Designing, structural determination and biological effects of rifaximin loaded chitosan- carboxymethyl chitosan nanogel.

Due to the poor solubility and permeability of rifaximin (RFX), it is not effective against intracellular pathogens although it shows strong activity against most bacteria. To develop an effective mucoadhesive drug delivery system with a targeted release in bacterial infection site, RFX-loaded chitosan (CS)/carboxymethyl-chitosan (CMCS) nanogel was designed and systematically evaluated. FTIR, DSC, and XRD demonstrated that the nanogel was formed by interactions between the positively charged NH on CS and CMCS, and the negatively charged COO on CMCS.

Down-Regulation of USP8 Suppresses HER-3 Positive Gastric Cancer Cells Proliferation.

Background: Ubiquitin specific peptidase 8 (USP8) has been reported to induce the degradation of several receptor tyrosine kinases such as epidermal growth factor receptor (EGFR), among which human epidermal growth factor receptor-3 (HER-3) is one of them. However, the role and functional mechanisms of USP8 and HER-3 in gastric cancer (GC) remain unknown.

Objective: To explore the function and mechanism of USP8 and HER-3 in the progression of GC.

EPS8 regulates an NLRP3 inflammasome-independent caspase-1 activation pathway in monosodium urate crystal-treated RAW264.7 macrophages.

Gout is an inflammatory arthritis caused by the phagocytosis of monosodium urate (MSU) crystal deposition in joints. NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome-dependent caspase-1 activation is implicated in the processing of interleukin-1β (IL-1β), which is the major effector cytokine in the acute inflammatory response of gout. Mechanisms underlying caspase-1 activation remain unclear.

LSD1 deletion represses gastric cancer migration by upregulating a novel miR-142-5p target protein CD9.

LSD1 (histone lysine specific demethylase 1) takes part in the physiological process of cell differentiation, EMT (epithelial-mesenchymal transition) and immune response. In this study, we found LSD1 expression in metastatic gastric cancer tissues was significantly higher than that in normal tissues. Furthermore, LSD1 deletion was found to suppress gastric cancer migration by decreasing intracellular miR-142-5p, which further led to the upregulation of migration suppressor CD9, a newly identified target of miR-142-5p.

Src is required for migration, phagocytosis, and interferon beta production in Toll-like receptor-engaged macrophages.

As an evolutionarily conserved mechanism, innate immunity controls self-nonself discrimination to protect a host from invasive pathogens. Macrophages are major participants of the innate immune system. Through the activation of diverse Toll-like receptors (TLRs), macrophages are triggered to initiate a variety of functions including locomotion, phagocytosis, and secretion of cytokines that requires the participation of tyrosine kinases.

Validation of Interstitial Fractional Volume Quantification by Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Porcine Skeletal Muscles.

Objectives: The aim of our study was to assess the accuracy of fractional interstitial volume determination in low perfused and low vascularized tissue by using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).

Materials And Methods: The fractional interstitial volume (ve) was determined in the medial thigh muscle of 12 female pigs by using a 3-dimensional gradient echo sequence with k-space sharing and administering gadolinium-based contrast agent (gadoterate meglumine). Analysis was performed using 3 pharmacokinetic models: the simple Tofts model (TM), the extended TM (ETM), and the 2-compartment exchange model (2CXM).

The contributions of the tissue inhibitor of metalloproteinase-1 genotypes to triple negative breast cancer risk.

The tissue inhibitors of metalloproteinases (TIMPs) are a family of multifunctional proteins which have been shown to be upregulated in various types of cancers. However, the contribution of TIMPs in breast cancer is not fully understood, not to mention triple negative breast cancer (TNBC). This study's aim was to evaluate the contribution of TIMP-1 rs4898, rs6609533, and rs2070584 genotypes to the risk of breast cancer, especially the subtype of TNBC.

The iNOS/Src/FAK axis contributes to lithium chloride-mediated macrophage migration.

Lithium chloride (LiCl) has long been used as a mood stabilizer for bipolar mood depression patients. However, its biological effects on immune cells are unclear yet. In this study, we observed that upon LiCl stimulation, the motility and the content of total protein tyrosine phosphorylation in RAW264.

