Association between CYP2C9 and VKORC1 genetic polymorphisms and efficacy and safety of warfarin in Chinese patients.

OBJECTIVES: Genetic variation has been a major contributor to interindividual variability of warfarin dosage requirement. The specific genetic factors contributing to warfarin bleeding complications are largely unknown, particularly in Chinese patients. In this study, 896 Chinese patients were enrolled to explore the effect of CYP2C9 and VKORC1 genetic variations on both the efficacy and safety of warfarin therapy. METHODS AND RESULTS: Univariate analyses unveiled significant associations between two specific single nucleotide polymorphisms rs1057910 in CYP2C9 and rs9923231 in VKORC1 and stable warfarin dosage ( P  < 0.001). Further, employing multivariate logistic regression analysis adjusted for age, sex and height, the investigation revealed that patients harboring at least one variant allele in CYP2C9 exhibited a heightened risk of bleeding events compared to those with the wild-type genotype (odds ratio = 2.16, P  = 0.04). Moreover, a meta-analysis conducted to consolidate findings confirmed the associations of both CYP2C9 (rs1057910) and VKORC1 (rs9923231) with stable warfarin dosage. Notably, CYP2C9 variant genotypes were significantly linked to an increased risk of hemorrhagic complications ( P  < 0.00001), VKORC1 did not demonstrate a similar association. CONCLUSION: The associations found between specific genetic variants and both stable warfarin dosage and bleeding risk might be the potential significance of gene detection in optimizing warfarin therapy for improving patient efficacy and safety.

Left ventricular global longitudinal strain using a novel fully automated method: A head-to-head comparison with a manual layer-specific strain and establishment of normal reference ranges.

BACKGROUND: A novel automated method for measuring left ventricular (LV) global longitudinal strain (GLS) along the endocardium has advantages in terms of its rapid application and excellent reproducibility. However, it remains unclear whether the available normal range for conventional GLS using the manual method is applicable to the automated GLS method. This study aimed to compare automated GLS head-to-head with manual layer-specific GLS, and to identify whether a specialized normal reference range for automated GLS is needed and explore the main determinants. METHODS: In total, 1683 healthy volunteers (men, 43%; age, 18-80 years) were prospectively enrolled from 55 collaborating laboratories. LV GLS was measured using both manual layer-specific and automated methods. RESULTS: Automated GLS was higher than endocardial, mid-myocardial, and epicardial GLS. Women had a higher automated GLS than men. GLS had no significant age dependency in men, but first increased and then decreased with age in women. Accordingly, sex- and age-specific normal ranges for automated GLS were proposed. Moreover, GLS appeared to have different burdens in relation to dominant determinants between the sexes. GLS in men showed no dominant determinants; however, GLS in women correlated with age, body mass index, and heart rate. CONCLUSIONS: Using the novel automated method, was LV GLS higher than when using the manual GLS method. The normal ranges of automated GLS stratified according to sex and age were provided, with dominant determinants showing sex disparities that require full consideration in clinical practice.

AT1R autoantibody promotes phenotypic transition of smooth muscle cells by activating AT1R-OAS2.

Phenotypic transition of vascular smooth muscle cells (VSMCs) is an early event in the onset and progression of several cardiovascular diseases. As an important mediator of the renin-angiotensin system (RAS), activation of the angiotensin II type 1 receptor (AT1R) induces phenotypic transition of VSMCs. AT1R autoantibodies (AT1-AAs), which are agonistic autoantibodies of AT1R, have been detected in the sera of patients with a variety of cardiovascular diseases associated with phenotypic transition. However, the effect of AT1-AA on phenotypic transition is currently unknown. In this study, AT1-AA-positive rat model was established by active immunization to detect markers of VSMCs phenotypic transition. The results showed that AT1-AA-positive rats showed phenotypic transition of VSMCs, which was evidenced by the decrease of contractile markers, while the increase of synthetic markers in the thoracic aorta. However, in AT1-AA-positive AT1R knockout rats, the phenotypic transition-related proteins were not altered. In vitro, after stimulating human aortic smooth muscle cells with AT1-AA for 48 h, 2'-5' oligoadenylate synthase 2 (OAS2) was identified as the key differentially expressed gene by RNA sequencing and bioinformatics analysis. Furthermore, high expression of OAS2 was found in aorta of AT1-AA-positive rats; knockdown of OAS2 by siRNA can reverse the phenotypic transition of VSMCs induced by AT1-AA. In summary, this study suggests that AT1-AA can promote phenotypic transition of VSMCs through AT1R-OAS2 pathway, and OAS2 might serve as a potential therapeutic target to prevent pathological phenotypic transition of smooth muscle cells.

