Targeting hTERT Promoter G-Quadruplex DNA Structures with Small-Molecule Ligand to Downregulate hTERT Expression for Triple-Negative Breast Cancer Therapy.

Human telomerase reverse transcriptase (hTERT) may have noncanonical functions in transcriptional regulation and metabolic reprogramming in cancer cells, but it is a challenging target. We thus developed small-molecule ligands targeting hTERT promoter G-quadruplex DNA structures (hTERT G4) to downregulate hTERT expression. Ligand 5 showed high affinity toward hTERT G4 (Kd = 1.1 µM) and potent activity against triple-negative breast cancer cells (MDA-MB-231, IC50 = 1 µM). In cell-based assays, 5 not only exerts markedly inhibitory activity on classical telomere functions including decreased telomerase activity, shortened telomere length, and cellular senescence but also induces DNA damage, acute cellular senescence, and apoptosis. This study reveals that hTERT G4-targeting ligand may cause mitochondrial dysfunction, disrupt iron metabolism and activate ferroptosis in cancer cells. The in vivo antitumor efficacy of 5 was also evaluated in an MDA-MB-231 xenograft mouse model and approximately 78.7% tumor weight reduction was achieved. No observable toxicity against the major organs was observed.

The influence of drying methods on extract content, tyrosinase activity inhibition, and mechanism in Ascophyllum nodosum: A combined microstructural and kinetic study.

This study evaluates vacuum drying (VD), microwave drying (MD), hot air drying (HAD), and freeze drying (FD), on the color and microstructure changes of Ascophyllum nodosum (A. nodosum), which affect the extraction of polyphenols and flavonoids. During drying, VD and FD show slight color change and looser structure, aiding in active compound preservation and extraction. Polyphenols extracted from A. nodosum (PEAn) using these methods show higher anti-tyrosinase activity, with VD treatment exhibiting the strongest inhibition. Kinetic studies demonstrate competitive inhibition between PEAn and tyrosinase. The binding constant (Ki) values indicate that PEAn treated with VD exhibits the most effective inhibition on tyrosinase, and the Zeta potential suggests the formation of the most stable complex. Circular dichroism (CD) spectroscopy shows significant enzyme rearrangement with VD-treated PEAn. Molecular docking confirms strong binding affinity. This study aims to enhance the utility of A. nodosum and develop novel uses for tyrosinase inhibitors in food.

Mediation Analysis of Acute Carotid Stenting in Tandem Lesions: Effect on Functional Outcome in a Multicenter Registry.

BACKGROUND AND OBJECTIVES: Current evidence suggests that acute carotid artery stenting (CAS) for cervical lesions is associated with better functional outcomes in patients with acute stroke with tandem lesions (TLs) treated with endovascular therapy (EVT). However, the underlying causal pathophysiologic mechanism of this relationship compared with a non-CAS strategy remains unclear. We aimed to determine whether, and to what degree, reperfusion mediates the relationship between acute CAS and functional outcome in patients with TLs. METHODS: This subanalysis stems from a multicenter retrospective cohort study across 16 stroke centers from January 2015 to December 2020. Patients with anterior circulation TLs who underwent EVT were included. Successful reperfusion was defined as a modified Thrombolysis in Cerebral Infarction scale ≥2B by the local team at each participating center. Mediation analysis was conducted to examine the potential causal pathway in which the relationship between acute CAS and functional outcome (90-day modified Rankin Scale) is mediated by successful reperfusion. RESULTS: A total of 570 patients were included, with a median age (interquartile range) of 68 (59-76), among whom 180 (31.6%) were female. Among these patients, 354 (62.1%) underwent acute CAS and 244 (47.4%) had a favorable functional outcome. The remaining 216 (37.9%) patients were in the non-CAS group. The CAS group had significantly higher rates of successful reperfusion (91.2% vs 85.1%; p = 0.025) and favorable functional outcomes (52% vs 29%; p = 0.003) compared with the non-CAS group. Successful reperfusion was a strong predictor of functional outcome (adjusted common odds ratio [acOR] 4.88; 95% CI 2.91-8.17; p < 0.001). Successful reperfusion partially mediated the relationship between acute CAS and functional outcome, as acute CAS remained significantly associated with functional outcome after adjustment for successful reperfusion (acOR 1.89; 95% CI 1.27-2.83; p = 0.002). Successful reperfusion explained 25% (95% CI 3%-67%) of the relationship between acute CAS and functional outcome. DISCUSSION: In patients with TL undergoing EVT, successful reperfusion predicted favorable functional outcomes when CAS was performed compared with non-CAS. A considerable proportion (25%) of the treatment effect of acute CAS on functional outcome was found to be mediated by improvement of successful reperfusion rates.

