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The present review summarizes the current knowledge concerning physiological effects of resveratrol (RSV) with emphasis on the RSV action on female reproductive processes. The review outlines provenance, properties, mechanisms of action, physiological and therapeutic actions of RSV on female reproduction and other physiological processes, as well as areas of possible application of R. This review is based on the search for the related full papers indexed in Medline/Pubmed, Web of Science and SCOPUS databases between the year 2000 and 2021 according to the criteria of preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews and other related guidelines. The analysis of the available information suggests that RSV has a number of properties which enable its influence on various physiological processes including female reproduction at various regulatory levels via various extra- and intracellular signalling pathways. Despite some contradictions and limitations in the available data, they indicate applicability of both stimulatory and inhibitory effects of RSV for control and influence of various reproductive and non-reproductive processes and treatment of their disorders in phytotherapy, animal production, medicine, biotechnology and assisted reproduction. To establish the clinical efficacy of RSV, further high quality studies are needed.

In recent years, several novel aspects of GPCR pharmacology have been described, which are thought to play a role in determining the in vivo efficacy of a compound. Fluorescent ligands have been used to study many of these, which have also required the development of new experimental approaches. Fluorescent ligands offer the potential to use the same fluorescent probe to perform a broad range of experiments, from single‐molecule microscopy to in vivo BRET. This review provides an overview of the in vitro use of fluorescent ligands in further understanding emerging pharmacological paradigms within the GPCR field, including ligand‐binding kinetics, allosterism and intracellular signalling, along with the use of fluorescent ligands to study physiologically relevant therapeutic agents.

Background and Purpose: The intracellular signalling molecule cGMP, formed by NO-sensitive GC (NO–GC), has an established function in the vascular system. Despite numerous reports about NO-induced cGMP effects in the heart, the underlying cGMP signals are poorly characterized. Experimental Approach: Therefore, we analysed cGMP signals in cardiac myocytes and fibroblasts isolated from knock-in mice expressing a FRET-based cGMP indicator. Key Results: Whereas in cardiac myocytes, none of the known NO–GC-activating substances (NO, GC activators, and GC stimulators) increased cGMP even in the presence of PDE inhibitors, they induced substantial cGMP increases in cardiac fibroblasts. As cardiac myocytes and fibroblasts are electrically connected via gap junctions, we asked whether cGMP can take the same route. Indeed, in cardiomyocytes co-cultured on cardiac fibroblasts, NO-induced cGMP signals were detectable, and two groups of unrelated gap junction inhibitors abolished these signals. Conclusion and Implication: We conclude that NO-induced cGMP formed in cardiac fibroblasts enters cardiac myocytes via gap junctions thereby turning cGMP into an intercellular signalling molecule. The findings shed new light on NO/cGMP signalling in the heart and will potentially broaden therapeutic opportunities for cardiac disease.

Membrane contact sites (MCSs) are specialized subcellular compartments formed by closely apposed membranes from two organelles. The intermembrane gap is separated by a distance ranging from 10 nm to 35 nm. MCSs are typically maintained through dynamic protein-protein and protein-lipid interactions. These inter-membrane contact sites constitute important intracellular signaling hotspots to mediate a plethora of cellular processes, including calcium homeostasis, lipid metabolism, membrane biogenesis and organelle remodeling. In recent years, a series of genetically-encoded probes and chemogenetic or optogenetic actuators have been invented to aid the visualization and interrogation of MCSs in both fixed and living cells. These molecular tools have greatly accelerated the pace of mechanistic dissection of membrane contact sites at the molecular level. In this review, we present an overview on the latest progress in this endeavor, and provide a general guide to the selection of methods and molecular tools for probing interorganellar membrane contact sites.