Cascade-heterogated biphasic gel iontronics for electronic-to-multi-ionic signal transmission.

Currently, electronics and iontronics in abiotic-biotic systems can only use electrons and single-species ions as unitary signal carriers. Thus, a mechanism of gating transmission for multiple biosignals in such devices is needed to match and modulate complex aqueous-phase biological systems. Here we report the use of cascade-heterogated biphasic gel iontronics to achieve diverse electronic-to-multi-ionic signal transmission. The cascade-heterogated property determined the transfer free energy barriers experienced by ions and ionic hydration-dehydration states under an electric potential field, fundamentally enhancing the distinction of cross-interface transmission between different ions by several orders of magnitude. Such heterogated or chemical-heterogated iontronics with programmable features can be coupled with multi-ion cross-interface mobilities for hierarchical and selective cross-stage signal transmission. We expect that such iontronics would be ideal candidates for a variety of biotechnology applications.

Normal reference values for mitral annular plane systolic excursion by motion-mode and speckle tracking echocardiography: a prospective, multicentre, population-based study.

AIMS: Mitral annular plane systolic excursion (MAPSE) is a simple and reliable index for evaluating left ventricular (LV) systolic function, particularly in patients with poor image quality; however, the lack of reference values limits its widespread use. This study aimed to establish the normal ranges for MAPSE measured using motion-mode (M-mode) and two-dimensional speckle tracking echocardiography (2D-STE) and to explore its principal determinants. METHODS AND RESULTS: This multicentre, prospective, cross-sectional study included 1952 healthy participants [840 men (43%); age range, 18-80 years] from 55 centres. MAPSE was measured using M-mode echocardiography and 2D-STE. The results showed that women had a higher MAPSE than men and MAPSE decreased with age. The age- and sex-specific reference values for MAPSE were established for these two methods. Multiple linear regression analyses revealed that MAPSE on M-mode echocardiography correlated with age and MAPSE on 2D-STE with age, blood pressure (BP), heart rate, and LV volume. Moreover, MAPSE measured by 2D-STE correlated more strongly with global longitudinal strain compared with that measured using M-mode echocardiography. CONCLUSION: Normal MAPSE reference values were established based on age and sex. BP, heart rate, and LV volume are potential factors that influence MAPSE and should be considered in clinical practice. Normal values are useful for evaluating LV longitudinal systolic function, especially in patients with poor image quality, and may further facilitate the use of MAPSE in routine assessments.

High systemic immune-inflammation index is relevant to osteoporosis among middle-aged and older people: A cross-sectional study.

BACKGROUND: As one of novel inflammatory indexes proposed in recent years, systemic immune-inflammation index (SII) can comprehensively reflect the inflammatory and immune state of the body. This study aims to explore the relationship between SII and osteoporosis among middle-aged and older people. MATERIALS AND METHODS: Our study includes 20,497 individuals from National Health and Nutrition Examination Survey (NHANES) 2005-2008, and target study population are confined to people aged 45 years and above. SII is calculated as platelet count × neutrophil count/lymphocyte count. Multivariate logistic regression analysis is used to explore the link between SII and osteoporosis, and receiver operating characteristics curve is used to screen optimal cut-off value of SII for indicating the occurrence of osteoporosis. RESULTS: A total of 435 people with osteoporosis are screened among 4625 middle-aged and older people, and individuals in osteoporosis group have higher SII than those in nonosteoporosis group (p = .024). Logistic regression analysis indicates that with the enhancement of SII, prevalence of osteoporosis in each tertile category also increases (p < .001). This tendency is also not changed in univariate model (p < .001), as well as the adjustments for different parameters. Moreover, we also identify that SII of 530.09 is the optimal cut-off value for indicating the occurrence of osteoporosis among middle-aged and older people. CONCLUSIONS: This present NHANES-based study noticed that higher SII is positively linked to osteoporosis among middle-aged and older people, and SII should not exceed 530.09 for them to obtain a potentially lower risk of osteoporosis.

