Efficacy and Safety of Risankizumab in Patients with Psoriatic Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Currently, the cause of psoriatic arthritis (PsA) is unknown, and the effectiveness of current drug treatments is unsatisfactory. In March 2019, the US Food and Drug Administration (FDA) approved risankizumab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody targeting the p19 subunit of interleukin (IL)-23, for the treatment of PsA in adults. This study aimed to conduct a meta-analysis of double-blind, randomized, placebo-controlled trials to evaluate the effectiveness and safety of risankizumab in moderate-to-severe PsA. METHODS: We conducted a thorough search of relevant databases from the establishment of the databases to October 1, 2023. We conducted a meta-analysis using Stata 12.0 and utilized I2 and Egger tests to assess heterogeneity and publication bias among the studies. Bias assessment was performed using the risk bias map and bias risk summary diagram generated by Revman5.4 software. The review protocols were registered on PROSPERO (CRD42023451894) and adhered to the preferred reporting item of system evaluation (PRISMA) guideline. RESULTS: Six randomized controlled trials (RCTs) involving 5038 patients with PsA treated with either risankizumab or placebo were included in the analysis. At 24 weeks, the risankizumab group demonstrated a significantly higher American College of Rheumatology-20 (ACR20) response rate compared to the placebo group (RR 1.760, 95% CI 1.568-1.977, P < 0.001). Additionally, the risankizumab group showed a significantly higher Minimal Disease Activity (MDA) response rate compared to the placebo group (RR 1.827, 95% CI 1.048-3.184, P < 0.05). The risankizumab group also exhibited improvement in Short Form 36 Questionnaire (SF-36) score (SMD 0.51, 95% CI 0.33-0.69, P < 0.001), with significantly lower Health Assessment Questionnaire Disability Index (HAQ-DI) score (SMD - 0.27, 95% CI - 0.37 to - 0.17, P < 0.001) and higher Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score (SMD 0.27, 95% CI 0.20-0.35, P < 0.001) compared to the placebo group. Moreover, the risankizumab group had a significantly lower Psoriasis Area and Severity Index (PASI) score (SMD - 6.12, 95% CI - 10.02 to 2.23, P < 0.001). A study by Mease et al. indicated that patients receiving risankizumab generally demonstrated numerical improvements in the Leeds Enthesitis Index (LEI), although the small sample size limits the evidence. Further research is necessary to provide evidence-based guidelines. There were no significant differences in the incidence of serious adverse events (SAE) and serious treatment-emergent adverse events (STEAE) between the risankizumab and placebo groups (RR 0.76, 95% CI 0.45-1.28, P = 0.31; RR 0.99, 95% CI 0.49-1.99, P = 0.97, respectively), and the overall incidence of adverse events (AE) was not comparable (RR 1.10, 95% CI 0.63-1.94, P = 0.73). CONCLUSION: Risankizumab showed superior efficacy across multiple outcome measures compared to placebo, with no significant increase in adverse events. Our findings endorse risankizumab as an excellent treatment option for PsA, offering valuable insights for clinicians and patients when choosing appropriate therapeutic interventions. TRIAL REGISTRATION: Retrospectively registered (CRD42023451894, 16 August 2023).

Effective enrichment of trace exosomes for the label-free SERS detection via low-cost thermophoretic profiling.

Exosome-based liquid biopsies possess great potential in monitoring cancer development However, current exosome detection biosensors require large exosome volumes, showing the weak detection sensitivity. Besides, these methods pay little attention to in situ analysis of exosomes, hence limiting the provision of more accurate clinically-relevant information. Herein, we develop an innovative label-free biosensor combining the low-cost thermophoretic enrichment method with the surface-enhanced Raman spectroscopy (SERS) detection. Based on the thermophoretic enrichment strategy, exosomes and gold nanoparticles can be enriched together into a small area with a scale of 500 µm within 10 min. The Raman signals of various exosomes derived from normal, cancerous cell lines and human serum are dynamically monitored in situ, with the limit of detection of 102-103 particles per microliter, presenting higher sensitivity compared with the similar label-free SERS detection. The spectral data set of different exosomes is applied to train for multivariate classification of cell types and to estimate how the normal exosome data resemble cancer cell exosome. The reliable classification and identification of different exosomes can be realized. The current biosensor is convenient, low-cost and requires small exosome volumes (∼3 µL), and if validated in larger cohorts may contribute to the tumor prediction and diagnosis.

