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1.
BMC Mol Cell Biol ; 23(1): 54, 2022 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-36517743

RESUMO

BACKGROUND: Pyroptosis of endothelial cells is a new cause of endothelial dysfunction in multiple diseases. Ceramide acts as a potential bioactive mediator of inflammation and increases vascular endothelial permeability in many diseases, whether it can aggravate vascular endothelial injury by inducing cell pyroptosis remains unknown. This study was established to explore the effects of C8-ceramide (C8-Cer) on human umbilical vein vascular endothelial cells (HUVECs) and its possible underlying mechanism. METHODS: HUVECs were exposed to various concentrations of C8-Cer for 12 h, 24 h, 48 h. The cell survival rate was measured using the cell counting kit-8 assay. Western blotting and Real-time polymerase chain reaction (RT-PCR) were used to detect the pyroptosis-releated protein and mRNA expressions, respectively. Caspase-1 activity assay was used to detect caspase-1 activity. Hoechst 33342/propidium iodide double staining and flow cytometry were adopted to measure positive staining of cells. Lactate dehydrogenase release assay and enzyme-linked immunosorbent assay were adopted to measure leakage of cellular contents. FITC method was used to detect the permeability of endothelial cells. ROS fluorescence intensity were detected by flow cytometry. RESULTS: The viability of HUVECs decreased gradually with the increase in ceramide concentration and time. Ceramide upregulated the expression of thioredoxin interacting protein (TXNIP), NLRP3, GSDMD, GSDMD-NT, caspase-1 and Casp1 p20 at the protein and mRNA level in a dose-dependent manner. It also enhanced the PI uptake in HUVECs and upregulated caspase-1 activity. Moreover, it promoted the release of lactate dehydrogenase, interleukin-1ß, and interleukin-18. Meanwhile, we found that ceramide led to increased vascular permeability. The inhibitor of NLRP3 inflammasome assembly, MCC950, was able to disrupt the aforementioned positive loop, thus alleviating vascular endothelial cell damage. Interestingly, inhibition of TXNIP either chemically using verapamil or genetically using small interfering RNA (siRNA) can effectively inhibit ceramide-induced pyroptosis and improved cell permeability. In addition, ceramide stimulated reactive oxygen species (ROS) generation. The pretreatment of antioxidant N-acetylcysteine (NAC), ROS scavenger, blocked the expression of pyroptosis markers induced by C8-cer in HUVECs. CONCLUSION: The current study demonstrated that C8-Cer could aggravate vascular endothelial cell damage and increased cell permeability by inducing cell pyroptosis. The results documented that the ROS-dependent TXNIP/NLRP3/GSDMD signalling pathway plays an essential role in the ceramide-induced pyroptosis in HUVECs.


Assuntos
Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Humanos , Piroptose/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ceramidas/farmacologia , Caspase 1/genética , Caspase 1/metabolismo , Caspase 1/farmacologia , Células Endoteliais da Veia Umbilical Humana , RNA Mensageiro/genética , Lactato Desidrogenases/metabolismo , Proteínas de Transporte , Proteínas de Ligação a Fosfato/metabolismo , Proteínas de Ligação a Fosfato/farmacologia , Proteínas Citotóxicas Formadoras de Poros/metabolismo
2.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 47(9): 1171-1181, 2022.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-36411700

RESUMO

OBJECTIVES: Trimethylamine oxide (TMAO) is a metabolite of intestinal flora and is known to promote the progression of atherosclerotic plaques. However, how TMAO works, including its effect on vascular endothelial cells, is not fully understood. This study aims to explore the biological role of TMAO in human umbilical vein endothelial cells (HUVECs) and the underlying mechanism. METHODS: Cell pyroptosis and the loss of plasma membrane integrity were induced under TMAO stimulation in HUVECs. The plasma membrane integrity of the cells was measured by Hoechst 33342/propidium iodide (PI) staining and lactate dehydrogenase leakage assay, and the changes in cell morphology were observed by atomic force microscope. The expression of proteins related to pyroptosis was determined by Western blotting or immunofluorescence. Mitochondrial acetaldehyde dehydrogenase 2 (ALDH2) activity in HUVECs was measured by the ALDH2 activity assay kit, and the level of reactive oxygen species (ROS) was detected by fluorescent probe DCFH-DA. RESULTS: TMAO induced pyroptotic cell death, manifesting by the presence of propidium iodide-positive cells, the leakage of lactate dehydrogenase, the production of N-terminal gasdermin D (GSDMD-N), and the formation of plasma membrane pores. Moreover, TMAO induced elevated expression of inflammasome components, nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and caspase-1 in cells. TMAO significantly inhibited ALDH2 activity and increased intracellular ROS production. However, the activation of ALDH2 by pharmacological manipulation attenuated TMAO-induced inflammasome activation and GSDMD-N production. CONCLUSIONS: TMAO induces pyroptosis of vascular endothelial cells through the ALDH2/ROS/NLRP3/GSDMD signaling pathway, which may be a potential therapeutic target for improving the treatment of atherosclerosis.


Assuntos
Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Humanos , Inflamassomos/metabolismo , Espécies Reativas de Oxigênio , Propídio/farmacologia , Células Endoteliais da Veia Umbilical Humana , Lactato Desidrogenases/metabolismo , Aldeído-Desidrogenase Mitocondrial/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Proteínas de Ligação a Fosfato/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
3.
J Neuroinflammation ; 19(1): 262, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36289519

