Investigating the role of itaconate in macrophage activation and oxidative stress injury in sepsis-associated acute kidney injury.

BACKGROUND: Sepsis may be linked to oxidative stress and can be controlled by itaconate, an activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Nevertheless, the itaconate impact on sepsis-associated acute kidney injury (SA-AKI) has yet to be definitively established. METHODS: We employed SA-AKI mouse model through a cecal ligation and puncture (CLP) procedure for the in vivo investigation of the potential nephroprotective effect of itaconate in this study. A plasmid was transfected into RAW264.7 cells to examine the Nrf2 pathway function after itaconate administration. Finally, the immune-responsive gene 1-knockout (IRG1-/-) mice were used to study the itaconate impacts on oxidative stress-induced SA-AKI. RESULTS: We have shown that 4-octyl itaconate (OI) significantly reduced CD11b-positive macrophage aggregation and activated the Nrf2 pathway in the bone marrow-derived macrophages (BMDM). The impacts of Nrf2 inhibitor ML385 on the anti-inflammatory and antioxidant properties of itaconate were found to be partial. OI inhibited lipopolysaccharide-induced oxidative stress injury in RAW264.7 macrophages and activated Nrf2 in the nucleus to hinder the expression of nuclear factor kappa B p65, thereby suppressing oxidative stress injury in the macrophages. Additionally, the introduction of the transfected plasmid resulted in a partial inhibition of the anti-inflammatory impact of itaconate. The kidney injury caused by sepsis exhibited greater severity in the IRG1-/- mice than in the wild type mice. Exogenous OI partially attenuated the kidney injury induced by sepsis in the IRG1-/- mice and suppressed the oxidative stress injury in macrophages. CONCLUSIONS: This investigation offers new proof to support the itaconate function in the development and progression of SA-AKI and shows a new possible therapeutic agent for the SA-AKI treatment.

Selective-Area-Grown PbTe-Pb Planar Josephson Junctions for Quantum Devices.

Planar Josephson junctions are predicted to host Majorana zero modes. The material platforms in previous studies are two-dimensional electron gases (InAs, InSb, InAsSb, and HgTe) coupled to a superconductor such as Al or Nb. Here, we introduce a new material platform for planar JJs, the PbTe-Pb hybrid. The semiconductor, PbTe, was grown as a thin film via selective area epitaxy. The Josephson junction was defined by a shadow wall during the deposition of superconductor Pb. Scanning transmission electron microscopy reveals a sharp semiconductor-superconductor interface. Gate-tunable supercurrents and multiple Andreev reflections are observed. A perpendicular magnetic field causes interference patterns of the switching current, exhibiting Fraunhofer-like and SQUID-like behaviors. We further demonstrate a prototype device for Majorana detection wherein phase bias and tunneling spectroscopy are applicable.

Short-term postoperative bacteriobilia or fungibilia in liver transplantation patients with donation after circulatory death allografts associated with a longer hospital stay: A single-center retrospective observational study in China.

BACKGROUND: Normal bile is sterile. Studies have shown that cholangitis after liver transplantation (LT) was associated with a relatively poor prognosis. It remains unclear whether the bacteriobilia or fungibilia impact the patient outcomes in LT recipients, especially with donation after circulatory death (DCD) allografts, which was correlated with a higher risk of allograft failure. METHODS: This retrospective study included 139 LT recipients of DCD grafts from 2019 to 2021. All patients were divided into two groups according to the presence or absence of bacteriobilia or fungibilia. The prevalence and microbial spectrum of postoperative bacteriobilia or fungibilia and its possible association with outcomes, especially hospital stay were analyzed. RESULTS: Totally 135 and 171 organisms were isolated at weeks 1 and 2, respectively. Among all patients included in this analysis, 83 (59.7%) developed bacteriobilia or fungibilia within 2 weeks post-transplantation. The occurrence of bacteriobilia or fungibilia (ß = 7.43, 95% CI: 0.02 to 14.82, P = 0.049), particularly the detection of Pseudomonas (ß = 18.84, 95% CI: 6.51 to 31.07, P = 0.003) within 2 weeks post-transplantation was associated with a longer hospital stay. However, it did not affect the graft and patient survival. CONCLUSIONS: The occurrence of bacteriobilia or fungibilia, particularly Pseudomonas within 2 weeks post-transplantation, could influence the recovery of liver function and was associated with prolonged hospital stay but not the graft and patient survival.

