Solid tumors, including breast carcinomas, are heterogeneous but typically characterized by elevated cellular turnover and metabolism, diffusion limitations based on the complex tumor architecture, and abnormal intra- and extracellular ion compositions particularly as regards acid-base equivalents. Carcinogenesis-related alterations in expression and function of ion channels and transporters, cellular energy levels, and organellar H sequestration further modify the acid-base composition within tumors and influence cancer cell functions, including cell proliferation, migration, and survival. Cancer cells defend their cytosolic pH and HCO concentrations better than normal cells when challenged with the marked deviations in extracellular H, HCO, and lactate concentrations typical of the tumor microenvironment. Ionic gradients determine the driving forces for ion transporters and channels and influence the membrane potential. Cancer and stromal cells also sense abnormal ion concentrations via intra- and extracellular receptors that modify cancer progression and prognosis. With emphasis on breast cancer, the current review first addresses the altered ion composition and the changes in expression and functional activity of ion channels and transporters in solid cancer tissue. It then discusses how ion channels, transporters, and cellular sensors under influence of the acidic tumor microenvironment shape cancer development and progression and affect the potential of cancer therapies.

Cancer is a collection of diseases caused by specific changes at the genomic level that support cell proliferation indefinitely. Traditionally, ion channels are known to control a variety of cellular processes including electrical signal generation and transmission, secretion, and contraction by controlling ionic gradients. However, recent studies had brought to light important facts on ion channels in cancer biology.In this review we discuss the mechanism linking potassium or chloride ion channel activity to biochemical pathways controlling proliferation in cancer cells and the potential advantages of targeting ion channels as an anticancer therapeutic option.

In the last years, the field of inheritable ventricular arrhythmia disease modelling has changed significantly with a push towards the use of novel cellular cardiomyocyte based models. However, there is a growing need for new in vivo models to study the disease pathology at the tissue and organ level. Zebrafish provide an excellent opportunity for in vivo modelling of inheritable ventricular arrhythmia syndromes due to the remarkable similarity between their cardiac electrophysiology and that of humans. Additionally, many state-of-the-art methods in gene editing and electrophysiological phenotyping are available for zebrafish research. In this review, we give a comprehensive overview of the published zebrafish genetic models for primary electrical disorders and arrhythmogenic cardiomyopathy. We summarise and discuss the strengths and weaknesses of the different technical approaches for the generation of genetically modified zebrafish disease models, as well as the electrophysiological approaches in zebrafish phenotyping. By providing this detailed overview, we aim to draw attention to the potential of the zebrafish model for studying arrhythmia syndromes at the organ level and as a platform for personalised medicine and drug testing.

The existence of a formal Endocannabinoid System in C. elegans has been questioned due to data showing the absence of typical cannabinoid receptors in the worm; however, the presence of a full metabolism for endocannabinoids, alternative ligands, and receptors for these agents and a considerable number of orthologous and homologous genes regulating physiological cannabinoid-like signals and responses - several of which are similar to those of mammals - demonstrates a well-structured and functional complex system in nematodes. In this review, we describe and compare similarities and differences between the Endocannabinoid System in mammals and nematodes, highlighting the basis for the integral study of this novel system in the worm.

Epithelial cells that line the proximal tubule of the kidney rely on an intertwined ecosystem of vesicular membrane trafficking pathways to ensure the reabsorption of essential nutrients. To function effectively and to achieve homeostasis, these specialized cells require the sorting and recycling of a wide array of cell surface proteins within the endolysosomal network, including signaling receptors, nutrient transporters, ion channels, and polarity markers. The dysregulation of the endolysosomal system can lead to a generalized proximal tubule dysfunction, ultimately causing severe metabolic complications and kidney disease.In this chapter, we highlight the biological functions of the genes that code endolysosomal proteins from the perspective of understanding - and potentially reversing - the pathophysiology of endolysosomal disorders affecting the proximal tubule of the kidney. These insights might ultimately lead to potential treatments for currently intractable diseases and transform our ability to regulate kidney homeostasis and health.

