Single-particle rotational microrheology enables pathological staging of macrophage foaming and antiatherosclerotic studies.

The formation of macrophage-derived foam cells has been recognized as the pathological hallmark of atherosclerotic diseases. However, the pathological evolution dynamics and underlying regulatory mechanisms remain largely unknown. Herein, we introduce a single-particle rotational microrheology method for pathological staging of macrophage foaming and antiatherosclerotic explorations by probing the dynamic changes of lysosomal viscous feature over the pathological evolution progression. The principle of this method involves continuous monitoring of out-of-plane rotation-caused scattering brightness fluctuations of the gold nanorod (AuNR) probe-based microrheometer and subsequent determination of rotational relaxation time to analyze the viscous feature in macrophage lysosomes. With this method, we demonstrated the lysosomal viscous feature as a robust pathological reporter and uncovered three distinct pathological stages underlying the evolution dynamics, which are highly correlated with a pathological stage-dependent activation of the NLRP3 inflammasome-involved positive feedback loop. We also validated the potential of this positive feedback loop as a promising therapeutic target and revealed the time window-dependent efficacy of NLRP3 inflammasome-targeted drugs against atherosclerotic diseases. To our knowledge, the pathological staging of macrophage foaming and the pathological stage-dependent activation of the NLRP3 inflammasome-involved positive feedback mechanism have not yet been reported. These findings provide insights into in-depth understanding of evolutionary features and regulatory mechanisms of macrophage foaming, which can benefit the analysis of effective therapeutical drugs as well as the time window of drug treatment against atherosclerotic diseases in preclinical studies.

Gal-1-mediated cytochrome p450 activation promotes fibroblast into myofibroblast differentiation in pulmonary fibrosis.

Pulmonary fibrosis (PF) results from excessive extracellular matrix (ECM) deposition and tissue remodeling after activation of fibroblasts into myofibroblasts. Abnormally deposited fibrotic ECM, in turn, promotes fibroblast activation and accelerates loss of lung structure and function. However, the molecular mediators and exact mechanisms by which fibrotic ECM promotes fibroblast activation are unclear. In a bleomycin-induced PF mouse model, we found Galectin-1 (Gal-1) expression was significantly increased in lung tissue, and overexpression of Gal-1 plasmid-transfected fibroblasts were activated into myofibroblasts. Using the decellularization technique to prepare decellularized fibrotic ECM and constructing a 3D in vitro co-culture system with fibroblasts, we found that decellularized fibrotic ECM induced a high expression of Gal-1 and promoted the activation of fibroblasts into myofibroblasts. Therefore, Gal-1 has been identified as a pivotal mediator in PF. Further, we found that decellularized fibrotic ECM delivered mechanical signals to cells through the Gal-1-mediated FAK-Src-P130Cas mechanical signalling pathway, while the CYP450 enzymes (mainly involved in CYP1A1, CYP24A1, CYP3A4, and CYP2D6 isoforms) acted as a chemical signalling pathway to receive mechanical signals transmitted from upstream Gal-1, thereby promoting fibroblast activation. The Gal-1 inhibitor OTX008 or the CYP1A1 inhibitor 7-Hydroxyflavone prevented PF in mice and inhibited the role of fibrotic ECM in promoting fibroblast activation into myofibroblasts, preventing PF. These results reveal novel molecular mechanisms of lung fibrosis formation and identify Gal-1 and its downstream CYP1A1 as potential therapeutic targets for PF disease treatmnts.

Simultaneous In Vivo Imaging of Neutrophil Elastase and Oxidative Stress in Atherosclerotic Plaques Using a Unimolecular Photoacoustic Probe.

Atherosclerosis is a primary global health concern due to its high morbidity and mortality. This disease is characterized by a complex interplay of chronic inflammation, oxidative stress, and proteolytic enzymes. Traditional imaging techniques struggle to capture the dynamic biochemical processes within atherosclerotic plaques. Herein, we have developed a novel unimolecular photoacoustic probe (UMAPP) that combines specific recognition sites for neutrophil elastase (NE) and the redox pair O2•‒/GSH into a cohesive molecular platform, allowing in vivo monitoring of oxidative stress and activated neutrophils within plaques. UMAPP features a boron-dipyrromethene (BODIPY) core linked to a hydrophilic NE-cleavable tetrapeptide, and dual oxidative stress-responsive catechol moieties, enabling NE-mediated modulation of photoinduced electron transfer, affecting the photoacoustic intensity at 685 nm (PA685), while oxidation and reduction of the catechol groups by O2•‒ and GSH lead to reversible, ratiometric changes in the photoacoustic spectrum. Preliminary applications of UMAPP have successfully differentiated between atherosclerotic and healthy mice, assessed the impact of pneumonia on plaque composition, and validated the probe's efficacy in drug-treatment studies, detecting molecular changes prior to observable histopathological alterations. UMAPP's integrated molecular imaging approach holds significant promise for advancing the diagnosis and management of atherosclerosis by enabling earlier and more precise detection of vulnerable plaques.

