H3K27me3 timely dictates uterine epithelial transcriptome remodeling and thus transformation essential for normal embryo implantation.

Uterine luminal epithelia (LE), the first layer contacting with the blastocyst, acquire receptivity for normal embryo implantation. Besides the well-accepted transcriptional regulation dominated by ovarian estrogen and progesterone for receptivity establishment, the involvement of epigenetic mechanisms remains elusive. This study systematically profiles the transcriptome and genome-wide H3K27me3 distribution in the LE throughout the preimplantation. Combining genetic and pharmacological approaches targeting the PRC2 core enzyme Ezh1/2, we demonstrate that the defective remodeling of H3K27me3 in the preimplantation stage disrupts the differentiation of LE, and derails uterine receptivity, resulting in implantation failure. Specifically, crucial epithelial genes, Pgr, Gata2, and Sgk1, are transcriptionally silenced through de novo deposition of H3K27me3 for LE transformation, and their sustained expression in the absence of H3K27me3 synergistically confines the nuclear translocation of FOXO1. Further functional studies identify several actin-associated genes, including Arpin, Tmod1, and Pdlim2, as novel direct targets of H3K27me3. Their aberrantly elevated expression impedes the morphological remodeling of LE, a hindrance alleviated by treatment with cytochalasin D which depolymerizes F-actin. Collectively, this study uncovers a previously unappreciated epigenetic regulatory mechanism for the transcriptional silencing of key LE genes via H3K27me3, essential for LE differentiation and thus embryo implantation.

Trophoblastic signals facilitate endometrial interferon response and lipid metabolism, ensuring normal decidualization.

The decidua plays a crucial role in providing structural and trophic support to the developing conceptus before placentation. Following embryo attachment, embryonic components intimately interact with the decidual tissue. While evidence indicates the participation of embryo-derived factors in crosstalk with the uterus, the extent of their impact on post-implantation decidual development requires further investigation. Here, we utilize transgenic mouse models to selectively eliminate primary trophoblast giant cells (pTGCs), the embryonic cells that interface with maternal tissue at the forefront. pTGC ablation impairs decidualization and compromises decidual interferon response and lipid metabolism. Mechanistically, pTGCs release factors such as interferon kappa (IFNK) to strengthen the decidual interferon response and lipoprotein lipase (LPL) to enhance lipid accumulation within the decidua, thereby promoting decidualization. This study presents genetic and metabolomic evidence reinforcing the proactive role of pTGC-derived factors in mobilizing maternal resources to strengthen decidualization, facilitating the normal progression of early pregnancy.

Med1 inhibits ferroptosis and alleviates liver injury in acute liver failure via Nrf2 activation.

BACKGROUND: Extensive hepatocyte mortality and the absence of specific medical therapy significantly contribute to the unfavorable prognosis of acute liver failure (ALF). Ferroptosis is a crucial form of cell death involved in ALF. In this study, we aimed to determine the impact of Mediator complex subunit 1 (Med1) on ferroptosis and its potential hepatoprotective effects in ALF. RESULTS: Med1 expression is diminished in the liver of lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced ALF mice, as well as in hepatocytes damaged by H2O2 or TNF-α/D-GalN in vitro. Med1 overexpression mitigates liver injury and decreases the mortality rate of ALF mice by ferroptosis inhibition. The mechanism by which Med1 inhibits erastin-induced ferroptosis in hepatocytes involves the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant genes heme oxygenase-1 (HO-1), glutamate cysteine ligase catalytic (GCLC), and NAD(P)H quinone oxidoreductase 1 (NQO1). Furthermore, Med1 overexpression suppresses the transcription of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the liver of mice with LPS/D-GalN-induced ALF. CONCLUSION: Overall, our research findings indicate that Med1 suppresses ferroptosis and alleviates liver injury in LPS/D-GalN-induced ALF through the activation of Nrf2. These findings substantiate the therapeutic viability of targeting the Med1-Nrf2 axis as a means of treating individuals afflicted with ALF.

Transcatheter arterial chemoembolization combined with PD-1 inhibitors and Lenvatinib for hepatocellular carcinoma with portal vein tumor thrombus.

