RÉSUMÉ
Introduction: The COVID-19 pandemic represented one of the most significant challenges to researchers and healthcare providers. Several factors determine the disease severity, whereas none alone can explain the tremendous variability. The Single nucleotide variants (SNVs) in angiotensin-converting enzyme-2 (ACE2) and transmembrane serine protease type-2 (TMPRSS2) genes affect the virus entry and are considered possible risk factors for COVID-19. Methods: We compiled a panel of gene variants from both genes and used in-silico analysis to predict their significance. We performed biological validation to assess their capacity to alter the ACE2 interaction with the virus spike protein. Subsequently, we conducted a retrospective comparative genome analysis on those variants in the Emirati patients with different disease severity (total of 96) along with 69 healthy control subjects. Results: Our results showed that the Emirati population lacks the variants that were previously reported as associated with disease severity, whereas a new variant in ACE2 "Chr X:g.15584534" was associated with disease severity specifically among female patients. In-silico analysis revealed that the new variant can determine the ACE2 gene transcription. Several cytokines (GM-CSF and IL-6) and chemokines (MCP-1/CCL2, IL-8/CXCL8, and IP-10/CXCL10) were markedly increased in COVID-19 patients with a significant correlation with disease severity. The newly reported genetic variant of ACE2 showed a positive correlation with CD40L, IL-1ß, IL-2, IL-15, and IL-17A in COVID-19 patients. Conclusion: Whereas COVID-19 represents now a past pandemic, our study underscores the importance of genetic factors specific to a population, which can influence both the susceptibility to viral infections and the level of severity; subsequently expected required preparedness in different areas of the world.
Sujet(s)
Angiotensin-converting enzyme 2 , COVID-19 , Cytokines , Polymorphisme de nucléotide simple , SARS-CoV-2 , Serine endopeptidases , Humains , COVID-19/génétique , Angiotensin-converting enzyme 2/génétique , Femelle , Mâle , SARS-CoV-2/physiologie , Cytokines/sang , Cytokines/génétique , Serine endopeptidases/génétique , Émirats arabes unis/épidémiologie , Adulte d'âge moyen , Adulte , Études rétrospectives , Indice de gravité de la maladie , Sujet âgéRÉSUMÉ
Prostate cancer is the second most commonly diagnosed cancer in men. The mammalian insulin-like growth factor (IGF) family is made up of three ligands (IGF-I, IGF-II, and insulin), three receptors (IGF-I receptor (IGF-1R), insulin receptor (IR), and IGF-II receptor (IGF-2R)), and six IGF-binding proteins (IGFBPs). IGF-I and IGF-II were identified as potent mitogens and were previously associated with an increased risk of cancer development including prostate cancer. Several reports showed controversy about the expression of the IGF family and their connection to prostate cancer risk due to the high degree of heterogeneity among prostate tumors, sampling bias, and evaluation techniques. Despite that, it is clear that several IGF family members play a role in prostate cancer development, metastasis, and androgen-independent progression. In this review, we aim to expand our understanding of prostate tumorigenesis and regulation through the IGF system. Further understanding of the role of IGF signaling in PCa shows promise and needs to be considered in the context of a comprehensive treatment strategy.
