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1.
Mater Sci Eng C Mater Biol Appl ; 128: 112258, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474818

RESUMO

A novel polyelectrolyte nanocarrier was synthesized via layer-by-layer self-assembly of polycationic and polyanionic chains. The nanocarrier is composed of polyglutamate grafted chitosan core, dextran sulfate as a complexing agent, and polyethyleneimine shell decorated with folic acid. This polyelectrolyte complex has unique physicochemical properties so that the core is considered as an efficient carrier for LTX-315 and melittin peptides, and the shell is suitable for delivery of miR-34a. The spherical nanocarriers with an average size of 123 ± 5 nm and a zeta potential of -36 ± 1 mV demonstrated controlled-release of gene and peptides ensured a synergistic effect in establishing multiple cell death pathways on chemoresistance human breast adenocarcinoma cell line, MDA-MB-231. In vitro cell viability assays also revealed no cytotoxicity for the nanocarriers, and an IC50 of 15 µg/mL and 150 µg/mL for melittin and LTX-315, respectively, after 48 h, whereas co-delivery of melittin with miR-34a increased smart death induction by 54%.


Assuntos
Neoplasias da Mama , Quitosana , MicroRNAs/administração & dosagem , Nanopartículas , Neoplasias da Mama/tratamento farmacológico , Morte Celular , Linhagem Celular Tumoral , Feminino , Humanos , Meliteno/farmacologia , MicroRNAs/genética , Oligopeptídeos , Polieletrólitos
2.
Nat Commun ; 12(1): 5217, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471116

RESUMO

Lethal hit delivery by cytotoxic T lymphocytes (CTL) towards B lymphoma cells occurs as a binary, "yes/no" process. In non-hematologic solid tumors, however, CTL often fail to kill target cells during 1:1 conjugation. Here we describe a mechanism of "additive cytotoxicity" by which time-dependent integration of sublethal damage events, delivered by multiple CTL transiting between individual tumor cells, mediates effective elimination. Reversible sublethal damage includes perforin-dependent membrane pore formation, nuclear envelope rupture and DNA damage. Statistical modeling reveals that 3 serial hits delivered with decay intervals below 50 min discriminate between tumor cell death or survival after recovery. In live melanoma lesions in vivo, sublethal multi-hit delivery is most effective in interstitial tissue where high CTL densities and swarming support frequent serial CTL-tumor cell encounters. This identifies CTL-mediated cytotoxicity by multi-hit delivery as an incremental and tunable process, whereby accelerating damage magnitude and frequency may improve immune efficacy.


Assuntos
Citotoxicidade Imunológica , Melanoma/terapia , Perforina/metabolismo , Linfócitos T Citotóxicos/imunologia , Animais , Apoptose/imunologia , Morte Celular , Linhagem Celular Tumoral , Dano ao DNA , Feminino , Humanos , Cinética , Células MCF-7 , Masculino , Camundongos Endogâmicos C57BL , Perforina/genética
3.
Nat Commun ; 12(1): 5214, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471131

RESUMO

Dyslipidemia and resulting lipotoxicity are pathologic signatures of metabolic syndrome and type 2 diabetes. Excess lipid causes cell dysfunction and induces cell death through pleiotropic mechanisms that link to oxidative stress. However, pathways that regulate the response to metabolic stress are not well understood. Herein, we show that disruption of the box H/ACA SNORA73 small nucleolar RNAs encoded within the small nucleolar RNA hosting gene 3 (Snhg3) causes resistance to lipid-induced cell death and general oxidative stress in cultured cells. This protection from metabolic stress is associated with broad reprogramming of oxidative metabolism that is dependent on the mammalian target of rapamycin signaling axis. Furthermore, we show that knockdown of SNORA73 in vivo protects against hepatic steatosis and lipid-induced oxidative stress and inflammation. Our findings demonstrate a role for SNORA73 in the regulation of metabolism and lipotoxicity.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Substâncias Protetoras/farmacologia , RNA Nucleolar Pequeno/metabolismo , Animais , Células CHO , Morte Celular/efeitos dos fármacos , Cricetulus , Diabetes Mellitus Tipo 2/metabolismo , Fígado Gorduroso/genética , Homeostase , Inflamação , Metabolismo dos Lipídeos , Lipídeos/farmacologia , Masculino , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , RNA Longo não Codificante , RNA Nucleolar Pequeno/genética , Transdução de Sinais/efeitos dos fármacos
4.
Molecules ; 26(16)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34443670

