Targeting Catechol-O-Methyltransferase Induces Mitochondrial Dysfunction and Enhances the Efficacy of Radiotherapy in Glioma.

Radiotherapy (RT) is commonly used to try to eliminate any remaining tumor cells following surgical resection of glioma. However, tumor recurrence is prevalent, highlighting the unmet medical need to develop therapeutic strategies to enhance the efficacy of RT in glioma. Focusing on the radiosensitizing potential of currently approved drugs known to cross the blood-brain barrier can facilitate rapid clinical translation. Here, we assessed the role of catechol-o-methyltransferase (COMT), a key enzyme to degrade catecholamines and a drug target for Parkinson's disease, in glioma treatment. Analysis of TCGA data showed significantly higher COMT expression levels in both low-grade glioma and glioblastoma compared to normal brain tissues. Inhibition of COMT by genetic knockout or FDA-approved COMT inhibitors significantly sensitized glioma cells to RT in vitro and in vivo. Mechanistically, COMT inhibition in glioma cells led to mitochondria dysfunction and increased mitochondrial RNA release into the cytoplasm, activating the cellular antiviral double-stranded RNA sensing pathway and type I interferon (IFN) response. Elevated type I IFNs stimulated the phagocytic capacity of microglial cells, enhancing RT efficacy. Given the long-established safety record of the COMT inhibitors, these findings provide a solid rationale to evaluate them in combination with RT in glioma patients.

Fucoxanthin Mitigates High-Fat-Induced Lipid Deposition and Insulin Resistance in Skeletal Muscle through Inhibiting PKM1 Activity.

Glucose and lipid metabolism dysregulation in skeletal muscle contributes to the development of metabolic disorders. The efficacy of fucoxanthin in alleviating lipid metabolic disorders in skeletal muscle remains poorly understood. In this study, we systematically investigated the impact of fucoxanthin on mitigating lipid deposition and insulin resistance in skeletal muscle employing palmitic acid-induced lipid deposition in C2C12 cells and ob/ob mice. Fucoxanthin significantly alleviated PA-induced skeletal muscle lipid deposition and insulin resistance. In addition, fucoxanthin prominently upregulated the expression of lipid metabolism-related genes (Pparα and Cpt-1), promoting fatty acid ß-oxidation metabolism. Additionally, fucoxanthin significantly increased the expression of Pgc-1α and Tfam, elevated the mtDNA/nDNA ratio, and reduced ROS levels. Further, we identified pyruvate kinase muscle isozyme 1 (PKM1) as a high-affinity protein for fucoxanthin by drug affinity-responsive target stability and LC-MS and confirmed their robust interaction by CETSA, microscale thermophoresis, and circular dichroism. Supplementation with pyruvate, the product of PKM1, significantly attenuated the beneficial effects of fucoxanthin on lipid deposition and insulin resistance. Mechanistically, fucoxanthin reduced glucose glycolysis rate and enhanced mitochondrial biosynthesis and fatty acid ß-oxidation through inhibiting PKM1 activity, thereby alleviating lipid metabolic stress. These findings present a novel clinical strategy for treating metabolic diseases using fucoxanthin.

Bruton's tyrosine kinase inhibition ameliorated neuroinflammation during chronic white matter ischemia.

Chronic cerebral hypoperfusion (CCH), a disease afflicting numerous individuals worldwide, is a primary cause of cognitive deficits, the pathogenesis of which remains poorly understood. Bruton's tyrosine kinase inhibition (BTKi) is considered a promising strategy to regulate inflammatory responses within the brain, a crucial process that is assumed to drive ischemic demyelination progression. However, the potential role of BTKi in CCH has not been investigated so far. In the present study, we elucidated potential therapeutic roles of BTK in both in vitro hypoxia and in vivo ischemic demyelination model. We found that cerebral hypoperfusion induced white matter injury, cognitive impairments, microglial BTK activation, along with a series of microglia responses associated with inflammation, oxidative stress, mitochondrial dysfunction, and ferroptosis. Tolebrutinib treatment suppressed both the activation of microglia and microglial BTK expression. Meanwhile, microglia-related inflammation and ferroptosis processes were attenuated evidently, contributing to lower levels of disease severity. Taken together, BTKi ameliorated white matter injury and cognitive impairments induced by CCH, possibly via skewing microglia polarization towards anti-inflammatory and homeostatic phenotypes, as well as decreasing microglial oxidative stress damage and ferroptosis, which exhibits promising therapeutic potential in chronic cerebral hypoperfusion-induced demyelination.

