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Panax polysaccharides are biopolymers that are isolated and purified from the roots, stems, leaves, flowers, and fruits of Panax L. plants, which have attracted considerable attention because of their immunomodulatory activities. In this paper, the composition and structural characteristics of purified polysaccharides are reviewed. Moreover, the immunomodulatory activities of polysaccharides are described both in vivo and in vitro. In vitro, Panax polysaccharides exert immunomodulatory functions mainly by activating macrophages, dendritic cells, and the complement system. In vivo, Panax polysaccharides can increase the immune organ indices and stimulate lymphocytes. In addition, this paper also discusses the membrane receptors and various signalling pathways of immune cells. Panax polysaccharides have many beneficial therapeutic effects, including enhancing or activating the immune response, and may be helpful in treating cancer, sepsis, osteoporosis, and other conditions. Panax polysaccharides have the potential for use in the development of novel therapeutic agents or adjuvants with beneficial immunomodulatory properties.

Piezo1 is a mechanosensitive ion channel with essential roles in cardiovascular, lung, urinary, and immune functions. Piezo1 is widely distributed in different tissues in the human body and its specific roles have been identified following a decade of research; however, not all are well understood. Many structural and functional characteristics of Piezo1 have been discovered and are known to differ greatly from the characteristics of other mechanosensitive ion channels. Understanding the mechanisms by which this ion channel functions may be useful in determining its physiological roles in various organ systems. This review provides insight into the signalling pathways activated by mechanical stimulation of Piezo1 in various organ systems and cell types. We discuss downstream targets of Piezo1 and the overall effects resulting from Piezo1 activation, which may provide insights into potential treatment targets for diseases involving this ion channel.

Ameloblastomas are benign but locally invasive neoplasms which may grow to massive proportions and cause significant morbidity. Although some types of ameloblastoma can be treated predictably with aggressive surgical treatment, recurrent ameloblastoma and metastasising ameloblastoma are still difficult to treat. Recent studies have identified recurrent somatic and activating mutations in the mitogen-activated protein kinase (MAPK) and sonic hedgehog (SHH) signalling pathways in ameloblastoma. This development provided a possibility that molecular targeted therapies can be used as neoadjuvant treatment. In this review, we provide a summary of the latest WHO classification of ameloblastoma, the current understanding of genetic mutations and novel molecular targeted therapies arising from the recent developments.

Chemoprevention and chemotherapeutics with traditional and complimentary system has gained importance with increase in the relapse cases treated with modern system of medicine. The increased mortality rate due to severe toxicity is another concern. The role of phytochemicals from different class viz-dietary polyphenols and saponins in chemoprevention along with different mechanistic pathways has created remarkable progress as the toxicity issues are of lesser concern. Phytochemicals can prevent the carcinogenesis process via antioxidant or anti-inflammatory action by modulating the proteins involved in different pathways like NF-kB, Nrf-2, AP-1, MAPK, and COX-2. In this review, we have focused on the potential molecular targets and signalling pathways that provoke the tumorigenesis process and the various phytochemicals that are targeted towards these signalling pathways by chemoprevention. Keywords: Nutraceuticals cancer modulation, Chemoprevention, Modulating pathways for cancer, Phytochemicals modulation in cancer

Plants alter their morphology and cellular homeostasis to promote resilience under a variety of heat regimes. Molecular processes that underlie these responses have been intensively studied and found to encompass diverse mechanisms operating across a broad range of cellular components, timescales and temperatures. This review explores recent progress throughout this landscape with a particular focus on thermosensing in the model plant Arabidopsis. Direct temperature sensors include the photosensors phytochrome B and phototropin, the clock component ELF3 and an RNA switch. In addition, there are heat‐regulated processes mediated by ion channels, lipids and lipid‐modifying enzymes, taking place at the plasma membrane and the chloroplast. In some cases, the mechanism of temperature perception is well understood but in others, this remains an open question. Potential novel thermosensing mechanisms are based on lipid and liquid–liquid phase separation. Finally, future research directions of high temperature perception and signalling pathways are discussed., Knowledge of how plants sense elevated temperatures and initiate protective responses has greatly increased in recent years. Diverse mechanisms, involving changes in proteins, RNA and lipids, function in thermosensing across a range of timescales, locations and temperatures.

There is growing evidence of the importance of miRNAs for intestinal functional properties and nutritional uptake. Comparative miRNAs profiles of the jejunal mucosa were established against two genetic backgrounds (Lohmann Brown-Classic (LB) and Lohmann LSL-Classic (LSL), which are similar in egg production but differ in physiological traits including mineral utilization, along the production periods of laying hens. The target genes of miRNAs higher expressed in LB vs. LSL (miR-126-3p, miR-214, miR-24-3p, miR-726-5p, miR-29b-3p) were enriched for energy pathways at all stages. The target genes of the miRNAs higher in LSL (miR-1788-5p, miR-103-3p, miR-22-5p, miR-221-3p, miR-375) were more enriched for immune and the bone signalling pathways . The most prominent expression differences were between 16 and 24 weeks of age before and after onset of laying. Our results evidence central roles of intestinal miRNAs as regulators of gene expression, influencing intestinal homeostasis and adaptation to environment in different strains and production phases.

The intersection of phytohormone signalling pathways with SUMOylation, a key post-translational modification, offers an additional layer of control to the phytohormone signalling for sophisticated regulation of plant development. Plants live in a constantly changing environment that are often challenging for the growth and development of plants. Phytohormones play a critical role in modulating molecular-level changes for enabling plants to resist climatic aberrations. The orchestration of such effective molecular responses entails rapid regulation of phytohormone signalling at transcriptional, translational and post-translational levels. Post-translational modifications have emerged as a key player in modulating hormonal pathways. The current review lays emphasis on the role of SUMOylation, a key post-translational modification, in manipulating individual hormone signalling pathways for better plant adaptability. Here, we discuss the recent advancement in the field and highlights how SUMO targets key signalling intermediates including transcription factors to provide a quick response to different biotic or abiotic stresses, sometimes even prior to changes in hormone levels. The understanding of the convergence of SUMOylation and hormonal pathways will offer an additional layer of control to the phytohormone signalling for an intricate and sophisticated regulation of plant development and can be utilised as a tool to generate climate-resilient crops.

