Search Results (82)

β-adrenoreceptor (ADRB) ligands are actively used in the therapy of bronchopulmonary and cardiovascular diseases. When using these drugs, it is important to assess changes in ADRB content in different tissues. In most cases, the direct measurement of ADRB content in lung and heart cells is not possible. ADRB2 content in peripheral blood lymphocytes (or mononuclear cells) was shown to correlate with that in myocardial cells. It has been suggested that blood lymphocytes can be used to monitor ADRB content in solid organs. However, the estimation of ADRB1 content in myocardium from its content in peripheral lymphocytes is not possible due to the low content of ADRB1 in lymphocytes. In the present study, we performed simultaneous determination of ADRB1 and ADRB2 both in the total population of PBMCs and in isolated subpopulations of monocytes, T-lymphocytes, and NK-cells from 23 healthy donors using the modified radioligand method. The highest amount of ADRB2 was detected in NK cells, followed by PBMCs, monocytes, and T cells. The content of these receptors in all blood cell subpopulations was significantly correlated with each other, suggesting the possibility of using PBMCs to monitor ADRB2 in solid organs. For the first time, ADRB1 was detected in monocytes and NK cells. Full article

This study looked into the underlying mechanisms and causal relationship between alcoholic liver disease (ALD) and the blood metabolite uridine using a variety of analytical methods, such as Mendelian randomization and molecular dynamics simulations. We discovered uridine to be a possible hepatotoxic agent aggravating ALD by using Mendelian randomization (MR) analysis with genome-wide association study (GWAS) data from 1416 ALD cases and 217,376 controls, as well as with 1091 blood metabolites and 309 metabolite concentration ratios as exposure factors. According to network toxicology analysis, uridine interacts with important targets such as SRC, FYN, LYN, ADRB2, and GSK3B. The single-cell RNA sequencing analysis of ALD tissues revealed that SRC was upregulated in hepatocytes and activated hepatic stellate cells. Subsequently, we determined the stable binding between uridine and SRC through molecular docking and molecular dynamics simulation (RMSD = 1.5 ± 0.3 Å, binding energy < −5.0 kcal/mol). These targets were connected to tyrosine kinase activity, metabolic reprogramming, and GPCR signaling by Gene Ontology (GO) and KEGG studies. These findings elucidate uridine’s role in ALD progression via immunometabolic pathways, offering novel therapeutic targets for precision intervention. These findings highlight the necessity of systems biology frameworks in drug safety evaluation, particularly for metabolites with dual therapeutic and toxicological roles. Full article

Background: The treatment and management of atrial fibrillation poses substantial complexity. A delicate balance in the trade-off between the minimising risk of stroke without increasing the risk of bleeding through anticoagulant optimisations. Natural compounds are often associated with low-toxicity effects, and their effects on atrial fibrillation have yet to be fully understood. Whilst deep learning (a subtype of machine learning that uses multiple layers of artificial neural networks) methods may be useful for drug compound interaction and discovery analysis, graphical processing units (GPUs) are expensive and often required for deep learning. Furthermore, in limited-resource settings, such as low- and middle-income countries, such technology may not be easily available. Objectives: This study aims to discover the presence of any new therapeutic candidates from a large set of natural compounds that may support the future treatment and management of atrial fibrillation anywhere using a low-cost technique. The objective is to develop a deep learning approach under a low-resource setting where suitable high-performance NVIDIA graphics processing units (GPUs) are not available and to apply to atrial fibrillation as a case study. Methods: The primary training dataset is the MINER-DTI dataset from the BIOSNAP collection. It includes 13,741 DTI pairs from DrugBank, 4510 drug compounds, and 2181 protein targets. Deep cross-modal attention modelling was developed and applied. The Database of Useful Decoys (DUD-E) was used to fine-tune the model using contrastive learning. This application and evaluation of the model were performed on the natural compound NPASS 2018 dataset as well as a dataset curated by a clinical pharmacist and a clinical scientist. Results: the new model showed good performance when compared to existing state-of-the-art approaches under low-resource settings in both the validation set (PR AUC: 0.8118 vs. 0.7154) and test set (PR AUC: 0.8134 vs. 0.7206). Tenascin-C (TNC; NPC306696) and deferoxamine (NPC262615) were identified as strong natural compound interactors of the arrhythmogenic targets ADRB1 and HCN1, respectively. A strong natural compound interactor of the bleeding-related target Factor X was also identified as sequoiaflavone (NPC194593). Conclusions: This study presented a new high-performing model under low-resource settings that identified new natural therapeutic candidates for pharmacological cardioversion and anticoagulation. Full article