Three-Dimensional Computed Tomography Scanning Study of the Superior Labial Artery in Chinese Individuals for Assessing Filler Injection Safety.

BACKGROUND: Lip filler injection is one of the most common minimally invasive cosmetic procedures involving the face; however, vascular complications are not uncommon. The aim of this study was to investigate the anatomy of the superior labial artery (SLA) and provide precise topographic information for dermal filler injection into the lips. METHODS: Computed tomography (CT) scans of 52 cadaveric heads injected with lead oxide were obtained. We then used Mimics software to construct 3D images of the SLA described by a coordinate system based on the bilateral external auditory canal and the left orbit. This study aimed to classify the SLA in the Han Chinese population, measure its diameter at specific points, and determine the thickness of the lip at those points. Ultimately, we utilized a thermal imaging technique to illustrate the course and depth of the SLA within the lip. The objective of this study was to provide safe guidance for clinical injections. RESULTS: In this study, the SLA was successfully identified in all cadavers. The mean overall diameter of the superior labial arteries was 1.36 ± 0.28 mm. The superior labial artery showed a general course from deep to shallow with an average depth of 5.68 ± 1.68 mm from the oral commissure to the midline. CONCLUSIONS: There are anatomical differences in the superior labial arteries among Chinese people. Furthermore, 3D CT images can digitally elucidate the exact positions of the superior labial artery via a coordinate system, improving the safety of upper lip filler injections in clinical settings. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Clinical characteristics and prognosis of primary thymic adenocarcinoma: A single-center retrospective analysis.

BACKGROUND: Primary thymic adenocarcinoma (PTAC) is an extremely rare disease with a poor prognosis. In the present study, we sought to analyze the clinical characteristics and prognostic factors of patients with PTAC. METHODS: A total of 14 patients with PTAC treated at our center from January 2000 to January 2019 were included in this study. We retrospectively collected information on sex, age, history of smoking, family history of cancer, comorbidities, symptoms, imaging tests, serum tumor marker levels, tumor, node, metastasis (TNM) staging, and treatment records. Follow-up information was obtained by telephone interviews or outpatient clinic visit. Univariate and multivariate Cox regression analyses were performed to investigate the clinicopathological factors associated with survival. RESULTS: Among 14 patients with PTAC, there were five males and nine females, with an average age of 48.7 ± 9.3 years. A total of 23.1% of the patients had a history of smoking. The clinical symptoms of the patients were nonspecific and seven patients had elevated levels of serum tumor markers. Surgery was performed for nine patients, among which only four received R0 resection. The median survival time of the 14 patients was 16.0 months, and the 1-, 3- and 5-year survival rates were 57.1%, 35.7% and 21.4%, respectively. TNM stage was identified as an independent prognostic factor for PTAC patients (the median survival time of stage I-IIIA vs. stage IV was 44.0 months vs. 9.0 months, p = 0.002). CONCLUSIONS: PTAC is highly aggressive malignancy with poor prognosis. Surgical treatment is feasible, but R0 resection is challenging. TNM staging is significantly associated with patient survival.

