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1.
Sci Rep ; 11(1): 16212, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376762

RESUMO

During 2020, understanding the molecular mechanism of SARS-CoV-2 infection (the cause of COVID-19) became a scientific priority due to the devastating effects of the COVID-19. Many researchers have studied the effect of this viral infection on lung epithelial transcriptomes and deposited data in public repositories. Comprehensive analysis of such data could pave the way for development of efficient vaccines and effective drugs. In the current study, we obtained high-throughput gene expression data associated with human lung epithelial cells infected with respiratory viruses such as SARS-CoV-2, SARS, H1N1, avian influenza, rhinovirus and Dhori, then performed comparative transcriptome analysis to identify SARS-CoV-2 exclusive genes. The analysis yielded seven SARS-CoV-2 specific genes including CSF2 [GM-CSF] (colony-stimulating factor 2) and calcium-binding proteins (such as S100A8 and S100A9), which are known to be involved in respiratory diseases. The analyses showed that genes involved in inflammation are commonly altered by infection of SARS-CoV-2 and influenza viruses. Furthermore, results of protein-protein interaction analyses were consistent with a functional role of CSF2 and S100A9 in COVID-19 disease. In conclusion, our analysis revealed cellular genes associated with SARS-CoV-2 infection of the human lung epithelium; these are potential therapeutic targets.


Assuntos
Células Epiteliais Alveolares/metabolismo , COVID-19/genética , Transcriptoma , Células Epiteliais Alveolares/virologia , COVID-19/metabolismo , COVID-19/virologia , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , SARS-CoV-2/patogenicidade
2.
Neoplasia ; 23(9): 1002-1015, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34380074

RESUMO

Ovarian cancer (OC) is one of the most lethal type of cancer in women due to a lack of effective targeted therapies and high rates of treatment resistance and disease recurrence. Recently Poly (ADP-ribose) polymerase inhibitors (PARPi) have shown promise as chemotherapeutic agents; however, their efficacy is limited to a small fraction of patients with BRCA mutations. Here we show a novel function for the Hedgehog (Hh) transcription factor Glioma associated protein 1 (GLI1) in regulation of key Fanconi anemia (FA) gene, FANCD2 in OC cells. GLI1 inhibition in HR-proficient OC cells induces HR deficiency (BRCAness), replication stress and synergistic lethality when combined with PARP inhibition. Treatment of OC cells with combination of GLI1 and PARP inhibitors shows enhanced DNA damage, synergy in cytotoxicity, and strong in vivo anticancer responses.

3.
Molecules ; 26(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299512

RESUMO

Systemic steroids are used to treat acute graft-versus-host disease (aGVHD) caused by allogenic bone marrow transplantation (allo-BMT); however, their prolonged use results in complications. Hence, new agents for treating aGVHD are required. Recently, a new compound A (CpdA), with anti-inflammatory activity and reduced side effects compared to steroids, has been identified. Here, we aimed to determine whether CpdA can improve the outcome of aGVHD when administered after transplantation in a mouse model (C57BL/6 in B6D2F1). After conditioning with 9Gy total body irradiation, mice were infused with bone marrow (BM) cells and splenocytes from either syngeneic (B6D2F1) or allogeneic (C57BL/6) donors. The animals were subsequently treated (3 days/week) with 7.5 mg/kg CpdA from day +15 to day +28; the controls received 0.9% NaCl. Thereafter, the incidence and severity of aGVHD in aGVHD target organs were analyzed. Survival and clinical scores did not differ significantly; however, CpdA-treated animals showed high cell infiltration in the target organs. In bulk mixed lymphocyte reactions, CpdA treatment reduced the cell proliferation and expression of inflammatory cytokines and chemokines compared to controls, whereas levels of TNF, IL-23, chemokines, and chemokine receptors increased. CpdA significantly reduced proliferation in vitro but increased T cell infiltration in target organs.