Sujet(s)
Tumeurs de la prostate , Somatomédines , Humains , Tumeurs de la prostate/métabolisme , Tumeurs de la prostate/anatomopathologie , Mâle , Somatomédines/métabolisme , Animaux , Transduction du signal , Facteur de croissance IGF-I/métabolisme , Protéines de liaison aux IGF/métabolisme ,RÉSUMÉ
Tumor microenvironment is an intricate web of stromal and immune cells creating an immune suppressive cordon around the tumor. In hepatocellular carcinoma (HCC), Tumor microenvironment is a formidable barrier towards novel immune therapeutic approaches recently evading the oncology field. In this study, the main aim was to identify the intricate immune evasion tactics mediated by HCC cells and to study the epigenetic modulation of the immune checkpoints; Programmed death-1 (PD-1)/ Programmed death-Ligand 1 (PD-L1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT)/Cluster of Differentiation 155 (CD155) at the tumor-immune synapse. Thus, liver tissues, PBMCs and sera were collected from Hepatitis C Virus (HCV), HCC as well as healthy individuals. Screening was performed to PD-L1/PD-1 and CD155/TIGIT axes in HCC patients. PDL1, CD155, PD-1 and TIGIT were found to be significantly upregulated in liver tissues and peripheral blood mononuclear cells (PBMCs) of HCC patients. An array of long non-coding RNAs (lncRNAs) and microRNAs validated to regulate such immune checkpoints were screened. The lncRNAs; CCAT-1, H19, and MALAT-1 were all significantly upregulated in the sera, PBMCs, and tissues of HCC patients as compared to HCV patients and healthy controls. However, miR-944-5p, miR-105-5p, miR-486-5p, miR-506-5p, and miR-30a-5p were downregulated in the sera and liver tissues of HCC patients. On the tumor cell side, knocking down of lncRNAs-CCAT-1, MALAT-1, or H19-markedly repressed the co-expression of PD-L1 and CD155 and accordingly induced the cytotoxicity of co-cultured primary immune cells. On the immune side, ectopic expression of the under-expressed microRNAs; miR-486-5p, miR-506-5p, and miR-30a-5p significantly decreased the transcript levels of PD-1 in PBMCs with no effect on TIGIT. On the other hand, ectopic expression of miR-944-5p and miR-105-5p in PBMCs dramatically reduced the co-expression of PD-1 and TIGIT. Finally, all studied miRNAs enhanced the cytotoxic effects of PBMCs against Huh7 cells. However, miR-105-5p showed the highest augmentation for PBMCs cytotoxicity against HCC cells. In conclusion, this study highlights a novel co-targeting strategy using miR-105-5p mimics, MALAT-1, CCAT-1 and H19 siRNAs to efficiently hampers the immune checkpoints; PD-L1/PD-1 and CD155/TIGIT immune evasion properties in HCC.
RÉSUMÉ
The discovery of non-coding RNAs (ncRNAs) has unveiled a wide range of transcripts that do not encode proteins but play key roles in several cellular and molecular processes. Long noncoding RNAs (lncRNAs) are specific class of ncRNAs that are longer than 200 nucleotides and have gained significant attention due to their diverse mechanisms of action and potential involvement in various pathological conditions. In the current review, the authors focus on the role of lncRNAs, specifically highlighting the Myocardial Infarction Associated Transcript (MIAT), in non-oncological context. MIAT is a nuclear lncRNA that has been directly linked to myocardial infarction and is reported to control post-transcriptional processes as a competitive endogenous RNA (ceRNA) molecule. It interacts with microRNAs (miRNAs), thereby limiting the translation and expression of their respective target messenger RNA (mRNA) and regulating protein expression. Yet, MIAT has been implicated in other numerous pathological conditions such as other cardiovascular diseases, autoimmune disease, neurodegenerative diseases, metabolic diseases, and many others. In this review, the authors emphasize that MIAT exhibits distinct expression patterns and functions across different pathological conditions and is emerging as potential diagnostic, prognostic, and therapeutic agent. Additionally, the authors highlight the regulatory role of MIAT and shed light on the involvement of lncRNAs and specifically MIAT in various non-oncological pathological conditions.
