Identifying acute mesenteric ischemia via mesenteric fractional flow reserve in patients with spontaneous isolated superior mesenteric artery dissection: case report.

There is no definitive approach for assessing mesenteric ischemia and determining the optimal timing for endovascular intervention in the management of spontaneous isolated dissection of the superior mesenteric artery (SISMAD). A 56-year-old male with acute abdominal pain was diagnosed with SISMAD. After evaluating mesenteric ischemia through mesenteric fractional flow reserve (FFR), FFR was 0.72, and the patient was recommended conservative treatment for SISMAD, which involves fasting, total parenteral nutrition, and anticoagulation. The patient's syndrome was relieved after conservative treatment for 14 days without stent implantation. Over the next 5 years, no recurrence of abdominal pain or worsening of SISMAD was observed in the patient. Assessing the severity of mesenteric ischemia can be done through mesenteric FFR. Upon confirmation of the exclusion of risks related to dilatation or rupture of SISMAD aneurysm, an approach in favor of conservative management for SISMAD may indeed be considered pragmatic when the FFR exceeds 0.72.

Skeletal muscle: molecular structure, myogenesis, biological functions, and diseases.

Skeletal muscle is an important motor organ with multinucleated myofibers as its smallest cellular units. Myofibers are formed after undergoing cell differentiation, cell-cell fusion, myonuclei migration, and myofibril crosslinking among other processes and undergo morphological and functional changes or lesions after being stimulated by internal or external factors. The above processes are collectively referred to as myogenesis. After myofibers mature, the function and behavior of skeletal muscle are closely related to the voluntary movement of the body. In this review, we systematically and comprehensively discuss the physiological and pathological processes associated with skeletal muscles from five perspectives: molecule basis, myogenesis, biological function, adaptive changes, and myopathy. In the molecular structure and myogenesis sections, we gave a brief overview, focusing on skeletal muscle-specific fusogens and nuclei-related behaviors including cell-cell fusion and myonuclei localization. Subsequently, we discussed the three biological functions of skeletal muscle (muscle contraction, thermogenesis, and myokines secretion) and its response to stimulation (atrophy, hypertrophy, and regeneration), and finally settled on myopathy. In general, the integration of these contents provides a holistic perspective, which helps to further elucidate the structure, characteristics, and functions of skeletal muscle.

Design and modeling of order of addition experiment with component effects.

An order of addition experiment is an experiment to study how the order of addition of components affect the results, with the objective of predicting and determining the optimal order of addition of components. Order of addition experiment are also commonly used in the drug combination therapy, where experimenting with all drugs combinations is unaffordable. To solve this problem, we constructed a new design table, two-level component factorial design table (TLCF), which combine the component orthogonal array design table and the two-level partial factorial design table by matrix product. TLCF can explore the order and dosage effect of components on the results and can greatly reduce the number of experiments. We also prove that the relative D-efficiency of the TLCF can reach 100% and solve an explicit expression for the D-efficiency of the full design. In the simulation experiment, we compare the D-efficiency of the TLCF with the random design table to prove the superiority of TLCF. Finally, we give a treatment plan for the combination of three drugs for glioblastoma based on the TLCF, which provides a new perspective for the precision treatment of patients.

Corrigendum: Cinnamaldehyde suppressed EGF-induced EMT process and inhibits ovarian cancer progression through PI3K/AKT pathway.

[This corrects the article DOI: 10.3389/fphar.2022.779608.].

[Anti-inflammatory effect and its mechanism of Saracae Cortex based on zebrafish model and network pharmacology].

