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1.
Sci Total Environ ; 863: 160958, 2023 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-36535467

RESUMO

Ionic liquids (ILs) are emergent pollutants and their reproductive toxicities show hormesis, earning attentions on their environmental risk. Yet, their reproductive effects over generations and the mechanisms were seldom explored. In the present study, the reproductive effects of 1-ethyl-3-methylimidazolium hexafluorophosphate ([C2mim]PF6) on Caenorhabditis elegans were measured in 11 continuously exposed generations (F1 to F11) to explore the multi-generational effects, and also in the non-exposed generations of F1 and F11 (i.e., their great-grand-daughters, T4 and T4') to explore the trans-generational effects. In multi-generational reproductive effects, there were concentration-dependent hormetic effects with hazard-benefit alteration between low and high concentrations (e.g., in F3). There were also generation-dependent hormetic effects with hazard-benefit alterations over generations (e.g., between F4 and F5, between F8 and F9, and between F10 and F11). Meanwhile, the results also showed benefit-hazard alteration between F2 and F3, between F6 and F7, and between F9 and F10. Trans-generational effects showed common inhibitions in T4 and T4' at both low and high concentrations. In the biochemical analysis, hormones and hormone-like substances including progesterone (P), estradiol (E2), prostaglandin (PG) and testosterone (T) showed multi- and trans-generational changes with inhibition and stimulation, which contributed to the reproductive outcomes in each generation. Such contribution was also observed in the hormones' precursor cholesterol and the proteins that are essential for reproduction including vitellogenin (Vn) and major sperm protein (MSP). Moreover, the biochemicals showed significant involvement in the connection among generations. Furthermore, the multi- and trans-generational effects of [C2mim]PF6 and histidine showed similar modes of actions despite some differences, implying the contribution of their shared imidazole structure.


Assuntos
Caenorhabditis elegans , Sêmen , Animais , Masculino , Imidazóis/toxicidade , Testosterona/metabolismo , Reprodução
2.
Sci Total Environ ; : 160223, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36402327

RESUMO

Environmental antibiotics raise serious health concerns due to their contribution to the obesity prevalence. Moreover, antibiotics promote antibiotic-resistance bacteria (ARB) which represent another emerging pollutant. However, the interaction between antibiotic and ARB in the obesogenic effects remained unexplored. In the present study, the obesogenic effects of tetracycline antibiotic (TCH) and ARB containing tetA were studied on C. elegans, and E. coli OP50 (OP50) was referred as a normal bacterial food. Results showed that TCH stimulated nematode triglyceride contents, while ARB alone had no significant influences. The combination of TCH and ARB showed less obesogenic effects than TCH alone, showing antagonism. Biochemical assays showed that the combination of TCH and ARB showed similar effects to ARB alone, and had less increases in lipid metabolism enzymes or metabolites than those of TCH or ARB alone, supporting the antagonism. In the nontargeted metabolomic analysis, TCH with ARB showed less significantly changed metabolites (SCMs) in the nematodes than TCH or ARB alone, partially explaining the antagonism. The metabolomic results also pointed out the significant involvement of amino acids, the carboxylic acids and derivatives, and also the benzene and substituted derivatives in the obesogenic effects of TCH and ARB. The findings of the present study provided a direct support for interaction between antibiotics and ARB underlying their health risks.

3.
iScience ; 25(11): 105319, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36246577

RESUMO

SARS-CoV-2 infection induces imbalanced immune response such as hyperinflammation in patients with severe COVID-19. Here, we studied the immunometabolic regulatory mechanisms for the pathogenesis of COVID-19. We depicted the metabolic landscape of immune cells, especially macrophages, from bronchoalveolar lavage fluid of patients with COVID-19 at single-cell level. We found that most metabolic processes were upregulated in macrophages from lungs of patients with mild COVID-19 compared to cells from healthy controls, whereas macrophages from severe COVID-19 showed downregulation of most of the core metabolic pathways including glutamate metabolism, fatty acid oxidation, citrate cycle, and oxidative phosphorylation, and upregulation of a few pathways such as glycolysis. Rewiring cellular metabolism by amino acid supplementation, glycolysis inhibition, or PPARγ stimulation reduces inflammation in macrophages stimulated with SARS-CoV-2. Altogether, this study demonstrates that metabolic imbalance of bronchoalveolar macrophages may contribute to hyperinflammation in patients with severe COVID-19 and provides insights into treating COVID-19 by immunometabolic modulation.

