Incorporating clinician insight and care plans into an audit and feedback initiative for antipsychotic prescribing to Medicaid-enrolled youth in Philadelphia.

BACKGROUND: Audit and feedback (A/F), which include initiatives like report cards, have an inconsistent impact on clinicians' prescribing behavior. This may be attributable to their focus on aggregate prescribing measures, a one-size-fits-all approach, and the fact that A/F initiatives rarely engage with the clinicians they target. METHODS: In this study, we describe the development and delivery of a report card that summarized antipsychotic prescribing to publicly-insured youth in Philadelphia, which was introduced by a Medicaid managed care organization in 2020. In addition to measuring aggregate prescribing behavior, the report card included different elements of care plans, including whether youth were receiving polypharmacy, proper medication management, and the concurrent use of behavioral health outpatient services. The A/F initiative elicited feedback from clinicians, which we refer to as an "audit and feedback loop." We also evaluate the impact of the report card by comparing pre-post differences in prescribing measures for clinicians who received the report card with a group of clinicians who did not receive the report card. RESULTS: Report cards indicated that many youth who were prescribed antipsychotics were not receiving proper medication management or using behavioral health outpatient services alongside the antipsychotic prescription, but that polypharmacy was rare. In their feedback, clinicians who received report cards cited several challenges related to antipsychotic prescribing, such as the logistical difficulties of entering lab orders and family members' hesitancy to change care plans. The impact of the report card was mixed: there was a modest reduction in the share of youth receiving polypharmacy following the receipt of the report card, while other measures did not change. However, we documented a large reduction in the number of youth with one or more antipsychotic prescription fill among clinicians who received a report card. CONCLUSIONS: A/F initiatives are a common approach to improving the quality of care, and often target specific practices such as antipsychotic prescribing. Report cards are a low-cost and feasible intervention but there is room for quality improvement, such as adding measures that track medication management or eliciting feedback from clinicians who receive report cards. To ensure that the benefits of antipsychotic prescribing outweigh its risks, it is important to promote quality and safety of antipsychotic prescribing within a broader care plan.

Exploration of the Polymorphism Distribution of Bovine HMGA2 Gene in Worldwide Breeds and Its Associations with Ovarian Traits.

The high-mobility group AT-hook 2(HMGA2) gene has been widely studied in the context of cancer and animal growth. However, recently, several studies have uncovered its critical role in cell proliferation. A genome-wide association study (GWAS) further suggests that the HMGA2 gene is a candidate gene in fertility, indicating its connection not only to growth traits but also to reproduction, specifically ovarian traits. Thus, this study aimed to analyze the distribution of the HMGA2 gene in 54 bovine breeds worldwide, identify important short fragment variants (indels), and investigate the relationship between HMGA2 and ovarian development. The dataset included genotypic information from a bovine population of 634 individuals (n = 634). After genotyping and analyzing four selected loci, we found that one out of four loci, rs133750033 (P4-D22-bp), was polymorphic. Our results also reveal that this indel of HMGA2 is significantly associated with certain ovarian traits (p < 0.05). Specifically, it has connection with ovarian length (p = 0.004) and ovarian height (p = 0.026) during diestrus. Additionally, we discovered a higher expression of the HMGA2 gene in Asian cattle breeds. In summary, this study suggests that HMGA2 has the potential to serve as an animal fertility testing marker gene. Moreover, these findings contribute to a more promising outlook for the bovine industry.

Bovine FRAS1: mRNA Expression Profile, Genetic Variations, and Significant Correlations with Ovarian Morphological Traits, Mature Follicle, and Corpus Luteum.