RÉSUMÉ
PURPOSE: This study investigated the levels of salivary proinflammatory cytokines in the saliva of patients living with type II diabetes mellitus (DM) compared to those in healthy individuals three times: before tooth extraction and at 2 hours and 2 days after tooth extraction. METHODS: The study included 27 participants. Among them, 20 (n = 20; 74%) had type II DM, and seven (n = 7; 26%) were healthy control subjects. Saliva samples were collected at three time intervals: before tooth extraction and 2 hours and 2 days after tooth extraction. The salivary biomarkers were investigated using a Luminex multiplex assay. These salivary biomarkers included tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin 1-beta (IL-1ß), and interferon-gamma (IFN-γ). RESULTS: At baseline, patients with type II DM had significantly lower levels of IL-1ß (P = 0.016). Moreover, 2 hours after extraction, patients with type II DM had significantly lower levels of IL-1ß and TNF-α than did healthy control subjects (P = 0.046 and P = 0.020, respectively). In addition, 2 days after tooth extraction, the DM group had significantly greater IL-6 levels (P = 0.010) than the control group. CONCLUSIONS: In patients with type II DM, salivary proinflammatory biomarker levels are generally comparable or lower than those in healthy control subjects. Proinflammatory cytokines manifest differently in patients with type II DM after tooth extraction than in normal healthy individuals. There is generally a delayed early response of salivary proinflammatory markers in patients living with type II DM who undergo tooth extraction.
Sujet(s)
Diabète de type 2 , Interleukine-6 , Humains , Diabète de type 2/complications , Facteur de nécrose tumorale alpha , Cytokines , Marqueurs biologiques , Extraction dentaireRÉSUMÉ
BACKGROUND: Embryonic pluripotency markers are recognized for their role in ER- BC aggressiveness, but their significance in ER+ BC remains unclear. This study aims to investigate the prevalence of expression of pluripotency markers in ER+ BC and their effect on survival and prognostic indicators. METHODS: We analyzed data of ER+ BC patients from three large cancer datasets to assess the expression of three pluripotency markers (NANOG, SOX-2, and OCT4), and the stem cell marker ALDH1A1. Additionally, we investigated associations between gene expression, through mRNA-Seq analysis, and overall survival (OS). The prevalence of mutational variants within these genes was explored. Using immunohistochemistry (IHC), we examined the expression and associations with clinicopathologic prognostic indicators of the four markers in 81 ER+ BC patients. RESULTS: Through computational analysis, NANOG and ALDH1A1 genes were significantly upregulated in ER+ BC compared to ER- BC patients (p < 0.001), while POU5F1 (OCT4) was downregulated (p < 0.001). NANOG showed an adverse impact on OS whereas ALDH1A1 was associated with a highly significant improved survival in ER+ BC (p = 4.7e-6), except for the PR- and HER2+ subgroups. Copy number alterations (CNAs) ranged from 0.4% to 1.6% in these genes, with the highest rate detected in SOX2. In the IHC study, approximately one-third of tumors showed moderate to strong expression of each of the four markers, with 2-4 markers strongly co-expressed in 56.8% of cases. OCT-4 and ALDH1A1 showed a significant association with a high KI-67 index (p = 0.009 and 0.008, respectively), while SOX2 showed a significant association with perinodal fat invasion (p = 0.017). CONCLUSION: Pluripotency markers and ALDH1A1 are substantially expressed in ER+ BC tumors with different, yet significant, associations with prognostic and survival outcomes. This study suggests these markers as targets for prospective clinical validation studies of their prognostic value and their possible therapeutic roles.
Sujet(s)
Tumeurs du sein , Humains , Femelle , Tumeurs du sein/anatomopathologie , Études prospectives , Marqueurs biologiques tumoraux/génétique , Marqueurs biologiques tumoraux/métabolisme , Pronostic , Oestrogènes , Cellules souches embryonnaires/métabolisme , Aldéhyde déshydrogénase-1 , Retinal dehydrogenase/génétiqueRÉSUMÉ
The host immune system status remains an unresolved mystery among several malignancies. An immune-compromised state or smart immune-surveillance tactics orchestrated by cancer cells are the primary cause of cancer invasion and metastasis. Taking a closer look at the tumour-immune microenvironment, a complex network and crosstalk between infiltrating immune cells and cancer cells mediated by cytokines, chemokines, exosomal mediators and shed ligands are present. Cytokines such as interleukins can influence all components of the tumour microenvironment (TME), consequently promoting or suppressing tumour invasion based on their secreting source. Interleukin-10 (IL-10) is an interlocked cytokine that has been associated with several types of malignancies and proved to have paradoxical effects. IL-10 has multiple functions on cellular and non-cellular components within the TME. In this review, the authors shed the light on the regulatory role of IL-10 in the TME of several malignant contexts. Moreover, detailed epigenomic and pharmacogenomic approaches for the regulation of IL-10 were presented and discussed.