RESUMO

Enterococci and methicillin-resistant S. aureus (MRSA) are among the menacing bacterial pathogens. Novel antibiotics are urgently needed to tackle these antibiotic-resistant bacterial infections. This article reports the design, synthesis, and antimicrobial studies of 30 novel pyrazole derivatives. Most of the synthesized compounds are potent growth inhibitors of planktonic Gram-positive bacteria with minimum inhibitory concertation (MIC) values as low as 0.25 µg/mL. Further studies led to the discovery of several lead compounds, which are bactericidal and potent against MRSA persisters. Compounds 11, 28, and 29 are potent against S. aureus biofilms with minimum biofilm eradication concentration (MBEC) values as low as 1 µg/mL.


Assuntos
Bactérias/crescimento & desenvolvimento , Farmacorresistência Bacteriana/efeitos dos fármacos , Inibidores do Crescimento/síntese química , Inibidores do Crescimento/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Bactérias/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/fisiologia , Inibidores do Crescimento/química , Células HEK293 , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/fisiologia , Testes de Sensibilidade Microbiana , Pirazóis/química
5.
Molecules ; 26(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34443682

RESUMO

Atherosclerosis is the main cause of cardiovascular diseases which in turn, lead to the highest number of mortalities globally. This pathophysiological condition is developed due to a constant elevated level of plasma cholesterols. Statin is currently the widely used treatment in reducing the level of cholesterols, however, it may cause adverse side effects. Therefore, there is an urgent need to search for new alternative treatment. PCSK9 is an enzyme responsible in directing LDL-receptor (LDL-R)/LDL-cholesterols (LDL-C) complex to lysosomal degradation, preventing the receptor from recycling back to the surface of liver cells. Therefore, PCSK9 offers a potential target to search for small molecule inhibitors which inhibit the function of this enzyme. In this study, a marine invertebrate Acanthaster planci, was used to investigate its potential in inhibiting PCSK9 and lowering the levels of cholesterols. Cytotoxicity activity of A. planci on human liver HepG2 cells was carried out using the MTS assay. It was found that methanolic extract and fractions did not exhibit cytotoxicity effect on HepG2 cell line with IC50 values of more than 30 µg/mL. A compound deoxythymidine also did not exert any cytotoxicity activity with IC50 value of more than 4 µg/mL. Transient transfection and luciferase assay were conducted to determine the effects of A. planci on the transcriptional activity of PCSK9 promoter. Methanolic extract and Fraction 2 (EF2) produced the lowest reduction in PCSK9 promoter activity to 70 and 20% of control at 12.5 and 6.25 µg/mL, respectively. In addition, deoxythymidine also decreased PCSK9 promoter activity to the lowest level of 60% control at 3.13 µM. An in vivo study using Sprague Dawley rats demonstrated that 50 and 100 mg/kg of A. planci methanolic extract reduced the total cholesterols and LDL-C levels to almost similar levels of untreated controls. The level of serum glutamate oxalate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) showed that the administration of the extract did not produce any toxicity effect and cause any damage to rat liver. The results strongly indicate that A. planci produced a significant inhibitory activity on PCSK9 gene expression in HepG2 cells which may be responsible for inducing the uptake of cholesterols by liver, thus, reducing the circulating levels of total cholesterols and LDL-C. Interestingly, A. planci also did show any adverse hepato-cytotoxicity and toxic effects on liver. Thus, this study strongly suggests that A. planci has a vast potential to be further developed as a new class of therapeutic agent in lowering the blood cholesterols and reducing the progression of atherosclerosis.


