Mitophagy in acute central nervous system injuries: regulatory mechanisms and therapeutic potentials.

Acute central nervous system injuries, including ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, traumatic brain injury, and spinal cord injury, are a major global health challenge. Identifying optimal therapies and improving the long-term neurological functions of patients with acute central nervous system injuries are urgent priorities. Mitochondria are susceptible to damage after acute central nervous system injury, and this leads to the release of toxic levels of reactive oxygen species, which induce cell death. Mitophagy, a selective form of autophagy, is crucial in eliminating redundant or damaged mitochondria during these events. Recent evidence has highlighted the significant role of mitophagy in acute central nervous system injuries. In this review, we provide a comprehensive overview of the process, classification, and related mechanisms of mitophagy. We also highlight the recent developments in research into the role of mitophagy in various acute central nervous system injuries and drug therapies that regulate mitophagy. In the final section of this review, we emphasize the potential for treating these disorders by focusing on mitophagy and suggest future research paths in this area.

Detailed analysis of learning phases and outcomes in robotic and endoscopic thyroidectomy.

BACKGROUND: Thyroid surgery has undergone significant transformation with the introduction of minimally invasive techniques, particularly robotic and endoscopic thyroidectomy. These advancements offer improved precision and faster recovery but also present unique challenges. This study aims to compare the learning curves, operational efficiencies, and patient outcomes of robotic versus endoscopic thyroidectomy. METHODS: A retrospective cohort study was conducted, analyzing 258 robotic (da Vinci) and 214 endoscopic thyroidectomy cases. Key metrics such as operation duration, drainage volume, lymph node dissection outcomes, and hypoparathyroidism incidence were assessed to understand surgical learning curves and efficiency. RESULTS: Robotic thyroidectomy showed a longer learning curve with initially longer operation times and higher drainage volumes but superior lymph node dissection outcomes. Both techniques were safe, with no permanent hypoparathyroidism or recurrent laryngeal nerve damage reported. The study delineated four distinct stages in the robotic and endoscopic surgery learning curve, each marked by specific improvements in proficiency. Endoscopic thyroidectomy displayed a shorter learning curve, leading to quicker operational efficiency gains. CONCLUSION: Robotic and endoscopic thyroidectomies are viable minimally invasive approaches, each with its learning curves and efficiency metrics. Despite initial challenges and a longer learning period for robotic surgery, its benefits in complex dissections may justify specialized training. Structured training programs tailored to each technique are crucial for improving outcomes and efficiency. Future research should focus on optimizing training protocols and increasing accessibility to these technologies, enhancing patient care in thyroid surgery.

Immune responses and transcription landscape of adults with the third dose of homologous and heterologous booster vaccines of COVID-19.

Background: Heterologous booster vaccines are more effective than homologous booster vaccines in combating the coronavirus disease 2019 (COVID-19) outbreak. However, our understanding of homologous and heterologous booster vaccines for COVID-19 remains limited. Methods: We recruited 34 healthy participants from two cohorts who were primed with two-dose inactivated COVID-19 vaccine before, vaccinated with COVID-19 inactivated vaccine and adenovirus-vectored vaccine (intramuscular and aerosol inhalation of Ad5-nCoV) as a third booster dose. We assessed the immune responses of participants before and 14 days after vaccination, including levels of neutralizing antibodies, IgG, and cytokines, and quantified the transcriptional profile of peripheral blood mononuclear cells (PBMCs). Results: The Ad5-nCoV group showed a significantly higher neutralizing antibody geometric mean titer (GMT) compared to the ICV group after 14 days of heterologous boosting. The intramuscular Ad5-nCoV group had a GMT of 191.8 (95% CI 129.0, 285.1) compared to 38.1 (95% CI 23.1, 62.8) in the ICV1 group (p<0.0001). The aerosolized Ad5-nCoV group had a GMT of 738.4 (95% CI 250.9-2173.0) compared to 244.0 (95% CI 135.0, 441.2) in the ICV2 group (p=0.0434). Participants in the aerosolized Ad5-nCoV group had median IFN-γ+ spot counts of 36.5 (IQR 15.3-58.8) per 106 PBMCs, whereas, both intramuscular Ad5-nCoV and CoronaVac immunization as the third dose showed lower responses. This suggests that a third dose of booster Ad5-nCoV vaccine (especially aerosolized inhalation) as a heterologous vaccine booster induces stronger humoral and cellular immune responses, which may be more potent against VOCs than the use of inactivated vaccine homologs. In transcriptomic analyses, both aerosolized inhalation/intramuscular injection of the Ad5-nCoV vaccine and inactivated vaccine induced a large number of differentially expressed genes that were significantly associated with several important innate immune pathways including inflammatory responses, regulation of the defense response, and regulation of cytokine production. In addition, we identified crucial molecular modules of protective immunity that are significantly correlated with vaccine type and neutralizing antibodies level. Conclusion: This study demonstrated that inhalation/intramuscular injection of the Ad5-nCoV vaccine-mediated stronger humoral and cellular immune responses compared with the inactivated vaccine, and correlated significantly with innate immune function modules, supporting a heterologous booster immunization strategy.

