Monoclonal full-length antibody against TAR DNA binding protein 43 reduces related proteinopathy in neurons.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), 2 incurable neurodegenerative disorders, share the same pathological hallmark named TDP43 (TAR DNA binding protein 43) proteinopathy. This event is characterized by a consistent cytoplasmic mislocalization and aggregation of the protein TDP43, which loses its physiological properties, leading neurons to death. Antibody-based approaches are now emerging interventions in the field of neurodegenerative disorders.

Mitigation of ALS Pathology by Neuron-Specific Inhibition of Nuclear Factor Kappa B Signaling.

To investigate the role of neuronal NF-κB activity in pathogenesis of amyotrophic lateral sclerosis (ALS), we generated transgenic mice with neuron-specific expression of a super-repressor form of the NF-κB inhibitor (IκBα-SR), which were then crossed with mice of both sexes, expressing ALS-linked gene mutants for TAR DNA-binding protein (TDP-43) and superoxide dismutase 1 (SOD1). Remarkably, neuronal expression of IκBα-SR transgene in mice expressing TDP-43 or TDP-43 mice led to a decrease in cytoplasmic to nuclear ratio of human TDP-43. The mitigation of TDP-43 neuropathology by IκBα-SR, which is likely due to an induction of autophagy, was associated with amelioration of cognitive and motor deficits as well as reduction of motor neuron loss and gliosis.

Protective effects of Withania somnifera extract in SOD1 mouse model of amyotrophic lateral sclerosis.

Withania somnifera (WS; commonly known as Ashwagandha or Indian ginseng) is a medicinal plant whose extracts have been in use for centuries in various regions of the world as a rejuvenator. There is now a growing body of evidence documenting neuroprotective functions of the plant extracts or its purified compounds in several models of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Based on the extract's beneficial effect in a mouse model of ALS with TDP-43 proteinopathy, the current study was designed to test its efficacy in another model of familial ALS.

Recent advances in Japanese encephalitis.

Japanese encephalitis is a flaviviral disease that is endemic to the South, Southeast Asia, and Asia Oceania regions. Given that about 60% of the world's population (about 7.4 billion) resides in this region (about 4.

Withania somnifera Reverses Transactive Response DNA Binding Protein 43 Proteinopathy in a Mouse Model of Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration.

Abnormal cytoplasmic mislocalization of transactive response DNA binding protein 43 (TARDBP or TDP-43) in degenerating neurons is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Our previous work suggested that nuclear factor kappa B (NF-κB) may constitute a therapeutic target for TDP-43-mediated disease. Here, we investigated the effects of root extract of Withania somnifera (Ashwagandha), an herbal medicine with anti-inflammatory properties, in transgenic mice expressing a genomic fragment encoding human TDP-43 mutant.

Ubiquilin-2 drives NF-κB activity and cytosolic TDP-43 aggregation in neuronal cells.

Background: Mutations in the gene encoding Ubiquilin-2 (UBQLN2) are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). UBQLN2 plays a central role in ubiquitin proteasome system (UPS) and UBQLN2 mutants can form cytoplasmic aggregates in vitro and in vivo.

Results: Here, we report that overexpression of WT or mutant UBQLN2 species enhanced nuclear factor κB (NF-κB) activation in Neuro2A cells.

Inflammation Induces TDP-43 Mislocalization and Aggregation.

TAR DNA-binding protein 43 (TDP-43) is a major component in aggregates of ubiquitinated proteins in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we report that lipopolysaccharide (LPS)-induced inflammation can promote TDP-43 mislocalization and aggregation. In culture, microglia and astrocytes exhibited TDP-43 mislocalization after exposure to LPS.

TLR7 is a key regulator of innate immunity against Japanese encephalitis virus infection.

Toll-like receptor 7 (TLR7) known to recognize guanidine-rich ssRNA has been shown to mount vital host defense mechanism against many viruses including flaviviruses. Signal transduction through TLR7 has been shown to produce type-1 interferon and proinflammatory mediators, thereby initiating essential innate immune response against ssRNA viruses in hosts. Systemic and brain specific TLR7 knock-down mice (TLR7(KD)) were generated using vivo-morpholinos.

