Current Opinion in Physiology最新文献

The diagnosis of breast cancer in the early stage is essential for a favorable prognosis. Extracellular vesicles isolated from body fluids have a central role in breast cancer development due to their biochemical components. Among the biochemical components, surface proteins mediate vesicle interactions with elements of the extracellular milieu, the extracellular matrix, and neighboring cells. The identification of specific surface proteomic profile has been regarded as an easy and reproducible means to define cancer parameters, identify markers for a diagnosis, and determine targets for therapeutical treatments. In this review, we will focus on annexins, tetraspanins, integrins, immune checkpoint proteins, and growth factor receptors that have been identified on the surface of extracellular vesicles isolated from the serum of patients with breast cancer and that have been found to be relevant diagnostic and prognostic biomarkers.

The lethality of heart failure, particularly in the context of post-acute sequelae SARS-CoV-2 infection-related myocarditis, necessitates the discovery of the cellular pathways implicated in cardiovascular disease. We summarize the signaling mechanisms of the catecholamine-binding β-adrenergic receptors (β-ARs), with an emphasis on the role of β-arrestins. β-ARs, a subset of G protein-coupled receptors (GPCRs), canonically propagate signals through heterotrimeric G proteins. However, since their discovery in the late 1980s, β-arrestins have been shown to both (i) quench G protein signaling and (ii) initiate their own independent signaling cascades, which is influenced by posttranslational modifications. β-arrestin-biased agonism by the beta-blocker carvedilol and its allosteric modulation can serve a cardioprotective role. The increasingly labyrinthine nature of GPCR signaling suggests that ligand-dependent β-AR signaling, either stimulated by an agonist or blocked by an antagonist, is selectively enhanced or suppressed by allosteric modulations, which are orchestrated by novel drugs or endogenous posttranslational modifications.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is diagnosed by the presence of two of the following three characteristics: hyperandrogenemia and/or hyperandrogenism, oligo-/amenorrhea, and polycystic ovarian morphology. PCOS is associated with reproductive and nonreproductive complications, including obesity, insulin resistance and diabetes, dyslipidemia, and increased blood pressure. There is an urgent need for biomarkers that address both the reproductive and nonreproductive aspects of this complex syndrome. This review focuses on biomarkers, or potential ones, associated with the reproductive and nonreproductive aspects of PCOS, including anthropometric and clinical biomarkers, insulin and the insulin-like growth factor 1 system, lipids, anti-Müllerian hormone and gonadotropins, steroids, inflammatory and renal injury biomarkers, oxidative stress, and noncoding RNAs. We expect that this review will bring some light on the recent updates in the field and encourage researchers to join the exciting and promising field of PCOS biomarkers.

It is well-established that mechanosensitive (MS) ion channels differentially respond to membrane tension, bilayer thinning, and curvature. The thesis that the lipid bilayer acted as the terminal transducer of force directly to the channel became known as the force-from-lipids gating paradigm (also less frequently referred to as the ‘bilayer model’). This principle allows cells to detect and respond to mechanical forces in their environment, which is important for various physiological processes, including blood pressure regulation, touch sensation, and many others. Our understanding of how mechanical force drives MS channel gating has been greatly enhanced by new insights into the molecular interactions between the lipid bilayer and channel proteins. In this short review, we revisit the role of the force-from-lipids principle within the current understanding of MS channel gating and focus on its molecular underpinnings.

Adrenergic receptors (ARs) and catalytic receptors (CRs), two major classes of cell-surface receptors, play essential roles in a wide range of physiological and pathological processes. Studies over the years have revealed that ARs and CRs, along with their associated signaling transduction pathways, are not isolated in the cells. Instead, there exists functional crosstalk, involving either activation or inhibition, among specific members of ARs and CRs. Although the dynamics and mechanism of individual receptors within each family have been extensively studied, we have just begun to understand the spatiotemporal dynamics, functional consequences, and underlying mechanisms of the crosstalk between ARs and CRs. In this review, we will provide a concise overview of recent progress in identifying and elucidating the crosstalk, either unidirectional or bidirectional, between ARs and CRs.

Cancer progression involves complex interactions between tumor cells and the surrounding microenvironment. Chronic psychosocial stress and sympathetic nervous system activation lead to abnormal catecholamine release, impacting tumor cells directly and indirectly and fuelling cancer-promoting effects. However, the same adrenergic Receptor (AR) that mediate these effects could also convey exercise-related beneficial changes. Epidemiological studies show conflicting associations between stress, AR inhibitors, and breast cancer (BC) metastatic progression. Adrenergic sympathetic stress triggers sustained inflammatory and hypoxic-related signaling pathways, alters function and distribution of immune cell populations, and remodels blood vessels, leading to immunosuppression and premetastatic site formation. Activated AR initiate feedback loops with tyrosine kinase receptors and chemokine receptors, affecting stem-related transcription factors, pro-inflammatory mediators, angiogenic factors, and energy metabolism regulators, promoting tumor growth and invasion. Understanding molecular mechanisms of agonistic and antagonistic AR ligands and crosstalk with other signaling pathways is crucial for developing effective therapies targeting adrenergic-driven BC progression.

Adrenergic receptors (AR) are essential regulators of vascular physiology and are largely used as pharmacological targets. This chapter will review the main roles of the vascular AR in both the endothelium and vascular smooth muscle. We will discuss the ability of ARs to regulate key functions in endothelial and smooth muscle cells and their involvement in several pathologic conditions such as hypertension, atherosclerosis, and heart failure.

High endothelial venules (HEVs), high-walled cuboidal blood vessels, through their expression of adhesion molecules and chemokines, allow the entrance of lymphoid cells into primary, secondary, and tertiary lymphoid structures (TLSs) (aka tertiary lymphoid organs). HEV heterogeneity exists between various lymphoid organs in their expression of peripheral node addressin and mucosal vascular addressin adhesion molecule 1. Transcriptomic analyses reveal extensive heterogeneity, plasticity, and regulation of HEV gene expression in ontogeny, acute inflammation, and chronic inflammation within and between lymphoid organs. Rules regulating HEV development are flexible in inflammation. HEVs in tumor TLSs are diagnostic of favorable clinical outcome and response to immunotherapy, including immune checkpoint blockade. Immunotherapy induces HEVs and provides an entrance for naive, central memory, and effector cells and a niche for stem-like precursor cells. Understanding HEV regulation will permit their exploitation as routes for drug delivery to autoimmune lesions, rejecting organs, and tumors.

In the human heart, adrenaline activates the β₂-adrenoceptor (β₂AR) to cause powerful increases in contractile force and acceleration of contraction. This is explained by tight coupling of the β₂AR to the Gsα-protein–cyclic AMP–PKA signaling pathway with phosphorylation of proteins, including the L-type Ca²⁺ channel, ryanodine receptor, phospholamban, and sarcomeric proteins troponin I and C-protein. Experimentally, it has been shown that activation of β₂ARs is arrhythmogenic in the human failing heart. From cell- and animal model-based experiments, there is increased awareness of the broader signaling repertoire of the β₂AR. The β₂AR has the ability to couple simultaneously to Gsα- and Giα-proteins and activate β-arrestin signaling pathways. In addition to the orthosteric binding site, modes of conformation stabilization exist through the allosteric binding site and with pepducins. Beneficial effects, including cardioprotection, have been observed, waiting for translation to the human diseased heart and fuelling optimism for advancement of therapeutics for heart disease.