Asparagus saponins: effective natural beneficial ingredient in functional foods, from preparation to applications.

Asparagus species is recognized as a perennial herb with several valuable functional ingredients, and has been widely used as medicine and food since ancient times. Among its main chemical constituents, saponins play a vital role in the health benefits and biological activities including anti-cancer, antioxidant, immunomodulatory, anti-microbial, anti-inflammatory, and hypoglycemic. This review summarizes the preparation methods, structure and classification, biological functions, as well as the food and non-food applications of asparagus saponins, with a special emphasis on its anti-cancer effects in vitro and in vivo. Further, the main challenges and limitations of the current research trends in asparagus saponins are highlighted after a detailed analysis of the recent research information. This review bridges the gap between bioactive components and human health and aids current research on functional and health-promoting foods and medicinal application of Asparagus saponins.

Exploration of walnut components and their association with health effects.

Traditionally, walnuts have occupied an imperative position in the functional food market with consistently recognized nutritious and functional properties. In the past years, the lipid profile of walnuts has brought much scientific attention via linking a cascade of biological attributes and health-promoting effects. Over time, researchers have focused on diversified composition (polyphenols and vitamins) of different parts of walnut (flower, pellicle, and kernel) and emphasized their physiological significance. Consequently, a plethora of reports has emerged on the potential role of walnut consumption against a series of diseases including cancer, gut dysbiosis, cardiovascular, and neurodegenerative diseases. Therefore, we accumulated the updated data on composition and classification, extraction methods, and utilization of different parts of walnuts as well as associated beneficial effects under in vivo and clinical studies. Altogether, this review summarized the ameliorative effects of a walnut-enriched diet in chronic diseases which can be designated to the synergistic or individual effects of walnut components mainly through anti-oxidative and anti-inflammatory role.

Identification and validation of EMT-immune-related prognostic biomarkers CDKN2A, CMTM8 and ILK in colon cancer.

Colon cancer (CC) is a disease with high incidence and mortality rate. The interaction between epithelial-mesenchymal transition (EMT) and immune status has important clinical significance. We aim to identify EMT-immune-related prognostic biomarkers in colon cancer. The GEO2R and GEPIA 2.0 were utilized to calculate the differential expression genes between CC and normal mucosa. Immport, InnateDB and EMTome databases were used to define EMT-immune-related genes. We conducted batch prognostic analysis by TCGA data. The expression patterns were verified by multiple datasets and lab experiments. GEPIA 2.0 and TIMER 2.0 were utilized to analyze the correlation of the hub genes with EMT markers and immune infiltration. GeneMANIA, STRING, and Metascape were used for co-expression and pathway enrichment analysis. Finally, we established a signature by the method of multivariate Cox regression analysis. CDKN2A, CMTM8 and ILK were filtered out as prognostic genes. CDKN2A and CMTM8 were up-regulated, while ILK was down-regulated in CC. CDKN2A was positively correlated with infiltration of macrophages, Th2 cells, Treg cells, and negatively correlated with NK cells. CMTM8 was negatively correlated with CD8+ T cells, dendritic cells, and NK cells. ILK was positively correlated with CD8+ T cells and dendritic cells. Moreover, CDKN2A, CMTM8 and ILK were significantly correlated with EMT markers. The three genes could participate in the TGF-ß pathway. The prognosis model established by the three hub genes was an independent prognosis factor, which can better predict the prognosis. CDKN2A, CMTM8 and ILK are promising prognostic biomarkers and may be potential therapeutic targets in colon cancer.

Soluble TREM-1, as a new ligand for the membrane receptor Robo2, promotes hepatic stellate cells activation and liver fibrosis.