A metabolome-wide Mendelian randomization study prioritizes causal circulating metabolites for reproductive disorders including primary ovarian insufficiency, polycystic ovary syndrome, and abnormal spermatozoa.

BACKGROUND: Accumulating studies have highlighted the significant role of circulating metabolomics in the etiology of reproductive system disorders. However, the causal effects between genetically determined metabolites (GDMs) and reproductive diseases, including primary ovarian insufficiency (POI), polycystic ovary syndrome (PCOS), and abnormal spermatozoa (AS), still await thorough clarification. METHODS: With the currently most comprehensive genome-wide association studies (GWAS) data of metabolomics, systematic two-sample Mendelian randomization (MR) analyses were conducted to disclose causal associations between 1,091 blood metabolites and 309 metabolite ratios with reproductive disorders. The inverse-variance weighted (IVW) method served as the primary analysis approach, and multiple effective MR methods were employed as complementary analyses including MR-Egger, weighted median, constrained maximum likelihood (cML-MA), contamination mixture method, robust adjusted profile score (MR-RAPS), and debiased inverse-variance weighted method. Heterogeneity and pleiotropy were assessed via MR-Egger intercept and Cochran's Q statistical analysis. Outliers were detected by Radial MR and MR-PRESSO methods. External replication and metabolic pathway analysis were also conducted. RESULTS: Potential causal associations of 63 GDMs with POI were unearthed, and five metabolites with strong causal links to POI were emphasized. Two metabolic pathways related to the pathogenesis of POI were pinpointed. Suggestive causal effects of 70 GDMs on PCOS were detected, among which 7 metabolites stood out for strong causality with elevated PCOS risk. Four metabolic pathways associated with PCOS mechanisms were recognized. For AS, 64 GDMs as potential predictive biomarkers were identified, particularly highlighting two metabolites for their strong causal connections with AS. Three pathways underneath the AS mechanism were identified. Multiple assessments were conducted to further confirm the reliability and robustness of our causal inferences. CONCLUSION: By extensively assessing the causal implications of circulating GDMs on reproductive system disorders, our study underscores the intricate and pivotal role of metabolomics in reproductive ill-health, laying a theoretical foundation for clinical strategies from metabolic insights.

Perfect correlation vortices.

We introduce perfect correlation vortices and show that the degree of coherence of any such vortex at the source is nearly statistically homogeneous and independent of the topological charge of the vortex. We demonstrate that while slowly diffracting in free space, perfect correlation vortices maintain their "perfect" vortex structure; they are capable of preserving said structure even in strong atmospheric turbulence. Structural resilience to diffraction and turbulence sets the discovered perfect vortices apart from their coherent cousins and makes them suitable for free-space optical communications.

Determination of hexachlorophene residue in fruits and vegetables by ultra-high performance liquid chromatography-tandem mass spectrometry.

A modified QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) -LC-MS/MS method was developed for the determination of hexachlorophene in fruits and vegetables. Samples were extracted by acetonitrile and then salted with an acetate buffer system. Extractants neutral alumina (Al-N), strong cation exchange silica gel bonded adsorbent (SCX) and graphitized carbon black (GCB) were used for sample purification. The method demonstrates excellent accuracy and reproducibility. Under optimized conditions, the correlation coefficients of hexachlorophene were higher than 0.995 in the range of 0.5-20 ng/mL. The limit of quantification (LOQ) was 2.0 µg/kg. The average recoveries, assessed at three spiked levels (2.0, 4.0, and 20.0µg/kg) across various matrices including cabbage, celery, tomato, eggplant, potato, radish, cowpea, chives, apple, peach, grape, citrus, bitter melon, banana and hami melon ranged from 72.0 to 100.5% with relative standard deviations from 3.2 to 9.8% (n = 6).