VHL loss enhances antitumor immunity by activating the anti-viral DNA-sensing pathway.

von Hippel-Lindau (VHL), known as a tumor suppressor gene, is frequently mutated in clear cell renal cell carcinoma (ccRCC). However, VHL mutation is not sufficient to promote tumor formation. In most cases other than ccRCC, VHL loss alters cellular homeostasis and causes cell stress and metabolic changes by stabilizing hypoxia-inducible factor (HIF) levels, resulting in a fitness disadvantage. In addition, the function of VHL in regulating immune response is still not well established. In this study, we demonstrate that VHL loss enhances the efficacy of anti-programmed death 1 (PD1) treatment in multiple murine tumor models in a T cell-dependent manner. Mechanistically, we discovered that upregulation of HIF1α/2α induced by VHL loss decreased mitochondrial outer membrane potential and caused the cytoplasmic leakage of mitochondrial DNA, which triggered cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation and induced type I interferons. Our study thus provided mechanistic insights into the role of VHL gene loss in boosting antitumor immunity.

Association Between Heart Rate at Diagnosis and Long-Term Recurrence Risk of Pulmonary Embolism in a Historical Cohort Study of Elder Women.

To investigate the association between heart rate (HR) at diagnosis and long-term pulmonary embolism (PE) recurrence among elderly (≥ 50 year-old) female patients after acute PE (APE). Hospitalized patients with APE were grouped separately according to whether they experienced recurrent PE and whether the HR was < 80 beats/min. Logistic regression and COX regression analysis were employed to assess the risk of PE recurrence. Kaplan-Meier method was applied to compare the recurrence-free survival of PE recurrence. Eighty-five patients were included, including 24 ones with HR < 80 beats/min and 11 recurrent PE cases. The mean time of PE recurrence were 71.7 ± 26.9 months (n = 6) and 27.7 ± 25.2 months (n = 5) among the patients with low HR and with high HR, respectively (P < .001). The HR (< 80 beats/min) was a negative predictor of PE recurrence (OR 0.071 (0.090-0.572), P = .013; HR 0.091 (0.016-0.523), P = .007), even after the adjustment for age, BMI, albumin, risk stratification, surgery, immobility ≥ 4 days, the blood cells counts, bilirubin and complications. The cumulative recurrence-free rates of PE recurrence at the 1st-, 2nd-, 5th-, and 10th-years for the low HR group were 100%, 100%, 87.5%, and 58.3%, compared to the 1st-, 2nd-, and 3rd-years of 94.0%, 93.4%, and 48.0% for the high HR group (log-rank = 0.019). The low HR (< 80 beats/min at diagnosis) among elderly (≥ 50 years old) female patients at APE diagnosis would benefit to the long-term PE recurrence. But limited recurrent cases should be noted.

Universal subunit vaccine protects against multiple SARS-CoV-2 variants and SARS-CoV.

Although Omicron RBD of SARS-CoV-2 accumulates many mutations, the backbone region (truncated RBD) of spike protein is highly conserved. Here, we designed several subunit vaccines by keeping the conserved spike backbone region of SARS-CoV-2 Omicron BA.1 subvariant (S-6P-no-RBD), or inserting the RBD of Delta variant (S-6P-Delta-RBD), Omicron (BA.5) variant (S-6P-BA5-RBD), or ancestral SARS-CoV-2 (S-6P-WT-RBD) to the above backbone construct, and evaluated their ability to induce immune responses and cross-protective efficacy against various SARS-CoV-2 variants and SARS-CoV. Among the four subunit vaccines, S-6P-Delta-RBD protein elicited broad and potent neutralizing antibodies against all SARS-CoV-2 variants tested, including Alpha, Beta, Gamma, and Delta variants, the BA.1, BA.2, BA.2.75, BA.4.6, and BA.5 Omicron subvariants, and the ancestral strain of SARS-CoV-2. This vaccine prevented infection and replication of SARS-CoV-2 Omicron, and completely protected immunized mice against lethal challenge with the SARS-CoV-2 Delta variant and SARS-CoV. Sera from S-6P-Delta-RBD-immunized mice protected naive mice against challenge with the Delta variant, with significantly reduced viral titers and without pathological effects. Protection correlated positively with the serum neutralizing antibody titer. Overall, the designed vaccine has potential for development as a universal COVID-19 vaccine and/or a pan-sarbecovirus subunit vaccine that will prevent current and future outbreaks caused by SARS-CoV-2 variants and SARS-related CoVs.

