Search Results (78)

Skeletal muscle aging, or sarcopenia, involves progressive muscle mass and function loss, which limits mobility and independence in elderly populations. This decline is driven by chronic inflammation, oxidative stress, and insulin resistance, all of which impair muscle regeneration and accelerate protein breakdown. Mineralocorticoid receptors (MRs), known for their roles in electrolyte balance, have emerged as key regulators of these processes in skeletal muscle. MR activation promotes inflammatory signaling, increases oxidative stress, and worsens insulin resistance, accelerating sarcopenia progression. This review examines the impact of MRs on muscle health and highlights the therapeutic potential of targeting these receptors to counteract age-related muscle loss. MR antagonists, such as spironolactone, show promise in reducing inflammation and oxidative damage, potentially slowing sarcopenia. Physical exercise, an established intervention for muscle health, may enhance MR antagonism effects by improving insulin sensitivity and reducing inflammation. However, more research is needed to determine the efficacy and safety of combined MR antagonists and exercise protocols for preventing sarcopenia in older adults. Full article

Background: Permanent atrial fibrillation (AF) frequently coexists with heart failure (HF), leading to structural remodeling and progressive sinus node dysfunction. As the condition advances, bradyarrhythmia or tachy-brady syndrome may develop. Right ventricular pacing and cardiac resynchronization therapy may impair left ventricular function due to non-physiological ventricular activation. His bundle pacing (HBP) offers a more physiological alternative. This study evaluates HBP’s impact on left ventricular function in patients with bradyarrhythmia or tachy-brady syndrome and permanent AF. Methods: A retrospective analysis included 41 patients with HF who underwent HBP implantation due to bradyarrhythmia or tachy-brady syndrome in permanent AF. LVEF, LVEDD, and MR were assessed before and after implantation, alongside the impact of comorbidities (e.g., ischemic heart disease and chronic kidney disease) and pharmacotherapy (digoxin, metoprolol, and mineralocorticoid receptor antagonists). Statistical analyses included the Wilcoxon test (LVEF and MR), paired Student’s t-test (LVEDD), Spearman’s correlation, and linear regression. Significance was set at p < 0.05. Results: HBP significantly improved LVEF (median increase: 14.58%; p < 0.001) and reduced LVEDD (mean reduction: 5.41 ± 1.30 mm; p < 0.001). MR severity also decreased (p < 0.001). Patients with lower baseline LVEF showed greater improvement in this parameter after HBP (ρ = −0.671, p < 0.001). Only chronic kidney disease was associated with a lower likelihood of MR improvement (p = 0.0486). Conclusions: HBP improves left ventricular function and reduces MR severity in patients with permanent AF and bradyarrhythmia or tachy-brady syndrome. A low baseline LVEF was the strongest predictor of subsequent improvement. Further studies are needed to confirm long-term benefits. Full article

Smoltification is stressful for salmonids, and cortisol is one of the central endocrine regulators for seawater adaptation. It has been established that cortisol plays both mineralocorticoid and glucocorticoid functions by MR and GR, respectively, since the aldosterone hormone is absent. Recently, investigations have proposed that the 11-deoxycorticosterone (DOC) mineralocorticoid precursor might support cortisol effects, but this mechanism remains unclear. Hence, we assessed the early effects of DOC on rainbow trout pre-smolts, the key smoltification stage, via metabolic and transcriptomic approaches. Thirty-six juveniles (~120 g) were treated for 3 h with DOC (1 mg/kg) and/or mineralocorticoid (eplerenone) or glucocorticoid (mifepristone) receptor antagonists (n = 6 for each group). DOC decreased plasma glucose and pyruvate and increased phosphate and liver glycogen. DOC also downregulated carbohydrate metabolism-related genes in the liver. Finally, gill RNA-seq analysis presented 1660 differentially expressed transcripts in DOC versus vehicle, 1022 for eplerenone + DOC versus DOC and 3324 for mifepristone + DOC versus DOC. The enrichment analysis mainly revealed the upregulation of ion transmembrane transport and carbohydrate metabolism and the downregulation of stress and innate immune responses. This suggests a significant role of DOC in liver carbohydrate metabolism and gill osmoregulation of pre-smolts through both receptors. Hence, this could contribute to improving animal welfare monitoring during smoltification by featuring novel and potential biomarkers. Full article

