We sought to explore the protective effect of the combination of fenchone (FE) and sodium hyaluronate (SH) on ice water-induced IBS-C rats and the potential mechanism. The neurotransmitter levels, including substance P (SP), motilin (MTL), 5-hydroxytryptamine (5-HT), and vasoactive intestinal peptide (VIP), were determined by ELISA methods. The stem cell factors (SCF)/c-Kit signaling pathway-related protein and mRNA levels were determined by western blot and reverse transcription quantitative polymerase chain reaction (RT-qPCR) analyses, respectively. The expressions of tight ZO-1, Occludin, and Claudin-1 were also measured by western blot assay and immunofluorescence staining. The 16S rRNA gene sequence was used to measure the composition of gut microbiota. The co-administration of FE and SH improved the body weight, number of fecal pellets, fecal moisture, abdominal with drawal reflex score, and gastrointestinal transit rate in IBS-C rats. The unique efficacy of combination depended on the regulation of balance between excitatory and inhibitory neurotransmitters, enhancement of intestinal barrier function, and activation of SCF/c-Kit pathway. The gut microbiota structure was also restored. The ability of FE combined with SH to regulate SCF/c-Kit signaling pathway, enhance intestinal barrier function, and modulate gut microbiota contributes to their efficacy in managing IBS-C in rats.

In this study we sought to elucidate the therapeutic effects of fenchone on constipation-predominant irritable bowel syndrome (IBS-C) and the underlying mechanisms. An IBS-C model was established in rats by administration of ice water by gavage for 14 days. Fenchone increased the reduced body weight, number of fecal pellets, fecal moisture, and intestinal transit rate, and decreased the enhanced visceral hypersensitivity in the rat model of IBS-C. In addition, fenchone increased the serum content of excitatory neurotransmitters and decreased the serum content of inhibitory neurotransmitters in the IBS-C rat model. Meanwhile, western blot and immunofluorescence experiments indicated that fenchone increased the expressions of SCF and c-Kit. Furthermore, compared with the IBS-C model group, fenchone increased the relative abundance of Lactobacillus, Blautia, Allobaculum, Subdoligranulum, and Ruminococcaceae_UCG-008, and reduced the relative abundance of Bacteroides, Enterococcus, Alistipes, and Escherichia-Shigella on the genus level. Overall, fenchone ameliorates IBS-C via modulation of the SCF/c-Kit pathway and gut microbiota, and could therefore serve as a novel drug candidate against IBS-C.

Juglone, mainly isolates from the green walnut husks of Juglans mandshurica, exhibits anti-cancer and anti-inflammaroty activities. But its protection on ulcerative colitis (UC) has never been explored. In this study, we first evaluated whether juglone ameliorated UC, and investigated its effects on gut microbiota and Th17/Treg balance in DSS-induced UC mice model. The model was established by administrating 2.7% DSS for seven days. Juglone was given daily by gavage for ten days, once a day. The disease activity index (DAI) decrease and pathological characteristics improvement demonstrated that the UC in mice was alleviated by juglone. Juglone treatment significantly inhibited the protein levels of IL-6, TNF-α and IL-1β, improved the protein expression of IL-10. In addition, juglone altered microbial diversity and gut microbiota composition, including the enhancement of the ratio of Firmicutes to Bacteroidota and the abundance of Actinobacteriota, and decrease of the abundance of Verrucomicrobiota. Juglone treatment also inhibited the protein expressions of IL-6, STAT3 and RORγt, meanwhile improved the protein level of FOXP3. Furthermore, juglone inhibited Th17 development and increased Treg generation, beneficial to Th17/Treg balance. Together, we herein provided the first evidence to support that juglone, especially the high dose, possibly protected mice against UC by modulating gut microbiota and restoring Th17/Treg homeostasis.

