Search

Red deer (Cervus elaphus) can cause considerable damage to forest stands by bark stripping. Here, we examined the probability of bark stripping of susceptible Norway spruce (Picea abies) during winter in relation to local environmental characteristics in the western Harz Mountains, Lower Saxony, Germany. We present the results of a multiple logistic regression model for recent bark stripping damage by red deer which we developed from two systematic cluster sampling inventories after two winter periods along with associated meteorological data and records of bagged deer. Our model suggests that the risk of bark stripping increased significantly (Pââ0.05) with rising slope angle, cumulating snow depth and increasing index values of red deer population density. Spruces growing in closed forest stands were debarked at a higher probability than spruces located close to forest edges. Further on, spruce stands on eastern slopes had a lower probability of bark damage than spruce stands on northern slopes. Other tested variables (altitude, length of daily solar irradiation, duration of snow cover, age of spruce stand within the age range of 16â50 years) had no significant effect on the probability of new bark stripping. We conclude that red deer in the western Harz Mountains seem to use bark as food resource at preferred locations and in times of low food availability. To improve fit and predictive power of bark stripping models we recommend including stand characteristics. We propose to reduce the population size of red deer in order to diminish bark stripping damages to an economically acceptable level.

Background and Purpose: Cardioprotective miRNAs (protectomiRs) are promising therapeutic tools. Here, we aimed to identify protectomiRs in a translational porcine model of acute myocardial infarction (AMI) and to validate their cardiocytoprotective effect. Experimental Approach: ProtectomiR candidates were selected after systematic analysis of miRNA expression changes in cardiac tissue samples from a closed‐chest AMI model in pigs subjected to sham operation, AMI and ischaemic preconditioning, postconditioning or remote preconditioning, respectively. Cross‐species orthologue protectomiR candidates were validated in simulated ischaemia–reperfusion injury (sI/R) model of isolated rat ocardiomyocytes and in human AC16 cells as well. For miR‐450a, we performed target prediction and analysed the potential mechanisms of action by GO enrichment and KEGG pathway analysis. Key Results: Out of the 220 detected miRNAs, four were up‐regulated and 10 were down‐regulated due to all three conditionings versus AMI. MiR‐450a and miR‐451 mimics at 25 nM were protective in rat cardiomyocytes, and miR‐450a showed protection in human cardiomyocytes as well. MiR‐450a has 3987 predicted mRNA targets in pigs, 4279 in rats and 8328 in humans. Of these, 607 genes are expressed in all three species. A total of 421 common enriched GO terms were identified in all three species, whereas KEGG pathway analysis revealed 13 common pathways. Conclusion and Implications: This is the first demonstration that miR‐450a is associated with cardioprotection by ischaemic conditioning in a clinically relevant porcine model and shows cardiocytoprotective effect in human cardiomyocytes, making it a promising drug candidate. The mechanism of action of miR‐450a involves multiple cardioprotective pathways. LINKED ARTICLES: This article is part of a themed issue Non‐coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc [ABSTRACT FROM AUTHOR]

Three types of highly promising small RNA therapeutics, namely, small interfering RNAs (siRNAs), microRNAs (miRNAs) and the RNA subtype of antisense oligonucleotides (ASOs), offer advantages over small‐molecule drugs. These small RNAs can target any gene product, opening up new avenues of effective and safe therapeutic approaches for a wide range of diseases. In preclinical research, synthetic small RNAs play an essential role in the investigation of physiological and pathological pathways as silencers of specific genes, facilitating discovery and validation of drug targets in different conditions. Off‐target effects of small RNAs, however, could make it difficult to interpret experimental results in the preclinical phase and may contribute to adverse events of small RNA therapeutics. Out of the two major types of off‐target effects we focused on the hybridization‐dependent, especially on the miRNA‐like off‐target effects. Our main aim was to discuss several approaches, including sequence design, chemical modifications and target prediction, to reduce hybridization‐dependent off‐target effects that should be considered even at the early development phase of small RNA therapy. Because there is no standard way of predicting hybridization‐dependent off‐target effects, this review provides an overview of all major state‐of‐the‐art computational methods and proposes new approaches, such as the possible inclusion of network theory and artificial intelligence (AI) in the prediction workflows. Case studies and a concise survey of experimental methods for validating in silico predictions are also presented. These methods could contribute to interpret experimental results, to minimize off‐target effects and hopefully to avoid off‐target‐related adverse events of small RNA therapeutics. LINKED ARTICLES: This article is part of a themed issue Non‐coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc [ABSTRACT FROM AUTHOR]

Natural products (NPs) have long been used as a rich source of bioactive compounds for drug development. Recent technological advancements have revitalised natural products research as evidenced by increased publications in this field. In this editorial review, we highlight key points from the 2020 British Journal of Pharmacology (BJP) practical guide, which outlines standards for natural products research reports, and provide papers published in BJP between years 2020 to 2023 that demonstrate adherence to these guidelines. Looking ahead, we discuss the potential of chemical proteomics approaches to elucidate natural products mechanisms of action and identify therapeutic targets for future research. By fostering innovation, we aim to advance natural products research and contribute to the development of novel therapeutics that will have a significant impact on healthcare. [ABSTRACT FROM AUTHOR]