P7C3 suppresses astrocytic senescence to protect dopaminergic neurons: Implication in the mouse model of Parkinson's disease.

AIMS: Astrocytic senescence is inextricably linked to aging and neurodegenerative disorders, including Parkinson's disease (PD). P7C3 is a small, neuroprotective aminopropyl carbazole compound that exhibits anti-inflammatory properties. However, the effects of P7C3 on astrocytic senescence in PD remain to be elucidated. METHODS: An in vitro, long culture-induced, replicative senescence cell model and a 1-methyl-4-phenylpyridinium (MPP+)/rotenone-induced premature senescence cell model were used to investigate the effects of P7C3 on astrocytic senescence. An in vivo, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse PD model was used to study the role of P7C3 in astrocytic senescence. Immunoblotting, real-time quantitative RT-PCR (qPCR), immunofluorescence, subcellular fractionation assays, and immunohistochemistry were utilized to confirm the effects of P7C3 on astrocytic senescence and elucidate its underlying mechanisms. RESULTS: This study determined that P7C3 suppressed the senescence-associated secretory phenotype (SASP) in both cell models, as demonstrated by the reduction in the critical senescence marker p16 and proinflammatory factors (IL-6, IL-1ß, CXCL10, and MMP9) and increased laminB1 levels, implying that P7C3 inhibited replicative astrocytic senescence and MPP+/rotenone-induced premature astrocytic senescence, Most importantly, we demonstrated that P7C3 prevented the death of dopamine (DA) neurons and reduced the behavioral deficits in the MPTP-induced mouse model of PD, which is accompanied by a decrease in senescent astrocytes in the substantia nigra compacta (SNc). Mechanistically, P7C3 promoted Nrf2/Sirt3-mediated mitophagy and reduced mitochondrial reactive oxygen species (mitoROS) generation, which contributed to the suppression of astrocytic senescence. Furthermore, Sirt3 deficiency obviously abolished the inhibitory effects of P7C3 on astrocytic senescence. CONCLUSION: This study revealed that P7C3 inhibited astrocytic senescence via increased Nrf2/Sirt3-mediated mitophagy and suppression of mitoROS, which further protected against DA neuronal loss. These observations provide a prospective theoretical basis for P7C3 in the treatment of age-associated neurodegenerative diseases, such as PD.

The progress of induced pluripotent stem cells derived from pigs: a mini review of recent advances.

Pigs (Sus scrofa) are widely acknowledged as an important large mammalian animal model due to their similarity to human physiology, genetics, and immunology. Leveraging the full potential of this model presents significant opportunities for major advancements in the fields of comparative biology, disease modeling, and regenerative medicine. Thus, the derivation of pluripotent stem cells from this species can offer new tools for disease modeling and serve as a stepping stone to test future autologous or allogeneic cell-based therapies. Over the past few decades, great progress has been made in establishing porcine pluripotent stem cells (pPSCs), including embryonic stem cells (pESCs) derived from pre- and peri-implantation embryos, and porcine induced pluripotent stem cells (piPSCs) using a variety of cellular reprogramming strategies. However, the stabilization of pPSCs was not as straightforward as directly applying the culture conditions developed and optimized for murine or primate PSCs. Therefore, it has historically been challenging to establish stable pPSC lines that could pass stringent pluripotency tests. Here, we review recent advances in the establishment of stable porcine PSCs. We focus on the evolving derivation methods that eventually led to the establishment of pESCs and transgene-free piPSCs, as well as current challenges and opportunities in this rapidly advancing field.

Large-scale 2D heterostructures from hydrogen-bonded organic frameworks and graphene with distinct Dirac and flat bands.