H2S-Responsive NIR-II Fluorescent Nanozyme that Regulates Tumor Microenvironment for Activatable Synergistic CO Therapy/Catalytic Therapy/Immunotherapy.

Nanozyme catalytic therapy triggered by the tumor microenvironment (TME)-responsive enzyme-like catalytic activities is an emerging approach for tumor treatment. However, the poor catalytic efficiency of nanozymes in tumors and the toxic side effects on normal tissues limit their further development, primarily due to the limited uptake and penetration depth of nanozyme in tumor tissues. Here, a tumor-targeting TME and electric field stimuli-responsive nanozyme (AgPt@CaCO3-FA) is developed, which is capable of catalyzing the generation of ROS to induce cell death and releasing carbon monoxide (CO) specifically in tumor tissues for on-demand CO therapy and immunotherapy. Benefiting from the endogenous H2S activated NIR-II fluorescence (FL) imaging guidance, AgPt@CaCO3-FA can be delivered into the deeper site of tumor tissues resulted from the TME regulation via generated CO during the electrolysis process to improve the catalytic efficiency of nanozymes in tumors. Moreover, CO effectively relieve immunosuppression TME via reeducating tumor-supportive M2-like macrophages to tumoricidal M1-like macrophages and induce mitochondrial dysfunction by reducing mitochondrial membrane potential, triggering tumor cells apoptosis. The enzyme-like activities combined with CO therapy arouse distinct immunogenic cell death (ICD) effect. Therefore, AgPt@CaCO3-FA permits synergistic CO gas, catalytic therapy and immunotherapy, effectively eradicating orthotopic breast tumors and preventing tumor metastasis and recurrence.

Epidemiological trends of subarachnoid hemorrhage at global, regional, and national level: a trend analysis study from 1990 to 2021.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a subtype of hemorrhagic stroke characterized by high mortality and low rates of full recovery. This study aimed to investigate the epidemiological characteristics of SAH between 1990 and 2021. METHODS: Data on SAH incidence, mortality, and disability-adjusted life-years (DALYs) from 1990 to 2021 were obtained from the Global Burden of Disease Study (GBD) 2021. Estimated annual percentage changes (EAPCs) were calculated to evaluate changes in the age-standardized rate (ASR) of incidence and mortality, as well as trends in SAH burden. The relationship between disease burden and sociodemographic index (SDI) was also analyzed. RESULTS: In 2021, the incidence of SAH was found to be 37.09% higher than that in 1990; however, the age-standardized incidence rates (ASIRs) showed a decreased [EAPC: -1.52; 95% uncertainty interval (UI) -1.66 to -1.37]. Furthermore, both the number and rates of deaths and DALYs decreased over time. It was observed that females had lower rates compared to males. Among all regions, the high-income Asia Pacific region exhibited the highest ASIR (14.09/100,000; 95% UI 12.30/100,000 - 16.39/100,000) in 2021, with an EPAC for ASIR < 0 indicating decreasing trend over time for SAH ASIR. Oceania recorded the highest age-standardized mortality rates (ASMRs) and age-standardized DALYs rates among all regions in 2021 at values of respectively 8.61 (95% UI 6.03 - 11.95) and 285.62 (95% UI 209.42 - 379.65). The burden associated with SAH primarily affected individuals aged between 50 - 69 years old. Metabolic risks particularly elevated systolic blood pressure were identified as the main risk factors contributing towards increased disease burden associated with SAH when compared against environmental or occupational behavioral risks evaluated within the GBD framework. CONCLUSIONS: The burden of SAH varies by gender, age group, and geographical region. Although the ASRs have shown a decline over time, the burden of SAH remains significant, especially in regions with middle and low-middle SDI levels. High systolic blood pressure stands out as a key risk factor for SAH. More specific supportive measures are necessary to alleviate the global burden of SAH.