The formation and release of neutrophil extracellular traps (NETs) discovered in 2004 by Volker Brinkmann and Arturo Zychlinsky cast a new light on the role of neutrophils in the non-specific immune response of the body. This discovery has resulted in the rapid development of neutrophil studies in different bacterial and autoimmune diseases as well as neoplasms. Research is also being performed on the role of different signalling pathways engaged in the induction of NETosis, a unique form of a programmed cell death leading to the creation of NETs. The literature provides information on the structure and composition of neutrophil extracellular traps. This review presents the latest data on NET formation and the role of their key components, as well as describing the intracellular signalling pathways leading to the generation of NETs that have been discovered.

Costimulatory signals are required to achieve robust chimeric antigen receptor (CAR) T cell expansion, function, persistence and antitumor activity. These can be provided by incorporating intracellular signalling domains from one or more T cell costimulatory molecules, such as CD28 or 4‐1BB, into the CAR. The selection and positioning of costimulatory domains within a CAR construct influence CAR T cell function and fate, and clinical experience of autologous anti‐CD19 CAR T cell therapies suggests that costimulatory domains have differential impacts on CAR T cell kinetics, cytotoxic function and potentially safety profile. The clinical impacts of combining costimulatory domains and of alternative costimulatory domains are not yet clearly established, and may be construct‐ and disease‐specific. The aim of this review is to summarise the function and effect of established and emerging costimulatory domains and their combinations within CAR T cells.

Photoactivated probes have gained interest as experimental tools to study intracellular signalling pathways all the way to the molecular level. However technical limitations of the means to activate such compounds have put constraints on their use in spatially highly restricted subcellular areas. The Mosaic digital illumination system uses a high-speed array of individually addressable, tiltable micromirrors to direct continuous-wave laser light onto a specimen with diffraction-limited precision. The system, integrated into a Nikon A1R confocal microscope, was used to uncage Ca2+ or IP3 and conduct photobleaching experiments from multiple geometrically complex subcellular regions while simultaneously measuring [Ca2+]i with high-speed confocal imaging.

Ca2+ is one of the most important and universal intracellular signalling agents, controlling a multitude of vitally important cellular processes. This article is protected by copyright. All rights reserved

G-Protein-coupled receptors (GPCRs) integrate extracellular cues into intracellular signals to modulate the cellular state. Owing to their diverse modulatory functions, GPCRs represent one of the major drug targets of the pharmaceutical industry. Until now, the characterization and control of GPCRs and their intracellular signalling cascades have mainly relied on chemical compounds, which either activate or inhibit GPCR pathways, albeit with limited receptor and cell-type specificity. Recently, new approaches have been developed to control signalling cascades in cell- and receptor-type-specific ways. The chemical approach focuses on GPCR design and activation by an inert chemical compound, whereas the physical approach uses designer GPCRs and activation by physical stimuli, such as light.

Die Gase Stickoxid (NO), Kohlenmonoxid (CO) und Schwefelwasserstoff (H2S) werden aufgrund ihrer Wirkung als Signalstoffe als “Gasotransmitter” zusammengefasst. Diese Gase spielen eine wichtige Rolle als intra- und interzellularer Signalstoff im Verdauungs-, Atmungs- oder Urogenitalsystem, bei der Steuerung des Herzschlags oder Nervenaktivitaten. Die Forschung ist dabei, Funktionen und weitere Details der Wirkmechanismen dieser Gase und ihre Implikationen fur Physiologie, Pathophysiologie und Pharmakologie zu erarbeiten. Vom bisher neuesten Kandidaten – dem H2S – gibt es Hinweise, dass er in hoher Konzentration im Gehirn und in den Hoden vorkommt und bei Lern-/Gedachtnisprozessen sowie bei Geschlechtsfunktionen eine Rolle spielt. Durch Entwicklung von Wirksubstanzen zur Beeinflussung der H2S-Produktion oder entsprechender Zielorte konnte sich hieraus ein interessantes pharmakologisches Potenzial entwickeln. Gasotransmitters – gases as cellular signalling molecules The gases nitric oxide (NO), carbon monoxide (CO) and hydrogen sulphide (H2S) because of their capacity as signalling molecules have been now collectively termed “gasotransmitters”. These gases play an important role in inter- and intracellular signalling, as in the digestive, respiratory or urogenital tract, in controlling heart activity or in nerve function. Research now tries to work out functions and further details about the mechanism of action of these gases and their implications for physiology, pathophysiology and pharmacology. The most recent candidate, H2S, is found in high concentrations in the brain and in the testis and hence is involved in learning/memory and in reproductive functions. The development of new substances interfering with the production of H2S or its targets may constitute an interesting pharmacological potential.

