Preparation of Activated Carbon Nanostructured Al@CuO with Low Static Sensitivity and High Reactivity.

The porous skeleton structure of oxidizers can effectively enlarge the contact area with fuels and boost the reactivity of thermites, but the overly complex preparation processes tend to limit their use to some extent. To overcome this issue, water-soluble starch and copper nitrate were used as a template to form a carbon skeleton copper oxide (C-CuO) after spray drying and calcination. By adding nanoaluminum into the spray drying process, the n-Al@C-CuO was prepared and compared with the physically mixed n-Al/C-CuO in the context. Scanning electron microscopy and differential scanning calorimetry were used to observe the morphology and analyze the thermal process. The pressure-time test and the electrostatic sensitivity test were used to measure the energy release properties and the safety of the thermites. Results indicated that the n-Al@C-CuO had 60.97 °C earlier initial exothermic temperature and 1.74 times higher peak pressure than that of the physically mixed sample. The n-Al@C-CuO was not ignited under 25 kV in the electrostatic sensitivity test, showing the great electrostatic safety of the sample. These findings are expected to facilitate the development of spray drying and promote energy release of traditional thermites.

Tigroid Enhancement: A Characteristic Enhancement Pattern of the Cerebellar Hemisphere on MRI With Intracranial Dural Arteriovenous Fistulas.

PURPOSE: This study aims to investigate a characteristic cerebellar hemisphere enhancement pattern on magnetic resonance imaging (MRI) that could aid in early and specific diagnosis of intracranial dural arteriovenous fistulas (DAVFs). MATERIALS AND METHODS: Pretreatment MR images of 57 patients with intracranial DAVFs between January 1, 2017, and February 28, 2023, were retrospectively analyzed. A total of 128 patients with confirmed alternative cerebellar lesions during the same period were included as a control group. All patients underwent enhanced MRI with a 3.0T scanner. The presence or absence of parallel enhanced linear striations on the surface of the cerebellar lesions was documented. Statistically significant differences were determined by the Fisher exact test. RESULTS: Cerebellar lesions were identified in 4 intracranial DAVF patients (7.0%). All 4 patients were male, with an average age of 64 years (range: 58-76 years). The pretreatment MR images of all 4 DAVF patients with cerebellar lesions demonstrated the characteristic tigroid enhancement pattern. Tortuous flow voids were present in the MR images of 3 of the 4 patients. Tigroid enhancement pattern was not observed in the remaining 53 intracranial DAVF patients and all control patients. The differences in the incidence of the pattern were significant (p=0.01). CONCLUSION: A characteristic tigroid enhancement pattern of the cerebellar hemisphere on MRI may aid in the early and specific diagnosis of intracranial DAVFs, allowing timely treatment and improving outcomes. CLINICAL IMPACT: The identification of a characteristic tigroid enhancement pattern on MRI for cerebellar hemisphere lesions holds significant promise for clinical practice. This pattern serves as a distinctive marker aiding in the early and specific diagnosis of intracranial dural arteriovenous fistulas (DAVFs). Clinicians can now utilize this innovative finding to expedite diagnostic workflows, enabling timely intervention and management strategies. The incorporation of this novel imaging feature enhances diagnostic accuracy, potentially reducing misdiagnosis rates and preventing delays in treatment initiation. Ultimately, this advancement may lead to improved patient outcomes and quality of care in neurosurgical and neuroradiological practice.

Anat-SFSeg: Anatomically-guided superficial fiber segmentation with point-cloud deep learning.

Diffusion magnetic resonance imaging (dMRI) tractography is a critical technique to map the brain's structural connectivity. Accurate segmentation of white matter, particularly the superficial white matter (SWM), is essential for neuroscience and clinical research. However, it is challenging to segment SWM due to the short adjacent gyri connection in a U-shaped pattern. In this work, we propose an Anatomically-guided Superficial Fiber Segmentation (Anat-SFSeg) framework to improve the performance on SWM segmentation. The framework consists of a unique fiber anatomical descriptor (named FiberAnatMap) and a deep learning network based on point-cloud data. The spatial coordinates of fibers represented as point clouds, as well as the anatomical features at both the individual and group levels, are fed into a neural network. The network is trained on Human Connectome Project (HCP) datasets and tested on the subjects with a range of cognitive impairment levels. One new metric named fiber anatomical region proportion (FARP), quantifies the ratio of fibers in the defined brain regions and enables the comparison with other methods. Another metric named anatomical region fiber count (ARFC), represents the average fiber number in each cluster for the assessment of inter-subject differences. The experimental results demonstrate that Anat-SFSeg achieves the highest accuracy on HCP datasets and exhibits great generalization on clinical datasets. Diffusion tensor metrics and ARFC show disorder severity associated alterations in patients with Alzheimer's disease (AD) and mild cognitive impairments (MCI). Correlations with cognitive grades show that these metrics are potential neuroimaging biomarkers for AD. Furthermore, Anat-SFSeg could be utilized to explore other neurodegenerative, neurodevelopmental or psychiatric disorders.