RESUMO

BACKGROUND: Glaucoma, the major cause of irreversible blindness worldwide, is characterized by progressive degeneration of retinal ganglion cells (RGCs). Current treatments for glaucoma only slow or partially prevent the disease progression, failing to prevent RGCs death and visual field defects completely. Glutamate excitotoxicity via N-methyl-D-aspartic acid (NMDA) receptors plays a vital role in RGCs death in glaucoma, which is often accompanied by oxidative stress and NLRP3 inflammasome activation. However, the exact mechanisms remain unclear. METHODS: The glutamate-induced R28 cell excitotoxicity model and NMDA-induced mouse glaucoma model were established in this study. Cell counting kit-8, Hoechst 33342/PI dual staining and lactate dehydrogenase release assay were performed to evaluate cell viability. Annexin V-FITC/PI double staining was used to detect apoptosis and necrosis rate. Reactive oxygen species (ROS) and glutathione (GSH) were used to detect oxidative stress in R28 cells. Levels of proinflammatory cytokines were measured by qRT-PCR. Transmission electron microscopy (TEM) was used to detect necroptotic morphological changes in RGCs. Retinal RGCs numbers were detected by immunofluorescence. Hematoxylin and eosin staining was used to detect retinal morphological changes. The expression levels of RIP1, RIP3, MLKL and NLRP3 inflammasome-related proteins were measured by immunofluorescence and western blotting. RESULTS: We found that glutamate excitotoxicity induced necroptosis in RGCs through activation of the RIP1/RIP3/MLKL pathway in vivo and in vitro. Administration of the RIP3 inhibitor GSK872 and RIP1 inhibitor necrostatin-1 (Nec-1) prevented glutamate-induced RGCs loss, retinal damage, neuroinflammation, overproduction of ROS and a decrease in GSH. Furthermore, after suppression of the RIP1/RIP3/MLKL pathway by GSK872 and Nec-1, glutamate-induced upregulation of key proteins involved in NLRP3 inflammasome activation, including NLRP3, pro-caspase-1, cleaved-caspase-1, and interleukin-1ß (IL-1ß), was markedly inhibited. CONCLUSIONS: Our findings suggest that the RIP1/RIP3/MLKL pathway mediates necroptosis of RGCs and regulates NLRP3 inflammasome activation induced by glutamate excitotoxicity. Moreover, GSK872 and Nec-1 can protect RGCs from necroptosis and suppress NLRP3 inflammasome activation through inhibition of RIP1/RIP3/MLKL pathway, conferring a novel neuroprotective treatment for glaucoma.


Assuntos
Glaucoma , Necroptose , Camundongos , Animais , Espécies Reativas de Oxigênio/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Interleucina-1beta/metabolismo , N-Metilaspartato , Inflamassomos/metabolismo , Caspase 1/metabolismo , Células Ganglionares da Retina/metabolismo , Ácido Glutâmico/toxicidade , Hematoxilina , Amarelo de Eosina-(YS) , Apoptose , Glaucoma/induzido quimicamente , Glaucoma/tratamento farmacológico , Glutationa/metabolismo , Lactato Desidrogenases/metabolismo
4.
BMC Vet Res ; 18(1): 371, 2022 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-36253770

RESUMO

BACKGROUND: Abnormal or stereotyped behaviours in dairy cows are common in large-scale indoor farms and are usually accompanied by high physiological stress levels. Feed tossing is an abnormal behaviour commonly seen in cows while being fed, making farm management difficult. However, the reasons behind this behaviour have not been sufficiently reported. The objective of this study was to explore the changes in rumen fermentation, serum indicators, inflammatory conditions and the performance of cows with feed tossing behaviour. Holstein cows with similar lactation stages in the same barn were subjected to behaviour observations two times per day for 21 consecutive days. Ten cows with feed tossing behaviour (FT) and ten cows without abnormal behaviours (CON) were selected for further sampling. Plasma samples, rumen fluid, milk yield data of cows, and an indoor environment temperature-humidity index (THI) were collected. RESULTS: There was no significant difference in average daily milk yield during the observation period between feed-tossing cows (n = 68) and the other cows (n = 112). The number of cows showing FT behaviour had a moderately strong negative linear correlation with the THI of the environment. Compared to the CON cows, the FT cows had higher cortisol, norepinephrine and urea nitrogen levels in plasma, as well as higher plasma levels of inflammatory indicators, including total protein, lactate dehydrogenase, albumin, aspartate aminotransferase levels, and the ratio of aspartate aminotransferase to alanine aminotransferase. The FT cows had no significant variations from the CON cows regarding their rumen fermentation indicators, such as pH, ammonia nitrogen, and volatile fatty acids. In addition, 16S rRNA analysis revealed that there might be no clear association between the diversity and abundance of rumen bacteria and feed tossing behaviour. CONCLUSIONS: Our findings suggested that cows might have suffered from high levels of physiological stress and immune state for a long period when they exhibited FT behaviour. The environmental THI could affect the FT behaviour of cows; as the THI increases, the willingness of cows to throw decreases. This work provided the first evidence that feed tossing might be a response associated with high levels of physiological stress and immune. It also explored our insights into a commonly observed behavioural response to cow welfare traits.


Assuntos
Amônia , Rúmen , Alanina Transaminase , Albuminas/metabolismo , Amônia/análise , Ração Animal/análise , Animais , Aspartato Aminotransferases , Bovinos , Dieta/veterinária , Ácidos Graxos Voláteis/metabolismo , Feminino , Fermentação , Hidrocortisona/metabolismo , Lactato Desidrogenases/metabolismo , Lactação , Leite/química , Nitrogênio/metabolismo , Norepinefrina , RNA Ribossômico 16S , Rúmen/metabolismo , Estresse Fisiológico , Ureia/análise
5.
Int J Mol Sci ; 23(19)2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36232743

RESUMO

Glutamate-induced neural toxicity in autophagic neuron death is partially mediated by increased oxidative stress. Therefore, reducing oxidative stress in the brain is critical for treating or preventing neurodegenerative diseases. Selaginella tamariscina is a traditional medicinal plant for treating gastrointestinal bleeding, hematuria, leucorrhea, inflammation, chronic hepatitis, gout, and hyperuricemia. We investigate the inhibitory effects of Selaginella tamariscina ethanol extract (STE) on neurotoxicity and autophagic cell death in glutamate-exposed HT22 mouse hippocampal cells. STE significantly increased cell viability and mitochondrial membrane potential and decreased the expression of reactive oxygen species, lactate dehydrogenase release, and cell apoptosis in glutamate-exposed HT22 cells. In addition, while glutamate induced the excessive activation of mitophagy, STE attenuated glutamate-induced light chain (LC) 3 II and Beclin-1 expression and increased p62 expression. Furthermore, STE strongly enhanced the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) phosphorylation activation. STE strongly inhibited glutamate-induced autophagy by activating the PI3K/Akt/mTOR signaling pathway. In contrast, the addition of LY294002, a PI3K/Akt inhibitor, remarkably suppressed cell viability and p-Akt and p62 expression, while markedly increasing the expression of LC3 II and Beclin-1. Our findings indicate that autophagy inhibition by activating PI3K/Akt/mTOR phosphorylation levels could be responsible for the neuroprotective effects of STE on glutamate neuronal damage.


