T-2 toxin induces cardiac fibrosis by causing metabolic disorders and up-regulating Sirt3/FoxO3α/MnSOD signaling pathway-mediated oxidative stress.

T-2 toxin, an omnipresent environmental contaminant, poses a serious risk to the health of humans and animals due to its pronounced cardiotoxicity. This study aimed to elucidate the molecular mechanism of cardiac tissue damage by T-2 toxin. Twenty-four male Sprague-Dawley rats were orally administered T-2 toxin through gavage for 12 weeks at the dose of 0, 10, and 100 nanograms per gram body weight per day (ng/(g·day)), respectively. Morphological, pathological, and ultrastructural alterations in cardiac tissue were meticulously examined. Non-targeted metabolomics analysis was employed to analyze alterations in cardiac metabolites. The expression of the Sirt3/FoxO3α/MnSOD signaling pathway and the level of oxidative stress markers were detected. The results showed that exposure to T-2 toxin elicited myocardial tissue disorders, interstitial hemorrhage, capillary dilation, and fibrotic damage. Mitochondria were markedly impaired, including swelling, fusion, matrix degradation, and membrane damage. Metabonomics analysis unveiled that T-2 toxin could cause alterations in cardiac metabolic profiles as well as in the Sirt3/FoxO3α/MnSOD signaling pathway. T-2 toxin could inhibit the expressions of the signaling pathway and elevate the level of oxidative stress. In conclusion, the T-2 toxin probably induces cardiac fibrotic impairment by affecting amino acid and choline metabolism as well as up-regulating oxidative stress mediated by the Sirt3/FoxO3α/MnSOD signaling pathway. This study is expected to provide targets for preventing and treating T-2 toxin-induced cardiac fibrotic injury.

Associated Factors of Trauma Severity and Mortality in Pediatric Patients Admitted to Intensive Care Unit; a 10-Year Retrospective Study.

Introduction: Trauma is a significant global public health concern and the leading cause of morbidity and mortality in children. This study aimed to assess the independent predictors of trauma severity as well as mortality in pediatric patients admitted to the intensive care unit (ICU). Methods: In this cross-sectional study, following the STROBE checklist, we retrospectively analyzed the clinical and baseline characteristics of pediatric patients with trauma injuries admitted to the ICU of Children's Hospital of Zhejiang University School of Medicine, China, over a decade. Results: 951 pediatric patients with a mean age of 4.79 ± 3.24 years (60.78% Boys) were studied (mortality rate 8.41%). Significant associations were observed between ISS and place of residence (p = 0.021), location of the injury (p = 0.010), year of injury (p <0.001), and injury mechanism (p <0.001). The two independent factors of trauma severity were the year of injury (ß = 0.47; 95%CI: 0.28 - 0.65) and injury mechanism (ß = -0.60; 95%CI: -0.88 - -0.31). Significant differences were observed between survived and non-survived regarding age (p <0.001), ISS score (p <0.001), time elapsed from injury to ICU (p <0.001), duration of mechanical ventilation (p <0.001), GCS score (p <0.001), and the proportion of patients requiring mechanical ventilation (p <0.001 ). The results of multivariate analysis indicated that age (OR = 0.805; 95%CI: 0.70 - 0.914; p = 0.001) and GCS score at ICU admission (OR = 0.629; 95%CI: 0.53 - 0.735; p < 0.001) acted as protective factors, whereas mechanical ventilation in the ICU (OR = 7.834; 95%CI: 1.766 - 34.757; p = 0.007) and ISS score at ICU admission (OR = 1.088; 95%CI: 1.047 - 1.130; p < 0.001) served as risk factors for mortality. Conclusion: Automobile-related injuries represent the leading cause of trauma in children, with escalating severity scores year over year among pediatric patients admitted to the ICU with trauma injuries. Based on the findings the independent predictors of mortality of pediatric trauma patients admitted to the ICU were age, GCS score at ICU admission; mechanical ventilation in the ICU, and ISS score at ICU admission. Also, the year of injury and injury mechanism were independent predictors of trauma severity.