The Utilization of Metal-Organic Frameworks and Their Derivatives Composite in Supercapacitor Electrodes.

Up to now, the mainstream adoption of renewable energy has brought about substantial transformations in the electricity and energy sector. This shift has garnered considerable attention within the scientific community. Supercapacitors, known for their exceptional performance metrics like good charge/discharge capability, strong power density, as well as extended cycle longevity, have gained widespread traction across various sectors, including transportation and aviation. Metal-organic frameworks (MOFs) with unique traits including adaptable structure, highly customizable synthetic methods, and high specific surface area, have emerged as strong candidates for electrode materials. For enhancing the performance, MOFs are commonly compounded with other conducting materials to increase capacitance. This paper provides a detailed analysis of various common preparation strategies and characteristics of MOFs. It summarizes the recent application of MOFs and their derivatives as supercapacitor electrodes alongside other carbon materials, metal compounds, and conductive polymers. Additionally, the challenges encountered by MOFs in the realm of supercapacitor applications are thoroughly discussed. Compared to previous reviews, the content of this paper is more comprehensive, offering readers a deeper understanding of the diverse applications of MOFs. Furthermore, it provides valuable suggestions and guidance for future progress and development in the field of MOFs.

A green aqueous binder to enhance the electrochemical performance of Li-rich disordered rock salt cathode material.

Li-rich disordered rock-salt oxides (DRX) are considered an attractive cathode material in the future battery field due to their excellent energy density and specific capacity. Nevertheless, anionic redox provides high capacity while causing O2 over-oxidation to O2, resulting in voltage hysteresis and capacity decay. Herein, the crystal structure of Li1.3Mn0.4Ti0.3O1.7F0.3 (LMTOF) cathode is stabilized by using sodium carboxymethylcellulose (CMC) binders replacing traditional polyvinylidene difluoride (PVDF) binders. The electrochemical impedance spectroscopy (EIS) and galvanostatic intermittent titration technique (GITT) reveal that the CMC-based LMTOF electrode has higher electronic conductivity and lithium-ion diffusion kinetics. Moreover, CMC has been demonstrated to improve the O2- reversibility, reduce the amounts of byproducts from electrolyte decomposition and suppress transition metal dissolution by Na+/Li+ exchange reaction. Furthermore, the CMC-based LMTOF electrode also exhibits less volume change upon lithiation/delithiation processes compared to the PVDF-based electrode, resulting in enhanced structural stability during cycling. Benefiting from these features, the CMC binders can effectively improve the cycling life and rate performance of the LMTOF cathode, and the CMC-based LMTOF electrode shows good capacity retention of 94.5 % after 30 cycles at 20 mA/g and 66.7 % after 100 cycles at 200 mA/g. This finding indicates that CMC as a binder can efficiently stabilize the structure and improve the electrochemical performance of Li-rich disordered rock-salt oxides cathode, making it possible for practical Li-ion battery applications.

The Absence of Intra-Tumoral Tertiary Lymphoid Structures is Associated with a Worse Prognosis and mTOR Signaling Activation in Hepatocellular Carcinoma with Liver Transplantation: A Multicenter Retrospective Study.

Tertiary lymphoid structure (TLS) can predict the prognosis and sensitivity of tumors to immune checkpoint inhibitors (ICIs) therapy, whether it can be noninvasively predicted by radiomics in hepatocellular carcinoma with liver transplantation (HCC-LT) has not been explored. In this study, it is found that intra-tumoral TLS abundance is significantly correlated with recurrence-free survival (RFS) and overall survival (OS). Tumor tissues with TLS are characterized by inflammatory signatures and high infiltration of antitumor immune cells, while those without TLS exhibit uncontrolled cell cycle progression and activated mTOR signaling by bulk and single-cell RNA-seq analyses. The regulators involved in mTOR signaling (RHEB and LAMTOR4) and S-phase (RFC2, PSMC2, and ORC5) are highly expressed in HCC with low TLS. In addition, the largest cohort of HCC patients is studied with available radiomics data, and a classifier is built to detect the presence of TLS in a non-invasive manner. The classifier demonstrates remarkable performance in predicting intra-tumoral TLS abundance in both training and test sets, achieving areas under receiver operating characteristic curve (AUCs) of 92.9% and 90.2% respectively. In summary, the absence of intra-tumoral TLS abundance is associated with mTOR signaling activation and uncontrolled cell cycle progression in tumor cells, indicating unfavorable prognosis in HCC-LT.