MicroRNA-204-5p Attenuates Oxidative Stress, Apoptosis and Inflammation by Targeting TXNIP in Diabetic Cataract.

Diabetic cataract (DC) is a major cause of blindness in diabetic patients and it is characterized by early onset and rapid progression. MiR-204-5p was previously identified as one of the top five down-regulated miRNAs in human DC lens tissues. We aimed to determine the expression of miR-204-5p in human lens epithelial cells (HLECs) and explore its effects and mechanisms in regulating the progression of DC. The expression of miR-204-5p in the anterior capsules of DC patients and HLECs was examined by RT-qPCR. Bioinformatics tools were then used to identify the potential target of miR-204-5p. The relationship between miR-204-5p and the target gene was confirmed through a dual luciferase reporter assay. Additionally, the regulatory mechanism of oxidative stress, apoptosis, and inflammation in DC was investigated by overexpressing miR-204-5p using miR-204-5p agomir. The expression of miR-204-5p was downregulated in the anterior capsules of DC patients and HLECs. Overexpression of miR-204-5p reduced ROS levels, pro-apoptosis genes (Bid, Bax, caspase-3), and IL-1ß production in HG-treated HLECs. TXNIP was the direct target of miR-204-5p by dual luciferase reporter assay. Therefore, this study demonstrated that miR-204-5p effectively reduced oxidative damage, apoptosis, and inflammation in HLECs under HG conditions by targeting TXNIP. Targeting miR-204-5p could be a promising therapeutic strategy for the potential treatment of DC.

[Differences and drivers of leaf stable carbon and nitrogen isotope in herbs under different vegetation types on the eastern Qinghai-Tibet Plateau]. / é’è—é«˜åŽŸä¸œç¼˜ä¸åŒæ¤è¢«ç±»åž‹ä¸‹è‰æœ¬æ¤ç‰©å¶ç‰‡ç¢³æ°®ç¨³å®šåŒä½ç´ å·®å¼‚åŠå ¶é©±åŠ¨å› ç´ .

The natural abundance of stable carbon and nitrogen isotopes (δ13C and δ15N) in leaves can provide comprehensive information on the physiological and ecological processes of plants and has been widely used in ecological research. However, recent studies on leaf δ13C and δ15N have focused mainly on woody species, few studies have been conducted on herbs in different vegetation types, and their differences and driving factors are still unclear. In this study, we focused on the herbs in subalpine coniferous forests, alpine shrublands, and alpine mea-dows on the eastern Qinghai-Tibet Plateau, and investigated the differences in leaf δ13C and δ15N of herbs and the driving factors. The results showed that there were significant differences in leaf δ13C and δ15N values of herbs among different vegetation types, with the highest δ13C and δ15N values in alpine meadows, followed by alpine shrublands, and the lowest in subalpine coniferous forests. Using variation partitioning analysis, we revealed that differences in leaf δ13C and δ15N of herbs among various vegetation types were driven by both leaf functional traits and climate factors, with the contribution of leaf functional traits being relatively higher than that of climate factors. Hierarchical partitioning results indicated that mean annual temperature (MAT), chlorophyll content index, leaf nitrogen content per unit area (Narea), and leaf mass per area were the main drivers of leaf δ13C variations of herbs across different vegetation types, while the relative importance of Narea and MAT for variation in leaf δ15N of herbs was much higher than those other variables. There was a strong coupling relationship between leaf δ13C and δ15N as indicated by the result of the ordinary least squares regression. Our findings could provide new insights into understanding the key drivers of leaf δ13C and δ15N variations in herbs across different vegetation types.

