Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 50.699
Filtrar
1.
Oxid Med Cell Longev ; 2021: 7866992, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34497683

RESUMO

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is posing a great threat to the global economy and public health security. Together with the acknowledged angiotensin-converting enzyme 2, glucose-regulated protein 78, transferrin receptor, AXL, kidney injury molecule-1, and neuropilin 1 are also identified as potential receptors to mediate SARS-CoV-2 infection. Therefore, how to inhibit or delay the binding of SARS-CoV-2 with the abovementioned receptors is a key step for the prevention and treatment of COVID-19. As the third gasotransmitter, hydrogen sulfide (H2S) plays an important role in many physiological and pathophysiological processes. Recently, survivors were reported to have significantly higher H2S levels in COVID-19 patients, and mortality was significantly greater among patients with decreased H2S levels. Considering that the beneficial role of H2S against COVID-19 and COVID-19-induced comorbidities and multiorgan damage has been well-examined and reported in some excellent reviews, this review will discuss the recent findings on the potential receptors of SARS-CoV-2 and how H2S modulates the above receptors, in turn blocking SARS-CoV-2 entry into host cells.


Assuntos
Antivirais/farmacologia , Sulfeto de Hidrogênio/farmacologia , Receptores de Superfície Celular/metabolismo , SARS-CoV-2/metabolismo , Animais , Humanos , Especificidade de Órgãos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , SARS-CoV-2/efeitos dos fármacos
2.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445339

RESUMO

Both agonist studies and loss-of-function models indicate that PPARγ plays an important role in cutaneous biology. Since PPARγ has a high level of basal activity, we hypothesized that epidermal PPARγ would regulate normal homeostatic processes within the epidermis. In this current study, we performed mRNA sequencing and differential expression analysis of epidermal scrapings from knockout mice and wildtype littermates. Pparg-/-epi mice exhibited a 1.5-fold or greater change in the expression of 11.8% of 14,482 identified transcripts. Up-regulated transcripts included those for a large number of cytokines/chemokines and their receptors, as well as genes associated with inflammasome activation and keratinization. Several of the most dramatically up-regulated pro-inflammatory genes in Pparg-/-epi mouse skin included Igfl3, 2610528A11Rik, and Il1f6. RT-PCR was performed from RNA obtained from non-lesional full-thickness skin and verified a marked increase in these transcripts, as well as transcripts for Igflr1, which encodes the receptor for Igfl3, and the 2610528A11Rik receptor (Gpr15). Transcripts for Il4 were detected in Pparg-/-epi mouse skin, but transcripts for Il17 and Il22 were not detected. Down-regulated transcripts included sebaceous gland markers and a number of genes associated with lipid barrier formation. The change in these transcripts correlates with an asebia phenotype, increased transepidermal water loss, alopecia, dandruff, and the appearance of spontaneous inflammatory skin lesions. Histologically, non-lesional skin showed hyperkeratosis, while inflammatory lesions were characterized by dermal inflammation and epidermal acanthosis, spongiosis, and parakeratosis. In conclusion, loss of epidermal Pparg alters a substantial set of genes that are associated with cutaneous inflammation, keratinization, and sebaceous gland function. The data indicate that epidermal PPARγ plays an important role in homeostatic epidermal function, particularly epidermal differentiation, barrier function, sebaceous gland development and function, and inflammatory signaling.


Assuntos
Dermatite/genética , Epiderme/metabolismo , PPAR gama/fisiologia , Fenômenos Fisiológicos da Pele/genética , Animais , Células Cultivadas , Dermatite/metabolismo , Dermatite/patologia , Dermatite/fisiopatologia , Epiderme/fisiologia , Homeostase/genética , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Especificidade de Órgãos/genética , PPAR gama/genética , PPAR gama/metabolismo
3.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445369