Clinicopathological and Molecular Profile of Sellar Neurocytoma.

OBJECTIVE: To investigate the clinical features, imaging characteristics and molecular profile of Sellar neurocytoma (SN). METHODS: Clinical, imaging, and pathological features of eleven cases of sellar neurocytoma were retrospectively analyzed. Electron microscopy was performed in five cases. Molecular features were detected in tumor tissue by RNA sequencing, qPCR and IHC. RESULTS: The clinical features of SN patients showed high incidence of hyponatremia (73%,8/11) and the tumors tended to invaded lateral side of saddle area from preoperative imaging analysis. The tumors had positive NeuN, SYN, NF, SSTR2 immunohistochemistry staining. Tumor transcriptomic analysis suggested a new LMCD1-AS1:GRM7-AS1 fusion gene event and increased expression of 10 hypothalamus-secreted hormones in SN. 15 differentially expressed genes were verified for qPCR verification. SSTR2 has been verified by immunohistochemistry. CONCLUSIONS: Hyponatremia is the dominant clinical features of SN. Preoperative imaging suggests that growth toward the dorsal region is the imaging feature of SN. SSTR2 expression and LMCD1-AS1:GRM7-AS1 fusion gene event expected to become a new molecular marker for SN. Somatostatin receptor ligand therapy may be a potential therapy for SN.

Ferrielectricity controlled widely-tunable magnetoelectric coupling in van der Waals multiferroics.

The discovery of various primary ferroic phases in atomically-thin van der Waals crystals have created a new two-dimensional wonderland for exploring and manipulating exotic quantum phases. It may also bring technical breakthroughs in device applications, as evident by prototypical functionalities of giant tunneling magnetoresistance, gate-tunable ferromagnetism and non-volatile ferroelectric memory etc. However, two-dimensional multiferroics with effective magnetoelectric coupling, which ultimately decides the future of multiferroic-based information technology, has not been realized yet. Here, we show that an unconventional magnetoelectric coupling mechanism interlocked with heterogeneous ferrielectric transitions emerges at the two-dimensional limit in van der Waals multiferroic CuCrP2S6 with inherent antiferromagnetism and antiferroelectricity. Distinct from the homogeneous antiferroelectric bulk, thin-layer CuCrP2S6 under external electric field makes layer-dependent heterogeneous ferrielectric transitions, minimizing the depolarization effect introduced by the rearrangements of Cu+ ions within the ferromagnetic van der Waals cages of CrS6 and P2S6 octahedrons. The resulting ferrielectric phases are characterized by substantially reduced interlayer magnetic coupling energy of nearly 50% with a moderate electric field of 0.3 V nm-1, producing widely-tunable magnetoelectric coupling which can be further engineered by asymmetrical electrode work functions.

Imagine before you leap: Episodic future thinking combined with transcranial direct current stimulation training for impulsive choice in repetitive negative thinking.

Background: Immediate reward preference in repetitive negative thinking (RNT) has a high clinical correlation with a variety of maladaptive behaviors, whereas episodic future thinking (EFT) may be conducive to dealing with non-adaptive thinking and decision-making. Objectives: This study aimed to evaluate the efficacy of EFT training combined with transcranial direct current stimulation (tDCS) stimulation over the ventromedial PFC (vmPFC) in inhibiting impulsive choice of RNT individuals. Method: Study 1 explored the effects of EFT on immediate reward preference of participants with high and low RNT (N = 48). Study 2 conducted a randomized controlled trial (RCT) to examine the treatment effect of the EFT-neural training on impulsive choice of high RNT individuals (N = 103). Results: In study 1, individuals with high RNT were more likely to choose smaller and sooner (SS) rewards, however, there were no significant differences between the high-RNT group and the low-RNT group under the positive EFT condition. In study 2, a significant decrease was shown in the proportion of choosing SS rewards under the 8-week EFT-neural training, and the effect was maintained at 1 month follow-up. Conclusion: RNT is a vulnerability factor for short-sighted behaviors, and EFT-neural training could be suitable for reducing RNT and improving immediate reward preference.