Triggering receptor expressed on myeloid cells-1 (TREM-1) exists in two forms: a transmembrane form and a soluble form (sTREM-1). The levels of sTREM-1 are elevated in supernatants of activated HSCs. However, the role of sTREM-1 in HSC activation and liver fibrosis remains undefined. Previous studies have primarily focused on the transmembrane form of TREM-1; we innovatively observed the function of sTREM-1 as a ligand in liver fibrosis and screened its receptor. Here, recombinant sTREM-1 was used as a stimulator which induced HSC activation and further aggravated liver fibrosis. Then, screening for sTREM-1 interacting membrane receptors was performed using pull-down assay followed by mass spectrometry, and the membrane receptor roundabout guidance receptor 2 (Robo2) was identified as a candidate receptor for sTREM-1. The interaction between sTREM-1 and Robo2 was verified by pull-down and immunofluorescence. The role of Robo2 on sTREM-1-induced HSC activation and its downstream signal pathways was assessed by knockdown of Robo2 in LX-2 cells. Furthermore, HSC-specific knockdown of Robo2 was achieved in a mouse model of liver fibrosis by using a recombinant adeno-associated virus (AAV) vector to confirm the role of the receptor, and we proved that Robo2 knockdown inhibited the activation of HSC and liver fibrosis, which also led to the inactivation of Smad2/3 and PI3K/Akt pathways in sTREM-1-induced HSC activation and liver fibrosis. In conclusion, sTREM-1 acts as a new ligand of Robo2; the binding of sTREM-1 to Robo2 initiates the activation of the downstream Smad2/3 and PI3K/Akt signalling pathways, thereby promoting HSC activation and liver fibrosis.

Transcranial random noise stimulation over the left dorsolateral prefrontal cortex attenuates pain expectation and perception.

OBJECTIVE: The dorsolateral prefrontal cortex (DLPFC) has been increasingly used as a neuromodulatory target in pain management. Transcranial random noise stimulation (tRNS) was shown to effectively elevate cortical excitability. Hence, this study aimed to characterize how tRNS over the left DLPFC affects pain expectation and perception, as well as the efficacy of conditioned-pain modulation (CPM) that reflects the function of the endogenous pain-inhibitory pathway. METHODS: Using a randomized, double-blinded, and sham-controlled design, healthy participants were randomly recruited to receive tRNS with a direct current offset or sham stimulation. Their expectations and perceptions of painful electrocutaneous stimuli, as well as CPM efficacy were assessed before, immediately after, and 30 min after tRNS. RESULTS: Compared with sham stimulation, perceived-pain ratings to the painful stimuli, and expected-pain ratings before painful stimuli, attenuated immediately after tRNS, whereas this analgesic effect was ineffective 30 min after tRNS. Importantly, the immediate analgesia induced by tRNS could be accounted for by tRNS effect on attenuating expected-pain ratings before certain painful stimuli. However, CPM efficacy was not significantly affected by tRNS. CONCLUSIONS: These results demonstrate analgesia immediately after applying tRNS over the left DLPFC. SIGNIFICANCE: This study provides evidence for analgesia of DLPFC-tRNS on an experimental pain model.

Prostaglandin F2α synthase promotes oxaliplatin resistance in colorectal cancer through prostaglandin F2α-dependent and F2α-independent mechanism.

BACKGROUND: Oxaliplatin (Oxa) is the first-line chemotherapy drug for colorectal cancer (CRC), and Oxa resistance is crucial for treatment failure. Prostaglandin F2α synthase (PGF2α) (PGFS), an enzyme that catalyzes the production of PGF2α, is involved in the proliferation and growth of a variety of tumors. However, the role of PGFS in Oxa resistance in CRC remains unclear. AIM: To explore the role and related mechanisms of PGFS in mediating Oxa resistance in CRC. METHODS: The PGFS expression level was examined in 37 pairs of CRC tissues and paracancerous tissues at both the mRNA and protein levels. Overexpression or knockdown of PGFS was performed in CRC cell lines with acquired Oxa resistance (HCT116-OxR and HCT8-OxR) and their parental cell lines (HCT116 and HCT8) to assess its influence on cell proliferation, chemoresistance, apoptosis, and DNA damage. For determination of the underlying mechanisms, CRC cells were examined for platinum-DNA adducts and reactive oxygen species (ROS) levels in the presence of a PGFS inhibitor or its products. RESULTS: Both the protein and mRNA levels of PGFS were increased in the 37 examined CRC tissues compared to the adjacent normal tissues. Oxa induced PGFS expression in the parental HCT116 and HCT8 cells in a dose-dependent manner. Furthermore, overexpression of PGFS in parental CRC cells significantly attenuated Oxa-induced proliferative suppression, apoptosis, and DNA damage. In contrast, knockdown of PGFS in Oxa-resistant HCT116 and HCT8 cells (HCT116-OxR and HCT8-OxR) accentuated the effect of Oxa treatment in vitro and in vivo. The addition of the PGFS inhibitor indomethacin enhanced the cytotoxicity caused by Oxa. Treatment with the PGFS-catalyzed product PGF2α reversed the effect of PGFS knockdown on Oxa sensitivity. Interestingly, PGFS inhibited the formation of platinum-DNA adducts in a PGF2α-independent manner. PGF2α exerts its protective effect against DNA damage by reducing ROS levels. CONCLUSION: PGFS promotes resistance to Oxa in CRC via both PGF2α-dependent and PGF2α-independent mechanisms.

