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1.
Exp Neurol ; 347: 113915, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34758342

RESUMO

Neuropathic pain occurs in more than half of the patients suffering from peripheral neuropathies. We investigated the role of microRNA (miR)-21 in neuropathic pain using a murine-human translational approach. We applied the spared nerve injury (SNI) model at the sciatic nerve of mice and assessed the potential analgesic effect of perineurial miR-21-5p inhibitor application. Immune-related targets of miR-21-5p were determined by a qRT-PCR based cytokine and chemokine array. Bioinformatical analysis identified potential miR-21-5p targets interacting with CC-chemokine ligand (CCL)5. We validated CCL5 and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein (YWHAE), an interaction partner of miR-21-5p and CCL5, by qRT-PCR in murine common peroneal and tibial nerves. Validated candidates were then investigated in white blood cell and sural nerve biopsy samples of patients with focal to generalized pain syndromes, i.e. small fiber neuropathy (SFN), polyneuropathy (PNP), and nerve lesion (NL). We showed that perineurial miR-21-5p inhibition reverses SNI-induced mechanical and heat hypersensitivity in mice and found a reduction of the SNI-induced increase of the pro-inflammatory mediators CCL5 (p < 0.01), CCL17 (p < 0.05), and IL-12ß (p < 0.05) in miR-21-5p inhibitor-treated mice. In silico analysis revealed several predicted and validated targets for miR-21-5p with CCL5 interaction. Among these, we found lower YWHAE gene expression in mice after SNI and perineurial injections of a scrambled oligonucleotide compared to naïve mice (p < 0.05), but this was not changed by miR-21-5p inhibition. Furthermore, miR-21-5p inhibition led to a further increase of the SNI-induced increase in TGFß (p < 0.01). Patient biomaterial revealed different systemic expression patterns of miR-21-5p, with higher expression in SFN and lower expression in NL. Further, we showed higher systemic expression of pro-inflammatory mediators in white blood cells of SFN patients compared to healthy controls. We have conducted a translational study comparing results from animal models to human patients with three different neuropathic pain syndromes. We identified CCL5 as a miR-21 dependent common player in the mouse SNI model and the human painful disease SFN.


Assuntos
Proteínas 14-3-3/biossíntese , Quimiocina CCL5/biossíntese , MicroRNAs/biossíntese , Neuralgia/metabolismo , Medição da Dor/métodos , /métodos , Proteínas 14-3-3/genética , Proteínas 14-3-3/imunologia , Animais , Quimiocina CCL5/genética , Quimiocina CCL5/imunologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , MicroRNAs/imunologia , Neuralgia/genética , Neuralgia/imunologia
2.
PLoS One ; 16(12): e0261971, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34965271

RESUMO

MicroRNAs (miRNAs) are important molecules that mediate virus-host interactions, mainly by regulating gene expression via gene silencing. Here, we demonstrated that HIV-1 infection upregulated miR-210-5p in HIV-1-inoculated cell lines and in the serum of HIV-1-infected individuals. Luciferase reporter assays and western blotting confirmed that a target protein of miR-210-5p, TGIF2, is regulated by HIV-1 infection. Furthermore, HIV-1 Vpr protein induced miR-210-5p expression. The use of a miR-210-5p inhibitor and TGIF2 overexpression showed that Vpr upregulated miR-210-5p and thereby downregulated TGIF2, which might be one of the mechanisms used by Vpr to induce G2 arrest. Moreover, we identified a transcription factor, NF-κB p50, which upregulated miR-210-5p in response to Vpr protein. In conclusion, we identified a mechanism whereby miR-210-5p, which is induced upon HIV-1 infection, targets TGIF2. This pathway was initiated by Vpr protein activating NF-κB p50, which promoted G2 arrest. These alterations orchestrated by miRNA provide new evidence on how HIV-1 interacts with its host during infection and increase our understanding of the mechanism by which Vpr regulates the cell cycle.


Assuntos
Infecções por HIV , HIV-1/imunologia , Proteínas de Homeodomínio/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , MicroRNAs/imunologia , Proteínas Repressoras/imunologia , Produtos do Gene vpr do Vírus da Imunodeficiência Humana/imunologia , Linhagem Celular , Pontos de Checagem da Fase G2 do Ciclo Celular , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos
3.
Front Immunol ; 12: 784028, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34956213

