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10 paginas, 15 fguras, Psychedelics produce fast and persistent antidepressant effects and induce neuroplasticity resembling the effects of clinically approved antidepressants. We recently reported that pharmacologically diverse antidepressants, including fluoxetine and ketamine, act by binding to TrkB, the receptor for BDNF. Here we show that lysergic acid diethylamide (LSD) and psilocin directly bind to TrkB with affinities 1,000-fold higher than those for other antidepressants, and that psychedelics and antidepressants bind to distinct but partially overlapping sites within the transmembrane domain of TrkB dimers. The effects of psychedelics on neurotrophic signaling, plasticity and antidepressant-like behavior in mice depend on TrkB binding and promotion of endogenous BDNF signaling but are independent of serotonin 2A receptor (5-HT2A) activation, whereas LSD-induced head twitching is dependent on 5-HT2A and independent of TrkB binding. Our data confirm TrkB as a common primary target for antidepressants and suggest that high-affinity TrkB positive allosteric modulators lacking 5-HT2A activity may retain the antidepressant potential of psychedelics without hallucinogenic effects, Open access funding provided by University of Helsinki including Helsinki University Central Hospital. The group of E.C. was supported by the Academy of Finland (294710, 303124, 307416 and 327192), Sigrid Jusélius Foundation and Jane and Aatos Erkko Foundation. The group of I.V. was supported by the Helsinki Institute of Life Science (HiLIFE) Fellow Program, Human Frontier Science Program (RGP0059/2019), Sigrid Juselius Foundation, Academy of Finland (331349, 335527 and 346135) and Cancer Foundation Finland. We also acknowledge CSC–IT Center for Science for providing computing resources and the HiLIFE NMR unit at the University of Helsinki, Instruct-ERIC Finland, FINStruct and Biocenter Finland for providing facilities and expertise. The group of M.S. was supported by the Jane and Aatos Erkko Foundation. The group of K.S.M. was supported by the Russian Science Foundation (22-14-00130 issued to G.S.A.). The group of P.P. was supported by the Jane and Aatos Erkko foundation and the Academy of Finland (323435). The group of E.R.K. was supported by the Academy of Finland (317399) and the Finnish Foundation for Alcohol Studies. The group of M.Va. was supported by the Academy of Finland (288475 and 294173), Sigrid Juselius Foundation, Finnish Cancer Foundation and Biocentrum Finland. R.M. was supported by the Brain & Mind Doctoral Programme (University of Helsinki) and received a grant from the Boehringer Ingelheim Foundation for methodological training. C.C. was supported by the Finnish Cultural Foundation (002100254). L.V.E. was supported by the Finnish Cultural Foundation (00180226) and the Finnish Foundation for Alcohol Studies. The authors dedicate this manuscript to the memory of Tomasz Róg.

Cutaneous wound healing is a complex process that encompasses alterations in all aspects of the skin including the extracellular matrix (ECM). ECM consist of large structural proteins such as collagens and elastin as well as smaller proteins with mainly regulative properties called matricellular proteins. Matricellular proteins bind to structural proteins and their functions include but are not limited to interaction with cell surface receptors, cytokines, or protease and evoking a cellular response. The signaling initiated by matricellular proteins modulates differentiation and proliferation of cells having an impact on the tissue regeneration. In this review we give an overview of the matricellular proteins that have been found to be involved in cutaneous wound healing and summarize the information known to date about their functions in this process.

Cardiovascular diseases lead the mortality and morbidity disease metrics worldwide. A multitude of chemical base modifications in ribonucleic acids (RNAs) have been linked with key events of cardiovascular diseases and metabolic disorders. Named either RNA epigenetics or epitranscriptomics, the post-transcriptional RNA modifications, their regulatory pathways, components, and downstream effects substantially contribute to the ways our genetic code is interpreted. Here we review the accumulated discoveries to date regarding the roles of the two most common epitranscriptomic modifications, N-6-methyl-adenosine (m(6)A) and adenosine-to-inosine (A-to-I) editing, in cardiovascular disease.

Publisher Copyright: © 2021 The Authors Antimicrobial peptides (AMPs) are potent, mostly cationic, and amphiphilic broad-spectrum host defense antimicrobials that are produced by all organisms ranging from prokaryotes to humans. In addition to their antimicrobial actions, they modulate inflammatory and immune responses and promote wound healing. Although they have clear benefits over traditional antibiotic drugs, their wide therapeutic utilization is compromised by concerns of toxicity, stability, and production costs. Recent advances in nanotechnology have attracted increasing interest to unleash the AMPs’ immense potential as broad-spectrum antibiotics and anti-biofilm agents, against which the bacteria have less chances to develop resistance. Topical application of AMPs promotes migration of keratinocytes and fibroblasts, and contributes significantly to an accelerated wound healing process. Delivery of AMPs by employing nanotechnological approaches avoids the major disadvantages of AMPs, such as instability and toxicity, and provides a controlled delivery profile together with prolonged activity. In this review, we provide an overview of the key properties of AMPs and discuss the latest developments in topical AMP therapy using nanocarriers. We use chronic hard-to-heal wounds—complicated by infections, inflammation, and stagnated healing—as an example of an unmet medical need for which the AMPs’ wide range of therapeutic actions could provide the most potential benefit. The use of innovative materials and sophisticated nanotechnological approaches offering various possibilities are discussed in more depth.

