Inhibition of PCSK9 prevents and alleviates cholesterol gallstones through PPARα-mediated CYP7A1 activation.

BACKGROUND & AIMS: Dysregulated cholesterol metabolism is the major factor responsible for cholesterol gallstones (CGS). Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in cholesterol homeostasis and its inhibitors secure approval for treating various cholesterol metabolic disorders such as hypercholesterolemia and cardiovascular diseases, but its role in CGS remains unclear. Our study aims to clarify mechanisms by which PCSK9 promotes CGS formation and explore the application of the PCSK9 inhibitor, alirocumab, in preventing and treating CGS. APPROACH & RESULTS: The expressions of PCSK9 were notably increased in CGS patients' serum, bile, and liver tissues compared to those without gallstones. Moreover, among CGS patients, hepatic PCSK9 was positively correlated with hepatic cholesterol and negatively correlated with hepatic bile acids (BAs), suggesting PCSK9 was involved in disrupted hepatic cholesterol metabolism related to CGS. Mechanistically, in vitro experiments demonstrated that inhibition of PCSK9 enhanced nuclear expression of PPARα by diminishing its lysosomal degradation and subsequently activated CYP7A1 transcription. Finally, inhibition of PCSK9 prevented CGS formation and dissolved the existing stones in CGS mice by elevating the conversion of cholesterol into BAs through PPARα-mediated CYP7A1 activation. Additionally, serum PCSK9 level may function as a prognostic signature to evaluate the therapeutic efficacy of PCSK9 inhibitors. CONCLUSIONS: Inhibition of PCSK9 exerts preventive and therapeutic effects on CGS by activating PPARα-mediated CYP7A1 expression and facilitating the conversion of cholesterol into BAs, which highlights the potential of PCSK9 inhibition as a promising candidate for preventing and treating CGS in clinical applications. IMPACT AND IMPLICATIONS: PCSK9 plays a pivotal role in cholesterol metabolism and its inhibitors are approved for clinical use in cardiovascular diseases. Our study observes inhibition of PCSK9 prevents and dissolves CGS by activating PPARα-mediated CYP7A1 expression and facilitating the conversion of cholesterol into BAs. Mechanistically, PCSK9 inhibition enhanced the nuclear expression of PPARα by diminishing its lysosomal degradation and subsequently activated CYP7A1 transcription. Our study sheds light on the new function and mechanism of PCSK9 in CGS, providing a novel preventive and therapeutic target with potential clinical applications.

Rapid intraoperative multi-molecular diagnosis of glioma with ultrasound radio frequency signals and deep learning.

BACKGROUND: Molecular diagnosis is crucial for biomarker-assisted glioma resection and management. However, some limitations of current molecular diagnostic techniques prevent their widespread use intraoperatively. With the unique advantages of ultrasound, this study developed a rapid intraoperative molecular diagnostic method based on ultrasound radio-frequency signals. METHODS: We built a brain tumor ultrasound bank with 169 cases enrolled since July 2020, of which 43483 RF signal patches from 67 cases with a pathological diagnosis of glioma were a retrospective cohort for model training and validation. IDH1 and TERT promoter (TERTp) mutations and 1p/19q co-deletion were detected by next-generation sequencing. We designed a spatial-temporal integration model (STIM) to diagnose the three molecular biomarkers, thus establishing a rapid intraoperative molecular diagnostic system for glioma, and further analysed its consistency with the fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5). We tested STIM in 16-case prospective cohorts, which contained a total of 10384 RF signal patches. Two other RF-based classical models were used for comparison. Further, we included 20 cases additional prospective data for robustness test (ClinicalTrials.govNCT05656053). FINDINGS: In the retrospective cohort, STIM achieved a mean accuracy and AUC of 0.9190 and 0.9650 (95% CI, 0.94-0.99) respectively for the three molecular biomarkers, with a total time of 3 s and a 96% match to WHO CNS5. In the prospective cohort, the diagnostic accuracy of STIM is 0.85 ± 0.04 (mean ± SD) for IDH1, 0.84 ± 0.05 for TERTp, and 0.88 ± 0.04 for 1p/19q. The AUC is 0.89 ± 0.02 (95% CI, 0.84-0.94) for IDH1, 0.80 ± 0.04 (95% CI, 0.71-0.89) for TERTp, and 0.85 ± 0.06 (95% CI, 0.73-0.98) for 1p/19q. Compared to the second best available method based on RF signal, the diagnostic accuracy of STIM is improved by 16.70% and the AUC is improved by 19.23% on average. INTERPRETATION: STIM is a rapid, cost-effective, and easy-to-manipulate AI method to perform real-time intraoperative molecular diagnosis. In the future, it may help neurosurgeons designate personalized surgical plans and predict survival outcomes. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Quantitative analysis using intraoperative contrast-enhanced ultrasound in adult-type diffuse gliomas with isocitrate dehydrogenase mutations: association between hemodynamics and molecular features.