Acoustic Metagrating Holograms.

Metasurface holograms represent a common category of metasurface devices that utilize in-plane phase gradients to shape wavefronts, forming holographic images through the application of the generalized Snell's law (GSL). While conventional metasurfaces focus solely on phase gradients, metagratings, which incorporate higher-order wave diffraction, further expand the GSL's generality. Recent advances in certain acoustic metagratings demonstrate an updated GSL extension capable of reversing anomalous transmission and reflection, whose reversal is characterized by the parity of the number of wave propagation trips through the metagrating. However, the current extension of GSL remains limited to 1D metagratings, unable to access 2D holographic images in 3D spaces. Here, the GSL extension to 2D metagratings for manipulating waves within 3D spaces is investigated. Through this analysis, a series of acoustic metagrating holograms is experimentally demonstrated. These holographic images exhibit the unique ability to switch between transmission and reflection types independently. This study introduces an additional dimension to modern holography design and metasurface wavefront manipulation.

Lightweight and drift-free magnetically actuated millirobots via asymmetric laser-induced graphene.

Millirobots must have low cost, efficient locomotion, and the ability to track target trajectories precisely if they are to be widely deployed. With current materials and fabrication methods, achieving all of these features in one millirobot remains difficult. We develop a series of graphene-based helical millirobots by introducing asymmetric light pattern distortion to a laser-induced polymer-to-graphene conversion process; this distortion resulted in the spontaneous twisting and peeling off of graphene sheets from the polymer substrate. The lightweight nature of graphene in combine with the laser-induced porous microstructure provides a millirobot scaffold with a low density and high surface hydrophobicity. Magnetically driven nickel-coated graphene-based helical millirobots with rapid locomotion, excellent trajectory tracking, and precise drug delivery ability were fabricated from the scaffold. Importantly, such high-performance millirobots are fabricated at a speed of 77 scaffolds per second, demonstrating their potential in high-throughput and large-scale production. By using drug delivery for gastric cancer treatment as an example, we demonstrate the advantages of the graphene-based helical millirobots in terms of their long-distance locomotion and drug transport in a physiological environment. This study demonstrates the potential of the graphene-based helical millirobots to meet performance, versatility, scalability, and cost-effectiveness requirements simultaneously.

Mitochondria-Selective Dicationic Small-Molecule Ligand Targeting G-Quadruplex Structures for Human Colorectal Cancer Therapy.

Mitochondria are important drug targets for anticancer and other disease therapies. Certain human mitochondrial DNA sequences capable of forming G-quadruplex structures (G4s) are emerging drug targets of small molecules. Despite some mitochondria-selective ligands being reported for drug delivery against cancers, the ligand design is mostly limited to the triphenylphosphonium scaffold. The ligand designed with lipophilic small-sized scaffolds bearing multipositive charges targeting the unique feature of high mitochondrial membrane potential (MMP) is lacking and most mitochondria-selective ligands are not G4-targeting. Herein, we report a new small-sized dicationic lipophilic ligand to target MMP and mitochondrial DNA G4s to enhance drug delivery for anticancer. The ligand showed marked alteration of mitochondrial gene expression and substantial induction of ROS production, mitochondrial dysfunction, DNA damage, cellular senescence, and apoptosis. The ligand also exhibited high anticancer activity against HCT116 cancer cells (IC50, 3.4 µM) and high antitumor efficacy in the HCT116 tumor xenograft mouse model (∼70% tumor weight reduction).