Best evidence summary for aspiration prevention and management in critically ill patients with nasogastric feeding.

AIM: To evaluate and summarize the available evidence on the prevention and management of nasogastric aspiration in critically ill patients to inform the development of evidence-based clinical practice. DESIGN: This study was an evidence summary according to the evidence summary reporting standard of the Fudan University Center for Evidence-Based Nursing. METHOD: According to the '6S' model of evidence resources, evidence on the prevention and management of aspiration in critically ill patients on nasogastric feeding was retrieved, including clinical decision-making, best practices, guidelines, evidence summaries, expert consensus and systematic evaluations. DATA: UpToDate, BMJ Best Practice, JBI, National Guideline Clearing-house, Guidelines International Network, Scottish Intercollegiate Guidelines Network, National Institute for Health and Care Excellence, Registered Nurses Association of Ontario, Yi Mai tong Guidelines Network, the Cochrane Library, PubMed, Web of Science, Embase, OVID, Sinomed, CNKI, Wan Fang database. The search period was from January 2013 to June 2023. RESULTS: We included a total of 30 high-quality articles and summarized 36 pieces of evidence from them. These pieces of evidence covered 11 dimensions of multidisciplinary management, aspiration risk assessment, tube location, nutritional infusion management, position management, airway management, and oral hygiene. The level of evidence in the study was predominantly level 1 and level 5, with 27 pieces of evidence recommended as 'strong' and 9 pieces of evidence recommended as 'weak'. CONCLUSION: This study summarizes 36 pieces of evidence on preventing and managing aspiration in critically ill patients with nasogastric feeding. But the characteristics of hospitals should be considered in the application of future evidence. IMPACT: Aspiration is the most serious complication during nasogastric feeding, which seriously affects the prognosis of patients. Preventing and managing aspiration in nasogastric patients has proven to be a challenging clinical problem. This study summarized 36 pieces of best evidence in 11 dimensions, including multidisciplinary team, assessment and identification, line position, feeding management, and so on. The implementation of these evidences is conducive to standardizing the operation behaviour of nasogastric feeding in clinical medical staff and reducing the occurrence of aspiration. REPORTING METHOD: This research followed the evidence summary reporting specifications of the Fudan University Center for Evidence-based Nursing. TRIAL REGISTRATION: The registration number is 'ES20221368'.

Perioperative outcomes of transvaginal specimen extraction laparoscopic total gastrectomy and conventional laparoscopic-assisted total gastrectomy.

BACKGROUND: Natural orifice specimen extraction surgery (NOSES) has emerged as a promising alternative compared to conventional laparoscopic-assisted total gastrectomy (LATG) for treating gastric cancer (GC). However, evidence regarding the efficacy and safety of NOSES for GC surgery is limited. This study aimed to compare the safety and feasibility, in addition to postoperative complications of NOSES and LATG. AIM: To discuss the postoperative effects of two different surgical methods in patients with GC. METHODS: Dual circular staplers were used in Roux-en-Y digestive tract reconstruction for transvaginal specimen extraction LATG, and its outcomes were compared with LATG in a cohort of 51 GC patients with tumor size ≤ 5 cm. The study was conducted from May 2018 to September 2020, and patients were categorized into the NOSES group (n = 22) and LATG group (n = 29). Perioperative parameters were compared and analyzed, including patient and tumor characteristics, postoperative outcomes, and anastomosis-related complications, postoperative hospital stay, the length of abdominal incision, difference in tumor type, postoperative complications, and postoperative survival. RESULTS: Postoperative exhaust time, operation duration, mean postoperative hospital stay, length of abdominal incision, number of specific staplers used, and Brief Illness Perception Questionnaire score were significant in both groups (P < 0.01). In the NOSES group, the postoperative time to first flatus, mean postoperative hospital stay, and length of abdominal incision were significantly shorter than those in the LATG group. Patients in the NOSES group had faster postoperative recovery, and achieved abdominal minimally invasive incision that met aesthetic requirements. There were no significant differences in gender, age, tumor type, postoperative complications, and postoperative survival between the two groups. CONCLUSION: The application of dual circular staplers in Roux-en-Y digestive tract reconstruction combined with NOSES gastrectomy is safe and convenient. This approach offers better short-term outcomes compared to LATG, while long-term survival rates are comparable to those of conventional laparoscopic surgery.

