Study on the underlying mechanism of Huachansu Capsule induced cardiotoxicity of normal rat by integrating transcriptomics, metabolomics and network toxicology.

ETHNOPHARMACOLOGICAL RELEVANCE: Huachansu Capsule (HCSc) is a simple enteric-coated capsule refined from the skin of the dried toad, a traditional medicinal herb. It has been used clinically for many years to treat a variety of malignant tumors with remarkable efficacy. To date, a number of main components of HCSc have been reported to be cardiotoxic, but the specific mechanism of cardiotoxicity is still unknown. AIM OF THE STUDY: The aim of this study was to elucidate the possible cardiotoxic symptoms caused by high-doses of HCSc and to further reveal the complex mechanisms by which it causes cardiotoxicity. MATERIALS AND METHODS: UPLC-Q-Exactive Orbitrap MS and network toxicology were used to identify and predict the potential toxic components, related signaling pathways. Then, we used acute and sub-acute toxicity experiments to reveal the apparent phenomenon of HCSc-induced cardiotoxicity. Finally, we combined transcriptomics and metabolomics to elucidate the potential mechanism of action, and verified the putative mechanism by molecular docking, RT-qPCR, and Western blot. RESULTS: We found 8 toad bufadienolides components may be induced cardiac toxicity HCSc main toxic components. Through toxicity experiments, we found that high dose of HCSc could increase a variety of blood routine indexes, five cardiac enzymes, heart failure indexes (BNP), troponin (cTnI and cTnT), heart rate and the degree of heart tissue damage, while low-dose of HCSc had no such changes. In addition, by molecular docking, found that 8 kinds of main toxic components and cAMP, AMPK, IL1ß, mTOR all can be a very good combination, especially in the cAMP. Meanwhile, RT-qPCR and Western blot results showed that HCSc could induce cardiotoxicity by regulating a variety of heart-related differential genes and activating the cAMP signaling pathway. CONCLUSIONS: In this study, network toxicology, transcriptomics and metabolomics were used to elucidate the complex mechanism of possible cardiotoxicity induced by high-dose HCSc. Animal experiments, molecular docking, Western blot and RT-qPCR experiments were also used to verify the above mechanism. These findings will inform further mechanistic studies and provide theoretical support for its safe clinical application.

Studies on the Preparation of a Microemulsion Formulation of Matricaria Recutita Essential Oil and the Treatment of 2,4-Dinitro-Chlorobenzene- Induced Eczema in Mice by Inhibiting Inflammation.

BACKGROUND: Eczema, an inflammatory skin disease causing intense itching, is a function of a range of internal and external factors, impacting individuals of all ages and leading to economic loss. Inflammation is the most important manifestation of eczema, and Matricaria recutita essential oil (MREO) extracted from Matricaria recutita possesses excellent antibacterial and anti-inflammatory properties. METHODS: In this study, Matricaria recutita microemulsions were prepared by the trans-phase emulsification method and their stability was determined by evaluating the relevant indexes. Establishment of 2,4-dinitro-chlorobenzene-induced AD model in mice. Detection of serum indexes of IL-6, IL-17, and TNF-α, and on pathological tissue sections, the HE staining, toluidine blue staining, immunohistochemistry, and observation were performed. RESULTS: The study obtained optimal conditions for the preparation of microemulsion formulations of Matricaria recutita. Through quality evaluation, it was found that the microemulsion increased stability, reduced irritation, and retained anti-inflammatory activity and therapeutic effects on eczema compared to Matricaria recutita essential oil (MREO). Studies have demonstrated that microemulsion formulations of Matricaria recutita and Matricaria recutita significantly down regulate the proinflammatory factors TNF-α, IL-17, and IL-6. It was shown by hematoxylin-eosin (HE) staining that both Matricaria recutita essential oil (MREO) and Matricaria recutita microemulsion (MRME) improved the inflammatory status of eczematous skin tissues in mice. The number of mast cells expressed in the tissues was decreased in the surface-treated group, as shown by toluidine blue staining. Additionally, the number of mast cells expressed in the tissues in the surface-treated group was reduced, as demonstrated by immunohistochemistry. Furthermore, immunohistochemistry revealed that MREO and MRME have immunomodulatory effects on the tissues. CONCLUSION: The study showed that microemulsion formulations of Matricaria recutita may serve as a novel remedy for eczema.

