Bisabolane sesquiterpenes from Clausena sanki with their potential anti-inflammatory activities.

The investigation on the stems and leaves of Clausena sanki led to the isolation of a previously undescribed bisabolane sesquiterpene, clausemargic A (1), together with six known analogues (2-7). The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with data reported in the literature. All known compounds (2-7) were isolated from C. sanki for the first time. All isolated compounds were evaluated for their anti-inflammatory activities via examining the inhibitory activity on nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells in vitro. Compounds 1-7 showed significant inhibitory activities with IC50 values comparable to that of hydrocortisone.

Carbazole alkaloids from Clausena emarginata with their potential antiproliferative activities.

A phytochemical investigation on the stems and leaves of Clausena emarginata led to the isolation of a previously undescribed carbazole alkaloid, clausemargine A (1), together with 11 known analogues (2-12). The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with data reported in the literature. All known compounds (2-12) were isolated from C. emarginata for the first time. All isolated compounds were evaluated for their their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1-12 showed significant antiproliferative effects with IC50 values ranging from 0.28 to 15.18 µM.

Structurally diverse diterpenoids from Trigonostemon howii.

Phytochemical investigation on the stems and leaves of Trigonostemon howii resulted in the isolation of a new abietane diterpenoid, trigohowimine A (1), along with seven known structurally diverse diterpenoids (2-8). The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparison with data reported in the literature. New compound 1 was evaluated for its cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480. Compound 1 showed significant inhibitory effects against various human cancer cell lines with IC50 values ranging from 0.82 to 8.53 µM.

Furanocoumarins with potential antiproliferative activities from Clausena lenis.

A phytochemical investigation on the stems and leaves of Clausena lenis led to the isolation of a new furanocoumarin, clauselenisin A (1), together with five known analogues (2-6). The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with data reported in the literature. All known compounds (2-6) were isolated from C. lenis for the first time. All isolated compounds were evaluated for their their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1-6 showed significant antiproliferative effects with IC50 values ranging from 0.36 to 16.48 µM.

Adjuvant Chemotherapy Seemed Not to Have Survival Benefit in Rectal Cancer Patients with ypTis-2N0 After Preoperative Radiotherapy and Surgery from a Population-Based Propensity Score Analysis.

BACKGROUND: Adjuvant chemotherapy is currently offered routinely, as standard, after radical resection for patients with rectal cancer receiving neo-adjuvant chemoradiation. However, the efficacy of adjuvant chemotherapy in patients with ypTis-2N0M0 has not been documented to the same extent, and the survival benefit remained controversial. The purpose of this work was to determine the role of chemotherapy in patients with ypTis-2N0M0 classification. MATERIALS AND METHODS: Data were obtained from the Surveillance, Epidemiology, and End Results database (n = 4,217). A propensity score model was utilized to balance baseline covariates. RESULTS: Of the 4,217 included patients, 335 with ypTis-2N0M0 did not receive adjuvant chemotherapy. There were comparable cancer-specific survivals (CSS) between those undergoing adjuvant chemotherapy or not (log-rank test = 0.136, p = .712) in the overall sample. After propensity score matching, the cancer-specific survival did not differ between the chemotherapy and observation groups (log-rank test = 0.089, p = .765). Additionally, the Cox model did not demonstrate adjuvant chemotherapy as the prognostic factor, with hazard ratio = 0.95 (95% confidence interval 0.69-1.32) for CSS. Furthermore, the 10-year cumulative CSS was 78.7% and 79.4% between the chemotherapy and observation groups, indicating no significance, and no impact of adjuvant chemotherapy on survival was observed in different subgroups stratified by T stage, histological grade, histology, lymph nodes, and tumor size. CONCLUSION: Patients with ypTis-2N0 rectal cancer did not benefit from adjuvant chemotherapy after preoperative radiology and radical surgery in this cohort study. These results provided new insight into the routine use of adjuvant chemotherapy for patients with rectal cancer with completed neo-adjuvant radiotherapy and curative surgery. IMPLICATIONS FOR PRACTICE: Inconsistent recommendations for patients with rectal cancer receiving neo-adjuvant chemoradiation are offered by clinical guidelines. Adjuvant chemotherapy had no cancer-specific survival benefit, not only in the whole cohort, but also in the propensity score-matched cohort. A Cox model also confirmed adjuvant chemotherapy was not a significant prognostic factor in ypTis-2N0 rectal cancer. No survival benefit conferred by adjuvant chemotherapy was observed, regardless of whether T stage, histological type, grade, lymph nodes and tumor size varied.

Baseline Peripheral Blood Leukocytosis Is Negatively Correlated With T-Cell Infiltration Predicting Worse Outcome in Colorectal Cancers.