An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis.

Myeloid cells are known to suppress antitumour immunity1. However, the molecular drivers of immunosuppressive myeloid cell states are not well defined. Here we used single-cell RNA sequencing of human and mouse non-small cell lung cancer (NSCLC) lesions, and found that in both species the type 2 cytokine interleukin-4 (IL-4) was predicted to be the primary driver of the tumour-infiltrating monocyte-derived macrophage phenotype. Using a panel of conditional knockout mice, we found that only deletion of the IL-4 receptor IL-4Rα in early myeloid progenitors in bone marrow reduced tumour burden, whereas deletion of IL-4Rα in downstream mature myeloid cells had no effect. Mechanistically, IL-4 derived from bone marrow basophils and eosinophils acted on granulocyte-monocyte progenitors to transcriptionally programme the development of immunosuppressive tumour-promoting myeloid cells. Consequentially, depletion of basophils profoundly reduced tumour burden and normalized myelopoiesis. We subsequently initiated a clinical trial of the IL-4Rα blocking antibody dupilumab2-5 given in conjunction with PD-1/PD-L1 checkpoint blockade in patients with relapsed or refractory NSCLC who had progressed on PD-1/PD-L1 blockade alone (ClinicalTrials.gov identifier NCT05013450 ). Dupilumab supplementation reduced circulating monocytes, expanded tumour-infiltrating CD8 T cells, and in one out of six patients, drove a near-complete clinical response two months after treatment. Our study defines a central role for IL-4 in controlling immunosuppressive myelopoiesis in cancer, identifies a novel combination therapy for immune checkpoint blockade in humans, and highlights cancer as a systemic malady that requires therapeutic strategies beyond the primary disease site.

Dyslipidemia in rheumatoid arthritis: the possible mechanisms.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, of which the leading cause of death is cardiovascular disease (CVD). The levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c) in RA decrease especially under hyperinflammatory conditions. It is conflictive with the increased risk of CVD in RA, which is called "lipid paradox". The systemic inflammation may explain this apparent contradiction. The increased systemic proinflammatory cytokines in RA mainly include interleukin-6(IL-6)、interleukin-1(IL-1)and tumor necrosis factor alpha(TNF-α). The inflammation of RA cause changes in the subcomponents and structure of HDL particles, leading to a weakened anti-atherosclerosis function and promoting LDL oxidation and plaque formation. Dysfunctional HDL can further worsen the abnormalities of LDL metabolism, increasing the risk of cardiovascular disease. However, the specific mechanisms underlying lipid changes in RA and increased CVD risk remain unclear. Therefore, this article comprehensively integrates the latest existing literature to describe the unique lipid profile of RA, explore the mechanisms of lipid changes, and investigate the impact of lipid changes on cardiovascular disease.

Early life exposure to low-dose perfluorooctane sulfonate disturbs gut barrier homeostasis and increases the risk of intestinal inflammation in offspring.

Perfluorooctane sulfonate (PFOS), one of the legacy per- and poly-fluoroalkyl substances (PFAS), is associated with multiple adverse health effects on children. However, much remains to be known about its potential impacts on intestinal immune homeostasis during early life. Our study found that PFOS exposure during pregnancy in rats significantly increased the maternal serum levels of interleukin-6 (IL-6) and zonulin, a gut permeability biomarker, and decreased gene expressions of Tight junction protein 1 (Tjp1) and Claudin-4 (Cldn4), the tight junction proteins, in maternal colons on gestation day 20 (GD20). Being exposed to PFOS during pregnancy and lactation in rats significantly decreased the body weight of pups and increased the offspring's serum levels of IL-6 and tumor necrosis factor-α (TNF-α) on postnatal day 14 (PND14), and induced a disrupted gut tight junction, manifested by decreased expressions of Tjp1 in pup's colons on PND14 and increased pup's serum concentrations of zonulin on PND28. By integrating high-throughput 16S rRNA sequencing and metabolomics, we demonstrated that early-life PFOS exposure altered the diversity and composition of gut microbiota that were correlated with the changed metabolites in serum. The altered blood metabolome was associated with increased proinflammatory cytokines in offspring. These changes and correlations were divergent at each developmental stage, and pathways underlying immune homeostasis imbalance were significantly enriched in the PFOS-exposed gut. Our findings provide new evidence for the developmental toxicity of PFOS and its underlying mechanism and explain in part the epidemiological observation of its immunotoxicity.