Live Cell Imaging and Real-Time Monitoring of Nucleolus Morphology and Mitophagy with a Red Fluorescent and Photostable rRNA-Specific Probe in Human Cancer Cells.

rRNAs are prevalent in living organisms. They are produced in nucleolus and mitochondria and play essential cellular functions. In addition to the primary biofunction in protein synthesis, rRNAs have been recognized as the emerging signaling molecule and drug target for studies on nucleolus morphology, mitochondrial autophagy, and tumor cell malignancy. Currently, only a few rRNA-selective probes have been developed, and most of them encounter the drawbacks of low water solubility, poor nuclear membrane permeability, short emission wavelength, low stability against photobleaching, and high cytotoxicity. These unfavorable properties of rRNA probes limit their potential applications. In the present study, we reported a new rRNA-selective and near-infrared fluorescent turn-on probe, 4MPS-TO, capable of tracking rRNA in live human cancer cells. The real-time monitoring performance in nucleolus morphology and mitochondrial autophagy is demonstrated in HeLa cells. The probe shows great application potential for being used as a rRNA-selective, sensitive, and photostable imaging tool in chemical biology study and drug screening.

Rotor-based image-guided therapy of glioblastoma.

Glioblastoma (GBM), deep in the brain, is more challenging to diagnose and treat than other tumors. Such challenges have blocked the development of high-impact therapeutic approaches that combine reliable diagnosis with targeted therapy. Herein, effective cyanine dyes (IRLy) with the near-infrared two region (NIR-II) adsorption and aggregation-induced emission (AIE) have been developed via an "extended conjugation & molecular rotor" strategy for multimodal imaging and phototherapy of deep orthotopic GBM. IRLy was synthesized successfully through a rational molecular rotor modification with stronger penetration, higher signal-to-noise ratio, and a high photothermal conversion efficiency (PCE) up to ∼60%, which can achieve efficient NIR-II photo-response. The multifunctional nanoparticles (Tf-IRLy NPs) were further fabricated to cross the blood-brain barrier (BBB) introducing transferrin (Tf) as a targeting ligand. Tf-IRLy NPs showed high biosafety and good tumor enrichment for GBM in vitro and in vivo, and thus enabled accurate, efficient, and less invasive NIR-II multimodal imaging and photothermal therapy. This versatile Tf-IRLy nanosystem can provide a reference for the efficient, precise and low-invasive multi-synergistic brain targeted photo-theranostics. In addition, the "extended conjugation & molecular rotor" strategy can be used to guide the design of other photothermal agents.

Synthesis and Evaluation of [18F]AlF-NOTA-c-DVAP: A Novel PET Probe for Imaging GRP78 in Cancer.