Sujet(s)
Interleukine-10 , Tumeurs , Humains , Interleukine-10/génétique , Épigénomique , Pharmacogénétique , Cytokines , Tumeurs/traitement médicamenteux , Tumeurs/génétique , Microenvironnement tumoral/génétiqueRÉSUMÉ
Ozone has been successfully used in medicine for over 100 years due to its microbiological qualities. Its powerful oxidation impact, which results in the production of free radicals, and its ability to cause the direct death of nearly all microorganisms is the basis for its bactericide, virucide, and fungicide properties. Ozone also has a medicinal impact that speeds up blood flow and aids wound healing. Ozone may be applied as a gas or dissolved in water for medical purposes. Despite the benefits of using ozone therapeutically, concerns about its use in dentistry still exist. We aimed to provide a summary of the current uses of ozone in medicine and dentistry. An electronic search was performed for all English scientific papers published between 2012 and 2023 using PubMed, Cochrane, and Google Scholar search engines. Ozone, clinical applications, medicine, and dentistry were the search terms used. Seventy full-text articles describing the use of ozone therapy in medicine and dentistry were included in the present review. Ozone has shown several beneficial effects in the medical field. However, despite the encouraging in vitro evidence, the clinical use of ozone in dentistry has not yet been demonstrated as highly effective.
RÉSUMÉ
The role of "Family with sequence similarity 105, member A" (FAM105A) in pancreatic ß-cell function in relation to type 2 diabetes mellitus (T2D) is not fully understood. To address this issue, various molecular and functional experiments were conducted on primary human islets and INS-1 cells. RNA-seq expression analysis showed that FAM105A is highly expressed in human islets and its expression is reduced in diabetic islets compared to healthy islets. FAM105A expression correlated negatively with HbA1c levels and body mass index (BMI). Co-expression analysis showed a significant correlation between FAM105A with PDX1, GCK, GLUT1 and INSR, but not the INS gene. Silencing of Fam105a impaired insulin release, content, glucose uptake, and mitochondria ATP content but did not affect cell viability, reactive oxygen species (ROS) or apoptosis levels. Silencing of Fam105a was associated with reduced Pdx1 and Glut2 expression at mRNA and protein levels. RNA-seq analysis of dysregulated genes in Fam105a-silenced cells showed an overall downregulation of gene expression in ß-cells and insulin secretion pathway. Disrupting Pdx1 did not affect Fam105a expression in INS-1 cells. Overall, the results suggest that FAM105A plays an important role in pancreatic ß-cells biology and may be involved in the development of T2D.
Sujet(s)
Diabète de type 2 , Cellules à insuline , Ilots pancréatiques , Humains , Sécrétion d'insuline , Diabète de type 2/génétique , Diabète de type 2/métabolisme , Cellules à insuline/métabolisme , Insuline/métabolisme , Survie cellulaire/génétique , Glucose/métabolisme , Ilots pancréatiques/métabolismeRÉSUMÉ
Lymphocytes infiltration is a key mechanism that drives asthma lung inflammation. Our previous results demonstrated a significant increase in the frequency and persistence of central memory T (TCM) cells in inflamed lung tissue. This could be due to an increase in the infiltration of TCM in the lung tissue, or the possible differentiation of lung effector memory T (TEM) cells into TCM during lung inflammation. Thus, targeting the accumulation of memory T cells provides a potential approach for asthma treatment. Simvastatin and other statins were shown to impact both the structural and immune lung cells, presenting a distinct immunomodulatory effect on T lymphocyte activation, infiltration, and function. Therefore, we sought to evaluate the effect of simvastatin on the frequency and function of CD4 and CD8 TEM and TCM cells in an ovalbumin (OVA)-induced mouse model of asthma. Simvastatin treatment significantly attenuated the infiltration of both TEM and TCM memory subtypes, along with their production of IL-4 and IL-13 cytokines in a T helper 2 (Th2) OVA-sensitized mouse model. Furthermore, we detected a reduction in ICAM-1 and VCAM-1 levels in the lung homogenate of OVA-sensitized and challenged mice, as well as in human umbilical vein endothelial cells (HUVECs) following treatment with simvastatin. The reduction in leucocyte homing receptors following simvastatin treatment might have contributed to the observed decrease in infiltrated memory T cell numbers. In conclusion, this study demonstrated how statin drug may attenuate allergic asthma lung inflammation by targeting memory T cells and reducing their numbers, whilst limiting their cytokine production at the site of inflammation. Longer clinical trials are required to assess the effectiveness and safety of statin treatment in different asthma phenotypes.
