A Surge of DNA Damage Links Transcriptional Reprogramming and Hematopoietic Deficit in Fanconi Anemia.

Impaired DNA crosslink repair leads to Fanconi anemia (FA), characterized by a unique manifestation of bone marrow failure and pancytopenia among diseases caused by DNA damage response defects. As a germline disorder, why the hematopoietic hierarchy is specifically affected is not fully understood. We find that reprogramming transcription during hematopoietic differentiation results in an overload of genotoxic stress, which causes aborted differentiation and depletion of FA mutant progenitor cells. DNA damage onset most likely arises from formaldehyde, an obligate by-product of oxidative protein demethylation during transcription regulation. Our results demonstrate that rapid and extensive transcription reprogramming associated with hematopoietic differentiation poses a major threat to genome stability and cell viability in the absence of the FA pathway. The connection between differentiation and DNA damage accumulation reveals a novel mechanism of genome scarring and is critical to exploring therapies to counteract the aplastic anemia for the treatment of FA patients.

Nuclear VCP drives colorectal cancer progression by promoting fatty acid oxidation.

Fatty acid oxidation (FAO) fuels many cancers. However, knowledge of pathways that drive FAO in cancer remains unclear. Here, we revealed that valosin-containing protein (VCP) upregulates FAO to promote colorectal cancer growth. Mechanistically, nuclear VCP binds to histone deacetylase 1 (HDAC1) and facilitates its degradation, thus promoting the transcription of FAO genes, including the rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A). FAO is an alternative fuel for cancer cells in environments exhibiting limited glucose availability. We observed that a VCP inhibitor blocked the upregulation of FAO activity and CPT1A expression triggered by metformin in colorectal cancer (CRC) cells. Combined VCP inhibitor and metformin prove more effective than either agent alone in culture and in vivo. Our study illustrates the molecular mechanism underlying the regulation of FAO by nuclear VCP and demonstrates the potential therapeutic utility of VCP inhibitor and metformin combination treatment for colorectal cancer.

Inhibition of NLRP3 inflammasome by MCC950 under hypoxia alleviates photoreceptor apoptosis via inducing autophagy in Müller glia.

NLRP3 inflammasome activation has emerged as a critical initiator of inflammatory response in ischemic retinopathy. Here, we identified the effect of a potent, selective NLRP3 inhibitor, MCC950, on autophagy and apoptosis under hypoxia. Neonatal mice were exposed to hyperoxia for 5 days to establish oxygen-induced retinopathy (OIR) model. Intravitreal injection of MCC950 was given, and then autophagy and apoptosis markers were assessed. Retinal autophagy, apoptosis, and related pathways were evaluated by western blot, immunofluorescent labeling, transmission electron microscopy, and TUNEL assay. Autophagic activity in Müller glia after NLRP3 inflammasome inhibition, together with its influence on photoreceptor death, was studied using western blot, immunofluorescence staining, mRFP-GFP-LC3 adenovirus transfection, cell viability, proliferation, and apoptosis assays. Results showed that activation of NLRP3 inflammasome in Müller glia was detected in OIR model. MCC950 could improve impaired retinal autophagic flux and attenuate retinal apoptosis while it regulated the retinal AMPK/mTOR/ULK-1 pathway. Suppressed autophagy and depressed proliferation capacity resulting from hypoxia was promoted after MCC950 treatment in Müller glia. Inhibition of AMPK and ULK-1 pathway significantly interfered with the MCC950-induced autophagy activity, indicating MCC950 positively modulated autophagy through AMPK/mTOR/ULK-1 pathway in Müller cells. Furthermore, blockage of autophagy in Müller glia significantly induced apoptosis in the cocultured 661W photoreceptor cells, whereas MCC950 markedly preserved the density of photoreceptor cells. These findings substantiated the therapeutic potential of MCC950 against impaired autophagy and subsequent apoptosis under hypoxia. Such protective effect might involve the modulation of AMPK/mTOR/ULK-1 pathway. Targeting NLRP3 inflammasome in Müller glia could be beneficial for photoreceptor survival under hypoxic conditions.

