Anthracyclines remain a cornerstone of anticancer therapy, but their clinical use is limited by cancer therapy-related cardiac dysfunction, a major contributor to long-term cardiovascular morbidity in cancer survivors. Although traditionally attributed to oxidative stress, DNA damage and mitochondrial toxicity, emerging evidence identifies disruption of metabolism as a central mechanism of anthracycline-induced cardiotoxicity. Anthracycline exposure promotes a distinct metabolic phenotype characterized by impaired mitochondrial oxidative phosphorylation, dysregulated metabolism of fatty acids and glucose, along with decreased metabolic flexibility, ultimately resulting in inefficient myocardial energetics. These changes are modulated by the patient's underlying cardiometabolic status, suggesting that metabolic reserve influences susceptibility to injury. In addition to direct myocardial effects, anthracyclines induce systemic metabolic changes that affect substrate availability and inter-organ communication. This review focuses on cardiotoxicity induced by anthracyclines, particularly by doxorubicin, highlighting mitochondrial dysfunction, altered substrate utilization and metabolic inflexibility in comparison with other cardiac diseases. We also discuss the newly emerging metabolic strategies aimed at improving cardioprotection.
BACKGROUND AND PURPOSE:The rise of multidrug-resistant (MDR) bacteria poses a significant threat to global health. MDR Klebsiella pneumoniae is of particular concern because of its increasing antibiotic resistance. With limited therapeutic options, antimicrobial photodynamic therapy (aPDT), which employs light-activated photosensitizers to produce reactive oxygen species (ROS), represents a promising alternative. EXPERIMENTAL APPROACH:We assessed the antimicrobial activity of two ruthenium-based photosensitisers, PSRu-379 and PSRu-381, against both susceptible and MDR K. pneumoniae strains and explored their mode of action. Bacterial survival was measured after activation with 61.2 J·cm-2 of blue light. ROS production was analysed using fluorescent probes; transcriptional responses were examined by RT-qPCR and RNA sequencing; cytotoxicity was tested in human cell lines; and interactions with cefotaxime were evaluated using fractional inhibitory concentration (FIC) analysis. KEY RESULTS:The minimum effective concentration was 4 μg·ml-1 for the susceptible strain and 8 μg·ml-1 for MDR strains. ROS analysis indicated predominant singlet oxygen generation, with minimal contribution from hydrogen peroxide, supporting a predominantly Type II photodynamic mechanism. Transcriptomic analysis revealed upregulation of sulphur metabolism and oxidative stress response pathways, along with downregulation of aminoacid biosynthesis, capsule formation and metal ion transport. The photosensitisers exhibited synergistic interactions with cefotaxime, reducing MIC values and yielding an FIC index of 0.08. Low cytotoxicity was observed in human cell lines under the tested conditions. CONCLUSIONS AND IMPLICATIONS:Ruthenium-based photosensitisers appear to act predominantly through singlet oxygen-mediated oxidative stress, enhancing cefotaxime efficacy while exhibiting low cytotoxicity, and therefore represent promising adjunct therapies against MDR K. pneumoniae.
