Plasma campesterol and ABCG5/ABCG8 gene loci on the risk of cholelithiasis and cholecystitis: evidence from Mendelian randomization and colocalization analyses.

The causal relationships between plasma metabolites and cholelithiasis/cholecystitis risks remain elusive. Using two-sample Mendelian randomization, we found that genetic proxied plasma campesterol level showed negative correlation with the risk of both cholelithiasis and cholecystitis. Furthermore, the increased risk of cholelithiasis is correlating with the increased level of plasma campesterol. Lastly, genetic colocalization study showed that the leading SNP, rs4299376, which residing at the ABCG5/ABCG8 gene loci, was shared by plasma campesterol level and cholelithiasis, indicating that the aberrant transportation of plant sterol/cholesterol from the blood stream to the bile duct/gut lumen might be the key in preventing cholesterol gallstone formation.

Effect of Premedication With Pronase Before Upper Gastrointestinal Endoscopy: A Multicenter Prospective Randomized Controlled Study.

OBJECTIVES: This study aimed to confirm whether premedication with pronase before endoscopy improves mucosal visualization and increases precancerous lesion and cancer lesion detection rates. MATERIALS AND METHODS: From June 2018 to April 2019, out-patients scheduled for endoscopy from 13 hospitals were screened to be randomly allocated in a 2:1 ratio to premedication with pronase (group A) and water (group B). The primary endpoint was mucosal visibility scores, and the secondary endpoint was precancerous and cancer lesion detection rates. This trial was registered at Chinese Clinical Trial Registry, and the registration number was ChiCTR1800016853. RESULTS: Group A showed significantly lower mucosal visibility scores (better mucosal visibility) of esophagus, stomach, and duodenum than group B, with all P -values <0.001. The overall cancer detection rates between group A and group B were 0.83 and 1.08%, and overall detection rates of precancerous and cancer lesion were 4.4 and 4.9%, both without significant difference ( P =1.000 and 0.824). In addition, the flushing volume (milliliter) of group A (10.52±23.41) was less than group B (36.30±52.11) ( P <0.001), and the flushing frequency of group A (0.46±1.01) was fewer than group B (1.62±2.12) ( P <0.001). CONCLUSIONS: Premedication with pronase could achieve better mucosal visibility and decrease flushing frequency and volume, but may not increase lesion detection rates.

Disease Burden of Total and Early-Onset Colorectal Cancer in China from 1990 to 2019 and Predictions of Cancer Incidence and Mortality.

Background: Understanding the temporal trends in the epidemiology of colorectal cancer (CRC) and early-onset CRC (EOCRC) in China is essential for policymakers to develop appropriate strategies to reduce the CRC burden. Methods: The prevalence, incidence, mortality, years of life lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life years (DALYs) of CRC were obtained from the Global Burden of Disease (GBD) Study 2019. The incidence and mortality of CRC over the next 25 years were predicted. Results: From 1990 to 2019, the prevalence, incidence, and mortality of total CRC and EOCRC significantly increased in males, with milder trends in females. In 2019, the number of people living with CRC (or EOCRC) in China was approximately 3.4 (0.59) million, which was over seven (five) times higher than that in 1990. The DALYs, YLDs, and YLLs moderately increased from 1990 to 2019 in both sexes. The age-standardized mortality rate (ASMR) for females has shown a stable trend in total CRC, and a downward trend in EOCRC since 2000. While the ASMR for males showed increasing trends in total CRC and EOCRC. In 2019, the highest incidence, prevalence, YLDs, YLLs, and DALYs were all observed in the 65 to 69 age group, while the highest mortality was in the 70 to 74. By 2044, the incidence and deaths of CRC are expected to reach 1310 thousand and 484 thousand, respectively. For EOCRC, the incidence will peak at about 101 thousand around 2034, and the mortality will continuously decrease to a nadir at about 18 thousand around 2044. Conclusion: Although the age-standardized incidence and mortality of total CRC and EOCRC in China will reach a plateau, the number of incident cases and deaths of CRC have been increasing in the last three decades and will continue to increase in the next 25 years.

