RESUMO
CONTEXT: Sepsis-induced acute lung injury (ALI) is a severe condition with limited effective therapeutics; nicotinamide mononucleotide (NMN) has been reported to exert anti-inflammatory activities. OBJECTIVE: This study explores the potential mechanisms by which NMN ameliorates sepsis-induced ALI in vivo and in vitro. MATERIALS AND METHODS: Cultured MH-S cells and a murine model were used to evaluate the effect of NMN on sepsis-induced ALI. MH-S cells were stimulated with LPS (1 µg/mL) and NMN (500 µM) for 12 h grouping as control, LPS, and LPS + NMN. Cell viability, apoptotic status, and M1/2 macrophage-related markers were detected. The mice were pretreated intraperitoneally with NMN (500 mg/kg) and/or EX-527 (5 mg/kg) 1 h before LPS injection and randomized into 7 groups (n = 8): control, LPS, LPS + NMN, NMN, LPS + NMN + EX-527 (a SIRT1 inhibitor), LPS + EX-527, and EX-527. After 12 h, lung histopathology, W/D ratio, MPO activity, NAD+ and ATP levels, M1/2 macrophage-related markers, and expression of the SIRT1/NF-κB pathway were detected. RESULTS: In MH-S cells, NMN significantly decreased the apoptotic rate from 12.25% to 5.74%. In septic mice, NMN improved the typical pathologic findings in lungs and reduced W/D ratio and MPO activity, but increased NAD+ and ATP levels. Additionally, NMN suppressed M1 but promoted M2 polarization, and upregulated the expression of SIRT1, with inhibition of NF-κB-p65 acetylation and phosphorylation. Furthermore, inhibition of SIRT1 reversed the effects of NMN-induced M2 macrophage polarization. CONCLUSIONS: NMN protects against sepsis-induced ALI by promoting M2 macrophage polarization via the SIRT1/NF-κB pathway, it might be an effective strategy for preventing or treating sepsis-induced ALI.
Assuntos
Lesão Pulmonar Aguda , Sepse , Animais , Camundongos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/prevenção & controle , Trifosfato de Adenosina/metabolismo , Endotoxinas/toxicidade , Lipopolissacarídeos/toxicidade , Pulmão , Macrófagos/metabolismo , NAD/metabolismo , NF-kappa B/metabolismo , Mononucleotídeo de Nicotinamida/farmacologia , Sepse/induzido quimicamente , Sepse/complicações , Sepse/tratamento farmacológico , Sirtuína 1RESUMO
BACKGROUND: Facilitating the recurrence of spontaneous voiding is considered to be a way to prevent urinary retention after surgery, which is of great importance in cholecystectomy. This study aimed to assess the effect of transcutaneous electrical acupoint stimulation (TEAS) on spontaneous voiding recovery after laparoscopic cholecystectom. METHODS: Participants who underwent elective laparoscopic cholecystectomy were randomly assigned to either the TEAS group or the sham group. Active TEAS or sham TEAS at specific acupuncture points was conducted intraoperatively and postoperatively. The primary outcome was the recovery speed of spontaneous voiding ability after surgery and secondary outcomes included postoperative urinary retention (POUR), voiding dysfunction, pain, anxiety and depression, and early recovery after surgery. RESULTS: A total of 1,948 participants were recruited and randomized to TEAS (n = 975) or sham (n = 973) between August 2018 and June 2020. TEAS shortens the time delay of the first spontaneous voiding after laparoscopic cholecystectomy (5.6 h [IQR, 3.7-8.1 h] in the TEAS group vs 7.0 h [IQR, 4.7-9.7 h] in the sham group) (p < 0.001). The TEAS group experienced less POUR (p = 0.020), less voiding difficulty (p < 0.001), less anxiety and depression (p < 0.001), reduced pain (p = 0.007), and earlier ambulation (p = 0.01) than the sham group. CONCLUSIONS: Our results showed that TEAS is an effective approach to accelerate the recovery of spontaneous voiding and reduce POUR which facilitates recovery for patients after laparoscopic cholecystectomy.