Global, regional, and national burden of incidence, prevalence, and years lived with disability for facial fractures from 1990 to 2019: a systematic analysis for the Global Burden of Disease study 2019.

BACKGROUND: Facial fractures are common injuries causing cosmetic, functional, and psychological damage. The purpose of this study was to assess the incidence, prevalence, and years lived with disability (YLDs) of facial fractures from 1990 to 2019 using the Global Burden of Disease (GBD). METHODS: Detailed data for the disease burden of facial fractures were obtained from online available public data (Global Health Data Exchange) derived from the GBD study. The incidence, prevalence, and YLDs of facial fractures from 1990 to 2019 were analyzed by country, region, age, gender, sociodemographic index (SDI), and cause. The age-standardized incidence rate (ASIR), age-standardized prevalence rate (ASPR), age-standardized YLDs rate (ASYR), and estimated annual percentage change (EAPC) were calculated to evaluate the disease burden and quantify the trends over time. The main causes of facial fractures in different years and ages were assessed. RESULTS: Globally, there were 8.9 million incident cases, 1.5 million cases prevalent cases, and 98.1 thousand years YLDs in 2019. Compared with 1990, the number of incident cases, prevalent cases, and YLDs increased, while ASIR (EAPC, - 0.47; 95% uncertainty interval [UI], - 0.57 to - 0.37), ASPR (EAPC, - 0.39; 95% UI, - 0.46 to - 0.31), ASYR (EAPC, - 0.39; 95% UI, - 0.47 to - 0.32) showed a downward trend. The high SDI region held the highest ASIR, ASPR, and ASYR both in 1990 and 2019, such as New Zealand, Slovenia, and Australia. The burden was higher in men than in women from 1990 to 2019, while the ASRs in women exceeded that of men in the elderly. The ASIR peaked in the young adult group, however, the ASPR and ASYR increased with age. Falls and road injuries were the leading causes of facial fractures. CONCLUSIONS: Facial fractures continue to cause a heavy burden on public health worldwide. More targeted strategies need to be established to control the burden of facial fractures.

NXPH4 can be used as a biomarker for pan-cancer and promotes colon cancer progression.

NXPH4 promotes cancer proliferation and invasion. However, its specific role and mechanism in cancer remain unclear. Transcriptome and clinical data for pan-cancer were derived from the TCGA database. K-M survival curve and univariate Cox were used for prognostic analysis. CIBERSORT and TIMER algorithms were employed to calculate immune cell infiltration. Gene set enrichment analysis (GSEA) was employed for investigating the function of NXPH4. Western blot verified differential expression of NXPH4 in colon cancer. Functional assays (CCK-8, plate clonogenicity assay, wound healing assay, and Transwell assay) confirmed the impact of NXPH4 on proliferation, invasion, and migration of colon cancer cells. Dysregulation of NXPH4 in pan-cancer suggests its potential as a diagnostic and prognostic marker for certain cancers, including colon and liver cancer. High expression of NXPH4 in pan-cancer might be associated with the increase in copy number and hypomethylation. NXPH4 expression in pan-cancer is substantially linked to immune cell infiltration in the immune microenvironment. NXPH4 expression is associated with the susceptibility to immunotherapy and chemotherapy. Western blot further confirmed the higher expression of NXPH4 in colon cancer. Knockdown of NXPH4 significantly suppresses proliferation, invasion, and migration of colon cancer cell lines HT-29 and HCT116, as validated by functional assays.

Case report: Paralytic ileus resulted from nirmatrelvir/ritonavir-tacrolimus drug-drug interaction in a systemic lupus erythematosus patient with COVID-19.