The current strategies for building 2D organic-inorganic heterojunctions involve mostly wet-chemistry processes or exfoliation and transfer, leading to interface contaminations, poor crystallizing, or limited size. Here we show a bottom-up procedure to fabricate 2D large-scale heterostructure with clean interface and highly-crystalline sheets. As a prototypical example, a well-ordered hydrogen-bonded organic framework is self-assembled on the highly-oriented-pyrolytic-graphite substrate. The organic framework adopts a honeycomb lattice with faulted/unfaulted halves in a unit cell, resemble to molecular "graphene". Interestingly, the topmost layer of substrate is self-lifted by organic framework via strong interlayer coupling, to form effectively a floating organic framework/graphene heterostructure. The individual layer of heterostructure inherits its intrinsic property, exhibiting distinct Dirac bands of graphene and narrow bands of organic framework. Our results demonstrate a promising approach to fabricate 2D organic-inorganic heterostructure with large-scale uniformity and highly-crystalline via the self-lifting effect, which is generally applicable to most of van der Waals materials.

N6-methyladenosine modified circPAK2 promotes lymph node metastasis via targeting IGF2BPs/VEGFA signaling in gastric cancer.

Circular RNAs (circRNAs) have emerged as key regulators of cancer occurrence and progression, as well as promising biomarkers for cancer diagnosis and prognosis. However, the potential mechanisms of circRNAs implicated in lymph node (LN) metastasis of gastric cancer remain unclear. Herein, we identify a novel N6-methyladenosine (m6A) modified circRNA, circPAK2, which is significantly upregulated in gastric cancer tissues and metastatic LN tissues. Functionally, circPAK2 enhances the migration, invasion, lymphangiogenesis, angiogenesis, epithelial-mesenchymal transition (EMT), and metastasis of gastric cancer in vitro and in vivo. Mechanistically, circPAK2 is exported by YTH domain-containing protein 1 (YTHDC1) from the nucleus to the cytoplasm in an m6A methylation-dependent manner. Moreover, increased cytoplasmic circPAK2 interacts with Insulin-Like Growth Factor 2 mRNA-Binding Proteins (IGF2BPs) and forms a circPAK2/IGF2BPs/VEGFA complex to stabilize VEGFA mRNA, which contributes to gastric cancer vasculature formation and aggressiveness. Clinically, high circPAK2 expression is positively associated with LN metastasis and poor prognosis in gastric cancer. This study highlights m6A-modified circPAK2 as a key regulator of LN metastasis of gastric cancer, thus supporting circPAK2 as a promising therapeutic target and prognostic biomarker for gastric cancer.

Deep Learning-Based Prediction Modeling of Major Adverse Cardiovascular Events After Liver Transplantation.

Objective: To validate deep learning models' ability to predict post-transplantation major adverse cardiovascular events (MACE) in patients undergoing liver transplantation (LT). Patients and Methods: We used data from Optum's de-identified Clinformatics Data Mart Database to identify liver transplant recipients between January 2007 and March 2020. To predict post-transplantation MACE risk, we considered patients' demographics characteristics, diagnoses, medications, and procedural data recorded back to 3 years before the LT procedure date (index date). MACE is predicted using the bidirectional gated recurrent units (BiGRU) deep learning model in different prediction interval lengths up to 5 years after the index date. In total, 18,304 liver transplant recipients (mean age, 57.4 years [SD, 12.76]; 7158 [39.1%] women) were used to develop and test the deep learning model's performance against other baseline machine learning models. Models were optimized using 5-fold cross-validation on 80% of the cohort, and model performance was evaluated on the remaining 20% using the area under the receiver operating characteristic curve (AUC-ROC) and the area under the precision-recall curve (AUC-PR). Results: Using different prediction intervals after the index date, the top-performing model was the deep learning model, BiGRU, and achieved an AUC-ROC of 0.841 (95% CI, 0.822-0.862) and AUC-PR of 0.578 (95% CI, 0.537-0.621) for a 30-day prediction interval after LT. Conclusion: Using longitudinal claims data, deep learning models can efficiently predict MACE after LT, assisting clinicians in identifying high-risk candidates for further risk stratification or other management strategies to improve transplant outcomes based on important features identified by the model.

