DDID: a comprehensive resource for visualization and analysis of diet-drug interactions.

Diet-drug interactions (DDIs) are pivotal in drug discovery and pharmacovigilance. DDIs can modify the systemic bioavailability/pharmacokinetics of drugs, posing a threat to public health and patient safety. Therefore, it is crucial to establish a platform to reveal the correlation between diets and drugs. Accordingly, we have established a publicly accessible online platform, known as Diet-Drug Interactions Database (DDID, https://bddg.hznu.edu.cn/ddid/), to systematically detail the correlation and corresponding mechanisms of DDIs. The platform comprises 1338 foods/herbs, encompassing flora and fauna, alongside 1516 widely used drugs and 23 950 interaction records. All interactions are meticulously scrutinized and segmented into five categories, thereby resulting in evaluations (positive, negative, no effect, harmful and possible). Besides, cross-linkages between foods/herbs, drugs and other databases are furnished. In conclusion, DDID is a useful resource for comprehending the correlation between foods, herbs and drugs and holds a promise to enhance drug utilization and research on drug combinations.

Association of Overweight and Inflammatory Indicators with Breast Cancer: A Cross-Sectional Study in Chinese Women.

Objective: This cross-sectional study aimed to explore the association of overweight and inflammatory indicators with breast cancer risk in Chinese patients. Methods: Weight, height, and peripheral blood inflammatory indicators, including white blood cell count (WBC), neutrophil count (NE), lymphocyte count (LY), platelet count (PLT) and the concentration of hypersensitivity C-reactive protein (hsCRP), were collected in 383 patients with benign breast lumps (non-cancer) and 358 patients with malignant breast tumors (cancer) at the First Affiliated Hospital of Soochow University, China, from March 2018 to July 2020. Body mass index (BMI), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) were determined according to the ratio equation. The correlations among overweight, inflammatory indicators, and the proportion of non-cancer or cancer cases were analyzed. Results: BMI is associated with an increased breast cancer risk. Compared with non-cancer patients, the average WBC count, NE count, NLR, and level of hsCRP were significantly higher in cancer patients. The level of hsCRP was closely associated with the size of malignant breast tumors. Conclusion: We conclude that overweight and high levels of hsCRP may serve as putative risk factors for malignant breast tumors in Chinese women.

Analysis of care-seeking and diagnosis delay among pulmonary tuberculosis patients in Beijing, China.

Background: Tuberculosis (TB) remains a significant public health challenge in China. Early detection and diagnosis of TB cases are crucial to interrupt disease transmission and prevent its progression. This study aims to describe the delay in seeking care and diagnosis among patients with pulmonary tuberculosis (PTB) and identify the influencing factors in two counties in Beijing. Methods: A retrospective analysis was carried out to investigate care-seeking and diagnosis delay in two counties in Beijing. Basic information of PTB patients from January 1 to December 31, 2021, was extracted from the Tuberculosis Information Management System of China (TBIMS), and all enrolled patients were interviewed via telephone using a standard questionnaire. Statistical description was performed using the median and interquartile range (IQR). Chi-square test and multivariate logistic regression model were used to analyze the influencing factors. Results: 537 patients were enrolled. The median duration of care-seeking and diagnosis delay was 11 (IQR: 5-26) days and 8 (IQR: 0-18) days, with 41.71 and 35.20% of patients experiencing delays (>14 days). The study found that being asymptomatic (OR = 2.791, 95%CI: 1.710-4.555) before seeking medical care and not attending work during treatment (OR = 2.990, 95%CI: 1.419-6.298) were identified as risk factors for care-seeking delay. Patients who were tracked (OR = 2.632, 95%CI: 1.062-6.521) and diagnosed at tuberculosis control and prevention institutions (OR = 1.843, 95%CI: 1.061-3.202) had higher odds of diagnostic delays. 44.69% of patients presented a total delay (>28 days), with a median duration of 25 (IQR: 13-39) days. A multivariate logistic regression analysis showed that healthy examination (OR = 0.136, 95%CI: 0.043-0.425) was a protective factor for total delay. Conclusion: Public interventions are necessary to improve the efficiency of PTB patients detection and treatment in Beijing. Medical services should focus on the target population and improve access to medical care to further reduce delays for PTB patients.

