Effective enrichment and separation of three flavonoids from Ohwia caudata (Thunberg) H. Ohashi using magnetic layered double hydroxide/ZIF-8 composites and pCEC.

In this study, Fe3O4@ZnCr-layered double hydroxide/zeolitic imidazolate frameworks-8 (MLDH/ZIF-8) magnetically functionalized composites were synthesized by co-precipitation and in situ growth based on the advantages of LDHs and ZIF-8 using Fe3O4 nanoparticles as a magnetic substrate to obtain adsorbents with excellent performance. Moreover, the composite was used for the efficient enrichment of flavonoids in Chinese herbal medicines. The internal structures and surface properties were characterized by SEM, Fourier transform infrared spectroscopy, X-ray diffraction and so on. MLDH/ZIF-8 exhibited a large specific surface area and good paramagnetic properties. The MLDH/ZIF-8 magnetic composite was used as a magnetic solid-phase extraction (MSPE) adsorbent, and a MLDH/ZIF-8 MSPE-pressurized capillary electrochromatography coupling method was developed for the separation and detection of flavonoids (luteolin, kaempferol and apigenin) in a sample of the Chinese herb Ohwia caudata (Thunberg) H. Ohashi. The relevant parameters affecting the extraction efficiency were optimized to determine the ideal conditions for MSPE. 5 mg of adsorbent in sample solution at pH 6, vortex extraction for 5 min, elution with 1.5 mL of ethyl acetate for 15 min. The method showed good linearity in the concentration range of 3-50 µg mL-1 with correlation coefficients of 0.9934-0.9981, and displayed a relatively LODs of 0.07-0.09 µg mL-1. The spiked recoveries of all analytes ranged from 84.5% to 122.0% with RSDs (n=3) between 4.5% and 7.7%. This method is straightforward and efficient, with promising potential in the separation and analysis of active ingredients in various Chinese herbal medicines.

Oral anticoagulants and cognitive impairment in patients with atrial fibrillation: A systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: This systematic review assesses the likelihood of developing dementia and cognitive impairment in patients with atrial fibrillation (AF) receiving non-vitamin K antagonist oral anticoagulants (NOACs) as opposed to vitamin K antagonists (VKAs). METHODS: We performed a systematic review with meta-analysis and trial sequential analysis (TSA), which encompassed both randomized controlled trials (RCTs) and observational studies. The objective was to assess the impact of NOACs and VKAs on the incidence of dementia in individuals diagnosed with AF. RESULTS: Out of 1914 studies that were screened, 31 studies were included in the final analysis, which consisted of nine RCTs or their subsequent post-hoc analyses, in addition to 22 observational studies. The meta-analysis shows that NOACs were associated with a decreased probability of developing dementia of any cause [Rate Ratio (RR): 0.88; 95 % confidence interval (95 % CI): 0.82-0.94], especially in patients below the age of 75 (RR: 0.78; 95 % CI: 0.73-0.84). Consistent patterns were observed across all forms of dementia and cognitive function decline. The overall evidence indicates notable variability in the outcome with a moderate-to-low degree of certainty. The TSA suggests that the total sample size of the included trials (155,647 patients) was significantly smaller than the required information size of 784,692 patients to discern the true effect of NOAC versus VKA in terms of reducing dementia risk. CONCLUSION: NOACs may reduce the likelihood of developing dementia in patients with AF, particularly in those under the age of 75. This review highlights the urgent necessity for thorough research to determine the efficacy of NOACs in safeguarding cognitive health.

Exploring Temporal and Intensity Effects of Resistance Exercise on Inhibition: A Four-Arm Crossover Randomized Controlled Trial.

