Carnosol attenuates angiotensin II-induced cardiac remodeling and inflammation via directly binding to p38 and inhibiting p38 activation.

Chronic inflammation is a significant contributor to hypertensive heart failure. Carnosol (Car), primarily derived from the sage plant (Salvia carnosa), exhibits anti-inflammatory properties in a range of systems. Nevertheless, the influence of angiotensin II (Ang II) on cardiac remodeling remains uncharted. Car was shown to protect mice's hearts against Ang II-induced heart damage at dosages of 20 and 40 mg/kg/d. This protection was evident in a concentration-related decrease in the remodeling of the heart and dysfunction. Examination of the transcriptome revealed that the pivotal roles in mediating the protective effects of Car involved inhibiting Ang II-induced inflammation and the activation of the mitogen-activated protein kinase (MAPK) pathway. Furthermore, Car was found to inhibit p38 phosphorylation, therefore reducing the level of inflammation in cultured cardiomyocytes and mouse hearts. This effect was attributed to the direct binding to p38 and inhibition of p38 protein phosphorylation by Car both in vitro and in vivo. In addition, the effects of Car on inflammation were neutralized when p38 was blocked in cardiomyocytes.

Endothelial deubiquinatase YOD1 mediates Ang II-induced vascular endothelial-mesenchymal transition and remodeling by regulating ß-catenin.

Hypertension is a prominent contributor to vascular injury. Deubiquinatase has been implicated in the regulation of hypertension-induced vascular injury. In the present study we investigated the specific role of deubiquinatase YOD1 in hypertension-induced vascular injury. Vascular endothelial endothelial-mesenchymal transition (EndMT) was induced in male WT and YOD1-/- mice by administration of Ang II (1 µg/kg per minute) via osmotic pump for four weeks. We showed a significantly increased expression of YOD1 in mouse vascular endothelial cells upon Ang II stimulation. Knockout of YOD1 resulted in a notable reduction in EndMT in vascular endothelial cells of Ang II-treated mouse; a similar result was observed in Ang II-treated human umbilical vein endothelial cells (HUVECs). We then conducted LC-MS/MS and co-immunoprecipitation (Co-IP) analyses to verify the binding between YOD1 and EndMT-related proteins, and found that YOD1 directly bound to ß-catenin in HUVECs via its ovarian tumor-associated protease (OTU) domain, and histidine at 262 performing deubiquitination to maintain ß-catenin protein stability by removing the K48 ubiquitin chain from ß-catenin and preventing its proteasome degradation, thereby promoting EndMT of vascular endothelial cells. Oral administration of ß-catenin inhibitor MSAB (20 mg/kg, every other day for four weeks) eliminated the protective effect of YOD1 deletion on vascular endothelial injury. In conclusion, we demonstrate a new YOD1-ß-catenin axis in regulating Ang II-induced vascular endothelial injury and reveal YOD1 as a deubiquitinating enzyme for ß-catenin, suggesting that targeting YOD1 holds promise as a potential therapeutic strategy for treating ß-catenin-mediated vascular diseases.

Curcumin improves insulin sensitivity in high-fat diet-fed mice through gut microbiota.

BACKGROUND: Insulin resistance precedes metabolic syndrome which increases the risk of type 2 diabetes and cardiovascular disease. However, there is a lack of safe and long-lasting methods for the prevention and treatment of insulin resistance. Gut microbiota dysbiosis can lead to insulin resistance and associated glucose and lipid metabolic dysfunction. Thus, the role of gut microbiota in metabolic diseases has garnered growing interest. Curcumin, the active ingredient of tropical plant Curcuma longa, has excellent prospects for the prevention and treatment of metabolic diseases. However, due to the extremely low bioavailability of curcumin, the mechanisms by which curcumin increases insulin sensitivity remains to be elucidated. This study aimed to elucidate the role of gut microbiota in mediating the effects of curcumin on improving insulin sensitivity in high-fat diet (HFD)-fed mice. METHODS: Glucose, insulin, and pyruvate tolerance were tested and hepatic triglycerides (TGs) content was measured in HFD-fed mice treated with curcumin (100 mg kg-1 d-1, p.o.) or vehicle for 4 weeks and aforementioned mice after gut microbiota depletion via antibiotic treatment for 4 weeks. Fecal microbiota transplantation (FMT) was conducted in endogenous gut microbiota-depleted HFD-fed mice. Glucose and lipid metabolic phenotypes were also measured in recipient mice colonized microbiota from vehicle- or curcumin-treated HFD-fed mice. The mechanisms underlying the effects of curcumin on increasing insulin sensitivity were testified by Western blotting, real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). RESULTS: Curcumin ameliorated HFD-induced glucose intolerance, insulin resistance, pyruvate intolerance, and hepatic TGs accumulation, while these effects were mediated by gut microbiota. Curcumin induced insulin-stimulated Akt phosphorylation levels in insulin-regulated peripheral tissues. The inhibitory effects of curcumin on the expressions of genes involved in hepatic gluconeogenesis and de novo lipogenesis were dependent on gut microbiota. Meanwhile, curcumin upregulated the expression of fibroblast growth factor 15 (FGF15) through gut microbiota. CONCLUSIONS: The effects of curcumin on promoting insulin sensitivity were dependent on gut microbiota in HFD-fed mice. Moreover, curcumin at least partly exerted its effects on increasing insulin sensitivity via FGF15 upregulation. This study provided new ideas on nutritional manipulations of gut microbiota for the treatment of metabolic diseases.