Two-dimensional speckle-tracking echocardiography in left ventricular systolic function in patients with systemic lupus erythematosus.

OBJECTIVES: To investigate whether two-dimensional speckle-tracking echocardiography (2DSTE) can be considered a criterion for early left ventricular (LV) systolic impairment in patients with systemic lupus erythematosus (SLE) and to further explore the association with each other. METHODS: We included 38 patients with SLE and assessed the degree of disease activity according to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) 2000 scoring criteria, together with 38 healthy controls who were matched by sex and age. Routine LV systolic function evaluation parameters were obtained by echocardiography as well as 2DSTE measurement of LV strain parameters to obtain global longitudinal strain (GLS) values, respectively. RESULTS: (I) On routine LV function parameters such as ejection fractions (EF) and left ventricular end-diastolic internal diameter (LVIDd), the SLE group and the control group did not reflect differences. In contrast, on the LV strain parameter obtained from 2DSTE measurements, the GLS values in all cardiac planes were lower in the SLE group than in the control group and showed statistically significant differences. (II) Correlation analysis showed that there was a correlation between SLEDAI and GLS, especially a meaningful correlation with GLS Avg and GLS A4C, with correlation coefficients of 0.35 and 0.47, respectively. CONCLUSIONS: The use of 2DSTE can detect early impaired LV systolic function in SLE patients, and GLS is progressively gaining attention as an indicator of subclinical myocardial injury and LV function in SLE patients. The correlation that exists between GLS and SLEDAI might contribute to a better assessment of cardiac involvement in SLE patients. Key Points • Cardiac involvement has become one of the major factors in the poor prognosis of SLE patients, which directly affects the mortality of SLE patients. Traditional echocardiography is difficult to detect early left ventricular function impairment, thus affecting clinicians' judgment and diagnosis. • 2DSTE can recognize subclinical myocardial injury in SLE patients at an early stage, and its derived strain parameters may be used as an indicator to evaluate myocardial involvement and reflect disease activity in SLE patients.

Development and evaluation of genomics informed real-time PCR assays for the detection and strain typing of Mycobacterium avium subsp. paratuberculosis.

AIMS: This study aimed to identify specific genomic targets for the detection and strain typing of Map and analyse their sensitivity and specificity, and detect Map directly from faeces. METHODS AND RESULTS: A comparative genomics approach was used to identify specific genomic targets for the detection and strain typing of Map. A Map specific qPCR using the primer pair 7132 that targets a DNA segregation ATPase protein was able to detect all strains of Map and is more sensitive than the current Johne's disease PCR assays with a sensitivity of 0.0002 fg µl-1. A strain specific qPCR using the Atsa primer pair that targets the arylsulfase gene was able to differentiate between Type S and Type C strains of Map and was more sensitive than the IS1311 PCR and REA with a sensitivity of 40 fg µl-1 and was specific for Type S Map. Both assays successfully detected Map directly from faeces. CONCLUSION: This study developed and validated two genomics informed qPCR assays, 7132B Map and Atsa Type S and found both assays to be highly specific and sensitive for the detection of Map from culture and directly from faeces. This is the first time that a probe-based qPCR has been designed and developed for Map strain typing, which will greatly improve the response time during outbreak investigations.

Severity of COVID-19 infection in patients with COVID-19 combined with diabetes.

PURPOSE: This study aimed to analyse the correlation between blood glucose control and the severity of COVID-19 infection in patients with diabetes. METHODS: Clinical and imaging data of a total of 146 patients with diabetes combined with COVID-19 who visited our hospital between December 2022 and January 2023 were retrospectively collected. The patients were divided into the 'good blood glucose control' group and the 'poor blood glucose control' group based on an assessment of their blood glucose control. The clinical data, computed tomography (CT) appearance and score and the severity of COVID-19 infection of the two groups were compared, with the severity of COVID-19 infection being the dependent variable to analyse other influencing factors. RESULTS: The group with poor blood glucose control showed a higher lobar involvement degree and total CT severity score (CTSS) than the group with good blood glucose control (13.30 ± 5.25 vs. 10.38 ± 4.84, p < 0.05). The two groups exhibited no statistically significant differences in blood lymphocyte, leukocyte, C-reaction protein, pleural effusion, consolidation, ground glass opacity or crazy-paving signs. Logistic regression analysis showed that the total CTSS significantly influences the clinical severity of patients (odds ratio 1.585, p < 0.05), whereas fasting plasma glucose and blood glucose control are not independent factors influencing clinical severity (both p > 0.05). The area under the curve (AUC) of CTSS prediction of critical COVID-19 was 0.895 with sensitivity of 79.3% and specificity of 88.1% when the threshold value is 12. CONCLUSION: Blood glucose control is significantly correlated with the CTSS; the higher the blood glucose is, the more severe the lung manifestation. The CTSS can also be used to evaluate and predict the clinical severity of COVID-19.