BACKGROUND AND PURPOSE:Gamma-glutamyl dipeptides are essentially produced after glutathione (GSH) degradation. While several γ-glutamyl dipeptides have been detected in different organs and body fluids, their biological activity remains elusive. This is the case for γ-Glutamyl-Glycine (γ-Glu-Gly) which has been found in different brain areas. γ-Glutamyl-glycine may bind to ionotropic glutamate receptors. Here, we have investigated whether γ-Glu-Gly could exhibit modulatory actions on excitatory synaptic transmission and plasticity by performing its functional characterization on glutamate, GABA and glycine receptors. EXPERIMENTAL APPROACH:Electrophysiological and calcium imaging experiments were performed on cells heterologously expressing either Glutamate, GABA or Glycine receptors and on cultured hippocampal neurons and acute hippocampal slices. The γ-Glu-Gly production by cultured cells and hippocampal slices was measured by LC-MS analysis, following incubation with modulators of the glutathione metabolic cycle. KEY RESULTS:γ-Glu-Gly exerted partial agonist effects on both NMDA GluN1 and mGlu5 receptors, but without any binding to the glutamate binding domain on both AMPA and NMDA GluN2A receptors. γ-Glu-Gly was devoid of any effect on GABA, glycine and GluN3A receptors. γ-Glu-Gly was able to trigger a long-term increase in synaptic transmission in the CA1 area of mouse hippocampus. CONCLUSION AND IMPLICATIONS:γ-Glu-Gly partially retains the excitatory actions of glutamate on specific receptor sub-types and may trigger plastic events in the hippocampus. Its accumulation under pathological conditions associated with oxidative stress and a high GSH consumption could thus interfere with endogenous synaptic transmission and disrupt natural plasticity, which is a hallmark of neurodegenerative diseases.
Extracellular vesicles (EVs) are a diverse population of membrane nanoparticles secreted by nearly all cell types, playing a key role in intercellular communication by transferring bioactive macromolecular cargo. In cancer, EVs shape both the local tumour microenvironment and distant premetastatic niches. They are essential regulators of tumour initiation, progression, immune modulation, angiogenesis and metastatic dissemination. Due to their abundance in biofluids, EVs have attracted attention as diagnostic and prognostic biomarkers for early detection and assessment of therapeutic response. Additionally, EVs represent a promising therapeutic platform for delivering chemotherapeutic agents, nucleic acids and gene-editing tools, with enhanced specificity and reduced systemic toxicity. This review summarises current therapeutic applications of EVs across breast, lung, colorectal, prostate and pancreatic cancers and glioblastoma. Key findings are presented for each formulation, with emphasis on the EV physicochemical properties and engineered modifications, their cargo and mechanisms underlying their biological effects. Although the clinical translation of EV-based advances remains limited and challenging, this review highlights significant preclinical findings and examples of clinical trials where EVs have been used as therapeutic agents.
BACKGROUND AND PURPOSE:Arsenic trioxide (ATO) therapy for acute promyelocytic leukaemia (APL) can induce neurological disorders, including cognitive impairment (CI) and depression, severely impacting patient quality of life, yet effective interventions are lacking. Clinical observations indicate ATO treatment is associated with gut microbiota dysbiosis. Given the crucial role of gut microbes and their metabolites in neurological health, this study investigated indole-3-propionic acid (IPA), a neuroprotective microbiota-derived metabolite capable of crossing the blood-brain barrier. RESULTS:In ATO-treated mice, behavioural tests confirmed significant cognitive decline. 16S rRNA genotyping revealed a reduction in Bifidobacterium abundance, and metabolomics identified a concomitant decrease in its metabolite, IPA, alongside disruptions in the tricarboxylic acid cycle and glycolysis. IPA supplementation alleviated ATO-induced intestinal inflammation and behavioural deficits. Mechanistically, IPA inhibited ATO-induced BRD4 degradation and the associated reduction in H4 acetylation, thereby restoring the expression of the metabolic enzyme PFKM and the synaptic protein PSD95. CONCLUSION:IPA mitigates ATO-induced intestinal injury and glycolytic dysfunction via the 'BRD4-H4ac-PFKM' axis, providing novel insights for preventing and treating ATO-induced neurotoxicity.