Obesity is defined as abnormal or excessive accumulation of body fat and contributes to several metabolic disorders. White adipose tissue (WAT) releases energy as free fatty acids and glycerol from triglycerides through a process called lipolysis. People with obesity have impaired catecholamine-stimulated lipolysis, but comprehensive understanding of this lipolysis is still unclear. We previously showed that expression of WW domain-containing E3 ubiquitin ligase 1 (WWP1), a member of the HECT-type E3 family of ubiquitin ligases, was increased in WAT of obese mice. In this study, we generated Wwp1 knockout (KO) mice to evaluate the effect of WWP1 in WAT of obese mice. The mRNA levels of beta-3 adrenergic receptor (Adrb3), which were decreased with a high-fat diet, were increased by Wwp1 KO in WAT. Moreover, Wwp1 KO mice showed increased phosphorylated hormone-sensitive lipase levels in WAT. In contrast, noradrenaline and its metabolism were not altered in WAT of obese Wwp1 KO mice. These findings indicate that WWP1, which is increased in adipocytes because of obesity, is a candidate for suppressing lipolysis independently of noradrenaline metabolism. We anticipate that inhibition of WWP1 is a promising approach for a new treatment of obesity and type-2 diabetes using Adrb3 agonists. Full article

Pain management in children remains a challenge. Postoperative pain assessment, which currently relies on behavioral and subjective scales, could be enhanced by the identification of single nucleotide polymorphisms effect on pain thresholds and opioid metabolism. This study explores the impact of nine SNPs—rs1799971, rs4680, rs4633, rs6269, rs4818 (with catechol-o-methyltransferase haplotypes), rs7832704, rs1801253, and rs1045642—on postoperative pain intensity, opioid requirements, coanalgesic use, C-reactive protein levels, and post-anesthesia care unit length of stay. This study involved 42 pediatric patients undergoing scoliosis correction surgery with postoperative sufentanil infusion. The genotyping was performed using real-time PCR with peripheral blood samples. Patients with the rs1801253 ADRB1 GG genotype showed significantly lower 24 h NRS pain ratings (p = 0.032) and lower sufentanil infusion rates at the level of statistical tendency (p = 0.093). Patients with the rs1205 CRP CT genotype had a shorter PACU length of stay (p = 0.012). In contrast, those with the rs1045642 ABCB1 GG genotype had a longer PACU stay by 0.72 h (p = 0.046). No significant associations were found for OPRM1 rs1799971, COMT, or ENPP2 SNPs. ADRB1 rs1801253may be a novel SNP indicating higher postoperative pain risk, while rs1205 CRP and rs1045642 ABCB1 could predict increased care requirements in PACUs. The ADRB1 rs1801253 SNP may also predict opioid demand. These results suggest SNPs should be considered in acute pain assessment. Full article

Background/Objectives: A systematic review was conducted to compile all the evidence on the impact of ADRB1 and ADRB2 genetic variants on the response to β-blockers, used for the management of cardiovascular diseases. Methods: After searching in PubMed, PharmGKB, and the Cochrane Central Register of Controlled Trials including terms related to these drugs, genes, and pathologies, 1182 articles were retrieved, 29 of which met the inclusion criteria. A β-adrenoreceptor (ADRB) blockade qualitative variable was inferred for all the associations between genetic variants and clinical phenotypes. Results: The relationship between ADRB1 rs1801253 (G>C) C allele and higher receptor blockade showed a moderate overall level of evidence, reaching a high level on its relationship with higher reduction in the systolic (SBP) and diastolic blood pressure and heart rate (HR). The relationship between ADRB1 rs1801252 (A>G) G allele and lower receptor blockade reached an overall high level of evidence, considering its impact on the reduction in the SBP, HR, left ventricular end-diastolic diameter, and incidence of major cardiovascular events. The relationship between ADRB2 rs1042714 (G>C) C allele and lower receptor blockade reached a moderate overall level of evidence due to its impact on HR, pulmonary wedge pressure, and left ventricular ejection fraction response. The ADRB2 rs1042713 (G>A) A allele was associated with higher receptor blockade and higher HR reduction with a low level of evidence. Conclusions: The genotyping of both ADRB1 variants may be clinically useful; further investigation is required on the relevance of both ADRB2 variants. Further research is warranted to determine the clinical usefulness of ADRB preemptive genotyping. Full article