To describe the contribution of women radiobiologists in Ireland to the development of the discipline internationally and at home and to discuss the history of radiobiology in Ireland to date. This parallels the history of the evolution of a small radiobiology group in Kevin Street, Dublin Institute of Technology (DIT) which was formerly part of the City of Dublin Vocational Education Committee. There followed years of development first as a radiobiological research center which evolved in the FOCAS Research Institute now embedded within Technological University Dublin (TU Dublin).Over the last 45 years, the women of the Radiation and Environmental Science Centre (RESC) contributed to the major paradigm shift in low dose radiobiology contributing exciting new research concerning non-targeted effects, including discovery of lethal mutations, medium transfer bystander mechanisms, and signaling pathways. They also developed translational research using human explant culture systems with unique immunocytochemical methods and more recently evolved to molecular and spectroscopic analysis of clinical samples. The RESC also developed unique in vitro research methods into effects of radiation on non-human species of concern in ecosystems.

With rapid advances in sequencing technologies, tremendous progress has been made in understanding the molecular pathogenesis of acute myeloid leukaemia (AML), thus revealing enormous genetic and clonal heterogeneity, and paving the way for precision medicine approaches. The successful development of precision medicine for patients with AML has been exemplified by the introduction of targeted FLT3, IDH1/IDH2 and BCL-2 inhibitors. When used as single agents, these inhibitors display moderate antileukaemic activity. However, augmented clinical activity has been demonstrated when they are administered in combination with drugs with broader mechanisms of action targeting epigenetic and/or other oncogenic signalling pathways or with conventional cytotoxic agents. The development of immunotherapies has been hampered by the expression of antigens that are expressed by both leukaemic and non-malignant haematopoietic progenitor cells; nonetheless, a diverse range of immunotherapies are now entering clinical development. This myriad of emerging agents also creates challenges, such as how to safely combine agents with different mechanisms of action, the need to circumvent primary and secondary resistance, and new challenges in future clinical trial design. In this Review, we discuss the current state of precision medicine for AML, including both the potential to improve patient outcomes and the related challenges. Advances in sequencing technology have rapidly improved our understanding of the biology of acute myeloid leukaemia and led to the development of several novel targeted therapies. In this Review, the authors summarize the landscape of novel targeted therapies for patients with acute myeloid leukaemia and provide guidance on future research directions.

Motivation The analysis of longitudinal datasets and construction of gene regulatory networks (GRNs) provide a valuable means to disentangle the complexity of microRNA (miRNA)–mRNA interactions. However, there are no computational tools that can integrate, conduct functional analysis and generate detailed networks from longitudinal miRNA–mRNA datasets. Results We present TimiRGeN, an R package that uses time point-based differential expression results to identify miRNA–mRNA interactions influencing signaling pathways of interest. miRNA–mRNA interactions can be visualized in R or exported to PathVisio or Cytoscape. The output can be used for hypothesis generation and directing in vitro or further in silico work such as GRN construction. Availability and implementation TimiRGeN is available for download on Bioconductor (https://bioconductor.org/packages/TimiRGeN) and requires R v4.0.2 or newer and BiocManager v3.12 or newer. Supplementary information Supplementary data are available at Bioinformatics online.

Different cellular mechanisms contribute to the hearing sense, so it is obvious that any disruption in such processes leads to hearing impairment that greatly influences the global economy and quality of life of the patients and their relatives. In the past two decades, transmembrane inner ear (TMIE) protein has received a great deal of research interest because its impairments cause hereditary deafness in humans. This evolutionarily conserved membrane protein contributes to a fundamental complex that plays role in the maintenance and function of the sensory hair cells. Although the critical roles of the TMIE in mechanoelectrical transduction or hearing procedures have been discussed, there are little to no review papers summarizing the roles of the TMIE in the auditory system. In order to fill this gap, herein, we discuss the important roles of this protein in the auditory system including its role in mechanotransduction, olivocochlear synapse, morphology and different signalling pathways; we also review the genotype‐phenotype correlation that can per se show the possible roles of this protein in the auditory system.

Ferroptosis is a new type of programmed cell death characterized by intracellular iron accumulation and lipid peroxidation that leads to oxidative stress and cell death. The metabolism of iron, lipids, and amino acids and multiple signalling pathways precisely regulate the process of ferroptosis. Emerging evidence has demonstrated that ferroptosis participates in the occurrence and progression of various pathological conditions and diseases, such as infections, neurodegeneration, tissue ischaemia-reperfusion injury and immune diseases. Recent studies have also indicated that ferroptosis plays a critical role in the pathogenesis of acute lung injury, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary infection and asthma. Herein, we summarize the latest knowledge on the regulatory mechanism of ferroptosis and its association with iron, lipid and amino acid metabolism as well as several signalling pathways. Furthermore, we review the contribution of ferroptosis to the pathogenesis of lung diseases and discuss ferroptosis as a novel therapeutic target for various lung diseases.

Vascular endothelial cell stimulation is associated with the activation of different signalling pathways and transcription factors. Acute shear stress is known to induce different pro-inflammatory mediators such as IL-8. Nrf2 is activated by prolonged high shear stress promoting an antiinflammatory and athero-protective environment. However, little is known about the impact of acute shear stress on Nrf2 and Keap1 function and its role in IL-8 regulation. We aimed to examine Nrf2-Keap1 complex activation in-vitro and its role in regulating IL-8 transcripts under acute arterial shear stress (12 dyn/cm2) in venous endothelial cells (ECs). We note that acute high shear stress caused a significant upregulation of Nrf2 target genes, HO-1 and GCLM and an increased IL-8 upregulation at 90 and 120 minutes. Mechanistically, acute high shear did not affect Nrf2 nuclear translocation but resulted in reduced nuclear Keap1, suggesting that the reduction in nuclear Keap1 may result in increased free nuclear nrf2 to induce transcription. Consistently, the suppression of Keap1 using shRNA (shKeap1) resulted in significant upregulation of IL-8 transcripts in response to acute shear stress. Interestingly; the over expression of Nrf2 using Nrf2-Ad-WT or Sulforaphane was also associated with significant upregulation of IL-8 compared to controls. This study highlights the role of Keap1 in Nrf2 activation under shear stress and indicates that activation of Nrf2 may be deleterious in ECs in the context of acute haemodynamic injury.

