Gamma-glutamyl transferase 5 overexpression in cerebrovascular endothelial cells improves brain pathology, cognition, and behavior in APP/PS1 mice.

JOURNAL/nrgr/04.03/01300535-202502000-00030/figure1/v/2024-05-28T214302Z/r/image-tiff In patients with Alzheimer's disease, gamma-glutamyl transferase 5 (GGT5) expression has been observed to be downregulated in cerebrovascular endothelial cells. However, the functional role of GGT5 in the development of Alzheimer's disease remains unclear. This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer's disease, as well as the underlying mechanism. We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer's disease (Aß1-42-treated hCMEC/D3 and bEnd.3 cells), as well as in the APP/PS1 mouse model. Additionally, injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits. Interestingly, increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-ß in the brains of APP/PS1 mice. This effect may be attributable to inhibition of the expression of ß-site APP cleaving enzyme 1, which is mediated by nuclear factor-kappa B. Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer's disease pathogenesis, and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice. These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer's disease.

Identification of genetic susceptibility for Chinese migraine with depression using machine learning.

Background: Migraine is a common primary headache that has a significant impact on patients' quality of life. The co-occurrence of migraine and depression is frequent, resulting in more complex symptoms and a poorer prognosis. The evidence suggests that depression and migraine comorbidity share a polygenic genetic background. Objective: The aim of this study is to identify related genetic variants that contribute to genetic susceptibility to migraine with and without depression in a Chinese cohort. Methods: In this case-control study, 263 individuals with migraines and 223 race-matched controls were included. Eight genetic polymorphism loci selected from the GWAS were genotyped using Sequenom's MALDI-TOF iPLEX platform. Results: In univariate analysis, ANKDD1B rs904743 showed significant differences in genotype and allele distribution between migraineurs and controls. Furthermore, a machine learning approach was used to perform multivariate analysis. The results of the Random Forest algorithm indicated that ANKDD1B rs904743 was a significant risk factor for migraine susceptibility in China. Additionally, subgroup analysis by the Boruta algorithm showed a significant association between this SNP and migraine comorbid depression. Migraineurs with depression have been observed to have worse scores on the Beck Anxiety Inventory (BAI) and the Migraine Disability Assessment Scale (MIDAS). Conclusion: The study indicates that there is an association between ANKDD1B rs904743 and susceptibility to migraine with and without depression in Chinese patients.

Identification of Isoliensinine as a Ferroptosis Suppressor with Iron-Chelating Activity.

Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of lipid peroxides. The high involvement of ferroptosis in diverse human diseases highlights the need for the identification of new chemotypes with anti-ferroptotic activity. Here, we performed a natural product library screening in HT1080 fibrosarcoma cells and identified licochalcone A (LA), isoeugenyl acetate (ISA), and isoliensinine (ISL) as suppressors of either RSL3- or IKE-induced ferroptosis. Mechanistically, ferroptosis resistance conferred by these compounds is mainly through GPX4/NRF2-independent mechanisms. Among them, only ISL could effectively rescue ferroptosis induced by FINO2, which is a stable oxidant of ferrous iron, suggesting that ISL may have the properties of an iron chelator. Consistent with the hypothesis, both computational tools and X-ray photoelectron spectroscopy supported the binding between ISL and iron ions. And ISL greatly inhibited excessive iron-dependent ferroptotic cell death through limiting intracellular iron accumulation. Furthermore, its iron chelator activity also protected mice from organ injury in an acute iron overload model. In conclusion, this study provided valuable insights for developing effective anti-ferroptosis agents from natural products, which represent a potential therapeutic strategy for treating ferroptosis-associated organ damage.

Genome-wide CRISPR screening identifies critical role of phosphatase and tensin homologous (PTEN) in sensitivity of acute myeloid leukemia to chemotherapy. / å ¨åŸºå› ç»„CRISPR筛选揭示PTENåŸºå› åœ¨æ€¥æ€§é«“ç³»ç™½è¡€ç— åŒ–ç–—æ•æ„Ÿæ€§ä¸­çš„å ³é”®ä½œç”¨.

