Patients with COVID-19 may develop abnormal inflammatory response, followed in some cases by severe disease and long-lasting syndromes. We show here that in vitro exposure to SARS-CoV-2 activates the ...expression of the human endogenous retrovirus (HERV) HERV-W proinflammatory envelope protein (ENV) in peripheral blood mononuclear cells from a subset of healthy donors, in ACE2 receptor and infection-independent manner. Plasma and/or sera of 221 COVID-19 patients from different cohorts, infected with successive SARS-CoV-2 variants including the Omicron, had detectable HERV-W ENV, which correlated with ENV expression in T lymphocytes and peaked with the disease severity. HERV-W ENV was also found in postmortem tissues of lungs, heart, gastrointestinal tract, brain olfactory bulb, and nasal mucosa from COVID-19 patients. Altogether, these results demonstrate that SARS-CoV-2 could induce HERV-W envelope protein expression and suggest its involvement in the immunopathogenesis of certain COVID-19-associated syndromes and thereby its relevance in the development of personalized treatment of patients.
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•SARS-CoV-2 induces endogenous retrovirus envelope in a subset of healthy donors•HERV-W ENV is detected on lymphocytes, in serum and tissues of COVID-19 patients•HERV-W ENV protein in serum and lymphocytes correlates with COVID-19 severity•Prognostic value of HERV-W ENV expression may allow targeted therapy of COVID-19
Health sciences; Virology; Molecular Genetics
The aim of this study was to detect genotypic differences between three populations of healthy volunteers from Northern Spain (204 subjects), Nicaragua (120 subjects), and El Salvador (112 subjects) ...regarding CYP3A4*1B and CYP3A5*3 polymorphisms. No significant differences were found by comparing allelic frequencies between the two Central American populations. The CYP3A5*3 allele frequency was significantly different (P < 0.01) between Central Americans (76%) and Spaniards (91%). By contrast, CYP3A4*1B allele was more prevalent among Central Americans (12.5%) than among North Spaniards (4%) (P < 0.01). Analysis of CYP3A4-3A5 genotype combinations revealed that individuals carrying CYP3A4*1B/CYP3A5*1 were more represented in Central Americans (16.9%) than in Spaniards (5.4%), suggesting a marked linkage disequilibrium. These data are compatible with a higher CYP3A enzyme activity in Central Americans as opposed to Spaniards and other white groups, which could imply differences in dose requirements for drugs metabolized by CYP3A and should be considered in allele-disease association studies.
Gaucher disease (GD), has a pan-ethnic distribution with incidence in non-Ashkenazi Jewish population about 1/70-140 thousand inhabitants. The deficiency in lysosomal acid beta-glucosidase enzyme ...secondary to variants in the GBA gene with autosomal recessive inheritance gives rise to a variable clinical picture. It appears at any age with symptoms that include anemia, thrombocytopenia, pain and vascular bone lesions, visceral enlargement, persistent fatigue. It was the first EDL to have enzymatic replacement and substrate reduction therapy that impact in the awareness of the disease. In 1993, the Spanish Registry of Gaucher Disease was created (REsEG), within the Spanish Foundation for the Study and Therapeutics of EG (FEETEG), with the aim of providing support to all those involved in the management of patients with EG and summarize experience at the national level. This work review the characteristics at diagnosis of type 1 adult GD (GD1) patients, diagnosed outside active early diagnosis programs, along of twenty five years of REsEG existence focus on leading diagnostic symptoms in order to answer the current challenges in patients suspicions. Aim: To analyze the evolving profile of GD1 patients diagnosed before and after 2000 based on the principal manifestations including visceral, hematological involvement, bone pain, bleeding in order to define the current suspicious characteristics in our population. Methods: Patients 18+ years old included in the REsEG were selected. Demographic, genetic, clinical (hematological, visceral, bone, neurological) data, severity index, biomarkers and other relevant information were included in a database created for this purpose. Platelets <140x109/L were considered as thrombocytopenia and hemoglobin below 12 g/dL in females and 13 g/dL in males were considered as anemia. Ethic board of SpRGD and FEETEG approved the development of the present work. To analyze the evolution in the diagnostic features of adult GD1 patients, a cut-off settled according the year of diagnosis, <2000 or 2000+, was used. The use of this cut-off was made considering the awareness for diagnostic increased progressively since ERT availability in mid 90's in Spain. The statistical analysis were made using comparative methods with a level of 95% interval of confidence. Results: Since 1993 a total of 223 GD1 with 18+ years old patients were diagnosed and included in the registry. 