Assuntos
Anti-Inflamatórios/farmacologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Aguda , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Transplante de Medula Óssea/métodos , Proliferação de Células/efeitos dos fármacos , Quimiocinas/metabolismo , Modelos Animais de Doenças , Feminino , Doença Enxerto-Hospedeiro/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/efeitos dos fármacos
4.
Cell Death Dis ; 12(7): 664, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215725

RESUMO

Various retinal degenerative disorders manifest in alterations of the AKT/mTOR axis. Despite this, consensus on the therapeutic targeting of mTOR in degenerating retinas has not yet been achieved. Therefore, we investigated the role of AKT/mTOR signaling in rd16 retinas, in which we restored the AKT/mTOR axis by genetic ablation of pseudokinase TRB3, known to inhibit phosphorylation of AKT and mTOR. First, we found that TRB3 ablation resulted in preservation of photoreceptor function in degenerating retinas. Then, we learned that the mTOR downstream cellular pathways involved in the homeostasis of photoreceptors were also reprogrammed in rd16 TRB3-/- retinas. Thus, the level of inactivated translational repressor p-4E-BP1 was significantly increased in these mice along with the restoration of translational rate. Moreover, in rd16 mice manifesting decline in p-mTOR at P15, we found elevated expression of Beclin-1 and ATG5 autophagy genes. Thus, these mice showed impaired autophagy flux measured as an increase in LC3 conversion and p62 accumulation. In addition, the RFP-EGFP-LC3 transgene expression in rd16 retinas resulted in statistically fewer numbers of red puncta in photoreceptors, suggesting impaired late autophagic vacuoles. In contrast, TRIB3 ablation in these mice resulted in improved autophagy flux. The restoration of translation rate and the boost in autophagosome formation occurred concomitantly with an increase in total Ub and rhodopsin protein levels and the elevation of E3 ligase Parkin1. We propose that TRB3 may retard retinal degeneration and be a promising therapeutic target to treat various retinal degenerative disorders.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Células Fotorreceptoras de Vertebrados/enzimologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Degeneração Retiniana/enzimologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Autofagossomos/genética , Autofagossomos/metabolismo , Autofagossomos/patologia , Autofagia , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Proteínas de Ciclo Celular/genética , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Células Fotorreceptoras de Vertebrados/patologia , Degeneração Retiniana/genética , Degeneração Retiniana/patologia , Rodopsina/metabolismo , Transdução de Sinais , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
5.
Methods Mol Biol ; 2328: 171-182, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34251625

RESUMO

With the advent of recent next-generation sequencing (NGS) technologies in genomics, transcriptomics, and epigenomics, profiling single-cell sequencing became possible. The single-cell RNA sequencing (scRNA-seq) is widely used to characterize diverse cell populations and ascertain cell type-specific regulatory mechanisms. The gene regulatory network (GRN) mainly consists of genes and their regulators-transcription factors (TF). Here, we describe the lightning-fast Python implementation of the SCENIC (Single-Cell reEgulatory Network Inference and Clustering) pipeline called pySCENIC. Using single-cell RNA-seq data, it maps TFs onto gene regulatory networks and integrates various cell types to infer cell-specific GRNs. There are two fast and efficient GRN inference algorithms, GRNBoost2 and GENIE3, optionally available with pySCENIC. The pipeline has three steps: (1) identification of potential TF targets based on co-expression; (2) TF-motif enrichment analysis to identify the direct targets (regulons); and (3) scoring the activity of regulons (or other gene sets) on single cell types.


Assuntos
Redes Reguladoras de Genes/genética , RNA-Seq/métodos , Análise de Célula Única/métodos , Fatores de Transcrição/metabolismo , Algoritmos , Motivos de Aminoácidos/genética , Análise por Conglomerados , Linguagens de Programação , Fatores de Transcrição/genética
6.
Diabetes ; 70(8): 1738-1753, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33975909

RESUMO

The current understanding of the molecular pathogenesis of diabetic retinopathy does not provide a mechanistic link between early molecular changes and the subsequent progression of the disease. In this study, we found that human diabetic retinas overexpressed TRIB3 and investigated the role of TRIB3 in diabetic retinal pathobiology in mice. We discovered that TRIB3 controlled major molecular events in early diabetic retinas via HIF1α-mediated regulation of retinal glucose flux, reprogramming cellular metabolism, and governing of inflammatory gene expression. These early molecular events further defined the development of neurovascular deficit observed in mice with diabetic retinopathy. TRIB3 ablation in the streptozotocin-induced mouse model led to significant retinal ganglion cell survival and functional restoration accompanied by a dramatic reduction in pericyte loss and acellular capillary formation. Under hypoxic conditions, TRIB3 contributed to advanced proliferative stages by significant upregulation of GFAP and VEGF expression, thus controlling gliosis and aberrant vascularization in oxygen-induced retinopathy mouse retinas. Overall, our data reveal that TRIB3 is a master regulator of diabetic retinal pathophysiology that may accelerate the onset and progression of diabetic retinopathy to proliferative stages in humans and present TRIB3 as a potentially novel therapeutic target for diabetic retinopathy.


