The role of PKM2 in cancer progression and its structural and biological basis.

Pyruvate kinase M2 (PKM2), a subtype of pyruvate kinase (PK), has been shown to play an important role in the development of cancer. It regulates the last step of glycolytic pathway. PKM2 has both pyruvate kinase and protein kinase activity, and the conversion of these two functions of PKM2 depends on the mutual change of dimer and tetramer. The dimerization of PKM2 can promote the proliferation and growth of tumor cells, so inhibiting the dimerization of PKM2 is essential to curing cancer. The aggregation of PKM2 is regulated by both endogenous and exogenous cofactors as well as post-translational modification (PTM). Although there are many studies on the different aggregation of PKM2 in the process of tumor development, there are few summaries in recent years. In this review, we first introduce the role of PKM2 in various biological processes of tumor growth. Then, we summarize the aggregation regulation mechanism of PKM2 by various endogenous cofactors such as Fructose-1, 6-diphosphate (FBP), various amino acids, and post-translational modification (PTMs). Finally, the related inhibitors and agonists of PKM2 are summarized to provide reference for regulating PKM2 aggregation in the treatment of cancer in the future.

Investigation of nonlinear optical properties in α-A2BB'O6 (A = Li, Na, K; B = Ti, Zr, Hf; B' = Se, Te) by first-principles calculations.

Nonlinear optical (NLO) crystals based on oxides typically have wide bandgaps and large laser damage thresholds (LDTs), which are important for generating high-power and continuous terahertz radiation. Recently, a new family of NLO materials α-A2BB'O6 including Li2TiTeO6 (LTTO) with a strong second harmonic generation (SHG) efficiency of 26 × KH2PO4 (KDP) and a large LDT of 550 MW cm-2 were reported. Herein, we systematically study the electronic structures and NLO properties of α-A2BB'O6 (A = Li, Na, K; B = Ti, Zr, Hf; B' = Se, Te) to explore the relationship between the structure and SHG coefficient. First, 15 members of the A2BB'O6 family are demonstrated to be highly stable and NLO materials, excluding K2TiTeO6, K2TiSeO6 and K2ZrSeO6. Then, the electronic band structure, dipole moment and distortion of BO6/B'O6 octahedrons, SHG coefficient and terahertz absorption spectrum are calculated comprehensively with the element variation of A-site, B-site and B'-site. Finally, the magnitude of the SHG coefficient is found to be directly proportional to the value of total dipole moment and distortion, and inversely proportional to the bandgap value. Most importantly, among the A2BB'O6 materials, K2HfSeO6 shows the smallest direct bandgap of 2.99 eV, the largest SHG coefficient d33 of about 5 × LTTO and low terahertz absorbance from 0.1 to 9 THz. Our results provide new NLO crystals that may have potential application in terahertz radiation sources and other nonlinear electronics.

Insight into the mechanism of Xiao-Chai-Hu-Tang alleviates irinotecan-induced diarrhea based on regulating the gut microbiota and inhibiting Gut ß-GUS.