Screening and Identification of a Novel Anti-Siglec-15 Human Antibody 3F1 and Relevant Antitumor Activity.

Sialic acid-binding Ig-like lectin-15 is an important immunosuppressive molecule considered to be a key target in next-generation tumor immunotherapy. In this study, we screened 22 high-affinity antibodies that specifically recognize human Siglec-15 by using a large human phage antibody library, and five representative sequences were selected for further study. The results showed the binding activity of five antibodies to Siglec-15 (EC50 ranged from 0.02368 µg/mL to 0.07949 µg/mL), and in two Siglec-15-overexpressed cell lines, three antibodies had the strongest binding activity, so the two clones were discarded for further study. Subsequently, the affinity of three antibodies were measured by bio-layer interferometry technology (5-9 × 10E-09M). As the reported ligands of Siglec-15, the binding activity of Siglec-15 and sialyl-Tn, cluster of differentiation 44, myelin-associated glycoprotein, and leucine-rich repeat-containing protein 4C can be blocked by three of the antibodies. Among these, 3F1 had a competitive advantage. Then, the antibody 3F1 showed an obvious antibody-dependent cell-mediated cytotoxicity effect (EC50 was 0.85 µg/mL). Further, antibody 3F1 can reverse the inhibitory effect of Siglec-15 on lymphocyte proliferation (especially CD4+T and CD8+T) and cytokine release Interferon-γ. Given the above results, 3F1 was selected as a candidate for the in vivo pharmacodynamics study. In the tumor model of Balb/c Nude mice, 3F1 (10 mg/kg) showed certain antitumor effects [tumor growth inhibition (TGI) was 31.5%], while the combination of 3F1 (5 mg/kg) and Erbitux (5 mg/kg) showed significant antitumor effects (TGI was 48.7%) compared with the PBS group. In conclusion, novel human antibody 3F1 has antitumor activity and is expected to be an innovative candidate drug targeting Siglec-15 for tumor immunotherapy. SIGNIFICANCE STATEMENT: Siglec-15 is considered as an important target in the next generation of tumor immunotherapy. 3F1 is expected to be the most promising potential candidate for targeting Siglec-15 for cancer treatment and could provide a reference for the development of antitumor drugs.

A Novel Humanized Anti-Abrin A Chain Antibody Inhibits Abrin Toxicity In Vitro and In Vivo.

Abrin, a type-II ribosome inactivating protein from the seed of Abrus precatorius, is classified as a Category B bioterrorism warfare agent. Due to its high toxicity, ingestion by animals or humans will lead to death from multiple organ failure. Currently, no effective agents have been reported to treat abrin poisoning. In this study, a novel anti-abrin neutralizing antibody (S008) was humanized using computer-aided design, which possessed lower immunogenicity. Similar to the parent antibody, a mouse anti-abrin monoclonal antibody, S008 possessed high affinity and showed a protective effect against abrin both in vitro and in vivo, and protected mice that S008 was administered 6 hours after abrin. S008 was found that it did not inhibit entry of abrin into cells, suggesting an intracellular blockade capacity against the toxin. In conclusion, this work demonstrates that S008 is a high affinity anti-abrin antibody with both a neutralizing and protective effect and may be an excellent candidate for clinical treatment of abrin poisoning.

Selection and Characterization of FD164, a High-Affinity Signal Regulatory Protein α Variant with Balanced Safety and Effectiveness, from a Targeted Epitope Mammalian Cell-Displayed Antibody Library.

