Landscapes of gut bacterial and fecal metabolic signatures and their relationship in severe preeclampsia.

BACKGROUND: Preeclampsia is a pregnancy-specific disease leading to maternal and perinatal morbidity. Hypertension and inflammation are the main characteristics of preeclampsia. Many factors can lead to hypertension and inflammation, including gut microbiota which plays an important role in hypertension and inflammation in humans. However, alterations to the gut microbiome and fecal metabolome, and their relationships in severe preeclampsia are not well known. This study aims to identify biomarkers significantly associated with severe preeclampsia and provide a knowledge base for treatments regulating the gut microbiome. METHODS: In this study, fecal samples were collected from individuals with severe preeclampsia and healthy controls for shotgun metagenomic sequencing to evaluate changes in gut microbiota composition. Quantitative polymerase chain reaction analysis was used to validate the reliability of our shotgun metagenomic sequencing results. Additionally, untargeted metabolomics analysis was performed to measure fecal metabolome concentrations. RESULTS: We identified several Lactobacillaceae that were significantly enriched in the gut of healthy controls, including Limosilactobacillus fermentum, the key biomarker distinguishing severe preeclampsia from healthy controls. Limosilactobacillus fermentum was significantly associated with shifts in KEGG Orthology (KO) genes and KEGG pathways of the gut microbiome in severe preeclampsia, such as flagellar assembly. Untargeted fecal metabolome analysis found that severe preeclampsia had higher concentrations of Phenylpropanoate and Agmatine. Increased concentrations of Phenylpropanoate and Agmatine were associated with the abundance of Limosilactobacillus fermentum. Furthermore, all metabolites with higher abundances in healthy controls were enriched in the arginine and proline metabolism pathway. CONCLUSION: Our research indicates that changes in metabolites, possibly due to the gut microbe Limosilactobacillus fermentum, can contribute to the development of severe preeclampsia. This study provides insights into the interaction between gut microbiome and fecal metabolites and offers a basis for improving severe preeclampsia by modulating the gut microbiome.

The role of TRPV4 in programmed cell deaths.

Programmed cell death is a major life activity of both normal development and disease. Necroptosis is early recognized as a caspase-independent form of programmed cell death followed obviously inflammation. Apoptosis is a gradually recognized mode of cell death that is characterized by a special morphological changes and unique caspase-dependent biological process. Ferroptosis, pyroptosis and autophagy are recently identified non-apoptotic regulated cell death that each has its own characteristics. The transient receptor potential vanilloid 4 (TRPV4) is a kind of nonselective calcium-permeable cation channel, which is received more and more attention in biology studies. It is widely expressed in human tissues and mainly located on the membrane of cells. Several researchers have identified that the influx Ca2+ from TRPV4 acts as a key role in the loss of cells by apoptosis, ferroptosis, necroptosis, pyroptosis and autophagy via mediating endoplasmic reticulum (ER) stress, oxidative stress and inflammation. This effect is bad for the normal function of organs on the one hand, on the other hand, it is benefit for anticancer activities. In this review, we will summarize the current discovery on the role and impact of TRPV4 in these programmed cell death pathological mechanisms to provide a new prospect of gene therapeutic target of related diseases.

MT1G, an emerging ferroptosis-related gene: A novel prognostic biomarker and indicator of immunotherapy sensitivity in prostate cancer.