50.7% (113) were females, mean age at diagnosis 38.5 (18-87). The symptoms that led to the diagnostic of GD1 were: splenomegaly 71.1%, (3 of them detected during pregnancy work out), thrombocytopenia 83.3%, isolated anemia 39.0%, pancytopenia 8.5%, hepatomegaly 22.5%, bone pain: 57.9%(bone crisis 48.8% pathological fractures 3 cases), hemorrhagic diathesis (ecchymosis, epistaxis): 20.6%, peripartum bleeding: 3 cases, family study: 19.3%, early Parkinson's study 3 cases, other reasons for referral were MGUS 4 cases, hyperferritinemia 7 cases. Also we have recorded that bone marrow aspiration or biopsy was the first test in the diagnosis process in about 80% of cases. According the year of diagnosis 131 (58.7%) patients were diagnosed before 2000 (group A), mean age at diagnosis 36 (18-87) y.o and 92 (41.3%) after 2000 (group B). mean age at diagnosis 41.8 (18-79) y.o. General characteristics and genotype distribution are detailed in tables 1 and 2. Concerning profile's patient diagnosed before 2000 showing a more clinical aggressive behavior, even the presence of thrombocytopenia was similar in both groups, the severity of thrombocytopenia were higher in group A (69.8; 16-129 x109/L) vs group B (83.4; 14-131 x109/L) (p=0.006), also anemia, bone pain and visceral enlargement show higher incidences. During this time there 7 cases have developed Parkinson's disease, 2 patients with de novo mutations, 21 neoplasms and other interesting findings. Conclusion: In our population we have found that the classical main characteristics of GD1 adult patients at diagnosis has evolved to a less severe phenotype in the present century. Features like bone pain, anemia, thrombocytopenia, visceral involvement are decreasing in percentage and severity; in parallel mild genetic variants were more prevalent. These data suggest that we need to continue the efforts on training in young hematologist to increase the awareness and visibility of disease, also among primary care providers in order to improve the early diagnosis.
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No relevant conflicts of interest to declare.
Adipose tissue (AT) expands under obesogenic conditions. Yet, when the growth exceeds a certain limit, AT becomes dysfunctional and surplus lipids start depositing ectopically. Polymerase I and ...transcription release factor (PTRF) has been proposed as a mechanism leading to a dysfunctional AT by decreasing the adipogenic potential of human adipocyte precursors. However, whether or not PTRF can be secreted by the adipocytes into the bloodstream is not yet known. For this work, PTRF presence was investigated in plasma. We also produced a recombinant PTRF (rPTRF) and examined its impact on the functional interactions between the adipocyte and the hepatocyte in vitro. We demonstrated that PTRF can be found in human plasma, and is at least in part, carried by exosomes. In vitro treatment with rPTRF increased the hypertrophy and senescence of 3T3-L1 adipocytes. In turn, those rPTRF-treated adipocytes increased lipid accumulation in hepatocytes. Lastly, we found a positive correlation between circulating PTRF and the concentration of PTRF in the visceral fat depot. All these findings point toward the presence of an enlarged and dysfunctional visceral adipose tissue which secretes PTRF. This circulating PTRF behaves as an adipokine and may partially contribute to the well-known detrimental effects of visceral fat accumulation.
Cyclooxygenase-2 (Cox-2) metabolites produced by endothelial cells, particularly prostacyclin and prostaglandin E
2, profoundly affect vascular tone, regional blood flow, and angiogenesis. We have ...previously shown that reactive oxygen species induce Cox-2 expression in human endothelial cells (HUVEC), either on their own or as components of the signaling pathway triggered by TNFα, the prototypical inflammatory cytokine. Here we investigated the role of Cox-2 induced by hydrogen peroxide (H
2O
2), either exogenous or endogenously generated by TNFα, in the repair of a mechanically wounded HUVEC monolayer and probed the sources of H
2O
2 that are involved in TNFα signaling and the pathways through which H
2O
2 modulates Cox-2 expression. Results indicate that H
2O
2-induced Cox-2 activity participates in the repair of wounded monolayers. Both NADPH oxidase and the mitochondrial electron transport chain are involved in H
2O
2 generation. Signaling triggered by H
2O
2 for Cox-2 induction acts by increasing the protein tyrosine kinase phosphorylation that follows inhibition of protein phosphatase activity. The activation of p38 MAPK and its interaction in the inhibition of serine/threonine phosphatase activity are both critical steps in this event. We conclude that Cox-2 induced by H
2O
2 plays an important role in promoting endothelial wound repair after injury, so that the cardioprotective effect of Cox-2 is due at least in part to its power of healing damaged endothelium.