BACKGROUND AND PURPOSE:Pathological cardiac hypertrophy precipitates heart failure. Empagliflozin (EMPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, confers cardiovascular protection beyond glycaemic control, but the molecular basis of its direct anti-hypertrophic action remains undefined. EXPERIMENTAL APPROACH:Angiotensin II (Ang II)-induced hypertrophy was modelled in AC16 and H9c2 cardiomyocytes, and pressure overload was modelled in mice undergoing transverse aortic constriction (TAC). Outcomes were assessed by cell surface area, marker expression, histology and echocardiography. Mechanistic studies included transcriptomic profiling, integrin subunit analysis, pharmacological integrin blockade with ATN-161, downstream signalling, in silico EMPA-SP1 docking and SP1 knockdown. Blood glucose, body weight and urinary glucose were monitored. KEY RESULTS:EMPA attenuated Ang II-induced cardiomyocyte hypertrophy in vitro and TAC-induced dysfunction, hypertrophy and interstitial fibrosis in vivo. Transcriptomic analysis revealed enrichment of extracellular matrix-receptor interaction, focal adhesion and cytoskeleton pathways, implicating integrin signalling. TAC up-regulated integrin subunits, which EMPA normalized. ATN-161 abrogated EMPA-mediated suppression of hypertrophic readouts and restored FAK/Src/Akt activation, demonstrating functional integrin dependency. Docking predicted a high-affinity EMPA-SP1 interaction; SP1 knockdown reduced basal integrin expression and abolished EMPA-mediated reversal of Ang II-induced ITGA5/ITGB1 up-regulation, providing functional support. CONCLUSIONS AND IMPLICATIONS:EMPA inhibits pathological cardiac hypertrophy by modulating integrin-dependent signal transduction and downstream FAK/Src/Akt signalling, potentially through an SP1-associated transcriptional program that influences integrin expression.
BACKGROUND AND PURPOSE:Cullin 4B (Cul4B), a scaffold protein of CUL4B-RING E3 ligase complex, functions primarily as a negative regulator of inflammation. This study aims to investigate its role in acute lung injury (ALI) and NLRP3 ubiquitination. EXPERIMENTAL APPROACH:Cul4B expression and distribution were examined in two sepsis-induced ALI mouse models. Lung-specific overexpression and myeloid-specific Cul4B deletion were applied to evaluate its effects on lung histopathology, pulmonary inflammation, and alveolar capillary barrier dysfunction. The role of Cul4B in NLRP3 inflammasome activation was evaluated in THP-1 cells and Cul4B-deficient BMDMs. Cul4B-NLRP3 interaction and Cul4B-mediated NLRP3 ubiquitination were determined. The involvement of Cul4B in MN-08-mediated ALI protection and inflammasome suppression was also investigated. KEY RESULTS:Cul4B was significantly downregulated in lung tissues of sepsis-induced ALI mice. Pulmonary overexpression of Cul4B attenuated lung injury and inflammation, whereas myeloid-specific deletion of Cul4B exacerbated epithelial barrier damage and inflammatory responses, along with enhanced Nigericin-induced NLRP3 inflammasome activation. Cul4B was shown to interact with both endogenous and exogenous NLRP3 and suppressed NLRP3 inflammasome activation by promoting NLRP3 ubiquitination. MN-08, a small molecule previously reported to alleviate lipopolysaccharide (LPS)-induced ALI, was found to upregulate Cul4B expression and inhibit NLRP3 inflammasome activation by promoting NLRP3 ubiquitination. CONCLUSIONS AND IMPLICATIONS:Upregulating Cul4B promotes NLRP3 ubiquitination, thereby inhibiting inflammasome activation and mitigating pulmonary epithelial barrier dysfunction and inflammation in ALI. Cul4B emerges as a potential therapeutic target, and these findings provide new insights into the mechanism by which MN-08 protects against sepsis-induced ALI.
