A Study on the Protective Impact of Resveratrol on Liver Damage in Rats with Obstructive Jaundice.

BACKGROUND: Obstructive Jaundice (OJ) is a common clinical condition with potential outcomes, including hepatocyte necrosis, bile duct hyperplasia, significant cholestatic liver fibrosis, and, in severe cases, liver failure. Resveratrol (RES), a polyphenol present in grapes and berries, has demonstrated efficacy in improving OJ. However, the precise mechanism of its action remains unclear. METHODS: In this study, we employed network pharmacology to investigate the underlying molecular mechanism of RES in the treatment of OJ. The targets of RES were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), SuperPred, and SwissTargetPrediction database. The targets related to OJ were gathered from the DisGeNET, GeneCards, DrugBank, and Online Mendelian Inheritance in Man (OMIM) databases, and the intersection of these targets was determined using Venny2.1.0. Subsequently, an active component-target network was constructed using Cytoscape software. The Protein-Protein Interaction (PPI) network was generated using the String database and Cytoscape software. Following this, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted using the Bioconductor platform. Finally, quantitative Real-Time PCR (qRT-PCR), Western Blotting (WB), and Enzyme-Linked Immunosorbent Assay (ELISA) were employed to assess RNA and protein expression levels in related pathways. RESULTS: The findings revealed a selection of 56 potential targets for RES, and a search through the online database identified 2,742 OJ-related targets with overlapping in 27 targets. In the PPI network, mTOR, CYP2C9, CYP1A1, CYP3A4, AHR, ESR1, and HSD17B1 emerged as core targets. KEGG analyses demonstrated that the primary pathways of RES in treating OJ, particularly those related to lipid metabolism, include linoleic acid metabolism, arachidonic acid metabolism, metabolism of xenobiotics by cytochrome P450, lipid and atherosclerosis, tyrosine metabolism, steroid hormone biosynthesis, and pentose and glucuronate interconversions signaling pathways. Furthermore, in vivo experiments indicated that RES significantly ameliorated liver injury induced by Common Bile Duct Ligation (CBDL) in rats with OJ. It lowered serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, reduced liver tissue MDA levels, increased glutathione (GSH) content, and enhanced activity of superoxide dismutase (SOD), alleviating liver damage. Metabolomics analysis revealed that the therapeutic effect of RES in OJ involved alterations in lipid metabolic pathways, hinting at the potential mechanism of RES in treating OJ. ELISA, qRTPCR, and WB analyses confirmed lower expression levels of mTOR, CYP1A1, and CYP2C9 in the RES group compared to the model group, validating their involvement in the lipid metabolism pathway. CONCLUSION: In conclusion, RES exhibited a protective effect on liver function in rats with OJ. The underlying mechanism appears to be linked to antioxidant activity and modulation of lipid metabolism pathways.

Peripheral arterial rather than venous blood is a better source of circulating tumor cells in early lung cancer.

BACKGROUND: Circulating tumor cells (CTCs) play a crucial role in the early diagnosis and prognosis of lung cancer. Identification of a more suitable sample source could be a breakthrough towards enhancing CTC detectability in early-stage lung cancer. We investigated the differences in detectable CTCs between peripheral arterial and venous blood in early- and mid-stage lung cancer patients undergoing surgery and analyzed the association between clinicopathological factors and detectable CTCs in peripheral arterial and venous blood. METHODS: Peripheral arterial and venous blood was collected in 5-mL samples from 56 patients with surgically resected and pathologically clear at early- or mid-stage lung cancer. Blood specimens were enriched for CTCs based on isolation by size of epithelial tumor cells. The CTCs were identified using Swiss Giemsa staining and immunohistochemistry for CD45/CD31. RESULTS: In stage I lung cancer, CTC-positive rate was significantly higher in peripheral arterial than in venous blood (45.45% vs. 17.39%). There was no significant difference in the number of detectable CTCs between peripheral arterial and venous blood. A low degree of differentiation was associated with a high positive rate of CTCs in peripheral venous blood. The number of circulating tumor microemboli was significantly higher in patients with tumor size >3 cm compared with ≤3 cm. CONCLUSION: CTC levels in peripheral arterial and venous blood differed little in lung cancer patients.Compared to peripheral venous blood, peripheral arterial blood had a higher CTC positivity rate in early-stage lung cancer.This study was favorable for early detection and monitoring of lung cancer.