Identification of a 9-gene signature to enhance biochemical recurrence prediction in primary prostate cancer: A benchmarking study using ten machine learning methods and twelve patient cohorts.

Prostate cancer (PCa) is a prevalent malignancy among men worldwide, and biochemical recurrence (BCR) after radical prostatectomy (RP) is a critical turning point commonly used to guide the development of treatment strategies for primary PCa. However, the clinical parameters currently in use are inadequate for precise risk stratification and informing treatment choice. To address this issue, we conducted a study that collected transcriptomic data and clinical information from 1662 primary PCa patients across 12 multicenter cohorts globally. We leveraged 101 algorithm combinations that consisted of 10 machine learning methods to develop and validate a 9-gene signature, named BCR SCR, for predicting the risk of BCR after RP. Our results demonstrated that BCR SCR generally outperformed 102 published prognostic signatures. We further established the clinical significance of these nine genes in PCa progression at the protein level through immunohistochemistry on Tissue Microarray (TMA). Moreover, our data showed that patients with higher BCR SCR tended to have higher rates of BCR and distant metastasis after radical radiotherapy. Through drug target prediction analysis, we identified nine potential therapeutic agents for patients with high BCR SCR. In conclusion, the newly developed BCR SCR has significant translational potential in accurately stratifying the risk of patients who undergo RP, monitoring treatment courses, and developing new therapies for the disease.

Novel insights into RB1 in prostate cancer lineage plasticity and drug resistance.

Prostate cancer is the second most common malignancy among men in the world, posing a serious threat to men's health and lives. RB1 is the first human tumor suppressor gene to be described, and it is closely associated with the development, progression, and suppression of a variety of tumors. It was found that the loss of RB1 is an early event in prostate cancer development and is closely related to prostate cancer development, progression and treatment resistance. This paper reviews the current status of research on the relationship between RB1 and prostate cancer from three aspects: RB1 and prostate cell lineage plasticity; biological behavior; and therapeutic resistance. Providing a novel perspective for developing new therapeutic strategies for RB1-loss prostate cancer.

A Novel Sequence-to-Sequence-Based Deep Learning Model for Multistep Load Forecasting.

Load forecasting is critical to the task of energy management in power systems, for example, balancing supply and demand and minimizing energy transaction costs. There are many approaches used for load forecasting such as the support vector regression (SVR), the autoregressive integrated moving average (ARIMA), and neural networks, but most of these methods focus on single-step load forecasting, whereas multistep load forecasting can provide better insights for optimizing the energy resource allocation and assisting the decision-making process. In this work, a novel sequence-to-sequence (Seq2Seq)-based deep learning model based on a time series decomposition strategy for multistep load forecasting is proposed. The model consists of a series of basic blocks, each of which includes one encoder and two decoders; and all basic blocks are connected by residuals. In the inner of each basic block, the encoder is realized by temporal convolution network (TCN) for its benefit of parallel computing, and the decoder is implemented by long short-term memory (LSTM) neural network to predict and estimate time series. During the forecasting process, each basic block is forecasted individually. The final forecasted result is the aggregation of the predicted results in all basic blocks. Several cases within multiple real-world datasets are conducted to evaluate the performance of the proposed model. The results demonstrate that the proposed model achieves the best accuracy compared with several benchmark models.

Integrated 4D Analysis of Intramuscular Fat Deposition: Quantitative Proteomic and Transcriptomic Studies in Wannanhua Pig Longissimus Dorsi Muscle.

