Plantamajoside modulates immune dysregulation and hepatic lipid metabolism in rats with nonalcoholic fatty liver disease via AMPK/Nrf2 elevation.

Nonalcoholic fatty liver disease (NAFLD) is a hepatic metabolic syndrome with a rapidly increasing prevalence globally. Plantamajoside (PMS), a phenylethanoid glycoside component extracted from Plantago asiatica, has various biological properties. However, its effect on NAFLD remains unknown. The study aimed to explore the effect and mechanism of PMS on NAFLD in the high-fat diet (HFD)-feeding rats. PMS induced a decrease in body and liver weight, and the amelioration in the blood lipid parameters and pathological symptoms in HFD-feeding rats. The increase in the serum concentrations and the relative protein expressions of proinflammatory factors was decreased by the PMS treatment in HFD-induced NAFLD rats. Additionally, PMS reduced the excessive lipid vacuoles, and modified the relative expressions of proteins involved in the fatty acid synthesis and uptake in HFD-feeding rats. Mechanically, the downregulation of AMPK/Nrf2 pathway in HFD-feeding rats was restored by the PMS treatment. Inhibition of AMPK pathway reversed the PMS-induced the increase in the level of inflammatory factors, pathological symptoms, excessive lipid vacuoles, and the relative expression of proteins involved in the fatty acid synthesis and uptake. Collectively, PMS ameliorated immune dysregulation and abnormal hepatic lipid metabolism by activating AMPK/Nrf2 pathway in rats with NAFLD.

COVID-19 Immunobiology: Lessons Learned, New Questions Arise.

There is strong evidence that COVID-19 pathophysiology is mainly driven by a spatiotemporal immune deregulation. Both its phenotypic heterogeneity, spanning from asymptomatic to severe disease/death, and its associated mortality, are dictated by and linked to maladaptive innate and adaptive immune responses against SARS-CoV-2, the etiologic factor of the disease. Deregulated interferon and cytokine responses, with the contribution of immune and cellular stress-response mediators (like cellular senescence or uncontrolled inflammatory cell death), result in innate and adaptive immune system malfunction, endothelial activation and inflammation (endothelitis), as well as immunothrombosis (with enhanced platelet activation, NET production/release and complement hyper-activation). All these factors play key roles in the development of severe COVID-19. Interestingly, another consequence of this immune deregulation, is the production of autoantibodies and the subsequent development of autoimmune phenomena observed in some COVID-19 patients with severe disease. These new aspects of the disease that are now emerging (like autoimmunity and cellular senescence), could offer us new opportunities in the field of disease prevention and treatment. Simultaneously, lessons already learned from the immunobiology of COVID-19 could offer new insights, not only for this disease, but also for a variety of chronic inflammatory responses observed in autoimmune and (auto)inflammatory diseases.

Case Report: Diagnosis of Myelodysplastic Syndrome in a 72-Year-Old Female With Interstitial Lung Disease.

Acute fibrinous and organizing pneumonia (AFOP) is an entity that can be secondary to various conditions leading to lung injury, such as infections, malignancies, and various autoimmune conditions or idiopathic interstitial lung disease, when no obvious underlying cause is identified. Myelodysplastic syndromes (MDS), on the other hand, are a spectrum of clonal myeloid disorders, with a higher risk of acute leukemia, characterized by ineffective bone marrow (BM) hematopoiesis and, thus, peripheral blood (PB) cytopenias. Immune deregulation is thought to take part in the pathophysiology of the disease, including abnormal T and/or B cell responses, innate immunity, and cytokine expression. In the literature, there are a few case reports of patients with MDS that have presented pulmonary infiltrates and were diagnosed as having AFOP or organizing pneumonia (OP). It is rare, though, to have isolated pulmonary infiltrates without Sweet's syndrome or even the pulmonary infiltrates to precede the diagnosis and treatment of MDS, which was our case. We present a 72-year-old female developing new lung infiltrates refractory to antibiotic treatment that responded well to corticosteroids and was histologically described as having OP. The treatment was gradually successfully switched to mycophenolate mofetil (MMF). The patient was later diagnosed with MDS. This interesting case report suggests firstly that a diagnosis of AFOP or OP should alert the clinician to search for an underlying cause including MDS and vice versa, the use of systemic steroids should not be postponed, and, finally, that MMF can successfully be used in these patients.