Antitumor effect of tubeimoside-I on murine colorectal cancers through PKM2-dependent pyroptosis and immunomodulation.

Induction of cancer cell death is an established treatment strategy, but chemotherapy drug-mediated apoptosis can be evaded by many tumors. Pyroptosis is a type of inflammatory programmed cell death (PCD) that is important for organism immunity. Tubeimoside-I (TBMS1) is a plant-derived component that exhibits antitumor activity. However, it is unclear how TBMS1 induces pyroptosis to inhibit colorectal cancer (CRC). In this study, we demonstrated that TBMS1 is able to induce pyroptosis in murine CRC cells and releases pro-inflammatory cytokines. Mechanistically, we found that TBMS1 inhibits CRC cell proliferation and migration and induces pyroptosis by activating caspase-3 and cleaving gasdermin E (GSDME) through the inhibition of PKM2. In the animal experiments, TBMS1 attenuated the weight of solid tumors, increased the proportion of CD8+ cytotoxic T cells, and reduced the content of M2-type macrophages in the spleen of tumor-bearing mice. Furthermore, TBMS1 inhibited M2-type polarization by blocking STAT6 pathway activation in RAW 264.7 cells. To sum up, our findings suggest that TBMS1 triggers pyroptosis in CRC by acting on the PKM2/caspase-3/GSDME signaling pathway. Additionally, it modulates the antitumor immune response in CRC murine models. This study provides a promising basis for the potential use of TBMS1 in treating CRC.

Protective effects of liriodendrin on myocardial infarction-induced fibrosis in rats via the PI3K/Akt autophagy pathway: A network pharmacology study.

BACKGROUND: Liriodendrin (LIR) has been reported to improve cardiac function in rats following myocardial infarction. However, its role and mechanism in reparative myocardial fibrosis remain unclear. METHODS: In this study, a rat model of myocardial fibrosis was established via left anterior descending artery ligation and randomly divided into three groups (n = 6 per group): sham-operated, myocardial infarction, and LIR intervention (100 mg/kg/day) groups. The pharmacological effects of LIR were assessed using echocardiography, hematoxylin, and eosin (H&E) staining, and Masson staining. Network pharmacology and bioinformatics were utilized to identify potential mechanisms of LIR, which were further validated via western blot analysis. RESULTS: Our findings demonstrated that LIR improved cardiac function, histology scores, and collagen volume fraction. Moreover, LIR downregulated the expression of Beclin-1, LC3-II, and LC3-I while upregulating the expression of p62, indicating LIR-activated autophagy in the heart after myocardial infarction. Further analysis revealed that the PI3K/Akt signaling pathway was significantly enriched and validated by western blot. This analysis suggested that the ratios of p-PI3K/PI3K, p Akt/Akt, and p-mTOR/mTOR were significantly increased. CONCLUSION: LIR may attenuate myocardial infarction-induced fibrosis in rats by inhibiting excessive myocardial autophagy, with the potential mechanism involving the activation of the PI3K/Akt/mTOR pathway.

Verbenalin alleviates acute lung injury induced by sepsis and IgG immune complex through GPR18 receptor.

Acute lung injury is significantly associated with the aberrant activation and pyroptosis of alveolar macrophages. Targeting the GPR18 receptor presents a potential therapeutic approach to mitigate inflammation. Verbenalin, a prominent component of Verbena in Xuanfeibaidu (XFBD) granules, is recommended for treating COVID-19. In this study, we demonstrate the therapeutic effect of verbenalin on lung injury through direct binding to the GPR18 receptor. Verbenalin inhibits the activation of inflammatory signaling pathways induced by lipopolysaccharide (LPS) and IgG immune complex (IgG IC) via GPR18 receptor activation. The structural basis for verbenalin's effect on GPR18 activation is elucidated through molecular docking and molecular dynamics simulations. Furthermore, we establish that IgG IC induces macrophage pyroptosis by upregulating the expression of GSDME and GSDMD through CEBP-δ activation, while verbenalin inhibits this process. Additionally, we provide the first evidence that IgG IC promotes the formation of neutrophil extracellular traps (NETs), and verbenalin suppresses NETs formation. Collectively, our findings indicate that verbenalin functions as a "phytoresolvin" to promote inflammation regression and suggests that targeting the C/EBP-δ/GSDMD/GSDME axis to inhibit macrophage pyroptosis may represent a novel strategy for treating acute lung injury and sepsis.