Smartphone-assisted detection of trace methyl orange in water by ratiometric nanosensors based on down/up-conversion luminescence.

A ratiometric nanosensor was developed for detecting methyl orange (MO) based on down/up-conversion luminescence achieved by a triplet-triplet annihilation upconversion luminescence (TTA-UCL) system. The probe, utilizing sensitizer and annihilator fluorophores encapsulated in nanomicelles, demonstrated high sensitivity and selectivity for MO detection. The energy transfer from UCL to MO endowed the sensor with responsive capabilities. The unaffected triplet-triplet energy transfer process maintained the phosphorescence signal constant, serving as a reference to construct the ratiometric sensor along with the UCL signal. Additionally, a smartphone-assisted colorimetric detection method was also developed based on the ratiometric sensor, enabling rapid and convenient detection of MO without the need for a spectrometer. The performance of the nanosensor in real water samples confirmed its potential for practical environmental applications.

A natural adhesive-based nanomedicine initiates photothermal-directed in situ immunotherapy with durability and maintenance.

Tumor immunotherapies have emerged as a promising frontier in the realm of cancer treatment. However, challenges persist in achieving localized, durable immunostimulation while counteracting the tumor's immunosuppressive environment. Here, we develop a natural mussel foot protein-based nanomedicine with spatiotemporal control for tumor immunotherapy. In this nanomedicine, an immunoadjuvant prodrug and a photosensitizer are integrated, which is driven by their dynamic bonding and non-covalent assembling with the protein carrier. Harnessing the protein carrier's bioadhesion, this nanomedicine achieves a drug co-delivery with spatiotemporal precision, by which it not only promotes tumor photothermal ablation but also broadens tumor antigen repertoire, facilitating in situ immunotherapy with durability and maintenance. This nanomedicine also modulates the tumor microenvironment to overcome immunosuppression, thereby amplifying antitumor responses against tumor progression. Our strategy underscores a mussel foot protein-derived design philosophy of drug delivery aimed at refining combinatorial immunotherapy, offering insights into leveraging natural proteins for cancer treatment.

[Cloning and functional verification of farnesyl pyrophosphate synthase gene(AvFPS) from Aconitum vilmorinianum].

Aconitum vilmorinianum is an authentic and superior medicinal herbal in Yunnan, which is rich in yunaconitine and other diterpene alkaloids. Diterpene alkaloids are its main active components. Farnesyl pyrophosphate synthase(FPS) is a key enzyme in the terpene biosynthetic pathway and plays an important role in diterpene alkaloid biosynthesis. Functional studies of FPS help to reveal the molecular mechanism of diterpene alkaloid biosynthesis. In this study, one FPS gene(AvFPS) was selected based on the transcriptome data of A. vilmorinianum. Its full-length sequence was cloned, and bioinformatic analysis, functional verification, and gene expression analysis were performed. The open reading frame(ORF) of AvFPS was 1 056 bp, encoding 351 amino acids. Its molecular weight was 41 kDa. AvFPS had two typical conserved functional domains of isopentenyl transferase, " DDIMD" and " DDYXD". The recombinant protein of AvFPS was expressed in Escherichia coli, and purified recombinant protein was used for in vitro enzymatic reaction. The results revealed that AvFPS was able to catalyze the synthesis of farnesyl pyrophosphate(FPP). The results of qRT-PCR analysis showed that AvFPS was expressed in the roots, stems, leaves, and flowers of A. vilmorinianum, with the highest expression level in the roots. The expression level of AvFPS was significantly up-regulated by MeJA induction. This study clarified the catalytic function of AvFPS, revealed the expression pattern of AvFPS in different tissue, as well as at different time induced by MeJA, and provided a reference for a deeper understanding of the function of FPS in the biosynthesis of diterpenoid components.

Predicting postoperative prognosis in clear cell renal cell carcinoma using a multiphase CT-based deep learning model.