The root of Paeonia lactiflora Pall. (Chishao, CS) and Ligusticum chuanxiong Hort. (Chuanxiong, CX) were widely used as a drug pair in Chinese Medicine, and the combination of CS and CX showed a more significant inhibition on neuronal apoptosis in our previous study. In the present study, total paeony glycosides (TPGs) from CS and total ligustici phenolic acids (TLPAs) from CX were combined to evaluate the synergistic effects against focal cerebral ischemia both in vitro and in vivo. The combination of TPGs and TLPAs at 7:3 had the best anti-oxidative stress and anti-inflammatory effect on OGD-induced HUVEC. Additionally, the infarction area proportion and neuron apoptosis of rats by TPGs:TLPAs (7:3) was significantly lower than their alone in MCAO rats. Moreover, TPGs: TLPAs of 7:3 showed a more significant effect on decreasing the expression of MMP-2 and MMP-9, and increasing the protein expression or mRNA level of TIMP-1 than other combinations. The optimal ratio of TPGs and TLPAs at 7:3 could bring more remarkable protective effects against focal cerebral ischemia in MCAO rats by alleviating oxidative stress, inflammatory and neuronal apoptosis to protect the blood-brain barrier. Overall, the present study provided benefical evidence for clinical application of CS and CX as a "drug pair".

The morbidity and mortality of colorectal cancer (CRC) remained to be very high worldwide. Recently, circRNAs had been revealed to have a crucial role in cancer prognosis and progression. Numerous researches have shown that RNA sequencing technology and in silico method were widely used to identify pathogenic mechanisms and uncover promising targets for diagnosis and therapy. In this study, these methods were analyzed to obtain differentially expressed circRNAs (DECs). We identified upregulated 316 circRNAs and reduced 76 circRNAs in CRC samples, in comparison with those in normal tissues. In addition, a competitive endogenous network of circRNA-miRNA-mRNA was established to predict the mechanisms of circRNAs. Bioinformatics analysis revealed that these circRNAs participated in metabolism regulation and cell cycle progression. Of note, we observed the hub genes and miRNAs in this ceRNA network were associated with the survival time in CRC. We think this study could provide potential prognostic biomarkers and targets for CRC.

Endoplasmic reticulum (ER) stress-associated inflammation is a critical molecular mechanism involved in the pathogenesis of endothelial dysfunction (ED). Hence, strategies for alleviating ER stress-induced inflammation may be essential for the prevention of cardiovascular diseases. Paeoniflorin (PF), a bioactive compound from Paeonia lactiflora Pallas is known for its functional properties against vascular inflammation. However, to date, PF-mediated protection against ER stress-dependent inflammation has not been identified. Herein, we investigate the protective effect of PF on lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cell (HUVEC) injury and explore its underlying mechanism. The result of the cell viability assay indicates that PF promotes the cell survival rate in LPS-stimulated HUVECs. In addition, the LPS-induced over-production of inflammatory cytokines (interleukin-6 (IL-6) and monocyte chemotactic protein 1 (MCP-1)) and ER stress markers (78 kDa glucose regulated protein (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP)) are significantly decreased by PF and the ER stress inhibitor 4-phenylbutric acid (4-PBA). The transmission electron microscopy (TEM) assay implies that the ultrastructural abnormalities in ER are reversed by PF treatment, which is similar to the protective effect of 4-PBA. Impressively, we find that the inositol-requiring enzyme 1α (IRE1α)/nuclear factor-kappa B (NF-κB) pathway is significantly activated and contributes to the progress of LPS-induced HUVEC injury by promoting inflammatory cytokine production. IRE1α siRNA, AEBSF (ATF6 inhibitor), GSK2656157 (PERK inhibitor), PDTC (NF-κB inhibitor) and thapsigargin (TG, IRE1 activator) are used to confirm the role of the IRE1α/NF-κB pathway in PF-mediated protection against LPS-induced HUVEC injury. Our findings indicate that PF has an inhibitory effect on endothelial injury. To summarize, PF might be a potential therapeutic agent to inhibit ER stress-associated vascular inflammation.