NJGCG: A node-based joint Gaussian copula graphical model for gene networks inference across multiple states.

Inferring the interactions between genes is essential for understanding the mechanisms underlying biological processes. Gene networks will change along with the change of environment and state. The accumulation of gene expression data from multiple states makes it possible to estimate the gene networks in various states based on computational methods. However, most existing gene network inference methods focus on estimating a gene network from a single state, ignoring the similarities between networks in different but related states. Moreover, in addition to individual edges, similarities and differences between different networks may also be driven by hub genes. But existing network inference methods rarely consider hub genes, which affects the accuracy of network estimation. In this paper, we propose a novel node-based joint Gaussian copula graphical (NJGCG) model to infer multiple gene networks from gene expression data containing heterogeneous samples jointly. Our model can handle various gene expression data with missing values. Furthermore, a tree-structured group lasso penalty is designed to identify the common and specific hub genes in different gene networks. Simulation studies show that our proposed method outperforms other compared methods in all cases. We also apply NJGCG to infer the gene networks for different stages of differentiation in mouse embryonic stem cells and different subtypes of breast cancer, and explore changes in gene networks across different stages of differentiation or different subtypes of breast cancer. The common and specific hub genes in the estimated gene networks are closely related to stem cell differentiation processes and heterogeneity within breast cancers.

Preparation of photo-controlled release ROS-responsive Ce6/elemene co-loaded liposomes and study on the effect on enhancing apoptosis of NMIBC.

At present, chemotherapy combined with photodynamic therapy is exerting satisfactory therapeutic effects in the treatment of tumors. Chlorin e6 (Ce6) is a photosensitizer with high efficiency and low dark toxicity. At the same time, elemene (ELE) contains high-efficiency and low-toxicity anti-cancer active ingredients, which can effectively penetrate tumor tissue and inhibit its recovery and proliferation. Due to the poor water solubility of these two drugs, we prepared ELE/Ce6 co-loaded liposomes (Lipo-ELE/Ce6) to improve their water solubility, thereby enhancing the anti-tumor effect. The characterization of Lipo-ELE/Ce6 showed that Lipo-ELE/Ce6 had suitable encapsulation efficiency (EE), particle size, polydispersity (PDI), zeta potential, and good photo-controlled release properties. In vitro, Lipo-ELE/Ce6 effectively inhibited the growth of T24 cells and induced apoptosis, and more importantly, in vivo experiments showed that Lipo-ELE/Ce6 had significant anti-tumor effects, which was significantly better than free drugs. The above results suggest that Lipo-ELE/Ce6 can significantly enhance the induction of apoptosis of non-muscle invasive bladder cancer (NMIBC) by light-controlled release and ROS response.

Extraction, purification, structural features, and pharmacological properties of polysaccharides from Houttuynia cordata: A review.

Houttuynia cordata Thunb, also known as "Chinese medicine antibiotic", is a medicine food homology plant. It has functions of clearing heat, eliminating toxins, in folk medicine. The extraction purification and bioactivity of Houttuynia cordata polysaccharides (HCPs) have been of wide interest to researchers in recent years studies. Studies have confirmed that HCPs exhibit various biofunctionalities, such as anti-inflammatory, antiviral, antibacterial, antioxidant, immunomodulatory, regulation of gut microbiota, and gut-lung axis, as well as anti-radiation, and anti-cancer properties. Therefore, a comprehensive systematic review is needed to summarize the recent advances of HCPs and facilitate a better understanding of their biofunctionalities. This paper reviews the research progress of HCPs in extraction and purification methods, chemical structures, biological activities, possible mechanisms of action, and potential application prospects, which can provide some valuable insights and updated information for their further development and application of HCPs in the fields of therapeutic agents, functional foods, cosmetics, animal feeds.

Recent advances of injectable in situ-forming hydrogels for preventing postoperative tumor recurrence.