Assuntos
Morte Celular Autofágica , Fármacos Neuroprotetores , Selaginellaceae , Animais , Autofagia , Proteína Beclina-1/farmacologia , Etanol/farmacologia , Ácido Glutâmico/toxicidade , Lactato Desidrogenases/metabolismo , Mamíferos/metabolismo , Camundongos , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Selaginellaceae/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
6.
Int J Mol Sci ; 23(20)2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36293342

RESUMO

Doxorubicin (DOXO) is an effective drug that is used in the treatment of a large number of cancers. Regardless of its important chemotherapeutic characteristics, its usage is restricted because of its serious side effects; the most obvious is cardiotoxicity, which can manifest acutely or years after completion of treatment, leading to left ventricular dysfunction, dilated cardiomyopathy, and heart failure. Galectin 3 (Gal-3) is a beta galactoside binding lectin that has different roles in normal and pathophysiological conditions. Gal-3 was found to be upregulated in animal models, correlating with heart failure, atherosclerosis, and myocardial infarction. Male C57B6/J and B6.Cg-Lgals3 <tm 1 Poi>/J Gal-3 knockout (KO) mice were used for a mouse model of acute DOXO-induced cardiotoxicity. Mice were given DOXO or vehicle (normal saline), after which the mice again had free access to food and water. Heart and plasma samples were collected 5 days after DOXO administration and were used for tissue processing, staining, electron microscopy, and enzyme-linked immunosorbent assay (ELISA). There was a significant increase in the heart concentration of Gal-3 in Gal-3 wild type DOXO-treated mice when compared with the sham control. There were significantly higher concentrations of heart cleaved caspase-3, plasma troponin I, plasma lactate dehydrogenase, and plasma creatine kinase in Gal-3 KO DOXO-treated mice than in Gal-3 wild type DOXO-treated mice. Moreover, there were significantly higher heart antioxidant proteins and lower oxidative stress in Gal-3 wild type DOXO-treated mice than in Gal-3 KO DOXO-treated mice. In conclusion, Gal-3 can affect the redox pathways and regulate cell survival and death of the myocardium following acute DOXO injury.


Assuntos
Galectina 3 , Insuficiência Cardíaca , Masculino , Camundongos , Animais , Galectina 3/genética , Galectina 3/metabolismo , Caspase 3/metabolismo , Cardiotoxicidade/etiologia , Troponina I/metabolismo , Miócitos Cardíacos/metabolismo , Antioxidantes/farmacologia , Solução Salina , Camundongos Endogâmicos C57BL , Doxorrubicina/efeitos adversos , Estresse Oxidativo , Camundongos Knockout , Insuficiência Cardíaca/metabolismo , Creatina Quinase/metabolismo , Água/metabolismo , Lactato Desidrogenases/metabolismo
7.
Pharm Biol ; 60(1): 2011-2024, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36239618

RESUMO

CONTEXT: Shenlian extract (SL) is a combination of Salvia miltiorrhiza Bge. (Labiatae) and Andrographis paniculata (Burm. F.) Wall. Ex Nees (Acanthaceae) extracts, which promote blood circulation and clear endogenous heat toxins. Myocardial ischaemia-reperfusion injury (MI/RI) is aggravated myocardial tissue damage induced by reperfusion therapy after myocardial infarction. OBJECTIVES: This study explores the effect of SL on MI/RI and the underlying mechanism. MATERIALS AND METHODS: Primary peritoneal macrophages (pMACs) were treated with LPS and SL (5, 10 or 20 µg/mL) for 24 h. The myocardial ischaemia-reperfusion (MI/R) model was established after administration of different doses of SL (90, 180 or 360 mg/kg). Myocardial tissue injury was assessed by methylthiazolyl tetrazolium (TTC) staining and levels of creatine kinase (CK), lactate dehydrogenase (LDH) and superoxide dismutase (SOD) in mice. The double immunofluorescence staining of iNOS/F4/80 and CD86/F4/80 was used to detect macrophage M1 polarization. The levels of miR-155, inflammatory factors and chemokines were detected by qRT-PCR or ELISA. CD86, iNOS, SOCS3, JAK2, p-JAK2, STAT3 and p-STAT3 proteins expressions in macrophages were analyzed by western blotting. Conditioned medium transfer systems were designed to unite M1 macrophages with H/R cardiomyocytes, and cell apoptosis was detected by TUNEL staining, western blotting or immunohistochemistry. RESULTS: SL reduced apoptosis, diminished CK and LDH levels, raised SOD concentration and decreased infarct size in the MI/R model. Meanwhile, SL decreased miR-155 level, inhibited M1 macrophage polarization and inflammation. Furthermore, SL promoted SOCS3 expression and blocked JAK2/STAT3 pathway in vitro. CONCLUSIONS: SL may be a promising TCM candidate for MI/RI. The underlying mechanisms could be associated with inhibition of M1 macrophage polarization via down-regulating miR-155.


