Acute kidney injury (AKI) is a global health challenge of vast proportions, as approx. 13.3% of people worldwide are affected annually. The pathophysiology of AKI is very complex, but its main causes ...are sepsis, ischemia, and nephrotoxicity. Nephrotoxicity is mainly associated with the use of drugs. Drug-induced AKI accounts for 19–26% of all hospitalized cases. Drug-induced nephrotoxicity develops according to one of the three mechanisms: (1) proximal tubular injury and acute tubular necrosis (ATN) (a dose-dependent mechanism), where the cause is related to apical contact with drugs or their metabolites, the transport of drugs and their metabolites from the apical surface, and the secretion of drugs from the basolateral surface into the tubular lumen; (2) tubular obstruction by crystals or casts containing drugs and their metabolites (a dose-dependent mechanism); (3) interstitial nephritis induced by drugs and their metabolites (a dose-independent mechanism). In this article, the mechanisms of the individual types of injury will be described. Specific groups of drugs will be linked to specific injuries. Additionally, the risk factors for the development of AKI and the methods for preventing and/or treating the condition will be discussed.
The Role of Fe, Zn, and Cu in Pregnancy Grzeszczak, Konrad; Kwiatkowski, Sebastian; Kosik-Bogacka, Danuta
Biomolecules (Basel, Switzerland),
08/2020, Letnik:
10, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Iron (Fe), copper (Cu), and zinc (Zn) are microelements essential for the proper functioning of living organisms. These elements participatein many processes, including cellular metabolism and ...antioxidant and anti-inflammatory defenses, and also influence enzyme activity, regulate gene expression, and take part in protein synthesis. Fe, Cu, and Zn have a significant impact on the health of pregnant women and in the development of the fetus, as well as on the health of the newborn. A proper concentration of these elements in the body of women during pregnancy reduces the risk of complications such as anemia, induced hypertension, low birth weight, preeclampsia, and postnatal complications. The interactions between Fe, Cu, and Zn influence their availability due to their similar physicochemical properties. This most often occurs during intestinal absorption, where metal ions compete for binding sites with transport compounds. Additionally, the relationships between these ions have a great influence on the course of reactions in the tissues, as well as on their excretion, which can be stimulated or delayed. This review aims to summarize reports on the influence of Fe, Cu, and Zn on the course of single and multiple pregnancies, and to discuss the interdependencies and mechanisms occurring between Fe, Cu, and Zn.
Protein Histidine Methylation Kwiatkowski, Sebastian; Drozak, Jakub
Current protein & peptide science,
01/2020, Letnik:
21, Številka:
7
Journal Article
Recenzirano
Protein histidine methylation is a rarely studied posttranslational modification in eukaryotes. Although the presence of N-methylhistidine was demonstrated in actin in the early 1960s, so far, only a ...limited number of proteins containing N-methylhistidine have been reported, including S100A9, myosin, skeletal muscle myosin light chain kinase (MLCK 2), and ribosomal protein Rpl3. Furthermore, the role of histidine methylation in the functioning of the protein and in cell physiology remains unclear due to a shortage of studies focusing on this topic. However, the molecular identification of the first two distinct histidine-specific protein methyltransferases has been established in yeast (Hpm1) and in metazoan species (actin-histidine N-methyltransferase), giving new insights into the phenomenon of protein methylation at histidine sites. As a result, we are now beginning to recognize protein histidine methylation as an important regulatory mechanism of protein functioning whose loss may have deleterious consequences in both cells and in organisms. In this review, we aim to summarize the recent advances in the understanding of the chemical, enzymological, and physiological aspects of protein histidine methylation.
Abstract l -2-Keto-3-deoxyfuconate 4-dehydrogenase ( l -KDFDH) catalyzes the NAD + -dependent oxidization of l -2-keto-3-deoxyfuconate ( l -KDF) to l -2,4-diketo-3-deoxyfuconate ( l -2,4-DKDF) in the ...non-phosphorylating l -fucose pathway from bacteria, and its substrate was previously considered to be the acyclic α-keto form of l -KDF. On the other hand, BDH2, a mammalian homolog with l -KDFDH, functions as a dehydrogenase for cis -4-hydroxy- l -proline (C4LHyp) with the cyclic structure. We found that l -KDFDH and BDH2 utilize C4LHyp and l -KDF, respectively. Therefore, to elucidate unique substrate specificity at the atomic level, we herein investigated for the first time the crystal structures of l -KDFDH from Herbaspirillum huttiense in the ligand-free, l -KDF and l -2,4-DKDF, d -KDP ( d -2-keto-3-deoxypentonate; additional substrate), or l -2,4-DKDF and NADH bound forms. In complexed structures, l -KDF, l -2,4-DKDF, and d -KDP commonly bound as a α-furanosyl hemiketal. Furthermore, l -KDFDH showed no activity for l -KDF and d -KDP analogs without the C5 hydroxyl group, which form only the acyclic α-keto form. The C1 carboxyl and α-anomeric C2 hydroxyl groups and O5 oxygen atom of the substrate (and product) were specifically recognized by Arg148, Arg192, and Arg214. The side chain of Trp252 was important for hydrophobically recognizing the C6 methyl group of l -KDF. This is the first example showing the physiological role of the hemiketal of 2-keto-3-deoxysugar acid.