Venetoclax combined with hypomethylating agents has improved treatment for older or unfit patients with acute myeloid leukaemia (AML), but resistance and relapse remain common. This review analyses the rationale for combining venetoclax with inhibitors of histone deacetylase (HDAC). Class I histone deacetylase 1/2/3-dependent suppression of myeloid cell leukaemia 1 and de-repression of pro-apoptotic BCL-2 homology domain 3 (BH3)-only genes provide the strongest mechanistic basis, whereas HDAC6/heat shock protein 90, autophagy, immune-modulatory and super-enhancer mechanisms remain context-dependent and incompletely validated in primary AML under venetoclax exposure. Effects of HDAC inhibition must also be interpreted in the context of tumour protein 53 status. Early HDAC inhibitor-containing composite regimens, particularly chidamide-based CACAG-VEN (chidamide, venetoclax, azacitidine, low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor), report high response rates, including overall response rate of 76.5-98.0%, complete remission/complete remission with incomplete count recovery or composite complete remission of 73.5-93.3%, and measurable residual disease negativity of 44-61%. This six-component regimen does not isolate the contribution of HDAC inhibition. Future development should prioritise biomarker-selected trials that hold non-HDAC components constant, incorporate pharmacodynamic HDAC engagement and BH3 profiling, and account for cytochrome P450 3A-mediated drug interactions. HDAC inhibitor-venetoclax combinations are mechanistically rational, but standard-of-care positioning requires randomised or pharmacodynamic validation.
BACKGROUND AND PURPOSE:Senile osteoporosis presents a significant and growing health burden. Currently, no pharmacological agents are specifically approved for this condition. The dietary flavonoid naringenin (NAR) exhibits osteoprotective potential; however, its efficacy and direct molecular target in the context of senile osteoporosis remain undefined. EXPERIMENTAL APPROACH:The effects of NAR were evaluated in a natural ageing mouse model by assessing skeletal mass, microstructure and strength. In vivo analyses included bone histomorphometry, serum bone turnover marker assays and biomechanical testing. Osteogenic and osteoclastogenic differentiation was examined in cell cultures. To identify the molecular target of NAR, we employed RNA sequencing, siRNA transfection, biotin-conjugated pull-down assays, molecular dynamics simulations, competitive pull-down with immunoblotting, SPR, CETSA, DARTS and western blotting. KEY RESULTS:NAR treatment significantly increased bone mineral density, improved trabecular microarchitecture and enhanced bone strength in ageing mice. It promoted bone formation, elevated the mineral apposition and bone formation rates and concurrently suppressed osteoclast differentiation and bone resorption. In vitro, NAR enhanced osteogenic differentiation and mineralization. Mechanistically, NAR directly bound to the key osteogenic transcription factor Runx2 and activated Runx2-dependent gene expression. Silencing Runx2 markedly attenuated the osteogenic effects of NAR. CONCLUSION AND IMPLICATIONS:These findings demonstrate that NAR promotes bone formation while limiting resorption, thereby alleviating age-related bone loss by activating Runx2. This study identifies Runx2 as a direct molecular target of NAR and supports its potential use in the management of senile osteoporosis.
BACKGROUND AND PURPOSE:Little is known about how synthetic cannabinoid receptor agonist (SCRA) co-use with other psychoactive substances may exacerbate risk of death. This study aimed to characterise the polypharmacy of deaths where SCRAs were detected at post-mortem, investigate the cardiotoxicity of SCRAs and probe their inhibition of human ether-a-go-go-related gene (hERG) channel function. EXPERIMENTAL APPROACH:Deaths with detections of SCRA(s) were analysed from the National Programme on Substance Use Mortality. Isolated hearts from guinea pigs were perfused with modified Krebs solution. Methadone and the SCRA 5F-ADB (5F-MDMB-PINACA) were applied singly and in combination, with electrocardiogram recording. Software tools and patch-clamp electrophysiology were employed to investigate 5F-ADB-hERG channel interaction. KEY RESULTS:In deaths with SCRA detections, pharmacoepidemiological analyses showed that methadone was the most commonly co-detected medication with long QT liability. Sub-analysis of SCRA-methadone deaths revealed a significantly lower median blood concentration of methadone proved fatal, compared to deaths solely attributed to methadone. In perfused guinea pig hearts, sole application of methadone, but not 5F-ADB, prolonged the QTc interval, compared to baseline. Co-application significantly increased the QTc interval. The in silico and in vitro analyses showed 5F-ADB to be a low affinity hERG channel inhibitor. CONCLUSIONS AND IMPLICATIONS:The reduction in the toxicity threshold of methadone and the facilitation of its QT prolongation by the SCRA 5F-ADB suggests the former may result from pro-arrhythmia. Use of QT-prolonging medications by people who use SCRAs may result in a drug-drug interaction that increases the risk of pro-arrhythmic death.