The Invasive Species Reynoutria japonica Houtt. as a Promising Natural Agent for Cardiovascular and Digestive System Illness.

Polygoni Cuspidati Rhizoma et Radix, the dry roots and stems of Reynoutria japonica Houtt (called Huzhang, HZ in Chinese), is a traditional and popular chinese medicinal herb for thousands of years. As a widely used ethnomedicine in Asia including China, Japan, and Korea, HZ can invigorate the blood, cool heat, and resolve toxicity, which is commonly used in the treatment of favus, jaundice, scald, and constipation. However, HZ is now considered an invasive plant in the United States and many European countries. Therefore, in order to take advantage of HZ and solve the problem of biological invasion, scholars around the world have carried out abundant research studies on HZ. Until now, about 110 compounds have been isolated and identified from HZ, in which anthraquinones, stilbenes, and flavonoids would be the main bioactive ingredients for its pharmacological properties, such as microcirculation improvement, myocardial protective effects, endocrine regulation, anti-atherosclerotic activity, anti-oxidant activity, anti-tumor activity, anti-viral activity, and treatment of skin inflammation, burns, and scalds. HZ has a variety of active ingredients and broad pharmacological activities. It is widely used in health products, cosmetics, and even animal husbandry feed and has no obvious toxicity. Efforts should be made to develop more products such as effective drugs, health care products, cosmetics, and agricultural and animal husbandry products to benefit mankind.

Examination of serum metabolome altered by cigarette smoking identifies novel metabolites mediating smoking-BMI association.

OBJECTIVE: The authors hypothesize that an untargeted metabolomics study will identify novel mechanisms underlying smoking-associated weight loss. METHODS: This study performed cross-sectional analyses among 1,252 participants in the Bogalusa Heart Study and assessed 1,202 plasma metabolites for mediation effects on smoking-BMI associations. Significant metabolites were tested for associations with smoking genetic risk scores among a subset of participants (n = 654) with available genomic data, followed by direction dependence analysis to investigate causal relationships between the metabolites and smoking and BMI. All analyses controlled for age, sex, race, education, alcohol drinking, and physical activity. RESULTS: Compared with never smokers, current and former smokers had a 3.31-kg/m2 and 1.77-kg/m2 lower BMI after adjusting for all covariables, respectively. A total of 22 xenobiotics and 94 endogenous metabolites were significantly associated with current smoking. Eight xenobiotics were also associated with former smoking. Forty metabolites mediated the smoking-BMI associations, and five showed causal relationships with both smoking and BMI. These metabolites, including 1-oleoyl-GPE (18:1), 1-linoleoyl-GPE (18:2), 1-stearoyl-2-arachidonoyl-GPE (18:0/20:4), α-ketobutyrate, and 1-palmitoyl-GPE (16:0), mediated 26.0% of the association between current smoking and BMI. CONCLUSIONS: This study cataloged plasma metabolites altered by cigarette smoking and identified five metabolites that partially mediated the association between current smoking and BMI.

Lifelong smoking status, weight gain, and subsequent risk of major adverse cardiovascular events: Long-term follow-up of a middle-aged Chinese population.

OBJECTIVE: The aim of this study was to explore the association of lifelong smoking status with risk of major adverse cardiovascular events (MACE) accounting for weight change in a Chinese cohort. METHODS: The cohort of the People's Republic of China-United States of America (PRC-USA) Collaborative Study of Cardiovascular and Cardiopulmonary Epidemiology was established in 1983 to 1984, resurveyed during 1987 to 1988 and 1993 to 1994, and followed up to 2005. A total of 5,849 participants who survived in 1993 to 1994 were classified into never smokers, long-term quitters, short-term quitters, short-term relapsers and new smokers, long-term relapsers and new smokers, and persistent smokers according to the information on lifelong smoking status collected in all three surveys. The associations of lifelong smoking status with MACE in the subsequent 10 years were explored with Cox proportional hazards models. RESULTS: During a median follow-up of 10.2 years, 694 participants had MACE. Compared with persistent smokers, the multivariable-adjusted hazard ratio of developing MACE was 0.83 (95% CI: 0.61-1.12) for short-term quitters, 0.75 (95% CI: 0.54-1.02) for long-term quitters, and 0.68 (95% CI: 0.54-0.85) for never smokers (ptrend = 0.001). In comparison, the hazard ratio was 1.03 (95% CI: 0.77-1.35) for long-term relapsers and new smokers and 0.78 (95% CI: 0.46-1.22) for short-term relapsers and new smokers (ptrend = 0.018). These associations were not significantly altered by further adjusting for weight change in the past 10 years. CONCLUSIONS: Lifelong smoking status is significantly associated with risk of MACE. As time duration increased, health benefit to quitters would become close to that of never smokers, and harms to relapsers and new smokers would become close to that of persistent smokers.

