Is There a Role for SGLT2 Inhibitors in Patients with End-Stage Kidney Disease?

PURPOSE OF REVIEW: Chronic kidney disease and end-stage kidney disease (ESKD) are well-established risk factors for cardiovascular disease (CVD), the leading cause of mortality in the dialysis population. Conventional therapies, such as statins, blood pressure control, and renin-angiotensin-aldosterone system blockade, have inadequately addressed this cardiovascular risk, highlighting the unmet need for effective treatment strategies. Sodium-glucose transporter 2 (SGLT2) inhibitors have demonstrated significant renal and cardiovascular benefits among patients with type 2 diabetes, heart failure, or CKD at risk of progression. Unfortunately, efficacy data in dialysis patients is lacking as ESKD was an exclusion criterion for all major clinical trials of SGLT2 inhibitors. This review explores the potential of SGLT2 inhibitors in improving cardiovascular outcomes among patients with ESKD, focusing on their direct cardiac effects. RECENT FINDINGS: Recent clinical and preclinical studies have shown promising data for the application of SGLT2 inhibitors to the dialysis population. SGLT2 inhibitors may provide cardiovascular benefits to dialysis patients, not only indirectly by preserving the remaining kidney function and improving anemia but also directly by lowering intracellular sodium and calcium levels, reducing inflammation, regulating autophagy, and alleviating oxidative stress and endoplasmic reticulum stress within cardiomyocytes and endothelial cells. This review examines the current clinical evidence and experimental data supporting the use of SGLT2 inhibitors, discusses its potential safety concerns, and outlines ongoing clinical trials in the dialysis population. Further research is needed to evaluate the safety and effectiveness of SGLT2 inhibitor use among patients with ESKD.

Nanoplastic impact on bone microenvironment: A snapshot from murine bone cells.

Our world is made of plastic. Plastic waste deeply affects our health entering the food chain. The degradation and/or fragmentation of plastics due to weathering processes result in the generation of nanoplastics (NPs). Only a few studies tested NPs effects on human health. NPs toxic actions are, in part, mediated by oxidative stress (OS) that, among its effects, affects bone remodeling. This study aimed to assess if NPs influence skeleton remodeling through OS. Murine bone cell cultures (MC3T3-E1 preosteoblasts, MLOY-4 osteocyte-like cells, and RAW264.7 pre-osteoclasts) were used to test the NPs detrimental effects on bone cells. NPs affect cell viability and induce ROS production and apoptosis (by caspase 3/7 activation) in pre-osteoblasts, osteocytes, and pre-osteoclasts. NPs impair the migration capability of pre-osteoblasts and potentiate the osteoclastogenesis of preosteoclasts. NPs affected the expression of genes related to inflammatory and osteoblastogenic pathways in pre-osteoblasts and osteocytes, related to the osteoclastogenic commitment of pre-osteoclasts. A better understanding of the impact of NPs on bone cell activities resulting in vivo in impaired bone turnover could give more information on the possible toxicity consequence of NPs on bone mass and the subsequent public health problems, such as bone disease.

Micro and nano-plastics, a threat to human health?

Micro and nanosize plastic polymers degrading from large plastic compounds are accumulating in the natural environment and expose potential biological threats to human health. These particles are largely persistent and consequently accumulate in the exposed individuals. The presence of microplastics has already been demonstrated in various human organs including the lung, the gastrointestinal system and the blood raising concerns about their possible harmful effects. The chemical composition, size and shape of microplastics as well as their weathering status represent important factors influencing the potential impact of microplastics on tissues. In addition, microplastics can function as vectors for adsorbed chemical compounds and may harbour and deliver live microbial pathogens or their ligands. In vitro and in vivo animal studies demonstrated that microplastics are taken up to cells in a size and cell type dependent manner. Once inside the targeted cell they activate oxidative processes, mitochondrial dysfunction and ER-stress. These molecular processes result in the activation or repression of cell type specific functions and potentially in the induction of cytotoxicity. The microplastic elicited events may result in inflammation, organ damage and fibrosis of the targeted organs as well as in systemic immunological and metabolic conditions. In addition, microplastics may impact on the gut microbiota which may exert further gastrointestinal and systemic metabolic and immunological effects. In this minireview, we evaluate the factors and mechanisms that influence potential microplastic induced cellular and organ pathologies in humans and discuss limitations of current understanding regarding microplastic elicited conditions as well as future perspectives for research.

