Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy

Cui, Donghong; Peng, Yanmin; Zhang, Chengfang; Li, Zezhi; Su, Yousong; Qi, Yadan; Xing, Mengjuan; Li, Jia; Kim, Grace; Su, Kevin; Xu, Jimin; Wang, Meiti; Ding, Wenhua; Piecychna, Marta; Leng, Lin; Hirasawa, Michiru; Jiang, Kaida; Young, Lawrence H.; Xu, Yifeng; Qi, Dake; Bucala, Richard

doi:10.1172/jci93090

Cited by 35 publications

(35 citation statements)

References 54 publications

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“…Traditionally, the diagnosis of preoperative LN status in PDAC depends on imaging examinations. Studies have shown that the accuracy of CECT diagnosis for LN metastasis is 48%, and even with 18fluorodeoxyglucose PET/CT, the accuracy is only approximately 68% [38]. In this study, the diagnostic accuracy of CT-reported LN status in the primary cohort was 60, and 68% in the validation cohort.…”

Section: Discussionmentioning

confidence: 54%

Contrast-enhanced CT radiomics for predicting lymph node metastasis in pancreatic ductal adenocarcinoma: a pilot study

Yao

Xiao

et al. 2020

Cancer Imaging

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Background:We developed a computational model integrating clinical data and imaging features extracted from contrast-enhanced computed tomography (CECT) images, to predict lymph node (LN) metastasis in patients with pancreatic ductal adenocarcinoma (PDAC).Methods: This retrospective study included 159 patients with PDAC (118 in the primary cohort and 41 in the validation cohort) who underwent preoperative contrast-enhanced computed tomography examination between 2012 and 2015. All patients underwent surgery and lymph node status was determined. A total of 2041 radiomics features were extracted from venous phase images in the primary cohort, and optimal features were extracted to construct a radiomics signature. A combined prediction model was built by incorporating the radiomics signature and clinical characteristics selected by using multivariable logistic regression. Clinical prediction models were generated and used to evaluate both cohorts. Results: Fifteen features were selected for constructing the radiomics signature based on the primary cohort. The combined prediction model for identifying preoperative lymph node metastasis reached a better discrimination power than the clinical prediction model, with an area under the curve of 0.944 vs. 0.666 in the primary cohort, and 0.912 vs. 0.713 in the validation cohort.Conclusions: This pilot study demonstrated that a noninvasive radiomics signature extracted from contrastenhanced computed tomography imaging can be conveniently used for preoperative prediction of lymph node metastasis in patients with PDAC.

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Section: Discussionmentioning

confidence: 54%

Contrast-enhanced CT radiomics for predicting lymph node metastasis in pancreatic ductal adenocarcinoma: a pilot study

Yao

Xiao

et al. 2020

Cancer Imaging

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“…After calculations using this software, a total of ~30 adult WT mice and ~30 adult Cd74 −/− mice (both sexes) were used for both in vivo and in vitro studies. Plasma MIF levels were measured using a commercial R&D human MIF kit per manufacturer's instruction (Cui et al, ).…”

Section: Methodsmentioning

confidence: 99%

CD74 knockout protects against LPS‐induced myocardial contractile dysfunction through AMPK‐Skp2‐SUV39H1‐mediated demethylation of BCLB