Role of pattern recognition receptors in flavivirus infections.

The flaviviral encephalitis has now become a major health concern in global scale. The efficient detection of viral infection and induction of the innate antiviral response by host's innate immune system are crucial to determine the outcome of infection. The intracellular pattern recognition receptors TLRs, RLRs, NLRs and CLRs play a central role in detection and initiation of robust antiviral response against flaviviral infection.

Neural stem/progenitor cells induce conversion of encephalitogenic T cells into CD4+-CD25+- FOXP3+ regulatory T cells.

An immune role of neural stem/progenitor cells (NSPCs) has been proposed in many recent studies; however much still remains to be elucidated. In the current investigation, we report that NSPCs possess the ability to convert encephalitogenic T cells into CD4(+)-CD25(+)-FOXP3(+) regulatory T cells (T(reg)). Encephalitogenic and nonencephalitogenic T cells isolated from sham and Japanese encephalitis virus (JEV) infected animals were co-cultured with mouse NSPCs.

Japanese encephalitis virus infection modulates the expression of suppressors of cytokine signaling (SOCS) in macrophages: implications for the hosts' innate immune response.

Viruses have evolved various mechanisms to subvert the host's immune system and one of them is preventing the infected cells from sending out chemotactic signals to activate the adaptive immune response. Japanese encephalitis virus (JEV) is a neuropathologic flavivirus that is responsible for significant number of child mortalities in various parts of South-East Asia. In this study we show that JEV modulates suppressors of cytokine signaling (SOCS)1 and 3 expression in macrophages to bring about changes in the JAK-STAT signaling cascade, so as to inhibit proinflammatory cyto/chemokine release.

Japanese encephalitis in India: risk of an epidemic in the National Capital Region.

Japanese encephalitis (JE) is a mosquitoborne viral disease that is the primary cause of acute encephalitis syndrome in India. This virus mainly infects the central nervous system and causes massive inflammation which, if left unchecked, may prove fatal. Survivors often suffer from mild to severe neuropsychiatric sequelae.

Chandipura virus induces neuronal death through Fas-mediated extrinsic apoptotic pathway.

Chandipura virus (CHPV; genus Vesiculovirus, family Rhabdoviridae) is an emerging tropical pathogen with a case fatality rate of 55 to 75% that predominantly affects children in the age group of 2 to 16 years. Although it has been established as a neurotropic virus causing encephalitis, the molecular pathology leading to neuronal death is unknown. The present study elucidates for the first time the mechanism of cell death in neurons after CHPV infection that answers the basic cause of CHPV-mediated neurodegeneration.

Histone deacetylase inhibition by Japanese encephalitis virus in monocyte/macrophages: a novel viral immune evasion strategy.

Japanese encephalitis virus (JEV) is a common cause of encephalitis in humans who are dead-end hosts producing negligible viremia. The virus reaches the brain and causes massive inflammation. Our study seeks to understand the virus-host interaction using the murine monocyte/macrophage cell line RAW264.

Azithromycin in combination with riboflavin decreases the severity of Staphylococcus aureus infection induced septic arthritis by modulating the production of free radicals and endogenous cytokines.

Objective And Design: To determine alternate therapeutic measures to combat Staphylococcus aureus induced arthritis. Thus, azithromycin was combined with riboflavin, which may combat the ROS production and inflammation.

Methods: An in vivo model of S.

Ampicillin alone and in combination with riboflavin modulates Staphylococcus aureus infection induced septic arthritis in mice.

Effects of ampicillin (Amp) in combination with riboflavin on septic arthritis in mice infected with Staphylococcus aureus have been reported. Ampicillin was given at 100 mg/kg after 24 h of infection, followed by riboflavin (Ribo) at 20 mg/kg body wt, after 2 h of Amp treatment. Mice were sacrificed at 3, 9, 15 days post infection (dpi).