RESUMO

Annexin (Ann) is a polygenic, evolutionarily conserved, calcium-dependent and phospholipid-binding protein family, which plays key roles in plant growth, development, and stress response. However, a comprehensive understanding of CaAnn genes of pepper (Capsicum annuum) at the genome-wide level is limited. Based on the available pepper genomic information, we identified 15 members of the CaAnn gene family. Phylogenetic analysis showed that CaAnn proteins could be categorized into four different orthologous groups. Real time quantitative RT-PCR analysis showed that the CaAnn genes were tissue-specific and were widely expressed in pepper leaves after treatments with cold, salt, and drought, as well as exogenously applied MeJA and ABA. In addition, the function of CaAnn9 was further explored using the virus-induced gene silencing (VIGS) technique. CaAnn9-silenced pepper seedlings were more sensitive to salt stress, reflected by the degradation of chlorophyll, the accumulation of reactive oxygen species (ROS), and the decrease of antioxidant defense capacity. This study provides important information for further study of the role of pepper CaAnn genes and their coding proteins in growth, development, and environmental responses.


Assuntos
Anexinas/genética , Capsicum/crescimento & desenvolvimento , Perfilação da Expressão Gênica/métodos , Tolerância ao Sal , Ácido Abscísico/farmacologia , Acetatos/farmacologia , Capsicum/efeitos dos fármacos , Capsicum/genética , Ciclopentanos/farmacologia , Evolução Molecular , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Especificidade de Órgãos , Oxilipinas/farmacologia , Filogenia , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/genética , Folhas de Planta/crescimento & desenvolvimento , Proteínas de Plantas/genética , Sequenciamento Completo do Genoma
4.
Nat Commun ; 12(1): 5078, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34426578

RESUMO

Genome-wide association studies (GWAS) have identified loci for kidney disease, but the causal variants, genes, and pathways remain unknown. Here we identify two kidney disease genes Dipeptidase 1 (DPEP1) and Charged Multivesicular Body Protein 1 A (CHMP1A) via the triangulation of kidney function GWAS, human kidney expression, and methylation quantitative trait loci. Using single-cell chromatin accessibility and genome editing, we fine map the region that controls the expression of both genes. Mouse genetic models demonstrate the causal roles of both genes in kidney disease. Cellular studies indicate that both Dpep1 and Chmp1a are important regulators of a single pathway, ferroptosis and lead to kidney disease development via altering cellular iron trafficking.


Assuntos
Dipeptidases/genética , Ferroptose/genética , Loci Gênicos , Predisposição Genética para Doença , Nefropatias/genética , Proteínas de Transporte Vesicular/genética , Animais , Nitrogênio da Ureia Sanguínea , Cromatina/metabolismo , Cisplatino , Metilação de DNA/genética , Dipeptidases/deficiência , Dipeptidases/metabolismo , Ácido Fólico , Edição de Genes , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Haploinsuficiência/genética , Humanos , Ferro/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Camundongos , Necroptose/genética , Especificidade de Órgãos , Mapeamento Físico do Cromossomo , Piroptose/genética , Locos de Características Quantitativas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Transporte Vesicular/deficiência , Proteínas de Transporte Vesicular/metabolismo
5.
Sci Rep ; 11(1): 16814, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413339

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has emerged as a pandemic. Paucity of information concerning the virus and therapeutic interventions have made SARS-CoV-2 infection a genuine threat to global public health. Therefore, there is a growing need for understanding the molecular mechanism of SARS-CoV-2 infection at cellular level. To address this, we undertook a systems biology approach by analyzing publicly available RNA-seq datasets of SARS-CoV-2 infection of different cells and compared with other lung pathogenic infections. Our study identified several key genes and pathways uniquely associated with SARS-CoV-2 infection. Genes such as interleukin (IL)-6, CXCL8, CCL20, CXCL1 and CXCL3 were upregulated, which in particular regulate the cytokine storm and IL-17 signaling pathway. Of note, SARS-CoV-2 infection strongly activated IL-17 signaling pathway compared with other respiratory viruses. Additionally, this transcriptomic signature was also analyzed to predict potential drug repurposing and small molecule inhibitors. In conclusion, our comprehensive data analysis identifies key molecular pathways to reveal underlying pathological etiology and potential therapeutic targets in SARS-CoV-2 infection.


