The gut microbiota-aromatic hydrocarbon receptor (AhR) axis mediates the anticolitic effect of polyphenol-rich extracts from Sanghuangporus.

Inflammatory bowel disease (IBD) is a significant global health concern. The gut microbiota plays an essential role in the onset and development of IBD. Sanghuangporus (SH), a traditional Chinese medicinal mushroom, has excellent anti-inflammatory effects and is effective at modulating the gut microbiota. Despite these attributes, the specific anticolitic effects of SH and the mechanisms through which the gut microbiota mediates its benefits remain unclear. Herein, we demonstrated that polyphenol-rich extract from SH effectively alleviated the pathological symptoms of dextran sodium sulfate (DSS)-induced colitis in mice by modulating the gut microbiota. Treatment with SH distinctly enriched Alistipes, especially Alistipes onderdonkii, and its metabolite 5-hydroxyindole-3-acetic acid (5HIAA). Oral gavage of live A. onderdonkii or 5HIAA potently mitigated DSS-induced colitis in mice. Moreover, both 5HIAA and SH significantly activated the aromatic hydrocarbon receptor (AhR), and the administration of an AhR antagonist abrogated their protective effects against colitis. These results underscore the potent efficacy of SH in diminishing DSS-induced colitis through the promotion of A. onderdonkii and 5HIAA, ultimately activating AhR signaling. This study unveils potential avenues for developing therapeutic strategies for colitis based on the interplay between SH and the gut microbiota.

Machine learning to predict lymph node metastasis in T1 esophageal squamous cell carcinoma：a multicenter study.

BACKGROUND: Existing models do poorly when it comes to quantifying the risk of Lymph node metastases (LNM). This study aimed to develop a machine learning model for LNM in patients with T1 esophageal squamous cell carcinoma (ESCC). METHODS AND RESULTS: The study is multicenter, and population based. Elastic net regression (ELR), random forest (RF), extreme gradient boosting (XGB), and a combined (ensemble) model of these was generated. The contribution to the model of each factor was calculated. The models all exhibited potent discriminating power. The Elastic net regression performed best with externally validated AUC of 0.803, whereas the NCCN guidelines identified patients with LNM with an AUC of 0.576 and logistic model with an AUC of 0. 670. The most important features were lymphatic and vascular invasion and depth of tumor invasion. CONCLUSIONS: Models created utilizing machine learning approaches had excellent performance estimating the likelihood of LNM in T1 ESCC.

Overexpression of NtGPX8a Improved Cadmium Accumulation and Tolerance in Tobacco (Nicotiana tabacum L.).

Cadmium (Cd)-induced oxidative stress detrimentally affects hyperaccumulator growth, thereby diminishing the efficacy of phytoremediation technology aimed at Cd pollution abatement. In the domain of plant antioxidant mechanisms, the role of glutathione peroxidase (GPX) in conferring Cd tolerance to tobacco (Nicotiana tabacum) remained unclear. Our investigation employed genome-wide analysis to identify 14 NtGPX genes in tobacco, revealing their organization into seven subgroups characterized by analogous conserved domain patterns. Notably, qPCR analysis highlighted NtGPX8a as markedly responsive to Cd2+ stress. Subsequent exploration through yeast two-hybridization unveiled NtGPX8a's utilization of thioredoxins AtTrxZ and AtTrxm2 as electron donors, and without interaction with AtTrx5. Introduction of NtGPX8a into Escherichia coli significantly ameliorated Cd-induced adverse effects on bacterial growth. Transgenic tobacco overexpressing NtGPX8a demonstrated significantly augmented activities of GPX, SOD, POD, and CAT under Cd2+ stress compared to the wild type (WT). Conversely, these transgenic plants exhibited markedly reduced levels of MDA, H2O2, and proline. Intriguingly, the expression of NtGPX8a in both E. coli and transgenic tobacco led to increased Cd accumulation, confirming its dual role in enhancing Cd tolerance and accumulation. Consequently, NtGPX8a emerges as a promising candidate gene for engineering transgenic hyperaccumulators endowed with robust tolerance for Cd-contaminated phytoremediation.

Responses of Trollius chinensis to drought stress and rehydration: From photosynthetic physiology to gene expression.