Assuntos
Colesterol/sangue , Pró-Proteína Convertase 9/antagonistas & inibidores , Estrelas-do-Mar/química , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Morte Celular , Proliferação de Células , LDL-Colesterol/sangue , Células Hep G2 , Humanos , Luciferases/metabolismo , Masculino , Metanol , Regiões Promotoras Genéticas/genética , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Ratos Sprague-Dawley , Timidina/farmacologia , Triglicerídeos/sangue
6.
Nano Lett ; 21(16): 6998-7004, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34339204

RESUMO

Solar-driven reactive oxygen species (ROS) generation is an attractive disinfection technique for cell death and water purification. However, most photocatalysts require high stability in the water environment and the production of ROS with a sufficient amount and diffusion length to damage pathogens. Here, a ROS generation system was developed consisting of tapered crystalline silicon microwires coated with anatase titanium dioxide for a conformal junction. The system effectively absorbed >95% of sunlight over 300-1100 nm, resulting in effective ROS generation. The system was designed to produce various ROS species, but a logistic regression analysis with cellular survival data revealed that the diffusion length of the ROS is ∼9 µm, implying that the most dominant species causing cell damage is H2O2. Surprisingly, a quantitative analysis showed that only 15 min of light irradiation on the system would catalyze a local bactericidal effect comparable to the conventional germicidal level of H2O2 (∼3 mM).


Assuntos
Peróxido de Hidrogênio , Luz Solar , Morte Celular , Espécies Reativas de Oxigênio , Titânio
7.
FASEB J ; 35(9): e21795, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34403508

RESUMO

Intervertebral disc degeneration is an irreversible process associated with accumulation of senescent nucleus pulposus (NP) cells. This study investigates the hypothesis that Tumor necrosis factor-α (TNF-α)-treated senescent NP cells propagate senescence of neighboring healthy cells via a paracrine effect that involves p-Stat3 signaling and the cytokine interleukin-6 (IL-6). NP cells isolated from bovine caudal intervertebral disc (IVD) were treated with TNF-α to induce senescence which was confirmed by demonstrating upregulation of senescence-associated ß-galactosidase and p16. This was correlated with downregulation of NP-associated markers, Aggrecan, Col2A1, and Sox9. Direct contact and non-contact co-culture of healthy and senescent cells showed that TNF-α-treated cells increased the senescence in healthy cells via a paracrine effect. The senescent cells have a secretory phenotype as indicated by increased gene and protein levels of IL-6. Phosphorylated Signal Transducer and Activator of Transcription 3 (pStat3) levels were also high in treated cells and appeared to upregulate IL-6 as inhibition of Stat3 phosphorylation by StatticV downregulated IL-6 mRNA expression in cells and protein levels in the culture media. All trans retinoic acid, an IL-6 inhibitor, also decreased the secretion of IL-6 and reduced the paracrine effect of senescent cells on healthy cells. Decreased pStat3 levels and inhibition of IL-6 secretion did not fully restore NP gene expression of Col2A1 but importantly, appeared to cause senescent cells to undergo apoptosis and cell death. This study demonstrated the paracrine effect of senescent NP cells which involves Stat3 and IL-6 and may explain why senescent NP cells accumulate in IVD with age. The role of pSTAT3 and IL-6 in mediating NP senescence requires further study as it may be a novel strategy for modulating the senescent-inducing effects of TNF-α.


Assuntos
Senescência Celular/efeitos dos fármacos , Núcleo Pulposo/citologia , Núcleo Pulposo/efeitos dos fármacos , Comunicação Parácrina/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Animais , Apoptose/efeitos dos fármacos , Bovinos , Morte Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Núcleo Pulposo/metabolismo , Fosforilação , Fator de Transcrição STAT3/metabolismo
8.
Nat Commun ; 12(1): 4856, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381034