Wannanhua (WH) is a pig breed indigenous to Anhui Province, China. This breed has a high intramuscular fat (IMF) content, making it an ideal model for investigating lipid deposition mechanisms in pigs. IMF content is one of the main indicators of meat quality in pigs and is regulated by multiple genes and metabolic pathways. Building upon our prior transcriptomic investigation, the present study focused on the longissimus dorsi muscle tissue of Wannanhua (WH) pigs in the rapid fat-deposition stages (120 and 240 days of age). Employing 4D label-free quantitative proteomic analysis, we identified 106 differentially expressed proteins (DEPs). Parallel reaction monitoring (PRM) technology was used to verify the DEPs, and the results showed that the 4D label-free results were reliable and valid. Functional enrichment and protein-protein interaction analyses showed that the DEPs were mainly involved in the skeletal-muscle-associated structural proteins, mitochondria, energy metabolism, and fatty acid metabolism. By integrating transcriptomic data, we identified seven candidate genes including ACADL, ACADM, ANKRD2, MYOZ2, TNNI1, UCHL1, and ART3 that play a regulatory role in fat deposition and muscle development. These findings establish a theoretical foundation for future analyses of lipid deposition traits, contributing to potential enhancements in pig meat quality during breeding and advancing the selection process for Chinese indigenous breeds.

Immune Response Gene-1 [IRG1]/itaconate protect against multi-organ injury via inhibiting gasdermin D-mediated pyroptosis and inflammatory response.

Sepsis is a multiple organ dysfunction syndrome due to a dysregulated response to infection with unacceptably high mortality. Currently, no effective treatment exists for sepsis. IRG1/itaconate has been considered to play a protective role for various inflammatory diseases. In the present study, we explored the protective role and mechanisms of IRG1/itaconate on lipopolysaccharide (LPS)-induced multi-organ injury. The LPS-induced sepsis model was used. IRG1-/- and wild type mice were used to explore the protective role of IRG1/itaconate on multi-organ injury. GSDMD-/- mice were used to explore the effect of GSDMD-mediated pyroptosis on LPS-induced model. RAW264.7 cells and bone-marrow-derived macrophages (BMDMs) were used for in vitro studies. In vivo experiments, we found IRG1 deficiency aggravated LPS-induced multi-organ injury especially lung injury. 4-Octyl itaconate (4-OI), a derivative of itaconate, significantly ameliorated LPS-induced acute lung, liver, and kidney injury. Furthermore, IRG1/4-OI decreased serum interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α) level, macrophage infiltration, and TUNEL-positive cells in lung and liver tissue. Western blot showed IRG1/itaconate decreased the expressions of p-ERK, p-P38, p-JNK, and p-P65 and increased the expression of Nrf2/HO-1 in lung tissue. Meanwhile, 4-OI inhibited the expression of GSDMD-N. In vitro experiments, 4-OI inhibited ROS production and promoted apoptosis under LPS stimulation in RAW264.7 cells. Furthermore, 4-OI inhibited nuclear factor-kappaB/mitogen-activated protein kinase pathways and GSDMD-medicated pyroptosis in BMDMs. Finally, we used GSDMD-/- mice to explore the effect of pyroptosis on LPS-induced multi-organ injury. The results showed that GSDMD deficiency significantly ameliorated lung injury. In conclusion, our data demonstrated that IRG1/itaconate protect against multi-organ injury via inhibiting inflammation response and GSDMD-indicated pyroptosis, which may be a promising agent for protecting against sepsis.

Metabolite itaconate in host immunoregulation and defense.

Metabolic states greatly influence functioning and differentiation of immune cells. Regulating the metabolism of immune cells can effectively modulate the host immune response. Itaconate, an intermediate metabolite derived from the tricarboxylic acid (TCA) cycle of immune cells, is produced through the decarboxylation of cis-aconitate by cis-aconitate decarboxylase in the mitochondria. The gene encoding cis-aconitate decarboxylase is known as immune response gene 1 (IRG1). In response to external proinflammatory stimulation, macrophages exhibit high IRG1 expression. IRG1/itaconate inhibits succinate dehydrogenase activity, thus influencing the metabolic status of macrophages. Therefore, itaconate serves as a link between macrophage metabolism, oxidative stress, and immune response, ultimately regulating macrophage function. Studies have demonstrated that itaconate acts on various signaling pathways, including Keap1-nuclear factor E2-related factor 2-ARE pathways, ATF3-IκBζ axis, and the stimulator of interferon genes (STING) pathway to exert antiinflammatory and antioxidant effects. Furthermore, several studies have reported that itaconate affects cancer occurrence and development through diverse signaling pathways. In this paper, we provide a comprehensive review of the role IRG1/itaconate and its derivatives in the regulation of macrophage metabolism and functions. By furthering our understanding of itaconate, we intend to shed light on its potential for treating inflammatory diseases and offer new insights in this field.