This paper aims to explore the anti-inflammatory mechanism of Saracae Cortex by using network pharmacology and molecular docking methods and verify it through the inflammation model of zebrafish. The effective components, potential core targets, and signaling pathways of Saracae Cortex were obtained by using network pharmacology. A lipopolysaccharide(LPS)-induced inflammation model of zebrafish was established to evaluate the anti-inflammatory activity of aqueous extract and 70% ethanol extract of Saracae Cortex with cell apoptosis rate and reactive oxygen species(ROS) production rate as indicators. q PCR was performed to verify the main targets predicted by network pharmacology. The prediction found that there were 121 potential anti-inflammatory targets in Saracae Cortex. Protein-protein interaction(PPI) analysis showed that Saracae Cortex mainly acted on signal transducer and activator of transcription 3(STAT3), vascular endothelial growth factor A( VEGFA), epidermal growth factor( EGF), tumor necrosis factor( TNF),tumor protein p53(TP53), matrix metalloprotein 9(MMP9), c-fos proto-oncogene protein(FOS), estrogen receptor 1(ESR1), cx-c motif chemokine ligand 8(CXCL8), cluster of differentiation 8(CD8), and other targets. Gene Ontology(GO) analysis showed the biological process mainly acted on the inhibition of apoptosis, the positive regulation of gene expression, and the positive regulation of cell proliferation. Kyoto Encyclopedia of Genes and Genomes(KEGG) analysis showed that the mitogen-activated protein kinase(MAPK) signaling pathway, PI3K-Akt signaling pathway, and hypoxia-inducible factor 1(HIF-1) signaling pathway may play a key role in anti-inflammation of Saracae Cortex. Molecular docking verified that five key compounds had a strong binding force with their corresponding core target. Zebrafish animal experiments showed that Saracae Cortex could significantly inhibit ROS formation and reduce cell apoptosis in juvenile fish caused by inflammation and inhibit the further enhancement of inflammatory response in tissue. In addition, compared with the blank group, the transcription levels of nuclear factor kappa-B(NF-κB), TP53, FOS, adaptor protein complex-1(AP-1), and mitogen-activated protein kinases P38(P38) were significantly up-regulated in the model group. Compared with the model group, the m RNA expression of NF-κB, TP53, FOS, AP-1, and P38 was significantly down-regulated in zebrafish tissue treated with aqueous extract and 70% ethanol extract of Saracae Cortex. Saracae Cortex plays an anti-inflammatory role through multiple components and targets, and its anti-inflammatory effect may be related to the inhibition of the MAPK signaling pathway.

Pre-Existing and New-Onset Metabolic Dysfunctions Increase Cirrhosis and Its Complication Risks in Chronic Hepatitis B.

INTRODUCTION: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing among the chronic hepatitis B (CHB) population. This study aimed to explore the impact of metabolic dysfunction (MD) on cirrhosis and cirrhotic complication risks in CHB. METHODS: Patients with CHB were consecutively recruited between 2006 and 2021. The presence of MD was based on the 5 cardiometabolic criteria specified in the MASLD definition. Patients were categorized into MD/non-MD groups based on these criteria. RESULTS: Eleven thousand five hundred two treatment-naive noncirrhotic patients with CHB were included with a median follow-up of 5.3 years. Patients in the MD group (n = 7,314) were older and had lower hepatitis B virus DNA levels than non-MD patients (n = 4,188). After adjustment for clinical and viral factors, MD patients had significantly higher risks of cirrhosis (adjusted hazard ratio [aHR]: 1.82, 95% confidence interval [CI]: 1.40-2.37, P < 0.001) and cirrhotic complications (aHR: 1.30 per MD, 95% CI: 1.03-1.63, P = 0.025) in a dose-dependent manner. Furthermore, new-onset diabetes mellitus during the follow-up aggravated the risk of cirrhotic complications (aHR: 2.87, 95% CI: 1.34-6.11, P = 0.006). Hepatic steatosis was associated with lower risks of cirrhosis (aHR: 0.57 within 5 years, 95% CI: 0.44-0.74, P < 0.001) and cirrhotic complications (aHR: 0.45, 95% CI 0.23-0.88, P = 0.020). Among individuals with hepatic steatosis, patients with MASLD exhibited a higher cirrhosis risk than non-MD patients. DISCUSSION: Concurrent and new-onset MDs increase the risks of cirrhosis and cirrhotic complications in patients with CHB, independent of hepatic steatosis. Proactively investigating metabolic comorbidities in CHB is critical to stratify the risk of liver disease progression.