Phagocytic resistance plays a key role in tumor-mediated immune escape, so phagocytosis immune checkpoints are a potential target for cancer immunotherapy. CD47 is one of the important phagocytosis immune checkpoints; thus, blocking the interaction between CD47 and signal regulatory protein α (SIRPα) may provide new options for cancer treatment. Using computer-aided targeted epitope mammalian cell-displayed antibody library, we screened and obtained an engineered SIRPα variant fragment crystallizable fusion protein, FD164, with higher CD47-binding activity than wild-type SIRPα Compared with wild-type SIRPα, FD164 has approximately 3-fold higher affinity for binding to CD47, which further enhanced its phagocytic effect in vitro and tumor suppressor activity in vivo. FD164 maintains the similar antitumor activity of the clinical research drug Hu5F9 in the mouse xenograft model. Furthermore, FD164 combined with rituximab can significantly improve the effect of single-agent therapy. On the other hand, compared with Hu5F9, FD164 does not cause hemagglutination, and its ability to bind to red blood cells or white blood cells is weaker at the same concentration. Finally, it was confirmed by computer structure prediction and alanine scanning experiments that the N45, E47, 52TEVYVK58, K60, 115EVTELTRE122, and E124 residues of CD47 are important for SIRPα or FD164 recognition. Briefly, we obtained a high-affinity SIRPα variant FD164 with balanced safety and effectiveness. SIGNIFICANCE STATEMENT: Up to now, few clinically marketed drugs targeting CD47 have been determined to be effective and safe. FD164, a potential signal regulatory protein α variant fragment crystallizable protein with balanced safety and effectiveness, could provide a reference for the development of antitumor drugs.

Identification of a novel protective human monoclonal antibody, LXY8, that targets the key neutralizing epitopes of staphylococcal enterotoxin B.

Staphylococcal enterotoxin B (SEB), one of the exotoxins produced by Staphylococcus aureus, is the key toxin that causes poisoning reactions and toxic shock syndrome. In the current research work, a novel human antibody named LXY8 was screened from a human phage display antibody library, and LXY8 blocked the interaction between SEB and the T cell receptor (TCR). The binding activity between LXY8 and SEB was 0.525 nM. Furthermore, LXY8 could effectively inhibit the SEB-induced activation of peripheral blood mononuclear cells and release of cytokines. In the BALB/c mouse model, LXY8 effectively neutralized SEB toxicity in vivo. Finally, based on computer-guided molecular modeling, we designed a series of SEB mutation sites; these sites facilitated the determination of the key residues (i.e.176EFNN179) of SEB recognized by LXY8. The research revealed that the 176EFNN179 residues of SEB are important for specific antibody-antigen recognition. The results may be helpful for the development of antibody-based therapy for SEB-induced toxic shock syndrome.

MiR-129-5p induces cell cycle arrest through modulating HOXC10/Cyclin D1 to inhibit gastric cancer progression.

MicroRNAs (miRNAs) play important roles in posttranscriptional regulation and may serve as targets for the diagnosis and treatment of cancers. Nevertheless, a comprehensive understanding of miRNAs profiles in gastric cancer progression is still lacking. Here, we report that miR-129-5p is downregulated in gastric cancer by analyzing TCGA database (n = 41) and clinical tumor samples (n = 60). MiR-129-5p transfection suppressed gastric cancer cell proliferation through inducing G1 phase arrest in vitro and inhibit xenograft tumor growth in vivo. MiR-129-5p directly targeted the 3' untranslated regions (3' UTR) of HOXC10 mRNA and downregulated its expression. Importantly, miR-129-5p could reverse the oncogenic effect induced by HOXC10. We systemically screened the downstream target of HOXC10 by ChIP sequencing, and found that HOXC10 could transcriptionally regulate the expression of Cyclin D1 and facilitate G1/S cell cycle transition. Notably, high levels of HOXC10 and Cyclin D1 were related with poor prognosis of gastric cancer patients (n = 90). These findings reveal a novel role of miR-129-5p/HOXC10/Cyclin D1 axis in modulating cell cycle and gastric tumorigenesis, which might provide potential prognostic biomarkers and therapeutic targets for gastric cancer patients.