Endothelial cells are at the interface between circulating blood and tissues. This position confers on them a crucial role in controlling oxygen and nutrient exchange and cellular trafficking between blood and the perfused organs. The endothelium adopts a structure that is specific to the needs and function of each tissue and organ and is subject to tissue-specific signalling input. In adults, endothelial cells are quiescent, meaning that they are not proliferating. Quiescence was considered to be a state in which endothelial cells are not stimulated but are instead slumbering and awaiting activating signals. However, new evidence shows that quiescent endothelium is fully awake, that it constantly receives and initiates functionally important signalling inputs and that this state is actively regulated. Signalling pathways involved in the maintenance of functionally quiescent endothelia are starting to be identified and are a combination of endocrine, autocrine, paracrine and mechanical inputs. The paracrine pathways confer a microenvironment on the endothelial cells that is specific to the perfused organs and tissues. In this Review, we present the current knowledge of organ-specific signalling pathways involved in the maintenance of endothelial quiescence and the pathologies associated with their disruption. Linking organ-specific pathways and human vascular pathologies will pave the way towards the development of innovative preventive strategies and the identification of new therapeutic targets., In this Review, Simons and colleagues present the current knowledge of organ-specific signalling pathways involved in the maintenance of endothelial quiescence and the pathologies associated with their disruption. This knowledge will assist the development of innovative preventive strategies and identification of new therapeutic targets., Key points Quiescent endothelial cells require active maintenance to preserve normalcy in a tissue-specific manner.Dysregulation of signalling pathways involved in endothelial normalcy maintenance leads to endothelial dysfunction and vascular pathologies.Endothelial quiescence and normalcy are important for disease resilience.Identification of organ-specific signalling pathways that maintain endothelial normalcy and quiescence will lead to new therapeutic targets supporting disease resilience and treatment of associated vascular pathologies.

Cardiovascular diseases (CVD) are a leading cause of human death worldwide. Over the past two decades, the emerging field of cardioimmunology has demonstrated how cells of the immune system play vital roles in the pathogenesis of CVD. MicroRNAs (miRNAs) are critical regulators of cellular identity and function. Cell-intrinsic, as well as cell-extrinsic, roles of immune and inflammatory cell-derived miRNAs have been, and continue to be, extensively studied. Several ‘immuno-miRNAs’ appear to be specifically expressed or demonstrate greatly enriched expression within leucocytes. Identification of miRNAs as critical regulators of immune system signalling pathways has posed the question of whether and how targeting these molecules therapeutically, may afford opportunities for disease treatment and/or management. As the field of cardioimmunology rapidly continues to advance, this review discusses findings from recent human and murine studies which contribute to our understanding of how leucocytes of innate and adaptive immunity are regulated—and may also regulate other cell types, via the actions of the miRNAs they express, in the context of CVD. Finally, we focus on available information regarding miRNA regulation of regulatory T cells and argue that targeted manipulation of miRNA regulated pathways in these cells may hold therapeutic promise for the treatment of CVD and associated risk factors.

Cerebellar development begins during the late embryological period and continues to undergo organizational changes long after birth. The cerebellum is particularly susceptible to developmental abnormalities on exposure to oxidants and free radicals, thus leading to oxidative stress. Oxidative stress occurs when there is an imbalance between reactive oxygen species generation and antioxidant defences which may disrupt signalling pathways, leading to cerebellar anomalies and dysfunction. In this regard, this review assesses current research underlining the importance of the cerebellum, provides an update on substances affecting cerebellar development and highlights some promising antioxidants that may play a role in attenuating toxicity in the developing cerebellum. To accomplish this, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) system was employed and key scientific databases such as Science Direct, PubMed, Scopus, Web of Science and Google Scholar were searched to explore and collect information on the cerebellum and the role of antioxidants during its development. Originally, 109 articles were obtained but 22 articles which met the inclusion criteria were selected for the review. These findings provide an updated compilation of antioxidants capable of attenuating oxidative damage in the developing cerebellum, thus allowing future interdisciplinary studies in the form of clinical applications for screening and possible development of novel therapeutic agents from the identified products.

International audience; Although there is evidence of a significant rise of neuroendocrine neoplasms (NENs) incidence, current treatments are largely insufficient due to somewhat poor knowledge of these tumours. Despite showing differentiated features, NENs exhibit therapeutic resistance to most common treatments, similar to other cancers in many instances. Molecular mechanisms responsible for this resistance phenomenon are badly understood. We aimed at identifying signalling partners responsible of acquired resistance to treatments in order to develop novel therapeutic strategies. We engineered QGP-1 cells resistant to current leading treatments, the chemotherapeutic agent oxaliplatin and the mTor inhibitor everolimus. Cells were chronically exposed to the drugs and assessed for acquired resistance by viability assay. We used microarray-based kinomics to obtain highthroughput kinase activity profiles from drug sensitive vs resistant cells and identified 'hit' kinases hyperactivated in drug-resistant cells, including kinases from FGFR family, cyclin-dependant kinases and PKCs in oxaliplatin-resistant (R-Ox) QGP-1 cells. We then validated these 'hit' kinases and observed that ERK signalling is specifically enhanced in QGP-1 R-Ox cells. Finally, we assessed drug-resistant cells sensitivity to pharmacological inhibition of 'hit' kinases or their signalling partners. We found that FGFR inhibition markedly decreased ERK signalling and cell viability in QGP-1 R-Ox cells. These results suggest that the FGFR/ERK axis is hyperactivated in response to oxaliplatin-based chemotherapeutic strategy. Thus, this sensitive approach, based on the study of kinome activity, allows identifying potential candidates involved in drug resistance in NENs and may be used to broadly investigate markers of NENs therapeutic response.

Although the vertebrate head has evolved to a wide collection of adaptive shapes, the fundamental signalling pathways and cellular events that outline the head skeleton have proven to be highly conserved. This conservation suggests that major morphological differences are due to changes in differentiation and morphogenetic programs downstream of a well-maintained developmental prepattern. Here we provide a brief examination of the mechanisms and pathways responsible for vertebrate head development, as well as an overview of the animal models suitable for studying face development. In addition, we describe the criteria for neurocristopathy classification, highlighting the contribution of zebrafish to the modelling of Treacher Collins/Franceschetti Syndrome, an emblematic neurocristopathy. The contributions from our laboratory reveal that proper zebrafish head development depends on the fine-tuning of developmental-gene expression mediated by nucleic acid binding proteins able to regulate DNA conformation and / or the neuroepithelium redox state.

