordyceps militaris, has been shown to possess neuroprotective and anti-inflammatory activity. However, the effects of cordycepin in rotenone-induced PD models and the possible mechanisms are still not fully understood. Here, we observed that motor dysfunction and dopaminergic neurons loss induced by rotenone exposure were ameliorated by cordycepin. Cordycepin also reversed Drp1-mediated aberrant mitochondrial fragmentation through increasing AMPK phosphorylation and maintained normal mitochondrial morphology. Additionally, cordycepin effectively increased adenosine 5'-triphosphate (ATP) content, mitochondrial membrane potential (MMP), and reduced mitochondrial ROS levels, as well as inhibited complex 1 activity. More importantly, cordycepin administration inhibited the expression of NLRP3 inflammasome components and the release of pro-inflammatory cytokine in rotenone-induced rats and cultured neuronal PC12 cells. Moreover, we demonstrated that the activation of NLRP3 inflammasome within neurons could be suppressed by the mitochondrial division inhibitor (Mdivi-1). Collectively, the present study provides evidence that cordycepin exerts neuroprotective effects partially through preventing neural NLRP3 inflammasome activation induced by Drp1-dependent mitochondrial fragmentation in rotenone-injected PD models.

The role of heat shock proteins in the regulation of fibrotic diseases.

Heat shock proteins (HSPs) are key players to restore cell homeostasis and act as chaperones by assisting the folding and assembly of newly synthesized proteins and preventing protein aggregation. Recently, evidence has been accumulating that HSPs have been proven to have other functions except for the classical molecular chaperoning in that they play an important role in a wider range of fibrotic diseases via modulating cytokine induction and inflammation response, including lung fibrosis, liver fibrosis, and idiopathic pulmonary fibrosis. The recruitment of inflammatory cells, a large number of secretion of pro-fibrotic cytokines such as transforming growth factor-ß1 (TGF-ß1) and increased apoptosis, oxidative stress, and proteasomal system degradation are all events occurring during fibrogenesis, which might be associated with HSPs. However, their role on fibrotic process is not yet fully understood. In this review, we discuss new discoveries regarding the involvement of HSPs in the regulation of organ and tissue fibrosis, and note recent findings suggesting that HSPs may be a promising therapeutic target for improving the current frustrating outcome of fibrotic disorders.

Drp1, a potential therapeutic target for Parkinson's disease, is involved in olfactory bulb pathological alteration in the Rotenone-induced rat model.

Olfaction is often affected in parkinsonian patients and its disturbances precede the classical cognitive and locomotor dysfunction. The olfactory bulb might be the region of onset in Parkinson's disease (PD) pathogenesis, evidenced by the presence of disease-related protein aggregates and disturbed olfactory information processing. However, the underlying molecular mechanism that governs the olfactory bulb impairments remains unclear. This study was designed to investigate the relationship between olfactory bulb and inflammatory pathological alterations and the potential mechanisms. Here we found that rotenone led to typical parkinsonian symptoms and decreased tyrosine hydroxylase (TH)-positive neurons in the olfactory bulb. Additionally, increased NF-κB nuclear translocation and NLRP3 inflammasome components expressions caused by rotenone injection were observed accompanied by the activation of microglia and astrocytes in the olfactory bulb. Rotenone also triggered Drp1-mediated mitochondrial fission and this in turn caused mitochondrial damage. Furthermore, Mdivi-1(a selective Drp1 inhibitor) markedly ameliorated the morphologic disruptions of mitochondria and Drp1 translocation, inhibited the nuclear translocation of NF-κB, eventually blocked the downstream pathway of the NLRP3/caspase-1/IL-1ß axis and expression of iNOS. Overall, these findings suggest that Drp1-dependent mitochondrial fission induces NF-κB nuclear translocation and NLRP3 inflammasome activation that may further contribute to olfactory bulb disturbances.

Role of GTPases in the regulation of mitochondrial dynamics in Parkinson's disease.

Mitochondria are highly dynamic organelle that undergo frequent fusion and division, and the balance of these opposing processes regulates mitochondrial morphology, distribution, and function. Mitochondrial fission facilitates the replication and distribution of mitochondria during cell division, whereas the fusion process including inner and outer mitochondrial membrane fusion allows the exchange of intramitochondrial material between adjacent mitochondria. Despite several GTPase family proteins have been implicated as key modulators of mitochondrial dynamics, the mechanisms by which these proteins regulate mitochondrial homeostasis and function remain not clearly understood. Neuronal function and survival are closely related to mitochondria dynamics, and disturbed mitochondrial fission/fusion may influence neurotransmission, synaptic maintenance, neuronal survival and function. Recent studies have shown that mitochondrial dysfunction caused by aberrant mitochondrial dynamics plays an essential role in the pathogenesis of both sporadic and familial Parkinson's disease (PD). Collectively, we review the molecular mechanism of known GTPase proteins in regulating mitochondrial fission and fusion, but also highlight the causal role for mitochondrial dynamics in PD pathogenesis.

Effects of breviscapine on amyloid beta 1-42 induced Alzheimer's disease mice: A HPLC-QTOF-MS based plasma metabonomics study.

Herba Erigerontis has long been used to cure apoplexy hemiplegia and precordial pain in China. In addition, the bioactivities of its total flavonoids-breviscapine included inhibiting amyloid beta (Aß) fibril formation, antioxidation and metal chelating, which are beneficial to treat Alzheimer's disease (AD). Hence, A HPLC-QTOF-MS based plasma metabonomics approach was applied to investigate the neuroprotective effects of breviscapine on intracerebroventricular injection of aggregated Aß 1-42 induced AD mice for the first time in the study. Ten potential biomarkers were screened out by multivariate statistical analysis, eight of which were further identified as indoleacrylic acid, C16 sphinganine, LPE (22:6), sulfolithocholic acid, LPC (16:0), PA (22:1/0:0), taurodeoxycholic acid, and PC (0:0/18:0). According to their metabolic pathways, it was supposed that breviscapine ameliorated the learning and memory deficits of AD mice predominantly by regulating phospholipids metabolism, elevating serotonin level and lowering cholesterols content in vivo.

