Self-Nucleic Acid Sensing: A Novel Crucial Pathway Involved in Obesity-Mediated Metaflammation and Metabolic Syndrome

Obesity and overweight are a global health problem affecting almost one third of the world population. There are multiple complications associated with obesity including metabolic syndrome that commonly lead to development of type II diabetes and non-alcoholic fatty liver disease. The development of metabolic syndrome and severe complications associated with obesity is attributed to the chronic low-grade inflammation that occurs in metabolic tissues such as the liver and the white adipose tissue. In recent years, nucleic acids (mostly DNA), which accumulate systemically in obese individuals, were shown to aberrantly activate innate immune responses and thus to contribute to metabolic tissue inflammation. This minireview will focus on (i) the main sources and forms of nucleic acids that accumulate during obesity, (ii) the sensing pathways required for their detection, and (iii) the key cellular players involved in this process. Fully elucidating the role of nucleic acids in the induction of inflammation induced by obesity would promote the identification of new and long-awaited therapeutic approaches to limit obesity-mediated complications

The Role of Nucleases and Nucleic Acid Editing Enzymes in the Regulation of Self-Nucleic Acid Sensing

Detection of microbial nucleic acids by the innate immune system is mediated by numerous intracellular nucleic acids sensors. Upon the detection of nucleic acids these sensors induce the production of inflammatory cytokines, and thus play a crucial role in the activation of anti-microbial immunity. In addition to microbial genetic material, nucleic acid sensors can also recognize self-nucleic acids exposed extracellularly during turn-over of cells, inefficient efferocytosis, or intracellularly upon mislocalization. Safeguard mechanisms have evolved to dispose of such self-nucleic acids to impede the development of autoinflammatory and autoimmune responses. These safeguard mechanisms involve nucleases that are either specific to DNA (DNases) or RNA (RNases) as well as nucleic acid editing enzymes, whose biochemical properties, expression profiles, functions and mechanisms of action will be detailed in this review. Fully elucidating the role of these enzymes in degrading and/or processing of self-nucleic acids to thwart their immunostimulatory potential is of utmost importance to develop novel therapeutic strategies for patients affected by inflammatory and autoimmune diseases.IdEx Bordeau

Biotic soil-plant interaction processes explain most of hysteretic soil CO2 efux response to temperature in cross-factorial mesocosm experiment

Ecosystem carbon fux partitioning is strongly infuenced by poorly constrained soil CO2 efux (Fsoil). Simple model applications (Arrhenius and Q10) do not account for observed diel hysteresis between Fsoil and soil temperature. How this hysteresis emerges and how it will respond to variation in vegetation or soil moisture remains unknown. We used an ecosystem-level experimental system to independently control potential abiotic and biotic drivers of the Fsoil-T hysteresis. We hypothesized a principally biological cause for the hysteresis. Alternatively, Fsoil hysteresis is primarily driven by thermal convection through the soil profle. We conducted experiments under normal, fuctuating diurnal soil temperatures and under conditions where we held soil temperature near constant. We found (i) signifcant and nearly equal amplitudes of hysteresis regardless of soil temperature regime, and (ii) the amplitude of hysteresis was most closely tied to baseline rates of Fsoil, which were mostly driven by photosynthetic rates. Together, these fndings suggest a more biologically-driven mechanism associated with photosynthate transport in yielding the observed patterns of soil CO2 efux being out of sync with soil temperature. These fndings should be considered on future partitioning models of ecosystem respiration.French governmentFrench National Research Agency (ANR) ANR-10-IDEX-0001-02 PSL ANR-11-INBS-0001ENSUniversity of Arizona (UofA)Philecology Foundation (Fort Worth, Texas, USA)Thomas R. Brown Family FoundationRegion Ile-de-France I-05-098/R 2011-11017735European Union (EU)National Science Foundation (NSF) 1417101 1331408European Union (EU) 625988UofA Office of Global InitiativesOffice of the Vice President of Research at the UofAUMI iGLOBES program at the Uof

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Cushing's syndrome: Treatment and new therapeutic approaches

International audienceOvert Cushing's syndrome is a severe condition responsible for multiple comorbidities and increased mortality. Effective treatment is essential to reduce mortality, improve comorbidities and long-term quality of life. Surgical resection of the causal lesion(s) is generally the first-line and most effective treatment to normalize cortisol secretion. Adjunctive symptomatic treatments of co-morbidities are often necessary both during the active phase of the disease and for persisting co-morbidities after cessation of hypercortisolism. Second-line treatments include various pharmacological treatments, bilateral adrenalectomy, and radiotherapy of corticotroph tumors. The choice of these treatments is complex, must be performed in a multidisciplinary expert team to be individualized for each patient, and use a shared decision-making approach

