Hypoxia in aquatic environment is often a recurrent stressor which can affect growth and health of fishes. However, nutritional intervention can help aquatic animals to cope up with environmental ...stressors so as to alleviate the adverse effects. Here, we examined the impact of L-Arginine (Arg) supplementation on hypoxia-induced changes in immune responses and resistance to Aeromonas hydrophila infection in Indian Major Carp, Cirrhinus mrigala. The fish were fed with graded levels of Arg for 60 days and exposed to 72 h sublethal level of hypoxia (0.50 ± 0.16 mg/L dissolved oxygen DO). The six treatment groups with three replicates having different levels of Arginine such as N0.0 (0% Arg + Normoxia), H0.0 (0% Arg + Hypoxia), N0.7 (0.70% Arg + Normoxia), H0.7 (0.70% Arg + Hypoxia), N1.4 (1.40% Arg + Normoxia), and H1.4 (1.40% Arg + Hypoxia) were used in the study. Subsequently, the fish of different treatment groups were challenged with A. hydrophila. The hypoxia exposed fish exhibited significantly higher (P < .05) cumulative mortality compared to the unexposed fish, while Arg-fed groups showed reduced mortality irrespective of the level of dissolved oxygen. The albumin-globulin ratio, complement-3 response, respiratory burst, myeloperoxidase, serum antiprotease and lysozyme activities were significantly lower (P < .05) in hypoxia-exposed carp, revealing the increased susceptibility of fish to A. hydrophila is due to the immunosuppressive effect of hypoxia, which was improved in Arg-supplemented groups. We conclude that there is a possible role of hypoxia in sporadic outbreaks of bacterial diseases in carps as acute hypoxia causes immunosuppression which can be reversed by 0.7% Arg supplementation.
•The susceptibility of Cirrhinus mrigala to Aeromonas hydrophila increased due to hypoxia.•Arginine fed groups showed reduced mortality with Aeromonas hyrophila challenge.•The non-specific immune parameters were decreased (P < .05) due to hypoxia.•Arginine feeding restored the hypoxia-induced reduction in non-specific immune parameters.
Epidemiological studies have shown that ambient fine particulate matter (PM) can cause various neurodegenerative diseases, including Alzheimer's disease. Reactive astrocytes are strongly induced by ...ambient fine PM, although their role is poorly understood. Herein, we show that A1 reactive astrocytes (A1s) were induced by neuroinflammatory microglia activated by PM with an aerodynamic diameter ≤ 0.2 μm (PM0.2). The activated-microglia induced A1s by secreting interleukin-1α, tumor necrosis factor-α, and complement 1q, and these cytokines acting together were necessary and sufficient to induce A1s. PM0.2-induced A1s could promote synaptic damage in neurons by secreting complement 3 (C3). SB 290157, a highly selective C3aR nonpeptide antagonist, partially ameliorated glial conditioned medium-induced synaptic injury. In vitro synaptic damage was partially prevented when A1 formation was blocked by minocycline. Finally, this study showed that N-acetyl-L-cysteine ameliorated PM0.2-induced neural damage independent of A1 differentiation. Collectively, these findings explain why central nervous system neurons suffer synaptic damage and neuroinflammation after PM0.2 exposure and suggest that this exposure induces A1s to contribute to synaptic damage of neurons. This study indicates a potential approach for developing improved treatment of these diseases induced by particulate exposure.
PM0.2-activated neuroinflammatory microglia induced A1 reactive astrocytes (A1s) by secreting IL-1α, TNF-α, and C1q. PM0.2-induced A1s could promote synaptic damage of neuron by secreting complement 3.
This study found that microglia were activated by PM0.2 and secreted interleukin (IL)-1α, tumor necrosis factor (TNF)-α, and complement 1q (C1q). These cytokines induced astrocytes to differentiate into A1 type (A1s). A1s lost the ability to promote neuronal synaptogenesis and induced synaptic damage of neurons by secreting C3. Moreover, the activated microglia produced many ROS, directly leading to neuronal damage. Display omitted
•PM0.2-activated neuroinflammatory microglia secreted IL-1α, TNF-α, and C1q to induce A1s.•PM0.2-induced A1s could promote synaptic damage of neuron by secreting C3.•Minocycline ameliorated PM0.2-induced synaptic damage by blocking A1 differentiation.•NAC ameliorated PM0.2-induced synaptic damage independent of A1 differentiation.
Background and Objective
Neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody (MOG-IgG) associated disease (MOGAD) are autoimmune inflammatory ...demyelinating diseases of the central nervous system (CNS). As the clinical features of NMOSD are similar to MOGAD, diagnostic confusion exists between the two diseases. To better discriminate NMOSD from MOGAD, we investigated whether the plasma levels of complement 3 (C3) and complement 4 (C4) are different in NMOSD and MOGAD during the acute attacks of the diseases. We sought to determine whether C3 or C4 has an influence on the features of NMOSD.