Objective: Given the recognized benefits of resistance exercise on both physical and cognitive domains, elucidating how to maximize its benefit is pivotal. This study aims to evaluate these effects in terms of their timing and intensity on cognitive performance. Methods: This was a four-arm, crossover randomized controlled trial. Healthy college-aged male adults with recreational resistance training experience participated in this study. Participants completed three separate sessions of circuit barbell resistance exercises, including back squat, press, and deadlift. Each session corresponded to a different intensity level: 65% 1RM, 72% 1RM, and 78% 1RM. Each session consisted of 5 repetitions across 3 sets, with a 3-minute rest between exercises and sets. For the control condition, participants engaged in a reading activity for the same duration. The subjective exercise intensity was measured using the rating of perceived exertion and repetitions in reserve immediately after each set. The primary outcome was the temporal effect of acute resistance exercise on inhibition, measured by the Stroop color-word task. The secondary outcome was the effect of different intensities. Results: 30 out of 31 recruited participants were randomized, with 28 completing all experiment sessions. Using repeated measures correlation (rrm), a linear temporal effect was observed on accuracy-adjusted congruent reaction time: rrm = 0.114, p = 0.045, 95% CI [0.002, 0.223]. Participants responded 19.1 ms faster than the control condition approximately 10 minutes post-intervention. This advantage, however, gradually declined at a rate of 4.3 ms every 15 minutes between 10-55 minutes post-intervention. In contrast, no significant effects were detected for incongruent trials or the Stroop effect. When examining the linear relationship across exercise intensities, no significant correlations emerged for congruent trials. Conclusion: Resistance exercise demonstrates a temporal effect on cognitive performance, particularly in reaction speed for congruent trials, without significant changes in incongruent trials or the overall Stroop effect. The findings highlight the importance of timing in leveraging the cognitive benefits of acute resistance exercise, suggesting a window of enhanced cognitive performance following exercise. However, this study has a limitation regarding Type I error inflation, due to multiple measurements of cognitive performance being undertaken, suggesting caution in interpreting the observed temporal effects. Practically, scheduling crucial, cognitively demanding tasks within 10-60 minutes post-exercise may maximize benefits, as positive effects diminish after this period.

Efficacy and Safety of Crisaborole Ointment 2% in Chinese Patients Aged ≥ 2 Years with Mild to Moderate Atopic Dermatitis.

INTRODUCTION: Atopic dermatitis (AD) is a chronic immuno-inflammatory skin disease. Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor approved for the treatment of mild to moderate AD. This post hoc analysis assesses the efficacy and safety of crisaborole in Chinese patients aged ≥ 2 years with mild to moderate AD. METHODS: We evaluated the efficacy and safety of crisaborole in Chinese patients from the vehicle-controlled, phase 3 CrisADe CLEAR study. Patients were randomly assigned 2:1 to receive crisaborole or vehicle twice daily, respectively, for 28 days. The primary endpoint was percent change from baseline in Eczema Area and Severity Index (EASI) total score at day 29. Key secondary endpoints were improvement in Investigator's Static Global Assessment (ISGA), ISGA success, and change from baseline in weekly average Peak Pruritus Numerical Rating Scale (PP-NRS) score. Adverse events were documented. RESULTS: Of 391 patients in the overall study, 237 were from China, 157 assigned to crisaborole and 80 assigned to vehicle. A greater reduction in percent change from baseline in EASI total score at day 29 was shown in the crisaborole vs. vehicle group (least squares mean [LSM]: -66.34 [95% (confidence interval) CI -71.55 to -61.12] vs. -50.18 [95% CI -58.02 to -42.34]). Response rates for achievement of ISGA improvement (43.2% [95% CI 35.4-51.1] vs. 33.4% [95% CI 22.5-44.2]) and ISGA success (31.7% [95% CI 24.3-39.0] vs. 21.5% [95% CI 12.1-30.9]) at day 29 were higher in the crisaborole vs. vehicle group. A greater reduction in change from baseline in weekly average PP-NRS score at week 4 was observed in the crisaborole vs. vehicle group (LSM: -1.98 [95% CI -2.34 to -1.62] vs. -1.08 [95% CI -1.63 to -0.53]). No new safety signals were observed. CONCLUSION: Crisaborole was effective and well tolerated in Chinese patients aged ≥ 2 years with mild to moderate AD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04360187.

Cytochrome GmGLY1 is Involved in the Biosynthesis of Glycitein in Soybean.