The ameliorative effect on chemotherapy-induced injury and tumor immunosuppressive microenvironment of the polysaccharide from the rhizome of Menispermum dauricum DC.

Combined medication has attracted increasing attention as an important treatment option for tumors due to the serious adverse effects of chemotherapy. In this study, as a new therapy strategy, a combination treatment of MDP (a polysaccharide from the rhizome of Menispermum dauricum DC.) with cyclophosphamide (CTX) was investigated. The results showed that combination treatment with MDP and CTX exerted a significantly synergistic anti-tumor effect in Lewis tumor-bearing mice, improved CTX-induced emaciation and hair loss, as well as increased the number of leukocytes, erythrocytes, hemoglobin, and platelets in the peripheral blood. In addition, compared with CTX alone, the thymus index and spleen index of the MDP + CTX group were increased, the number of CD3 + T cells, CD8 + T cells, white blood cells and B cells in spleen also increased significantly. MDP could also ameliorate the increase in liver and kidney index caused by CTX. In the Lewis lung cancer model, MDP showed a certain degree of anti-tumor effects, which may be related to its promotion of tumor-associated macrophages (TAMs) to M1 phenotype polarisation, enhancement of the number of T cells in tumor tissues and promotion of Th cells in tumor tissues to Th1 phenotype polarisation, thus alleviating the immunosuppressive microenvironment in tumor tissues. This study laid the foundation for the development of MDP as a polysaccharide drug for the treatment or adjuvant therapy of tumors and has important significance for the further clinical application of polysaccharides.

Silent information regulator sirtuin 1 ameliorates acute liver failure via the p53/glutathione peroxidase 4/gasdermin D axis.

BACKGROUND: Acute liver failure (ALF) has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis. The silent information regulator sirtuin 1 (SIRT1)-mediated deacetylation affects multiple biological processes, including cellular senescence, apoptosis, sugar and lipid metabolism, oxidative stress, and inflammation. AIM: To investigate the association between ferroptosis and pyroptosis and the upstream regulatory mechanisms. METHODS: This study included 30 patients with ALF and 30 healthy individuals who underwent serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) testing. C57BL/6 mice were also intraperitoneally pretreated with SIRT1, p53, or glutathione peroxidase 4 (GPX4) inducers and inhibitors and injected with lipopolysaccharide (LPS)/D-galactosamine (D-GalN) to induce ALF. Gasdermin D (GSDMD)-/- mice were used as an experimental group. Histological changes in liver tissue were monitored by hematoxylin and eosin staining. ALT, AST, glutathione, reactive oxygen species, and iron levels were measured using commercial kits. Ferroptosis- and pyroptosis-related protein and mRNA expression was detected by western blot and quantitative real-time polymerase chain reaction. SIRT1, p53, and GSDMD were assessed by immunofluorescence analysis. RESULTS: Serum AST and ALT levels were elevated in patients with ALF. SIRT1, solute carrier family 7a member 11 (SLC7A11), and GPX4 protein expression was decreased and acetylated p5, p53, GSDMD, and acyl-CoA synthetase long-chain family member 4 (ACSL4) protein levels were elevated in human ALF liver tissue. In the p53 and ferroptosis inhibitor-treated and GSDMD-/- groups, serum interleukin (IL)-1ß, tumour necrosis factor alpha, IL-6, IL-2 and C-C motif ligand 2 levels were decreased and hepatic impairment was mitigated. In mice with GSDMD knockout, p53 was reduced, GPX4 was increased, and ferroptotic events (depletion of SLC7A11, elevation of ACSL4, and iron accumulation) were detected. In vitro, knockdown of p53 and overexpression of GPX4 reduced AST and ALT levels, the cytostatic rate, and GSDMD expression, restoring SLC7A11 depletion. Moreover, SIRT1 agonist and overexpression of SIRT1 alleviated acute liver injury and decreased iron deposition compared with results in the model group, accompanied by reduced p53, GSDMD, and ACSL4, and increased SLC7A11 and GPX4. Inactivation of SIRT1 exacerbated ferroptotic and pyroptotic cell death and aggravated liver injury in LPS/D-GalN-induced in vitro and in vivo models. CONCLUSION: SIRT1 activation attenuates LPS/D-GalN-induced ferroptosis and pyroptosis by inhibiting the p53/GPX4/GSDMD signaling pathway in ALF.