Protective effect of liriodendrin on IgG immune complex-induced acute lung injury via inhibiting SRC/STAT3/MAPK signaling pathway: a network pharmacology research.

The primary objectives of this research were to investigate the protective effects of liriodendrin against IgG immune complex (IgG-IC)-induced acute lung injury (ALI) and to elucidate the underlying mechanisms. This study employed a mouse and cell model of IgG-IC-induced acute lung injury. Lung tissue was stained with hematoxylin-eosin to observe pathological alterations and arterial blood gas analysis was tested. Inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor-alpha (TNF-α), were measured using ELISA. The mRNA expression of inflammatory cytokines was assessed via RT-qPCR. Molecular docking and enrichment analysis were combined to identify the most potential signaling pathways modulated by liriodendrin, which were then verified using western blot analysis in IgG-IC-induced ALI models. We identified 253 shared targets between liriodendrin and IgG-IC-induced acute lung injury from the database. Through network pharmacology, enrichment analysis, and molecular docking, SRC was determined to be the most closely associated target of liriodendrin in IgG-IC-induced ALI. Pretreatment with liriodendrin notably reduced the increased cytokine secretion of IL-1ß, IL-6, and TNF-α. Histopathological analysis of lung tissue demonstrated a protective effect of liriodendrin on IgG-IC-induced acute lung injury in mice. Arterial blood gas analysis showed liriodendrin ameliorated acidosis and hypoxemia efficiently. Further studies revealed that liriodendrin pretreatment substantially attenuated the elevated phosphorylation levels of SRC's downstream components (JNK, P38, and STAT3), suggesting that liriodendrin may protect against IgG-IC-induced ALI via the SRC/STAT3/MAPK pathway. Our findings indicate that liriodendrin protects against IgG-IC-induced acute lung injury by inhibiting the SRC/STAT3/MAPK signaling pathway, suggesting that liriodendrin may serve as a potential treatment for acute lung injury caused by IgG-IC.

[Effect of Liangxue Huoxue decoction on intestinal flora and NLRP3/caspase-1/GSDMD signaling pathway in mice model of sepsis-induced acute kidney injury].

OBJECTIVE: To investigate the effect of Liangxue Huoxue decoction on intestinal flora, intestinal barrier and NOD-like receptor protein 3 (NLRP3)/caspase-1/gasdermin D (GSDMD) pyroptosis signaling pathway in mice model of sepsis-induced acute kidney injury (AKI). METHODS: The model of AKI was established by cecal ligation and perforation (CLP). Thirty male C57BL/6 mice were randomly divided into sham operation group (Sham group), sepsis group (CLP group) and sepsis+Liangxue Huoxue decoction (CLP+LXHX group), with 10 mice in each group. Mice in Sham group only underwent laparotomy. Two hours before model establishment, mice in CLP+LXHX group were treated with Liangxue Huoxue decoction (6 g/kg) by gavage; mice in Sham group and CLP group were given equal volume of normal saline by gavages. After 24 hours of modeling, all mice were sacrificed under anesthesia, and the colon and kidney tissues and fresh feces in the colon were taken. The pathological changes of kidney and colon were observed by hematoxylin-eosin (HE) staining under light microscope. Real-time polymerase chain reaction (RT-PCR) was used to detect inflammatory factors (interleukins, IL-1ß and IL-18) in renal tissue. The expressions of NLRP3, caspase-1 and GSDMD were detected by Western blotting. The changes of intestinal flora in mice were detected by 16S rDNA high-throughput sequencing. RESULTS: Compared with the Sham group, the inflammatory cell infiltration of the kidney tissue was increased and the kidney became vacuolated in CLP group, the mRNA expressions of IL-1ß, IL-18, and the protein expressions of NLRP3, caspase-1 and GSDMD were significantly increased in CLP group, the species richness of intestinal microflora decreased significantly, the relative abundance of Enterococcus and Escherichia-Shigella increased significantly, and the relative abundance of Ileibacterium, Alloprevotella, Lachnospiraceae, Klebsiella and Parasutterella increased significantly in CLP group. Compared with CLP group, Liangxue Huoxue decoction can significantly reduce the pathological changes of kidney and colon tissue, reduce the pathological score (1.75±0.43 vs. 3.50±0.50 for kidney tissue, 1.25±0.43 vs. 4.50±0.50 for colon tissue, both P < 0.05), improve the composition of intestinal flora, reduce the relative abundance of Enterococcus and Escherichia-Shigella, and significantly increase the relative abundance of Lactobacillus and Akkermansia. In addition, Liangxue Huoxue decoction can significantly reduce mRNA expressions of IL-1ß and IL-18 in kidney tissue [IL-1ß mRNA (2-ΔΔCt): 1.59±0.05 vs. 4.61±0.88, IL-18 mRNA (2-ΔΔCt): 1.69±0.17 vs. 2.86±0.63, both P < 0.05] and the protein expressions of NLRP3, caspase-1 and GSDMD (NLRP3/GAPDH: 0.71±0.04 vs. 0.89±0.01, caspase-1/GAPDH: 1.04±0.04 vs. 1.48±0.04, GSDMD/GAPDH: 0.90±0.01 vs. 1.41±0.02, all P < 0.05). CONCLUSIONS: Liangxue Huoxue decoction has obvious protective effect on AKI induced by sepsis. It can improve intestinal barrier by regulating intestinal flora, thereby inhibiting the activation of NLRP3/caspase-1/GSDMD signaling pathway in kidney tissue and reducing the expression of proptosis-related inflammatory factors.