YTHDC1-dependent m6A modification modulated FOXM1 promotes glycolysis and tumor progression through CENPA in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) exhibits heightened aggressiveness compared with other breast cancer (BC) subtypes, with earlier relapse, a higher risk of distant metastasis, and a worse prognosis. Transcription factors play a pivotal role in various cancers. Here, we found that factor forkhead box M1 (FOXM1) expression was significantly higher in TNBC than in other BC subtypes and normal tissues. Combining the findings of Gene Ontology (GO) enrichment analysis and a series of experiments, we found that knockdown of the FOXM1 gene attenuated the ability of TNBC cells to proliferate and metastasize both in vivo and in vitro. In addition, Spearman's test showed that FOXM1 significantly correlated with glycolysis-related genes, especially centromere protein A (CENPA) in datasets (GSE76250, GSE76124, GSE206912, and GSE103091). The effect of silencing FOXM1 on the inhibition of CENPA expression, TNBC proliferation, migration, and glycolysis could be recovered by overexpression of CENPA. According to MeRIP, the level of m6A modification on FOMX1 decreased in cells treated with cycloleucine (a m6A inhibitor) compared with that in the control group. The increase in FOXM1 expression caused by YTHDC1 overexpression could be reversed by the m6A inhibitor, which indicated that YTHDC1 enhanced FOXM1 expression depending on m6A modification. Therefore, we concluded that the YTHDC1-m6A modification/FOXM1/CENPA axis plays an important role in TNBC progression and glycolysis.

Elastomer Composites with High Damping and Low Thermal Resistance via Hierarchical Interactions and Regulating Filler.

Modern microelectronics and emerging technologies such as wearable electronics and soft robotics require elastomers to integrate high damping with low thermal resistance to avoid damage caused by vibrations and heat accumulation. However, the strong coupling between storage modulus and loss factor makes it generally challenging to simultaneously increase both thermal conductance and damping. Here, a strategy of introducing hierarchical interaction and regulating fillers in polybutadiene/spherical aluminum elastomer composites is reported to simultaneously achieve extraordinary damping ability of tan δ > 1.0 and low thermal resistance of 0.15 cm2 K W-1, which surpasses state-of-the-art elastomers and their composites. The enhanced damping is attributed to increased energy dissipation via introducing the hierarchical hydrogen bond interactions in polybutadiene networks and the addition of spherical aluminum, which also functions as a thermally conductive filler to achieve low thermal resistance. As a proof of concept, the polybutadiene/spherical aluminum elastomer composites are used as thermal interface materials, showing effective heat dissipation for electronic devices in vibration scenarios. The combination of outstanding damping performance and extraordinary heat dissipation ability of the elastomer composites may create new opportunities for their applications in electronics.

A Strategy for Enhancing Perpendicular Magnetic Anisotropy in Yttrium Iron Garnet Films.

In future information storage and processing, magnonics is one of the most promising candidates to replace traditional microelectronics. Yttrium iron garnet (YIG) films with perpendicular magnetic anisotropy (PMA) have aroused widespread interest in magnonics. Obtaining strong PMA in a thick YIG film with a small lattice mismatch (η) has been fascinating but challenging. Here, a novel strategy is proposed to reduce the required minimum strain value for producing PMA and increase the maximum thickness for maintaining PMA in YIG films by slight oxygen deficiency. Strong PMA is achieved in the YIG film with an η of only 0.4% and a film thickness up to 60 nm, representing the strongest PMA for such a small η reported so far. Combining transmission electron microscopy analyses, magnetic measurements, and a theoretical model, it is demonstrated that the enhancement of PMA physically originates from the reduction of saturation magnetization and the increase of magnetostriction coefficient induced by oxygen deficiency. The Gilbert damping values of the 60-nm-thick YIG films with PMA are on the order of 10-4. This strategy improves the flexibility for the practical applications of YIG-based magnonic devices and provides promising insights for the theoretical understanding and the experimental enhancement of PMA in garnet films.

Antiferroelectricity-Induced Negative Thermal Expansion in Double Perovskite Pb2 CoMoO6.