Patients with systemic autoimmune rheumatic diseases are at a high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and effective antiviral treatments including nirmatrelvir/ritonavir can improve their outcomes. However, there might be potential drug-drug interactions when these patients take nirmatrelvir/ritonavir together with immunosuppressants with a narrow therapeutic window, such as tacrolimus and cyclosporine. We present a case of paralytic ileus resulting from tacrolimus toxicity mediated by the use of nirmatrelvir/ritonavir in a patient with systemic lupus erythematosus (SLE). A 37-year-old female SLE patient was prescribed nirmatrelvir/ritonavir without discontinuing tacrolimus. She presented to the emergency room with symptoms of paralytic ileus including persistent abdominal pain, nausea, and vomiting, which were verified to be associated with tacrolimus toxicity. The blood concentration of tacrolimus was measured >30 ng/mL. Urgent medical intervention was initiated, while tacrolimus was withheld. The residual concentration was brought within the appropriate range and tacrolimus was resumed 8 days later. Physicians must be aware of the potential DDIs when prescribing nirmatrelvir/ritonavir, especially to those taking immunosuppresants like tacrolimus.

Nobiletin alleviates cisplatin-induced ototoxicity via activating autophagy and inhibiting NRF2/GPX4-mediated ferroptosis.

Nobiletin, a citrus polymethoxy flavonoid with antiapoptotic and antioxidative properties, could safeguard against cisplatin-induced nephrotoxicity and neurotoxicity. Cisplatin, as the pioneer of anti-cancer drug, the severe ototoxicity limits its clinical applications, while the effect of nobiletin on cisplatin-induced ototoxicity has not been identified. The current study investigated the alleviating effect of nobiletin on cisplatin-induced ototoxicity and the underlying mechanisms. Apoptosis and ROS formation were evaluated using the CCK-8 assay, Western blotting, and immunofluorescence, indicating that nobiletin attenuated cisplatin-induced apoptosis and oxidative stress. LC3B and SQSTM1/p62 were determined by Western blotting, qPCR, and immunofluorescence, indicating that nobiletin significantly activated autophagy. Nobiletin promoted the nuclear translocation of NRF2 and the transcription of its target genes, including Hmox1, Nqo1, and ferroptosis markers (Gpx4, Slc7a11, Fth, and Ftl), thereby inhibiting ferroptosis. Furthermore, RNA sequencing analysis verified that autophagy, ferroptosis, and the NRF2 signaling pathway served as crucial points for the protection of nobiletin against ototoxicity caused by cisplatin. Collectively, these results indicated, for the first time, that nobiletin alleviated cisplatin-elicited ototoxicity through suppressing apoptosis and oxidative stress, which were attributed to the activation of autophagy and the inhibition of NRF2/GPX4-mediated ferroptosis. Our study suggested that nobiletin could be a prospective agent for preventing cisplatin-induced hearing loss.

Understanding the Effects of Ligand Configuration on Protoporphyrinogen IX Oxidase with Rationally Designed 3-(N-Phenyluracil)but-2-enoates.

Protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) is a promising target for green herbicide discovery. However, the ligand configuration effects on PPO activity were still poorly understood. Herein, we designed 3-(N-phenyluracil)but-2-enoates using our previously developed active fragments exchange and link (AFEL) approach and synthesized a series of novel compounds with nanomolar ranges of Nicotiana tabacum PPO (NtPPO) inhibitory potency and promising herbicidal potency. Our systematic structure-activity relationship investigations showed that the E isomers of 3-(N-phenyluracil)but-2-enoates displayed improved bioactivity than their corresponding Z isomers. Using molecular simulation studies, we found that the E isomers showed a relatively lower entropy change and could sample more stable binding conformation to the receptor than the Z isomers. Our density functional theory (DFT) calculations showed that the E isomers showed higher chemical reactivity and lower electronic chemical potential than their corresponding Z isomers. Compound E-Ic emerged as the optimal compound with a Ki value of 3.0 nM against NtPPO, exhibiting a broader spectrum of weed control than saflufenacil at 37.5-75 g ai/ha and also safe to maize at 75 g ai/ha, which could be considered as a promising lead herbicide for further development.

Aberrant dynamic functional network connectivity in progressive supranuclear palsy.

