Reviews of Physiology Biochemistry and Pharmacology最新文献

Being originally discovered as cellular recycling bins, lysosomes are today recognized as versatile signaling organelles that control a wide range of cellular functions that are essential not only for the well-being of normal cells but also for malignant transformation and cancer progression. In addition to their core functions in waste disposal and recycling of macromolecules and energy, lysosomes serve as an indispensable support system for malignant phenotype by promoting cell growth, cytoprotective autophagy, drug resistance, pH homeostasis, invasion, metastasis, and genomic integrity. On the other hand, malignant transformation reduces the stability of lysosomal membranes rendering cancer cells sensitive to lysosome-dependent cell death. Notably, many clinically approved cationic amphiphilic drugs widely used for the treatment of other diseases accumulate in lysosomes, interfere with their cancer-promoting and cancer-supporting functions and destabilize their membranes thereby opening intriguing possibilities for cancer therapy. Here, we review the emerging evidence that supports the supplementation of current cancer therapies with lysosome-targeting cationic amphiphilic drugs.

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.

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.

Lipid droplets have a unique structure among organelles consisting of a dense hydrophobic core of neutral lipids surrounded by a single layer of phospholipids decorated with various proteins. Often labeled merely as passive fat storage repositories, they in fact have a remarkably dynamic life cycle. Being formed within the endoplasmic reticulum membrane, lipid droplets rapidly grow, shrink, traverse the cytosol, and engage in contacts with other organelles to exchange proteins and lipids. Their lipid and protein composition changes dynamically in response to cellular states and nutrient availability. Remarkably, their biogenesis is induced when cells experience various forms of nutrient, energy, and redox imbalances, including lipid excess and complete nutrient deprivation. Cancer cells are continuously exposed to nutrient and oxygen fluctuations and have the capacity to switch between alternative nutrient acquisition and metabolic pathways in order to strive even during severe stress. Their supply of lipids is ensured by a series of nutrient uptake and scavenging mechanisms, upregulation of de novo lipid synthesis, repurposing of their structural lipids via enzymatic remodeling, or lipid recycling through autophagy. Importantly, most of these pathways of lipid acquisition converge at lipid droplets, which combine different lipid fluxes and control their usage based on specific cellular needs. It is thus not surprising that lipid droplet breakdown is an elaborately regulated process that occurs via a complex interplay of neutral lipases and autophagic degradation. Cancer cells employ lipid droplets to ensure energy production and redox balance, modulate autophagy, drive membrane synthesis, and control its composition, thereby minimizing stress and fostering tumor progression. As regulators of (poly)unsaturated fatty acid trafficking, lipid droplets are also emerging as modulators of lipid peroxidation and sensitivity to ferroptosis. Clearly, dysregulated lipid droplet turnover may also be detrimental to cancer cells, which should provide potential therapeutic opportunities in the future. In this review, we explore how lipid droplets consolidate lipid acquisition and trafficking pathways in order to match lipid supply with the requirements for cancer cell survival, growth, and metastasis.

Endoplasmic reticulum (ER)-mitochondria regions are specialized subdomains called also mitochondria-associated membranes (MAMs). MAMs allow regulation of lipid synthesis and represent hubs for ion and metabolite signaling. As these two organelles can module both the amplitude and the spatiotemporal patterns of calcium (Ca²⁺) signals, this particular interaction controls several Ca²⁺-dependent pathways well known for their contribution to tumorigenesis, such as metabolism, survival, sensitivity to cell death, and metastasis. Mitochondria-mediated apoptosis arises from mitochondrial Ca²⁺ overload, permeabilization of the mitochondrial outer membrane, and the release of mitochondrial apoptotic factors into the cytosol. Decreases in Ca²⁺ signaling at the ER-mitochondria interface are being studied in depth as failure of apoptotic-dependent cell death is one of the predominant characteristics of cancer cells. However, some recent papers that linked MAMs Ca²⁺ crosstalk-related upregulation to tumor onset and progression have aroused the interest of the scientific community.In this review, we will describe how different MAMs-localized proteins modulate the effectiveness of Ca²⁺-dependent apoptotic stimuli by causing both increases and decreases in the ER-mitochondria interplay and, specifically, by modulating Ca²⁺ signaling.