Materials with negative thermal expansion (NTE) attract significant research attention owing to their unique physical properties and promising applications. Although ferroelectric phase transitions leading to NTE are widely investigated, information on antiferroelectricity-induced NTE remains limited. In this study, single-crystal and polycrystalline Pb2 CoMoO6 samples are prepared at high pressure and temperature conditions. The compound crystallizes into an antiferroelectric Pnma orthorhombic double perovskite structure at room temperature owing to the opposite displacements dominated by Pb2+ ions. With increasing temperature to 400 K, a structural phase transition to cubic Fm-3m paraelectric phase occurs, accompanied by a sharp volume contraction of 0.41%. This is the first report of an antiferroelectric-to-paraelectric transition-induced NTE in Pb2 CoMoO6 . Moreover, the compound also exhibits remarkable NTE with an average volumetric coefficient of thermal expansion αV = -1.33 × 10-5 K-1 in a wide temperature range of 30-420 K. The as-prepared Pb2 CoMoO6 thus serves as a prototype material system for studying antiferroelectricity-induced NTE.

Effects of Bifidobacterium breve 207-1 on regulating lifestyle behaviors and mental wellness in healthy adults based on the microbiome-gut-brain axis: a randomized, double-blind, placebo-controlled trial.

PURPOSE: Our study aimed to explore the efficacy of Bifidobacterium breve 207-1 on specific neurotransmitters and hormones and the ability to regulate lifestyle behaviors in healthy adults. METHODS: In total, 120 healthy adults with high mental stress, overweight, insomnia, and constipation were randomly assigned to receive low-dose B. breve 207-1 (LD, n = 40), high-dose B. breve 207-1 (HD, n = 40), or placebo (n = 40) for 28 days. Fecal and blood samples were collected and questionnaires were answered before and after the trial. Neurotransmitters and serum hormones were detected using enzyme-linked immunosorbent assay. The gut microbiota composition was assessed using 16 S rRNA sequencing. Short-chain fatty acids (SCFAs) concentrations were determined via gas chromatography-mass spectrometry (GC-MS). RESULTS: The primary outcome of our study was changes in mental wellness, including neurotransmitters, the hypothalamic-pituitary-adrena (HPA) axis hormones, and the psychological scales. The results showed that γ-aminobutyric acid (GABA) increased significantly and the HPA axis hormones were suppressed overall in the probiotic groups while 5-hydroxytryptamine (5-HT) did not change significantly. However, there was no significant change in mood scale scores. The secondary outcome focused on the ability of 207-1 to regulate the body and lifestyle of healthy adults (e.g., sleep, diet, exercise, etc.). The PSQI scores in the probiotics groups significantly decreased, indicating improved sleep quality. Meanwhile, the probiotic groups had a slight increase in exercise consumption while dietary intake stabilized. By physical examination, the participants showed weight loss although no statistically significant difference was observed between the groups. Then, validated by gut microbiota, changes in the gut microbiota were observed under the effective intervention of 207-1 while short-chain fatty acids (SCFAs) increased in the LD group, particularly acetic and propionic acids. There was a slight decrease in alpha-diversity in the HD group. CONCLUSION: Bifidobacterium breve 207-1 entered the organism and affected neurotransmitter and the HPA axis hormone levels via the microbiome-gut-brain axis. Meanwhile, 207-1 supplementation improved daily lifestyle behaviors in healthy adults, which may in turn lead to changes in their bodies (e.g. weight and lipid metabolism). However, this study did not find significant mood-modulating efficacy. The mechanism of the overall study is unclear, but we hypothesize that SCFAs may be the key pathway, and more experiments are needed for validation in the future. TRIAL REGISTRATION: This trial was retrospectively registered in the Chinese Clinical Trial Registry under the accession number ChiCTR2300069453 on March 16, 2023.

Unveiling the relationship between social anxiety, loneliness, motivations, and problematic smartphone use: A network approach.