BACKGROUND: Prostate cancer is a leading cause of cancer-related deaths in men worldwide. Despite advances in treatment strategies, there is still a need for novel therapeutic targets and approaches. Ferroptosis has emerged as a critical process in the development and progression of several cancers, including prostate cancer (PCA). In this study, we investigate the role of MT1G, a gene implicated in immune responses and ferroptosis, in the pathogenesis of PCA. Our objective is to elucidate its prognostic significance and its impact on the tumor microenvironment, while exploring its potential in enhancing the sensitivity to immune checkpoint inhibitor (ICI) therapy. METHODS: We utilized a combination of in silico analysis and experimental techniques to investigate the role of MT1G in PCA. First, we analyzed large-scale genomic datasets to assess the expression pattern and prognostic significance of MT1G in PCA patients. Subsequently, we performed functional assays to explore the impact of MT1G in PCA and its potential involvement in modulating immune responses. In addition, we conducted in vivo experiments to evaluate the effect of MT1G on tumor growth and response to ICI therapy. RESULTS: Our analysis revealed that MT1G expression is significantly downregulated in PCA tissues compared to normal prostate tissues and is associated with poor prognosis. Furthermore, MT1G overexpression inhibited the growth of PCA cells in vitro and in vivo. Importantly, we found that MT1G regulates the tumor microenvironment by modulating immune cell infiltration and inhibiting immunosuppressive factors. Furthermore, our study reveals a significant correlation between MT1G expression levels and the response to immune checkpoint inhibitor (ICI) therapy in prostate cancer (PCA) patients, as MT1G upregulation leads to an increase in PDL-1 expression. These findings underscore the potential of MT1G as a promising predictive biomarker for ICI therapy response in PCA patients. CONCLUSION: Our study elucidates the pivotal role played by MT1G in the pathogenesis of prostate cancer (PCA) and its profound implications for prognosis. Moreover, it raises the intriguing possibility that MT1G could pave the way for novel therapeutic approaches in PCA treatment. This potential arises from its ability to orchestrate immune infiltration within the tumor microenvironment, consequently enhancing sensitivity to immune checkpoint inhibitor (ICI) therapy. Therefore, our findings hold substantial promise for advancing our comprehension of PCA and exploring innovative therapeutic strategies.

Establishment of a prognostic model to predict chemotherapy response and identification of RAC3 as a chemotherapeutic target in bladder cancer.

Cisplatin-based chemotherapy is considered the primary treatment option for patients with advanced bladder cancer (BCa). However, the objective response rate to chemotherapy is often unsatisfactory, leading to a poor 5-year survival rate. Furthermore, current strategies for evaluating chemotherapy response and prognosis are limited and inefficient. In this study, we aimed to address these challenges by establishing a chemotherapy response type gene (CRTG) signature consisting of 9 genes and verified the prognostic value of this signature using TCGA and GEO BCa cohorts. The risk scores based on the CRTG signature were found to be associated with advanced clinicopathological status and demonstrated favorable predictive power for chemotherapy response in the TCGA cohort. Meanwhile, tumors with high risk scores exhibited a tendency toward a "cold tumor" phenotype. These tumors showed a low abundance of T cells, CD8+ T cells and cytotoxic lymphocytes, along with a high abundance of cancer-associated fibroblasts. Moreover, they displayed higher mRNA levels of these immune checkpoints: CD200, CD276, CD44, NRP1, PDCD1LG2 (PD-L2), and TNFSF9. Furthermore, we developed a nomogram that integrated the CRTG signature with clinicopathologic risk factors. This nomogram proved to be a more effective tool for predicting the prognosis of BCa patients. Additionally, we identified Rac family small GTPase 3 (RAC3) as a biomarker in our model. RAC3 was found to be overexpressed in chemoresistant BCa tissues and enhance the chemotherapeutic resistance of BCa cells in vitro and in vivo by regulating the PAK1-ERK1/2 pathway. In conclusion, our study presents a novel CRTG model for predicting chemotherapy response and prognosis in BCa. We also highlight the potential of combining chemotherapy with immunotherapy as a promising strategy for chemoresistant BCa and that RAC3 might be a latent target for therapeutic intervention.

Cognitive-exercise dual-task attenuates chronic cerebral ischemia-induced cognitive impairment by activating cAMP/PKA pathway through inhibiting EphrinA3/EphA4.

BACKGROUND: The prevalence of vascular cognitive impairment induced by chronic cerebral ischemia (CCI) is increasing year by year. Cognitive-exercise dual-task intervention has shown beneficial effects on improving cognitive performance in ischemic patients. It is well known that the tyrosine kinase ligand-receptor (Ephrin-Eph) system plays an important role in synaptic transmission and that the cAMP/PKA pathway is associated with cognitive function. However, it is unclear whether they are responsible for the dual-task improving cognitive impairment in CCI. METHODS: Bilateral common carotid artery occlusion (BCCAO) in SD rats was used to establish the CCI model. The effects of dual-task and single-task on cognitive function and the expressions of EphrinA3, EphA4, cAMP, and PKA in rats were detected by the novel object recognition (NOR) test, immunofluorescence staining, quantitative real-time polymerase chain reaction (qPCR), and Western blotting (WB), respectively. Overexpression or knockdown of EphrinA3 in astrocytes or rats were constructed by lentivirus infection to verify the effects of EphrinA3/EphA4 on the cAMP/PKA pathway. RESULTS: After dual-task intervention, the discrimination index of rats increased significantly compared with the rats in the CCI group. The expressions of EphrinA3 and EphA4 were decreased, while the expressions of cAMP and PKA were increased. Furthermore, knockdown of EphrinA3 alleviated the trend of CCI-induced cognitive decline in rats and OGD-stimulated cellular damage. It also increased cAMP/PKA expression in hippocampal neurons. CONCLUSION: Cognitive-exercise dual-task can significantly improve the cognitive impairment induced by CCI, and this effect may be better than that of the cognitive or exercise single-task intervention. The improvement may be related to the inhibition of EphrinA3/EphA4, followed by activation of the cAMP/PKA pathway.