Two natural compounds alisol A 24-acetate (24A) and alisol B 23-acetate (23B) are abundant in Rhizoma alismatis. In the present study, we evaluated the induction of 24A and 23B on apoptosis and possible nephrotoxicity of human renal proximal tubular (HK-2) cells by activating autophagy and also explored its regulation on PI3K/Akt/mTOR signaling pathway. Presently, Clusterin, Kim-1, and TFF-3 were considered to be new bioindicators of nephrotoxicity. Interestingly, the protein expression and mRNA levels of Clusterin, Kim-1 and TFF-3 could be significantly increased by 23B and 24A in vivo and in vitro. Furthermore, cell apoptosis could be triggered by 23B and 24A via significantly decreasing the protein expression and mRNA levels of Bcl-2 and Bcl-xl. Autophagy of HK-2 cells could be induced by both 23B and 24A via significantly enhancing the ratio of LC3II/LC3I, the protein expression of Beclin-1 as well as the mRNA levels of LC3 and Beclin-1. Meanwhile, PI3K/Akt/mTOR signaling pathway could be inhibited by these two compounds. An autophagy inhibitor, 3-methyladenine, could partially reverse cell viability and conversely change the ratio of LC3II/LC3I and the protein expression of Bcl-2 and Kim-1. Thus this study helped to understand that 23B and 24A induced autophagy resulted in apoptosis and nephrotoxicity through inhibiting PI3K/Akt/mTOR signaling pathway, facilitating further studies for nephrotoxicity induced by these two compounds and could be beneficial for safe use of Rhizoma alismatis in clinic.

Isoalantolactone is a bioactive sesquiterpene lactone isolated from the flowering plant Inula helenium L. This study was conducted to assess the anti-migratory and anti-invasive activities of isoalantolactone in MDA-MB-231 cells, and to explore the underlying mechanisms. Wound-healing and Transwell chambers assays demonstrated that isoalantolactone inhibited the adhesion, migration and invasion of MDA-MB-231 cells. The activity and expression of MMP-2 and MMP-9 were downregulated by isoalantolactone in a dose-dependent manner. Additionally, isoalantolactone markedly decreased the p-p38 MAPK level, whereas no significant change in p-ERK1/2 and p-JNK1/2 was noted. The downregulation of MMP-2 and MMP-9 protein expression and suppression of in vitro invasion might be associated with the blockade of p38 MAPK activation. Furthermore, isoalantolactone blocked the translocation of NF-κB p65 from the cytoplasm into the nucleus. These results revealed that isoalantolactone inhibited the adhesion, migration and invasion of MDA-MB-231 cells via suppression of the p38 MAPK/NF-κB signaling pathway, and isoalantolactone might be an alternative treatment for breast cancer.

