Propofol Attenuated Acute Kidney Injury after Orthotopic Liver Transplantation via Inhibiting Gap Junction Composed of Connexin 32

Luo, Chenfang; Yuan, Ding; Li, Xiaoyun; Yao, Weifeng; Luo, Gangjian; Chi, Xinjin; Li, Haobo; Irwin, Michael G.; Xia, Zhengyuan; Hei, Ziqing

doi:10.1097/aln.0000000000000448

Cited by 57 publications

(93 citation statements)

References 49 publications

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“…Oxidative stress and the inflammatory reaction interact in a complex way to act in the pathogenesis of lung damage. Studies have demonstrated that ROS are fundamental to oxidative stress and the inflammatory reaction (38,39). The current study demonstrated that NAC and AP application inhibited NAPDH oxidase in the earlier phase and reduced or eliminated ROS production.…”

Section: Discussionmentioning

confidence: 58%

Propofol alleviates acute lung injury following orthotopic autologous liver transplantation in rats via inhibition of the NADPH oxidase pathway

Luo

Zhu

Yuan

et al. 2014

Molecular Medicine Reports

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Abstract. Acute lung injury (ALI) induced by liver transplantation is detrimental to patient survival, and therapeutic strategies remain limited. Thus, the protective effects of propofol, a commonly used anesthetic with antioxidative and anti-inflammatory properties, were investigated in the present study on ALI induced by orthotopic autologous liver transplantation (OALT). The protective mechanism of propofol was determined to be associated with the inhibition of NADPH oxidase, by comparing its effects with the positive controls apocynin (AP; an NADPH oxidase inhibitor) and N-acegysteine (NAC; a scavenger of reactive oxygen species). The results demonstrated that two proteins (p47phox and gp91phox) of the NADPH oxidase system presented increased expression in rats with ALI induced by OALT, thus leading to increased activation of the oxidative stress and inflammatory reactions. Preconditioning with NAC or AP eliminated this increase, suggesting that antioxidative treatment, particularly with inhibitors of NADPH oxidase, is a promising protective strategy against ALI induced by OALT. Propofol preconditioning at a high (100 mg/kg) or low (50 mg/kg) dose promoted similar protective effects, with the high-dose propofol producing a more marked effect than the low dose. The results suggested that propofol may protect against ALI induced by OALT, the mechanism of which may involve a reduced oxidative stress and inflammatory reaction mediated by NADPH oxidase inhibition.

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Section: Discussionmentioning

confidence: 58%

Propofol alleviates acute lung injury following orthotopic autologous liver transplantation in rats via inhibition of the NADPH oxidase pathway

Luo

Zhu

Yuan

et al. 2014

Molecular Medicine Reports

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“…Several animal studies suggested that propofol is effective in attenuating AKI in different models (8)(9)(10). Although it is commonly observed that therapeutic and preventive strategies related to AKI are successful in animal models and fail in human trials, a recent randomized controlled study showed that propofol anesthesia was associated with a reduction in AKI incidence in patients undergoing valvular heart surgery compared with sevoflurane anesthesia (11).…”

Section: Introductionmentioning

confidence: 99%

Renal Outcomes in Critically Ill Patients Receiving Propofol or Midazolam

Leite

Macedo

Martins

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Propofol has been shown to provide protection against renal ischemia/reperfusion injury experimentally, but clinical evidence is limited to patients undergoing cardiac surgery. There are no data about its association with oliguria and AKI in critically ill patients.Design, setting, participants, & measurements We obtained data from the Multiparameter Intelligent Monitoring in Intensive Care II database (2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008). Patient selection criteria included adult patients in their first intensive care unit (ICU) admission, need for mechanical ventilation, and treatment with propofol or midazolam. Propensity score analysis (1:1) was used and renal-related outcomes (AKI, oliguria, cumulative fluid balance, and need for RRT) were evaluated during the first 7 days of ICU stay.Results There were 1396 propofol/midazolam-matched patients. AKI in the first 7-day ICU time period was statistically lower in propofol-treated patients compared with midazolam-treated patients (55.0% versus 67.3%, P,0.001). Propofol was associated with lower AKI incidence using both urine output (45.0% versus 55.7%, P,0.001) and serum creatinine criteria (28.8% versus 37.2%, P=0.001). Patients receiving propofol had oliguria (,400 ml/d) less frequently (12.4% versus 19.6%, P=0.001) and had diuretics prescribed less often (8.5% versus 14.3%, P=0.001). In addition, during the first 7 days of ICU stay, patients receiving propofol less frequently achieved cumulative fluid balance .5% of body weight (50.1% versus 58.3%, P=0.01). The need for RRT in the first 7 days of ICU stay was also less frequent in propofol-treated patients (3.4% versus 5.9%, P=0.03). ICU mortality was lower in propofol-treated patients (14.6% versus 29.7%, P,0.001). ConclusionsIn this large, propensity-matched ICU population, patients treated with propofol had a lower risk of AKI, fluid-related complications, and need for RRT.

