Bip-Yorkie interaction determines oncogenic and tumor-suppressive roles of Ire1/Xbp1s activation.

Unfolded protein response (UPR) is the mechanism by which cells control endoplasmic reticulum (ER) protein homeostasis. ER proteostasis is essential to adapt to cell proliferation and regeneration in development and tumorigenesis, but mechanisms linking UPR, growth control, and cancer progression remain unclear. Here, we report that the Ire1/Xbp1s pathway has surprisingly oncogenic and tumor-suppressive roles in a context-dependent manner. Activation of Ire1/Xbp1s up-regulates their downstream target Bip, which sequesters Yorkie (Yki), a Hippo pathway transducer, in the cytoplasm to restrict Yki transcriptional output. This regulation provides an endogenous defensive mechanism in organ size control, intestinal homeostasis, and regeneration. Unexpectedly, Xbp1 ablation promotes tumor overgrowth but suppresses invasiveness in a Drosophila cancer model. Mechanistically, hyperactivated Ire1/Xbp1s signaling in turn induces JNK-dependent developmental and oncogenic cell migration and epithelial-mesenchymal transition (EMT) via repression of Yki. In humans, a negative correlation between XBP1 and YAP (Yki ortholog) target gene expression specifically exists in triple-negative breast cancers (TNBCs), and those with high XBP1 or HSPA5 (Bip ortholog) expression have better clinical outcomes. In human TNBC cell lines and xenograft models, ectopic XBP1s or HSPA5 expression alleviates tumor growth but aggravates cell migration and invasion. These findings uncover a conserved crosstalk between the Ire1/Xbp1s and Hippo signaling pathways under physiological settings, as well as a crucial role of Bip-Yki interaction in tumorigenesis that is shared from Drosophila to humans.

Regulation mechanism of plant response to heavy metal stress mediated by endophytic fungi.

Endophytic fungi exist widely in plants and play an important role in the growth and adaptation of plants. They could be used in phytoremediation techniques against heavy metal contaminated soil since beneficial microbial symbionts can endow plants with resistance to external heavy metal stresses. This review summarized the regulation mechanism of plant response to heavy metal stress mediated by endophytic fungi. Potential endophytic fungi in enhancing plant's adaption to heavy metal stresses include arbuscular mycorrhizal fungi, dark septate endophytic fungi, plant growth promoting endophytic fungi. The mechanisms involve coevolution strategy, immune regulation and detoxification transport to improve the ability of plants to adapt to heavy metal stress. They can increase the synthesis of host hormones and maintaining the balance of endogenous hormones, strengthen osmotic regulation, regulate carbon and nitrogen metabolism, and increase immune activity, antioxidant enzyme and glutathione activity. They also help to improve the detoxification transport and heavy metal emission capacity of the host by significantly producing iron carrier, metallothionein and 1-aminocyclopropane-1-carboxylic acid deaminase. The combination of endophytic fungi and hyperaccumulation plants provides a promising technology for the ecological restoration of heavy metal contaminated soil. Endophytic fungi reserves further development on enhancing host plant's adaptability to heavy metal stresses.

Phytoremediation is an effective method for ecological remediation of heavy metal contaminated soil. Endophytic fungi such as arbuscular mycorrhizal fungi, dark septate endophytic fungi, plant growth promoting endophytic fungi can synergistically improve the adaptability to heavy metal stress. This review comprehensively summarizes the regulation mechanism of plant response to heavy metal stress mediated by endophytic fungi for the first time, and provides new insights and proposals for exploring novel hyperaccumulator for phytoremediation more effectively. HIGHLIGHTSEndophytic fungi combined with phytoremediation could enhance plant's adaptition to heavy metal stress and ecological restoration efficiency.Promising endophytic fungi in improving phytoremediation for heavy metal contaminated soil are presented.The regulation mechanism of plant response to heavy metal stress mediated by endophytic fungi is firstly summarized.

MLS-Net: An Automatic Sleep Stage Classifier Utilizing Multimodal Physiological Signals in Mice.