Association Between Baseline Buccal Telomere Length and Progression of Kidney Function: The Health and Retirement Study.

We aimed to evaluate associations of baseline telomere length with overall and annual change in estimated glomerular filtration rate (eGFR) and trajectory of kidney function during an 8-year follow-up. A total of 3 964 participants of the Health and Retirement Study were included. We identified 3 trajectory groups of kidney function: consistently normal (n = 1 163 or 29.3%), normal to impaired (n = 2 306 or 58.2%), and consistently impaired groups (n = 495 or 12.5%). After controlling for age, sex, race, education, smoking, drinking, diabetes, heart disease, blood pressure, body mass index, total cholesterol, and hemoglobin A1c, participants with longer telomere length were 20% less likely (odds ratio = 0.80, 95% confidence interval: 0.69-0.93, p = .003) to have a normal to impaired kidney function trajectory than a consistently normal function trajectory. Telomere length was not associated with changing rate of eGFR over 8 years (p = .45). Participants with longer telomere length were more likely to have consistently normal kidney function.

A DNA tetrahedron docking assembly for imaging telomerase activity in cancerous cells.

The detection of telomerase activity inside cells is valuable for early cancer diagnosis and telomerase function study. However, besides cancerous cells, telomerase is also found to be expressed in few non-cancerous cells, which influences the assay reliability. By virtue of the extracellular pH, we design a DNA tetrahedron docking assembly (DTDA) for only responding telomerase activity in cancerous cells. The DTDA maintains structural integrity with extracellular acid pH of cancerous cells, but releases a telomerase substrate-containing strand after its cell internalization due to intracellular alkaline pH. The strand gets elongated by intracellular telomerase, docks to the vertex of tetrahedron, and returns to the DTDA after its separation, accompanied by fluorescence enhancement. For non-cancerous cells, the telomerase substrate-containing strand is already dissociated with extracellular alkaline pH and cannot enter into cells to achieve subsequent docking event. DTDA well distinguishes cancerous cells from non-cancerous cells in which telomerase are both expressed. The strategy can provide a more reliable way for telomerase-based cancer diagnosis and telomerase oncogenic study.

Solution-Based SERS Detection of Weak Surficial Affinity Molecules Using Cysteamine-Modified Au Bipyramids.

To achieve ultrasensitive detection of trace targets through solution-based surface-enhanced Raman spectroscopy (SERS), direct adsorption of the target molecules on a SERS-active surface is vital. In this work, cetyltrimethylammonium bromide (CTAB)-capped gold nano-bipyramids (Au BPs) with different aspect ratios (ARs) are prepared and the surface is successfully modified by a simple ligand exchange method. Cysteamine-capped gold nano-bipyramids (cyst-Au BPs) are obtained by means of replacement of CTAB by cysteamine using Au-S covalent bonding and applied in the solution-based SERS detection of different pigment molecules, which always have weak affinity to the gold surface. The hydrogen bonding between the pigment molecule and cysteamine causes the aggregation of Au BPs to generate local electromagnetic field enhancement. The influence of the AR and concentration of Au BPs on SERS properties is investigated. The SERS detection of weak-affinity molecules to an extremely low limit shows that the cyst-Au BPs are highly sensitive compared to CTAB-capped Au BPs. The limit of detection (LOD) of allura red as low as 0.1 ppb and that of sunset yellow as low as 1 ppb show that the proposed strategy has many advantages due to its simplicity and fast and rapid detection for the sensitivity analysis of weak-affinity molecules.