The key cellular senescence related molecule RRM2 regulates prostate cancer progression and resistance to docetaxel treatment.

BACKGROUND: Prostate cancer is a leading cause of cancer-related deaths among men worldwide. Docetaxel chemotherapy has proven effective in improving overall survival in patients with castration-resistant prostate cancer (CRPC), but drug resistance remains a considerable clinical challenge. METHODS: We explored the role of Ribonucleotide reductase subunit M2 (RRM2), a gene associated with senescence, in the sensitivity of prostate cancer to docetaxel. We evaluated the RRM2 expression, docetaxel resistance, and ANXA1 expression in prostate cancer cell lines and tumour xenografts models. In addition, We assessed the impact of RRM2 knockdown, ANXA1 over-expression, and PI3K/AKT pathway inhibition on the sensitivity of prostate cancer cells to docetaxel. Furthermore, we assessed the sensitivity of prostate cancer cells to the combination treatment of COH29 and docetaxel. RESULTS: Our results demonstrated a positive association between RRM2 expression and docetaxel resistance in prostate cancer cell lines and tumor xenograft models. Knockdown of RRM2 increased the sensitivity of prostate cancer cells to docetaxel, suggesting its role in mediating resistance. Furthermore, we observed that RRM2 stabilizes the expression of ANXA1, which in turn activates the PI3K/AKT pathway and contributes to docetaxel resistance. Importantly, we found that the combination treatment of COH29 and docetaxel resulted in a synergistic effect, further augmenting the sensitivity of prostate cancer cells to docetaxel. CONCLUSION: Our findings suggest that RRM2 regulates docetaxel resistance in prostate cancer by stabilizing ANXA1-mediated activation of the PI3K/AKT pathway. Targeting RRM2 or ANXA1 may offer a promising therapeutic strategy to overcome docetaxel resistance in prostate cancer.

Genomic insight into domestication of rubber tree.

Understanding the genetic basis of rubber tree (Hevea brasiliensis) domestication is crucial for further improving natural rubber production to meet its increasing demand worldwide. Here we provide a high-quality H. brasiliensis genome assembly (1.58 Gb, contig N50 of 11.21 megabases), present a map of genome variations by resequencing 335 accessions and reveal domestication-related molecular signals and a major domestication trait, the higher number of laticifer rings. We further show that HbPSK5, encoding the small-peptide hormone phytosulfokine (PSK), is a key domestication gene and closely correlated with the major domestication trait. The transcriptional activation of HbPSK5 by myelocytomatosis (MYC) members links PSK signaling to jasmonates in regulating the laticifer differentiation in rubber tree. Heterologous overexpression of HbPSK5 in Russian dandelion (Taraxacum kok-saghyz) can increase rubber content by promoting laticifer formation. Our results provide an insight into target genes for improving rubber tree and accelerating the domestication of other rubber-producing plants.

Reinforcing Hydrogel by Nonsolvent-Quenching-Facilitated In Situ Nanofibrosis.

Nanofibrous hydrogels are pervasive in load-bearing soft tissues, which are believed to be key to their extraordinary mechanical properties. Enlighted by this phenomenon, a novel reinforcing strategy for polymeric hydrogels is proposed, where polymer segments in the hydrogels are induced to form nanofibers in situ by bolstering their controllable aggregation at the nanoscale level. Poly(vinyl alcohol) hydrogels are chosen to demonstrate the virtue of this strategy. A nonsolvent-quenching step is introduced into the conventional solvent-exchange hydrogel preparation approach, which readily promotes the formation of nanofibrous hydrogels in the following solvent-tempering process. The resultant nanofibrous hydrogels demonstrate significantly improved mechanical properties and swelling resistance, compared to the conventional solvent-exchange hydrogels with identical compositions. This work validates the hypothesis that bundling polymer chains to form nanofibers can lead to nanofibrous hydrogels with remarkably enhanced mechanical performances, which may open a new horizon for single-component hydrogel reinforcement.