4.
Sci Total Environ ; 853: 158560, 2022 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-36087672

RESUMO

Plastics contamination in the environment is a major concern. Risk assessment of micro- and nanoplastics (MPL and NPL) poses significant challenges due to MPL and NPL heterogeneity regarding compositional polymers, particle sizes and morphologies in the environment. Yet, there exists considerable toxicological literature on commercial polystyrene (PS) micro- and nanospheres. Although such particles do not directly represent the environmental MPL and NPL, their toxicity data should be used to advance the hazard assessment of plastics. Here, toxicity data of PS micro- and nanospheres for microorganisms, aquatic and terrestrial invertebrates, fish, and higher plants was collected and analyzed. The evaluation of 294 papers revealed that aquatic invertebrates were the most studied organisms, nanosized PS was studied more often than microsized PS, acute exposures prevailed over chronic exposures, the toxicity of PS suspension additives was rarely addressed, and ∼40 % of data indicated no organismal effects of PS. Toxicity mechanisms were mainly studied in fish and nematode Caenorhabditis elegans, providing guidance for relevant studies in higher organisms. Future studies should focus on environmentally relevant plastics concentrations, wide range of organisms, co-exposures with other pollutants, and method development for plastics identification and quantification to fill the gap of bioaccumulation assessment of plastics.


Assuntos
Poluentes Ambientais , Nanosferas , Poluentes Químicos da Água , Animais , Poliestirenos/toxicidade , Microplásticos/toxicidade , Nanosferas/toxicidade , Plásticos/toxicidade , Invertebrados , Poluentes Químicos da Água/toxicidade , Poluentes Químicos da Água/análise , Organismos Aquáticos
5.
Environ Toxicol Pharmacol ; 95: 103962, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35998805

RESUMO

The reproductive toxicities over generations are essential to assess the long-term impacts environmental fluoroquinolone antibiotics (FQs). In the present study, the multi-generational effects of ofloxacin (OFL) and norfloxacin (NOR) on reproduction were studied on Caenorhabditis elegans from 9 successive generations (F1-F9). Results showed that OFL showed no effects in F1, stimulation in F2 to F4, and inhibition F5 to F9. The effects of NOR also showed oscillation between stimulation and inhibition across generations. Further biochemical analysis demonstrated that the reproductive toxicities of OFL and NOR were more closely connected with total cholesterol (TCHO), progesterone (P) and testosterone (T), than major sperm protein (MSP) and vitellogenin (Vn). Moreover, OFL and NOR also showed significant trans-generational reproductive toxicities in T4 and T4', the great-grand-daughter of F1 and F9. Differences between T4 and T4' and between OFL and NOR, indicated influences of multi-generational exposure and urged more exploration on different mechanisms between FQs.


Assuntos
Caenorhabditis elegans , Norfloxacino , Animais , Antibacterianos/toxicidade , Colesterol , Fluoroquinolonas , Masculino , Norfloxacino/toxicidade , Ofloxacino , Progesterona , Reprodução , Sêmen , Testosterona/farmacologia , Vitelogeninas
6.
Sci Total Environ ; 846: 157468, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-35868368

