A potential slow-release fertilizer based on biogas residue biochar: Nutrient release patterns and synergistic mechanism for improving soil fertility.

The large yield of anaerobic digestates and the suboptimal efficacy of nutrient slow-release severely limit its practical application. To address these issues, a new biochar based fertilizer (MAP@BRC) was developed using biogas residue biochar (BRC) to recover nitrogen and phosphorus from biogas slurry. The nutrient release patterns of MAP@BRC and mechanisms for enhancing soil fertility were studied, and it demonstrated excellent performance, with 59% total nitrogen and 50% total phosphorus nutrient release rates within 28 days. This was attributed to the coupling of the mechanism involving the dissolution of struvite skeletons and the release of biochar pores. Pot experiments showed that crop yield and water productivity were doubled in the MAP@BRC group compared with unfertilized planting. The application of MAP@BRC also improved soil nutrient levels, reduced soil acidification, increased microbial populations, and decreased soil heavy metal pollution risk. The key factors that contributed to the improvement in soil fertility by MAP@BRC were an increase in available nitrogen and the optimization of pH levels in the soil. Overall, MAP@BRC is a safe, slow-release fertilizer that exhibits biochar-fertilizer interactions and synergistic effects. This slow-release fertilizer was prepared by treating a phosphorus-rich biogas slurry with a nitrogen-rich biogas slurry, and it simultaneously addresses problems associated with livestock waste treatment and provides a promising strategy to promote zero-waste agriculture.

The role of immune reconstitution in relapse after allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Leukemia relapse following stem cell transplantation remains a significant barrier to long-term remission. Timely and balanced immune recovery after transplantation is crucial for preventing leukemia relapse. AREAS COVERED: After an extensive literature search of PubMed and Web of Science through October 2023, we provide an overview of the dynamics of immune reconstitution and its role in controlling leukemia relapse. We also discuss strategies to promote immune reconstitution and reduce disease recurrence following allogeneic hematopoietic stem cell transplantation. EXPERT OPINION: Immune reconstitution after transplantation has substantial potential to prevent relapse and might predict disease recurrence and prognosis. High dimensional cytometry, multi-omics, and T cell repertoire analysis allow for a more comprehensive and detailed understanding of the immune system's dynamics post-transplantation, and contribute to the identification of rare immune cell subsets or potential biomarkers associated with successful immune reconstitution or increased risk of complications. Strategies to enhance the immune system, such as adoptive immunotherapy and cytokine-based therapy, have great potential for reducing leukemia relapse after transplantation. Future research directions should focus on refining patient selection for these therapies, implementing appropriate and timely treatment, investigating combination approaches to maximize therapeutic outcomes, and achieving a robust graft-versus-leukemia (GVL) effect while minimizing graft-versus-host disease (GVHD) for optimal results.

Attenuation of neuronal ferroptosis in intracerebral hemorrhage by inhibiting HDAC1/2: Microglial heterogenization via the Nrf2/HO1 pathway.

AIM: The class I histone deacetylases (HDACs) implicate in microglial heterogenization and neuroinflammation following Intracerebral hemorrhage (ICH). Ferroptosis has also been reported in the ICH model. However, the relationship between HDAC1/2's role in microglial heterogenization and neuronal ferroptosis remains unclear. METHODS: In both in vivo and in vitro models of ICH, we used Romidepsin (FK228), a selective HDAC1/2 inhibitor, to investigate its effects on microglial heterogenization and neuronal ferroptosis. In the in vitro ICH model using Hemin, a transwell system was utilized to examine how microglia-driven inflammation and ICH-triggered neuronal ferroptosis interact. Immunostaining, Western blotting and RT-qPCR were used to evaluate the microglial heterogenization and neuronal ferroptosis. Microglial heterogenization, neuronal ferroptosis, and neurological dysfunctions were assessed in vivo ICH mice model performed by autologous blood injection. RESULTS: HDAC1/2 inhibition altered microglial heterogenization after ICH, as showing the reducing neuroinflammation and shifting microglia towards an anti-inflammatory phenotype by immunostaining and qPCR results. HDAC1/2 inhibition reduced ferroptosis, characterized by high ROS and low GPx4 expression in HT22 cells, and reduced iron and lipid deposition post-ICH in vivo. Additionally, the Nrf2/HO1 signaling pathway, especially acetyl-Nrf2, activated in the in vivo ICH model due to HDAC1/2 inhibition, plays a role in regulating microglial heterogenization. Furthermore, HDAC1/2 inhibition improved sensorimotor and histological outcomes post-ICH, offering a potential mechanism against ICH. CONCLUSION: Inhibition of HDAC1/2 reduces neuro-ferroptosis by modifying the heterogeneity of microglia via the Nrf2/HO1 pathway, with a particular focus on acetyl-Nrf2. Additionally, this inhibition aids in the faster removal of hematomas and lessens prolonged neurological impairments, indicating novel approach for treating ICH.