Effects of High-Definition Transcranial Direct Current Stimulation Over the Primary Motor Cortex on Cold Pain Sensitivity Among Healthy Adults.

Some clinical studies have shown promising effects of transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) on pain relief. Nevertheless, a few studies reported no significant analgesic effects of tDCS, likely due to the complexity of clinical pain conditions. Human experimental pain models that utilize indices of pain in response to well-controlled noxious stimuli can avoid many confounds that are present in the clinical data. This study aimed to investigate the effects of high-definition tDCS (HD-tDCS) stimulation over M1 on sensitivity to experimental pain and assess whether these effects could be influenced by the pain-related cognitions and emotions. A randomized, double-blinded, crossover, and sham-controlled design was adopted. A total of 28 healthy participants received anodal, cathodal, or sham HD-tDCS over M1 (1 mA for 20 min) in different sessions, in which montage has the advantage of producing more focal stimulation. Using a cold pressor test, several indices reflecting the sensitivity to cold pain were measured immediately after HD-tDCS stimulation, such as cold pain threshold and tolerance and cold pain intensity and unpleasantness ratings. Results showed that only anodal HD-tDCS significantly increased cold pain threshold when compared with sham stimulation. Neither anodal nor cathodal HD-tDCS showed significant analgesic effects on cold pain tolerance, pain intensity, and unpleasantness ratings. Correlation analysis revealed that individuals that a had lower level of attentional bias to negative information benefited more from attenuating pain intensity rating induced by anodal HD-tDCS. Therefore, single-session anodal HD-tDCS modulates the sensory-discriminative aspect of pain perception as indexed by the increased pain threshold. In addition, the modulating effects of HD-tDCS on attenuating pain intensity to suprathreshold pain could be influenced by the participant's negative attentional bias, which deserves to be taken into consideration in the clinical applications.

REC8 enhances stemness and promotes metastasis of colorectal cancer through BTK/Akt/ß-catenin signaling pathway.

Cancer/testis antigens (CTAs) are often aberrantly expressed in cancer stem cells (CSCs) which are responsible for tumor metastasis. Rec8 meiotic recombination protein (REC8), a member of CTAs, shares distinct roles in various cancers, while its contribution to CSCs and colorectal cancer (CRC) remains unclear. We found that overexpression of REC8 facilitated the migration and invasion of CRC cells (DLD-1 and SW480 cells) in vitro and promoted the liver metastasis of CRC in vivo. Moreover, REC8 is highly expressed in CRC stem-like cells and is required for the maintenance of CSC stemness. Mechanistic studies suggested that REC8 mediated through the activation of Bruton tyrosine kinase (BTK). Inhibition of BTK by ibrutinib not only suppressed the migration and invasion-promoting ability, but also declined the increased expression of p-BTK, p-Akt, ß-catenin, and CSC markers upon REC8 overexpression. Importantly, high expression of REC8 in cancerous tissues was related to advanced clinical stage and lymph node metastasis of 62 CRC patients, and REC8 was enriched in the cancerous cells positive for CSC markers. Collectively, our results indicate that REC8 promotes CRC metastasis by increasing cell stemness through BTK/Akt/ß-catenin pathway.

Effects of transcranial direct current stimulation on experimental pain perception: A systematic review and meta-analysis.

OBJECTIVE: Many studies have examined the effectiveness of transcranial direct current stimulation (tDCS) on human pain perception in both healthy populations and pain patients. Nevertheless, studies have yielded conflicting results, likely due to differences in stimulation parameters, experimental paradigms, and outcome measures. Human experimental pain models that utilize indices of pain in response to well-controlled noxious stimuli can avoid many confounds present in clinical data. This study aimed to assess the robustness of tDCS effects on experimental pain perception among healthy populations. METHODS: We conducted three meta-analyses that analyzed tDCS effects on ratings of perceived pain intensity to suprathreshold noxious stimuli, pain threshold and tolerance. RESULTS: The meta-analyses showed a statically significant tDCS effect on attenuating pain-intensity ratings to suprathreshold noxious stimuli. In contrast, tDCS effects on pain threshold and pain tolerance were statistically non-significant. Moderator analysis further suggested that stimulation parameters (active electrode size and current density) and experimental pain modality moderated the effectiveness of tDCS in attenuating pain-intensity ratings. CONCLUSION: The effectiveness of tDCS on attenuating experimental pain perception depends on both stimulation parameters of tDCS and the modality of experimental pain. SIGNIFICANCE: This study provides some theoretical basis for the application of tDCS in pain management.