Sujet(s)
Asthme , Inhibiteurs de l'hydroxyméthylglutaryl-CoA réductase , Souris , Humains , Animaux , Ovalbumine/usage thérapeutique , Simvastatine/pharmacologie , Simvastatine/usage thérapeutique , Inhibiteurs de l'hydroxyméthylglutaryl-CoA réductase/pharmacologie , Inhibiteurs de l'hydroxyméthylglutaryl-CoA réductase/usage thérapeutique , Cellules endothéliales , Souris de lignée BALB C , Poumon , Inflammation/traitement médicamenteux , Modèles animaux de maladie humaine , Lymphocytes auxiliaires Th2 , Liquide de lavage bronchoalvéolaireRÉSUMÉ
COVID-19 is a recent pandemic that mandated the scientific society to provide effective evidence-based therapeutic approaches for the prevention and treatment for such a global threat, especially to those patients who hold a higher risk of infection and complications, such as patients with autoimmune diseases and cancer. Recent research has examined the role of various fat-soluble vitamins (vitamins A, D, E, and K) in reducing the severity of COVID-19 infection. Studies showed that deficiency in fat-soluble vitamins abrogates the immune system, thus rendering individuals more susceptible to COVID-19 infection. Moreover, another line of evidence showed that supplementation of fat-soluble vitamins during the course of infection enhances the viral clearance episode by promoting an adequate immune response. However, more thorough research is needed to define the adequate use of vitamin supplements in cancer and autoimmune patients infected with COVID-19. Moreover, it is crucial to highlight the vitamin-drug interactions of the COVID-19 therapeutic modalities and fat-soluble vitamins. With an emphasis on cancer and autoimmune patients, the current review aims to clarify the role of fat-soluble vitamins in SARS-CoV-2 infection and to estimate the risk-to-benefit ratio of a fat-soluble supplement administered to patients taking FDA-approved COVID-19 medications such as antivirals, anti-inflammatory, receptor blockers, and monoclonal antibodies.
RÉSUMÉ
Colorectal cancer (CRC) is one of the most prevalent cancer types worldwide, with a high mortality rate due to metastasis. The tumor microenvironment (TME) contains multiple interactions between the tumor and the host, thus determining CRC initiation and progression. Various immune cells exist within the TME, such as tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), and tumor-associated neutrophils (TANs). The immunotherapy approach provides novel opportunities to treat solid tumors, especially toward immune checkpoints. Despite the advances in the immunotherapy of CRC, there are still obstacles to successful treatment. In this review, we highlighted the role of these immune cells in CRC, with a particular emphasis on immune checkpoint molecules involved in CRC pathogenesis.