Gender differences in cognitive improvements after two months of atypical antipsychotic treatment in first episode schizophrenia.

Aims: This study aims to explore the gender differences in cognitive improvements after two months of atypical antipsychotic treatment in first episode schizophrenia (FES). Methods: 82 patients with FES, including 50 male patients and 32 female patients, were enrolled in the present study. Positive and Negative Syndrome Scale (PANSS) and MATRICS Consensus Cognitive Battery (MCCB) were respectively conducted to evaluate the clinical symptoms and cognitive function of patients with FES at baseline and after treatment. Repeated measure ANOVA was performed to compare gender differences in cognitive domains scores between baseline and 2-month follow-up. Stepwise liner regression model was performed to explore the effect factors of cognitive improvements in patients. Results: There was no significant difference in age of onset, education years, PANSS scores, duration of untreated psychosis and Olanzapine equivalent doses between male and female patients (all p > 0.05). In the comparisons of cognition function, male patients exhibited better performance in social cognition compared with female patients at baseline (t = 3.20, p < 0.05). After treatment, improvements of attention/vigilance and working memory were both found in male patients and female patients (attention/vigilance, F = 11.867, p < 0.05; working memory, F = 18.265, p < 0.05). In addition, improvement of speed of information processing was only found in female patients (F = 11.65, p < 0.01). Significant interaction between time and gender was found in speed information of processing (F = 4.140, p = 0.045). Stepwise liner regression model revealed that improvements of negative symptoms promote improvements of cognitive function in female patients (all p < 0.05). Conclusions: Our findings revealed gender differences of cognitive improvements in patients with FES after 2-month treatment. It provides new evidence for gender differences in cognitive symptoms of schizophrenia, and also provides preliminary clues for further individualized cognitive intervention strategies.

Bioorthogonal Cu Single-Atom Nanozyme for Synergistic Nanocatalytic Therapy, Photothermal Therapy, Cuproptosis and Immunotherapy.

Single-atom nanozymes (SAzymes) with atomically dispersed active sites are potential substitutes for natural enzymes. A systematic study of its multiple functions can in-depth understand SAzymes's nature, which remains elusive. Here, we develop a novel ultrafast synthesis of sputtered SAzymes by in situ bombarding-embedding technique. Using this method, sputtered copper (Cu) SAzymes (CuSA) is developed with unreported unique planar Cu-C3 coordinated configuration. To enhance the tumor-specific targeting, we employ a bioorthogonal approach to engineer CuSA, denoted as CuSACO. CuSACO not only exhibits minimal off-target toxicity but also possesses exceptional ultrahigh catalase-, oxidase-, peroxidase-like multienzyme activities, resulting in reactive oxygen species (ROS) storm generation for effective tumor destruction. Surprisingly, CuSACO can release Cu ions in the presence of glutathione (GSH) to induce cuproptosis, enhancing the tumor treatment efficacy. Notably, CuSACO's remarkable photothermal properties enables precise photothermal therapy (PTT) on tumors. This, combined with nanozyme catalytic activities, cuproptosis and immunotherapy, efficiently inhibiting the growth of orthotopic breast tumors and gliomas, and lung metastasis. Our research highlights the potential of CuSACO as an innovative strategy to utilize multiple mechanism to enhance tumor therapeutic efficacy, broadening the exploration and development of enzyme-like behavior and physiological mechanism of action of SAzymes.

Modifiable Lifestyle, Sedentary Behaviors and the Risk of Frailty: A Univariate and Multivariate Mendelian Randomization Study.