Impact of Oat (Avena sativa L.) on Metabolic Syndrome and Potential Physiological Mechanisms of Action: A Current Review.

Oat (Avena sativa L.), an annual herbaceous plant belonging to the Gramineae family, is widely grown in various regions including EU, Canada, America, Australia, etc. Due to the nutritional and pharmacological values, oats have been developed into various functional food including fermented beverage, noodle, cookie, etc. Meanwhile, numerous studies have demonstrated that oats may effectively improve metabolic syndrome, such as dyslipidemia, hyperglycemia, atherosclerosis, hypertension, and obesity. However, the systematic pharmacological mechanisms of oats on metabolic syndrome have not been fully revealed. Therefore, in order to fully explore the benefits of oat in food industry and clinic, this review aims to provide up-to-date information on oat and its constituents, focusing on the effects on metabolic syndrome.

Recent advances in the study of sepsis-induced depression.

Progress in medicine such as the use of anti-infective drugs and development of the advanced life support equipment has greatly improved the survival rate of patients with sepsis. However, the incidence of sepsis-related diseases is increasing. These include severe neurologic and psychologic disorders, cognitive decline, anxiety, depression, and post-traumatic stress disorder. Cerebral dysfunction occurs via multiple interacting mechanisms, with different causative pathogens having distinct effects. Because sepsis-related diseases place a substantial burden on patients and their families, it is important to elucidate the underlying pathophysiologic mechanisms to develop effective treatments.

Oxytocin alleviates cognitive and memory impairments by decreasing hippocampal microglial activation and synaptic defects via OXTR/ERK/STAT3 pathway in a mouse model of sepsis-associated encephalopathy.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction, characterized by cognitive and memory impairments closely linked to hippocampal dysfunction. Though it is well-known that SAE is a diffuse brain dysfunction with microglial activation, the pathological mechanisms of SAE are not well established and effective clinical interventions are lacking. Oxytocin (OXT) is reported to have anti-inflammatory and neuroprotective roles. However, the effects of OXT on SAE and the underlying mechanisms are not clear. METHODS: SAE was induced in adult C57BL/6J male mice by cecal ligation and perforation (CLP) surgery. Exogenous OXT was intranasally applied after surgery. Clinical score, survivor rate, cognitive and memory behaviors, and hippocampal neuronal and non-neuronal functions were evaluated. Cultured microglia challenged with lipopolysaccharide (LPS) were used to investigate the effects of OXT on microglial functions, including inflammatory cytokines release and phagocytosis. The possible intracellular signal pathways involved in the OXT-induced neuroprotection were explored with RNA sequencing. RESULTS: Hippocampal OXT level decreases, while the expression of OXT receptor (OXTR) increases around 24 h after CLP surgery. Intranasal OXT application at a proper dose increases mouse survival rate, alleviates cognitive and memory dysfunction, and restores hippocampal synaptic function and neuronal activity via OXTR in the SAE model. Intraperitoneal or local administration of the OXTR antagonist L-368,899 in hippocampal CA1 region inhibited the protective effects of OXT. Moreover, during the early stages of sepsis, hippocampal microglia are activated, while OXT application reduces microglial phagocytosis and the release of inflammatory cytokines, thereby exerting a neuroprotective effect. OXT may improve the SAE outcomes via the OXTR-ERK-STAT3 signaling pathway. CONCLUSION: Our study uncovers the dysfunction of the OXT signal in SAE and shows that intranasal OXT application at a proper dose can alleviate SAE outcomes by reducing microglial overactivation, suggests that OXT may be a promising therapeutic approach in managing SAE patients.

