Icariin improves oxidative stress injury during ischemic stroke via inhibiting mPTP opening.

BACKGROUND: Ischemic stroke presents a significant threat to human health due to its high disability rate and mortality. Currently, the clinical treatment drug, rt-PA, has a narrow therapeutic window and carries a high risk of bleeding. There is an urgent need to find new effective therapeutic drugs for ischemic stroke. Icariin (ICA), a key ingredient in the traditional Chinese medicine Epimedium, undergoes metabolism in vivo to produce Icaritin (ICT). While ICA has been reported to inhibit neuronal apoptosis after cerebral ischemia-reperfusion (I/R), yet its underlying mechanism remains unclear. METHODS: PC-12 cells were treated with 200 µM H2O2 for 8 h to establish a vitro model of oxidative damage. After administration of ICT, cell viability was detected by Thiazolyl blue tetrazolium Bromide (MTT) assay, reactive oxygen species (ROS) and apoptosis level, mPTP status and mitochondrial membrane potential (MMP) were detected by flow cytometry and immunofluorescence. Apoptosis and mitochondrial permeability transition pore (mPTP) related proteins were assessed by Western blotting. Middle cerebral artery occlusion (MCAO) model was used to establish I/R injury in vivo. After the treatment of ICA, the neurological function was scored by ZeaLonga socres; the infarct volume was observed by 2,3,5-Triphenyltetrazolium chloride (TTC) staining; HE and Nissl staining were used to detect the pathological state of the ischemic cortex; the expression changes of mPTP and apoptosis related proteins were detected by Western blotting. RESULTS: In vitro: ICT effectively improved H2O2-induced oxidative injury through decreasing the ROS level, inhibiting mPTP opening and apoptosis. In addition, the protective effects of ICT were not enhanced when it was co-treated with mPTP inhibitor Cyclosporin A (CsA), but reversed when combined with mPTP activator Lonidamine (LND). In vivo: Rats after MCAO shown cortical infarct volume of 32-40%, severe neurological impairment, while mPTP opening and apoptosis were obviously increased. Those damage caused was improved by the administration of ICA and CsA. CONCLUSIONS: ICA improves cerebral ischemia-reperfusion injury by inhibiting mPTP opening, making it a potential candidate drug for the treatment of ischemic stroke.

A Triazine Membrane for Sustainable Acquisition of Au(III) from Wastewater.

The recovery of Au(III) from solution using adsorbents in the form of granules or powders is challenging due to issues such as instability during the recovery process or mass loss caused by small particle size. This study introduces a PEI-TCT/PVDF composite membrane designed to intercept and capture Au(III) in wastewater. Experimental results demonstrated that the PEI-TCT/PVDF membrane exhibits a broad pH range (1-8) and a high retention efficiency for Au(III) of 97.8%, with a maximum adsorption capacity of 294.5 mg/g. The mechanism of Au(III) adsorption on the PEI-TCT/PVDF membrane was mainly through electrostatic adsorption, which caused AuCl4- to aggregate on the surface of the membrane and gradually reduced to Au0 and Au+. Furthermore, the membrane can be entirely regenerated within 20 min and maintains its performance in subsequent adsorption cycles. This study highlights the potential of PEI-TCT/PVDF membranes for the recovery of precious Au(III).

Normobaric Hyperoxia Combined With Endovascular Treatment Based on Temporal Gradient: A Dose-Escalation Study.