Although significant progress has been made in the development of novel targeted drugs for the treatment of acute myeloid leukemia (AML) in recent years, chemotherapy still remains the mainstay of treatment and the overall survival is poor in most patients. Here, we demonstrated the antileukemia activity of a novel small molecular compound NL101, which is formed through the modification on bendamustine with a suberanilohydroxamic acid (SAHA) radical. NL101 suppresses the proliferation of myeloid malignancy cells and primary AML cells. It induces DNA damage and caspase 3-mediated apoptosis. A genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) library screen revealed that phosphatase and tensin homologous (PTEN) gene is critical for the regulation of cell survival upon NL101 treatment. The knockout or inhibition of PTEN significantly reduced NL101-induced apoptosis in AML and myelodysplastic syndrome (MDS) cells, accompanied by the activation of protein kinase B (AKT) signaling pathway. The inhibition of mammalian target of rapamycin (mTOR) by rapamycin enhanced the sensitivity of AML cells to NL101-induced cell death. These findings uncover PTEN protein expression as a major determinant of chemosensitivity to NL101 and provide a novel strategy to treat AML with the combination of NL101 and rapamycin.

ß-Caryophyllene Confers Cardioprotection by Scavenging Radicals and Blocking Ferroptosis.

Ferroptosis is a form of regulated cell death triggered by iron-dependent lipid peroxidation and has been associated with heart diseases. However, there are currently no approved drugs that specifically inhibit ferroptosis in clinical practice, which largely limits the translational potential of this novel target. Here, we demonstrated that ß-caryophyllene (BCP; 150 µM), a natural dietary cannabinoid, protects cardiomyocytes against ferroptotic cell death induced by cysteine deprivation or glutathione peroxidase 4 (GPX4) inactivation. Moreover, BCP preserved the mitochondrial morphology and function during ferroptosis induction. Unexpectedly, BCP supported ferroptosis resistance independent of canonical antiferroptotic pathways. Our results further suggested that BCP may terminate radical chain reactions through interactions with molecular oxygen, which also explains why its oxidation derivative failed to suppress ferroptosis. Finally, oral BCP administration (50 mg/kg, daily) significantly alleviated doxorubicin (15 mg/kg, single i.p. injection)-induced cardiac ferroptosis and cardiomyopathy in mice. In conclusion, our data revealed the role of BCP as a natural antiferroptotic compound and suggest pharmacological modification based on BCP as a promising therapeutic strategy for treating ferroptosis-associated heart disorders.

Enzyme-Responsive DNA Origami-Antibody Conjugates for Targeted and Combined Therapy of Choroidal Neovascularization.

Monotherapy, especially the use of antibodies targeting vascular endothelial growth factor (VEGF), has shown limitations in treating choroidal neovascularization (CNV) since reactive oxygen species (ROS) also exacerbate CNV formation. Herein, we developed a combination therapy based on a DNA origami platform targeting multiple components of ocular neovascularization. Our study demonstrated that ocular neovascularization was markedly suppressed by intravitreal injection of a rectangular DNA origami sheet modified with VEGF aptamers (Ap) conjugated to an anti-VEGF antibody (aV) via matrix metalloproteinase (MMP)-cleavable peptide linkers in a mouse model of CNV. Typically, the DNA origami-based therapeutic platform selectively accumulates in neovascularization lesions owing to the dual-targeting ability of the aV and Ap, followed by the cleavage of the peptide linker by MMPs to release the antibody. Together, the released antibody and Ap inhibited VEGF activity. Moreover, the residual bare DNA origami could effectively scavenge ROS, reducing oxidative stress at CNV sites and thus maximizing the synergistic effects of inhibiting neovascularization.

Does HPV vaccination during periconceptional or gestational period increase the risk of adverse pregnancy outcomes?-An updated systematic review and meta-analysis based on timing of vaccination.