Gut microbiota mediates the effects of curcumin on enhancing Ucp1-dependent thermogenesis and improving high-fat diet-induced obesity.

Due to extremely poor systemic bioavailability, the mechanism by which curcumin increases energy expenditure remains unelucidated. Accumulating evidence suggests a strong association between the gut microbiota (GM) and energy metabolism. We investigated whether the GM mediates the effects of curcumin on improving energy homeostasis. High-fat diet (HFD)-fed wild type, uncoupling protein 1 (Ucp1) knockout and G protein-coupled membrane receptor 5 (TGR5) knockout mice were treated with curcumin (100 mg kg-1 d-1, p.o.). Curcumin-treated HFD-fed mice displayed decreased body weight gain and augmented cold tolerance due to enhanced adaptive thermogenesis as compared with that in control mice. The anti-obesity effects of curcumin were abolished by Ucp1 knockout. 16S ribosomal DNA sequencing analysis revealed that curcumin restructured the GM in HFD-fed mice. Fecal microbiota transplantation (FMT) and endogenous GM depletion indicated that the GM mediated the enhanced effect of curcumin on Ucp1-dependent thermogenesis. Curcumin altered bile acid (BA) metabolism with increased fractions of circulating deoxycholic acid (DCA) and lithocholic acid (LCA), which are the two most potent ligands for TGR5. Consistently, the enhanced effect of curcumin on Ucp1-dependent thermogenesis was eliminated by TGR5 knockout. Curcumin requires the GM and TGR5 to activate the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway in thermogenic adipose tissue. Here, we demonstrated that the GM mediates the effects of curcumin on enhancing Ucp1-dependent thermogenesis and ameliorating HFD-induced obesity by influencing BA metabolism. We disclosed the potential of nutritional and pharmacologic manipulations of the GM to enhance Ucp1-dependent thermogenesis in the prevention and treatment of obesity.

Cutoff of 25% for Ki67 expression is a good classification tool for prognosis in colorectal cancer in the AJCC­8 stratification.

Ki­67 expression has been widely used in clinical practice as an index to evaluate the proliferative activity of tumor cells. The cutoff for Ki67 expression in order to increase the prognostic value of Ki67 expression in colorectal cancer varies. The present study assessed the relationship between the 25% cutoff for Ki67 expression and prognosis in colorectal cancer in the AJCC­8 (American Joint Committee on Cancer 8 edition) stratification. The current trial included 1,090 colorectal cancer patients enrolled from 2006 to 2012 at Huzhou Central Hospital. Ki67 expression was classified according to 25% intervals, dividing the patients into four groups. Measurement data were analyzed by ANOVA, and count data by Crosstabs. Bivariate correlation analysis was performed to assess clinicopathological indicators based on Ki67 expression. Disease­free survival (DFS) and overall survival (OS) based on Ki67 levels were analyzed by the Kaplan­Meier method. A total of 1,090 patients of the 2,080 enrolled CRC cases were evaluated (52.4%). Invasive depth, tumor differentiation, tumor size, AJCC­8, positive number of lymph nodes and chemotherapy status showed significant differences in the various Ki67 expression groups (all P<0.05), with significant correlations (Spearman rho: 0.170, 0.456, 0.22, 0.195, 0.514 and ­0.201, respectively, all P<0.001). DFS and OS for the different Ki67 level groups based on AJCC­8 stratification were analyzed, and no significance was found in stage IV (P=0.334). DFS and OS survival rates were assessed at different Ki67 expression levels, and no significant differences were found (all P>0.05). Cox regression analysis showed that invasive depth, lymph node metastasis, tumor differentiation, AJCC­8 and Ki67 were independent factors affecting colorectal cancer (P=0.030, all others P<0.001). In conclusion, a cutoff of 25% for Ki67 expression is a good classification tool. High Ki67 has a close association with poor prognosis in colorectal cancer and independently predicts prognosis in the AJCC­8 stratification.

