Highlights • Sirtuin 3 (Sirt3) is developmentally regulated in microglia in the rat brain. • Sirt3 expression is induced in activated microglia in vitro and in vivo. • Sirt3 induces antioxidants ...through nuclear translocation of Foxo3a, in microglia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Astrocyte activation plays important roles both in physiological and pathological process in the CNS. In the latter, the process is further aggravated by hyperglycemia, leading to diabetes ...complications of CNS. We report here that high glucose (HG) treatment stimulated astrocytic morphological alteration coupled with changes in glial fibrillary acidic protein (GFAP) and vimentin expression. Additionally, HG upregulated the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), interleukin-4 (IL-4), and vascular endothelial growth factor (VEGF); however, its effects on transforming growth factor-β (TGF-β) expression were not evident. HG treatment induced increased production of reactive oxygen species (ROS) as well as activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator transcription 3 (STAT 3). HG-induced expression of TNF-α, IL-6, IL-1β, IL-4, and VEGF was blocked by ROS scavenger and inhibitors specific for NF-κB and STAT 3, respectively. The results suggest that the aforementioned multiple inflammatory cytokines and mediators that may be linked to the pathogenesis of the diabetes complications of CNS are induced by HG via the key signaling pathways.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Microglial activation has been implicated as one of the causative factors for neuroinflammation in various neurodegenerative diseases. The sphingolipid metabolic pathway plays an important ...role in inflammation, cell proliferation, survival, chemotaxis, and immunity in peripheral macrophages. In this study, we demonstrate that sphingosine kinase1 (SphK1), a key enzyme of the sphingolipid metabolic pathway, and its receptors are expressed in the mouse BV2 microglial cells and SphK1 alters the expression and production of proinflammatory cytokines and nitric oxide in microglia treated with lipopolysaccharide (LPS). LPS treatment increased the SphK1 mRNA and protein expression in microglia as revealed by the RT–PCR, Western blot and immunofluorescence. Suppression of SphK1 by its inhibitor, N, N Dimethylsphingosine (DMS), or siRNA resulted in decreased mRNA expression of TNF-α, IL-1β, and iNOS and release of TNF-α and nitric oxide (NO) in LPS-activated microglia. Moreover, addition of sphingosine 1 phosphate (S1P), a breakdown product of sphingolipid metabolism, increased the expression levels of TNF-α, IL-1β and iNOS and production of TNF-α and NO in activated microglia. Hence to summarize, suppression of SphK1 in activated microglia inhibits the production of proinflammatory cytokines and NO and the addition of exogenous S1P to activated microglia enhances their inflammatory responses. Since the chronic proinflammatory cytokine production by microglia has been implicated in neuroinflammation, modulation of SphK1 and S1P in microglia could be looked upon as a future potential therapeutic method in the control of neuroinflammation in neurodegenerative diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The blood–retinal barrier (BRB) plays an important role in the homeostatic regulation of the microenvironment in the retina. It consists of inner and outer components, the inner BRB (iBRB) being ...formed by the tight junctions between neighbouring retinal capillary endothelial cells and the outer barrier (oBRB) by tight junctions between retinal pigment epithelial cells. Astrocytes, Müller cells and pericytes contribute to the proper functioning of the iBRB. In many clinically important conditions including diabetic retinopathy, ischaemic central retinal vein occlusion, and some respiratory diseases, retinal hypoxia results in a breakdown of the iBRB. Disruption of the iBRB associated with increased vascular permeability, results in vasogenic oedema and tissue damage, with consequent adverse effects upon vision. Factors such as enhanced production of vascular endothelial growth factor (VEGF), NO, oxidative stress and inflammation underlie the increased permeability of the iBRB and inhibition of these factors is beneficial. Experimental studies in our laboratory have shown melatonin to be a protective agent for the iBRB in hypoxic conditions.
Although oBRB breakdown can occur in conditions such as accelerated hypertension and the toxaemia of pregnancy, both of which are associated with choroidal ischaemia and in age-related macular degeneration (ARMD), and is a feature of exudative (serous) retinal detachment, our studies have shown that the oBRB remains intact in hypoxic/ischaemic conditions.
Clinically, anti-VEGF therapy has been shown to improve vision in diabetic maculopathy and in neovascular ARMD. The visual benefit in both conditions appears to arise from the restoration of BRB integrity with a reduction of retinal oedema.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
► l-Cysteine stimulated proliferation and differentiation of NSCs. ► l-Cysteine-induced proliferation was associated with phosphorylation of ERK1/2. ► l-Cysteine-induced differentiation was due to ...the differentiation-related genes. ► AOAA or CBS siRNA attenuated the effects of l-cysteine on proliferation and differentiation of NSCs.
