Photoinduced Precise Synthesis of Diatomic Ir1 Pd1 -In2 O3 for CO2 Hydrogenation to Methanol via Angstrom-Scale-Distance Dependent Synergistic Catalysis.

The atomically dispersed metal catalysts with full atomic utilization and well-defined site structure hold great promise for various catalytic reactions. However, the single metallic site limits the comprehensive reaction performance in most reactions. Here, we demonstrated a photo-induced neighbour-deposition strategy for the precise synthesis of diatomic Ir1 Pd1 on In2 O3 applied for CO2 hydrogenation to methanol. The proximity synergism between diatomic sites enabled a striking promotion in both CO2 conversion (10.5 %) and methanol selectivity (97 %) with good stability of 100 h run. It resulted in record-breaking space-time yield to methanol (187.1 gMeOH gmetal -1  hour-1 ). The promotional effect mainly originated from stronger CO2 adsorption on Ir site with assistance of H-spillover from Pd site, thus leading to a lower energy barrier for *HCOO pathway. It was confirmed that this synergistic effect strongly depended on the dual-site distance in an angstrom scale, which was attributed to weaker *H spillover and less electron transfer from Pd to Ir site as the Pd-to-Ir distance increased. The average dual-site distance was evaluated by our firstly proposed photoelectric model. Thus, this study introduced a pioneering strategy to precisely synthesize homonuclear/heteronuclear diatomic catalysts for facilitating the desired reaction route via diatomic synergistic catalysis.

Paeoniflorin inhibits hepatocellular carcinoma growth by reducing PD-L1 expression.

Abnormal expression of programmed death-ligand 1 (PD-L1) on cancer cells contributes to immune escape in hepatocellular carcinoma (HCC). Paeoniflorin has been shown to inhibit the growth of HCC; however, whether its inhibitory effect involves reducing PD-L1 expression on HCC cells remains unknown. We investigated the antitumor effects of paeoniflorin and its potential regulatory mechanisms in HCC. The effects of paeoniflorin on tumor growth and tumor immunity were determined in H22-xenografted mice and DEN-induced HCC rats. Small interfering RNA against suppressor of cytokine signaling 3 (SOCS3) was transfected into HepG2 cells to verify the effect of paeoniflorin on the SOCS3/signal transducer and activator of transcription 3 (STAT3)/PD-L1signaling pathway. The levels of SOCS3/STAT3/PD-L1 signaling pathway-related mRNAs and proteins were determined by real time-polymerase chain reaction and western blotting, respectively. Interleukin-2 (IL-2), interferon-γ (IFN-γ), granzyme B (GrB), and perforin 1 (PRF1) levels were detected in an H22 and mouse T cell co-culture system. Paeoniflorin can trigger T cell-mediated anti-tumor immune responses by increasing CD8+ T cell counts in tumor tissues, thereby inhibiting tumor growth. Moreover, paeoniflorin increased IL-2, IFN-γ, GrB, and PRF1 levels in the co-culture system. PD-L1 expression was suppressed by paeoniflorin, and this effect was mediated by the SOCS3/STAT3 signaling pathway. Paeoniflorin might thus act via enhancing SOCS3 to inhibit STAT3/PD-L1 signaling and subsequently restore T cell sensitivity to kill tumor cells. Our findings provide novel insights into the anticancer effects of paeoniflorin.

Evaluation of the effectiveness and mechanism of action of the Chang-Kang-Fang formula combined with bifid triple viable capsules on diarrhea-predominant irritable bowel syndrome.