Formation of higher-order supramolecular complexes has emerged as a common principle underlying activity of a number of immune and regulated cell-death signalling pathways in animals, plants and fungi. Some of these signalosomes employ functional amyloid motifs in their assembly process. The description of such systems in fungi finds its origin in earlier studies on a fungal prion termed [Het-s], originally identified as a non-Mendelian cytoplasmic infectious element. Janine Beisson has been a key contributor to such early studies. Recent work on this and related systems offers a more integrated view framing this prion in a broader picture including related signalling systems described in animals. We propose here an auto-commentary centred on three recent studies on amyloid signalling in microbes. Collectively, these studies increase our understanding of fold conservation in functional amyloids and the structural basis of seeding, highlight the relation of fungal amyloid motifs to mammalian RHIM (RIP homotypic interaction motif) and expand the concept of Nod-like receptor-based amyloid signalosomes to the prokaryote reign.

In recent years, the development and implementation of animal-free approaches to chemical and pharmaceutical hazard and risk assessment has taken off. Alternative approaches are being developed starting from the perspective of human biology and physiology. Neural tube closure is a vital step that occurs early in human development. Correct closure of the neural tube depends on a complex interplay between proteins along a number of protein concentration gradients. The sensitivity of neural tube closure to chemical disturbance of signalling pathways such as the retinoid pathway, is well known. To map the pathways underlying neural tube closure, literature data on the molecular regulation of neural tube closure were collected. As the process of neural tube closure is highly conserved in vertebrates, the extensive literature available for the mouse was used whilst considering its relevance for humans. Thus, important cell compartments, regulatory pathways, and protein interactions essential for neural tube closure under physiological circumstances were identified and mapped. An understanding of aberrant processes leading to neural tube defects (NTDs) requires detailed maps of neural tube embryology, including the complex genetic signals and responses underlying critical cellular dynamical and biomechanical processes. The retinoid signaling pathway serves as a case study for this ontology because of well-defined crosstalk with the genetic control of neural tube patterning and morphogenesis. It is a known target for mechanistically-diverse chemical structures that disrupt neural tube closure The data presented in this manuscript will set the stage for constructing mathematical models and computer simulation of neural tube closure for human-relevant AOPs and predictive toxicology.

Biofilms are complex microbial architectures that encase microbial cells in a matrix comprising self-produced extracellular polymeric substances. Microorganisms living in biofilms are much more resistant to hostile environments than their planktonic counterparts and exhibit enhanced resistance against the microbicides. From the human perspective, biofilms can be classified into beneficial, neutral, and harmful. Harmful biofilms impact food safety, course plant and animal diseases, and threaten medical fields, making it urgent to develop effective and robust strategies to control harmful biofilms. In this review, we discuss various strategies to control biofilm formation on infected tissues, implants, and medical devices. We classify the current strategies into three main categories: (i) changing the properties of susceptible surfaces to prevent biofilm formation; (ii) regulating signaling pathways to inhibit biofilm formation; (iii) applying external forces to eradicate the biofilm. We hope this review would motivate the development of innovative and effective strategies for controlling harmful biofilms.

Background. Inflammation is a host defense mechanism in the body after it is infected and damaged. If inflammation is not treated in time, then it may cause a variety of diseases, such as cancer and autoimmune diseases. Herbal essential oils are natural extracts that can suppress inflammation effectively and are expected to be used in therapeutic drugs for anti-inflammatory diseases in the future. Aim of the review. We review the anti-inflammatory and immunomodulatory effects of essential oils derived from 16 herbs. Materials and methods. We searched the literature of the fields of anti-inflammatory and immunomodulatory herbal essential oil activity published in English within the past five years via databases (PubMed, EMBASE, Scopus, and The Web of Science). Results. A total of 1932 papers were found by searching, and 132 papers were screened after removing duplicates and reading article titles. Fifteen articles met the requirements to be included in this review. Among those selected, 11 articles reported in vivo research results, and 10 articles showed research results. Conclusion. Essential oils extracted from herbs can reduce inflammation by regulating the release of inflammatory cytokines involved in multiple signalling pathways. Herbal essential oils are expected to be developed as anti-inflammatory drugs.

The application of medicinal plants has captured the interest of researchers in recent times due to their potent therapeutic properties and a better safety profile. The prominent role of herbal products in treating and preventing multiple diseases dates back to ancient history and most of the modern drugs today originated from their significant sources owing to their ability to control multiple targets via different signalling pathways. Among them, flavonoids consist of a large group of polyphenols, which are well known for their various therapeutic benefits. Rutin is considered one of the attractive phytochemicals and important flavonoids in the pharmaceutical industry due to its diverse pharmacological activities via various underlying molecular mechanisms. It is usually prescribed for various disease conditions such as varicosities, haemorrhoids and internal haemorrhage. In this review, we have discussed and highlighted the different molecular mechanisms attributed to the various pharmacological activities of rutin, such as antioxidant, anti-inflammatory, anticancer, anti-allergic and antidiabetic. This review will be beneficial to herbal, biological and molecular scientists in understanding the pharmacological relevance of rutin at the molecular level.

Bacteria, archaeae, fungi and viruses of the intestinal microbiome play an important role as symbionts in the complex human ecosystem. Parasites, which account for about 40 % of the earth's biodiversity, depend on hosts to complete their life cycle. This article explains how they use them and which signalling pathways play a role in this, using toxoplasmosis and malaria as examples. The parasitic manipulation hypothesis is based on impressive observations in the wild and under laboratory conditions, especially in invertebrates. For the assumption of an adaptive manipulation, every step from the genotype, the translated messenger, and its source via the used signalling pathways to the altered host behaviour must be proven. The assumption of an adaptive manipulation of humans by T. gondii in the sense of a cause-effect relationship is not proven. Alternative explanations include the inflammatory and immunological processes on the host side, which change the neuronal signal transduction as concomitant symptoms of an infection. Even without confirmation of parasitic manipulation in humans, it could be worthwhile to further investigate the observed associations in order to develop new possibilities for diagnosis and therapy, e. g. for schizophrenia.

Regarded as constitutively active enzymes, known to participate in many, diverse biological processes, the intracellular regulation bestowed on the CK1 family of serine/threonine protein kinases is critically important, yet poorly understood. Here, we provide an overview of the known CK1-dependent cellular functions and review the emerging roles of CK1-regulating proteins in these processes. We go on to discuss the advances, limitations and pitfalls that CK1 researchers encounter when attempting to define relationships between CK1 isoforms and their substrates, and the challenges associated with ascertaining the correct physiological CK1 isoform for the substrate of interest. With increasing interest in CK1 isoforms as therapeutic targets, methods of selectively inhibiting CK1 isoform-specific processes is warranted, yet challenging to achieve given their participation in such a vast plethora of signalling pathways. Here, we discuss how one might shut down CK1-specific processes, without impacting other aspects of CK1 biology.