This research conducted a two-sample univariate and multivariate Mendelian Randomization (MR) analysis to explore the causal link between different types of leisure sedentary behavior (LSB) and frailty. Independent instrumental variables significantly associated with sedentary behaviors (p < 5 × 10-8) are obtained from a genome-wide association study (GWAS) of 422,218 individuals, and Frailty Index (FI) are derived from the latest GWAS dataset of 175,226 individuals. MR analysis is conducted using inverse variance weighting, MR-Egger, weighted median, simple mode, and weighted mode, supplemented by MRAPSS. Univariate MR revealed that sedentary behaviors such as watching television increased the risk of frailty (OR, 1.271; 95% CI: 1.202-1.345; p = 6.952 × 10-17), as sedentary driving behaviors are done (OR, 1.436; 95% CI: 1.026-2.011; p = 0.035). Further validation through APSS, taking into account cryptic relatedness, stratification, and sample overlap, maintained the association between television viewing and increased frailty risk (OR, 1.394; 95% CI: 1.266-1.534; p = 1.143 × 10-11), while the association with driving dissipated. In multivariate inverse variance weighted (IVW) analysis, after adjusting for C-reactive protein (CRP) levels, television Sedentary behavior (SB) inversely affected frailty (OR, 0.782; 95% CI: 0.724-0.845; p = 4.820 × 10-10). This study indicates that televisio SB significantly increases the risk of frailty, suggesting potential biological heterogeneity behind specific sedentary activities. This process may interact with inflammation, influencing the development of frailty.

Case Report: Giant left atrial cystic tumor: myxoma or intracardiac blood cyst?

Background: Primary cardiac tumors are uncommon, with the majority being benign myxomas. Cystic myxoma, a particularly rare type of benign cardiac tumor, demands cautious differential diagnosis from other cardiac tumors. Case summary: A 43-year-old male patient presenting with intermittent dyspnea was referred to our department for surgical evaluation. Transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) unveiled an intra-left atrial cyst, which was subsequently found to be blood-filled during a video-assisted microinvasive heart surgery. Pathological examination depicted a cyst wall filled with small stellate and fat spindle cells, along with a mucoid matrix, indicating a diagnosis of cystic myxoma. Conclusions: We herein presented a rare case of an adult patient with cystic myxoma, initially misdiagnosed as an intracardiac blood cyst (CBC) prior to surgery, and ultimately verified via pathological findings.

Benzoylaconitine: A promising ACE2-targeted agonist for enhancing cardiac function in heart failure.

Benzoylaconitine is a natural product in the treatment of cardiovascular disease. However, its pharmacological effect, direct target protein, and molecular mechanisms for the treatment of heart failure are unclear. In this study, benzoylaconitine inhibited Ang II-induced cell hypertrophy and fibrosis in rat primary cardiomyocytes and rat fibroblasts, while attenuating cardiac function and cardiac remodeling in TAC mice. Using the limited proteolysis-mass spectrometry (LiP-MS) method, the angiotensin-converting enzyme 2 (ACE2) was confirmed as a direct binding target of benzoylaconitine for the treatment of heart failure. In ACE2-knockdown cells and ACE2-/- mice, benzoylaconitine failed to ameliorate cardiomyocyte hypertrophy, fibrosis, and heart failure. Online RNA-sequence analysis indicated p38/ERK-mediated mitochondrial reactive oxygen species (ROS) and nuclear factor kappa B (NF-κB) activation are the possible downstream molecular mechanisms for the effect of BAC-ACE2 interaction. Further studies in ACE2-knockdown cells and ACE2-/- mice suggested that benzoylaconitine targeted ACE2 to suppress p38/ERK-mediated mitochondrial ROS and NF-κB pathway activation. Our findings suggest that benzoylaconitine is a promising ACE2 agonist in regulating mitochondrial ROS release and inflammation activation to improve cardiac function in the treatment of heart failure.

Nonylphenol and its derivatives: Environmental distribution, treatment strategy, management and future perspectives.

In recent years, emerging pollutants, including nonylphenol (NP) and nonylphenol ethoxylate (NPE), have become a prominent topic. These substances are also classified as persistent organic pollutants. NP significantly affects the hormone secretion of organisms and exhibits neurotoxicity, which can affect the human hippocampus. Therefore, various countries are paying increased attention to NP regulation. NPEs are precursors of NPs and are widely used in the manufacture of various detergents and lubricants. NPEs can easily decompose into NPs, which possess strong biological and environmental toxicity. This review primarily addresses the distribution, toxicity mechanisms and performance, degradation technologies, management policies, and green alternative reagents of NPs and NPEs. Traditional treatment measures have been unable to completely remove NP from wastewater. With the progressively tightening management and regulatory policies, identifying proficient and convenient treatment methods and a sustainable substitute reagent with comparable product effectiveness is crucial.