Assuntos
Colecistectomia Laparoscópica , Estimulação Elétrica Nervosa Transcutânea , Retenção Urinária , Humanos , Colecistectomia Laparoscópica/efeitos adversos , Estimulação Elétrica Nervosa Transcutânea/métodos , Retenção Urinária/etiologia , Retenção Urinária/terapia , Pontos de Acupuntura , Complicações Pós-Operatórias , DorRESUMO
In this paper, the influence of external terahertz electromagnetic fields with different frequencies of 4 THz, 10 THz, 15 THz, and 20 THz on the permeability of the Kv1.2 voltage-gated potassium ion channel on the nerve cell membrane was studied using the combined model of the "Constant Electric Field-Ion Imbalance" method by molecular dynamics. We found that although the applied terahertz electric field does not produce strong resonance with the -C=O groups of the conservative sequence T-V-G-Y-G amino acid residue of the selective filter (SF) of the channel, it would affect the stability of the electrostatic bond between potassium ions and the carbonyl group of T-V-G-Y-G of SF, and it would affect the stability of the hydrogen bond between water molecules and oxygen atoms of the hydroxyl group of the 374THR side chain at the SF entrance, changing the potential and occupied states of ions in the SF and the occurrence probability of the permeation mode of ions and resulting in the change in the permeability of the channel. Compared with no external electric field, when the external electric field with 15 THz frequency is applied, the lifetime of the hydrogen bond is reduced by 29%, the probability of the "soft knock on" mode is decreased by 46.9%, and the ion flux of the channel is activated by 67.7%. Our research results support the view that compared to "direct knock-on", "soft knock-on" is a slower permeation mode.
Assuntos
Campos Eletromagnéticos , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Simulação de Dinâmica Molecular , Íons/metabolismo , Permeabilidade , Potássio/metabolismo , Canal de Potássio Kv1.2/química , Canal de Potássio Kv1.5/metabolismoRESUMO
Electroacupuncture (EA) can protect against acute urinary retention (AUR); however, the underlying mechanism remains unclear. Non-vesicular ATP release mediated by transient receptor potential (TRP) channels were identified as a key contributor to signaling in urothelial cells. In this study, the AUR model was established by urethral outlet obstruction in female Sprague-Dawley rats. EA was performed at SP6 and BL32 for 0.5 h prior to induction of AUR. EA reduced TRPV1 expression and urinary ATP concentrations in rat bladder, decreased the peak intravesical pressure during AUR, and attenuated abnormal voiding patterns and bladder pathological injury induced by AUR. Besides, 179 patients who experienced postoperative urinary retention were recruited and found that EA reduced urinary ATP concentrations and accelerated the recovery of spontaneous voiding. These observations indicate that EA exerts protection against AUR-induced bladder dysfunction by reducing urinary ATP concentrations through the regulation of TRPV1.
Assuntos
Eletroacupuntura , Retenção Urinária , Trifosfato de Adenosina/metabolismo , Animais , Feminino , Humanos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Canais de Cátion TRPV/metabolismo , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Doenças da Bexiga Urinária/prevenção & controle , Doenças da Bexiga Urinária/terapia , Retenção Urinária/complicações , Retenção Urinária/etiologia , Retenção Urinária/metabolismoRESUMO
Endotoxin-induced acute lung injury (ALI) is a challenging life-threatening disease for which no specific therapy exists. Mitochondrial dysfunction is corroborated as hallmarks in sepsis which commonly disrupt mitochondria-centered cellular communication networks, especially mitonuclear crosstalk, where the ubiquitous cofactor nicotinamide adenine dinucleotide (NAD+) is essential for mitonuclear communication. Heme oxygenase-1 (HO-1) is critical for maintaining mitochondrial dynamic equilibrium and regulating endoplasmic reticulum (ER) and Golgi stress to alleviating acute lung injury. However, it is unclear whether HO-1 regulates NAD+-mediated mitonuclear communication to exert the endogenous protection during endotoxin-induced ALI. In this study, we observed HO-1 attenuated endotoxin-induced ALI by regulated NAD+ levels and NAD+ affected the mitonuclear communication, including mitonuclear protein imbalance and UPRmt to alleviate lung damage. We also found the protective effect of HO-1 depended on NAD+ and NAD+-mediated mitonuclear communication. Furtherly, the inhibition of the PGC1α/PPARγ signaling exacerbates the septic lung injury by reducing NAD+ levels and repressing the mitonuclear protein imbalance and UPRmt. Altogether, our study certified that HO-1 ameliorated endotoxin-induced acute lung injury by regulating NAD+ and NAD+-mediated mitonuclear communications through PGC1α/PPARγ pathway. The present study provided complementary evidence for the cytoprotective effect of HO-1 as a potential target for preventing and attenuating of endotoxin-induced ALI.