Gi/o GPCRs drive the formation of actin-rich tunneling nanotubes in cancer cells via a Gßγ/PKCα/FARP1/Cdc42 axis.

The functional association between stimulation of G-protein-coupled receptors (GPCRs) by eicosanoids and actin cytoskeleton reorganization remains largely unexplored. Using a model of human adrenocortical cancer cells, here we established that activation of the GPCR OXER1 by its natural agonist, the eicosanoid 5-oxo-eicosatetraenoic acid, leads to the formation of filopodia-like elongated projections connecting adjacent cells, known as tunneling nanotube (TNT)-like structures. This effect is reduced by pertussis toxin and GUE1654, a biased antagonist for the Gßγ pathway downstream of OXER1 activation. We also observed pertussis toxin-dependent TNT biogenesis in response to lysophosphatidic acid, indicative of a general response driven by Gi/o-coupled GPCRs. TNT generation by either 5-oxo-eicosatetraenoic acid or lysophosphatidic acid is partially dependent on the transactivation of the epidermal growth factor receptor and impaired by phosphoinositide 3-kinase inhibition. Subsequent signaling analysis reveals a strict requirement of phospholipase C ß3 and its downstream effector protein kinase Cα. Consistent with the established role of Rho small GTPases in the formation of actin-rich projecting structures, we identified the phosphoinositide 3-kinase-regulated guanine nucleotide exchange factor FARP1 as a GPCR effector essential for TNT formation, acting via Cdc42. Altogether, our study pioneers a link between Gi/o-coupled GPCRs and TNT development and sheds light into the intricate signaling pathways governing the generation of specialized actin-rich elongated structures in response to bioactive signaling lipids.

Astrocytic AT1R deficiency ameliorates Aß-induced cognitive deficits and synaptotoxicity through ß-arrestin2 signaling.

Alzheimer's disease (AD) seriously influences human health, and there is no effective treatment to prevent or cure AD. Recent studies have shown that angiotensin II type 1 receptor (AT1R) blockers significantly reduce the prevalence of AD, while the precise role and mechanism of AT1R in AD remain obscure. In this study, for the first time, we identified that astrocytic but not neuronal AT1R levels were significantly increased in AD model rats and found that astrocyte-specific knockout of AT1R significantly ameliorated amyloid ß (Aß)-induced cognitive deficits and synaptotoxicity. Pretreating astrocytes with an AT1R blocker also alleviated Aß-induced synaptotoxicity in the coculture system of hippocampal neurons and astrocytes. Moreover, AT1R could directly bind to Aß1-42 and activate the astrocytic ß-arrestin2 pathway in a biased manner, and biased inhibition of the astrocytic AT1R/ß-arrestin2 pathway relieved Aß-induced neurotoxicity. Furthermore, we demonstrated that astrocytic AT1R/ß-arrestin2 pathway-mediated synaptotoxicity was associated with the aggregation of autophagosomes, which triggered the disordered degradation of Aß. Our findings reveal a novel molecular mechanism of astrocytic AT1R in Aß-induced neurodegeneration and might contribute to establishing new targets for AD prevention and therapy.

Advances in the allostery of angiotensin II type 1 receptor.

Angiotensin II type 1 receptor (AT1R) is a promising therapeutic target for cardiovascular diseases. Compared with orthosteric ligands, allosteric modulators attract considerable attention for drug development due to their unique advantages of high selectivity and safety. However, no allosteric modulators of AT1R have been applied in clinical trials up to now. Except for the classical allosteric modulators of AT1R such as antibody, peptides and amino acids, cholesterol and biased allosteric modulators, there are non-classical allosteric modes including the ligand-independent allosteric mode, and allosteric mode of biased agonists and dimers. In addition, finding the allosteric pockets based on AT1R conformational change and interaction interface of dimers are the future of drug design. In this review, we summarize the different allosteric mode of AT1R, with a view to contribute to the development and utilization of drugs targeting AT1R allostery.