The structure-function paradigm has guided investigations into the molecules involved in cellular signalling for decades. The peripheries of this paradigm, however, start to unravel when considering the co-operation between proteins and the membrane in signalling processes. Intrinsically disordered regions hold distinct advantages over folded domains in terms of their binding promiscuity, sensitivity to their particular environment and their ease of modulation through post-translational modifications. Low sequence complexity and bias towards charged residues are also favourable for the multivalent electrostatic interactions that occur at the surfaces of lipid bilayers. This review looks at the principles behind the successful marriage between protein disorder and membranes in addition to the role of this partnership in modifying and regulating signalling in cellular processes. The HVR (hypervariable region) of small GTPases is highlighted as a well-studied example of the nuanced role a short intrinsically disordered region can play in the fine-tuning of signalling pathways.

This research utilized the systematic biological and proteomics strategies to explore the regulatory mechanism of Danshen Yin Modified (DSYM) on atherosclerosis (AS) biological network. The traditional Chinese medicine database and HPLC was used to find the active compounds of DSYM, Pharmmapper database was used to predict potential targets, and OMIM database and GeneCards database were used to collect AS targets. String database was utilized to obtain the other protein of proteomics proteins and the protein‐protein interaction (PPI) data of DSYM targets, AS genes, proteomics proteins and other proteins. The Cytoscape 3.7.1 software was utilized to construct and analyse the network. The DAVID database is used to discover the biological processes and signalling pathways that these proteins aggregate. Finally, animal experiments and proteomics analysis were used to further verify the prediction results. The results showed that 140 active compounds, 405 DSYM targets and 590 AS genes were obtained, and 51 differentially expressed proteins were identified in the DSYM‐treated ApoE‐/‐ mouse AS model. A total of 4 major networks and a number of their derivative networks were constructed and analysed. The prediction results showed that DSYM can regulate AS‐related biological processes and signalling pathways. Animal experiments have also shown that DSYM has a therapeutic effect on ApoE‐/‐mouse AS model (P

Substances with good effectiveness that intervene in specific signalling pathways have been used increasingly in recent years in the treatment of patients with advanced breast cancer, and new therapies and approaches have now been added, which actually relate to quite specific changes, such as the treatment of patients with HR+/HER2 tumours with a PIK3CA mutation. The treatment of patients with a BRCA1 or BRCA2 mutation has also been improved by the introduction of PARP inhibitors. Attempts are now being made increasingly to extend treatment indications based on molecular patterns, to identify other patients who could benefit from a treatment and to integrate the newly established treatment methods in existing therapy sequences. This review articles summarises the latest information in this connection.

Context Pulmonary fibrosis (PF) is a highly heterogeneous and lethal pathological process having no effective drug. Engeletin exerts multiple biological activities including anti-inflammatory and lung repair. Whether engeletin has therapeutic effects on PF remains unclear. Objective Examining effect and mechanism of engeletin on PF in vivo and in vitro. Materials and methods L929 cells (1 × 106/well) were treated with TGF-β1 (5 ng/mL). Sixty male C57BL/6 mice were divided into three groups and given saline or single intratracheal instillation bleomycin (5 mg/kg) or both bleomycin and intraperitoneally injected engeletin (25 mg/kg). Results Histological staining showed engeletin inhibited myofibrobasts activation and improved alveolar structure. Engeletin elevated forced vital capacity from 12 induced by bleomycin to 17. CCK-8 assay reported IC50 value of engeletin was 270 μg/mL. Real-time cellular analysis showed engeletin reduced proliferation and migration of myofibroblasts by 2.5- and 2-fold. Engeletin blocked α-SMA, vimentin, and collagen expression. RNA sequencing revealed PERK-ATF4 signalling pathway relating to ER stress involved in anti-fibrotic function of engeletin. Engeletin reduced ATF4, CHOP and BIP expression. Chemical inhibitors of smad2/3- (SB431542) and JNK- (SP600125) signalling pathways blocked expression of long noncoding RNA (lncRNA) – lnc949. Engeletin inhibited phosphorylation of smad2/3 and JNK leading to lower level of lnc949. Knockdown lnc949 inhibited ATF4, CHOP and BIP expression. Conclusions We reported gene expression profiling of engeletin through RNA-seq; and identified lnc949-mediated TGF-β1-Smad2/3 and JNK were upstream signalling pathways of ER stress induced by engeletin. Our results showed engeletin remedies pulmonary fibrogenesis and may be a new drug candidate.

International audience; The rapid development of green energy sources and new medical technologies contributes to the increased exploitation of rare earth elements (REEs). They can be subdivided into light (LREEs) and heavy (HREEs) REEs. Mining, industrial processing, and end-use practices of REEs has led to elevated environmental concentrations and raises concerns about their toxicity to organisms and their impact on ecosystems. REE toxicity has been reported, but its precise underlying molecular effects have not been well described. Here, transcriptomic and proteomic approaches were combined to decipher the molecular responses of the model organism Saccharomyces cerevisiae to La (LREE) and Yb (HREE). Differences were observed between the early and late responses to La and Yb. Several crucial pathways were modulated in response to both REEs, such as oxidative-reduction processes, DNA replication, and carbohydrate metabolism. REE-specific responses involving the cell wall and pheromone signalling pathways were identified, and these responses have not been reported for other metals. REE exposure also modified the expression and abundance of several ion transport systems, with strong discrepancies between La and Yb. These findings are valuable for prioritizing key genes and proteins involved in La and Yb detoxification mechanisms that deserve further characterization to better understand REE environmental and human health toxicity.

Breakthroughs in our understanding of the complex interplay between cellular nanoenvironment and biomolecular signalling pathways are facilitating development of targeted osteogenic platforms. As critical biomolecules for osteogenesis, growth factors stimulate osteogenesis by activating key genes and transcription factors. The first half of this review presents emerging interconnectedness and recent discoveries of osteogenic signalling pathways initiating from growth factors for example, bone morphogenetic protein 2 (BMP-2). To complement this, the second half of review proposes a number of strategies to induce osteogenesis which include metallic, organic implants, nanotopological environments as well as growth factor immobilization techniques. The drawbacks of traditional osteogenic implants and how these have been overcome by biomedical engineers in the recent years without producing side-effects have also been summarized.