When do defecation function and quality of life recover for patients with non-ostomy and ostomy surgery of rectal cancer?

BACKGROUND: Rectal cancer (RC) surgery often results in permanent colostomy, seriously limiting the quality of life (QOL) in patients in terms of bowel function. This study aimed to examine defecation function and QOL in RC patients who underwent non-ostomy or ostomy surgery, at different time-points after surgery. METHODS: In total, 82 patients who underwent an ostomy and 141 who did not undergo an ostomy for the treatment of RC at our colorectal surgery department between January 2013 and January 2015 were enrolled. Surgical methods, tumor distance from the anal margin (TD), anastomosis distance from the anal margin (AD) and complications were compered between the non-ostomy and ostomy surgery groups. QOL was compared between the two groups at years 2, 3, and 4 after surgery. The Wexner score and the validated cancer-specific European Organization for Research and Treatment of Cancer (EORTC QLQ-CR30) questionnaire scores were assessed for all patients in January 2017. SPSS 21.0 was utilized for all data analyses. RESULTS: Surgical methods, TD, and AD significantly differed between the non-ostomy and ostomy surgery groups (all P < .001). However, no differences were found in the number of complications between the groups (P = .483). For the 192 patients undergoing Dixon surgery, role function (RF), global QOL (GQOL), sleep disturbance, and the incidence of constipation showed significant differences between the two groups (P = .012, P = .025, P = .036, and P = .015, respectively). In the 31 cases of permanent ostomy, we observed significant differences in GQOL scores, dyspnea incidence, and financial difficulties across the different years (P = .002, P = .036, and P < .01, respectively). Across all 223 cases, there were significant differences in social function and GQOL scores in the second year after surgery (P = .014 and P < .001, respectively). However, no differences were observed in the other indices across the three time-points. CONCLUSIONS: RC patients undergoing ostomy surgery, especially those with low and super-low RC, revealed poorer defecation function and QOL in the present study. However, 2 years after surgery, most of the defecation and QOL indicators showed recovery.

Comparison of the eighth version of the American Joint Committee on Cancer manual to the seventh version for colorectal cancer: A retrospective review of our data.

AIM: To analyze the survival trends in colorectal cancer (CRC) based on the different classifications recommended by the seventh and eighth editions of the American Joint Committee on Cancer staging system (AJCC-7th and AJCC-8th). METHODS: The database from our institution was queried to identify patients with pathologically confirmed stage 0-IV CRC diagnosed between 2006 and 2012. Data from 2080 cases were collected and 1090 cases were evaluated through standardized inclusion and exclusion criteria. CRC was staged by AJCC-7th and then restaged by AJCC-8th. Five-year disease-free survival (DFS) and overall survival (OS) were compared. SPSS 21.0 software was used for all data. DFS and OS were compared and analyzed by Kaplan-Meier and Log-rank test. RESULTS: Linear regression and automatic linear regression showed lymph node positive functional equations by tumor-node-metastasis staging from AJCC-7th and tumor-node-metastasis staging from AJCC-8th. Neurological invasion, venous infiltration, lymphatic infiltration, and tumor deposition put forward stricter requirements for pathological examination in AJCC-8th compared to AJCC-7th. After re-analyzing our cohort with AJCC-8th, the percentage of stage IVB cases decreased from 2.8% to 0.8%. As a result 2% of the cases were classified under the new IVC staging. DFS and OS was significantly shorter (P = 0.012) in stage IVC patients compared to stage IVB patients. CONCLUSION: The addition of stage IVC in AJCC-8th has shown that peritoneal metastasis has a worse prognosis than distant organ metastasis in our institution's CRC cohort. Additional datasets should be analyzed to confirm these findings.

The role of tissue and serum carcinoembryonic antigen in stages I to III of colorectal cancer-A retrospective cohort study.