Introduction: The Chang-Kang-Fang (CKF) formula, a traditional Chinese herbal formula, can decrease serotonin (5-HT) levels and treat irritable bowel syndrome (IBS). Probiotics have a better synergistic effect on diarrhea-predominant IBS (IBS-D) when combined with 5-HT3 receptor antagonists. The present study aimed to elucidate the efficacy and the mechanisms of action of the CKF formula combined with bifid triple viable capsules (PFK) against IBS-D. Methods: The rat models of IBS-D were induced by gavage with senna decoction plus restraint stress. The CKF formula, PFK and their combination were administered to the rats. Their effects were evaluated based on general condition of the rats and the AWR score. The levels of 5-HT and fos protein in the colon and hippocampus were measured by immunohistochemistry. The levels of SP and VIP, as well as ZO-1 and occludin in the colon, were determined by enzyme-linked immunosorbent assay and immunohistochemistry. The intestinal microbiota in faeces was analyzed by 16S rRNA high-throughput sequencing. Results: The results showed that the oral CKF formula combined with PFK (CKF + PFK) could significantly relieve the symptoms of IBS-D, including elevating the weight rate and decreasing the AWR score. Compared with the MC group, administration of CKF + PFK significantly reduced the expression of fos in the colon and hippocampus and that of 5-HT, SP and VIP in the colon and increased the levels of 5-HT in the hippocampus and ZO-1 and occludin in the colon. The above indexes exhibited statistical significance in the CKF + PFK group relative to those in the other groups. Moreover, treatment with CKF + PFK improved the diversity of intestinal microbiota and the abundance of Firmicutes, Lachnospiraceae and Ruminococcaceae but decreased those of Bacteroidetes and Prevotellaceae. Conclusions: The CKF formula combined with PFK may have a synergistic effect on IBS-D by slowing gastrointestinal motility, lowering visceral hypersensitivity, enhancing the intestinal barrier function and modulating the composition of intestinal microbiota.

Experimental Investigation of the Dynamic Mechanical Properties of Polypropylene-Fiber-Reinforced Foamed Concrete at High Temperatures.

Polypropylene-fiber-reinforced foamed concrete (PPFRFC) is often used to reduce building structure weight and develop engineering material arresting systems (EMASs). This paper investigates the dynamic mechanical properties of PPFRFC with densities of 0.27 g/cm3, 0.38 g/cm3, and 0.46 g/cm3 at high temperatures and proposes a prediction model to characterize its behavior. To conduct the tests on the specimens over a wide range of strain rates (500~1300 s-1) and temperatures (25~600 °C), the conventional split-Hopkinson pressure bar (SHPB) apparatus was modified. The test results show that the temperature has a substantial effect on the strain rate sensitivity and density dependency of the PPFRFC. Additionally, the analysis of failure models demonstrates that with the melting of polypropylene fibers, the level of damage in PPFRFC under dynamic loading increases, resulting in the generation of a greater number of fragments.

A comparative study of the ameliorative effects of hyaluronic acid oligosaccharides and hyaluronic acid on DSS-induced colitis in mice and research on relevant mechanisms.

As a dietary supplement, hyaluronic acid (HA) has exhibited appreciable immunomodulatory activity and an ameliorative effect on rodent colitis. However, its high viscosity is not only refractory to absorb through the gut, but also causes flatulence. In contrast to HA, hyaluronic acid oligosaccharides (o-HAs) can overcome the above-mentioned constraints, but their treatment effect still remains ill-defined contemporarily. Herein, the current study intends to compare the modulatory effects of HA and o-HA on colitis and assess the underlying molecular mechanism. We first showed that o-HA had a better preventive effect than HA in alleviating colitis symptoms, as evidenced by lower body weight loss, lower disease activity index scores, a lower inflammatory response (TNF-α, IL-6, IL-1ß, p-NF-κB), and more intact colon epithelial integrity in vivo. The best efficiency was observed in the o-HA treated group with a dosage of 30 mg kg-1. In an in vitro barrier function assay, o-HA exerted a better protective effect on the transepithelial electrical resistance (TEER), FITC permeability, and wound healing and modulated the expression of tight junction (TJ) proteins (ZO-1, occludin) in lipopolysaccharide (LPS)-stimulated Caco-2 cells. In summary, both HA and o-HA showed the potential to reduce inflammation and ameliorate intestinal damage in DSS-induced colitis and LPS-induced inflammation, but o-HA had improved outcomes. The results also provided a glimpse of the latent mechanism by which HA and o-HA enhanced intestinal barrier function via MLCK/p-MLC signaling pathway suppression.

Discovery of pyrazolo[3,4-b]pyridine derivatives as novel and potent Mps1 inhibitors for the treatment of cancer.