Vascular smooth muscle cells (VSMCs) are the most abundant cell type in blood vessels, participating in cardiovascular diseases in various ways, among which their transformation into macrophage-like cells has become a research hotspot. In this study, rats were infused with aldosterone for 12 weeks, and VSMCs stimulated with aldosterone in vitro were used to observe aortic injury and the role of VSMC transformation. Vascular changes were detected via small animal ultrasound and H&E staining. Moreover, immunohistochemistry, immunofluorescence, Western blot, and flow cytometry were used to verify that the transformation of VSMCs into macrophage-like cells is regulated by mineralocorticoid receptor (MR) activation and macrophage colony-stimulating factor (M-CSF) and its receptor. Rat vasculature and in vitro cellular experiments revealed that VSMCs transformed into macrophage-like cells and secreted inflammatory factors such as interleukin-1β (IL-1β) and monocyte chemoattractant protein-1 (MCP-1), thereby exacerbating inflammatory vascular lesions, which was inhibited by the MR antagonist esaxerenone. These results reveal that increased levels of aldosterone activate MR, leading to the secretion of M-CSF by VSMCs. This further promotes the transformation of VSMCs into macrophage-like cells, which participate in inflammatory vascular lesions. Therefore, inhibiting the formation of macrophage-like cells can effectively reduce inflammatory vascular lesions. Full article

(1) Background: Despite previous studies linking inflammatory cytokines to lung adenocarcinoma (LUAD), their causal mechanisms remain unclear. This study aims to explore the causal relationship between inflammatory cytokines and LUAD to fill this knowledge gap. (2) Methods: This study employs a comprehensive approach, integrating Mendelian randomization (MR) analysis, single-cell RNA sequencing (scRNA-seq), and transcriptomic sequencing (RNA-seq) data to investigate the relationship between inflammatory cytokines and LUAD. (3) Results: In forward MR analysis, elevated levels of hepatocyte growth factor (HGF), interleukin-1 receptor antagonist (IL-1RA), IL-5, monocyte chemoattractant protein-3, and monokine induced by interferon-γ were causally associated with an increased risk of LUAD. In reverse MR analysis, LUAD exhibited a positive causal relationship with the levels of regulated upon activation normal T cell expressed and secreted factor (RANTES) and stromal cell-derived factor-1α. The scRNA-seq data further identified specific cell populations that may influence LUAD onset and progression through the expression of particular inflammatory genes and intercellular communication. RNA-seq data analysis highlighted the role of the HGF gene in LUAD diagnosis, demonstrating its strong correlation with patient prognosis and immune cell infiltration within the tumor microenvironment. (4) Conclusions: The findings reveal a causal relationship between inflammatory cytokines and LUAD, with HGF emerging as a potential biomarker of significant clinical relevance. This study provides new insights into the molecular mechanisms underlying LUAD and lays the foundation for future therapeutic strategies. Full article