The unavoidable residual tumor tissue from surgery and the strong aggressiveness of tumor cells pose challenges to the postoperative treatment of tumor patients, accompanied by in situ tumor recurrence and decreased quality of life. Therefore, there is an urgent need to explore appropriate postoperative therapeutic strategies to remove residual tumor cells after surgery to inhibit tumor recurrence and metastasis after surgery. In recent years, with the rapid development of biomedical materials, the study of local delivery systems as postoperative delivery of therapeutic agents has gradually attracted the attention of researchers. Injectable in situ-forming hydrogel is a locally administered agent injected in situ as a solution that can be loaded with various therapeutic agents and rapidly gels to form a semi-solid gel at the treatment site. This type of hydrogel tightly fills the surgical site and covers irregular excision surfaces. In this paper, we review the recent advances in the application of injectable in situ-forming hydrogels in postoperative therapy, focusing on the matrix materials of this type of hydrogel and its application in the postoperative treatment of different types of tumors, as well as discussing the challenges and prospects of its clinical application.

Bile acids attenuate hepatic inflammation during ischemia/reperfusion injury.

Background & Aims: Persistent cholestasis has been associated with poor prognosis after orthotopic liver transplantation. In this study, we aimed to investigate how the accumulation of tauro-beta-muricholic acid (TßMCA), resulting from the reprogramming of bile acid (BA) metabolism during liver ischemia/reperfusion (IR) stress, attenuates liver inflammation. Methods: Ingenuity Pathway Analysis was performed using transcriptome data from a murine hepatic IR model. Three different models of hepatic IR (liver warm IR, bile duct separation-IR, common bile duct ligation-IR) were employed. We generated adeno-associated virus-transfected mice and CD11b-DTR mice to assess the role of BAs in regulating the myeloid S1PR2-GSDMD axis. Hepatic BA levels were analyzed using targeted metabolomics. Finally, the correlation between the reprogramming of BA metabolism and hepatic S1PR2 levels was validated through RNA-seq of human liver transplant biopsies. Results: We found that BA metabolism underwent reprogramming in murine hepatocytes under IR stress, leading to increased synthesis of TßMCA, catalyzed by the enzyme CYP2C70. The levels of hepatic TßMCA were negatively correlated with the severity of hepatic inflammation, as indicated by the serum IL-1ß levels. Inhibition of hepatic CYP2C70 resulted in reduced TßMCA production, which subsequently increased serum IL-1ß levels and exacerbated IR injury. Moreover, our findings suggested that TßMCA could inhibit canonical inflammasome activation in macrophages and attenuate inflammatory responses in a myeloid-specific S1PR2-GSDMD-dependent manner. Additionally, Gly-ßMCA, a derivative of TßMCA, could effectively attenuate inflammatory injury in vivo and inhibit human macrophage pyroptosis in vitro. Conclusions: IR stress orchestrates hepatic BA metabolism to generate TßMCA, which attenuates hepatic inflammatory injury by inhibiting the myeloid S1PR2-GSDMD axis. Bile acids have immunomodulatory functions in liver reperfusion injury that may guide therapeutic strategies. Impact and implications: Our research reveals that liver ischemia-reperfusion stress triggers reprogramming of bile acid metabolism. This functions as an adaptive mechanism to mitigate inflammatory injury by regulating the S1PR2-GSDMD axis, thereby controlling the release of IL-1ß from macrophages. Our results highlight the crucial role of bile acids in regulating hepatocyte-immune cell crosstalk, which demonstrates an immunomodulatory function in liver reperfusion injury that may guide therapeutic strategies targeting bile acids and their receptors.

Isolation, structures, bioactivities, and utilizations of polysaccharides from Dictyophora species: A review.

Dictyophora species is an edible and medicinal fungus belonging to the Basidiomycotina, Gasteromycetes, Phallales, family Phallaceae, and genus Dictyophora, which is popular with consumers in China and across various Asian regions. Polysaccharides from Dictyophora species (DPs) are important bioactive macromolecules with multiple health benefits, according to published studies, including anti-tumor, antioxidative, anti-obesity, anti-hyperlipidemic, hepatoprotective, immunomodulatory, anti-inflammatory, regulation of gut microbiota, antibacterial, renoprotective, and other pharmacological effects. Based on their rich pharmacological activities, the preparation techniques, structural characteristics and pharmacological activities of DPs have been extensively studied. However, to the best of our knowledge, there is no dedicated review to shed light on recent advances in DPs. Therefore, in order to fill this gap, this review provides a comprehensive overview of the research on DPs, including the latest advances in extraction, isolation and purification, structural characteristics, pharmacological properties, safety assessment and potential utilizations, which will provide a theoretical basis for the research and development of subsequent DPs-related products.