INTRODUCTION: The human papillomavirus (HPV) vaccine is crucial in preventing cervical cancer, and a significant number of women in 135 countries worldwide may have unknowingly received the vaccine during peri-pregnancy or pregnancy due to a lack of regular pregnancy testing. Previous studies on the safety of pregnancy outcomes with vaccination before and after pregnancy have not reached definitive conclusions. Thus, we subdivided the vaccination time frame and conducted an updated study to further examine whether exposure to the HPV vaccine during pregnancy or the periconceptional period increases the likelihood of adverse pregnancy outcomes. MATERIAL AND METHODS: The clinical trials and cohort studies published before August 1, 2023, were retrieved from PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials. The Newcastle-Ottawa Scale and Cochrane risk of bias assessment tool were adopted to evaluate the risk of bias in the included studies. In addition, the quality assessment was carried out using the Review Manager 5.4 Software, and a meta-analysis was conducted using the Stata 16 Software. RESULTS: Eleven studies were located. The results showed that receiving 4vHPV during the periconceptional or gestational period had no relationship with an increased risk of spontaneous abortion, stillbirth, preterm birth, birth defects, small for gestational age, and ectopic pregnancy. Neither receiving 2vHPV nor 9vHPV was associated with a higher risk of stillbirth, preterm birth, birth defects, small for gestational age, and ectopic pregnancy; however, receiving 2vHPV during the period from 45 days before last menstrual period (LMP) to LMP and 9vHPV during the period from 90 days before LMP to 45 days after LMP seemed to be related to an increased risk of spontaneous abortion (RR = 1.59, 95% CI: 1.04-2.45, RR = 2.04, 95% CI: 1.28-3.24). CONCLUSIONS: In conclusion, the likelihood of an elevated risk of spontaneous abortion caused by HPV vaccination during the periconceptional or gestational period could not be completely ruled out. Given the lack of evidence, further research is needed to examine the effect of HPV vaccination on spontaneous abortion.

Steering the Site Distance of Atomic Cu-Cu Pairs by First-Shell Halogen Coordination Boosts CO2-to-C2 Selectivity.

Electrocatalytic reduction of CO2 into C2 products of high economic value provides a promising strategy to realize resourceful CO2 utilization. Rational design and construct dual sites to realize the CO protonation and C-C coupling to unravel their structure-performance correlation is of great significance in catalysing electrochemical CO2 reduction reactions. Herein, Cu-Cu dual sites with different site distance coordinated by halogen at the first-shell are constructed and shows a higher intramolecular electron redispersion and coordination symmetry configurations. The long-range Cu-Cu (Cu-I-Cu) dual sites show an enhanced Faraday efficiency of C2 products, up to 74.1%, and excellent stability. In addition, the linear relationships that the long-range Cu-Cu dual site is accelerated to C2H4 generation and short-range Cu-Cu (Cu-Cl-Cu) dual site is beneficial for C2H5OH formation are disclosed. In situ electrochemical attenuated total reflection surface enhanced infrared absorption spectroscopy, in situ Raman and theoretical calculations manifest that long-range Cu-Cu dual sites can weaken reaction energy barriers of CO hydrogenation and C-C coupling, as well as accelerating deoxygenation of *CH2CHO. This study uncovers the exploitation of site-distance-dependent electrochemical property to steer the CO2 reduction pathway, as well as a potential generic tactic to target C2 synthesis by constructing the desired Cu-Cu dual sites.

Ultralow Thermal Conductivity in Vacancy-Ordered Halide Perovskite Cs3Bi2Br9 with Strong Anharmonicity and Wave-Like Tunneling of Low-Energy Phonons.