The mineralocorticoid receptor (MR) is a steroid hormone receptor that plays a key role in regulating sodium and water homeostasis and blood pressure. MR antagonists are a guideline recommended for therapy for the treatment of hypertension and cardiovascular disease but can cause hyperkalaemia. Modelling was performed for binding of the endogenous ligands aldosterone and cortisol and MR antagonist spironolactone to the ligand binding domain (LBD) of the MR. A molecular docking screen of compounds that were structurally similar to known antagonists was performed, leading to the identification of two novel compounds, C79 and E67. Molecular dynamics (MD) assessed the dynamic interactions with C79, E76, endogenous ligands, and spironolactone with the MR ligand binding domain (LBD). Analysis of the protein backbone showed modest changes in the overall structure of the MR LBD in response to binding of antagonists, with movement in helix 12 consistent with previous observations. All ligands tested maintained stable binding within the MR LBD throughout the simulations. Hydrogen bond formation played a more prominent role in the binding of endogenous ligands compared to antagonists. MM-PBSA binding free energy calculations showed that all ligands had similar binding affinities, with binding facilitated by key residues within the binding site. The novel antagonists demonstrated similar binding properties to spironolactone, warranting further evaluation. This study provides insights into the molecular mechanisms of MR activation and inhibition, which can aid in the development of novel therapeutic strategies for cardiovascular diseases. Full article

Diabetic nephropathy (DN), one of the most common complications of diabetes mellitus (DM), accounts for a major cause of chronic kidney disease (CKD) worldwide, with a complicated pathogenesis and limited effective strategies nowadays. The mineralocorticoid receptor (MR) is a classical ligand-activated nuclear transcription factor. It is expressed in the renal intrinsic and immune cells, especially macrophages. Over-activation of the MR was observed in patients with DN and was associated with DN prognosis. The renoprotective role of a new generation of non-steroidal selective mineralocorticoid receptor antagonist (MRA), finerenone, has been confirmed in DM and CKD patients. However, the mechanism by which finerenone improves renal inflammation in DN has yet to be completely understood. It was found in this research that the oral administration of finerenone attenuated the kidney injuries in established DN in db/db mice, and particularly improved the pathological changes in the renal tubulointerstitia. Specifically, finerenone inhibited the over-activation of the MR in macrophages, thereby reducing the expression of G protein subunit alpha i2 (GNAI2, Gnαi2), a key downstream component of the C5aR1 pathway. Animal experiments demonstrated that C5aR1 knockout alleviated renal injuries, confirming the critical pathogenic role of C5aR1 in DN. Moreover, finerenone mitigated inflammatory and chemotaxis responses by downregulating Gnαi2 in macrophages. These effects were reflected by reduced expressions of the pro-inflammatory chemokines CXCL15 and CCL2, the regulation of macrophage polarization and improvements in apoptosis. This study intends to understand the protective role of finerenone in DN, which is conducive to revealing the pathophysiological mechanism of DN and further optimizing the treatment of DN patients. Full article

Thrombosis is one of the most prevalent and serious health issues amongst humans. A key component of thrombotic events is the activation and aggregation of platelets, of which the P2Y₁ and P2Y₁₂ receptors play a crucial role in this process. Despite a breadth of knowledge on thrombosis and its mechanisms and treatment in various disorders in humans, there is less of an understanding of the expression and exact role of these receptors in companion animals such as dogs and cats. Therefore, this study aimed to investigate P2Y₁ and P2Y₁₂ receptors on dog and cat platelets in platelet-rich plasma and compare them to human platelets. Immunoblotting revealed the presence of P2Y₁ and P2Y₁₂ receptor proteins on dog and cat platelets, although relative amounts of each receptor appeared to contrast those of human platelets, with increased amounts of P2Y₁ compared to P2Y₁₂ receptors in dogs and cats. Using a modified 384-well plate aggregation assay, designed for use with small volumes, the human P2Y₁ and P2Y₁₂ receptor agonists adenosine 5′-diphosphate and 2-methylthio-adenosine 5′-diphosphate caused aggregation of dog and cat platelets. This aggregation was near-completely inhibited by the selective P2Y₁₂ antagonist ticagrelor. Aggregation of dog and cat platelets was partly inhibited by the human P2Y₁ receptor antagonist MRS2179. The agonist and antagonist responses in dog and cat platelets were like those of human platelets. In contrast, the aggregation of dog platelets in the absence of added nucleotides was two-fold greater than that of cats and humans. This study indicates that platelets of cats and dogs possess functional P2Y₁ and P2Y₁₂ receptors that can be inhibited by human antagonists. The data presented suggest differing roles or responses of the platelet P2Y receptors in dogs and cats compared to humans but also highlight the potential of using currently available P2Y₁ or P2Y₁₂ antiplatelet drugs such as ticagrelor for the treatment of thrombosis in these companion animals. Full article