BACKGROUND: Some clinicopathological risk stratification systems (CRSSs) such as the leibovich score have been used to predict the postoperative prognosis of patients with clear cell renal cell carcinoma (ccRCC), but there are no reliable noninvasive preoperative indicators for predicting postoperative prognosis in clinical practice. PURPOSE: To assess the value of a deep learning (DL) model based on CT images in predicting the postoperative prognosis of patients with ccRCC. MATERIALS AND METHODS: A total of 382 patients with ccRCC were retrospectively enrolled andallocated to training (n = 229) or testing (n = 153) cohorts at a 6:4 ratio. The features were extracted from precontrast-phase (PCP), corticomedullary-phase (CMP) and nephrographic-phase (NP) CT images with ResNet50, and then extreme learning machines (ELMs) were used to construct classification models. The DL model and Leibovich score were compared and combined. A receiver operating characteristic (ROC) curve and integrated discrimination improvement (IDI) were used to evaluate model performance. RESULTS: Compared with other single-phase DL models, the three-phase CT-based DL model achieved the best performance, with an area under the curve (AUC) of 0.839. Combining the three-phase DL model and the Leibovich score (AUC = 0.823) into a nomogram (AUC = 0.888) statistically improved performance (IDINomogram vs. Three-phase = 0.1358, IDINomogram vs. Leibovich = 0.1393, [Formula: see text]< 0.001). CONCLUSION: The CT-based DL model could be valuable for preoperatively predicting the prognosis of patients with ccRCC, and combining it with the Leibovich score can further improve its predictive performance.

Nerve growth factor gene polymorphisms may be associated with heroin dependence in women but do not mediate specific personality traits.

Heroin dependence (HD) is a complex disease with a substantial genetic contribution and is associated with traits of impulsivity and specific personality traits. The neurotrophic factor nerve growth factor (NGF) may mediate the reward processes in HD. This study aims to investigate whether NGF gene polymorphisms are associated with the co-occurrence of HD and impulsivity/specific personality traits in HD patients. To minimize the potential confounding effects of population stratification, we selected a homogeneous Han Chinese population and recruited 1364 participants (831 HD patients and 533 healthy controls). In addition, 163 female HD patients completed the Chinese version of the Barratt Impulsiveness Scale Version 11 (BIS-11), and 440 HD patients completed the Chinese version of the Tridimensional Personality Questionnaire (TPQ) for subsequent analysis. We identified three polymorphisms with altered allele and genotype frequency in HD patients versus controls (p = 0.035 for rs2254527; p = 0.005 for rs6678788; p = 0.006 for rs7523654), especially in the female subgroup. Four associations identified via haplotype analysis were significant in the female subgroup (p = 0.003 for T-T-A haplotype and p = 0.002 for C-C-A haplotype in block 1; p = 0.011 for T-T haplotype and p = 0.009 for C-T haplotypes in block 2), but not in the male subgroup. Male HD patients had higher novelty-seeking (NS) scores, and female HD patients had higher harm avoidance (HA) scores. However, there was no significant association between the selected NGF polymorphisms and BIS or TPQ scores in HD patients. NGF variants may contribute to the risk of HD development in females but do not mediate the relationship between impulsivity and specific personality traits in the female population.

N-acetylcysteine mitigates oxidative damage to the ovary in D-galactose-induced ovarian failure in rabbits.