Cecal Metabolomic Fingerprint of Unscathed Rats: Does It Reflect the Good Response to a Provocative Decompression?

On one side, decompression sickness (DCS) with neurological disorders lead to a reshuffle of the cecal metabolome of rats. On the other side, there is also a specific and different metabolomic signature in the cecum of a strain of DCS-resistant rats, that are not exposed to hyperbaric protocol. We decide to study a conventional strain of rats that resist to an accident-provoking hyperbaric exposure, and we hypothesize that the metabolomic signature put forward may correspond to a physiological response adapted to the stress induced by diving. The aim is to verify and characterize whether the cecal compounds of rats resistant to the provocative dive have a cecal metabolomic signature different from those who do not dive. 35 asymptomatic diver rats are selected to be compared to 21 rats non-exposed to the hyperbaric protocol. Because our aim is essentially to study the differences in the cecal metabolome associated with the hyperbaric exposure, about half of the rats are fed soy and the other half of maize in order to better rule out the effect of the diet itself. Lower levels of IL-1ß and glutathione peroxidase (GPX) activity are registered in blood of diving rats. No blood cell mobilization is noted. Conventional and ChemRICH approaches help the metabolomic interpretation of the 185 chemical compounds analyzed in the cecal content. Statistical analysis show a panel of 102 compounds diet related. 19 are in common with the hyperbaric protocol effect. Expression of 25 compounds has changed in the cecal metabolome of rats resistant to the provocative dive suggesting an alteration of biliary acids metabolism, most likely through actions on gut microbiota. There seem to be also weak changes in allocations dedicated to various energy pathways, including hormonal reshuffle. Some of the metabolites may also have a role in regulating inflammation, while some may be consumed for the benefit of oxidative stress management.

Oxidative Stress and Abnormal Tendon Sonographic Features in Elite Soccer Players (A Pilot Study).

Objective Sound experimental data suggest that oxidative stress plays an important role in the pathogenesis of tendinopathies. However, this hypothesis in humans remains speculative given that clinical data are lacking to confirm it. Recently, a new methodology has allowed to quantify the oxidative stress in vivo by measuring the concentration of hydroperoxides of organic compounds, which have been utilized as an oxidative stress-related marker in several pathologic and physiologic conditions. Given the reliability of this test and the lack of information in subjects with tendinopathies, the aim of the present study was to assess the oxidative stress status in elite professional soccer players with and without ultrasonographic features of tendon damage. Methods In 73 elite players, blood metabolic parameters were evaluated and oxidative stress was measured by means of a specific test (expressed as U-Carr units). Therefore, an ultrasonographic evaluation of the Achilles and patellar tendons was performed. Results No significant relationships were observed between metabolic parameters and oxidative stress biomarkers. The Achilles and patellar tendons showed a normal echographic pattern in 58 athletes, and sonographic abnormalities in 15. The athletes with ultrasonographic alterations, compared to those with normal US picture, showed significantly higher U-Carr levels ( p = 0.000), body mass index (BMI) values ( p = 0.03) and were older ( p = 0.005). The difference in U-Carr values among the subjects remained significant also after adjustment for age and BMI. Conclusion The results of the present study support the hypothesis that oxidative substances, also increased at systemic and not only at local level, may favor tendon damage. Level of Evidence IV (pilot study).

How to construct neuroscience-informed psychiatric classification? Towards nomothetic networks psychiatry.