Assuntos
MicroRNAs , Traumatismo por Reperfusão Miocárdica , Animais , Apoptose , Creatina Quinase/metabolismo , Creatina Quinase/farmacologia , Creatina Quinase/uso terapêutico , Meios de Cultivo Condicionados/metabolismo , Lactato Desidrogenases/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Superóxido Dismutase/metabolismo
8.
Biomed Res Int ; 2022: 6560693, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36277894

RESUMO

The objective of this research is to investigate the mediating impact of salvianolic acid B (SalB) on SIRT1 signaling pathway and the mechanism by which it inhibits Nod-like receptor protein 3 (NLRP3), as well as to examine how SalB affects myocardial injury brought on by tumor lesions at the junction of the tube and the stomach. Through the establishment of the integration of a stomach tube tumor lesion rats combined with the experimental rat model, this study establishes the normal group, model group, and different SalB dose groups. For each group of cells, cell activity and cell apoptosis were determined and compared using colorimetry and enzyme-linked immunosorbent method about lactate dehydrogenase (LDH). Interleukin-1 beta levels are measured. DCFH-DA fluorescent probe was applied to identify intracellular "reactive oxygen species" (ROS). "Western blot" was used to determine NLRP3, caspase-1, and apoptosis-related spotted protein (ASC) in each group of cells. And SIRT1 signaling pathway related to SIRT1, phosphorylated AMP protein-activated kinase α (P-AMPK α), AMP protein-activated kinase α (AMPKα), and "peroxisome-proliferator-activated receptor γ coactivator 1α (PGC-1α) protein expression" are used. According to the final findings, SalB mediated the SIRT1 signaling pathway and had a beneficial impact on the upregulation of SIRT1, P-AMPK/AMPK, and PGC-1 protein expressions. SalB positively affects the downregulation of NLRP3 inflammasome-related proteins. Caspase-1 and ASC protein expression suggesting that SalB may inhibit the activation of NLRP3 inflammasome induced by oxidative stress by activating SIRT1/AMPK/PGC-1α signaling pathway. This plays an antimyocardial injury effect.


Assuntos
Neoplasias , Sirtuína 1 , Ratos , Animais , Sirtuína 1/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Interleucina-1beta/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas NLR/metabolismo , Inflamassomos/metabolismo , Corantes Fluorescentes , Imunoadsorventes , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Caspase 1/metabolismo , Oxigênio/metabolismo , Lactato Desidrogenases/metabolismo , Monofosfato de Adenosina
9.
Vet Res ; 53(1): 87, 2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36273217

RESUMO

Muscle larvae of Trichinella spiralis parasitize the host intestinal epithelium. The mechanisms of exosomes participating in the invasion of T. spiralis muscle larvae are unclear. Hence, the purpose of this study was to explore the effect of exosomes derived from T. spiralis infective larvae (TsExos) on the barrier function of porcine small intestinal epithelial cells (IPEC-J2). First, TsExos were successfully obtained, and their ingestion by epithelial cells was validated. Furthermore, the optimal induction condition was determined by the CCK8 kit, and we found that exposure to 150 µg/mL TsExos for 12/24 h decreased the viability of IPEC-J2 cells by 30%. Based on this outcome, the effects of TsExos on cell biological processes and tight junctions were studied. After coincubation of TsExos and IPEC-J2 cells, the results showed a significant increase in the content of FITC-dextran and in the levels of lactate dehydrogenase (LDH) and reactive oxygen species (ROS). The rate of apoptosis increased by 12.57%, and nuclear pyknosis and nuclear rupture were observed. After the cells were induced by TsExos, the expression of IL-1 was upregulated, but the expression of IL-10, TGF-ß, TLR-5, MUC-1 and MUC-2 was downregulated. TsExo induction also led to a decrease in the levels of ZO-1, CLDN-3, and OCLN. In conclusion, TsExos are involved in several cellular biological processes, and they function by disrupting physiological and biochemical processes, hyperactivating innate immunity, and damaging tight junctions.


Assuntos
Exossomos , Trichinella spiralis , Suínos , Animais , Trichinella spiralis/fisiologia , Interleucina-10/metabolismo , Interleucina-10/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Receptor 5 Toll-Like/metabolismo , Mucosa Intestinal , Células Epiteliais/metabolismo , Larva/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Lactato Desidrogenases/metabolismo , Interleucina-1/metabolismo
10.
Oral Health Prev Dent ; 20(1): 355-362, 2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36259438

RESUMO

PURPOSE: To investigate the effects and mechanisms of lemon essential oil products on dental caries prevention. MATERIALS AND METHODS: Lemon essential oil microemulsions (LEOM) with concentrations of 1/8 minimum inhibitory concentration (MIC), 1/4 MIC, and 1/2 MIC were applied to S. mutans at concentrations of 0.2%, 1%, and 5% glucose, respectively. Changes in acid production capacity of S. mutans were measured based on changes in pH. The effect of the reductive coenzyme I oxidation method on LDH activity was examined. The effect of lemon essential oil microemulsion on the expression of the lactate dehydrogenase gene (ldh) was detected by a quantitative real-time polymerase chain reaction. RESULTS: Lemon essential oil microemulsion at 1/2 MIC concentration reduced the environmental pH value at different glucose concentrations, compared to those observed in the control group (p < 0.05). LDH activity of S. mutans was decreased at three subinhibitory concentrations of lemon essential oil microemulsions (p < 0.05). The effect of lemon essential oil microemulsions on S. mutans LDH activity and bacterial acid production were positively correlated (r = 0.825, p < 0.05). Lemon essential oil microemulsion at 1/2 MIC concentration downregulated the expression of the ldh gene of S. mutans at different glucose concentrations (p < 0.05). In different glucose environments, lemon essential oil microemulsions at subminimum inhibitory concentrations can inhibit the acid production of S. mutans by reducing ldh expression and LDH activity in the glycolytic pathway, proving its anti-caries potential. CONCLUSIONS: LEOM can effectively prevent dental caries and maintain the microecological balance of the oral environment.