Background/Objectives: To analyze the genotype that predicts the phenotypic characteristics of a cohort of patients with glaucoma and ocular hypertension (OHT) and explore their influence on the response to ocular hypotensive treatment. Methods: This was a prospective study that included 193 eyes of 109 patients with glaucoma or OHT under monotherapy with beta-blockers, prostaglandin, or prostamide analogues (BBs, PGAs, PDs). Eight single-nucleotide polymorphisms were genotyped using real-time PCR assays: prostaglandin-F2α receptor (PTGFR) (rs3766355, rs3753380); beta-2-adrenergic receptor (ADRB2) (rs1042714); and cytochrome P450 2D6 (CYP2D6) (*2 rs16947; *35 rs769258; *4 rs3892097; *9 rs5030656, and *41 rs28371725). The main variables studied were baseline (bIOP), treated (tIOP), and rate of variation in intraocular pressure (vIOP), and mean deviation of the visual field (MD). The metabolizer phenotype and the CYP2D6 copy number variation were also evaluated. Results: In total, 112 eyes were treated with PGAs (58.0%), 59 with BBs (30.6%), and 22 with PDs (11.4%). For PTGFR (rs3753380), statistically significant differences were observed in vIOP in the PGA group (p = 0.032). Differences were also observed for ADRB2 (rs1042714) in MD (p < 0.001) and vIOP (p = 0.017). For CYP2D6, ultrarapid metabolizers exhibited higher tIOP (p = 0.010) and lower vIOP (p = 0.046) compared to the intermediate and poor metabolizers of the BB group. Additionally, systemic treatment metabolized by CYP2D6 showed a significant influence on vIOP (p = 0.019) in this group. Conclusions: These preliminary findings suggest the future potential of pharmacogenetic-based treatments in glaucoma to achieve personalized treatment for each patient, and thus optimal clinical management. Full article

Adrenergic receptors (AR) play a vital role in cardiovascular system regulation. The ADRB2 gene, encoding the β2-AR receptor, has genetic variability potentially impacting blood pressure (BP) regulation. Evidence for such associations has been inconsistent. This study investigates the relationship between two ADRB2 polymorphisms (rs1042713, Gly16Arg, and rs1042714, Glu27Gln) and BP changes during the cold pressor test (CPT) in young, healthy men, including combat athletes. The study included two groups: combat athletes and non-athlete students. BP (systolic, SBP; diastolic, DBP) was measured at rest and at pain tolerance during CPT. Genetic analysis was conducted for rs1042713 and rs1042714 polymorphisms. Athletes had higher SBP and DBP than students, with both values increasing during pain tolerance compared to rest. Differences in BP responses during CPT were genotype-dependent. Students with the Gly16Gly16 genotype had significantly higher SBP than Arg16 allele carriers, while this variation was not observed in athletes. Athletes with the Glu27 allele exhibited higher SBP than 27Gln homozygotes, unlike students. Gly16 and Glu27 alleles are linked to elevated stress-induced BP responses in young Polish men. However, BP regulation involves multiple genetic and environmental factors not explored in this study. Full article

G-protein coupled receptors (GPCRs), the largest family of integral membrane proteins, enable cells to sense and appropriately respond to the environment through mediating extracellular signaling to intercellular messenger molecules. GPCRs’ pairing with a diverse array of G protein subunits and related downstream secondary messengers, combined with their ligand versatility-from conventional peptide hormone to numerous bioactive metabolites, allow GPCRs to comprehensively regulate metabolism and physiology. Consequently, GPCRs have garnered significant attention for their therapeutic potential in metabolic diseases. This review focuses on six GPCRs, GPR40, GPR120, GLP-1R, and ß-adrenergic receptors (ADRB1, ADRB2, and ADRB3), with GLP-1R recognized as a prominent regulator of system-level metabolism, while the roles of GPR40, GPR120 and ß-adrenergic receptors in central carbon metabolism and energy homeostasis are increasingly appreciated. Here, we discuss their physiological functions in metabolism, the current pharmacological landscape, and the intricacies of their signaling pathways via G protein and ß-arrestin activation. Additionally, we discuss the limitations of existing GPCR-targeted strategies for treating metabolic diseases and offer insights into future perspectives for advancing GPCR pharmacology. Full article