Advances in the knowledge on the role of apoptosis repressor with caspase recruitment domain in hemorrhagic stroke.

The apoptosis repressor with caspase recruitment domain (ARC) plays a critical role in extrinsic apoptosis initiation via death receptor ligands, physiological stress, infection response in a tissue-dependent manner, endoplasmic reticulum (ER) stress, genotoxic drugs, ionizing radiation, oxidative stress, and hypoxia. Recent studies have suggested that regulating apoptosis-related pathways can improve outcomes for patients with neurological diseases, such as hemorrhagic stroke. ARC expression is significantly correlated with acute cerebral hemorrhage. However, the mechanism by which it mediates the anti-apoptosis pathway remains poorly known. Here, we discuss the function of ARC in hemorrhagic stroke and argue that it could serve as an effective target for the treatment of hemorrhagic stroke.

Sustained-release nitrate combined with microbial fuel cell: A novel strategy for PAHs and odor removal from sediment.

Nitrate addition is a biostimulation technique that can improve both the oxidation of acid volatile sulfide (AVS) through autotrophic denitrification and the biodegradation of polycyclic aromatic hydrocarbons (PAHs) via heterotrophic denitrification. However, during the remediation, parts of the dissolved nitrate in the sediment migrates from the sediment to the overlying water, leading to the loss of effective electron acceptor. To overcome this limitation, a combined approached was proposed, which involved nitrocellulose addition and a microbial fuel cell (MFC). Results indicated the nitrate could be slowly released and maintained at a higher concentration over long term. In the combined system, the removal efficiencies of PAHs and AVS were 71.56% and 89.76%, respectively. Furthermore, the voltage attained for the MFC-nitrocellulose treatment was maintained at 146.1 mV on Day 70, which was 5.37 times higher than that of the MFC-calcium nitrate treatment. Sediments with nitrocellulose resulted in lower levels of nitrate and ammonium in the overlying water. Metagenomic results revealed that the combined technology improved the expression of nitrogen-cycling genes. The introduction of MFC inhibited sulfide regeneration during incubation by suppressing the enzyme activity like EC4.4.1.2. The enhanced biostimulation provided potential for in-situ bioremediation utilizing MFC coupled with slow-released nitrate (i.e., nitrocellulose) treatment.

Detoxification mechanisms of ginseng to aconite: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Aconite (Fuzi, FZ), the processed root tuber of Aconitum carmichaelii Debx., is utilized as a classic medicine to treat diseases of the cardiovascular system and immune system. Resulting from the narrow margin of safety between a therapeutic dose and a toxic dose, FZ often causes cardiotoxicity including hypotension, palpitation, and bradycardia. Contributing to the detoxification effects of the other famous herbal medicine ginseng (Renshen, RS), which is the dried root and rhizome of Panax ginseng C. A. Meyer, people broadly combine FZ and RS as compatibility more than 1800 years to attenuate the toxicity of FZ. However, the systematic detoxification mechanisms of RS to FZ have not been fully revealed. AIM OF THE REVIEW: Aiming to provide a comprehensive interpretation of the attenuation processes of FZ via RS, this review summarizes the up-to-date information about regulatory mechanisms of RS to FZ to shed the light on the essence of detoxification. MATERIALS AND METHODS: Literature was searched in electronic databases, including PubMed, Web of Science ScienceDirect, Google Scholar, CNKI and WanFang Data. Relevant studies on detoxification mechanisms were included while irrelevant and duplicate studies were excluded. According to the study design, subject, intervention regime, outcome, first author and year of publication of included data, detoxification mechanisms of RS to FZ were summarized and visualized. RESULTS: A total of 144 studies were identified through databases from their inception up to Oct. 2022. Included information indicated that diester-diterpenoid alkaloids (DDAs) were the main toxic substances of FZ. The main mechanisms that RS attenuates the toxicity of FZ were transforming toxic compounds of FZ, affecting the absorption and metabolism of FZ as well as the FZ-induced cell toxicity alleviation. CONCLUSION: FZ, as a famous traditional Chinese medicine, has good prospects for utilization. The narrow margin of safety between a therapeutic dose and a toxic dose of FZ limits its clinical effect and safety while RS is always combined with FZ to alleviate its toxicity. However, mechanisms responsible for the detoxification process have not been well identified. Therefore, detoxification mechanisms of RS to FZ are reviewed to ensure the safety and effectiveness of FZ.