RÉSUMÉ
Background: Breast cancer (BC) has become the most common cancer globally in 2020 as well as in the United Arab Emirates. The breast tumor microenvironment is composed of various immune cell types, including lymphocytes. Tumour-infiltrating lymphocytes (TILs) play a crucial role in tumor eradication and progression. Further, immune checkpoint markers such as programmed death receptor ligand 1 (PD-L1) and indoleamine-2,3-dioxygenase (IDO) have been associated with tumor evasion from the immune system. In this study, we aimed to explore the status of TILs, PD-L1 and IDO as well as to investigate their association with the clinicopathological parameters. Materials and methods: A total of 59 patients diagnosed with primary infiltrating BC were selected, after which tissue sections were stained to identify TILs along with immunohistochemical staining of PD-L1 and IDO. Moreover, in-silico tools were used to assess the expression of PD-L1, IDO and CD3ε in various molecular subtypes of BC. Results: It was found that the percentage of TILs correlated with estrogen receptor (ER) and progesterone receptor (PR) expression. This was supported by the finding that most of the triple-negative breast cancer (TNBC) cases belonged to the group with a high percentage of TILs (h-TILs). Similarly, the expression of PD-L1 and IDO was correlated with the ER and PR, whereas TNBC cases showed a high expression of PD-L1 and IDO. This goes in line with the in-silico findings where the TNBC group showed the highest expression of PD-L1 and IDO as well as the T cell marker CD3ε. Conclusion: This study highlighted a possible link between the immunosuppressive markers PD-L1 and IDO with TILs density in the BC microenvironment.
RÉSUMÉ
Since its emergence as a pandemic in March 2020, coronavirus disease (COVID-19) outcome has been explored via several predictive models, using specific clinical or biochemical parameters. In the current study, we developed an integrative non-linear predictive model of COVID-19 outcome, using clinical, biochemical, immunological, and radiological data of patients with different disease severities. Initially, the immunological signature of the disease was investigated through transcriptomics analysis of nasopharyngeal swab samples of patients with different COVID-19 severity versus control subjects (exploratory cohort, n=61), identifying significant differential expression of several cytokines. Accordingly, 24 cytokines were validated using a multiplex assay in the serum of COVID-19 patients and control subjects (validation cohort, n=77). Predictors of severity were Interleukin (IL)-10, Programmed Death-Ligand-1 (PDL-1), Tumor necrosis factors-α, absolute neutrophil count, C-reactive protein, lactate dehydrogenase, blood urea nitrogen, and ferritin; with high predictive efficacy (AUC=0.93 and 0.98 using ROC analysis of the predictive capacity of cytokines and biochemical markers, respectively). Increased IL-6 and granzyme B were found to predict liver injury in COVID-19 patients, whereas interferon-gamma (IFN-γ), IL-1 receptor-a (IL-1Ra) and PD-L1 were predictors of remarkable radiological findings. The model revealed consistent elevation of IL-15 and IL-10 in severe cases. Combining basic biochemical and radiological investigations with a limited number of curated cytokines will likely attain accurate predictive value in COVID-19. The model-derived cytokines highlight critical pathways in the pathophysiology of the COVID-19 with insight towards potential therapeutic targets. Our modeling methodology can be implemented using new datasets to identify key players and predict outcomes in new variants of COVID-19.
Sujet(s)
COVID-19 , Cytokines , Évolution de la maladie , Humains , Pandémies , SARS-CoV-2 , Indice de gravité de la maladieRÉSUMÉ
BACKGROUND AND AIM: Despite the fact that it has been over a year with the pandemic COVID-19 infection, ongoing research and analysis reveal many complications and comorbidities associated with COVID-19. In this study, we aimed at investigating the clinical and laboratory assessments in COVID-19 patients with and without liver injury. METHODS: Symptomatic 541 COVID-19 positive patients, who were admitted to Al Kuwait Hospital, Dubai, United Arab Emirates (UAE), were recruited in this study. Their data was collected retrospectively, including demographic data, blood tests, symptoms, radiographical assessments, and clinical outcomes of COVID-19. RESULTS: Around 19% of the recruited COVID-19 patients displayed signs of acute liver injury. Also, there was an increase in the percentage of critical, ICU-admitted and mortality rates in COVID-19 cases with liver injury, as well as a higher percentage of septic shock and acute respiratory distress syndrome (ARDS). COVID-19 patients with liver injury had more pronounced bilateral consolidation, lymphopenia and neutrophilia. Additionally, these patients had higher levels of CRP, LDH, procalcitonin, ferritin and D dimer levels. Finally, there was a higher percentage of patients taking various COVID-19 therapies in the COVID-19 patients with liver injury group. CONCLUSION: COVID-19 patients with acute liver injury are at a higher risk for serious outcomes including death.