BACKGROUND: Hepatocellular carcinoma (HCC) patients complicated with portal vein tumor thrombus (PVTT) exhibit poor prognoses and treatment responses. AIM: To investigate efficacies and safety of the combination of PD-1 inhibitor, transcatheter arterial chemoembolization (TACE) and Lenvatinib in HCC subjects comorbid with PVTT. METHODS: From January 2019 to December 2020, HCC patients with PVTT types I-IV were retrospectively enrolled at Beijing Ditan Hospital. They were distributed to either the PTL or TACE/Lenvatinib (TL) group. The median progression-free survival (mPFS) was set as the primary endpoint, while parameters like median overall survival, objective response rate, disease control rate (DCR), and toxicity level served as secondary endpoints. RESULTS: Forty-one eligible patients were finally recruited for this study and divided into the PTL (n = 18) and TL (n = 23) groups. For a median follow-up of 21.8 months, the DCRs were 88.9% and 60.9% in the PTL and TL groups (P = 0.046), res-pectively. Moreover, mPFS indicated significant improvement (HR = 0.25; P < 0.001) in PTL-treated patients (5.4 months) compared to TL-treated (2.7 months) patients. There were no treatment-related deaths or differences in adverse events in either group. CONCLUSION: A triplet regimen of PTL was safe and well-tolerated as well as exhibited favorable efficacy over the TL regimen for advanced-stage HCC patients with PVTT types I-IV.

Characterization and comparison of flavors in fresh and aged fermented peppers: Impact of different varieties.

The flavor profiles of fresh and aged fermented peppers obtained from four varieties were thoroughly compared in this study. A total of 385 volatile compounds in fermented pepper samples were detected by flavoromics (two-dimensional gas chromatography-time-of-flight mass spectrometry). As fermentation progressed, both the number and the total concentration of volatile compounds changed, with esters, alcohols, acids, terpenoids, sulfur compounds, and funans increasing, whereas hydrocarbons and benzenes decreased. In contrast to the fresh fermented peppers, the aged fermented samples exhibited lower values of pH, total sugars, and capsaicinoids but higher contents of organic acids and free amino acids. Furthermore, the specific differences and characteristic aroma substances among aged fermented peppers were unveiled by multivariate statistical analysis. Overall, 64 volatiles were screened as differential compounds. In addition, Huanggongjiao samples possessed the most abundant differential volatiles and compounds with odor activity values > 1, which were flavored with fruity, floral, and slightly phenolic odors. Correlation analysis demonstrated that the levels of 23 key aroma compounds (e.g., ethyl 2-methylbutyrate, 1-butanol, and ethyl valerate) showed a significantly positive correlation with Asp, Glu and 5 organic acids. By contrast, there is a negative association between the pH value and total sugar. Overall, aging contributed significantly to the flavor attributes of fermented peppers.

AOB Nitrosospira cluster 3a.2 (D11) dominates N2O emissions in fertilised agricultural soils.

Ammonia-oxidation process directly contribute to soil nitrous oxide (N2O) emissions in agricultural soils. However, taxonomy of the key nitrifiers (within ammonia oxidising bacteria (AOB), archaea (AOA) and complete ammonia oxidisers (comammox Nitrospira)) responsible for substantial N2O emissions in agricultural soils is unknown, as is their regulation by soil biotic and abiotic factors. In this study, cumulative N2O emissions, nitrification rates, abundance and community structure of nitrifiers were investigated in 16 agricultural soils from major crop production regions of China using microcosm experiments with amended nitrogen (N) supplemented or not with a nitrification inhibitor (nitrapyrin). Key nitrifier groups involved in N2O emissions were identified by comparative analyses of the different treatments, combining sequencing and random forest analyses. Soil cumulative N2O emissions significantly increased with soil pH in all agricultural soils. However, they decreased with soil organic carbon (SOC) in alkaline soils. Nitrapyrin significantly inhibited soil cumulative N2O emissions and AOB growth, with a significant inhibition of the AOB Nitrosospira cluster 3a.2 (D11) abundance. One Nitrosospira multiformis-like OTU phylotype (OTU34), which was classified within the AOB Nitrosospira cluster 3a.2 (D11), had the greatest importance on cumulative N2O emissions and its growth significantly depended on soil pH and SOC contents, with higher growth at high pH and low SOC conditions. Collectively, our results demonstrate that alkaline soils with low SOC contents have high N2O emissions, which were mainly driven by AOB Nitrosospira cluster 3a.2 (D11). Nitrapyrin can efficiently reduce nitrification-related N2O emissions by inhibiting the activity of AOB Nitrosospira cluster 3a.2 (D11). This study advances our understanding of key nitrifiers responsible for high N2O emissions in agricultural soils and their controlling factors, and provides vital knowledge for N2O emission mitigation in agricultural ecosystems.