RESUMO

Ionic liquids (ILs) are difficult to degrade and even accumulate in the environment. Accordingly, their long-term toxicities are particularly important to demonstrate their accurate risk assessment. However, their long-term toxicities over generations and the toxicity mechanisms lacked thorough investigation. Presently, N-butylpyridinium bromide ([bpyr]Br), a representative IL, was chosen to measure its long-term effects on Caenorhabditis elegans for seven consecutive generations at 0.0225 and 22.5 mg/L. Toxicity mechanisms were explored in F1, F3, F5 and F7 by combining both antioxidant responses and lipid metabolism. Results showed that [bpyr]Br at low concentration provoked oscillatory effects on the reproduction over 7 generations, with inhibition in F1 and F7 and stimulation in F2, F4 and F5. At high concentration, [bpyr]Br showed similar multi-generational oscillation with greater inhibition in F1 and greater stimulation in F5. The effects of [bpyr]Br on the antioxidant responses to oxidative stress also showed oscillation over generations. The integrated biomarker response (IBR) values showed that [bpyr]Br at low concentration did not provoke significant influences on the overall antioxidant homeostasis in F1 and F3, but significantly stimulated it in F5 and F7. Meanwhile, [bpyr]Br at high concentration stimulated the antioxidant homeostasis in F1 and F7 with non-significant influences in F3 and F5. The IBR values regarding indicators in lipid metabolism showed that [bpyr]Br significantly and commonly stimulated the overall metabolism without concentration-dependent differences. Further analysis implied that [bpyr]Br provoked different mechanisms underlying the responses at low and high concentrations.


Assuntos
Antioxidantes , Caenorhabditis elegans , Animais , Antioxidantes/farmacologia , Brometos , Caenorhabditis elegans/fisiologia , Metabolismo dos Lipídeos , Compostos de Piridínio , Reprodução
7.
J Neural Transm (Vienna) ; 129(8): 1031-1038, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35648256

RESUMO

Multiple sclerosis (MS) is a kind of central nervous system (CNS) autoimmune disease, which mainly damages nerves, the brain, and the spinal cord. Recently, several clinical cases reported the relativity between Coronavirus Disease 2019 (COVID-19) and the development of MS, but the mechanism of how COVID-19 affects the occurrence of MS was still not clear. It is bioinformatics technology that we use to explore the potential association at the gene level. The genetic information related to the two diseases was collected from the DisGNET platform for functional protein network analysis and used STRING to identify the complete gene set. The protein-protein interaction (PPI) network was analyzed by STRING. Finally, in the GEO database, we selected peripheral blood mononuclear cell (PBMC) RNA sequencing data (GSE164805, GSE21942) from COVID-19 patients and MS patients to verify the potential cross mechanism between the two diseases. The similar gene set of immune or inflammation existed between the patients with COVID-19 and ones with MS, including L2RA, IFNG, IL1B, NLRP3, and TNF. Interaction network analysis among proteins revealed that IL1B, P2RX7, IFNB1, IFNB1, TNF, and CASP1 enhanced the network connectivity between the combined gene set of COVID-19 and MS associated with NOD-like receptor (NLR) signaling. The involvement of NLR signaling in both diseases was further confirmed by comparing peripheral blood monocyte samples from COVID-19 and MS patients. Activation of NLR signaling was found in both COVID-19 and MS. The PBMC samples analyses also indicated the involvement of the NLR signaling pathway. Taken together, our data analyses revealed that the NLR signaling pathway might play a critical role in the COVID-19-related MS.


Assuntos
COVID-19 , Esclerose Múltipla , COVID-19/complicações , Biologia Computacional , Humanos , Leucócitos Mononucleares/metabolismo , Esclerose Múltipla/complicações , Esclerose Múltipla/genética , Proteínas NLR , Transdução de Sinais
8.
Adv Sci (Weinh) ; 9(18): e2104780, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35474450