Omega-3 (ω-3) polyunsaturated fatty acids in fish oil have been shown to prevent diet-induced obesity in lean mice and to promote heat production in adipose tissue. However, the effects of fish oil on obese animals remain unclear. This study investigated the effects of fish oil in obese mice. C57BL/6J mice were fed a lard-based high-fat diet (LD) for 8 weeks and then assigned to either a fish oil-based high-fat diet (FOD) or continued the LD for additional 8 weeks. A control group was fed a standard diet for 16 weeks. Mice fed the FOD showed weight loss, reduced adipose tissue mass, and lower plasma insulin and leptin levels compared to those fed the LD. Rectal temperatures were higher in the FOD and LD groups compared to the control group. Energy intake was lower in the FOD group than the LD group but similar to the control group. The FOD and LD groups exhibited increased expression of heat-producing genes such as Ppargc1a, Ucp1, Adrb3, and Ppara in brown adipose tissue but not in white adipose tissue. The FOD reduced food consumption and increased rectal temperature and heat-producing genes in brown adipose tissue. Fish oil may therefore be a potential therapeutic approach to obesity. Full article

Osteoporosis is characterized by increased resorption and decreased bone formation; it is predominantly influenced by genetic factors. G-protein coupled receptors (GPCRs) play a vital role in bone homeostasis, and mutations in these genes are associated with osteoporosis. This study aimed to investigate the impact of single nucleotide polymorphism (SNP) rs1042713 in the ADRB2 gene, encoding the beta-2-adrenergic receptor, on osteoblastogenesis. Herein, using quantitative polymerase chain reaction, western immunoblotting, immunofluorescence assays, and flow cytometry, we examined the expression of ADRB2 and markers of bone matrix synthesis in mesenchymal stem cells (MSCs) derived from osteoporosis patient (OP-MSCs) carrying ADRB2 SNP in comparison with MSCs from healthy donor (HD-MSCs). The results showed significantly reduced ADRB2 expression in OP-MSCs at both the mRNA and protein levels, alongside decreased type 1 collagen expression, a key bone matrix component. Notably, OP-MSCs exhibited increased ERK kinase expression during differentiation, indicating sustained cell cycle progression, unlike that going to HD-MSC. These results provide novel insights into the association of ADRB2 gene polymorphisms with osteogenic differentiation. The preserved proliferative activity of OP-MSCs with rs1042713 in ADRB2 contributes to their inability to undergo effective osteogenic differentiation. This research suggests that targeting genetic factors may offer new therapeutic strategies to mitigate osteoporosis progression. Full article

G-protein-coupled receptors (GPCRs) have emerged as critical regulators of bone development and remodeling. In this study, we aimed to identify specific GPCR mutations in osteoporotic patients via next-generation sequencing (NGS). We performed NGS sequencing of six genomic DNA samples taken from osteoporotic patients and two genomic DNA samples from healthy donors. Next, we searched for single-nucleotide polymorphisms (SNPs) in GPCR genes that are associated with osteoporosis. For three osteoporotic patients and one healthy donor, bone biopsies were used to generate patient-specific mesenchymal stem cell (MSC) lines, and their ability to undergo osteodifferentiation was analyzed. We found that MSCs derived from osteoporotic patients have a different response to osteoinductive factors and impaired osteogenic differentiation using qPCR and histochemical staining assays. The NGS analysis revealed specific combinations of SNPs in GPCR genes in these patients, where SNPs in ADRB2 (rs1042713), GIPR (rs1800437), CNR2 (rs2501431, rs3003336), and WLS (rs3762371) were associated with impaired osteogenic differentiation capacity. By integrating NGS data with functional assessments of patient-specific cell lines, we linked GPCR mutations to impaired bone formation, providing a foundation for developing personalized therapeutic strategies. SNP analysis is recognized as a proactive approach to osteoporosis management, enabling earlier interventions and targeted preventive measures for individuals at risk. Furthermore, SNP analysis contributes to the development of robust, holistic risk prediction models that enhance the accuracy of risk assessments across the population. This integration of genetic data into public health strategies facilitates healthcare initiatives. This approach could guide treatment decisions tailored to the patient’s genetic profile and provide a foundation for developing personalized therapeutic strategies. Full article