Over the past decades, feature-based statistical machine learning and deep neural networks have been extensively utilized for automatic sleep stage classification (ASSC). Feature-based approaches offer clear insights into sleep characteristics and require low computational power but often fail to capture the spatial-temporal context of the data. In contrast, deep neural networks can process raw sleep signals directly and deliver superior performance. However, their overfitting, inconsistent accuracy, and computational cost were the primary drawbacks that limited their end-user acceptance. To address these challenges, we developed a novel neural network model, MLS-Net, which integrates the strengths of neural networks and feature extraction for automated sleep staging in mice. MLS-Net leverages temporal and spectral features from multimodal signals, such as EEG, EMG, and eye movements (EMs), as inputs and incorporates a bidirectional Long Short-Term Memory (bi-LSTM) to effectively capture the spatial-temporal nonlinear characteristics inherent in sleep signals. Our studies demonstrate that MLS-Net achieves an overall classification accuracy of 90.4% and REM state precision of 91.1%, sensitivity of 84.7%, and an F1-Score of 87.5% in mice, outperforming other neural network and feature-based algorithms in our multimodal dataset.

Differential Ire1 determines loser cell fate in tumor-suppressive cell competition.

Tumor-suppressive cell competition (TSCC) is a conserved surveillance mechanism in which neighboring cells actively eliminate oncogenic cells. Despite overwhelming studies showing that the unfolded protein response (UPR) is dysregulated in various tumors, it remains debatable whether the UPR restrains or promotes tumorigenesis. Here, using Drosophila eye epithelium as a model, we uncover a surprising decisive role of the Ire1 branch of the UPR in regulating cell polarity gene scribble (scrib) loss-induced TSCC. Both mutation and hyperactivation of Ire1 accelerate elimination of scrib clones via inducing apoptosis and autophagy, respectively. Unexpectedly, relative Ire1 activity is also crucial for determining loser cell fate, as dysregulating Ire1 signaling in the surrounding healthy cells reversed the "loser" status of scrib clones by decreasing their apoptosis. Furthermore, we show that Ire1 is required for cell competition in mammalian cells. Together, these findings provide molecular insights into scrib-mediated TSCC and highlight Ire1 as a key determinant of loser cell fate.

A comparison review of Hehuan flowers and Hehuan bark on the traditional applications, phytochemistry and pharmacological effects.

ETHNOPHARMACOLOGICAL RELEVANCE: Albizia julibrissin Durazz is a well-known medicinal plant with the Chinese name Hehuan []. Hehuan bark and Hehuan flowers have long been recognized as traditional Chinese herbal medicine for treating anxiety, melancholy, insomnia, bruises, pulmonary abscess, fractures, carbuncle, amnesia, acute conjunctivitis, blurred vision, neonatal tetanus and stroke for thousands of years. They are recorded in Chinese Pharmacopoeia separately with different properties. Until now, new chemical constituents and pharmacological activities of Hehuan have been continuously studied and revealed. THE AIM OF THE REVIEW: This review aims to provide a comprehensive summary of traditional applications, phytochemistry, pharmacology effects, and toxicology of Hehuan bark and Hehuan flowers, and give critical assessment and point out the promising direction for further research on Hehuan. MATERIAL AND METHODS: A literature search was undertaken on Hehuan bark and Hehuan flowers by analyzing the information from scientific databases (SciFinder, Pubmed, Elsevier, Google Scholar, Web of Science, and Baidu Scholar). We also gathered the information of Hehuan from classic herbal literatures and conference papers on ethnopharmacology. RESULTS: According to Chinese and English documents, the medicinal history of Hehuan in China can be traced back to ad 25. Meanwhile, its medicinal history as a kind of herbal medicine can also be found in other Asian countries. So far about 140 compounds have been isolated from Hehuan bark and Hehuan flowers, including triterpenoids, flavonoids, lignans, phenolic acids, alkaloids, etc. Among them, flavonoids mainly exist in Hehuan flowers, while Hehuan bark contains lignans and saponins. The composition differences between the barks and flowers of Hehuan account for the different effects and applications. Modern pharmacological studies have indicated that crude extracts and pure compounds of Hehuan flowers and Hehuan bark have multiple pharmacological activities, such as antineoplastic, immunomodulatory, anti-inflammatory, anxiolytic, antidepressant, metabolic regulation, anti-insomnia, neuroprotective, hepatoprotective, sedative, and anti-osteolytic activities. CONCLUSIONS: Hehuan (Albizia julibrissin Durazz) is traditionally used to relieve depression, calm nerves, promote blood circulation and reduce swelling. Modern pharmacological studies have revealed that natural products from Hehuan bark and Hehuan flowers possess extensive pharmacological activities in treating cancer, enhancing immunity, regulating metabolism, improving mental state, etc. These properties make it great clinical application potential. Further research on natural pharmaceutical chemistry, pharmacology, toxicology, pharmacokinetics, and quality standards of Hehuan are still required to verify the efficacy and safety for future clinical applications.

Unconjugated bilirubin alleviates experimental ulcerative colitis by regulating intestinal barrier function and immune inflammation.