Assuntos
Proteínas de Ciclo Celular/genética , Retinopatia Diabética/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Repressoras/genética , Retina/metabolismo , Animais , Capilares/metabolismo , Capilares/patologia , Proteínas de Ciclo Celular/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Progressão da Doença , Humanos , Camundongos , Pericitos/metabolismo , Pericitos/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Repressoras/metabolismo , Retina/patologia
7.
JCI Insight ; 6(10)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34027893

RESUMO

Despite the high morbidity and mortality among patients with extensive cutaneous burns in the intensive care unit due to the development of acute respiratory distress syndrome, effective therapeutics remain to be determined. This is primarily because the mechanisms leading to acute lung injury (ALI) in these patients remain unknown. We test the hypothesis that cutaneous chemical burns promote lung injury due to systemic activation of neutrophils, in particular, toxicity mediated by the deployment of neutrophil extracellular traps (NETs). We also demonstrate the potential benefit of a peptidyl arginine deiminase 4 (PAD4) inhibitor to prevent NETosis and to preserve microvascular endothelial barrier function, thus reducing the severity of ALI in mice. Our data demonstrated that phenylarsine oxide (PAO) treatment of neutrophils caused increased intracellular Ca2+-associated PAD4 activity. A dermal chemical burn by lewisite or PAO resulted in PAD4 activation, NETosis, and ALI. NETs disrupted the barrier function of endothelial cells in human lung microvascular endothelial cell spheroids. Citrullinated histone 3 alone caused ALI in mice. Pharmacologic or genetic abrogation of PAD4 inhibited lung injury following cutaneous chemical burns. Cutaneous burns by lewisite and PAO caused ALI by PAD4-mediated NETosis. PAD4 inhibitors may have potential as countermeasures to suppress detrimental lung injury after chemical burns.

8.
Clin Chim Acta ; 519: 247-254, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34015304

RESUMO

BACKGROUND: Thrombophilia is a substantial source of indisposition and mortality in several countries, including Arab populations. Deep venous thrombosis (DVT) with or without pulmonary embolism (PE) is the prevalent clinical manifestation of thrombophilia. While many genetic risk factors for DVT are known, almost all associated with hemostasis, many genetic factors remain unexplained. Nowadays, Next Generation Sequencing (NGS) offers a potential solution that allows several candidate genes to be analyzed simultaneously at a reasonable expense. METHODS: We performed variant screening in the thrombophilia associated genes in Factor V Leiden (FVL) mutation-negative patients using Ion Torrent Next-generation sequencing (NGS). Ion AmpliSeq panel for 18 genes was designed. Twenty-nine unrelated patients with idiopathic VTE were recruited for NGS. RESULTS: We were able to identify 19 variants (1 novel and 18 previously reported) in 10 out of 18 targeted genes. Pathogenic variants were identified in 22 patients demonstrating mutation detection rates of 76%. Previously reported variants in the F5, MTHFR, PROS1, PROC, F8, F9, SERPINA10, SERPIND1, and HRG genes were recognized in 21 patients. More than one variant in the targeted genes was detected in some of the patients with VTE. We identified SERPINA10 recurrent variant p.(R88*) in seven patients representing 32% of VTE cases. Additionally, we report one novel variant c.356G > T, p.(G119V) in the F7 gene, considered to be pathogenic in this study. CONCLUSIONS: Our studies finding illustrates the ability of targeted next-generation sequencing to uncover uncommon/unknown genetic variants that may predispose to thrombophilia. The finding of the novel variant in the F7 gene extends the spectrum of variants affecting thrombosis. While a comparatively small number of subjects have been included in our cohort, the findings summarize the possible genetic features of thrombophilia.