Assuntos
Lesão Pulmonar Aguda , Heme Oxigenase-1 , Lesão Pulmonar Aguda/metabolismo , Endotoxinas/toxicidade , Heme Oxigenase-1/metabolismo , Humanos , NAD/efeitos adversos , NAD/metabolismo , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Transdução de SinaisRESUMO
INTRODUCTION: Electroacupuncture (EA) treatment has been demonstrated to have the potential to prevent sepsis-induced hippocampal injury; however, the mechanisms underlying the protective effects of EA against such injury remain unclear. Herein, to elucidate these mechanisms, we constructed a mouse model of lipopolysaccharide (LPS)-induced hippocampal injury to investigate the protection mechanism of EA and to determine whether heme oxygenase-1 (HO-1)-mediated mitochondrial function is involved in the protective effect of EA. MATERIALS AND METHODS: The sepsis model of hippocampal injury was induced by administering LPS. The Zusanli and Baihui acupoints were stimulated using EA for 30 min once a day, for 5 d before LPS exposure and the first day after administering LPS. Hippocampal injury was investigated by hematoxylin and eosin staining and Nissl staining. HO-1 levels were measured using Western blotting. Mitochondrial metabolism was validated by assessing adenosine triphosphate, superoxide dismutase, malondialdehyde levels, reactive oxygen species production, and mitochondrial respiratory chain activity. Mitochondrial morphology was analyzed by transmission electron microscopy. RESULTS: EA treatment alleviated neuronal injury, impeded oxidative stress, and improved mitochondrial respiratory function, energy metabolism, and mitochondrial morphology in LPS-exposed mice. In addition, HO-1 knockout aggravated LPS-induced hippocampal injury, aggravated oxidative stress, and reduced mitochondrial respiratory function and aggravated mitochondrial swelling, crest relaxation, and vacuole degeneration. Moreover, EA was unable to reverse the hippocampal damage and mitochondrial dysfunction caused by LPS exposure after HO-1 knockout. CONCLUSIONS: EA improves LPS-induced hippocampal injury by regulating HO-1-mediated mitochondrial function. Furthermore, HO-1 plays a critical role in maintaining mitochondrial function and resisting oxidative injury.
Assuntos
Eletroacupuntura , Sepse , Animais , Heme Oxigenase-1/metabolismo , Hipocampo/metabolismo , Lipopolissacarídeos , Camundongos , Mitocôndrias/metabolismo , Estresse Oxidativo , Sepse/metabolismo , Sepse/terapiaRESUMO
BACKGROUND: After surgery, millions of people suffer from delayed healing or wound dehiscence with subsequent severe complications, even death. Previous studies have reported that ropivacaine exhibits anti-proliferative and anti-migratory activities on numerous cells. Whether ropivacaine is able to influence the proliferation and migration of keratinocytes is still unclear. This study aimed to investigate the effect of ropivacaine on keratinocytes and its underlying molecular mechanism. METHODS: Adult male Sprague-Dawley rats were allocated to establish wound healing models with or without 0.75% ropivacaine treatment and assessed the epidermal thickness by HE staining. HaCaT cells were cultured to evaluate the effect of ropivacaine on wound healing. The cell proliferation, apoptosis status and migration were detected in vitro. Moreover, western blotting was used to examine expression to with PI3K/AKT/mTOR signaling pathways for molecular studies and the changes in inflammatory factors (IL-6, IL-10, TNF-α) were detected by ELISA. RESULTS: In the present study, we found that ropivacaine delayed wound closure in vivo. In vitro experiments, it was demonstrated that ropivacaine significantly inhibited the proliferation and migration of HaCaT cells via the suppression of PI3K/AKT/mTOR signaling pathway. Activation of PI3K/AKT/mTOR signaling pathway reversed the effects of ropivacaine on the proliferation and migration of HaCaT cells. Furthermore, ropivacaine contributed to the release of pro-inflammatory cytokines (IL-6 and TNF-α) and inhibited the secretion of anti-inflammatory cytokines of keratinocytes (IL-10). CONCLUSIONS: Our research demonstrated that ropivacaine treatment showed a more decreased wound closure rate. Mechanistically, we found that ropivacaine suppressed the proliferation and migration of keratinocytes and altered the expression of cytokines by inhibiting PI3K/AKT/mTOR pathway.
Assuntos
Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Animais , Proliferação de Células , Citocinas/metabolismo , Humanos , Interleucina-10 , Interleucina-6/metabolismo , Queratinócitos/metabolismo , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Ropivacaina/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , CicatrizaçãoRESUMO
BACKGROUND: The aim of this study is to investigate the difference of serum pepsinogen (PG) baseline levels in different regions of China and its influencing factors. METHODS: From October 2016 to October 2018, asymptomatic health checkup people who underwent nasal endoscopy in nine health management centers in different regions of China were collected. Lifestyle questionnaires were conducted, and serum PG and gastroscopy were performed. The differences in PG levels in baseline population (OLGA-0 grade) were studied according to geographical subregions of China. SPSS software was used for statistical analysis. RESULTS: 1922 patients were included in the final analysis. Compared with the non-atrophy (OLGA-0) group, PGR levels in atrophy group (OLGA-I to IV) were significantly decreased with the atrophy degree (p < 0.05). A total of 1590 baseline people (OLGA-0) were included in the study, including 254 from South China, 574 from East China, 210 from Southwest China, 332 from Northeast China, and 220 from Central/Northern China. There were significant differences in baseline PGI levels among the five regions (p < 0.05). The PGII levels were also different among the five regions, except for Central/Northern versus Southern China. PGR (PGI/PGII ratio) levels in Southern China were higher than other four regions. Further studies were conducted on the related factors that might affect the baseline PG level, which was affected by nationality, dietary habits, smoking, Helicobacter pylori infection and other related factors. CONCLUSION: Influenced by many factors, the baseline PG levels are different in different regions of China. In the follow-up studies of PG cut-off value, different PG cut-off value based on region may be more effective in the screening of gastric cancer and precancerous lesions in China.