BACKGROUND AND PURPOSE:Clozapine and d-cycloserine improve negative symptoms of treatment-resistant schizophrenia, whereas combined administration of d-cycloserine plus clozapine aggravates them. However, the underlying mechanisms of these inconsistent effects remain unclear. EXPERIMENTAL APPROACH:Effects of chronic administration of MK-801 (0.1 mg·kg-1·day-1), d-cycloserine (2 mg·kg-1·day-1), clozapine (5 mg·kg-1·day-1) and memantine (10 mg·kg-1·day-1) for 14 days on sucrose preference, GluN2A/GluN2B expression and basal and N-methyl-d-aspartate (NMDA)-evoked releases of l-glutamate/d-serine in the orbitofrontal cortex of male rats were determined. KEY RESULTS:Chronic MK-801 administration decreased sucrose preference, GluN2A/GluN2B expression and NMDA-evoked release but increased basal extracellular l-glutamate/d-serine levels in the orbitofrontal cortex. Chronic administration of clozapine or d-cycloserine restored MK-801-induced sucrose preference impairments and NMDA-evoked release but left unaffected basal extracellular levels or GluN2A/GluN2B expression. Conversely, combined administration of clozapine + d-cycloserine further enhanced the MK-801-induced sucrose preference impairments, NMDA-evoked releases and GluN2A/GluN2B expressions and the increasing basal extracellular levels. Adding memantine to MK-801 + clozapine or MK-801 + clozapine + d-cycloserine reversed the sucrose preference, NMDA-evoked release and GluN2A/GluN2B expressions and the increasing basal extracellular levels. Tachyphylactic dose of d-cycloserine (25 mg·kg-1·day-1) decreased GluN2A/GluN2B expression, which was antagonised by the glycine-binding-site inhibitor MDL29951(10 mg·kg-1·day-1). Clozapine suppressed PP2A signalling. Chronic monotherapy with d-cycloserine or PP2A inhibitor LB-100 (1.5 mg·kg-1·day-1) left unaffected GluN2A/GluN2B expression, whereas their combined administration down-regulated them. CONCLUSION AND IMPLICATIONS:These results suggest that potentiation of the NMDA receptor is involved in improving negative symptoms, but down-regulating NMDA receptor and enhanced extrasynaptic-NMDA receptor conversely contribute to the aggravation of negative symptoms.
Ischaemia-reperfusion (I/R) injury affects vital organs, including the heart, brain, liver and kidney, and represents a major pathological process associated with high morbidity and mortality. I/R injury initiates complex molecular and cellular cascades that drive cellular dysfunction, structural damage and both acute and chronic organ failure. Despite advances in supportive care, pharmacological intervention remains the primary strategy for protecting organs from I/R injury. Tanshinones, a group of lipophilic abietane diterpenoids derived from Salvia miltiorrhiza, display convergent, multi-target pharmacological activities that closely correspond to the core pathogenic mechanisms of I/R injury. Over the past two decades, tanshinones, particularly Tan IIA, Tan I and cryptotanshinone, have shown cardioprotective and neuroprotective effects. Increasing evidence further indicates that tanshinones also protect against I/R injury in other organs. This review synthesizes current findings on bioactive tanshinone analogues, their pharmacodynamic properties and underlying mechanisms of action and discusses biomarker-guided strategies to advance tanshinones as practical, pleiotropic therapeutic candidates for multi-organ I/R injury.