Risk of rituximab-induced hepatitis B flare after antiviral discontinuation in rheumatic patients with chronic hepatitis B virus.

OBJECTVES: Among immunosuppressants, rituximab is most strongly associated with the risk of hepatitis B virus (HBV) reactivation in chronic HBV individuals. Current guidelines recommending antiviral prophylaxis for these patients on rituximab are predominantly based on studies in oncology. However, limited data existed for the precise risk of HBV flares, effectiveness and optimal duration of antiviral prophylaxis in rituximab-treated rheumatic patients, whose immune status and treatment regimen differ significantly from those of oncology patients. Therefore, we aimed to assess the incidence and clinical outcome of HBV reactivation in HBsAg-positive patients receiving rituximab for various autoimmune diseases who discontinue the antiviral agents. METHODS: A retrospective analysis was performed on 95 hepatitis B surface antigen (HBsAg)-positive patients treated with rituximab for autoimmune diseases in a single centre in Taiwan. HBV related hepatitis, defined as alanine aminotransferase (ALT) more than 3 times of baseline level and concurrent HBV reactivation, after anti-viral discontinuation, was the primary endpoint. Factors associated with HBV hepatitis flare and off-antiviral hepatitis flare were also analysed. RESULTS: With nucleos(t)ide analogues (NA) prophylaxis, no hepatitis flares occurred. However, without prophylaxis, 59% had flare (24.5 per 100 person-years) and 8% experienced liver decompensation. Concurrent steroid use was a dose-dependent risk factor for flare. After NA discontinuation, rituximab "retreatment" led to flares in 75% of cases and liver decompensation in 63% of patients. Stopping NAs within one-year post-rituximab, even without further rituximab treatment, resulted in a 38% flare rate. CONCLUSIONS: This study offers the direct evidence for the necessity of universal antiviral prophylaxis in rheumatic patients with chronic HBV receiving rituximab. After NA discontinuation, rituximab "retreatment" led to even higher flare rate and worse outcome. Patients who completed rituximab treatment should also keep antiviral agents for at least one more year to prevent hepatitis flare.

Metabolic profiles of children aged 2-5 years born after frozen and fresh embryo transfer: A Chinese cohort study.

BACKGROUND: Frozen embryo transfer (FET) has become a widely employed assisted reproductive technology technique. There have historically been concerns regarding the long-term metabolic safety of FET technology in offspring due to pregnancy-induced hypertension and large for gestational age, both of which are well-recognized factors for metabolic dysfunction of children. Therefore, we aimed to compare the metabolic profiles of children born after frozen versus fresh embryo transfer at 2 to 5 years of age. METHODS AND FINDINGS: This was a prospective cohort study. Using data from the "Assisted Reproductive Technology borned KIDs (ARTKID)," a birth cohort of offspring born from assisted reproductive technology at the Institute of Women, Children and Reproductive Health, Shandong University, China. We included 4,246 singletons born after FET (n = 2,181) and fresh embryo transfer (n = 2,065) enrolled between 2008 and 2019 and assessed the glucose and lipid variables until the age of 2 to 5 years. During a mean follow-up of 3.6 years, no significant differences were observed in fasting blood glucose, fasting insulin, Homeostatic Model Assessment of Insulin Resistance Index, total cholesterol, triglycerides, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol levels between offspring conceived by fresh and frozen embryo transfer in the crude model and adjusted model (adjusted for parental age, parental body mass index, parental education level, paternal smoking, parity, offspring age and sex). These results remained consistent across subgroup analyses considering offspring age, the stage of embryo transfer, and the mode of fertilization. Results from sensitivity analysis on children matched for age within the cohort remains the same. The main limitation of our study is the young age of the offspring. CONCLUSIONS: In this study, the impact of FET on glucose and lipid profiles during early childhood was comparable to fresh embryo transfer. Long-term studies are needed to evaluate the metabolic health of offspring born after FET.

Itaconate protects ferroptotic neurons by alkylating GPx4 post stroke.