The amelioration of bovine fertility caused by a multi-factorial problem has always been a hot topic, among which the detection of available target genes is the most crucial. It was hypothesized that the Fraser extracellular matrix complex subunit 1 (FRAS1) gene detected by GWAS is involved in physiological activities such as ovarian development. Herein, unilateral ovaries from 2111 cows were used to examine the mRNA expression profile and polymorphisms of bovine FRAS1 and their associations with fertility-related characteristics. Firstly, it was confirmed that FRAS1 gene transcripts are expressed in various bovine tissues. Then, among five potential insertion-deletion (indel) loci, the 20 bp (named P3-D20-bp) and 15 bp (P4-D15-bp) deletion mutations were confirmed to be polymorphic with linkage equilibrium. Secondly, the P3-D20-bp polymorphism was significantly associated with ovarian weight and corpus luteum diameter in the metaestrus phase and ovarian length in the dioestrum stage. Additionally, both ovarian length and mature follicle diameter in metaestrus are significantly correlated with different genotypes of P4-D15-bp. Thirdly, the transcriptional expression of the FRAS1 gene in groups with a minimum value of ovarian weight or volume was significantly higher than the expression in groups with a maximum value. Instead of that, the more corpus luteum and mature follicles there are, the higher the transcription expression of the FRAS1 gene is. Furthermore, FRAS1 expression in cows with a heterozygous genotype (ID) of P3-D20-bp was significantly higher than others. Eventually, P3-D20-bp deletion could disturb the binding efficiency of WT1-I and Sox2 to FRAS1 sequence according to binding prediction, indicating that mutation may affect gene expression and traits by influencing the binding of transcription factors. Overall, the polymorphisms of P3-D20-bp and P4-D15-bp of the bovine FRAS1 gene significantly correlated to follicle or ovarian traits that could be applied in optimizing female fertility in cow MAS breeding programs.

Ligand recognition and G-protein coupling of trace amine receptor TAAR1.

Trace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis1. They recognize diverse endogenous trace amines and subsequently activate a range of G-protein-subtype signalling pathways2,3. Notably, TAAR1 has emerged as a promising therapeutic target for treating psychiatric disorders4,5. However, the molecular mechanisms underlying its ability to recognize different ligands remain largely unclear. Here we present nine cryo-electron microscopy structures, with eight showing human and mouse TAAR1 in a complex with an array of ligands, including the endogenous 3-iodothyronamine, two antipsychotic agents, the psychoactive drug amphetamine and two identified catecholamine agonists, and one showing 5-HT1AR in a complex with an antipsychotic agent. These structures reveal a rigid consensus binding motif in TAAR1 that binds to endogenous trace amine stimuli and two extended binding pockets that accommodate diverse chemotypes. Combined with mutational analysis, functional assays and molecular dynamic simulations, we elucidate the structural basis of drug polypharmacology and identify the species-specific differences between human and mouse TAAR1. Our study provides insights into the mechanism of ligand recognition and G-protein selectivity by TAAR1, which may help in the discovery of ligands or therapeutic strategies for neurological and metabolic disorders.

Understanding the "individual drug reaction" from the perspective of the interaction between probiotics and lovastatin in vitro and in vivo.

BACKGROUND: The existence of the gut microbiota produces an "individual drug reaction." As members of the intestinal microbiota, probiotics, although they have prebiotic functions, may accelerate the degradation of drugs, thereby affecting drug efficacy. Lovastatin is one of the well-recognized lipid-lowering drugs. Its main action site is the liver. Therefore, if it is degraded in advance by gastrointestinal probiotics, its efficacy may be reduced. RESULTS: Here, we designed a two-stage experiment in vitro and in vivo to explore the degradation of lovastatin by probiotics. In vitro, the degradation of lovastatin by 83 strains of Lactiplantibacillus plantarum and the "star strain" Lacticaseibacillus paracasei strain Shirota was investigated by high-performance liquid chromatography (HPLC). The results showed that probiotics could degrade lovastatin to varying degrees. Subsequently, we selected Lactiplantibacillus plantarum A5 (16.87%) with the strongest ability to degrade lovastatin, Lactiplantibacillus plantarum C3 (4.61%) with the weakest ability to degrade lovastatin and Lacticaseibacillus paracasei strain Shirota (17.6%) as representative probiotics for in vivo experiments. In vivo, the therapeutic effect of lovastatin combined with probiotics on golden hamsters with mixed hyperlipidemia was evaluated by measuring blood indicators, intestinal microbiota metagenomic sequencing, and the liver transcriptome. The results showed that the intake of probiotics did not affect the efficacy of lovastatin and could slow the inflammatory reaction of the liver. CONCLUSIONS: The supplementation of probiotics produced beneficial metabolites in the intestine by promoting beneficial microbes. Intestinal metabolites affected the expression of the liver genes through the gut-liver axis, increased the relative content of the essential amino acids, and finally improved the liver inflammatory response of the host. This study aims to reveal the impact of probiotics on the human body from a unique perspective, suggesting the impact of taking probiotics while taking drugs. Video Abstract.