The additive effects of bioactive glasses and photobiomodulation on enhancing bone regeneration.

Bioactive glasses (BG) have been generally used in bone defects repair for its good osteoinductivity and osteoconductivity. However, the early angiogenesis of BG in the repair of large-sized bone defects may not be sufficient enough to support new bone formation, resulting in the failure of bone repair. Photobiomodulation (PBM) therapy, which is superior on promoting early angiogenesis, may contribute to the angiogenesis of BG and further enhance the repair of bone defects. Therefore, we applied BG and PBM in combination and preliminarily investigated their additive effects on bone regeneration both in vitro and in vivo. The in vitro results revealed that BG combined with PBM remarkably enhanced human bone marrow mesenchymal stem cells proliferation, osteogenic-related genes expression and mineralization, which was better than applying BG or PBM respectively. For in vivo studies, the histological staining results showed that BG induced new bone formation in the interior of defects and promoted new bone reconstruction at 6 weeks post-operation. The micro-computed tomography results further confirmed that BG combined with PBM accelerated bone formation and maturation, improved the speed and quality of bone regeneration, and promoted bone repair. In conclusion, with the optimum BG and PBM parameters, BG combined with PBM generated additive effects on promoting bone regeneration.

Primary clear cell adenocarcinoma of female urinary tract: a case report and literature review.

BACKGROUND: Primary clear cell adenocarcinoma of the urethra is extremely rare, reported only in single case reports, and its histological origin is not clear. There is no standard treatment for CCAU at present, and surgery is still the main treatment for CCAU without distant metastasis. CASE PRESENTATION: A 67-year-old female complained of gross hematuria with frequent micturition and urgency. No urethral diverticulum was found by cystoscopy or MRI, and the mass grew around the urethra. Urethral and anterior pelvic viscera resection was performed. Clear cell adenocarcinoma was confirmed by immunohistochemistry after the operation, and no recurrence or metastasis was found after one year of follow-up. CONCLUSION: CCAU is very rare, and most cases originate from the urethral diverticulum and some may also originate from tissues around the urethra. For CCAU patients without distant metastasis, the main treatment is still surgery, and radiotherapy and chemotherapy can be performed for patients with distant metastasis. Gene detection may provide guidance for the precise chemotherapy of CCAU.

HSF1 facilitates the multistep process of lymphatic metastasis in bladder cancer via a novel PRMT5-WDR5-dependent transcriptional program.

BACKGROUND: Lymphatic metastasis has been associated with poor prognosis in bladder cancer patients with limited therapeutic options. Emerging evidence shows that heat shock factor 1 (HSF1) drives diversified transcriptome to promote tumor growth and serves as a promising therapeutic target. However, the roles of HSF1 in lymphatic metastasis remain largely unknown. Herein, we aimed to illustrate the clinical roles and mechanisms of HSF1 in the lymphatic metastasis of bladder cancer and explore its therapeutic potential. METHODS: We screened the most relevant gene to lymphatic metastasis among overexpressed heat shock factors (HSFs) and heat shock proteins (HSPs), and analyzed its clinical relevance in three cohorts. Functional in vitro and in vivo assays were performed in HSF1-silenced and -regained models. We also used Co-immunoprecipitation to identify the binding proteins of HSF1 and chromatin immunoprecipitation and dual-luciferase reporter assays to investigate the transcriptional program directed by HSF1. The pharmacological inhibitor of HSF1, KRIBB11, was evaluated in popliteal lymph node metastasis models and patient-derived xenograft models of bladder cancer. RESULTS: HSF1 expression was positively associated with lymphatic metastasis status, tumor stage, advanced grade, and poor prognosis of bladder cancer. Importantly, HSF1 enhanced the epithelial-mesenchymal transition (EMT) of cancer cells in primary tumor to initiate metastasis, proliferation of cancer cells in lymph nodes, and macrophages infiltration to facilitate multistep lymphatic metastasis. Mechanistically, HSF1 interacted with protein arginine methyltransferase 5 (PRMT5) and jointly induced the monomethylation of histone H3 at arginine 2 (H3R2me1) and symmetric dimethylation of histone H3 at arginine 2 (H3R2me2s). This recruited the WD repeat domain 5 (WDR5)/mixed-lineage leukemia (MLL) complex to increase the trimethylation of histone H3 at lysine 4 (H3K4me3); resulting in upregulation of lymphoid enhancer-binding factor 1 (LEF1), matrix metallopeptidase 9 (MMP9), C-C motif chemokine ligand 20 (CCL20), and E2F transcription factor 2 (E2F2). Application of KRIBB11 significantly inhibited the lymphatic metastasis of bladder cancer with no significant toxicity. CONCLUSION: Our findings reveal a novel transcriptional program directed by the HSF1-PRMT5-WDR5 axis during the multistep process of lymphatic metastasis in bladder cancer. Targeting HSF1 could be a multipotent and promising therapeutic strategy for bladder cancer patients with lymphatic metastasis.