BACKGROUND: Normobaric hyperoxia (NBO) has neuroprotective effects in acute ischemic stroke. Thus, we aimed to identify the optimal NBO treatment duration combined with endovascular treatment. METHODS: This is a single-center, randomized controlled, open-label, blinded-end point dose-escalation clinical trial. Patients with acute ischemic stroke who had an indication for endovascular treatment at Tianjin Huanhu Hospital were randomly assigned to 4 groups (1:1 ratio) based on NBO therapy duration: (1) control group (1 L/min oxygen for 4 hours); (2) NBO-2h group (10 L/min for 2 hours); (3) NBO-4h group (10 L/min for 4 hours); and (4) NBO-6h group (10 L/min for 6 hours). The primary outcome was cerebral infarction volume at 72 hours after randomization using an intention-to-treat analysis model. The primary safety outcome was the 90-day mortality rate. RESULTS: Between June 2022 and September 2023, 100 patients were randomly assigned to the following groups: control group (n=25), NBO-2h group (n=25), NBO-4h group (n=25), and NBO-6h group (n=25). The 72-hour cerebral infarct volumes were 39.4±34.3 mL, 30.6±30.1 mL, 19.7±15.4 mL, and 22.6±22.4 mL, respectively (P=0.013). The NBO-4h and NBO-6h groups both showed statistically significant differences (adjusted P values: 0.011 and 0.027, respectively) compared with the control group. Compared with the control group, both the NBO-4h and NBO-6h groups showed significant differences (P<0.05) in the National Institutes of Health Stroke Scale scores at 24 hours, 72 hours, and 7 days, as well as in the change of the National Institutes of Health Stroke Scale scores from baseline to 24 hours. Additionally, there were no significant differences among the 4 groups in terms of 90-day mortality rate, symptomatic intracranial hemorrhage, early neurological deterioration, or severe adverse events. CONCLUSIONS: The effectiveness of NBO therapy was associated with oxygen administration duration. Among patients with acute ischemic stroke who underwent endovascular treatment, NBO therapy for 4 and 6 hours was found to be more effective. Larger-scale multicenter studies are needed to validate these findings. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05404373.

The combination model of serum occludin and clinical risk factors improved the efficacy for predicting hemorrhagic transformation in stroke patients with recanalization.

Background: and Purpose: Hemorrhagic transformation (HT) is one of the severe complications in acute ischemic stroke, especially for the patients who undergo recanalization treatment. It is crucial to screen patients who have high risk of HT before recanalization. However, current prediction models based on clinical factors are not ideal for clinical practice. Serum occludin, a biomarker for cerebral ischemia-induced blood-brain barrier disruption, has potential for predicting HT. This study was to investigate whether the combination of serum occludin and clinical risk factors improved the efficacy of predicting HT. Methods: This was a single-center prospective observational study. Baseline clinical data and blood samples of recanalization patients were collected upon admission to our hospital. The level of serum occludin was measured using enzyme-linked immunosorbent assay. The diagnosis of HT was confirmed by CT scans within 36 h post recanalization. Results: A total of 324 patients with recanalization were enrolled and 68 patients presented HT occurrence. HT patients had the higher level of baseline occludin than patients without HT (p < 0.001). Multivariate regression analysis showed that serum occludin level, Alberta Stroke Program Early CT Scores and endovascular therapy were independent risk factors (p < 0.05) for HT after adjusting potential confounders. The combination of serum occludin and clinical risk factors significantly improved the accuracy of predicting HT [area under the curve (AUC, 0.821 vs 0.701, p < 0.001), and net reclassification improvement (31.1 %), integrated discrimination improvement (21.5 %), p < 0.001] compared to a model employing only clinical risk factors. The modified AUC (0.806) of combined model based on 10-fold-cross-validation was still higher than clinical risk model (0.701). Conclusion: The combination of serum occludin and clinical risk factors significantly improved the prediction efficacy for HT, providing a novel potential prediction model to screen for patients with high risk of HT before recanalization in acute ischemic stroke.

Optimal omegas - barriers and novel methods to narrow omega-3 gaps. A narrative review.

Dietary intakes of omega-3 long chain polyunsaturated fatty acids (O3LC-PUFAs) such as eicosapentaenoic and docosahexaenoic acid are central to development and health across the life course. O3LC-PUFAs have been linked to neurological development, maternal and child health and the etiology of certain non-communicable diseases including age-related cognitive decline, cardiovascular disease, and diabetes. However, dietary inadequacies exist in the United Kingdom and on a wider global scale. One predominant dietary source of O3LC-PUFAs is fish and fish oils. However, growing concerns about overfishing, oceanic contaminants such as dioxins and microplastics and the trend towards plant-based diets appear to be acting as cumulative barriers to O3LC-PUFAs from these food sources. Microalgae are an alternative provider of O3LC-PUFA-rich oils. The delivery of these into food systems is gaining interest. The present narrative review aims to discuss the present barriers to obtaining suitable levels of O3LC-PUFAs for health and wellbeing. It then discusses potential ways forward focusing on innovative delivery methods to utilize O3LC-PUFA-rich oils including the use of fortification strategies, bioengineered plants, microencapsulation, and microalgae.

Ligand engineering to achieve synergistic properties in a 2D bilayer supertetrahedral chalcogenide cluster-based assembled material.