Neuronal ferroptosis plays a key role in neurologic deficits post intracerebral hemorrhage (ICH). However, the endogenous regulation of rescuing ferroptotic neurons is largely unexplored. Here, we analyzed the integrated alteration of metabolomic landscape after ICH using LC-MS and MALDI-TOF/TOF MS, and demonstrated that aconitate decarboxylase 1 (Irg1) and its product itaconate, a derivative of the tricarboxylic acid cycle, were protectively upregulated. Deficiency of Irg1 or depletion of neuronal Irg1 in striatal neurons was shown to exaggerate neuronal loss and behavioral dysfunction in an ICH mouse model using transgenic mice. Administration of 4-Octyl itaconate (4-OI), a cell-permeable itaconate derivative, and neuronal Irg1 overexpression protected neurons in vivo. In addition, itaconate inhibited ferroptosis in cortical neurons derived from mouse and human induced pluripotent stem cells in vitro. Mechanistically, we demonstrated that itaconate alkylated glutathione peroxidase 4 (GPx4) on its cysteine 66 and the modification allosterically enhanced GPx4's enzymatic activity by using a bioorthogonal probe, itaconate-alkyne (ITalk), and a GPx4 activity assay using phosphatidylcholine hydroperoxide. Altogether, our research suggested that Irg1/itaconate-GPx4 axis may be a future therapeutic strategy for protecting neurons from ferroptosis post ICH.

Tracking the scaling of urban open spaces in China from 1990 to 2020.

Urban open spaces (UOS) are crucial for urban life, offering benefits across individual and societal levels. However, the understanding of the systematic dynamic of UOS scaling with city size and its potential non-linear performance remains a limited clarity area. This study bridges this gap by integrating urban scaling laws with remote sensing data from 1990 to 2020, creating a framework to analyze UOS trends in China. Our findings reveal that UOS growth is sub-linear scaling with city size, exhibiting economies of scale with scaling exponents between 0.55 and 0.65 and suggesting potential shortages. The distribution structure of UOS across cities is becoming increasingly balanced, as indicated by the rising Zipf's slope from 0.66 to 0.88. Southeastern coastal cities outperform, highlighting spatial variations and path dependency in UOS development. Additionally, using metrics of Scale-adjusted metropolitan indicator (SAMI) and the ratio of open space consumption to population growth rates (OCRPGR), we observe a trend towards more coordinated development between UOS and population, with a declining proportion of uncoordinated cities. Our long-term, large sample coverage study of UOS in China may offer positive significance for urban ecological planning and management in similar rapidly urbanizing countries, contributing to critical insights for quantifying and monitoring urban sustainable development.

BCMA-CD19 compound CAR T cells for systemic lupus erythematosus: a phase 1 open-label clinical trial.

OBJECTIVES: This study aims to evaluate the safety and efficacy of BCMA-CD19 compound chimeric antigen receptor T cells (cCAR) to dual reset the humoral and B cell immune system in patients with systemic lupus erythematosus (SLE) with lupus nephritis (LN). METHODS: This is a single-arm open-label multicentre phase 1 study of BCMA and CD19-directed cCAR in patients suffering from SLE/LN with autoantibodies produced by B cells and plasma/long-lived plasma cells. In this clinical trial, we sequentially assigned biopsy-confirmed (classes III-V) LN patients to receive 3×106 cCAR cells/kg postcessation of all SLE medications and conditioning. The primary endpoint of safety and toxicity was assessed. Complete immune reset was indicated by B cell receptor (BCR) deep sequencing and flow cytometry analysis. Patient 11 (P11) had insufficient lymphocyte counts and was underdosed as compassionate use. RESULTS: P1 and P2 achieved symptom and medication-free remission (MFR) from SLE and complete remission from lymphoma. P3-P13 (excluding P11) received an initial dose of 3×106 cCAR cells /kg and were negative for all autoantibodies, including those derived from long-lived plasma cells, 3 months post-cCAR and the complement returned to normal levels. These patients achieved symptom and MFR with post-cCAR follow-up to 46 months. Complete recovery of B cells was seen in 2-6 months post-cCAR. Mean SLE Disease Activity Index 2000 reduced from 10.6 (baseline) to 2.7 (3 months), and renal function significantly improved in 10 LN patients ≤90 days post-cCAR. cCAR T therapy was well tolerant with mild cytokine-release syndrome. CONCLUSIONS: Data suggest that cCAR therapy was safe and effective in inducing MFR and depleting disease-causing autoantibodies in patients with SLE.