Assuntos
Trombofilia , Tromboembolia Venosa , Fator V/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Arábia Saudita , Trombofilia/genética , Tromboembolia Venosa/genética
9.
Sci Rep ; 11(1): 7373, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795737

RESUMO

Macrophages are ubiquitous custodians of tissues, which play decisive role in maintaining cellular homeostasis through regulatory immune responses. Within tissues, macrophage exhibit extremely heterogeneous population with varying functions orchestrated through regulatory response, which can be further exacerbated in diverse genetic backgrounds. Gene regulatory networks (GRNs) offer comprehensive understanding of cellular regulatory behavior by unfolding the transcription factors (TFs) and regulated target genes. RNA-Seq coupled with ATAC-Seq has revolutionized the regulome landscape influenced by gene expression modeling. Here, we employ an integrative multi-omics systems biology-based analysis and generated GRNs derived from the unstimulated bone marrow-derived macrophages of five inbred genetically defined murine strains, which are reported to be linked with most of the population-wide human genetic variants. Our probabilistic modeling of a basal hemostasis pan regulatory repertoire in diverse macrophages discovered 96 TFs targeting 6279 genes representing 468,291 interactions across five inbred murine strains. Subsequently, we identify core and distinctive GRN sub-networks in unstimulated macrophages to describe the system-wide conservation and dissimilarities, respectively across five murine strains. Our study concludes that discrepancies in unstimulated macrophage-specific regulatory networks not only drives the basal functional plasticity within genetic backgrounds, additionally aid in understanding the complexity of racial disparity among the human population during stress.

10.
Insects ; 12(3)2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33800231

RESUMO

The tropical fire ant Solenopsis geminata (Hymenoptera: Formicidae) is a serious invasive species that causes a decline in agricultural production, damages infrastructure, and harms human health. This study was aimed to develop a model using the maximum entropy (MaxEnt) algorithm to predict the current and future distribution of S. geminata on a global scale for effective monitoring and management. In total, 669 occurrence sites of S. geminata and six bioclimatic variables of current and future climate change scenarios for 2050 and 2100 were used for the modeling. The annual mean temperature, annual precipitation, and precipitation in the driest quarter were the key influential factors for determining the distribution of S. geminata. Although the potential global distribution area of S. geminata is predicted to decrease slightly under global warming, the distribution of favorable habitats is predicted to expand to high latitudes under climate scenarios. In addition, some countries in America and East Asia, such as Brazil, China, South Korea, the USA, and Uruguay, are predicted to be threatened by S. geminata invasion under future climate change. These findings can facilitate the proactive management of S. geminata through monitoring, surveillance, and quarantine measures.

11.
Sci Transl Med ; 13(585)2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731433

RESUMO

The mechanisms by which environmental exposures contribute to the pathogenesis of lung fibrosis are unclear. Here, we demonstrate an increase in cadmium (Cd) and carbon black (CB), common components of cigarette smoke (CS) and environmental particulate matter (PM), in lung tissue from subjects with idiopathic pulmonary fibrosis (IPF). Cd concentrations were directly proportional to citrullinated vimentin (Cit-Vim) amounts in lung tissue of subjects with IPF. Cit-Vim amounts were higher in subjects with IPF, especially smokers, which correlated with lung function and were associated with disease manifestations. Cd/CB induced the secretion of Cit-Vim in an Akt1- and peptidylarginine deiminase 2 (PAD2)-dependent manner. Cit-Vim mediated fibroblast invasion in a 3D ex vivo model of human pulmospheres that resulted in higher expression of CD26, collagen, and α-SMA. Cit-Vim activated NF-κB in a TLR4-dependent fashion and induced the production of active TGF-ß1, CTGF, and IL-8 along with higher surface expression of TLR4 in lung fibroblasts. To corroborate ex vivo findings, mice treated with Cit-Vim, but not Vim, independently developed a similar pattern of fibrotic tissue remodeling, which was TLR4 dependent. Moreover, wild-type mice, but not PAD2-/- and TLR4 mutant (MUT) mice, exposed to Cd/CB generated high amounts of Cit-Vim, in both plasma and bronchoalveolar lavage fluid, and developed lung fibrosis in a stereotypic manner. Together, these studies support a role for Cit-Vim as a damage-associated molecular pattern molecule (DAMP) that is generated by lung macrophages in response to environmental Cd/CB exposure. Furthermore, PAD2 might represent a promising target to attenuate Cd/CB-induced fibrosis.