Isoflavones, the major secondary metabolites of interest due to their benefits to both human and plant health, are exclusively produced by legumes. In this study, we profiled the isoflavone content in dry seeds from 211 soybean [Glycine max (L.) Merr.] accessions grown across five environments. Broad and discernible phenotypic variations were observed among accessions, regions, and years of growth. Twenty-six single-nucleotide polymorphisms (SNPs) associated with the sum of glycitein (GLE), glycitin (GL), 6″-O-acetylglycitin (AGL), and 6″-O-malonylglycitin (MGL) contents were detected in multiple environments via a genome-wide association study (GWAS). These SNPs were located on chromosome 11 (8,148,438 bp to 8,296,956 bp, renamed qGly11-01). Glyma.11g108300 (GmGLY1), a gene that encodes a P450 family protein, was identified via sequence variation analysis, functional annotation, weighted gene coexpression network analysis (WGCNA), and expression profile analysis of candidate gene, and hairy roots transformation in soybean. Overexpression of GmGLY1 increased the glycitein content (GLC) in soybean hairy roots and transgenic seeds, while CRISPR/Cas9-generated mutants exhibited decreased GLC and increased daidzein content (DAC). Haplotype analysis revealed that GmGLY1 allelic variations significantly affect the GLC accumulation. These findings enhance our understanding of genes influencing GLC in soybean and may guide breeding for lines with high and stable GLC.

NIR-activated electrospun nanodetonator dressing enhances infected diabetic wound healing with combined photothermal and nitric oxide-based gas therapy.

Diabetic wounds pose a challenge to healing due to increased bacterial susceptibility and poor vascularization. Effective healing requires simultaneous bacterial and biofilm elimination and angiogenesis stimulation. In this study, we incorporated polyaniline (PANI) and S-Nitrosoglutathione (GSNO) into a polyvinyl alcohol, chitosan, and hydroxypropyltrimethyl ammonium chloride chitosan (PVA/CS/HTCC) matrix, creating a versatile wound dressing membrane through electrospinning. The dressing combines the advantages of photothermal antibacterial therapy and nitric oxide gas therapy, exhibiting enduring and effective bactericidal activity and biofilm disruption against methicillin-sensitive Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and Escherichia coli. Furthermore, the membrane's PTT effect and NO release exhibit significant synergistic activation, enabling a nanodetonator-like burst release of NO through NIR irradiation to disintegrate biofilms. Importantly, the nanofiber sustained a uniform release of nitric oxide, thereby catalyzing angiogenesis and advancing cellular migration. Ultimately, the employment of this membrane dressing culminated in the efficacious amelioration of diabetic-infected wounds in Sprague-Dawley rats, achieving wound closure within a concise duration of 14 days. Upon applying NIR irradiation to the PVA-CS-HTCC-PANI-GSNO nanofiber membrane, it swiftly eradicates bacteria and biofilm within 5 min, enhancing its inherent antibacterial and anti-biofilm properties through the powerful synergistic action of PTT and NO therapy. It also promotes angiogenesis, exhibits excellent biocompatibility, and is easy to use, highlighting its potential in treating diabetic wounds.

The inputs of autochthonous organic carbon driven by mangroves reduce metal mobility and bioavailability in intertidal regions.

The significance of mangroves in carbon storage is widely acknowledged. However, the potential role of carbon enhancement driven by mangroves in mitigating the risk of metal exposure remains unclear. In this study, a natural mangrove reserve located in Futian was selected to investigate the potential role of autochthonous organic carbon on metal bioavailability. The presence of mangroves seemed to have little effect on the accumulations of Cu(II), Zn(II), Cr(VI/III), Pb(II), and Ni(II) in surface sediments. Metal mobility and bioavailability, however, were found to be directly influenced by the presence of mangroves. Compared with mudflat, mangrove sediments exhibited an obvious in the bioavailability of Cu(II), Zn(II), Cr(VI/III), Pb(II), and Ni(II) by 19-79 %, with the highest reduction occurring in the interior of mangroves dominated by K. obovata. Mangroves also significantly enhanced the accumulation of organic carbon in sediments, regardless of carbon components. Moreover, the results from random forest analysis further showed that autochthonous organic carbon was the most important carbon component that negatively related to metal bioavailability. In summary, this is the first study to provide a linkage between mangrove cover and increased autochthonous organic carbon input, which decreases metal bioavailability. The present data also suggest that mangroves are an efficient natural barrier to alleviate the risk of metal exposure in intertidal regions.