RESUMO

Background: Extracellular vesicles (EVs) are mediators of cell-to-cell communication in inflammatory lung diseases. They function as carriers for miRNAs which regulate mRNA transcripts and signaling pathways after uptake into recipient cells. We investigated whether miRNAs associated with circulating EVs regulate immunologic processes in COVID-19. Methods: We prospectively studied 20 symptomatic patients with COVID-19 pneumonia, 20 mechanically ventilated patients with severe COVID-19 (severe acute respiratory corona virus-2 syndrome, ARDS) and 20 healthy controls. EVs were isolated by precipitation, total RNA was extracted, profiled by small RNA sequencing and evaluated by differential gene expression analysis (DGE). Differentially regulated miRNAs between groups were bioinformatically analyzed, mRNA target transcripts identified and signaling networks constructed, thereby comparing COVID-19 pneumonia to the healthy state and pneumonia to severe COVID-19 ARDS. Results: DGE revealed 43 significantly and differentially expressed miRNAs (25 downregulated) in COVID-19 pneumonia when compared to controls, and 20 miRNAs (15 downregulated) in COVID-19 ARDS patients in comparison to those with COVID-19 pneumonia. Network analysis for comparison of COVID-19 pneumonia to healthy controls showed upregulated miR-3168 (log2FC=2.28, padjusted<0.001), among others, targeting interleukin-6 (IL6) (25.1, 15.2 - 88.2 pg/ml in COVID-19 pneumonia) and OR52N2, an olfactory smell receptor in the nasal epithelium. In contrast, miR-3168 was significantly downregulated in COVID-19 ARDS (log2FC=-2.13, padjusted=0.003) and targeted interleukin-8 (CXCL8) in a completely activated network. Toll-like receptor 4 (TLR4) was inhibited in COVID-19 pneumonia by miR-146a-5p and upregulated in ARDS by let-7e-5p. Conclusion: EV-derived miRNAs might have important regulative functions in the pathophysiology of COVID-19: CXCL8 regulates neutrophil recruitment into the lung causing epithelial damage whereas activated TLR4, to which SARS-CoV-2 spike protein binds strongly, increases cell surface ACE2 expression and destroys type II alveolar cells that secrete pulmonary surfactants; both resulting in pulmonary-capillary leakage and ARDS. These miRNAs may serve as biomarkers or as possible therapeutic targets.


Assuntos
Biomarcadores/sangue , COVID-19/imunologia , Vesículas Extracelulares/imunologia , MicroRNAs/imunologia , Idoso , Idoso de 80 Anos ou mais , COVID-19/patologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia/imunologia , Pneumonia/patologia , SARS-CoV-2 , Transdução de Sinais/imunologia
4.
Biomed Pharmacother ; 144: 112247, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34601190

RESUMO

COVID-19 is a pneumonia-like disease with highly transmittable and pathogenic properties caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which infects both animals and humans. Although many efforts are currently underway to test possible therapies, there is no specific FDA approved drug against SARS-CoV-2 yet. miRNA-directed gene regulation controls the majority of biological processes. In addition, the development and progression of several human diseases are associated with dysregulation of miRNAs. In this regard, it has been shown that changes in miRNAs are linked to severity of COVID-19 especially in patients with respiratory diseases, diabetes, heart failure or kidney problems. Therefore, targeting these small noncoding-RNAs could potentially alleviate complications from COVID-19. Here, we will review the roles and importance of host and RNA virus encoded miRNAs in COVID-19 pathogenicity and immune response. Then, we focus on potential miRNA therapeutics in the patients who are at increased risk for severe disease.


Assuntos
Antivirais/administração & dosagem , COVID-19/terapia , Terapia Genética/métodos , MicroRNAs/administração & dosagem , Animais , Antivirais/imunologia , COVID-19/genética , COVID-19/imunologia , Sistemas de Liberação de Medicamentos/métodos , Humanos , MicroRNAs/genética , MicroRNAs/imunologia
5.
J Immunol ; 207(11): 2770-2784, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34697227

RESUMO

Circular RNAs (circRNAs) are a subgroup of endogenous noncoding RNA that is covalently closed rings and widely expressed. In recent years, there is accumulating evidence indicating that circRNAs are a class of important regulators, which play an important role in various biological processes. However, the biological functions and regulation mechanism of circRNAs in lower vertebrates are little known. In this study, we discovered a circRNA Samd4a (circSamd4a) that is related to the antiviral immune response of teleost fish. It can act as a key regulator of the host's antiviral response and play a key role in inhibiting Sininiperca chuatsi rhabdovirus replication. Further studies have shown that circSamd4a may act as a competing endogenous RNA, which can enhance the STING-mediated NF-κB/IRF3 signaling pathway by adsorbing miR-29a-3p, thereby enhancing the antiviral immune response. Therefore, circSamd4a plays an active regulatory role in the antiviral immune response of bony fish. Our research results provide a strong foundation for circular RNA to play a regulatory role in the antiviral immune response of teleost fish.