Overexpression of miR-124 in Motor Neurons Plays a Key Role in ALS Pathological Processes.

miRNA(miR)-124 is an important regulator of neurogenesis, but its upregulation in SOD1G93A motor neurons (mSOD1 MNs) was shown to associate with neurodegeneration and microglia activation. We used pre-miR-124 in wild-type (WT) MNs and anti-miR-124 in mSOD1 MNs to characterize the miR-124 pathological role. miR-124 overexpression in WT MNs produced a miRNA profile like that of mSOD1 MNs (high miR-125b; low miR-146a and miR-21), and similarly led to early apoptosis. Alterations in mSOD1 MNs were abrogated with anti-miR-124 and changes in their miRNAs mostly recapitulated by their secretome. Normalization of miR-124 levels in mSOD1 MNs prevented the dysregulation of neurite network, mitochondria dynamics, axonal transport, and synaptic signaling. Same alterations were observed in WT MNs after pre-miR-124 transfection. Secretome from mSOD1 MNs triggered spinal microglia activation, which was unno-ticed with that from anti-miR-124-modulated cells. Secretome from such modulated MNs, when added to SC organotypic cultures from mSOD1 mice in the early symptomatic stage, also coun-teracted the pathology associated to GFAP decrease, PSD-95 and CX3CL1-CX3CR1 signaling im-pairment, neuro-immune homeostatic imbalance, and enhanced miR-124 expression levels. Data suggest that miR-124 is implicated in MN degeneration and paracrine-mediated pathogenicity. We propose miR-124 as a new therapeutic target and a promising ALS biomarker in patient sub-populations.

COVID 19 pneumonia in Down syndrome patients: About 2 cases.

INTRODUCTION: Covid-19 is a severe emerging infection with high rate of mortality. Patients with Covid-19 and Down syndrome represent a high rate of morbidity and mortality. CASE PRESENTATION: Case 1: A 27-year-old white male with Down's syndrome admitted to the ICU for Covid-19 infection with lung damage of 30-50%. The patient improved and referred to the pulmonology department.Case 2: A 49-year-old man admitted to the ICU for Covid-19 infection with a lung damage of 50%. The evolution was lethal and he passed away after 12 days of his admission. CONCLUSION: People suffering from Down syndrome should be given priority in the management of acute respiratory distress following infection with SARS COV2, or even candidates for early immunosuppressive treatment and possible vaccination once started.

Increased proportion and altered properties of intermediate monocytes in the peripheral blood of patients with lower risk Myelodysplastic Syndrome.

Immune deregulation has a critical role in the pathogenesis of lower risk myelodysplastic syndromes (MDS). The cells of the macrophage/monocyte lineage have been reported to contribute to the inflammatory process in MDS through impaired phagocytosis of the apoptotic hemopoietic cells and abnormal production of cytokines. In the present study we assessed the number of peripheral blood (PB) monocyte subsets, namely the classical CD14bright/CD16-, intermediate CD14bright/CD16+ and non-classical CD14dim/CD16+ cells, in patients with lower risk (low/intermediate-I) MDS (n = 32). We also assessed the production of tumor necrosis factor (TNF)α by patient PB monocytes in response to immune stimulus as well as their transcriptome profile. Compared to age- and sex-matched healthy individuals (n = 19), MDS patients had significantly lower number of classical and increased number of intermediate monocytes. Patient intermediate monocytes displayed increased production of TNFα following stimulation with lipopolysaccharide, compared to healthy individuals. Transcriptional profiling comparison of CD16+ monocytes from patients and controls revealed 43 differentially expressed genes mostly associated with biological pathways/processes relevant to hemopoiesis, immune signaling and cell adhesion. These data provide evidence for the first-time that distinct monocyte subsets display abnormal quantitative and functional characteristics in lower risk MDS substantiating their role in the immune deregulation associated with the disease.

Analyzing the Potential Biological Determinants of Autism Spectrum Disorder: From Neuroinflammation to the Kynurenine Pathway.