Berberine reduces Toll-like receptor-mediated macrophage migration by suppression of Src enhancement.

Berberine is an isoquinoline with anti-inflammatory activity. We previously demonstrated that there was a loop of signal amplification between nuclear factor kappa B and Src for macrophage mobility triggered by the engagement of Toll-like receptors (TLRs). The simultaneous suppression of lipopolysaccharide (LPS)-mediated upregulation of inducible nitric oxide synthase, cyclooxygenase 2, and cell mobility in berberine-treated macrophages suggested Src might be a target of berberine.

Lipopolysaccharide-promoted proliferation of Caco-2 cells is mediated by c-Src induction and ERK activation.

As a major component of the cell wall of Gram-negative bacteria, lipopolysaccharide (LPS) can be released into the bloodstream to cause a spectrum of pathophysiological reactions. Despite the fact that colon epithelium cells in situ are continuously exposed to LPS, their biological responses as provoked by LPS as well as the underlying mechanisms are poorly defined. In the present study, we observed that LPS directly stimulated growth of Caco-2 cells as well as enhanced the amounts of c-Src, which could be partly attributable to increased c-src transcript.

Contribution of personalized Cyclin D1 genotype to triple negative breast cancer risk.

Aim: Cell cycle regulator is a pivotal regulator for G1/S phase transition, playing a critical part in initiation of carcinogenesis. Triple negative breast cancer comprises a very heterogeneous group of cancer cells, but little is known about what is wrong in the genome of these patients. This study investigated contribution of genotype to individual triple negative breast cancer susceptibility.

TLR7/8 agonists activate a mild immune response in rabbits through TLR8 but not TLR7.

Toll-like receptors 7 (TLR7) and 8 (TLR8) recognize viral single-stranded RNA and small molecular weight agonists to activate anti-viral immune responses. TLR8s from different species have distinct ligand recognitions. For example, human TLR8 is responsive to ligand stimulation, but mouse and rat TLR8 are activated by small molecular weight agonists only in the presence of polyT-oligodeoxynucleotides.

The inducible nitric-oxide synthase (iNOS)/Src axis mediates Toll-like receptor 3 tyrosine 759 phosphorylation and enhances its signal transduction, leading to interferon-β synthesis in macrophages.

Double-stranded RNA (dsRNA) induces phosphorylation of Toll-like receptor 3 (TLR3) at tyrosine 759 and subsequently triggers signaling pathways to promote interferon-β (IFN-β) production. In this study, we found that dsRNA stimulation induces biphasic TLR3 Tyr-759 phosphorylation in macrophages. In addition to the immediate TLR3 Tyr-759 phosphorylation, we identified a second wave of Tyr-759 phosphorylation accompanied by an increase of both Src and ifn-β transcription in the later phase of dsRNA stimulation.

Elevated peripheral eosinophils are associated with new-onset and persistent wheeze and airflow obstruction in world trade center-exposed individuals.

Background: Exposure to World Trade Center (WTC) dust and fumes is associated with the onset of asthma-like respiratory symptoms in rescue and recovery workers and exposed community members. Eosinophilic inflammation with increased lung and peripheral eosinophils has been described in subpopulations with asthma. We hypothesized that persistent asthma-like symptoms in WTC-exposed individuals would be associated with systemic inflammation characterized by peripheral eosinophils.

Expression of Eps8 correlates with poor survival in oral squamous cell carcinoma.

Aims: Epidermal growth factor receptor pathway substrate 8 (Eps8) is a signaling protein implicated in the development of many human cancers including oral squamous cell carcinoma (OSCC). This study examined the expression of Eps8 and assessed its significance in patients with OSCC.

Methods: Immunohistochemical staining for Eps8 was conducted in 205 cases of OSCC collected over 7 years.

Eps8 protein facilitates phagocytosis by increasing TLR4-MyD88 protein interaction in lipopolysaccharide-stimulated macrophages.