The Key Drivers of Brain Injury by Systemic Inflammatory Responses after Sepsis: Microglia and Neuroinflammation.

Sepsis is a leading cause of intensive care unit admission and death worldwide. Most surviving patients show acute or chronic mental disorders, which are known as sepsis-associated encephalopathy (SAE). Although accumulating studies in the past two decades focused on the pathogenesis of SAE, a systematic review of retrospective studies which exclusively focuses on the inflammatory mechanisms of SAE has been lacking yet. This review summarizes the recent advance in the field of neuroinflammation and sheds light on the activation of microglia in SAE. Activation of microglia predominates neuroinflammation. As the gene expression profile changes, microglia show heterogeneous characterizations throughout all stages of SAE. Here, we summarize the systemic inflammation following sepsis and also the relationship of microglial diversity and neuroinflammation. Moreover, a collection of neuroinflammation-related dysfunction has also been reviewed to illustrate the possible mechanisms for SAE. In addition, promising pharmacological or non-pharmacological therapeutic strategies, especially those which target neuroinflammation or microglia, are also concluded in the final part of this review. Collectively, clarification of the vital relationship between neuroinflammation and SAE-related mental disorders would significantly improve our understanding of the pathophysiological mechanisms in SAE and therefore provide potential targets for therapies of SAE aimed at inhibiting neuroinflammation.

Analysis of the effects of low/intermediate dose of coagulation factor Ⅷ on 30 adult patients with severe hemophilia A in a single center / 中华血液学杂志

Objective: To evaluate the clinical effects of low- and intermediate-dose factor Ⅷ (F Ⅷ) prophylaxis in Chinese adult patients with severe hemophilia A. Methods: Thirty adult patients with severe hemophilia A who received low- (n=20) /intermediate-dose (n=10) F Ⅷ prophylaxis at Nanjing Drum Tower Hospital affiliated with Nanjing University Medical College were included in the study. The annual bleeding rate (ABR), annual joint bleeding rate (AJBR), number of target joints, functional independence score of hemophilia (FISH), quality of life score, and health status score (SF-36) before and after preventive treatment were retrospectively analyzed and compared. Results: The median follow-up was 48 months. Compared with on-demand treatment, low- and intermediate-dose prophylaxis significantly reduced ABR, AJBR, and the number of target joints (P<0.05) ; the improvement in the intermediate-dose prophylaxis group was better than that in the low-dose prophylaxis group (P<0.05). Compared with on-demand treatment, the FISH score, quality of life score, and SF-36 score significantly improved in both groups (P<0.05), but there was no significant difference between the two groups (P>0.05) . Conclusion: In Chinese adults with severe hemophilia A, low- and intermediate-dose prophylaxis can significantly reduce bleeding frequency, delay the progression of joint lesions, and improve the quality of life of patients as compared with on-demand treatment. The improvement in clinical bleeding was better with intermediate-dose prophylaxis than low-dose prophylaxis.

Haematopoietic stem-cell transplantation in China in the era of targeted therapies: current advances, challenges, and future directions.