Association of Blood Copper With the Subclinical Carotid Atherosclerosis: An Observational Study.

BACKGROUND: Copper exposure is reported to be associated with increased risk of stroke. However, the association of copper exposure with subclinical carotid atherosclerosis remains unclear. METHODS AND RESULTS: This observational study included consecutive participants from Xinqiao Hospital between May 2020 and August 2021. Blood metals were measured using inductively coupled plasma mass spectrometry and carotid atherosclerosis was assessed using ultrasound. Modified Poisson regression was performed to evaluate the associations of copper and other metals with subclinical carotid plaque presence. Blood metals were analyzed as categorical according to the quartiles. Multivariable models were adjusted for age, sex, body mass index, education, smoking, drinking, hypertension, diabetes, dyslipidemia, estimated glomerular filtration rate, and coronary artery disease history. Bayesian Kernel Machine Regression was conducted to evaluate the overall association of metal mixture with subclinical carotid plaque presence. One thousand five hundred eighty-five participants were finally enrolled in our study, and carotid plaque was found in 1091 subjects. After adjusting for potential confounders, metal-progressively-adjusted models showed that blood copper was positively associated with subclinical carotid plaque (relative risk according to comparing quartile 4 to quartile 1 was 1.124 [1.021-1.238], relative risk according to per interquartile increment was 1.039 [1.008-1.071]). Blood cadmium and lead were also significantly associated with subclinical carotid plaque. Bayesian Kernel Machine Regression analyses suggested a synergistic effect of copper-cadmium-lead mixture on subclinical carotid plaque presence. CONCLUSIONS: Our findings identify copper as a novel risk factor of subclinical carotid atherosclerosis and show the potential synergistic proatherogenic effect of copper, cadmium, and lead mixture.

Association between vitamin B2 intake and prostate-specific antigen in American men: 2003-2010 National Health and Nutrition Examination Survey.

BACKGROUND: Accumulating evidence suggests a pivotal role of vitamin B2 in the pathogenesis and progression of prostate cancer (PCa). Vitamin B2 intake has been postulated to modulate the screening rate for PCa by altering the concentration of prostate-specific antigen(PSA). However, the relationship between vitamin B2 and PSA remains indeterminate. Hence, we conducted a comprehensive evaluation of the association between vitamin B2 intake and PSA levels, utilizing data from the National Health and Nutrition Examination Survey (NHANES) database. METHODS: From a pool of 20,371 participants in the NHANES survey conducted between 2003 and 2010, a cohort of 2,323 participants was selected for the present study. The male participants were classified into four distinct groups based on their levels of vitamin B2 intake. We employed a multiple linear regression model and a non-parametric regression method to investigate the relationship between vitamin B2 and PSA levels. RESULTS: The study cohort comprised of 2,323 participants with a mean age of 54.95 years (± 11.73). Our findings revealed a statistically significant inverse correlation between vitamin B2 intake (mg) and PSA levels, with a reduction of 0.13 ng/ml PSA concentration for every unit increase in vitamin B2 intake. Furthermore, we employed a fully adjusted model to construct a smooth curve to explore the possible linear relationship between vitamin B2 intake and PSA concentration. CONCLUSIONS: Our study in American men has unveiled a notable inverse association between vitamin B2 intake and PSA levels, potentially posing a challenge for the identification of asymptomatic prostate cancer. Specifically, our findings suggest that individuals with higher vitamin B2 intake may be at a greater risk of being diagnosed with advanced prostate cancer in the future, possibly indicating a detection bias. These results may offer a novel explanation for the observed positive correlation between vitamin B2 intake and prostate cancer.

CPT-11 mitigates autoimmune diseases by suppressing effector T cells without affecting long-term anti-tumor immunity.