SERS and fluorescence detection of circulating tumor cells (CTCs) with specific capture-release mode based on multifunctional gold nanomaterials and dual-selective recognition.

Herein, a dual-selective recognition and multi-enhanced surface-enhanced Raman scattering (SERS)-fluorescence dual mode detection platform is designed for the detection of circulating tumor cells (CTCs). The gold nanoflowers (AuNFs) substrate was synthesized and the CTCs were captured on the surface area of AuNFs/ITO substrate by aptamers modified. At the same time, the novel nanoprobe was designed, anti-EpCAM (AE) and trigger DNA were modified onto the surface of gold nanostars (AuNSs) through a PEG linker. The novel nanoprobe identified CTCs through the specific recognition reaction between AE and the cell epithelial adhesion molecule of the CTCs. The dual-recognition cellular mechanism of the aptamers and AE improves selectivity. Then, the complementary sequence (CS) hybridize with aptamers to release the captured CTCs into the culture medium. The number of CTCs released was detected by SERS and fluorescence. The limit of SERS detection was 5 cells/mL with a linear relationship from 5 to 200 cells/mL. The limit of fluorescence detection was 10 cells/mL with a linear relationship from 10 to 200 cells/mL. Thus, the developed CTCs detection platform demonstrates promising applications for clinical diagnosis.

The U-shaped association of altitudes with prevalence of hypertension among residents in Tibet, China.

We aimed to evaluate the association of altitudes with the prevalence of hypertension among residents aged 15 years and above in Tibet, China. Data for 11,407 Tibetan residents from the National Health Services Survey in 2013 were analyzed. Association between altitudes and prevalence of physician-diagnosed hypertension was assessed by two logistic regression models as follows: (i) a base model adjusted for age and gender, and (ii) a full model additionally adjusted for body mass index, education, marital status, area of residence, distance to the nearest medical institute, smoking, drinking, and exercise. Nonlinear relationship between altitudes and prevalence of hypertension was explored by restricted cubic spline analyses. Sensitivity analyses were conducted by restricting to residents of rural and/or nomadic areas. The prevalence of hypertension was estimated to be 37.6%. We found a U-shaped association between altitudes and prevalence of physician-diagnosed hypertension with a turning point at around 3800 m (12,467 ft). For residents living above 3800 m, a 1000 m increase in altitudes was associated with 2.05 (95% confidence interval [CI]: 1.62-2.61) times higher odds of having physician-diagnosed hypertension, after adjusting for age and gender. When further controlling for all covariates, the odds ratio (OR) dropped to 1.87 (95% CI: 1.46-2.41). For residents living below 3800 m, a 1000 m increase was associated with 0.29 (95% CI: 0.19-0.44) times less likelihood of having physician-diagnosed hypertension in the full model. Sensitivity analyses among residents in rural and/or nomadic areas showed similar associations. To conclude, altitudes were in a U-shaped association with prevalence of hypertension.

The effect of leptin on blood pressure considering smoking status: a Mendelian randomization study.

Studies on leptin and blood pressure (BP) associations have yielded inconsistent findings. The current study aimed to evaluate the effect of genetically determined leptin on BP and to explore whether smoking status modified this effect. We conducted a Mendelian randomization analysis using the baseline data of 3860 participants in the Framingham Heart Study 3rd generation cohort. Pairwise associations among leptin genetic risk score (GRS), log-transformed leptin (log-leptin), and BP were assessed by multivariate linear regression models. Age and sex were adjusted in the base model, and education, smoking, drinking, and physical activity were adjusted in the full model. The interaction between leptin GRS and smoking was evaluated by adding an interaction term, GRS × smoking, in the fully adjusted model. In the age- and sex-adjusted analyses, log-leptin was positively associated with systolic BP (SBP) (P = 2.35 × 10-79), diastolic BP (DBP) (P = 6.19 × 10-76), mean arterial pressure (MAP) (P = 1.10 × 10-90), and pulse pressure (P = 4.38 × 10-19). Leptin GRS significantly increased log-leptin (P = 0.00001). Leptin GRS was associated with reduced SBP (P = 0.04), DBP (P = 0.006), and MAP (P = 0.008) among current smokers. In the fully adjusted model, significant interactions between GRS and smoking were identified for SBP (P = 0.02), DBP (P = 0.002), and MAP (P = 0.003). Sensitivity analyses among participants not taking antihypertensive or glucose-lowering medications revealed similar associations. Our study provided evidence for a potentially causal relationship between leptin and BP among current smokers.