BACKGROUND: Irinotecan (CPT-11, Camptosar@) is a first-line drug for metastatic colorectal cancer. CPT-11-induced diarrhea, which is closely related to the concentrations of ß-glucuronidase (ß-GUS) and SN-38 in the gut, largely limits its clinical application. PURPOSE: Herein, Xiao-Chai-Hu-Tang (XCHT), a traditional Chinese formula, was applied to mitigate CPT-11-induced toxicity. This study initially explored the mechanism by which XCHT alleviated diarrhea, especially for ß-GUS from the gut microbiota. METHODS: First, we examined the levels of the proinflammatory cytokines and the anti-inflammatory cytokines in the intestine. Furthermore, we researched the community abundances of the gut microbiota in the CPT-11 and XCHT-treated mice based on 16S rRNA high-throughput sequencing technology. Meanwhile, the level of SN-38 and the concentrations of ß-GUS in intestine were examined. We also resolved the 3D structure of ß-GUS from gut microbiota by X-ray crystallography technology. Moreover, we used virtual screening, SPR analysis, and enzyme activity assays to confirm whether the main active ingredients from XCHT could selectively inhibit ß-GUS. RESULTS: In XCHT-treated mice, the levels of the proinflammatory cytokines decreased, the anti-inflammatory cytokines increased, and the community abundances of beneficial Firmicutes and Bacteroidota improved in the gut microbiota. We also found that the concentrations of ß-GUS and the level of SN-38, the major ingredient that induces diarrhea in the gut, significantly decreased after coadministration of XCHT with CPT-11 in the intestine. Additionally, we revealed the structural differences of ß-GUS from different gut microbiota. Finally, we found that EcGUS had good affinity with baicalein and meanwhile could be selectively inhibited by baicalein from XCHT. CONCLUSIONS: Overall, XCHT could relieve the delayed diarrhea induced by CPT-11 through improving the abundance of beneficial gut microbiota and reduced inflammation. Furthermore, based on the three-dimensional structure, baicalein, especially, could be used as a candidate EcGUS inhibitor to alleviate CPT-11-induced diarrhea.

Circular RNA mitochondrial translation optimization 1 correlates with less lymph node metastasis, longer disease-free survival, and higher chemotherapy sensitivity in gastric cancer.

OBJECTIVE: Circular-mitochondrial translation optimization 1 (circ-MTO1) inhibits the progression of gastric cancer by regulating the growth, apoptosis, and invasion of tumor cells. However, its clinical potential as a biomarker for gastric cancer remains to be further evaluated. This study aimed to assess circ-MTO1 expression and its correlation with clinical features and prognosis in gastric cancer patients, as well as the effect of circ-MTO1 on the sensitivity to chemotherapy in gastric cancer cells. METHODS: Circ-MTO1 in tumor and adjacent tissues of 97 gastric cancer patients undergoing resection was examined by reverse transcription-quantitative polymerase chain reaction. HGC-27 and NCI-N87 cells transfected by circ-MOT1 overexpression plasmid (OE-circ-MOT1) and negative control (OE-NC) were treated with 0-6.4 µM oxaliplatin. Relative cell viability was detected using Cell Counting Kit-8. RESULTS: Circ-MTO1 was insufficiently expressed in gastric tumor tissue (median (interquartile range): 0.403 (0.288-0.518)) compared with adjacent tissue (median (interquartile range): 1.000 (0.715-1.524)) (p < 0.001). Besides, tumor circ-MTO1 was correlated with less lymph node metastasis (p = 0.014) and low TNM stage (p = 0.039), while was not correlated with demographic features or other clinical characteristics (all p > 0.05). Furthermore, tumor circ-MTO1 high expression was independently correlated with prolonged disease-free survival (DFS) (p = 0.013, adjusted hazard ratio (95% confidential interval): 0.314 (0.126-0.782)), but was not correlated with overall survival (p > 0.05). Lastly, in gastric cancer cells, OE-circ-MTO1 apparently decreased relative cell viabilities at oxaliplatin concentrations of 0.4, 0.8, 1.6, and 3.2 µM (all p < 0.05). CONCLUSION: Circ-MTO1 correlates with less lymph node metastasis, prolonged DFS, and improved chemotherapy sensitivity in gastric cancer.

Partial splenic embolization using Bletilla striata particles for hypersplenism in cirrhosis: a prospective study.