Objectives This study aims to evaluate the oral bioavailability and dissolution of tanshinone IIA (tanIIA) by preparation of solid dispersions (SDs) with porous silica. Methods SDs of tanIIA were prepared using a solvent method. The physicochemical properties, dissolution property, drug stability and in-vivo performance of the SDs prepared were all evaluated. Key findings Compared with tanIIA alone and corresponding physical mixtures, tanIIA from SDs showed remarkably improved in-vitro dissolution rate. After forming the SDs, tanIIA changed into an amorphous state, which can infer from differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). Fourier transform infrared spectroscopy (FTIR) also revealed the presence of interactions between tanIIA and porous silica in SDs. During the stability study, there is no significant decreasing in either the in-vitro dissolution or the drug content, which was observed following storage at room temperature for 12 months. The results of a pharmacokinetic study in rats showed the areas under the concentration–time curve from 0 h to 24 h (AUC0–24h) for the SDs and tanIIA were 1019.87 ± 161.819 mg/h per litre and 343.70 ± 75.628 mg/h per litre, respectively. Conclusions SDs with porous silica as carrier could achieve superior oral bioavailability by improving drug dissolution, whereas drug stability could be maintained. Database : Wiley Online Library Title : Differential Hematopoietic Activity in White Adipose Tissue Depending on its Localization Author : Elodie Luche, Coralie Sengenès, Emmanuelle Arnaud, Patrick Laharrague, Louis Casteilla and Beatrice Cousin Journal : Journal of Cellular Physiology: Accepted manuscript online: 18 MAY 2015 05:51PM EST | DOI: 10.1002/jcp.25045 Abstract : White adipose tissue (WAT) can be found in different locations in the body, and these different adipose deposits exhibit specific physiopathological importance according to the subcutaneous or abdominal locations. We have shown previously the presence of functional hematopoietic stem/progenitor cells (HSPC) in subcutaneous adipose tissue (SCAT). These cells exhibit a specific hematopoietic activity that contributes to the renewal of the immune cell compartment within this adipose deposit. In this study we investigated whether HSPC can be found in visceral adipose tissue (VAT) and whether a putative difference in in situ hematopoiesis may be related to anatomical location and to site-specific immune cell content in VAT compared to SCAT. Therein, we identified for the first time the presence of HSPC in VAT. Using both in vitro assays and in vivo competitive repopulation experiments with sorted HSPC from VAT or SCAT, we showed that the hematopoietic activity of HSPC was lower in VAT, compared to SCAT. In addition, this altered hematopoietic activity of HSPC in VAT was due to their microenvironment, and may be related to a specific combination of secreted factors and extracellular matrix molecules expressed by adipose derived stromal cells. Our results indicate that WAT specific hematopoietic activity may be generalized to all adipose deposits, although with specificity according to the fat pad location. Considering the abundance of WAT in the body, this emphasizes the potential importance of this hematopoietic activity in physiopathological situations. White adipose tissue (WAT) can be found in different locations in the body, and these different adipose deposits exhibit specific physiopathological importance according to the subcutaneous or abdominal locations. We have shown previously the presence of functional hematopoietic stem/progenitor cells (HSPC) in subcutaneous adipose tissue (SCAT). These cells exhibit a specific hematopoietic activity that contributes to the renewal of the immune cell compartment within this adipose deposit. In this study we investigated whether HSPC can be found in visceral adipose tissue (VAT) and whether a putative difference in in situ hematopoiesis may be related to anatomical location and to site-specific immune cell content in VAT compared to SCAT. Therein, we identified for the first time the presence of HSPC in VAT. Using both in vitro assays and in vivo competitive repopulation experiments with sorted HSPC from VAT or SCAT, we showed that the hematopoietic activity of HSPC was lower in VAT, compared to SCAT. In addition, this altered hematopoietic activity of HSPC in VAT was due to their microenvironment, and may be related to a specific combination of secreted factors and extracellular matrix molecules expressed by adipose derived stromal cells. Our results indicate that WAT specific hematopoietic activity may be generalized to all adipose deposits, although with specificity according to the fat pad location. Considering the abundance of WAT in the body, this emphasizes the potential importance of this hematopoietic activity in physiopathological situations. Database : Wiley Online Library Title : GLP-2 as Beneficial Factor in the Glucose Homeostasis in Mice Fed a High Fat Diet Author : Sara Baldassano, Francesca Rappa, Antonella Amato, Francesco Cappello and Flavia Mulè Journal : Journal of Cellular Physiology: Accepted manuscript online: 12 MAY 2015 01:42PM EST | DOI: 10.1002/jcp.25039 Abstract : lucagon like peptide-2 (GLP-2) is a gastrointestinal hormone released in response to dietary nutrients, which acts through a specific receptor, the GLP-2 receptor (GLP2R). The physiological effects of GLP-2 are multiple, involving also the intestinal adaptation to high fat diet (HFD). In consideration of the well-known relationship between chronic HFD and impaired glucose metabolism, in the present study we examined if the blocking of the GLP-2 signaling by chronic treatment with the GLP2R antagonist, GLP-2 (3–33), leads to functional consequences in the regulation of glucose metabolism in HFD-fed mice. lucagon like peptide-2 (GLP-2) is a gastrointestinal hormone released in response to dietary nutrients, which acts through a specific receptor, the GLP-2 receptor (GLP2R). The physiological effects of GLP-2 are multiple, involving also the intestinal adaptation to high fat diet (HFD). In consideration of the well-known relationship between chronic HFD and impaired glucose metabolism, in the present study we examined if the blocking of the GLP-2 signaling by chronic treatment with the GLP2R antagonist, GLP-2 (3–33), leads to functional consequences in the regulation of glucose metabolism in HFD-fed mice. Compared with animals fed standard diet (STD), mice at the tenth week of HFD showed hyperglycaemia, glucose intolerance, high plasma insulin level after glucose load, increased pancreas weight and β cell expansion, but not insulin resistance. In HFD fed mice, GLP-2 (3-33) treatment for four weeks (from the sixth to the tenth week of diet) did not affect fasting glycaemia, but it significantly increased the glucose intolerance, both fasting and glucose-induced insulin levels, and reduced the sensitivity to insulin leading to insulin-resistance. In GLP-2 (3-33)treated HFD mice pancreas was significantly heavier and displayed a significant increase in β-cell mass in comparison with vehicle-treated HFD mice. In STD mice, the GLP-2 (3-33) treatment did not affect fasted or glucose-stimulated glycemia, insulin, insulin sensitivity, pancreas weight and beta cell mass. The present study suggests that endogenous GLP-2 may act as a protective factor against the dysregulation of the glucose metabolism that occurs in HFD mice, because GLP-2 (3-33) worsens glucose metabolism disorders. Database : Wiley Online Library Title : Complementary and alternative medicine for the prevention and treatment of migraine headache: an overview of systematic reviews Author : Paul Posadzki, Abdullah MN AlBedah, Mohamed MK Khalil, Meshari S AlQaed, Myeong S Lee, Edzard Ernst and Josip Car Journal : Focus on Alternative and Complementary Therapies: Volume 20, Issue 2, pages 58– 73, June 2015 Abstract : Background Complementary and alternative medicine (CAM) is very popular among migraineurs. Background Complementary and alternative medicine (CAM) is very popular among migraineurs. Objectives The aim of this article is to summarise and critically evaluate the evidence from systematic reviews (SRs) of CAM for the prevention and treatment of migraine headache. Method Ten electronic databases were searched from 1946 to August 2014. Retrieved papers were also hand-searched for relevant references. Systematic reviews were eligible for inclusion if they reported the prevention and treatment of migraine headache using any type of CAM. Oxman criteria were used to appraise the methodological quality of the included SRs. Results Thirty-three SRs, with a total of 45 886 migraine sufferers, were included in the analyses. The majority (64%) of the SRs were of high methodological quality (mean Oxman score=4.87, SD=3.96). Most (60.6%) SRs arrived at positive conclusions (16 of which were of high quality); two (6.0%) SRs arrived at negative conclusions (of which one was of high quality), and 11 (33.3%) arrived at equivocal conclusions (of which four were of high quality). The majority of the high-quality SRs (Oxman score=6–9) were based on moderate-quality RCTs. For multiple SRs, unanimously positive conclusions were reached for acupuncture and biofeedback. There was conflicting evidence regarding the effectiveness of homeopathy, herbal medicines such as Petasites hybridus and Tanacetum parthenium L., and spinal manipulative therapy. Conclusion The evidence from SRs evaluating the effectiveness of CAM for the prevention or treatment of migraine headache is mostly positive. However, several caveats should be taken into account, and only for acupuncture and biofeedback are the conclusions unanimously positive. Database : Wiley Online Library Title : Making polymeric membranes antifouling via “grafting from” polymerization of zwitterions Author : Qian Li, Joseph Imbrogno, Georges Belfort, Xiao-L