The endonuclease FEN1 mediates activation of STAT3 and facilitates proliferation and metastasis in breast cancer.

BACKGROUND: The metastasis accounts for most deaths from breast cancer (BRCA). Understanding the molecular mechanisms of BRCA metastasis is urgently demanded. Flap Endonuclease 1 (FEN1), a pivotal factor in DNA metabolic pathways, contributes to tumor growth and drug resistance, however, little is known about the role of FEN1 in BRCA metastasis. METHODS AND RESULTS: In this study, FEN1 expression and its clinical correlation in BRCA were investigated using bioinformatics, showing being upregulated in BRCA samples and significant relationships with tumor stage, node metastasis, and prognosis. Immunohistochemistry (IHC) staining of local BRCA cohort indicated that the ratio of high FEN1 expression in metastatic BRCA tissues rose over that in non-metastatic tissues. The assays of loss-of-function and gain-of-function showed that FEN1 enhanced BRCA cell proliferation, migration, invasion, xenograft growth as well as lung metastasis. It was further found that FEN1 promoted the aggressive behaviors of BRCA cells via Signal Transducer and Activator of Transcription 3 (STAT3) activation. Specifically, the STAT3 inhibitor Stattic thwarted the FEN1-induced enhancement of migration and invasion, while the activator IL-6 rescued the decreased migration and invasion caused by FEN1 knockdown. Additionally, overexpression of FEN1 rescued the inhibitory effect of nuclear factor-κB (NF-κB) inhibitor BAY117082 on phosphorylated STAT3. Simultaneously, the knockdown of FEN1 attenuated the phosphorylation of STAT3 promoted by the NF-κB activator tumor necrosis factor α (TNF-α). CONCLUSIONS: These results indicate a novel mechanism that NF-κB-driven FEN1 contributes to promoting BRCA growth and metastasis by STAT3 activation.

Investigating diagnostic potential of long non-coding RNAs in head and neck squamous cell carcinoma using TCGA database and clinical specimens.

Head and neck squamous cell carcinoma (HNSCC) is a prevalent and prognostically challenging cancer worldwide. The role of long non-coding RNAs (lncRNAs) in cancer regulation is progressively being understood. This study aims to identify lncRNAs with diagnostic potential as biomarkers for HNSCC. Statistical analysis was performed on expression data from the Cancer Genome Atlas (TCGA) database to identify potential lncRNAs associated with HNSCC. Four selected lncRNAs were validated using real-time quantitative reverse transcription polymerase chain reaction and correlated with clinical factors. Functional roles were further investigated. A total of 488 differentially expressed lncRNAs were identified in TCGA-HNSC. After rigorous evaluation based on p-values, survival analysis, and ROC analysis, 24 lncRNAs were prioritized for additional investigation. LINC00460, LINC00941, CTC-241F20.4, and RP11-357H14.17 were established as candidate diagnostic biomarkers. These lncRNAs exhibited elevated expression in HNSCC tissues and were associated with poor prognosis. Combining them showed high diagnostic accuracy. Notably, LINC00460 and CTC-241F20.4 demonstrated a significant elevation in the advanced stages of HNSCC. We constructed an lncRNA-mRNA regulatory network, and the array of significant regulatory pathways identified included focal adhesion, regulation of epithelial cell migration, and others. Additionally, these lncRNAs were found to influence immune responses by modulating immune cell infiltration in the HNSCC microenvironment. Our research indicates that LINC00460, LINC00941, RP11-357H14.17, and CTC-241F20.4 may have diagnostic and prognostic importance in HNSCC. Furthermore, we have gained insights into their potential functional roles, particularly about immune responses and interactions in the microenvironment.