Drought stress occurs more frequently in recent years due to the global climate change. Widely distributed in northern China, Mongolia, and Russia, Trollius chinensis Bunge has high medicinal and ornamental values and is often exposed to drought stress, while the mechanism underlying its drought response is still unclear. In this study, we applied 74-76% (control, CK), 49-51% (mild drought), 34-36% (moderate drought), and 19-21% (severe drought, SD) of the soil gravimetric water content to T. chinensis, and measured leaf physiological characteristics on the 0, 5th, 10th, 15th day after the soil reaching the set drought severities, and on the 10th day after rehydration. The results showed that many physiological parameters, such as chlorophyll contents, Fv/Fm, ΦPSⅡ, Pn, and gs decreased with the deepening of severity and duration of drought stress and recovered to some extent after rehydration. On the 10th day of drought stress, leaves in SD and CK were selected for RNA-Seq, and 1649 differentially expressed genes (DEGs) were found, including 548 up-regulated and 1101 down-regulated DEGs. Gene Ontology enrichment found that the DEGs were mainly enriched in catalytic activity and thylakoid. Koyto Encyclopedia of Genes and Genomes enrichment found that DEGs were enriched in some metabolic pathways such as carbon fixation and photosynthesis. Among them, the differential expression of genes related to photosynthesis process, ABA biosynthesis and signaling pathway, such as NCED, SnRK2, PsaD, PsbQ, and PetE, might explain why T. chinensis could tolerate and recover from as long as 15 days of severe drought conditions.

High-Dose Ionizing Radiation Accelerates Atherosclerotic Plaque Progression by Regulating P38/NCOA4-Mediated Ferritinophagy/Ferroptosis of Endothelial Cells.

PURPOSE: Radiation therapy (RT) significantly increased the incidence of coronary artery diseases, especially atherosclerosis. Endothelial dysfunction has been the major side effect of RT among tumor patients who received RT. However, the involvement between endothelial dysfunction and radiation-induced atherosclerosis (RIA) remains unclear. Here, we constructed a murine model of RIA, aiming to uncover its underlying mechanisms and identify novel strategies for RIA prevention and treatment. METHODS AND MATERIALS: Eight-week-old ApoE-/- mice that were fed a Western diet were subjected to partial carotid ligation (PCL). Four weeks later, ionizing radiation (IR) of 10 Gy was performed to verify the detrimental role of IR on atherogenesis. Ultrasound imaging, RT quantitative polymerase chain reaction, histopathology and immunofluorescence, and biochemical analysis were performed 4 weeks after IR. To study the involvement of endothelial ferroptosis induced by IR in RIA, mice after IR were administrated with ferroptosis agonist (cisplatin) or antagonist (ferrostatin-1) intraperitoneally. Western blotting, autophagic flux measurement, reactive oxygen species level detection, and coimmunoprecipitation assay were carried out in vitro. Furthermore, to determine the effect of ferritinophagy inhibition on RIA, in vivo knockdown of NCOA4 was carried out by pluronic gel. RESULTS: We verified that accelerated plaque progression was concomitant with endothelial cell (EC) ferroptosis after IR induction, as suggested by a higher level of lipid peroxidation and changes in ferroptosis-associated genes in the PCL + IR group than in the PCL group within vasculature. In vitro experiments further validated the devastating effects of IR on oxidative stress and ferritinophagy in ECs. Mechanistic experiments revealed that IR induced EC ferritinophagy and subsequent ferroptosis in a P38/NCOA4-dependent manner. Both in vitro and in vivo experiments confirmed the therapeutic effect of NCOA4 knockdown in alleviating IR-induced ferritinophagy/ferroptosis of EC and RIA. CONCLUSIONS: Our findings provide novel insights into the regulatory mechanisms of RIA and first prove that IR accelerates atherosclerotic plaque progression by regulating ferritinophagy/ferroptosis of ECs in a P38/NCOA4-dependent manner.

NR1D1 Deletion Induces Rupture-Prone Vulnerable Plaques by Regulating Macrophage Pyroptosis via the NF-κB/NLRP3 Inflammasome Pathway.