RÉSUMÉ
OBJECTIVES: To compare risk factors and clinical outcomes among COVID-19 patients with or without diabetes in the United Arab Emirates (UAE). METHODS: Data of 350 COVID-19 positive patients, admitted to Al Kuwait Hospital in Dubai, UAE, from February to May 2020 was collected retrospectively, including demographic data, clinical symptoms, blood tests, as well as radiographical assessments, and clinical outcomes of COVID-19. The design of the study is a retrospective cohort study. RESULTS: COVID-19 patients with diabetes belong to an older age group, had a higher percentage of male patients, exhibited more lymphopenia and neutrophilia, and higher ferritin levels. Additionally, patients with diabetes presented fever and shortness of breath (SOB), displayed more bilateral airspace consolidation and opacities in their chest x-ray and CT scans, compared to non-diabetics. A higher percentage of critical, ICU-admitted, and death of COVID-19 cases in the diabetic group was also reported. This was along with a concomitant increase in C-reactive protein, procalcitonin, and lactate dehydrogenase levels. CONCLUSIONS: Diabetes is considered a comorbidity as diabetic patients showed more severe COVID-19 symptoms that led to critical clinical outcomes such as ICU admission and death.
Sujet(s)
COVID-19/épidémiologie , Complications du diabète/épidémiologie , Adulte , Sujet âgé , COVID-19/diagnostic , Dépistage de la COVID-19 , Études cas-témoins , Comorbidité , Complications du diabète/diagnostic , Femelle , Humains , Mâle , Adulte d'âge moyen , Pronostic , Études rétrospectives , Facteurs de risque , Indice de gravité de la maladie , Émirats arabes unis/épidémiologieRÉSUMÉ
The United Arab Emirates National Diabetes and Lifestyle Study (UAEDIAB) has identified obesity, hypertension, obstructive sleep apnea, and dyslipidemia as common phenotypic characteristics correlated with diabetes mellitus status. As these phenotypes are usually linked with genetic variants, we hypothesized that these phenotypes share single nucleotide polymorphism (SNP)-clusters that can be used to identify causal genes for diabetes. Materials and We explored the National Human Genome Research Institute-European Bioinformatics Institute Catalog of Published Genome-Wide Association Studies (NHGRI-EBI GWAS) to list SNPs with documented association with the UAEDIAB-phenotypes as well as diabetes. The shared chromosomal regions affected by SNPs were identified, intersected, and searched for Enriched Ontology Clustering. The potential SNP-clusters were validated using targeted DNA next-generation sequencing (NGS) in two Emirati diabetic patients. RNA sequencing from human pancreatic islets was used to study the expression of identified genes in diabetic and non-diabetic donors. Eight chromosomal regions containing 46 SNPs were identified in at least four out of the five UAEDIAB-phenotypes. A list of 34 genes was shown to be affected by those SNPs. Targeted NGS from two Emirati patients confirmed that the identified genes have similar SNP-clusters. ASAH1, LRP4, FES, and HSD17B12 genes showed the highest SNPs rate among the identified genes. RNA-seq analysis revealed high expression levels of HSD17B12 in human islets and to be upregulated in type 2 diabetes (T2D) donors. Our integrative phenotype-genotype approach is a novel, simple, and powerful tool to identify clinically relevant potential biomarkers in diabetes. HSD17B12 is a novel candidate gene for pancreatic ß-cell function.