Building an Integrated Data Infrastructure to Examine the Spectrum of Suicide Risk Factors in Philadelphia Medicaid.

While there are many data-driven approaches to identifying individuals at risk of suicide, they tend to focus on clinical risk factors, such as previous psychiatric hospitalizations, and rarely include risk factors that occur in nonclinical settings, such as jails or emergency shelters. A better understanding of system-level encounters by individuals at risk of suicide could help inform suicide prevention efforts. In Philadelphia, we built a community-level data infrastructure that encompassed suicide death records, behavioral health claims, incarceration episodes, emergency housing episodes, and involuntary commitment petitions to examine a broader spectrum of suicide risk factors. Here, we describe the development of the data infrastructure, present key trends in suicide deaths in Philadelphia, and, for the Medicaid-eligible population, determine whether suicide decedents were more likely to interact with the behavioral health, carceral, and housing service systems compared to Medicaid-eligible Philadelphians who did not die by suicide. Between 2003 and 2018, there was an increase in the number of annual suicide deaths among Medicaid-eligible individuals, in part due to changes in Medicaid eligibility. There were disproportionately more suicide deaths among Black and Hispanic individuals who were Medicaid-eligible, who were younger on average, compared to suicide decedents who were never Medicaid-eligible. However, when we accounted for the racial and ethnic composition of the Medicaid population at large, we found that White individuals were four times as likely to die by suicide, while Asian, Black, Hispanic, and individuals of other races were less likely to die by suicide. Overall, 58% of individuals who were Medicaid-eligible and died by suicide had at least one Medicaid-funded behavioral health claim, 10% had at least one emergency housing episode, 25% had at least one incarceration episode, and 22% had at least one involuntary commitment. By developing a data infrastructure that can incorporate a broader spectrum of risk factors for suicide, we demonstrate how communities can harness administrative data to inform suicide prevention efforts. Our findings point to the need for suicide prevention in nonclinical settings such as jails and emergency shelters, and demonstrate important trends in suicide deaths in the Medicaid population.

High-efficiency broadband achromatic metalenses for visible full-stokes polarization imaging.

Polarization-imaging technology has important applications in target detection, communication, biomedicine, and other fields. A polarization imaging system based on metalenses, which provides new possibilities for the realization of highly integrated full-Stokes polarization imaging systems, can solve the problems of traditional polarization imaging systems, such as complex structures, large volumes, and the inability to simultaneously obtain linear and circular polarization states. However, currently designed metalens arrays that can achieve real-time full-Stokes polarization imaging can generally only be used for monochromatic detection, which significantly limits the amount of measured information of the object. Broad-spectrum polarization color imaging allows more image degrees of freedom, enabling more accurate characterization of polarization for multi-target object scenes in complex environments. To achieve broad-spectrum polarization imaging, we propose and design a metalens array that can achieve full-Stokes polarization imaging in the broadband visible range, in which the design process of metalenses for splitting and focusing broadband orthogonal circularly polarized light is emphasized. To design metalenses that can achieve polarization splitting and efficient focusing, we simulate and optimize the height and period of the nano-units and show that smaller periods and larger heights do not always result in higher-performance devices when designing multifunctional metalenses. The designed metalens array can split and diffraction-limited focus the orthogonal polarized incident light to the designated position with average focusing efficiencies of 59.2% under 460-680 nm TM linearly polarized light, 53.1% under TE linearly polarized light, 58.8% under left-handed circularly polarized light, and 52.7% under right-handed circularly polarized light. The designed metalenses can be applied to imaging systems, such as polarization imaging and polarization light-field imaging systems.

LINC00426, a novel m6A-regulated long non-coding RNA, induces EMT in cervical cancer by binding to ZEB1.