Effects of different hot-air drying methods on the dynamic changes in color, nutrient and aroma quality of three chili pepper (Capsicum annuum L.) varieties.

The effects of constant and variable temperature hot-air drying methods on drying time, colors, nutrients, and volatile compounds of three chili pepper varieties were investigated in this study. Overall, the variable temperature drying could facilitate the removal of water, preserve surface color, and reduce the loss of total sugar, total acid, fat and capsaicin contents. Electronic-nose (E-nose) and gas chromatography-ion mobility spectroscopy (GC-IMS) analyses found that aldehydes, ketones, alcohols and esters contributed to the aroma of chili peppers. The drying process led to an increase in acids, furans and sulfides contents, while decreasing alcohols, esters and olefins levels. In addition, the three chili pepper varieties displayed distinct physical characteristics, drying times, chromatic values, nutrients levels and volatile profiles during dehydration. This study suggests variable temperature drying is a practical approach to reduce drying time, save costs, and maintain the commercial appeal of chili peppers.

An actor-critic framework based on deep reinforcement learning for addressing flexible job shop scheduling problems.

With the rise of Industry 4.0, manufacturing is shifting towards customization and flexibility, presenting new challenges to meet rapidly evolving market and customer needs. To address these challenges, this paper suggests a novel approach to address flexible job shop scheduling problems (FJSPs) through reinforcement learning (RL). This method utilizes an actor-critic architecture that merges value-based and policy-based approaches. The actor generates deterministic policies, while the critic evaluates policies and guides the actor to achieve the most optimal policy. To construct the Markov decision process, a comprehensive feature set was utilized to accurately represent the system's state, and eight sets of actions were designed, inspired by traditional scheduling rules. The formulation of rewards indirectly measures the effectiveness of actions, promoting strategies that minimize job completion times and enhance adherence to scheduling constraints. The experimental evaluation conducted a thorough assessment of the proposed reinforcement learning framework through simulations on standard FJSP benchmarks, comparing the proposed method against several well-known heuristic scheduling rules, related RL algorithms and intelligent algorithms. The results indicate that the proposed method consistently outperforms traditional approaches and exhibits exceptional adaptability and efficiency, particularly in large-scale datasets.

Adenine's impact on mice's gut and kidney varies with the dosage administered and relates to intestinal microorganisms and enzyme activities.

This study aimed to investigate the effects of different dosages of adenine on intestinal microorganisms and enzyme activities, laying the experimental groundwork for subsequent exploration of the microbial mechanisms underlying diarrhea with kidney yang deficiency syndrome. Twenty-four mice were assigned to the following four groups: the control (NC) group, low-dosage adenine (NML) group, middle-dosage adenine (NMM) group, and high-dosage adenine (NMH) group. Mice in the NML, NMM, and NMH groups received 25 mg/(kg·d), 50 mg/(kg·d), and 100 mg/(kg·d) of adenine, respectively, 0.4 mL/each, once a day for 14 days. The NC group received 0.4 mL sterile water. Parameters including body weight, rectal temperature, intestinal microorganisms, enzyme activities, and microbial activity were measured. Results indicated that mice in the experimental group displayed signs of a poor mental state, curled up with their backs arched, and felt sleepy and lazy, with sparse fur that was easily shed, and damp bedding. Some mice showed fecal adhesion contamination in the perianal and tail areas. Dosage-dependent effects were observed, with decreased food intake, body weight, rectal temperature, and microbial activity and increased water intake and fecal water content. Enzyme activity analyses revealed significantly higher activities of protease, sucrase, amylase, and cellulase in intestinal contents and lactase, sucrase, amylase, and cellulase in the mucosa of the NMM group compared to those of other groups. Ultimately, the higher adenine dosage was associated with more pronounced symptoms of kidney yang deficiency syndrome, with 50 mg/kg adenine exhibiting the most substantial impact on the number of intestinal microbial colonies and enzyme activities.