PURPOSE: The relationship between contrast-enhanced ultrasound (CEUS) hemodynamics and the molecular biomarkers of adult-type diffuse gliomas, particularly isocitrate dehydrogenase (IDH), remains unclear. This study was conducted to provide a comprehensive description of the vascularization of adult-type diffuse gliomas using quantitative indicators. Additionally, it was designed to identify any variables with the potential to intraoperatively predict IDH mutation status. METHODS: This prospective study enrolled patients with adult-type diffuse gliomas between November 2021 and September 2022. Intraoperative CEUS was performed, and CEUS videos were recorded for 90-second periods. Hemodynamic parameters, including the peak enhancement (PE) difference, were calculated based on the time-intensity curve of the region of interest. A differential analysis was performed on the CEUS parameters with respect to molecular biomarkers and grades. Receiver operating characteristic curves for various parameters were analyzed to evaluate the ability of those parameters to predict IDH mutation status. RESULTS: Sixty patients with adult-type diffuse gliomas were evaluated. All hemodynamic parameters, apart from rising time, demonstrated significant differences between IDH-mutant and IDH-wildtype adult-type diffuse gliomas. The PE difference emerged as the optimal indicator for differentiating between IDH-wildtype and IDH-mutant gliomas, with an area under the curve of 0.958 (95% confidence interval, 0.406 to 0.785). Additionally, the hemodynamic parameters revealed significant differences across both grades and types of adult-type diffuse gliomas. CONCLUSION: Hemodynamic parameters can be used intraoperatively to effectively distinguish between IDHwildtype and IDH-mutant adult-type diffuse gliomas. Additionally, quantitative CEUS equips neurosurgeons with dynamic perfusion information for various types and grades of adult-type diffuse gliomas.

Interface Engineering of a 2D-C3N4/NiFe-LDH Heterostructure for Highly Efficient Photocatalytic Hydrogen Evolution.

Photocatalytic water splitting offers an economic and sustainable pathway for producing hydrogen as a zero-emission fuel, but it still suffers from low efficiencies limited by visible-light absorption capacity and charge separation kinetics. Herein, we report an interface-engineered 2D-C3N4/NiFe layered double hydroxide (CN/LDH) heterostructure that shows highly enhanced photocatalytic hydrogen evolution reaction (HER) rate with excellent long-term stability. The morphology and band gap structure of NiFe-LDH are precisely regulated by employing NH4F as a structure-directing agent, which enables a fine interfacial tuning via coupling with 2D-C3N4. The formation of a type II interface in CN/LDH enlarges the active surface area and promotes the charge separation efficiency, leading to an HER rate of 3087 µmol g-1 h-1, which is 14 times higher than that of 2D-C3N4. This study highlights a rational interface engineering strategy for the formation of a heterostructure with a proper hole transport co-catalyst for designing effective water-splitting photocatalysts.

Photocatalytic CO2 Reduction Enabled by Interfacial S-Scheme Heterojunction between Ultrasmall Copper Phosphosulfide and g-C3N4.

Transition metal phosphosulfides (TMPSs) have gained much interest due to their highly enhanced photocatalytic activities compared to their corresponding phosphides and sulfides. However, the application of TMPSs on photocatalytic CO2 reduction remains a challenge due to their inappropriate band positions and rapid recombination of photogenerated electron-hole pairs. Herein, we report ultrasmall copper phosphosulfide (us-Cu3P|S) nanocrystals anchored on 2D g-C3N4 nanosheets. Systematic studies on the interaction between us-Cu3P|S and g-C3N4 indicate the formation of an S-scheme heterojunction via interfacial P-N chemical bonds, which acts as an electron transfer channel and facilitates the separation and migration of photogenerated charge carriers. Upon the composite formation, the band structures of us-Cu3P|S and g-C3N4 are altered to enable the enhanced photocatalytic CO generation rate of 137 µmol g-1 h-1, which is eight times higher than that of pristine g-C3N4. The unique phosphosulfide structure is also beneficial for the enhanced electron transfer rate and provides abundant active sites. This first application of Cu3P|S to photocatalytic CO2 reduction marks an important step toward the development of TMPSs for photocatalytic applications.

Surface Engineering of MoS2 via Laser-Induced Exfoliation in Protic Solvents.

With excellent performance in the hydrogen evolution reaction (HER), molybdenum disulfide (MoS2 ) is considered a promising nonprecious candidate to substitute Pt-based catalysts. Herein, pulsed laser irradiation in liquid is used to realize one-step exfoliation of bulk 2H-MoS2 to ultrastable few-layer MoS2 nanosheets. Such prepared MoS2 nanosheets are rich in S vacancies and metallic 1T phase, which significantly contribute to the boosted catalytic HER activity. Protic solvents play a pivotal role in the production of S vacancies and 2H-to-1T phase transition under laser irradiation. MoS2 exfoliated in an optimal solvent of formic acid exhibits outstanding HER activity with an overpotential of 180 mV at 10 mA cm-2 and Tafel slope of 54 mV dec-1 .