Unveiling the secrets of gastrointestinal mucous adenocarcinoma survival after surgery with artificial intelligence: A population-based study.

BACKGROUND: Research on gastrointestinal mucosal adenocarcinoma (GMA) is limited and controversial, and there is no reference tool for predicting postoperative survival. AIM: To investigate the prognosis of GMA and develop predictive model. METHODS: From the Surveillance, Epidemiology, and End Results database, we collected clinical information on patients with GMA. After random sampling, the patients were divided into the discovery (70% of the total, for model training), validation (20%, for model evaluation), and completely blind test cohorts (10%, for further model evaluation). The main assessment metric was the area under the receiver operating characteristic curve (AUC). All collected clinical features were used for Cox proportional hazard regression analysis to determine factors influencing GMA's prognosis. RESULTS: This model had an AUC of 0.7433 [95% confidence intervals (95%CI): 0.7424-0.7442] in the discovery cohort, 0.7244 (GMA: 0.7234-0.7254) in the validation cohort, and 0.7388 (95%CI: 0.7378-0.7398) in the test cohort. We packaged it into Windows software for doctors' use and uploaded it. Mucinous gastric adenocarcinoma had the worst prognosis, and these were protective factors of GMA: Regional nodes examined [hazard ratio (HR): 0.98, 95%CI: 0.97-0.98, P < 0.001)] and chemotherapy (HR: 0.62, 95%CI: 0.58-0.66, P < 0.001). CONCLUSION: The deep learning-based tool developed can accurately predict the overall survival of patients with GMA postoperatively. Combining surgery, chemotherapy, and adequate lymph node dissection during surgery can improve patient outcomes.

A Support Vector Machine-Assisted Metabolomics Approach for Non-Targeted Screening of Multi-Class Pesticides and Veterinary Drugs in Maize.

The contamination risks of plant-derived foods due to the co-existence of pesticides and veterinary drugs (P&VDs) have not been fully understood. With an increasing number of unexpected P&VDs illegally added to foods, it is essential to develop a non-targeted screening method for P&VDs for their comprehensive risk assessment. In this study, a modified support vector machine (SVM)-assisted metabolomics approach by screening eligible variables to represent marker compounds of 124 multi-class P&VDs in maize was developed based on the results of high-performance liquid chromatography-tandem mass spectrometry. Principal component analysis and orthogonal partial least squares discriminant analysis indicate the existence of variables with obvious inter-group differences, which were further investigated by S-plot plots, permutation tests, and variable importance in projection to obtain eligible variables. Meanwhile, SVM recursive feature elimination under the radial basis function was employed to obtain the weight-squared values of all the variables ranging from large to small for the screening of eligible variables as well. Pairwise t-tests and fold changes of concentration were further employed to confirm these eligible variables to represent marker compounds. The results indicate that 120 out of 124 P&VDs can be identified by the SVM-assisted metabolomics method, while only 109 P&VDs can be found by the metabolomics method alone, implying that SVM can promote the screening accuracy of the metabolomics method. In addition, the method's practicability was validated by the real contaminated maize samples, which provide a bright application prospect in non-targeted screening of contaminants. The limits of detection for 120 P&VDs in maize samples were calculated to be 0.3~1.5 µg/kg.

NLR, MLR, and PLR are adverse prognostic variables for sleeve lobectomy within non-small cell lung cancer.