γ-Glutamylcysteine ameliorates blood-brain barrier permeability and neutrophil extracellular traps formation after ischemic stroke by modulating Wnt/ß-catenin signalling in mice.

During the inflammatory response after stroke, the blood-brain barrier (BBB) is significantly disrupted, compromising its integrity. This disruption allows many peripheral neutrophils to infiltrate the injury site in the brain and release neutrophil extracellular traps (NETs), which further increase BBB permeability. In this study, we aimed to investigate the protective effects of γ-Glutamylcysteine (γ-GC), an immediate precursor of GSH, against BBB breakdown and NET formation after ischemic stroke. Our data indicated that γ-GC treatment effectively attenuated BBB damage, decreased neutrophil infiltration, and suppressed the release of NETs, ultimately leading to the amelioration of ischemic injury. Transcriptomic data and subsequent validation studies revealed that mechanistically, γ-GC exerts its effect by activating the Wnt/ß-catenin pathway after ischemic stroke. This research suggests that γ-GC may hold promise as a therapeutic agent for alleviating brain injury following an ischemic stroke.

Safety of SARS-CoV-2 vaccine in patients with autoimmune neurological conditions: A systematic review and meta-analysis.

Introduction: Risk of adverse effects and exacerbation in autoimmune neurological conditions (ANC)are frequently cited reasons for COVID-19 vaccine hesitancy. This study evaluates the ANC safety of COVID-19 vaccines in the real world. Methods: Electronic databases were searched to identify studies reporting the use of the COVID-19 vaccine in ANC. We selected studies that provided data on adverse effects and worsening conditions related to ANC after vaccination. The pooled incidence rates for various adverse effects, stratified for the disease category, dosage, and type of vaccine, were estimated. Results: Twenty-eight studies (31 vaccination cohorts) were included. The pooled incidence rate of general adverse events was 0.35 (95%CI, 0.27-0.43, I2 = 100 %). The pooled incidence rates of local injection reaction, fatigue, weakness, myalgia, fever, headache, and chills were 0.27 (0.18-0.36, I2 = 98 %), 0.16(0.11-0.21, I2 = 93 %), 0.15(0.00-0.31, I2 = 97 %), 0.13(0.08-0.19, I2 = 97 %), 0.11(0.07-0.15, I2 = 95 %), 0.11(0.07-0.16, I2 = 97 %), and 0.09 (0.03-0.16, I2 = 96 %), respectively. The pooled incidence rate of exacerbation adverse events was 0.05 (95%CI, 0.04-0.07, I2 = 84 %). Conclusion: According to available evidence, the administration of COVID-19 vaccines in individuals with autoimmune neurological disorders seems well-tolerated, with few reports of adverse events. Furthermore, exacerbation of autoimmune neurological conditions following vaccination appears to be infrequent.

Lipid Metabolism-Related Gene Markers Used for Prediction Prognosis, Immune Microenvironment, and Tumor Stage of Pancreatic Cancer.

Recently, more and more evidence shows that lipid metabolism disorder has been observed in tumor, which impacts tumor cell proliferation, survival, invasion, metastasis, and response to the tumor microenvironment (TME) and tumor treatment. However, hitherto there has not been sufficient research to demonstrate the role of lipid metabolism in pancreatic cancer. This study contrives to get an insight into the relationship between the characteristics of lipid metabolism and pancreatic cancer. We collected samples of patients with pancreatic cancer from the Gene Expression Omnibus (GEO), the Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and the International Cancer Genome Consortium (ICGC) databases. Firstly, we implemented univariate regression analysis to get prognosis-related lipid metabolism genes screened and a construction of protein-protein interaction (PPI) network ensued. Then, contingent on our screening results, we explored the molecular subtypes mediated by lipid metabolism-related genes and the correlated TME cell infiltration. Additionally, we studied the disparately expressed genes among disparate lipid metabolism subtypes and established a scoring model of lipid metabolism-related characteristics using the least absolute shrinkage and selection operator (LASSO) regression analysis. At last, we explored the relationship between the scoring model and disease prognosis, tumor stage, tumor microenvironment, and immunotherapy. Two subtypes, C1 and C2, were identified, and lipid metabolism-related genes were studied. The result indicated that the patients with subtype C2 have a significantly lower survival rate than that of the patients with subtype C1, and we found difference in abundance of different immune-infiltrating cells. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed the association of these differentially expressed genes with functions and pathways related to lipid metabolism. Finally, we established a scoring model of lipid metabolism-related characteristics based on the disparately expressed genes. The results show that our scoring model have a substantial effect on forecasting the prognosis of patients with pancreatic cancer. The lipid metabolism model is an important biomarker of pancreatic cancer. Using the model, the relationship between disease prognosis, molecular subtypes, TME cell infiltration characteristics, and immunotherapy in pancreatic cancer patients could be explored.