RESUMO

Carbonaceous materials are considered strong candidates as anode materials for sodium-ion batteries (SIBs), which are expected to play an indispensable role in the carbon-neutral era. Herein, novel braided porous carbon fibres (BPCFs) are prepared using the chemical vapour deposition (CVD) method. The BPCFs possess interwoven porous structures and abundant vacancies. The growth mechanism of the BPCFs can be attributed to the polycrystalline transformation of the nanoporous copper catalyst in the early stage of CVD process. Density functional theory calculations suggest that the Na+ adsorption energies of the mono-vacancy edges of the BPCFs (-1.22 and -1.09 eV) are lower than that of an ideal graphene layer (-0.68 eV), clarifying in detail the adsorption-dominated sodium storage mechanism. Hence, the BPCFs as an anode material present an outstanding discharge capacity of 401 mAh g-1 at 0.1 A g-1 after 500 cycles. Remarkably, this BPCFs anode, under high-mass-loading of 5 mg cm-2, shows excellent long-term cycling ability with a reversible capacity of 201 mAh g-1 at 10 A g-1 over 1000 cycles. This study provided a novel strategy for the development of high-performance carbonaceous materials for SIBs.

9.
Int J Biol Sci ; 18(2): 652-660, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35002515

RESUMO

Brain endothelial cells (ECs) are an important component of the blood-brain barrier (BBB) and play key roles in restricting entrance of possible toxic components and pathogens into the brain. However, identifying endothelial genes that regulate BBB homeostasis remains a time-consuming process. Although somatic genome editing has emerged as a powerful tool for discovery of essential genes regulating tissue homeostasis, its application in brain ECs is yet to be demonstrated in vivo. Here, we used an adeno-associated virus targeting brain endothelium (AAV-BR1) combined with the CRISPR/Cas9 system (AAV-BR1-CRISPR) to specifically knock out genes of interest in brain ECs of adult mice. We first generated a mouse model expressing Cas9 in ECs (Tie2Cas9). We selected endothelial ß-catenin (Ctnnb1) gene, which is essential for maintaining adult BBB integrity, as the target gene. After intravenous injection of AAV-BR1-sgCtnnb1-tdTomato in 4-week-old Tie2Cas9 transgenic mice resulted in mutation of 36.1% of the Ctnnb1 alleles, thereby leading to a dramatic decrease in the level of CTNNB1 in brain ECs. Consequently, Ctnnb1 gene editing in brain ECs resulted in BBB breakdown. Taken together, these results demonstrate that the AAV-BR1-CRISPR system is a useful tool for rapid identification of endothelial genes that regulate BBB integrity in vivo.


Assuntos
Dependovirus , Células Endoteliais/metabolismo , Edição de Genes , Proteínas Luminescentes/genética , beta Catenina/genética , Animais , Barreira Hematoencefálica/metabolismo , Sistemas CRISPR-Cas , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Masculino , Camundongos , Camundongos Transgênicos , Células NIH 3T3 , /genética
10.
J Mech Behav Biomed Mater ; 126: 104986, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34856483

RESUMO

Although the polyether ether ketone (PEEK) has excellent comprehensive properties, its non-antibacterial and low wear-resistant limit the wide application in the field of artificial joint materials. In this paper, Nano-ZnO was generated in situ on the surface of PEEK powder by one-step hydrothermal method, which improved the binding force of Nano-ZnO and PEEK matrix. Then the PEEK-based nanocomposites were prepared by melt blending with the synthesized Nano-ZnO-PEEK powders and PEEK powders. The microstructure, mechanical, biological and tribological properties of PEEK-based nanocomposites were studied. The results showed that the compressive strength of PEEK-based nanocomposites can reach up to 319.2 ± 2.4 MPa. Both PEEK and PEEK-based nanocomposites were non-toxic to cells. Meanwhile, PEEK-based nanocomposites showed good antibacterial activity against E.coli and Staphylococcus aureus, and the antibacterial activity was better with the increase of Nano-ZnO content. In addition, when the Nano-ZnO content was 5%, the wear rate of PEEK-based nanocomposites was about 68% lower than that of pure PEEK materials. Thus, PEEK-based nanocomposites has a dual function of good antibacterial property and excellent wear resistance.


