196 research outputs found
Transcriptomic Profiling Reveals That HMGB1 Induces Macrophage Polarization Different from Classical M1
Macrophages are key inflammatory immune cells that display dynamic phenotypes and functions in response to their local microenvironment. In different conditions, macrophage polarization can be induced by high-mobility group box 1 (HMGB1), a nuclear DNA-binding protein that activates innate immunity via the Toll-like receptor (TLR) 4, the receptor for advanced glycation end products (RAGE), and C-X-C chemokine receptor (CXCR) 4. This study investigated the phenotypes of murine bone-marrow-derived macrophages (BMDMs) stimulated with different HMGB1 redox isoforms using bulk RNA sequencing (RNA-Seq). Disulfide HMGB1 (dsHMGB1)-stimulated BMDMs showed a similar but distinct transcriptomic profile to LPS/IFNÎł- and LPS-stimulated BMDMs. Fully reduced HMGB1 (frHMGB1) did not induce any significant transcriptomic change. Interestingly, compared to LPS/IFNÎł- and LPS-, dsHMGB1-stimulated BMDMs showed lipid metabolism and foam cell differentiation gene set enrichment, and oil red O staining revealed that both dsHMGB1 and frHMGB1 alleviated oxidized low-density lipoprotein (oxLDL)-induced foam cells formation. Overall, this work, for the first time, used transcriptomic analysis by RNA-Seq to investigate the impact of HMGB1 stimulation on BMDM polarization. Our results demonstrated that dsHMGB1 and frHMGB1 induced distinct BMDM polarization phenotypes compared to LPS/IFNÎł- and LPS- induced phenotypes.publishedVersio
Human Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes.
Many lines of evidence suggest that the Parkinson's disease (PD)-related protein α-synuclein (α-SYN) can propagate from cell to cell in a prion-like manner. However, the cellular mechanisms behind the spreading remain elusive. Here, we show that human astrocytes derived from embryonic stem cells actively transfer aggregated α-SYN to nearby astrocytes via direct contact and tunneling nanotubes (TNTs). Failure in the astrocytes' lysosomal digestion of excess α-SYN oligomers results in α-SYN deposits in the trans-Golgi network followed by endoplasmic reticulum swelling and mitochondrial disturbances. The stressed astrocytes respond by conspicuously sending out TNTs, enabling intercellular transfer of α-SYN to healthy astrocytes, which in return deliver mitochondria, indicating a TNT-mediated rescue mechanism. Using a pharmacological approach to inhibit TNT formation, we abolished the transfer of both α-SYN and mitochondria. Together, our results highlight the role of astrocytes in α-SYN cell-to-cell transfer, identifying possible pathophysiological events in the PD brain that could be of therapeutic relevance.SIGNIFICANCE STATEMENT Astrocytes are the major cell type in the brain, yet their role in Parkinson's disease progression remains elusive. Here, we show that human astrocytes actively transfer aggregated α-synuclein (α-SYN) to healthy astrocytes via direct contact and tunneling nanotubes (TNTs), rather than degrade it. The astrocytes engulf large amounts of oligomeric α-SYN that are subsequently stored in the trans-Golgi network region. The accumulation of α-SYN in the astrocytes affects their lysosomal machinery and induces mitochondrial damage. The stressed astrocytes respond by sending out TNTs, enabling intercellular transfer of α-SYN to healthy astrocytes. Our findings highlight an unexpected role of astrocytes in the propagation of α-SYN pathology via TNTs, revealing astrocytes as a potential target for therapeutic intervention
Sustainable performance of lignocellulose-based ethanol and biogas co-produced in innovative biorefinery systems
Prolyl oligopeptidase inhibition by KYP-2407 increases alpha-synuclein fibril degradation in neuron-like cells
Growing evidence emphasizes insufficient clearance of pathological alpha-synuclein (alpha SYN) aggregates in the progression of Parkinson's disease (PD). Consequently, cellular degradation pathways represent a potential therapeutic target. Prolyl oligopeptidase (PREP) is highly expressed in the brain and has been suggested to increase alpha SYN aggregation and negatively regulate the autophagy pathway. Inhibition of PREP with a small molecule inhibitor, KYP-2407, stimulates autophagy and reduces the oligomeric species of alpha SYN aggregates in PD mouse models. However, whether PREP inhibition has any effects on intracellular alpha SYN fibrils has not been studied before. In this study, the effect of KYP2407 on alpha SYN preformed fibrils (PFFs) was tested in SH-SY5Y cells and human astmcytes. Immunostaining analysis revealed that both cell types accumulated alpha SYN PFFs intracellularly but KYP-2047 decreased intracellular alpha SYN deposits only in SH-SY5Y cells, as astrocytes did not show any PREP activity. Western blot analysis confirmed the reduction of high molecular weight alpha SYN species in SH-SY5Y cell lysates, and secretion of aSYN from SH-SY5Y cells also decreased in the presence of KYP-2407. Accumulation of alpha SYN inside the SH-SY5Y cells resulted in an increase of the auto-lysosomal proteins p62 and LC3BII, as well as calpain 1 and 2, which have been shown to be associated with PD pathology. Notably, treatment with KYP-2407 significantly reduced p62 and LC3BII levels, indicating an increased autophagic flux, and calpain 1 and 2 levels returned to normal in the presence of KYP-2407. Our findings indicate that PREP inhibition can potentially be used as therapy to reduce the insoluble intracellular alpha SYN aggregates
Neuroinflammatory markers associate with cognitive decline after major surgery:Findings of an explorative study
OBJECTIVE
Longâterm cognitive decline is an adverse outcome after major surgery associated with increased risk for mortality and morbidity. We studied the cerebrospinal fluid (CSF) and serum biochemical inflammatory response to a standardized orthopedic surgical procedure and the possible association with longâterm changes in cognitive function. We hypothesized that the CSF inflammatory response pattern after surgery would differ in patients having longâterm cognitive decline defined as a composite cognitive z score of â„1.0 compared to patients without longâterm cognitive decline at 3 months postsurgery.