MTDH enhances radiosensitivity of head and neck squamous cell carcinoma by promoting ferroptosis based on a prognostic signature.

Ionizing radiation (IR) induces ferroptosis in head and neck squamous cell carcinoma (HNSCC). But, it remains unclear whether ferroptosis affects the prognosis of HNSCC patients after receiving radiotherapy. This study aims to develop a ferroptosis signature to predict the radiosensitivity and prognosis of HNSCC. Ferroptosis-related genes, clinical data and RNA expression profiles were obtained from the FerrDb database, The Cancer Genome Atlas and GEO database. Prognostic genes were identified by random survival forest, univariate Cox regression, Kaplan-Meier and ROC analyses. Principal component analysis, multivariate Cox regression, nomogram and DCA analyses were conducted to estimate its predictive ability. Functional enrichment and immune-related analyses were performed to explore potential biological mechanisms and tumor immune microenvironment. The effect of the hub gene on ferroptosis and radiosensitivity was verified using flow cytometry, quantitative real-time PCR and clonogenic survival assay. We constructed a ferroptosis-related signature, including IL6, NCF2, metadherin (MTDH) and CBS. We classified patients into high-risk (HRisk) and low-risk groups according to the risk scores. The risk score was confirmed to be an independent predictor for overall survival (OS). Combining the clinical stage with the risk score, we established a predictive nomogram for OS. Furthermore, pathways related to tumorigenesis and tumor immune suppression were mainly enriched in HRisk. MTDH was verified to have a potent effect on IR-induced ferroptosis and consequently promoted radiosensitivity. We constructed a ferroptosis-related signature to predict radiosensitivity and OS in HNSCC patients. MTDH was identified as a promising therapeutic target in radioresistant HNSCC patients.

LLDT-8 ameliorates experimental autoimmune encephalomyelitis by mediating macrophage functions in the priming stage.

Multiple sclerosis (MS) is an inflammatory demyelinating disease in the central nervous system caused by T cell activation mediated by peripheral macrophages, resulting in severe neurological deficits and disability. Due to the currently limited and expensive treatments for MS, we here introduce an economic Chinese medicine extract, (5R)-5-Hydroxytriptolide (LLDT-8), which shows low toxicity and high immunosuppressive activity. We used the widely accepted mouse model of MS, experimental autoimmune encephalomyelitis (EAE), to examine the immunosuppressive effect of LLDT-8 in vivo. Through the RNA-sequence analysis of peripheral macrophages in EAE mice, we discovered that LLDT-8 alleviates the symptoms of EAE by inhibiting the proinflammatory effect of macrophages, thereby blocking the activation and proliferation of T cells. In all, we found that LLDT-8 could be a potential treatment for MS.

The Emerging Role of Deubiquitinases in Radiosensitivity.

Radiation therapy is a primary treatment for cancer, but radioresistance remains a significant challenge in improving efficacy and reducing toxicity. Accumulating evidence suggests that deubiquitinases (DUBs) play a crucial role in regulating cell sensitivity to ionizing radiation. Traditional small-molecule DUB inhibitors have demonstrated radiosensitization effects, and novel deubiquitinase-targeting chimeras (DUBTACs) provide a promising strategy for radiosensitizer development by harnessing the ubiquitin-proteasome system. This review highlights the mechanisms by which DUBs regulate radiosensitivity, including DNA damage repair, the cell cycle, cell death, and hypoxia. Progress on DUB inhibitors and DUBTACs is summarized, and their potential radiosensitization effects are discussed. Developing drugs targeting DUBs appears to be a promising alternative approach to overcoming radioresistance, warranting further research into their mechanisms.