Myrrh Essential Oil Improves DSS-Induced Colitis by Modulating the MAPK Signaling Pathway: In vitro and in vivo Studies.

Objective: To explore the mechanism and active components of the anti-colitis effects of myrrh essential oil (MEO). Methods: In this study, we investigated the anti-inflammatory effects and molecular mechanisms of MEO on dextran sulfate sodium (DSS)-induced colitis with in vitro cell experiments, RNA-seq (RNA Sequencing), Weighted gene co-expression network analysis (WGCNA), combined with "weighting coefficient" network pharmacology, as and in vivo pharmacodynamic experiments. A 3% DSS solution was used to induce colitis in BALB/c mice and MEO was administered orally. We performed gas chromatography-mass spectrometry (GC-MS) analysis of the MEO components. The disease activity index (DAI) was evaluated by observing body weight, fecal characteristics, and blood in the stool of mice. The levels of inflammatory cytokines (TNF-α and IL-1ß) in mouse serum were measured using ELISA (Enzyme-linked immunosorbent assay) kits. Additionally, the expression of MAPK-related proteins (JNK, p-JNK, ERK, and p-ERK) in mouse colonic tissues was detected by Western blotting and immunohistochemistry. Results: MEO (0.0625-0.125µg/g, p.o). significantly inhibited the expression of the inflammatory mediator Nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. After treatment, there was a significant increase in body weight and alleviation of diarrhea and bloody stools in colitis mice. It also reduced inflammatory cell infiltration. Furthermore, it decreased the serum levels of TNF-α and IL-1ß, and reduced the activity of p-JNK and p-ERK in the MAPK pathway. Conclusion: MEO relieved DSS-induced colitis by modulating the MAPK pathway. The experimental results indicate that the MAPK pathway might be inhibited by the synergistic effect of gamma-Muurolene, Curzerene, beta-Elemene, and Furanoeudesma 1.3-diene in MEO, which provides a novel idea for subsequent research and development of new anti-colitis drugs.

A primate-specific endogenous retroviral envelope protein sequesters SFRP2 to regulate human cardiomyocyte development.

Endogenous retroviruses (ERVs) occupy a significant part of the human genome, with some encoding proteins that influence the immune system or regulate cell-cell fusion in early extra-embryonic development. However, whether ERV-derived proteins regulate somatic development is unknown. Here, we report a somatic developmental function for the primate-specific ERVH48-1 (SUPYN/Suppressyn). ERVH48-1 encodes a fragment of a viral envelope that is expressed during early embryonic development. Loss of ERVH48-1 led to impaired mesoderm and cardiomyocyte commitment and diverted cells to an ectoderm-like fate. Mechanistically, ERVH48-1 is localized to sub-cellular membrane compartments through a functional N-terminal signal peptide and binds to the WNT antagonist SFRP2 to promote its polyubiquitination and degradation, thus limiting SFRP2 secretion and blocking repression of WNT/ß-catenin signaling. Knockdown of SFRP2 or expression of a chimeric SFRP2 with the ERVH48-1 signal peptide rescued cardiomyocyte differentiation. This study demonstrates how ERVH48-1 modulates WNT/ß-catenin signaling and cell type commitment in somatic development.

Discovery of pyrrolo[2,3-d]pyrimidin-4-one derivative YCH3124 as a potent USP7 inhibitor for cancer therapy.

USP7 is one of the most studied deubiquitinating enzymes, which is involved in the regulation of multiple cell signaling pathways and has been shown to be associated with the occurrence and progression of a variety of cancers. Inhibitors targeting USP7 have been studied by several teams, but most of them lack selectivity and have low activities. Herein, we reported a serious of pyrrole[2,3-d]pyrimidin-4-one derivatives through scaffold hopping of recently reported 4-hydroxypiperidine compounds. The representative compound Z33 (YCH3124) exhibited highly potent USP7 inhibition activity as well as anti-proliferative activity against four kinds of cancer cell lines. Further study revealed that YCH3124 effectively inhibited the downstream USP7 pathway and resulted in the accumulation of both p53 and p21 in a dose-dependent manner. Notably, YCH3124 disrupted cell cycle progression through restricting G1 phase and induced significant apoptosis in CHP-212 cells. In summary, our efforts provided a series of novel pyrrole[2,3-d]pyrimidin-4-one analogs as potent USP7 inhibitors with excellent anti-cancer activity.