Characteristics of Atrial Fibrillation Patients Suffering Esophageal Injury Caused by Ablation for Atrial Fibrillation.

The close proximity of esophagus to the left atrial posterior wall predisposes esophagus to thermal injury during catheter ablation for atrial fibrillation (AF). In this retrospective study, we aimed to investigate risk factors of esophageal injury (EI) caused by catheter ablation for AF. Patients who underwent first-time AF ablation from July 2013 to June 2018 were included. The esophagus was visualized by oral soluble contrast during ablation for all patients and a subset of patients were selected to undergo endoscopic ultrasonography (EUS) to estimate EI post ablation. Degree of EI was categorized as Kansas City classification: type 1: erythema; type 2: ulcers (2a: superficial ulcers; 2b: deep ulcers); type 3: perforation (3a: perforation without communication with the atria; 3b: atrioesophageal fistula [AEF]). Of 3,852 patients, 236 patients (61.5 ± 9.7 years; male, 69%) received EUS (EUS group) and 3616 (63.2 ± 10.9 years; male, 61.1%) without EUS (No-EUS group). In EUS group, EI occurred in 63 patients (type 1 EI in 35 and type 2 EI in 28), and no type 3 EI was observed during follow up. In a multivariable logistic regression analysis, an overlap between the ablation lesion and esophagus was an independent predictor of EI (odds ratio, 21.2; 95% CI: 6.23-72.0; P < 0.001). In No-EUS group, esophagopericardial fistula (EPF; n = 3,0.08%) or AEF (n = 2,0.06%) was diagnosed 4-37 days after ablation. In 3 EPF patients, 2 completely recovered with conservative management and 1 died. Two AEF patients died. Ablation at the vicinity of the esophagus predicts risk of EI. EUS post ablation may prevent the progression of EI and should be considered in management of EI. It remains challenging to identify patients with high risk of EI.

Endoscopic submucosal dissection for localised gastric amyloidosis mimicking malignancy / Disección submucosa endoscópica para la amiloidosis localizada gástrica que simula una malignidad

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Surgical versus endoscopic resection of large sessile duodenal and papillary lesions.

BACKGROUND: Data on the endoscopic resection of duodenal and papillary lesions less than 15 mm in size have been well supported by systematic studies. However, for large sessile lesions of the duodenum or papilla (LSL-D/P), surgery is often performed despite significant morbidity and mortality. This study aimed to compare the outcomes and costs between endoscopic and surgical resection of such lesions. METHODS: Patients who underwent endoscopic or surgical resection of LSL-D/P at Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University from 2013 to 2017 were retrospectively analyzed. Endoscopic and surgical outcomes and costs were compared. RESULTS: A total of 68 lesions were evaluated (47.1% of patients were male; mean lesion size 25 mm); 46 were treated by endoscopic resection, and 22 were managed by surgical resection. At the initial procedure, complete resection was achieved in 93.4%. Major complications (perforation, delayed bleeding, pancreatitis, infections and admission to the ICU) occurred in 15.3% of the endoscopic group and 22.6% of the surgical group. For recurrence at the first surveillance endoscopic examination, there was a 12.1% recurrence rate in the endoscopic group and a 5.3% recurrence rate in the surgical group (P = 0.654). Compared with surgical resection, regardless of lesion location, endoscopic resection had a shorter procedural time and hospital stay, a lower morbidity rate and was less costly. CONCLUSION: In centers specialized in complex endoscopic resection, patients with LSL-D/P would likely benefit from advanced endoscopic management, which offers a lower morbidity profile and reduced costs.

Purification of water contaminated with Hg using horizontal subsurface constructed wetlands.