Chronic kidney disease (CKD) is a major public health concern around the world. It is a significant risk factor for cardiovascular disease (CVD), and, as it progresses, the risk of cardiovascular events increases. Furthermore, end-stage kidney disease severely affects life expectancy and quality of life. Type 2 diabetes and hypertension are not only primary causes of CKD but also independent risk factors for CVD, which underscores the importance of effective treatment strategies for these conditions. The current therapies, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and sodium–glucose co-transporter 2 inhibitors, are administered to control hypertension, slow the progression of CKD, and reduce cardiovascular risk. However, their efficacy remains suboptimal in certain instances. Mineralocorticoid receptor (MR), a nuclear receptor found in various tissues, such as the kidney and heart, plays a pivotal role in the progression of CKD. Overactivation of MR triggers inflammation and fibrosis, which exacerbates kidney damage and accelerates disease progression. MR antagonists (MRAs) have substantial beneficial effects in patients with cardiac and renal conditions; however, their use has been constrained because of adverse effects, such as hyperkalemia and kidney dysfunction. Recently, novel non-steroidal MRAs are more efficacious and have superior safety profiles to steroidal MRAs, making them promising potential components of future treatment strategies. Here, we discuss recent findings and the roles of MRAs in the management of hypertension and CKD, with a focus on the evidence obtained from fundamental research and major clinical trials. Full article

Hypertension remains a global health challenge due to its high prevalence and association with premature morbidity and mortality. Aldosterone, a mineralocorticoid hormone, and its receptor, the mineralocorticoid receptor (MR), are highly implicated in hypertension pathogenesis. Aldosterone synthase is the sole enzyme responsible for producing aldosterone in humans. We established transgenic mice carrying the human aldosterone synthase gene (cyp11B2) and showed dramatically increased levels of aldosterone in female hemizygotes. High-salt diets persistently increased blood pressure in these mice, and salt-induced hypertension was significantly ameliorated by reducing aldosterone levels via an aldosterone synthase inhibitor or blocking MR via an MR inhibitor. Since both hypertension and hyperaldosteronism specifically induce chronic kidney disease, in this model, we demonstrated that chronic high-salt diets induced hypertension in this mouse line and resulted in kidney inflammation and injury. Both the aldosterone synthase inhibitor and the MR antagonist markedly blocked high-salt-diet-mediated kidney injury. Thus, this transgenic mouse line can be used to study the pathogenic mechanisms underlying aldosterone and its receptor and to screen therapeutic compounds for aldosterone-mediated hypertension and related complications, such as kidney disease, in humans. Full article

Ticagrelor, a reversible platelet P2Y₁₂ receptor antagonist, exerts various pleiotropic actions, some of which are at least partially mediated through adenosine. We studied the ticagrelor and adenosine effect on the angiogenic properties of progenitor CD34⁺-derived endothelial colony-forming cells (ECFCs). Angiogenesis studies were performed in vitro using capillary-like tube formation and spheroid-based angiogenesis assays. The effects of adenosine receptor antagonists, including DPCPX (A₁ antagonist), SCH58621 (A_2A antagonist), MRS1706 (A_2B inverse agonist and antagonist), MRS1220 (A₃ antagonist) and adenosine deaminase (ADA), were also investigated. Ticagrelor, adenosine, and their combination increased capillary-like tube formation and spheroid sprout formation by ECFCs in a dose-dependent manner. This effect was significantly reduced by SCH58621, MRS1706, and their combination, as well as by ADA. By contrast, DPCPX and MRS1220 did not exhibit any inhibitory effects. Similar results were obtained when mature human umbilical vein endothelial cells (HUVECs) were studied. These results show that ticagrelor stimulates angiogenesis by progenitor and mature endothelial cells in an adenosine-dependent pathway in which the adenosine receptors A_2A and A_2B play major roles. The significance of these results at the clinical level in patients with atherothrombotic events and treated with ticagrelor needs to be investigated. Full article