Sclerostin inhibition in rare bone diseases: Molecular understanding and therapeutic perspectives.

Sclerostin emerges as a novel target for bone anabolic therapy in bone diseases. Osteogenesis imperfecta (OI) and X-linked hypophosphatemia (XLH) are rare bone diseases in which therapeutic potential of sclerostin inhibition cannot be ignored. In OI, genetic/pharmacologic sclerostin inhibition promoted bone formation of mice, but responses varied by genotype and age. Serum sclerostin levels were higher in young OI-I patients, while lower in adult OI-I/III/IV. It's worth investigating whether therapeutic response of OI to sclerostin inhibition could be clinically predicted by genotype and age. In XLH, preclinical/clinical data suggested factors other than identified FGF23 contributing to XLH. Higher levels of circulating sclerostin were detected in XLH. Sclerostin inhibition promoted bone formation in Hyp mice, while restored phosphate homeostasis in age-/gender-dependent manner. The role of sclerostin in regulating phosphate metabolism deserves investigation. Sclerostin/FGF23 levels of XLH patients with/without response to FGF23-antibody warrants study to develop precise sclerostin/FGF23 inhibition strategy or synergistic/additive strategy. Notably, OI patients were associated with cardiovascular abnormalities, so were XLH patients receiving conventional therapy. Targeting sclerostin loop3 promoted bone formation without cardiovascular risks. Further, blockade of sclerostin loop3-LRP4 interaction while preserving sclerostin loop2-ApoER2 interaction could be a potential precise sclerostin inhibition strategy for OI and XLH with cardiovascular safety. The Translational Potential of this Article. Preclinical data on the molecular understanding of sclerostin inhibition in OI and therapeutic efficacy in mouse models of different genotypes, as well as clinical data on serum sclerostin levels in patients with different phenotypes of OI, were reviewed and discussed. Translationally, it would facilitate to develop clinical prediction strategies (e.g. based on genotype and age, not just phenotype) for OI patients responsive to sclerostin inhibition. Both preclinical and clinical data suggested sclerostin as another factor contributing to XLH, in addition to the identified FGF23. The molecular understanding and therapeutic effects of sclerostin inhibition on both promoting bone anabolism and improving phosphate homostasis in Hyp mice were reviewed and discussed. Translationaly, it would facilitate the development of precise sclerostin/FGF23 inhibition strategy or synergistic/additive strategy for the treatment of XLH. Cardiovascular risk could not be ruled out during sclerostin inhibition treatment, especially for OI and XLH patients with cardiovascular diseases history and cardiovascular abnormalities. Studies on the role of sclerostin in inhiting bone formation and protecting cardiovascular system were reviewed and discussed. Translationaly, blockade of sclerostin loop3-LRP4 interaction while preserving sclerostin loop2-ApoER2 interaction could be a potential precise sclerostin inhibition strategy for OI and XLH with cardiovascular safety.

Sextuple knockouts of a highly conserved and coexpressed AUXIN/INDOLE-3-ACETIC ACID gene set confer shade avoidance-like responses in Arabidopsis.

AUXIN/INDOLE-3-ACETIC ACIDs are transcriptional repressors for auxin signalling. Aux/IAAs of Arabidopsis thaliana display some functional redundancy. The IAA3/SHY2 clade (IAA1, IAA2, IAA3 and IAA4) show strong sequence similarity, but no higher-order mutants have been reported. Here, through CRISPR/Cas9 genome editing, we generated loss-of-function iaa1/2/3/4 mutants. The quadruple mutants only exhibited a weak phenotype. Thus, we additionally knocked out IAA7/AXR2 and IAA16, which are coexpressed with IAA1/2/3/4. Remarkably, under white light control conditions, the iaa1/2/3/4/7/16 mutants exhibited a shade avoidance-like phenotype with over-elongated hypocotyls and petioles and hyponastic leaves. The sextuple mutants were highly sensitive to low light intensity, and the hypocotyl cells of the mutants were excessively elongated. Transcriptome profiling and qRT-PCR analyses revealed that the sextuple mutation upregulated IAA19/MSG2 and IAA29, two shared shade/auxin signalling targets. Besides, genes encoding cell wall-remodelling proteins and shade-responsive transcription regulators were upregulated. Using dual-luciferase reporter assays, we verified that IAA2/IAA7 targeted the promoters of cell wall-remodelling genes to inhibit their transcription. Our work indicates that the IAA1/2/3/4/7/16 gene set is required for the optimal integration of auxin and shade signalling. The mutants generated here should be valuable for exploring the complex interactions among signal sensors, transcription activators and transcription repressors during hormone/environmental responses.