BACKGROUND: Previous studies suggested social anxiety as an essential risk factor for problematic smartphone use, but the complex interactions and the most influential components affecting this relationship remain unclear. This study capitalizes on network analysis to identify the central factors and possible mediating paths among social anxiety, loneliness, five types of motivation, and problematic smartphone use. MATERIAL AND METHODS: Employing 549 emerging adults, we obtained a stable network of the above variables. The central components and the stability of this network were also identified. RESULTS: Within this network, the edge linking withdrawal behavior and use of application (APP) exhibits the most robust edge intensity. The central components include social comfort, use of APP, withdrawal behavior, and companionship while the bridge central nodes include social anxiety and escapism motivation. The direct link between social anxiety and PSU revealed only fragile edges with both withdrawal behavior and use of APP. Considering the possible mediating pathways, three pathways were observed in our network. Loneliness and escapism mediated the relationship between social anxiety and social comfort. Moreover, another mediating way was from social anxiety, loneliness, social interaction motivation, and escapism motivation to social comfort. DISCUSSION: Based on the above identification of related components and pathways, future researchers could intervene against problematic smartphone usage in this socially anxious population.

Association between negative life events and suicidal behavior in adolescents: roles of core self-evaluation, depression and gender.

PURPOSE: Negative life events are essential proximal factors that may induce suicidal behavior in adolescents, but the mechanisms connecting this link remain to further explored. The present study aimed to investigate the relationship between negative life events (NLEs) and adolescents' suicidal behavior, and the roles of core self-evaluation, depression and gender playing between them. METHODS: Using the whole-group sampling approach, 5296 Chinese adolescents (51.5% males, Meanage = 12.93) took part in this cross-sectional study in September 2021 and completed a battery of surveys including NLEs, suicidal behavior, CSE (core self-evaluation) and depression. Logistic regression and latent structural equation models were used to test the direct and indirect effects between NLEs and suicide behavior with multi-group path analysis, gender differences in this serial mediating effect were also tested. RESULTS: After controlling for age and gender, NLEs were directly associated with adolescents' suicidal behavior. CSE and depression played significant serial mediating effects in this relationship. Moreover, significant gender differences were obtained in these serial mediating pathways, with stronger effects in girls. CONCLUSION: Integrating the environmental, individual cognitive and emotional factors, our findings would be helpful in understanding the mechanism of these antecedents on adolescents' suicide behavior, which has specific practical significance for preventing and reducing suicidal behavior.

Species-level understanding of the bacterial community in Daqu based on full-length 16S rRNA gene sequences.

Daqu is used as the fermentation starter of Baijiu and contributes diversified functional microbes for saccharifying grains and converting sugars into ethanol and aroma components in Baijiu products. Daqu is mainly classified into three types, namely low (LTD), medium (MTD) and high (HTD) temperature Daqu, according to the highest temperatures reached in their fermentation processes. In this study, we used the PacBio small-molecule real-time (SMRT) sequencing technology to determine the full-length 16 S rRNA gene sequences from the metagenomes of 296 samples of different types of Daqu collected from ten provinces in China, and revealed the bacterial diversity at the species level in the Daqu samples. We totally identified 310 bacteria species, including 78 highly abundant species (with a relative abundance >0.1% each) which accounted for 91.90% of the reads from all the Daqu samples. We also recognized the differentially enriched bacterial species in different types of Daqu, and in the Daqu samples with the same type but from different provinces. Specifically, Lactobacillales, Enterobacterales and Bacillaceae were significantly enriched in the LTD, MTD and HTD groups, respectively. The potential co-existence and exclusion relationships among the bacteria species involved in all the Daqu samples and in the LTD, MTD and HTD samples from a specific region were also identified. These results provide a better understanding of the bacterial diversity in different types of Daqu at the species level.

Diterpenoid Alkaloids from Delphinium ajacis and Their Anti-inflammatory Activity.

Three novel diterpenoid alkaloids, comprising two C19 -diterpenoid alkaloids (1 and 2) and one C20 -diterpenoid alkaloid (3), were isolated from Delphinium ajacis, alongside the six known compounds (4-9). Their structures were elucidated by spectroscopic methods (MS, UV, IR, 1D and 2D NMR) and chemical properties. Simultaneously, the anti-inflammatory properties of all compounds (1-9) was conducted, focusing on nitric oxide (NO) production in LPS-induced BV-2 cells. The results indicated compounds 1-3, 7, and 8 have potential anti-inflammatory activity.