Oxytocin has recently gained significant attention because of its role in the pathophysiology and management of dominant neuropsychiatric disorders. Oxytocin, a peptide hormone synthesized in the hypothalamus, is released into different brain regions, acting as a neurotransmitter. Receptors for oxytocin are present in many areas of the brain, including the hypothalamus, amygdala, and nucleus accumbens, which have been involved in the pathophysiology of depression, anxiety, schizophrenia, autism, Alzheimer's disease, Parkinson's disease, and attention deficit hyperactivity disorder. Animal studies have spotlighted the role of oxytocin in social, behavioral, pair bonding, and mother-infant bonding. Furthermore, oxytocin protects fetal neurons against injury during childbirth and affects various behaviors, assuming its possible neuroprotective characteristics. In this review, we discuss some of the concepts and mechanisms related to the role of oxytocin in the pathophysiology and management of some neuropsychiatric, neurodegenerative, and neurodevelopmental disorders.

Chitosan is a natural polysaccharide widespread in nature. It has many unique and attractive properties for the pharmaceutical field: it is biodegradable, safe, hypoallergenic, biocompatible with the body, free of toxicity, with proven anticholesterolemic, antibacterial, and antimycotic action. In this review we highlighted the physical, chemical, mechanical, mucoadhesive, etc. properties of chitosan to be taken into account when obtaining various pharmaceutical forms. The methods by which the pharmaceutical forms based on chitosan are obtained are very extensive, and in this study only the most common ones were presented.

Among neoplasia-associated epigenetic alterations, changes in cellular glycosylation have recently received attention as a key component of hematological malignancy progression. Alterations in glycosylation appear to not only directly impact cell growth and survival, but also alter the adhesion of tumor cells and their interactions with the microenvironment, facilitating cancer-induced immunomodulation and eventual metastasis. Changes in glycosylation arise from altered expression of glycosyltransferases, enzymes that catalyze the transfer of saccharide moieties to a wide range of acceptor substrates, such as proteins, lipids, and other saccharides in the endoplasmic reticulum (ER) and Golgi apparatus. Novel glycan structures in hematological malignancies represent new targets for the diagnosis and treatment of blood diseases. This review summarizes studies of the aberrant expression of glycans commonly found in hematological malignancies and their potential mechanisms and defines the specific roles of glycans as drivers or passengers in the development of hematological malignancies.

Forty years ago, the introduction of a new electrophysiological technique, the patch clamp, revolutionized the fields of Cellular Physiology and Biophysics, providing for the first time the possibility of describing the behavior of a single protein, an ion-permeable channel of the cell plasma membrane, in its physiological environment. The new approach was actually much more potent and versatile than initially envisaged, and it has evolved into several different modalities that have radically changed our knowledge of how cells (not only the classical "electrically excitable "ones, such as nerves and muscles) use electrical signaling to modulate and organize their activity. This review aims at telling the history of the background from which the new technique evolved and at analyzing some of its more recent developments.

Pulmonary hypertension (PH) is a disease with high pulmonary arterial pressure, pulmonary vasoconstriction, pulmonary vascular remodeling, and microthrombosis in complex plexiform lesions, but it has been unclear of the exact mechanism of PH. A new understanding of the pathogenesis of PH is occurred and focused on the role of crosstalk between the cells on pulmonary vessels and pulmonary alveoli. It was found that the crosstalks among the endothelial cells, smooth muscle cells, fibroblasts, pericytes, alveolar epithelial cells, and macrophages play important roles in cell proliferation, migration, inflammation, and so on. Therefore, the heterogeneity of multiple pulmonary blood vessels and alveolar cells and tracking the transmitters of cell communication could be conducive to the further insights into the pathogenesis of PH to discover the potential therapeutic targets for PH.