Aims To analyse the relevance of body composition and blood markers for long-term outcomes in very old patients after transcatheter aortic valve replacement (TAVR). Methods and results A total of 403 very old patients were characterized with regard to subcutaneous, visceral, and epicardial fat, psoas muscle area, plasma growth differentiation factor 15 (GDF-15), and leptin. Cohorts grouped by body mass index (BMI) were analysed for long-term outcomes. Patients underwent transapical and transfemoral TAVR (similar 30-day/1-year survival). Body mass index >35 kg/m2 showed increased 2- and 3-year mortality compared with BMI 25–34.9 kg/m2 but not compared with BMI <25 kg/m2. Fat areas correlated positively to BMI (epicardial: R 2 = 0.05, P < 0.01; visceral: R 2 = 0.20, P < 0.001; subcutaneous: R 2 = 0.13, P < 0.001). Increased epicardial or visceral but not subcutaneous fat area resulted in higher long-term mortality. Patients with high BMI (1781.3 mm2 ± 75.8, P < 0.05) and lean patients (1729.4 ± 52.8, P < 0.01) showed lower psoas muscle area compared with those with mildly elevated BMI (2055.2 ± 91.7). Reduced psoas muscle area and increased visceral fat and epicardial fat areas were independent predictors of long-term mortality. The levels of serum GDF-15 were the highest in BMI >40 kg/m2 (2793.5 pg/mL ± 123.2) vs. BMI <25 kg/m2 (2017.6 pg/mL ±130.8), BMI 25–30 kg/m2 (1881.8 pg/mL ±127.4), or BMI 30–35 kg/m2 (2054.2 pg/mL ±124.1, all P < 0.05). Increased GDF-15 level predicted mortality (2587 pg/mL, area under the receiver operating characteristic curve 0.94). Serum leptin level increased with BMI without predictive value for long-term mortality. Conclusion Morbidly visceral and epicardial fat accumulation, reduction in muscle area, and GDF-15 increase are strong predictors of adverse outcomes in very old patients post-TAVR. [ABSTRACT FROM AUTHOR]

LINKED ARTICLES: This article is part of a themed issue Non‐coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc [ABSTRACT FROM AUTHOR]

In 2023, seventy novel drugs received market authorization for the first time in either Europe (by the EMA and the MHRA) or in the United States (by the FDA). Confirming a steady recent trend, more than half of these drugs target rare diseases or intractable forms of cancer. Thirty drugs are categorized as "first‐in‐class" (FIC), illustrating the quality of research and innovation that drives new chemical entity discovery and development. We succinctly describe the mechanism of action of most of these FIC drugs and discuss the therapeutic areas covered, as well as the chemical category to which these drugs belong. The 2023 novel drug list also demonstrates an unabated emphasis on polypeptides (recombinant proteins and antibodies), Advanced Therapy Medicinal Products (gene and cell therapies) and RNA therapeutics, including the first‐ever approval of a CRISPR‐Cas9‐based gene‐editing cell therapy. [ABSTRACT FROM AUTHOR]

Background and Purpose: To protect against SARS‐CoV‐2 infection, the first mRNA‐based vaccines, Spikevax (mRNA‐1273, Moderna) and Comirnaty (BNT162b2, Pfizer/Biontech), were approved in 2020. The structure and assembly of the immunogen—in both cases, the SARS‐CoV‐2 spike (S) glycoprotein—are determined by a messenger RNA sequence that is translated by endogenous ribosomes. Cardiac side‐effects, which for the most part can be classified by their clinical symptoms as myo‐ and/or pericarditis, can be caused by both mRNA‐1273 and BNT162b2. Experimental Approach: As persuasive theories for the underlying pathomechanisms have yet to be developed, this study investigated the effect of mRNA‐1273 and BNT162b2 on the function, structure, and viability of isolated adult rat cardiomyocytes over a 72 h period. Key Results: In the first 24 h after application, both mRNA‐1273 and BNT162b2 caused neither functional disturbances nor morphological abnormalities. After 48 h, expression of the encoded spike protein was detected in ventricular cardiomyocytes for both mRNAs. At this point in time, mRNA‐1273 induced arrhythmic as well as completely irregular contractions associated with irregular as well as localized calcium transients, which provide indications of significant dysfunction of the cardiac ryanodine receptor (RyR2). In contrast, BNT162b2 increased cardiomyocyte contraction via significantly increased protein kinase A (PKA) activity at the cellular level. Conclusion and Implications: Here, we demonstrated for the first time, that in isolated cardiomyocytes, both mRNA‐1273 and BNT162b2 induce specific dysfunctions that correlate pathophysiologically to cardiomyopathy. Both RyR2 impairment and sustained PKA activation may significantly increase the risk of acute cardiac events. [ABSTRACT FROM AUTHOR]