Showing papers by "Pascal De Tullio published in 2022"

Myoferlin targeting triggers mitophagy and primes ferroptosis in pancreatic cancer cells

Abstract: Myoferlin, an emerging oncoprotein, has been associated with a low survival in several cancer types including pancreas ductal adenocarcinoma where it controls mitochondria structure and respiratory functions. Owing to the high susceptibility of KRAS-mutated cancer cells to iron-dependent cell death, ferroptosis, and to the high iron content in mitochondria, we investigated the relation existing between mitochondrial integrity and iron-dependent cell death. We discovered that myoferlin targeting with WJ460 pharmacological compound triggered mitophagy and ROS accumulation culminating with lipid peroxidation and apoptosis-independent cell death. WJ460 caused a reduction of the abundance of ferroptosis core regulators xc- cystine/glutamate transporter and GPX-4. Mitophagy inhibitor Mdivi1 and iron chelators inhibited the myoferlin-related ROS production and restored cell growth. Additionally, we reported a synergic effect between ferroptosis inducers, erastin and RSL3, and WJ460.

Trypanosoma brucei: Metabolomics for analysis of cellular metabolism and drug discovery

Abstract: Trypanosoma brucei is the causative agent of Human African Trypanosomiasis (also known as sleeping sickness), a disease causing serious neurological disorders and fatal if left untreated. Due to its lethal pathogenicity, a variety of treatments have been developed over the years, but which have some important limitations such as acute toxicity and parasite resistance. Metabolomics is an innovative tool used to better understand the parasite's cellular metabolism, and identify new potential targets, modes of action and resistance mechanisms. The metabolomic approach is mainly associated with robust analytical techniques, such as NMR and Mass Spectrometry. Applying these tools to the trypanosome parasite is, thus, useful for providing new insights into the sleeping sickness pathology and guidance towards innovative treatments.The present review aims to comprehensively describe the T. brucei biology and identify targets for new or commercialized antitrypanosomal drugs. Recent metabolomic applications to provide a deeper knowledge about the mechanisms of action of drugs or potential drugs against T. brucei are highlighted. Additionally, the advantages of metabolomics, alone or combined with other methods, are discussed.Compared to other parasites, only few studies employing metabolomics have to date been reported on Trypanosoma brucei. Published metabolic studies, treatments and modes of action are discussed. The main interest is to evaluate the metabolomics contribution to the understanding of T. brucei's metabolism.

Kidney-targeted irradiation triggers renal ischaemic preconditioning in mice.

Abstract: Renal ischemia/reperfusion (I/R) causes acute kidney injury (AKI). Ischemic preconditioning (IPC) attenuates I/R-associated AKI. Whole-body irradiation induces renal IPC in mice. Still, the mechanisms remain largely unknown. Furthermore, the impact of kidney-centered irradiation on renal resistance against I/R has not been studied. Renal irradiation (8.5Gy) was done in male 8-12-week-old C57bl/6 mice using Small Animal Radiation Therapy (SmART) device. Left renal I/R was performed by clamping the renal pedicles for 30 minutes, with simultaneous right nephrectomy, at 7, 14, and 28 days post-irradiation. The renal reperfusion lasted 48 hours. Following I/R, blood urea nitrogen (BUN) and creatinine (SCr) levels were lower in pre-irradiated mice compared to controls, so was the histological Jablonski score of AKI. The metabolomics signature of renal I/R was attenuated in pre-irradiated mice. The numbers of PCNA-, CD11b-, and F4-80-positive cells in the renal parenchyma post-I/R were reduced in pre-irradiated versus control groups. Such an IPC was significantly observed as early as D14 post-irradiation. RNA-Seq showed an up-regulation of angiogenesis- and stress response-related signaling pathways in irradiated non-ischemic kidneys at D28. RT-qPCR confirmed the increased expression of VEGF, ALK5, HO1, PECAM1, NOX2, HSP70, and HSP27 in irradiated kidneys compared to controls. In addition, irradiated kidneys showed an increased CD31-positive vascular area compared to controls. A 14-day gavage of irradiated mice with the anti-angiogenic drug Sunitinib before I/R abrogated the irradiation-induced IPC at both functional and structural levels. Our observations suggest that kidney-centered irradiation activates pro-angiogenic pathways and induces IPC, with preserved renal function and attenuated inflammation post-I/R.

Design, Synthesis, and Evaluation of Novel Pyruvate Dehydrogenase Kinase Inhibitors.

Abstract: AIMS The present work describes the synthesis and the biological evaluation of novel compounds acting as pyruvate dehydrogenase kinase (PDK) inhibitors. These drugs should become a new therapeutic approach for the treatment of pathologies improved by the control of the blood lactate level. METHODS Four series of compounds belonging to N-(4-(N-alkyl/aralkylsulfamoyl)phenyl)-2-methylpropanamides and to 1,2,4-benzothiadiazine 1,1-dioxides were prepared and evaluated as PDK inhibitors. RESULTS The newly synthesized N-(4-(N-alkyl/aralkylsulfamoyl)phenyl)-2-methylpropanamides structurally related to previously reported reference compounds 4 and 5 were found to be potent PDK inhibitors (i.e. 10d: IC50 = 41 nM). 1,2,4-Benzothiadiazine 1,1-dioxides carrying a (methyl/trifluoromethyl)-propanamide moiety at the 6-position were also designed as conformationally restricted ring-closed analogues of N-(4-(N-alkyl/aralkylsulfamoyl)phenyl)-2-hydroxy-2-methylpropanamides. Most of them were found to be less potent than their ring-opened analogues. Interestingly, the best choice of hydrocarbon side chain at the 4-position was the benzyl chain, providing 11c (IC50 = 3.6 µM) belonging to "unsaturated" 1,2,4-benzothiadiazine 1,1-dioxides, and 12c (IC50 = 0.5 µM) belonging to "saturated' 1,2,4-benzothiadiazine 1,1-dioxides. CONCLUSION This work showed that ring-closed analogues of N-(4-(N-alkyl/aralkylsulfamoyl)phenyl)-2-hydroxy-2-methylpropanamides were less active as PDK inhibitors than their corresponding ring-opened analogues. However, the introduction of a bulkier substituent at the 4-position of the 1,2,4-benzothiadiazine 1,1-dioxide core structure, such as a benzyl or a phenethyl side chain, was allowed, opening the way to the design of new inhibitors with improved PDK inhibitory activity.

Recent metabolomic developments for antimalarial drug discovery

Abstract: Malaria is a parasitic disease that remains a global health issue, responsible for a significant death and morbidity toll. Various factors have impacted the use and delayed the development of antimalarial therapies, such as the associated financial cost and parasitic resistance. In order to discover new drugs and validate parasitic targets, a powerful omics tool, metabolomics, emerged as a reliable approach. However, as a fairly recent method in malaria, new findings are timely and original practices emerge frequently. This review aims to discuss recent research towards the development of new metabolomic methods in the context of uncovering antiplasmodial mechanisms of action in vitro and to point out innovative metabolic pathways that can revitalize the antimalarial pipeline.