Isobavachalcone Activates Antitumor Immunity on Orthotopic Pancreatic Cancer Model: A Screening and Validation.

Pancreatic cancer is accompanied by poor prognosis and accounts for a significant number of deaths every year. Since Psoralea corylifolia L. (PCL) possesses a broad spectrum of bioactivities, it is commonly used in traditional Chinese medicine. The study explored potential antitumor agents of PCL and underlying mechanisms in vitro and vivo. Based on network pharmacology, bioinformatics, and molecular docking, we considered isobavachalcone (IBC) as a valuable compound. The activity and potential mechanisms of IBC were investigated by RT-qPCR, immunohistochemistry, immunofluorescence, and flow cytometry. It was confirmed that IBC could inhibit Panc 02 cell proliferation and induce apoptosis via increasing the production of reactive oxygen species. IBC could attenuate the weight of solid tumors, increase CD8+ T cells, and reduce M2 macrophages in the tumor tissue and spleen. Another promising finding was that IBC alleviated the proportion of myeloid-derived suppressor cells (MDSCs) in the tumor tissue but had no change in the spleen. The study of pharmacological effects of IBC was carried out and suggested IBC restrained M2-like polarization of RAW 264.7 cells by inhibiting the expression of ARG1 and MRC1 and suppressed the expression of ARG1 and TGF-ß in bone marrow-derived MDSC. In summary, this research screened IBC as an antineoplastic agent, which could attenuate the growth of pancreatic cancer via activating the immune activity and inducing cell apoptosis. It might be a reference for the antitumor ability of IBC and the treatment of the tumor microenvironment in pancreatic cancer.

[Effect of Xuanfu Daizhe decoction on stemness of esophageal cancer cells].

Objective: To investigate the effect of Xuanfu Daizhe decoction on the stemness of esophageal cancer cells. Methods: The BALB/c nude mice were randomly divided into the control group and experimental group, 5 mice in each group, which were continuously administered with normal saline and Xuanfu Daizhe decoction (9.89 g/kg) by gastrogavage, respectively. Human esophageal carcinoma cells ECA-109 (5×106) were subcutaneously injected into the mice on the 8th day. Tumor volume was measured twice a week. The mice were sacrificed 4 weeks after injection, and the tumor tissue and mouse serum were collected. The expressions of the major stemness-regulating transcription factors, i.e., NANOG, OCT4 and SOX2, were detected by RT-qPCR, Western Blot and immunohistochemistry. ECA-109 cells were treated with 10% fetal bovine serum and serum from the above two groups of mice for 48 hours respectively, and three replicate wells were set in each group, and the expressions of NANOG, OCT4, SOX2 and the levels of AKT and p-AKT were detected by RT-qPCR and Western Blot, respectively. ALDH activity in tumor cells was detected by flow cytometry; the number of spheroids of tumor cells was detected by the spheroidization experiment. Results: Compared with the control group, the growth and size of esophageal cancer tumors were significantly inhibited by Xuanfu Daizhe Decoction; the expressions of NANOG, OCT4, SOX2, the ALDH activity, the number of spheroids, and the levels of AKT and phosphorylated AKT (p-AKT) in esophageal cancer cells were significantly reduced by Xuanfu Daizhe Decoction both in vivo and in vitro. Conclusion: Xuanfu Daizhe Decoction inhibits the stemness of esophageal cancer cells, it may be a potentially effective drug for the treatment of esophageal cancer and provides a theoretical basis for the exploration of new effective drugs for the treatment of esophageal cancer.