Assuntos
COVID-19/imunologia , Interleucina-17/genética , SARS-CoV-2/fisiologia , Biologia de Sistemas/métodos , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Quimiocina CCL20/genética , Quimiocina CXCL1/genética , Quimiocinas CXC/genética , Reposicionamento de Medicamentos , Humanos , Interleucina-17/metabolismo , Interleucina-6/genética , Interleucina-8/genética , Especificidade de Órgãos , Transdução de Sinais , Transcriptoma
6.
Sci Rep ; 11(1): 16843, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413390

RESUMO

Elevated angiotensin-converting enzyme 2 (ACE2) expression in organs that are potential targets of severe acute respiratory syndrome coronavirus 2 may increase the risk of coronavirus disease 2019 (COVID-19) infection. Previous reports show that ACE2 alter its tissue-specific expression patterns under various pathological conditions, including renal diseases. Here, we examined changes in pulmonary ACE2 expression in two mouse chronic kidney disease (CKD) models: adenine-induced (adenine mice) and aristolochic acid-induced (AA mice). We also investigated changes in pulmonary ACE2 expression due to renin-angiotensin system (RAS) blocker (olmesartan) treatment in these mice. Adenine mice showed significant renal functional decline and elevated blood pressure, compared with controls. AA mice also showed significant renal functional decline, compared with vehicles; blood pressure did not differ between groups. Renal ACE2 expression was significantly reduced in adenine mice and AA mice; pulmonary expression was unaffected. Olmesartan attenuated urinary albumin excretion in adenine mice, but did not affect renal or pulmonary ACE2 expression levels. The results suggest that the risk of COVID-19 infection may not be elevated in patients with CKD because of their stable pulmonary ACE2 expression. Moreover, RAS blockers can be used safely in treatment of COVID-19 patients with CKD.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Rim/metabolismo , Insuficiência Renal Crônica/metabolismo , SARS-CoV-2/fisiologia , Adenina , Enzima de Conversão de Angiotensina 2/genética , Animais , Ácidos Aristolóquicos , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Imidazóis/administração & dosagem , Rim/patologia , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Tetrazóis/administração & dosagem
7.
Nature ; 596(7871): 211-220, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34381231

RESUMO

Deciphering the principles and mechanisms by which gene activity orchestrates complex cellular arrangements in multicellular organisms has far-reaching implications for research in the life sciences. Recent technological advances in next-generation sequencing- and imaging-based approaches have established the power of spatial transcriptomics to measure expression levels of all or most genes systematically throughout tissue space, and have been adopted to generate biological insights in neuroscience, development and plant biology as well as to investigate a range of disease contexts, including cancer. Similar to datasets made possible by genomic sequencing and population health surveys, the large-scale atlases generated by this technology lend themselves to exploratory data analysis for hypothesis generation. Here we review spatial transcriptomic technologies and describe the repertoire of operations available for paths of analysis of the resulting data. Spatial transcriptomics can also be deployed for hypothesis testing using experimental designs that compare time points or conditions-including genetic or environmental perturbations. Finally, spatial transcriptomic data are naturally amenable to integration with other data modalities, providing an expandable framework for insight into tissue organization.


Assuntos
Perfilação da Expressão Gênica/métodos , Especificidade de Órgãos/genética , Transcriptoma , Animais , Análise de Dados , Doença/genética , Humanos , Transcrição Genética/genética
8.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445541