Molecular regulatory mechanisms of erythropoiesis and related diseases.

The metabolism of cells and blood circulation allow for the constant production and destruction of red blood cells. Erythrocyte formation allows red blood cells to regenerate, which is crucial for maintaining the equilibrium of the organism. Erythrocyte formation is a multi-step, intricate process with distinct structural and functional characteristics at each stage. Erythropoiesis is regulated by a number of signaling pathways; malfunctional regulatory mechanisms may result in disease and aberrant erythropoiesis. Therefore, this article focuses on a review of the erythroid formation process, related signaling pathways, and red blood cell lineage diseases.

Local therapy treatment conditions for oligometastatic non-small cell lung cancer.

Standard treatments for patients with metastatic non-small cell lung cancer (NSCLC) include palliative chemotherapy and radiotherapy, but with limited survival rates. With the development of improved immunotherapy and targeted therapy, NSCLC prognoses have significantly improved. In recent years, the concept of oligometastatic disease has been developed, with randomized trial data showing survival benefits from local ablation therapy (LAT) in patients with oligometastatic NSCLC (OM-NSCLC). LAT includes surgery, stereotactic ablation body radiation therapy, or thermal ablation, and is becoming an important treatment component for OM-NSCLC. However, controversy remains on specific management strategies for the condition. In this review, we gathered current randomized trial data to analyze prognostic factors affecting patient survival, and explored ideal treatment conditions for patients with OM-NSCLC with respect to long-term survival.

Novel compound heterozygous variants in the LHX3 gene caused combined pituitary hormone deficiency: A case report.

BACKGROUND: Combined pituitary hormone deficiency 3 (CPHD3; OMIM: 221750) is caused by mutations within the LHX3 gene (OMIM: 600577), which located on the subtelomeric region of chromosome 9 at band 9q34.3, has seven coding exons and six introns. LIM homeobox (LHX) 3 protein is the key regulator of pituitary development in fetal life. CASE SUMMARY: We have diagnosed and treate an 11-year-old boy with combined pituitary hormone deficiency (CPHD). The main clinical manifestations were pituitary hormone deficiency, hydrocele of the tunica vaginalis, pituitary dwarfism, gonadal dysplasia, micropenis, clonic convulsion, and mild facial dysmorphic features. We collected peripheral blood from the patient, the patient's older brother, as well as their parents, and sequenced them by using high-throughput whole-exosome sequencing, which was verified by Sanger sequencing. The results showed that there were two compound heterozygous variants of c.613G>C (p.V205L) and c.220T>C (p.C74R) in the LHX3 gene. c.613G>C (p.V205L) was inherited from his mother and c.220T>C (p.C74R) from his father. His brother also has both variants and symptoms. CONCLUSION: This study reported ununreported genetic mutations of LHX3, and recorded the treatment process of the patients, providing data for the diagnosis and treatment of CPHD.

Two novel mutations in the VPS33B gene in a Chinese patient with arthrogryposis, renal dysfunction and cholestasis syndrome 1: A case report.

BACKGROUND: The VPS33B (OMIM: 608552) gene is located on chromosome 15q26.1. We found a female infant with autosomal recessive arthrogryposis, renal dysfunction and cholestasis syndrome 1 (ARCS1) caused by mutation in VPS33B. The child was diagnosed with ARCS1 (OMIM: 208085) after the whole exome sequencing revealed two heterozygous mutations (c.96+1G>C, c.242delT) in the VPS33B gene. CASE SUMMARY: We report a Chinese female infant with neonatal cholestasis disorder, who was eventually diagnosed with ARCS1 by genetic analysis. Genetic testing revealed two new mutations (c.96+1G>C and c.242delT) in VPS33B, which is the causal gene. The patient was compound heterozygous, and her parents were both heterozygous. CONCLUSION: This study extends the mutational spectrum of the VPS33B gene to provide a molecular basis for the etiological diagnosis of ARCS1 and for genetic counseling of the family.