Assuntos
Interferons/imunologia , MicroRNAs/imunologia , RNA Circular/imunologia , Regulação para Cima/imunologia , Animais , Células Cultivadas , Perciformes
6.
PLoS Pathog ; 17(9): e1009950, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34591940

RESUMO

STING is a nodal point for cellular innate immune response to microbial infections, autoimmunity and cancer; it triggers the synthesis of the antiviral proteins, type I interferons. Many DNA viruses, including Herpes Simplex Virus 1 (HSV1), trigger STING signaling causing inhibition of virus replication. Here, we report that HSV1 evades this antiviral immune response by inducing a cellular microRNA, miR-24, which binds to the 3' untranslated region of STING mRNA and inhibits its translation. Expression of the gene encoding miR-24 is induced by the transcription factor AP1 and activated by MAP kinases in HSV1-infected cells. Introduction of exogenous miR-24 or prior activation of MAPKs, causes further enhancement of HSV1 replication in STING-expressing cells. Conversely, transfection of antimiR-24 inhibits virus replication in those cells. HSV1 infection of mice causes neuropathy and death; using two routes of infection, we demonstrated that intracranial injection of antimiR-24 alleviates both morbidity and mortality of the infected mice. Our studies reveal a new immune evasion strategy adopted by HSV1 through the regulation of STING and demonstrates that it can be exploited to enhance STING's antiviral action.


Assuntos
Herpes Simples/imunologia , Evasão da Resposta Imune/imunologia , Proteínas de Membrana/imunologia , MicroRNAs/imunologia , Animais , Regulação da Expressão Gênica/imunologia , Herpes Simples/metabolismo , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Celular/imunologia , Proteínas de Membrana/metabolismo , Camundongos
7.
Int J Mol Sci ; 22(18)2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34576006

RESUMO

Tumor immune escape is a common process in the tumorigenesis of non-small cell lung cancer (NSCLC) cells where programmed death ligand-1 (PD-L1) expression, playing a vital role in immunosuppression activity. Additionally, epidermal growth factor receptor (EGFR) phosphorylation activates Janus kinase-2 (JAK2) and signal transduction, thus activating transcription 3 (STAT3) to results in the regulation of PD-L1 expression. Chemotherapy with commercially available drugs against NSCLC has struggled in the prospect of adverse effects. Nobiletin is a natural flavonoid isolated from the citrus peel that exhibits anti-cancer activity. Here, we demonstrated the role of nobiletin in evasion of immunosuppression in NSCLC cells by Western blotting and real-time polymerase chain reaction methods for molecular signaling analysis supported by gene silencing and specific inhibitors. From the results, we found that nobiletin inhibited PD-L1 expression through EGFR/JAK2/STAT3 signaling. We also demonstrated that nobiletin exhibited p53-independent PD-L1 suppression, and that miR-197 regulates the expression of STAT3 and PD-L1, thereby enhancing anti-tumor immunity. Further, we evaluated the combination ability of nobiletin with an anti-PD-1 monoclonal antibody in NSCLC co-culture with peripheral blood mononuclear cells. Similarly, we found that nobiletin assisted the induction of PD-1/PD-L1 blockade, which is a key factor for the immune escape mechanism. Altogether, we propose nobiletin as a modulator of tumor microenvironment for cancer immunotherapy.


Assuntos
Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Flavonas/farmacologia , Neoplasias Pulmonares/imunologia , MicroRNAs/imunologia , Proteínas de Neoplasias/imunologia , RNA Neoplásico/imunologia , Fator de Transcrição STAT3/imunologia , Transdução de Sinais/efeitos dos fármacos , Evasão Tumoral/efeitos dos fármacos , Células A549 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Transdução de Sinais/imunologia
8.
J Biol Chem ; 297(4): 101199, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34536420

RESUMO

Growing numbers of studies have shown that circular RNAs (circRNAs) can function as regulatory factors to regulate the innate immune response, cell proliferation, cell migration, and other important processes in mammals. However, the function and regulatory mechanism of circRNAs in lower vertebrates are still unclear. Here, we discovered a novel circRNA derived from the gene encoding Bcl-2-like protein 1 (BCL2L1) gene, named circBCL2L1, which was related to the innate immune responses in teleost fish. Results indicated that circBCL2L1 played essential roles in host antiviral immunity and antibacterial immunity. Our study also identified a microRNA, miR-30c-3-3p, which could inhibit the innate immune response by targeting inflammatory mediator TRAF6. And TRAF6 is a key signal transduction factor in innate immune response mediated by TLRs. Moreover, we also found that the antiviral and antibacterial effects inhibited by miR-30c-3-3p could be reversed with the expression of circBCL2L1. Our data revealed that circBCL2L1 functioned as a competing endogenous RNA (ceRNA) of TRAF6 by competing for binding with miR-30c-3-3p, leading to activation of the NF-κB/IRF3 inflammatory pathway and then enhancing the innate immune responses. Our results suggest that circRNAs can play an important role in the innate immune response of teleost fish.