Identification of potential prognostic biomarkers for hepatocellular carcinoma.

Background: The incidence of liver cancer is increasing every year. Hepatocellular carcinoma (HCC) accounts for nearly 90% of liver cancer, and the overall 5-year survival rate of become of Hepatocellular carcinoma patients less than 20%. However, the molecular mechanism of HCC progression and prognosis still requires further exploration. Methods: In this study, we downloaded the gene expression data from the Cancer Genome Atlas (TCGA) Genomic Data and the official website of GEO database. Weighted gene co-expression network analysis (WGCNA) and Pearson's correlation coefficient were utilized to detect the gene modules. The shared differentially-expressed genes (DEGs) were screened out by a Venn diagram, and the hub genes were identified through protein-protein interaction (PPI) network analyses. GO and KEGG enrichment analyses were constructed for these hub genes. Overall survival (OS) and correlation analysis were conducted to investigate the relationship between the hub genes and clinical features. Results: We screened out 27 shared DEGs, and the mainly enriched GO terms were mitotic nuclear division, chromosomal region, and tubulin binding. Furthermore, the top three enriched KEGG pathways were "cell cycle", "oocyte meiosis", and "p53 signaling pathway". According to the Maximal Clique Centrality (MCC) algorithm, the top 10 candidate hub genes were MYC, MCM3, CDC20, CCNB1, BIRC5, UBE2C, TOP2A, RRM2, TK1, and PTTG1, among which BIRC5, CDC20, and UBE2C showed a strong correlation with the OS. Conclusions: Three hub genes (BIRC5, CDC20, and UBE2C) were identified and found to be correlated to the progression and prognosis of HCC. These may become potential targets for HCC therapy.

Dihydroartemisinin inhibits the growth of pancreatic cells by inducing ferroptosis and activating antitumor immunity.

Dihydroartemisinin (DHA) exhibits a direct antitumor effect in various tumor models. However, the mechanism of DHA inducing ferroptosis and activating antitumor immunity remains obscure. Therefore, our study was dedicated to investigate the effect of DHA on ferroptosis and tumor microenvironment and elucidate the underlying molecular mechanism. PDAC orthotopic tumor model was used to investigate tumor proliferation and the population of immune cell in vivo, including M2-type macrophages (M2), myeloid-derived suppressor cells (MDSCs), CD4+T cells, CD8+T cells, NK cells and NKT cells. Levels of GPX4, SLC7A11, P53 and ALOX12 were determined by Real-time PCR and Western blot. CCK8 assay was performed to detect cell viability, and the ferroptosis was distinguished by flow cytometry. Our results showed that DHA inhibited pancreatic cancer cell proliferation. In addition, DHA induced cell ferroptosis by up-regulating the expression of P53 and ALOX12, which was blocked by baicalein (a selective ALOX12 inhibitor). However, DHA also up-regulated the expression of GPX4 and SLC7A11. On the other hand, DHA significantly decreased the suppressive expansion of M2 and MDSCs. Moreover, DHA increased the immune cell population of CD8+T cells, NK cells and NKT cells in the tumor tissues of the tumor-bearing mice. Whereas, the DHA treatment did not affect the frequencies of M2, MDSCs, CD4+T, CD8+T, NK and NKT cells in the spleen. Our research provided experimental evidences on the activity and mechanism of ferroptosis induced by DHA and revealed that DHA regulated tumor local immunosuppressive microenvironment.

Quantitative Scintigraphy Evaluated the Relationship between 131I Therapy and Salivary Glands Function in DTC Patients: A Retrospective Analysis.