BACKGROUND AND PURPOSE:Patients with Parkinson's disease (PD) show intestinal epithelial barrier (IEB) alterations, enteric gliosis and inflammation that could contribute to gastrointestinal symptoms. Moreover, changes in leucine rich-repeat kinase 2 (LRRK2) expression/activity have been associated with PD development and related intestinal inflammation. However, the molecular determinants linking LRRK2, enteric gliosis and IEB impairment remain unclear. Therefore, we investigated the role of LRRK2 in IEB changes associated with PD, focusing on its role in the interplay between enteric glial cells (EGCs) and intestinal epithelial cells (IECs). EXPERIMENTAL APPROACH:Human A53T α-synuclein transgenic (Tg) mice (9 months old) were provided a model of early PD. Central neuroinflammation was studied by IBA-1 staining. Intestinal motility, colonic α-synuclein and LRRK2 expression were assessed. Enteric gliosis was evaluated by detection of GFAP+ cells co-expressing LRRK2; IEB was tested by mucins detection and quantification of Muc-2, tight junction proteins and secretory autophagy. In vitro co-cultures between EGCs and IECs were performed to investigate glial LRRK2-mediated gut barrier alterations. KEY RESULTS:A53T mice, without central neuroinflammation, showed intestinal disturbances, colonic α-synuclein accumulation and an increase in colonic GFAP+/LRRK2+ glial cells before brain pathology. Moreover, PD animals displayed IEB alterations and increased colonic autophagosomes, suggesting a shift towards secretory autophagy. In co-culture experiments, α-synuclein and lipopolysaccharide promoted enteric gliosis and LRRK2 up-regulation in glial cells, contributing to IEB impairment via secretory autophagy. CONCLUSIONS AND IMPLICATIONS:These changes could influence bowel symptoms and central pathology associated with PD, via the gut-brain axis.
The current obesity drug landscape, dominated by GLP-1 receptor agonists and emerging multi-agonist therapies, has reinforced that long-term weight loss is achieved in large part through central mechanisms that suppress appetite and reshape energy balance. Consequently, there is a renewed focus on how peripherally administered agents access the brain to exert these pharmacological effects. Circumventricular organs (CVOs) constitute specialised brain-blood interfaces that detect circulating metabolic, hormonal and inflammatory signals and relay them to neural circuits regulating cardiovascular function, reproduction and energy homeostasis. We recapitulate the organisation and physiological roles of CVOs, with particular emphasis on the median eminence and area postrema. These structures represent key sites of action for anti-obesity drugs, gating the entry and signalling of GLP-1 receptor agonists, and integrating information on energy status and inflammatory challenges. We discuss how dysregulation of these interfaces may contribute to obesity pathogenesis and how targeting CVO-specific mechanisms may refine future pharmacotherapies.
BACKGROUND AND PURPOSE:Chikungunya virus (CHIKV) causes severe acute and chronic disease, yet no approved specific antiviral treatment exists. To rapidly identify potential treatments, we aimed to screen an FDA-approved drug library for inhibitors of CHIKV infection. Tirbanibulin, a dual-microtubule polymerization and Src kinase inhibitor, was assessed for its potential anti-CHIKV activity. METHODS:We performed a high-throughput screen of an FDA-approved drug library. Mechanism-of-action studies included entry-step analysis, surface plasmon resonance (SPR) binding assays and molecular docking. In vivo efficacy was evaluated in lethal murine neuroinfection and CHIKV-induced arthritis models following oral administration of the candidate compound. EXPERIMENTAL APPROACH:Tirbanibulin exhibited nanomolar to low-micromolar antiviral activity (EC50 range: 0.035-75.64 μM) across multiple cell lines, with high selective indices in key target HT22 and Huh7 cells. It acted at a post-attachment entry step, inhibiting clathrin-mediated endocytosis and potentially viral fusion. Surface plasmon resonance confirmed direct, high-affinity binding to the CHIKV E1 and E2 glycoprotein complex (K_D = 73 nM). In the lethal neuroinfection model, oral tirbanibulin significantly improved survival and reduced brain viral loads; in the arthritis model, it markedly attenuated footpad swelling and inflammatory pathology. CONCLUSION AND IMPLICATIONS:Tirbanibulin is a novel, orally bioavailable entry-stage inhibitor that directly targets the E2 glycoprotein. Multiple preclinical and clinical studies have confirmed its favourable oral bioavailability and safety. Given its established clinical safety profile, it represents a promising repurposing candidate for clinical evaluation against Chikungunya fever.