Assuntos
Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , China/epidemiologia , Estudos Transversais , Infecções por Helicobacter/epidemiologia , Humanos , Pepsinogênio A , Pepsinogênio CRESUMO
BACKGROUND: Electroacupuncture has been reported to protect the body from organ damages, but its mechanisms remain to be explored. This research was designed to investigate the function of electroacupuncture in lung injury resulted from hind limb ischemia-reperfusion (LIR) and whether p38 mitogen-activated protein kinase (p38 MAPK)-mediated nuclear factor erythroid-2-related factor-2 (Nrf2)/heme oxygenase (HO)-1 pathway contributes to the protective effect of electroacupuncture on LIR-originated lung damage. MATERIALS AND METHODS: Rabbits were subjected to occluding femoral artery for 2 h. Then they received reperfusion for 4 h to establish lung injury model. Electroacupuncture stimulation was performed bilaterally at Feishu and Zusanli acupoints for 15 min once a day for 5 d before the experiment and throughout the hind LIR model performing in the experimental day. Blood samples and lung tissues were collected to examine the role of electroacupuncture treatment in inflammatory response, oxidative stress, and lung injury. Both the protein expression and the messenger RNA level of Nrf2 and HO-1 were detected. RESULTS: The results showed that electroacupuncture treatment remarkably alleviated lung injury, decreased inflammatory cytokines secretion, attenuated lung oxidative stress, increased the amount of Nrf2 and HO-1, and increased the ratio of phospho-p38 MAPK to p38 MAPK after LIR. However, the protective effects exerted by electroacupuncture were reversed to some extent by the preconditioning with SB203580, a p38 MAPK-specific inhibitor. CONCLUSIONS: These results suggested that electroacupuncture could attenuate lung injury in rabbits subjected to LIR by inhibition of proinflammatory cytokine response and oxidative stress through activating p38 MAPK-mediated Nrf2/HO-1 pathway.
Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Eletroacupuntura , Extremidades/irrigação sanguínea , Sistema de Sinalização das MAP Quinases/imunologia , Traumatismo por Reperfusão/complicações , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Modelos Animais de Doenças , Artéria Femoral/cirurgia , Heme Oxigenase-1/metabolismo , Humanos , Imidazóis/farmacologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Piridinas/farmacologia , Coelhos , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/terapia , Resultado do Tratamento , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND Our previous studies have shown that electroacupuncture (EA) can alleviate lung injury induced by limb ischemia-reperfusion, but the specific mechanism is still unclear. MATERIAL AND METHODS The animals were randomly divided into sham operation group (Sham), model group (IR), electroacupuncture group (EA), sham electroacupuncture group (SEA), and EA+luzindole group (EA+luzindole). The limb ischemia-reperfusion model was established according to previously described, the rabbits in the EA and EA+luzindole groups were given EA at ST36 and BL13 for 7 days before the model preparation and during the model implementation, however, sham EA was mainly used to stimulate the rabbits in the SEA group with shallow needling at the points 0.5 cm near ST36 and BL13. Then, 30 mg/kg of luzindole was intraperitoneally injected 30 minutes before the model preparation in the EA+luzindole group. RESULTS The wet weight/dry weight (W/D) ratio, lung injury score, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1ß, IL-6, and malondialdehyde (MDA) contents in the EA group at 4 hours after reperfusion were significantly lower than those in the IR, SEA, and EA+luzindole groups. The levels of serum melatonin at T0 in the EA and EA+luzindole groups were significantly higher than those in the Sham group. The levels of serum melatonin at T1 and T2 in the IR group were significantly lower than those in the Sham group. There was no significant difference in the expression levels of melatonin receptor 1 (MR-1) and MR-2 in lung tissues among the 5 groups. CONCLUSIONS EA could alleviate the lung injury induced by limb ischemia-reperfusion by promoting the secretion of melatonin, while having no effect on the expression of melatonin receptor in lung tissues.