The transient receptor potential (TRP) channels, classified into six (-A, -V, -P, -C, -M, -ML, -N and -Y) subfamilies, are important membrane sensors and mediators of diverse stimuli including pH, light, mechano-force, temperature, pain, taste, and smell. The mammalian TRP superfamily of 28 members share similar membrane topology with six membrane-spanning helices (S1-S6) and cytosolic N-/C-terminus. Abnormal function or expression of TRP channels is associated with cancer, skeletal dysplasia, immunodeficiency, and cardiac, renal, and neuronal diseases. The majority of TRP members share common functional regulators such as phospholipid PIP2, 2-aminoethoxydiphenyl borate (2-APB), and cannabinoid, while other ligands are more specific, such as allyl isothiocyanate (TRPA1), vanilloids (TRPV1), menthol (TRPM8), ADP-ribose (TRPM2), and ML-SA1 (TRPML1). The mechanisms underlying the gating and regulation of TRP channels remain largely unclear. Recent advances in cryogenic electron microscopy provided structural insights into 19 different TRP channels which all revealed close proximity of the C-terminus with the N-terminus and intracellular S4-S5 linker. Further studies found that some highly conserved residues in these regions of TRPV, -P, -C and -M members mediate functionally critical intramolecular interactions (i.e., within one subunit) between these regions. This review provides an overview on (1) intramolecular interactions in TRP channels and their effect on channel function; (2) functional roles of interplays between PIP2 (and other ligands) and TRP intramolecular interactions; and (3) relevance of the ligand-induced modulation of intramolecular interaction to diseases.

People suffering from obesity and associated metabolic disorders including diabetes are increasing exponentially around the world. Adipose tissue (AT) distribution and alteration in their biochemical properties play a major role in the pathogenesis of these diseases. Emerging evidence suggests that AT heterogeneity and depot-specific physiological changes are vital in the development of insulin resistance in peripheral tissues like muscle and liver. Classically, AT depots are classified into white adipose tissue (WAT) and brown adipose tissue (BAT); WAT is the site of fatty acid storage, while BAT is a dedicated organ of metabolic heat production. The discovery of beige adipocyte clusters in WAT depots indicates AT heterogeneity has a more central role than hither to ascribed. Therefore, we have discussed in detail the current state of understanding on cellular and molecular origin of different AT depots and their relevance toward physiological metabolic homeostasis. A major focus is to highlight the correlation between altered WAT distribution in the body and metabolic pathogenesis in animal models and humans. We have also underscored the disparity in the molecular (including signaling) changes in various WAT tissues during diabetic pathogenesis. Exercise-mediated beneficial alteration in WAT physiology/distribution that protects against metabolic disorders is evolving. Here we have discussed the depot-specific biochemical adjustments induced by different forms of exercise. A detailed understanding of the molecular details of inter-organ crosstalk via substrate utilization/storage and signaling through chemokines provide strategies to target selected WAT depots to pharmacologically mimic the benefits of exercise countering metabolic diseases including diabetes.

Transient receptor potential vanilloid type 4 (TRPV4) channels are Ca-permeable non-selective cation channels which mediate a wide range of physiological functions and are activated and modulated by a diverse array of stimuli. One of this ion channel's least discussed functions is in relation to the generation and maintenance of certain pain sensations. However, in the two decades which have elapsed since the identification of this ion channel, considerable data has emerged concerning its function in mediating pain sensations. TRPV4 is a mediator of mechanical hyperalgesia in the various contexts in which a mechanical stimulus, comprising trauma (at the macro-level) or discrete extracellular pressure or stress (at the micro-level), results in pain. TRPV4 is also recognised as constituting an essential component in mediating inflammatory pain. It also plays a role in relation to many forms of neuropathic-type pain, where it functions in mediating mechanical allodynia and hyperalgesia.Here, we review the role of TRPV4 in mediating pain sensations.

Alcohol is one of the most consumed drugs in the world, even during pregnancy. Its use is a risk factor for developing adverse outcomes, e.g. fetal death, miscarriage, fetal growth restriction, and premature birth, also resulting in fetal alcohol spectrum disorders. Ethanol metabolism induces an oxidative environment that promotes the oxidation of lipids and proteins, triggers DNA damage, and advocates mitochondrial dysfunction, all of them leading to apoptosis and cellular injury. Several organs are altered due to this harmful behavior, the brain being one of the most affected. Throughout pregnancy, the human placenta is one of the most important organs for women's health and fetal development, as it secretes numerous hormones necessary for a suitable intrauterine environment. However, our understanding of the human placenta is very limited and even more restricted is the knowledge of the impact of toxic substances in its development and fetal growth. So, could ethanol consumption during this period have wounding effects in the placenta, compromising proper fetal organ development? Several studies have demonstrated that alcohol impairs various signaling cascades within G protein-coupled receptors and tyrosine kinase receptors, mainly through its action on insulin and insulin-like growth factor 1 (IGF-1) signaling pathway. This last cascade is involved in cell proliferation, migration, and differentiation and in placentation. This review tries to examine the current knowledge and gaps in our existing understanding of the ethanol effects in insulin/IGFs signaling pathway, which can explain the mechanism to elucidate the adverse actions of ethanol in the maternal-fetal interface of mammals.