Incorporating functional organic linkers into supertetrahedral chalcogenolate cluster-based materials is an effective synthetic strategy to expand structural diversity and generate tunable optical and photoelectric properties arising from synergistic effects. Herein, a mixed ligand engineering approach was adopted to design a supertetrahedral cluster-based assembled material [(Cd6Ag4(SPh)16(TPPA)(BPE)0.5)·2DMF]n (denoted as SCCAM-3) with a 2D bilayer architecture and broader visible-light absorption. Interestingly, SCCAM-3 demonstrates a long-lived afterglow at 83 K and efficient photocatalytic activity for degrading tetracycline in water.

Aucubin alleviates doxorubicin-induced cardiotoxicity through crosstalk between NRF2 and HIPK2 mediating autophagy and apoptosis.

BACKGROUND: Doxorubicin (DOX) is widely used for the treatment of a variety of cancers. However, its clinical application is limited by dose-dependent cardiotoxicity. Recent findings demonstrated that autophagy inhibition and apoptosis of cardiomyocytes induced by oxidative stress dominate the pathophysiology of DOX-induced cardiotoxicity (DIC), however, there are no potential molecules targeting on these. PURPOSE: This study aimed to explore whether aucubin (AU) acting on inimitable crosstalk between NRF2 and HIPK2 mediated the autophagy, oxidative stress, and apoptosis in DIC, and provide a new and alternative strategy for the treatment of DIC. METHODS AND RESULTS: We first demonstrated the protection of AU on cardiac structure and function in DIC mice manifested by increased EF and FS values, decreased serum CK-MB and LDH contents and well-aligned cardiac tissue in HE staining. Furthermore, AU alleviated DOX-induced myocardial oxidative stress, mitochondrial damage, apoptosis, and autophagy flux dysregulation in mice, as measured by decreased ROS, 8-OHdG, and TUNEL-positive cells in myocardial tissue, increased SOD and decreased MDA in serum, aligned mitochondria with reduced vacuoles, and increased autophagosomes. In vitro, AU alleviated DOX-induced oxidative stress, autophagy inhibition, and apoptosis by promoting NRF2 and HIPK2 expression. We also identified crosstalk between NRF2 and HIPK2 in DIC as documented by overexpression of NRF2 or HIPK2 reversed cellular oxidative stress, autophagy blocking, and apoptosis aggravated by HIPK2 or NRF2 siRNA, respectively. Simultaneously, AU promoted the expression and nuclear localization of NRF2 protein, which was reversed by HIPK2 siRNA, and AU raised the expression of HIPK2 protein as well, which was reversed by NRF2 siRNA. Crucially, AU did not affect the antitumor activity of DOX against MCF-7 and HepG2 cells, which made up for the shortcomings of previous anti-DIC drugs. CONCLUSION: These collective results innovatively documented that AU regulated the unique crosstalk between NRF2 and HIPK2 to coordinate oxidative stress, autophagy, and apoptosis against DIC without compromising the anti-tumor effect of DOX in vitro.

Effects of whole-body vibration training on physical function, activities of daily living, and quality of life in patients with stroke: a systematic review and meta-analysis.

Purpose: This systematic review and meta-analysis aimed to evaluate the efficacy of whole-body vibration training (WBVT) in patients with stroke, specifically focusing on its effects on physical function, activities of daily living (ADL), and quality of life (QOL). Additionally, potential moderators influencing WBVT outcomes were explored. Methods: We conducted a systematic search of PubMed, Embase, and Cochrane Library from inception to September 2022. Eligible studies were randomized controlled trials employing WBVT in patients with stroke. Two investigators independently extracted the data and calculated the standardized mean difference (SMD) using random-effect models. Results: Twenty-five studies involving 991 patients were included in this meta-analysis. WBVT demonstrated significant reductions in spasticity (SMD = -0.33, 95% CI = -0.61 to -0.06, p = 0.02), improvements in motor function (SMD = 0.39, 95% CI = 0.16 to 0.61, p < 0.01), and enhancements in balance function (SMD = 0.28, 95% CI = 0.09 to 0.47, p < 0.01) in patients with stroke. However, no significant effects were observed for gait (SMD = -0.23, 95% CI = -0.50 to 0.04, p = 0.10), ADL (SMD = -0.01, 95% CI = -0.46 to 0.44, p = 0.97), or QOL (SMD = 0.12, 95% CI = -0.30 to 0.53, p = 0.59). Subgroup analyses revealed that variable frequency vibration and side-alternating vibration exhibited significant efficacy in reducing spasticity and improving motor and balance functions, while fixed frequency vibration and vertical vibration did not yield significant therapeutic benefits in these domains. Conclusion: Our findings indicate that WBVT may serve as a viable adjunct therapy for stroke patients to alleviate spasticity and enhance motor and balance functions. Variable frequency and side-alternating vibration appear to be crucial factors influencing the therapeutic effects of WBVT on these dysfunctions. Nonetheless, WBVT did not show significant effects on gait, ADL, or QOL in stroke patients. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier (CRD42022384319).