BACKGROUND: The clinical symptoms of progressive supranuclear palsy (PSP) may be mediated by aberrant dynamic functional network connectivity (dFNC). While earlier research has found altered functional network connections in PSP patients, the majority of those studies have concentrated on static functional connectivity. Nevertheless, in this study, we sought to evaluate the modifications in dynamic characteristics and establish the correlation between these disease-related changes and clinical variables. METHODS: In our study, we conducted a study on 53 PSP patients and 65 normal controls. Initially, we employed a group independent component analysis (ICA) to derive resting-state networks (RSNs), while employing a sliding window correlation approach to produce dFNC matrices. The K-means algorithm was used to cluster these matrices into distinct dynamic states, and then state analysis was subsequently employed to analyze the dFNC and temporal metrics between the two groups. Finally, we made a correlation analysis. RESULTS: PSP patients showed increased connectivity strength between medulla oblongata (MO) and visual network (VN) /cerebellum network (CBN) and decreased connections were found between default mode network (DMN) and VN/CBN, subcortical cortex network (SCN) and CBN. In addition, PSP patients spend less fraction time and shorter dwell time in a diffused state, especially the MO and SCN. Finally, the fraction time and mean dwell time in the distributed connectivity state (state 2) is negatively correlated with duration, bulbar and oculomotor symptoms. DISCUSSION: Our findings were that the altered connectivity was mostly concentrated in the CBN and MO. In addition, PSP patients had different temporal dynamics, which were associated with bulbar and oculomotor symptoms in PSPRS. It suggest that variations in dynamic functional network connectivity properties may represent an essential neurological mechanism in PSP.

Brandt's vole hole detection and counting method based on deep learning and unmanned aircraft system.

Rodents are essential to the balance of the grassland ecosystem, but their population outbreak can cause major economic and ecological damage. Rodent monitoring is crucial for its scientific management, but traditional methods heavily depend on manual labor and are difficult to be carried out on a large scale. In this study, we used UAS to collect high-resolution RGB images of steppes in Inner Mongolia, China in the spring, and used various object detection algorithms to identify the holes of Brandt's vole (Lasiopodomys brandtii). Optimizing the model by adjusting evaluation metrics, specifically, replacing classification strategy metrics such as precision, recall, and F1 score with regression strategy-related metrics FPPI, MR, and MAPE to determine the optimal threshold parameters for IOU and confidence. Then, we mapped the distribution of vole holes in the study area using position data derived from the optimized model. Results showed that the best resolution of UAS acquisition was 0.4 cm pixel-1, and the improved labeling method improved the detection accuracy of the model. The FCOS model had the highest comprehensive evaluation, and an R2 of 0.9106, RMSE of 5.5909, and MAPE of 8.27%. The final accuracy of vole hole counting in the stitched orthophoto was 90.20%. Our work has demonstrated that UAS was able to accurately estimate the population of grassland rodents at an appropriate resolution. Given that the population distribution we focus on is important for a wide variety of species, our work illustrates a general remote sensing approach for mapping and monitoring rodent damage across broad landscapes for studies of grassland ecological balance, vegetation conservation, and land management.

Photoperiod-regulated mitophagy in the germ cells of Brandt's voles (Lasiopodomys brandtii).

Photoperiod is a pivotal factor in affecting testicular function and spermatogenesis in seasonal-breeding animals. Mitophagy is essential for spermatogenesis, but its association with seasonal photoperiods has not been studied extensively. To explore this, we exposed male Brandt's voles (Lasiopodomys brandtii) to long-photoperiod (LP, 16 h/day) and short-photoperiod (SP, 8 h/day) conditions from their embryonic stages. Our results indicated that testis weight, volume, and relative testes weight were all significantly increased in LP compared to SP. Additionally, blood testosterone levels were markedly higher in LP than SP. Histological examination revealed that seminiferous diameter and epithelium thickness were greater in LP, with an increased abundance of germ cell types and cell numbers compared to SP. RT-qPCR analysis showed that mitophagy-promoting genes, such as Pink1, Prkn, Tomm7, Mnf2, Lc3, Optn, Gabarap, and Nbr1 were all upregulated in LP. Fluorescence in situ hybridization indicated that Pink1 expression was present in spermatogonia in SP, while in LP, Pink1 expression extended to almost all germ cell types with significantly higher mean optical density. Prkn expression was found in all germ cell types in both LP and SP, with a significantly higher mean optical density of 10-week-old LP males. Transmission electron microscopy showed normal mitochondrial morphology with clear membranes in SP, while the LP group had reduced cristae in mitochondria and damaged mitochondria undergoing autophagy. This study suggests that mitophagy may be involved in the photoperiodic spermatogenesis in Brandt's voles, providing insights into the role of photoperiod in seasonal reproduction in wild animals.

An antibacterial biologic patch based on bacterial cellulose for repair of infected hernias.