Monopolar spindle kinase 1 (Mps1) is a key element of the mitotic checkpoint and clinically evaluated as a target in the treatment of aggressive tumors. With this aim, a set of pyrazolo[3,4-b]pyridine-based compounds as new Mps1 inhibitors was investigated through a multidisciplinary approach, based on virtual screening, chemical synthesis and biological evaluation. One of the representative compounds, 31, exhibited strong kinase inhibitory potency against Mps1 with an IC50 value of 2.596 nM and significantly inhibited proliferation of cancer cells, especially MDA-MB-468 and MV4-11 cells. Compound 31 also displayed reasonable kinome selectivity against a panel of 606 wild-type kinases at 1 µM. Moreover, compound 31 exhibited suitable preclinical pharmacokinetic parameters and a promising pharmacodynamic profile. Further, compound 31 showed good antitumor efficacy in MDA-MB-468 xenograft model with no obvious toxicity. Overall, compound 31 was identified as a potential Mps1 inhibitor for cancer therapy and deserve further research.

Shaoyao decoction restores the mucus layer in mice with DSS-induced colitis by regulating Notch signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Restoring the mucus layer is a potential strategy for treating ulcerative colitis (UC). Previous studies reported that a Chinese medicine formula Shaoyao Decoction (SYD) effectively improved UC. However, the role and mechanism of SYD in restoring the mucus layer are still vague. AIM OF THE STUDY: This study aimed to research the therapeutical effects and unravel the involved mechanism of SYD on DSS-evoked UC. MATERIALS AND METHODS: First, the constituents of SYD were detected by UPLC-QTOF-MS/MS. Then, the DSS-induced UC model was introduced to investigate the pharmacologic action and molecular mechanism of SYD on UC. Pharmacodynamic indicators were assessed including body weight, colon length, ulcerations, disease activity index (DAI), inflammatory cytokines and histological parameters. To investigate the integrality and functions of the mucous layer, AB-PAS stain and UEA-1 stain were used to evaluate the completeness of mucous layer, as well as the maturation of goblet cells (GCs). The bacterial invasion was detected by fluorescence in situ hybridization. As to mechanism exploration, the expressions of Notch/Hes1 pathway were investigated by using agonists in lipopolysaccharides (LPS) -stimulated LS174T cell. RESULTS: After modeling in mice, SYD remarkedly ameliorated the symptoms of mouse colitis, the expression of pro-inflammatory factors declined, and increased IL-10 expression was observed in SYD-treated mice. Besides, SYD repaired the structure of the mucus layer and prevented bacterial invasion. Mechanism investigation discovered that SYD promoted GCs differentiation by inhibiting the Notch pathway, which was consistent with the results in LPS-challenged LS174 cell. CONCLUSIONS: These findings demonstrated that SYD could restore the mucus layer to prevent UC via suppressing the Notch signaling pathway, which provided evidences for the UC treatment of SYD in the clinic.

Aloin A prevents ulcerative colitis in mice by enhancing the intestinal barrier function via suppressing the Notch signaling pathway.

BACKGROUND: Previous studies reported that Aloe vera ameliorated DSS-induced colitis and promoted mucus secretion. However, the effect of Aloin A (AA), a major compound of Aloe vera, on colitis and its exact mechanism remains uncovered. METHODS: C57BL/6 mice were successively subjected to 3% DSS solution for 5 days and distilled water for 2 days. Concurrently, AA (25, 50 mg/kg) and 5-aminosalicylic (500 mg/kg) were administrated intragastrically from day 1 to day 7. Colitis was evaluated by disease active index (DAI), colon length, inflammation response, and intestinal barrier function. In vitro LS174T cells challenged with 50 ng/ml of lipopolysaccharides (LPS) were used to validate the modulatory action of AA on the Notch signaling pathway. RESULTS: Our results showed that oral administration with AA prominently prevented DSS-induced colitis symptoms in terms of decreased DAI, prevention of colon shortening, and reduced pathological damage. AA mitigated the inflammatory response evidenced by the decreased proinflammatory cytokines (TNF-α, IL-1ß, IL-6) and increased anti-inflammatory cytokine (IL-10). Besides, AA inhibited apoptosis and facilitated proliferation in colons. Moreover, AA treatment up-regulated the expression of tight junction (TJ) proteins (ZO-1, Occludin) and promoted the secretion of MUC2 to decrease colon permeability. Mechanistically, AA inhibited the Notch pathway to promote the secretion of MUC2, which was consistent with LPS-challenged LS174 cells. CONCLUSION: These results suggested that AA could prevent colitis by enhancing the intestinal barrier function via suppressing the Notch signaling pathway. Thus, AA might be a prospective remedy for ulcerative colitis.