The skin photoprotective effect of trilinolein: Induction of cellular autophagy via the AMPK-mTOR signaling pathway.

Trilinolein (TL) is an active substance contained in traditional Chinese herbs; modern studies have shown that trilinolein has anti-inflammatory and antioxidant effects on the body. This study delves into the photoprotective effect of trilinolein on UVB-irradiated Human Skin Fibroblast (HSF) cells and the underlying mechanisms. Our findings reveal that trilinolein had a photoprotective effect on HSF cells: trilinolein enhanced cellular autophagy, restored UVB-inhibited cell proliferative viability, and curbing UVB-induced reactive oxygen species (ROS) and apoptosis. Intriguingly, after inhibition of TL-induced autophagy via wortmannin, diminished trilinolein's photoprotective effects. Meanwhile, trilinolein was shown to modulate the AMPK-mTOR signaling pathway, thus enhance cellular autophagy in HSF cells, and this tendency was suppressed after the administration of compound C (AMPK inhibitor). In a mouse model of skin photodamage, trilinolein significantly mitigated photodamage extent through morphological and histopathological analyses. This study illuminates trilinolein could inhibit the photodamaging effects of UVB irradiation by regulating cellular autophagy through the AMPK-mTOR signaling pathway, suggesting its promising application in combating UV-induced skin disorders.

Characterisation of flavour profiles and microbial communities of fermented peppers with different fermentation years by combining flavouromics and metagenomics.

The changes in flavours, volatile aromas and microbial communities of fermented peppers with different fermentation years and their relationships were investigated in this study. Results indicated a gradual increase in organic acids during fermentation, whereas free amino acids and capsaicinoids reached stability after 1 year of fermentation. Overall, the analysis detected 340 volatile compounds in fermented peppers and regarded 69 of them as differential compounds. Peppers fermented for 2 (FY2) and 4 years (FY4) possessed a greater number of differential volatiles with large odour activity values, thus endowing them with more favourable flavours. Hence, metagenomic analysis compared their microbial communities and functional annotations. Results revealed that Lactiplantibacillus plantarum and Zygosaccharomyces rouxii were the dominant bacterium and fungus, and metabolism was the main Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway in FY2. Correlation analysis demonstrated that Hyphopichia, Kazachstania and Clavispora were highly positively correlated with 12 key aroma flavours.

Physicochemical properties and pork preservation effects of lotus seed drill core powder starch-based active packaging films.

Lotus seed drill core powder starch (LCPS)-based active packaging films incorporated with cellulose nanocrystals (CNC) and grapefruit essential oil-corn nanostarch Pickering emulsion (ECPE) were characterized, and their pork preservation effects were investigated in this study. In contrast with corn, potato and rice starches, LCPS showed higher amylose content, elliptical and circular shape with more uniform size distribution. Furthermore, LCPS film exhibited lower light transmittance, stronger tensile strength, and smaller elongation at break compared to the other starch films. Then, the LCPS film containing 4 % CNC and 9 % ECPE was fabricated which had stronger mechanical properties, lower water vapor permeability and oxygen transmission rate, and denser network structure. FTIR and XRD analyses also confirmed that CNC and ECPE were successfully implanted into the LCPS matrix without damaging the crystalline structure of LCPS. Herein, the LCPS/CNC/ECPE film exerted potential antibacterial activity against Escherichia coli and Staphylococcus aureus. Besides, packaging with this composite film significantly preserved the pork during cold storage via decreasing its juice loss rate, pH value, total number of colonies, total volatile base nitrogen and thiobarbituric acid reactive substance values. The present study will provide a theoretical basis for the application of LCPS as new biodegradable active films.