In the era of targeted therapies, haematopoietic stem-cell transplantation (HSCT), both allogeneic and autologous, remains a curative approach for patients with chemosensitive and immunesensitive malignant and non-malignant haematological disease in China. Since 2000, we have seen a substantial increase in the number of HSCTs, especially haploidentical HSCT, in patients with acute leukaemia and severe aplastic anaemia. Haploidentical donors have been the most common allograft donors in China since 2013. Key components of allogeneic HSCT include best donor selection for acute leukaemia, incorporation of target therapy, especially chimeric antigen receptor T cells, allografts for acute leukaemia outcome improvement, total therapy for relapsed or refractory acute leukaemia and haploidentical allografts as upfront therapy for severe aplastic anaemia. Despite many challenges in the HSCT setting in China, such as how to redefine the roadmap for HSCT, improve the health-related quality of life of long-term surviving transplant recipients, and promote national and international collaboration, allogeneic HSCT and autologous HSCT will continue to have an important role in treating diverse diseases between now and 2050. The development of HSCT in China will contribute to the worldwide development of HSCT.

Transcriptomic and metabolomic analyses reveal how girdling promotes leaf color expression in Acer rubrum L.

BACKGROUND: Acer rubrum L. (red maple) is a popular tree with attractive colored leaves, strong physiological adaptability, and a high ornamental value. Changes in leaf color can be an adaptive response to changes in environmental factors, and also a stress response to external disturbances. In this study, we evaluated the effect of girdling on the color expression of A. rubrum leaves. We studied the phenotypic characteristics, physiological and biochemical characteristics, and the transcriptomic and metabolomic profiles of leaves on girdled and non-girdled branches of A. rubrum. RESULTS: Phenotypic studies showed that girdling resulted in earlier formation of red leaves, and a more intense red color in the leaves. Compared with the control branches, the girdled branches produced leaves with significantly different color parameters a*. Physiological and biochemical studies showed that girdling of branches resulted in uneven accumulation of chlorophyll, carotenoids, anthocyanins, and other pigments in leaves above the band. In the transcriptomic and metabolomic analyses, 28,432 unigenes including 1095 up-regulated genes and 708 down-regulated genes were identified, and the differentially expressed genes were mapped to various KEGG (kyoto encyclopedia of genes and genomes) pathways. Six genes encoding key transcription factors related to anthocyanin metabolism were among differentially expressed genes between leaves on girdled and non-girdled branches. CONCLUSIONS: Girdling significantly affected the growth and photosynthesis of red maple, and affected the metabolic pathways, biosynthesis of secondary metabolites, and carbon metabolisms in the leaves. This resulted in pigment accumulation in the leaves above the girdling site, leading to marked red color expression in those leaves. A transcriptome analysis revealed six genes encoding anthocyanin-related transcription factors that were up-regulated in the leaves above the girdling site. These transcription factors are known to be involved in the regulation of phenylpropanoid biosynthesis, anthocyanin biosynthesis, and flavonoid biosynthesis. These results suggest that leaf reddening is a complex environmental adaptation strategy to maintain normal metabolism in response to environmental changes. Overall, the results of these comprehensive phenotype, physiological, biochemical, transcriptomic, and metabolomic analyses provide a deeper and more reliable understanding of the coevolution of red maple leaves in response to environmental changes.

Diastereoselective Synthesis of Chromeno[3,2-d]isoxazoles via Brønsted Acid Catalyzed Tandem 1,6-Addition/Double Annulations of o-Hydroxyl Propargylic Alcohols.

A Brønsted acid catalyzed tandem process to access densely functionalized chromeno[3,2-d]isoxazoles with good to excellent yields and diastereoselectivities was disclosed. The procedure is proposed to involve a 1,6-conjugate addition/electrophilic addition/double annulations process of alkynyl o-quinone methides (o-AQMs) in situ generated from o-hydroxyl propargylic alcohols with nitrones. Mild conditions, good functional group compatibility, easy scale-up of the reaction, and further product transformation demonstrated its potential application.

Immune Reconstitution of Patients Who Recovered From Steroid-Refractory Acute Graft-Versus-Host Disease After Basiliximab Treatment.