Psychiatry remains in a permanent state of crisis, which fragmented psychiatry from the field of medicine. The crisis in psychiatry is evidenced by the many different competing approaches to psychiatric illness including psychodynamic, biological, molecular, pan-omics, precision, cognitive and phenomenological psychiatry, folk psychology, mind-brain dualism, descriptive psychopathology, and postpsychiatry. The current "gold standard" Diagnostic and Statistical Manual of Mental Disorders/International Classification of Diseases taxonomies of mood disorders and schizophrenia are unreliable and preclude to employ a deductive reasoning approach. Therefore, it is not surprising that mood disorders and schizophrenia research was unable to revise the conventional classifications and did not provide more adequate therapeutic approaches. The aim of this paper is to explain the new nomothetic network psychiatry (NNP) approach, which uses machine learning methods to build data-driven causal models of mental illness by assembling risk-resilience, adverse outcome pathways (AOP), cognitome, brainome, staging, symptomatome, and phenomenome latent scores in a causal model. The latter may be trained, tested and validated with Partial Least Squares analysis. This approach not only allows to compute pathway-phenotypes or biosignatures, but also to construct reliable and replicable nomothetic networks, which are, therefore, generalizable as disease models. After integrating the validated feature vectors into a well-fitting nomothetic network, clustering analysis may be applied on the latent variable scores of the R/R, AOP, cognitome, brainome, and phenome latent vectors. This pattern recognition method may expose new (transdiagnostic) classes of patients which if cross-validated in independent samples may constitute new (transdiagnostic) nosological categories.

Castanea sativa Mill. bark extract cardiovascular effects in a rat model of high-fat diet.

Ellagitannins may have a beneficial impact in cardiovascular diseases. The aim of the study was to evaluate the effect of high-fat diet (HFD) and the efficacy of Castanea sativa Mill. bark extract (ENC) on cardiac and vascular parameters. Rats were fed with regular diet, (RD, n = 15), HFD (n = 15), RD + ENC (20 mg/kg/day by gavage, n = 15), and HFD + ENC (same dose, n = 15) and the effects on body weight, biochemical serum parameters, and inflammatory cytokines determined. Cardiac functional parameters and aorta contractility were also assessed on isolated atria and aorta. Results showed that ENC reduced weight gain and serum lipids induced by HFD. In in vitro assays, HFD decreased the contraction force of left atrium, increased right atrium chronotropy, and decreased aorta K+ -induced contraction; ENC induced transient positive inotropic and negative chronotropic effects on isolated atria from RD and HFD rats and a spasmolytic effect on aorta. In ex vivo experiments, ENC reverted inotropic and chronotropic changes induced by HFD and enhanced Nifedipine effect more on aorta than on heart. In conclusion, ENC restores metabolic dysfunction and cardiac cholinergic muscarinic receptor function, and exerts spasmolytic effect on aorta in HFD rats, highlighting its potential as nutraceutical tool in obesity.

Salmon acyl-ghrelin increases food intake and reduces doxorubicin-induced myocardial apoptosis in rats, likely by anti-oxidative activity.

We had reported that orally administered ghrelin-containing salmon stomach extract prevents doxorubicin (DOX)-induced cardiotoxicity. In this study, we investigated the binding affinity of salmon ghrelin to rat ghrelin receptor and the cardioprotective effects of subcutaneous (sc) injected synthetic salmon ghrelin in rats with DOX-induced acute heart failure in order to clarify the potential efficacy of salmon ghrelin. Intracellular calcium mobilization assay was performed on rat GHS-R1a-expressing CHO cells to reveal ghrelin activity. Rats were divided into five groups; the normal control (I), and toxic control (II) groups were given saline (sc, twice daily), and the salmon acyl-ghrelin (sAG) (III), salmon unacylated-ghrelin (sUAG) (IV), and rat acyl-ghrelin (rAG) (V) groups were given corresponding synthetic ghrelins (sc, twice daily), respectively. After seven days of treatment, DOX (20 mg/kg BW) or saline was administered to the corresponding groups by intraperitoneal injection. The toxic control group was the negative control group for the DOX-induced cardiotoxicity groups. While sAG displayed similar affinity to rAG upon application to GHS-R1a-expressing cells, and also decreased DOX-induced apoptosis and increased food intake, sUAG did not. Both sAG and rAG improved DOX-induced deterioration, showing anti-oxidative activity. The anti-oxidative activity of sAG might contribute to the protective effects on cardiomyocytes. The results also suggest that, similar to rAG, sAG is a potent protectant against DOX-induced cardiotoxicity and a potential functional component in orally administered ghrelin-containing salmon stomach extract, which prevented DOX-induced cardiotoxicity in our previous study.