Revealing the mechanisms of blood-brain barrier in chronic neurodegenerative disease: an opportunity for therapeutic intervention.

The brain microenvironment is tightly regulated, and the blood-brain barrier (BBB) plays a pivotal role in maintaining the homeostasis of the central nervous system. It effectively safeguards brain tissue from harmful substances in peripheral blood. However, both acute pathological factors and age-related biodegradation have the potential to compromise the integrity of the BBB and are associated with chronic neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), as well as Epilepsy (EP). This association arises due to infiltration of peripheral foreign bodies including microorganisms, immune-inflammatory mediators, and plasma proteins into the central nervous system when the BBB is compromised. Nevertheless, these partial and generalized understandings do not prompt a shift from passive to active treatment approaches. Therefore, it is imperative to acquire a comprehensive and in-depth understanding of the intricate molecular mechanisms underlying vascular disease alterations associated with the onset and progression of chronic neurodegenerative disorders, as well as the subsequent homeostatic changes triggered by BBB impairment. The present article aims to systematically summarize and review recent scientific work with a specific focus on elucidating the fundamental mechanisms underlying BBB damage in AD, PD, and EP as well as their consequential impact on disease progression. These findings not only offer guidance for optimizing the physiological function of the BBB, but also provide valuable insights for developing intervention strategies aimed at early restoration of BBB structural integrity, thereby laying a solid foundation for designing drug delivery strategies centered around the BBB.

Advancing targeted combination chemotherapy in triple negative breast cancer: nucleolin aptamer-mediated controlled drug release.

BACKGROUND: Triple-negative breast cancer (TNBC) is a recurrent, heterogeneous, and invasive form of breast cancer. The treatment of TNBC patients with paclitaxel and fluorouracil in a sequential manner has shown promising outcomes. However, it is challenging to deliver these chemotherapeutic agents sequentially to TNBC tumors. We aim to explore a precision therapy strategy for TNBC through the sequential delivery of paclitaxel and fluorouracil. METHODS: We developed a dual chemo-loaded aptamer with redox-sensitive caged paclitaxel for rapid release and non-cleavable caged fluorouracil for slow release. The binding affinity to the target protein was validated using Enzyme-linked oligonucleotide assays and Surface plasmon resonance assays. The targeting and internalization abilities into tumors were confirmed using Flow cytometry assays and Confocal microscopy assays. The inhibitory effects on TNBC progression were evaluated by pharmacological studies in vitro and in vivo. RESULTS: Various redox-responsive aptamer-paclitaxel conjugates were synthesized. Among them, AS1411-paclitaxel conjugate with a thioether linker (ASP) exhibited high anti-proliferation ability against TNBC cells, and its targeting ability was further improved through fluorouracil modification. The fluorouracil modified AS1411-paclitaxel conjugate with a thioether linker (FASP) exhibited effective targeting of TNBC cells and significantly improved the inhibitory effects on TNBC progression in vitro and in vivo. CONCLUSIONS: This study successfully developed fluorouracil-modified AS1411-paclitaxel conjugates with a thioether linker for targeted combination chemotherapy in TNBC. These conjugates demonstrated efficient recognition of TNBC cells, enabling targeted delivery and controlled release of paclitaxel and fluorouracil. This approach resulted in synergistic antitumor effects and reduced toxicity in vivo. However, challenges related to stability, immunogenicity, and scalability need to be further investigated for future translational applications.

Adherence to a Healthy Diet and Risk of Multiple Carotid Atherosclerosis Subtypes: Insights from the China MJ Health Check-Up Cohort.