OBJECTIVES:Shikonin is an active naphthoquinone pigment isolated from the root of Lithospermum erythrorhizon. This study was designed to explore the inhibition of Shikonin on cell viability, adhesion, migration and invasion ability of gastric cancer (GC) and its possible mechanism. METHODS:3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed for cell viability and adhesion ability of MGC-803 cells. Cell scratch repair experiments were conducted for the determination of migration ability while transwell assay for cell invasion ability. Western blot analysis and real-time polymerase chain reaction assay were used for the detection of protein and mRNA expressions. KEY FINDINGS:Fifty per cent inhibitory concentration of Shikonin on MGC-803 cells was 1.854 μm. Shikonin (1 μm) inhibited significantly the adhesion, invasion and migratory ability of MGC-803 cells. Interestingly, Shikonin in the presence or absence of anti-Toll-like receptor 2 (TLR2) antibody (2 μg) and nuclear factor-kappa B (NF-κB) inhibitor MG-132 (10 μm) could decrease these ability of MGC-803 cells markedly, as well as the expression levels of matrix metalloproteinases (MMP)-2, MMP-7, TLR2 and p65 NF-κB. In addition, the co-incubation of Shikonin and anti-TLR2/MG-132 has a significant stronger activity than anti-TLR2 or MG-132 alone. CONCLUSIONS:The results indicated that Shikonin could suppress the cell viability, adhesion, invasion and migratory ability of MGC-803 cells through TLR2- or NF-κB-mediated pathway. Our findings provide novel information for the treatment of Shikonin on GC.