BACKGROUND AND PURPOSE:The NLRP3 inflammasome is an attractive therapeutic target for multiple inflammatory conditions. Although inhibitors have been developed, their chemical diversity is limited, and their properties are not ideal for brain penetrance, which is desirable for treating neuroinflammatory disorders. EXPERIMENTAL APPROACH:We applied our chemoproteomics platform to survey our electrophilic fragment collection to identify inhibitors of NLRP3. We focused our attention on compounds that bind Cys463, as this residue was identified as an allosteric sensor of NLRP3 function. KEY RESULTS:A novel inhibitor series was identified bearing a butynamide electrophile and a unique spirocyclic lactam core. Compounds from this series displayed mid-nanomolar potency and were found to inhibit IL-1β secretion in a Cys463-dependent manner. Cryo-EM structures revealed that ligand binding to Cys463 stabilizes an inactive conformation, thereby preventing structural rearrangements required for inflammasome activation. These compounds displayed attractive pharmacokinetic properties and, notably, Kp,uu values >0.5, suggesting the potential to address neuroinflammatory disorders. Administration of a representative compound to humanized mice resulted in clear NLRP3 Cys463 target-engagement and profound suppression of LPS- and ATP-induced IL-1β secretion, demonstrating clear proof-of-concept in vivo. CONCLUSION AND IMPLICATIONS:Chemoproteomics-based ligand discovery is intrinsically function-agnostic and has the potential to identify novel pockets on even well-characterized protein targets. Here, optimization of ligands targeting Cys463 of NLRP3 within a previously uncharacterized allosteric pocket led to a unique and potent inhibitor series with attractive physicochemical and pharmacokinetic properties for the potential treatment of diseases involving aberrant innate immune activation in both central and peripheral tissues.
BACKGROUND AND PURPOSE:Peripherally derived adiponectin crosses the blood-brain barrier and targets severa0l brain regions. Adiponectin receptors are highly expressed in the hippocampus, and play a pro-cognitive role as adiponectin markedly influences the functioning of hippocampal synapses. Trafficking of AMPA receptors underlies activity-dependent hippocampal synaptic plasticity, but it is unclear if adiponectin influences this process. Here, we examined the effects of he adiponectin receptor agonist, AdipoRon, on AMPA receptor trafficking and hippocampal excitatory synaptic function. EXPERIMENTAL APPROACH:Immunocytochemistry combined with confocal microscopy was used to monitor the surface expression of the AMPA receptor subunit, GluA1, in hippocampal neurons cultured from neonatal (P0-4) rats. Extracellular field potential recordings were used to monitor excitatory synaptic transmission in hippocampal slices from juvenile male (P14-24) Sprague Dawley rats. KEY RESULTS:AdipoRon increased GluA1 surface expression and delivered GluA1-containing AMPA receptors to synapses. In hippocampal slices, AdipoRon increased excitatory synaptic transmission, maintained during recordings, and AdipoRon enhanced hippocampal long-term potentiation. Effects of AdipoRon on AMPA receptor trafficking involved AdipoRon receptors, as these effects were mirrored by the adiponectin receptor agonist, ADP355 and blocked by the antagonist, ADP400. AdipoRon-driven increases in surface GluA1 required GluN2A-containing NMDA receptor activation. Effects of AdipoRon on GluA1 expression and synaptic plasticity involved AMPK signalling. CONCLUSIONS AND IMPLICATIONS:These data show that AdipoRon trafficked GluA1-containing AMPA receptors to synapses and facilitated hippocampal synaptic plasticity via activation of AMPK. These findings have important implications for the role of adiponectin in regulating hippocampal synaptic function in health and disease.