Reappraisal and refined diagnosis of ultrasonography and histological findings for hydatidiform moles: a multicentre retrospective study of 821 patients.

AIMS: Specific identification of a hydatidiform mole (HM) and subclassification of a complete hydatidiform mole (CHM) or partial hydatidiform mole (PHM) are critical. This study aimed to reappraise the diagnostic performance of ultrasonography and histology with a refined diagnosis. METHODS: This was a retrospective, multicentre cohort study of 821 patients with histologically suspected HM specimens. Refined diagnostic algorithms with p57 immunohistochemistry and short tandem repeat (STR) genotyping were performed and used as the true standard for assessing the diagnostic performance of the original ultrasonography and morphology methods. The diagnostic performance was calculated using accuracy, agreement rate, sensitivity and the positive predictive value (PPV) compared with refined diagnostic results. RESULTS: Of the 821 histologically suspected HM cases included, 788 (95.98%) were successfully reclassified into 448 CHMs, 213 PHMs and 127 non-molar (NM) abortuses. Ultrasonography showed an overall accuracy of 44.38%, with a sensitivity of 44.33% for CHM and 37.5% for PHM. The overall classification accuracy of the original morphological diagnosis was 65.97%. After exclusion of the initially untyped HMs, the overall agreement rate was 59.11% (κ=0.364, p<0.0001) between the original and refined diagnoses, with a sensitivity of 40.09% and PPV of 96.05% for diagnosing CHMs and a sensitivity of 84.98% and a PPV of 45.59% for diagnosing PHMs. The interinstitutional variability of morphology in diagnosing HMs was significant among the 15 centres (range, 8.33%-100.00%, p<0.0001). CONCLUSION: The current diagnosis of HM based solely on ultrasound or morphology remains problematic, and ancillary techniques, particularly p57 immunohistochemistry and DNA genotyping, should be integrated into routine practice as much as possible.

Advances on Delivery System of Active Ingredients of Dried Toad Skin and Toad Venom.

Dried toad skin (TS) and toad venom (TV) are the dried skin of the Bufo bufo gargarizans Cantor and the Bufo melanostictus Schneider, which remove the internal organs and the white secretions of the skin and retroauricular glands. Since 2005, cinobufacini preparations have been approved by the State Food and Drug Administration for use as adjuvant therapies in the treatment of various advanced cancers. Meanwhile, bufalenolides has been identified as the main component of TS/TV, exhibiting antitumor activity, inducing apoptosis of cancer cells and inhibiting cancer cell proliferation or metastasis through a variety of signaling pathways. However, clinical agents frequently face limitations such as inherent toxicity at high concentrations and insufficient tumor targeting. Additionally, the development and utilization of these active ingredients are hindered by poor water solubility, low bioavailability, and rapid clearance from the bloodstream. To address these challenges, the design of a targeted drug delivery system (TDDS) aims to enhance drug bioavailability, improve targeting within the body, increase drug efficacy, and reduce adverse reactions. This article reviews the TDDS for TS/TV, and their active components, including passive, active, and stimuli-responsive TDDS, to provide a reference for advancing their clinical development and use.

Pro-apoptotic gene BAX is a pan-cancer predictive biomarker for prognosis and immunotherapy efficacy.

BACKGROUND: Apoptosis Regulator BCL2 Associated X (BAX) is a pro-apoptotic gene. Apoptosis is one of the important components of immune response and immune regulation. However, there is no systematic pan-cancer analysis of BAX. METHODS: Original data of this study were downloaded from TCGA databases and GTEX databases. We conducted the gene expression analysis and survival analysis of BAX in 33 types of cancer via Gene Expression Profiling Interactive Analysis (GEPIA) database. Real-time PCR and immunohistochemistry (IHC) were further performed to examine the BAX expression in cancer cells and tissues. Moreover, the relationship between BAX and immune infiltration and gene alteration was studied by the Tumor Immune Estimation Resource (TIMER) and cBioPortal tools. Protein-protein interaction analysis was performed in the STRING database. Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were utilized to evaluate the enrichment analysis. RESULTS: BAX was highly expressed in most cancers and was associated with poor prognosis in nine cancer types. In addition, BAX showed significant clinical relevance, and the mRNA expression of BAX was also strongly associated with drug sensitivity of many drugs. Furthermore, BAX may participate in proliferation and metastasis of many cancers and was associated with methylation. Importantly, BAX expression was positively correlated with most immune infiltrating cells. CONCLUSION: Our findings suggested that BAX can function as an oncogene and may be used as a potential predictive biomarker for prognosis and immunotherapy efficacy of human cancer, which could provide a new approach for cancer therapy.