This narrative review explores the relationship between genetics and elite endurance athletes, summarizes the current literature, highlights some novel findings, and provides a physiological basis for understanding the mechanistic effects of genetics in sport. Key genetic markers include ACTN3 R577X (muscle fiber composition), ACE I/D (cardiovascular efficiency), and polymorphisms in PPARA, VEGFA, and ADRB2, influencing energy metabolism, angiogenesis, and cardiovascular function. This review underscores the benefits of a multi-omics approach to better understand the complex interactions between genetic polymorphisms and physiological traits. It also addresses long-standing issues such as small sample sizes in studies and the heterogeneity in heritability estimates influenced by factors like sex. Understanding the mechanistic relationship between genetics and endurance performance can lead to personalized training strategies, injury prevention, and improved health outcomes. Future studies should focus on standardized classification of sports, replication studies involving diverse populations, and establishing solid physiological associations between polymorphisms and endurance traits to advance the field of sports genetics. Full article

Background: Etoricoxib is a widely used anti-inflammatory drug, but its safety profile concerning cardiovascular and renal health remains inadequately explored. This study aimed to assess the nephro- and cardiotoxic effects of etoricoxib in a murine model, with a focus on its impact on arachidonic acid-metabolizing enzymes and beta-adrenergic receptors associated with drug-induced toxicity. Methods: Thirty-five BALB/C mice were randomly assigned to five groups: control, low-dose etoricoxib, high-dose etoricoxib, low-dose celecoxib, and high-dose celecoxib (a well-known nephro- and cardiotoxic NSAID). The treatments were administered for 28 days, after which hearts and kidneys were excised for physical and histopathological analysis, and the expression of arachidonic acid-metabolizing enzymes (cytochrome P450s, lipoxygenases, cyclooxygenases) and beta-1 adrenergic receptor (adrb1) and angiotensin-converting enzyme (ace2) genes were quantified using quantitative reverse transcription PCR (qRT-PCR). Results: Etoricoxib administration resulted in dose-dependent nephro- and cardiotoxic effects. Renal histology revealed glomerular atrophy or hypertrophy and significant damage to the proximal and distal convoluted tubules, including epithelial flattening, cytoplasmic vacuolation, and luminal widening. Cardiac analysis showed disorganized muscle fibers and hyaline degeneration. These changes were associated with altered gene expression: the downregulation of cox2, cyp1a1, and cyp2c29 in the kidneys and the upregulation of cyp4a12, cox2, and adrb1, along with the downregulation of cyp2c29 and ace2 in the heart. Conclusions: Etoricoxib induces nephro- and cardiotoxicity, marked by alterations in arachidonic acid metabolism and beta-adrenergic signaling pathways. The drug affects the expression of arachidonic acid-metabolizing enzymes and adrb1 in the heart while downregulating cox2 and other related enzymes in the kidneys. These findings underscore the need for caution when prescribing etoricoxib, particularly in patients with pre-existing renal or cardiac conditions. Full article

Background: Obesity is a pressing public health issue in Malaysia, involving not only excess weight but also complex metabolic and physiological changes. Addressing these complexities requires comprehensive strategies, including understanding the population-level differences in obesity susceptibility. This review aims to compile the genetic variants studied among Malaysians and emphasize their implications for obesity risk. Methods: Relevant articles published up to March 2024 were extracted from the Scopus, PubMed, and ScienceDirect databases. The review process was conducted in accordance with the PRISMA-ScR guidelines. From an initial pool of 579 articles, 35 of these were selected for the final review. Results: The identified gene variants, including LEPR (K656N), LEP (G2548A—Indian only), ADIPOQ (rs17366568), UCP2 (45bp-I/D), ADRB3 (rs4994), MC3R (rs3827103), PPARγ (pro12Ala—Malay only), IL1RA (intron 2 VNTR), NFKB1 (rs28362491), and FADS1 (rs174547—Indian only), showed significant associations with obesity as measured by the respective studies. Conclusions: Overall, more intensive genetic research is needed, starting with population-based profiling of genetic data on obesity, including among children. Sociocultural contexts and environmental factors influence variations in genetic elements, highlighting the need for targeted interventions to mitigate the impacts of obesity in the population. Full article