2 Year Wencheng Waxy Yam Pesticide Residue Investigation and Quality Evaluation.

Wencheng waxy yam is famous for its glutinous and resilient taste, similar to waxy rice, but there is currently a lack of systematic research on the quality of this featured product, and little is known about its pesticide residues. We carried out a 2 year investigation of Wencheng waxy yam at seven sites from 2021 to 2022 to determine the oxidase content and phytochemical characteristics, namely, amylose, amylopectin, protein, reducing sugar, and mineral contents, such as K, Fe, and Zn, including the status of pesticide residues. The results showed that the oxidase content was affected by rainfall, and adequate water reduced the production of oxidase, including polyphenol oxidase, peroxidase, and superoxide dismutase, during the late growth stage of waxy yam, which was beneficial for reducing browning in yam processing. Radar map analysis showed that, with comprehensive evaluation, standardized production sites 1 and 2 had a relatively higher quality than 3-7 with small farmers. The results of pesticide multiresidue testing showed that no pesticides were detected in 64.29% of the samples, and the detected residues in the samples were very low, making the consumption of yam safe for consumers. These findings could be beneficial for the exploitation of the health benefits of waxy yam tubers and the innovation of yam-based functional products.

A pragmatic randomized controlled trial to evaluate the efficacy and safety of an oral short-course regimen including bedaquiline for the treatment of patients with multidrug-resistant tuberculosis in China: study protocol for PROSPECT.

INTRODUCTION: The lack of safe, effective, and simple short-course regimens (SCRs) for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment has significantly impeded TB control efforts in China. METHODS: This phase 4, randomized, open-label, controlled, non-inferiority trial aims to assess the efficacy and safety of a 9-month all-oral SCR containing bedaquiline (BDQ) versus an all-oral SCR without BDQ for adult MDR-TB patients (18-65 years) in China. The trial design mainly mirrors that of the "Evaluation of a Standardized Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR-TB" (STREAM) stage 2 study, while also incorporating programmatic data from South Africa and the 2019 consensus recommendations of Chinese MDR/RR-TB treatment experts. Experimental arm participants will receive a modified STREAM regimen C that replaces three group C drugs, ethambutol (EMB), pyrazinamide (PZA), and prothionamide (PTO), with two group B drugs, linezolid (LZD) and cycloserine (CS), while omitting high-dose isoniazid (INH) for confirmed INH-resistant cases. BDQ duration will be extended from 6 to 9 months for participants with Mycobacterium tuberculosis-positive sputum cultures at week 16. The control arm will receive a modified STREAM regimen B without high-dose INH and injectable kanamycin (KM) that incorporates experimental arm LZD and CS dosages, treatment durations, and administration methods. LZD (600 mg) will be given daily for ≥ 24 weeks as guided by observed benefits and harm. The primary outcome measures the proportion of participants with favorable treatment outcomes at treatment completion (week 40), while the same measurement taken at 48 weeks post-treatment completion is the secondary outcome. Assuming an α = 0.025 significance level (one-sided test), 80% power, 15% non-inferiority margin, and 10% lost to follow-up rate, each arm requires 106 participants (212 total) to demonstrate non-inferiority. DISCUSSION: PROSPECT aims to assess the safety and efficacy of a BDQ-containing SCR MDR-TB treatment at seventeen sites across China, while also providing high-quality data to guide SCRs administration under the direction of the China National Tuberculosis Program for MDR-TB. Additionally, PROSPECT will explore the potential benefits of extending the administration of the 9-month BDQ-containing SCR for participants without sputum conversion by week 16. TRIAL REGISTRATION: ClinicalTrials.gov NCT05306223. Prospectively registered on 16 March 2022 at https://clinicaltrials.gov/ct2/show/NCT05306223?term=NCT05306223&draw=1&rank=1 {2}.