Hypertension (HTN) is a major contributor to kidney damage, leading to conditions such as nephrosclerosis and hypertensive nephropathy, significant causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). HTN is also a risk factor for stroke and coronary heart disease. Oxidative stress, inflammation, and activation of the renin–angiotensin–aldosterone system (RAAS) play critical roles in causing kidney injury in HTN. Genetic and environmental factors influence the susceptibility to hypertensive renal damage, with African American populations having a higher tendency due to genetic variants. Managing blood pressure (BP) effectively with treatments targeting RAAS activation, oxidative stress, and inflammation is crucial in preventing renal damage and the progression of HTN-related CKD and ESRD. Interactions between genetic and environmental factors impacting kidney function abnormalities are central to HTN development. Animal studies indicate that genetic factors significantly influence BP regulation. Anti-natriuretic mechanisms can reset the pressure–natriuresis relationship, requiring a higher BP to excrete sodium matched to intake. Activation of intrarenal angiotensin II receptors contributes to sodium retention and high BP. In HTN, the gut microbiome can affect BP by influencing energy metabolism and inflammatory pathways. Animal models, such as the spontaneously hypertensive rat and the chronic angiotensin II infusion model, mirror human essential hypertension and highlight the significance of the kidney in HTN pathogenesis. Overproduction of reactive oxygen species (ROS) plays a crucial role in the development and progression of HTN, impacting renal function and BP regulation. Targeting specific NADPH oxidase (NOX) isoforms to inhibit ROS production and enhance antioxidant mechanisms may improve renal structure and function while lowering blood pressure. Therapies like SGLT2 inhibitors and mineralocorticoid receptor antagonists have shown promise in reducing oxidative stress, inflammation, and RAAS activity, offering renal and antihypertensive protection in managing HTN and CKD. This review emphasizes the critical role of NOX in the development and progression of HTN, focusing on its impact on renal function and BP regulation. Effective BP management and targeting oxidative stress, inflammation, and RAAS activation, is crucial in preventing renal damage and the progression of HTN-related CKD and ESRD. Full article

Neuropathic pain (NPP) is a devastating and unbearable painful condition. As prevailing treatment strategies have failed to mitigate its complications, there remains a demand for effective therapies. Electroacupuncture (EA) has proved a potent remedial strategy in NPP management in humans and mammals. However, past studies have investigated the underlying mechanism of the analgesic effects of EA on NPP, focusing primarily on adenosine receptors in peripheral tissues. Herein, we elucidate the role of the adenosine (Adora-3) signaling pathway in mediating pain relief through EA in the central nervous system, which is obscure in the literature and needs exploration. Specific pathogen-free (SPF) male adult mice (C57BL/6 J) were utilized to investigate the effect of EA on adenosine metabolism (CD73, ADA) and its receptor activation (Adora-3), as potential mechanisms to mitigate NPP in the central nervous system. NPP was induced via spared nerve injury (SNI). EA treatment was administered seven times post-SNI surgery, and lumber (L4–L6) spinal cord was collected to determine the molecular expression of mRNA and protein levels. In the spinal cord of mice, following EA application, the expression results revealed that EA upregulated (p < 0.05) Adora-3 and CD73 by inhibiting ADA expression. In addition, EA triggered the release of adenosine (ADO), which modulated the nociceptive responses and enhanced neuronal activation. Meanwhile, the interplay between ADO levels and EA-induced antinociception, using an Adora-3 agonist and antagonist, showed that the Adora-3 agonist IB-MECA significantly increased (p < 0.05) nociceptive thresholds and expression levels. In contrast, the antagonist MRS1523 exacerbated neuropathic pain. Furthermore, an upregulated effect of EA on Adora-3 expression was inferred when the Adora-3 antagonist was administered, and the EA treatment increased the fluorescent intensity of Adora-3 in the spinal cord. Taken together, EA effectively modulates NPP by regulating the Adora-3 signaling pathway under induced pain conditions. These findings enhance our understanding of NPP management and offer potential avenues for innovative therapeutic interventions. Full article