Phenotypic and proteomic approaches of the response to iron-limited condition in Staphylococcus lugdunensis.

BACKGROUND: Staphylococcus lugdunensis is a coagulase-negative Staphylococcus part of the commensal skin flora but emerge as an important opportunistic pathogen. Because iron limitation is a crucial stress during infectious process, we performed phenotypic study and compared proteomic profiles of this species incubated in absence and in presence of the iron chelator 2,2'-dipyridyl (DIP). RESULTS: No modification of cell morphology nor cell wall thickness were observed in presence of DIP. However iron-limitation condition promoted biofilm formation and reduced the ability to cope with oxidative stress (1 mM H2O2). In addition, S. lugdunensis N920143 cultured with DIP was significantly less virulent in the larvae of Galleria mellonella model of infection than that grown under standard conditions. We verified that these phenotypes were due to an iron limitation by complementation experiments with FeSO4. By mass spectrometry after trypsin digestion, we characterized the first iron-limitation stress proteome in S. lugdunensis. Among 1426 proteins identified, 349 polypeptides were differentially expressed. 222 were more and 127 less abundant in S. lugdunensis incubated in iron-limitation condition, and by RT-qPCR, some of the corresponding genes have been shown to be transcriptionally regulated. Our data revealed that proteins involved in iron metabolism and carriers were over-expressed, as well as several ABC transporters and polypeptides linked to cell wall metabolism. Conversely, enzymes playing a role in the oxidative stress response (especially catalase) were repressed. CONCLUSIONS: This phenotypic and global proteomic study allowed characterization of the response of S. lugdunensis to iron-limitation. We showed that iron-limitation promoted biofilm formation, but decrease the oxidative stress resistance that may, at least in part, explained the reduced virulence of S. lugdunensis observed under low iron condition.

[Ischemia-reperfusion injury after kidney transplantation]. / Ischémie reperfusion en transplantation rénale.

Ischemia-reperfusion injury is an inescapable phenomenon in kidney transplantation. It combines lesional processes of biochemical origin associated with oxydative stress and of immunological origin in connection with the recruitment and activation of innate immunity cells. Histological lesions associate acute tubular necrosis and interstitial œdema, which can progress to interstitial fibrosis. The extent of these lesions depends on donor characteristics (age, expanded criteria donor, etc.) and cold ischemia time. In the short term, ischemia-reperfusion results in delayed recovery of graft function. Cold ischemia time also impacts long-term graft survival. Preclinical models, such as murine and porcine models, have furthered understanding of the pathophysiological mechanisms of ischemia-reperfusion injury. Due to its renal anatomical proximity to humans, the porcine model is relevant to assessment of the molecules administered to a donor or recipient, and also of additives to preservation solutions. Different donor resuscitation and graft perfusion strategies can be studied. In humans, prevention of ischemia-reperfusion injury is a research subject as concerns donor conditioning, additive molecules in preservation solutions, graft reperfusion modalities and choice of the molecules administered to the recipient. Pending significant advances in research, the goal is to achieve the shortest possible cold ischemia time.

Iron and heart failure. / Hierro e insuficiencia cardiaca.