Mounting evidence suggests that the gut microbiome impacts brain development and function. Gut-brain connections may be mediated by an assortment of microbial molecules that are produced in the gastrointestinal tract, which can subsequently permeate many organs, including sometimes the brain. Studies in animal models have identified molecular cues propagated from intestinal bacteria to the brain that can affect neurological function and/or neurodevelopmental and neurodegenerative conditions. Herein, we describe bacterial metabolites with known or suspected neuromodulatory activity, define mechanisms of signalling pathways from the gut microbiota to the brain and discuss direct effects that gut bacterial molecules are likely exerting on specific brain cells. Many discoveries are recent, and the findings described in this Perspective are largely novel and yet to be extensively validated. However, expanding research into the dynamic molecular communications between gut microorganisms and the CNS continues to uncover critical and previously unappreciated clues in understanding the pathophysiology of behavioural, psychiatric and neurodegenerative diseases.

International audience; From surviving fraction to tumour curability, definitions of tumour radioresistance may vary depending on the view angle. Yet, mechanisms of radioresistance have been identified and involve tumour-specific oncogenic signalling pathways, tumour metabolism and proliferation, tumour microenvironment/hypoxia, genomics. Correlations between tumour biology (histology) and imaging allow theragnostic approaches that use non-invasive biological imaging using tracer functionalization of tumour pathway biomarkers, imaging of hypoxia, etc. Modelling dose prescription function based on their tumour radio-resistant factor enhancement ratio, related to metabolism, proliferation, hypoxia is an area of investigation. Yet, the delivery of dose painting by numbers/voxel-based radiotherapy with low lineal energy transfer particles may be limited by the degree of modulation complexity needed to achieve the doses needed to counteract radioresistance. Higher lineal energy transfer particles or combinations of different particles, or combinations with drugs and devices such as done with radioenhancing nanoparticles may be promising

Subcutaneous transplantation of mesenchymal stromal cells (MSC) emerged as an alternative to intravenous administration because it avoids the pulmonary embolism and prolongs post‐transplantation lifetime. The goal of this study was to investigate the mechanisms by which these cells could affect remote organs. To this aim, murine bone marrow–derived MSC were subcutaneously transplanted in different anatomical regions and the survival and behaviour have been followed. The results showed that upon subcutaneous transplantation in mice, MSC formed multicellular aggregates and did not migrate significantly from the site of injection. Our data suggest an important role of hypoxia‐inducible signalling pathways in stimulating local angiogenesis and the ensuing modulation of the kinetics of circulating cytokines with putative protective effects at distant sites. These data expand the current understanding of cell behaviour after subcutaneous transplantation and contribute to the development of a non‐invasive cell‐based therapy for distant organ protection.

Introduction Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, obesity, and insulin resistance, that leads to subfertility. Sam68 is an RNA-binding protein with signaling functions that is ubiquitously expressed, including gonads. Sam68 is recruited to leptin signaling, mediating different leptin actions. Objective We aimed to investigate the role of Sam68 in leptin signaling, mediating the effect on aromatase expression in granulosa cells and the posible implication of Sam68 in the leptin resistance in PCOS. Materials and methods Granulosa cells were from healthy donors (n = 25) and women with PCOS (n = 25), within the age range of 20 to 40 years, from Valencian Infertility Institute (IVI), Seville, Spain. Sam68 expression was inhibited by siRNA method and overexpressed by expression vector. Expression level was analysed by qPCR and immunoblot. Statistical significance was assessed by ANOVA followed by different post-hoc tests. A P value of Results We have found that leptin stimulation increases phosphorylation and expression level of Sam68 and aromatase in granulosa cells from normal donors. Downregulation of Sam68 expression resulted in a lower activation of MAPK and PI3K pathways in response to leptin, whereas overexpression of Sam68 increased leptin stimulation of signaling, enhancing aromatase expression. Granulosa cells from women with PCOS presented lower expression of Sam68 and were resistant to the leptin effect on aromatase expression. Conclusions These results suggest the participation of Sam68 in leptin receptor signaling, mediating the leptin effect on aromatase expression in granulosa cells, and point to a new target in leptin resistance in PCOS.

Prematurity is one of the main causes of neonatal morbidity and mortality. The association between periodontitis and premature delivery and low weight at birth has been suggested in many literature. Pregnancy totally depends on physiological immune tolerance of a women. During pregnancy shifts in the microbial composition of the subgingival dental plaque biofilm promotes the formation of more hazardous and destructive microbial community. In women suffering with periodontitis, the infected periodontal tissues may act as source of bacteria and their products can reach to the foetus-placenta unit through circulation. This helps the bacterial agents and their products to activate inflammatory signalling pathways locally and in extra-oral sites, including the placenta-foetal unit, which may not only induce preterm labor but also restrict the intrauterine growth. Number of literature has shown about the effectiveness of providing periodontal treatment in preventing gestational complications by controlling the infection and inflammation in periodontitis patients during pregnancy. In this review we aimed to throw the light on the current data of association between pregnancy and periodontitis, pathogenic mechanisms underlying this association, evidence of this association and effect of providing periodontal treatment as a safety precaution to the mothers.

Mistletoe has been used as treatment of many diseases in traditional and folk medicine. To date, anticancer, immunomodulatory, cardiac, antidiabetic, hepatoprotective, neuropharmacological, antibacterial and antifungal properties of mistletoe extracts have been studied the most. In this review, we summarized in vitro and in vivo studies on the pharmacological activity of Viscum species. Furthermore, we proposed the possible mechanisms of action of this herb, which might include many signalling pathways. Mistletoe could regulate either similar or different targets in various pathways that act on membrane receptors, enzymes, ion channels, transporter proteins and transcriptional targets. Still, pharmacological activities of mistletoe have been investigated mainly for crude extracts. It is a new field for scientists to determined which chemical compounds are responsible for the individual biological activities of mistletoe and how these activities are achieved. As a result, mistletoe might become a source of new complementary therapies supporting the treatment of many diseases.