The incidence of autoimmune diseases has significantly increased over the past 20 years. Excessive host immunoreactions and disordered immunoregulation are at the core of the pathogenesis of autoimmune diseases. The traditional anti-tumor chemotherapy drug CPT-11 is associated with leukopenia. Considering that CPT-11 induces leukopenia, we believe that it is a promising drug for the control of autoimmune diseases. Here, we show that CPT-11 suppresses T cell proliferation and pro-inflammatory cytokine production in healthy C57BL/6 mice and in complete Freund's adjuvant-challenged mice. We found that CPT-11 effectively inhibited T cell proliferation and Th1 and Th17 cell differentiation by inhibiting glycolysis in T cells. We also assessed CPT-11 efficacy in treating autoimmune diseases in models of experimental autoimmune encephalomyelitis and psoriasis. Finally, we proved that treatment of autoimmune diseases with CPT-11 did not suppress long-term immune surveillance for cancer. Taken together, these results show that CPT-11 is a promising immunosuppressive drug for autoimmune disease treatment.

Tolypocladium sinense Mycelium Polysaccharide Alleviates Obesity, Lipid Metabolism Disorder, and Inflammation Caused by High Fat Diet via Improving Intestinal Barrier and Modulating Gut Microbiota.

SCOPE: Tolypocladium sinense is a fungus isolated from Cordyceps. Cordyceps has some medicinal value and is also a daily health care product. This study explores the preventive effects of T. sinense mycelium polysaccharide (TSMP) on high-fat diet-induced obesity and chronic inflammation in mice. METHODS AND RESULTS: Here, the study establishes an obese mouse model induced by high-fat diet. In this study, the mice are administered TSMP daily basis to evaluate its effect on alleviating obesity. The results show that TSMP can significantly inhibit obesity and alleviate dyslipidemia by regulating the expression of lipid metabolism-related genes such as liver kinase B1 (LKB1), phosphorylated AMP-activated protein kinase (pAMPK), peroxisome proliferator activated receptor α (PPARα), fatty acid synthase (FAS), and hydroxymethylglutaryl-CoA reductase (HMGCR) in the liver. TSMP can increase the protein expression of zona occludens-1 (ZO-1), Occludin, and Claudin-1 in the colon, improve the intestinal barrier dysfunction, and reduce the level of serum LPS, thereby reducing the inflammatory response. 16S rDNA sequencing shows that TSMP alters the intestinal microbiota by increasing the relative abundance of Akkermansia, Lactobacillus, and Prevotellaceae_NK3B31_group, while decreasing the relative abundance of Faecalibaculum. CONCLUSION: The findings show that TSMP can inhibit obesity and alleviates obesity-related lipid metabolism disorders, inflammatory responses, and oxidative stress by modulating the gut microbiota and improving intestinal barrier.

MiR-3682-3p promotes esophageal cancer progression by targeting FHL1 and activating the Wnt/ß-catenin signaling pathway.

BACKGROUND: Esophageal cancer (EC) is highly ranked among all cancers in terms of its incidence and mortality rates. MicroRNAs (miRNAs) are considered to play key regulatory parts in EC. Multiple research studies have indicated the involvement of miR-3682-3p and four and a half LIM domain protein 1 (FHL1) in the achievement of tumors. The aim of this research was to clarify the significance of these genes and their possible molecular mechanism in EC. METHODS: Data from a database and the tissue microarray were made to analyze the expression and clinical significance of miR-3682-3p or FHL1 in EC. Reverse transcription quantitative PCR and Western blotting were used to detect the expression levels of miR-3682-3p and FHL1 in EC cells. CCK8, EdU, wound healing, Transwell, flow cytometry, and Western blotting assays were performed to ascertain the biological roles of miR-3682-3p and FHL1 in EC cells. To confirm the impact of miR-3682-3p in vivo, a subcutaneous tumor model was created in nude mice. The direct interaction between miR-3682-3p and FHL1 was demonstrated through a luciferase assay, and the western blotting technique was employed to assess the levels of crucial proteins within the Wnt/ß-catenin pathway. RESULTS: The noticeable increase in the expression of miR-3682-3p and the decrease in the expression of FHL1 were observed, which correlated with a negative impact on the patients' overall survival. Upregulation of miR-3682-3p expression promoted the growth and metastasis of EC, while overexpression of FHL1 partially reversed these effects. Finally, miR-3682-3p motivates the Wnt/ß-catenin signal transduction by directly targeting FHL1. CONCLUSION: MiR-3682-3p along the FHL1 axis activated the Wnt/ß-catenin signaling pathway and thus promoted EC malignancy.