RESUMO

Totipotent cells have the ability to generate embryonic and extra-embryonic tissues. Interestingly, a rare population of cells with totipotent-like potential, known as 2 cell (2C)-like cells, has been identified within ESC cultures. They arise from ESC and display similar features to those found in the 2C embryo. However, the molecular determinants of 2C-like conversion have not been completely elucidated. Here, we show that the CCCTC-binding factor (CTCF) is a barrier for 2C-like reprogramming. Indeed, forced conversion to a 2C-like state by the transcription factor DUX is associated with DNA damage at a subset of CTCF binding sites. Depletion of CTCF in ESC efficiently promotes spontaneous and asynchronous conversion to a 2C-like state and is reversible upon restoration of CTCF levels. This phenotypic reprogramming is specific to pluripotent cells as neural progenitor cells do not show 2C-like conversion upon CTCF-depletion. Furthermore, we show that transcriptional activation of the ZSCAN4 cluster is necessary for successful 2C-like reprogramming. In summary, we reveal an unexpected relationship between CTCF and 2C-like reprogramming.


Assuntos
Fator de Ligação a CCCTC/metabolismo , Reprogramação Celular , Células-Tronco Totipotentes/citologia , Animais , Sítios de Ligação , Fator de Ligação a CCCTC/genética , Morte Celular , Dano ao DNA , Embrião de Mamíferos , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Camundongos , Células-Tronco Totipotentes/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
9.
Adv Exp Med Biol ; 1301: 1-5, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34370284

RESUMO

Ferroptosis is a newly discovered form of cell death that is rapidly becoming associated to a variety of diseases and explaining their pathological mechanisms. This book addresses new emerging topics in the field of ferroptosis, with special attention to diseases more recently explained through ferroptotic mechanisms, including infectious diseases and neurodegeneration. In this chapter, we will provide the readers with an introduction to the concepts and pathways involved in ferroptosis to further move into a more detailed exposition of the topics advertised in this book. In special, we aim for this book to broaden the perspectives on how ferroptosis is regulated and connected to human diseases and motivate new studies in this emerging field.


Assuntos
Ferroptose , Morte Celular , Humanos
10.
Adv Exp Med Biol ; 1301: 7-24, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34370285

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers with a dismal 5-year survival rate of 5% and very limited efficacy of the current therapeutic regimens. The lethality of PDAC stems from asymptomatic early stage of the disease, its propensity to rapidly disseminate, as well as unusual, dense and highly active surrounding stroma. Fortunately, promising literature data suggests that exploiting newly contextualized type of cell death, termed "ferroptosis", has great potential for overcoming the major problems regarding PDAC treatment. A major player in this type of cell death is Glutamate/Cystine antiporter - xCT, which is responsible for the uptake of oxidized form of cysteine, and thus maintenance of intracellular amino acid and redox homeostasis. xCT seems to fulfill all requirements of the solid and specific molecular target for ferroptosis-based anti-cancer therapy. In this chapter we summarized mounting literature data supporting this hypothesis, but also, we pointed out some of the underexamined aspects of xCT-dependent (patho)physiology of the cancer cell, which have to be addressed in future studies. The abstract could be used as "informative abstract" for the online version.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/tratamento farmacológico , Morte Celular , Cistina/metabolismo , Humanos , Oxirredução , Neoplasias Pancreáticas/tratamento farmacológico
11.
Adv Exp Med Biol ; 1301: 59-79, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34370288

RESUMO

Ferroptosis is a distinct form regulated necrotic cell death mainly characterized by the accumulation of toxic lipid peroxides. The importance of this form of cell death has been recognized in several diseases. An imbalance between free radicals and antioxidant molecules has been reported to play role in several pathologies and is commonly associated with worse outcomes of these maladies. Emerging evidence suggests that ferroptosis and/or its regulators may modulate other forms of cell death leading to the induction of necro-inflammatory response and consequently organ failure. Herein, we review the major forms of necrotic cell death triggered by pathogens highlighting mechanisms in which oxidative stress and cellular antioxidants may limit or favor pathogen dissemination defining host cell fate. Specially, we discuss the role of ferroptosis and how its molecular components may modulate disease progression.