Survival in the circulation, extravasation from vasculature, and colonizing new tissues represent major steps of the metastatic cascade and pose a big challenge for metastasizing tumor cells. Tumor cells circulating in blood and lymph vessels need to overcome anoikis, cope with mechanical stimuli including shear stress, and defeat attacks by the immune system. Once adhered to the vessel wall, a circulating tumor cell (CTC) can trick the endothelial cells into loosening their intercellular junctions so that the endothelium becomes penetrable for the tumor cell. Since tumor cells tend to metastasize to predestinated target organs and tissues, called organotropism, the distribution of metastases is anything but random. The molecular-physiological mechanisms underlying CTC survival, extravasation, and organotropism are very likely to include the presence and activity of ion channels/transporters due to the latter's key function in cytophysiological processes. To date, a very limited number of studies explicitly show the involvement of ion transport. This review describes the contribution of ion channels and transporters to CTC survival, extravasation, and organotropism where known and possible. In addition, supposed connections between ion transport and CTC behavior are demonstrated and imply the potential to be therapeutically taken advantage of.

NO (nitric oxide) is an important regulator of neutrophil functions and has a key role in diverse pathophysiological conditions. NO production by nitric oxide synthases (NOS) is under tight control at transcriptional, translational, and post-translational levels including interactions with heterologous proteins owing to its potent chemical reactivity and high diffusibility; this limits toxicity to other cellular components and promotes signaling specificity. The protein-protein interactions govern the activity and spatial distribution of NOS isoform to regulatory proteins and to their intended targets. In comparison with the vast literature available for endothelial, macrophages, and neuronal cells, demonstrating neuronal NOS (nNOS) interaction with other proteins through the PDZ domain, neutrophil nNOS, however, remains unexplored. Neutrophil's key role in both physiological and pathological conditions necessitates the need for further studies in delineating the NOS mediated NO modulations in signaling pathways operational in them. nNOS has been linked to depression, schizophrenia, and Parkinson's disease, suggesting the importance of exploring nNOS/NO-mediated neutrophil physiology in relation to such neuronal disorders. The review thus presents the scenario of neutrophil nNOS from the genetics to the functional level, including protein-protein interactions governing its intracellular sequestration in diverse cell types, besides speculating possible regulation in neutrophils and also addressing their clinical implications.

Metalloproteinases are a group of proteinases that plays a substantial role in extracellular matrix remodeling and its molecular signaling. Among these metalloproteinases, ADAMs (a disintegrin and metalloproteinases) and ADAM-TSs (ADAMs with thrombospondin domains) have emerged as highly efficient contributors mediating proteolytic processing of various signaling molecules. ADAMs are transmembrane metalloenzymes that facilitate the extracellular domain shedding of membrane-anchored proteins, cytokines, growth factors, ligands, and their receptors and therefore modulate their biological functions. ADAM-TSs are secretory, and soluble extracellular proteinases that mediate the cleavage of non-fibrillar extracellular matrix proteins. ADAMs and ADAM-TSs possess pro-domain, metalloproteinase, disintegrin, and cysteine-rich domains in common, but ADAM-TSs have characteristic thrombospondin motifs instead of the transmembrane domain. Most ADAMs and ADAM-TSs are activated by cleavage of pro-domain via pro-protein convertases at their N-terminus, hence directing them to various signaling pathways. In this article, we are discussing not only the structure and regulation of ADAMs and ADAM-TSs, but also the importance of these metalloproteinases in various human pathophysiological conditions like cardiovascular diseases, colorectal cancer, autoinflammatory diseases (sepsis/rheumatoid arthritis), Alzheimer's disease, proliferative retinopathies, and infectious diseases. Therefore, based on the emerging role of ADAMs and ADAM-TSs in various human pathologies, as summarized in this review, these metalloproteases can be considered as critical therapeutic targets and diagnostic biomarkers.