Assuntos
Cárie Dentária , Óleos Voláteis , Humanos , Streptococcus mutans , Receptores de Fator Estimulador de Colônias de Granulócitos/metabolismo , Óleos Voláteis/farmacologia , Óleos Voláteis/metabolismo , Fatores de Virulência/genética , Fatores de Virulência/metabolismo , Fatores de Virulência/farmacologia , Cárie Dentária/prevenção & controle , Cárie Dentária/microbiologia , NAD/metabolismo , NAD/farmacologia , Cariostáticos/farmacologia , Lactato Desidrogenases/metabolismo , Glucose/farmacologia , Biofilmes
11.
Braz J Med Biol Res ; 55: e12040, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36259797

RESUMO

Naringin (Nar) has been reported to exert potential hepatoprotective effects against acetaminophen (APAP)-induced injury. Mitochondrial dysfunction plays an important role in APAP-induced liver injury. However, the protective mechanism of Nar against mitochondrial damage has not been elucidated. Therefore, the aim of this study was to investigate the hepatoprotective effects of Nar against APAP and the possible mechanisms of actions. Primary rat hepatocytes and HepG2 cells were utilized to establish an in vitro model of APAP-induced hepatotoxicity. The effect of APAP and Nar on cell viability was evaluated by a CCK8 assay and detection of the concentrations of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase. The cellular concentrations of biomarkers of oxidative stress were measured by ELISA. The mRNA expression levels of APAP-related phase II enzymes were determined by real-time PCR. The protein levels of Nrf2, phospho (p)-AMPK/AMPK, and biomarkers of mitochondrial dynamics were determined by western blot analysis. The mitochondrial membrane potential (MMP) was measured by high-content analysis and confocal microscopy. JC-1 staining was performed to evaluate mitochondrial depolarization. Nar pretreatment notably prevented the marked APAP-induced hepatocyte injury, increases in oxidative stress marker expression, reductions in the expression of phase II enzymes, significant loss of MMP, mitochondrial depolarization, and mitochondrial fission in vitro. In conclusion, Nar alleviated APAP-induced hepatocyte and mitochondrial injury by activating the AMPK/Nrf2 pathway to reduce oxidative stress in vitro. Applying Nar for the treatment of APAP-induced liver injury might be promising.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Doença Hepática Induzida por Substâncias e Drogas , Animais , Ratos , Acetaminofen/toxicidade , Acetaminofen/metabolismo , Alanina/metabolismo , Alanina/farmacologia , Alanina Transaminase , Proteínas Quinases Ativadas por AMP/metabolismo , Aspartato Aminotransferases , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Lactato Desidrogenases/metabolismo , Fígado/metabolismo , Dinâmica Mitocondrial , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , RNA Mensageiro/metabolismo , Transdução de Sinais
12.
Mol Med ; 28(1): 126, 2022 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-36284300

RESUMO

BACKGROUND: Pyroptosis is a form of programmed cell death involved in the pathophysiological progression of hypoxic pulmonary hypertension (HPH). Emerging evidence suggests that N6-methyladenosine (m6A)-modified transcripts of long noncoding RNAs (lncRNAs) are important regulators that participate in many diseases. However, whether m6A modified transcripts of lncRNAs can regulate pyroptosis in HPH progression remains unexplored. METHODS: The expression levels of FENDRR in hypoxic pulmonary artery endothelial cells (HPAECs) were detected by using quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH). Western blot, Lactate dehydrogenase (LDH) release assay, Annexin V-FITC/PI double staining, Hoechst 33342/PI fluorescence staining and Caspase-1 activity assay were used to detect the role of FENDRR in HPAEC pyroptosis. The relationship between FENDRR and dynamin-related protein 1 (DRP1) was explored using bioinformatics analysis, Chromatin Isolation by RNA Purification (CHIRP), Electrophoretic mobility shift assay (EMSA) and Methylation-Specific PCR (MSP) assays. RNA immunoprecipitation (RIP) and m6A dot blot were used to detect the m6A modification levels of FENDRR. A hypoxia-induced mouse model of pulmonary hypertension (PH) was used to test preventive effect of conserved fragment TFO2 of FENDRR. RESULTS: We found that FENDRR was significantly downregulated in the nucleus of hypoxic HPAECs. FENDRR overexpression inhibited hypoxia-induced HPAEC pyroptosis. Additionally, DRP1 is a downstream target gene of FENDRR, and FENDRR formed an RNA-DNA triplex with the promoter of DRP1, which led to an increase in DRP1 promoter methylation that decreased the transcriptional level of DRP1. Notably, we illustrated that the m6A reader YTHDC1 plays an important role in m6A-modified FENDRR degradation. Additionally, conserved fragment TFO2 of FENDEE overexpression prevented HPH in vivo. CONCLUSION: In summary, our results demonstrated that m6A-induced decay of FENDRR promotes HPAEC pyroptosis by regulating DRP1 promoter methylation and thereby provides a novel potential target for HPH therapy.


Assuntos
Hipertensão Pulmonar , RNA Longo não Codificante , Camundongos , Animais , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Metilação de DNA , Células Endoteliais/metabolismo , Piroptose , Artéria Pulmonar , Hipertensão Pulmonar/genética , Hibridização in Situ Fluorescente , Hipóxia/genética , Dinaminas/genética , Dinaminas/metabolismo , Cromatina , Lactato Desidrogenases/genética , Lactato Desidrogenases/metabolismo , Caspases
13.
Molecules ; 27(19)2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36234730