Assuntos
Doenças Transmissíveis , Ferroptose , Antioxidantes , Morte Celular , Humanos , Peroxidação de Lipídeos
12.
Adv Exp Med Biol ; 1301: 123-138, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34370290

RESUMO

The past decades witnessed the discovery of novel modes of cell death, such as ferroptosis, pyroptosis and necroptosis, all of them presenting common necrotic traits. In this chapter, we revisit the early discoveries that unveiled necroptosis as a distinct cell death mechanism. We describe necroptosis, its main regulators and their role in maintaining cellular homeostasis and in the disease state. We conclude by discussing its phenotypic similarities with ferroptosis and the possible crosstalk between these pathways.


Assuntos
Necroptose , Proteína Serina-Treonina Quinases de Interação com Receptores , Apoptose , Caspases/genética , Morte Celular , Humanos , Proteína Serina-Treonina Quinases de Interação com Receptores/genética
13.
Adv Exp Med Biol ; 1301: 81-121, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34370289

RESUMO

Ferroptosis is a dedicated mode of cell death involving iron, reactive oxygen species and lipid peroxidation. Involved in processes such as glutathione metabolism, lysosomal iron retention or interference with lipid metabolism, leading either to activation or inhibition of ferroptosis. Given the implications of ferroptosis in diseases such as cancer, aging, Alzheimer and infectious diseases, new molecular mechanisms underlying ferroptosis and small molecules regulators that target those mechanisms have prompted a great deal of interest. Here, we discuss the current scenario of small molecules modulating ferroptosis and critically assess what is known about their mechanisms of action.


Assuntos
Ferroptose , Morte Celular , Humanos , Ferro , Peroxidação de Lipídeos , Espécies Reativas de Oxigênio
14.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361745

RESUMO

The edible parts of the plants Camellia sinensis, Vitis vinifera and Withania somnifera were extensively used in ancient practices such as Ayurveda, owing to their potent biomedical significance. They are very rich in secondary metabolites such as polyphenols, which are very good antioxidants and exhibit anti-carcinogenic properties. This study aims to evaluate the anti-cancerous properties of these plant crude extracts on human liver cancer HepG2 cells. The leaves of Camellia sinensis, Withania somnifera and the seeds of Vitis vinifera were collected and methanolic extracts were prepared. Then, these extracts were subjected to DPPH, α- amylase assays to determine the antioxidant properties. A MTT assay was performed to investigate the viability of the extracts of HepG2 cells, and the mode of cell death was detected by Ao/EtBr staining and flow cytometry with PI Annexin- V FITC dual staining. Then, the protein expression of BAX and BCl2 was studied using fluorescent dye to determine the regulation of the BAX and BCl2 genes. We observed that all the three extracts showed the presence of bioactive compounds such as polyphenols or phytochemicals. The W. somnifera bioactive compounds were found to have the highest anti-proliferative activity on human liver cancer cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Camellia sinensis/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Vitis/química , Withania/química , Alcaloides/química , Alcaloides/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antioxidantes/química , Antioxidantes/isolamento & purificação , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/química , Morte Celular/efeitos dos fármacos , Flavonoides/química , Flavonoides/isolamento & purificação , Células Hep G2 , Humanos , Picratos/antagonistas & inibidores , Picratos/química , Extratos Vegetais/química , Folhas de Planta/química , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sementes/química , Transdução de Sinais , Taninos/química , Taninos/isolamento & purificação , Terpenos/química , Terpenos/isolamento & purificação , alfa-Amilases/genética , alfa-Amilases/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
15.
Artigo em Inglês | MEDLINE | ID: mdl-34444449