Ballistic PbTe Nanowire Devices.

Disorder is the primary obstacle in the current Majorana nanowire experiments. Reducing disorder or achieving ballistic transport is thus of paramount importance. In clean and ballistic nanowire devices, quantized conductance is expected, with plateau quality serving as a benchmark for disorder assessment. Here, we introduce ballistic PbTe nanowire devices grown by using the selective-area-growth (SAG) technique. Quantized conductance plateaus in units of 2e2/h are observed at zero magnetic field. This observation represents an advancement in diminishing disorder within SAG nanowires as most of the previously studied SAG nanowires (InSb or InAs) have not exhibited zero-field ballistic transport. Notably, the plateau values indicate that the ubiquitous valley degeneracy in PbTe is lifted in nanowire devices. This degeneracy lifting addresses an additional concern in the pursuit of Majorana realization. Moreover, these ballistic PbTe nanowires may enable the search for clean signatures of the spin-orbit helical gap in future devices.

Integrative Proteomic Analysis Reveals the Cytoskeleton Regulation and Mitophagy Difference Between Ischemic Cardiomyopathy and Dilated Cardiomyopathy.

Ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) are the two primary etiologies of end-stage heart failure. However, there remains a dearth of comprehensive understanding the global perspective and the dynamics of the proteome and phosphoproteome in ICM and DCM, which hinders the profound comprehension of pivotal biological characteristics as well as differences in signal transduction activation mechanisms between these two major types of heart failure. We conducted high-throughput quantification proteomics and phosphoproteomics analysis of clinical heart tissues with ICM or DCM, which provided us the system-wide molecular insights into pathogenesis of clinical heart failure in both ICM and DCM. Both protein and phosphorylation expression levels exhibit distinct separation between heart failure and normal control heart tissues, highlighting the prominent characteristics of ICM and DCM. By integrating with omics results, Western blots, phosphosite-specific mutation, chemical intervention, and immunofluorescence validation, we found a significant activation of the PRKACA-GSK3ß signaling pathway in ICM. This signaling pathway influenced remolding of the microtubule network and regulated the critical actin filaments in cardiac construction. Additionally, DCM exhibited significantly elevated mitochondria energy supply injury compared to ICM, which induced the ROCK1-vimentin signaling pathway activation and promoted mitophagy. Our study not only delineated the major distinguishing features between ICM and DCM but also revealed the crucial discrepancy in the mechanisms between ICM and DCM. This study facilitates a more profound comprehension of pathophysiologic heterogeneity between ICM and DCM and provides a novel perspective to assist in the discovery of potential therapeutic targets for different types of heart failure.

Identification and validation of PCSK9 as a prognostic and immune-related influencing factor in tumorigenesis: a pan-cancer analysis.