Methods
In this observational study, data from 73 aquaporin-4 antibodies (AQP4-IgG) positive NMOSD patients and 22 MOG-IgG positive MOGAD patients were collected retrospectively. Demographics, clinical characteristics, plasma parameters, and cerebrospinal fluid (CSF) findings will be analyzed for comparability between the two groups. Immunoglobulin-G (IgG) and albumin were measured in both plasma and CSF. Plasma levels of C3 and C4 were measured and compared between the NMOSD, MOGAD, and 42 healthy controls (HC). The correlations between plasma C3, C4, and NMOSD clinical parameters were analyzed.
Results
The ages of onset were later in the AQP4-IgG positive NMOSD group and females predominated, which differed from the MOGAD group, whose ages were younger and with a slight male preponderance. The AQP4-IgG positive NMOSD patients presented with the clinical symptoms of optic neuritis (ON) and transverse myelitis (TM), whereas encephalitis symptoms were more prevalent in MOGAD patients. CSF analysis shows that slight but not significantly higher white cell count (WCC) and protein were observed in the MOGAD group than in the AQP4-IgG positive NMOSD group. The plasma levels of IgG in MOGAD patients are significantly lower (
p
= 0.027) than in NMOSD patients. On the contrary, the plasma levels of albumin in MOGAD were higher than in NMOSD, which reached statistical significance (
p
= 0.039). Both the plasma C3 and C4 levels in the NMOSD group were significantly lower than in MOGAD and HC. The receiver operating characteristic (ROC) curve of the prediction model comprises C3 and C4 to distinguish NMOSD from MOGAD area under the curve (AUC): 0.731, 0.645, which are considered to have discriminatory values. The results of Spearman’s analysis revealed that there was a significant positive correlation between the plasma C3 and the CSF WCC (r = 0.383,
p
= 0.040). There was an inverse correlation between plasma C4 and plasma IgG (r = -0.244,
p
= 0.038). Plasma C3 or C4 was significantly positively correlated with CSF albumin and Q-Alb, which is considered a measure of blood-brain barrier (BBB) disruption.
Conclusion
During the acute phase of NMOSD and MOGAD, plasma C3 and C4 may become potential biomarkers for distinguishing the two diseases and reflecting the NMOSD BBB damage.
A 45-day feeding trial was conducted to study the effect of feeding graded level of gelatinized starch (GS) on stress parameters, growth and immunity of Labeo rohita. Fish were fed with four ...semi-purified diets containing 30% crude protein with graded level of gelatinized starch, 30% (T1), 35% (T2), 40% (T3) and 45% (T4). The results exhibited higher weight gain % (WG), specific growth rate (SGR) and protein efficiency ratio (PER) in 45% GS fed group (T4) with significantly (p<0.05) lowest feed conversion ratio (FCR). The blood NBT and serum complement 3 (C3), serum protein, albumin and globulin contents were increased with the increase in GS level in the diet. The SOD, catalase, alanine transaminase (ALT) and aspartate transaminase (AST) in liver increased significantly (p>0.05) with the increasing level of GS in the diet. In addition, the high carbohydrate level (CHO) 40% and 45% significantly upregulated the mRNA level of immune related genes like Nuclear Factor Kappa B (NFkB) and Interleukin (IL8) in both liver and kidney. Furthermore, highest percentage of survival was found in T4 group after challenged with Aeromonas hydrophila followed by T3 group. The results of the present study suggest that Labeo rohita fingerlings can utilize the high digestible carbohydrate upto 45% without affecting growth and immunity.
•The effect of graded level of gelatinized starch on antioxidant parameters, growth and immunity of Labeo rohita were evaluated.•The carbohydrate level of 40% has upregulated the expression of immune related genes like Nuclear Factor Kappa B (NFkB) and Interleukin (IL8) in kidney and liver.•The NBT and serum complement 3 (C3), serum protein, albumin and globulin contents were increased with the increase in gelatinized starch level in the diet.
The IL-6R antibody tocilizumab has been proven effective in treating Takayasu arteritis (TA). However, some patients show silent vascular stenosis progression (VSP) despite treatment with ...tocilizumab. The aim of the study was to explore the related risk factors of VSP in patients treated with tocilizumab.
Patients receiving tocilizumab were enrolled from the prospective living ongoing East China Takayasu Arteritis cohort. Their medical information was uniformly recorded with a homogenized evaluation method. Magnetic resonant angiography or computed tomographic angiography was employed to monitor VSP during the follow-up period, and Cox regression analysis was performed to explore the related risk factors.