RESUMO

Ethanol consumption remains a major concern at a world scale in terms of transient or irreversible neurological consequences, with motor, cognitive, or social consequences. Cerebellum is particularly vulnerable to ethanol, both during development and at the adult stage. In adults, chronic alcoholism elicits, in particular, cerebellar vermis atrophy, the anterior lobe of the cerebellum being highly vulnerable. Alcohol-dependent patients develop gait ataxia and lower limb postural tremor. Prenatal exposure to ethanol causes fetal alcohol spectrum disorder (FASD), characterized by permanent congenital disabilities in both motor and cognitive domains, including deficits in general intelligence, attention, executive function, language, memory, visual perception, and communication/social skills. Children with FASD show volume deficits in the anterior lobules related to sensorimotor functions (Lobules I, II, IV, V, and VI), and lobules related to cognitive functions (Crus II and Lobule VIIB). Various mechanisms underlie ethanol-induced cell death, with oxidative stress and endoplasmic reticulum (ER) stress being the main pro-apoptotic mechanisms in alcohol abuse and FASD. Oxidative and ER stresses are induced by thiamine deficiency, especially in alcohol abuse, and are exacerbated by neuroinflammation, particularly in fetal ethanol exposure. Furthermore, exposure to ethanol during the prenatal period interferes with neurotransmission, neurotrophic factors and retinoic acid-mediated signaling, and reduces the number of microglia, which diminishes expected cerebellar development. We highlight the spectrum of cerebellar damage induced by ethanol, emphasizing physiological-based clinical profiles and biological mechanisms leading to cell death and disorganized development.


Assuntos
Ataxia Cerebelar , Transtornos do Espectro Alcoólico Fetal , Morte Celular , Cerebelo , Etanol/toxicidade , Feminino , Humanos , Gravidez
16.
Cell Rep ; 36(8): 109614, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34433041

RESUMO

Zoonotic pathogens, such as COVID-19, reside in animal hosts before jumping species to infect humans. The Carnivora, like mink, carry many zoonoses, yet how diversity in host immune genes across species affect pathogen carriage is poorly understood. Here, we describe a progressive evolutionary downregulation of pathogen-sensing inflammasome pathways in Carnivora. This includes the loss of nucleotide-oligomerization domain leucine-rich repeat receptors (NLRs), acquisition of a unique caspase-1/-4 effector fusion protein that processes gasdermin D pore formation without inducing rapid lytic cell death, and the formation of a caspase-8 containing inflammasome that inefficiently processes interleukin-1ß. Inflammasomes regulate gut immunity, but the carnivorous diet has antimicrobial properties that could compensate for the loss of these immune pathways. We speculate that the consequences of systemic inflammasome downregulation, however, can impair host sensing of specific pathogens such that they can reside undetected in the Carnivora.


Assuntos
Carnívoros/metabolismo , Evolução Molecular , Inflamassomos/metabolismo , Zoonoses/patologia , Animais , Caspase 1/genética , Caspase 1/metabolismo , Caspase 8/metabolismo , Caspases Iniciadoras/genética , Caspases Iniciadoras/metabolismo , Morte Celular , Linhagem Celular , Humanos , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas NLR/genética , Proteínas NLR/metabolismo , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Salmonella typhi/patogenicidade , Zoonoses/imunologia , Zoonoses/parasitologia
17.
Viruses ; 13(8)2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34452468

RESUMO

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), a global pandemic characterized by an exaggerated immune response and respiratory illness. Age (>60 years) is a significant risk factor for developing severe COVID-19. To better understand the host response of the aged airway epithelium to SARS-CoV-2 infection, we performed an in vitro study using primary human bronchial epithelial cells from donors >67 years of age differentiated on an air-liquid interface culture. We demonstrate that SARS-CoV-2 infection leads to early induction of a proinflammatory response and a delayed interferon response. In addition, we observed changes in the genes and pathways associated with cell death and senescence throughout infection. In summary, our study provides new and important insights into the temporal kinetics of the airway epithelial innate immune response to SARS-CoV-2 in older individuals.