Human fused NKG2D-IL-15 protein controls xenografted human gastric cancer through the recruitment and activation of NK cells.

Interleukin (IL)-15 plays an important role in natural killer (NK) and CD8+ T-cell proliferation and function and is more effective than IL-2 for tumor immunotherapy. The trans-presentation of IL-15 by neighboring cells is more effective for NK cell activation than its soluble IL-15. In this study, the fusion protein dsNKG2D-IL-15, which consisted of two identical extracellular domains of human NKG2D coupled to human IL-15 via a linker, was engineered in Escherichia coli. DsNKG2D-IL-15 could efficiently bind to major histocompatibility complex class I chain-related protein A (MICA) of human tumor cells with the two NKG2D domains and trans-present IL-15 to NK or CD8+ T cells. We transplanted human gastric cancer (SGC-7901) cells into nude mice and mouse melanoma cells with ectopic expression of MICA (B16BL6-MICA) into C57BL/6 mice. Then, we studied the anti-tumor effects mediated by dsNKG2D-IL-15 in the two xenografted tumor models. Human dsNKG2D-IL-15 exhibited higher efficiency than IL-15 in suppressing gastric cancer growth. Exogenous human dsNKG2D-IL-15 was centrally distributed in the mouse tumor tissues based on in vivo live imaging. The frequencies of human CD56+ cells infiltrated into the tumor tissues following the injection of peripheral blood mononuclear cells into nude mice bearing human gastric cancer were significantly increased by human dsNKG2D-IL-15 treatment. Human dsNKG2D-IL-15 also delayed the growth of transplanted melanoma (B16BL6-MICA) by activating and recruiting mouse NK and CD8+ T cells. The anti-melanoma effect of human dsNKG2D-IL-15 in C57BL/6 mice was mostly decreased by the in vivo depletion of mouse NK cells. These data highlight the potential use of human dsNKG2D-IL-15 for tumor therapy.Cellular & Molecular Immunology advance online publication, 14 September 2015; doi:10.1038/cmi.2015.81.

[Efffect of baicalin on antipyresis and influence on cytokine].

OBJECTIVE: To study the antipyretic effect of baicalin in inhibiting yeast-induced fever in rats and the influence on inflammatory cytokine, then explore the possible mechanism of baicalin in inhibiting yeast-induced fever in rats. METHODS: Rat modles of pyrexia were established by subcutaneous injection of yeast (2 g x kg(-1)); the rats of were divided into the normal control, model, baicalin high, medium and low-dose group and the effect of baicalin on the changes of the rats' temperature were observed. Dual antibody ELISA method was used to test the changes of IL-6, IL-1beta and TNF-alpha contents in in serum , hypothalamus and cerebral spinal fluid (CSF). Then analyze the correlation between the inhibition ratio of temperature heighten on three different dose of baicalin and the inhibition ratio of the contents heighten on IL-6, IL-1beta and TNF-alpha. RESULT: The high dose of baicalin significantly inhibited the yeast-induced fever of rats, and decresesed IL-6, IL-1beta and TNF-alpha contents in serum, hypothalamus and CSF. The inhibition ratio of temperature heighten of baicalin had direct correlation with the inhibition ratio of the heighten on IL-1beta content in serum, hypothalamus and CSF (r = 0.873, P < 0.05), also dose TNF-alpha (r = 0.862, P < 0.01). CONCLUSION: Baicalin may have obvious antipyretic effect by decreasing the increasing contents of IL-1beta and TNF-alpha in rats.

[Effects of human recombinant interleukin-1 receptor antagonist on isolated trachea smooth muscle of the guinea pig].

AIM: To study the effects of human recombinant interleukin-1 receptor antagonist (IL-1ra) on isolated trachea smooth muscle (TSM) of the guinea pig. METHODS: Changes of the tension of isolated trachea were measured by force-displacement transducer and MedLab recording system in vitro. RESULTS: IL-1ra showed direct relaxed effect on TSM in normal and ovalbumin sensitized guinea pig. The EC50 values were 8.06 x 10(-8) and 5.88 x 10(-7) mol.L-1 respectively. IL-1ra (1 x 10(-7)-1 x 10(-5) mol.L-1) concentration-dependently inhibited the contraction of TSM induced by 1 x 10(-3) mol.L-1 histamine (His), 1 x 10(-3) mol.L-1 acetylcholine (ACh) and 1 x 10(-6) mol.L-1 5-hydroxytryptamine (5-HT) (P < 0.05 or 0.01). When IL-1ra was given in advance, the contractile actions of His, ACh and 5-HT were antagonized by IL-1ra (1 x 10(-7)-1 x 10(-5) mol.L-1), the pD'2 value for His was 6.6 +/- 0.3. However, the contractile action of ACh was enhanced by IL-1ra at low concentration of 1 x 10(-9)-1 x 10(-8) mol.L-1. IL-1ra significantly prevented and inhibited the contraction of sensitized TSM induced by antigen ovalbumin, the IC50 value was 4.48 x 10(-7) mol.L-1. CONCLUSION: The results indicate that IL-1ra, within certain concentration, can relax the normal, contracted and sensitized ISM of the guinea pig in vitro.