Effectiveness and safety of injectable PCSK9 inhibitors in dyslipidaemias’ treatment and cardiovascular disease prevention: An overview of 86 systematic reviews and a network metaanalysis / Eficacia y seguridad de los inyectables inhibidores de la PCSK9 en el tratamiento de dislipidemias y la prevención de enfermedades cardiovasculares: una visión general de 86 revisiones sistemáticas y un metaanálisis en red

Objective Multiple systematic reviews (SR) have been performed on the effects of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), often providing conflicting findings. This overview and network meta-analysis (NMA) aimed to summarize SR findings on the efficacy and safety of PCSK9i and provide an updated NMA. Materials and methods MEDLINE (Pubmed), Scopus, Cochrane, Epistemonikos and Google Scholar were searched from inception to September 21, 2023 for SRs of randomized controlled trials (RCTs) and from January 1, 2020 to September 21, 2023 for additional RCTs. Double-independent study selection, data extraction and quality assessment were performed. Qualitative analysis was performed for SRs and a frequentist random-effects model NMA was performed for RCTs. Results Totally, 86 SRs and 76 RCTs were included. Alirocumab (77/86 [90%]) and evolocumab (73/86 [85%]) were mostly analyzed. Associations from SRs (35/42 [83%]) and the updated NMA indicated PCSK9i benefit on major adverse cardiovascular events (MACEs). Reductions were also noted for cerebrovascular events (47/66 [71%]), coronary revascularization (29/33 [88%]) and myocardial infarction (41/63 [65%]). Alirocumab was associated with reductions on all-cause mortality (RR=0.82, 95%CI [0.72,0.94]). Data on any CV event reduction were conflicting (7/16 [44%]). Inclisiran appeared effective only on MACEs (RR=0.76, 95%CI [0.61,0.94]). No reductions in heart failure were observed (0/16). No increases were identified between PCSK9i and any (0/35) or serious adverse events (0/52). However, PCSK9i were associated with injection-site reactions (20/28 [71%]). Conclusion PCSK9i appeared to be effective in CV outcomes and their clinical application was generally safe. (AU)

Objetivo Las revisiones sistemáticas (RS) sobre los efectos de los inhibidores de la proproteína convertasa subtilisina/kexina tipo 9 (PCSK9i), presentan resultados contradictorios. Esta revisión general y metaanálisis en red (MER) tiene como objetivo resumir los hallazgos sobre la eficacia y seguridad de los PCSK9i. Materiales y métodos Se realizaron búsquedas en MEDLINE (PubMed), Scopus, Cochrane, Epistemonikos y Google Scholar desde sus inicios hasta el 21 de septiembre de 2023 para las RS de ensayos controlados aleatorios (ECA) y desde el 1 de enero de 2020 hasta 21 de septiembre de 2023 para los ECA adicionales. La selección de estudios, extracción de datos y evaluación de calidad se llevaron a cabo de manera doble e independiente. Se realizó un análisis cualitativo de las SR y un modelo de efectos aleatorios frecuentistas MER para los ECA. Resultados En total, se incluyeron 86 SR y 76 RCT. Alirocumab (77/86 [90%]) y evolocumab (73/86 [85%]) fueron los más analizados. Se reconocieron beneficios de los PCSK9i en eventos cardiovasculares adversos mayores (ECVAM), reducción de eventos cerebrovasculares (47/66 [71%]), revascularización coronaria (29/33 [88%]) e infartos de miocardio (41/63 [65%]). Alirocumab redujo la mortalidad por todas las causas (RR: 0,82; IC del 95%: 0,72-0,94). Los resultados sobre la reducción de cualquier evento cardiovascular (CV) fueron contradictorios (7/16 [44%]). Inclisiran pareció ser efectivo solo en la reducción de ECVAM (RR: 0,76; IC del 95%: 0,61-0,94). No se observaron reducciones en insuficiencia cardíaca (0/16) o relación con eventos adversos serios (0/52). Sin embargo, se asociaron con reacciones en el lugar de la inyección (20/28 [71%]). (AU)

2',3'-Cyclic nucleotide 3'-phosphodiesterase: a novel RNA-binding protein that inhibits protein synthesis.