METHODS
Serum and CSF biomarkers of inflammation and bloodâbrain barrier (BBB) integrity were measured preoperatively and up to 48 hours postoperatively, and cognitive function was assessed preoperatively and at 2 to 5âdays and 3 months postoperatively.
RESULTS
Surgery was associated with a pronounced increase in inflammatory biomarkers in both CSF and blood throughout the 48âhour study period. A principal component (PC) analysis was performed on 52 inflammatory biomarkers. The 2 first PC (PC1 and PC2) construct outcome variables on CSF biomarkers were significantly associated with longâterm cognitive decline at 3 months, but none of the PC construct serum variables showed a significant association with longâterm cognitive decline at 3 months. Patients both with and patients without longâterm cognitive decline showed early transient increases of the astroglial biomarkers Sâ100B and glial fibrillary acidic protein in CSF, and in BBB permeability (CSF/serum albumin ratio).
INTERPRETATION
Surgery rapidly triggers a temporal neuroinflammatory response closely associated with longâterm cognitive outcome postsurgery. The findings of this explorative study require validation in a larger surgical patient cohort. ANN NEUROL 202
The microbial detection array for detection of emerging viruses in clinical samples - a useful panmicrobial diagnostic tool
Emerging viruses are usually endemic to tropical and sub-tropical regions of the world, but increased global travel, climate change and changes in lifestyle are believed to contribute to the spread of these viruses into new regions. Many of these viruses cause similar disease symptoms as other emerging viruses or common infections, making these unexpected pathogens difficult to diagnose. Broad-spectrum pathogen detection microarrays containing probes for all sequenced viruses and bacteria can provide rapid identification of viruses, guiding decisions about treatment and appropriate case management. We report a modified Whole Transcriptome Amplification (WTA) method that increases unbiased amplification, particular of RNA viruses. Using this modified WTA method, we tested the specificity and sensitivity of the Lawrence Livermore Microbial Detection Array (LLMDA) against a wide range of emerging viruses present in both non-clinical and clinical samples using two different microarray data analysis methods
Neutralization of LINGO-1 during In Vitro Differentiation of Neural Stem Cells Results in Proliferation of Immature Neurons
Identifying external factors that can be used to control neural stem cells division and their differentiation to neurons, astrocytes and oligodendrocytes is of high scientific and clinical interest. Here we show that the Nogo-66 receptor interacting protein LINGO-1 is a potent regulator of neural stem cell maturation to neurons. LINGO-1 is expressed by cortical neural stem cells from E14 mouse embryos and inhibition of LINGO-1 during the first days of neural stem cell differentiation results in decreased neuronal maturation. Compared to neurons in control cultures, which after 6 days of differentiation have long extending neurites, neurons in cultures treated with anti-LINGO-1 antibodies retain an immature, round phenotype with only very short processes. Furthermore, neutralization of LINGO-1 results in a threefold increase in ÎČIII tubulin-positive cells compared to untreated control cultures. By using BrdU incorporation assays we show that the immature neurons in LINGO-1 neutralized cultures are dividing neuroblasts. In contrast to control cultures, in which no cells were double positive for ÎČIII tubulin and BrdU, 36% of the neurons in cultures treated with anti-LINGO-1 antibodies were proliferating after three days of differentiation. TUNEL assays revealed that the amount of cells going through apoptosis during the early phase of differentiation was significantly decreased in cultures treated with anti-LINGO-1 antibodies compared to untreated control cultures. Taken together, our results demonstrate a novel role for LINGO-1 in neural stem cell differentiation to neurons and suggest a possibility to use LINGO-1 inhibitors to compensate for neuronal cell loss in the injured brain