Amomum villosum Lour.: An insight into ethnopharmacological, phytochemical, and pharmacological overview.

ETHNOPHARMACOLOGICAL RELEVANCE: Amomum villosum Lour. is a widely esteemed species of medicinal plant on a global scale. Its medicinal properties have been documented as early as the Tang Dynasty, particularly the fruit, which holds significant medicinal and culinary value. This plant is extensively found in tropical and subtropical regions across Asia. It possesses the properties of warming the middle and dispelling cold, regulating Qi to invigorate the spleen, harmonizing the stomach to alleviate vomiting, and nourishing deficiencies. In recent years, A. villosum has garnered global attention for its remarkable biological activity. Currently, numerous bioactive compounds have been successfully isolated and identified, showcasing a diverse array of pharmacological activities and medicinal benefits. AIM OF THE WORK: This review aims to provide a comprehensive analysis of the research advancements in the geographical distribution, botany, traditional applications, phytochemistry, pharmacological activity, quality control, clinical applications, and toxicology of A. villosum. Furthermore, a critical summary of the current research and future prospects of this plant is presented. MATERIALS AND METHODS: Obtain information about A. villosum from ancient literature, doctoral and master's theses, and scholarly databases including Google Scholar, Web of Science, PubMed, China National Knowledge Infrastructure (CNKI), ScienceDirect, plant directories, and clinical reports. RESULTS: At present, about 500 compounds have been isolated and identified from various organs of A. villosum, including monoterpenoids, sesquiterpenoids, diterpenoids, flavonoids, phenols, polysaccharides, and other components. Modern pharmacological studies have revealed that A. villosum exhibits exceptional biological activities in vitro and in vivo, such as anti-inflammatory, antioxidant, liver protection, anti-tumor, hypoglycemic, anti-microbial, regulating gastrointestinal activity, immune regulation, regulating flora, anti-obesity, estrogen, and more. Some of these activities have found extensive application in clinical practice. CONCLUSION: A. villosum, as a well-established medicinal herb, holds significant therapeutic potential and is also valued for its culinary applications. Currently, the research on the active components or crude extracts of A. villosum and their potential mechanisms of action remains limited. Furthermore, certain pharmacological activities require further elucidation for a comprehensive understanding of its internal mechanisms. Moreover, it is strongly recommended to prioritize research on pharmacokinetics and toxicity studies. These efforts will facilitate a thorough exploration of the potential of A. villosum and establish a robust foundation for its potential clinical applications.

Evidence of synergistic mechanisms of hepatoprotective botanical herbal preparation of Pueraria montana var. lobata and Schisandra sphenanthera.

Background: Pueraria montana var. lobata (Willd.) Maesen & S.M.Almeida ex Sanjappa & Predeep (syn. Pueraria lobata (Willd.) Ohwi) and Schisandra sphenanthera Rehder & E.H. Wilson are traditional edible and medicinal hepatoprotective botanical drugs. Studies have shown that the combination of two botanical drugs enhanced the effects of treating acute liver injury (ALI), but the synergistic effect and its action mechanisms remain unclear. This study aimed to investigate the synergistic effect and its mechanism of the combination of Pueraria montana var. lobata (Willd.) Maesen & S.M.Almeida ex Sanjappa & Predeep (syn. Pueraria lobata (Willd.) Ohwi) (PM) and Schisandra sphenanthera Rehder & E.H. Wilson (SS) in the treatment of ALI. Methods: High performance liquid chromatography (HPLC) were utilized to conduct the chemical interaction analysis. Then the synergistic effects of botanical hybrid preparation of PM-SS (BHP PM-SS) against ALI were comprehensively evaluated by the CCl4 induced ALI mice model. Afterwards, symptom-oriented network pharmacology, transcriptomics and metabolomics were applied to reveal the underlying mechanism of action. Finally, the key target genes were experimentally by RT-qPCR. Results: Chemical analysis and pharmacodynamic experiments revealed that BHP PM-SS was superior to the single botanical drug, especially at 2:3 ratio, with a better dissolution rate of active ingredients and synergistic anti-ALI effect. Integrated symptom-oriented network pharmacology combined with transcriptomics and metabolomics analyses showed that the active ingredients of BHP PM-SS could regulate Glutathione metabolism, Pyrimidine metabolism, Arginine biosynthesis and Amino acid sugar and nucleotide sugar metabolism, by acting on the targets of AKT1, TNF, EGFR, JUN, HSP90AA1 and STAT3, which could be responsible for the PI3K-AKT signaling pathway, MAPK signaling pathway and Pathway in cancer to against ALI. Conclusion: Our study has provided compelling evidence for the synergistic effect and its mechanism of the combination of BHP PM-SS, and has contributed to the development and utilization of BHP PM-SS dietary supplements.