Vulnerable plaque rupture is the main trigger of most acute cardiovascular events. But the underlying mechanisms responsible for the transition from stable to vulnerable plaque remain largely unknown. Nuclear receptor subfamily 1 group D member 1 (NR1D1), also known as REV-ERB α, is a nuclear receptor that has shown the protective role in cardiovascular system. However, the effect of NR1D1 on vulnerable plaque rupture and its underlying mechanisms are still unclear. By generating the rupture-prone vulnerable plaque model in hypercholesterolemic ApoE-/- mice and NR1D1-/-ApoE-/- mice, we demonstrated that NR1D1 deficiency significantly augmented plaque vulnerability/rupture, with higher incidence of intraplaque hemorrhage (78.26% vs. 47.82%, P = 0.0325) and spontaneous plaque rupture with intraluminal thrombus formation (65.21% vs. 39.13%, P = 0.1392). In vivo experiments indicated that NR1D1 exerted a protective role in the vasculature. Mechanically, NR1D1 deficiency aggravates macrophage infiltration, inflammation, and oxidative stress. Compared with the ApoE-/- mice, NR1D1-/-ApoE-/- mice exhibited a significantly higher expression level of pyroptosis-related genes in macrophages within the plaque. Further investigation based on mice bone marrow-derived macrophages (BMDMs) confirmed that NR1D1 exerted a protective effect by inhibiting macrophage pyroptosis in a NLRP3-inflammasome-dependent manner. Besides, pharmacological activation of NR1D1 by SR9009, a specific NR1D1 agonist, prevented plaque vulnerability/rupture. In general, our findings provide further evidences that NR1D1 plays a protective role in the vasculature, regulates inflammation and oxidative stress, and stabilizes rupture-prone vulnerable plaques.

Effects of experimental fire in combination with climate warming on greenhouse gas fluxes in Arctic tundra soils.

The frequency and severity of fire is increasing in Arctic tundra regions with climate change. Here we investigated effects of experimental low-intensity fire and shrub cutting, in combination with warming, on soil biogeochemical cycles and post-fire greenhouse gas (GHG) emissions in a dry heath tundra, West Greenland. We performed in vitro incubation experiments based on soil samples collected for up to two years after the fire. We observed tendency for increased soil nitrate (14-fold) and significant increases in soil ammonium and phosphate (four-fold and five-fold, respectively) two years after the fire, but no effects of shrub cutting on these compounds. Thus, changes appear to be largely due to fire effects rather than indirect effects by vegetation destruction. Two years after fire, nitrous oxide (N2O) and carbon dioxide (CO2) production was significantly increased (three-fold and 32% higher, respectively), in burned than unburned soils, while methane (CH4) uptake remained unchanged. This stimulated N2O and CO2 production by the fire, however, was only apparent under conditions when soil was at maximum water holding capacity, suggesting that fire effects can be masked under dry conditions in this tundra ecosystem. There were positive effects by modest 2.5 °C warming on CO2 production in control but not in burned soils, suggesting that fire may decrease the temperature response in soil respiration. Methane uptake was neither altered by the modest warming in shrub-cut nor in burned soils after two years, suggesting that the removal of vegetation may play a key role in controlling future temperature response of CH4 oxidation. Altogether, our results show that post-fire tundra soils have the potential to enhance soil GHG emissions (e.g. N2O and CO2) especially during episodes with wet soil conditions. On the other hand, the lack of warming responses in post-fire soil respiration may weaken this positive feedback to climate change.

Uric acid participating in female reproductive disorders: a review.

Uric acid (UA) is the end metabolic product of purine metabolism. Early on, UA was considered to be a metabolite with a certain antioxidant capacity. As research has progressed, other properties of UA have been explored, and its association with many diseases has been found. The association between UA and kidney disease and cardiovascular disease is well established; however, there is still a paucity of reviews on the association between UA and the female reproductive system. An increasing number of epidemiological studies have shown elevated serum UA levels in patients with polycystic ovary syndrome (PCOS), endometriosis, etc. Additionally, serum UA can be used as a predictor of pregnancy complications and adverse foetal outcomes. An increasing number of animal experiments and clinical studies have revealed possible mechanisms related to the involvement of UA in certain female reproductive disorders: oxidative stress, chronic inflammation, mitochondrial dysfunction, etc. This article reviews the current mainstream mechanisms regarding the pathogenesis of UA and the role of UA in certain specific female reproductive disorders (direct involvement in the development of certain diseases or enhancement of other risk factors) in the hope of contributing to clinical prevention, diagnosis, treatment and improvement in prognosis.