Histone deacetylases (HDACs) are a family of 18 members that participate in the epigenetic regulation of gene expression. In addition to histones, some HDACs also deacetylate transcription factors and specific cytoplasmic proteins.Monocytes, as part of the innate immune system, maintain tissue homeostasis and help fight infections and cancer. In these cells, HDACs are involved in multiple processes including proliferation, migration, differentiation, inflammatory response, infections, and tumorigenesis. Here, a systematic description of the role that most HDACs play in these functions is reviewed. Specifically, some HDACs induce a pro-inflammatory response and play major roles in host defense. Conversely, other HDACs reprogram monocytes and macrophages towards an immunosuppressive phenotype. The right balance between both types helps monocytes to respond correctly to the different physiological/pathological stimuli. However, aberrant expressions or activities of specific HDACs are associated with autoimmune diseases along with other chronic inflammatory diseases, infections, or cancer.This paper critically reviews the interesting and extensive knowledge regarding the role of some HDACs in these pathologies. It also shows that as yet, very little progress has been made toward the goal of finding effective HDAC-targeted therapies. However, given their obvious potential, we conclude that it is worth the effort to develop monocyte-specific drugs that selectively target HDAC subtypes with the aim of finding effective treatments for diseases in which our innate immune system is involved.

Ion transporting proteins (ITPs) comprise a wide range of ion channels, exchangers, pumps and ionotropic receptors many of which are expressed in tumours and contribute dynamically to the different components and stages of the complex cancer process, from initiation to metastasis. In this promising major field of biomedical research, several candidate ITPs have emerged as clinically viable. Here, we consider a series of general issues concerning the oncological potential of ITPs focusing on voltage-gated sodium channels as a 'case study'. First, we outline some key properties of 'cancer' as a whole. These include epigenetics, stemness, metastasis, heterogeneity, neuronal characteristics and bioelectricity. Cancer specificity of ITP expression is evaluated in relation to tissue restriction, splice variance, functional specificity and macro-molecular complexing. As regards clinical potential, diagnostics is covered with emphasis on enabling early detection. For therapeutics, we deal with molecular approaches, drug repurposing and combinations. Importantly, we emphasise the need for carefully designed clinical trials. We highlight also the area of 'social responsibility' and the need to involve the public (cancer patients and healthy individuals) in the work of cancer research professionals as well as clinicians. In advising patients how best to manage cancer, and live with it, we offer the following four principles: Awareness and prevention, early detection, specialist, integrated care, and psychological support. Finally, we highlight four key prerequisites for commercialisation of ITP-based technologies against cancer. We conclude that ITPs offer significant potential as regards both understanding the intricacies of the complex process of cancer and for developing much needed novel therapies.

The development and function of a particular organ and the pathogenesis of various diseases remain intimately linked to the features of each cell type in the organ. Conventional messenger RNA- or protein-based methodologies often fail to elucidate the contribution of rare cell types, including some subpopulations of stem cells, short-lived progenitors and circulating tumour cells, thus hampering their applications in studies regarding organ development and diseases. The scRNA-seq technique represents a new approach for determining gene expression variability at the single-cell level. Organoids are new preclinical models that recapitulate complete or partial features of their original organ and are thought to be superior to cell models in mimicking the sophisticated spatiotemporal processes of the development and regeneration and diseases. In this review, we highlight recent advances in the field of scRNA-seq, organoids and their current applications and summarize the advantages of using a combination of scRNA-seq and organoid technology to model diseases and organ development.

Alveolar macrophages (AMs) are extremely versatile cells with complex functions involved in health or diseases such as pneumonia, asthma, and pulmonary alveolar proteinosis. In recent years, it has been widely identified that the different functions and states of macrophages are the results from the complex interplay between microenvironmental signals and macrophage lineage. Diverse and complicated signals to which AMs respond are mentioned when they are described individually or in a particular state of AMs. In this review, the microenvironmental signals are divided into autocrine, paracrine, and endocrine signals based on their secreting characteristics. This new perspective on classification provides a more comprehensive and systematic introduction to the complex signals around AMs and is helpful for understanding the roles of AMs affected by physiological environment. The existing possible treatments of AMs are also mentioned in it. The thorough understanding of AMs signals modulation may be contributed to the development of more effective therapies for AMs-related lung diseases.