Innate lymphoid cell-based immunomodulatory hydrogel microspheres containing Cutibacterium acnes extracellular vesicles for the treatment of psoriasis.

Psoriasis is a chronic skin inflammation influenced by dysregulated skin microbiota, with the role of microbiota in psoriasis gaining increasing prominence. Bacterial extracellular vesicles (bEVs) serve as crucial regulators in the interaction between hosts and microbiota. However, the mechanism underlying the therapeutic potential of bEVs from commensal bacteria in psoriasis remains unclear. Here, we investigated the therapeutic role of Cutibacterium acnes (C. acnes)-derived extracellular vesicles (CA-EVs) in psoriasis treatment. To prolong the active duration of CA-EVs, we encapsulated them in gelatin methacrylate (GelMA) to fabricate hydrogel microspheres (CA-EVs@GHM) with sustained release properties. As GelMA degraded, CA-EVs were gradually released, maintaining a high concentration in mouse skin even 96 h post-treatment. In human keratinocyte cells (HaCaT), CA-EVs@GHM enhanced resistance to Staphylococcus aureus (S. aureus), promoted proliferation and migration of HaCaT cells exposed to S. aureus, and significantly reduced the expression of inflammatory genes such as interleukin (IL)-6 and C-X-C motif chemokine ligand 8 (CXCL8). In vivo, CA-EVs@GHM, more potent than CA-EVs alone, markedly attenuated proinflammatory gene expression, including tumor necrosis factor (TNF), Il6, Il17a, Il22 and Il23a in imiquimod (IMQ)-induced psoriasis-like mice, and restored skin barrier function. 16S rRNA sequencing revealed that CA-EVs@GHM might provide therapeutic effects against psoriasis by restoring microbiota diversity on the back skin of mice, reducing Staphylococcus colonization, and augmenting lipid metabolism. Furthermore, flow cytometry analysis showed that CA-EVs@GHM prevented the conversion of type 2 innate lymphoid cells (ILC2) to type 3 innate lymphoid cells (ILC3) in psoriasis-like mouse skin, reducing the pathogenic ILC3 population and suppressing the secretion of IL-17 and IL-22. In summary, our findings demonstrate that the long-term sustained release of CA-EVs alleviated psoriasis symptoms by controlling the transformation of innate lymphoid cells (ILCs) subgroups and restoring skin microbiota homeostasis, thus offering a promising therapy for psoriasis treatment. STATEMENT OF SIGNIFICANCE: Cutibacterium acnes, which is reduced in psoriasis skin, has been reported to promote skin homeostasis by regulating immune balance. Compared to live bacteria, bacterial extracellular vesicles (bEVs) are less prone to toxicity and safety concerns. bEVs play a pivotal role in maintaining bacterial homeostasis and modulating the immune system. However,bEVs without sustained release materials are unable to function continuously in chronic diseases. Therefore, we utilized hydrogel microspheres to encapsulate Cutibacterium acnes (C. acnes)-derived extracellular vesicles (CA-EVs), enabling long term sustained release. Our findings indicate that, CA-EVs loaded gelatin methacrylate hydrogel microspheres (CA-EVs@GHM) showed superior therapeutic effects in treating psoriasis compared to CA-EVs. CA-EVs@GHM exhibited a more significant regulation of pathological type 3 innate lymphoid cells (ILC3) and skin microbiota, providing a promising approach for microbiota-derived extracellular vesicle therapy in the treatment of skin inflammation.