Iron deficiency has become a new target to improve functional outcomes in patients with heart failure, and intravenous preparations seem to be the only effective treatment for that purpose. However, the relation among iron and oxygen in this population is far from understood as hepcidin is generally upregulated, potentially avoiding iron availability and harm in the context of excess oxidative stress. Laboratory markers used to detect tissue iron deficiency are highly dependent on needs for hemoglobin synthesis, so that reaching peak hemoglobin for each individual should rationally be the first goal of any attempt with therapeutic iron. A subset of patients receiving intravenous iron may have a worse outcome related to admissions and mortality compared to placebo, suggesting that the laboratory thresholds used to detect iron deficiency in heart failure are highly sensitive but less specific to identify patients that would not benefit of this therapy. A gradual delivery of iron over time with parallel measurement of its uptake for hemoglobin synthesis could therefore be recommended to fulfill tissue needs. Standard oral iron therapy should not be dismissed in heart failure patients with anemia and depleted iron stores (ferritin <30 ng/ml) as, contrary to intravenous iron trials, these patients were not included in a trial resulting in neglectable effect of oral iron on exercise capacity.

The Neuroprotective Effects of Melatonin: Possible Role in the Pathophysiology of Neuropsychiatric Disease.

Melatonin is a hormone that is secreted by the pineal gland. To date, melatonin is known to regulate the sleep cycle by controlling the circadian rhythm. However, recent advances in neuroscience and molecular biology have led to the discovery of new actions and effects of melatonin. In recent studies, melatonin was shown to have antioxidant activity and, possibly, to affect the development of Alzheimer's disease (AD). In addition, melatonin has neuroprotective effects and affects neuroplasticity, thus indicating potential antidepressant properties. In the present review, the new functions of melatonin are summarized and a therapeutic target for the development of new drugs based on the mechanism of action of melatonin is proposed.

PERK-Mediated Unfolded Protein Response Activation and Oxidative Stress in PARK20 Fibroblasts.

PARK20, an early onset autosomal recessive parkinsonism is due to mutations in the phosphatidylinositol-phosphatase Synaptojanin 1 (Synj1). We have recently shown that the early endosomal compartments are profoundly altered in PARK20 fibroblasts as well as the endosomal trafficking. Here, we report that PARK20 fibroblasts also display a drastic alteration of the architecture and function of the early secretory compartments. Our results show that the exit machinery from the Endoplasmic Reticulum (ER) and the ER-to-Golgi trafficking are markedly compromised in patient cells. As a consequence, PARK20 fibroblasts accumulate large amounts of cargo proteins within the ER, leading to the induction of ER stress. Interestingly, this stressful state is coupled to the activation of the PERK/eIF2α/ATF4/CHOP pathway of the Unfolded Protein Response (UPR). In addition, PARK20 fibroblasts reveal upregulation of oxidative stress markers and total ROS production with concomitant alteration of the morphology of the mitochondrial network. Interestingly, treatment of PARK20 cells with GSK2606414 (GSK), a specific inhibitor of PERK activity, restores the level of ROS, signaling a direct correlation between ER stress and the induction of oxidative stress in the PARK20 cells. All together, these findings suggest that dysfunction of early secretory pathway might contribute to the pathogenesis of the disease.

Methemoglobinemia as a biomarker of dapsone-induced mania severity.

BACKGROUND: The underlying mechanism involved in dapsone-induced mania remains unknown. METHODS: We report the case of a 54-year-old man with a dapsone-induced mania. RESULTS: The maximum of manic symptoms was correlated with the maximum of methemoglobinemia and mania decreased concomitantly with the methemoglobinemia level. LIMITATIONS: This is a single case. CONCLUSIONS: This case shows that dapsone-induced mania severity is correlated with methemoglobinemia level, leading for the first time to the hypothesis of a physiopathological mechanism by which dapsone could induce mania.

Does supplemental zeolite (clinoptilolite) affect growth performance, meat texture, oxidative stress and production of polyunsaturated fatty acid of Turkey poults?