Case report: Heterogeneous mutations of SOX10 gene in a Chinese infant with Waardenburg syndrome type 4C.

A 5-month-old patient presented with grayish-blue iris bilaterally, skin and mucosal pigmentation loss, Hirschsprung's disease, full-blown growth retardation, and sensorineural deafness. The patient's whole exon gene sequencing revealed a spontaneous heterozygous code-shifting mutation in the SOX10 gene: c.803del:p.K268Sfs*18. The parents of the child were wild-type, and the site of the mutation is novel.

Gi-protein-coupled ß 1-adrenergic receptor: re-understanding the selectivity of ß 1-adrenergic receptor to G protein.

ß 1-adrenergic receptor (ß 1-AR), a member in the family of G-protein-coupled receptors, is a transmembrane receptor of great significance in the heart. Physiologically, catecholamines activate ß 1-AR to initiate a positive chronotropic, inotropic, and dromotropic change. It is believed that ß 1-AR couples to Gs protein and transmits the signal through second messenger cAMP. However, increasing research shows that ß 1-AR can also bind with Gi protein in addition to Gs. When ß 1-AR-Gi is biasedly activated, cardioprotective effects are introduced by the activated cGMP-protein kinase G (PKG) pathway and the transactivation of epidermal growth factor receptor (EGFR) pathway. The discovery of ß 1-AR-Gi signaling makes us reconsider the selectivity of G protein with regard to ß 1-AR, which also provides new ideas for the treatment of heart diseases. This review summarizes the discovery of ß 1-AR-Gi pathway, including the evidence that supports ß 1-AR's capability to couple Gi, details of the transduction process and functions of the ß 1-AR-Gi signaling pathway.

Macrophage polarization is involved in liver fibrosis induced by ß 1-adrenoceptor autoantibody.

Accumulating evidence suggests that liver injury can be induced by the over-expression of ß 1-adrenergic receptors (ß 1-ARs). High titers of autoantibodies specific to ß 1-adrenergic receptors (ß 1-AA) are detected in the sera of heart failure patients, potentially playing agonist-like roles. However, the role of ß 1-AA in liver function has not been characterized. In this study, we collect the sera of primary biliary cholangitis (PBC) patients, a condition which easily develops into liver fibrosis, and analyze the relationship between PBC and ß 1-AA. A passive immunization model is established to assess the effect of ß 1-AA on the liver. Subsequently, the effect of ß 1-AA on macrophages is investigated in vitro. Results show that PBC patients have a high titer and ratio of ß 1-AA, compared to controls. Liver injury and fibrosis are induced by ß 1-AA. In vitro experiments with ROS probe demonstrate that ß 1-AA induces macrophages to produce ROS and secrete TNFα. These effects can be partially reversed by metoprolol, a blocker for ß 1-AR. Results from the transwell and phagocytosis assays show that ß 1-AA promotes macrophage migration and phagocytosis. FCM tests suggest that ß 1-AA induces the alteration of M1 rather than M2 markers in macrophages. Finally, the Annexin V/PI assay indicates that macrophage culture supernatants stimulated by ß 1-AA cause hepatocyte apoptosis. Overall, these results suggest that ß 1-AA is involved in PBC. The ß 1-AA-induced activation, phagocytosis and phenotypic modification of macrophages may play an important role in the development of hepatic fibrosis and injury.

Clinical manifestations and gene analysis of Hutchinson-Gilford progeria syndrome: A case report.

BACKGROUND: This case report describes a child with Hutchinson-Gilford progeria syndrome (HGPS, OMIM: 176670) caused by LMNA (OMIM: 150330) gene mutation, and we have previously analyzed the clinical manifestations and imaging characteristics of this case. After 1-year treatment and follow-up, we focus on analyzing the changes in the clinical manifestations and genetic diagnosis of the patient. CASE SUMMARY: In April 2020, a 2-year-old boy with HGPS was found to have an abnormal appearance, and growth and development lagged behind those of children of the same age. The child's weight did not increase normally, the veins of the head were clearly visible, and he had shallow skin color and sparse yellow hair. Peripheral blood DNA samples obtained from the patient and his parents were sequenced using high-throughput whole-exosome sequencing, which was verified by Sanger sequencing. The results showed that there was a synonymous heterozygous mutation of C.1824 C>T (P. G608G) in the LMNA gene. CONCLUSION: Mutation of the LMNA gene provides a molecular basis for diagnosis of HGPS and genetic counseling of the family.

