Induction of CXCR3- and CCR5-associated chemokines during acute hepatitis C virus infection.

Background & Aims: Characterization of inflammatory mediators, such as chemokines, during acute hepatitis C virus (HCV) infection might shed some light on viral clearance mechanisms.

Methods: Plasma levels of CXCR3 (CXCL9-11)- and CCR5 (CCL3-4)-associated chemokines, ALT, and HCV RNA were measured in nine injection drug users (median 26 samples/patient) before and during 10 acute (eight primary and two secondary) HCV infections. Using functional data analysis, we estimated smooth long-term trends in chemokine expression levels to obtain the magnitude and timing of overall changes.

Peripheral CXCR3-associated chemokines as biomarkers of fibrosis in chronic hepatitis C virus infection.

Background: CXCR3-associated chemokines CXCL9-CXCL11 promote histologic progression in chronic hepatitis C virus (HCV) infection, as indicated by elevated intrahepatic levels of messenger RNA in patients with advanced inflammation and fibrosis. We evaluated the potential of peripheral chemokine levels to discriminate among patients with chronic HCV infection who had different stages of fibrosis.

Methods: Peripheral levels of CXCR3-associated chemokines were measured by enzyme-linked immunosorbent assay of plasma samples obtained from 93 patients with chronic HCV infection.

Intrahepatic levels of CXCR3-associated chemokines correlate with liver inflammation and fibrosis in chronic hepatitis C.

Unlabelled: Chemokines, chemotactic cytokines, may promote hepatic inflammation in chronic hepatitis C virus (HCV) infection through the recruitment of lymphocytes to the liver parenchyma. We evaluated the association between inflammation and fibrosis and CXCR3-associated chemokines, interferon-gamma (IFN-gamma)-inducible protein 10 (IP-10/CXCL10), monokine induced by IFN-gamma (Mig/CXCL9), and interferon-inducible T cell alpha chemoattractant (I-TAC/CXCL11), in HCV infection. Intrahepatic mRNA expression of these chemokines was analyzed in 106 chronic HCV-infected patients by real-time PCR.

Interferon gamma-inducible protein 10: a predictive marker of successful treatment response in hepatitis C virus/HIV-coinfected patients.

Background: Elevated pretreatment interferon (IFN) gamma-inducible protein 10 (IP-10/CXCL10) levels are a marker of treatment nonresponse in hepatitis C virus (HCV)-monoinfected patients. We undertook this study to determine if IP-10 is a marker of treatment outcome in HCV/HIV-coinfected patients.

Methods: Nineteen HCV/HIV-coinfected patients were treated with weight-based pegylated (PEG) IFNalpha-2b (1.

3-Nitropropionic acid toxicity in hippocampus: protection through N-methyl-D-aspartate receptor antagonism.

The over-activation of glutamate receptors can lead to excitotoxic cell death and is believed to be involved in the progression of neurodegenerative events in the vulnerable hippocampus. Here, we used an in vitro slice model to study toxicity produced in the hippocampus by the mitochondrial toxin 3-nitropropionic acid (3-NP). The organotypic slice cultures exhibit native cellular organization as well as dense arborization of neuronal processes and synaptic contacts.

Cellular responses to protein accumulation involve autophagy and lysosomal enzyme activation.

Protein oligomerization and aggregation are key events in age-related neurodegenerative disorders, causing neuronal disturbances including microtubule destabilization, transport failure and loss of synaptic integrity that precede cell death. The abnormal buildup of proteins can overload digestive systems and this, in turn, activates lysosomes in different disease states and stimulates the inducible class of lysosomal protein degradation, macroautophagy. These responses were studied in a hippocampal slice model well known for amyloidogenic species, tau aggregates, and ubiquitinated proteins in response to chloroquine-mediated disruption of degradative processes.

Dual modulation of endocannabinoid transport and fatty acid amide hydrolase protects against excitotoxicity.

The endocannabinoid system has been suggested to elicit signals that defend against several disease states including excitotoxic brain damage. Besides direct activation with CB1 receptor agonists, cannabinergic signaling can be modulated through inhibition of endocannabinoid transport and fatty acid amide hydrolase (FAAH), two mechanisms of endocannabinoid inactivation. To test whether the transporter and FAAH can be targeted pharmacologically to modulate survival/repair responses, the transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) and the FAAH inhibitor palmitylsulfonyl fluoride (AM374) were assessed for protection against excitotoxicity in vitro and in vivo.

Blocking cannabinoid activation of FAK and ERK1/2 compromises synaptic integrity in hippocampus.

The cannabinoid CB1 receptor allows endocannabinoids to act as intercellular and retrograde messengers in the central nervous system. Endocannabinoid actions have been implicated in both synaptic plasticity and neuroprotection. Here, cannabinergic activation of extracellular signal regulated-kinase (ERK) and focal adhesion kinase (FAK) occurred correspondingly in long-term hippocampal slice cultures.

Intracellular deposition, microtubule destabilization, and transport failure: an "early" pathogenic cascade leading to synaptic decline.

Protein deposition is a common event in age-related neurological diseases that are characterized by neuronal dysfunction and eventual cell death. Here, cultured hippocampal slices were infused with the lysosomal disrupter chloroquine to examine the link between abnormal protein processing/deposition and early synaptopathogenesis. Tau species of 55 to 69 kDa increased over several days of treatment with chloroquine, while the protein and message levels of synaptic markers were selectively reduced.

Peptidyl alpha-keto amide inhibitor of calpain blocks excitotoxic damage without affecting signal transduction events.

The cysteine protease calpain is activated by calcium and has a wide range of substrates. Calpain-mediated cellular damage is associated with many neuropathologies, and calpain also plays a role in signal transduction events that are essential for cell maintenance, including the activation of important kinases and transcription factors. In the present study, the hippocampal slice culture was used as a model of excitotoxicity to test whether the neuroprotection elicited by selective calpain inhibition is associated with changes in cell signaling.

Survival signaling and selective neuroprotection through glutamatergic transmission.

In the brain, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors mediate glutamatergic neurotransmission and, when intensely activated, can induce excitotoxic cell death. In addition to their ionotropic properties, however, AMPA receptors have been functionally coupled to a variety of signal transduction events involving Src-family kinases, G-proteins, and the mitogen-activated protein kinase (MAPK). In the present study, we tested whether AMPA receptors are linked to appropriate signaling events in order to prevent neuronal injury and/or enhance recovery.