Assuntos
Benzofenonas , Polímeros , Antibacterianos/farmacologia , Cetonas
11.
Environ Pollut ; 294: 118615, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34863891

RESUMO

Environmental obesogens contributed significantly to the obesity prevalence. Recently, antibiotics joined the list of environmental obesogens, while the underlying mechanisms remained to be explored. In the present study, effects of erythromycin (ERY), one widely used macrolide antibiotic, were measured on C. elegans to investigate the obesogenic mechanism. Results showed that ERY at 0.1 µg/L significantly increased the fat content by 17.4% more than the control and also stimulated triacylglycerol (TAG) levels by 25.7% more than the control. Regarding the obesogenic mechanisms, ERY provoked over-eating by stimulation on the pharyngeal pumping and reduction on the satiety quiescence percentage and duration. Such effects were resulted from stimulation on the neurotransmitters including serotonin (5-HT), dopamine (DA) and acetylcholine (ACh). The nervous responses involved the up-regulation of Gsα (e.g., ser-7, gsa-1, acy-1 and kin-2) signaling pathway and the down-regulation of TGFß (daf-7) but not via cGMP-dependent regulations (e.g., egl-4). Moreover, ERY stimulated the activities of fatty acid synthase (FAS) and glycerol-3-phosphateacyl transferases (GPAT) that catalyze lipogenesis, while ERY inhibited those of acyl-CoA synthetase (ACS), carnitine palmitoyl transferase (CPT) and acyl-CoA oxidase (ACO) that catalyze lipolysis. The unbalance between lipogenesis and lipolysis resulted in the fat accumulation which was consistent with up-regulation on mgl-1 and mgl-3 which are the down-steam of TGFß regulation. Such consistence supported the close connection between nervous regulation and lipid metabolism. In addition, ERY also disturbed insulin which connects lipid with glucose in metabolism.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Eritromicina/farmacologia , Metabolismo dos Lipídeos , Animais , Proteínas de Caenorhabditis elegans/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipólise , Obesidade
12.
Sci Total Environ ; 804: 150250, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34798755

RESUMO

Antibiotics are ubiquitous environmental pollutants and they can provoke multi-generational impacts due to their pseudo-persistence. However, their multi-generational effects and potential mechanisms remained poorly studied. Presently, effects of enrofloxacin (ENR) were studied on Caenorhabditis elegans with a continuous exposure over 9 generations (from F1 to F9) at an environmentally realistic level. Regarding reproduction, ENR showed stimulation in F1 (1.18-fold of the control) and F2 (1.08), inhibition in F3 (0.70), stimulation in F4 (1.86), F5 (3.18) and F6 (1.53), inhibition in F7 (0.73) and F8 (0.69) and stimulation again in F9 (1.89). That is to say, ENR provoked multi-generational oscillatory effects on the reproduction. Such oscillation was also observed in effects on lifespan with much less magnitudes than those on reproduction. Biochemical assays were performed in F1, F3, F4 and F9 which represented the oscillation over generations. Results showed more antioxidants (e.g., superoxide dismutase and glutathione), mild oxidative stress (e.g., reactive oxygen species) and less oxidative damage (i.e., protein carbonyl) underlying the generation-dependent stimulation. Moreover, ENR provoked multi-generational oscillation on the enzymes that regulate the lipogenesis (e.g., fatty acid synthase and acetyl-CoA carboxylase) and lipolysis (e.g., acyl-CoA synthetase), with similarities to the effects on the oxidative stress and damage. Further analysis on SKN-1 and its activating PMK-1 and GSK-3 demonstrated their involvement in regulating both antioxidant detoxification and lipid metabolism.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Antioxidantes , Proteínas de Caenorhabditis elegans/genética , Proteínas de Ligação a DNA , Enrofloxacina , Quinase 3 da Glicogênio Sintase , Metabolismo dos Lipídeos , Longevidade , Estresse Oxidativo , Reprodução , Fatores de Transcrição
13.
Org Lett ; 24(1): 390-394, 2022 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-34964636

RESUMO

A metal-free sulfenylation/spirocyclization of indolyl-ynones realized by organosulfenyl chloride, generated in situ from the reaction of disulfides and PhICl2, is presented. This cascade one-pot process enables a chemoselective synthesis of diverse sulfenylated spiroindolenines depending on the substituent pattern at the two-position of indolyl-ynones.