The presence of blastocyst within the uteri facilitates lumenal epithelium transformation for implantation via upregulating lysosome proteostasis activity.

ABBREVIATIONS: ACTB: actin beta; AREG: amphiregulin; ATP6V0A4: ATPase, H+ transporting, lysosomal V0 subunit A4; Baf A1: bafilomycin A1; BSA: bovine serum albumin; CLDN1: claudin 1; CTSB: cathepsin B; DEGs: differentially expressed genes; E2: 17ß-estradiol; ESR: estrogen receptor; GATA2: GATA binding protein 2; GLA: galactosidase, alpha; GO: gene ontology; HBEGF: heparin-binding EGF-like growth factor; IGF1R: insulin-like growth factor 1 receptor; Ihh: Indian hedgehog; ISH: in situ hybridization; LAMP1: lysosomal-associated membrane protein 1; LCM: laser capture microdissection; Le: lumenal epithelium; LGMN: legumain; LIF: leukemia inhibitory factor; LIFR: LIF receptor alpha; MSX1: msh homeobox 1; MUC1: mucin 1, transmembrane; P4: progesterone; PBS: phosphate-buffered saline; PCA: principal component analysis; PPT1: palmitoyl-protein thioesterase 1; PGR: progesterone receptor; PSP: pseudopregnancy; PTGS2/COX2: prostaglandin-endoperoxide synthase 2; qPCR: quantitative real-time polymerase chain reaction; SP: pregnancy; TFEB: transcription factor EB.

Trimethylamine N-oxide promotes abdominal aortic aneurysm by inducing vascular inflammation and vascular smooth muscle cell phenotypic switching.

OBJECTIVE: Inflammation and vascular smooth muscle cell (VSMC) phenotypic switching are implicated in the pathogenesis of abdominal aortic aneurysm (AAA). Trimethylamine N-oxide (TMAO) has emerged as a crucial risk factor in cardiovascular diseases, inducing vascular inflammation and calcification. We aimed to evaluate the effect of TMAO on the formation of AAA. APPROACH AND RESULTS: Here, we showed that TMAO was elevated in plasma from AAA patients compared with nonaneurysmal subjects by liquid chromatography‒mass spectrometry (LC‒MS) detection. Functional studies revealed that increased TMAO induced by feeding a choline-supplemented diet promoted Ang II-induced AAA formation. Immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and Western blot analyses revealed that TMAO induced macrophage infiltration and inflammatory factor release. Conversely, inhibition of TMAO by supplementation with DMB suppressed AAA formation and the inflammatory response. Molecular studies revealed that TMAO regulated VSMC phenotypic switching. Flow cytometry analyses showed that TMAO induces macrophage M1-type polarization. Furthermore, pharmacological intervention experiments suggested that the nuclear factor-κB (NF-κB) signaling pathway was critical for TMAO to trigger AAA formation. CONCLUSIONS: TMAO promotes AAA formation by inducing vascular inflammation and VSMC phenotypic switching through activation of the NF-κB signaling pathway. Thus, TMAO is a prospective therapeutic AAA target.

Evaluation of toxicological effects of chemical substances by gut microbiota: The example of adenine damage to the kidney and gut.

This study explored the effects of different doses of adenine intake on mice in terms of kidney function, oxidative stress and gut content microbiota to elucidate interactions between adenine-induced kidney function impairment and gut content microbiota disorder. Mice were gavaged with low-dosage adenine suspension (NML), middle-dosage adenine suspension (NMM), high-dosage adenine suspension (NMH) and sterile water (NC). Behaviour, kidney structure and function, colonic structure, oxidative stress and gut content microbiota were detected. Mice in NML, NMM, and NMH groups had significantly lower body weight, anal temperature and food intake, increased water intake, the mice had loose and deformed feces with obvious water stains through the paper. NMM mice presented significantly structural damage to kidney and colonic tissues, considerably higher BUN and Cr, MDA and lower SOD. MDA and SOD levels in NMM and NMH groups were closely associated with Cr and BUN. Moreover, different doses of adenine intake effected the mice gut content microbiota, and enriched the different characteristic bacteria. Characteristic bacteria Lactobacillus and Bifidobacterium presented significant correlations with MDA. Eventually, Lactobacillus and Bifidobacterium mediated oxidative stress pathway involved in the process of adenine-induced kidney injure in mice.