Purpose: Quantitative scintigraphy to evaluate salivary gland function changes in patients with differentiated thyroid cancer (DTC) after iodine-131 (131I) treatment. Methods: A total of 458 patients with DTC grouped by sex and age were included. Salivary gland scintigraphy was performed to evaluate salivary gland function before and after 131I treatment. The uptake fraction (UF), uptake index (UI), and excretion fraction (EF) of two pairs of parotid glands and submandibular glands were measured and compared. The Chi-square test was conducted according to function impairment count. Results: Salivary gland function in different age groups and sexes were quite different, especially for women <55 years old, who had decreased UF, UI, and EF of all four glands without basal injury. The secretion or uptake function of some salivary glands with basic function impairment before 131I treatment was increased after iodine treatment. Only a small percentage of males showed reduced functional parameters after several treatments. The most significant difference in the count of impairment for the four salivary glands were the first and third examinations, which was more evident in women. The submandibular gland had the most significant reduction in uptake. Conclusion: Changes in salivary gland function are more common in young females being treated for DTC. Impairment of salivary gland function is correlated with the number of treatments and the cumulative dose of 131I. Some salivary gland functions impaired before 131I treatment were enhanced in the early treatment.

Cathepsin F genetic mutation is associated with familial papillary thyroid cancer.

BACKGROUND: Thyroid cancer is one of the most common cancers in the world. Genetic factors are important in the occurrence and development of thyroid cancer, and genetic diagnosis has become an important basis for the prognosis of benign and malignant nodules. We identify a family of six siblings with inherited thyroid cancer susceptibility. All six members of this generation have been definitely diagnosed with papillary thyroid carcinoma. This work aims at confirming the relevant causative genes for thyroid cancer in this pedigree. METHODS: We extract DNA from the peripheral blood of six individuals and perform whole genome sequencing. Sanger sequencing and immunohistochemistry further testify the cathepsin F (CTSF) mutation and expression. RESULTS: We identify 57 single nucleotide variations (SNVs) out of at least 4 affected family members via certain filter criteria. The CTSF gene found in five of the six family members is here considered the most promising candidate gene mutation for familial thyroid cancer. Besides, our research also proves several known genes including CTSB, TEKT4, ESR1, MSH6, DIRC3, GNAS, and BANCR that act as probable oncogenic drivers in this family. The Sanger sequencing identifies the existence and veracity of CTSF somatic mutations. The CTSF immunohistochemistry of thyroid cancer tissue specimens displays that higher CTSF expression in mutated patients than that in wild-type patient as well as pericarcinomatous tissue. CONCLUSIONS: We conclude that the evaluation of CTSF gene mutations of patients in thyroid cancer families may be predictive and valuable for the familial heredity of thyroid cancer.

Syringaresinol Resisted Sepsis-Induced Acute Lung Injury by Suppressing Pyroptosis Via the Oestrogen Receptor-ß Signalling Pathway.

Acute lung injury (ALI) is a common lung disease characterized by severe acute inflammatory lung injury in patients with sepsis. Syringaresinol (SYR) has been reported to have anti-apoptotic and anti-inflammatory effects, but whether it could prevent pyroptosis to improve sepsis-induced ALI remains unclear. The purpose of this work was to examine the impact of SYR on sepsis-induced ALI and investigate the underlying mechanisms. The ALI model was induced by caecal ligation and puncture (CLP) in C57BL/6 mice, structural damage in the lung tissues was determined using haematoxylin and eosin (HE) staining, and the levels of related inflammatory cytokines and macrophage polarization were examined by enzyme-linked immunosorbent assays (ELISAs) and flow cytometry, respectively. The activation of the NLRP3 inflammasome and the protein levels of TLR4, NF-κB and MAPKs was measured by western blotting. The results demonstrated that SYR pretreatment significantly reduced lung tissue histological damage, inhibited the production of proinflammatory cytokines and albumin in bronchoalveolar lavage fluid (BALF), and decreased myeloperoxidase (MPO) levels, thereby alleviating lung tissue injury. Meanwhile, septic mice treated with SYR displayed a higher survival rate and lower percentage of M1 macrophages in the BALF and spleen than septic mice. In addition, lung tissues from the CLP + SYR group exhibited downregulated protein expression of NLRP3, ASC, GSDMD caspase-1 p20 and TLR4, along with decreased phosphorylated levels of NF-κB, ERK, JNK and P38, indicating that SYR administration effectively prevented CLP-induced pyroptosis in the lung. SYR also suppressed LPS-induced pyroptosis in RAW 264.7 cells by inhibiting the activation of the NLRP3 inflammasome, which was abolished by an oestrogen receptor-ß (ERß) antagonist (PHTPP). In conclusion, SYR exerted protective effects on CLP-induced ALI via the oestrogen receptor-ß signalling pathway.