Assuntos
Eletroacupuntura/métodos , Melatonina/farmacologia , Traumatismo por Reperfusão/terapia , Animais , Modelos Animais de Doenças , Lesão Pulmonar/terapia , Melatonina/metabolismo , Coelhos , Reperfusão , Traumatismo por Reperfusão/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: The protective effects of carbon monoxide against the lipopolysaccharide (LPS)-induced lung injury were attributed to maintenance of mitochondrial dynamics, but the mechanisms remain unexplored. MATERIALS AND METHODS: Using a rat model of acute lung injury induced by LPS and the LPS attacking cell model, we investigated the effects of pretreatment of carbon monoxide molecule-2 (CORM-2) on the acute lung injury and expressions of mitofusin proteins that play a critical role in mitochondrial dynamics. RESULTS: We found that preadministration of CORM-2, not the inactive form of CORM-2, significantly reduced the lung injury, levels of inflammatory cytokines, and the degree of oxidative stress caused by LPS. What was more, it increased the expressions of mitofusin proteins. Similar findings were also found in LPS-stimulating cell model. However, when the cells were treated in combination with LPS, CORM-2, and SB203580, it completely abolished the protection of CORM-2, reflected by increased levels of inflammatory cytokines and malonaldehyde, decreased activities of superoxide dismutase, along with the lower expressions of mitofusin proteins and the ratio of p-p38 mitogen activated protein kinase to p38 mitogen activated protein kinase. CONCLUSIONS: Our observations suggest that pretreatment with CORM-2 could attenuate LPS-induced lung injury by inducing the expressions of mitofusin proteins via p38 mitogen activated protein kinase pathway.
Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Lesão Pulmonar Aguda/imunologia , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , GTP Fosfo-Hidrolases/metabolismo , Humanos , Imidazóis/farmacologia , Lipopolissacarídeos/imunologia , Masculino , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Compostos Organometálicos/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Acute respiratory distress syndrome (ARDS) is one of the most devastating complications of sepsis lacking of effective therapy. Mitochondrial dynamics undergoing continuous fusion and fission play a crucial role in mitochondrial structure and function. Fis1, as a small protein located on the outer membrane of mitochondria, has been thought to be an important protein mediated mitochondrial fission. During ARDS, alveolar macrophages suffer from increased oxidative stress and apoptosis, and also accompanied by disrupted mitochondrial dynamics. In addition, as one of the products of heme degradation catalyzed by heme oxygenase, carbon monoxide (CO) possesses powerful protective properties in vivo or in vitro models, such as anti-inflammatory, antioxidant and anti-apoptosis function. However, there is little evidence that CO alleviates oxidative stress damage through altering mitochondrial fission in alveolar macrophages. In the present study, our results showed that CO increased cell vitality, improved mitochondrial SOD activity, reduced reactive oxygen species (ROS) production and inhibited cell apoptosis in NR8383 exposed to LPS. Meanwhile, CO decreased the expression of Fis1, increased mitochondrial membrane potential and sustained elongation of mitochondria in LPS-incubated NR8383. Overall, our study underscored a critical role of CO in suppressing the expression of Fis1 and alleviating LPS- induced oxidative stress damage in alveolar macrophages.
Assuntos
Monóxido de Carbono/farmacologia , Regulação para Baixo/efeitos dos fármacos , Proteínas Mitocondriais/genética , Estresse Oxidativo/efeitos dos fármacos , Animais , Linhagem Celular , Regulação para Baixo/genética , Lipopolissacarídeos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Proteínas Mitocondriais/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RatosRESUMO
BACKGROUND: Sepsis-associated acute lung injury remains the major cause of mortality in critically ill patients and is characterized by marked oxidative stress and mitochondrial dysfunction. Mitochondrial dynamics are indispensable for functional integrity. Additionally, heme oxygenase (HO)-1/carbon monoxide conferred cytoprotection against end-organ damage during endotoxic shock. Herein, we tested the hypothesis that HO-1/carbon monoxide played a critical role in maintaining the dynamic process of mitochondrial fusion/fission to mitigate lung injury in Sprague-Dawley rats or RAW 264.7 macrophages exposed to endotoxin. METHODS: The production of reactive oxygen species, the respiratory control ratio (RCR), and the expressions of HO-1 and mitochondrial dynamic markers were determined in macrophages. Concurrently, alterations in the pathology of lung tissue, lipid peroxidation, and the expressions of the crucial dynamic proteins were detected in rats. RESULTS: Endotoxin caused a 31% increase in reactive oxygen species and a 41% decrease in RCR levels (n = 5 per group). In parallel, the increased expression of HO-1 was observed in lipopolysaccharide-stimulated macrophages, concomitantly with excessive mitochondrial fission. Furthermore, carbon monoxide-releasing molecule-2 or hemin normalized mitochondrial dynamics, which were abrogated by zinc protoporphyrin IX. Additionally, impaired mitochondrial dynamic balance was shown in Sprague-Dawley rats that received lipopolysaccharide, accompanied by pathologic injury, elevated malondialdehyde contents, decreased manganese superoxide dismutase activities, and lowered RCR levels in rat lung mitochondria. However, the above parameters were augmented by zinc protoporphyrin IX and were in turn reversed by hemin. CONCLUSIONS: The HO-1/carbon monoxide system modulated the imbalance of the dynamic mitochondrial fusion/fission process evoked by lipopolysaccharide and efficiently ameliorated endotoxin-induced lung injury in vivo and in vitro.