The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid ÎČ fibril formation
Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer's disease (AD) by increasing generation or altering conformation of amyloid beta (A beta). Here, we describe the Uppsala APP mutation (Delta 690-695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of AD, with the exception of normal cerebrospinal fluid (CSF) A beta 42 and only slightly pathological amyloid-positron emission tomography signals. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing beta-secretase cleavage and affecting alpha-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated A beta, A beta Upp1-42(Delta 19-24), accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain
Kunskapsunderlag för ekosystembaserad havsförvaltning i Bottenhavet
Ekosystembaserad havsförvaltning anges som ett viktigt verktyg för att nĂ„ Sveriges miljömĂ„l. Denna rapport tar ett första steg i riktning mot ett vetenskapligt underlag för att stödja ekosystembaserad havsförvaltning i ett pilotomrĂ„de i södra Bottenhavet. Ekosystemkomponenter (dvs. arter och livsmiljöer) som Ă€r viktiga för modellering av ekosystemet identifieras och deras status samt faktorer som pĂ„verkar dem redovisas. Ăven kunskapsluckor kopplade till pĂ„verkansfaktorer diskuteras, samt hur dessa pĂ„verkansfaktorer integreras med ekosystemkomponenterna, liksom vilka ekosystemtjĂ€nster som ekosystemkomponenterna bidrar till. MĂ„nga av ekosystemkomponenterna har inte god miljöstatus, sĂ€rskilt grunda bottnar som har ett högt exploateringstryck. OrovĂ€ckande nog saknas det övervakning av bĂ„de grunda kustnĂ€ra mjukbottnar och utsjöbankar, fastĂ€n dessa omrĂ„den Ă€r av intresse för exploatering samtidigt som de har hög biodiversitet och Ă€r kopplade till mĂ„nga ekosystemtjĂ€nster. Dock finns det en del data tillgĂ€ngligt i omrĂ„det som kan anvĂ€ndas vid modellering för att ta fram kartor över ekosystemkomponenter och Ă€ven ekosystemtjĂ€nster, som kan vara viktiga underlag för ekosystembaserad förvaltning i södra Bottenhavet. I flera fall Ă€r kunskapen om belastningar i södra Bottenhavet och hur de kopplar till statusen av ekosystemkomponenter relativt god, men det saknas information om kumulativa effekter av pĂ„verkansfaktorer. MĂ„nga av de marina arter som finns lĂ€ngst in i Ăstersjön lever hĂ€r vid sin nordliga utbredningsgrĂ€ns, vilket kan innebĂ€ra att de Ă€r extra kĂ€nsliga för mĂ€nskliga belastningar och klimatförĂ€ndring. Storskaligt fiske efter strömming i utsjön och dess effekter pĂ„ strömmingsbestĂ„nden kan pĂ„verka ekosystemets funktion. Strömmingen Ă€r talrik och spelar en stor roll i södra Bottenhavets ekosystem. Eftersom strömming vandrar mellan utsjön och kusten kan den koppla samman nĂ€ringsvĂ€var i kust och utsjö. I Bottenhavets omrĂ„de kan man se tydliga intressekonflikter gĂ€llande resursförvaltning. Traditionella lokala nĂ€ringar baserar sig mycket pĂ„ fiske av strömming och laxfisk, men vikande fĂ„ngster av den mer storvuxna strömming som fiskas för humankonsumtion, liksom av laxfisk, skapar problem för det kustnĂ€ra yrkesfisket. HĂ€r finns en uppenbar konkurrenssituation bĂ„de med det storskaliga pelagiska fisket i utsjön och med naturliga predatorer. Dessa konflikter Ă€r svĂ„ra att lösa med de förvaltningsmetoder som anvĂ€nds idag. Södra Bottenhavets ekosystem skulle sannolikt gynnas av en mer helhetsbaserad förvaltning av fiskbestĂ„nden och livsmiljöer, utifrĂ„n samtliga faktorer som pĂ„verkar dem. I kustomrĂ„det gĂ€ller detta Ă€ven, inte minst, de omrĂ„den dĂ€r gösens och sikens status Ă€r mycket svag, liksom viktiga omrĂ„den för rekrytering av gĂ€dda. En sĂ„dan mer helhetsbaserad förvaltning innefattar en samplanering av fiskeregleringar, skyddade omrĂ„den och Ă„tgĂ€rder för att restaurera och skydda diverse livsmiljöer. FörbĂ€ttring av livsmiljöer för fisk förvĂ€ntas Ă€ven gynna andra delar av den biologiska mĂ„ngfalden och ekosystemtjĂ€nster, inklusive olika arters motstĂ„ndskraft och förmĂ„ga att anpassa sig till pĂ„gĂ„ende klimatförĂ€ndringar
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