PURPOSE: To explore the function and molecular mechanism of LINC00426 in Cervical Cancer (CC), and to explore the clinical treatment strategy of LINC00426 for CC. METHODS: Bioinformatics analysis was used to explore the expression of LINC00426 and patient prognosis of CC. Cell function experiments were conducted to explore the potential effect of LINC00426 on CC malignant phenotypes. The difference in m6A modification level between the high and low expression groups of LINC00426 was analyzed by detecting the total m6A level. The luciferase reporter assay was used to confirm the binding of miR-200a-3p to LINC00426. The RIP assay was used to confirm the binding of LINC00426 to ZEB1. Cell viability assay was performed to detect the effect of LINC00426 on cellular drug resistance. RESULTS: LINC00426 is up-regulated in CC, which can enhance the proliferation, migration and invasion of CC cells. METTL3 promotes the expression of LINC00426 by m6A methylation modification. In addition, the LINC00426/miR-200a-3p/ZEB1 axis affects the proliferation, migration, and invasion of CC by regulating the expression of EMT markers. Through the detection of cell viability, we observed that overexpression LINC00426 in cells resulted in resistance to cisplatin and bleomycin, and more sensitive to imatinib. CONCLUSION: LINC00426 is a cancer-promoting lncRNA related to m6A modification. The process of EMT in CC is regulated by the LINC00426/miR-200a/3p/ZEB1 axis. LINC00426 can affect the sensitivity of CC cells to chemotherapy drugs, and is expected to become a therapeutic target for CC.

Association of lactate-to-albumin ratio with in-hospital and intensive care unit mortality in patients with intracerebral hemorrhage.

Background: Intracerebral hemorrhage (ICH) is a severe stroke subtype with a high mortality rate; the lactate-to-albumin ratio (LAR) is a new biomarker for predicting clinical outcomes in patients with ICH. However, the relationship between LAR and mortality in patients with ICH treated in the intensive care unit (ICU) remains controversial. Therefore, in this study, we aimed to investigate the association between LAR and in-hospital and ICU mortality in patients with ICH. Methods: Patients with ICH were selected from the Medical Information Mart for Intensive Care III (MIMIC-III) database; their clinical information, including baseline characteristics, vital signs, comorbidities, laboratory test results, and scoring systems, was extracted. Univariate and multivariate Cox proportional hazards analyses were used to investigate the association of LAR with in-hospital and ICU mortality. The maximum selection statistical method and subgroup analysis were used to investigate these relationships further. Kaplan-Meier (KM) analysis was used to draw survival curves. Results: This study enrolled 237 patients with ICH whose lactate and albumin levels, with median values of 1.975 and 3.6 mg/dl, respectively, were measured within the first 24 h after ICU admission. LAR had an association with increased risk of in-hospital mortality [unadjusted hazards ratio (HR), 1.79; 95% confidence interval (CI), 1.32-2.42; p < 0.001] and ICU mortality (unadjusted HR, 1.88; 95% CI, 1.38-2.55; p < 0.001). A cut-off value of 0.963 mg/dl was used to classify patients into high LAR (≥0.963) and low LAR (<0.963) groups, and survival curves suggested that those two groups had significant survival differences (p = 0.0058 and 0.0048, respectively). Furthermore, the high LAR group with ICH had a significantly increased risk of in-hospital and ICU mortality compared to the low LAR group. Conclusion: Our study suggests that a high LAR is associated with an increased risk of in-hospital and ICU mortality in patients with ICH. Thus, the LAR is a useful prognostic predictor of clinical outcomes in patients with ICH.

Post-transcriptional regulation of tumor suppressor gene lncRNA CARMN via m6A modification and miRNA regulation in cervical cancer.

PURPOSE: The abnormal regulation of lncRNA CARMN has been proved to be a tumor suppressor gene of cervical cancer (CC). However, its role in CC is still elusive. The regulation of CARMN post-transcriptional level by m6A modification and miRNA has not been studied. This study aims to analyze the molecular mechanism of m6A modification and miRNA on the abnormal expression of CARMN in CC cells, so as to provide a new theoretical basis for the diagnosis and treatment of CC. METHODS: MeRIP-seq was used to identify the differential m6A-modified genes between tumor and normal cervical tissues. RT-qPCR assay was used to detect gene expression levels in tissues or cells. The m6A modification sites of CARMN was predicted by bioinformatics, and the modification of m6A and its regulatory effect on CARMN were analyzed by MeRIP-qPCR, Actinomycin D assay and RIP assay. RIP-microarray combined with bioinformatics methods to screen miRNAs that may target CARMN. The regulation mechanism between miRNA and CARMN was verified by RT-qPCR, nucleo-plasmic separation assay, mRNA stability assay, dual-luciferase reporter assay, and in vivo experiments. RESULTS: MeRIP-seq found that CARMN is a significant different gene in the abundance of m6A in CC, and the modification level of m6A in CC tissues was higher than that in normal cervical tissues. Further, this study verified that m6A reader YTHDF2 could recognize m6A-modified CARMN and promote its degradation in CC cells. miR-21-5p was proved to be the downstream target gene of CARMN, and miR-21-5p could negatively regulate the expression of CARMN. Further experiments showed that miR-21-5p could directly bind to CARMN and lead to the degradation of CARMN. The in vivo experimental results indicated that the level of miR-21-5p in the overexpressed CARMN group was significantly lower than that in the control group. CONCLUSION: m6A modification and miR-21-5p play important roles in promoting the occurrence and development of tumors by regulating CARMN, provide new potential targets for the treatment of CC.