Halide perovskites are of great interest due to their exceptional optical and optoelectronic properties. However, thermal conductivity of many halide perovskites remains unexplored. In this study, an ultralow lattice thermal conductivity κL (0.24 W m-1 K-1 at 300 K) is reported and its weak temperature dependence (≈T-0.27) in an all-inorganic vacancy-ordered halide perovskite, Cs3Bi2Br9. The intrinsically ultralow κL can be attributed to the soft low-lying phonon modes with strong anharmonicity, which have been revealed by combining experimental heat capacity and Raman spectroscopy measurements, and first-principles calculations. It is shown that the highly anharmonic phonons originate from the Bi 6s2 lone pair expression with antibonding states of Bi 6s and Br 4p orbitals driven by the dynamic BiBr6 octahedral distortion. Theoretical calculations reveal that these low-energy phonons are mostly contributed by large Br motions induced dynamic distortion of BiBr6 octahedra and large Cs rattling motions, verified by the synchrotron X-ray pair distribution function analysis. In addition, the weak temperature dependence of κL can be traced to the wave-like tunneling of phonons, induced by the low-lying phonon modes. This work reveals the strong anharmonicity and wave-like tunneling of low-energy phonons for designing efficient vacancy-ordered halide perovskites with intrinsically low κL.

Residential greenspace and COVID-19 Severity: A cohort study of 313,657 individuals in Greater Manchester, United Kingdom.

BACKGROUND: Greenspaces contribute positively to mental and physical well-being, promote social cohesion, and alleviate environmental stressors, such as air pollution. Ecological studies suggest that greenspace may affect incidence and severity of Coronavirus Disease 2019 (COVID-19). OBJECTIVE: This study examines the association between residential greenspace and COVID-19 related hospitalization and death. METHOD: In this retrospective cohort based on patient records from the Greater Manchester Care Records, all first COVID-19 cases diagnosed between March 1, 2020, and May 31, 2022 were followed until COVID-19 related hospitalization or death within 28 days. Residential greenspace availability was assessed using the Normalized Difference Vegetation Index per lower super output area in Greater Manchester. The association of greenspace with COVID-19 hospitalization and mortality were estimated using multivariate logistic regression models after adjusting for potential individual, temporal, and spatial confounders. We explored potential effect modifications of the associations with greenspace and COVID-19 severity by age, sex, body mass index, smoking, deprivation, and certain comorbidities. Combined effects of greenspace and air pollution (NO2 and PM2.5) were investigated by mutually adjusting pairs with correlation coefficients ≤ 0·7. RESULTS: Significant negative associations were observed between greenspace availability and COVID-19 hospitalization and mortality with odds ratios [OR] (95 % Confidence Intervals [CI]) of 0·96 (0·94-0·97) and 0·84 (0·80-0·88) (per interquartile range [IQR]), respectively. These were significantly modified by deprivation (P-value for interaction < 0.05), showing that those most deprived obtained largest benefits from greenspace. Inclusion of NO2 and PM2.5 diminished associations to null for COVID-19 hospitalization, but only reduced them slightly for mortality, where inverse associations remained. CONCLUSION: In the Greater Manchester area, residential greenspace is associated with reduced risk of hospitalization or death in individuals with COVID-19, with deprived groups obtaining the greatest benefits. Associations were strongest for COVID-19 mortality, which were robust to inclusion of air pollutants in the models.

Suppressing UBE2N ameliorates Alzheimer's disease pathology through the clearance of amyloid beta.

INTRODUCTION: Aging is one of the risk factors for the early onset of Alzheimer's disease (AD). We previously discovered that the age-dependent increase in Ubiquitin Conjugating Enzyme E2 N (UBE2N) plays a role in the accumulation of misfolded proteins through K63 ubiquitination, which has been linked to AD pathogenesis. However, the impact of UBE2N on amyloid pathology and clearance has remained unknown. RESULTS: We observed the elevated UBE2N during the amyloid beta (Aß) generation in the brains of 5×FAD, APP/PS1 mice, and patients with AD, in comparison to healthy individuals. UBE2N overexpression exacerbated amyloid deposition in 5×FAD mice and senescent monkeys, whereas knocking down UBE2N via CRISPR/Cas9 reduced Aß generation and cognitive deficiency. Moreover, pharmacological inhibition of UBE2N ameliorated Aß pathology and subsequent transcript defects in 5×FAD mice. DISCUSSION: We have discovered that age-dependent expression of UBE2N is a critical regulator of AD pathology. Our findings suggest that UBE2N could serve as a potential pharmacological target for the advancement of AD therapeutics. HIGHLIGHTS: Ubiquitin Conjugating Enzyme E2 N (UBE2N) level was elevated during amyloid beta (Aß) deposition in AD mouse and patients' brains. UBE2N exacerbated Aß generation in the AD mouse and senescent monkey. Drug inhibition of UBE2N ameliorated Aß pathology and cognitive deficiency.