GRP78, a member of the HSP70 superfamily, is an endoplasmic reticulum chaperone protein overexpressed in various cancers, making it a promising target for cancer imaging and therapy. Positron emission tomography (PET) imaging offers unique advantages in real time, noninvasive tumor imaging, rendering it a suitable tool for targeting GRP78 in tumor imaging to guide targeted therapy. Several studies have reported successful tumor imaging using PET probes targeting GRP78. However, existing PET probes face challenges such as low tumor uptake, inadequate in vivo distribution, and high abdominal background signal. Therefore, this study introduces a novel peptide PET probe, [18F]AlF-NOTA-c-DVAP, for targeted tumor imaging of GRP78. [18F]AlF-NOTA-c-DVAP was radiolabeled with fluoride-18 using the aluminum-[18F]fluoride ([18F]AlF) method. The study assessed the partition coefficients, stability in vitro, and metabolic stability of [18F]AlF-NOTA-c-DVAP. Micro-PET imaging, pharmacokinetic analysis, and biodistribution studies were carried out in tumor-bearing mice to evaluate the probe's performance. Docking studies and pharmacokinetic analyses of [18F]AlF-NOTA-c-DVAP were also performed. Immunohistochemical and immunofluorescence analyses were conducted to confirm GRP78 expression in tumor tissues. The probe's binding affinity to GRP78 was analyzed by molecular docking simulation. [18F]AlF-NOTA-c-DVAP was radiolabeled in just 25 min with a high yield of 51 ± 16%, a radiochemical purity of 99%, and molar activity within the range of 20-50 GBq/µmol. [18F]AlF-NOTA-c-DVAP demonstrated high stability in vitro and in vivo, with a logD value of -3.41 ± 0.03. Dynamic PET imaging of [18F]AlF-NOTA-c-DVAP in tumors showed rapid uptake and sustained retention, with minimal background uptake. Biodistribution studies revealed rapid blood clearance and excretion through the kidneys following a single-compartment reversible metabolic model. In PET imaging, the T/M ratios for A549 tumors (high GRP78 expression), MDA-MB-231 tumors (medium expression), and HepG2 tumors (low expression) at 60 min postintravenous injection were 10.48 ± 1.39, 6.25 ± 0.47, and 3.15 ± 1.15% ID/g, respectively, indicating a positive correlation with GRP78 expression. This study demonstrates the feasibility of using [18F]AlF-NOTA-c-DVAP as a PET tracer for imaging GRP78 in tumors. The probe shows promising results in terms of stability, specificity, and tumor targeting. Further research may explore the clinical utility and potential therapeutic applications of this PET tracer for cancer diagnosis.

Mechanism study of cross presentation of exogenous antigen induced by cholera toxin-like chimeric protein.

Tumor subunit vaccines have great potential in personalized cancer immunotherapy. They are usually administered with adjuvant owing to their low immunogenicity. Cholera toxin (CT) is a biological adjuvant with diverse biological functions and a long history of use. Our earlier study revealed that a CT-like chimeric protein co-delivered with murine granulocyte-macrophage colony stimulating factor (mGM-CSF) and prostate cancer antigen epitope could co-stimulate dendritic cells (DCs) and enhance cross presentation of tumor epitope. To further study the molecular mechanism of CT-like chimeric protein in cross presentation, major histocompatibility complex class I (MHC I)-restricted epitope 257-264 of ovalbumin (OVAT) was used as a model antigen peptide in this study. Recombinant A subunit and pentameric B subunit of CT protein were respectively genetically constructed and purified. Then both assembled into AB5 chimeric protein in vitro. Three different chimeric biomacromolecules containing mGM-CSF and OVAT were constructed according to the different fusion sites and whether the endoplasmic reticulum (ER) retention sequence was included. It was found that A2 domain and B subunit of CT were both available for loading epitopes and retaining GM1 affinity. The binding activity of GM1 was positively correlated with antigen endocytosis. Once internalized, DCs became mature and cross-presented antigen. KDEL helped the whole molecule to be retained in the ER, and this improved the cross presentation of antigen on MHC I molecules. In conclusion, hexameric CT-like chimeric protein with dual effects of GM1 affinity and ER retention sequence were potential in improvement of cross presentation. The results laid a foundation for designing personalized tumor vaccine based on CT-like chimeric protein molecular structure.

An acoustic method (Spectral Flux) to analyze ECG signals for optimizing timing for defibrillation in a porcine model of ventricular fibrillation.