We aimed to identify the characteristics of immune reconstitution (IR) in patients who recovered from steroid-refractory acute graft-versus-host disease (SR-aGVHD) after basiliximab treatment. A total of 179, 124, 80, and 92 patients were included in the analysis for IR at 3, 6, 9, and 12 months, respectively, after haploidentical donor hematopoietic stem cell transplantation (HID HSCT). We observed that IR was fastest for monocytes and CD8+ T cells, followed by lymphocytes, CD3+ T cells, and CD19+ B cells and slowest for CD4+ T cells. Almost all immune cell subsets recovered comparably between patients receiving <5 doses and ≥5 doses of basiliximab. Most immune cell subsets recovered comparably between SR-aGVHD patients who recovered after basiliximab treatment and event-free HID HSCT recipients. Patients who recovered from SR-aGVHD after basiliximab treatment experienced satisfactory IR, which suggested that basiliximab may not have prolonged the negative impact on IR in these patients.

Reliability and validity of the Chinese version of the kiddie-schedule for affective disorders and schizophrenia-present and lifetime version DSM-5 (K-SADS-PL-C DSM-5).

BACKGROUND: As the Diagnostic and Statistical Manual of Mental Disorders fifth version (DSM-5) was published, the Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime version (K-SADS-PL) was modified to adapt the new version (K-SADS-PL DSM-5). We translated it to Chinese (K-SADS-PL-C DSM-5) and described its reliability and validity. METHODS: A total of 154 groups of 6 to 18-year-old children and their guardians were included. Trained interviewers interviewed subjects using the K-SADS-PL-C DSM-5. Interrater reliability was assessed by audio recording. Parent-reported scales, like child behavior checklist (CBCL), the Chinese version of Swan-son Nolan and Pelham, version IV scale-parent form (SNAP-IV), social responsiveness scale (SRS-1), and children-reported scales like depression self-rating scale for children (DSRSC) and the screen for child anxiety related emotional disorders (SCARED) were used to examine the validity of depressive disorder, ADHD, ASD, and ODD. RESULTS: The K-SADS-PL-C DSM-5 had fair to excellent interrater (0.537-1.000) and test-retest (0.468-0.885) reliability of affective disorder and neurodevelopment disorder. The convergent validity of affective disorder and neurodevelopment disorder was good, and their divergent validity was acceptable. LIMITATIONS: i) Clinical questionnaires were insensitive in classifying disorders and had limitations in derived diagnoses. ii) Samples only came from clinical environment, iii) covered limited disease species, and iv) were small. CONCLUSION: The K-SADS-PL-C DSM-5 can support reliable and valid diagnoses for children with affect, neurodevelopmental, and behavioral disorders in China.

Downregulation of CDC42 inhibits the proliferation and stemness of human trophoblast stem cell via EZRIN/YAP inactivation.

Placental dysplasia increases the risk of recurrent spontaneous abortion (RSA). However, the underlying mechanism regulating placental development remains unclear. In this study, we showed that the expression of CDC42 was decreased in the villous tissue of RSA samples compared to healthy controls. Further examination demonstrated that CDC42 deficiency led to the differentiation of human trophoblast stem cells (hTSCs) and inhibited their proliferation. Genetic manipulation of YAP and EZRIN in hTSCs revealed that CDC42 regulates the stemness and proliferation of hTSCs; this is dependent on EZRIN, which translocates YAP into the nucleus. Moreover, the expression pattern of EZRIN, YAP, and Ki67 was also abnormal in the villous tissue of RSA samples, consistent with in vitro experiments. In summary, these findings suggest that the CDC42/EZRIN/YAP pathway plays an important role in placental development.

The circular RNA circHMGB2 drives immunosuppression and anti-PD-1 resistance in lung adenocarcinomas and squamous cell carcinomas via the miR-181a-5p/CARM1 axis.