[Relationship between gut microbiome and neurodevelopment in early life].

OBJECTIVE: To compare the differences in gut microbiome composition between children with good neurodevelopment and those with delayed neurodevelopment, and to analyze the relationship between gut microbiome and the neurodevelopment status of infants in early life. METHODS: The mothers were included at the Second West China Hospital from November 2020 to April 2021. Their infant stools were collected on day 0 and day 90 after birth, and the follow-up questionnaires at the corresponding time points were completed. Additionally, the Ages and Stages Questionnaires-Third Edition(ASQ-3) were completed by mothers at 12 months of age. The structure and diversity of gut microbiota were examined by 16S rRNA sequencing, and the relationship between gut microbiome and ASQ-3 questionnaire scores in early life was analyzed. RESULTS: According to the ASQ-3 scores, mothers and infants into neurodevelopment good group(G group, n=18) and neurodevelopmental delay group(D group, n=10). Compared with the D group, the relative abundance of the Firmicutes was significantly higher in the G group at day 0(P<0.05), while the level of the Proteobacteria was lower(P<0.05). At day 90 after birth, the relative abundance of the Actinobacteria, Bifidobacteriaceae and Enterococcaceae was significantly higher in the G group(P<0.05). In addition, alpha diversity was not statistically different between the two groups. Spearman's correlation analysis showed that Clostridiaceae of the postnatal day 0 infants was positively correlated with the communication domain score, but negatively associated with gross motor domain score in children at 12 months of age, whereas the relative abundance of Proteobacteria and Enterobacteriaceae of children at postnatal day 90 was negatively associated with communication development, while the relative abundance of Erysipelatoclostridiaceae showed a negative correlation with gross motor domain scores. CONCLUSION: The structure of the gut microbiome in early life between neurodevelopment good and delayed infants, and were associated with the development of communication and gross motor domain in infants at 12 months of age, suggesting that gut microbiome in early life may be related to the level of neurodevelopment in infants.

Interactions of glial cells with neuronal synapses, from astrocytes to microglia and oligodendrocyte lineage cells.

The mammalian brain is a complex organ comprising neurons, glia, and more than 1 × 1014 synapses. Neurons are a heterogeneous group of electrically active cells, which form the framework of the complex circuitry of the brain. However, glial cells, which are primarily divided into astrocytes, microglia, oligodendrocytes (OLs), and oligodendrocyte precursor cells (OPCs), constitute approximately half of all neural cells in the mammalian central nervous system (CNS) and mainly provide nutrition and tropic support to neurons in the brain. In the last two decades, the concept of "tripartite synapses" has drawn great attention, which emphasizes that astrocytes are an integral part of the synapse and regulate neuronal activity in a feedback manner after receiving neuronal signals. Since then, synaptic modulation by glial cells has been extensively studied and substantially revised. In this review, we summarize the latest significant findings on how glial cells, in particular, microglia and OL lineage cells, impact and remodel the structure and function of synapses in the brain. Our review highlights the cellular and molecular aspects of neuron-glia crosstalk and provides additional information on how aberrant synaptic communication between neurons and glia may contribute to neural pathologies.

Identification of genetic and immune signatures for the recurrence of HER2-positive breast cancer after trastuzumab-based treatment.

PURPOSE: To determine the genetic and immune features associated with the recurrence of human epidermal growth factor receptor2-positive (HER2 +) breast cancer (BC) after trastuzumab-based treatment. METHODS: A retrospective cohort study of 48 patients who received trastuzumab-based treatment was divided into recurrent and non-recurrent groups according to clinical follow-up. Baseline samples from all 48 patients were analyzed for genetic variation, HLA allele type, gene expression, and immune features, which were linked to HER2 + BC recurrence. Statistics included logistic regression models, Kaplan-Meier plots, and Univariate Cox proportional hazards models. RESULTS: Compared with the non-recurrent group, the extracellular matrix-related pathway and 3 Hallmark gene sets were enriched in the recurrent group. The infiltration levels of immature B cells and activated B cells were significantly increased in the non-recurrent group, which correlated remarkably with improved overall survival (OS) in two other published gene expression datasets, including TCGA and METABRIC. In the TCGA cohort (n = 275), activated B cells (HR 0.23, 95%CI 0.13-0.43, p < 0.0001), and immature B cells (HR 0.26, 95%CI 0.12-0.59, p < 0.0001). In the METABRIC cohort (n = 236), activated B cells (HR 0.60, 95%CI 0.43-0.83, p = 0.002), and immature B cells (HR 0.65, 95%CI 0.47-0.91, p = 0.011). Cox regression suggested that immature B cells and activated B cells were protective factors for outcome OS. CONCLUSIONS: Aberrant activation of multiple pathways and low baseline tumor-infiltrating B cells are related to HER2 + BC trastuzumab-based recurrence, which primarily affects the antitumor activity of trastuzumab.