Preparation, structural characteristics and pharmacological activity of polysaccharides from Polygala tenuifolia: A review.

Polygala tenuifolia is a traditional Chinese medicine with a long history of application, with the efficacy of suppressing cough, calming asthma, tranquilizing the mind, and benefiting the intellect. It is classified as a top-quality medicine in Shennong's Classic of Materia Medica. Polysaccharide is an important active ingredient in Polygala tenuifolia, which consists of several monosaccharides, including Ara, Gal, Glc, and so on. In this review, the preparation methods, structural characteristics, and biological activities of polysaccharides from Polygala tenuifolia are summarized, and the problems in the current studies are discussed to support further research, development, and utilization.

Role of BP-ANN in simulating greenhouse gas emissions from global aquatic ecosystems via carbon component-environmental factor coupling.

Inland waters (IW), estuarine areas (EA), and offshore areas (OA) function as aquatic systems in which the transport of carbon components results in the release of greenhouse gases (GHGs). Interconnected subsystems exhibit a greater greenhouse effect than individual systems. Despite this, there is a lack of research on how carbon loading and its components impact GHG emissions in various aquatic systems. In this study, we analyzed 430 aquatic sites to explore trade-off mechanisms among dissolved organic carbon (DOC), particulate organic carbon, dissolved inorganic carbon (DIC), and GHGs. The results revealed that IW emerged as the most significant GHG source, possessing a comprehensive global warming potential (GWP) of 0.78 ± 0.08 (10-2 Pg CO2-ep ha-1 year-1) for combined carbon dioxide, methane, and nitrous oxide. This surpassed the cumulative potentials of EA and OA (0.35 ± 0.05 (10-2 Pg CO2-ep ha-1 year-1)). Additionally, structural equation modeling indicated that GHG emissions resulted from a combination of carbon component loading and environmental factors. DOC exhibited a positive correlation with GWPs when influenced by biodegradable DOC. Total alkalinity and pH influenced DIC, leading to elevated pCO2 in aquatic systems, thereby enhancing GWPs. Predictive modeling using backpropagation artificial neural networks (BP-ANN) for GWPs, incorporating carbon components and environmental factors, demonstrated a good fit (R2 = 0.6078, RMSEaverage = 0.069, p > 0.05) between observed and predicted values. Enhancing the estimation of aquatic region feedback to GHG changes was achieved by incorporating corresponding water quality parameters. In summary, this study underscores the pivotal role of carbon components and environmental factors in aquatic regions for GHG emissions. The application of BP-ANN to estimate greenhouse effects from aquatic regions is highlighted, providing theoretical and experimental support for future advancements in monitoring and developing policies concerning the influence of water quality on GHG emissions.

Biomimetic Total Synthesis of Bimagnolignan: A Natural Anti-Breast Cancer Agent.

A short scalable biomimetic route to bioactive natural product bimagnolignan (1) was accomplished. Compound 1 was successfully prepared through a three-step metal-free synthesis from honokiol (2). Alternatively, 1 was also synthesized by biomimetic transformations that mimic tyrosinase in four steps. The key reactions feature a regioselective acetylation, a highly efficient C(sp2)-H oxidation, a cascade aerobic oxidative cyclization/coupling, and a Cu-catalyzed direct oxidative coupling. In addition, cell-based assays validate that 1 is a promising natural lead for HER2-positive breast cancer treatment.

Extraction, structure and bioactivities of polysaccharide from root of Arctium lappa L.: A review.