Integration of cloud-based molecular networking and docking for enhanced umami peptide screening from Pixian douban.

This study presents an innovative cloud-based approach, using Pixian Douban, a well-known Chinese fermented seasoning, as a case study, to improve the identification of umami peptides and explore their interactions with the T1R1/T1R3 receptor. A feature-based molecular networking method was utilized to rapidly identify a total of eighteen peptides, including seven previously unrecorded ones. Notably, the umami threshold of QIVK in an aqueous solution was determined to be 0.3215 mmol/L, surpassing the majority of peptides reported in the past three years. Molecular docking analysis further revealed the strong binding of QIVK to T1R3 receptor residues through hydrogen bonds, as well as interactions via salt bridges and electrostatic attractions. As a result, this research significantly contributes to the efficient screening of umami peptides and the elucidation of the molecular basis of umami sensory perception in complex food systems.

Autophagy-related biomarkers in preeclampsia: the underlying mechanism, correlation to the immune microenvironment and drug screening.

BACKGROUND: Preeclampsia is a life-threatening disease of pregnancy that lacks effective pharmaceuticals which can target its pathogenesis. Since preeclampsia involves complex pathological processes, including autophagy, this study aims to explore autophagy-related mechanisms of preeclampsia and to screen potential drugs. METHODS: Firstly, the datasets GSE75010, GSE24129, GSE66273, and autophagic genes lists were downloaded from public databases. Then, a weighted gene co-expression network analysis (WGCNA) was applied to filter autophagic-related hub genes of preeclampsia. The differential expression levels of the hub genes were validated with datasets GSE24129 and GSE66273. Next, the GO and KEGG enrichment, protein-protein interacting (PPI) network, as well as the downstream pathways was analyzed via the starBase, STRING and Cytoscape to determine the functions and regulatory network of the hub genes. Additionally, the immune microenvironment of preeclampsia was investigated by the CIBERSORTX database. Finally, three herb ingredients, berberine, baicalein, and luteolin were screened by molecular docking in comparison to pravastatin, metformin, and aspirin, to predict potential drugs for treating preeclampsia. RESULTS: A total of 54 autophagy-related genes were filtered by WGCNA. After filtering with |GS| > 0.5 and |MM| > 0.8, three hub genes, namely PKM, LEP, and HK2, were identified and validated. Among these genes, PKM and LEP were overexpressed in women older than 35 years old ( p<0.05; p<0.05); the expression of PKM, LEP, and HK2 differed remarkably in women with different BMI (all p<0.05); PKM overexpressed in women with hypertension (p<0.05). The regulatory network of hub genes demonstrated that they were mainly enriched in metabolic pathways, including the AMPK signaling pathway, glucagon signaling pathway, adipocytokine signaling pathway, and central carbon metabolism. Then, immune microenvironment analysis turned out that M2 macrophages were reduced in preeclampsia women (p<0.0001) and were negatively correlated with the expression of PKM (r=-0.2, p<0.05), LEP (r=-0.4, p<0.0001), and HK2 (r=-0.3, p<0.001). Lastly, molecular docking showed baicalein and luteolin could bind intimately to hub genes. CONCLUSION: PKM, LEP, and HK2 could be promising biomarkers for preeclampsia, which might regulate the pathogenesis of preeclampsia via metabolism pathways and immune microenvironment. Baicalein and luteolin could be potential therapeutics for preeclampsia.

Clinical utility of metagenomic next-generation sequencing in pathogen detection for lower respiratory tract infections and impact on clinical outcomes in southernmost China.