Elimination of optical phase sensitivity in a shift, scale, and rotation invariant hybrid opto-electronic correlator via off-axis operation.

The hybrid opto-electronic correlator (HOC) uses a combination of optics and electronics to perform target recognition. Achieving a stable output from this architecture has previously presented a significant challenge due to a high sensitivity to optical phase variations, limiting the real-world feasibility of the device. Here we present a modification to the architecture that essentially eliminates the dependence on optical phases, and demonstrate verification of the proposed approach. Experimental results are shown to agree with the theory and simulations, for scale, rotation and shift invariant image recognition. This approach represents a major innovation in making the HOC viable for real-world applications.

Inhibition of vascular endothelial growth factor alleviates neovascular retinopathy with regulated neurotrophic/proinflammatory cytokines through the modulation of DBI-TSPO signaling.

Diazepam binding inhibitor (DBI)-translocator protein (18kDa) (TSPO) signaling in the retina was reported to possess coordinated macroglia-microglia interactions. We investigated DBI-TSPO signaling and its correlation with vascular endothelial growth factor (VEGF), neurotrophic or inflammatory cytokines in neovascular retinopathy, and under hypoxic conditions. The vitreous expression of DBI, VEGF, nerve growth factor (NGF), and interleukin-1beta (IL-1ß) were examined in proliferative diabetic retinopathy (PDR) patients with or without anti-VEGF therapy and nondiabetic controls. Retinal DBI-TSPO signaling and the effect of the anti-VEGF agent were evaluated in a mouse model of oxygen-induced retinopathy (OIR). Interactions between Müller cell-derived VEGF and DBI, as well as cocultured microglial cells under hypoxic conditions, were studied, using Western blot, real-time RT-PCR, enzyme-linked immunosorbent assay (ELISA), flow cytometry, and immunofluorescent labeling. Results showed that vitreous levels of DBI, VEGF, NGF, and IL-1ß were significantly higher in PDR patients compared with controls, which further changed after anti-VEGF therapy. A statistical association was found between vitreous DBI and VEGF, NGF, IL-1ß, and age. The application of the anti-VEGF agent in the OIR model induced retinal expression of DBI and NGF, and attenuated inflammation and microglial cell activation. Inhibition of Müller cell-derived VEGF could increase its DBI expression under hypoxic conditions, while the DBI-TSPO signaling pathway is essential for anti-VEGF agents exerting anti-inflammatory and neuroprotective effects, as well as limiting inflammatory magnitude, promoting its neurotrophin production and anti-inflammatory (M2) polarization in microglial cells. These findings suggest the beneficial effect of anti-VEGF therapy on inflammation and neurotrophy of retinal glial cells through modulation of the DBI-TSPO signaling pathway.

Successive Promotion of Formal [3+2] Cycloaddition of Aryl Methyl Ketones by I2 and Zn: Access to 2-Hydroxy-4-morpholin-2,5-diarylfuran-3(2H)-ones with a Quaternary Carbon Center.

2-Hydroxy-4-morpholin-2,5-diarylfuran-3(2H)-one derivatives were constructed sequentially using iodine and zinc dust from simple and readily available methyl ketone and morpholine as the starting materials. Under mild conditions, C-C, C-N, and C-O bonds formed in a one-pot synthesis. A quaternary carbon center was successfully constructed, and the active drug fragment morpholine was introduced into the molecule.