Assuntos
Proteínas de Peixes/imunologia , Imunidade Inata , MicroRNAs/imunologia , Perciformes/imunologia , RNA Circular/imunologia , Fator 6 Associado a Receptor de TNF/imunologia , Animais , Perciformes/microbiologia , Perciformes/virologia
9.
Mol Immunol ; 139: 157-167, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34543842

RESUMO

The short non-coding microRNAs (miRNAs) have emerged as reliable modulators of various pathological conditions including autoimmune diseases in mammals. The current study, aims to identify new potential differential expressed miRNAs and their downstream mRNA targets of the autoimmune disease, Multiple sclerosis (MS). The study identifies a new set of miRNA(s) that are probably implicated in MS using computational tools. The study further carried-out different in vivo and in vitro experiments to check these identified miRNAs could be role in as therapeutic and prognostic applications. Preliminary insilico screening revealed that miR-659-3p, miR-659-5p, miR-684, miR-3607-3p, miR-3607-5p, miR-3682-3p, miR-3682-5p miR-4647, miR-7188-3p, miR-7188-5p and miR-7235 are specifically elevated in the secondary lymphoid cells of EAE mice. In addition, expression of the downstream target mRNA of these miRNAs such as FXBO33, SGMS-1, ZDHHC-9, GABRA-3, NRXN-2 were reciprocal to miRNA expression in lymphoid cells. These confirmed by applying the mimic and silencing miRNA models, suggesting new inflammatory target genes of these promising miRNA markers. The in vivo adoptive transfer model revealed that the suppression of miRNA-7188-5p and miR-7235 changed the pattern of astrocytes and CNS pathophysiology. The current study opens a new miRNA and their mRNA targets in MS disease. The absence of miRNA-7188-5p and miR-7235 enhanced the disease alleviation, confirms the regulatory effect of these targets. These optimized results highlights new set of miRNA's with therapeutic potential in experimental MS. Further studies are required to confirm these miRNA as therapeutic biomarker.


Assuntos
Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Regulação da Expressão Gênica/imunologia , MicroRNAs/genética , MicroRNAs/imunologia , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia
10.
Biochem Biophys Res Commun ; 573: 100-106, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34403805

RESUMO

Extracellular vesicles (EVs) in utero play a role in cellular interactions between endometrium-conceptuses (embryo plus extraembryonic membranes) during peri-implantation periods. However, how intrauterine EVs function on endometrium have not been well characterized. In our previous study, bta-miR-98 found in intrauterine EVs from uterine flushing fluids (UFs) on pregnant day 20 (a half day after initial conceptus attachment, P20) could regulate the maternal immune system and collaborate with other miRNAs and/or components of EVs for conceptus implantation. We, therefore, hypothesized that in addition to bta-miR-98, other miRNAs present in bovine intrauterine EVs may regulate the maternal immune system in the endometrial epithelium. A global analysis of differentially expressed proteins between EVs from P17 and P20 UFs revealed that components of intrauterine P20 EVs had the effect on the down-regulation of "neutrophil activation involved in immune response" and "neutrophil mediated immunity". In silico analyses predicted bta-miR-26b as one of potential miRNA to regulate maternal immune system. In our cell culture experiments, bta-miR-26b negatively regulated several immune system-related genes PSMC6, CD40, and IER3 in bovine endometrial epithelial cells. Our findings revealed that intrauterine EV-derived bta-miR-26b contributes to the down-regulation of the maternal immune system, allowing conceptus implantation to the uterine endometrium. Furthermore, our results suggest that intrauterine EVs extracted from P20 UFs could regulate neutrophils, the first line of immunological defense, to modulate endometrial immune and inflammatory responses for implanting conceptuses.


Assuntos
Implantação do Embrião/imunologia , Vesículas Extracelulares/imunologia , Sistema Imunitário/imunologia , MicroRNAs/imunologia , Animais , Bovinos , Células Cultivadas , MicroRNAs/genética
11.
Biomed Res Int ; 2021: 8112783, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34447853

RESUMO

Long noncoding RNAs (lncRNAs) have been reported to participate in regulating many biological processes, including immune response to influenza A virus (IAV). However, the association between lncRNA expression profiles and influenza infection susceptibility has not been well elucidated. Here, we analyzed the expression profiles of lncRNAs, miRNAs, and mRNAs among IAV-infected adult rat (IAR), normal adult rat (AR), IAV-infected junior rat (IJR), and normal junior rat (JR) by RNA sequencing. Compared with differently expressed lncRNAs (DElncRNAs) between AR and IAR, 24 specific DElncRNAs were found between IJR and JR. Then, based on the fold changes and P value, the top 5 DElncRNAs, including 3 upregulated and 2 downregulated lncRNAs, were chosen to establish a ceRNA network for further disclosing their regulatory mechanisms. To visualize the differentially expressed genes in the ceRNA network, GO and KEGG pathway analysis was performed to further explore their roles in influenza infection of junior rats. The results showed that the downregulated DElncRNA-target genes were mostly enriched in the IL-17 signaling pathway. It indicated that the downregulated lncRNAs conferred the susceptibility of junior rats to IAV via mediating the IL-17 signaling pathway.