A characteristic bacterial SERS marker for direct identification of Salmonella in real samples assisted by a high-performance SERS chip and a selective culture medium.

Salmonella should be absent in pharmaceutical preparations and foods according to the regulations. However, up to now, rapid and convenient identification of Salmonella is still full of challenge. Herein, we reported a label-free surface-enhanced Raman scattering (SERS) method for direct identification of Salmonella spiked in drug samples based on a characteristic bacterial SERS marker assisted by a high-performance SERS chip and a selective culture medium. The SERS chip being fabricated through in situ growth of bimetallic Au-Ag nanocomposites on silicon wafer within 2 h, featured a high SERS activity (EF > 107), good uniformity and batch-to-batch consistency (RSD < 10 %), and satisfactory chemical stability. The directly-visualized SERS marker at 1222 cm-1 originated from bacterial metabolite hypoxanthine was robust and exclusive for discrimination of Salmonella with other bacterial species. Moreover, the method was successfully used for direct discrimination of Salmonella in mixed pathogens by using a selective culture medium, and could identify Salmonella contaminant at ∼1 CFU spiked level in a real sample (Wenxin granule, a botanical drug) after 12 h of enrichment. The combined results showed that developed SERS method is practical and reliable, and could be a promising alternative for rapid identification of Salmonella contamination in pharmaceutical and foods industries.

An improved UAV target detection algorithm based on ASFF-YOLOv5s.

Object detection in drone-captured scenarios is a recent popular task. Due to the high flight altitude of unmanned aerial vehicle (UAV), the large variation of target scales, and the existence of dense occlusion of targets, in addition to the high requirements for real-time detection. To solve the above problems, we propose a real-time UAV small target detection algorithm based on improved ASFF-YOLOv5s. Based on the original YOLOv5s algorithm, the new shallow feature map is passed into the feature fusion network through multi-scale feature fusion to improve the extraction capability for small target features, and the Adaptively Spatial Feature Fusion (ASFF) is improved to improve the multi-scale information fusion capability. To obtain anchor frames for the VisDrone2021 dataset, we improve the K-means algorithm to obtain four different scales of anchor frames on each prediction layer. The Convolutional Block Attention Module (CBAM) is added in front of the backbone network and each prediction network layer to improve the capture capability of important features and suppress redundant features. Finally, to address the shortcomings of the original GIoU loss function, the SIoU loss function is used to accelerate the convergence of the model and improve accuracy. Extensive experiments conducted on the dataset VisDrone2021 show that the proposed model can detect a wide range of small targets in various challenging environments. At a detection rate of 70.4 FPS, the proposed model obtained a precision value of 32.55%, F1-score of 39.62%, and a mAP value of 38.03%, which improved 2.77, 3.98, and 5.1%, respectively, compared with the original algorithm, for the detection performance of small targets and to meet the task of real-time detection of UAV aerial images. The current work provides an effective method for real-time detection of small targets in UAV aerial photography in complex scenes, and can be extended to detect pedestrians, cars, etc. in urban security surveillance.

Immune-Related Genes' Prognostic, Therapeutic and Diagnostic Value in Ovarian Cancer Immune-Related Gene Biomarker in Ovarian Cancer.