Comparative effects of different enzymatic hydrolysates of konjac glucomannan on gut flora and constipation in rats.

This study aimed to compare the effects of different hydrolysates (named GKOS and MKOS) on constipated rats, which were obtained by degradation from konjac glucomannan by ß-glucanase and ß-mannanase, respectively. GKOS and MKOS were characterized and administered by gavage at 100 mg kg-1 to constipated rats. The variation of the gut flora, content of short-chain fatty acids (SCFAs), defecation function, gastrointestinal motility, and intestinal mucus secretion were determined to evaluate their regulatory effects on constipation. The results revealed the more prominent augmentation of species richness in MKOS than with GKOS. They also possessed diverse modulatory effects on different genera, such as Prevotella and Parabacteroides. Unexpectedly, there was no statistical divergence between GKOS and MKOS in defecation parameters, gastrointestinal transit, serum parameters, and mucous secretion. Overall, MKOS and GKOS exhibited differential regulatory function on gut microbiota in vivo, but with nearly consistent therapeutic effects on constipation.

Target identification and occupancy measurement of necrosis avid agent rhein using bioorthogonal chemistry-enabling probes.

Necrosis is an important biomarker, which only occurs in pathological situations. Tracking of necrosis avid agents is of crucial importance toward understanding their mechanisms. Herein, we developed a modular probe strategy based on bioorthogonal copper-free click chemistry. Structural modification of rhein with transcyclooctene (TCO) led to the identification of rhein-TCO2 as the most active probe with specific necrosis affinity. In a systematic evaluation, the colocalization of rhein-TCO2 in the nucleus (exposed DNA and rRNA) of necrotic cells was observed. This work provides a foundation for the development of target-identified of rhein compounds, and binding to exposed DNA and rRNA may be an important target of rhein compounds in necrotic cells.

Cyclocarya paliurus triterpenoids suppress hepatic gluconeogenesis via AMPK-mediated cAMP/PKA/CREB pathway.

BACKGROUND: Abnormal enhancement of hepatic gluconeogenesis is a vital mechanism of the pathogenesis of Type 2 diabetes mellitus (T2DM); thus, its suppression may present an efficient therapeutic strategy for T2DM. Cyclocarya paliurus (CP), a plant species native to China, has been reported to have anti-hyperglycemia activity. Our previous studies have revealed that Cyclocarya paliurus triterpenic acids (CPT) exert the favorable glucose-lowering activity, but the regulatory effect of CPT on hepatic gluconeogenesis is still unclarified. PURPOSE: This study aimed to investigate the potential role and mechanism of CPT in gluconeogenesis. STUDY DESIGN: In this study, the ameliorative effect and underlying mechanism of CPT on gluconeogenesis were investigated: high-fat diet and streptozotocin-induced T2DM mice and glucagon-challenged mouse primary hepatocytes. METHODS: T2DM model mice with or without oral administration of CPT for 4 weeks were monitored for body weight, glucose and lipid metabolism. Hematoxylin and eosin staining was used to observe liver lipid deposition. Real-time PCR assays were performed to examine the mRNA expression of glucose-6-phosphate (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK), two key enzymes involved in liver gluconeogenesis. Western blotting was used to determine AMP-dependent protein kinase (AMPK) expression and induction of the glucagon signaling pathway. The possible mechanism of CPT on liver gluconeogenesis was further explored in glucagon-induced mouse primary hepatocytes. RESULTS: In vivo and in vitro experiments revealed that CPT treatment significantly reduced fasting blood glucose, total cholesterol and triglyceride levels, and improved insulin resistance. Furthermore, CPT could obviously decreased the mRNA and protein expression of G6Pase and PEPCK, the cyclic AMP content, the phosphorylation level of protein kinase A and cyclic AMP response element-binding protein. But CPT promoted the phosphorylation of AMP-dependent protein kinase (AMPK) and activation of phosphodiesterase 4B. Mechanistically, intervention with Compound C (an AMPK inhibitor) partially blocked the suppressive effect of CPT on hepatic gluconeogenesis. CONCLUSION: These findings suggested that CPT may inhibit hepatic gluconeogenesis against T2DM by activating AMPK.