Extracellular vesicles (EVs) have recently emerged as an important carrier for various genetic materials including microRNAs (miRs). Growing evidences suggested that several miRs transported by EVs were particularly involved in modulating cardiac function. However, it has remained unclear what miRs are enriched in EVs and play an important role in the pathological condition. Therefore, we established the miR expression profiles in EVs from murine normal and failing hearts and consecutively identified substantially altered miRs. In addition, we have performed bioinformatics approach to predict potential cardiac outcomes through the identification of miR targets. Conclusively, we observed approximately 63% of predicted targets were validated with previous reports. Notably, the predicted targets by this approach were often involved in both beneficial and malicious signalling pathways, which may reflect heterogeneous cellular origins of EVs in tissues. Lastly, there has been an active debate on U6 whether it is a proper control. Through further analysis of EV miR profiles, miR‐676 was identified as a superior reference control due to its consistent and abundant expressions. In summary, our results contribute to identifying specific EV miRs for the potential therapeutic targets in heart failure and suggest that miR‐676 as a new reference control for the EV miR studies.

For decades, the treatment of GCA has relied on glucocorticoids. Work over the past two decades has supported a modest efficacy of MTX but no clear benefit from anti-TNF-based therapies. More recently, the therapeutic armamentarium for GCA has expanded. The availability of agents targeting specific cytokines, cytokine receptors or signalling pathways, along with a better, although still limited, understanding of the immunopathology of GCA, are opening further therapeutic possibilities. Blocking IL-6 receptor with tocilizumab has been effective in maintaining remission and reducing glucocorticoid exposure and tocilizumab has been approved for the treatment of GCA. However, nearly half of the patients do not benefit from tocilizumab and additional options need to be investigated. This review focuses on standard therapeutic approaches and on targeted therapies that have been or are currently under investigation.

DNase I has been reported to improve diabetic wound healing through the clearance of neutrophils extracellular traps (NETs) caused by neutrophil aggregation. However, the function of DNase I on diabetic corneal wound healing remains unclear. Here, we investigated the effect and mechanism of topical DNase I application on diabetic mouse corneal epithelial and nerve regeneration. Corneal epithelial defects, inflammatory response, regeneration‐related signalling pathways, oxidative stress, corneal innervation and sensation were examined and compared between the diabetic and normal mice. The results confirmed firstly the increased NETs production during the delayed corneal epithelial wound healing of diabetic mice, which was significantly improved through either DNase I or Cl‐amidine administration. Mechanistically, DNase I improved inflammation resolution, reactivated epithelial regeneration‐related signalling pathways and attenuated the accumulation of reactive oxygen species (ROS). Moreover, DNase I application also promoted corneal nerve regeneration and restored the impaired corneal sensitivity in diabetic mice. Therefore, these results indicate that topical DNase I application promotes corneal epithelial wound healing and mechanical sensation restoration in diabetic mice, representing the potential therapeutic approach for diabetic keratopathy.

Introduction Porcine epidemic diarrhoea virus (PEDV) infection causes watery diarrhoea, vomiting, anorexia, and weight loss, especially among neonatal piglets, inflicting on them morbidity and mortality potentially reaching 90%–100%. Despite it being known that certain mammalian cell phases are arrested by PEDV, the mechanisms have not been elucidated, and PEDV pathogenesis is poorly understood. This study determined the effect of an epidemic PEDV strain on cell cycle progression. Material and Methods We observed the effect of the PEDV SHpd/2012 strain on an infected Vero cell cycle through flow cytometry and Western blot, investigating the interrelationships of cell-cycle arrest, the DNA damage–signalling pathway caused by PEDV and the phosphorylation levels of the key molecules Chk.2 and H2A.X involved upstream and downstream in this pathway. Results PEDV induced Vero cell-cycle arrest at the G1/G0 phase. The phosphorylation levels of Chk.2 and H2A.X increased with the prolongation of PEDV infection, and no significant cell-cycle arrest was observed after treatment with ATM or Chk.2 inhibitors. The proliferation of PEDV was also inhibited by treatment with ATM or Chk.2 inhibitors. Conclusion PEDV-induced cell-cycle arrest is associated with activation of DNA damage–signalling pathways. Our findings elucidate the molecular basis of PEDV replication and provide evidence to support further evaluation of PEDV pathogenesis.

Large (big)-conductance calcium-activated potassium (BKCa) channels are expressed in migraine-related structures such as the cranial arteries, trigeminal ganglion and trigeminal spinal nucleus, and they play a substantial role in vascular tonus and neuronal excitability. Using synthetic BKCa channels openers was associated with headache as a frequent adverse effect in healthy volunteers. Additionally, BKCa channels are downstream molecules in migraine signalling pathways that are activated by several compounds known to provoke migraine, including calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP) and glyceryl trinitrate (GTN). Also, there is a high affinity and a close coupling between BKCa channels and ATP-sensitive potassium (KATP) channels, the role of which has recently been established in migraine pathophysiology. These observations raise the question as to whether direct BKCa channel activation can provoke migraine in migraine patients, and whether the BKCa channel could be a potential novel anti-migraine target. Hence, randomized and placebo-controlled clinical studies on BKCa channel openers or blockers in migraine patients are needed.

The phytohormone auxin acts as an amazingly versatile coordinator of plant growth and development. With its morphogen-like properties, auxin controls sites and timing of differentiation and/or growth responses both, in quantitative and qualitative terms. Specificity in the auxin response depends largely on distinct modes of signal transmission, by which individual cells perceive and convert auxin signals into a remarkable diversity of responses. The best understood, or so-called canonical mechanism of auxin perception ultimately results in variable adjustments of the cellular transcriptome, via a short, nuclear signal transduction pathway. Additional findings that accumulated over decades implied that an additional, presumably, cell surface-based auxin perception mechanism mediates very rapid cellular responses and decisively contributes to the cell's overall hormonal response. Recent investigations into both, nuclear and cell surface auxin signalling challenged this assumed partition of roles for different auxin signalling pathways and revealed an unexpected complexity in transcriptional and non-transcriptional cellular responses mediated by auxin.

Secreted frizzled‐related protein 5 (SFRP5), an anti‐inflammatory adipokine secreted by adipocytes, has been demonstrated to exert its anti‐inflammatory effect via antagonizing the non‐canonical wingless‐type family member 5A (WNT5A) signalling pathways. The WNT5A protein, as a potent pro‐inflammatory signalling molecule, is strongly involved in a variety of inflammatory disorders such as obesity, type 2 diabetes mellitus (T2DM) and atherosclerosis. In this review, we systematically outlined the current understanding on the roles of SFRP5 in the pathogenesis of three inflammatory diseases including obesity, T2DM and coronary heart disease (CHD). Our review might stimulate future research using SFRP5 as a promising novel therapeutic target for the treatment of obesity, T2DM and CHD.