LILRB2 promotes immune escape in breast cancer cells via enhanced HLA-A degradation.

PURPOSE: Increased expression of leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) is associated with immune evasion in breast cancer (BC). The aim of this study to elucidate the role of LILRB2 in BC progression. METHODS: LILRB2 expression in tumor tissues was detected by immunohistochemical staining. Human leukocyte antigen A (HLA-A) expression in BC cells was detected by Western blotting, and HLA-A ubiquitination was detected by immunoprecipitation and histidine pulldown assay. An in-situ tumor model was established in nude BALB/c mice to verify the role of LILRB2 in immune escape. Finally, the functions and potential mechanisms of LILRB2 in BC progression were explored using in silico data. RESULTS: LILRB2 was upregulated in BC tissues and cells, and correlated positively with poor prognosis. LILRB2 promoted BC progression by downregulating HLA-A expression. Mechanistically, LILRB2 facilitates the ubiquitination and subsequent degradation of HLA-A by promoting the interaction between the ubiquitin ligase membrane-associated ring finger protein 9 (MARCH9) and HLA-A. In syngeneic graft mouse models, LILRB2-expressing BC cells evaded CD8 + T cells and inhibited the secretion of cytokines by the cytotoxic CD8 + T cells. CONCLUSION: LILRB2 downregulates HLA-A to promote immune evasion in BC cells and is a promising new target for BC treatment.

In-situ growth of Mn-Ni3S2 on nickel foam for catalytic ozonation of p-nitrophenol.

In this study, a new catalyst for catalytic ozonation was obtained by in-situ growth of Mn-Ni3S2 nanosheets on the surface of nickel foam (NF). The full degradation of p-nitrophenol (PNP) was accomplished under optimal conditions in 40 min. The effects of material dosage, ozone dosage, pH and the presence of inorganic anions on the degradation efficiency of PNP were investigated. ESR analysis showed that singlet oxygen (1O2) and superoxide radical (O2•-) are the main contributors of PNP degradation. This study offers a new combination of supported catalysts with high efficiency and easy recovery, which provides a new idea for wastewater treatment.

Identification of hub genes and key pathways in spinal cord injury via bioinformatics analysis.

This study aimed to explore the hub genes and related key pathways in Spinal Cord Injury (SCI) based on the bioinformatics analysis. Two microarray datasets (GSE45006, GSE45550) were obtained from the GEO database and were merged and batch-corrected. The differentially expressed genes (DEGs) in SCI were explored with the Limma, and the weighted gene co-expression network analysis (WGCNA) was conducted to explore the module genes. Functional enrichment analysis and Gene set variation analysis (GSVA) were used to investigate the biological functions and key pathways of the key genes related to SCI. Then the protein-protein interaction (PPI) network was generated using the STING online tool, and the hub genes in SCI were identified. Receiver operating characteristic (ROC) curves were applied to assess the diagnostic value of the selected hub genes. We identified 554 DEGs in SCI, and 1236 key genes in SCI were selected via WGCNA. Totally 111 key genes related to SCI were discovered. Furthermore, the functional enrichment analysis showed that these key mRNAs were primarily enriched in the extracellular matrix (ECM)-related pathways and processes associated with wound healing and cell growth. The PPI network further filtered six hub genes (Cd44, Timp1, Loxl1, Col6a1, Col3a1, Col5a1) ranked by the degree, and the diagnostic value of the six hub genes was confirmed by the ROC curves. Six hub genes including Cd44, Timp1, Loxl1, Col6a1, Col3a1, and Col5a1 were identified in SCI, with differential expression and excellent diagnostic value, which might provide insight into the targeted therapy of SCI.