Safety and efficacy of histotripsy delivery through overlying gas-filled small bowel in an ex vivo swine model.

PURPOSE: To evaluate the safety and efficacy of performing histotripsy through overlying gas-filled bowel in an ex vivo swine model. METHODS: An ex vivo model was created to simulate histotripsy treatment of solid organs through gas-filled bowel. Spherical 2.5 cm histotripsy treatments were performed in agar phantoms for each of five treatment groups: 1) control with no overlying bowel (n = 6), 2) bowel 0 cm above phantom (n = 6), 3) bowel 1 cm above phantom (n = 6), 4) bowel 2 cm above phantom (n = 6), and 5) bowel 0 cm above the phantom with increased treatment amplitude (n = 6). Bowel was inspected for gross and microscopic damage, and treatment zones were measured. A ray-tracing simulation estimated the percentage of therapeutic beam path blockage by bowel in each scenario. RESULTS: All histotripsy treatments through partial blockage were successful (24/24). No visible or microscopic damage was observed to intervening bowel. Partial blockage resulted in a small increase in treatment volume compared to controls (p = 0.002 and p = 0.036 for groups with bowel 0 cm above the phantom, p > 0.3 for bowel 1 cm and 2 cm above the phantom). Gas-filled bowel was estimated to have blocked 49.6%, 35.0%, and 27.3% of the therapeutic beam at 0, 1, and 2 cm, respectively. CONCLUSION: Histotripsy has the potential to be applied through partial gas blockage of the therapeutic beam path, as shown by this ex vivo small bowel model. Further work in an in vivo survival model appears indicated.

Identification of HLA-A*11:01 and A*02:01-Restricted EBV Peptides Using HLA Peptidomics.

Epstein-Barr Virus (EBV) is closely linked to nasopharyngeal carcinoma (NPC), notably prevalent in southern China. Although type II latency of EBV plays a crucial role in the development of NPC, some lytic genes and intermittent reactivation are also critical for viral propagation and tumor progression. Since T cell-mediated immunity is effective in targeted killing of EBV-positive cells, it is important to identify EBV-derived peptides presented by highly prevalent human leukocyte antigen class I (HLA-I) molecules throughout the EBV life cycle. Here, we constructed an EBV-positive NPC cell model to evaluate the presentation of EBV lytic phase peptides on streptavidin-tagged specific HLA-I molecules. Utilizing a mass spectrometry (LC-MS/MS)-based immunopeptidomic approach, we characterized eleven novel EBV peptides as well as two previously identified peptides. Furthermore, we determined these peptides were immunogenic and could stimulate PBMCs from EBV VCA/NA-IgA positive donors in an NPC endemic southern Chinese population. Overall, this work demonstrates that highly prevalent HLA-I-specific EBV peptides can be captured and functionally presented to elicit immune responses in an in vitro model, which provides insight into the epitopes presented during EBV lytic cycle and reactivation. It expands the range of viral targets for potential NPC early diagnosis and treatment.

Peptide REF1 is a local wound signal promoting plant regeneration.

Plants frequently encounter wounding and have evolved an extraordinary regenerative capacity to heal the wounds. However, the wound signal that triggers regenerative responses has not been identified. Here, through characterization of a tomato mutant defective in both wound-induced defense and regeneration, we demonstrate that in tomato, a plant elicitor peptide (Pep), REGENERATION FACTOR1 (REF1), acts as a systemin-independent local wound signal that primarily regulates local defense responses and regenerative responses in response to wounding. We further identified PEPR1/2 ORTHOLOG RECEPTOR-LIKE KINASE1 (PORK1) as the receptor perceiving REF1 signal for plant regeneration. REF1-PORK1-mediated signaling promotes regeneration via activating WOUND-INDUCED DEDIFFERENTIATION 1 (WIND1), a master regulator of wound-induced cellular reprogramming in plants. Thus, REF1-PORK1 signaling represents a conserved phytocytokine pathway to initiate, amplify, and stabilize a signaling cascade that orchestrates wound-triggered organ regeneration. Application of REF1 provides a simple method to boost the regeneration and transformation efficiency of recalcitrant crops.