BACKGROUND: The goal of the research was to examine the value of peripheral blood indicators in forecasting survival and recurrence among people suffering central-type non-small cell lung cancer (NSCLC) undergoing sleeve lobectomy (SL). METHODS: Clinical information was gathered from 146 individuals suffering from NSCLC who had SL at our facility between January 2014 and May 2023. Peripheral blood neutrophil lymphocyte ratio (NLR), monocyte lymphocyte ratio (MLR), and platelet lymphocyte ratio (PLR) levels were determined by receiver operating characteristic (ROC) curve to establish the threshold points. Kaplan-Meier survival analysis was employed to evaluate the prognostic value of different groupings, and both univariate and multivariate Cox proportional hazards model (referred to as COX) were performed. RESULTS: The disease-free survival (DFS) and overall survival (OS) cutoff values were carried out via ROC analysis. Kaplan-Meier survival analysis revealed notable differences in OS for NLR (≥2.196 vs. <2.196, p = 0.0009), MLR (≥0.2763 vs. <0.2763, p = 0.0018), and PLR (≥126.11 vs. <126.11, p = 0.0354). Similarly, significant differences in DFS were observed for NLR (≥3.010 vs. <3.010, p = 0.0005), MLR (≥0.2708 vs. <0.2708, p = 0.0046), and PLR (≥126.11 vs. <126.11, p = 0.0028). Univariate Cox analysis showed that NLR (hazard ratio [HR]: 2.469; 95% confidence interval [CI]: 1.416-4.306, p < 0.001), MLR (HR: 2.192, 95% CI: 1.319-3.643, p = 0.002) and PLR (HR: 1.696, 95% CI: 1.029-2.795, p = 0.038) were correlated alongside OS. Multivariate Cox analysis showed that NLR (HR: 2.036, 95% CI: 1.072-3.864, p = 0.030) was a separate OS risk variable. Additionally, the pN stage (HR: 3.163, 95% CI: 1.660-6.027, p < 0.001), NLR (HR: 2.530, 95% CI: 1.468-4.360, p < 0.001), MLR (HR: 2.229, 95% CI: 1.260-3.944, p = 0.006) and PLR (HR: 2.249, 95% CI: 1.300-3.889, p = 0.004) were connected to DFS. Multivariate Cox analysis showed that pN stage (HR: 3.098, 95% CI: 1.619-5.928, p < 0.001) was a separate DFS risk variable. CONCLUSION: The study demonstrates that NLR, MLR, and PLR play a convenient and cost-effective role in predicting survival and recurrence among individuals alongside central-type NSCLC having SL.

Zinc finger BED-type containing 3 promotes hepatic steatosis by interacting with polypyrimidine tract-binding protein 1.

AIMS/HYPOTHESIS: The relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus, insulin resistance and the metabolic syndrome is well established. While zinc finger BED-type containing 3 (ZBED3) has been linked to type 2 diabetes mellitus and the metabolic syndrome, its role in MASLD remains unclear. In this study, we aimed to investigate the function of ZBED3 in the context of MASLD. METHODS: Expression levels of ZBED3 were assessed in individuals with MASLD, as well as in cellular and animal models of MASLD. In vitro and in vivo analyses were conducted using a cellular model of MASLD induced by NEFA and an animal model of MASLD induced by a high-fat diet (HFD), respectively, to investigate the role of ZBED3 in MASLD. ZBED3 expression was increased by lentiviral infection or tail-vein injection of adeno-associated virus. RNA-seq and bioinformatics analysis were employed to examine the pathways through which ZBED3 modulates lipid accumulation. Findings from these next-generation transcriptome sequencing studies indicated that ZBED3 controls SREBP1c (also known as SREBF1; a gene involved in fatty acid de novo synthesis); thus, co-immunoprecipitation and LC-MS/MS were utilised to investigate the molecular mechanisms by which ZBED3 regulates the sterol regulatory element binding protein 1c (SREBP1c). RESULTS: In this study, we found that ZBED3 was significantly upregulated in the liver of individuals with MASLD and in MASLD animal models. ZBED3 overexpression promoted NEFA-induced triglyceride accumulation in hepatocytes in vitro. Furthermore, the hepatocyte-specific overexpression of Zbed3 promoted hepatic steatosis. Conversely, the hepatocyte-specific knockout of Zbed3 resulted in resistance of HFD-induced hepatic steatosis. Mechanistically, ZBED3 interacts directly with polypyrimidine tract-binding protein 1 (PTBP1) and affects its binding to the SREBP1c mRNA precursor to regulate SREBP1c mRNA stability and alternative splicing. CONCLUSIONS/INTERPRETATION: This study indicates that ZBED3 promotes hepatic steatosis and serves as a critical regulator of the progression of MASLD. DATA AVAILABILITY: RNA-seq data have been deposited in the NCBI Gene Expression Omnibus ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE231875 ). MS proteomics data have been deposited to the ProteomeXchange Consortium via the iProX partner repository ( https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD041743 ).