Effect of grape seed power on the structural and physicochemical properties of wheat gluten in noodle preparation system.

Noodles were prepared using wheat flour supplemented with 1%, 3%, and 5% grape seed power (GSP). The farinograph properties of wheat flour, the textural properties of the dough, and thermal properties of the gluten were determined. The microstructure was analyzed by scanning electron and atomic force microscopy, and the effects of the addition of GSP on the physicochemical and structural properties (free sulfhydryl content, surface hydrophobic region, and secondary structure) of wheat gluten protein were analyzed. 1% GSP promoted the aggregation of gluten proteins by promoting hydrophobic interactions and hydrogen bonding, thus enhanced the noodle quality. Whereas, 3% and 5% GSP addition disrupted the disulfide bonds between gluten protein molecules and formed macromolecular aggregates linked to gluten proteins through non-covalent bonds and hydrophobic interactions, which prevented the formation of the gluten protein reticulation structure. Our study emphasized the interaction between wheat proteins and GSP in noodle making dough.

Y-box binding protein 1 augments sorafenib resistance via the PI3K/Akt signaling pathway in hepatocellular carcinoma.

BACKGROUND: Sorafenib is the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Y-box binding protein 1 (YB-1) is closely correlated with tumors and drug resistance. However, the relationship between YB-1 and sorafenib resistance and the underlying mechanism in HCC remain unknown. AIM: To explore the role and related mechanisms of YB-1 in mediating sorafenib resistance in HCC. METHODS: The protein expression levels of YB-1 were assessed in human HCC tissues and adjacent nontumor tissues. Next, we constructed YB-1 overexpression and knockdown hepatocarcinoma cell lines with lentiviruses and stimulated these cell lines with different concentrations of sorafenib. Then, we detected the proliferation and apoptosis in these cells by terminal deoxynucleotidyl transferase dUTP nick end labeling, flow cytometry and Western blotting assays. We also constructed a xenograft tumor model to explore the effect of YB-1 on the efficacy of sorafenib in vivo. Moreover, we studied and verified the specific molecular mechanism of YB-1 mediating sorafenib resistance in hepatoma cells by digital gene expression sequencing (DGE-seq). RESULTS: YB-1 protein levels were found to be higher in HCC tissues than in corresponding nontumor tissues. YB-1 suppressed the effect of sorafenib on cell proliferation and apoptosis. Consistently, the efficacy of sorafenib in vivo was enhanced after YB-1 was knocked down. Furthermore, KEGG pathway enrichment analysis of DGE-seq demonstrated that the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was essential for the sorafenib resistance induced by YB-1. Subsequently, YB-1 interacted with two key proteins of the PI3K/Akt signaling pathway (Akt1 and PIK3R1) as shown by searching the BioGRID and HitPredict websites. Finally, YB-1 suppressed the inactivation of the PI3K/Akt signaling pathway induced by sorafenib, and the blockade of the PI3K/Akt signaling pathway by LY294002 mitigated YB-1-induced sorafenib resistance. CONCLUSION: Overall, we concluded that YB-1 augments sorafenib resistance through the PI3K/Akt signaling pathway in HCC and suggest that YB-1 is a key drug resistance-related gene, which is of great significance for the application of sorafenib in advanced-stage HCC.

Prevalence and intervention of preoperative anemia in Chinese adults: A retrospective cross-sectional study based on national preoperative anemia database.