The P2Y₆ receptor (P2Y₆R), a G_q-coupled receptor, is a potential drug discovery target for various inflammatory and degenerative conditions. Antagonists have been shown to attenuate colitis, acute lung injury, etc. In the search for competitive antagonists, we have investigated the SAR of 3-nitro-2-(trifluoromethyl)-2H-chromene derivatives, although high affinity is lacking. We now reveal that long-chain amino-functionalized congeners display greatly enhanced affinity in the antagonism of UDP-induced Ca²⁺ mobilization in human (h) P2Y₆R-transfected 1321N1 astrocytoma cells. A 6-(Boc-amino-n-heptylethynyl) analogue 30 (MRS4940) had an IC₅₀ of 162 nM, which was a 123-fold greater affinity than the corresponding unprotected primary alkylamine, 107-fold greater than the corresponding pivaloyl derivative 30, and 132-fold selective compared to the P2Y₁₄R. However, similar Boc-amino chains attached at the 8-position produced weak µM affinity. Thus, the P2Y₆R affinity depended on the chain length, attachment point, and terminal functionality. Off-target activities, at 45 sites, were tested for acylamino derivatives 20, 24, 26, 30, 31, and 37, which showed multiple interactions, particularly at the biogenic amine receptors. The more potent analogues may be suitable for evaluation in inflammation and cancer models, which will be performed in future studies. Full article

Many liqueurs, including spirits infused with botanicals, are crafted not only for their taste and flavor but also for potential medicinal benefits. However, the scientific evidence supporting their medicinal effects remains limited. This study aims to verify in vitro anticancer activity and bioactive compounds in shochu spirits infused with Cordyceps militaris, a Chinese medicine. The results revealed that a bioactive fraction was eluted from the spirit extract with 40% ethanol. The infusion time impacted the inhibitory effect of the spirit extract on the proliferation of colon cancer-derived cell line HCT-116 cells, and a 21-day infusion showed the strongest inhibitory effect. Furthermore, the spirit extract was separated into four fractions, A-D, by high-performance liquid chromatography (HPLC), and Fractions B, C, and D, but not A, exerted the effects of proliferation inhibition and apoptotic induction of HCT-116 cells and HL-60 cells. Furthermore, Fractions B, C, and D were, respectively, identified as adenosine, cordycepin, and N⁶-(2-hydroxyethyl)-adenosine (HEA) by comprehensive chemical analyses, including proton nuclear magnetic resonance (¹H-NMR), Fourier transform infrared spectroscopy (FT-IR), and electrospray ionization mass spectrometry (ESI-MS). To better understand the bioactivity mechanisms of cordycepin and HEA, the agonist and antagonist tests of the A3 adenosine receptor (A3AR) were performed. Cell viability was suppressed by cordycepin, and HEA was restored by the A3AR antagonist MR1523, suggesting that cordycepin and HEA possibly acted as agonists to activate A3ARs to inhibit cell proliferation. Molecular docking simulations revealed that both adenosine and cordycepin bound to the same pocket site of A3ARs, while HEA exhibited a different binding pattern, supporting a possible explanation for the difference in their bioactivity. Taken together, the present study demonstrated that cordycepin and HEA were major bioactive ingredients in Cordyceps militaries-infused sweet potato shochu spirits, which contributed to the in vitro anticancer activity. Full article