Breastfeeding might partially contribute to gut microbiota construction and stabilization of propionate metabolism in cesarean-section infants.

PURPOSE: This study was aimed to determine how delivery mode and feeding pattern influence the infant's gut microbiota construction and the variation of fecal microbial metabolites from a birth cohort. METHODS: Fecal samples collected from 61 full-term born Chinese infants at four time points: day 0, day 7, month 1, and month 3. Based on delivery mode (vaginal delivery [V] or cesarean section [C]) and feeding pattern (breastfeeding [B] or mixed feeding [M]), infants were divided into four groups, namely VB, CB, VM, and CM groups. The gut microbiota composition and bacterial diversity were assessed using 16S rRNA sequencing. Short-chain fatty acid (SCFA) concentrations were determined via gas chromatography-mass spectrometry (GC-MS). RESULTS: The CM group had a significantly higher relative abundance of Firmicutes (day 0 and month 1), Enterococcaceae (month 3), and Enterococcus (month 3) than the VB group and a significantly higher abundance of Firmicutes (month 1) and Blautia (month 3) than the CB group. The VB and CB groups exhibited a stable SCFA variation and a significantly lower level of propionate compared with the VM and CM groups. All groups showed an intense transition of enterotypes within 1 month and became stable at 3 months. The correlation between SCFA and enterotypes showed a significant positive correlation between Bifidobacteriaceae and acetate in the CB group (day 7 and month 3) and a significant positive correlation between Clostridiaceae and butyrate in the CB and VB groups (day 7 and month 3), respectively. CONCLUSION: These results indicated that C-section was associated with higher abundance of the phylum Firmicutes and family Enterococcaceae, and intense fluctuation of SCFA, at least propionate. And breastfeeding might partially contribute to gut microbiota construction and stabilization propionate metabolism in cesarean-section infants.

Ferroptosis inhibitor liproxstatin-1 alleviates metabolic dysfunction-associated fatty liver disease in mice: potential involvement of PANoptosis.

Ferroptosis is a new form of regulated cell death characterized by excessive iron accumulation and uncontrollable lipid peroxidation. The role of ferroptosis in metabolic dysfunction-associated fatty liver disease (MAFLD) is not fully elucidated. In this study we compared the therapeutic effects of ferroptosis inhibitor liproxstatin-1 (LPT1) and iron chelator deferiprone (DFP) in MAFLD mouse models. This model was established in mice by feeding a high-fat diet with 30% fructose in water (HFHF) for 16 weeks. The mice then received LPT1 (10 mg·kg-1·d-1, ip) or DFP (100 mg·kg-1·d-1, ig) for another 2 weeks. We showed that both LPT1 and DFP treatment blocked the ferroptosis markers ACSL4 and ALOX15 in MAFLD mice. Furthermore, LPT1 treatment significantly reduced the liver levels of triglycerides and cholesterol, lipid peroxidation markers 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), and ameliorated the expression of lipid synthesis/oxidation genes (Pparα, Scd1, Fasn, Hmgcr and Cpt1a), insulin resistance, mitochondrial ROS content and liver fibrosis. Importantly, LPT1 treatment potently inhibited hepatic apoptosis (Bax/Bcl-xL ratio and TUNEL+ cell number), pyroptosis (cleavages of Caspase-1 and GSDMD) and necroptosis (phosphorylation of MLKL). Moreover, LPT1 treatment markedly inhibited cleavages of PANoptosis-related caspase-8 and caspase-6 in MAFLD mouse liver. In an in vitro MAFLD model, treatment with LPT1 (100 nM) prevented cultured hepatocyte against cell death induced by pro-PANoptosis molecules (TNF-α, LPS and nigericin) upon lipid stress. On the contrary, DFP treatment only mildly attenuated hepatic inflammation but failed to alleviate lipid deposition, insulin resistance, apoptosis, pyroptosis and necroptosis in MAFLD mice. We conclude that ferroptosis inhibitor LPT1 protects against steatosis and steatohepatitis in MAFLD mice, which may involve regulation of PANoptosis, a coordinated cell death pathway that involves apoptosis, pyroptosis and necroptosis. These results suggest a potential link between ferroptosis and PANoptosis.