As a global pollutant, Hg (Hg) since the turn of the last century has received increased attention. Decreasing the emission of Hg into the food chain and the atmosphere is an effective way to reduce the Hg damage. The current study provided information about pilot-scale horizontal subsurface flow (HSSF) constructed wetlands (CWs) to remove different Hg species in polluted water. Synthetic wastewater was fed to two HSSF CWs, one was planted with Acorus calamus L and the other was unplanted as a control. The total Hg (THg), dissolved Hg (DHg), and particulate Hg (PHg) from five sites along the HSSF CWs were analyzed to describe the process of Hg removal. Results show that the CWs have high removal efficiency of Hg which is more than 90%. The removal efficiencies of THg and DHg from the unplanted CW were 92.1 ± 3.6% and 72.4 ± 13.1%, respectively. While, the removal efficiencies of THg and DHg in planted CW were 95.9 ± 7.5% and 94.9 ± 4.9%, which were higher than that in blank CW. The PHg was mainly removed in the first quarter of the CWs, which was also revealed by the partition coefficient Kd. To a certain extent, the effect of plants depends on the hydraulic retention time (HRT). The results in the current study show the potential of the HSSF-CWs for restoration from Hg-contaminated water.

Investigation on the carbon sequestration capacity of vegetation along a heavy traffic load expressway.

Carbon sequestration by vegetation plays an important role in the global carbon cycle. More emphasis on the carbon sequestration of roadside vegetation will help to reduce the total carbon emissions from the transportation sector. In the current study, the Shanghai-Nanjing G42 expressway in east China was selected to investigate and calculate the carbon sequestration of roadside vegetation including trees, shrubs and herbs. Findings of the current study revealed that the total carbon sequestration of all the vegetation was about 97,000 tons per year. Results also indicated that trees have a higher carbon sequestration capacity (γ) in unit land area compared to shrubs and herbs. The γ value of most of the shrubs was lower than that of tree; however, species such as Nerium indicum, Jasminum mesnyi and Forsythia suspense have better carbon sequestration capacity than some other tree species. The γ value of herbs was too low, compared with trees and shrubs. The findings of the current study will be of great benefit to make the vegetation planting strategy for express highways in the areas with similar geographic characteristics and climate.

Accuracy of ASGE high-risk criteria in evaluation of patients with suspected common bile duct stones.

BACKGROUND AND AIMS: ERCP is recommended for patients considered high risk for choledocholithiasis after biochemical testing and abdominal US. Our aim was to determine whether the American Society for Gastrointestinal Endoscopy (ASGE) guidelines accurately select patients for whom the risk of ERCP is justified. METHODS: Consecutive patients hospitalized with suspected choledocholithiasis at Sir Run Run Shaw Hospital who received biochemical testing, abdominal US, and definitive testing for choledocholithiasis (MRCP, EUS, ERCP, intraoperative cholangiogram, and/or common bile duct [CBD] exploration) were identified. Patients with choledocholithiasis on abdominal US, with bilirubin levels >4 mg/dL (normal values <1.2 mg/dL), bilirubin levels ≥1.8 mg/dL plus a dilated CBD and/or clinical cholangitis were considered high risk per ASGE guidelines. RESULTS: Of 2724 patients with suspected choledocholithiasis, 1171 (43%) met high-risk criteria. Definitive testing (MRCP in 2442 [90%], EUS in 67 [2%], ERCP in 659 [24%], intraoperative cholangiogram in 229 [8%], and CBD exploration in 447 [16%]) revealed choledocholithiasis in 1076 [40%] patients. The specificity of the ASGE high-risk criteria was 74% (95% confidence interval [CI], 72%-77%) and positive predictive value was 64% (95% CI, 61%-67%). Using a more restrictive criteria (choledocholithiasis on abdominal US, bilirubin >4 mg/dL plus dilated CBD) improved the specificity to 94% (95% CI, 93%-95%) and positive predictive value to 85% (95% CI, 82%-88%). Doubling or more of bilirubin to >4 mg/dL and ≥1.8 mg/dL at second testing had specificities of 98% (95% CI, 96%-99%) and 95% (95% CI, 93%-96%), with positive predictive values of 62% (95% CI, 48%-76%) and 54% (95% CI, 44%-65%), respectively. CONCLUSIONS: Although ASGE high-risk criteria demonstrated >50% probability of the patient having choledocholithiasis, more than a third of the patients would receive diagnostic ERCPs. Criteria with choledocholithiasis on abdominal US and/or bilirubin levels >4 mg/dL plus a dilated CBD showed higher specificity and positive predictive value.