Aim: Spectral Flux (SF), which is based on common algorithms in the audio processing field, was applied to quantitatively analyze ECG signals to optimize the timing of defibrillation. With the aim of proving the performance in optimizing the timing of defibrillation, SF was compared with Amplitude Spectrum Area (AMSA) in a porcine model of ventricular fibrillation (VF) in a retrospective analysis experiment. Methods: A total of 56 male domestic pigs, weighing 40 ± 5 kg, were induced to undergo VF. Animals were then left untreated for 10 min, and after 6 min of cardiopulmonary resuscitation (CPR) defibrillation was performed. The respective SF and AMSA values were calculated every minute during VF and CPR. Comparisons were made through receiver operating characteristic (ROC) curves, one-way analyses of variance (one-way ANOVA), and scatterplots for the successful initial defibrillation sample (positive samples, Group R) and the failed initial defibrillation sample (negative samples, Group N) to illustrate the performance in optimizing the timing of defibrillation for the AMSA and SF methods. Result: Values of SF and AMSA gradually decreased during the 10 min VF period and increased in during the 6 min CPR period. The scatterplots showed that both metrics had the ability to distinguish positive and negative samples (p < .001). Meanwhile, ROC curves showed that SF (area under the curve, AUC = 0.798, p < .001) had the same ability as AMSA (AUC = 0.737, p < .001) to predict the successful defibrillation (Z = 1.35, p = 0.177). Moreover, when comparing the values for AMSA and SF between the successful initial defibrillation samples (Group R) and the failed initial defibrillation samples (Group N), the results showed that the values of both AMSA and SF in Group R were significantly higher than those in Group N (p < .001). Conclusion: In the present study, SF method had the same ability as AMSA to predict successful defibrillation with significantly higher values in cases of successful defibrillation than the instances in which defibrillation failed. Additionally, SF method might be more stable than AMSA for filtering out the higher frequency interference signals due to the narrower frequency range and had higher specificity and predictive accuracy than AMSA. So SF method had high clinical potential to optimize the timing of defibrillation. Nevertheless, further animal and clinical studies are still needed to confirm the effectiveness and practicality of SF as a predictive module for defibrillators in clinical practice.

Identification method of thyroid nodule ultrasonography based on self-supervised learning dual-branch attention learning framework.

Thyroid ultrasound is a widely used diagnostic technique for thyroid nodules in clinical practice. However, due to the characteristics of ultrasonic imaging, such as low image contrast, high noise levels, and heterogeneous features, detecting and identifying nodules remains challenging. In addition, high-quality labeled medical imaging datasets are rare, and thyroid ultrasound images are no exception, posing a significant challenge for machine learning applications in medical image analysis. In this study, we propose a Dual-branch Attention Learning (DBAL) convolutional neural network framework to enhance thyroid nodule detection by capturing contextual information. Leveraging jigsaw puzzles as a pretext task during network training, we improve the network's generalization ability with limited data. Our framework effectively captures intrinsic features in a global-to-local manner. Experimental results involve self-supervised pre-training on unlabeled ultrasound images and fine-tuning using 1216 clinical ultrasound images from a collaborating hospital. DBAL achieves accurate discrimination of thyroid nodules, with a 88.5% correct diagnosis rate for malignant and benign nodules and a 93.7% area under the ROC curve. This novel approach demonstrates promising potential in clinical applications for its accuracy and efficiency.

Woven EndoBridge versus stent-assisted coil embolization for the treatment of ruptured wide-necked aneurysms: A multicentric experience.