Infection-associated complications and repair failures and antibiotic resistance have emerged as a formidable challenge in hernia repair surgery. Consequently, the development of antibiotic-free antibacterial patches for hernia repair has become an exigent clinical necessity. Herein, a GBC/Gel/LL37 biological patch (biopatch) with exceptional antibacterial properties is fabricated by grafting 2-Methacryloyloxyethyl trimethylammonium chloride (METAC), a unique quaternary ammonium salt with vinyl, onto bacterial cellulose (GBC), followed by compounding with gelatin (Gel) and LL37. The GBC/Gel/LL37 biopatch exhibits stable swelling capacity, remarkable mechanical properties, flexibility, and favorable biocompatibility. The synergistic effect of METAC and LL37 confers upon the GBC/Gel/LL37 biopatch excellent antibacterial efficacy against Staphylococcus aureus and Escherichia coli, effectively eliminating invading bacteria without the aid of exogenous antibiotics in vivo while significantly reducing local acute inflammation caused by infection. Furthermore, the practical efficacy of the GBC/Gel/LL37 biopatch is evaluated in an infected ventral hernia model, revealing that the GBC/Gel/LL37 biopatch can prevent the formation of visceral adhesions, facilitate the repair of infected ventral hernia, and effectively mitigate chronic inflammation. The prepared antibacterial GBC/Gel/LL37 biopatch is very effective in dealing with the risk of infection in hernia repair surgery and offers potential clinical opportunities for other soft injuries, exhibiting considerable clinical application prospects.

Femtosecond Laser Fabrication of Three-Dimensional Bubble-Propelled Microrotors for Multicomponent Mechanical Transmission.

Inspired by the reverse thrust generated by fuel injection, micromachines that are self-propelled by bubble ejection are developed, such as microrods, microtubes, and microspheres. However, controlling bubble ejection sites to build micromachines with programmable actuation and further enabling mechanical transmission remain challenging. Here, bubble-propelled mechanical microsystems are constructed by proposing a multimaterial femtosecond laser processing method, consisting of direct laser writing and selective laser metal reduction. The polymer frame of the microsystems is first printed, followed by the deposition of catalytic platinum into the desired local site of the microsystems by laser reduction. With this method, a variety of designable microrotors with selective bubble ejection sites are realized, which enable excellent mechanical transmission systems composed of single and multiple mechanical components, including a coupler, a crank slider, and a crank rocker system. We believe the presented bubble-propelled mechanical microsystems could be extended to applications in microrobotics, microfluidics, and microsensors.

Liquid Metal as Energy Conversion Sensitizers: Materials and Applications.

Energy can exist in nature in a wide range of forms. Energy conversion refers to the process in which energy is converted from one form to another, and this process will be greatly enhanced by energy conversion sensitizers. Recently, an emerging class of new materials, namely liquid metals (LMs), shows excellent prospects as highly versatile materials. Notably, in terms of energy delivery and conversion, LMs functional materials are chemical responsive, heat-responsive, photo-responsive, magnetic-responsive, microwave-responsive, and medical imaging responsive. All these intrinsic virtues enabled promising applications in energy conversion, which means LMs can act as energy sensitizers for enhancing energy conversion and transport. Herein, first the unique properties of the light, heat, magnetic and microwave converting capacity of gallium-based LMs materials are summarized. Then platforms and applications of LM-based energy conversion sensitizers are highlighted. Finally, some of the potential applications and opportunities of LMs are prospected as energy conversion sensitizers in the future, as well as unresolved challenges. Collectively, it is believed that this review provides a clear perspective for LMs mediated energy conversion, and this topic will help deepen knowledge of the physical chemistry properties of LMs functional materials.

4-octyl itaconate alleviates cisplatin-induced ferroptosis possibly via activating the NRF2/HO-1 signalling pathway.

