Integrated analysis of RNA-seq datasets reveals novel targets and regulators of COVID-19 severity.

During the COVID-19 pandemic, RNA-seq datasets were produced to investigate the virus-host relationship. However, much of these data remains underexplored. To improve the search for molecular targets and biomarkers, we performed an integrated analysis of multiple RNA-seq datasets, expanding the cohort and including patients from different countries, encompassing severe and mild COVID-19 patients. Our analysis revealed that severe COVID-19 patients exhibit overexpression of genes coding for proteins of extracellular exosomes, endomembrane system, and neutrophil granules (e.g., S100A9, LY96, and RAB1B), which may play an essential role in the cellular response to infection. Concurrently, these patients exhibit down-regulation of genes encoding components of the T cell receptor complex and nucleolus, including TP53, IL2RB, and NCL Finally, SPI1 may emerge as a central transcriptional factor associated with the up-regulated genes, whereas TP53, MYC, and MAX were associated with the down-regulated genes during COVID-19. This study identified targets and transcriptional factors, lighting on the molecular pathophysiology of syndrome coronavirus 2 infection.

A relevância da odontologia na Síndrome Treacher Collins: relato de caso / The relevance of dentistry in Treacher Collins Syndrome: case report

Treacher Collins também chamada de disostose mandibulofacial, é uma alteração genética dominante rara caracterizada pela má-formação dos ossos e tecidos da face. É uma síndrome crânio-facial que apresenta alterações bilaterais e simétricas de estruturas originadas do primeiro e segundo arcos branquiais. A maioria dos casos possui transmissão autossômica dominante e expressividade variável. O objetivo do presente estudo é realizar um relato de caso sobre o impacto do tratamento odontológico na qualidade de vida do paciente portador de Treacher Collins. Paciente, 39 anos, sexo feminino compareceu a uma clínica odontológica em Belo Horizonte, com a queixa principal de falhas dentárias e sensibilidade. Durante a anamnese a paciente relatou ter a STC, durante o exame clínico extraoral verificou a presença de hipoplasia malar e mandibular, malformação dos pavilhões auriculares com perda auditiva, obliquidade e coloboma palpebral inferior. Ao exame intraoral observou ser classe II de Angle, ausência dos dentes 11, 12, 13, 21 e 22 e extrusão do dente 41 e recessão gengival e periodontite estágio I grau A. Após exames de periodontograma e complementares foi realizado uma raspagem nas áreas com profundidade de sondagem maior que 3mm, frenectomia labial inferior, aplicação de laser para sensibilidade, enxerto gengival e colocação de prótese parcial removível. A paciente ao final do tratamento relatou ter se sentido realizada e contente com a sua conclusão, ela foi encaminhada ao Sistema único de Saúde para realizar as cirurgias para corrigir as alterações crânio-faciais. O tratamento odontológico deve ser adaptado a cada indivíduo de acordo com sua necessidade, tendo uma abordagem multidisciplinar, possibilitando uma melhora na qualidade de vida e estética do paciente(AU)

Treacher Collins syndrome is a rare dominant genetic disorder characterized by malformation of the bones and tissues of the face. It is a craniofacial syndrome that presents bilateral and symmetrical alterations of structures originating from the first and second branchial arches. The aim of the present study is to perform a case report on the impact of dental treatment on the quality of life of a patient with CTS. Patient, 39 years old, female, attended a dental clinic in Belo Horizonte, with the main complaint of dental flaws and sensitivity. During the anamnesis the patient reported having CTS, during the extraoral clinical examination she verified the presence of malar and mandibular hypoplasia, malformation of the pinnae with hearing loss, obliquity and lower eyelid coloboma. Intraoral examination revealed Angle class II, missing teeth 11, 12, 13, 21 and 22, extrusion of tooth 41, gingival recession and stage I periodontitis grade A. After periodontogram and complementary exams it was performed a scaling in areas with a probing depth greater than 3mm, lower lip frenectomy, laser application for sensitivity, gingival graft and placement of partial removable prosthesis. The patient at the end of treatment reported feeling fulfilled and happy with its completion, she was referred to the Unique Health System to undergo surgery to correct the craniofacial changes. The current treatment aims at functional and aesthetic correction and the need for psychosocial support, having the joint participation of a multidisciplinary team to achieve this goal(AU)

APE1/Ref-1 Role in Inflammation and Immune Response.

Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional enzyme that is essential for maintaining cellular homeostasis. APE1 is the major apurinic/apyrimidinic endonuclease in the base excision repair pathway and acts as a redox-dependent regulator of several transcription factors, including NF-κB, AP-1, HIF-1α, and STAT3. These functions render APE1 vital to regulating cell signaling, senescence, and inflammatory pathways. In addition to regulating cytokine and chemokine expression through activation of redox sensitive transcription factors, APE1 participates in other critical processes in the immune response, including production of reactive oxygen species and class switch recombination. Furthermore, through participation in active chromatin demethylation, the repair function of APE1 also regulates transcription of some genes, including cytokines such as TNFα. The multiple functions of APE1 make it an essential regulator of the pathogenesis of several diseases, including cancer and neurological disorders. Therefore, APE1 inhibitors have therapeutic potential. APE1 is highly expressed in the central nervous system (CNS) and participates in tissue homeostasis, and its roles in neurodegenerative and neuroinflammatory diseases have been elucidated. This review discusses known roles of APE1 in innate and adaptive immunity, especially in the CNS, recent evidence of a role in the extracellular environment, and the therapeutic potential of APE1 inhibitors in infectious/immune diseases.

Chemical Inhibition of Apurinic-Apyrimidinic Endonuclease 1 Redox and DNA Repair Functions Affects the Inflammatory Response via Different but Overlapping Mechanisms.

The presence of oxidized DNA lesions, such as 7,8-dihydro-8-oxoguanine (8-oxoG) and apurinic/apyrimidinic sites (AP sites), has been described as epigenetic signals that are involved in gene expression control. In mammals, Apurinic-apyrimidinic endonuclease 1/Redox factor-1 (APE1/Ref-1) is the main AP endonuclease of the base excision repair (BER) pathway and is involved in active demethylation processes. In addition, APE1/Ref-1, through its redox function, regulates several transcriptional factors. However, the transcriptional control targets of each APE1 function are not completely known. In this study, a transcriptomic approach was used to investigate the effects of chemical inhibition of APE1/Ref-1 redox or DNA repair functions by E3330 or methoxyamine (MX) in an inflammatory cellular model. Under lipopolysaccharide (LPS) stimulation, both E3330 and MX reduced the expression of some cytokines and chemokines. Interestingly, E3330 treatment reduced cell viability after 48 h of the treatment. Genes related to inflammatory response and mitochondrial processes were downregulated in both treatments. In the E3330 treatment, RNA processing and ribosome biogenesis genes were downregulated, while they were upregulated in the MX treatment. Furthermore, in the E3330 treatment, the cellular stress response was the main upregulated process, while the cellular macromolecule metabolic process was observed in MX-upregulated genes. Nuclear respiratory factor 1 (NRF1) was predicted to be a master regulator of the downregulated genes in both treatments, while the ETS transcription factor ELK1 (ELK1) was predicted to be a master regulator only for E3330 treatment. Decreased expression of ELK1 and its target genes and a reduced 28S/18S ratio were observed, suggesting impaired rRNA processing. In addition, both redox and repair functions can affect the expression of NRF1 and GABPA target genes. The master regulators predicted for upregulated genes were YY1 and FLI1 for the E3330 and MX treatments, respectively. In summary, the chemical inhibition of APE1/Ref-1 affects gene expression regulated mainly by transcriptional factors of the ETS family, showing partial overlap of APE1 redox and DNA repair functions, suggesting that these activities are not entirely independent. This work provides a new perspective on the interaction between APE1 redox and DNA repair activity in inflammatory response modulation and transcription.

Resveratrol decreases the expression of genes involved in inflammation through transcriptional regulation.

Oxidative stress generated during inflammation is associated with a wide range of pathologies. Resveratrol (RESV) displays anti-inflammatory and antioxidant activities, being a candidate for the development of adjuvant therapies for several inflammatory diseases. Despite this potential, the cellular responses induced by RESV are not well known. In this work, transcriptomic analysis was performed following lipopolysaccharide (LPS) stimulation of monocyte cultures in the presence of RESV. Induction of an inflammatory response was observed after LPS treatment and the addition of RESV led to decreases in expression of the inflammatory mediators, tumor necrosis factor-alpha (TNF-α), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1), without cytotoxicity. RNA sequencing revealed 823 upregulated and 2098 downregulated genes (cutoff ≥2.0 or ≤-2.0) after RESV treatment. Gene ontology analysis showed that the upregulated genes were associated with metabolic processes and the cell cycle, consistent with normal cell growth and differentiation under an inflammatory stimulus. The downregulated genes were associated with inflammatory responses, gene expression, and protein modification. The prediction of master regulators using the iRegulon tool showed nuclear respiratory factor 1 (NRF1) and GA-binding protein alpha subunit (GABPA) as the main regulators of the downregulated genes. Using immunoprecipitation and protein expression assays, we observed that RESV was able to decrease protein acetylation patterns, such as acetylated apurinic/apyrimidinic endonuclease-1/reduction-oxidation factor 1 (APE1/Ref-1), and increase histone methylation. In addition, reductions in p65 (nuclear factor-kappa B (NF-κB) subunit) and lysine-specific histone demethylase-1 (LSD1) expression were observed. In conclusion, our data indicate that treatment with RESV caused significant changes in protein acetylation and methylation patterns, suggesting the induction of deacetylase and reduction of demethylase activities that mainly affect regulatory cascades mediated by NF-кB and Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling. NRF1 and GABPA seem to be the main regulators of the transcriptional profile observed after RESV treatment.