Evolutionary study and structural basis of proton sensing by Mus GPR4 and Xenopus GPR4

Cell, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

---

Kidney metabolism and acid–base control: back to the basics

Pflügers Archiv - European Journal of Physiology, Год журнала: 2022, Номер 474(8), С. 919 - 934

Опубликована: Май 5, 2022

Kidneys are central in the regulation of multiple physiological functions, such as removal metabolic wastes and toxins, maintenance electrolyte fluid balance, control pH homeostasis. In addition, kidneys participate systemic gluconeogenesis production or activation hormones. Acid-base conditions influence all these functions concomitantly. Healthy properly coordinate a series responses face acute chronic acid-base disorders. However, injured have reduced capacity to adapt challenges. Chronic kidney disease patients an example individuals typically exposed progressive acidosis. Their organisms undergo alterations that brake large detrimental changes homeostasis several parameters, but may also operate further drivers damage. disorders lead not only mechanisms involved balance maintenance, they affect other tightly wired it. this review article, we explore basic renal activities show how interconnected cell energy metabolism important intracellular activities. These intertwined relationships been investigated for more than century, modern conceptual organization events is lacking. We propose indissociably interacts with pathways drive progression disease, inflammation metabolism, independent etiology.

Язык: Английский

---

The pathophysiology of distal renal tubular acidosis

Nature Reviews Nephrology, Год журнала: 2023, Номер 19(6), С. 384 - 400

Опубликована: Апрель 4, 2023

Язык: Английский

---

Current Advances on Nanomaterials Interfering with Lactate Metabolism for Tumor Therapy

Advanced Science, Год журнала: 2023, Номер 11(3)

Опубликована: Ноя. 8, 2023

Abstract Increasing numbers of studies have shown that tumor cells prefer fermentative glycolysis over oxidative phosphorylation to provide a vast amount energy for fast proliferation even under oxygen‐sufficient conditions. This metabolic alteration not only favors cell progression and metastasis but also increases lactate accumulation in solid tumors. In addition serving as byproduct glycolytic cells, plays central role the construction acidic immunosuppressive microenvironment, resulting therapeutic tolerance. Recently, targeted drug delivery inherent properties nanomaterials attracted great attention, research on modulating metabolism based enhance antitumor therapy has exploded. this review, advanced strategies interfere with are discussed, including inhibiting anabolism, promoting catabolism, disrupting “lactate shuttle”. Furthermore, recent advances combining modulation other therapies, chemotherapy, immunotherapy, photothermal therapy, reactive oxygen species‐related etc., which achieved cooperatively enhanced outcomes, summarized. Finally, foreseeable challenges prospective developments reviewed future development field.

Язык: Английский

---

A Narrative Review of Cytokine Networks: Pathophysiological and Therapeutic Implications for Inflammatory Bowel Disease Pathogenesis

Biomedicines, Год журнала: 2023, Номер 11(12), С. 3229 - 3229

Опубликована: Дек. 6, 2023

Inflammatory bowel disease (IBD) is a lifelong inflammatory immune mediated disorder, encompassing Crohn's (CD) and ulcerative colitis (UC); however, the cause specific pathogenesis of IBD yet incompletely understood. Multiple cytokines produced by different cell types results in complex functional networks that constitute highly regulated messaging network signaling pathways. Applying biological mechanisms underlying at single omic level, technologies genetic engineering enable quantification pattern released new insights into cytokine landscape IBD. We focus on existing literature dealing with biology pro- or anti-inflammatory interactions facilitate cell-based modulation system for inflammation. summarize main roles substantial related to homeostatic tissue functions remodeling IBD, which may be specifically valuable successful cytokine-targeted therapies via marketed products. Cytokines their receptors are validated targets multiple therapeutic areas, we review current strategies intervention developing therapies. New biologics have shown efficacy last few decades management IBD; unfortunately, many patients nonresponsive develop therapy resistance over time, creating need novel therapeutics. Thus, treatment options beyond immune-modifying anti-TNF agents combination expanding rapidly. Further studies needed fully understand response, cytokines, direct pathogenetic relevance regarding individually tailored, safe efficient targeted-biotherapeutics.