RESUMO

Cardiac and hepatotoxicities are major concerns in the development of new drugs. Better alternatives to other treatments are being sought to protect these vital organs from the toxicities of these pharmaceuticals. In this regard, a preclinical study is designed to investigate the histopathological effects of a new succinimide derivative (Comp-1) on myocardial and liver tissues, and the biochemical effects on selected cardiac biomarkers, hepatic enzymes, and lipid profiles. For this, an initially lethal/toxic dose was determined, followed by a grouping of selected albino rats into five groups (each group had n = 6). The control group received daily oral saline for 8 days. The 5-FU (5-Fluorouracil) group received oral saline daily for 8 days, added with the administration of a single dose of 5-FU (150 mg/kg I.P.) on day 5 of the study. The atenolol group received oral atenolol (20 mg/kg) for 8 days and 5-FU (150 mg/kg I.P.) on day 5 of the protocol. Similarly, two groups of rats treated with test compound (Comp-1) were administered with 5 mg/kg I.P. and 10 mg/kg I.P. for 8 days, followed by 5-FU (150 mg/kg I.P.) on day 5. Toxicity induced by 5-FU was manifested by increases in the serum creatinine kinase myocardial band (CK-MB), troponin I (cTnI) and lactate dehydrogenase (LDH), lipid profile, and selected liver enzymes, including ALP (alkaline phosphatase), ALT (alanine transaminase), AST (aspartate aminotransferase), BT (bilirubin total), and BD (direct bilirubin). These biomarkers were highly significantly decreased after the administration of the mentioned doses of the test compound (5 mg/kg and 10 mg/kg). Similarly, histological examination revealed cardiac and hepatic tissue toxicity by 5-FU. However, those toxic effects were also significantly recovered/improved after the administration of Comp-1 at the said doses. This derivative showed dose-dependent effects and was most effective at a dose of 10 mg/kg body weight. Binding energy data computed via docking simulations revealed that our compound interacts toward the human beta2-adrenergic G protein-coupled receptor (S = -7.89 kcal/mol) with a slight stronger affinity than the calcium channel T-type (S = -7.07 kcal/mol). In conclusion, the histological and biochemical results showed that the test compound (Comp-1) had prominent cardioprotective, hepatoprotective, and lipolytic effects against 5-FU-induced toxicity in the subjected animal model.


Assuntos
Fosfatase Alcalina , Troponina I , Adrenérgicos/metabolismo , Adrenérgicos/farmacologia , Alanina Transaminase , Fosfatase Alcalina/metabolismo , Animais , Aspartato Aminotransferases , Atenolol , Bilirrubina/metabolismo , Biomarcadores/metabolismo , Canais de Cálcio/metabolismo , Creatinina/metabolismo , Fluoruracila/farmacologia , Humanos , Lactato Desidrogenases/metabolismo , Lipídeos/farmacologia , Fígado , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Succinimidas/metabolismo , Troponina I/metabolismo
14.
Phytomedicine ; 107: 154484, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36215787

RESUMO

BACKGROUND: Translocator protein (TSPO) is an 18-kDa transmembrane protein found primarily in the mitochondrial outer membrane, and it is implicated in inflammatory responses, such as cytokine release. Koumine (KM) is an indole alkaloid extracted from Gelsemium elegans Benth. It has been reported to be a high-affinity ligand of TSPO and to exert anti-inflammatory and immunomodulatory effects in our recent studies. However, the protective effect of KM on sepsis-associated liver injury (SALI) and its mechanisms are unknown. PURPOSE: To explore the role of TSPO in SALI and then further explore the protective effect and mechanism of KM on SALI. METHODS: The effect of KM on the survival rate of septic mice was confirmed in mouse models of caecal ligation and puncture (CLP)-induced and lipopolysaccharide (LPS)-induced sepsis. The protective effect of KM on CLP-induced SALI was comprehensively evaluated by observing the morphology of the mouse liver and measuring liver injury markers. The serum cytokine content was detected in mice by flow cytometry. Macrophage polarization in the liver was examined using western blotting. TSPO knockout mice were used to explore the role of TSPO in sepsis liver injury and verify the protective effect of KM on sepsis liver injury through TSPO. RESULTS: KM significantly improved the survival rate of both LPS- and CLP-induced sepsis in mice. KM has a significant liver protective effect on CLP-induced sepsis in mice. KM treatment ameliorated liver ischaemia, improved liver pathological injuries, and decreased the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and proinflammatory cytokines in serum. Western blotting results showed that KM inhibited M1 polarization of macrophages and promoted M2 polarization. In TSPO knockout mice, we found that TSPO knockout can improve the survival rate of septic mice, ameliorate liver ischaemia, improve liver pathological injuries, and decrease the levels of ALT, AST, and LDH. In addition, TSPO knockout inhibits the M1 polarization of macrophages in the liver of septic mice and promotes M2 polarization and the serum levels of proinflammatory cytokines. Interestingly, in TSPO knockout septic mice, these protective effects of KM were no longer effective. CONCLUSIONS: We report for the first time that TSPO plays a critical role in sepsis-associated liver injury by regulating the polarization of liver macrophages and reducing the inflammatory response. KM, a TSPO ligand, is a potentially desirable candidate for the treatment of SALI that may regulate macrophage M1/M2 polarization through TSPO in the liver.


Assuntos
Lipopolissacarídeos , Sepse , Alanina Transaminase/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Aspartato Aminotransferases/metabolismo , Proteínas de Transporte/metabolismo , Citocinas/metabolismo , Alcaloides Indólicos/farmacologia , Lactato Desidrogenases/metabolismo , Ligantes , Lipopolissacarídeos/farmacologia , Fígado/metabolismo , Macrófagos , Camundongos , Camundongos Knockout , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/metabolismo
15.
Arch Immunol Ther Exp (Warsz) ; 70(1): 25, 2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36219249

RESUMO

Interleukin (IL)-35 plays an immunosuppressive role in infectious diseases, autoimmune disorders, and cancers. However, IL-35 expression and its regulation of CD8+ T cells in infectious mononucleosis (IM) are not fully understood. In this study, three groups of participants were compared, including twenty-three patients of IM without liver inflammation, twenty-eight patients of IM with liver inflammation, and twenty-one controls. Plasma and peripheral blood mononuclear cells (PBMCs) were isolated. CD8+ T cells were purified. Plasma IL-35 was measured by ELISA. PBMCs and CD8+ T cells were stimulated with recombinant human IL-35 in vitro. Perforin and granzyme B secretion was assessed by ELISPOT. Immune checkpoint molecule expression was investigated by flow cytometry. CD8+ T cells were co-cultured with HepG2 cells in direct contact and indirect contact manner. The cytotoxicity of CD8+ T cells was calculated by measuring lactate dehydrogenase release and proinflammatory cytokine expression. There was no significant difference in plasma IL-35 levels between patients with IM without liver inflammation and the controls, but the IL-35 level was notably increased in patients with IM who presented with liver inflammation and negatively correlated with aminotransferase. CD8+ T cells in patients with IM with liver inflammation showed stronger cytotoxicity. IL-35 stimulation inhibited CD8+ T cell-induced target cell death in patients with IM, mainly through suppression of IFN-γ/TNF-α secretion and elevation of immune checkpoint molecule expression, but did not affect perforin or granzyme B secretion. The current data indicated that IL-35 dampened the cytotoxicity of CD8+ T cells in patients with IM probably via repression of cytokine secretion. Elevated IL-35 may protect against CD8+ T cell-induced liver inflammation in patients with IM.