Background: Today, metagenomic next-generation sequencing (mNGS) has emerged as a diagnostic tool for infections. However, since Hainan has a complicated pathogen spectrum, the diagnostic value and impact on patient outcomes of mNGS in Hainan are to be explored. Methods: From April 2020 to October 2021, 266 suspected lower respiratory tract infections (LRTIs) patients in Hainan were enrolled, and specimens were collected before antibiotic treatment. Bronchoalveolar lavage fluid (BALF) samples were subjected to mNGS and culture to compare the diagnostic performance. Other conventional microbiological tests (CMT) were also performed. Patients' treatments and clinical outcomes were recorded, and the antibiotic resistance genes (ARGs) were detected via mNGS workflow. Results: The positive rate of mNGS outperformed that of culture (87.55% vs. 39.30%, p<0.001) and CMT (87.12% vs. 52.65%, p<0.001). Specifically, mNGS detected more P. aeruginosa (12.03% vs 9.02%, p<0.05), H. influenzae (9.77% vs 2.26%, p<0.001), Aspergillus fumigatus (3.00% vs 0.75%, p<0.05), Candida albicans (26.32% vs 7.52%, p<0.001) and uncommon pathogens. It also demonstrated great diagnostic advantages in Mycobacterium tuberculosis with 80% sensitivity and 97.4% specificity. Over half of the patients (147, 55.26%) had modified empirical treatment according to mNGS results and 89.12% of them responded well. For three deaths with modified treatment, multiple drug resistance was predicted by mNGS and confirmed by antibiotic susceptibility test. Conclusions: The application of mNGS can benefit clinics in pathogen identification and antimicrobial treatment stewardship. Physicians should be alert to some emerging uncommon pathogens, including Chlamydia Psittaci, Nocardia otitidiscaviarum, and rare NTM.

Modelling and Research on Intuitionistic Fuzzy Goal-Based Attack and Defence Game for Infrastructure Networks.

Network attack and defence games are gradually becoming a new approach through which to study the protection of infrastructure networks such as power grids and transportation networks. Uncertainty factors, such as the subjective decision preferences of attackers and defenders, are not considered in existing attack and defence game studies for infrastructure networks. In this paper, we introduce, respectively, the attacker's and defender's expectation value, rejection value, and hesitation degree of the target, as well as construct an intuitionistic fuzzy goal-based attack and defence game model for infrastructure networks that are based on the maximum connectivity slice size, which is a network performance index. The intuitionistic fuzzy two-player, zero-sum game model is converted into a linear programming problem for solving, and the results are analysed to verify the applicability and feasibility of the model proposed in this paper. Furthermore, different situations, such as single-round games and multi-round repeated games, are also considered. The experimental results show that, when attacking the network, the attacker rarely attacks the nodes with higher importance in the network, but instead pays more attention to the nodes that are not prominent in the network neutrality and median; meanwhile, the defender is more inclined to protect the more important nodes in the network to ensure the normal performance of the network.

Associations between insomnia and large vessel occlusion acute ischemic stroke: An observational study.

OBJECTIVES: This study explored the association between insomnia and the clinical outcome of large vessel occlusion Acute Ischemic Stroke (AIS) and attempted to explore its potential mechanisms from the perspectives of inflammation and oxidative stress. METHODS: AIS patients who underwent endovascular treatment for large vessel occlusion at Binzhou Central Hospital from 2018 to 2022 (n = 508) were included. Patients were divided into an insomnia group and a non-insomnia group. Insomnia was judged by self-reported Athens Insomnia Scale score. Regression analysis was used to compare the differences in the 24-hour and 7-day National Institutes of Health Stroke Scale (NIHSS) score, Early Neurological Deterioration (END), early adverse event incidence, 90-day prognosis and mortality, and serum biomarkers levels. RESULTS: The incidence of insomnia in the study population was 39.6% (n = 144, insomnia group; n = 364, non-insomnia group). Compared with the non-insomnia group, a worse prognosis outcome (63% vs. 49%, adjusted rate ratio: 1.8, 95% Confidence Interval: 1.2-3.7; p = 0.016), higher 24-h and 7-day NIHSS score (17 [9-36] vs. 13 [5-20]; p = 0.024, and 11 [4‒24) vs. 8 [2‒14]; p = 0.031, respectively), higher END (24% vs. 15%, p = 0.022), and higher incidence of adverse events were observed in the insomnia group (79% vs. 59%, p = 0.010). The 90-day mortality was higher in the insomnia group than that in the non-insomnia group (22% vs. 17%), however, such a difference was not statistically significant. CONCLUSION: Insomnia is closely related to the clinical outcome of AIS with large vessel occlusion, and inflammation and oxidative stress mechanisms may be involved.

