Effects of mitochondrial dysfunction on the immunological properties of microglia

<p>Abstract</p> <p>Background</p> <p>Neurodegenerative diseases are characterized by both mitochondrial dysfunction and activation of microglia, the macrophages of the brain. Here, we investigate the effects of mitochondrial dysfunction on the activation profile of microglial cells.</p> <p>Methods</p> <p>We incubated primary mouse microglia with the mitochondrial toxins 3-nitropropionic acid (3-NP) or rotenone. These mitochondrial toxins are known to induce neurodegeneration in humans and in experimental animals. We characterized lipopolysaccharide- (LPS-) induced microglial activation and the alternative, interleukin-4- (IL-4-) induced microglial activation in these mitochondrial toxin-treated microglial cells.</p> <p>Results</p> <p>We found that, while mitochondrial toxins did not affect LPS-induced activation, as measured by release of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β), they did inhibit part of the IL-4-induced alternative activation, as measured by arginase activity and expression, induction of insulin-like growth factor 1 (IGF-1) and the counteraction of the LPS induced cytokine release.</p> <p>Conclusions</p> <p>Mitochondrial dysfunction in microglial cells inhibits part of the IL-4-induced alternative response. Because this alternative activation is considered to be associated with wound healing and an attenuation of inflammation, mitochondrial dysfunction in microglial cells might contribute to the detrimental effects of neuroinflammation seen in neurodegenerative diseases.</p

Intergroup contact and social change: Implications of negative and positive contact for collective action in advantaged and disadvantaged groups

Previous research has shown that (1) positive intergroup contact with an advantaged group can discourage collective action among disadvantaged-group members and (2) positive intergroup contact can encourage advantaged-group members to take action on behalf of disadvantaged outgroups. Two studies investigated the effects of negative as well as positive intergroup contact. Study 1 (N = 482) found that negative but not positive contact with heterosexual people was associated with sexual-minority students’ engagement in collective action (via group identification and perceived discrimination). Among heterosexual students, positive and negative contact were associated with, respectively, more and less LGB activism. Study 2 (N = 1,469) found that only negative contact (via perceived discrimination) predicted LGBT students’ collective action intentions longitudinally while only positive contact predicted heterosexual/cisgender students’ LGBT activism. Implications for the relationship between intergroup contact, collective action, and social change are discussed

SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids

Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human induced pluripotent stem cell-derived kidney organoids with SARS-CoV-2. Single cell RNA-sequencing indicated injury and dedifferentiation of infected cells with activation of pro-fibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in Long-COVID

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The nucleic acid binding protein YB-1-controlled expression of CXCL-1 modulates kidney damage in liver fibrosis

Acute kidney injury is a common complication of advanced liver disease and increased mortality of these patients. Here, we analyzed the role of Y-box protein-1 (YB-1), a nucleic acid binding protein, in the bile duct ligation model of liver fibrosis and monitored liver and subsequent kidney damage. Following bile duct ligation, both serum levels of liver enzymes and expression of hepatic extracellular matrix components such as type I collagen were significantly reduced in mice with half-maximal YB-1 expression (Yb1(-/-)) as compared to their wild-type littermates. By contrast, expression of the chemokine CXCL1 was significantly augmented in these Yb1(-/-) mice. YB-1 was identified as a potent transcriptional repressor of the Cxc/1 gene. Precision-cut kidney slices from Yb1(-/-) mice revealed higher expression of the CXCL1 receptor CXCR2 as well as enhanced responsivity to CXCL1 compared to those from wild-type mice. Increased CXCL1 content in Yb1(-/-) mice led to pronounced bile duct ligation-induced damage of the kidneys monitored as parameters of tubular epithelial injury and immune cell infiltration. Pharmacological blockade of CXCR2 as well as application of an inhibitory anti-CXCL1 antibody significantly mitigated early systemic effects on the kidneys following bile duct ligation whereas it had only a modest impact on hepatic inflammation and function. Thus, our analyses provide direct evidence that YB-1 crucially contributes to hepatic fibrosis and modulates liver-kidney crosstalk by maintaining tight control over chemokine CXCL1 expression

The nucleic acid binding protein YB-1-controlled expression of CXCL-1 modulates kidney damage in liver fibrosis