Assuntos
Hepatite , Mononucleose Infecciosa , Linfócitos T CD8-Positivos , Citocinas/metabolismo , Granzimas/metabolismo , Hepatite/metabolismo , Humanos , Proteínas de Checkpoint Imunológico , Mononucleose Infecciosa/metabolismo , Inflamação/metabolismo , Interleucina-2/metabolismo , Interleucinas/metabolismo , Lactato Desidrogenases/metabolismo , Leucócitos Mononucleares , Perforina/metabolismo , Transaminases/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
16.
Int J Mol Sci ; 23(20)2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36293129

RESUMO

We investigated the nephroprotective effect of D-panthenol in rhabdomyolysis-induced acute kidney injury (AKI). Adult male Wistar rats were injected with 50% glycerol solution to induce rhabdomyolysis. Animals with rhabdomyolysis were injected with D-panthenol (200 mg/kg) for 7 days. On day 8, we examined AKI markers, renal histology, antioxidant capacity, and protein glutathionylation in kidneys to uncover mechanisms of D-panthenol effects. Rhabdomyolysis kidneys were shown to have pathomorphological alterations (mononuclear infiltration, dilatation of tubules, and hyaline casts in Henle's loops and collecting ducts). Activities of skeletal muscle damage markers (creatine kinase and lactate dehydrogenase) increased, myoglobinuria was observed, and creatinine, BUN, and pantetheinase activity in serum and urine rose. Signs of oxidative stress in the kidney tissue of rhabdomyolysis rats, increased levels of lipid peroxidation products, and activities of antioxidant enzymes (SOD, catalase, and glutathione peroxidase) were all alleviated by administration of D-panthenol. Its application improved kidney morphology and decreased AKI markers. Mechanisms of D-panthenol's beneficial effects were associated with an increase in total coenzyme A levels, activity of Krebs cycle enzymes, and attenuation of protein glutathionylation. D-Panthenol protects kidneys from rhabdomyolysis-induced AKI through antioxidant effects, normalization of mitochondrial metabolism, and modulation of glutathione-dependent signaling.


Assuntos
Injúria Renal Aguda , Rabdomiólise , Masculino , Ratos , Animais , Antioxidantes/metabolismo , Catalase/metabolismo , Creatinina/metabolismo , Glutationa Peroxidase/metabolismo , Glicerol/metabolismo , Ratos Wistar , Rabdomiólise/complicações , Rabdomiólise/tratamento farmacológico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/induzido quimicamente , Estresse Oxidativo , Rim/metabolismo , Glutationa/metabolismo , Creatina Quinase/metabolismo , Superóxido Dismutase/metabolismo , Coenzima A/metabolismo , Lactato Desidrogenases/metabolismo
17.
Int J Mol Sci ; 23(19)2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36232464

RESUMO

The intestinal barrier is vital for preventing inflammatory bowel disease (IBD). The objectives of this study were to assess whether the Lactobacillus rhamnosus CY12 could alleviate oxidative stress, inflammation, and the disruption of tight junction (TJ) barrier functions induced by lipopolysaccharide (LPS), and therefore to explore the potential underlying molecular mechanisms. Our results showed that LPS-induced Cancer coli-2 (Caco-2) cells significantly increased the levels of reactive oxygen species (ROS), lactate dehydrogenase, inflammatory cytokines interleukin-1ß, interleukin-6, interleukin-8, and tumor necrosis factor-α (IL-1ß, IL-6, IL-8, and TNF-α), and the cell apoptosis rate while decreasing the levels of TJ proteins occludin, zonula occludens-1 (ZO-1), and claudin and antioxidant enzymes, such as catalase, superoxide dismutase, and glutathione peroxidase(CAT, SOD, and GSH-Px) (p < 0.05). However, Lactobacillus rhamnosus CY12 could relieve cytotoxicity, apoptosis, oxidative stress, and pro-inflammatory cytokine expressions, and also inhibit the Toll-like receptor 4/nuclear factor kappa-B(TLR4/NF-κB) signaling pathway. Furthermore, the gene expression of antioxidant enzymes, as well as the mRNA and protein expressions of TJ proteins, was improved. Particularly, the concentration of 108 cfu/mL significantly prevented the inflammatory injury induced by LPS in Caco-2 cells (p < 0.05). These findings support a potential application of Lactobacillus rhamnosus CY12 as a probiotic to prevent LPS-induced intestinal injury and treat intestinal barrier dysfunction.