RESUMO

Mallotus japonicus is a valuable traditional medicinal plant in East Asia for applications as a gastrointestinal drug. However, the molecular components involved in the biosynthesis of bioactive metabolites have not yet been explored, primarily due to a lack of omics resources. In this study, we established metabolome and transcriptome resources for M. japonicus to capture the diverse metabolite constituents and active transcripts involved in its biosynthesis and regulation. A combination of untargeted metabolite profiling with data-dependent metabolite fragmentation and metabolite annotation through manual curation and feature-based molecular networking established an overall metabospace of M. japonicus represented by 2129 metabolite features. M. japonicus de novo transcriptome assembly showed 96.9% transcriptome completeness, representing 226,250 active transcripts across seven tissues. We identified specialized metabolites biosynthesis in a tissue-specific manner, with a strong correlation between transcripts expression and metabolite accumulations in M. japonicus. The correlation- and network-based integration of metabolome and transcriptome datasets identified candidate genes involved in the biosynthesis of key specialized metabolites of M. japonicus. We further used phylogenetic analysis to identify 13 C-glycosyltransferases and 11 methyltransferases coding candidate genes involved in the biosynthesis of medicinally important bergenin. This study provides comprehensive, high-quality multi-omics resources to further investigate biological properties of specialized metabolites biosynthesis in M. japonicus.


Assuntos
Regulação da Expressão Gênica de Plantas , Redes Reguladoras de Genes , Mallotus (Planta)/metabolismo , Metaboloma , Proteínas de Plantas/metabolismo , Transcriptoma , Perfilação da Expressão Gênica , Mallotus (Planta)/genética , Mallotus (Planta)/crescimento & desenvolvimento , Especificidade de Órgãos , Filogenia , Folhas de Planta/genética , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/metabolismo , Proteínas de Plantas/genética , Raízes de Plantas/genética , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo
9.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361776

RESUMO

In this study, we examined aqueous extracts of the edible mushrooms Pleurotus ostreatus (oyster mushroom) and Lentinula edodes (shiitake mushroom). Proteome analysis was conducted using LC-Triple TOF-MS and showed the expression of 753 proteins by Pleurotus ostreatus, and 432 proteins by Lentinula edodes. Bioactive peptides: Rab GDP dissociation inhibitor, superoxide dismutase, thioredoxin reductase, serine proteinase and lectin, were identified in both mushrooms. The extracts also included promising bioactive compounds including phenolics, flavonoids, vitamins and amino acids. The extracts showed promising antiviral activities, with a selectivity index (SI) of 4.5 for Pleurotus ostreatus against adenovirus (Ad7), and a slight activity for Lentinula edodes against herpes simplex-II (HSV-2). The extracts were not cytotoxic to normal human peripheral blood mononuclear cells (PBMCs). On the contrary, they showed moderate cytotoxicity against various cancer cell lines. Additionally, antioxidant activity was assessed using DPPH radical scavenging, ABTS radical cation scavenging and ORAC assays. The two extracts showed potential antioxidant activities, with the maximum activity seen for Pleurotus ostreatus (IC50 µg/mL) = 39.46 ± 1.27 for DPPH; 11.22 ± 1.81 for ABTS; and 21.40 ± 2.20 for ORAC assays. This study encourages the use of these mushrooms in medicine in the light of their low cytotoxicity on normal PBMCs vis à vis their antiviral, antitumor and antioxidant capabilities.


Assuntos
Antineoplásicos/química , Antioxidantes/química , Antivirais/química , Proteínas Fúngicas/química , Pleurotus/química , Proteoma/química , Cogumelos Shiitake/química , Aminoácidos/química , Aminoácidos/isolamento & purificação , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Antivirais/isolamento & purificação , Antivirais/farmacologia , Benzotiazóis/antagonistas & inibidores , Compostos de Bifenilo/antagonistas & inibidores , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Misturas Complexas/química , Flavonoides/química , Flavonoides/isolamento & purificação , Proteínas Fúngicas/classificação , Proteínas Fúngicas/isolamento & purificação , Humanos , Lectinas/química , Lectinas/isolamento & purificação , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Especificidade de Órgãos , Fenóis/química , Fenóis/isolamento & purificação , Picratos/antagonistas & inibidores , Pleurotus/metabolismo , Cultura Primária de Células , Proteoma/classificação , Proteoma/isolamento & purificação , Serina Proteases/química , Serina Proteases/isolamento & purificação , Cogumelos Shiitake/metabolismo , Ácidos Sulfônicos/antagonistas & inibidores , Superóxido Dismutase/química , Superóxido Dismutase/isolamento & purificação , Tiorredoxina Dissulfeto Redutase/química , Tiorredoxina Dissulfeto Redutase/isolamento & purificação , Vitaminas/química , Vitaminas/isolamento & purificação , Água/química
10.
Molecules ; 26(16)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34443678