BACKGROUND: Preoperative anemia is an important pillar of perioperative patient blood management. However, there was no literature comprehensively described the current situation of preoperative anemia in China. METHODS: We conducted a national retrospective cross-sectional study to assess the prevalence and intervention of preoperative anemia in Chinese adults. Data were from the National Preoperative Anemia Database based on hospital administration data from January 1, 2013 to December 31, 2018. FINDINGS: A total of 797,002 patients were included for analysis. Overall, 27.57% (95% CI 27.47-27.67) of patients had preoperative anemia, which varied by gender, age, regions, and type of operation. Patients who were female, age over 60 years old, from South China, from provinces with lower per capita GDP, underwent operations on the lymphatic and hematopoietic system, with laboratory abnormalities were more likely to have a high risk of preoperative anemia. Among patients with preoperative anemia, 5.16% (95% CI 5.07-5.26) received red blood cell transfusion, 7.79% (95% CI 7.67-7.91) received anemia-related medications such as iron, erythropoietin, folic acid or vitamin B12, and 12.25% (95% CI 12.10-12.40) received anemia-related therapy (red blood cell transfusion or anemia-related medications) before operation. The probability of preoperative RBC transfusion decreased by 54.92% (OR 0.46, 95% CI 0.46-0.47) as each 10-g/L increase in preoperative hemoglobin. Patients with preoperative hemoglobin less than 130 g/L was associated with longer hospital stay and more hospital costs. Patients with severe preoperative anemia given iron preoperatively had lower intra/post-operative RBC transfusion rate, shorter length of stay and less hospitalization costs, but no similar correlation was found in patients with mild and moderate preoperative anemia and patients given erythropoietin preoperatively. INTERPRETATION: Our present study shows that preoperative anemia is currently a relatively prevalent problem that has not been fully appreciated in China. More researches will be required to optimize the treatment of preoperative anemia. FUNDING: National Natural Science Foundation of China and the Logistics Support Department of the Central Military Commission.

Comparison of phenolic compounds extracted from Diaphragma juglandis fructus, walnut pellicle, and flowers of Juglans regia using methanol, ultrasonic wave, and enzyme assisted-extraction.

The phenols in Diaphragma juglandis fructus (DJF), walnut pellicle (WP), and flowers of Juglans regia (FJR) from walnut were extracted using three methods (methanolic condensation reflux extraction, ultrasonic wave extraction, and enzyme assisted-extraction), and phenolics and antioxidant capacities of different extractions were compared. Overall, 50 phenolics were identified by HPLC-MS/MS with 41 compounds in DJF, 32 in WP, and 29 in FJR. It was observed that tannins in WP was higher than those in DJF and FJR. As for PCA, more than 70% of the variance was explained with the obvious comparison between the phenolic constituents. The phenolics in walnut contributed to remarkable antioxidant effect, with the highest effect observed in WP. This study presents the analysis and comparison of the phenols can be further extended for the development of functional walnut instant foods.

[Effects of CDH1 gene promoter methylation on expression of E-cadherin and beta-catenin and its clinicopathological significance in colon carcinoma].

OBJECTIVE: To investigate the relationship between methylation of the CDH1 gene promoter on the expression of E-cadherin and ß-catenin, and to evaluate the correlation with clinicopathological characteristics of the colonic carcinoma. METHODS: Methylation specific PCR (MSP) was used to detect CDH1 gene promoter methylation in the cancer tissue, adjacent tissues and normal tissues in 68 patients. The expression of E-cadherin and ß-catenin was determined by immunohistochemistry staining. RESULTS: The positive rate of CDH1 gene promoter methylation was 32.4% in adjacent tissues and 57.4% in cancer tissue, while no detectable methylation was found in all the normal tissues. The difference was statistically significant. The positive rate of E-cadherin was 92.6% in the normal tissues, 66.2% in the adjacent tissues and 44.1% in the cancer tissues. In all normal tissues, ß-catenin was expressed only at the cellular membrane but not in the cytosol or nucleus, while the expression of ß-catenin was present in the cytosol or nucleus in 29.4% of the adjacent tissues and 50.0% of the cancer tissues. The positive rate of CDH1 gene promoter methylation was negatively correlated with E-cadherin expression(r=-0.312, P=0.01) and positively correlated with ß-catenin cytosolic/nucleus expression(r=0.309, P=0.018). The differentiation and metastasis of colonic carcinoma were associated with the aberrant expression of E-cadherin, ß-catenin, and methylation of CDH1 promoter (P<0.05). CONCLUSION: CDH1 gene promoter methylation may lead to aberrant expression of E-cadherin and ß-catenin in colonic carcinoma, and may play an important role in promoting the invasion of tumor.