Development of Duramycin-Based Molecular Probes for Cell Death Imaging.

Cell death is involved in numerous pathological conditions such as cardiovascular disorders, ischemic stroke and organ transplant rejection, and plays a critical role in the treatment of cancer. Cell death imaging can serve as a noninvasive means to detect the severity of tissue damage, monitor the progression of diseases, and evaluate the effectiveness of treatments, which help to provide prognostic information and guide the formulation of individualized treatment plans. The high abundance of phosphatidylethanolamine (PE), which is predominantly confined to the inner leaflet of the lipid bilayer membrane in healthy mammalian cells, becomes exposed on the cell surface in the early stages of apoptosis or accessible to the extracellular milieu when the cell suffers from necrosis, thus representing an attractive target for cell death imaging. Duramycin is a tetracyclic polypeptide that contains 19 amino acids and can bind to PE with excellent affinity and specificity. Additionally, this peptide has several favorable structural traits including relatively low molecular weight, stability to enzymatic hydrolysis, and ease of conjugation and labeling. All these highlight the potential of duramycin as a candidate ligand for developing PE-specific molecular probes. By far, a couple of duramycin-based molecular probes such as Tc-99 m-, F-18-, or Ga-68-labeled duramycin have been developed to target exposed PE for in vivo noninvasive imaging of cell death in different animal models. In this review article, we describe the state of the art with respect to in vivo imaging of cell death using duramycin-based molecular probes, as validated by immunohistopathology.

The role of exosomal CDC6 in the hirudin-mediated suppression of the malignant phenotype of bladder cancer cells.

BACKGROUND: Bladder cancer is a malignant tumor characterized by high recurrence and persistence due to the limited therapies that are currently available. Hirudin exerts a strong anticancer effect on several tumors. Thus, it is urgent to explore the biological function of hirudin in bladder cancer and the role of bladder cancer-derived exosomes in tumor inhibition. METHODS: First, a network pharmacology analysis was performed to explore the relationships among hirudin, bladder cancer, and exosomes. Then, the effects of hirudin were examined by CCK-8 assay, flow cytometry, Transwell assay, and tumorigenic ability experiments in vitro. Exosomes derived from cells were identified with transmission electron microscopy, fluorescence labeling, and Western blotting and collected for further microarray analysis. Only CDC6 expression and mRNA abundance in hirudin-treated cells and exosomes was subjected to further validation using quantitative PCR and Western blotting. RESULTS: Through network analysis, we found that hirudin affected bladder cancer, and this effect was related to exosomes. Our studies verified the effects of hirudin by revealing that hirudin inhibits malignant processes of bladder cancer cells in vitro, such as invasion, metastasis, and apoptosis. Similarly, the oncogenic effects of bladder cancer-derived exosomes were successfully isolated and identified. Via microarray assessment of the exosomes, we identified 600 differential mRNAs, of which the expression of the core target CDC6 was found to be significantly different in both The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. We further confirmed that hirudin suppresses CDC6 expression mRNA abundance in both cells and exosomes. CONCLUSION: Hirudin was able to decrease the expression of CDC6 in bladder cancer cells and exosomes, which effectively repressed the malignant processes of bladder cancer cells.

Functional variants of RPS6KB1 and PIK3R1 in the autophagy pathway genes and risk of bladder cancer.