RESUMO

Amyloidosis is a term referring to a group of various protein-misfolding diseases wherein normally soluble proteins form aggregates as insoluble amyloid fibrils. How, or whether, amyloid fibrils contribute to tissue damage in amyloidosis has been the topic of debate. In vitro studies have demonstrated the appearance of small globular oligomeric species during the incubation of amyloid beta peptide (Aß). Nerve biopsy specimens from patients with systemic amyloidosis have suggested that globular structures similar to Aß oligomers were generated from amorphous electron-dense materials and later developed into mature amyloid fibrils. Schwann cells adjacent to amyloid fibrils become atrophic and degenerative, suggesting that the direct tissue damage induced by amyloid fibrils plays an important role in systemic amyloidosis. In contrast, there is increasing evidence that oligomers, rather than amyloid fibrils, are responsible for cell death in neurodegenerative diseases, particularly Alzheimer's disease. Disease-modifying therapies based on the pathophysiology of amyloidosis have now become available. Aducanumab, a human monoclonal antibody against the aggregated form of Aß, was recently approved for Alzheimer's disease, and other monoclonal antibodies, including gantenerumab, solanezumab, and lecanemab, could also be up for approval. As many other agents for amyloidosis will be developed in the future, studies to develop sensitive clinical scales for identifying improvement and markers that can act as surrogates for clinical scales should be conducted.


Assuntos
Amiloide/metabolismo , Amiloidose/fisiopatologia , Amiloidose/terapia , Animais , Humanos , Especificidade de Órgãos , Agregados Proteicos , Células de Schwann/patologia
11.
FASEB J ; 35(9): e21834, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34403553

RESUMO

Two distinct genetic mutational pathways characterized by either chromosomal instability or high-frequency microsatellite instability (MSI-H) are recognized in the pathogenesis of colorectal cancer (CRC). Recently, it has been shown that patients with primary CRC that displays MSI-H have a significant, stage-independent, multivariate survival advantage. Biological properties of CMS1 (MSI-H type) can affect therapeutic efficiencies of agents used in the treatment of CRC, and therefore become a new predictive factor of the treatment. But, the predictive impact of MSI-H status for adjuvant chemotherapy remains controversial. This study will assess whether there is any unnecessary or inappropriate use of treatment agents recommended for adjuvant therapy of stage 2 and 3 of disease and for palliative or curative treatment of liver metastatic disease in microsatellite instability high group, a molecular subtype of colon cancer. Within this scope, the efficiencies of fluorouracil- and oxaliplatin-based chemotherapeutic agents will be shown on stage 3 microsatellite instability high colon tumor cell lines first, and then a microfluidic model will be created, imitating the metastasis of colon cancer to the liver. In the microfluidic chip model, we will create in liver tissue, where the metastasis of microsatellite instability high colon cancer will be simulated; the effectiveness of chemotherapeutic agents, immunotherapy agents, and targeted agents on tumor cells as well as drug response will be assessed according to cell viability through released biomarkers from the cells. The proposed hypothesis study includes the modeling and treatment of patient-derived post-metastatic liver cancer in microfluidics which has priority at the global and our region and consequently develop personal medication.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Dispositivos Lab-On-A-Chip , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Instabilidade de Microssatélites , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/genética , Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante , Neoplasias do Colo/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila/uso terapêutico , Humanos , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas/secundário , Modelos Biológicos , Metástase Neoplásica/patologia , Especificidade de Órgãos , Oxaliplatina/uso terapêutico
12.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360801

