Pharmacological research : the official journal of the Italian Pharmacological Society
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Iron is an essential biogenic element for both prokaryotic and eukaryotic cells. In humans iron is present in hundreds of different metalloproteins. ⋯ Therapeutic modulation of hepcidin is a new and promising approach to treatment of these conditions. In this review, a summary of the current knowledge of hepcidin function, regulation and pathological involvements are provided, followed by a section covering the therapeutic potential of hepcidin and the current strategies how to modulate its levels and biological functions for therapeutic purposes.
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Aromatic antiepileptic drugs (AEDs) are among the drugs most frequently involved in severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). This study investigated the associations between the genetic polymorphisms of HLA class-I and AED-induced SCARs in the Spanish population. HLA class-I genotypes were determined in AED (phenytoin[PHT],lamotrigine[LTG],carbamazepine[CBZ],phenobarbital[PB])-induced SJS/TEN (n=15) or DRESS (n=12) cases included in the Spanish SCAR registry, PIELenRed. ⋯ HLA-A*31:01 was significantly associated with the CBZ-cases [(A)OR:22.00, p=0.047;(B)OR:29.50, p=0.033;(C)OR:35.14, p=0.006]. In conclusion, we identified several significant genetic risk factors for the first time in the Spanish Caucasian population: HLA-A*02:01/Cw*15:02 combination as a risk factor for PHT-induced SJS/TEN, HLA-B*38:01 for LTG- and PHT- induced SJS/TEN, HLA-A*11:01 for CBZ-induced SJS/TEN, and HLA-A*24:02 for LTG- and PHT- induced DRESS. The strong association between HLA*31:01 and CBZ-DRESS in Europeans was confirmed in this study.
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The review focuses on the common kidney disorder of Autosomal Dominant Polycystic Kidney Disease (ADPKD). The potential pathogenetic role of the renin-angiotensin-aldosterone system (RAAS) in the renal cyst growth, the accompanying hypertension, and the frequency of increased left ventricular mass is considered. The therapeutic benefit of angiotensin converting enzyme inhibition (ACEI) in diminishing the renal cyst growth, treatment of the hypertension, and reversing the increased left ventricular mass in ADPKD is supportive of this possibility. The effects of ACEI related and unrelated to control of blood pressure are discussed.
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Meldonium (mildronate; 3-(2,2,2-trimethylhydrazinium)propionate; THP; MET-88) is a clinically used cardioprotective drug, which mechanism of action is based on the regulation of energy metabolism pathways through l-carnitine lowering effect. l-Carnitine biosynthesis enzyme γ-butyrobetaine hydroxylase and carnitine/organic cation transporter type 2 (OCTN2) are the main known drug targets of meldonium, and through inhibition of these activities meldonium induces adaptive changes in the cellular energy homeostasis. Since l-carnitine is involved in the metabolism of fatty acids, the decline in its levels stimulates glucose metabolism and decreases concentrations of l-carnitine related metabolites, such as long-chain acylcarnitines and trimethylamine-N-oxide. Here, we briefly reviewed the pharmacological effects and mechanisms of meldonium in treatment of heart failure, myocardial infarction, arrhythmia, atherosclerosis and diabetes.
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Mammalian cells can utilize hydrogen sulfide (H2S) to support mitochondrial respiration. The aim of our study was to explore the potential role of S-sulfhydration (a H2S-induced posttranslational modification, also known as S-persulfidation) of the mitochondrial inner membrane protein ATP synthase (F1F0 ATP synthase/Complex V) in the regulation of mitochondrial bioenergetics. Using a biotin switch assay, we have detected S-sulfhydration of the α subunit (ATP5A1) of ATP synthase in response to exposure to H2S in vitro. ⋯ In conclusion, H2S induces S-sulfhydration of ATP5A1 at C244 and C294. This post-translational modification may be a physiological mechanism to maintain ATP synthase in a physiologically activated state, thereby supporting mitochondrial bioenergetics. The sulfhydration of ATP synthase may be a dynamic process, which may be regulated by endogenous H2S levels under various pathophysiological conditions.