Long-term exposure to road traffic noise and acute lower respiratory infections in the Danish Nurse Cohort.

BACKGROUND: Long-term exposure to road traffic noise is associated with cardiovascular disease, but the evidence on respiratory diseases is just emerging. We aimed to examine the association between long-term exposure to road traffic noise and the incidence of acute lower respiratory infections (ALRIs) in adults. METHODS: We followed 23,141 female nurses (age ≥ 44 years) from the Danish Nurse Cohort from baseline (1993 or 1999) to their first hospital contact (inpatient, outpatient, or emergency room) for ALRI, death, emigration or the end of 2015. The residential annual mean levels of road traffic noise (Lden) during the follow-up were estimated using the Nord2000 model. We applied time-varying Cox models to estimate the association of 3-year mean exposure to Lden with ALRIs incidence and piecewise analysis to estimate the threshold of Lden. We examined the robustness of the results by adjusting for residential exposure to air pollution, and the effect modification by attained age, socioeconomic status (SES), comorbidity, and lifestyle. RESULTS: During 18.5 years of follow-up, 2,004 nurses developed ALRIs. In a linear model, we detected a statistically significant positive association between Lden and ALRI, with a hazard ratio (HR) of 1.11 (95 % confidence interval (CI): 1.04, 1.17) per 9.2 dB (interquartile range, IQR). We observed non-linear association with a threshold at 57 dB, above which the HR was 1.25 (95 % CI: 1.09, 1.43) per IQR. Further adjustment for PM2.5 reduced the HRs slightly to 1.21 (95 % CI: 1.04, 1.40). The associations were stronger for nurses with asthma, and in those with lowest SES. CONCLUSION: We present novel findings in support of the association between long-term exposure to road traffic noise and ALRIs, independent of air pollution, suggesting noise as a risk factor for infectious respiratory diseases.

Light-Triggered Anti-ambipolar Transistor Based on an In-Plane Lateral Homojunction.

Currently, the construction of anti-ambipolar transistors (AATs) is primarily based on asymmetric heterostructures, which are challenging to fabricate. AATs used for photodetection are accompanied by dark currents that prove difficult to suppress, resulting in reduced sensitivity. This work presents light-triggered AATs based on an in-plane lateral WSe2 homojunction without van der Waals heterostructures. In this device, the WSe2 channel is partially electrically controlled by the back gate due to the screening effect of the bottom electrode, resulting in a homojunction that is dynamically modulated with gate voltage, exhibiting electrostatically reconfigurable and light-triggered anti-ambipolar behaviors. It exhibits high responsivity (188 A/W) and detectivity (8.94 × 1014 Jones) under 635 nm illumination with a low power density of 0.23 µW/cm2, promising a new approach to low-power, high-performance photodetectors. Moreover, the device demonstrates efficient self-driven photodetection. Furthermore, ternary inverters are realized using monolithic WSe2, simplifying the manufacturing of multivalued logic devices.

Emission characteristics of lead and particulate matter from lead and zinc smelters in China.

Understanding the emission characteristics of particulate matter and associated heavy metals is essential for assessing their environmental and health impacts post-emission, as well as for identifying potential control technologies for the sources. Here, a field test was conducted at two advanced smelting plants equipped with comprehensive air pollution control devices. The particles emitted from different stages of lead and zinc smelting exhibited bi-modal size distributions, with peaks observed in PM0.1-1.0 and PM2.5-10, respectively. Particulate-bound Pb was identified as the predominant Pb species in the flue gas, primarily originating from ore crushing. Consequently, over 80 % of Pb was emitted in the form of coarse particles, a marked contrast to coal-fired power plants where Pb concentrated on fine particles. High efficiencies in Pb removal were achieved by dust collectors, flue gas purification systems, and acid plants with desulfurization systems, resulting in overall Pb emission factors in lead and zinc smelting were only 89.3 and 2.60 g t-1 (of metal production), respectively. Importantly, the contribution of gas-phase Pb, which accounts for approximately 16.6 % of total emissions, must not be neglected in future emission monitoring and control efforts.

van der Waals Stacking-Determined Polymorphs of Quasi-One-Dimensional BiSCl Grown by Chemical Vapor Deposition.