RESUMO

Senna and rhubarb are often used as routine laxatives, but there are differences in mechanism of action and potential side effects. Here, we studied metabolites of senna anthraquinones (SAQ), rhubarb anthraquinones (RAQ) and their chemical marker, sennoside A (SA), in a rat diarrhea model. In in vitro biotransformation experiments, SAQ, RAQ and SA were incubated with rat fecal flora solution and the metabolites produced were analyzed using HPLC. In in vivo studies, the same compounds were investigated for purgation induction, with measurement of histopathology and Aqps gene expression in six organs. The results indicated that SAQ and RAQ had similar principal constituents but could be degraded into different metabolites. A similar profile of Aqps down-regulation for all compounds was seen in the colon, suggesting a similar mechanism of action for purgation. However, in the kidneys and livers of the diarrhea-rats, down-regulation of Aqps was found in the RAQ-rats whereas up-regulation of Aqps was seen in the SAQ-rats. Furthermore, the RAQ-rats showed lower Aqp2 protein expression in the kidneys, whilst the SA-rats and SAQ-rats had higher Aqp2 protein expression in the kidneys. This may have implications for side effects of SAQ or RAQ in patients with chronic kidney or liver diseases.


Assuntos
Aquaporina 2/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/metabolismo , Fígado/metabolismo , Rheum/química , Senna (Planta)/química , Senosídeos/farmacologia , Animais , Masculino , Especificidade de Órgãos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Senosídeos/química
13.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208371

RESUMO

Metformin (MTF) is the first-line therapy for type 2 diabetes (T2DM). The euglycemic effect of MTF is due to the inhibition of hepatic glucose production. Literature reports that the principal molecular mechanism of MTF is the activation of 5'-AMP-activated protein kinase (AMPK) due to the decrement of ATP intracellular content consequent to the inhibition of Complex I, although this effect is obtained only at millimolar concentrations. Conversely, micromolar MTF seems to activate the mitochondrial electron transport chain, increasing ATP production and limiting oxidative stress. This evidence sustains the idea that MTF exerts a hormetic effect based on its concentration in the target tissue. Therefore, in this review we describe the effects of MTF on T2DM on the principal target organs, such as liver, gut, adipose tissue, endothelium, heart, and skeletal muscle. In particular, data indicate that all organs, except the gut, accumulate MTF in the micromolar range when administered in therapeutic doses, unmasking molecular mechanisms that do not depend on Complex I inhibition.


Assuntos
Hormese/efeitos dos fármacos , Metformina/farmacologia , Animais , Humanos , Modelos Biológicos , Especificidade de Órgãos/efeitos dos fármacos
14.
Nat Commun ; 12(1): 4407, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315870

RESUMO

Alcohol Use Disorder (AUD) affects a large portion of the population. Unfortunately, efficacious medications to treat the disease are limited. Studies in rodents suggest that mTORC1 plays a crucial role in mechanisms underlying phenotypes such as heavy alcohol intake, habit, and relapse. Thus, mTORC1 inhibitors, which are used in the clinic, are promising therapeutic agents to treat AUD. However, chronic inhibition of mTORC1 in the periphery produces undesirable side effects, which limit their potential use for the treatment of AUD. To overcome these limitations, we designed a binary drug strategy in which male mice were treated with the mTORC1 inhibitor RapaLink-1 together with a small molecule (RapaBlock) to protect mTORC1 activity in the periphery. We show that whereas RapaLink-1 administration blocked mTORC1 activation in the liver, RapaBlock abolished the inhibitory action of Rapalink-1. RapaBlock also prevented the adverse side effects produced by chronic inhibition of mTORC1. Importantly, co-administration of RapaLink-1 and RapaBlock inhibited alcohol-dependent mTORC1 activation in the nucleus accumbens and attenuated alcohol seeking and drinking.