Early-life exposure to severe famine is associated with higher methylation level in the IGF2 gene and higher total cholesterol in late adulthood: the Genomic Research of the Chinese Famine (GRECF) study.

OBJECTIVE: To evaluate the association of early-life exposure to the Chinese Great Famine (1959-1961) with DNA methylation in IGF2 and its subsequent influence on blood lipid levels in late adulthood among participants of the Genomic Research of the Chinese Famine (GRECF) study. METHODS: The GRECF study recruited 790 participants born between 1956 and 1964 from 2 neighbor provinces, Anhui and Jiangxi, in China through a multistage, clustered, random sampling. The current study included a random sample of 188 GRECF participants. IGF2 differential methylation region (DMR) is an intragenic DMR located upstream of the imprinted promoters of IGF2 exon 3. DNA methylation were quantified at 8 cytosine-phosphate-guanine dinucleotides (CpG) sites at the IGF2 DMR (chr11p15.5) using the Sequenom EpiTYPER method and the MassARRAY system. Multivariate linear regressions were used to evaluate pairwise associations among famine severity, DNA methylation in the IGF2 gene, and lipid levels. We controlled for age and sex in the base model and additionally controlled for education, smoking, and drinking status in the fully adjusted model. Mediation analysis was applied to assess the mediation effect of DNA methylation at the IGF2 gene on the association between early-life exposure to severe famine and adult lipid levels. RESULTS: Exposure to severe famine was associated with elevated methylation at CpG1 (chr11: 2126041, build 36) of the IGF2 DMR (ß = 0.07; P = 0.0008) and total cholesterol (ß = 0.72; P = 1.09 × 10-7). After adjustment for age and sex, each unit increase in methylation of the CpG1 site was associated with 1.09-unit increase in total cholesterol (P = 0.03). After further adjustment for all covariates, these associations were still significant (Pfamine-CpG1 = 0.002, Pfamine-total cholesterol = 1.28 × 10-6, and PCpG1-total cholesterol = 0.05). CONCLUSION: Increased methylation level in the IGF2 gene was associated with early-life exposure to severe famine, and this change was also positively associated with total cholesterol in late adulthood.

A DNA walker powered by endogenous enzymes for imaging uracil-DNA glycosylase activity in living cells.

A DNA walker powered by endogenous enzymes is constructed. It performs automatic walking in living cells and can detect the uracil-DNA glycosylase activity in situ.

Associations of the ages at menarche and menopause with blood pressure and hypertension among middle-aged and older Chinese women: a cross-sectional analysis of the baseline data of the China Health and Retirement Longitudinal Study.

We evaluated the associations of the ages at menarche and menopause with blood pressure (BP) and hypertension using the baseline data of 7893 women from the China Health and Retirement Longitudinal Study, a nationally representative survey among Chinese adults aged ≥45 years. Multivariate linear and logistic regression analyses were performed to evaluate the associations of the ages at menarche and men`opause with BP and hypertension, respectively. Nonlinear associations were evaluated using spline analyses. After controlling for age, education, marital status, living areas, smoking, drinking, and medication use if necessary, an early onset of menarche by 1 year was associated with a 6% (95% confidence interval [CI]: 3-9%) higher odds of hypertension and 0.82 mm Hg (P < 0.001) and 0.41 mm Hg (P < 0.001) higher systolic and diastolic BP, respectively. When further controlling for the body mass index (BMI), blood glucose, and lipids, the associations were still significant. Spline analyses did not support U-shaped relationships between menarche age and hypertension risk (P = 0.35), systolic BP (P = 0.60), or diastolic BP (P = 0.70). When stratified by location of residence, menarche age was only associated with BP and hypertension among women living in rural areas. The age of menopause was positively associated with hypertension (odds ratio [OR] = 1.02 per year delay of menopause, 95% CI: 1.01-1.03). However, when further controlling for BMI, such an association no longer existed (OR = 1.01, P = 0.32). These findings indicated that the associations of menarche age with BP and hypertension may be modified by factors related to the area of residence in China, and the association between menopause age and hypertension was driven by BMI.