Assuntos
Cádmio/toxicidade , Fibrose Pulmonar Idiopática , Fuligem/toxicidade , Vimentina , Animais , Células Cultivadas , Citrulinação , Fibroblastos , Pulmão , Masculino , Camundongos , Fumaça , Poluição por Fumaça de Tabaco , Fator de Crescimento Transformador beta1
14.
Clin Appl Thromb Hemost ; 27: 1076029620978532, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33448877

RESUMO

The rare Gln534 (Factor V Leiden; FVL) allele (1:169,519,049 T>C) is associated with an increased risk of venous thrombosis. The purpose of this study was to measure the prevalence of Factor V Leiden mutation in thrombophilia patients with deep vein thrombosis. Also, we investigated the functional and structural characteristics of this mutation p.(Arg534Gln) to be examined the cumulative impact on venous thrombosis risk as well correlated with different populations by Genome Wide Association Studies (GWAS). A total of 108 patients with idiopathic deep vein thrombosis were examined for Factor V Leiden gene mutation. Our preliminary data show that about 10% of patients were detected with the heterozygous and homozygous form of the Factor V Leiden mutation. An association analysis confirmed that the Factor V SNP variant (rs6025) was highly associated (P-value 4.91 x10-^ -39) with an increased risk of venous thrombosis. Also, we found that the recognized SNP was important among HapMap populations. Our results indicated that among the 3 populations (Asian, African, and American) studied, this association was highest in the African population based on the r(2) significant threshold (P-value 5e-190). In addition, this mutation was located at the domain F5/8 type A 2, which can disturb this domain and abolish its function. Because of aspartic acid nearby wild type position as form in the salt bridge due to this discharge will disturb the ionic interaction made by the wild type residue Arg534. This residue was not found to be in contact with other domains of which the function was known. However, contact with other molecules or domains (THPH2: MIM: 188055) were still possible and might be affected by this mutation that may cause thrombophilia due to activated protein C resistance.


Assuntos
Resistência à Proteína C Ativada/epidemiologia , Resistência à Proteína C Ativada/genética , Fator V/genética , Fator V/química , Feminino , Frequência do Gene , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Heterozigoto , Homozigoto , Humanos , Masculino , Modelos Moleculares , Mutação Puntual , Polimorfismo de Nucleotídeo Único , Prevalência , Arábia Saudita/epidemiologia , Trombose Venosa/epidemiologia , Trombose Venosa/genética
15.
Physiol Rev ; 101(2): 417-425, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32790578

RESUMO

The host immune system shapes the fate of tumor progression. Hence, manipulating patients' immune system to activate host immune responses against cancer pathogenesis is a promising strategy to develop effective therapeutic interventions for metastatic and drug-resistant cancers. Understanding the dynamic mechanisms within the tumor microenvironment (TME) that contribute to heterogeneity and metabolic plasticity is essential to enhance the patients' responsiveness to immune targeted therapies. Riera-Domingo et al. (Riera-Domingo C, Audige A, Granja S, Cheng WC, Ho PC, Baltazar F, Stockmann C, Mazzone, M. Physiol Rev 100: 1-102, 2020) describe the immune landscape within the TME and highlight the significance of metabolic and hypoxic signatures that impact immune function and response to immunotherapy strategies. Current literature in this field confirms that targeting tumor metabolism and the acidic microenvironment commonly associated with tumors may present viable strategies to modulate the host immune system in favor of response to immune targeted therapies. However, development of better tools to understand tumor-immune interactions and identify mechanisms driving nonresponders, more innovative clinical trial design, and new therapies will need to be identified to move the field forward. Personalized immune therapies incorporating metabolic and microbiome-based gene signatures to influence the therapeutic response and novel methods to generate immunologically "hot" tumors are at the forefront of immunotherapy currently. The combination of these approaches with clinically approved immunotherapies will be valuable moving forward.

