Cytotoxicity and toxicoproteomics analysis of thiazolidinedione exposure in human-derived cardiomyocytes.

Thiazolidinediones (TZDs) (e.g. pioglitazone and rosiglitazone), known insulin sensitiser agents for type II diabetes mellitus, exhibit controversial effects on cardiac tissue. Despite consensus on their association with increased heart failure risk, limiting TZD use in diabetes management, the underlying mechanisms remain uncharacterised. Herein, we report a comprehensive in vitro investigation utilising a novel toxicoproteomics pipeline coupled with cytotoxicity assays in human adult cardiomyocytes to elucidate mechanistic insights into TZD cardiotoxicity. The cytotoxicity assay findings showed a significant loss of mitochondrial adenosine triphosphate production upon exposure to either TZD agents, which may underpin TZD cardiotoxicity. Our toxicoproteomics analysis revealed that mitochondrial dysfunction primarily stems from oxidative phosphorylation impairment, with distinct signalling mechanisms observed for both agents. The type of cell death differed strikingly between the two agents, with rosiglitazone exhibiting features of caspase-dependent apoptosis and pioglitazone implicating mitochondrial-mediated necroptosis, as evidenced by the protein upregulation in the phosphoglycerate mutase family 5-dynamin-related protein 1 axis. Furthermore, our analysis revealed additional mechanistic aspects of cardiotoxicity, showcasing drug specificity. The downregulation of various proteins involved in protein machinery and protein processing in the endoplasmic reticulum was observed in rosiglitazone-treated cells, implicating proteostasis in the rosiglitazone cardiotoxicity. Regarding pioglitazone, the findings suggested the potential activation of the interplay between the complement and coagulation systems and the disruption of the cytoskeletal architecture, which was primarily mediated through the integrin-signalling pathways responsible for pioglitazone-induced myocardial contractile failure. Collectively, this study unlocks substantial mechanistic insight into TZD cardiotoxicity, providing the rationale for future optimisation of antidiabetic therapies.

Toxicometabolomics-based cardiotoxicity evaluation of Thiazolidinedione exposure in human-derived cardiomyocytes.

INTRODUCTION: Thiazolidinediones (TZDs), represented by pioglitazone and rosiglitazone, are a class of cost-effective oral antidiabetic agents posing a marginal hypoglycaemia risk. Nevertheless, observations of heart failure have hindered the clinical use of both therapies. OBJECTIVE: Since the mechanism of TZD-induced heart failure remains largely uncharacterised, this study aimed to explore the as-yet-unidentified mechanisms underpinning TZD cardiotoxicity using a toxicometabolomics approach. METHODS: The present investigation included an untargeted liquid chromatography-mass spectrometry-based toxicometabolomics pipeline, followed by multivariate statistics and pathway analyses to elucidate the mechanism(s)of TZD-induced cardiotoxicity using AC16 human cardiomyocytes as a model, and to identify the prognostic features associated with such effects. RESULTS: Acute administration of either TZD agent resulted in a significant modulation in carnitine content, reflecting potential disruption of the mitochondrial carnitine shuttle. Furthermore, perturbations were noted in purine metabolism and amino acid fingerprints, strongly conveying aberrations in cardiac energetics associated with TZD usage. Analysis of our findings also highlighted alterations in polyamine (spermine and spermidine) and amino acid (L-tyrosine and valine) metabolism, known modulators of cardiac hypertrophy, suggesting a potential link to TZD cardiotoxicity that necessitates further research. In addition, this comprehensive study identified two groupings - (i) valine and creatine, and (ii) L-tryptophan and L-methionine - that were significantly enriched in the above-mentioned mechanisms, emerging as potential fingerprint biomarkers for pioglitazone and rosiglitazone cardiotoxicity, respectively. CONCLUSION: These findings demonstrate the utility of toxicometabolomics in elaborating on mechanisms of drug toxicity and identifying potential biomarkers, thus encouraging its application in the toxicological sciences. (245 words).

Determinants of hyperphosphatemia and its relation with hemoglobin levels among hemodialysis patients in two hospitals from Syria: a prospective cross-sectional study.

Hyperphosphatemia and anemia were both associated with several complications in chronic kidney disease (CKD) patients. This study aimed to determine the risk factors of hyperphosphatemia and its relation with anemia among hemodialysis (HD) patients. Secondly, it aimed to determine the prevalence of hyperphosphatemia and anemia. Material and methods: A prospective cross-sectional study was conducted among 146 HD patients from two HD centers in Syria, between June 2021 and March 2022. All patients at least 18 years old on maintenance HD were enrolled. The threshold of phosphorus (phos) level was divided by the upper normal range among HD patients (5.5 mg/dl). We used parametric and nonparametric statistics, the Pearson and Spearman correlations with simple and multiple linear regressions between study variables. Results: 36.9% of patients had a serum phos level of 5.5 or less (norm phos group), and 63.1% of patients had a serum phos level higher than 5.5 (high phos group). Also, 60.9% of patients had hemoglobin (Hb) less than 10 g/dl, and 40.4% of patients had Hb at least 10 g/dl. Age, type of HD access, phos binders (P-binders), parathyroid hormone (PTH), and calcium (Ca) showed significant effects on phos levels. Most patients were using arteriovenous fistula (AVF) (89.7%) as a HD access, and the meantime on HD was higher in the norm phos group compared to the high phos group. In a multivariate and univariate logistic regression analysis, hyperphosphatemia increased with increasing urea (Ur) and creatinine (Cr) levels, while the odds declined with increasing time on HD. Hb did not show a significant relation with phos by using several statistical methods. Discussion/Conclusion: A high prevalence of hyperphosphatemia and anemia was encountered among this sample of HD patients from Syria. There was no correlation between phos and Hb levels in contrast to previous conflicting studies, which mandates future studies to evaluate this correlation and further efforts to determine the range of phos that could have a benefit on anemia with respect to other comorbidities.

Anterior displacement of an avulsed posterio-latero-central tibial plateau fracture repaired with Herbert screws.

Introduction: Tibial plateau fractures are very complex articular fractures with a rare incidence of approximately 10.3%. These fractures may constitute a severe injury to the knee joint and other complications. Presentation of case: A 23- year-old male injured his right knee after a crush accident and was diagnosed with a posterio-latero-central (PLC) sheared fracture of the tibial plateau without an injury to knee ligaments. CT with a reconstruction of the right knee showed that the fracture was accompanied by a free fragment inserted into the anterior compartment of the knee. The free fragment was repositioned to its native location and was fixed with three Herbert screws. Also, we found a peripheral avulsion of the posterio-lateral (PL) portion of the lateral meniscus from the capsular attachment, which was repaired with vicryl absorbable suture. An above knee cast was put in 15-degree flexion for three weeks followed by a restoration of knee movements and weight-bearing after ten weeks of surgery. The patient had a full range of motions and no signs of joint laxity after one year of operation. Discussion conclusion: This study revealed that the surgical repair allowed a quick return to movement for a PLC sheared fracture of the tibial plateau and can be fixed sufficiently to achieve excellent postoperative recovery.