Assuntos
Vírus da Influenza A/patogenicidade , MicroRNAs/genética , Infecções por Orthomyxoviridae/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Vírus da Influenza A/isolamento & purificação , Interleucina-17/genética , Interleucina-17/imunologia , MicroRNAs/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , RNA Longo não Codificante/imunologia , RNA Mensageiro/imunologia , Ratos , Ratos Sprague-Dawley
12.
Mol Immunol ; 139: 42-49, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34454184

RESUMO

Accumulating lines of evidence have revealed the involvement of long non-coding RNAs (lncRNAs) in the control and elimination of invading Mycobacterium tuberculosis (Mtb) by macrophage. In this study, we sought to elucidate the role of MIAT on autophagy and apoptosis of Mtb-infected macrophage and to reveal the molecular mechanism. We observed that the expression of MIAT was heightened while miR-665 level was declined in THP-1 cells with Bacillus Calmette-Guerin (BCG) infection in a time-dependent manner. Functionally, disruption of MIAT effectively facilitated cell viability and restricted apoptosis ability concomitant with the downregulation of Bax and cleaved caspase-3 along with an accumulation of Bcl-2 in BCG-infected THP-1 cells. Concurrently, the interference of MIAT dramatically disinhibited macrophage autophagy as characterized by diminution of autophagy related markers LC3-II and Beclin-1 as well as increment of p62 in THP-1 cells following BCG infection. Concordantly, depletion of MIAT was found to noticeably aggrandize Mtb survival. Importantly, MIAT served as a ceRNA for sponging miR-665 and negatively regulated its expression. ULK1 was identified as an authentic target of miR-665 and modulated by MIAT. Mechanistically, the functional role of MIAT depletion in macrophage apoptosis and autophagy were tremendously abrogated by the depression of miR-665 and enrichment of ULK1. Overall, the preceding observations clearly illuminated that MIAT was elevated in human macrophage response to BCG infection, and functioned as a negative regulator in autophagy and antimicrobial effects by manipulating miR-665/ULK1 axis during Mtb infection, which may provide a promising target for developing an anti-bacterial against TB.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Macrófagos/imunologia , MicroRNAs/imunologia , RNA Longo não Codificante/imunologia , Tuberculose/imunologia , Apoptose/imunologia , Autofagia/imunologia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Regulação da Expressão Gênica/imunologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/metabolismo , Macrófagos/microbiologia , MicroRNAs/metabolismo , Mycobacterium tuberculosis , RNA Longo não Codificante/metabolismo , Transdução de Sinais/imunologia , Células THP-1
13.
Biomolecules ; 11(8)2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34439811

RESUMO

Verticillium wilt, primarily induced by the soil-borne fungus Verticillium dahliae, is a serious threat to cotton fiber production. There are a large number of really interesting new gene (RING) domain-containing E3 ubiquitin ligases in Arabidopsis, of which three (At2g39720 (AtRHC2A), At3g46620 (AtRDUF1), and At5g59550 (AtRDUF2)) have a domain of unknown function (DUF) 1117 domain in their C-terminal regions. This study aimed to detect and characterize the RDUF members in cotton, to gain an insight into their roles in cotton's adaptation to environmental stressors. In this study, a total of 6, 7, 14, and 14 RDUF (RING-DUF1117) genes were detected in Gossypium arboretum, G. raimondii, G. hirsutum, and G. barbadense, respectively. These RDUF genes were classified into three groups. The genes in each group were highly conserved based on gene structure and domain analysis. Gene duplication analysis revealed that segmental duplication occurred during cotton evolution. Expression analysis revealed that the GhRDUF genes were widely expressed during cotton growth and under abiotic stresses. Many cis-elements related to hormone response and environment stressors were identified in GhRDUF promoters. The predicted target miRNAs and transcription factors implied that GhRDUFs might be regulated by gra-miR482c, as well as by transcription factors, including MYB, C2H2, and Dof. The GhRDUF genes responded to cold, drought, and salt stress and were sensitive to jasmonic acid, salicylic acid, and ethylene signals. Meanwhile, GhRDUF4D expression levels were enhanced after V. dahliae infection. Subsequently, GhRDUF4D was verified by overexpression in Arabidopsis and virus-induced gene silencing treatment in upland cotton. We observed that V. dahliae resistance was significantly enhanced in transgenic Arabidopsis, and weakened in GhRDUF4D silenced plants. This study conducted a comprehensive analysis of the RDUF genes in Gossypium, hereby providing basic information for further functional studies.