16.
J Invest Dermatol ; 141(4): 742-753.e10, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32971126

RESUMO

Skin squamous cell carcinomas (SCCs) are a major cause of death in patients who have undergone or will undergo organ transplantation. Moreover, these neoplasms cause significant disease and economic burden and diminish patients' life quality. However, no effective treatment or intervention strategies are available. In this study, we investigated the pathologic role of 5'-cap translation, which is regulated by the formation of a ternary initiation factor complex involving eIF4E, eIF4G, and eIF4A1. We detected increased expression of phosphorylated eIF4E, eIF4G, and eIF4A1 in human and murine skin SCCs. The increase in these ternary initiation factor complex proteins was associated with enhanced eIF4E translation targets cyclin D1 and c-Myc. Conversely, small interfering RNA-mediated depletion of eIF4E in human SCC cells (A431 and SCC-13) reduced eIF4G and proteins that regulate the cell cycle and proliferation. Notably, inhibition of Raf/MAPK/extracellular signal-regulated kinase signaling decreased eIF4E and phosphorylated eIF4E accumulation and significantly diminished cell-cycle gene expression and tumor volume of A431-derived xenograft tumors. Furthermore, disrupting the eIF4E with an allosteric inhibitor of eIF4E and eIF4G binding, 4EGI-1, decreased the eIF4E/eIF4G expression and reduced the proliferation. Finally, combined inhibition of the Raf/MAPK/extracellular signal-regulated kinase axis and eIF4E impaired 5'-cap‒dependent translation and abrogated tumor cell proliferation. These data demonstrate that 5'-cap‒dependent translation is a potential therapeutic target for abrogating lethal skin SCCs in patients who have undergone or will undergo organ transplantation.

17.
Cancer Prev Res (Phila) ; 14(2): 165-174, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33148679

RESUMO

Melanocytic nevi are benign proliferations of pigment cells that can occasionally develop into melanomas. There is a significant correlation between increased nevus numbers and melanoma development. Our previous reports revealed that 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) induced dysplastic nevi in C3H/HeN mice, with a potential to transform into melanomas. To understand the immune mechanisms behind this transformation, we applied increasing DMBA doses followed by TPA to the skin of C3H/HeN mice. We observed that increased doses of DMBA correlated well with increased numbers of nevi. The increased DMBA dose induced diminished immune responses and promoted the expansion of regulatory T cells (Treg) that resulted in increased IL10 and reduced IFNγ levels. Mice with increased nevus numbers had loss of p16 expression. These mice had increased migration of melanocytic cells to lymph nodes (LN) and a greater percent of LNs produced immortalized melanocytic cell lines. DMBA-induced immunosuppression was lost in CD4-knockout (KO) mice. Lymphocytes in the CD4KO mice produced less IL10 than CD8KO mice. Furthermore, CD4KO mice had significantly reduced nevus numbers and size compared with wild-type and CD8KO mice. These results suggest that Tregs play a vital role in the incidence of nevi and their progression to melanoma.Prevention Relevance: There has been little progress in developing novel strategies for preventing premalignant dysplastic nevi from becoming melanomas. In this study in mice, regulatory-T cells enhanced progression of benign nevi to malignant melanomas; and by inhibiting their activity, melanomas could be retarded. The findings identify new possibilities for melanoma prevention in high risk individuals.

18.
Semin Cancer Biol ; 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33242578

RESUMO

Understanding of cancer with the help of ever-expanding cutting edge technological tools and bioinformatics is revolutionizing modern cancer research by broadening the space of discovery window of various genomic and epigenomic processes. Genomics data integrated with multi-omics layering have advanced cancer research. Uncovering such layers of genetic mutations/modifications, epigenetic regulation and their role in the complex pathophysiology of cancer progression could lead to novel therapeutic interventions. Although a plethora of literature is available in public domain defining the role of various tumor driver gene mutations, understanding of epigenetic regulation of cancer is still emerging. This review focuses on epigenetic regulation association with the pathogenesis of non-melanoma skin cancer (NMSC). NMSC has higher prevalence in Caucasian populations compared to other races. Due to lack of proper reporting to cancer registries, the incidence rates for NMSC worldwide cannot be accurately estimated. However, this is the most common neoplasm in humans, and millions of new cases per year are reported in the United States alone. In organ transplant recipients, the incidence of NMSC particularly of squamous cell carcinoma (SCC) is very high and these SCCs frequently become metastatic and lethal. Understanding of solar ultraviolet (UV) light-induced damage and impaired DNA repair process leading to DNA mutations and nuclear instability provide an insight into the pathogenesis of metastatic neoplasm. This review discusses the recent advances in the field of epigenetics of NMSCs. Particularly, the role of DNA methylation, histone hyperacetylation and non-coding RNA such as long-chain noncoding (lnc) RNAs, circular RNAs and miRNA in the disease progression are summarized.