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“…We observed that ROS not only enhanced oxaliplatin sensitivity to CRC, but also contributed to epithelial-mesenchymal transition and cancer metastasis, which indicated that ROS may play an essential role in the development of cancers (10). Luo et al reported that GJs composed of Cx32 regulated the distribution of ROS (5). Therefore, we considered that ROS distribution modulated by GJs might contribute to the cytotoxicity of oxaliplatin.…”

Section: Discussionmentioning

confidence: 99%

“…The GJ enables cells to exchange ions and small molecules (with a molecule weight less than 1 kDa) directly, including calcium, glutathione, cyclic adenosine monophosphate and cyclic guanosine monophosphate. Molecules transferred through the GJ are essential for numerous physiological and pathological events (5,6). The connexin gene family constitutes 21 isoforms, the most significant of which is Cx43 (6).…”

Section: Introductionmentioning

confidence: 99%

Deficiency of gap junction composed of connexin43 contributes to oxaliplatin resistance in colon cancer cells

Zhang

2017

Oncology Letters

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Abstract. Although comprehensive strategies in the treatment of colorectal cancer have been developed for a number of years, the five-year survival rate of metastatic colon cancer remains less than 10%. Oxaliplatin, a commonly used chemotherapeutic agent for metastatic colon cancer, improves the response rate of patients and prolongs patients' progression-free survival. However, the generation of resistance limits the clinical application of oxaliplatin, and the mechanisms of this remain unclear. The present study mainly investigated the effect of the gap junction (GJ) composed of connexin43 (Cx43) on oxaliplatin cytotoxicity in colon cancer cells. Three different methods with distinct mechanisms were used to change the function of Cx43 GJs, including cell culture at different densities, pretreatment with a specific inhibitor or enhancer, and special gene knockdown, to observe the cytotoxicity of oxaliplatin and the level of reactive oxygen species (ROS) mediated by Cx43 GJs. The results revealed that the cytotoxicity of oxaliplatin and the level of ROS were decreased with the downregulation of Cx43 GJ function, but exacerbated with the upregulation of Cx43 GJ function. Moreover, ROS scavenging with N-acetyl-L-cysteine and apocynin decreased the cytotoxicity of oxaliplatin. We concluded that the loss of GJ composed of Cx43 contributed to the resistance of oxaliplatin in colon cancer cells, and the mechanism was associated with intracellular ROS alternation. IntroductionColorectal cancer (CRC) is considered to be one of the most frequent causes of cancer-related morbidity and mortality worldwide (1,2). Although comprehensive strategies in the treatment of CRC have been developed for a number of years, the five-year survival rate of metastatic colon cancer is only 10% (3). In the clinical treatment of metastatic colon cancer, oxaliplatin is commonly used as an essential chemotherapeutic agent, and not only improves the response rate of patients, but also prolongs patients' progression-free survival. Nevertheless, more than 40% of patients still develop significant resistance (3,4). Therefore, how to overcome resistance to oxaliplatin is a key scientific problem to be solved in the treatment of metastatic colon cancers.Connexins are integral membrane proteins, six of which make up a hemi-channel. Two hemi-channels in neighboring cells dock together to form an integral gap junction (GJ). The GJ enables cells to exchange ions and small molecules (with a molecule weight less than 1 kDa) directly, including calcium, glutathione, cyclic adenosine monophosphate and cyclic guanosine monophosphate. Molecules transferred through the GJ are essential for numerous physiological and pathological events (5,6). The connexin gene family constitutes 21 isoforms, the most significant of which is Cx43 (6). The loss of Cx43 is extremely common in the development of cancers and is even involved in advanced stages of tumor progression. The deficiency of Cx43 also contributes to the resistance of chemotherapeutic agents (7). It has been...

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Propofol Attenuated Acute Kidney Injury after Orthotopic Liver Transplantation via Inhibiting Gap Junction Composed of Connexin 32

Abstract: Cx32 plays a critical role in AOLT-induced AKI and that inhibition of Cx32 function may represent a new and major mechanism whereby propofol reduces oxidative stress and subsequently attenuates post-AOLT AKI.

Cited by 57 publications

References 49 publications

Propofol alleviates acute lung injury following orthotopic autologous liver transplantation in rats via inhibition of the NADPH oxidase pathway

Propofol alleviates acute lung injury following orthotopic autologous liver transplantation in rats via inhibition of the NADPH oxidase pathway

Renal Outcomes in Critically Ill Patients Receiving Propofol or Midazolam

Deficiency of gap junction composed of connexin43 contributes to oxaliplatin resistance in colon cancer cells

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