Introduction: Proprotein convertase subtilisin/kexin-9 (PCSK9) has been primarily studied in the cardiovascular field however, its role in cancer pathophysiology remains incompletely defined. Recently, a pivotal role for PCSK9 in cancer immunotherapy was proposed based on the finding that PCSK9 inhibition was associated with enhancing the antigen presentation efficacy of target programmed cell death-1 (PD-1). Herein, we provide results of a comprehensive pan-cancer analysis of PCSK9 that assessed its prognostic and immunological functions in cancer. Methods: Using a variety of available online cancer-related databases including TIMER, cBioPortal, and GEPIA, we identified the abnormal expression of PCSK9 and its potential clinical associations in diverse cancer types including liver, brain and lung. We also validated its role in progression-free survival (PFS) and immune infiltration in neuroblastoma. Results: Overall, the pan-cancer survival analysis revealed an association between dysregulated PCSK9 and poor clinical outcomes in various cancer types. Specifically, PCSK9 was extensively genetically altered across most cancer types and was consistently found in different tumor types and substages when compared with adjacent normal tissues. Thus, aberrant DNA methylation may be responsible for PCSK9 expression in many cancer types. Focusing on liver hepatocellular carcinoma (LIHC), we found that PCSK9 expression correlated with clinicopathological characteristics following stratified prognostic analyses. PCSK9 expression was significantly associated with immune infiltrate since specific markers of CD8+ T cells, macrophage polarization, and exhausted T cells exhibited different PCSK9-related immune infiltration patterns in LIHC and lung squamous cell carcinoma. In addition, PCSK9 was connected with resistance of drugs such as erlotinib and docetaxel. Finally, we validated PCSK9 expression in clinical neuroblastoma samples and concluded that PCSK9 appeared to correlate with a poor PFS and natural killer cell infiltration in neuroblastoma patients. Conclusion: PCSK9 could serve as a robust prognostic pan-cancer biomarker given its correlation with immune infiltrates in different cancer types, thus potentially highlighting a new direction for targeted clinical therapy of cancers.

Combination of PARP inhibitor and CDK4/6 inhibitor modulates cGAS/STING-dependent therapy-induced senescence and provides "one-two punch" opportunity with anti-PD-L1 therapy in colorectal cancer.

Although PARP inhibitor (PARPi) has been proven to be a promising anticancer drug in cancer patients harboring BRCA1/2 mutation, it provides limited clinical benefit in colorectal cancer patients with a low prevalence of BRCA1/2 mutations. In our study, we found PARPi talazoparib significantly induced cellular senescence via inhibiting p53 ubiquitination and activating p21. Furthermore, CDK4/6i palbociclib amplified this therapy-induced senescence (TIS) in vitro and in vivo. Mechanistically, talazoparib and palbociclib combination induced senescence-associated secretory phenotype (SASP), and characterization of SASP components revealed type I interferon (IFN)-related mediators, which were amplified by cGAS/STING signaling. More importantly, RNA sequencing data indicated that combination therapy activated T cell signatures and combination treatment transformed the tumor microenvironment (TME) into a more antitumor state with increased CD8 T cells and natural killer (NK) cells and decreased macrophages and granulocytic myeloid-derived suppressor cells (G-MDSCs). Moreover, clearance of the TIS cells by αPD-L1 promoted survival in immunocompetent mouse colorectal cancer models. Collectively, we elucidated the synergistic antitumor and immunomodulatory mechanisms of the talazoparib-palbociclib combination. Further combination with PD-L1 antibody might be a promising "one-two punch" therapeutic strategy for colorectal cancer patients.

Polydopamine-coated mesoporous silica nanoparticles co-loaded with Ziyuglycoside I and Oseltamivir for synergistic treatment of viral pneumonia.

Viral pneumonia (VP) is a serious health risk to humans, however, there is still a lack of specific treatments for VP. The spread of the virus in the body induces an excessive inflammatory response that can cause chronic or irreversible damage to lungs. Hence, VP treatment requires rapid clearance of the virus and sustained inflammation control. In this study, an innovative mesoporous silica medication delivery system co-loaded with Ziyuglycoside I(ZgI) and Oseltamivirv(OST) in fast and slow monomeric forms ZgI@MSNs-OST@ Polydopamine (PDA) was prepared for targeted treatment of VP. The prepared ZgI@MSNs-OST@PDA nanoparticles had a homogeneous and membrane-encapsulated spherical structure, with an average particle size of approximately 760 nm. in vitro release and in vivo pharmacokinetic studies demonstrated that ZgI@MSNs-OST@PDA achieved immediate release of OST and sustained release of ZgI, which was readily taken up by the cells. In vitro anti-H1N1 virus experiments showed that nanoparticles rapidly killed the virus in host cells, and the anti-inflammatory effect was sustained and long-lasting, providing excellent protection to host cells. In vivo antiviral pneumonia experiments confirmed the rapid clearance of influenza viruses from mouse lungs and the effective control of overactivated immune responses by ZgI@MSNs-OST@PDA nanoparticles. Through a mechanistic study, we found that the treatment of viral pneumonia with nanoparticles was associated with inhibition of the NLRP3 inflammasome pathway. In conclusion, the constructed nanoparticles achieved synergistic therapeutic effects of ZgI and OST on VP, that is, rapid killing of influenza viruses by OST and effective control of the virus-induced hyperinflammatory response by ZgI.