Diagnostic accuracy of DNA methylation in detection of gastric cancer: a meta-analysis.

Emerging studies demonstrate the diagnostic utility of DNA methylation-based blood test for gastric cancer. The aim of the meta-analysis is to evaluate the accuracy of blood DNA methylation markers for detecting patients with gastric cancer. A systematic literature search to November 2016 that evaluated DNA methylation markers utilizing blood specimen to detect gastric cancer were selected to derive pooled sensitivities and specificities. 32 studies including 4,172 patients (gastric cancer (N = 2,098), control (N = 2,074)) met the study criteria. Overall sensitivity of DNA methylation-based blood test for detecting gastric cancer was 57% (95% CI 50-63%); specificity was 97% (95% CI 95-98%). Among patients who received plasma-based testing, sensitivity was 71% (95% CI 59-81%); specificity was 89% (95% CI 78-94%). Among patients who received serum-based testing, sensitivity was 50% (95% CI 43-58%); specificity was 98% (95% CI 96-99%). Using multiple methylated genes had sensitivity of 76% (95% CI 64-84%); specificity of 85% (95% CI 65-95%). DNA methylation test had sensitivity of 55% (95% CI 47-64%) and specificity of 96% (95% CI 92-98%) for detecting TNM stage I+II gastric cancer. In conclusion, blood-based DNA methylation test had high specificity but modest sensitivity for detecting gastric cancer. Evaluating multiple methylated genes or using plasma sample may improve the diagnostic sensitivity.

A retrospective study of pyogenic liver abscess focusing on Klebsiella pneumoniae as a primary pathogen in China from 1994 to 2015.

Pyogenic liver abscess (PLA) is a common intra-abdominal infection in adults. In this study, we aim to explore demographic and clinical characteristics of PLA focusing on Klebsiella pneumoniae (K. pneumoniae) induced PLA (KP-PLA) in mainland China. A retrospective review of medical records from all patients with KP-PLA admitted to a tertiary teaching hospital over a 21-year period (1994-2015) was performed. Among 296 PLA cases with confirmed culture-positive data, K. pneumoniae was revealed as the predominant pathogen (n = 189, 63.9%), followed by Escherichia coli (n = 39, 13.2%). Strikingly, KP-PLA patients had a higher incidence of metabolic disorders, such as diabetes mellitus (49.7% vs. 36.4%, P = 0.027; odds ratio (OR): 1.725; 95% confidence interval (CI): 1.061-2.805), hypertension (38.1% vs. 19.6%, P = 0.001; OR: 2.520; 95% CI: 1.439-4.413), and fatty liver (32.3% vs. 14.0%, P = 0.001; OR: 2.923; 95% CI: 1.564-5.462) than those with non-K. pneumoniae induced PLA (non-KP-PLA). Moreover, patients with KP-PLA had higher susceptibility to septic metastatic infection at distant sites compared to those with non-KP-PLA (10.6% vs. 3.7%, p = 0.038). Our results indicate that K. pneumoniae is the predominant pathogen of PLA in mainland China. KP-PLA is frequently diagnosed in patients with metabolic diseases and has a higher risk for septic metastatic infection.

Computer-simulated biopsy marking system for endoscopic surveillance of gastric lesions: a pilot study.