Effects of maltodextrin and protein hydrolysate extracted from lotus seed peel powder on the fat substitution and lipid oxidation of lotus seed paste.

The fat substitution of maltodextrin from lotus seed peel powder (LSP-MD) and the lipid oxidation inhibitory effect of protein hydrolysate (LSP-PH) on lotus seed paste were investigated in this study. The LSP-MD with a dextrose equivalent value of 2.28 showed the smallest specific volume, strongest water-holding capacity and retrogradation. This LSP-MD effectively maintained the sensory quality, hardness and elasticity of low-fat lotus seed paste during storage at 25 °C. For protein hydrolysate, LSP-PH with a hydrolyzation degree of 13.45 % had the strongest DPPH· scavenging capacity and ferric reducing antioxidant power, which was further confirmed by FTIR spectra that enzymatic hydrolysis of LSP protein could facilitate the transformation of ß-sheet into ß-turn. Following 15 days of storage, supplementation with 0.5 % LSP-PH reduced the peroxide value and acid value of lotus seed paste, suggesting its excellent inhibitory effect on lipid peroxidation via interacting with hydrophobic polyunsaturated fatty acids.

Alterations in intestinal microbiota and enzyme activities under cold-humid stress: implications for diarrhea in cold-dampness trapped spleen syndrome.

Introduction: Cold and humid environments alter the intestinal microbiota, and the role of the intestinal microbiota in the development of diarrhea associated with cold-dampness trapped spleen syndrome in Chinese medicine is unclear. Methods: The 30 mice were randomly divided into normal and model groups, with the model group being exposed to cold and humid environmental stresses for 7 days. Then, mouse intestinal contents were collected and analyzed their intestinal microbiota and digestive enzymes. Results: Our findings revealed significant increases in sucrase and lactase activities, as well as microbial activity, in the model group (p < 0.05). ß-diversity analysis highlighted distinct intestinal microbiota compositions between the two groups. Specifically, the experimental group showed a unique dominance of the genera and strains Clostridium sensu stricto 1 and Clostridium sp. ND2. LEfSe analysis identified Helicobacter, Roseburia, and Eubacterium plexicaudatum ASF492 as differentially abundant species in them model group. Network analysis demonstrated that rare bacterial species mostly governed the microbial interactions, exhibiting increased mutual promotion. On the other hand, abundant species like Lactobacillus johnsonii and Lactobacillus reuteri showed mutual inhibitory relationships. Discussion: In summary, exposure to cold and humid conditions led to increased intestinal enzyme activities and a shift in microbial composition, favoring the growth of rare bacterial species. These changes suggest that rare bacteria in the intestinal microbiota play a critical role in the pathology of diarrhea associated with cold-dampness trapped spleen syndrome, revealing unique survival strategies among bacterial populations under stressful conditions.

Zhishi Daozhi decoction alleviates constipation induced by a high-fat and high-protein diet via regulating intestinal mucosal microbiota and oxidative stress.