With its emphasis on minimally invasive high-speed imaging of intact tissues at depth, video-rate two-photon microscopy has revolutionized cell biology. This is particularly true in immunology, where the orchestration of cell migration, cell-cell interactions and intracellular signalling events in multiple distinct anatomical compartments within secondary lymphoid organs is fundamental for achieving an effective immune response. Until recently, access to this powerful tool has been limited to a handful of laboratories with the necessary skills and resources to either custom-build or purchase a commercial two-photon microscope. However, with the entry of more commercial vendors into the market and availability of turnkey solutions, two-photon microscopy is now becoming more accessible. Here, we discuss the practical aspects of establishing a basic intravital two-photon microscopy facility specifically for immunological research and how recent advances in ultrafast lasers, non-linear optics and localized photochemistry can be used to build more sophisticated instruments to support applications such as photoactivation and photobleaching, spectral fingerprinting and automated single-cell tracking. In addition, we discuss the next generation of fluorescent dyes and reporter mice and some of the microsurgical principles required to expose the relevant biology to interrogation by two-photon excitation.

In April 2009, over one hundred microbiologists, primarily early career scientists, from 17 different countries met to discuss their work, under the broad heading of 'Microbe signalling, organization and pathogenesis'. The meeting took place at University College Cork, Ireland and was supported by the British Council, Society for General Microbiology, American Society for Microbiology, EMBO and others. The key and relatively unusual feature of this meeting was that it was specifically aimed to provide a platform for junior scientists to present their work to a broad audience. In this review, we have tried to summarize and highlight a number of particular areas covered during the meeting, including bacterial intracellular signalling and regulation; microbe-microbe communication; biogenesis; structure and transport of the bacterial cell envelope; and pathogenic versus probiotic microbe-host interactions. We draw attention to new findings, highlight unanswered questions and reveal the anticipated future directions of a variety of areas, as described in both oral and poster presentations. Overall, this meeting provided high-quality science, with many intriguing findings being eloquently reported, in a setting that fostered interactions between diverse young and talented microbiologists.

Plant roots are required for the acquisition of water and nutrients, for responses to abiotic and biotic signals in the soil, and to anchor the plant in the ground. Controlling plant root architecture is a fundamental part of plant development and evolution, enabling a plant to respond to changing environmental conditions and allowing plants to survive in different ecological niches. Variations in the size, shape and surface area of plant root systems are brought about largely by variations in root branching. Much is known about how root branching is controlled both by intracellular signalling pathays and by environmental signals. Here, we will review this knowledge, with particular emphasis on recent advances in the field that open new and exciting areas of research.

This article provides a brief and somewhat personalized review of the dramatic developments that have occurred over the last 45 years in our understanding of intracellular signalling pathways associated with G-protein-coupled receptor activation. Signalling via cyclic AMP, the phosphoinositides and Ca2+ is emphasized and these systems have already been revealed as new pharmacological targets. The therapeutic benefits of most of such targets are, however, yet to be realized, but it is certain that the discipline of pharmacology needs to widen its boundaries to meet these challenges in the future. British Journal of Pharmacology (2006) 147, S38–S45. doi:10.1038/sj.bjp.0706468

Dr Peter Jones gave the 1997 R.D. Lawrence Lecture to the Medical and Scientific Section of the British Diabetic Association. This prestigious award, made to an outstanding young researcher, is named in honour of the man who, with H.G. Wells, founded the British Diabetic Association, and was given to Dr Jones in acknowledgment of his work in the field of islet cell physiology and pathophysiology. In this article, Dr Jones recalls his lecture and describes the principles of intracellular signalling in insulin secretion and the need for beta-cells to live together.