Effect of PCI on ophthalmic artery hemodynamics in patients with acute coronary syndrome.

Purpose: We aimed to explore the effects of percutaneous coronary intervention (PCI) on the ophthalmic artery (OA) hemodynamics in patients with acute coronary syndrome (ACS). Methods: A total of 73 participants (Group0: healthy controls, Group1: Patients with ACS underwent PCI < 3 months, Group2: Patients with ACS underwent PCI ≥ 3 months) were enrolled. Computed tomographic angiography images were used to construct three-dimensional models of participants' OAs. Numerical simulations based on computational fluid dynamics were used to acquire hemodynamic parameters. Results: The angle between the OA and internal carotid artery in Group2 was significantly larger compared with Group0 and Group1 (P = 0.003 and P = 0.044). Hemodynamic simulation showed a significantly slower OA blood velocity in Group1 than in the control (P < 0.001) and Group2 (P = 0.033). Lower wall shear stress was found in Group1 than that in control (P = 0.040). Patients after PCI had a higher wall pressure than healthy controls (P = 0.012 and P = 0.004). Mass flow ratios were decreased in Group1 and Group2 (P = 0.021 and P = 0.002). The hemodynamic parameters of OA were correlated with several clinical indicators. Conclusions: The OA blood flow velocity of patients with ACS after PCI initially slowed down, which increased the risk of plaque formation, and then showed an increasing trend. There was a correlation between OA hemodynamic parameters and clinical indexes related to cardiac stress. Ischemia-reperfusion injury and changes in blood flow status after PCI may affect OA morphology and hemodynamics, leading to ocular lesions. Trial registration: ChiCTR2100050428.

Ultra-sensitive analysis of exhaled biomarkers in ozone-exposed mice via PAI-TOFMS assisted with machine learning algorithms.

Ground-level ozone ranks sixth among common air pollutants. It worsens lung diseases like asthma, emphysema, and chronic bronchitis. Despite recent attention from researchers, the link between exhaled breath and ozone-induced injury remains poorly understood. This study aimed to identify novel exhaled biomarkers in ozone-exposed mice using ultra-sensitive photoinduced associative ionization time-of-flight mass spectrometry and machine learning. Distinct ion peaks for acetonitrile (m/z 42, 60, and 78), butyronitrile (m/z 70, 88, and 106), and hydrogen sulfide (m/z 35) were detected. Integration of tissue characteristics, oxidative stress-related mRNA expression, and exhaled breath condensate free-radical analysis enabled a comprehensive exploration of the relationship between ozone-induced biological responses and potential biomarkers. Under similar exposure levels, C57BL/6 mice exhibited pulmonary injury characterized by significant inflammation, oxidative stress, and cardiac damage. Notably, C57BL/6 mice showed free radical signals, indicating a distinct susceptibility profile. Immunodeficient non-obese diabetic Prkdc-/-/Il2rg-/- (NPI) mice exhibited minimal biological responses to pulmonary injury, with little impact on the heart. These findings suggest a divergence in ozone-induced damage pathways in the two mouse types, leading to alterations in exhaled biomarkers. Integrating biomarker discovery with comprehensive biopathological analysis forms a robust foundation for targeted interventions to manage health risks posed by ozone exposure.

IL-8 activates fibroblasts to promote the invasion of HNSCC cells via STAT3-MMP1.

Matrix metalloproteinase-1 (MMP1) has an aberrant expression relevant to various behaviors of cancers. As dominant components of the tumor stroma, fibroblasts constitute an important source of Matrix metalloproteinase (MMPs) including mainly MMP1. The impacts of MMP1 derived from fibroblasts in tumor microenvironment, however, is not well defined. In this study, we demonstrated a part of crosstalk between fibroblasts and cancer cells that enhanced the invasiveness of cancer cells, IL8-induced activation of STAT3 signaling pathway as a key promoter to elevated MMP1 level in fibroblasts that supports the migration and invasion of head and neck squamous cell carcinoma (HNSCC) cells by extracellular matrix degradation. Importantly, once exposed to the inhibitor of STAT3 phosphorylation (TPCA-1), the enhanced induction of HNSCC cells invasion triggered by fibroblasts was significantly impaired.