Assuntos
Consumo de Bebidas Alcoólicas/patologia , Encéfalo/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Animais , Intolerância à Glucose/complicações , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Endogâmicos C57BL , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Especificidade de Órgãos , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Perda de Peso/efeitos dos fármacos
15.
Methods Mol Biol ; 2350: 95-104, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34331281

RESUMO

In multicellular organisms, most physiological and pathological processes involve an interplay between various cells and molecules that act both locally and systemically. To understand how these complex and dynamic processes occur in time and space, imaging techniques are key. Advances in tissue processing techniques and microscopy now allow us to probe these processes at a large scale and at the same time at a level of detail previously unachievable. Indeed, it is now possible to reliably quantify multiple protein expression levels at single-cell resolution in whole organs using three-dimensional fluorescence imaging techniques. Here we describe a method to prepare adult mouse bone tissue for multiplexed confocal imaging of thick tissue sections. Up to eight different fluorophores can be multiplexed using this technique and spectrally resolved using standard confocal microscopy. The optical clearing method described allows detection of these fluorophores up to a depth of >700 µm in the far-red. Although the method was initially developed for bone tissue imaging, we have successfully applied it to several other tissue types.


Assuntos
Imunofluorescência/métodos , Imageamento Tridimensional/métodos , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Animais , Medula Óssea , Osso e Ossos , Camundongos , Especificidade de Órgãos
16.
Sci Rep ; 11(1): 13971, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234167

RESUMO

To unravel the source of SARS-CoV-2 introduction and the pattern of its spreading and evolution in the United Arab Emirates, we conducted meta-transcriptome sequencing of 1067 nasopharyngeal swab samples collected between May 9th and Jun 29th, 2020 during the first peak of the local COVID-19 epidemic. We identified global clade distribution and eleven novel genetic variants that were almost absent in the rest of the world and that defined five subclades specific to the UAE viral population. Cross-settlement human-to-human transmission was related to the local business activity. Perhaps surprisingly, at least 5% of the population were co-infected by SARS-CoV-2 of multiple clades within the same host. We also discovered an enrichment of cytosine-to-uracil mutation among the viral population collected from the nasopharynx, that is different from the adenosine-to-inosine change previously reported in the bronchoalveolar lavage fluid samples and a previously unidentified upregulation of APOBEC4 expression in nasopharynx among infected patients, indicating the innate immune host response mediated by ADAR and APOBEC gene families could be tissue-specific. The genomic epidemiological and molecular biological knowledge reported here provides new insights for the SARS-CoV-2 evolution and transmission and points out future direction on host-pathogen interaction investigation.


Assuntos
COVID-19/epidemiologia , COVID-19/imunologia , Coinfecção/epidemiologia , Genômica , Imunidade Inata , Mutação , SARS-CoV-2/genética , Adulto , COVID-19/transmissão , Citidina Desaminase/genética , Feminino , Perfilação da Expressão Gênica , Genoma Viral/genética , Humanos , Masculino , Pessoa de Meia-Idade , Nasofaringe/virologia , Especificidade de Órgãos , SARS-CoV-2/imunologia
17.
Molecules ; 26(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34198975

RESUMO

The past decade has seen growing interest in marine natural pigments for biotechnological applications. One of the most abundant classes of biological pigments is the tetrapyrroles, which are prized targets due their photodynamic properties; porphyrins are the best known examples of this group. Many animal porphyrinoids and other tetrapyrroles are produced through heme metabolic pathways, the best known of which are the bile pigments biliverdin and bilirubin. Eulalia is a marine Polychaeta characterized by its bright green coloration resulting from a remarkably wide range of greenish and yellowish tetrapyrroles, some of which have promising photodynamic properties. The present study combined metabolomics based on HPLC-DAD with RNA-seq transcriptomics to investigate the molecular pathways of porphyrinoid metabolism by comparing the worm's proboscis and epidermis, which display distinct pigmentation patterns. The results showed that pigments are endogenous and seemingly heme-derived. The worm possesses homologs in both organs for genes encoding enzymes involved in heme metabolism such as ALAD, FECH, UROS, and PPOX. However, the findings also indicate that variants of the canonical enzymes of the heme biosynthesis pathway can be species- and organ-specific. These differences between molecular networks contribute to explain not only the differential pigmentation patterns between organs, but also the worm's variety of novel endogenous tetrapyrrolic compounds.