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.

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.

Neurodegenerative disorders are debilitating and largely untreatable conditions that pose a significant burden to affected individuals and caregivers. Overwhelming evidence supports a crucial preclinical role for endosomal dysfunction as an upstream pathogenic hub and driver in Alzheimer's disease (AD) and related neurodegenerative disorders. We present recent advances on the role of endosomal acid-base homeostasis in neurodegeneration and discuss evidence for converging mechanisms. The strongest genetic risk factor in sporadic AD is the ε4 allele of Apolipoprotein E (ApoE4), which potentiates pre-symptomatic endosomal dysfunction and prominent amyloid beta (Aβ) pathology, although how these pathways are linked mechanistically has remained unclear. There is emerging evidence that the Christianson syndrome protein NHE6 is a prominent ApoE4 effector linking endosomal function to Aβ pathologies. By functioning as a dominant leak pathway for protons, the Na⁺/H⁺ exchanger activity of NHE6 limits endosomal acidification and regulates β-secretase (BACE)-mediated Aβ production and LRP1 receptor-mediated Aβ clearance. Pathological endosomal acidification may impact both Aβ generation and clearance mechanisms and emerges as a promising therapeutic target in AD. We also offer our perspective on the complex role of endosomal acid-base homeostasis in the pathogenesis of neurodegeneration and its therapeutic implications for neuronal rescue and repair strategies.

Among the infectious diseases caused by pathogenic microorganisms such as bacteria, viruses, parasites, or fungi, the most prevalent ones today are malaria, tuberculosis, influenza, HIV/AIDS, Ebola, dengue fever, and methicillin-resistant Staphylococcus aureus (MRSA) infection, and most recently Covid-19 (SARS-CoV2). Others with a rather devastating history and high fatality rates such as plague, cholera, or typhus seem less threatening today but have not been eradicated, and with a declining efficacy of current antibiotics they ought to be watched carefully. Another emerging issue in this context is health-care associated infection. About 100,000 hospitalized patients in the USA ( www.cdc.gov ) and 33,000 in Europe ( https://www.ecdc.europa.eu ) die each year as a direct consequence of an infection caused by bacteria resistant to antibiotics. Among viral infections, influenza is responsible for about 3-5 million cases of severe illness, and about 250,000 to 500,000 deaths annually ( www.who.int ). About 37 million people are currently living with HIV infection and about one million die from it each year. Coronaviruses such as MERS-CoV, SARS-CoV, but in particular the recent outbreak of Covid-19 (caused by SARS-CoV2) have resulted in large numbers of infections worldwide with an estimated several hundred thousand deaths (anticipated fatality rate: <5%). With a comparatively low mortality rate dengue virus causes between 50 and 100 million infections every year, leading to 50,000 deaths. In contrast, Ebola virus is the causative agent for one of the deadliest viral diseases. The Ebola outbreak in West Africa in 2014 is considered the largest outbreak in history with more than 11,000 deaths. Many of the deadliest pathogens such as Ebola virus, influenza virus, mycobacterium tuberculosis, dengue virus, and cholera exploit the endo-lysosomal trafficking system of host cells for penetration into the cytosol and replication. Defects in endo-lysosomal maturation, trafficking, fusion, or pH homeostasis can efficiently reduce the cytotoxicity caused by these pathogens. Most of these functions critically depend on endo-lysosomal membrane proteins such as transporters and ion channels. In particular, cation channels such as the mucolipins (TRPMLs) or the two-pore channels (TPCs) are involved in all of these aspects of endo-lysosomal integrity. In this review we will discuss the correlations between pathogen toxicity and endo-lysosomal cation channel function, and their potential as drug targets for infectious disease therapy.