BACKGROUND AND PURPOSE:Previous studies have highlighted the significance of the bile acid receptor TGR5 (also known as Takeda G protein-coupled receptor 5) in regulating inflammation and mitochondrial homeostasis in various diseases, whereas the specific involvement of TGR5 in spinal cord injury (SCI) remains unclear. This study aimed to elucidate the effects of TGR5 on SCI, as well as the underlying mechanisms. EXPERIMENTAL APPROACH:The TGR5 agonist INT-777 was used to activate TGR5 in a mouse model of SCI, induced by contusion injury to T9-T10 vertebrae, and cultured cells. To determine the mechanism of TGR5 activation after SCI, public dataset analysis, behaviour assessment, histology and biochemical analysis relating to inflammation, pyroptosis and mitochondrial function were performed. KEY RESULTS:TGR5 levels were increased in a mouse model of spinal cord injury (SCI), and in primary microglia and BV2 cells treated with tert-butyl hydroperoxide. Furthermore, TGR5 activation by INT-777 improved functional recovery and tissue repair in SCI mice. Mechanistically, INT-777-mediated TGR5 activation exerted a neuroprotective effect by regulating cAMP/AMPK signalling, resulted in suppression of mitochondrial dysfunction and mitochondrial DNA (mtDNA) release, which inhibited absent in melanoma 2 (AIM2)-driven pyroptosis and the inflammatory response. Notably, AIM2 overexpression partly blocked the neuroprotective effects of TGR5 activation in SCI mice. Additionally, AMPK inhibition by dorsomorphin aggravated neural injury and inflammation was alleviated in AIM2 deletion mice following SCI. CONCLUSIONS AND IMPLICATIONS:INT-777 exerts anti-inflammatory and neuroprotective effects in the injured spinal cord by activating the TGR5/cAMP/AMPK pathway, thereby maintaining mitochondrial homeostasis and suppressing AIM2-mediated pyroptosis.
Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but are associated with a growing spectrum of cardiovascular immune-related adverse events. Among these, arrhythmias represent a rare yet potentially life-threatening complication. ICI-induced arrhythmias encompass a wide clinical spectrum, including atrial arrhythmias, conduction disturbances and malignant ventricular arrhythmias. This review summarizes the current evidence on the incidence, clinical presentation, pathophysiological mechanisms and management of ICI-associated arrhythmias. We discuss the limitations of available data, which are largely derived from case reports, small series and retrospective registries, and highlight the implications for clinical practice. Improved understanding of ICI-induced arrhythmias is essential to balance oncological efficacy with cardiovascular safety in this, rapidly expanding, patient population.
BACKGROUND AND PURPOSE:Binding kinetics are essentially based on rate constants. Yet, this view has been challenged by the idea that 'binding fluxes' are dynamic and therefore more relevant. Those fluxes refer to the rate at which a target/receptor changes from one state into another through ligand/drug binding or a conformational change. Besides acting as building blocks for many algebraic expressions, they also determine how the concentration of each individual target state evolves over time. Here we show that such fluxes offer additional opportunities for understanding and predicting ligand binding. EXPERIMENTAL APPROACH:Simulated binding data are obtained by solving the relevant set of flux-based differential equations for increasingly complex ligand binding models over very small time intervals by Euler's method. As input, they require only ligand concentration(s) and rate constants. KEY RESULTS:Compared to often-complex algebraic expressions, binding fluxes allow more intuitive/inductive insight into different aspects of ligand binding such as the occurrence of transient binding overshoots and the effect of a closing lid over the ligand's binding pocket on ligand dissociation. These examples disclose fundamental principles that govern ligand binding and, above all, they highlight the essential role of rate constants in all the examined binding models. CONCLUSIONS AND IMPLICATIONS:Binding fluxes and rate constants complement each other: They respectively indicate how and why binding processes evolve in a certain fashion. The presented flux-based approaches have the advantage to address pre-equilibrium as well as equilibrium conditions and can be applied to any ligand-binding model.