We report chemical vapor deposition (CVD) synthesis of two quasi-one-dimensional (quasi-1D) polymorphs of BiSCl, denoted by y-BiSCl and r-BiSCl. The length of the CVD samples can reach about 0.4 mm. Such quasi-1D samples of the two polymorphs can be readily separated into individual pieces for either characterization or application. The two polymorphs can be clearly differentiated by Raman spectroscopy. First-principles calculations and group analysis are used to assign each Raman peak to the corresponding vibrational mode. Ultraviolet-visible measurements on solution grown thin-film samples reveal that the two polymorphs exhibit significantly different band gaps of 2.08 eV (y-BiSCl) and 1.81 eV (r-BiSCl). First-principles calculation further shows that the interatomic chain binding energy is 18.1 meV/Å2, confirming that the van der Waals stacking determines the difference in their band gaps. Our findings highlight the possibility of realizing the desired functionalities in quasi-1D materials by controlling stacking orientation.

BOC targets SMO to regulate the Hedgehog pathway and promote proliferation, migration, and invasion of glioma cells.

The purpose of this study was to investigate the effects of BOC on glioblastoma cells and its underlying mechanisms. In vitro, BOC-knockdown was performed in glioma cell lines. CCK-8 and Transwell were used to assess the impact of BOC on the viability, invasion, and migration of gliobma cells. RNA-seq technology was employed to analyze the differential gene expression between BOC-knockdown glioma cells and the control group, and qRT-PCR was used to validate the expression of downstream differential genes. SMO-overexpression was performed to investigate the effects of SMO on glioma cells. A BOC-knockdown mouse subcutaneous tumor model was to verify the effects of BOC on mouse tumors. Tissue microarray technology was used to detect the expression of BOC and SMO in samples of normal human brain tissue and glioma tissue. In vitro, BOC-knockdown inhibited the viability, invasion, and migration of glioma cells, as well as downregulated the expression of downstream differential genes SMO, EGFR, HRAS, and MRAS. Conversely, SMO-overexpression upregulated the viability, invasion, and migration abilities of BOC-knockdown cells. In vivo, BOC-knockdown suppressed tumor growth in mice and downregulated the expression of downstream differential genes SMO, EGFR, HRAS, and MRAS. Tissue microarray results showed that both BOC and SMO were highly expressed in glioma tissues. BOC is aberrantly overexpressed in glioma patients and promotes glioma development. Mechanistically, BOC activates the Hedgehog (Hh) and RAS signaling pathways by upregulating the expression of SMO, EGFR, HRAS, and MRAS, thereby facilitating the Proliferation, invasion and migration of glioma cells.

Combinatorial strain improvement and bioprocess development for efficient production of ε-poly-L-lysine in Streptomyces albulus.

ε-Poly-L-lysine (ε-PL) is an amino acid homopolymer with diverse potential applications in the food, pharmaceutical and cosmetic industries. To improve its biomanufacturing efficiency, strain engineering and bioprocess optimization were combined in this study. Firstly, a cocktail strain breeding strategy was employed to generate a ε-PL high-production mutant, Streptomyces albulus GS114, with enhanced L-lysine uptake capability. Subsequently, the L-lysine feeding conditions during fed-batch fermentation were systematically optimized to improve the L-lysine supply, resulting in ε-PL production reaching 73.1 ± 1.4 g/L in 5 L bioreactor. Finally, an engineered strain, S. albulus L2, with enhanced uptake capability and polymerization ability of L-lysine was constructed, achieving ε-PL production of 81.4 ± 5.2 g/L by fed-batch fermentation. This represents the highest reported production of ε-PL to date. This study provided an efficient production strategy for ε-PL and valuable insights into the high-value utilization of L-lysine.