BACKGROUND: Oxidative damage to the ovaries is the primary cause of impaired reproductive functions in female animals. This study aimed to investigate the protective role of N-Acetyl-L-cysteine (NAC) in reducing oxidative damage in the ovaries of female rabbits. METHODS AND RESULTS: Female rabbit ovaries were treated in vitro with varying concentrations of D-galactose (D-gal): 0, 5, 10, and 15 mg/mL, and it was found that 10 mg/mL D-gal significantly disrupted follicular structures, causing disarray in granulosa cell arrangements and significantly reducing T-SOD and GSH levels (p < 0.01). Consequently, we selected 10 mg/mL D-gal to establish an ovarian failure model. These models were treated with multiple doses of NAC (0, 0.1, 0.3, 0.5 mg/mL). The results revealed that the disruption in granulosa cell arrangement caused by 10 mg/mL D-gal was effectively alleviated by 0.1 mg/mL NAC compared to the D-gal treatment group. Furthermore, 10 mg/mL D-gal significantly (p < 0.01) reduced GSH, T-SOD, and catalase (CAT) levels in the ovaries. However, 0.1 mg/mL NAC effectively (p < 0.01) suppressed these adverse effects. Moreover, the current results showed that 10 mg/mL D-gal alone significantly (p < 0.01) downregulated the expression of Nrf2, GPX, PRDX4, GSR, SOD1, and TAF4B, whereas 0.1 mg/mL NAC counteracted these suppressive effects (p < 0.01). CONCLUSIONS: It could be concluded that NAC may delay ovarian failure by reducing D-gal-induced ovarian oxidative damage in female rabbit, suggested NAC could be a promising therapeutic agent for protecting against ovarian failure and potentially delaying ovarian failure in female rabbits.

Molecular Photoswitching Unlocks Glucose Oxidase for Synergistically Reinforcing Fenton Reactions for Antitumor Chemodynamic Therapy.

We have developed a new type of nanoparticles with potent antitumor activity photoactivatable via the combination of molecular photoswitching of spiropyran (SP) and enzymatic reaction of glucose oxidase (GOx). As two key processes involved therein, Fe(III)-to-Fe(II) photoreduction in Fe(III) metal-organic frameworks (MOFs) brings about the release of free Fe2+/Fe3+ while the photoswitching of SP to merocyanine (MC) unlocks the enzymatic activity of GOx that was pre-passivated by SP. The release of free Fe3+ boosts its hydrolysis and therefore enables the acidification of microenvironment, which is further reinforced by one of the products of the GOx-mediated glucose oxidation reaction, gluconic acid (GlcA). Based on the generation of Fe2+ and acidic milieu together with another product of the oxidation reaction, hydrogen peroxide (H2O2), these two processes jointly present triple enabling factors for generating lethal hydroxyl radicals (•OH) species via Fenton reactions and therefore oxidative stress capable of inhibiting tumor. The antitumor potency of such nanoparticle is verified in tumor-bearing model mice in vivo, proclaiming its potential as a potent and safe agent based on the unique mechanism of optically manipulating enzyme activity for synergistic antitumor therapeutics with high spatial precision, enhanced efficacy and minimized side effects.

A review of organic small-molecule fluorescent probes for the gallium(III) ion.

Gallium metal and gallium compounds play significant roles in industry and medicine; however, their pollution and residue can pose potential risks to plants, animals and human health. Moreover, accurately detecting Ga3+ during tumor treatment holds great clinical significance. Therefore, it is crucial to reliably determine the content of Ga3+ in environmental and biological samples. Organic small-molecule fluorescent probe technology offers high selectivity and sensitivity, rapid detection speed, and non-destructive in situ bioimaging capabilities, making it an ideal approach for Ga3+ detection. The numerous reported probes for detecting Ga3+ highlight the immense application potential of fluorescent probes in this field. However, due to limited development of Ga3+-specific fluorescent probes thus far, several challenges associated with their design and development remain. This paper presents a comprehensive overview of the performance achieved by Ga3+ fluorescent probes, while addressing existing issues and proposing corresponding solutions. Additionally, future directions for developing highly efficient Ga3+ fluorescent probes are outlined as valuable guidance.

[Research progress in coatings with active compounds and extracts of traditional Chinese medicines for coronary intervention devices].