Syringaresinol attenuates sepsis-induced cardiac dysfunction by inhibiting inflammation and pyroptosis in mice.

The mortality of sepsis-induced cardiac dysfunction (SICD) is very high due to the complex pathophysiological mechanism. Syringaresinol (SYR) is a natural abstract which possesses anti-inflammatory property. The present study aims was to identify the protective impact of SYR on sepsis-induced cardiac dysfunction and investigate the specific mechanisms. We found that SYR improved the cardiac function and alleviated myocardial injury in mice that subjected to cecal ligation and puncture, in addition, SIRT1 expression was significantly elevated after SYR treatment compared to sepsis group both in vivo and in vitro, along with suppression of NLRP3 activation and proinflammatory cytokines release. However, SIRT1 inhibitor EX427 abolished the impact of SYR on LPS-induced pyroptosis in cardiomyocytes. Furthermore, molecular docking analysis predicted that there is high affinity between SYR and estrogen receptor (ER), ER inhibitor ICI182780, the specific ERß inhibitor PHTP and the specific ERαinhibitor AZD9496 were used to examine the role of ER in the protective effect of SYR against SICD, and the results suggested that ER activation was essential for the cardioprotective function of SYR. In conclusion, SYR ameliorates SICD via the ER/SIRT1/NLRP3/GSDMD pathway.

(-)-Syringaresinol suppressed LPS-induced microglia activation via downregulation of NF-κB p65 signaling and interaction with ERß.

Albiziae Cortex (AC) is a well-known traditional Chinese medicine with sedative-hypnotic effects and neuroprotective ability. However, the bioactive components of AC responsible for the neuro-protective actitivity remain unknown. Here, we investigated the anti-neuroinflammatory effects of (-)-syringaresinol (SYR) extracted from AC in microglia cells and wild-type mice. As a result, (-)-SYR significantly reduced lipopolysaccharide (LPS)-induced production of interleukin - 6 (IL-6), tumor necrosis factor α (TNF-α), interleukin -1 beta (IL-1ß), cycloxygenase-2 (COX-2), and nitric oxide (NO) in BV2 microglia cells. (-)-SYR also significantly reduced M1 marker CD40 expression and increased M2 marker CD206 expression. Moreover, we found that (-)-SYR inhibited LPS-induced NF-κB activation by suppressing the translocation of NF-κB p65 into the nucleus in a concentration-dependent manner. Meanwhile, estrogen receptor ß (ERß) was found to be implied in the anti-inflammatory activity of (-)-SYR in BV2 microglia. In vivo experiments revealed that administration of (-)-SYR in mice significantly reduced microglia/astrocytes activation and mRNA levels of proinflammatory mediators. Taken together, our data indicated that (-)-SYR exerted the anti-neuroinflammatory effects by inhibiting NF-κB activation and modulation of microglia polarization, and via interaction with ERß. The anti-neuroinflammatory activity of (-)-SYR may provide a new therapeutic avenue for the treatment of brain diseases associated with inflammation.

Chaihu Guizhi Ganjiang Decoction Ameliorates Pancreatic Fibrosis via JNK/mTOR Signaling Pathway.

Pancreatic fibrosis is a pathological characteristic of chronic pancreatitis (CP) and pancreatic cancer. Chaihu Guizhi Ganjiang Decoction (CGGD) is a traditional Chinese medicine, which is widely used in the clinical treatment of digestive diseases. However, the potential anti-fibrosis mechanism of CGGD in treating CP remains unclear. Here, we conducted a series of experiments to examine the effect of CGGD on the CP rat model and primary isolated pancreatic stellate cells (PSCs). The results revealed that CGGD attenuated pancreatic damage, decreased collagen deposition, and inhibited PSC activation in the pancreas of CP rats. However, compared with the CP group, CGGD had no effect on body weight and serum amylase and lipase. In addition, CGGD suppressed autophagy by downregulating Atg5, Beclin-1, and LC3B and facilitated phosphorylation of mTOR and JNK in pancreatic tissues and PSCs. Moreover, the CGGD-containing serum also decreased LC3B or collagen I expression after rapamycin (mTOR inhibitor) or SP600125 (JNK inhibitor) treatment in PSCs. In conclusion, CGGD attenuated pancreatic fibrosis and PSC activation, possibly by suppressing autophagy of PSCs through the JNK/mTOR signaling pathway.