Язык: Английский

---

Cryo-EM structure of an activated GPR4–Gs signaling complex

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 11, 2025

G protein-coupled receptor 4 (GPR4) belongs to the subfamily of proton-sensing GPCRs (psGPCRs), which detect pH changes in extracellular environment and regulate diverse physiological responses. GPR4 was found be overactivated acidic tumor microenvironment as well inflammation sites, with a triad residues within transmembrane domain identified crucial for proton sensing. However, 3D structure remains unknown, roles other conserved psGPCRs are not understood. Here we report cryo-electron microscopy (cryo-EM) structures active zebrafish at both 6.5 8.5, each highlighting distribution histidine region. Cell-based assays show that these ionizable moderately influence capacity GPR4, compared more significant effects residues. Furthermore, reveal cluster aromatic orthosteric pocket may propagate signaling intercellular region via repacking patch central This study provides framework future functional investigation psGPCRs. The low Here, authors cryo-EM provide insight into structural features sensing mechanism.

Язык: Английский

---

Role of proton-activated G protein-coupled receptors in pathophysiology

AJP Cell Physiology, Год журнала: 2022, Номер 323(2), С. C400 - C414

Опубликована: Июнь 27, 2022

Local acidification is a common feature of many disease processes such as inflammation, infarction, or solid tumor growth. Acidic pH not merely sequela but contributes to recruitment and regulation immune cells, modifies metabolism parenchymal, modulates fibrosis, vascular permeability, oxygen availability, consumption, invasiveness impacts on cell survival. Thus, multiple pH-sensing mechanisms must exist in cells involved these processes. These sensors play important roles normal physiology pathophysiology, hence might be attractive targets for pharmacological interventions. Among the mechanisms, OGR1 ( GPR68), GPR4 GPR4), TDAG8 GPR65) have emerged molecules. G protein-coupled receptors are widely expressed, upregulated inflammation tumors, sense changes extracellular range between 8 6, modulating key biology, fibrosis. This review discusses features highlights states pathways affected by their activity.

Язык: Английский

---

The acid-sensing receptor GPR65 on tumor macrophages drives tumor growth in obesity

Science Immunology, Год журнала: 2024, Номер 9(100)

Опубликована: Окт. 18, 2024

Multiple cancers, including colorectal cancer (CRC), are more frequent and often aggressive in individuals with obesity. Here, we showed that macrophages accumulated within tumors of patients obesity CRC obese mice they promoted accelerated tumor growth. These changes were initiated by oleic acid accumulation subsequent cell–derived production driven macrophage signaling through the acid-sensing receptor GPR65. We found a similar role for GPR65 hepatocellular carcinoma (HCC) mice. Tumors or HCC also exhibited increased expression, suggesting mechanism revealed here may contribute to growth range obesity-associated cancers represent potential therapeutic target.

Язык: Английский

---

Inhibition of proton sensor GPR68 suppresses endothelial dysfunction and acute lung injury caused by Staphylococcus aureus bacterial particles

The FASEB Journal, Год журнала: 2025, Номер 39(3)

Опубликована: Фев. 5, 2025

Abstract Lung bacterial infections, including hospital‐acquired pneumonia, remain a serious problem for public health. Endothelial cell (EC) exposure to heat‐killed Staphylococcus aureus (HKSA) represents clinical scenario of high titers killed particles present in the host after antibiotic therapy, which triggers inflammatory cascades, cytokine storms, and EC dysfunction leading acute lung injury (ALI). GPR68 is member proton‐sensing G protein‐coupled receptor family. Acting as pH sensor, becomes activated upon reduction contributes pathologic responses by activating ER stress unfolded protein response. This study investigated role HKSA‐induced ALI. HKSA robustly increased mRNA levels human pulmonary directly stimulated activity. A selective small molecule inhibitor, OGM‐8345, attenuated permeability protected junction integrity. OGM‐8345 inhibited activation genes TNF‐α, IL‐6, IL‐8, IL‐1β, CXCL5 decreased secretion HKSA‐challenged EC. Co‐treatment with activator Ogerin or medium acidification 6.5 augmented dysfunction, was rescued OGM‐8345. Intratracheal injection vascular leak inflammation mice were monitored Evans blue extravasation, count bronchoalveolar lavage, expression genes. ALI barrier We show first time mediating strong potential therapeutic treatment pathogen‐induced associated tissue acidification.

Язык: Английский

---

Cerebrospinal fluid pH regulation

Pflügers Archiv - European Journal of Physiology, Год журнала: 2024, Номер 476(4), С. 467 - 478

Опубликована: Фев. 22, 2024

Язык: Английский

---