Acute kidney injury is a common complication of advanced liver disease and increased mortality of these patients. Here, we analyzed the role of Y-box protein-1 (YB-1), a nucleic acid binding protein, in the bile duct ligation model of liver fibrosis and monitored liver and subsequent kidney damage. Following bile duct ligation, both serum levels of liver enzymes and expression of hepatic extracellular matrix components such as type I collagen were significantly reduced in mice with half-maximal YB-1 expression (Yb1(-/-)) as compared to their wild-type littermates. By contrast, expression of the chemokine CXCL1 was significantly augmented in these Yb1(-/-) mice. YB-1 was identified as a potent transcriptional repressor of the Cxc/1 gene. Precision-cut kidney slices from Yb1(-/-) mice revealed higher expression of the CXCL1 receptor CXCR2 as well as enhanced responsivity to CXCL1 compared to those from wild-type mice. Increased CXCL1 content in Yb1(-/-) mice led to pronounced bile duct ligation-induced damage of the kidneys monitored as parameters of tubular epithelial injury and immune cell infiltration. Pharmacological blockade of CXCR2 as well as application of an inhibitory anti-CXCL1 antibody significantly mitigated early systemic effects on the kidneys following bile duct ligation whereas it had only a modest impact on hepatic inflammation and function. Thus, our analyses provide direct evidence that YB-1 crucially contributes to hepatic fibrosis and modulates liver-kidney crosstalk by maintaining tight control over chemokine CXCL1 expression

Efeito da radiação gama em soluções de aflatoxinas

Os fungos filamentosos, seres ubíquos na natureza, são muitas vezes parasitas de produtos alimentares, nomeadamente produtos agrícolas. A sua presença, embora encarada como natural, poderá não ser inócua, uma vez que alguns fungos são capazes de produzir compostos tóxicos, nomeadamente micotoxinas (e.g., aflatoxinas). As aflatoxinas, metabolito secundário produzido por Aspergillus flavus e Aspergillus parasiticus, são altamente tóxicas, mutagénicas e carcinogénicas. Por forma a garantir a segurança alimentar no que se refere à presença destes metabolitos em alimentos várias alternativas têm vindo a ser testadas. A irradiação de alimentos (e.g, radiação gama) é uma dessas alternativas [1]; no entanto, a identificação dos produtos de degradação das micotoxinas pela utilização desta tecnologia, assim como a avaliação da sua toxicidade, está por realizar. Com o trabalho realizado pretendeu-se verificar qual o efeito da radiação gama em soluções de aflatoxinas (B1, B2, G1 e G2). Para tal, soluções de aflatoxinas (B1, B2, G1 e G2) foram submetidas à radiação gama nas seguintes doses: 0, 0,5; 1,0; 3,0; 6,0 kGy. Após irradiação, a quantificação de aflatoxinas e a deteção de produtos de degradação foi efetuada por cromatografia líquida, com deteção por fluorescência e derivatização pós-coluna. Os resultados obtidos mostraram que existe uma diminuição da concentração de aflatoxinas nas soluções irradiadas, embora a sensibilidade de cada toxina à irradiação seja diferente. Para a dose mais elevada de radiação testada (6,0 kGy) a diminuição foi superior a 80 % para G1, G2 e B1. Além disto, em todas as amostras irradiadas, verifica-se a formação de compostos de degradação de aflatoxinas. A concentração destes compostos aumenta até à dose de 1,0 kGy, diminuindo nas restantes doses. O estudo da estrutura e da toxicidade destes compostos tem que ser levados a cabo de modo a ponderar a eficácia desta metodologia no controlo de micotoxinas em alimentos

DC subset-specific induction of T cell responses upon antigen uptake via Fc gamma receptors in vivo

Dendritic cells (DCs) are efficient antigen-presenting cells equipped with various cell surface receptors for the direct or indirect recognition of pathogenic microorganisms. Interestingly, not much is known about the specific expression pattern and function of the individual activating and inhibitory Fc gamma receptors (Fc gamma Rs) on splenic DC subsets in vivo and how they contribute to the initiation of T cell responses. By targeting antigens to select activating and the inhibitory Fc gamma R in vivo, we show that antigen uptake under steady-state conditions results in a short-term expansion of antigen-specific T cells, whereas under inflammatory conditions especially, the activating Fc gamma RIV is able to induce superior CD4(+) and CD8(+) T cell responses. Of note, this effect was independent of Fc gamma R intrinsic activating signaling pathways. Moreover, despite the expression of Fc gamma RIV on both conventional splenic DC subsets, the induction of CD8(+) T cell responses was largely dependent on CD11c(+) CD8(+) DCs, whereas CD11c(+) CD8-DCs were critical for priming CD4(+) T cell responses