AIM: Early-stage phenotypes of carotid atherosclerosis (CAS), such as increased carotid intima-media thickness (cIMT), and advanced-stage phenotypes, such as carotid plaque (CP), are at risk for adverse ischemic stroke events. There is limited evidence regarding the causal association between dietary patterns and the risk of CAS in Chinese adults. We therefore examined multiple dietary patterns associated with the risk of CAS and identified the optimal dietary pattern for preventing CAS. METHODS: We analyzed data collected from the prospective MJ Health Check-up Study (2004-2020), including 13,989 participants 18-80 years of age without CAS. The dietary intake was measured using validated food frequency questionnaires, and dietary pattern scores were calculated for four a priori and four a posteriori dietary patterns. The Cox model was used to estimate the adjusted hazard ratios (HRs) relating various dietary pattern scores to the risk of CAS. RESULTS: During 43,903.4 person-years of follow-up, 3732 incidents of increased cIMT and 2861 incident CP events were documented. Overall, the seven dietary patterns, except for the high-protein diet, exhibited significant associations with the risk of increased cIMT and CP. Comparing the highest and lowest quartiles, the a posteriori high-fiber dietary pattern (HFIDP) score demonstrated the strongest inverse associations with the risk of increased cIMT (HR 0.65 [95% confidence interval (CI) 0.59-0.71]) and CP (HR 0.65 [95% CI 0.59-0.73]); conversely, another a posteriori high-fat dietary pattern (HFADP; i.e., incorporating high-fat and processed foods) demonstrated the strongest positive associations with the risk of increased cIMT (HR 1.96 [95% CI 1.75-2.20]) and CP (HR 1.83 [95% CI 1.61-2.08]) (all p for trend < 0.01). CONCLUSIONS: Multiple dietary patterns are significantly associated with the risk of early- and advanced-stage phenotypes of CAS. Notably, a high adherence to an HFIDP and low adherence to an HFADP may confer the greatest risk reduction for CAS.

Expression levels and clinical significance of serum miR-19a/CCL20 in patients with acute cerebral infarction.

Acute cerebral infarction (ACI) is a lethal disease whose early diagnosis is critical for treatment. microRNA (miR)-19a targets CC chemokine ligand 20 (CCL20) in myocardial infarction. We investigated the expression patterns of serum miR-19a and CCL20 of ACI patients and assessed their clinical values. Serum samples of 50 healthy subjects and110 ACI patients were collected. Serum levels of miR-19a, CCL20 mRNA, and biochemical indexes were assessed. miR-19a downstream target gene and the binding relationship between miR-19a and CCL20 were predicted and verified. miR-19a and CCL20 mRNA were subjected to correlation and diagnostic efficiency analysis. miR-19a was poorly expressed in the serum of ACI patients, especially in patients with unstable plaque and large infarction. tumor necrosis factor-α, low-density lipoprotein, and platelet/lymphocyte ratio negatively correlated with serum miR-19a level and positively correlated with CCL20. Dual-luciferase assay revealed that miR-19a could negatively regulate CCL20 expression. CCL20 was highly expressed in the serum of ACI patients. The area under receiver-operating characteristic curve of miR-19a combined with CCL20 was 0.9741 (98.00% specificity, 90.91% sensitivity), higher than their single diagnosis. Collectively, miR-19a had high diagnostic value for ACI and could target to restrain CCL20. The combination of miR-19a and CCL20 improved diagnostic value for ACI.

Biomass-Derived Materials for Advanced Rechargeable Batteries.

Biomass-derived materials generally exhibit uniform and highly-stable hierarchical porous structures that can hardly be achieved by conventional chemical synthesis and artificial design. When used as electrodes for rechargeable batteries, these structural and compositional advantages often endow the batteries with superior electrochemical performances. This review systematically introduces the innate merits of biomass-derived materials and their applications as the electrode for advanced rechargeable batteries, including lithium-ion batteries, sodium-ion batteries, potassium-ion batteries, and metal-sulfur batteries. In addition, biomass-derived materials as catalyst supports for metal-air batteries, fuel cells, and redox-flow batteries are also included. The major challenges for specific batteries and the strategies for utilizing biomass-derived materials are detailly introduced. Finally, the future development of biomass-derived materials for advanced rechargeable batteries is prospected. This review aims to promote the development of biomass-derived materials in the field of energy storage and provides effective suggestions for building advanced rechargeable batteries.