Autophagy plays a critical role in cancer, since it can either suppress tumorigenesis by inhibiting cancer cell survival, or facilitate tumorigenesis by promoting cancer cell proliferation and tumor growth. However, the role of genetic variants of autophagy-regulated key genes for bladder cancer risk remained unclear. Here, we aimed to explore the association of bladder cancer with genetic variants on genes involved in autophagy pathway. Gene-based analysis was performed with multi-marker analysis of genomic annotation (MAGMA) in 580 bladder cancer cases and 1101 controls. The logistic regression model was used to calculate the SNP effects on bladder cancer susceptibility. Expression quantitative trait loci (eQTL) analysis was conducted by the genotype-tissue expression (GTEx) project. Gene expression was evaluated based on the Cancer Genome Atlas (TCGA) database. Three potentially functional SNPs RPS6KB1 rs1292038, PIK3R1 rs34303, and rs56352616 were demonstrated to be associated with risk of bladder cancer (OR = 0.71, 95% CI = 0.61-0.82, P = 7.88 × 10-6 for rs1292038; OR = 1.25, 95% CI = 1.09-1.45, P = 2.11 × 10-3 for rs34303; OR = 0.74, 95% CI = 0.62-0.90, P = 2.47 × 10-3 for rs56352616). An increasing number of risk genotypes of these three SNPs were associated with a higher risk of developing bladder cancer. Besides, rs1292038 exhibited an eQTL effect for RPS6KB1 in whole blood (P = 3.90 × 10-7). Furthermore, the higher expression of RPS6KB1 and lower expression of PIK3R1 were both significantly associated with bladder cancer risk. Our findings indicated that genetic variants in autophagy pathway genes RPS6KB1 and PIK3R1 confer bladder cancer susceptibility.

Direct Cyclopropanation of Quinolinium Zwitterionic Thiolates via Dearomative Reactions.

A one-pot, two-step protocol for the synthesis of libraries of remarkable functionalized sulfone analogues of 9b,10,10a,10b-tetrahydro-1H-cyclopropa[c][1,4]thiazino[4,3-a]quinolines is described. A class of various functionalized molecular skeletons was obtained by cyclopropanation of quinolinium zwitterionic thiolates. The reaction pathway involves the formation of a [2 + 1] cycloaddition intermediate followed by a [5 + 1] cycloaddition.

Comparative study of the laxative effects of konjac oligosaccharides and konjac glucomannan on loperamide-induced constipation in rats.

Dietary fiber is the basic therapeutic method to relieve the symptoms of chronic constipation. The aim of this study was to compare the laxative effect of konjac glucomannan (KGM) and konjac oligosaccharides (KOS) on constipated rats. KGM and KOS were administered to loperamide-induced constipated rats at dosages of 100 mg per kg bw and 400 mg per kg bw for 15 days. Feces were collected to evaluate the defecation function. X-ray imaging and an electrophysiological system were used to determine gastrointestinal (GI) motility. Immunohistochemistry and western blotting were used to measure the protein levels. Magnetic resonance imaging (MRI) was performed to assess flatulence. Our results demonstrated that low-dose KOS (L-KOS) exerted the best laxative effect. Compared to the normal control (NC) group, the fecal number in the L-KOS group increased by 39.4%, and the fecal weight significantly increased by 31.9% which was higher than those in the low-dose KGM (L-KGM) and high-dose KGM (H-KGM) groups. The fecal moisture content and transit scores were significantly increased only in the L-KOS group. Meanwhile, less GI gas was produced by KOS. Additionally, further investigations suggested that KOS could upregulate the protein expression of stem cell factors (SCF)/c-kit, and significantly promoted the secretion of mucus. In conclusion, compared to KGM, KOS had a conspicuous laxative effect especially at a low dosage. The potential laxative mechanisms of KOS probably are regulating the SCF/c-kit signalling pathway and increasing mucus secretion. These findings indicated that as a kind of functional oligosaccharide, KOS is more conducive to alleviating constipation compared to polysaccharides.

Aloe vera mitigates dextran sulfate sodium-induced rat ulcerative colitis by potentiating colon mucus barrier.