BACKGROUND: Following the ban on the use of growth factors, the use of zeolite in poultry feed could be a solution to obtain healthier food products that are more demanded by the consumer. METHODS: Zeolite (Clinoptilolite) was added to turkey male and female feed at concentrations 1% or 2% and was evaluated for its effectiveness on performance of the production. The turkeys were given free and continuous access to a nutritionally non-limiting diet (in meal form) that was either a basal diet or a 'Zeolite supplemented-diet' (the basal diet supplemented with clinoptilolite at a level of 1% or 2%). RESULTS: It was found that adding zeolite in the turkey diet had a positive effect on growth performance and increased weight gain compared to the control. In addition, zeolite treatment had a positive effect on oxidative stress and organoleptic parameters that were measured. It was found that adding zeolite in the turkey diet reduced the MDA level in the liver and in the meat, as compared to the control. Quality of meat was measured as a significantly increase (p < 0.05) in pH for male meat, indicated that the zeolite could maintain the quality of longer period. The adding of zeolite in the turkey diet increased level of polyunsaturated fatty acid. CONCLUSION: This study showed the significance of using zeolite, as a feed additive for turkey, as part of a comprehensive program to improve growth performance and oxidative stress parameters and to increase level of polyunsaturated fatty acid on the turkey body.

A blend of two resveratrol derivatives abolishes hIAPP amyloid growth and membrane damage.

Type II diabetes mellitus (T2DM) is characterized by the presence of amyloid deposits of the human islet amyloid polypeptide (hIAPP) in pancreatic ß-cells. A wealth of data supports the hypothesis that hIAPP's toxicity is related to an abnormal interaction of amyloids with islet cell membranes. Thus, many studies aimed at finding effective therapies for T2DM focus on the design of molecules that are able to inhibit hIAPP's amyloid growth and the related membrane damage as well. Based on this view and inspired by its known anti-amyloid properties, we have functionalized resveratrol with a phosphoryl moiety (4'-O-PR) that improves its solubility and pharmacological properties. A second resveratrol derivative has also been obtained by conjugating resveratrol with a dimyristoylphosphatidyl moiety (4'-DMPR). The use of both compounds resulted in abolishing both amyloid growth and amyloid mediated POPC/POPS membrane damage in tube tests. We propose that a mixture of a water-soluble anti-aggregating compound and its lipid-anchored derivative may be employed as a general strategy to prevent and/or to halt amyloid-related membrane damage.

Caryocar coriaceum extracts exert leishmanicidal effect acting in promastigote forms by apoptosis-like mechanism and intracellular amastigotes by Nrf2/HO-1/ferritin dependent response and iron depletion: Leishmanicidal effect of Caryocar coriaceum leaf exracts.

Leishmania (L.) amazonensis is the American Cutaneous Leishmaniasis-causing agents, and the available drugs for this disease present toxicity, low efficiency and difficulty of administration. Plants belong23ing to the Caryocar genus are found in Brazilian Cerrado, where fruits are used as food and in folk medicine, and previous studies showed several biological effects of extracts of this plant. The present work evaluated the leishmanicidal and immunomodulatory activity of ethyl acetate (EAC) and methanol (MET) C. coriaceum leaf extracts EAC and MET showed an antipromastigote effect after 24, 48 and 72 h. The extracts also induced loss of mitochondrial membrane potential, reactive oxygen species (ROS) production, damage to the plasma membrane, and phosphatidylserine exposure on promastigote forms, and most parasites were going through a late apoptosis-like process. The range of concentrations used did not alter the viability of peritoneal macrophages of BALB/c mice; therefore, we observed that the treatment with extracts was able to reduce the infection of this cells. Thereafter, the extracts were able to significantly improve the levels of TNFα, IL-6, MCP-1, and IL-10, and reduced the levels of MDA and ROS without interfering on NO levels released by infected macrophages. In addition, both EAC and MET up-regulated Nrf2/HO-1/Ferritin expression and reduced the labile iron pool in infected macrophages. Based on the data obtained, it is possible to infer that different solvent extracts of the C. coriaceum leaves exert leishmanicidal effect, acting on promastigote forms through apoptosis-like mechanisms and intracellular amastigote forms involving a Nrf2/HO-1 dependent antioxidant response, which culminates in a depletion of available iron for L. amazonensis replication.