14.
RSC Med Chem ; 12(10): 1650-1671, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34778767

RESUMO

The nitrile group is an important functional group widely found in both pharmaceutical agents and natural products. More than 30 nitrile-containing pharmaceuticals have been approved by the FDA for the management of a broad range of clinical conditions in the last few decades. Incorporation of a nitrile group into lead compounds has gradually become a promising strategy in rational drug design as it can bring additional benefits including enhanced binding affinity to the target, improved pharmacokinetic profile of parent drugs, and reduced drug resistance. This paper reviews the existing drugs with a nitrile moiety that have been approved or in clinical trials, involving their targets, molecular mechanism of pharmacology and SAR studies, and classifies them into different categories based on their clinical usages.

15.
J Org Chem ; 86(23): 17274-17281, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34806887

RESUMO

An interrupted Pummerer reaction of PhICl2 and sulfoxides was found to in situ generate reactive organosulfenyl chloride, which enabled the intramolecular electrophilic cyclization of 2-alkynylanilines, generating 3-sulfenylated indole with a good to excellent yield under metal-free conditions. One striking feature of the approach is that sulfoxide regeneration can be realized via the oxidation of the formed sulfides by the generated hypervalent iodine species.

16.
Nat Commun ; 12(1): 4664, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34341353

RESUMO

Excessive inflammatory responses induced upon SARS-CoV-2 infection are associated with severe symptoms of COVID-19. Inflammasomes activated in response to SARS-CoV-2 infection are also associated with COVID-19 severity. Here, we show a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. N protein facilitates maturation of proinflammatory cytokines and induces proinflammatory responses in cultured cells and mice. Mechanistically, N protein interacts directly with NLRP3 protein, promotes the binding of NLRP3 with ASC, and facilitates NLRP3 inflammasome assembly. More importantly, N protein aggravates lung injury, accelerates death in sepsis and acute inflammation mouse models, and promotes IL-1ß and IL-6 activation in mice. Notably, N-induced lung injury and cytokine production are blocked by MCC950 (a specific inhibitor of NLRP3) and Ac-YVAD-cmk (an inhibitor of caspase-1). Therefore, this study reveals a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.


Assuntos
COVID-19/metabolismo , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , Inflamassomos/metabolismo , Inflamação/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , SARS-CoV-2/metabolismo , Animais , COVID-19/virologia , Células Cultivadas , Citocinas/metabolismo , Células HEK293 , Humanos , Inflamassomos/genética , Lesão Pulmonar/genética , Lesão Pulmonar/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fosfoproteínas/metabolismo , Ligação Proteica , SARS-CoV-2/fisiologia , Células THP-1
17.
Chem Commun (Camb) ; 57(60): 7426-7429, 2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34231573

RESUMO

A series of alkoxylated isobenzofuranones were conveniently synthesized from the reaction of 2-(1-arylvinyl)benzoic acids with PhI(OR)2, generated in situ from the reaction of iodosobenzene (PhIO) with alkyl alcohols. This hypervalent iodine mediated one-pot transformation is postulated to undergo a cascade reaction involving lactonization, 1,2-aryl migration and alkoxylation processes. The organocatalytic and chiral organoiodine-catalyzed asymmetric reactions of the current transformation were also probed.