NPV-BSK805, an Antineoplastic Jak2 Inhibitor Effective in Myeloproliferative Disorders, Causes Adiposity in Mice by Interfering With the Action of Leptin

The pathophysiology of body weight gain that is observed in patients suffering from myeloproliferative neoplasms treated with inhibitors of the janus kinase (Jak) 1 and 2 pathway remains unknown. Here we hypothesized that this class of drugs interferes with the metabolic actions of leptin, as this hormone requires functional Jak2 signaling. To test this, C57BL/6J chow-fed mice received either chronic intraperitoneal (ip) or repeated intracerebroventricular (icv) administration of the selective Jak2 inhibitor NVP-BSK805, which was proven efficacious in treating polycythemia in rodents. Changes in food intake, body weight and body composition were recorded. Icv NVP-BSK805 was combined with ip leptin to evaluate ability to interfere with the action of this hormone on food intake and on induction of hypothalamic phosphorylation of signal transducer and activator of transcription 3 (STAT3). We found that chronic peripheral administration of NVP-BSK805 did not alter food intake, but increased fat mass and feed efficiency. The increase in fat mass was more pronounced during repeated icv administration of the compound, suggesting that metabolic effects were related to molecular interference in brain structures regulating energy balance. Accordingly, acute icv administration of NVP-BSK805 prevented the ability of leptin to decrease food intake and body weight by impeding STAT3 phosphorylation within the hypothalamus. Consequently, acute icv administration of NVP-BSK805 at higher dose induced hyperphagia and body weight gain. Our results provide evidence for a specific anabolic effect exerted by antineoplastic drugs targeting the Jak2 pathway, which is due to interference with the actions of leptin. Consequently, assessment of metabolic variables related to increased fat mass gain should be performed in patients treated with Jak2 inhibitors

Pasireotide-LAR in acromegaly patients treated with a combination therapy: a real-life study

Purpose Little data are available regarding the safety and efficacy of switching to Pasireotide-LAR monotherapy in acromegaly patients with partial resistance to first-generation somatostatin agonists (1gSRL) who require combination treatment with cabergoline or pegvisomant. Method In this monocentric prospective study within a tertiary university hospital, 15 consecutive acromegalic adults partially resistant to 1gSRL treated with octreotide LAR or lanreotide SR, and cabergoline ( n = 4, 3.5 mg/week) or pegvisomant ( n = 11, median dose 100 mg/week), were switched to Pasireotide-LAR (8 with 40 mg/month; 7 with 60 mg/month). Immunohistochemical expression level of SSTR5 and the granulation pattern of nine somatotroph adenomas were retrospectively determined to test for a correlation with the therapeutic efficacy of Pasireotide-LAR. Results Median IGF-1 concentration at the first evaluation (median 3 months) was similar to baseline (1.0 vs 1.1 ULN). 11/15 patients had IGF-1 levels ≤1.3 ULN before and after the switch but individual changes were variable. Hyperglycemia was frequent and greater in diabetic patients. 7/15 patients stopped Pasireotide-LAR due to lack of control of IGF-1 or intolerance. 8/15 patients received Pasireotide-LAR for a median of 29 months with IGF-1 levels ≤1.3 ULN and acceptable glucose tolerance (median HbA1c 6.1%). Two patients required initiation of oral antidiabetic treatment. The intensity of SSTR5 expression and the granulation pattern of adenomas were of limited value for the prediction of Pasireotide-LAR effectiveness. Conclusion Pasireotide-LAR may represent a suitable therapeutic alternative in a subset of acromegalic patients requiring combination therapy involving a 1gSR

Corrigendum: The Role of Nucleases and Nucleic Acid Editing Enzymes in the Regulation of Self-Nucleic Acid Sensing (Frontiers in Immunology, (2021), 12, (629922), 10.3389/fimmu.2021.629922)

In the original article, there was a mistake in the legend for Figure 2 as published. The correct legend for Figure 2 was mistakenly omitted and replaced with the legend of figure 3. The correct legend appears below. DNASE1L3 deficiency leads to the accumulation of numerous forms of DNA including chromatin, MP associated DNA and NET-associated DNA. Accumulation of such DNA contributes to the aberrant activation of TLR7,9 in B cells and plasmacytoid dendritic cells (pDCs). In B cells TLR7,9 activation leads to their differentiation into plasma cells and antibody forming cells (AFC) that produce autoreactive antibodies mostly directed against dsDNA. In pDCs TLR7,9 activation induces the production of type I interferons (IFN-I) which also play an important role in the transition of B cells into AFC. The production of anti-dsDNA antibodies and of IFN-I will ultimately cause the development of Systemic Lupus Erythematosus (SLE). The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated. (Figure presented.)