2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNP) is one of the earliest myelin-related proteins to be specifically expressed in differentiating oligodendrocytes (ODCs) in the central nervous system (CNS) and is implicated in myelin biogenesis. CNP possesses an in vitro enzymatic activity, whose in vivo relevance remains to be defined, because substrates with 2',3,-cyclic termini have not yet been identified. To characterize CNP function better, we previously determined the structure of the CNP catalytic domain by NMR. Interestingly, the structure is remarkably similar to the plant cyclic nucleotide phosphodiesterase (CPDase) from A. thaliana and the bacterial 2'-5' RNA ligase from T. thermophilus, which are known to play roles in RNA metabolism. Here we show that CNP is an RNA-binding protein. Furthermore, by using precipitation analyses, we demonstrate that CNP associates with poly(A)(+) mRNAs in vivo and suppresses translation in vitro in a dose-dependent manner. With SELEX, we isolated RNA aptamers that can suppress the inhibitory effect of CNP on translation. We also demonstrate that CNP1 can bridge an association between tubulin and RNA. These results suggest that CNP1 may regulate expression of mRNAs in ODCs of the CNS.

New trends in anti-malarial agents.

Malaria is the major parasitic infection in many tropical and subtropical regions, leading to more than one million deaths (principally young African children) out of 400 million cases each year (WHO world health report 2000). More than half of the world's population live in areas where they remain at risk of malaria infection. During last years, the situation has worsened in many ways, mainly due to malarial parasites becoming increasingly resistant to several antimalarial drugs. Furthermore, the control of malaria is becoming more complicated by the parallel spread of resistance of the mosquito vector to currently available insecticides. Discovering new drugs in this field is therefore a health priority. Several new molecules are under investigation. This review describes the classical treatments of malaria and the latest discoveries in antimalarial agents, especially artemisinin and its recent derivatives as well as the novel peroxidic compounds.

Using protein synthesis inhibitors to establish the phylogenetic relationships of the Sulfolobales order.

The sensitivity of the cell-free protein synthesis systems from Acidanus brierleyi, Acidianus infernus, and Metallosphaera sedula, members of the archaeal order Sulfolobales, to 40 antibiotics with different specificities has been studied. The sensitivity patterns were compared to those of Sulfolobus solfataricus and other archaeal, bacterial, and eukaryotic systems. The comparative analysis shows that ribosomes from the sulfolobales are the most refractory to inhibitors of protein synthesis described so far. The sensitivity results have been used to ascertain in phylogenetic relationships among the members of the order Sulfolobales. The evolutionary significance of these results are analyzed in the context of the phylogenetic position of this group of extreme thermophilic microorganisms.

Rationale for the clinical use of immunotoxins: monoclonal antibodies conjugated to ribosome-inactivating proteins.

The use of chemotherapeutic drugs in combination with bone marrow transplantation to treat cancer patients has markedly improved the disease-free survival and cure rate. Part of the tumor cells, however, can escape from therapy due to resistance. Tumor-specific delivery of toxins that do not interfere with conventional drugs and are not cell cycle dependent seems to be a reasonable approach to overcome this problem. Natural ribosome-inhibiting-proteins (RIPs) from plants, bacteria and fungi which are extremely toxic inhibitors of protein synthesis are isolated and coupled to monoclonal antibodies (MoAbs) and receptor-specific ligands, immunotoxins (ITs), to fulfil this purpose. ITs are very suitable to eliminate malignant cells in vitro and in vivo. RIPs contain two or three active sites: a binding site which can be absent in a part of the RIPs and can be replaced by the MoAb; a translocation site that facilitates transport into the cytosol after internalization, and a cytotoxic site that enzymatically inhibits protein synthesis. Binding site containing toxins induce strong nonspecific cytotoxicity when coupled to MoAbs. Recent developments in recombinant DNA techniques enable genetic elimination of the binding site to reduce nonspecific cytotoxicity of these toxins. In this review the structures and mechanisms of action of RIPs as well as factors that influence cytotoxicity of immunotoxins are discussed. Moreover the problems dealing with in vivo application of ITs such as blood clearance by instability of the IT and hepatic entrapment, and production of antibodies directed against MoAb and toxin are reviewed.