Assuntos
Proteínas de Junções Íntimas , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Células CACO-2 , Catalase/metabolismo , Claudinas/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Inflamação , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Lactato Desidrogenases/metabolismo , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , Ocludina/genética , Ocludina/metabolismo , Estresse Oxidativo , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio , Superóxido Dismutase/metabolismo , Proteínas de Junções Íntimas/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
18.
Microbiol Spectr ; 10(5): e0348822, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36194127

RESUMO

Melioidosis is a serious infectious disease caused by Burkholderia pseudomallei. This bacterium is able to survive and multiply inside the immune cells such as macrophages. It is well established that Toll-like receptors (TLRs), particularly surface TLRs such as TLR2, TLR4, and TLR5, play an essential role in defending against this bacterial infection. However, the involvement of endosomal TLRs in the infection has not been elucidated. In this study, we demonstrated that the number of intracellular bacteria is reduced in TLR9-depleted RAW264.7 cells infected with B. pseudomallei, suggesting that TLR9 is involved in intracellular bacterial killing in macrophages. As several reports have previously demonstrated that pyroptosis is essential for restricting intracellular bacterial killing, particularly in B. pseudomallei infection, we also observed an increased release of cytosolic enzyme lactate dehydrogenase (LDH) in TLR9-depleted cells infected with B. pseudomallei, suggesting TLR9 involvement in pyroptosis in this context. Consistently, the increases in caspase-11 and gasdermind D (GSDMD) activations, which are responsible for the LDH release, were also detected. Moreover, we demonstrated that the increases in pyroptosis and bacterial killing in B. pseudomallei-infected TLR9-depleted cells were due to the augmentation of the IFN-ß, one of the key cytokines known to regulate caspase-11. Altogether, this finding showed that TLR9 suppresses macrophage killing of B. pseudomallei by regulating pyroptosis. This information provides a novel mechanism of TLR9 in the regulation of intracellular bacterial killing by macrophages, which could potentially be leveraged for therapeutic intervention. IMPORTANCE Surface TLRs have been well established to play an essential role in Burkholderia pseudomallei infection. However, the role of endosomal TLRs has not been elucidated. In the present study, we demonstrated that TLR9 plays a crucial role by negatively regulating cytokine production, particularly IFN-ß, a vital cytokine to control pyroptosis via caspase-11 activation. By depletion of TLR9, the percentage of pyroptosis was significantly increased, leading to suppression of intracellular survival in B. pseudomallei-infected macrophages. These findings provide a new role of TLR9 in macrophages.


Assuntos
Burkholderia pseudomallei , Melioidose , Camundongos , Animais , Burkholderia pseudomallei/metabolismo , Receptor Toll-Like 9/metabolismo , Receptor 2 Toll-Like/metabolismo , Piroptose , Receptor 4 Toll-Like/metabolismo , Receptor 5 Toll-Like/metabolismo , Melioidose/metabolismo , Melioidose/microbiologia , Macrófagos , Linhagem Celular , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Citocinas/metabolismo , Caspases/metabolismo , Lactato Desidrogenases/metabolismo
19.
Arch Biochem Biophys ; 730: 109419, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36183841

RESUMO

Exercise training provides several cardiovascular benefits in both physiological and pathological conditions; however, its use as a therapeutic tool for pulmonary arterial hypertension (PAH) has been poorly explored. This study aimed to extend the comprehension of the cardioprotective effects of exercise training in the set of PAH focusing on the metabolic changes promoted by exercise in the right ventricle (RV). The monocrotaline animal model of PAH was used and male Wistar rats were submitted to two weeks of treadmill exercise training (5 days/week, 60 min/day, 25 m/min) following disease establishment. Trained rats showed an improved diastolic function (lower end-diastolic pressure and tau) despite the presence of cardiac overload (increased peak systolic pressure, end-diastolic pressure and arterial elastance). This enhanced hemodynamic response was paralleled by an increased uptake of glucose to cardiomyocytes through glucose transporter type 4 (GLUT4) followed by increased lactate dehydrogenase (LDH) activity. Exercise did not reverse the decrease of fatty acid oxidation related to PAH but increased the content of the transcription factors peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and peroxisome proliferator-activated receptor gamma (PPAR-γ). Two weeks of exercise did not modulate the changes in amino acid metabolism secondary to PAH. Our work suggests that continuous aerobic exercise of moderate intensity, despite its short-term duration and application in a late stage of the disease, supports the RV response to PAH by promoting a shift in the cardiac metabolic phenotype.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Masculino , Ratos , Animais , Monocrotalina/efeitos adversos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Hipertensão Pulmonar/terapia , Hipertensão Pulmonar/patologia , PPAR gama/metabolismo , Transportador de Glucose Tipo 4 , Ratos Wistar , Modelos Animais de Doenças , Glucose , Lactato Desidrogenases/metabolismo , Aminoácidos , Ácidos Graxos
20.
Mediators Inflamm ; 2022: 3306559, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36262545

RESUMO

Background: Visfatin is an adipocytokine that has been demonstrated to be involved in cardiovascular diseases. This study aims at determining the role of visfatin in sepsis-induced cardiac injury and identify its possible mechanisms. Methods: Dynamic changes in visfatin expression in mice with lipopolysaccharide- (LPS-) induced septicemia were measured. Additionally, mice were pretreated with visfatin and further administered LPS to observe the effects of visfatin on cardiac injury. Finally, septic mice were also pretreated with JSH-23 to investigate whether visfatin regulates cardiac injury via the NF-κB p65 pathway. Results: Visfatin expression levels in both the heart and serum were increased in LPS-treated mice and peaked at 6 hours, and visfatin was derived from cardiac macrophages. In septic mice, pretreatment with visfatin reduced the survival rate, worsened cardiac dysfunction, and increased the expression of cardiac injury markers, including creatine kinase myocardial bound (CK-MB) and lactate dehydrogenase (LDH). Treatment with visfatin also increased the infiltration of CD3+ cells and F4/80+ cells, amplified the cardiac inflammatory response, and elevated myocardial cell apoptosis. Treatment with JSH-23 reversed the effects of visfatin in septic mice. Conclusions: This study showed that visfatin amplifies the cardiac inflammatory response and aggravates cardiac injury through the p65 signaling pathway. Visfatin may be a clinical target for preventing cardiac injury in sepsis.


Assuntos
Traumatismos Cardíacos , Nicotinamida Fosforribosiltransferase , Sepse , Animais , Camundongos , Adipocinas , Creatina Quinase/metabolismo , Lactato Desidrogenases/metabolismo , Lipopolissacarídeos/toxicidade , NF-kappa B/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Sepse/tratamento farmacológico , Sepse/metabolismo , Transdução de Sinais , Citocinas/metabolismo
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