Sujet(s)
17-Hydroxysteroid dehydrogenases/génétique , Diabète de type 2/génétique , Prédisposition génétique à une maladie , Étude d'association pangénomique , Obésité/génétique , Phénotype , Polymorphisme de nucléotide simple , Études cas-témoins , Biologie informatique , Diabète de type 2/épidémiologie , Diabète de type 2/anatomopathologie , Femelle , Séquençage nucléotidique à haut débit , Humains , Mâle , Adulte d'âge moyen , Obésité/épidémiologie , Obésité/anatomopathologie , Émirats arabes unis/épidémiologieRÉSUMÉ
OBJECTIVE: To investigate, in detail, the effects of rituximab (RTX), an off-label drug for treating multiple sclerosis (MS) disease on preventing and/or ameliorating experimental autoimmune encephalomyelitis (EAE). METHODS: Using bioinformatics analysis of publicly available transcriptomics data, we determined the accumulation of B cells, plasma cells and T cells in different compartments of multiple sclerosis patients (MS) and healthy individual brains. Based on these observations and on the literature search, we dosed RTX in EAE mice either orally, or injected intraperitoneally (IP). The latter route was used either prophylactically (asymptomatic stage; upon the induction of the disease), or therapeutically (acute stage; upon the appearance of the first sign of the disease). Further, we used RTX as a preventive drug either as a single agent or in combination with other routes of administration. RESULTS: Because no complete recovery was observed when RTX was used prophylactically or therapeutically, we devised another protocol of injecting this drug before the onset of the disease and designated this regiment as prevention. We demonstrated that the 20 µg/mouse prevention completely reduced the EAE clinical score, impaired infiltration of T and B cells into the perivascular space of mice brains, along with inhibiting the inflammation and demyelination. However, the 5 and 10 µg/mouse doses although reduced all aspects of inflammation in these mice, their effects were not as potent as the 20 µg/mouse RTX dose. Finally, we combined the 5 µg/mouse prevention treatment with either the prophylactic or therapeutic regimen and observed a robust effect. CONCLUSION: We observed that combinatorial regimens resulted in further reduction of inflammation, T and B cell extravasation into the brains of EAE mice and improved the re-myelination.
RÉSUMÉ
Pyroptosis is a newly discovered programmed cell death with inflammasome formation. Pattern recognition receptors that identify repetitive motifs of prospective pathogens such as LPS of gram-negative bacteria are crucial to pyroptosis. Upon stimulation by pathogen-associated molecular patterns or damage-associated molecular patterns, proinflammatory cytokines, mainly IL-1 family members IL-1ß and IL-18, are released through pyroptosis specific pore-forming protein, gasdermin D. Even though IL-1 family members are mainly involved in innate immunity, they can be factors in adaptive immunity. Given the importance of IL-1 family members in health and diseases, deciphering the role of pyroptosis in the regulation of innate and adaptive immunity is of great importance, especially with the recent progress in identifying the exact mechanism of such a pathway. In this review, we will focus on how the innate inflammatory mediators can regulate the adaptive immune system and vice versa via pyroptosis.
Sujet(s)
Immunité acquise , Immunité innée , Pyroptose/immunologie , Animaux , Humains , Inflammasomes/métabolisme , Médiateurs de l'inflammation/métabolisme , Modèles biologiquesRÉSUMÉ
The expression and functional impact of most orphan G-protein coupled receptors (GPCRs) in ß-cell is not fully understood. Microarray expression indicated that 36 orphan GPCRs are restricted in human islets, while 55 receptors overlapped between human islets and INS-1â¯cells. GPR183 showed higher expression in diabetic compared to non-diabetic human islets. GPR183 expression co-localized with ß-cells while it was lacking in α-cells in human islets. The GPR183 agonist (7α-25-DHC) potentiated insulin secretion and protected against glucotoxicity-induced ß-cell damage in human islets. Silencing of GPR183 in INS-1â¯cells decreased the expression of proinsulin genes, Pdx1, Mafa and impaired insulin secretion with a concomitant decrease in cAMP generation. Cultured INS-1â¯cells with 7α-25-DHC were associated with increased proliferation and expression of GPR183, INS2, PDX1, NeuroD, and INSR. In conclusion, the beneficial impact of GPR183 activation on ß-cell function makes it a potential therapeutic target to prevent or reverse ß-cell dysfunction.