Luo

Fan

Yang

et al. 2020

British J Pharmacology

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Background and Purpose Lipopolysaccharides (LPS), an outer membrane component of Gram‐negative bacteria, triggers myocardial anomalies in sepsis. Recent findings indicated a role for inflammatory cytokine MIF and its receptor, CD74, in septic organ injury, although little is known of the role of MIF‐CD74 in septic cardiomyopathy. Experimental Approach This study evaluated the impact of CD74 ablation on endotoxaemia‐induced cardiac anomalies. Echocardiographic, cardiomyocyte contractile and intracellular Ca2+ properties were examined. Key Results Our data revealed compromised cardiac function (lower fractional shortening, enlarged LV end systolic diameter, decreased peak shortening, maximal velocity of shortening/relengthening, prolonged duration of relengthening and intracellular Ca2+ mishandling) and ultrastructural derangement associated with inflammation, O2− production, apoptosis, excess autophagy, phosphorylation of AMPK and JNK and dampened mTOR phosphorylation. These effects were attenuated or mitigated by CD74 knockout. LPS challenge also down‐regulated Skp2, an F‐box component of Skp1/Cullin/F‐box protein‐type ubiquitin ligase, while up‐regulating that of SUV39H1 and H3K9 methylation of the Bcl2 protein BCLB. These effects were reversed by CD74 ablation. In vitro study revealed that LPS facilitated GFP‐LC3B formation and cardiomyocyte defects. These effects were prevented by CD74 ablation. Interestingly, the AMPK activator AICAR, the autophagy inducer rapamycin and the demethylation inhibitor difenoconazole inhibited the effects of CD74 ablation against LPS‐induced cardiac dysfunction, while the SUV39H1 inhibitor chaetocin or methylation inhibitor 5‐AzaC ameliorated LPS‐induced GFP‐LC3B formation and cardiomyocyte contractile dysfunction. Conclusion and Implications Our data suggested that CD74 ablation protected against LPS‐induced cardiac anomalies, O2− production, inflammation and apoptosis through suppression of autophagy in a Skp2‐SUV39H1‐mediated mechanism.

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“…However, opipramol is administered at doses up to 200 mg/day [23,38], making our observations at 1-10 µM relevant. Moreover, risperidone, which induces a modest antilipolytic effect, also modestly increases adiponectin levels in treated patients with schizophrenia, wheraes olanzapine decreases the circulating levels of this insulin-sensitizing adipokine [56] and increases pro-inflammatory cytokines [57]. This allows the supposition that opipramol could also have opposite effects to olanzapine when considering adipocyte functions other than lipolysis and glucose transport.…”

Section: Discussionmentioning

confidence: 99%

Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control

et al. 2020

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Treatment with several antipsychotic drugs exhibits a tendency to induce weight gain and diabetic complications. The proposed mechanisms by which the atypical antipsychotic drug olanzapine increases body weight include central dysregulations leading to hyperphagia and direct peripheral impairment of fat cell lipolysis. Several investigations have reproduced in vitro direct actions of antipsychotics on rodent adipocytes, cultured preadipocytes, or human adipose tissue-derived stem cells. However, to our knowledge, no such direct action has been described in human mature adipocytes. The aim of the present study was to compare in human adipocytes the putative direct alterations of lipolysis by antipsychotics (haloperidol, olanzapine, ziprazidone, risperidone), antidepressants (pargyline, phenelzine), or anxiolytics (opipramol). Lipolytic responses to the tested drugs, and to recognized lipolytic (e.g., isoprenaline) or antilipolytic agents (e.g., insulin) were determined, together with glucose transport and amine oxidase activities in abdominal subcutaneous adipocytes from individuals undergoing plastic surgery. None of the tested drugs were lipolytic. Surprisingly, only opipramol exhibited substantial antilipolytic properties in the micromolar to millimolar range. An opipramol antilipolytic effect was evident against isoprenaline-, forskolin-, or atrial natriuretic peptide-stimulated lipolysis. Opipramol did not impair insulin activation of glucose transport but inhibited monoamine oxidase (MAO) activity to the same extent as antidepressants recognized as MAO inhibitors (pargyline, harmine, or phenelzine), whereas antipsychotics were inefficient. Considering its unique properties, opipramol, which is not associated with weight gain in treated patients, is a good candidate for drug repurposing because it limits exaggerated lipolysis, prevents hydrogen peroxide release by amine oxidases in adipocytes, and is thereby of potential use to limit lipotoxicity and oxidative stress, two deleterious complications of diabetes and obesity.

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Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy

Cited by 35 publications

References 54 publications

Contrast-enhanced CT radiomics for predicting lymph node metastasis in pancreatic ductal adenocarcinoma: a pilot study

Contrast-enhanced CT radiomics for predicting lymph node metastasis in pancreatic ductal adenocarcinoma: a pilot study

CD74 knockout protects against LPS‐induced myocardial contractile dysfunction through AMPK‐Skp2‐SUV39H1‐mediated demethylation of BCLB

Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control

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