Thirty-eight patients were enrolled, among whom 18 (47.4%) experienced VSP, and seven and three patients experienced new and worsened vascular ischemic symptoms and events (VISE) during follow-up, respectively. The median period for VSP occurrence was 6.9 months during follow-up. Patients with VSP showed higher levels of baseline complement 3 (C3) than those in the patients without VSP. Multivariate Cox regression analysis revealed baseline C3 level (hazard ratio HR = 7.05, 95% confidence interval: 1.50-33.07, p = 0.013) was independently associated with VSP, with a cut-off value of 1.22 g/L.
47.4% of TA patients treated with tocilizumab would suffer VSP. A high C3 level is a risk factor for VSP in TA patients receiving tocilizumab, which may facilitate the option of tocilizumab in the future.
Takayasu arteritis (TA) is a rare disease, lacking convenient and feasible biomarkers to identify disease activity. We aimed to evaluate the value of complements in distinguishing active TA.
...Consecutive patients were enrolled from the prospective East China TA cohort from April 2008 to June 2019. Patients were divided into two groups according to their baseline Kerr score. The value of complements and other biomarkers in identifying disease activity were analysed with cluster analysis, ROC curves, and combined tests. An independent group of patients from July 2019 to December 2019 were employed to validate the results.
Of the enrolled 519 patients, 406 (72.2%) cases were identified as active disease. Higher erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), interleukin-6 (IL-6), and complement 3 (C3) levels were observed in the active group. Elevated C3 (≥ 1.085 g/L) had a high value to identify active TA with a sensitivity of 69.9%, specificity of 66.7%, and AUC of 0.715. Combining the CRP (≥ 10.65 g/L; sensitivity, 50.7%; specificity, 82.4%) and C3, the sensitivity could be improved to 85.1% in parallel test and the specificity could be improved to 94.1% in serial test. Validation was further performed to confirm the value of C3 for disease activity assessment. The accuracy of the parallel test of CRP and C3 in external validation with independent 53 TA cases was 72.73% with the AUC of 0.721.
Elevated C3 could effectively evaluate the disease activity of TA, and C3 combining with CRP could further improve the disease activity evaluation.
C3a is important in the regulation of the immune response as well as in the development of organ inflammation and injury. Furthermore, C3a contributes to liver regeneration but its role in intestinal ...stem cell function has not been studied. We hypothesized that C3a is important for intestinal repair and regeneration. Intestinal organoid formation, a measure of stem cell capacity, was significantly limited in C3-deficient and C3a receptor (C3aR) 1-deficient mice while C3a promoted the growth of organoids from normal mice by supporting Wnt-signaling but not from C3aR1-deficient mice. Similarly, the presence of C3a in media enhanced the expression of the intestinal stem cell marker leucine-rich repeat G-protein-coupled receptor 5 (Lgr5) and of the cell proliferation marker Ki67 in organoids formed from C3-deficient but not from C3aR1-deficient mice. Using
mice we showed significant expression of C3 in Lgr5
intestinal stem cells whereas C3aR1 was expressed on the surface of various intestinal cells. C3 and C3aR1 expression was induced in intestinal crypts in response to ischemia/reperfusion injury. Finally, C3aR1-deficient mice displayed ischemia/reperfusion injury comparable to control mice. These data suggest that C3a through interaction with C3aR1 enhances stem cell expansion and organoid formation and as such may have a role in intestinal regeneration.
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with selective degeneration of motor neurons. It has been reported that an increase in the levels of inflammatory cytokines ...and glial cells such as reactive astrocytes is closely involved in the pathological progression of ALS. Recently, the levels of neuropathic cytotoxic (A1) astrocytes among reactive astrocytes have reportedly increased in the central nervous system of ALS mice, which induce motor neuron degeneration through the production of inflammatory cytokines and secretion of neuropathic factors. Hence, elucidating the induction mechanism of A1 astrocytes in ALS is important to understand the mechanism of disease progression in ALS. In this study, we observed that the expression of peroxiredoxin 6 (PRDX6), a member of the peroxiredoxin family, was markedly upregulated in astrocytes of the lumbar spinal cord of SOD1
G93A
mice model for ALS. Additionally, when PRDX6 was transiently transfected into the mouse astrocyte cell line C8-D1A and human astrocytoma cell line U-251 MG, the mRNA expression of complement C3 (a marker for A1 astrocyte phenotype) and inflammatory cytokines was increased. Furthermore, the mRNA expression of C3 and inflammatory cytokine was increased in C8-D1A and U-251 MG cells stably expressing PRDX6, and the increased mRNA expression was significantly suppressed by MJ33 (lithium1-hexadecoxy-3-(2,2,2-trifluoroethoxy) propan-2-yl methyl phosphate), an inhibitor of the phospholipase A
2
activity of PRDX6. Our results suggest that the expression of PRDX6 in astrocytes plays an important role in the induction of A1 astrocytes and expression of inflammatory cytokines in the ALS mice model.
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