The additive effects of photobiomodulation and bioactive glasses on enhancing early angiogenesis.

Bioactive glasses (BG) have been widely utilized as a biomaterial for bone repair. However, the early angiogenesis of BG may be inadequate, which weakens its osteogenic effects in large-sized bone defects and often leads to the failure of bone regeneration. In this study, we explored the effects of photobiomodulation (PBM) combined with BG on early angiogenesis to solve this bottleneck problem of insufficient early angiogenesis.In vitro, human umbilical vein endothelial cells (HUVECs) were cultured with BG extracts and treated with PBM using 1 J cm-2. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, real-time reverse transcription-polymerase chain reaction (real-time RT-PCR) and tubule formation assay were utilized to detect HUVECs' proliferation, vascular growth factor genes expression and tubules formation.In vivo, bone defects at the femoral metaphysis in Sprague-Dawley rats were treated with BG particulates and PBM at 120 J cm-2. Hematoxylin-eosin staining was used to observe the inflammatory response, tissue formation and biomaterial absorption of bone defects. Immunohistochemical staining was applied to observe the vascular-like structure formation. Thein vitroresults showed that PBM combined with BG significantly promoted HUVECs' proliferation, genes expression and mature tubules formation. On days 2, 4 and 7, the mRNA expression of VEGF in BG + PBM group was 2.70-, 2.59- and 3.05-fold higher than control (P< 0.05), and significantly higher than PBM and BG groups (P< 0.05). On days 4 and 7, the bFGF gene expression in BG + PBM group was 2.42- and 1.82-fold higher than control (P< 0.05), and also higher than PBM and BG groups (P< 0.05). Tube formation assay showed that mature tubules were formed in BG + PBM and PBM groups after 4 h, and the number in BG + PBM group was significantly higher than other groups (P< 0.05).In vivoresults further confirmed PBM induced early angiogenesis, with more vascular-like structures observed in BG + PBM and PBM groups 2 week post-surgery. With the optimum PBM fluence and BG concentration, PBM combined with BG exerted additive effects on enhancing early angiogenesis.

Induction of Cartilage Regeneration by Nanoparticles Loaded with Dentin Matrix Extracted Proteins.

Due to the limited self-repair capacity of articular cartilage, tissue engineering has good application prospects for cartilage regeneration. Dentin contains several key growth factors involved in cartilage regeneration. However, it remains unknown whether dentin matrix extracted proteins (DMEP) can be utilized as a complex growth factor mixture to induce cartilage regeneration. In this work, we extracted DMEP from human dentin and improved the content and activity of chondrogenic-related growth factors in DMEP by alkaline conditioning. Afterward, mesoporous silica nanoparticles (MSNs) with particular physical and chemical properties were composed to selectively load and sustain the release of proteins in DMEP. MSN-DMEP promoted chondrogenic differentiation of rat bone marrow-derived mesenchymal stem cells with fewer growth factors than exogenously added transforming growth factor-ß1 (TGF-ß1). Therefore, MSN-DMEP may serve as a promising candidate for cartilage regeneration as an alternative to expensive synthetic growth factors. Impact statement Several growth factors embedded in dentin matrix could be involved in cartilage regeneration. This article reports that alkaline conditioning could improve the content and activity of chondrogenic-related growth factors in dentin matrix extracted proteins (DMEP). Mesoporous silica nanoparticles (MSNs) with particular physical and chemical properties performed well in loading and sustained releasing of proteins in DMEP. In vitro and in vivo studies suggest that MSN-DMEP could be a promising candidate for cartilage regeneration as an alternative to expensive synthetic growth factors.