Association between dietary intake of saturated fatty acid subgroups and breast cancer risk.

The impact of dietary saturated fatty acids (SFAs) on breast cancer risk may vary depending on their carbon chain lengths, attributable to the discrepancy in their dietary sources and biological activities. The associations between SFA subgroups classified by chain length and breast cancer risk remain controversial. In this case-control study, we aimed to investigate the association between the dietary intake of SFA subgroups, classified by chain lengths, and odds of breast cancer in China. This study included 1661 cases of breast cancer (confirmed as primary and histologically) and 1674 frequency-matched controls. Face-to-face interviews were used to collect basic information, while dietary intake information was obtained by a food frequency questionnaire. The unconditional logistic regression model was used to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs). All SFA subgroups were inversely associated with odds of breast cancer. The adjusted ORs (95% CIs) were 0.78 (0.61-0.99) for medium-chain SFAs, 0.50 (0.31-0.83) for long even-chain SFAs, 0.69 (0.54-0.88) for long odd-chain, and 0.67 (0.48-0.95) for very long-chain SFAs, respectively. In the restricted cubic spline (RCS) models, a non-linear M-shaped association was observed between long odd-chain SFAs and odds of breast cancer (Pnon-linearity = 0.007). However, the associations of medium-chain SFAs, long even-chain SFAs, and very long-chain SFAs did not reach statistical significance (Pnon-linearity > 0.05). No significant interactions were observed between all these four subgroups of SFAs and menopausal status or BMI. Our findings emphasize the significance of elucidating the associations of dietary SFAs according to chain lengths, providing insights into the etiology as well as the potential benefits of SFA-rich food intake in reducing the risk of breast cancer. Further prospective cohort studies and intervention studies are warranted to confirm these findings and identify the underlying mechanisms of the association between dietary SFAs and breast cancer.

Targeted macrophage phagocytosis by Irg1/itaconate axis improves the prognosis of intracerebral hemorrhagic stroke and peritonitis.

BACKGROUND: Macrophages are innate immune cells whose phagocytosis function is critical to the prognosis of stroke and peritonitis. cis-aconitic decarboxylase immune-responsive gene 1 (Irg1) and its metabolic product itaconate inhibit bacterial infection, intracellular viral replication, and inflammation in macrophages. Here we explore whether itaconate regulates phagocytosis. METHODS: Phagocytosis of macrophages was investigated by time-lapse video recording, flow cytometry, and immunofluorescence staining in macrophage/microglia cultures isolated from mouse tissue. Unbiased RNA-sequencing and ChIP-sequencing assays were used to explore the underlying mechanisms. The effects of Irg1/itaconate axis on the prognosis of intracerebral hemorrhagic stroke (ICH) and peritonitis was observed in transgenic (Irg1flox/flox; Cx3cr1creERT/+, cKO) mice or control mice in vivo. FINDINGS: In a mouse model of ICH, depletion of Irg1 in macrophage/microglia decreased its phagocytosis of erythrocytes, thereby exacerbating outcomes (n = 10 animals/group, p < 0.05). Administration of sodium itaconate/4-octyl itaconate (4-OI) promoted macrophage phagocytosis (n = 7 animals/group, p < 0.05). In addition, in a mouse model of peritonitis, Irg1 deficiency in macrophages also inhibited phagocytosis of Staphylococcus aureus (n = 5 animals/group, p < 0.05) and aggravated outcomes (n = 9 animals/group, p < 0.05). Mechanistically, 4-OI alkylated cysteine 155 on the Kelch-like ECH-associated protein 1 (Keap1), consequent in nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and transcriptional activation of Cd36 gene. Blocking the function of CD36 completely abolished the phagocytosis-promoting effects of Irg1/itaconate axis in vitro and in vivo. INTERPRETATION: Our findings provide a potential therapeutic target for phagocytosis-deficiency disorders, supporting further development towards clinical application for the benefit of stroke and peritonitis patients. FUNDING: The National Natural Science Foundation of China (32070735, 82371321 to Q. Li, 82271240 to F. Yang) and the Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education (KZ202010025033 to Q. Li).