Fas induces apoptosis in lymphocytes via a poorly defined intracellular signalling cascade. Previously, we have demonstrated the involvement and significance of a signalling cascade from the Fas receptor via sphingomyelinases and ceramide to Ras in Fas-induced apoptosis. Here we demonstrate rapid and transient synthesis of reactive oxygen intermediates (ROI) via activation of Ras after Fas. Genetic inhibition of Ras by transfection of transdominant inhibitory N17Ras blocked Fas-mediated ROI synthesis and programmed cell death. Likewise, the antioxidants N-acetyl-cysteine and N-t-butyl-phenylnitrone abolished Fas-induced cell death, pointing to an important role for Ras-triggered ROI synthesis in Fas-mediated programmed cell death.

Purpose Age-related macular degeneration (AMD) is the most common cause of irreversible visual loss in elderly populations in the western world. The mechanism of this disease is not yet fully understood, although vascular endothelial growth factor (VEGF) is thought to be the most significant growth factor in AMD, other growth factors, including FGF2 also stimulates the proliferation of human choroidal endothelial cells (hCEC). These factors may explain the only partial success of current anti-VEGF AMD treatments. Methods hCEC were isolated from cadaver eyes and cultured in EBM2-MV medium as previously published. hCEC proliferation after exposure to VEGF and FGF2 was measured using the WST-1 assay and angiogenesis assessed using a double layer Matrigel technique. Western blotting was used to examine the intracellular signalling stimulated by FGF2 and VEGF. Results hCEC proliferation was increased in response to both FGF2 and VEGF. This effect was cumulative, indicating that these work through different intracellular signalling pathways. Western blotting identified common and differential intracellular signalling between the two growth factors. Conclusion Currently VEGF is thought to be the most important growth factor which stimulates neovascularisation leading to AMD and treatments developed reflect this. However, these results show that FGF2 also stimulates neovascularisation and may play a role in AMD development. A treatment which targets downstream signalling common to both growth factors may provide a more targeted and therefore successful treatment.

Tuberous Sclerosis Complex (TSC) is now recognized as one of the medical conditions most commonly associated with autism. Between 1–5% of those with autism have TSC and up to 50% of people with TSC meet criteria for an autism spectrum disorder. The clinical characteristics of autism in TSC are qualitatively indistinguishable from those of idiopathic autism. So, what can TSC teach us about autism? We will present an overview of the neuropsychiatric features of TSC and will proceed with an examination of aetiological models of autism in TSC. Structural models (suggesting that autism is caused by brain lesions in specific neuroanatomical locations) and seizure models (suggesting that the age, type and control of seizures may predict autism) have both received some support, but with limited replication. More recently, molecular approaches have suggested that dysregulation of intracellular signalling through the TSC1/2-mTOR pathway may be sufficient to lead to socialization deficits and autism, and that drugs that act as mTOR inhibitors may reverse some aspects of the learning and social deficits in TSC.

The activation of alpha 1-adrenergic receptors in rat hippocampal slices enhances polyphosphoinositide (PPI) breakdown and cyclicAMP (cAMP) accumulation. The latter effect is antagonized by different protein kinase C (PKC) inhibitors and mimicked by a diacylglycerol (DAG) analogue, 1,2-diolein, which activates PKC, suggesting that cAMP synthesis is indirectly affected by alpha 1-adrenoceptors through the stimulated generation of DAG upon PPI hydrolysis. Furthermore the elevation of hippocampal cAMP decreases the ability of alpha 1-receptor agonists to enhance PPI breakdown. It is proposed that the observed effects are part of a complex cross-talk between PPI and AC signalling pathways operating in hippocampal neurons.