In recent years, the incidence and mortality rates of cardiovascular diseases in China have kept rising, with no significant reduction in disease burden observed. Percutaneous coronary intervention(PCI) is an effective approach for treating coronary artery disease. Drug-eluting stents and drug-coated balloons are currently the most common PCI devices used in clinical practice. However, challenges with restenosis and late-stage thrombotic events persist. Inhibiting the proliferation of vascular smooth muscle cells while enhancing endothelial cell activity is crucial for reducing restenosis and preventing thrombosis, and it remains a challenge in research. The active compounds and extracts of traditional Chinese medicine(TCM), particularly the combinations of active compounds in coatings, possess multi-target potential and serve as a supplement to coatings prepared from synthetic compounds. This review elucidates the application of TCM active compounds(such as arsenic trioxide, paclitaxel, hirudin, tetramethylpyrazine, emodin, oxymatrine, and curcumin), combinations of TCM active compounds(paclitaxel/hirudin, geniposide/baicalin), and TCM extracts(such as Curcumae Rhizoma extract and Tripterygium hypoglaucum extract) in the coatings for PCI devices in recent years. Furthermore, this review expounds the current challenges and future prospects in this field, giving insights into the innovation of PCI devices.

[Secondary metabolites of endophytic fungus Talaromyces malicola hosted in Armadillidium vulgare].

The secondary metabolites of the endophytic fungus Talaromyces malicola hosted in the arthropod Armadillidium vulgare were separated by silica gel column chromatography, gel column chromatography, and semi-preparative high-performance liquid chromatography. Eleven compounds(1-11) were obtained from the ethyl acetate fraction of the fermentation broth of T. malicola, and their structures were identified by NMR, HR-ESI-MS, UV, IR, and ECD. The 11 compounds were talarosesquiterpene A(1),(3ß,5α,6α,15α,22E)-5,6-epoxyergosta-8(14),22-diene-3,7,15-triol(2), vermistatin(3), hydroxyvermistatin(4), bercheminol A(5), penicillide(6), lunatinin(7), penipurdin A(8), emodin(9), BE-25327(10), and(-)-regiolone(11). Compound 1 was a new diaporol-type sesquiterpene. Compounds 2, 4-5, and 7-11 were isolated from Talaromyces for the first time.

[Traditional Chinese medicine theoretical mechanism of blood-activating and stasis-resolving therapy combined with thrombolysis/thrombectomy in improving clinical efficacy].

Thrombolysis/thrombectomy treatment is an emergency medical intervention for patients with acute ischemic stroke. Its core purpose is to reduce brain tissue damage and improve patient prognosis by restoring blood flow to the brain, which is significantly advantageous in timely restoring blood flow to the brain and reducing post-stroke sequelae. However, research shows that even with successful thrombolysis/thrombectomy treatment, some patients may still experience re-occlusion of the target vessel, leading to secondary damage and worsening of the condition. This study retrospectively examined clinical, experimental, and theoretical aspects of thrombolysis/thrombectomy in both traditional Chinese medicine(TCM) and western medicine, and analyzed the characteristics of blood-activating and stasis-resolving therapy in different stages of thrombolysis/thrombectomy and the synergistic mechanism of different types of blood-activating and stasis-resolving drugs with thrombolysis/thrombectomy in combination of previous clinical studies by the research team. Furthermore, the "vessel hyperactivity" characteristics embodied by Yang vessel irritability and Yin vessel stagnation was explained, revealing the TCM mechanism by which blood-activating TCM drugs reduce the incidence of vessel re-occlusion after thrombolysis/thrombectomy through multiple targets and pathways from a theoretical perspective. It also explored how blood-activating and stasis-resolving drugs promoted the excretion of pathological products such as phlegm, fluid, stasis, and toxins from damaged brain tissue, enhanced self-repair of damaged brain tissue, and accelerated the reconstruction of the brain by facilitating the transformation of Qi, blood, and essence within the body. This study aims to deeply elucidate the TCM theoretical mechanism of blood-activating and stasis-resolving therapy in reducing the occurrence of "cerebral infarction and vascular re-occlusion" during thrombolysis/thrombectomy, which holds significant theoretical and practical significance.

Helicobacter pylori CagA mediated mitophagy to attenuate the NLRP3 inflammasome activation and enhance the survival of infected cells.