Assuntos
Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Metabolômica/métodos , Poliquetos/genética , Tetrapirróis/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Epiderme/metabolismo , Redes e Vias Metabólicas , Especificidade de Órgãos , Fármacos Fotossensibilizantes/metabolismo , Poliquetos/metabolismo , Análise de Sequência de RNA , Especificidade da Espécie , Tetrapirróis/genética
18.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199411

RESUMO

The human testis and epididymis play critical roles in male fertility, including the spermatogenesis process, sperm storage, and maturation. However, the unique functions of the two organs had not been systematically studied. Herein, we provide a systematic and comprehensive multi-omics study between testis and epididymis. RNA-Seq profiling detected and quantified 19,653 in the testis and 18,407 in the epididymis. Proteomic profiling resulted in the identification of a total of 11,024 and 10,386 proteins in the testis and epididymis, respectively, including 110 proteins that previously have been classified as MPs (missing proteins). Furthermore, Five MPs expressed in testis were validated by the MRM method. Subsequently, multi-omcis between testis and epididymis were performed, including biological functions and pathways of DEGs (Differentially Expressed Genes) in each group, revealing that those differences were related to spermatogenesis, male gamete generation, as well as reproduction. In conclusion, this study can help us find the expression regularity of missing protein and help related scientists understand the physiological functions of testis and epididymis more deeply.


Assuntos
Epididimo/química , Perfilação da Expressão Gênica/métodos , Mapas de Interação de Proteínas , Proteômica/métodos , Testículo/química , Cromatografia Líquida , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação , Especificidade de Órgãos , Análise de Sequência de RNA , Espermatogênese , Espectrometria de Massas em Tandem
19.
Nutrients ; 13(7)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209243

RESUMO

Many studies have shown the beneficial effects of calorie restriction (CR) on rodents' aging; however, the molecular mechanism explaining these beneficial effects is still not fully understood. Previously, we conducted transcriptomic analysis on rat liver with short-term and mild-to-moderate CR to elucidate its early response to such diet. Here, we expanded transcriptome analysis to muscle, adipose tissue, intestine, and brain and compared the gene expression profiles of these multiple organs and of our previous dataset. Several altered gene expressions were found, some of which known to be related to CR. Notably, the commonly regulated genes by CR include nicotinamide phosphoribosyltransferase and heat shock protein 90, which are involved in declining the aging process and thus potential therapeutic targets for aging-related diseases. The data obtained here provide information on early response markers and key mediators of the CR-induced delay in aging as well as on age-associated pathological changes in mammals.


Assuntos
Restrição Calórica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Especificidade de Órgãos/genética , Animais , Regulação para Baixo/genética , Masculino , Metanálise como Assunto , Ratos Wistar , Regulação para Cima/genética
20.
Nutrients ; 13(6)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200366

RESUMO

Chronic alcohol-use disorder has been imputed as a possible cause of dietary magnesium depletion. The purpose of this study was to assess the prevalence of hypomagnesemia in chronic alcohol-use disorder, and to provide information on intracellular magnesium and on its renal handling. We carried out a structured literature search up to November 2020, which returned 2719 potentially relevant records. After excluding non-significant records, 25 were retained for the final analysis. The meta-analysis disclosed that both total and ionized circulating magnesium are markedly reduced in chronic alcohol-use disorder. The funnel plot and the Egger's test did not disclose significant publication bias. The I2-test demonstrated significant statistical heterogeneity between studies. We also found that the skeletal muscle magnesium content is reduced and the kidney's normal response to hypomagnesemia is blunted. In conclusion, magnesium depletion is common in chronic alcohol-use disorder. Furthermore, the kidney plays a crucial role in the development of magnesium depletion.


Assuntos
Alcoolismo/metabolismo , Magnésio/metabolismo , Alcoolismo/sangue , Doença Crônica , Espaço Extracelular/metabolismo , Humanos , Espaço Intracelular/metabolismo , Íons , Magnésio/sangue , Especificidade de Órgãos , Viés de Publicação
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...