The article evaluates the long-term follow-up results of PSE using Bletilla striata (BS) particles for hypersplenism in cirrhosis, as compared to PSE using gelfoam particles. Fifty-nine patients with cirrhosis-induced hypersplenism were treated with PSE. The patients were randomly assigned into two groups: gelfoam group, which includes 32 patients using gelfoam particles as the embolic material, and BS group, which includes 27 patients using BS particles. The peripheral blood cell counts and parameters for complications associated with PSE were measured during the follow-up. The mean values of leukocyte and thrombocyte, but not hemoglobin, were significantly increased after PSE (p < 0.01) in both groups. The values of leukocyte and thrombocyte during the long-term follow-up were significantly improved in BS group than that in gelfoam group (both p < 0.01). The frequency of bleeding episodes from esophageal varices in both groups was significantly reduced after PSE (both p < 0.01), but the post-PSE bleeding episodes showed no remarkable differences between the two groups (p = 0.084). Post-embolization syndrome consisted mainly of fever, nausea and vomiting, and abdominal pain in the two groups. The incidence of grade II to III abdominal pain in BS group (82.8%, 27/33) was significantly higher than in gelfoam group (57.9%, 33/57) (p = 0.020). The mean survival time was 61.5 ± 9.1 (median 60, 1-157) months in gelfoam group and 63.4 ± 9.9 (median 52, 0-161) months in BS group, which showed no significant difference (p = 0.930). In conclusion, BS particles could be used as the embolic material in PSE. Compared to gelfoam used in PSE, BS can achieve even better efficacy in alleviating hypersplenism. It provides a long-term effect on the hematological parameters, bleeding from esophageal varices and good palliation, and improved clinical status contributing to symptomatic control.

[Correlation of preoperative plasma levels of big endothelin-1 to prognosis of gastric carcinoma].

BACKGROUND & OBJECTIVE: Endothelin, a potent vasoconstrictor peptide, is involved in mitogenesis modulation, apoptosis, angiogenesis, tumor invasion and metastases. Big endothelin-1 (Big ET-1), the stable precursor of endothelin-1, is regarded as a marker of tumor progression and prognosis. This study was to detect the expression of Big ET-1 in gastric cancer patients, and explore its correlations to progression and prognosis of gastric cancer. METHODS: The plasma levels of Big ET-1 in 118 gastric cancer patients and 20 healthy subjects were detected by enzyme-linked immunosorbent assay (ELISA). The expression of Big ET-1 in primary tumor and para-cancerous gastric tissues of the 118 patients was detected by immunohistochemistry. RESULTS: The plasma level of Big ET-1 was significantly higher in patients with advanced gastric cancer than in patients with early stage gastric cancer and healthy subjects [(5.78+/-1.85) ng/L vs. (3.13+/-1.72) ng/L and (2.46+/-0.59) ng/L, P=0.026, P=0.008]. The plasma level of Big ET-1 was significantly higher in patients with lymph node metastases than in those without [(6.13+/-2.34) ng/L vs. (4.25+/-1.65) ng/L, P=0.006], and significantly higher in stage II, III, IV patients than in stage I patients. During follow-up, patients with high plasma levels of Big ET-1 had higher recurrence rate and lower 2-year survival rate as compared with those with low plasma levels of Big ET-1 (84.6% vs. 60.9%, P=0.034; 38.5% vs. 56.5%,P=0.017). The positive rate of Big ET-1 was significantly higher in stage II,III and IV patients than in stage I patients. CONCLUSION: The plasma level of Big ET-1 may play a vital role in the development, invasion and metastasis of gastric cancer, and may be a predictor of tumor disease severity and prognosis.

Pre- and post-operative plasma big endothelin-1 levels in patients with gastric carcinoma undergoing radical gastrectomy.