FBXO32-mediated degradation of PTEN promotes lung adenocarcinoma progression.

FBXO32, a member of the F-box protein family, is known to play both oncogenic and tumor-suppressive roles in different cancers. However, the functions and the molecular mechanisms regulated by FBXO32 in lung adenocarcinoma (LUAD) remain unclear. Here, we report that FBXO32 is overexpressed in LUAD compared with normal lung tissues, and high expression of FBXO32 correlates with poor prognosis in LUAD patients. Firstly, we observed with a series of functional experiments that FBXO32 alters the cell cycle and promotes the invasion and metastasis of LUAD cells. We further corroborate our findings using in vivo mouse models of metastasis and confirmed that FBXO32 positively regulates LUAD tumor metastasis. Using a proteomic-based approach combined with computational analyses, we found a positive correlation between FBXO32 and the PI3K/AKT/mTOR pathway, and identified PTEN as a FBXO32 interactor. More important, FBXO32 binds PTEN via its C-terminal substrate binding domain and we also validated PTEN as a bona fide FBXO32 substrate. Finally, we demonstrated that FBXO32 promotes EMT and regulates the cell cycle by targeting PTEN for proteasomal-dependent degradation. In summary, our study highlights the role of FBXO32 in promoting the PI3K/AKT/mTOR pathway via PTEN degradation, thereby fostering lung adenocarcinoma progression.

Pulse pressure is associated with decline in physical function in older adults.

OBJECTIVES: This study examined the associations between pulse pressure, hypertension, and the decline in physical function in a prospective framework. STUDY DESIGN: The Healthy Aging Longitudinal Study tracked a group of Taiwanese adults aged 55 or more over an average of 6.19 years to assess pulse pressure and decline in physical function, including in handgrip strength, gait speed, and 6-min walking distance, at baseline (2009-2013) and in the second phase of assessments (2013-2020). MAIN OUTCOME MEASURES: Pulse pressure was calculated as the difference between systolic and diastolic blood pressure values. Weakness, slowness, and low endurance were defined as decreases of ≥0.23 m/s (one standard deviation) in gait speed, ≥5.08 kg in handgrip strength, and ≥ 57.73 m in a 6-min walk, as determined from baseline to the second phase of assessment. Linear and logistic regressions were employed to evaluate the associations between pulse pressure, hypertension, and decline in physical function. RESULTS: Baseline pulse pressure was associated with future handgrip strength (beta = -0.017, p = 0.0362), gait speed (beta = -0.001, p < 0.0001), and 6-min walking distance (beta = -0.470, p < 0001). In multivariable models, only handgrip strength (beta = -0.016, p = 0.0135) and walking speed (beta = -0.001, p = 0.0042) remained significantly associated with future pulse pressure. Older adults with high systolic blood pressure (≥140 mmHg) and elevated pulse pressure (≥60 mmHg) exhibited a significantly increased risk of weakness (odds ratio: 1.30, 95 % confidence interval: 1.08-1.58), slowness (1.29, 1.04-1.59), and diminished endurance (1.25, 1.04-1.50) compared with the reference group, who exhibited systolic blood pressure of <140 mmHg and pulse pressure of <60 mmHg. CONCLUSIONS: Among older adults, pulse pressure is associated with a decline in physical function, especially in terms of strength and locomotion.

Cardiovascular Risk in Patients With Treated Isolated Diastolic Hypertension and Isolated Low Diastolic Blood Pressure.