BACKGROUND: The potentially higher risk of hemorrhagic complications is of concern in stent-assisted coiling (SAC) of ruptured wide-necked intracranial aneurysms (IAs). The Woven EndoBridge (WEB) is considered an appealing alternative since antiplatelet therapy is not required. Herein, we aimed to compare the safety and effectiveness of WEB vs. SAC for the treatment of ruptured wide-necked IAs. METHODS: This was an international cross-sectional study of consecutive patients treated for ruptured wide-neck IAs with WEB or SAC at four high-volume neurovascular centers between 2019 and 2022. Primary and secondary efficacy outcomes were radiographic aneurysm occlusion at follow-up and functional status at last follow-up. Safety outcomes included periprocedural hemorrhagic/ischemia-related complications. RESULTS: One hundred five patients treated with WEB and 112 patients treated with SAC were included. The median procedure duration of endovascular treatment was shorter for WEB than for SAC (69 vs. 76 min; p = 0.04). There were no significant differences in complete aneurysm occlusion rates (SAC: 64.5% vs. WEB: 60.9%; adjusted OR [aOR] = 0.70; 95%CI 0.34-1.43; p = 0.328). SAC had a significantly higher risk of complications (23.2% vs. 9.5%, p = 0.009), ischemic events (17% vs. 6.7%, p = 0.024), and EVD hemorrhage (16% vs. 0%, p = 0.008). The probability of procedure-related complications across procedure time was significantly lower with WEB compared with SAC (aOR = 0.40; 95%CI 0.20-1.13; p = 0.03). CONCLUSION: WEB and SAC demonstrated similar obliteration rates at follow-up when used for embolization of ruptured wide-necked IAs. However, SAC showed higher rates of procedure-related complications primarily driven by ischemic events and higher rates of EVD hemorrhage. The overall treatment duration was shorter for WEB than for SAC.

Interaction mechanism and binding mode of phycocyanin to lysozyme: Molecular docking and molecular dynamics simulation.

In this study, multispectral analysis and molecular simulations were performed to investigate the interaction mechanism between phycocyanin (PC) and lysozyme (Lys). The interaction was examined using surface plasmon resonance (SPR), and the structural changes were analyzed using Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), and transmission electron microscopy (TEM). The results suggest that the interaction between PC and Lys was primarily driven by electrostatic, hydrophobic, and hydrogen bonding forces. Molecular dynamics (MD) simulation revealed that Lys preferentially binds between the two subunits, alpha (α) and beta (ß), of PC, with residues ASP-13, GLU-106, and GLU-115 on PC and ARG-119, ARG-107, and ARG-98 on Lys being the main contributors to the binding interaction. Additionally, the formation of the PC-Lys complex resulted in increased kinetic and improved thermal stability of PC, which have important implications for PC applications.

Dietary Isoquercetin Ameliorates Bone Loss via Restoration of the Gut Microbiota and Lipopolysaccharide-Triggered Inflammatory Status in Ovariectomy Mice.

Osteoporosis is one of the skeletal degenerative diseases accompanied by bone loss and microstructure disruption. Given that the gut-bone signaling axis highly contributes to bone health, here, dietary isoquercetin (IQ) was shown to effectively improve postmenopausal osteoporosis (PMO) in an ovariectomy (OVX) mouse model through the modulation of the gut-bone cross-talk. An in vivo study showed that OVX induced striking disruption of the microbial community, subsequently causing gut leakage and gut barrier dysfunction. As a result, lipopolysaccharide (LPS)-triggered inflammatory cytokines released from the intestine to bone marrow were determined to be associated with bone loss in OVX mice. Long-term dietary IQ effectively improved microbial community and gut barrier function in the OVX mice and thus markedly improved bone loss and host inflammatory status by repressing the NF-κB signaling pathway. An in vitro study further revealed that IQ treatments dose-dependently inhibited LPS-induced inflammation and partly promoted the proliferation and differentiation of osteoblasts. These results provide new evidence that dietary IQ has the potential for osteoporosis treatment.

LDS-CNN: a deep learning framework for drug-target interactions prediction based on large-scale drug screening.