Increased resistance of immobilized-stressed mice to infection: correlation with behavioral alterations.

Immobilization is an easy and convenient method to induce both psychological and physical stress resulting in restricted motility and aggression and is believed to be the most severe type of stress in rodent models. Although it has been generally accepted that chronic stress often results in immunosuppression while acute stress has been shown to enhance immune responses, the effects of IS on the host resistance to Escherichia coli (E. coli) infection and associated behavioral changes are still not clear.

STING mediates neuronal innate immune response following Japanese encephalitis virus infection.

Flavivirus-mediated inflammation causes neuronal death, but whether the infected neurons can evoke an innate immune response to elicit their own protection, is unknown. In an earlier study we have shown that neuronal RIG-I, play a significant role in inducing production and release of molecules that are related to inflammation. In this study, using a neuronal cell line, we show that RIG-I acts with STING in a concerted manner following its interaction with Japanese encephalitis viral RNA to induce a type 1 interferon response.

RIG-I mediates innate immune response in mouse neurons following Japanese encephalitis virus infection.

Background: Neuroinflammation associated with Japanese encephalitis (JE) is mainly due to the activation of glial cells with subsequent release of proinflammatory mediators from them. The recognition of viral RNA, in part, by the pattern recognition receptor retinoic acid-inducible gene I (RIG-I) has been indicated to have a role in such processes. Even though neurons are also known to express this receptor, its role after JE virus (JEV) infections is yet to be elucidated.

Use of minocycline in viral infections.

Repurposing of old drugs is a useful concept as it helps to minimize costs associated with the research and development of a new drug. Minocycline, a common second generation antibiotic, has been shown to possess several other beneficial effects other than its intended uses. The antiviral role of minocycline has generated considerable interest from the last decade.

Chemotherapy in Japanese encephalitis: are we there yet?

Chemotherapy in Japanese encephalitis (JE) is at present entirely supportive and not targeted at the virus. There are no available drugs to effectively counter the viral infection, thereby making the fight against JE a daunting task. With approximately 50,000 reported cases per year, nearly 10,000 deaths and 3 billion people living in endemic regions, it is imperative that the hunt for an effective drug be expedited.

Japanese encephalitis virus-infected macrophages induce neuronal death.

Inflammation in the central nervous system (CNS) in Japanese encephalitis (JE) is shown to be the result of microglial activation that leads to the release of various proinflammatory mediators. Peripheral macrophages have been reported to infiltrate into the CNS in JE, though their contribution to the inflammatory process is yet to be elucidated. In this study, using an in vitro macrophage model, we have shown that upon JE virus infection, these cells secrete various soluble factors which may significantly add to the existing inflammatory milieu and lead to apoptotic or necrotic death of neurons.

Abrogated inflammatory response promotes neurogenesis in a murine model of Japanese encephalitis.

Background: Japanese encephalitis virus (JEV) induces neuroinflammation with typical features of viral encephalitis, including inflammatory cell infiltration, activation of microglia, and neuronal degeneration. The detrimental effects of inflammation on neurogenesis have been reported in various models of acute and chronic inflammation. We investigated whether JEV-induced inflammation has similar adverse effects on neurogenesis and whether those effects can be reversed using an anti-inflammatory compound minocycline.

Antiviral and neuroprotective role of octaguanidinium dendrimer-conjugated morpholino oligomers in Japanese encephalitis.

Background: Japanese encephalitis (JE), caused by a mosquito-borne flavivirus, is endemic to the entire south-east Asian and adjoining regions. Currently no therapeutic interventions are available for JE, thereby making it one of the most dreaded encephalitides in the world. An effective way to counter the virus would be to inhibit viral replication by using anti-sense molecules directed against the viral genome.

Possible protective role of chloramphenicol in TSST-1 and coagulase-positive Staphylococcus aureus-induced septic arthritis with altered levels of inflammatory mediators.

Chloramphenicol is mostly used against coagulase-negative Staphylococcus aureus, and its protective role against coagulase-positive S. aureus is not well studied. In our study, arthritis was induced in mice by S.