BACKGROUND: Previous studies have confirmed the oncogenic role of HMGB2 in various cancers, but the biological functions of HMGB2-derived circRNAs remain unknown. Thus, we intended to investigate the potential role of HMGB2-derived circRNAs in lung adenocarcinomas (LUAD) and squamous cell carcinomas (LUSC). METHODS: The expression profiles of HMGB2-derived circRNAs in LUAD and LUSC tissues and matched normal tissues were assessed using qRT-PCR. The role of circHMGB2 in the progression of the LUAD and LUSC was determined in vitro by Transwell, CCK-8, flow cytometry and immunohistochemistry assays, as well as in vivo in an immunocompetent mouse model and a humanized mouse model. In addition, in vivo circRNA precipitation assays, luciferase reporter assays and RNA pulldown assays were performed to explore the underlying mechanism by which circHMGB2 promotes anti-PD-1 resistance in the LUAD and LUSC. RESULTS: The expression of circHMGB2 (hsa_circ_0071452) was significantly upregulated in NSCLC tissues, and survival analysis identified circHMGB2 as an independent indicator of poor prognosis in the LUAD and LUSC patients. We found that circHMGB2 exerted a mild effect on the proliferation of the LUAD and LUSC cells, but circHMGB2 substantially reshaped the tumor microenvironment by contributing to the exhaustion of antitumor immunity in an immunocompetent mouse model and a humanized mouse model. Mechanistically, circHMGB2 relieves the inhibition of downstream CARM1 by sponging miR-181a-5p, thus inactivating the type 1 interferon response in the LUAD and LUSC. Moreover, we found that the upregulation of circHMGB2 expression decreased the efficacy of anti-PD-1 therapy, and we revealed that the combination of the CARM1 inhibitor EZM2302 and an anti-PD-1 antibody exerted promising synergistic effects in a preclinical model. CONCLUSION: circHMGB2 overexpression promotes the LUAD and LUSC progression mainly by reshaping the tumor microenvironment and regulating anti-PD-1 resistance in the LUAD and LUSC patients. This study provides a new strategy for the LUAD and LUSC treatment.

Irisin ameliorates neuroinflammation and neuronal apoptosis through integrin αVß5/AMPK signaling pathway after intracerebral hemorrhage in mice.

BACKGROUND: Neuroinflammation is a crucial factor in the development of secondary brain injury after intracerebral hemorrhage (ICH). Irisin is a newly identified myokine that confers strong neuroprotective effects in experimental ischemic stroke. However, whether this myokine can exert neuroprotection effects after ICH remains unknown. This study aimed to investigate the impact of irisin treatment on neuroinflammation and neuronal apoptosis and the underlying mechanism involving integrin αVß5/AMPK pathway after ICH. METHODS: Two hundred and eighty-five adult (8-week-old) male C57BL/6 mice were randomly assigned to sham and ICH surgery groups. ICH was induced via intrastriatal injection of autologous blood. Irisin was administered intranasally at 30 min after ICH. To elucidate the underlying mechanism, cilengitide (a selective integrin αVß5 inhibitor) and dorsomorphin (a selective phosphorylated AMPK inhibitor) were administered before irisin treatment. The short- and long-term neurobehavior tests, brain edema, quantitative-PCR, western blotting, Fluoro-Jade C, TUNEL, and immunofluorescence staining were performed to assess the neurofunctional outcome at the level of molecular, cell, histology, and function. RESULTS: Endogenous irisin and its receptor, integrin αVß5, were increased, peaked at 24 h after ICH. irisin post-treatment improved both short- and long-term neurological functions, reduced brain edema after ICH. Interestingly, integrin αVß5 was mainly located in the microglia after ICH, and irisin post-treatment inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization. Moreover, irisin treatment inhibited neutrophil infiltration and suppressed neuronal apoptotic cell death in perihematomal areas after ICH. Mechanistically, irisin post-treatment significantly increased the expression of integrin αVß5, p-AMPK and Bcl-2, and decreased the expression of IL-1ß, TNF-α, MPO, and Bax following ICH. The neuroprotective effects of irisin were abolished by both integrin αVß5 inhibitor cilengitide and AMPK inhibitor dorsomorphin. CONCLUSIONS: This study demonstrated that irisin post-treatment ameliorated neurological deficits, reduced brain edema, and ameliorated neuroinflammation and neuronal apoptosis, at least in part, through the integrin αVß5/AMPK signaling pathway after ICH. Thus, irisin post-treatment may provide a promising therapeutic approach for the early management of ICH.