Arctium lappa L. root is a well-known Chinese medicine with high medicinal and food values. Arctium lappa L. root polysaccharide (ALP), as the main component and bioactive substance, has a variety of biological activities, including anti-inflammatory, antioxidant, hypoglycemic, hypolipidemic, antithrombotic, immunomodulatory activity and improvement of intestinal flora. The biological activities of polysaccharides are closely related to their structures, and different extraction and purification methods will yield different polysaccharide structures. As a kind of natural polysaccharide, ALP has a broad application prospect in drug carrier. In this paper, we reviewed the research progress on the extraction, purification, structural characterization, biological activities, structure-activity relationship and drug carrier application of ALP, in order to provide basic reference for the development and application of medical and health care value. At the same time, the shortcomings of ALP research are discussed in depth, and the potential development prospect and future research direction are prospected.

Superlubricity Achieved by a Transparent Poly(vinylpyrrolidone) Composite Hydrogel with Glycerol Ethoxylate in Ocular Conditions.

Efficient and stable ocular lubrication is pivotal in safeguarding eye tissues from wear, especially under repetitive strain due to frequent blinking. Hydrogels have been reported to possess adjustable mechanical properties, biocompatibility, durability, and elevated water content and extensive utilization in medical fields. In this work, a kind of visible photo-cross-linking poly(vinylpyrrolidone) (PVP) hydrogel was designed and synthesized using 1-vinyl-2-pyrrolidone (NVP) and poly(ethylene glycol) diacrylate (PEGDA). To optimize the structure and improve the lubrication performance of hydrogels, we prepared and investigated glycerol ethoxylate (GE)-introduced composite hydrogels (GE/PVP). The results show that the addition of 3 wt % GE helped the hydrogel to form a uniform and dense porous matrix and reduce the frictional coefficient (COF) by over 50%, achieving superlubricity (COF ≈ 0.005). However, with the excessive increase of GE (6 wt %), the structure of the hydrogel is destroyed, inducing pore walls to thin and expand. After that, a lubrication mechanism of the GE/PVP composite hydrogel was proposed, in which the addition of GE reduced the surface tension of the hydrogel, enhanced the hydration ability of the hydrogel, and thus decreased the friction between sliding surfaces. Besides, the cytotoxicity tests show that the composite hydrogels possess good biocompatibility. Overall, the as-synthesized hydrogels hold great potential as lubricating medium for use in ocular applications.

Responses of soil seed bank and its above-ground vegetation to various reclamation patterns.

Coastal land reclamation has become a primary strategy for alleviating conflicts between human development and land resource utilization. However, anthropogenic activities associated with land reclamation inevitably result in significant changes to coastal wetland ecosystems. Previous studies have mainly focused on the ecological consequences of land reclamation on above-ground vegetation, while overlooking the distinctions between different reclamation patterns and the critical role of soil seed bank in maintaining ecosystem stability. In this study, the responses of soil seed bank and vegetation to various reclamation patterns, as well as the factors influencing changes in seed bank characteristics, were analyzed in a natural coastal wetland (NCW), a reclaimed wetland with sea embankments constructed on native wetland (SEW), and another reclaimed wetland formed through land reclamation from the sea (LRW). These findings suggest that seed banks and their vegetation adopt different adaptation strategies under various reclamation patterns. In the NCW, the proportion of non-halophytes (1.39%), diversity, and density of the seed bank were at their lowest levels, whereas the species compositions derived from the seed bank and vegetation were very similar (similarity coefficient = 0.67). Conversely, the seed bank in the SEW demonstrated the highest species diversity, which differed significantly from the species composition of its above-ground vegetation (similarity coefficient = 0.21). However, the highest proportion of non-halophytes (36.60%), vegetation diversity, and seed bank density occurred in LRW. Furthermore, differences in seed bank characteristics under different reclamation patterns may be related to changes in soil salinity and plant reproductive strategies after reclamation. Adjusting reclamation patterns and restoring soil properties could potentially optimize the types of local plant species and their distribution in reclaimed areas.

Identification of circular RNA hsa_circ_0034621 as a novel biomarker for carotid atherosclerosis and the potential function as a regulator of NLRP3 inflammasome.