Neuroendocrine tumours of the gastrointestinal tract are rare. The incidence has increased in recent years due to improvements in diagnostic methods for detecting these lesions. These tumours have a ...poor prognosis, especially when detected at an advanced stage. The basis of the treatment is resection, and non-surgical treatments are also standard in the treatment process. The situation is similar in even rarer neuroendocrine tumours of the reproductive tract, which are associated with an equally poor prognosis. In this article, we focus on learning about the risk factors (including genetic mutations) that increase the risk of the disease and comparing the effectiveness of non-surgical treatments-chemotherapy, radiotherapy, peptide receptor radionuclide therapy, somatostatin analogues, and immunotherapy. The efficacy of these treatments varies, and immunotherapy appears to be a promising form of treatment; however, this requires further research.
Carnosine (β-alanyl-L-histidine) and its methylated derivatives: anserine (β-alanyl-Nπ- methyl-L-histidine) and balenine (β-alanyl-Nτ-methyl-L-histidine) are abundant constituents of excitable ...tissues of vertebrates. While carnosine and anserine are present at high concentrations and in variable proportions in skeletal muscle and brain of most vertebrates, balenine appears to be rather more abundant in marine mammals and certain reptilian species. Since the discovery of these compounds at the beginning of 20th century, numerous studies have been devoted to identification of the biochemical and physiological properties of carnosine and related dipeptides. These led to the discovery of the pHbuffering, metal-chelation and antioxidant, capabilities of carnosine and anserine, although no definitive ideas concerning their physiological role has yet been formulated. Only recently the molecular identities of the enzymes catalyzing synthesis of carnosine (carnosine synthase, EC 6.3.2.11) and anserine (carnosine N-methyltransferase, EC 2.1.1.22) have been elucidated, which has given a new insight into their metabolism in vertebrates. These findings have opened new research areas and provide authentic opportunities for understanding the biological function of these "enigmatic" dipeptides. This review aims to summarize recent advances in our knowledge concerning enzymes responsible for the biosynthesis of carnosine and related dipeptides and to evaluate their importance in vertebrate physiology.
Selenium (Se) and manganese (Mn) are essential micronutrients that are important elements of cell metabolism. They are involved in the composition of enzyme systems and regulate enzyme activity. ...Disturbances in the homeostasis of these micronutrients affect the development of many diseases and carcinogenesis, which can be linked to increased levels of oxidative stress and impaired antioxidant properties of many enzymes. Selenium has a very important function in maintaining immune-endocrine, metabolic and cellular homeostasis. Manganese, on the other hand, is important in development, digestion, reproduction, antioxidant defense, energy production, immune response and regulation of neuronal activity. We review the role of selenium and manganese and their effects on tumor growth, metastasis potential and remodeling of the microenvironment. We also describe their role as potential biomarkers in the diagnosis and the potential for the use of Se- and Mn-containing compounds in composition for the treatment of cancer of the reproductive organs.
Cutaneous melanoma is a relatively common neoplasm, with fairly well understood pathogenesis, risk factors, prognosis and therapeutic protocols. The incidence of this disease is increasing every ...year. The situation is different for rare malignancies such as vulvar melanomas and for the even rarer vaginal melanomas. The risk factors for vulvovaginal tumors are not fully understood. The basis of treatment in both cases is surgical resection; however, other types of treatments such as immunotherapy are available. This paper focuses on comparing the pathogenesis and risk factors associated with these neoplasms as well as the efficacy of two groups of drugs—anti-PD-L1 and anti-CTLA4 inhibitors—against both cutaneous melanoma and melanoma of the lower genital tract (vulva and vagina). In the case of cutaneous melanoma, the situation looks more optimistic than for vulvovaginal melanoma, which has a much worse prognosis and, as it turns out, shows a poorer response to immune therapy.
Cardiac surgery-associated acute kidney injury (CSA-AKI) is one of the most common complications of cardiac surgery procedures. In this study, the authors attempt to provide new data regarding the ...application of novel kidney injury biomarkers in the early diagnostics of CSA-AKI. 128 adult patients undergoing elective cardiac surgery procedures with the use of cardiopulmonary by-pass (CPB) were enrolled in this study. Novel kidney injury biomarkers were marked in the plasma and urine 6 h after weaning from the CPB. A significant difference in the postoperative biomarkers' concentration between the AKI and no-AKI group was found, regarding plasma IL-8, plasma TNF-α and urine NGAL, normalized for creatinine excretion (NGAL/Cr). These were also independent predictors of CSA-AKI. An independent risk factor for CSA-AKI proved to be preoperative CKD. Plasma IL-8 and TNF-α, as well as urine NGAL/Cr, are independent early indicators of CSA-AKI and pose a promising alternative for creatinine measurements. The cut-off points for these biomarkers proposed in this investigation should be confronted with more data and revised to achieve a suitable diagnostic value.
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