Endoscopic tattoo with India ink injection for surveillance of premalignant gastric lesions is technically cumbersome and may not be durable. The aim of the study is to evaluate the accuracy of a novel, computer-simulated biopsy marking system (CSBMS) developed for the endoscopic marking of gastric lesions. Twenty-five patients with history of gastric intestinal metaplasia received both CSBMS-guided marking and India ink injection in five points in the stomach at index endoscopy. A second endoscopy was performed at three months. Primary outcome was accuracy of CSBMS (distance between CSBMS probe-guided site and tattoo site measured by CSBMS). The mean accuracy of CSBMS at angularis was 5.3 ± 2.2 mm, antral lesser curvature 5.7 ± 1.4 mm, antral greater curvature 6.1 ± 1.1 mm, antral anterior wall 6.9 ± 1.6 mm, and antral posterior wall 6.9 ± 1.6 mm. CSBMS (2.3 ± 0.9 versus 12.5 ± 4.6 seconds; P = 0.02) required less procedure time compared to endoscopic tattooing. No adverse events were encountered. CSBMS accurately identified previously marked gastric sites by endoscopic tattooing within 1 cm on follow-up endoscopy.

Rexinoid inhibits Nrf2-mediated transcription through retinoid X receptor alpha.

NF-E2 P45-related factor 2 (Nrf2) is a key transcription factor that controls genes encoding cytoprotective and detoxifying enzymes through antioxidant response elements (AREs) in their regulatory regions. We reported recently that retinoid X receptor alpha (RXRα) inhibits Nrf2 function by direct interaction with the Neh7 domain of Nrf2 in a ligand-independent manner. Here, we provide evidence that an RXRα-specific ligand, bexarotene, dose-dependently inhibits the mRNA expression of ARE-driven genes. Knock-down of RXRα by siRNA abolished the inhibitory effect of bexarotene. Conversely, the over-expression of RXRα enhanced the inhibition by bexarotene, indicating that the effect is mediated by RXRα. The inhibition by bexarotene was also found in the non-small-cell lung cancer cell line A549, which carries a dysfunctional somatic mutation of Kelch-like ECH-associated protein 1 (KEAP1), suggesting that KEAP1 is not involved. Our results demonstrate that rexinoid is able to inhibit the transcriptional activity of Nrf2, and that RXRα can repress the cytoprotection pathway in a ligand-dependent manner.

Oxaliplatin activates the Keap1/Nrf2 antioxidant system conferring protection against the cytotoxicity of anticancer drugs.

Oxaliplatin is an important drug in the treatment of advanced metastatic colorectal cancer. NF-E2 p45-related factor 2 (Nrf2) is a key transcription factor that controls genes encoding cytoprotective and detoxifying enzymes through antioxidant-response elements (AREs) in their regulatory regions. Here, we report that oxaliplatin is an activator of the Nrf2 signaling pathway, with upregulation of ARE-driven genes and glutathione elevation. An injection of oxaliplatin into mice enhanced the expression of glutathione transferases and antioxidant enzymes in the small and large intestines of wild-type (WT) mice but not Nrf2(-/-) mice, indicating that oxaliplatin activates Nrf2 in vivo. Oxaliplatin failed to increase Nrf2 accumulation in non-small-cell lung cancer A549 cells, which harbor a dysfunctional somatic mutation of KEAP1. However, forced expression of WT mKeap1 restored the ability of oxaliplatin to activate the transcription factor. Cys(151) in Keap1 was required for the response stimulated by oxaliplatin. In addition, dichloro(1,2-diaminocyclohexane) platinum, a metabolite of oxaliplatin, was found to have the same effect in activating the ARE-gene battery as its parent drug, whereas another metabolite, oxalate, was ineffective. Moreover, two other platinum derivatives, cisplatin and carboplatin, had no effect on the Keap1/Nrf2 system. Furthermore, activation of Nrf2 by oxaliplatin reduced the sensitivity of colon cancer cells to therapeutic drugs. Conversely, knockdown of Nrf2 by Nrf2 siRNA reduced oxaliplatin-induced chemoresistance. Our study showed that oxaliplatin exerts protection against the cytotoxicity of anticancer drugs via Nrf2, indicating an important role of Nrf2 in oxaliplatin-based chemotherapy.