Aptamer functionalized hypoxia-potentiating agent and hypoxia-inducible factor inhibitor combined with hypoxia-activated prodrug for enhanced tumor therapy.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. Hypoxia-activated prodrugs (HAPs) have shown promise as potential therapeutic agents for TNBC. While increasing hypoxia levels may promote the HAP activation, it raises concerns regarding HIF1α-dependent drug resistance. It is desirable to develop a targeted approach that enhances tumor hypoxia for HAP activation without promoting HIF1α-dependent drug resistance in TNBC treatment. Herein, we proposed a multi-responsive carrier-free self-assembled nanomedicine named AQ4N@CA4T1ASO. This nanomedicine first targeted tumors by the TNBC-targeting aptamers (T1), and then disassembled in the reductive and acidic conditions within tumors. The released Combretastatin 4 (CA4) could exacerbate hypoxia, thereby promoting the conversion of inactive Banoxantrone (AQ4N) to its active form, AQ4. Simultaneously, the released antisense oligonucleotide (ASO) could attenuate hypoxia-induced HIF1α mRNA expression, thereby sensitizing the tumor to chemotherapy. Overall, this smart nanomedicine represents a profound targeted therapy strategy, combining "hypoxia-potentiating, hypoxia-activated, chemo-sensitization" approaches for TNBC treatment. In vivo study demonstrated significant suppression of tumor growth, highlighting the promising potential of this nanomedicine for future clinical translation.

High-Sensitivity Troponin T, NT-proBNP, and Cognitive Outcomes in SPRINT.

BACKGROUND: Hs-cTnT (cardiac troponin T measured with a highly sensitive assay) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) may identify adults with hypertension who derive greater cognitive benefits from lower systolic blood pressure targets. METHODS: In the SPRINT (Systolic Blood Pressure Intervention Trial) MIND study, participants were categorized as having both hs-cTnT and NT-proBNP in the lower 2 tertiles (n=4226), one in the highest tertile (n=2379), and both in the highest tertile (n=1506). We assessed the effect of intensive versus standard treatment on the composite of mild cognitive impairment (MCI) or probable dementia (PD) across biomarker categories. RESULTS: Over a median follow-up of 5.1 years, 830 of 8111 participants (10.2%) developed MCI or PD. Participants in the highest biomarker category were at higher risk of MCI or PD compared with those in the lowest category (hazard ratio, 1.34 [95% CI, 1.00-1.56]). The effect of intensive treatment on reducing the risk of MCI or PD was greater among participants in the lowest biomarker category (hazard ratio, 0.64 [95% CI, 0.50-0.81]) than those in the intermediate (hazard ratio, 1.01 [95% CI, 0.80-1.28]) or highest categories (hazard ratio, 0.90 [95% CI, 0.72-1.13]; Pinteraction=0.02). The 5-year absolute risk differences in MCI or PD with intensive treatment were -2.9% (-4.4%, -1.3%), -0.2% (-3.0%, 2.6%), and -1.9% (-6.2%, 2.4%) in the lowest, intermediate, and highest biomarker categories, respectively. CONCLUSIONS: In SPRINT, the relative effect of intensive systolic blood pressure lowering on preventing cognitive impairment appears to be stronger among participants with lower compared with higher cardiac biomarker levels, though the absolute risk reductions were similar.

Bacillus amyloliquefaciens Protect Against Atherosclerosis Through Alleviating Foam Cell Formation and Macrophage Polarization.

This study was to investigate the therapeutic effect of Bacillus amyloliquefaciens (Ba) on atherosclerosis (AS). THP-1 monocyte was differentiated to THP-1 macrophage (THP-M) through phorbol 12-myristate 13-acetate. After pre-treatment by 108 cfu/ml Ba lasting 6 h, THP-M was induced with 100 mg/l ox-LDL lasting 48 h to form macrophage foam cell (THP-F). RT-qPCR and flow cytometry were employed to determine the polarization of THP-M and THP-F. ApoE-/- mice with high-fat and high-cholesterol diet were used for constructing an AS model to evaluate the effect of Ba on AS. Our in vitro results showed that Ba vegetative cells pre-treatment distinctly inhibited the levels of iNOS and CD16/CD32 (M1 macrophage markers), and increased the levels of FIZZ1, Ym1, Arg1, CD163, and CD206 (M2 macrophage markers), indicating that Ba pre-treatment promoted anti-inflammatory M2-like polarization both in THP-M and THP-F. Meanwhile, it also suppressed cholesterol uptake, esterification, and hydrolysis, and efflux by THP-M and THP-F. Additionally, our animal experiments demonstrated that Ba vegetative cells treatment suppressed high cholesterol, hyperglycemia, hyperlipidemia, and the release of inflammatory factors (TNF-α, IL-6 and IL-1ß) in ApoE-/- AS mice. In a word, our results indicated that Ba may protect against AS through alleviating foam cell formation and macrophage polarization through targeting certain stages of AS.