Background: Although many pathological changes have been associated with ischemic heart disease (IHD), molecular-level alterations specific to the ischemic myocardium and their potential to reflect disease severity or therapeutic outcome remain unclear. Currently, diagnosis occurs relatively late and evaluating disease severity is largely based on clinical symptoms, various imaging modalities, or the determination of risk factors. This study aims to identify IHD-associated signature RNAs from the atrial myocardium and evaluate their ability to reflect disease severity or cardiac surgery outcomes. Methods and Results: We collected right atrial appendage (RAA) biopsies from 40 patients with invasive coronary angiography (ICA)-positive IHD undergoing coronary artery bypass surgery and from 8 patients ICA-negative for IHD (non-IHD) undergoing valvular surgery. Following RNA sequencing, RAA transcriptomes were analyzed against 429 donors from the GTEx project without cardiac disease. The IHD transcriptome was characterized by repressed RNA expression in pathways for cell-cell contacts and mitochondrial dysfunction. Increased expressions of the CSRNP3, FUT10, SHD, NAV2-AS4, and hsa-mir-181 genes resulted in significance with the complexity of coronary artery obstructions or correlated with a functional cardiac benefit from bypass surgery. Conclusions: Our results provide an atrial myocardium-focused insight into IHD signature RNAs. The specific gene expression changes characterized here, pave the way for future disease mechanism-based identification of biomarkers for early detection and treatment of IHD. publishedVersion

Funding Information: Funding: This research was supported by Instrumentarium Science Foundation. Koite Health Oy provided support in the form of salaries for author S.N. and provided the materials for the study (VAT-2918895-9). The specific roles of the authors are articulated in the Author Contributions section. The funders had no additional role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: This research was supported by Instrumentarium Science Foundation. Koite Health Oy provided support in the form of salaries for author S.N. and provided the materials for the study (VAT-2918895-9). The specific roles of the authors are articulated in the Author Contributions section. The funders had no additional role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. New means to reduce excessive antibiotic use are urgently needed. This study tested dual-light aPDT against Staphylococcus aureus biofilm with different relative ratios of light energy with indocyanine green. We applied single-light aPDT (810 nm aPDT, 405 aBL) or dual-light aPDT (simultaneous 810 nm aPDT and 405 nm aBL), in both cases, together with the ICG photosensitizer with constant energy of 100 or 200 J/cm2. Single-dose light exposures were given after one-day, three-day, or six-day biofilm incubations. A repeated daily dose of identical light energy was applied during biofilm incubations for the three-and six-day biofilms. Using 100 J/cm2 light energy against the one-day biofilm, the dual-light aPDT consisting of more than half of aBL was the most effective. On a three-day maturated biofilm, single-dose exposure to aPDT or dual-light aPDT was more effective than aBL alone. With total light energy of 200 J/cm2, all dual-light treatments were effective. Dual-light aPDT improves the bactericidal effect onStaphylococcus aureus biofilm com-pared to aPDT or aBL and provides a sustained effect. An increase in the relative ratio of aBL strengthens the antibacterial effect, mainly when the treatment is repeatedly applied. Thus, the light components’ energy ratio is essential with dual-light.

Primary cilia (PC) are solitary, post-mitotic, microtubule-based, and membrane-covered protrusions that are found on almost every mammalian cell. PC are specialized cellular sensory organelles that transmit environmental information to the cell. Signaling through PC is involved in the regulation of a variety of cellular processes, including proliferation, differentiation, and migration. Conversely, defective, or abnormal PC signaling can contribute to the development of various pathological conditions. Our knowledge of the role of PC in organ development and function is largely based on ciliopathies, a family of genetic disorders with mutations affecting the structure and function of PC. In this review, we focus on the role of PC in their major signaling pathways active in skin cells, and their contribution to wound healing and scarring. To provide comprehensive insights into the current understanding of PC functions, we have collected data available in the literature, including evidence across cell types, tissues, and animal species. We conclude that PC are underappreciated subcellular organelles that significantly contribute to both physiological and pathological processes of the skin development and wound healing. Thus, PC assembly and disassembly and PC signaling may serve as attractive targets for antifibrotic and antiscarring therapies.