Nrf2 inhibition increases sensitivity to chemotherapy of colorectal cancer by promoting ferroptosis and pyroptosis.

Oxaliplatin is widely used in chemotherapy for colorectal cancer (CRC), but its sensitivity has become a major obstacle to limiting efficacy. Many literatures reported that Nrf2 activation promoted tumor chemoresistance. In this study, we explored the role and mechanism of Nrf2 inhibition in oxaliplatin-based chemosensitivity of CRC. In vitro experiments, we applied 4-octyl itaconate (4-OI) to activate Nrf2, and used lentivirus to knock down Nrf2 in CRC cell lines. By measuring cell viability, colony formation, apoptosis, reactive oxygen species production, and western blot, we found that oxaliplatin and lobaplatin suppressed the growth of HCT-116 and LOVO cells in a dose-dependent manner, and promoted the expression of Nrf2. 4-OI, an Nrf2 activator, reduced the sensibility of CRC cells to oxaliplatin and lobaplatin, while the knockdown of Nrf2 promoted the sensibility of CRC cells to oxaliplatin and lobaplatin. Through the public databases, we found that the expression of GPX4 in normal tissues was lower compared with cancer tissues in CRC, and the high GPX4 expression predicted a poor prognosis. Meanwhile, we found that oxaliplatin reduced the expression of GPX4 in vitro. The knockdown of Nrf2 enhanced the effects of oxaliplatin to reduce the expression of GPX4 and GSH content, and increase the MDA content, which enhanced oxaliplatin-induced ferroptosis. Subsequently, we found that oxaliplatin promoted the expression of GSDME-N, and induced LDH, IL-1ß, and TNF-a release, and the knockdown of Nrf2 aggravated the occurrence of GSMDE-mediated pyroptosis. Finally, we found that the knockdown of Nrf2 enhanced the inhibition of oxaliplatin on HCT116 xenograft tumor growth in vivo. Thus, our study showed that Nrf2 inhibition improved sensitivity to oxaliplatin of CRC cells by promoting ferroptosis and pyroptosis, which provided a new target for overcoming chemoresistance in CRC.

Transcriptomic Profiling of Meat Quality Traits of Skeletal Muscles of the Chinese Indigenous Huai Pig and Duroc Pig.

The Huai pig is a well-known indigenous pig breed in China. The main advantages of Huai pigs over Western commercial pig breeds include a high intramuscular fat (IMF) content and good meat quality. There are significant differences in the meat quality traits of the same muscle part or different muscle parts of the same variety. To investigate the potential genetic mechanism underlying the meat quality differences in different pig breeds or muscle groups, longissimus dorsi (LD), psoas major (PM), and biceps femoris (BF) muscle tissues were collected from two pig breeds (Huai and Duroc). There were significant differences in meat quality traits and amino acid content. We assessed the muscle transcriptomic profiles using high-throughput RNA sequencing. The IMF content in the LD, PM, and BF muscles of Huai pigs was significantly higher than that in Duroc pigs (p < 0.05). Similarly, the content of flavor amino acids in the three muscle groups was significantly higher in Huai pigs than that in Duroc pigs (p < 0.05). We identified 175, 110, and 86 differentially expressed genes (DEGs) between the LD, PM, and BF muscles of the Huai and Duroc pigs, respectively. The DEGs of the different pig breeds and muscle regions were significantly enriched in the biological processes and signaling pathways related to muscle fiber type, IMF deposition, lipid metabolism, PPAR signaling, cAMP signaling, amino acid metabolism, and ECM-receptor interaction. Our findings might help improve pork yield by using the obtained DEGs for marker-assisted selection and providing a theoretical reference for evaluating and improving pork quality.