Ecology of the cardiovascular system: A focus on air-related environmental factors.

Cardiology is a newcomer to environmental sciences. We aim to propose an original review of the scientific evidence regarding the effects of the environment on cardiovascular health. We report first influences of air-related environmental factors. Air temperature has a strong influence on cardiovascular mortality characterized by a V-like relationship confirming that both cold and hot periods have negative cardiovascular impacts. Furthermore, dynamic changes in temperature are likely more important than the absolute air temperature level. Cardiovascular reactions to air temperature are predominantly driven by increase in sympathetic tone. Indoor pollutants are mainly represented by smoke from cooking stoves and environmental tobacco smoke (ETS), and both are associated with increased cardiovascular mortality and morbidity. ETS is characterized by a curvilinear dose-effect relationship, showing already a significant effect even at low level of exposure and no threshold in effect appearance. Underlying ETS pathophysiology involves both effects of nicotinic stimulus on the sympathetic system and vascular oxidative stress. Smoking bans, as mitigation measures, were associated with a decrease in cardiovascular events. Long-term exposure to particulate air pollution was more recently recognized as an independent risk factor of cardiovascular mortality. Short-term increases in air pollution were also associated with an increased risk of myocardial infarction, stroke, and acute heart failure. Numerous experimental studies demonstrated that air pollution promotes a systemic vascular oxidative stress reaction followed by endothelial dysfunction, monocyte activation, and some proatherogenic changes of lipoproteins. Furthermore, air pollution favors thrombus formation as a result of increase in coagulation factors and platelet activation. Further studies are required to confirm that stricter air quality regulation or antioxidant regimen translate into some clinical benefits. In conclusion, ambient air temperature and pollution are major contributors to cardiovascular diseases. Improving air quality is now part of cardiovascular prevention.

Pre-silencing of genes involved in the electron transport chain (ETC) pathway is associated with responsiveness to abatacept in rheumatoid arthritis.

BACKGROUND: In the current context of personalized medicine, one of the major challenges in the management of rheumatoid arthritis (RA) is to identify biomarkers that predict drug responsiveness. From the European APPRAISE trial, our main objective was to identify a gene expression profile associated with responsiveness to abatacept (ABA) + methotrexate (MTX) and to understand the involvement of this signature in the pathophysiology of RA. METHODS: Whole human genome microarrays (4 × 44 K) were performed from a first subset of 36 patients with RA. Data validation by quantitative reverse-transcription (qRT)-PCR was performed from a second independent subset of 32 patients with RA. Gene Ontology and WikiPathways database allowed us to highlight the specific biological mechanisms involved in predicting response to ABA/MTX. RESULTS: From the first subset of 36 patients with RA, a combination including 87 transcripts allowed almost perfect separation between responders and non-responders to ABA/MTX. Next, the second subset of patients 32 with RA allowed validation by qRT-PCR of a minimal signature with only four genes. This latter signature categorized 81% of patients with RA with 75% sensitivity, 85% specificity and 85% negative predictive value. This combination showed a significant enrichment of genes involved in electron transport chain (ETC) pathways. Seven transcripts from ETC pathways (NDUFA6, NDUFA4, UQCRQ, ATP5J, COX7A2, COX7B, COX6A1) were significantly downregulated in responders versus non-responders to ABA/MTX. Moreover, dysregulation of these genes was independent of inflammation and was specific to ABA response. CONCLUSION: Pre-silencing of ETC genes is associated with future response to ABA/MTX and might be a crucial key to susceptibility to ABA response.