Helicobacter pylori (H. pylori) is one of the most common bacterial infections in the world, and its key virulence component CagA is the leading cause of gastric cancer. Mitophagy is a form of selective autophagy that eliminates damaged mitochondria and is essential for some viruses and bacteria to evade the immune system. However, the mechanisms by which CagA mediates H. pylori-induced mitophagy and NLRP3 inflammasome activation remain elusive. In this study, we reported that H. pylori primarily uses its CagA to induce mitochondrial oxidative damage, mitochondrial dysfunction, dynamic imbalance, and to block autophagic flux. Inhibition of mitophagy led to an increase in NLRP3 inflammasome activation and apoptosis and a decrease in the viability of H. pylori-infected cells. Our findings suggested that H. pylori induces mitochondrial dysfunction and mitophagy primarily via CagA. It reduces NLRP3 inflammasome activation to evade host immune surveillance and increases the survival and viability of infected cells, potentially leading to gastric cancer initiation and development. Our findings provide new insights into the pathogenesis of H. pylori-induced gastric cancer, and inhibition of mitophagy may be one of the novel techniques for the prevention and treatment of this disease.

Navigating therapeutic challenges in VEXAS syndrome: exploring IL-6 and JAK inhibitors at the forefront.

VEXAS syndrome, an uncommon yet severe autoimmune disorder stemming from a mutation in the UBA1 gene, is the focus of this paper. The overview encompasses its discovery, epidemiological traits, genetic underpinnings, and clinical presentations. Delving into whether distinct genotypes yield varied clinical phenotypes in VEXAS patients, and the consequent adjustment of treatment strategies based on genotypic and clinical profiles necessitates thorough exploration within the clinical realm. Additionally, the current therapeutic landscape and future outlook are examined, with particular attention to the potential therapeutic roles of IL-6 inhibitors and JAK inhibitors, alongside an elucidation of prevailing limitations and avenues for further research. This study contributes essential theoretical groundwork and clinical insights for both diagnosing and managing VEXAS syndrome.

The relationship between anesthesia, surgery and postoperative immune function in cancer patients: a review.

This review comprehensively examines the impact of anesthesia and surgical interventions on the immune function of cancer patients postoperatively. Recent studies have shown that surgery and its accompanying anesthesia management can significantly influence immune function in cancer patients, potentially affecting their prognosis. This review synthesizes clinical studies and basic research to summarize the specific effects of anesthesia methods, drugs, postoperative analgesia, intraoperative transfusion, surgical techniques, and trauma extent on the immune function of cancer patients post-surgery. Additionally, this review discusses optimization strategies based on current research, aiming to refine anesthesia and surgical management to maximize the preservation and enhancement of postoperative immune function in cancer patients, with the potential to improve clinical outcomes.

Inhibiting miRNA-146a suppresses mouse gallstone formation by regulating LXR/megalin/cubilin-media cholesterol absorption.

Background: miRNA has been implicated in regulating cholesterol homeostasis, a critical factor in gallstone formation. Here, we focused on elucidating the role of miR-146a in this pathological process. Methods: C57BL/6 mice were fed with lithogenic diet (LD) and injected with miR-146 antagomir (anta-146) via the tail vein for various weeks. The gallbladders and liver tissues were collected for cholesterol crystal imaging, gallstone mass quantification, and molecular analysis. Levels of cholesterol, bile salt, phospholipids, and metabolic parameters in serum and bile were assessed by ELISA. A 3' UTR reporter gene assay was used to verify the direct target genes for miR-146. The relative expression of metabolism genes was analyzed by quantitative real-time PCR and immunoblotting. Results: miR-146a-5p expression was reduced in mice and clinical samples with gallstones. Anta-146 treatment effectively prevented LD-induced gallstone formation in mice without hepatic and cholecystic damage. The mice treated with anta-146 exhibited beneficial alterations in bile cholesterol and bile acids and lipid levels in the blood. A key biliary cholesterol transporter-Megalin was identified as a direct target of miR-146. Anta-146 administration upregulated megalin expression, thereby ameliorating impaired gallbladder cholesterol absorption associated with the LXR-megalin/cubilin pathway. Conclusion: The data demonstrates that miR-146 modulates gallbladder cholesterol absorption by targeting megalin, and prevents the pathogenesis of cholesterol gallstones.