ETHNOPHARMACOLOGICAL RELEVANCE: Aloe vera (L.) Burm. f. (Aloe vera) is a medicinal herb that used in Traditional Chinese Medicine (TCM) practice for the treatment of gastrointestinal diseases such as constipation and colitis. Recent studies also reported its beneficial effect in mitigating ulcerative colitis (UC). Nevertheless, the underlying mechanisms of Aloe vera against UC remain largely unknown. AIM OF THE STUDY: This study aimed to explore a relation between the therapeutical effects of Aloe vera in UC and colonic mucus secretion, and further investigate the underlying pathways through which Aloe vera regulates colon mucus as well as preliminarily studied the main active constitute of Aloe vera to alleviate UC. MATERIALS AND METHODS: UPLC-MS/MS were employed to analyze the Aloe vera extract. The rat models of UC were induced by free subjected to fresh 3% dextran sulfate sodium (DSS) solution for 8 days and then accessed to tap water for 2 days. Aloe vera extract (18 mg/kg and 72 mg/kg) or 5-ASA (400 mg/kg) was administered orally from day 1-10. At the end of experiment, rats were sacrificed and the colon tissues were harvested for analysis. UC symptoms was evaluated by disease activity index (DAI), colon length and H&E staining. The Alcian blue stain were determined colon mucus layer. Myeloperoxidase (MPO) activity, mucin and inflammatory cytokines in colon tissues were determined by ELISA. The expression of related proteins on PI3K/AKT and PKC/ERK signaling pathway was analyzed by Western blot. We then evaluated the effects of three main components of Aloe vera (Aloe-emodin, aloin A and B) on mucin secretion and cytokine expression in vitro by ELISA. RESULTS: Oral supplement with Aloe vera extract resulted in a significantly decreased DSS-induced UC symptoms, including decreased DAI, prevention of the colon length shortening, and alleviation of the pathological changes occurring in colon. The expression of colonic pro-inflammatory mediators, including IL-6, IL-1ß and TNF-α were suppressed, yet the expression of IL-10 was up-regulated by Aloe vera treatment. Moreover, Aloe vera significantly up-regulated the expressions of mucin proteins (e.g., MUC2 and MUC5AC) and increased the thickness of mucus layer in the colon. Further, we revealed that Aloe vera significantly upregulated p-PKC and p-ERK expression and downregulated p-PI3K and p-AKT expression. Finally, we discovered that treat with aloin A markedly decreased IL-6 levels and increased MUC2 expression in LPS-stimulated LS174T cell. CONCLUSION: These results support that Aloe vera improved UC by enhancing colon mucus barrier functions in addition to reducing inflammation. Moreover, aloin A might be a main active components of Aloe vera to ameliorate UC.

Combining combretastatin A4 phosphate with ginsenoside Rd synergistically inhibited hepatocellular carcinoma by reducing HIF-1α via PI3K/AKT/mTOR signalling pathway.

OBJECTIVES: Combretastatin A4 phosphate (CA4P), a vascular disrupting agent (VDA), can cause rapid tumour vessel occlusion. Subsequently, extensive necrosis is discovered in the tumour center, which induces widespread hypoxia and the rise of the α subunit of hypoxia-inducible factor-1 (HIF-1α). The aim of this study was to evaluate the inhibition of hepatocellular carcinoma growth by combining CA4P with HIF-1 α inhibitor and investigate the mechanism of this combination. METHODS: Ginsenoside Rd (Rd) was used in combination with CA4P to estimate the inhibition effect in HepG2 cells and HepG2 xenograft mouse model. The efficacy of anti-tumour was evaluated by tumour growth curve. The protein expression of HIF-1α and PI3K/AKT/mTOR signalling pathway were analysed by western blot. KEY FINDINGS: Combination of CA4P and Rd inhibited HepG2 cell proliferation and induced apoptosis in vivo and in vitro. It also increased the necrotic area of the tumour and delayed the tumour growth. Moreover, Rd down-regulated HIF-1α protein expression by inhibiting PI3K/AKT/mTOR signalling pathway. CONCLUSIONS: Combination of CA4P and Rd had synergistic anti-tumour effects. The mechanism may be related to the inhibition of HIF-1α by PI3K/AKT/mTOR signalling pathway. This strategy provides a new thought for the combinative therapy of VDAs.