Ferroptosis, characterized by iron-dependent lipid reactive oxygen species (ROS) accumulation, plays a pivotal role in cisplatin-induced ototoxicity. Existing research has suggested that in cisplatin-mediated damage to auditory cells and hearing loss, ferroptosis is partially implicated. 4-Octyl itaconate (4-OI), derived from itaconic acid, effectively permeates cell membranes, showcasing potent anti-inflammatory as well as antioxidant effects in several disease models. Our study aimed to investigate the effect of 4-OI on cisplatin-induced ferroptosis and the underlying molecular mechanisms. The survival rates of HEI-OC1 cells and mice cochlea hair cells were measured by CCK8 and immunofluorescence, respectively. The auditory brainstem response (ABR) audiometry was used to detect changes in hearing thresholds in mice before and after treatment. Levels of ROS were evaluated by DCFH-DA. Real-time PCR quantified inflammatory cytokines TNF-α, IL-6 and IL-1ß. Network Pharmacology and RNA sequencing (RNA-seq) analysis of the potential mechanism of 4-OI resistance to cisplatin-induced ferroptosis. The expressions of ferroptosis-related factors (GPX4, SLC7A11 and PTGS2) and important antioxidant factors (NRF2, HO-1, GCLC and NQO1) were tested by real-time PCR, Western blot and immunofluorescence. Results demonstrated cisplatin-induced significant ROS and inflammatory factor release, reduced NRF2 expression, hindered nuclear translocation and activated ferroptosis. Pretreatment with 4-OI exhibited anti-inflammatory and antioxidant effects, along with resistance to ferroptosis, ultimately mitigating cisplatin-induced cell loss. In the present study, we show that 4-OI inhibits cisplatin-induced ferroptosis possibly through activation of the NRF2/HO-1 signalling pathway, thereby exerting a protective effect against cisplatin-induced damage to auditory cells, and providing a new therapeutic strategy for cisplatin-induced hearing loss.

Bioinformatics identifies key genes and potential drugs for energy metabolism disorders in heart failure with dilated cardiomyopathy.

Background: Dysfunction in myocardial energy metabolism plays a vital role in the pathological process of Dilated Cardiomyopathy (DCM). However, the precise mechanisms remain unclear. This study aims to investigate the key molecular mechanisms of energy metabolism and potential therapeutic agents in the progression of dilated cardiomyopathy with heart failure. Methods: Gene expression profiles and clinical data for patients with dilated cardiomyopathy complicated by heart failure, as well as healthy controls, were sourced from the Gene Expression Omnibus (GEO) database. Gene sets associated with energy metabolism were downloaded from the Molecular Signatures Database (MSigDB) for subsequent analysis. Weighted Gene Co-expression Network Analysis (WGCNA) and differential expression analysis were employed to identify key modules and genes related to heart failure. Potential biological mechanisms were investigated through Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and the construction of a competing endogenous RNA (ceRNA) network. Molecular docking simulations were then conducted to explore the binding affinity and conformation of potential therapeutic drugs with hub genes. Results: Analysis of the left ventricular tissue expression profiles revealed that, compared to healthy controls, patients with dilated cardiomyopathy exhibited 234 differentially expressed genes and 2 genes related to myocardial energy metabolism. Additionally, Benzoylaconine may serve as a potential therapeutic agent for the treatment of dilated cardiomyopathy. Conclusion: The study findings highlight the crucial role of myocardial energy metabolism in the progression of Dilated Cardiomyopathy. Notably, Benzoylaconine emerges as a potential candidate for treating Dilated Cardiomyopathy, potentially exerting its therapeutic effects by targeted modulation of myocardial energy metabolism through NRK and NT5.

Non-Necroptotic Roles of MLKL in Diet-Induced Obesity, Liver Pathology, and Insulin Sensitivity: Insights from a High-Fat, High-Fructose, High-Cholesterol Diet Mouse Model.

Chronic inflammation is a key player in metabolic dysfunction-associated fatty liver disease (MAFLD) progression. Necroptosis, an inflammatory cell death pathway, is elevated in MAFLD patients and mouse models, yet its role is unclear due to the diverse mouse models and inhibition strategies. In our study, we inhibited necroptosis by targeting mixed lineage kinase domain-like pseudokinase (MLKL), the terminal effector of necroptosis, in a high-fat, high-fructose, high-cholesterol (HFHFrHC) mouse model of diet-induced MAFLD. Despite the HFHFrHC diet upregulating MLKL (2.5-fold), WT mice livers showed no increase in necroptosis markers or associated proinflammatory cytokines. Surprisingly, Mlkl-/- mice experienced exacerbated liver inflammation without protection from diet-induced liver damage, steatosis, or fibrosis. In contrast, Mlkl+/- mice showed a significant reduction in these parameters that was associated with elevated Pparα and Pparγ levels. Both Mlkl-/- and Mlkl+/- mice on the HFHFrHC diet resisted diet-induced obesity, attributed to the increased beiging, enhanced oxygen consumption, and energy expenditure due to adipose tissue, and exhibited improved insulin sensitivity. These findings highlight the tissue-specific effects of MLKL on the liver and adipose tissue, and they suggest a dose-dependent effect of MLKL on liver pathology.