BACKGROUND AND AIMS: NLRP3 inflammasome plays a key role in vascular inflammation and atherosclerosis. Circular RNAs (circRNAs) are involved in disease development by regulating gene expression, and have emerged as promising novel disease biomarkers. This study aimed to identify the NLRP3 inflammasome-associated circRNA biomarkers of carotid atherosclerosis. METHODS: Based on the differential expression profiles of circRNAs in patients with carotid artery plaque (CAP) and healthy controls, hsa_circ_0043621, hsa_circ_0051995, and hsa_circ_0123388 were screened and validated using real-time quantitative polymerase chain reaction (RT-qPCR). Potential circRNA-miRNA-mRNA interactions were explored using a luciferase assay. The biological roles of the validated circRNAs were investigated in human umbilical vein endothelial cells (HUVECs) using Western blotting, transwell, and CCK-8 assays. Clinical significance was assessed using receiver operating characteristic (ROC) curves and logistic regression analysis. RESULTS: The expression levels of all candidate circRNAs were significantly higher in patients with CAP than in controls (p<0.05), which was consistent with the results of the microarray analysis. Overexpression of hsa_circ_0043621 significantly increased the expression of NLRP3, induced migration of HUVECs, and inhibited cell proliferation. hsa_circ_0043621 demonstrated reasonable diagnostic accuracy for CAP detection and increased intima-media thickness (IMT). hsa_circ_0043621 upregulation was an independent predictor of an increased risk of CAP and increased IMT. CONCLUSIONS: hsa_circ_0043621 is a valuable circulating biomarker of carotid atherosclerosis and may contribute to its pathogenesis by regulating the NLRP3 inflammasome.

Differentially disrupted spinal cord and muscle energy metabolism in spinal and bulbar muscular atrophy.

Prior studies showed that polyglutamine-expanded androgen receptor (AR) is aberrantly acetylated and that deacetylation of the mutant AR by overexpression of nicotinamide adenine dinucleotide-dependent (NAD+-dependent) sirtuin 1 is protective in cell models of spinal and bulbar muscular atrophy (SBMA). Based on these observations and reduced NAD+ in muscles of SBMA mouse models, we tested the therapeutic potential of NAD+ restoration in vivo by treating postsymptomatic transgenic SBMA mice with the NAD+ precursor nicotinamide riboside (NR). NR supplementation failed to alter disease progression and had no effect on increasing NAD+ or ATP content in muscle, despite producing a modest increase of NAD+ in the spinal cords of SBMA mice. Metabolomic and proteomic profiles of SBMA quadriceps muscles indicated alterations in several important energy-related pathways that use NAD+, in addition to the NAD+ salvage pathway, which is critical for NAD+ regeneration for use in cellular energy production. We also observed decreased mRNA levels of nicotinamide riboside kinase 2 (Nmrk2), which encodes a key kinase responsible for NR phosphorylation, allowing its use by the NAD+ salvage pathway. Together, these data suggest a model in which NAD+ levels are significantly decreased in muscles of an SBMA mouse model and intransigent to NR supplementation because of decreased levels of Nmrk2.

Blocking the dimerization of polyglutamine-expanded androgen receptor protects cells from DHT-induced toxicity by increasing AR turnover.

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular degenerative disease caused by a polyglutamine expansion in the androgen receptor (AR). This mutation causes AR to misfold and aggregate, contributing to toxicity in and degeneration of motor neurons and skeletal muscle. There is currently no effective treatment or cure for this disease. The role of an interdomain interaction between the amino- and carboxyl-termini of AR, termed the N/C interaction, has been previously identified as a component of androgen receptor-induced toxicity in cell and mouse models of SBMA. However, the mechanism by which this interaction contributes to disease pathology is unclear. This work seeks to investigate this mechanism by interrogating the role of AR homodimerization- a unique form of the N/C-interaction- in SBMA. We show that, although the AR N/C-interaction is reduced by polyglutamine-expansion, homodimers of 5α-dihydrotestosterone (DHT)-bound AR are increased. Additionally, blocking homodimerization results in decreased AR aggregation and toxicity in cell models. Blocking homodimerization results in the increased degradation of AR, which likely plays a role in the protective effects of this mutation. Overall, this work identifies a novel mechanism in SBMA pathology that may represent a novel target for the development of therapeutics for this disease.