Assuntos
Proteínas de Arabidopsis/genética , Resistência à Doença/genética , Gossypium/genética , Doenças das Plantas/genética , Imunidade Vegetal/genética , Ubiquitina-Proteína Ligases/genética , Adaptação Fisiológica/genética , Adaptação Fisiológica/imunologia , Arabidopsis/classificação , Arabidopsis/genética , Arabidopsis/imunologia , Arabidopsis/microbiologia , Proteínas de Arabidopsis/metabolismo , Ascomicetos/crescimento & desenvolvimento , Ascomicetos/patogenicidade , Sequência de Bases , Dedos de Zinco CYS2-HIS2/genética , Dedos de Zinco CYS2-HIS2/imunologia , Sequência Conservada , Regulação da Expressão Gênica de Plantas , Gossypium/classificação , Gossypium/imunologia , Gossypium/microbiologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , MicroRNAs/genética , MicroRNAs/imunologia , Família Multigênica , Filogenia , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Plantas Geneticamente Modificadas , Regiões Promotoras Genéticas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estresse Fisiológico , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Ubiquitina-Proteína Ligases/metabolismo
14.
Biomolecules ; 11(8)2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34439863

RESUMO

MicroRNAs (miRNAs) are members of the non-coding regulatory RNA family that play pivotal roles in physiological and pathological conditions, including immune response. They are particularly interesting as promising therapeutic targets, prognostic and diagnostic markers due to their easy detection in body fluids and stability. There is accumulating evidence that different miRNAs provide disease-specific signatures in liquid samples of distinct kidney injuries. Using experimental models and human samples, there have been numerous suggestions that immune-related miRNAs are also important contributors to the development of different kidney diseases as well as important markers for monitoring response after kidney transplantation. However, there are limited data for understanding their function in the molecular pathways of allograft pathologies. In our review, we focused on microRNAs that are related to different aspects of immune response after kidney transplantation.


Assuntos
Rejeição de Enxerto/imunologia , Imunidade Celular/imunologia , Transplante de Rim/efeitos adversos , MicroRNAs/imunologia , Complicações Pós-Operatórias/imunologia , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/genética , Infecções Bacterianas/imunologia , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/genética , Humanos , Nefropatias/diagnóstico , Nefropatias/imunologia , Nefropatias/cirurgia , Transplante de Rim/tendências , MicroRNAs/genética , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/genética
15.
Cells ; 10(8)2021 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-34440789

RESUMO

The clinical use of natural killer (NK) cells is at the forefront of cellular therapy. NK cells possess exceptional antitumor cytotoxic potentials and can generate significant levels of proinflammatory cytokines. Multiple genetic manipulations are being tested to augment the anti-tumor functions of NK cells. One such method involves identifying and altering microRNAs (miRNAs) that play essential roles in the development and effector functions of NK cells. Unique miRNAs can bind and inactivate mRNAs that code for cytotoxic proteins. MicroRNAs, such as the members of the Mirc11 cistron, downmodulate ubiquitin ligases that are central to the activation of the obligatory transcription factors responsible for the production of inflammatory cytokines. These studies reveal potential opportunities to post-translationally enhance the effector functions of human NK cells while reducing unwanted outcomes. Here, we summarize the recent advances made on miRNAs in murine and human NK cells and their relevance to NK cell development and functions.


Assuntos
Citocinas/imunologia , Regulação da Expressão Gênica/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , MicroRNAs/imunologia , Linfócitos T Citotóxicos/imunologia , Regiões 3' não Traduzidas/genética , Regiões 3' não Traduzidas/imunologia , Animais , Citocinas/metabolismo , Humanos , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/genética , Camundongos , MicroRNAs/genética , Linfócitos T Citotóxicos/metabolismo
16.
Front Immunol ; 12: 624753, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34239515