Effects of heat treatment and pH on the physicochemical and emulsifying properties of coconut (Cocos nucifera L.) globulins.

The present study aimed to assess the effects of heat treatment (70-90 °C) and pH (pH 3-11) on the physicochemical, structural, and emulsifying properties of coconut globulins (CG). The results revealed that the emulsifying property was improved with increasing temperature due to the denaturation degree of CG. CG had a better emulsifying property at pH 3 but showed the worst emulsifying property at pH 5 due to its lowest solubility, surface hydrophobicity, and absolute value of zeta potential. The best emulsifying stability was detected at pH 11 with 90 °C heating. SDS-PAGE indicated that the formation of aggregates cross-linked by covalent bonds was the main reason for the better emulsion stability at pH 3 and pH 11 with 90 °C heating. The secondary structure showed that CG had more α-helix and ß-turn contents as well as fewer ß-sheet contents at pH 3 and pH 11 with 90 °C heating.

A novel bioactive glass-based root canal sealer in endodontics.

BACKGROUND/PURPOSE: Bioactive glass (BG), one type of bioceramics, shows similar or better characteristics to calcium silicate which has been regarded as a promising root filling material in endodontics. This study aimed to develop a novel BG-based root canal sealer for endodontics. MATERIALS AND METHODS: The novel BG-based root canal sealer was composed of phytic acid derived bioactive calcium phosphosilicate glass named PSC mixed with zirconium oxide (ZrO2) as powder, and phosphate solution (PS) dissolved with sodium alginate (SA) named PS-SA as liquid. Moreover, the physicochemical properties, mineralization, sealing ability and biocompatibility of the novel BG-based root canal sealer were evaluated. RESULTS: This study developed a novel BG-based sealer named BGS-SA-Zr which contained the powder of PSC and ZrO2 and the liquid of PS-SA. Results indicated that the flow, film thickness and radiopacity of BGS-SA-Zr conformed to ISO 6876:2012. The setting time and solubility of BGS-SA-Zr were 53.7 ±â€¯1.5 min and 21.46 ±â€¯0.54%, respectively. The pH value of the simulated body fluid (SBF) immersed with BGS-SA-Zr raised slightly up to 7.70. The CCK-8 assay indicated that BGS-SA-Zr had no cytotoxic effects on MG-63 cells. After immersion in SBF for 4 weeks, dense hydroxyapatite crystals were observed on the surface of BGS-SA-Zr. Furthermore, there was no difference in the sealing ability between BGS-SA-Zr and the bioceramic sealer iRoot SP whether setting at 1 day or immersed in SBF for 4 weeks (P > 0.05). CONCLUSION: Our results suggest that the novel BG-based sealer may be a promising sealer for endodontic treatment.

Effect of ultrasonic treatment on the activity of sugar metabolism relative enzymes and quality of coconut water.

In this study, tender coconuts were treated with high-intensity ultrasound (US) for 20 min at a frequency of 20 kHz and a power of 2400 W. Compared with control group, US treated coconut water had a higher content of total soluble solid and sugar/acid ratio along with a lower pH value and conductivity, and the contents of sucrose, fructose and glucose were also higher. Results from HS-SPME/GC-MS showed that there was no significant difference in the content of volatile compounds in coconut water before and after US treatment. The activities of sugar metabolism enzymes such as sucrose phosphate synthase, sucrose synthase, acid invertase (AI) and neutral invertase were inhibited by US, of which AI had the strongest inactivation. Circular dichroism and fluorescence spectra showed that the secondary and tertiary structure of AI molecule were destroyed with the increase of US intensity and time, which was confirmed by the change of particle size distribution pattern and scanning electron microscopy. Molecular docking and molecular dynamics showed that US treatment prevented the recognition and binding of sucrose and AI molecules, thereby inhibiting the decomposition of sucrose. In conclusion, our results indicate that US can inhibit the activity of AI and maintain the sugar content to increase the quality as well as extend the shelflife of coconut water, which will bring more commercial value.

Gastric Bypass Increases Circulating Bile Acids and Activates Hepatic Farnesoid X Receptor (FXR) but Requires Intact Peroxisome Proliferator Activator Receptor Alpha (PPARα) Signaling to Significantly Reduce Liver Fat Content.