Assuntos
Brônquios/imunologia , Brônquios/virologia , Imunidade Inata , Mucosa Respiratória/imunologia , Mucosa Respiratória/virologia , SARS-CoV-2/imunologia , Idoso , Envelhecimento/imunologia , Brônquios/citologia , Brônquios/metabolismo , COVID-19/imunologia , Morte Celular/genética , Células Cultivadas , Senescência Celular/genética , Citocinas/biossíntese , Citocinas/genética , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Feminino , Humanos , Inflamação , Interferons/biossíntese , Interferons/genética , Masculino , RNA-Seq , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo , SARS-CoV-2/fisiologia , Transdução de Sinais/genética
18.
Viruses ; 13(8)2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34452499

RESUMO

The pre-clinical development of antiviral agents involves experimental trials in animals and ferrets as an animal model for the study of SARS-CoV-2. Here, we used mathematical models and experimental data to characterize the within-host infection dynamics of SARS-CoV-2 in ferrets. We also performed a global sensitivity analysis of model parameters impacting the characteristics of the viral infection. We provide estimates of the viral dynamic parameters in ferrets, such as the infection rate, the virus production rate, the infectious virus proportion, the infected cell death rate, the virus clearance rate, as well as other related characteristics, including the basic reproduction number, pre-peak infectious viral growth rate, post-peak infectious viral decay rate, pre-peak infectious viral doubling time, post-peak infectious virus half-life, and the target cell loss in the respiratory tract. These parameters and indices are not significantly different between animals infected with viral strains isolated from the environment and isolated from human hosts, indicating a potential for transmission from fomites. While the infection period in ferrets is relatively short, the similarity observed between our results and previous results in humans supports that ferrets can be an appropriate animal model for SARS-CoV-2 dynamics-related studies, and our estimates provide helpful information for such studies.


Assuntos
COVID-19/virologia , Modelos Animais de Doenças , Furões , SARS-CoV-2/fisiologia , Animais , Número Básico de Reprodução , COVID-19/imunologia , COVID-19/patologia , COVID-19/transmissão , Morte Celular , Humanos , Imunidade Inata , Modelos Biológicos , Sistema Respiratório/patologia , Sistema Respiratório/virologia , SARS-CoV-2/imunologia , Sensibilidade e Especificidade , Carga Viral , Eliminação de Partículas Virais
19.
Chem Pharm Bull (Tokyo) ; 69(8): 760-767, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34334519

RESUMO

Daldinins are a novel type of naturally occurring tricyclic heterocycles isolated from Daldinia concentrica. In this study, four daldinin A derivatives with different alkyl side chains were synthesized using the same synthetic protocol. Bioactivity tests first indicated that the daldinin A derivatives showed significant protection for endothelial cells against damage caused by high glucose. The derivative compound with three carbon atoms on the alkyl side exhibited the best effect.


Assuntos
Descoberta de Drogas , Células Endoteliais/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Hiperglicemia/tratamento farmacológico , Ascomicetos/química , Morte Celular/efeitos dos fármacos , Células Endoteliais/metabolismo , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Hiperglicemia/metabolismo , Estrutura Molecular
20.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443427

RESUMO

Pterostilbene, a natural metabolite of resveratrol, has been indicated as a potent anticancer molecule. Recently, several pterostilbene derivatives have been reported to exhibit better anticancer activities than that of the parent pterostilbene molecule. In the present study, a series of pterostilbene derivatives were designed and synthesized by the hybridization of pterostilbene, chalcone, and cinnamic acid. The cytotoxic effect of these hybrid molecules was determined using two oral cancer cell lines, HSC-3 and OECM-1. (E)-3-(2-((E)-4-Hydroxystyryl)-4,6-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (4d), with IC50 of 16.38 and 18.06 µM against OECM-1 and HSC-3, respectively, was selected for further anticancer mechanism studies. Results indicated that compound 4d effectively inhibited cell proliferation and induced G2/M cell cycle arrest via modulating p21, cyclin B1, and cyclin A2. Compound 4d ultimately induced cell apoptosis by reducing the expression of Bcl-2 and surviving. In addition, cleavage of PARP and caspase-3 were enhanced following the treatment of compound 4d with increased dose. To conclude, a number of pterostilbene derivatives were discovered to possess potent anticancer potentials. Among them, compound 4d was the most active, more active than the parent pterostilbene.


Assuntos
Antineoplásicos/farmacologia , Chalcona/farmacologia , Estilbenos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalcona/química , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Poli(ADP-Ribose) Polimerases/metabolismo , Estilbenos/química , Relação Estrutura-Atividade
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