RESUMO

The pathological mechanism underlying heat stroke (HS) is associated with the dysbalanced inflammation and coagulation cascade. Cell-derived circulating extracellular vesicles (EVs), as a novel pathway mediating intercellular communication, are associated with the immune response and inflammation in critical inflammatory syndromes, such as sepsis. Although these vesicles contain genetic material correlated with their biological function, their molecular cargo during HS remains unknown. In this study, we evaluate the presence of microRNAs (miRNAs) and messenger RNAs (mRNAs) associated with inflammatory responses and coagulation cascade in exosomes of patients with HS. Blood samples were collected from three patients with HS at the time of admission to the intensive care unit; three healthy volunteers were selected as control. Exosomes were isolated using ultracentrifugation, and their miRNA content was profiled using next-generation sequencing; mRNA content was evaluated using qPCR array. Compared with those from healthy volunteers, exosomes from patients with HS showed substantial changes in the expression of 202 exosomal miRNAs (154 upregulated and 48 downregulated miRNAs). The most upregulated miRNAs included miR-511-3p, miR-122-5p, miR-155-3p, miR-1290, and let7-5p, whereas the most downregulated ones included miR-150-3p, 146a-5p, and 151a-3p. Gene ontology enrichment of the miRNAs of patients with HS compared with control subjects were associated mostly with inflammatory response, including T cell activation, B cell receptor signaling, dendritic cell chemotaxis and leukocyte migration, and platelet activation and blood coagulation. The identified miRNAs were primarily enriched to the signal transduction pathways namely, T cell receptor signaling, Ras signaling, chemokine signaling, platelet activation, and leukocyte transendothelial migration, all of which are associated with inflammation and hemostasis. Multiple targeted mRNAs associated with the inflammatory response, blood coagulation, and platelet activation were further verified in serum exosomes. Exosomes from patients with HS convey miRNAs and mRNAs associated with pathogenic pathways, including inflammatory response and coagulation cascade. Exosomes may represent a novel mechanism for intercellular communication during HS.


Assuntos
Coagulação Sanguínea/genética , Exossomos/química , Golpe de Calor/sangue , Golpe de Calor/imunologia , Inflamação/genética , MicroRNAs/genética , MicroRNAs/imunologia , Adolescente , Adulto , Comunicação Celular , China , Regulação para Baixo , Exossomos/fisiologia , Golpe de Calor/fisiopatologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , MicroRNAs/análise , MicroRNAs/classificação , Estudos Retrospectivos , Transdução de Sinais , Regulação para Cima , Adulto Jovem
17.
Front Immunol ; 12: 687962, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248974

RESUMO

Non-coding RNAs have emerged as critical regulators of the immune response to infection. MicroRNAs (miRNAs) are small non-coding RNAs which regulate host defense mechanisms against viruses, bacteria and fungi. They are involved in the delicate interplay between Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), and its host, which dictates the course of infection. Differential expression of miRNAs upon infection with M. tuberculosis, regulates host signaling pathways linked to inflammation, autophagy, apoptosis and polarization of macrophages. Experimental evidence suggests that virulent M. tuberculosis often utilize host miRNAs to promote pathogenicity by restricting host-mediated antibacterial signaling pathways. At the same time, host- induced miRNAs augment antibacterial processes such as autophagy, to limit bacterial proliferation. Targeting miRNAs is an emerging option for host-directed therapies. Recent studies have explored the role of long non-coding RNA (lncRNAs) in the regulation of the host response to mycobacterial infection. Among other functions, lncRNAs interact with chromatin remodelers to regulate gene expression and also function as miRNA sponges. In this review we attempt to summarize recent literature on how miRNAs and lncRNAs are differentially expressed during the course of M. tuberculosis infection, and how they influence the outcome of infection. We also discuss the potential use of non-coding RNAs as biomarkers of active and latent tuberculosis. Comprehensive understanding of the role of these non-coding RNAs is the first step towards developing RNA-based therapeutics and diagnostic tools for the treatment of TB.


Assuntos
Imunidade Inata , MicroRNAs/imunologia , Mycobacterium tuberculosis/imunologia , RNA Longo não Codificante/imunologia , Tuberculose/imunologia , Animais , Apoptose , Autofagia , Proteína DEAD-box 58/imunologia , Proteína DEAD-box 58/metabolismo , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Mycobacterium tuberculosis/patogenicidade , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Receptores Toll-Like/imunologia , Receptores Toll-Like/metabolismo , Tuberculose/genética , Tuberculose/metabolismo , Tuberculose/microbiologia
18.
Cell Biochem Funct ; 39(7): 886-895, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34235754

RESUMO

Human dental pulp stem cells (hDPSCs) have significant potential of immunomodulatory for therapeutic and regenerative biomedical applications compared to other mesenchymal stem cells (MSCs). Nowadays, alteration of gene expression is an important way to improve the performance of MSCs in the clinic. MicroRNAs (miRs) and CD200 are known to modulate the immune system in MSCs. Curcumin is famous for its anti-inflammatory impacts. Phytosomal curcumin (PC) is a nanoparticle synthesized from curcumin that removes the drawbacks of curcumin. The purpose of this research was to assess the effects of PC on the expression of the CD200 and four key miRNAs in immune system. PC (30 µM) treatment of hDPSCs could ameliorate their immunoregulatory property, presented by reduced expressions of miR-21, miR-155 and miR-126, as well as enhanced expressions of miR-23 and CD200. The PC was also able to reduce PI3K\AKT1\NF-κB expressions that were target genes for these miRs and involved in inflammatory pathways. Moreover, PC was more effective than curcumin in improving the immune modulation of hDPSCs. Evidence in this study suggested that PC mediates immunoregulatory activities in hDPSC via miRs and CD200 to regulate PI3K\AKT1\NF-κB signalling pathways, which may provide a theoretical basis for PC in the treatment of many diseases. SIGNIFICANCE OF THE STUDY: Autoimmune diseases or tooth caries are partly attributed to global health problems and their common drug treatments have several side effects. The goal of this study is dentin regeneration and autoimmune diseases treatment via stem cell-based approaches with phytosomal curcumin (PC), for the first time. Because dental pulp stem cells have unique advantages (including higher immunomodulatory capacity) over other mesenchymal stem cells, we considered them the best option for treating these diseases. Using PC, we try to increase the immunomodulatory properties of these cells.