OBJECTIVES: The abnormal expression of immune-related genes (IRGs) plays an important role in the occurrence and progression of ovarian cancer (OC), which is the main cause of mortality among gynecological cancer patients. This study aims to establish a prognostic risk model and comprehensively analyze the relationship between OC risk score and prognosis, immune cell infiltration (ICI) and therapeutic sensitivity in OC. METHODS: We retrospectively evaluated the clinicopathological characteristics of consecutive OC patients in the Cancer Genome Atlas (TCGA) database. First, the prognostic risk model was constructed by bioinformatics methods. And then, we systematically assessed model robustness, and correlations between risk score and prognosis, and immune cell infiltration. The ICGC cohort was used to verify the prognostic risk model. Finally, we evaluated their value in the treatment of OC immunotherapy and chemotherapy. RESULTS: A total of 10 IRGs were identified to construct the prognostic risk model. Survival analysis revealed that patients in the low-risk group had a better prognosis (P < .01), and the risk score might be considered an independent predictor for predicting the prognosis. In addition, risk scores and patient clinical information were used to construct clinical nomograms, improving the prediction's precision. We also explored the relationship between the risk score and ICI, immunotherapy and drug sensitivity. CONCLUSIONS: Collectively, we identified a novel ten IRGs signature that may be applied as a prognostic predictor of OC, thereby benefiting clinical decision-making and personalized treatment of patients.

Lacticaseibacillus rhamnosus Probio-M9 enhanced the antitumor response to anti-PD-1 therapy by modulating intestinal metabolites.

BACKGROUND: Probiotics have been increasingly proposed for enhancing immune checkpoint blockade (ICB) treatments against cancer. However, its causal relationship with immunotherapeutic efficacy remains unclear, which promoted us to explore if and how probiotic Lacticaseibacillus rhamnosus Probio-M9 manipulates gut microbiome for expected outcomes. METHODS: We evaluated the effects of Probio-M9 on the anti-PD-1 treatment against colorectal cancer in mice via a multi-omics approach. We defined the mechanisms of Probio-M9-mediated antitumor immunity by comprehensive analyses of metagenome and metabolites of commensal gut microbes as well as the immunologic factors and serum metabolome of the host. FINDINGS: The results indicated that Probio-M9 intervention strengthened the anti-PD-1-based tumor inhibition. Both prophylactic and therapeutic administration of Probio-M9 showed conspicuous performance in controlling tumor growth with ICB treatment. The supplement of Probio-M9 modulated enhanced immunotherapy response through promoting beneficial microbes (e.g., Lactobacillus and Bifidobacterium animalis), producing beneficial metabolites including butyric acids in the gut, and accumulating blood-derived α-ketoglutaric acid, N-acetyl-l-glutamic acid and pyridoxine in particular, which promoted the infiltration and activation of cytotoxic T lymphocytes (CTLs) and suppressing the function of regulatory T cells (Tregs) in the tumor microenvironment (TME). Subsequently, we found that enhanced immunotherapeutic response was transmissible by transplanting either post-probiotic-treatment gut microbes or intestinal metabolites to new tumor-bearing mice. INTERPRETATION: This study offered valuable insight into the causal role of Probio-M9 in correcting the defects in gut microbiota that compromised anti-PD-1 therapeutic efficacy, which can be used as an alternative synergetic agent with ICB for clinical cancer treatment. FUNDING: This research was supported by Research Fund for the National Key R&D Program of China (2022YFD2100702), Inner Mongolia Science and Technology Major Projects (2021ZD0014), and China Agriculture Research System of MOF and MARA.

Allosteric modulation of G protein-coupled receptor signaling.

G protein-coupled receptors (GPCRs), the largest family of transmembrane proteins, regulate a wide array of physiological processes in response to extracellular signals. Although these receptors have proven to be the most successful class of drug targets, their complicated signal transduction pathways (including different effector G proteins and ß-arrestins) and mediation by orthosteric ligands often cause difficulties for drug development, such as on- or off-target effects. Interestingly, identification of ligands that engage allosteric binding sites, which are different from classic orthosteric sites, can promote pathway-specific effects in cooperation with orthosteric ligands. Such pharmacological properties of allosteric modulators offer new strategies to design safer GPCR-targeted therapeutics for various diseases. Here, we explore recent structural studies of GPCRs bound to allosteric modulators. Our inspection of all GPCR families reveals recognition mechanisms of allosteric regulation. More importantly, this review highlights the diversity of allosteric sites and presents how allosteric modulators control specific GPCR pathways to provide opportunities for the development of new valuable agents.