Alterations in the diversity, composition and function of the gut microbiota in Uyghur individuals with sarcopenia.

BACKGROUND: Research on the gut microbiota has emerged as a new direction for understanding pathophysiologic changes in diseases associated with aging, such as sarcopenia. Several studies have shown that there are differences in the gut microbiota between individuals with sarcopenia and without sarcopenia. However, these differences are not consistent across regions and ethnic groups, and additional research is needed. METHODS: In this study, we collected fresh fecal samples from 31 Uyghur individuals with sarcopenia and 31 healthy controls. We used 16S rRNA sequencing to obtain fecal base sequences and analyzed the diversity, composition and function of the gut microbiota. RESULTS: There was no significant difference in alpha diversity between the sarcopenia group and the healthy control group (P > 0.05). There was a significant difference in beta diversity between the groups (P < 0.05). In the sarcopenia group, the abundances of Alloprevotella, un_f_Prevotellaceae, Anaerovibrio, Prevotellaceae_NK3B31_group, Mitsuokella, Prevotella and Allisonella were lower than those in the heathy control group, and the abundances of Flavobacteriales, Flavobacteriaceae, Catenibacterium, Romboutsia, Erysipelotrichaceae_UCG-003, GCA-900066575, Lachnospiraceae_FCS020_group, and un_f_Flavobacteriaceae were higher than those in the heathy control group. Linear discriminant analysis effect size (LEfSe) revealed that the microbial species in the control group that were significantly different from those in the sarcopenia group were concentrated in the genus Alloprevotella, while the species in the sarcopenia group were concentrated in the genus Catenibacterium. Functional prediction analysis revealed that D-alanine, glycine, serine, and threonine metabolism and transcription machinery, among others, were enriched in the sarcopenia group, which indicated that metabolic pathways related to amino acid metabolism and nutrient transport may be regulated to varying degrees in the pathophysiological context of sarcopenia. CONCLUSIONS: There were significant differences in the composition and function of the gut microbiota between Xinjiang Uyghur sarcopenia individuals and healthy individuals. These findings might aid in the development of probiotics or microbial-based therapies for sarcopenia in Uyhur individuals.

DDAH1 recruits peroxiredoxin 1 and sulfiredoxin 1 to preserve its activity and regulate intracellular redox homeostasis.

Growing evidence suggests that dimethylarginine dimethylaminohydrolase 1 (DDAH1), a crucial enzyme for the degradation of asymmetric dimethylarginine (ADMA), is closely related to oxidative stress during the development of multiple diseases. However, the underlying mechanism by which DDAH1 regulates the intracellular redox state remains unclear. In the present study, DDAH1 was shown to interact with peroxiredoxin 1 (PRDX1) and sulfiredoxin 1 (SRXN1), and these interactions could be enhanced by oxidative stress. In HepG2 cells, H2O2-induced downregulation of DDAH1 and accumulation of ADMA were attenuated by overexpression of PRDX1 or SRXN1 but exacerbated by knockdown of PRDX1 or SRXN1. On the other hand, DDAH1 also maintained the expression of PRDX1 and SRXN1 in H2O2-treated cells. Furthermore, global knockout of Ddah1 (Ddah1-/-) or liver-specific knockout of Ddah1 (Ddah1HKO) exacerbated, while overexpression of DDAH1 alleviated liver dysfunction, hepatic oxidative stress and downregulation of PRDX1 and SRXN1 in CCl4-treated mice. Overexpression of liver PRDX1 improved liver function, attenuated hepatic oxidative stress and DDAH1 downregulation, and diminished the differences between wild type and Ddah1-/- mice after CCl4 treatment. Collectively, our results suggest that the regulatory effect of DDAH1 on cellular redox homeostasis under stress conditions is due, at least in part, to the interaction with PRDX1 and SRXN1.