Transcutaneous Electrical Acustimulation Improves Gastrointestinal Disturbances Induced by Transcatheter Arterial Chemoembolization in Patients With Liver Cancers.

BACKGROUND: Gastrointestinal (GI) disturbances occur in patients who receive chemotherapy via transcatheter arterial chemoembolization (TACE) and could last for an extended period of time in some cases. Antiemetic drugs have a potential risk of developing hepatic failure and are ineffective for delayed nausea and emesis. Transcutaneous electrical acustimulation (TEA) has recently been reported to exert antiemetic and prokinetic effects, but it is unknown whether it has an ameliorating effect on TACE-induced GI disturbances. AIM: This study was designed to evaluate effects and mechanisms of noninvasive TEA on GI symptoms in patients treated with TACE. MATERIALS AND METHODS: Seventy-four patients with liver cancers (eighteen female; age 63.4 ± 1.1 years) scheduled for TACE were randomized to TEA (n = 37) or sham-TEA (n = 37). TEA was performed via acupoints, ST36 and PC6 using parameters previously optimized for GI motility (1 h, bid) from the postoperative day 0 (POD0) to POD2. Sham-TEA was performed using the same parameters via non-acupoints. Symptom questionnaires were completed daily. The electrogastrogram (EGG) and electrocardiogram (ECG) were recorded in the fasting state for 30 mins to assess gastric slow waves and autonomic functions, respectively, before and after the 3-day treatment. RESULTS: 1) In the acute phase (<24 h), TEA showed no effects on any of GI symptoms, compared with sham-TEA. 2) In the delayed phase (>24 h), TEA, compared with sham-TEA, decreased the percentage of patients who experienced nausea on POD3 (0% vs. 13.5%, p = 0.021), the nausea score on POD3 (p = 0.022), the anorexia score on POD2 (p = 0.040) and POD3 (p = 0.004), and the bloating score (POD1-3: p < 0.01). 3) In comparison with sham-TEA, TEA increased the number of spontaneous bowel movements (p = 0.001) and the Bristol score of the first stool (p = 0.014) and decreased the number of patients with the use of laxatives (p = 0.022). 4) Physiologically, the 3-day TEA but not sham-TEA increased the percentage of normal gastric slow waves (p < 0.001) and vagal activity (p = 0.006). The vagal activity was negatively correlated with the anorexia score (r = -0.267, p = 0.026). It was found that the sympathovagal ratio and tumor size>5 cm were independent risk factors predicting the occurrence of nausea in patients after TACE. CONCLUSION: TEA improves major TACE-induced GI disturbances in the delayed phase, including nausea, bloating, impaired gastric pace-making activity, and constipation in patients with liver cancers via the autonomic pathway.

Combined effects of glacial retreat and penguin activity on soil greenhouse gas fluxes on South Georgia, sub-Antarctica.

The effects of soil succession after glacial retreat and fertilisation by marine animals are known to have major impacts on soil greenhouse gas (GHG) fluxes in polar terrestrial ecosystems. While in many polar coastal areas retreating glaciers open up new ground for marine animals to colonise, little is known about the combination of both factors on the local GHG budget. We studied the magnitude of GHG fluxes (CO2, CH4 and N2O) on the combined effect of glacial retreat and penguin-induced fertilisation along a transect protruding into the world's largest King Penguin (Aptenodytes patagonicus) colony at Saint Andrews Bay on sub-Antarctic South Georgia. GHG production and consumption rates were assessed based on laboratory incubations of intact soil cores and nutrients and water additional experimental incubations. The oldest soils along the transect show significant higher contents of soil carbon, nutrients and moisture and were strongly influenced by penguin activity. We found a net CH4 consumption along the entire transect with a marked decrease within the penguin colony. CO2 production strongly increased along the transect, while N2O production rates were low near the glacier front and increased markedly within the penguin colony. Controlled applications of guano resulted in a significant increase in CO2 and N2O production, and decrease in CH4 consumption, except for sites already strongly influenced by penguin activity. The results show that soil microbial activity promptly catalyses a turnover of soil C and atmospheric methane oxidation in de-glaciated forelands. The methane oxidizers, however, may increase relatively slowly in their capacity to oxidise atmospheric CH4. Results show also that the increase of nutrients by penguins reduces CH4 oxidation whereas N2O production is greatly increased. A future expansion of penguins into newly available ice-free polar coastal areas may therefore markedly increase the local GHG budget.