Assuntos
Lesão Pulmonar Aguda/metabolismo , Monóxido de Carbono/farmacologia , Heme Oxigenase-1/farmacologia , Lipopolissacarídeos/metabolismo , Macrófagos/metabolismo , Dinâmica Mitocondrial , Animais , Modelos Animais de Doenças , Endotoxinas , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de OxigênioRESUMO
BACKGROUND: We aimed to investigate the effect of electroacupuncture at Zusanli (ST36) and Sanyinjiao (SP6) on adrenocortical function in patients with etomidate anesthesia. MATERIAL AND METHODS: We randomly divided 80 patients who underwent elective surgery into 4 groups: group etomidate (ETO), group etomidate + electroacupuncture (ETO+EA), group etomidate + sham acupuncture (ETO+SEA), and group propofol (PRO). The patients in group ETO, ETO+EA, and ETO+SEA were induced with etomidate and sufentanil and maintained with intravenous infusion of etomidate and remifentanil. Group PRO was induced with propofol and sufentanil and maintained with propofol and remifentanil. Group ETO+EA received electro-acupuncture stimulation at Zusanli and Sanyinjiao throughout the operation, while group ETO+SEA received electro-acupuncture stimulation at non-acupoints. We recorded the values of MAP, HR, BIS, CVP, cortisol, ACTH, epinephrine, norepinephrine, and arterial blood gas during the perioperative period. RESULTS: Cortisol concentrations were significantly higher at all times except T0 in group ETO+EA compared with group ETO. The ACTH concentrations were lower in group ETO+EA than that in group ETO at point T3. CONCLUSIONS: Electroacupuncture at ST 36 and SP 6 can mitigate the adrenal cortical inhibition induced by etomidate and can reduce the secretion of catecholamines during surgery.
Assuntos
Pontos de Acupuntura , Córtex Suprarrenal/fisiologia , Anestesia , Eletroacupuntura , Etomidato/farmacologia , Córtex Suprarrenal/efeitos dos fármacos , Hormônio Adrenocorticotrópico/sangue , Gasometria , Pressão Sanguínea/efeitos dos fármacos , Demografia , Etomidato/administração & dosagem , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Propofol/administração & dosagem , Propofol/farmacologiaRESUMO
BACKGROUND: The anti-oxidative and anti-inflammatory activities of electro-acupuncture (EA), a traditional clinical method, are widely accepted, but its mechanisms are not yet well defined. In this study, we investigated the role of extracellular signal-regulated kinases1/2 (ERK1/2) pathways on electro-acupuncture - mediated up-regulation of heme oxygenase-1 (HO-1) in rabbit lungs injured by LPS-induced endotoxic shock. MATERIAL/METHODS: Seventy rabbits were randomly divided into 7 groups: group C, group M, group D, group SEAM, group EAM, group EAMPD, and group PD98059. Male New England white rabbits were given EA treatment on both sides once a day on days 1-5, and then received LPS to replicate the experimental model of injured lung induced by endotoxic shock. Then, they were killed by exsanguination at 6 h after LPS administration. The blood samples were collected for serum examination, and the lungs were removed for pathology examination, determination of wet-to-dry weight ratio, MDA content, SOD activity, serum tumor necrosis factor-α, determination of HO-1 protein and mRNA expression, and determination of ERK1/2 protein. RESULTS: The results revealed that after EA treatment, expression of HO-1and ERK1/2 was slightly increased compared to those in other groups, accompanied with less severe lung injury as indicated by lower index of lung injury score, lower wet-to-dry weight ratio, MDA content, and serum tumor necrosis factor-α levels, and greater SOD activity (p<0.05 for all). After pretreatment with ERK1/2 inhibitor PD98059, the effect of EA treatment and expression of HO-1 were suppressed (p<0.05 for all). CONCLUSIONS: After electro-acupuncture stimulation at ST36 and BL13, severe lung injury during endotoxic shock was attenuated. The mechanism may be through up-regulation of HO-1, mediated by the signal transductions of ERK1/2 pathways. Thus, the regulation of ERK1/2 pathways via electro-acupuncture may be a therapeutic strategy for endotoxic shock.
