Role of intraoperative oliguria in risk stratification for postoperative acute kidney injury in patients undergoing colorectal surgery with an enhanced recovery protocol: A propensity score matching analysis.

BACKGROUND: The enhanced recovery after surgery (ERAS) protocol for colorectal cancer resection recommends balanced perioperative fluid therapy. According to recent guidelines, zero-balance fluid therapy is recommended in low-risk patients, and immediate correction of low urine output during surgery is discouraged. However, several reports have indicated an association of intraoperative oliguria with postoperative acute kidney injury (AKI). We investigated the impact of intraoperative oliguria in the colorectal ERAS setting on the incidence of postoperative AKI. PATIENTS AND METHODS: From January 2017 to August 2019, a total of 453 patients underwent laparoscopic colorectal cancer resection with the ERAS protocol. Among them, 125 patients met the criteria for oliguria and were propensity score (PS) matched to 328 patients without intraoperative oliguria. After PS matching had been performed, 125 patients from each group were selected and the incidences of AKI were compared between the two groups. Postoperative kidney function and surgical outcomes were also evaluated. RESULTS: The incidence of AKI was significantly higher in the intraoperative oliguria group than in the non-intraoperative oliguria group (26.4% vs. 11.2%, respectively, P = 0.002). Also, the eGFR reduction on postoperative day 0 was significantly greater in the intraoperative oliguria than non-intraoperative oliguria group (-9.02 vs. -1.24 mL/min/1.73 m2 respectively, P < 0.001). In addition, the surgical complication rate was higher in the intraoperative oliguria group than in the non-intraoperative oliguria group (18.4% vs. 9.6%, respectively, P = 0.045). CONCLUSIONS: Despite the proven benefits of perioperative care with the ERAS protocol, caution is required in patients with intraoperative oliguria to prevent postoperative AKI. Further studies regarding appropriate management of intraoperative oliguria in association with long-term prognosis are needed in the colorectal ERAS setting.

XAV939, a Wnt/ß-catenin pathway modulator, has inhibitory effects on LPS-induced inflammatory response.

Aim: In this study, we report the anti-inflammatory activity of XAV939, a modulator of the Wnt/ß-catenin pathway. Methods: WNT/ß-catenin pathway and NF-κB signaling pathway were examined in LPS-stimulated human bronchial epithelial cells and effects of XAV939 on these pathways were analyzed. The effect of XAV939 was confirmed in human umbilical vein endothelial cells. Results: LPS-induced expressions of pro-inflammatory genes IL-6, IL-8, TNF-α, IL-1ß, MCP-1, MMP-9, iNOS and COX-2 were significantly and dose-dependently suppressed by XAV939. LPS-induced NF-κB signaling, such as IκB phosphorylation and degradation as well as nuclear translocation of NF-κB, was also suppressed by XAV939. Target DNA binding of NF-κB was significantly and dose-dependently suppressed by XAV939 during LPS-induced inflammatory response. The suppressive effects of XAV939 on NF-κB signaling, target DNA binding of NF-κB and pro-inflammatory gene expression were all rescued by over expression of ß-catenin, which shows that the anti-inflammatory effect of XAV939 is mediated by the modulation of ß-catenin, a central component of the WNT/ß-catenin pathway. Conclusion: The findings of this study showed that XAV939 exerts anti-inflammatory effects through the modulation of the Wnt/ß-catenin pathway.

Gangjihwan, a polyherbal composition, inhibits fat accumulation through the modulation of lipogenic transcription factors SREBP1C, PPARγ and C/EBPα.

ETHNOPHARMACOLOGICAL RELEVANCE: Gangjihwan (DF) which is composed of Ephedra intermedia, Lithospermum erythrorhizon, and Rheum palmatum has been used for the treatment of obesity in traditional medical clinics in Korea. AIM OF THE STUDY: This study was conducted to standardize DF and elucidate its mechanism of action for inhibiting fat accumulation in adipocytes and adipose tissues. MATERIALS AND METHODS: The herbal ingredients of DF were extracted in water, 30% ethanol or 70% ethanol and freeze-dried followed by HPLC analyses. 3T3-L1 adipocytes and high-fat diet-induced obese mice were treated with each of the three DF preparations. Messenger RNA and protein expression levels were measured by real-time qPCR and Western blotting. RNA-Seq analyses were conducted to examine the effects of DF treatment on whole transcriptome of adipocyte. RESULTS: (-)-Ephedrine and (+)-pseudoephedrine from E. intermedia, aloe-emodin and chrysophanol from R. palmatum and shikonin from L. erythrorhizon were identified as phytochemical components of DF. DF caused dose-dependent inhibition of fat accumulation in 3T3-L1 adipocytes. It also significantly reduced adipose tissue mass and adipocyte size in high-fat diet-induced obese mice. DF was found to down-regulate the expressions of the lipogenic transcription factors such as sterol regulatory element binding protein 1C (SREBP1C), peroxisome proliferator activated receptor gamma (PPARγ), and CCAAT/enhancer binding protein alpha (C/EBPα). Among the three preparations of DF, the 70% ethanol extract was the most effective. RNA-Seq analyses showed that DF treatment decreased the expression levels of up-regulators and increased those of down-regulators of lipogenic transcription factors. CONCLUSIONS: DF preparations, among which 70% ethanol extract was the most effective, reduced fat accumulation in 3T3-L1 adipocytes and high-fat diet-induced obese mice through the down-regulation of lipogenic transcription factors SREBP1C, PPARγ and C/EBPα.