Establishment and validation of a nomogram model for predicting the survival probability of differentiated thyroid carcinoma patients: a comparison with the eighth edition AJCC cancer staging system.

PURPOSE: This study aimed to develop a clinically predictive nomogram model to predict the survival probability of differentiated thyroid carcinoma patients and compare the value of this model with that of the eighth edition AJCC cancer staging system. METHODS: We selected 59,876 differentiated thyroid carcinoma patients diagnosed between 2004 and 2015 from the SEER database and separated those patients into a training set (70%) and a validation set (30%) randomly. We used Cox regression analysis to build the nomogram model (model 1) and the eighth edition AJCC cancer staging model (model 2). Then we compared the predictive accuracy, discrimination, and clinical usage of both models by calculating AUC (Area under the curve), C-index, as well as analyzing DCA (Decision Curve Analysis) performance respectively. RESULTS: AUCs of all predicted time points (12-month, 36-month, 60-month, and 120-month) of model 1 were 0.933, 0.913, 0.879, and 0.868 for the training set; 0.933, 0.926, 0.916, and 0.894 for the validation set. As for model 2, data were 0.938, 0.906, 0.866, and 0.847 for the training set; 0.924, 0.925, 0.912, and 0.867 for the validation set. C-indices of model 1 were higher than those of model 2 (0.923 vs. 0.918 for the training set, 0.938 vs. 0.930 for the validation set). DCA comparison showed that the net benefit of model 1 was bigger when comparing with that of model 2. CONCLUSIONS: Model 1 provided with both better predictive accuracy and clinical usage compared with those of model 2 and might be able to predict the survival probability of differentiated thyroid carcinoma patients visually and accurately with a higher net benefit.

Prediction model of random forest for the risk of hyperuricemia in a Chinese basic health checkup test.

OBJECTIVES: The present study aimed to develop a random forest (RF) based prediction model for hyperuricemia (HUA) and compare its performance with the conventional logistic regression (LR) model. METHODS: This cross-sectional study recruited 91,690 participants (14,032 with HUA, 77,658 without HUA). We constructed a RF-based prediction model in the training sets and evaluated it in the validation sets. Performance of the RF model was compared with the LR model by receiver operating characteristic (ROC) curve analysis. RESULTS: The sensitivity and specificity of the RF models were 0.702 and 0.650 in males, 0.767 and 0.721 in females. The positive predictive value (PPV) and negative predictive value (NPV) were 0.372 and 0.881 in males, 0.159 and 0.978 in females. AUC of the RF models was 0.739 (0.728-0.750) in males and 0.818 (0.799-0.837) in females. AUC of the LR models were 0.730 (0.718-0.741) for males and 0.815 (0.795-0.835) for females. The predictive power of RF was slightly higher than that of LR, but was not statistically significant in females (Delong tests, P=0.0015 for males, P=0.5415 for females). CONCLUSION: Compared with LR, the good performance in HUA status prediction and the tolerance of features associations or interactions showed great potential of RF in further application. A prospective cohort is necessary for HUA developing prediction. People with high risk factors should be encouraged to actively control to reduce the probability of developing HUA.

Anti-Inflammatory ent-Kaurane Diterpenoids from Isodon serra.

Ten new ent-kaurane diterpenoids, including two pairs of epimers 1/2 and 4/5 and a 6,7-seco-ent-kauranoid 10, were obtained from the aerial parts of Isodon serra. The structures of the new compounds were confirmed by extensive spectroscopic methods and electronic circular dichroism (ECD) data analysis. An anti-inflammatory assay was applied to evaluate their nitric oxide (NO) inhibitory activities by using LPS-stimulated BV-2 cells. Compounds 1 and 9 exhibited notable NO production inhibition with IC50 values of 15.6 and 7.3 µM, respectively. Moreover, the interactions of some bioactive diterpenoids with inducible nitric oxide synthase (iNOS) were explored by employing molecular docking studies.