Toll-like receptors (TLRs) are crucial in macrophage phagocytosis, which is pivotal in host innate immune response. However, the detailed mechanism is not fully defined. Here, we demonstrated that the induction of Src and Eps8 in LPS-treated macrophages was TLR4- and MyD88-dependent, and their attenuation reduced LPS-promoted phagocytosis.

Helicobacter pylori attenuates lipopolysaccharide-induced nitric oxide production by murine macrophages.

Intragastric growth of Helicobacter pylori and non-Helicobacter microorganisms is thought to be associated with elevated levels of pro-inflammatory cytokines and the production of NO these effects can lead to chronic inflammation. Microorganisms can activate the expression of iNOS and the production of NO by macrophages through stimulation with bacterial LPS. Helicobacter pylori can evade these vigorous immune responses, but the underlying mechanism remains unknown.

zVAD-induced autophagic cell death requires c-Src-dependent ERK and JNK activation and reactive oxygen species generation.

The treatment of L929 fibrosarcoma cells with zVAD has been shown to induce necroptosis. However, whether autophagy is involved or not in this event remains controversial. In this study, we re-examined the role of autophagy in zVAD-induced cell death in L929 cells and further elucidated the signaling pathways triggered by caspase inhibition and contributing to autophagic death.

The iNOS/Src/FAK axis is critical in Toll-like receptor-mediated cell motility in macrophages.

The Toll-like receptors (TLRs) play a pivotal role in innate immunity for the detection of highly conserved, pathogen-expressed molecules. Previously, we demonstrated that lipopolysaccharide (LPS, TLR4 ligand)-increased macrophage motility required the participation of Src and FAK, which was inducible nitric oxide synthase (iNOS)-dependent. To investigate whether this iNOS/Src/FAK pathway is a general mechanism for macrophages to mobilize in response to engagement of TLRs other than TLR4, peptidoglycan (PGN, TLR2 ligand), polyinosinic-polycytidylic acid (polyI:C, TLR3 ligand) and CpG-oligodeoxynucleotides (CpG, TLR9 ligand) were used to treat macrophages in this study.

The interplay between Eps8 and IRSp53 contributes to Src-mediated transformation.

As an oncoprotein, Eps8 participates in v-Src-induced cellular transformation. To delineate the underlying mechanism, we conducted a yeast two-hybrid screening and identified IRSp53S, a protein critical in cell mobilization, as one of the Eps8-binding partners from a human brain cDNA library. The association was mediated by the multiple proline-rich regions of Eps8 and the C-terminal SH3-WWB containing domains of IRSp53S.

Butyrate reduced lipopolysaccharide-mediated macrophage migration by suppression of Src enhancement and focal adhesion kinase activity.

Macrophage motility is vital in innate immunity. Lipopolysaccharide (LPS)-mediated macrophage migration requires the enhancement of Src expression and enzymatic activity, which can be regulated by inducible nitric oxide synthase (iNOS). As a major short-chain fatty acid with histone deacetylase (HDAC) inhibitor activity, butyrate exerts anti-inflammatory effect by regulating the expression of cytokines.

Mithramycin inhibits human epithelial carcinoma cell proliferation and migration involving downregulation of Eps8 expression.

Mithramycin is an inhibitor of the binding of the Sp-family transcription factor to the GC box. Many studies show that mithramycin may reduce the expression of many oncogenes by inhibiting the mRNA and protein synthesis and it has been used as an antibiotic chemotherapy drug for a long time. Recently, Eps8 (EGFR pathway substrate 8) has been revealed to be a novel proto-oncogene related to cellular transformation, Rac activation and actin barbed-end-capping activity.

Requirement of inducible nitric-oxide synthase in lipopolysaccharide-mediated Src induction and macrophage migration.

Previously, we have demonstrated the induction of Src in lipopolysaccharide (LPS)-stimulated macrophages. In this study, we observed that pharmacological blockade or knockout of inducible nitric-oxide synthase (iNOS) reduced LPS-mediated Src induction and macrophage migration. Either SNAP (a NO donor) or 8-Br-cGMP (a cGMP analogue) could rescue these defects in iNOS-null macrophages, which indicated the participation of NO/cGMP in LPS-elicited Src expression and mobilization.