Berberine activates AMPK to suppress proteolytic processing, nuclear translocation and target DNA binding of SREBP-1c in 3T3-L1 adipocytes.

AMP-activated protein kinase (AMPK) and sterol regulatory element binding protein (SREBP)­1c are major therapeutic targets in the treatment of metabolic diseases. In the present study, the fat­reducing mechanisms of berberine (BBR), a natural isoquinoline, was investigated by examining the AMPK­mediated modulation of SREBP­1c in 3T3­L1 adipocytes. BBR activated AMPK in a dose­ and time­dependent manner, and increased the phosphorylation of the 125­kDa precursor form of SREBP­1c, which suppressed its proteolytic processing into the mature 68­kDa form and its subsequent nuclear translocation. The binding of nuclear SREBP­1c to its E­box motif­containing target DNA sequence was decreased following treatment with BBR, which led to a decrease in the expression of lipogenic genes and subsequently reduced intracellular fat accumulation. Transfection with AMPKα1 siRNA, and not control siRNA, inhibited BBR­induced phosphorylation of the 125­kDa SREBP­1c, which confirmed that AMPK was responsible for phosphorylating SREBP­1c. AMPKα1 siRNA transfection rescued the proteolytic processing, nuclear translocation and target DNA binding of SREBP­1c that had been suppressed by BBR. In addition, BBR­induced suppression of lipogenic gene expression and intracellular fat accumulation were rescued by AMPKα1 siRNA transfection. In conclusion, the results of the present study demonstrate that BBR activates AMPK to induce phosphorylation of SREBP­1c, thereby suppressing proteolytic processing, nuclear translocation and target DNA binding of SREBP­1c, which leads to a reduction in lipogenic gene expression and intracellular fat accumulation. The results of the present study indicate that BBR may be a potential candidate for the development of drugs to treat obesity.

WNT/ß-catenin pathway modulates the TNF-α-induced inflammatory response in bronchial epithelial cells.

In this study, TNF-α was found to activate the WNT/ß-catenin pathway in BEAS-2B human bronchial epithelial cells. Levels of phospho-LRP6, Dvl-2, and phospho-GSK-3ß were elevated, while that of Axin was reduced by TNF-α treatment. Nuclear translocation of ß-catenin and the reporter activity of a ß-catenin-responsive promoter were increased by TNF-α treatment. Under the same experimental conditions, TNF-α activated the NF-κB signaling, which includes the phosphorylation and degradation of IκB and nuclear translocation and target DNA binding of NF-κB, and it was found that an inhibitor of NF-κB activation, JSH-23, inhibited TNF-α-induced Wnt signaling as well as NF-κB signaling. It was also found that recombinant Wnt proteins induced NF-κB nuclear translocations and its target DNA binding, suggesting that Wnt signaling and NF-κB signaling were inter-connected. TNF-α-induced modulations of IκB and NF-κB as well as pro-inflammatory cytokine expression were significantly suppressed by the transfection of ß-catenin siRNA compared to that of control siRNA. Transfection of a ß-catenin expression plasmid augmented the TNF-α-induced modulations of IκB and NF-κB as well as pro-inflammatory cytokine expression. These results clearly demonstrated that the WNT/ß-catenin pathway modulates the inflammatory response induced by TNF-α, suggesting that this pathway may be a useful target for the effective treatment of bronchial inflammation.

LPS-induced inflammatory response is suppressed by Wnt inhibitors, Dickkopf-1 and LGK974.

In this study, LPS-induced inflammatory responses in BEAS-2B human bronchial epithelial cells and human umbilical vein endothelial cell (HUVEC)s were found to be prevented by Dickkopf-1 (DKK-1), a secreted Wnt antagonist, and LGK974, a small molecular inhibitor of the Wnt secretion. LPS-induced IκB degradation and NF-κB nuclear translocation as well as the expressions of pro-inflammatory genes including IL-6, IL-8, TNF- α, IL-1ß, MCP-1, MMP-9, COX-2 and iNOS, were all suppressed by DKK-1 and LGK974 in a dose-dependent manner. The suppressive effects of LGK974 on NF-κB, IκB, and pro-inflammatory gene expression were rescued by ectopic expression of ß-catenin, suggesting that the anti-inflammatory activity of LGK974 is mediated by modulation of the Wnt/ß-catenin pathway and not by unrelated side effects. When Wnt recombinant proteins were treated to cells, Wnt3a and Wnt5a significantly induced pro-inflammatory gene expressions, while Wnt7a and Wnt10b showed little effects. It was also found that Wnt3a and Wnt5a expressions were significantly induced by LPS treatment. Consistently, knockdown of Wnt3a and Wnt5a blocked LPS-induced inflammatory responses, while treatment of recombinant Wnt3a and Wnt5a proteins rescued the inhibition of inflammatory responses by LGK974. Findings of this study showed that DKK-1 and LGK974 suppress LPS-induced inflammatory response by modulating Wnt/ß-catenin pathway.

Mammary duct ectasia with bloody nipple discharge in a child.

Mammary duct ectasia is a rare disease in children and often presents as a cystic mass with bloody nipple discharge. The pathophysiology of mammary duct ectasia is unclear, and the differential diagnosis of other cystic masses with hemorrhage, such as complicated lymphangioma, is necessary. Here, we report a 14-month-old boy who exhibited unilateral mammary duct ectasia with bloody nipple discharge that was treated with surgical excision. Because some authors have reported that mammary duct ectasia can be often be resolved without surgery, conservative therapy should be considered first when a child presents with a cystic mass with bloody nipple discharge. However, the optimal duration of follow-up and timing of surgical excision have not yet been established.