Ankylosing spondylitis is the most common form of the chronic inflammatory disease group known as spondyloarthritides. Recent discoveries of the CD4+ Th17 cells and IL-23/IL-17 axis have changed the paradigms in many autoimmune diseases. In this study, we aimed to evaluate the importance of IL-23/IL-17 pathway and IL-23 receptor polymorphism in the pathogenesis of ankylosing spondylitis. Blood samples for this study were obtained from 109 ankylosing spondylitis patients and 40 healthy control subjects. Serum levels of TNF-alpha, IL-6, IL-17, and IL-23 were measured by the ELISA method. The IL-23R gene polymorphisms rs11209026 (Arg381Gln) and rs4131362 (Val362Ile) were performed by the Sanger Sequence method. IL-6 levels were higher in the active and inactive ankylosing spondylitis groups than in the control group. However, levels of IL-17 and IL-23 were lower in the patient group. The frequency of IL-23R gene rs11209026 and rs4131362 polymorphism were 3.7% and 8.3% in the patient, respectively. As a result, dysregulation of the IL-23 / IL-17 pathway, which is caused by reduced levels of IL-17 and IL-23 in systemic circulation in patients with ankylosing spondylitis, may contribute to the pathogenesis of the disease by systemically producing chronic autoimmune inflammation. WOS:000517818400012 2-s2.0-85082200711 PubMed: 32140056

Brain ischaemia is a severe form of metabolic stress that activates a cascade of pathological events involving many signalling pathways. Modulation of these pathways is largely mediated by post-translational modifications (PTMs). Indeed, PTMs can rapidly modify pre-existing proteins by attaching chemical or polypeptide moieties to selected amino acid residues, altering their functions, stability, subcellular localizations, or interactions with other proteins. Subsequently, related signalling pathways can be substantially affected. Thus, PTMs are widely deployed by cells as an adaptive strategy at the front line to efficiently cope with internal and external stresses. Many types of PTMs have been identified, including phosphorylation, O-GlcNAcylation, small ubiquitin-like modifier (SUMO) modification (SUMOylation), and ubiquitination. All these PTMs have been studied in brain ischaemia to some extent. In particular, a large body of evidence has demonstrated that both global SUMOylation and ubiquitination are massively activated after brain ischaemia, and this activation may play a critical role in defining the fate and function of cells in the post-ischaemic brain. The goal of this review will be to summarize the current findings on SUMOylation and ubiquitination in brain ischaemia and discuss their clinical implications.

Evolution has altered the free energy landscapes of protein kinases to introduce different regulatory switches and modify their catalytic functions. In this work, we demonstrate how cyclin dependency has emerged in cyclin-dependent kinases (CDKs) by reconstructing their closest experimentally characterized cyclin-independent ancestor, CMGI, using molecular dynamics simulations. Four hypotheses are formulated to describe why CDKs require an additional regulatory switch, i.e. cyclin binding to adopt an active state. Each hypothesis is tested using all-atom molecular dynamics simulations of CDK2 and the ancestor. In both systems, the K33–E51 hydrogen bond and the alignment of regulatory-spine residues have similar stabilities. However, auto-inhibition due to a helical turn in the A-loop is observed to be less favorable in the ancestor. Unlike the ancestor, the aspartate of the DFG motif does not form a bidentate bond with a Mg2+ ion in CDK2. These results explain the experimental observation of cyclin independency of the ancestor. Our findings provide a mechanistic rationale for how evolution has added a new regulatory switch to CDKs to tightly regulate the signalling pathways. This approach is directly applicable to other proteins to study the emergence of different types of regulatory mechanisms.

Recovery from traumatic muscle injuries is typically prolonged and incomplete. Our previous study demonstrated that whole‐body low‐intensity vibration (LIV) enhances healing in a mouse laceration model. We sought to determine whether locally applied LIV (a) improves muscle repair following injury in mice and (b) is directly transduced by cultured muscle cells, via increased IGF‐1 activity. C57BL/6J mice were subjected to laceration of the gastrocnemius muscle and were treated with LIV applied directly to the lower leg for 30 min/day or non‐LIV sham treatment (controls) for 7 or 14 days. LIV was also applied to differentiating myotubes in culture for 30 min/day for 3 or 6 days. Compared with control mice, LIV increased myofiber cross‐sectional area, diameter, and percent area of peripherally nucleated fibers, and decreased percent damaged area after 14 days of treatment. In cultured myotubes, LIV increased fusion and diameter compared with controls after 6 days of treatment. These LIV‐induced effects were associated with increased total Akt on day 7 in injured muscle and on day 3 in myotubes, whereas phosphorylated‐to‐total Akt ratio increased on day 14 in injured muscle and on day 6 in myotubes but were not associated with increased IGF‐1 levels at any time point. These changes were also associated with LIV‐induced suppression of FOXO1 and Atrogin‐1 gene expression at day 7 in injured muscle. These findings demonstrate that muscle cells can directly transduce LIV signals into increased growth and differentiation, and this effect is associated with increased Akt signaling., Our findings demonstrate that muscle cells can directly transduce LIV signals into increased growth and differentiation, and this effect is associated with increased Akt signaling.

Activated Cdc42-associated kinase or ACK, is a non-receptor tyrosine kinase and an effector protein for the small G protein Cdc42. A substantial body of evidence has accumulated in the past few years heavily implicating ACK as a driver of oncogenic processes. Concomitantly, more is also being revealed regarding the signalling pathways involving ACK and molecular details of its modes of action. Some details are also available regarding the regulatory mechanisms of this kinase, including activation and regulation of its catalytic activity, however a full understanding of these aspects remains elusive. This review considers the current knowledge base concerning ACK and summarises efforts and future prospects to target ACK therapeutically in cancer., MRC

Fertilization happens when sperm and oocytes meet, which is a complicated process involving many important types of biological activation. Beginning in the 2-cell stage, an important event referred to as zygotic genome activation (ZGA) occurs, which governs the subsequent development of the embryo. In ZGA, multiple epigenetic modifications are involved and critical for pre-implantation development. These changes occur after ZGA, resulting in blastomeres segregate into two different lineages. Some blastomeres develop into the inner cell mass (ICM), and others develop into the trophectoderm (TE), which is considered the first cell fate decision. How this process is initiated and the exact molecular mechanisms involved are fascinating questions that remain to be answered. In this review, we introduce some possible developmental models of the first cell fate decision and discuss the signalling pathways and transcriptional networks regulating this process. Keywords: Fertilization, Cell fate, Developmental models, Signalling pathways