Serum Metabolomics Reveals Metabolomic Profile and Potential Biomarkers in Asthma.

PURPOSE: Asthma is a highly heterogeneous disease. Metabolomics plays a pivotal role in the pathogenesis and development of asthma. The main aims of our study were to explore the underlying mechanism of asthma and to identify novel biomarkers through metabolomics approach. METHODS: Serum samples from 102 asthmatic patients and 18 healthy controls were collected and analyzed using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) system. Multivariate analysis and weighted gene co-expression network analysis (WGCNA) were performed to explore asthma-associated metabolomics profile and metabolites. The Kyoto Encyclopedia of Genes and Genomes (KEGG) was used for pathway enrichment analysis. Subsequently, 2 selected serum hub metabolites, myristoleic acid and dodecanoylcarnitine, were replicated in a validation cohort using ultra-high performance LC-MS/MS system (UHPLC-MS/MS). RESULTS: Distinct metabolomics profile of asthma was revealed by multivariate analysis. Then, 116 overlapped asthma-associated metabolites between multivariate analysis and WGCNA, including 12 hub metabolites, were identified. Clinical features-associated hub metabolites were also identified by WGCNA. Among 116 asthma-associated metabolites, Sphingolipid metabolism and valine, leucine and isoleucine biosynthesis were revealed by KEGG analysis. Furthermore, serum myristoleic acid and dodecanoylcarnitine were significantly higher in asthmatic patients than in healthy controls in validation cohort. Additionally, serum myristoleic acid and dodecanoylcarnitine demonstrated high sensitivities and specificities in predicting asthma. CONCLUSIONS: Collectively, asthmatic patients showed a unique serum metabolome. Sphingolipid metabolism and valine, leucine and isoleucine biosynthesis were involved in the pathogenesis of asthma. Furthermore, our results suggest the promising values of serum myristoleic acid and dodecanoylcarnitine for asthma diagnosis in adults.

A study on the physical aging characteristics of the older people over 70 years old in China.

Aim: In China, with the increase of life expectancy and the decrease of fertility rate, the aging problem has become increasingly prominent, and the physical problems of the older people over 70 years are the key and difficult problems. Method: Based on the interactive logic between the aging problem and the older people health, in the study, a questionnaire survey and a nationwide physical fitness test were carried out on the older people over 70, to divide into different age groups (70-74 years old, 75-79 years old, 80-84 years old, 85 years old and older) and different genders. There were 8,400 valid samples, and 1,050 persons in each group. One-way ANOVA was used to compare the differences among groups of different ages, and a broken line chart was drawn to discuss the aging characteristics of various physical indexes of the older people over 70 in China. Result: (1) Body morphology: male waist circumference, male waist-to-height ratio and female BMI showed a gradual downward trend with the increase of age; (2) Physiological function: male and female vital capacity showed a decreasing trend with the increase of age, while female pulse pressure showed a gradual upward trend. (3) Physical quality: the indicators of male and female muscle strength, flexibility quality, aerobic endurance and balance showed a downward trend with the increase of age. Conclusion: Vital capacity, flexibility quality, muscle strength, aerobic endurance, balance ability and so on, decreased significantly with the growth of age. 80 years old is the inflection point of the rapid decline of various indicators. Blood pressure, silent pulse, BMI, waist-to-hip ratio, waist-to-height ratio and other indicators did not change regularly with age. Indicators such as blood pressure, BMI, waist-to-hip ratio and waist-to-height ratio were in the high-risk range of metabolic diseases and cardiovascular and cerebrovascular diseases. The study conducted physical fitness test on the older people over 70 years old in 7 geographical regions of China, which is the first nationwide physical fitness test for the older people, which is an extension and expansion of the national physical fitness monitoring system, and also shows that the test indicators involved in the "Health fitness scale" are simple and feasible. And the study added a series of test data over 70 years old, which is the basis for scientific and reasonable formulation of physical fitness evaluation standards for the older people, and is of great significance for improving the national physical fitness database and grasping the dynamic changes of national physical health status, and providing data support for scientific guidance of physical exercise for the older people.