18.
PLoS Pathog ; 17(7): e1008603, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34310658

RESUMO

Dengue virus (DENV) is a mosquito-borne pathogen that causes a spectrum of diseases including life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Vascular leakage is a common clinical crisis in DHF/DSS patients and highly associated with increased endothelial permeability. The presence of vascular leakage causes hypotension, circulatory failure, and disseminated intravascular coagulation as the disease progresses of DHF/DSS patients, which can lead to the death of patients. However, the mechanisms by which DENV infection caused the vascular leakage are not fully understood. This study reveals a distinct mechanism by which DENV induces endothelial permeability and vascular leakage in human endothelial cells and mice tissues. We initially show that DENV2 promotes the matrix metalloproteinase-9 (MMP-9) expression and secretion in DHF patients' sera, peripheral blood mononuclear cells (PBMCs), and macrophages. This study further reveals that DENV non-structural protein 1 (NS1) induces MMP-9 expression through activating the nuclear factor κB (NF-κB) signaling pathway. Additionally, NS1 facilitates the MMP-9 enzymatic activity, which alters the adhesion and tight junction and vascular leakage in human endothelial cells and mouse tissues. Moreover, NS1 recruits MMP-9 to interact with ß-catenin and Zona occludens protein-1/2 (ZO-1 and ZO-2) and to degrade the important adhesion and tight junction proteins, thereby inducing endothelial hyperpermeability and vascular leakage in human endothelial cells and mouse tissues. Thus, we reveal that DENV NS1 and MMP-9 cooperatively induce vascular leakage by impairing endothelial cell adhesion and tight junction, and suggest that MMP-9 may serve as a potential target for the treatment of hypovolemia in DSS/DHF patients.


Assuntos
Dengue/patologia , Células Endoteliais/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas não Estruturais Virais/metabolismo , Animais , Permeabilidade Capilar/fisiologia , Adesão Celular/fisiologia , Dengue/metabolismo , Dengue/virologia , Vírus da Dengue/metabolismo , Humanos , Camundongos , Junções Íntimas/metabolismo
19.
Aquat Toxicol ; 237: 105903, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34229255

RESUMO

Ammonia is a major pollutant in the water environment, which could cause severe harm to aquatic organisms. To explore the pathological and physiological effects of ammonia in Chinese striped-necked turtles (Mauremys sinensis), the individuals (body mass: 218.26 ± 12.65 g) were divided into two groups: control group and ammonia exposed group (6.25 mM total ammonia), then the expression levels of signaling factors involved in the endoplasmic reticulum stress and apoptotic pathways were determined. The results showed that ammonia exposure up-regulated the transcriptional and protein levels of endoplasmic reticulum stress marker gene Bip. Meanwhile, the relative mRNA levels of key genes (PERK, ATF6, eIF2α, ATF4, IRE1α and XBP1) involved in unfolded protein response up-regulated, and the phosphorylation levels of PERK, eIF2α and IRE1α increased correspondingly. In addition, the protein and transcriptional levels of CHOP and JNK related to apoptotic pathway induced by unfolded protein reaction increased under ammonia exposure. Moreover, Bcl-2 mRNA expression levels and protein levels decreased, whereas BAX and caspase-3 showed an opposite trend, and the cleaved protein of caspase-3 appeared when the turtles in the elevated ammonia. Furthermore, the apoptotic cells in liver increased after ammonia exposure. These results suggested ammonia exposure induced endoplasmic reticulum stress, then activated unfolded protein response, followed by apoptosis in M. sinensis. The results will contribute to a better understanding of the toxicity mechanism of ammonia to aquatic turtles.


Assuntos
Tartarugas , Poluentes Químicos da Água , Amônia/toxicidade , Animais , Apoptose , China , Estresse do Retículo Endoplasmático , Poluentes Químicos da Água/toxicidade
20.
J Org Chem ; 86(14): 9490-9502, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34184892

RESUMO

A highly substituent-dependent rearrangement allows for the novel and SOCl2-induced divergent synthesis of 3-methylthioquinolin-2-ones and 3-methylthiospiro[4.5]trienones through intramolecular electrophilic cyclization of N-aryl propyamides. DMSO acts as both solvent and sulfur source, and use of DMSO-h6/d6 enables the incorporation of SCH3 or SCD3 moieties to the 3-position of the heterocyclic framework. Different para-substituents trigger divergent reaction pathways leading to the formation of quinolin-2-ones for mild substituents and spiro[4,5]trienones for both electron-withdrawing and -donating substituents, respectively. On the basis of both computational and experimental results, a new mechanism has been put forward that accounts for the exclusive spirolization/defluorination process and the surprising substituent effects.


Assuntos
Dimetil Sulfóxido , Compostos de Espiro , Ciclização , Elétrons
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