Assuntos
Eletroacupuntura/métodos , Regulação Enzimológica da Expressão Gênica/fisiologia , Heme Oxigenase-1/metabolismo , Lipopolissacarídeos/efeitos adversos , Pulmão/enzimologia , Sistema de Sinalização das MAP Quinases/fisiologia , Choque Séptico/induzido quimicamente , Análise de Variância , Animais , Western Blotting , Primers do DNA , Técnicas Histológicas , Pulmão/patologia , Masculino , Reação em Cadeia da Polimerase , Coelhos , Choque Séptico/terapia , Superóxido Dismutase/sangue , Fator de Necrose Tumoral alfa/sangueRESUMO
Acute lung injury (ALI) remains a global public health issue without specific and effective treatment options available in the clinic. Alveolar macrophage polarization is involved in the initiation, development and progression of ALI; however, the underlying mechanism remains poorly understood. Heme oxygenase-1 (HO-1) acts as an antioxidant in pulmonary inflammation and has been demonstrated to be linked with the severity and prognosis of ALI. In this study, the therapeutic effects of HO-1 were examined, along with the mechanisms involved, mainly focusing on alveolar macrophage polarization. HO-1 depletion induced higher iNOS and CD86 (M1 phenotype) expression but was significantly decreased in Arg-1 and CD206 (M2 phenotype) expression in BALF alveolar macrophages after equivalent LPS stimulation. We also found that HO-1 deletion distinctly accelerated the expression of inflammasome-associated components NLRP3, ASC and caspase-1 in vivo and in vivo and in vitro. Moreover, on the basis of LPS for MH-S cells, levels of TXNIP, NLRP3, ASC and caspase-1 were increased and HO-1 depletion exacerbated these changes, whereas double depletion of HO-1 and TXNIP partially mitigated these elevations. Also, HO-1 knockdown induced more M1 phenotype and less M2 phenotype compared with LPS alone, whereas double silence of HO-1 and TXNIP partially changed the polarization state. Taken together, we demonstrated that HO-1 could modulate macrophage polarization via TXNIP/NLRP3 signaling pathway, which could be a potential therapeutic target for ALI treatment.
Assuntos
Lesão Pulmonar Aguda , Heme Oxigenase-1 , Humanos , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Inflamassomos/genética , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Endotoxinas/efeitos adversos , Endotoxinas/metabolismo , Lipopolissacarídeos/toxicidade , Lipopolissacarídeos/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/tratamento farmacológico , Macrófagos/metabolismo , Caspases/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismoRESUMO
PTEN-induced putative kinase 1 (PINK1) is a mitochondrial kinase that protects against oxidative stress-induced cellular death. PINK1 deletion, on the other hand, disrupts mitochondrial calcium (Ca2+) homeostasis in various brain disorders. This study looked at how PINK1 affects hippocampal intracellular Ca2+ changes in mice with septic encephalopathy. Mice were injected intraperitoneally with lipopolysaccharide (LPS, 5 mg/kg) to induce septic encephalopathy; then, fiber photometry was used to record hippocampal Ca2+ transients during behavioral tests in freely moving mice. Basal cytoplasmic Ca2+ levels were detected under a fluorescent microscope. LPS induced PINK1 expression and neuronal loss in the hippocampus of mice, whereas no difference in neuronal counts was shown between PINK1 knockout LPS mice and WT LPS mice. PINK1 deficiency led to inhibited Ca2+ transients and increased intracellular Ca2+ levels in the hippocampus of mice, thus, significantly aggravating the cognitive dysfunction in septic mice. An analysis of Parkin and PLC-γ1, downstream effectors of PINK1, showed that they are associated with the effects of PINK1. These results demonstrate that PINK1 deficiency disrupts intracellular Ca2+ homeostasis and exacerbates septic encephalopathy. This observation suggests a protective role of PINK1 in septic encephalopathy.