PURPOSE: Tissue carcinoembryonic antigen (t-CEA) and serum carcinoembryonic antigen (s-CEA) expression profiles are the most useful tumor markers for the diagnosis and evaluation of colorectal cancer (CRC) worldwide; however, their roles in CRC progression remain controversial. This study aimed to compare the prognostic values of both s-CEA and t-CEA in CRC. METHODS: A total of 517 patients from January 2006 to December 2010 with stages I-III CRC were retrospectively examined, with 5-year postoperative follow-up and death as end-points. T-CEA expression, s-CEA expression, and clinical pathological parameters were inputted into the SPSS 21.0 software. The Kaplan-Meier method was used to analyze the 5-year disease-free survival (DFS) rate of patients in different tumor node metastasis (TNM) stages based on t-CEA and s-CEA expression. RESULTS: Tumor differentiation and the number of positive lymph node harvests were significantly different among the t-CEA groups (P < 0.001, P = 0.002); however, clinicopathological features showed no significant difference. The groups with high s-CEA and t-CEA expression had a significantly poorer prognosis than those with low s-CEA (P = 0.021) and t-CEA (P < 0.01) expression, respectively. The multivariate analysis demonstrated that t-CEA was an independent prognostic factor in CRC (P < 0.001), but s-CEA was not (P = 0.339). The 5-year disease-free survival rates among the t-CEA groups were significantly different in stages I, II, and III of CRC (P = 0.001, P < 0.001, P < 0.001), whereas in the s-CEA groups, this difference was observed only in stage III (P = 0.014). CONCLUSION: This study shows that postoperative t-CEA expression is an independent factor associated with poorer CRC prognosis and has a higher prognostic value than that of preoperative s-CEA expression.

Geraniol and geranyl acetate induce potent anticancer effects in colon cancer Colo-205 cells by inducing apoptosis, DNA damage and cell cycle arrest.

PURPOSE: Colon cancer ranks second in mortality among all human malignancies, creating thus a need for exploration of novel molecules that would prove effective, cost-effective and with lower toxicity. In the recent past monoterpenes have gained tremendous attention for their anticancer activity. In the present study we evaluated the anticancer effects of two important monoterpenes, geraniol and geranyl acetate against colo-205 cancer cells. METHODS: The antiproliferative activity was determined by MTT assay. Apoptosis was assessed by DAPI staining and DNA damage was checked by comet assay. The cell cycle analysis was carried out by flow cytometry and protein expression was examined by western blotting. RESULTS: The results showed that both geraniol and geranyl acetate exhibited significant anticancer activity against colo-205 cancer cell line with IC50 values of 20 and 30 µM respectively. To find out the underlying mechanism, DAPI staining was carried out and it was observed that both the monoterpenes, geraniol and geranyl acetate, induced apoptosis in colo-205 cells. The apoptosis was also associated with upregulation of Bax and downregulation of Bcl-2 expressions, indicative of mitochondrial apoptosis. Moreover, these two monoterpenes could trigger DNA damage and G2/M cell cycle arrest in colo-205 cells. CONCLUSIONS: Taken together, we propose that geraniol and geranyl acetate may prove to be important lead molecular candidates for the treatment of colon cancer. Their anticancer activity can be attributed to the ability to trigger apoptosis, DNA damage and cell cycle arrest.

Comparisons of Efficacy, Safety, and Cost of Chemotherapy Regimens FOLFOX4 and FOLFIRINOX in Rectal Cancer: A Randomized, Multicenter Study.

BACKGROUND The currently available chemotherapeutic regimens do not use a specifically designed drug delivery system. The objective of this study was to compare outcome measures, adverse effects, and cost of FOLFOX4 and FOLFIRINOX treatments in rectal cancer patients. MATERIAL AND METHODS We enrolled patients who, after surgery, did not undergo chemotherapy or radiotherapy (Control group); were administered 200 mg/m² folinic acid, 400 mg/m² fluorouracil, and 85 mg/m² oxaliplatin (FFO group); or were administered 400 mg/m² folinic acid, 400 mg/m² fluorouracil, 180 mg/m² irinotecan, and 85 mg/m2 oxaliplatin (FFIO group). We recorded tumor and nodal staging, carbohydrate antigen 19-9, serum carcinoembryonic antigen, total cost of treatment, disease recurrence, overall survival, and adverse effects. We used the 2-tailed paired t test following Turkey post hoc test for adverse effects, recurrence analysis, and cost of treatment at 95% of confidence level. RESULTS Surgery (p=0.00089), FOLFOX4 (p=0.000167), and FOLFIRINOX (p=0.00013) improved disease-free conditions. Only surgery failed to maintain carbohydrate antigen and carcinoembryonic antigen 19-9 levels. The cost of chemotherapeutic treatments was in the order of FFIO group > FFO group > Control group. Non-fatal treatment-emergent adverse effects were due to chemotherapeutic drugs. However, fatal chemotherapeutic treatment-emergent adverse effects were observed only in the FFIO group. Overall survival, irrespective of cancerous condition, was higher in the FFO group. CONCLUSIONS FOLFIRINOX had less total cancer recurrence than FOLFOX4. However, FOLFIRINOX had more fatal treatment-emergent adverse effects and excessive cost of treatment than FOLFOX4 regimen.