Growing evidence has suggested that hydrogen sulfide (H2S) acts as a novel neuro-modulator and neuroprotective agent; however, it remains to be investigated whether H2S has a direct effect on neural stem cells (NSCs). We report here that NSCs expressed cystathionine β synthase (CBS) and addition of exogenous H2S donor, l-cysteine, stimulated proliferation and increased the differentiation potential of NSCs to neurons and astroglia. Moreover, pre-treatment with aminooxyacetic acid, the inhibitor of CBS or knockdown of CBS in using siRNA, significantly attenuated the effects of l-cysteine on elevated H2S levels and the cell proliferation; it also effectively suppressed l-cysteine-induced neurogenesis and astrocytogenesis. Further analysis revealed that l-cysteine-induced proliferation was associated with phosphorylation of extracellular signal-regulated kinases 1/2 and differentiation with altered expression of differentiation-related genes. Taken together, the present data suggest that l-cysteine can enhance proliferation and differentiation of NSCs via the CBS/H2S pathway, which may serve as a useful inference for elucidating its role in regulating the fate of NSCs in physiological and pathological settings.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The blood brain barrier (BBB) plays an important role in the homeostatic regulation of the brain microenvironment and maintains the immune-privileged status of the brain by restricting the entry of T ...lymphocytes. Structurally, the BBB is formed by tight junctions between the endothelial cells. Astrocytes, pericytes and perivascular microglia surround the endothelial cells contributing to proper functioning of the BBB. Hypoxia, associated with disorders such as stroke, cardiac arrest, respiratory distress, carbon monoxide poisoning among many others, disrupts the BBB. Alterations in the endothelial cells such as increased pinocytotic vesicles and derangement of the tight junction proteins may be responsible for increased permeability at the BBB resulting in swelling of astrocyte end feet. The disruption of BBB in hypoxic conditions is multifactorial and may involve factors such as enhanced production of vascular endothelial growth factor (VEGF), nitric oxide (NO) and inflammatory cytokines. Although future research is needed to look into possible therapeutic strategies to improve the functioning of BBB in hypoxic conditions, experimental studies so far have reported beneficial effect of curcumin, melatonin, simvastatin and minocycline in ameliorating the increased BBB permeability in hypoxic conditions.
Periventricular white matter damage (PWMD) also known as periventricular white matter injury, is one of the major causes of neurological impairment in premature newborns. The etiology of white matter ...injury is multifaceted with hypoxia-ischemia being an important underlying factor. The developing oligodendrocytes are susceptible to damage resulting in myelination deficits. Excess release of glutamate, free radical production, release of cytokines and iron accumulation are factors thought to mediate damage to the developing white matter. Recent studies have also suggested a role for vascular endothelial growth factor and nitric oxide in the pathogenesis of PWMD. Although the role of microglial cells in the development of PWMD is still debatable, our recent investigations have shed some light on their involvement in the pathogenesis of PWMD. Challenges for the future include in-depth investigation of crosstalk between microglia and immature oligodendrocytes as well as other glial cells and vascular endothelial cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We investigated the impact of breakpoint discrepancies between CLSI and EUCAST on susceptibility interpretation of clinical isolates at the Microbiology Laboratory, Mahosot Hospital, Vientiane, Laos ...and performed a literature search to compare our findings to published reports. Zone diameters for first-line antimicrobial agents tested against non-duplicate clinical isolates of Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa in 2017 were interpreted separately using EUCAST 2018 and CLSI 2018 breakpoints and greement measured. Applying EUCAST instead of CLSI breakpoints to 428 E. coli, 208 K. pneumoniae and 78 P. aeruginosa isolates would have increased rates of ciprofloxacin resistance (59.1% vs 46.5% in E. coli, 37.5% vs 13.9% in K. pneumoniae, 28.2% vs 10.3% in P. aeruginosa) and amoxicillinclavulanic acid resistance (52.3% vs 19.9% in E. coli, 35.6% vs 22.1% in K. pneumoniae). Our results are supported by a literature search which identified 20 articles whose main objective was comparing susceptibility interpretation between CLSI and EUCAST. 19/20 articles reported significant discrepancies in one or more pathogen-antimicrobial combinations, nearly always due to a reduction in susceptibility rates and/or increase in resistance rates when applying more restrictive EUCAST breakpoints. We conclude that breakpoint discrepancies between CLSI and EUCAST have a significant impact on susceptibility interpretation of clinical isolates and AMR surveillance initiatives, and highlight the need for globally harmonized clinical breakpoints.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Printable scaffolds with adequate mechanical strength and stiffness are sought after to ensure viability of printed cells and tissues. We report the first peptide bioinks–lysine-containing ...hexapeptides that self-assemble into stable, nanofibrous three-dimensional hydrogels with unprecedented stiffness of up to 40 kPa. These biocompatible scaffolds support the three-dimensional culture of human stem cells and differentiation of primary cells into organotypic (gastrointestinal and skin) structures for high-throughput screening, diagnosis, and tissue engineering.
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IJS, KILJ, NUK, PNG, UL, UM
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