Potent Antibody Response Elicited by a Third Booster Dose of Inactivated COVID-19 Vaccine in Healthy Subjects.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine has been used worldwide on a large scale because of its potent ability to contain the coronavirus disease 2019 (COVID-19) pandemic, and the antibody response induced by the vaccine needs to be elucidated. Thus, we conducted a prospective trial in healthy subjects to observe the antibody response after three doses of inactivated vaccines. Our results showed that neutralizing antibody (NAb) levels were significantly higher after the booster vaccination compared to the second, a 4.9-fold increase, with the peak occurring at 28 days. The NAb level could be maintained for a longer period after the third vaccination, with higher levels still observed after 3 months. We did not observe significantly higher levels of SARS-CoV-2 spike-specific immunoglobulin G (S-IgG) and immunoglobulin M (IgM) after the third vaccination compared with the second vaccination; this was especially true for SARS-CoV-2 spike-specific immunoglobulin M (S-IgM), which was barely expressed. Notably, those who did not undergo NAb seroconversion after two doses of the vaccine produced high and long-lasting NAb after the third vaccination, confirming that they were not completely unresponsive to the vaccine. The NAb titer in younger subjects (aged 20-40 years) rose 3.4-fold compared with older subjects (aged 40-60 years) after the second vaccination, but the difference was narrowed after the third vaccination (2.8-fold increase). In addition, the levels of antibodies in older men were 3.4-fold lower than those in the older women after the third vaccination. Overall, this study elucidates the dynamic change in antibodies after three doses of vaccination, which provides a reference for the improvement of vaccination strategies.

Modulo-addition operation enables terahertz programmable metasurface for high-resolution two-dimensional beam steering.

Electrically controlled terahertz (THz) beamforming antennas are essential for various applications such as wireless communications, security checks, and radar to improve coverage and information capacity. The emerging programmable metasurface provides a flexible, cost-effective platform for THz beam steering. However, scaling such arrays to achieve high-gain beam steering faces several technical challenges. Here, we propose a pixelated liquid crystal THz metasurface with a crossbar structure, thereby increasing the array scale to more than 3000. The coding pattern on the programmable device is generated by the modulo-addition of the coding sequences on the top and bottom layers. We experimentally demonstrate the programmable liquid crystal metasurface capable of active beam deflection in the upper half-space. This scale-up of programmable devices opens exciting opportunities in pencil beamforming, high-speed information processing, and optical computing.

Saponins of Panax japonicus ameliorates cardiac aging phenotype in aging rats by enhancing basal autophagy through AMPK/mTOR/ULK1 pathway.

Heart disease is a significant health concern for elderly individuals, with heart aging being the primary cause. Recent studies have shown that autophagy can play a protective role in preventing cardiac aging. Our previous research confirmed that Chikusetsu saponin IVa, a fundamental component of Saponins of Panax japonics (SPJ), can enhance basic autophagy levels in cardiomyocyte of isoproterenol induced cardiac fibrosis mice. However, it remains unclear whether SPJ possesses a protective effect on cardiac dysfunction during the natural aging process. Rats were randomly divided into four groups: adult control group (6 months old), aging group (24 months old), aging group treated with 10 mg/kg SPJ, and aging group treated with 30 mg/kg SPJ. The heart function, blood pressure, and heart mass index (HMI) were measured. Hematoxylin and eosin staining (H&E) and Wheat Germ Agglutinin (WGA) staining were used to observe the changes in morphology, while Masson staining was used to examine collagen deposition in the rat hearts and CD45 immunohistochemistry was conducted to examine the macrophage infiltration in heart tissues. TUNEL kit was used to detect apoptosis level of cardiomyocyte, and western blot was used to evaluate autophagy-related proteins as well as AMPK/mTOR/ULK1 pathway-related markers. SPJ treatment improved the cardiac function, reduced HMI, attenuated myocardial fiber disorder, inhibited inflammatory cell infiltration, and decreased collagen deposition and cardiomyocyte apoptosis in aging rats. Additionally, SPJ treatment decreased the expression of aging-related proteins and restored the expression of autophagy-related markers. SPJ activated autophagy through the activation of AMPK, which in turn increased the phosphorylation of ULK1(Ser555), while inhibited the phosphorylation of mTOR and ULK1(Ser757). Our study demonstrates that SPJ improves the cardiac function of aging rats by enhancing basal autophagy through the AMPK/mTOR/ULK1 pathway. These results offer a theoretical foundation and empirical evidence to support the clinical advancement of SPJ in enhancing age-related cardiac dysfunction.