Costunolide Protects Myocardium From Ischemia Reperfusion Injury by Inhibiting Oxidative Stress Through Nrf2/Keap1 Pathway Activation.

ABSTRACT: Costunolide (Cos) is a naturally occurring sesquiterpene lactone that exhibits antioxidative properties. In this study, we demonstrate the protective mechanism of Cos against ischemia/reperfusion (I/R)-induced myocardial injury. Cos significantly decreased levels of reactive oxygen species and ameliorated apoptosis of I/R cardiomyocytes both in vitro and in vivo. Further investigation revealed that Cos increased expression of the antioxidant proteins HO-1 and NQO-1 and decreased the Bax/Bcl-2 ratio, thus protecting cardiac cells. NF-E2-related factor 2 (Nrf2) silencing significantly attenuated the protective effects of Cos in tert-butyl hydroperoxide (TBHP)-treated H9C2 cells. Additionally, Cos significantly intensified the I/R- or TBHP-induced dissociation of the Kelch-like ECH-associated protein 1 (Keap1)/Nrf2 complex both in vitro and in vivo. These results suggest that activation of Nrf2/Keap1 using Cos may be a therapeutic strategy for myocardial I/R injury.

Structural insights into the recognition of telomeric variant repeat TTGGGG by broad-complex, tramtrack and bric-à-brac - zinc finger protein ZBTB10.

Multiple proteins bind to telomeric DNA and are important for the role of telomeres in genome stability. A recent study established a broad-complex, tramtrack and bric-à-brac - zinc finger (BTB-ZF) protein, ZBTB10 (zinc finger and BTB domain-containing protein 10), as a telomeric variant repeat-binding protein at telomeres that use an alternative method for lengthening telomeres). ZBTB10 specifically interacts with the double-stranded telomeric variant repeat sequence TTGGGG by employing its tandem C2H2 zinc fingers (ZF1-2). Here, we solved the crystal structure of human ZBTB10 ZF1-2 in complex with a double-stranded DNA duplex containing the sequence TTGGGG to assess the molecular details of this interaction. Combined with calorimetric analysis, we identified the vital residues in TTGGGG recognition and determined the specific recognition mechanisms that are different from those of TZAP (telomere zinc finger-associated protein), a recently defined telomeric DNA-binding protein. Following these studies, we further identified a single amino-acid mutant (Arg767Gln) of ZBTB10 ZF1-2 that shows a preference for the telomeric DNA repeat TTAGGG sequence. We solved the cocrystal structure, providing a structural basis for telomeric DNA recognition by C2H2 ZF proteins.

Leonurine attenuates angiotensin II-induced cardiac injury and dysfunction via inhibiting MAPK and NF-κB pathway.

BACKGROUND: Hypertension is a common risk factor for heart failure, and excessive angiotensin II (Ang II) leads to hypertensive cardiac alterations such as hypertrophy, cardiac fibrosis, remodeling, and dysfunction. Leonurine is the major active alkaloid compound obtained from the traditional Chinese herbal medicine, Leonurus japonicus Houtt. The effects of leonurine on Ang II-induced hypertensive cardiac injury remain unknown. HYPOTHESIS/PURPOSE: In the present study, we investigated the cardioprotective effects of leonurine in Ang II-infused mice and explored the underlying mechanisms in cardiomyocytes. METHODS: Cardiac injury was induced by Ang II infusion in experimental mice with or without leonurine (at 10 or 20 mg/kg) treatment. H9c2 cells and neonatal rat primary cardiomyocytes were used to investigate the mechanisms through which leonurine exerts its protection effects. RESULTS: The results showed that leonurine significantly alleviated Ang II-induced cardiac hypertrophy, fibrosis, and inflammation in both mice and cultured cardiomyocytes. Echocardiography revealed that leonurine preserved cardiac function in mice. Further investigations revealed that leonurine inhibited the activation of the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways to reduce inflammatory response and injuries in Ang II-challenged cardiomyocytes. Inhibition of MAPKs and NF-κB in cardiomyocytes abolished the anti-inflammatory effects of leonurine. CONCLUSIONS: Our study provides evidence that leonurine exerts protective effects against Ang II-induced hypertensive cardiac remodeling and dysfunction by inhibiting the MAPK and NF-κB pathways. Leonurine may be a promising agent for treating hypertensive heart failure.