Background: Drug-target interaction (DTI) is a vital drug design strategy that plays a significant role in many processes of complex diseases and cellular events. In the face of challenges such as extensive protein data and experimental costs, it is suggested to apply bioinformatics approaches to exploit potential interactions to design new targeted medications. Different data and interaction types bring difficulties to study involving incompatible and heterology formats. The analysis of drug-target interactions in a comprehensive and unified model is a significant challenge. Method: Here, we propose a general method for predicting interactions between small-molecule drugs and protein targets, Large-scale Drug target Screening Convolutional Neural Network (LDS-CNN), which used unified encoding to achieve the calculation of the different data formats in an integrated model to realize feature abstraction and potential object prediction. Result: On 898,412 interaction data involving 1683 small-molecule compounds and 14,350 human proteins from 8.8 billion records, the proposed method achieved an area under the curve (AUC) of 0.96, an area under the precision-recall curve (AUPRC) of 0.95, and an accuracy of 90.13%. The experimental results illustrated that the proposed method attained high accuracy on the test set, indicating its high predictive ability in drug-target interaction prediction. LDS-CNN is effective for the prediction of large-scale datasets and datasets composed of data with different formats. Conclusion: In this study, we propose a DTI prediction method to solve the problems of unified encoding of large-scale data in multiple formats. It provides a feasible way to efficiently abstract the features among different types of drug-related data, thus reducing experimental costs and time consumption. The proposed method can be used to identify potential drug targets and candidates for the treatment of complex diseases. This work provides a reference for DTI to process large-scale data and different formats with deep learning methods and provides certain suggestions for future research.

Predictors of tissue infarction from distal emboli after mechanical thrombectomy.

BACKGROUND: Distal embolization after endovascular thrombectomy (EVT) is common. We aimed to determine factors associated with tissue infarction in the territories of distal emboli. METHODS: This is a retrospective cohort study of consecutive patients with anterior circulation large vessel occlusions who underwent EVT from 2015 to 2021. Patients with Thrombolysis In Cerebral Infarction (TICI) 2b reperfusion and follow-up imaging were identified. Baseline characteristics, procedural details, and imaging findings were reviewed. Primary outcome was categorized according to the occurrence of infarction at the territory of distal embolus on follow-up diffusion-weighted imaging MRI. RESULTS: Of 156 subjects, 97 (62%) had at least one infarction in the territories at risk. Hypertension was significantly more prevalent in the infarct group (83% vs 53%, P=0.001). General anesthesia was more commonly used in the infarct group (60% vs 43%, P=0.037). The median number of distal emboli and diameter of the occluded vessel were similar. After adjusting for confounders, hypertension (aOR 4.73, 95% CI 1.81 to 13.25, P=0.002), higher blood glucose (aOR 1.01, 95% CI 1.00 to 1.03, P=0.023), and general anesthesia (aOR 2.75, 95% CI 1.15 to 6.84, P=0.025) were independently associated with infarction. The presence of angiographic leptomeningeal collaterals predicted tissue survival (aOR 0.13, 95% CI 0.05 to 0.33, P<0.001). 90-day modified Rankin scale (mRS) scores were worse for the infarction patients (mRS 0-2: infarct, 39% vs 55%, P=0.046). CONCLUSIONS: Nearly 40% of patients with TICI 2b had no tissue infarction in the territory of a distal embolus. The association of infarction with hypertension and general anesthesia suggests late or post-procedural blood pressure management could be a modifiable factor. Patients with poor leptomeningeal collaterals or hyperglycemia may benefit from further attempts at revascularization.

Mechanical thrombectomy beyond 24 hours from last known well in tandem lesions: A multicenter cohort study.