BACKGROUND: Unconjugated bilirubin (UCB) is generally considered toxic but has gained recent prominence for its anti-inflammatory properties. However, the effects of it on the interaction between intestinal flora and organisms and how it influences immune responses remain unresolved. AIM: To investigate the role of UCB in intestinal barrier function and immune inflammation in mice with dextran-sulfate-sodium-induced colitis. METHODS: Acute colitis was induced by 3% (w/v) dextran sulfate sodium salt in drinking water for 6 d followed by untreated water for 2 d. Concurrently, mice with colitis were administered 0.2 mL UCB (400 µmol/L) by intra-gastric gavage for 7 d. Disease activity index (DAI) was monitored daily. Mice were sacrificed at the end of the experiment. The length of the colon and weight of the spleen were recorded. Serum level of D-lactate, intestinal digestive proteases activity, and changes to the gut flora were analyzed. In addition, colonic specimens were analyzed by histology and for expression of inflammatory markers and proteins. RESULTS: Mice treated with UCB had significantly relieved severity of colitis, including lower DAI, longer colon length, and lower spleen weight (colon length: 4.92 ± 0.09 cm vs 3.9 ± 0.15 cm; spleen weight: 0.33 ± 0.04 vs 0.74 ± 0.04, P < 0.001). UCB administration inactivated digestive proteases (chymotrypsin: 18.70 ± 0.69 U/g vs 44.81 ± 8.60 U/g; trypsin: 1.52 ± 0.23 U/g vs 9.05 ± 1.77 U/g, P < 0.01), increased expression of tight junction (0.99 ± 0.05 vs 0.57 ± 0.03, P < 0.001), decreased serum level of D-lactate (31.76 ± 3.37 µmol/L vs 54.25 ± 1.45 µmol/L, P < 0.001), and lowered histopathological score (4 ± 0.57 vs 7 ± 0.57, P < 0.001) and activity of myeloperoxidase (46.79 ± 2.57 U/g vs 110.32 ± 19.19 U/g, P < 0.001). UCB also regulated the intestinal microbiota, inhibited expression of tumor necrosis factor (TNF) α and interleukin 1ß (TNF-α: 52.61 ± 7.81 pg/mg vs 105.04 ± 11.92 pg/mg, interleukin 1ß: 13.43 ± 1.68 vs 32.41 ± 4.62 pg/mg, P < 0.001), decreased expression of Toll-like receptor 4 (0.61 ± 0.09 vs 1.07 ± 0.03, P < 0.001) and myeloid differentiation primary response gene 88 (0.73 ± 0.08 vs 1.01 ± 0.07, P < 0.05), and increased expression of TNF-receptor-associated factor 6 (0.79 ± 0.02 vs 0.43 ± 0.09 P < 0.05) and inhibitor of kappa B α (0.93 ± 0.07 vs 0.72 ± 0.07, P < 0.05) in the colon. CONCLUSION: UCB can protect intestinal barrier function, regulate normal intestinal homeostasis, and suppress inflammation via the Toll-like receptor 4/ nuclear factor-κB signaling pathway.

Unconjugated bilirubin ameliorates the inflammation and digestive protease increase in TNBS-induced colitis.

The authors previously demonstrated that unconjugated bilirubin (UCB) may inhibit the activities of various digestive proteases, including trypsin and chymotrypsin. The digestive proteases in the lower gut are important in the pathogenesis of inflammatory bowel diseases. The effects of UCB on the inflammation and levels of digestive proteases in feces of rats with colitis have not yet been revealed. The present study investigated the effect of UCB on the inflammatory status and levels of trypsin and chymotrypsin in the feces of rats with trinitrobenzenesulfonic acid (TNBS)­induced colitis. The data indicated that treatment with TNBS resulted in a marked reduction in weight gain, which was significantly alleviated in UCB­treated rats. Furthermore, UCB treatment alleviated the inflammation induced by TNBS, detected via macroscopic damage and microscopic inflammation scores, and pro­inflammatory markers including myeloperoxidase (MPO), tumor necrosis factor (TNF)­α and interleukin (IL)­1ß. Furthermore, rats with colitis demonstrated significant increases in fecal trypsin and chymotrypsin levels, whereas UCB treatment significantly alleviated these increases. A significant positive correlation was additionally revealed among the pro­inflammatory markers (MPO, TNF­α and IL­1ß) and fecal digestive proteases (trypsin and chymotrypsin) in colitis. The results of the present study demonstrated that UCB ameliorated the inflammation and digestive protease increase in TNBS-induced colitis.