BACKGROUND: Big Endothelin-1 levels increase significantly in patients with various tumors, and raised plasma concentrations are associated with worse outcome. The aim of this study was to investigate plasma Big Endothelin-1 levels in patients with gastric carcinoma before and after radical gastrectomy and to explore its clinical significance. MATERIALS AND METHODS: One hundred and six patients with gastric carcinoma and 20 controls were studied. Big Endothelin-1 plasma levels in patients with advanced gastric cancer were examined by enzyme-linked immunosorbent assay before and on days 1, 3 and 10 after curative surgery and were then tested every 3 months. RESULTS: All patients, except those with stage I gastric cancer, had significantly higher mean plasma Big Endothelin-1 levels compared with the normal controls (p = 0.000). The plasma Big Endothelin-1 levels were markedly increased on the first post-operative day (1st POD) in all patients but decreased on the 3rd POD with no significant difference compared to the pre-operative levels. On the 10th POD, patients with stages I and II gastric cancer showed a marked reduction in the plasma Big Endothelin-1 levels (p=0.010 and p=0.000, respectively), whereas no significant difference was observed in stage III and IVpatients. During the follow-up, plasma Big Endothelin-1 levels immediately before recurrences occurred in stage II patients were significantly higher compared with the levels on the 10th POD (p=0.011). CONCLUSION: Plasma Big Endothelin-1 levels might be a reliable marker to determine the severity of gastric carcinoma. Monitoring plasma Big Endothelin-I levels after curative resection in stage II gastric cancer patients was valuable in predicting recurrences.

[Peripheral plasma Big endothelin 1 levels in patients with gastric carcinoma undergoing radical gastrectomy and its relationship with tumor recurrence].

OBJECTIVE: To investigate the plasma Big endothelin-1 levels in patients with gastric carcinoma before and after radical gastrectomy, and explore its clinical significance. METHODS: One hundred and six patients with gastric carcinoma and 20 controls were enrolled. The Big ET-1 plasma levels were examined by enzyme-linked immuno absorbent assay before and on the 1st, 3rd, and 10th day after curative surgery, and then were tested every 3 months in the patients with advanced gastric cancer. RESULTS: All patients, except those with stage I gastric cancer, had significantly higher mean plasma Big ET-1 levels compared with normal controls (P=0.000). Higher plasma Big ET-1 levels were associated with lymph node metastasis (P=0.020) and serosal infiltration (P=0.035). The plasma Big Endothelin-1 levels were markedly increased on the first post-operative day (1st POD) in all patients,but decreased on the 3rd POD with no significant difference compared to the preoperative levels. On the 10th POD, the patients with stage I and II gastric cancer showed marked reduction in plasma Big ET-1 levels (P=0.010 and P=0.000, respectively), whereas no significant difference was observed in stage III and IV patients. During the follow-up, the plasma Big ET-1 levels just before recurrence in stage II patients were significantly higher compared with the levels on the 10th POD (P=0.011). CONCLUSIONS: Plasma Big ET-1 might be a reliable marker to determine the severity of gastric carcinoma. Monitoring plasma Big ET-1 levels after curative resection in stage II gastric cancer patients is valuable to predict recurrence.

Effects of Ginkgo biloba extract on inflammatory mediators (SOD, MDA, TNF-alpha, NF-kappaBp65, IL-6) in TNBS-induced colitis in rats.

Inflammatory mediators play a critical role in ulcerative colitis immune and inflammatory processes. The aim of the study was to investigate the effects of Ginkgo biloba extract on inflammatory mediators (SOD, MDA, TNF-alpha, NF-kappaBp65, IL-6) in TNBS-induced colitis in rats. Colitis in rats was induced by colonic administration with 2,4,6-trinitrobenzene sulfonic acid (TNBS, 150 mg/kg). EGB in doses of (50, 100, 200 mg/kg) was administered for 4 weeks to protect colitis. The results showed that EGB could significantly ameliorate macroscopic and histological damage, evidently elevate the activities of SOD and reduce the contents of MDA, inhibit the protein and mRNA expressions of TNF-alpha, NF-kappaBp65, and IL-6 in the colon tissues of experimental colitis in a dose-dependent manner compared with the model group. We concluded that the probable mechanisms of EGB ameliorated inflammatory injury in TNBS-induced colitis in rats by its modulation of inflammatory mediators and antioxidation.