Assuntos
Encefalopatias , Proteínas Quinases , Animais , Camundongos , Encefalopatias/metabolismo , Hipocampo/metabolismo , Lipopolissacarídeos/toxicidade , Lipopolissacarídeos/metabolismo , Neurônios/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismoRESUMO
Acute lung injury (ALI) caused by endotoxin represents one of the common clinical emergencies. Mitochondria-associated endoplasmic reticulum membranes (MAM) serve as a critical link between mitochondria and endoplasmic reticulum (ER), which has an essential effect on maintaining intracellular homeostasis. As an important component of MAM, type-1 inositol-1,4,5-trisphosphate receptor (IP3R-1) mediates the ER-to-mitochondrial transport of Ca2+. This study explored the role of IP3R-1 and MAM in ALI. Besides the levels of inflammasome-associated components interleukin (IL)-6, tumor necrosis factor (TNF)-α, and malonyldialdehyde (MDA) were increased in both bronchoalveolar lavage fluid (BALF) and serum, increased cross-sectional area of mitochondria, elevated MAM formation, and decreased respiratory control ratio (RCR) were observed within lung tissues collected in lipopolysaccharide (LPS)-treated mice, accompanied by upregulation of IP3R-1 in total lung lysates and MAM. Ca2+ uptake level in the mitochondria, production of reactive oxygen species (ROS) in the mitochondria, and the formation of MAM were elevated within LPS-treated MLE-12 cells, and all those changes in response to LPS were partly inhibited by knocking down of IP3R-1 expression in MLE-12 cells. Collectively, IP3R-1 has a critical effect on MAM formation and mitochondrial dysfunction, which could be innovative therapeutic targets for ALI caused by endotoxin.
Assuntos
Lesão Pulmonar Aguda , Endotoxinas , Camundongos , Animais , Endotoxinas/toxicidade , Endotoxinas/metabolismo , Lipopolissacarídeos/toxicidade , Mitocôndrias/metabolismo , Retículo Endoplasmático/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismoRESUMO
Purpose: To investigate the effect of transcutaneous electrical acupoint stimulation (TEAS) on urinary retention after laparoscopic cholecystectomy in elderly patients, and to explore the relationship between TEAS and urinary ATP. Patients and Methods: The TEAS group was administered active TEAS at specific acupuncture points prior to induction of anesthesia and continued for 45 mins after surgery. In the control group, participants received sham stimulus at the same acupoints and no output current was delivered by disconnecting the device's output line. Urine samples were collected and evaluated in the first spontaneous voiding after surgery. In this study, postoperative urinary retention (POUR) was the primary outcome, which was diagnosed based on clinical symptoms, ultrasound assessments, and the need for bladder catheterization. Secondary outcomes include urinary ATP, postoperative spontaneous urination, urination symptoms, catheter-related bladder discomfort (CRBD), delirium, duration and hospitalization costs. Results: The study involved 598 patients recruited and randomized between August 2018 and June 2020. Among these patients, 547 (91.5%) completed the study and were analyzed. There were 64 cases of POUR, including 23 (8.4%, 95% confidence interval [CI]: 6.4-9.9%) in the TEAS group and 41 (15.0%, 95% CI: 9.3-13.4%) in the control group (p = 0.017). A significant difference was observed between the TEAS and control groups for urinary ATP concentration in the first spontaneous urine postoperatively (344 nmol/L versus 233 nmol/L, p=0.001). There was a shorter spontaneous voiding recovery time, smaller voiding threshold, less postoperative catheterization, less CRBD, and lower hospitalization costs in TEAS group compared with control group. Conclusion: TEAS reduces the incidence of POUR in elderly patients undergoing laparoscopic cholecystectomy, which may be related to an increase in bladder ATP release.
Assuntos
Retenção Urinária , Humanos , Idoso , Retenção Urinária/etiologia , Retenção Urinária/terapia , Estudos Prospectivos , Estimulação Elétrica , Trifosfato de AdenosinaRESUMO
Traumatic brain injury (TBI) is an increasingly common emergency disease that usually leads to prolonged physical and cognitive impairments. In this study, we investigated if sevoflurane could induce cognitive improvement in TBI rats. Rats were subjected to head trauma induced by a fluid percussion device. A two-hour exposure to 3% sevoflurane was performed in a chamber immediately after TBI. Sevoflurane inhalation reduced the neurological and cognitive deficits induced by TBI with ameliorated synaptic injuries in the hippocampus. Moreover, after sevoflurane treatment, the expression of nuclear factor erythroid-2-related factor-2 (Nrf-2) and hemeoxygenase-1 (HO-1) in the hippocampus was enhanced 1 d after TBI and maintained at high levels 14 days later, and oxidative stress induced by TBI was inhibited. However, the HO-1 inhibitor, Zinc protoporphyrin (ZnPP), used to demonstrate the involvement of HO-1, suppressed the protective effect of sevoflurane. These results indicate that sevoflurane administered immediately after TBI may protect against TBI-induced synaptic and cognitive impairments by promoting the antioxidant Nrf-2/HO-1 pathway. Sevoflurane may be a promising anesthetic for patients with TBI.