Autism Spectrum Disorder (ASD) etiopathogenesis is still unclear and no effective preventive and treatment measures have been identified. Research has focused on the potential role of neuroinflammation and the Kynurenine pathway; here we review the nature of these interactions. Pre-natal or neonatal infections would induce microglial activation, with secondary consequences on behavior, cognition and neurotransmitter networks. Peripherally, higher levels of pro-inflammatory cytokines and anti-brain antibodies have been identified. Increased frequency of autoimmune diseases, allergies, and recurring infections have been demonstrated both in autistic patients and in their relatives. Genetic studies have also identified some important polymorphisms in chromosome loci related to the human leukocyte antigen (HLA) system. The persistence of immune-inflammatory deregulation would lead to mitochondrial dysfunction and oxidative stress, creating a self-sustaining cytotoxic loop. Chronic inflammation activates the Kynurenine pathway with an increase in neurotoxic metabolites and excitotoxicity, causing long-term changes in the glutamatergic system, trophic support and synaptic function. Furthermore, overactivation of the Kynurenine branch induces depletion of melatonin and serotonin, worsening ASD symptoms. Thus, in genetically predisposed subjects, aberrant neurodevelopment may derive from a complex interplay between inflammatory processes, mitochondrial dysfunction, oxidative stress and Kynurenine pathway overexpression. To validate this hypothesis a new translational research approach is necessary.

Consequences of epigenetic derepression in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is caused either by the contraction of the D4Z4 macrosatellite repeat at the distal end of chromosome 4q to a size of 1 to 10 repeat units (FSHD1) or by mutations in D4Z4 chromatin modifiers such as Structural Maintenance of Chromosomes Hinge Domain Containing 1 (FSHD2). These two genotypes share a phenotype characterized by progressive and often asymmetric muscle weakening and atrophy, and common epigenetic alterations of the D4Z4 repeat. All together, these epigenetic changes converge the two genetic forms into one disease and explain the derepression of the DUX4 gene, which is otherwise kept epigenetically silent in skeletal muscle. DUX4 is consistently transcriptionally upregulated in FSHD1 and FSHD2 skeletal muscle cells where it is believed to exercise a toxic effect. Here we provide a review of the recent literature describing the progress in understanding the complex genetic and epigenetic architecture of FSHD, with a focus on one of the consequences that these epigenetic changes inflict, the DUX4-induced immune deregulation cascade. Moreover, we review the latest therapeutic strategies, with particular attention to the potential of epigenetic correction of the FSHD locus.

Gut microbiota and chronic kidney disease: implications for novel mechanistic insights and therapeutic strategies.

The complicated communities of microbiota colonizing the human gastrointestinal tract exert a strong function in health maintenance and disease prevention. Indeed, accumulating evidence has indicated that the intestinal microbiota plays a key role in the pathogenesis and development of chronic kidney disease (CKD). Modulation of the gut microbiome composition in CKD may contribute to the accumulation of gut-derived uremic toxins, high circulating level of lipopolysaccharides and immune deregulation, all of which play a critical role in the pathogenesis of CKD and CKD-associated complications. In this review, we discuss the recent findings on the potential impact of gut microbiota in CKD and the underlying mechanisms by which microbiota can influence kidney diseases and vice versa. Additionally, the potential efficacy of pre-, pro- and synbiotics in the restoration of healthy gut microbia is described in detail to provide future directions for research.

Síndrome de Evans: nuevo enfoque clínico. Revisión bibliográfica / Evans syndrome: new clinic approach. Bibliographical revision

El Síndrome de Evans es un desorden heterogéneo caracterizado por el desarrollo simultáneo o secuencial de trombocitopenia autoinmune y anemia hemolítica autoinmune. Esta enfermedad de curso crónico ha sido correlacionada con inmunodeficiencias primarias, enfermedades colágeno-vasculares, desórdenes linfoproliferativos, y síndromes linfoproliferativos auto inmunes (ALPS). Los nuevos conceptos en su patogénesis aumentan el campo de investigación clínica del paciente, y constituyen el punto de partida para futuras terapias.

Evans syndrome is a heterogeneous disorder characterized by simultaneous development and sequence of autoimmune thrombocytopenia and autoimmune hemolytic anemia. This disease of chronic course has been correlated with primary immunodeficiency, collagen- vascular diseases, linfoproliferative disorders, and autoimmune linfoproliferative syndromes (ALPS). The news concepts in his pathogenesis increase the field of clinic investigation of the patient, and constitute the point to begin future therapies.