CD146 Regulates Growth Factor-Induced mTORC2 Activity Independent of the PI3K and mTORC1 Pathways.

The mechanistic target of rapamycin complex 2 (mTORC2) coordinates cell proliferation, survival, and metabolism with environmental inputs, yet how extracellular stimuli such as growth factors (GFs) activate mTORC2 remains enigmatic. Here we demonstrate that in human endothelial cells, activation of mTORC2 signaling by GFs is mediated by transmembrane cell adhesion protein CD146. Upon GF stimulation, the cytoplasmic tail of CD146 is phosphorylated, which permits its positively charged, juxtamembrane KKGK motif to interact with Rictor, the defining subunit of mTORC2. The formation of the CD146-Rictor/mTORC2 complex protects Rictor from ubiquitin-proteasome-mediated degradation, thereby specifically upregulating mTORC2 activity with no intervention of the PI3K and mTORC1 pathways. This CD146-mediated mTORC2 activation in response to GF stimulation promotes cell proliferation and survival. Therefore, our findings identify a molecular mechanism by which extracellular stimuli regulate mTORC2 activity, linking environmental cues with mTORC2 regulation.

FIP-sch2, a new fungal immunomodulatory protein from Stachybotrys chlorohalonata, suppresses proliferation and migration in lung cancer cells.

Fungal immunomodulatory protein (FIP)-sch2, an immunomodulatory protein identified in the ascomycete Stachybotrys chlorohalonata by a sequence similarity search, is a novel member of the FIP family. FIP-sch2 shares high sequence identity, structure, and evolutionary conservation with previously reported FIPs. It was satisfactorily expressed in Escherichia coli with a glutathione S-transferase (GST) tag and purified by GST-affinity magnetic beads. To characterize the direct antitumor effects, human lung adenocarcinoma A549 cells were treated with different concentrations of recombinant FIP (rFIP)-sch2 in vitro, and the results showed that rFIP-sch2 could reduce cell viability dose-dependently with a half-maximal inhibitory concentration (IC50) of 9.48 µg/mL. Furthermore, rFIP-sch2 at 8 µg/mL could significantly induce apoptosis and interrupt migration in A549 cells. Notably, the antitumor effect of rFIP-sch2 was equivalent to that of rLZ-8 but was obviously increased compared to rFIP-fve. In addition, the exploration of the antitumor mechanism suggested that rFIP-sch2 induced lung cancer cell death by activating apoptosis and inhibiting migration. Our results indicated that rFIP-sch2 was a promising candidate for use in future cancer therapy.

Identification and Characterisation of a Novel Protein FIP-sch3 from Stachybotrys chartarum.

In this study, a novel FIP named FIP-sch3 has been identified and characterised. FIP-sch3 was identified in the ascomycete Stachybotrys chartarum, making it the second FIP to be identified outside the order of Basidiomycota. Recombinant FIP-sch3 (rFIP-shc3) was produced in Escherichia coli and purified using GST-affinity magnetic beads. The bioactive characteristics of FIP-sch3 were compared to those of well-known FIPs LZ-8 from Ganoderma lucidum and FIP-fve from Flammulina velutipes, which were produced and purified using the same method. The purified rFIP-sch3 exhibited a broad spectrum of anti-tumour activity in several types of tumour cells but had no cytotoxicity in normal human embryonic kidney 293 cells. Assays that were implemented to study these properties indicated that rFIP-sch3 significantly suppressed cell proliferation, induced apoptosis and inhibited cell migration in human lung adenocarcinoma A549 cells. The anti-tumour effects of rFIP-sch3 in A549 cells were comparable to those of rLZ-8, but they were significantly greater than those of rFIP-fve. Molecular assays that were built on real-time PCR further revealed potential mechanisms related to apoptosis and migration and that underlie phenotypic effects. These results indicate that FIP-shc3 has a unique anti-tumour bioactive profile, as do other FIPs, which provide a foundation for further studies on anti-tumour mechanisms. Importantly, this study also had convenient access to FIP-sch3 with potential human therapeutic applications.