Prediction and verification of potential lead analgesic and antiarrhythmic components in Corydalis yanhusuo W. T. Wang based on voltage-gated sodium channel proteins.

Corydalis yanhusuo W. T. Wang, a traditional Chinese herbal medicine, has been used as an analgesic for thousands of years and it also promotes blood circulation. In this study, 33 Corydalis yanhusuo alkaloid active components were acquired from Traditional Chinese Medicine Database and Analysis Platform (TCMSP). A total of 543 pain-related targets, 1774 arrhythmia targets, and 642 potential targets of these active components were obtained using Swiss Target Prediction, GeneCards, Open Target Platform, and Therapeutic Target Database. Fifty intersecting targets were visualized through a Venn diagram, KEGG and GO pathway enrichment analysis. The analysis proposed that sodium ion channels are likely potential targets of Corydalis yanhusuo active components as analgesia and anti-arrhythmia agents. Molecular docking showed that the 33 components could bind to Nav1.7 and Nav1.5 (two subtypes of ion channel proteins) with different binding energies. In a patch clamp study, dihydrosanguinarine and dihydrochelerythrine, two monomers with the strongest binding effects, could inhibit the peak currents and promote both activation and inactivation phases of Nav1.5. Meanwhile, dihydrosanguinarine and dihydrochelerythrine could also inhibit peak currents and promote the activation phase of Nav1.7. Therefore, the findings from this study provide valuable information for future uses of traditional Chinese medicines to treat pain and cardiovascular disease.

QR code model: a new possibility for GPCR phosphorylation recognition.

G protein-coupled receptors (GPCRs) are the largest family of membrane proteins in the human body and are responsible for accurately transmitting extracellular information to cells. Arrestin is an important member of the GPCR signaling pathway. The main function of arrestin is to assist receptor desensitization, endocytosis and signal transduction. In these processes, the recognition and binding of arrestin to phosphorylated GPCRs is fundamental. However, the mechanism by which arrestin recognizes phosphorylated GPCRs is not fully understood. The GPCR phosphorylation recognition "bar code model" and "flute" model describe the basic process of receptor phosphorylation recognition in terms of receptor phosphorylation sites, arrestin structural changes and downstream signaling. These two models suggest that GPCR phosphorylation recognition is a process involving multiple factors. This process can be described by a "QR code" model in which ligands, GPCRs, G protein-coupled receptor kinase, arrestin, and phosphorylation sites work together to determine the biological functions of phosphorylated receptors. Video Abstract.

Efficacy of levetiracetam in the treatment of pediatric epilepsy: A protocol for systematic review and meta-analysis.

BACKGROUND: To systematically collect, critically evaluate, and synthesize current evidence with respect to the efficacy, safety, and tolerability of levetiracetam as mono- or adjunctive therapy for children and adolescents with all types of epilepsy. METHODS: The presentation of methods and results in this systematic review was performed according to the evaluation guidelines for health care interventions provided in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol. Literature retrieval will use the Cochrane Library, Web of Science, PubMed, Embase, Allied and Complementary Medicine Database, China Biomedical Literature Database, China National Knowledge Infrastructure, China Science and Technology Journal Database, Wanfang Database, and Ongoing Clinical Trials Database.The risk of bias of included studies is estimated by taking into consideration the characteristics including random sequence generation, allocation concealment, blinding of patients, blinding of outcome assessment, completeness of outcome data, selective reporting and other bias by Cochrane Collaboration's tool. Data synthesis and analyses are performed using RevMan 5.4 software. RESULTS: The results of this systematic review and meta-analysis will be published in a peer-reviewed journal. CONCLUSION: Levetiracetam seems to be effective and safe for the treatment of pediatric epilepsy.