BACKGROUND: We interrogate effects of gastric bypass (RYGB), compared with a low-calorie diet, on bile acid (BA), liver fat, and FXR, PPARα, and targets in rats with obesity and non-alcoholic fatty liver disease (NAFLD). METHODS: Male Wistar rats received a high-fat diet (obese/NAFLD, n=24) or standard chow (lean, n=8) for 12 weeks. Obese/NAFLD rats had RYGB (n=11), sham operation pair-fed to RYGB (pair-fed sham, n=8), or sham operation (sham, n=5). Lean rats had sham operation (lean sham, n=8). Post-operatively, five RYGB rats received PPARα antagonist GW6417. Sacrifice occurred at 7 weeks. We measured weight changes, fasting total plasma BA, and liver % steatosis, triglycerides, and mRNA expression of the nuclear receptors FXR, PPARα, and their targets SHP and CPT-I. RESULTS: At sacrifice, obese sham was heavier (p<0.01) than all other groups that had lost similar weight loss. Obese sham had lower BA levels and lower hepatic FXR, SHP, and CPT-I mRNA expression than lean sham (P<0.05, for all comparisons). RYGB had increased BA levels compared with obese and pair-fed sham (P<0.05, for both), while pair-fed sham had BA levels, similar to obese sham. Compared with pair-fed sham, RYGB animals had increased liver FXR and PPARα expression and signaling (P<0.05). Percentage of steatosis was lower in RYGB and lean sham, relative to obese and pair-fed sham (P<0.05, for all comparisons). PPARα inhibition after RYGB resulted in similar weight loss but higher liver triglyceride content (P=0.01) compared with RYGB alone. CONCLUSIONS: RYGB led to greater liver fat loss than low-calorie diet, an effect associated to increased fasting BA levels and increased expression of modulators of liver fat oxidation, FXR, and PPARα. However, intact PPARα signaling was necessary for resolution of NAFLD after RYGB.

Channels that Cooperate with TRPV4 in the Brain.

Transient receptor potential vanilloid 4 (TRPV4) is a nonselective Ca2+-permeable cation channel that is a member of the TRP channel family. It is clear that TRPV4 channels are broadly expressed in the brain. As they are expressed on the plasma membrane, they interact with other channels and play a crucial role in nervous system activity. Under some pathological conditions, TRPV4 channels are upregulated and sensitized via cellular signaling pathways, and this can cause nervous system diseases. In this review, we focus on receptors that cooperate with TRPV4, including large-conductance Ca2+-activated K+(BKca) channels, N-methyl-D-aspartate receptors (NMDARs), α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors (AMPARs), inositol 1,4,5-trisphosphate receptors (IP3Rs), ryanodine receptors (RyRs), aquaporin 4 (AQP4), and other potential cooperative receptors in the brain. The data demonstrate how these channels work together to cause nervous system diseases under pathological conditions. The aim of this review was to discuss the receptors and signaling pathways related to TRPV4 based on recent data on the important physiological functions of TRPV4 channels to provide new clues for future studies and prospective therapeutic targets for related brain diseases.

VPAC1 couples with TRPV4 channel to promote calcium-dependent gastric cancer progression via a novel autocrine mechanism.

Although VPAC1 and its ligand vasoactive intestinal peptide (VIP) are important in gastrointestinal physiology, their involvements in progression of gastrointestinal tumor have not been explored. Here, we found that higher expression of VIP/VPAC1 was observed in gastric cancer compared to the adjacent normal tissues. The increased expression of VIP/VPAC1 in gastric cancer correlated positively with invasion, tumor stage, lymph node, distant metastases, and poor survival. Moreover, high expression of VIP and VPAC1, advanced tumor stage and distant metastasis were independent prognostic factors. VPAC1 activation by VIP markedly induced TRPV4-mediated Ca2+ entry, and eventually promoted gastric cancer progression in a Ca2+ signaling-dependent manner. Inhibition of VPAC1 and its signaling pathway could block the progressive responses. VPAC1/TRPV4/Ca2+ signaling in turn enhanced the expression and secretion of VIP in gastric cancer cells, enforcing a positive feedback regulation mechanism. Taken together, our study demonstrate that VPAC1 is significantly overexpressed in gastric cancer and VPAC1/TRPV4/Ca2+ signaling axis could enforce a positive feedback regulation in gastric cancer progression. VIP/VPAC1 may serve as potential prognostic markers and therapeutic targets for gastric cancer.