This study was designed to investigate the potential differences between Spaniards and Ecuadorian Mestizo people regarding CYP2A6*1A, CYP2A6*1B1, CYP2A6*1x2A, CYP2A6*9A, and CYP2A6*4A variant alleles ...at the CYP2A6 gene and also to compare the observed frequencies with those previously reported in different ethnic groups. DNA from 234 Spaniard and 300 Ecuadorian subjects were analyzed by either PCR or PCR‐restriction fragment length polymorphism. Differences between Spaniards and Mestizo Ecuadorians were detected in relation to the frequencies of the alleles linked to either absent enzyme activity, CYP2A6*4A (4 and 7.1%, respectively), or reduced CYP2A6 enzyme activity, CYP2A6*9A (6.4 and 10.3%, respectively). CYP2A6*4A and CYP2A6*9A frequencies in Ecuadorians were higher than those in Africans or Caucasian groups and lower than those in Asians. This study provides, for the first time, the result of the analysis of CYP2A6 allele frequency in a South American population and demonstrates the presence of ethnic differences in CYP2A6 genetic variants between Spaniards and Mestizo Ecuadorians, which should be considered in allele–disease association studies and, in particular, in those involving CYP2A6 genetic polymorphisms and tobacco‐related cancer.
This study was aimed to investigate the potential differences in allele frequencies of the CYP2B6 gene between Spaniards and Central Americans. Three single nucleotide polymorphisms of the CYP2B6 ...gene 516 G>T, 785 A>G and 1459 C>T were assayed by a polymerase chain reaction in 180 Spaniards and 182 Central Americans. The allele frequencies for CYP2B6*1, CYP2B6*4, CYP2B6*5, CYP2B6*6, CYP2B6*9 in Spaniards and Central Americans were 0.593 and 0.642, 0.062 and 0.073, 0.113 and 0.030, 0.215 and 0.230, 0.014 and 0.023, respectively. CYP2B6*5 was less prevalent among Central Americans than in Spaniards (P < 0.001). In comparison to other previously studied populations, the CYP2B6*5 allele frequency among Spaniards was similar to other Caucasian or African groups, and higher than that in Asian populations. The CYP2B6*5 allele frequency in Central Americans was lower than that in Africans or Caucasian groups and higher than in Asians. The results indicate the presence of ethnic differences in CYP2B6 genetic variants between Spaniards and Central Americans, and support the need for further investigations to explore whether these differences significantly alter the efficacy or toxicity of CYP2B6 substrate drugs.
To examine the role of platelets and platelet-derived products on cyclooxygenase-2 (Cox-2) induction in adherent monocytes and to address the signaling pathways involved.
Platelets and monocytes were ...obtained from peripheral blood of healthy donors. Adherent monocytes were co-cultured with autologous platelets or platelet releasates or exposed to mediators contained in platelet alpha-granules (either from platelet source or recombinant) for 4-24 h. Cox-2 protein and mRNA were determined by Western and RT-PCR analysis, respectively. Thromboxane B2 (TxB2) and prostaglandin E2 (PGE2) synthesis as index of Cox-2 activity, and levels of transforming growth factor-beta1 (TGF-beta1) in platelet releasates were measured by enzyme immunoassay (EIA).
Activated platelets induce rapid and transient Cox-2 de novo synthesis in adherent monocytes. The effect is dependent upon the platelet number but not upon cell-cell contact. Platelet-induced Cox-2 was not affected by prevention of platelet TxA2 synthesis or microparticle formation but was blunted by inhibition of platelet alpha-granule secretion. TGF-beta1, either platelet-derived or recombinant (rTGF-beta1), induced Cox-2 expression and activity in adherent monocytes at concentrations within the range of those detected in releasates from activated platelets; this effect was not shared by recombinant platelet-derived growth factor (rPDGFBB). The time course of Cox-2 induction by TGF-beta1 in monocytes was identical to that observed with platelet releasates. Moreover, TGF-beta1 receptor blockade completely abolished platelet-induced Cox-2 expression. p38 MAPK activation represents a common transduction pathway through which activated platelets and rTGF-beta1 induce Cox-2 in monocytes.
These findings suggest that TGF-beta1 released by activated platelets has a pivotal role in Cox-2 induction in monocytes and further supports the key role of platelets in the inflammatory and reparative responses.
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