Activation of ULK1 to trigger FUNDC1-mediated mitophagy in heart failure: Effect of Ginsenoside Rg3 intervention.

BACKGROUND: Although the development of therapies for heart failure (HF) continues apace, clinical outcomes are often far from ideal. Unc51-like-kinase 1 (ULK1)-mediated mitophagy prevents pathological cardiac remodeling and heart failure (HF). Molecularly ULK1-targeted agent to enhance mitophagy is scanty. HYPOTHESIS/PURPOSE: This study aimed to investigate whether Ginsenoside Rg3 (Rg3) can activate ULK1 to trigger FUNDC1-mediated mitophagy for protecting heart failure. METHODS: Molecular docking and surface plasmon resonance were used to detect the ULK1 binding behavior of Rg3. Established HF model in rats and transcriptome sequencing were used to evaluate the therapeutic effect and regulatory mechanism of Rg3. Loss-of-function approaches in vivo and in vitro were performed to determine the role of ULK1 in Rg3-elicited myocardial protection against HF. FUNDC1 recombinant plasmid of site mutation was applied to elucidate more in-depth mechanisms. RESULTS: Structurally, a good binding mode was unveiled between ULK1 and Rg3. In vivo, Rg3 improved cardiac dysfunction, adverse remodeling, and mitochondrial damage in HF rats. Furthermore, Rg3 promoted Ulk1-triggered mitophagy both in vivo and in vitro, manifested by the impetus of downstream Fundc1-Lc3 interaction. Of note, the protective effects conferred by Rg3 against mitophagy defects, pathological remodeling, and cardiac dysfunction were compromised by Ulk1 gene silencing both in vivo and in vitro. Mechanistically, Rg3 activated mitophagy by inducing ULK1-mediated phosphorylation of FUNDC1 at the Ser17 site, not the Ser13 site. CONCLUSION: Together these observations demonstrated that Rg3 acts as a ULK1 activator for the precise treatment of HF, which binds to ULK1 to activate FUNDC1-mediated mitophagy.

Laparoscopic versus open radical hysterectomy in FIGO 2018 early-stage cervical adenocarcinoma: Long-term survival outcomes after propensity score matching.

OBJECTIVE: To compare the long-term survival outcomes of laparoscopic radical hysterectomy (LRH) and open radical hysterectomy (ORH) in International Federation of Gynecology and Obstetrics (FIGO) 2018 early-stage cervical adenocarcinoma. METHODS: Based on the clinical diagnosis and treatment for cervical cancer in mainland China (Four C) database, the medical records of 1098 patients with FIGO 2018 early-stage cervical adenocarcinoma were retrospectively reviewed. Long-term and short-term survival outcomes of the two groups were compared using a multivariate Cox regression model and the log-rank method in the whole study population and after propensity score matching. RESULTS: There was no difference in disease-free survival (hazard ratio [HR] 0.921, 95% confidence interval [CI]: 0.532-1.595, p = 0.770) and overall survival (HR 1.168, 95% CI: 0.526-2.592, p = 0.702) between LRH (n = 468) and ORH (n = 468) in the risk-adjusted analysis. LRH resulted in significantly lower estimated blood loss (342.7 vs. 157.5 mL, p < 0.001) and shorter postoperative anal exhaust time (2.8 vs. 2.5 days, p < 0.001) in risk-adjusted analysis. The overall rates of intraoperative complications (2.4% vs. 4.3%, p = 0.100) and postoperative complications (7.5% vs. 6.2%, p = 0.437) showed no significant difference between the two groups. However, the LRH group had a significantly higher incidence of ureter injury (0.4% vs. 2.4%, p = 0.012) and great vessel injury (0.0% vs. 0.9%, p = 0.045) compared to the other group. No statistical variation in the site of recurrence was observed between the two groups (p = 0.613). CONCLUSIONS: LRH has comparable survival outcomes with ORH and was associated with earlier recovery in FIGO 2018 early-stage adenocarcinoma of the uterine cervix. However, the LRH group had higher risk of ureter injury and great vessel injury.