Background: A growing body of evidence has demonstrated that a high-fat and high-protein diet (HFHPD) causes constipation. This study focuses on understanding how the use of Zhishi Daozhi decoction (ZDD) affects the intricate balance of intestinal microorganisms. The insights gained from this investigation hold the potential to offer practical clinical approaches to mitigate the constipation-related issues associated with HFHPD. Materials and methods: Mice were randomly divided into five groups: the normal (MN) group, the natural recovery (MR) group, the low-dose ZDD (MLD) group, the medium-dose ZDD (MMD) group, and the high-dose ZDD (MHD) group. After the constipation model was established by HFHPD combined with loperamide hydrochloride (LOP), different doses of ZDD were used for intervention. Subsequently, the contents of cholecystokinin (CCK) and calcitonin gene-related peptide (CGRP) in serum, superoxide dismutase (SOD), and malondialdehyde (MDA) in the liver were determined. The DNA of intestinal mucosa was extracted, and 16S rRNA amplicon sequencing was used to analyze the changes in intestinal mucosal microbiota. Results: After ZDD treatment, CCK content in MR group decreased and CGRP content increased, but the changes were not significant. In addition, the SOD content in MR group was significantly lower than in MLD, MMD, and MHD groups, and the MDA content in MR group was significantly higher than in MN, MLD, and MHD groups. Constipation modeling and the intervention of ZDD changed the structure of the intestinal mucosal microbiota. In the constipation induced by HFHPD, the relative abundance of pathogenic bacteria such as Aerococcus, Staphylococcus, Corynebacterium, Desulfovibrio, Clostridium, and Prevotella increased. After the intervention of ZDD, the relative abundance of these pathogenic bacteria decreased, and the relative abundance of Candidatus Arthromitus and the abundance of Tropane, piperidine, and pyridine alkaloid biosynthesis pathways increased in MHD group. Conclusion: Constipation induced by HFHPD can increase pathogenic bacteria in the intestinal mucosa, while ZDD can effectively relieve constipation, reduce the relative abundance of pathogenic bacteria, and alleviate oxidative stress injury. In addition, high-dose ZDD can increase the abundance of beneficial bacteria, which is more conducive to the treatment of constipation.

Mesenchymal Stem Cells Promote Polarization of M2 Macrophages in Mice with Acute-On-Chronic Liver Failure via Mertk/JAK1/STAT6 Signaling.

Acute-on-chronic liver failure (ACLF) is a severe disease with a high mortality. Macrophage-related inflammation plays a crucial role in ACLF development. Mesenchymal stem cells (MSCs) treatment was demonstrated to be beneficial in ACLF in our previous study; however, the underlying mechanisms remain unknown. Therefore, mouse bone marrow-derived MSCs were used to treat an ACLF mouse model or cocultured with RAW264.7/J774A.1 macrophages that were stimulated with LPS. Histological and serological parameters and survival were analyzed to evaluate efficacy. We detected changes of Mer tyrosine kinase (Mertk), JAK1/STAT6, inflammatory cytokines, and markers of macrophage polarization in vitro and in vivo. In ACLF mice, MSCs improved liver function and 48-h survival of ACLF mice and alleviated inflammatory injury by promoting M2 macrophage polarization and elevated Mertk expression levels in macrophages. This is significant, as Mertk regulates M2 macrophage polarization via the JAK1/STAT6 signaling pathway.

Association of Short-Chain Fatty Acids with Gut Microbiota and Lipid Metabolism in Mice with Diarrhea Induced by High-Fat Diet in a Fatigued State.

SCOPE: Preliminary research finds that a high-fat diet (HFD) in a fatigued state triggers diarrhea, but the exact mechanism has not been clarified. To address concerns about the pathogenesis of diarrhea, the study evaluates the composition and metabolomics of the gut microbiota. METHODS AND RESULTS: The study uses the multiple platform apparatus device to induce fatigue in mice, combined with intragastric administration of lard-caused diarrhea. Subsequently, the characteristics and interaction relationship of gut microbiota, short-chain fatty acids (SCFAs), inflammatory biomarkers, brain-gut peptides, and lipid metabolism are analyzed at the end of the experiment. HFD in a fatigued state results in a significant increase in interleukin-17, interleukin-6, cholecystokinin, somatostatin, and malondialdehyde content in mice (p < 0.05), along with a substantial decrease in high-density lipoprotein (p < 0.05). Additionally, an HFD in a fatigued state causes changes in the structure and composition of the gut microbiota, with Lactobacillus murinus as its characteristic bacteria, and reduces the production of SCFAs. CONCLUSIONS: An HFD in a fatigued state triggers diarrhea, possibly associated with gut content microbiota dysbiosis, SCFAs deprivation, increased inflammation, and dysregulated lipid metabolism.