[Mechanism of Yupingfeng Powder on hepatic insulin resistance in type 2 diabetes mellitus rats by regulating IRS/PI3K/Akt pathway].

Based on the insulin receptor substrate(IRS)/phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt) pathway, the intervention effect of Yupingfeng Powder on type 2 diabetes mellitus(T2DM) rats was studied, and the potential mechanism of improving T2DM hepatic insulin resistance was explored. A T2DM rat model was established by feeding with high-fat and high-sugar feed combined with intraperitoneal injection of streptozotocin. Successfully modeled rats were selected and divided into a model group, a positive control group(MET), and a Yupingfeng Powder group. At the same time, a blank group was set up, and corresponding drugs were given by gavage. The model group and blank group were given an equal amount of physiological saline by gavage. During the experiment, body mass and fasting blood glucose were regularly measured, and glucose tolerance and insulin tolerance were measured at the end of the experiment. After the experiment, the levels of blood glucose, insulin, blood lipids, and related liver function indicators were measured; changes in liver pathological damage were observed, levels of liver monoamine oxidase were detected, and qRT-PCR was used to detect mRNA expression levels of IRS/PI3K/Akt pathway related genes. Compared with the model group, the Yupingfeng Powder group had an increase in body weight, a decrease in fasting blood glucose, fasting insulin, and steady-state model evaluation index, a decrease in the area under the curve of glucose tolerance and insulin tolerance tests, a decrease in serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol content, and an increase in high-density lipoprotein cholesterol content. Compared with the model group, the Yupingfeng Powder group showed a decrease in liver monoamine oxidase levels, a decrease in serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total bilirubin levels, and an increase in total protein and albumin levels. Hematoxylin-eosin(HE) staining showed a reduction in pathological liver cell damage. Compared with the model group, the Yupingfeng Powder group showed a significant increase in the mRNA expression levels of IRS1, PI3K, and Akt in the liver of rats, as well as a significant decrease in the mRNA expression levels of interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α). This indicates that Yupingfeng Powder can regulate the IRS/PI3K/Akt signaling pathway and glucose and lipid metabolism disorders, increase insulin sensitivity, improve hepatic insulin resistance, and thus play a therapeutic role in T2DM.

Spectroscopic and Theoretical Insights into H2 Activation on Uranium Monoxide: Homolytic H2 Cleavage Mediated by Intermediate OU(η2-H2).

Elucidating molecular-level interactions between dihydrogen (H2) and uranium oxides reveals fundamental insights into the intrinsic H2 activation mechanisms underlying processes such as heterogeneous catalysis over uranium oxides and corrosion of uranium induced by H2. Herein, the reactions of H2 with uranium monoxide (UO) molecules have been investigated via a combination of matrix-isolation infrared spectroscopy and quantum chemical calculations. A side-on bonded H2 complex, OU(η2-H2), is identified at 3733.7 and 800.3 cm-1. This species is regarded as a crucial intermediate along H2 activation pathways. Bonding analysis reveals cooperative U(π5f/6d) → H2(σ*) π// backdonation and U ← H2(σ) σ donation in OU(η2-H2) that facilitate the activation of the H2 moiety. Upon λ > 550 nm photoirradiation, OU(η2-H2) isomerizes into H2UO, indicating the homolytic H2 cleavage on UO. Mechanistic details of H2 adsorption and dissociation on UO molecules have been further elucidated.