BACKGROUND: While recent studies suggest a benefit of mechanical thrombectomy (MT) for the treatment of patients with isolated large vessel occlusions presenting after 24 hours from the last known well (LKW), the effect of MT for acute cervical tandem lesions (TLs) beyond 24 hours remains unknown. We aimed to evaluate the safety and effectiveness of MT beyond 24 hours of LKW in patients with TLs. METHODS: We conducted a subanalysis study of patients with anterior circulation TL enrolled in a large, multicenter registry between January 2015 and December 2020. Patients were divided into 2 groups: MT beyond 24 hours versus MT 0-24-hour window. Outcomes of interest were functional independence (90-day modified Rankin scale 0-2), complete reperfusion (modified thrombolysis in cerebral infarction 3), delta NIH Stroke Scale (NIHSS), symptomatic intracranial hemorrhage (sICH), parenchymal hematoma 2 (PH2), in-hospital mortality, and 90-day mortality. Inverse probability of treatment weighting (IPTW) was used to balance the groups. RESULTS: Overall, 589 participants were included, with 33 treated beyond 24 hours and 556 treated in the 0-24-hour window. After IPTW, we found no significant difference in the rates of achieving functional independence (odds ratio (OR) = 0.51; 95% confidence interval (CI) 0.22-1.16; p = 0.108), complete reperfusion (OR = 1.35; 95% CI 0.60-3.05; p = 0.464), sICH (OR = 1.96; 95% CI 0.37-10.5; p = 0.429), delta NIHSS (ß = -3.61; 95% CI -8.11 to 0.87; p = 0.114), PH2 (OR = 1.46; 95% CI 0.29-7.27; p = 0.642), in-hospital mortality (OR = 1.74; 95% CI 0.52-5.86; p = 0.370), or 90-day mortality (OR = 1.37; 95% CI 0.49-3.83; p = 0.544) across both time windows. CONCLUSIONS: Our results suggest that MT appears to benefit patients with TLs beyond 24 hours from LKW. Future prospective studies are warranted.

Discovery of a novel small molecule with efficacy in protecting against inflammation in vitro and in vivo by enhancing macrophages activation.

Immune response and inflammation highly contribute to many metabolic syndromes such as inflammatory bowel disease (IBD), ageing and cancer with disruption of host metabolic homeostasis and the gut microbiome. Icariin-1 (GH01), a small-molecule flavonoid derived from Epimedium, has been shown to protect against systemic inflammation. However, the molecular mechanisms by which GH01 ameliorates ulcerative colitis via regulation of microbiota-mediated macrophages polarization remain elusive. In this study, we found that GH01 effectively ameliorated dextran sulfate sodium (DSS)-induced colitis symptoms in mice. Disruption of intestinal barrier function, commensal microbiota and its metabolites were also significantly restored by GH01 in a dose-dependent manner. Of note, we also found that GH01 enhanced phagocytic ability of macrophages and switched macrophage phenotype from M1 to M2 both in vitro and in vivo. Such macrophage polarization was highly associated with intestinal barrier integrity and the gut microbial community. Consequently, GH01 exhibited strong anti-inflammatory capacity by inhibiting TLR4 and NF-κB pathways and proinflammatory factors (IL-6). These findings suggested that GH01 might be a potential nutritional intervention strategy for IBD treatment with the gut microbial community-meditated macrophage as the therapeutic targets.

A novel small molecule effectively ameliorates estrogen deficiency-induced osteoporosis by targeting the gut-bone signaling axis.

Postmenopausal osteoporosis stems mainly from estrogen deficiency leading to a gut microbiome-dependent disruption of host systemic immunity. However, the underlying mechanisms of estrogen deficiency-induced bone loss remain elusive and novel pharmaceutical intervention strategies for osteoporosis are needed. Here we reveal that ovariectomy (ovx)-induced estrogen deficiency in C57BL/6 mice causes significant disruption of gut microbiota composition, consequently leading to marked destruction of intestinal barrier function and gut leakage. As a result, signals transportation between intestinal microbiota and T cells from the gut to bone marrow is identified to contribute to osteoclastogenesis in ovx mice. Notably, we show that icariside I (GH01), a novel small molecule naturally occurring in Herbal Epimedium, has potential to alleviate or prevent ovx-induced bone loss in mice through regulation of gut-bone signaling axis. We find that GH01 treatment can effectively restore the gut microbiota composition, intestinal barrier function and host immune status markedly altered in ovx mice, thus significantly ameliorating bone loss and osteoporosis. These findings not only provide systematic understanding of the gut-immunity-bone axis-associated pathophysiology of osteoporosis, but also demonstrate the high potential of GH01 for osteoporosis treatment by targeting the gut-bone signaling axis.