Assuntos
Antígenos CD/genética , Curcumina/farmacologia , Polpa Dentária/efeitos dos fármacos , Inflamação/tratamento farmacológico , MicroRNAs/antagonistas & inibidores , Células-Tronco/efeitos dos fármacos , Antígenos CD/imunologia , Células Cultivadas , Curcumina/química , Polpa Dentária/imunologia , Humanos , Inflamação/imunologia , MicroRNAs/genética , MicroRNAs/imunologia , Nanopartículas/química , Células-Tronco/imunologia
19.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281269

RESUMO

The host-parasite schistosome relationship relies heavily on the interplay between the strategies imposed by the schistosome worm and the defense mechanisms the host uses to counter the line of attack of the parasite. The ultimate goal of the schistosome parasite entails five important steps: evade elimination tactics, survive within the human host, develop into adult forms, propagate in large numbers, and transmit from one host to the next. The aim of the parasitized host on the other hand is either to cure or limit infection. Therefore, it is a battle between two conflicting aspirations. From the host's standpoint, infection accompanies a plethora of immunological consequences; some are set in place to defend the host, while most end up promoting chronic disease, which ultimately crosses paths with oxidative stress and cancer. Understanding these networks provides attractive opportunities for anti-schistosome therapeutic development. Hence, this review discusses the mechanisms by which schistosomes modulate the human immune response with ultimate links to oxidative stress and genetic instability.


Assuntos
Citocinas/metabolismo , Interações Hospedeiro-Parasita/imunologia , Esquistossomose/imunologia , Esquistossomose/metabolismo , Animais , Linfócitos B Reguladores/imunologia , Basófilos/imunologia , Células Dendríticas/imunologia , Eosinófilos/imunologia , Humanos , Macrófagos/imunologia , Mastócitos/imunologia , MicroRNAs/imunologia , Modelos Imunológicos , Estresse Oxidativo , Schistosoma/imunologia , Schistosoma/patogenicidade , Esquistossomose/parasitologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia
20.
Hematology ; 26(1): 417-431, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34130612

RESUMO

BACKGROUND: Myelodysplastic syndrome (MDS) is a haematopoietic malignancy that is characterized by a heterogeneous clinical course and dysplastic maturation of blood lineages. Immune dysregulation has gained attention as one of the fundamental mechanisms responsible for the development of MDS. This study aimed to screen immune-related biomarkers and pathways in MDS. METHODS: Differentially expressed mRNAs (DE-mRNAs) and differentially expressed microRNAs (DE-miRNAs) in different subtypes of MDS were sourced from the Gene Expression Omnibus (GEO) database. DE-mRNAs were intersected with immune-related gene sets to collect immune-related mRNAs, which were put into the Search Tool for the Retrieval of Interacting Genes (STRING) to construct protein-protein interaction (PPI) networks. Target mRNAs of DE-miRNAs were predicted using the miRDB database and intersected with screened immune-related mRNAs to construct miRNA-mRNA interaction networks. Topological analysis of constructed networks was applied to screen key molecules, which were assessed in independent datasets and previous literature. Enrichment analysis was applied to screen dysregulated pathways in MDS. RESULTS: Screened key mRNAs were mainly from the Toll-like receptor (TLR) family, including TLR2, TLR4, TLR7, and from the chemokine family, including C-X-C motif chemokine ligand 10 (CXCL10) and CC chemokine ligand 4 (CCL4). Cytokine-cytokine receptor interactions were among the major pathways in the enrichment analysis results. Hsa-miR-30b, hsa-miR-30e and hsa-miR-221 were validated as key miRNAs and modulate cytokine-cytokine receptor interactions by targeting immune-related mRNAs. CONCLUSION: Dysregulated cytokines reflect the immunization status in MDS. Immune-related miRNA-mRNA interactions not only provide a perspective to our understanding of immunologic derangement in the pathogenesis of MDS but also provide new therapeutic opportunities.


Assuntos
MicroRNAs/genética , Síndromes Mielodisplásicas/genética , RNA Mensageiro/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Imunidade , MicroRNAs/imunologia , Síndromes Mielodisplásicas/imunologia , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/imunologia , Transcriptoma
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