Locked Nucleic Acid Nanomicelle with Cell-Penetrating Peptides for Glutathione-Triggered Drug Release and Cell Fluorescence Imaging.

Herein, we constructed a multifunctional spherical nanomicelle drug delivery system to improve the efficiency of cell uptake. The paclitaxel (PTX)-locked nucleic acid (LNA) monomer and the carboxyfluorescein (FAM)-labeled DNA were mixed together to assemble and form a spherical nanomicelle that was functionalized with transactivator of transcription (TAT), a cell-penetrating peptides (CPPs). A bioreductively activated disulfide was used to link the hydrophobic PTX to the LNA, allowing the PTX to be released freely in the presence of glutathione (GSH) upon cell uptake. Based on magnetic separation, the synthetic process of PTX-LNA monomers avoids time-consuming and labor-intensive shortcomings. Cellular uptake of PTX-LNA-TAT nanomicelle and the drug release occur rapidly as proved by fluorescence microscopy and flow cytometry. The resulting nanomicelle was greater stability, monodisperse size, and the high therapeutic potential. Furthermore, the system can readily achieve detection of GSH in the cancer cells. The detection limit for commercial GSH determined was 1.0 × 10-9 M by using PTX/Fluorescein isothiocyanate (FITC)-LNA/black hole quencher 1 (BHQ-1) as a probe.

Gas chromatography-mass spectrometry based metabolomics profile of hippocampus and cerebellum in mice after chronic arsenic exposure.

Intake of arsenic (As) via drinking water has been a serious threat to global public health. Though there are numerous reports of As neurotoxicity, its pathogenesis mechanisms remain vague especially its chronic effects on metabolic network. Hippocampus is a renowned area in relation to learning and memory, whilst recently, cerebellum is argued to be involved with process of cognition. Therefore, the study aimed to explore metabolomics alternations in these two areas after chronic As exposure, with the purpose of further illustrating details of As neurotoxicity. Twelve 3-week-old male C57BL/6J mice were divided into two groups, receiving deionized drinking water (control group) or 50 mg/L of sodium arsenite (via drinking water) for 24 weeks. Learning and memory abilities were tested by Morris water maze (MWM) test. Pathological and morphological changes of hippocampus and cerebellum were captured via transmission electron microscopy (TEM). Metabolic alterations were analyzed by gas chromatography-mass spectrometry (GC-MS). MWM test confirmed impairments of learning and memory abilities of mice after chronic As exposure. Metabolomics identifications indicated that tyrosine increased and aspartic acid (Asp) decreased simultaneously in both hippocampus and cerebellum. Intermediates (succinic acid) and indirect involved components of tricarboxylic acid cycle (proline, cysteine, and alanine) were found declined in cerebellum, indicating disordered energy metabolism. Our findings suggest that these metabolite alterations are related to As-induced disorders of amino acids and energy metabolism, which might therefore, play an important part in mechanisms of As neurotoxicity.

Postnatal Subacute Benzo(a)Pyrene Exposure Caused Neurobehavioral Impairment and Metabolomic Changes of Cerebellum in the Early Adulthood Period of Sprague-Dawley Rats.

Benzo(a)pyrene (BaP) is a widespread environmental contaminant that has been associated with neurotoxicity in mammals. It has strong toxic effects on the developing central nervous system. Cerebellum is associated with locomotor activity and anxiety behavior, but there is very little research about the toxic effects of BaP in cerebellum. The present study aims to investigate the global influence of BaP subacute exposure on the metabolome of rat cerebellum. Male neonatal rats (postnatal day 5) were divided into two groups: control group and BaP-treated group (2 mg/kg/day for 7 weeks). Open field test and transmission electron microscopy were performed to analyze neurobehavior and ultramicrostructure alteration. Gas chromatography-mass spectrometry (GC-MS) was used to analyze metabolites of the cerebellum in both groups. The results revealed that postnatal exposure to BaP promoted pathological changes in the cerebellum and increased locomotor and anxiety activities in early adulthood. Twenty differential significant metabolites were identified by multivariate statistical analysis. Further metabolic pathway impact analysis and network analysis suggested that the primary metabolic pathways affected included pathway involved in energy metabolism, methionine and cysteine metabolism, and glutathione metabolism. These findings suggest that BaP-induced cerebellum injury may be correlated with metabolic changes and provide an area to target to reduce the negative effects of BaP.