BACKGROUND: The prognosis of high or markedly low diastolic blood pressure (DBP) with normalized on-treatment systolic blood pressure on major adverse cardiovascular events (MACEs) is uncertain. This study examined whether treated isolated diastolic hypertension (IDH) and treated isolated low DBP (ILDBP) were associated with MACEs in patients with hypertension. METHODS AND RESULTS: A total of 7582 patients with on-treatment systolic blood pressure <130 mm Hg from SPRINT (Systolic Blood Pressure Intervention Trial) were categorized on the basis of average DBP: <60 mm Hg (n=1031; treated ILDBP), 60 to 79 mm Hg (n=5432), ≥80 mm Hg (n=1119; treated IDH). MACE risk was estimated using Cox proportional-hazards models. Among the SPRINT participants, median age was 67.0 years and 64.9% were men. Over a median follow-up of 3.4 years, 512 patients developed a MACE. The incidence of MACEs was 3.9 cases per 100 person-years for treated ILDBP, 1.9 cases for DBP 60 to 79 mm Hg, and 1.8 cases for treated IDH. Comparing with DBP 60 to 79 mm Hg, treated ILDBP was associated with an 1.32-fold MACE risk (hazard ratio [HR], 1.32, 95% CI, 1.05-1.66), whereas treated IDH was not (HR, 1.18 [95% CI, 0.87-1.59]). There was no effect modification by age, sex, atherosclerotic cardiovascular disease risk, or cardiovascular disease history (all P values for interaction >0.05). CONCLUSIONS: In this secondary analysis of SPRINT, among treated patients with normalized systolic blood pressure, excessively low DBP was associated with an increased MACE risk, while treated IDH was not. Further research is required for treated ILDBP management.

Global, regional and national burdens of depression in adolescents and young adults aged 10-24 years, from 1990 to 2019: findings from the 2019 Global Burden of Disease study.

BACKGROUND: Depression is a significant mental health concern affecting the overall well-being of adolescents and young adults. Recently, the prevalence of depression has increased among young people. Nonetheless, there is little research delving into the longitudinal epidemiology of adolescent depression over time. AIMS: To investigate the longitudinal epidemiology of depression among adolescents and young adults aged 10-24 years. METHOD: Our research focused on young people (aged 10-24 years) with depression, using data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. We explored the age-standardised prevalence, incidence and disability-adjusted life-years (DALYs) of depression in different groups, including various regions, ages, genders and sociodemographic indices, from 1990 to 2019. RESULTS: The prevalence, incidence and DALYs of depression in young people increased globally between 1990 and 2019. Regionally, higher-income regions like High-Income North America and Australasia recorded rising age-standardised prevalence and incidence rates, whereas low- or middle-income regions mostly saw reductions. Nationally, countries such as Greenland, the USA and Palestine reported the highest age-standardised prevalence and incidence rates in 2019, whereas Qatar witnessed the largest growth over time. The burden disproportionately affected females across age groups and world regions. The most prominent age effect on incidence and prevalence rates was in those aged 20-24 years. The depression burden showed an unfavourable trend in younger cohorts born after 1980, with females reporting a higher cohort risk than males. CONCLUSIONS: Between 1990 and 2019, the general pattern of depression among adolescents varied according to age, gender, time period and generational cohort, across regions and nations.

Macrophage: A key player in neuropathic pain.

Research on the relationship between macrophages and neuropathic pain has flourished in the past two decades. It has long been believed that macrophages are strong immune effector cells that play well-established roles in tissue homeostasis and lesions, such as promoting the initiation and progression of tissue injury and improving wound healing and tissue remodeling in a variety of pathogenesis-related diseases. They are also heterogeneous and versatile cells that can switch phenotypically/functionally in response to the micro-environment signals. Apart from microglia (resident macrophages of both the spinal cord and brain), which are required for the neuropathic pain processing of the CNS, neuropathic pain signals in PNS are influenced by the interaction of tissue-resident macrophages and BM infiltrating macrophages with primary afferent neurons. And the current review looks at new evidence that suggests sexual dimorphism in neuropathic pain are caused by variations in the immune system, notably macrophages, rather than the neurological system.

Neuropathic pain is defined by the International Association for the Study of Pain as pain triggered or caused by primary damage to or dysfunction of the nervous system. Following intensive research into the mechanisms of neuropathic pain, macrophages have been revealed to play an important role in pathologic pain following nerve injury. Macrophages dynamically monitor the microenvironment to maintain tissue homeostasis. Once a macrophage is exposed to a pathologic stimulus, it in turn alters its functional phenotype and interacts with nociceptors, leading to neuropathic pain. This review wants to delve into the biology of macrophages in the central and peripheral nervous system, how they are related to play a role in neuropathic pain and whether there is sexual dimorphism in macrophages.