The natural pesticide dihydrorotenone induces human plasma cell apoptosis by triggering endoplasmic reticulum stress and activating p38 signaling pathway
Authors: Zubin Zhang
Juan Tang
Sudan He
Xinliang Mao
Jie Li
Aaron D Schimmer
Jieyu Zhang
Biyin Cao
Journal: PLoS ONE (2013)
Discipline: Multidisciplinary
Keywords: Dihydrorotenone; pesticide; mitochondrial inhibitor; Parkinsonian syndrome; cytotoxicity
Affiliations: Cyrus Tang Hematology Center, Soochow University, Suzhou, China.

Abstract:  Dihydrorotenone (DHR) is a natural pesticide widely used in farming industry, such as organic produces. DHR is a potent mitochondrial inhibitor and probably induces Parkinsonian syndrome, however, it is not known whether DHR is toxic to other systems. In the present study, we evaluated the cytotoxicity of DHR on human plasma cells. As predicted, DHR impaired mitochondrial function by decreasing mitochondrial membrane potential in plasma cells. Because mito-dysfunction leads to unfolded protein response (UPR) and endoplasmic reticulum (ER) stress, we examined the signature proteins in ER stress, including GRP78, ATF4, and CHOP. After DHR treatment, these proteins were significantly upregulated. It is reported that activation of the mitogen-activated protein kinases p38 and JNK are involved in endoplasmic reticulum stress. However, in the subsequent study, DHR was found to activate p38 but not the JNK signaling. When pre-treated with p38 inhibitor SB203580, activation of p38 and cell apoptosis induced by DHR was partially blocked. Thus, we found that DHR induced human plasma cell death by activating the p38 but not the JNK signaling pathway. Because plasma cells are very important in the immune system, this study provided a new insight in the safety evaluation of DHR application. 

Retracted: No

PubPeer comments:
 June 2, 2020 mega-correction, which reads: After publication of this article [1], similarities were noted between the following figure panels: * Fig 1, FACS plots shown for OPM2 5u03bcM DHR and KMS11 5u03bcM DHR * u03b2-actin blots for KMS11 in Fig 3A and for OPM2 in Fig 5A An error was made in preparing Fig 1 such that the OPM2 FACS plot is duplicated in the KMS11 panel. In addition, there are errors in the percentages reported on the U266 0 u03bcM DHR and KMS11 30 u03bcM DHR panels. A corrected Fig 1 is provided with this Correction; dot plots and quantitative data for these FACS analyses are in S1 File. The experiments in Fig 3A and 3C are mislabeled: these experiments were conducted in OPM2 cells, not KMS11 cells, and used the same blots as the GPR78 experiment shown in Fig 5A. Hence, the same u03b2-actin control blot applied for Fig 3A and 5A. The u03b2-actin data shown in the indicated panels were obtained by cutting the blot used for the Bim experiment shown in Fig 3A and then probing the resultant membrane strips (from the same blot) for u03b2-actin, GAPDH, and Bim. The GPR78 experiment was done subsequently by stripping the Bim blot. The available original data for the Fig 3A and 3C experiments are in S1u2013S3 Files. Both u03b2-actin and GAPDH controls were included in these experiments but only a single loading control was included in each Fig. The control data shown in Fig 3C are mislabeled, these panels show GAPDH results. The LP1 u03b2-actin blot in the original published Fig 3A does not match the original data provided for this experiment and this is addressed in the updated Fig 3. In addition, incorrect percentages are reported in Fig 2C for the right quadrants of the KMS11 DHR+Z-VAD plot; in Fig 4A for DMSO, TMRM+; and in Fig 4C for the lower left quadrant of the 24 h panel. These errors have been corrected in the updated Figs with this notice. In the new version of Fig 4, the histograms in Fig 4A have been replaced to align with available raw data from the original experiments. Traces, dot plots, and quantitative data supporting these FACS results are in S1 File. The raw data files (.fcs) to support the flow cytometry results are no longer available. , 
 Duplications in Figure 1 as reported to the journal in 2014, six years ago. ![file] , 
 Thanks for your close attention. We have sent the corrected Figure 1 to the editorial office along with the original data. Please see Figure 1 below, I have no idea what happened in the process of the publication. ![file] , 
 Please check out the recent revision at https: journals.plos.org plosone article?id=10.1371 journal.pone.0234162. it was corrected. Thanks. ,