19.
Oncol Lett ; 20(6): 384, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33193845

RESUMO

Molecular pathology and personalized medicine are still being evolved in Saudi Arabia, and genetic testing for the detection of mutations as cancer markers have not been established in the diagnostics laboratories in Saudi Arabia. The aim of the present study was to determine the prevalence of isocitrate dehydrogenase (IDH1 and IDH2) mutations and epidermal growth factor receptor variant (EGFRv)III transcript expression in Saudi Arabian patients with glioma. Out of 117 brain tumors tested by reverse transcription-quantitative PCR for EGFRvIII, 41 cases tested positive. In the glioblastoma (GBM) category, 28/55 tumors were positive, in astrocytoma tumors 5/22, and in oligodendrogliomas 4/13 cases were positive respectively. EGFRvIII transcript was sequenced by capillary electrophoresis to demonstrate the presence of EGFRvIII-specific junction where exons 2-7 were deleted. In the present study 106 tumors were sequenced for IDH1 exon-4 mutations using the capillary sequencing method. The most common substitution missense mutation c.395G>A was found in 16 tumors. In the case of adamantinomatous craniopharyngioma, a novel missense mutation in c.472C>T was detected in IDH2 gene. Using next-generation sequencing (NGS), 74 tumors were sequenced for the IDH1 gene, and a total of 8 missense variants were identified in 36 tumors in a population of Saudi Arabia. The missense mutation (c.395G>A) was detected in 29/36 of tumors. A novel intronic mutation in c.414+9T>A was found in 13 cases in the IDH1 gene. In addition, one case exhibited a novel synonymous mutation in c.369A>G. Eleven tumors were found to have compound mutations in the IDH1 gene. In IDH2 gene, out of a total of 16 variants found in 6 out of 45 tumors, nine were missense, five were synonymous and one was intronic. This is the first report from Saudi Arabian laboratories analyzing glioma tumors for EGFRvIII expression, and the first study from Saudi Arabia to analyze IDH mutations in gliomas using the capillary and NGS methods.

20.
Ann N Y Acad Sci ; 1480(1): 155-169, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32885420

RESUMO

Lewisite and many other similar arsenicals are warfare vesicants developed and weaponized for use in World Wars I and II. These chemicals, when exposed to the skin and other epithelial tissues, cause rapid severe inflammation and systemic damage. Here, we show that topically applied arsenicals in a murine model produce significant acute kidney injury (AKI), as determined by an increase in the AKI biomarkers NGAL and KIM-1. An increase in reactive oxygen species and ER stress proteins, such as ATF4 and CHOP, correlated with the induction of these AKI biomarkers. Also, TUNEL staining of CHOP-positive renal tubular cells suggests CHOP mediates apoptosis in these cells. A systemic inflammatory response characterized by a significant elevation in inflammatory mediators, such as IL-6, IFN-α, and COX-2, in the kidney could be the underlying cause of AKI. The mechanism of arsenical-mediated inflammation involves activation of AMPK/Nrf2 signaling pathways, which regulate heme oxygenase-1 (HO-1). Indeed, HO-1 induction with cobalt protoporphyrin (CoPP) treatment in arsenical-treated HEK293 cells afforded cytoprotection by attenuating CHOP-associated apoptosis and cytokine mRNA levels. These results demonstrate that topical exposure to arsenicals causes AKI and that HO-1 activation may serve a protective role in this setting.


Assuntos
Injúria Renal Aguda , Apoptose/efeitos dos fármacos , Arsenicais , Substâncias para a Guerra Química/envenenamento , Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Fator 4 Ativador da Transcrição/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Injúria Renal Aguda/prevenção & controle , Animais , Biomarcadores/metabolismo , Ciclo-Oxigenase 2/metabolismo , Ativação Enzimática/efeitos dos fármacos , Células HEK293 , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Humanos , Interleucina-6/metabolismo , Camundongos , Camundongos Pelados , Fator 2 Relacionado a NF-E2/metabolismo , Fator de Transcrição CHOP/metabolismo
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