Prediction of Major Adverse Cardiovascular Events by Triglyceride Glucose Index in Predominantly Male Patients with Rheumatoid Arthritis.

Background: Rheumatoid arthritis (RA) is a systemic and chronic autoimmune disease that is characterized by persistent joint inflammation. RA patients experience a considerably increased risk of cardiovascular-related morbidity and mortality. The current study investigated the association between triglyceride glucose (TyG) index and major adverse cardiovascular events (MACEs) in a predominantly male cohort of RA patients. Methods: A total of 1613 RA patients (81.53% male) were selected from the Kailuan study. The TyG index was calculated as the logarithmic product of fasting blood triglyceride and fasting blood glucose divided by two. MACEs were defined as the composite of non-fatal myocardial infarctions and non-fatal strokes. Cox proportional hazards analysis was performed to study the association between the TyG index and MACEs. Results: A total of 59 MACEs occurred during the median follow-up time of 5.32 years. Following adjustment for age and gender, analysis by multivariable Cox proportional hazards (model 1) showed that an elevated TyG index was associated with an increased risk of MACEs (quartile 2, hazard ratio (HR): 2.741, 95% confidence interval (CI): 1.220-6.157, p = 0.015; quartile 4, HR: 2.521, 95% CI: 1.074-5.917, p = 0.034). After adjustment for other variables, Cox proportional hazards analysis (model 2) showed that an elevated TyG index was independently associated with an increased risk of MACEs (quartile 2, HR: 2.348, 95% CI: 1.009-5.465, p = 0.048). In addition, subgroup analysis showed a higher TyG index was significantly linked to an increased risk of MACEs in patients aged more than 65 years (quartile 2, HR: 6.048, 95% CI: 1.311-27.908, p = 0.021; quartile 4, HR: 12.074, 95% CI: 1.438-101.358, p = 0.022). Conclusions: The TyG index was associated with an increased risk of MACEs in a predominantly male cohort of RA patients. This index may be helpful for the prediction of MACEs in male patients with RA. Clinical Trial Registration: Registration number in the Chinese clinical trial registry: ChiCTR-TNRC-11001489.

Dual-Drug Loaded Nanobubbles Combined with Sonodynamic and Chemotherapy for Hepatocellular Carcinoma Therapy.

Purpose: Chemotherapy remains the primary therapeutic approach for advanced Hepatocellular Carcinoma (HCC). The therapeutic effect of chemotherapy is limited and the toxic side effects are serious. The aim of this study is to develop a nanobubble that is ultrasonically responsive to reduce the toxic side effects of direct chemotherapy. Methods: We developed curcumin/doxorubicin-cis-aconitic anhydride-polyethylene glycol nanobubble (C/DCNB) surface modified with acid-sensitive polyethylene glycol (PEG). And it is loaded with curcumin (CUR) and doxorubicin (DOX), as liposomes at the nanoscale for diagnosis and therapy of tumors. Results: In this study, the acid-sensitive PEG on the surface layer of nanobubbles serves to stabilize them in the blood circulatory system and in normal tissues, while peeling off in the acidic tumor microenvironment (pH 6.8). C/DCNB can identify tumor sites through contrast-enhanced ultrasound (CEUS). And ultrasound-mediated nanobubbles promote permeability of the tumor vascular, thus improving the enhanced permeability and retention (EPR) effects in the tumor, leading to the accumulation of nanobubbles in the tumor. After endocytosis of nanobubbles, drugs are released and curcumin generates reactive oxygen species (ROS) under ultrasound conditions. CUR can enhance the sensitivity of tumor cells to DOX by inhibiting the expression of P-glycoprotein. In vitro and vivo experiments demonstrate that C/DCNB can facilitate contrast-enhanced ultrasound imaging while simultaneously delivering drugs, enabling both imaging and treatment. Conclusion: The combination of C/DCNB and ultrasound provides an effective strategy for improving the efficiency of HCC therapy and imaging.