We aimed to explore the prognostic value of blood leukocyte and to generate a predictive model to refine risk stratification for colorectal cancers. 6,558 patients with colorectal cancers were identified eligible respectively in Fudan University Shanghai Cancer Center (FUSCC) between May, 2008 and October, 2016. Then the entire set is divided into a training set and a testing set. The prognostic value of pretreatment white blood cell count and clinicopathologic parameters in the context of tumor-infiltrating lymphocytes (TIL) and neutrophils was investigated. Conventional leukocytosis (≥10,000/µl) was significantly associated with decreased overall survival (OS) and disease-free survival (DFS) (p < 0.05). In fact, moderately elevated leukocyte (≥7,500/µl) has also been identified as an independent prognostic factor for survivals in the training, testing, and entire sets, respectively. And leukocytosis correlated with advanced T-stage (p < 0.001), M-stage (p < 0.001), poor differentiation tumor (p = 0.023) and Glasgow prognostic score, even predicted for worse relapse postoperatively (p = 0.001) and resistance to chemotherapy. In addition, nomograms on OS and DFS were established according to leukocytosis and other significant factors, demonstrating a great prediction accuracy. Importantly, pretreatment leukocytosis had a significantly lower intra-tumor CD3+ and CD8+ TIL infiltration (p < 0.001 and p = 0.033), whereas low CD3+ and CD8+ TIL expression in tumor were associated with worse OS and DFS (p = 0.02 and p = 0.015). In conclusion, our study validates leukocytosis as an independent prognostic factor in colorectal cancers. Our data provide for the first-time vital insight on the correlation of peripheral pretreatment leukocytosis with the tumor-infiltrating cells contexture and might be relevant for future risk stratification.

ITGAE Defines CD8+ Tumor-Infiltrating Lymphocytes Predicting a better Prognostic Survival in Colorectal Cancer.

BACKGROUND: Tumor-infiltrating lymphocytes (TIL) in colorectal tumor tissue are significantly correlated with a favorable prognosis, such as CD8+ lymphocytes, which are also called tumor-reactive lymphocytes. However, not all tumor-infiltrating T cells confer benefit to patients. Therefore, it is of substantial benefit to identify a biomarker to demarcate these tumor-reactive lymphocytes. METHODS: We investigated whether ITGAE could be used to discriminate reactive CD8+ lymphocytes in colorectal cancer (CRC). TCGA colorectal cancer data sets (n1 = 492, n2 = 386) and FUSCC set (n3 = 276) were used in this study. Further phenotyping of ITGAE+ cells and the mechanistic basis were investigated. FINDINGS: In the training and testing sets from TCGA, ITGAE expression, which is strongly correlated with cytotoxic T cell markers (CD8/CD3/PD1), independently predicted longer disease-free survival (DFS) and overall survival (OS). In line with this, the association between ITGAE+ lymphocytes and survival has been confirmed in the FUSCC cohort for validation (P = .026). ITGAE + cells in the series always co-stained with CD8 were preferentially located in the tumor. Interestingly, ITGAE+ lymphocytes tended to associate with the epithelial-mesenchymal transition (EMT) with decreased Snail and increased E-cadherin expression accompanied. Finally, gene set enrichment analysis showed that immune activation was significantly enriched in the high ITGAE+ TIL group, accompanied by enriched EMT-related pathways. INTERPRETATION: Because of the specified expression of tumor-reactive CD8+ T-cells, ITGAE may be a promising biomarker for the rapid identification of immune infiltration in CRC.

Osteoglycin-induced VEGF Inhibition Enhances T Lymphocytes Infiltrating in Colorectal Cancer.

BACKGROUND: OGN could modify tissue inflammation and immune response via local and circulating innate immune cells, which was suggestive of a reciprocal relationship between OGN and T cell infiltration in cancer. Hence, we aim to measure the OGN expression patterns and immune cells response in colorectal cancer(CRC). METHODS: This study enrolled three independent sets of patients from TCGA and the Fudan University Shanghai Cancer Center(FUSCC). The effect of OGN on T cell infiltration and the mechanism were examined in vitro and in vivo. FINDINGS: Tumor OGN expression levels were positively associated with CD3, CD8, and PTPRC expressions in the training and testing sets from TCGA, respectively. In validation set from FUSCC, OGN expression level also paralleled positively with CD8+ cell density in colorectal cancer tissue (p < .001). For a unit decrease in outcome quartile categories, multivariable OR in the lowest (vs highest) OGN expression was 0.17 (95% CI 0.08-0.33). Consistently, immunofluorescence validated that OGN was preferentially expressed with CD8+ cells in both normal epithelium and cancer tissue. Xenograft tumors arising from MC38 cells with OGN-over-expression displayed a significant increase in CD8+ cells recruitment. Hence, high expression of OGN was associated with a profound longer survival (P = .009). In mechanism, elevated OGN expression inhibited the activation of the transcriptional genes HIF-1α in CRC cells, then significantly impeded the expression of VEGF. As a result of this, T cell tumor infiltration was reduced. INTERPRETATION: OGN expression is positively associated with CD8+ cell density in colorectal cancer tissue, suggesting a possible influence of OGN expression on tumor reactive T cells in the tumor niche. FUND: No.

Novel γ-lactone derivatives from Trigonostemon heterophyllus with their potential antiproliferative activities.

Two novel γ-lactone derivatives, trigoheterophines A (1) and B (2), together with four known furan derivatives (3-6), were isolated from the stems and leaves of Trigonostemon heterophyllus. The structures of 1 and 2 were elucidated by extensive spectroscopic methods and the known compounds were identified by comparing with the data reported in literature. Among them, trigoheterophines A (1) and B (2) represent an unusual type of γ-lactone derivatives, possessing 21 carbon atoms on the carbon skeleton, and known compouds (3-6) are rare furan derivatives in the plant kingdom with diverse long-chain hydrocarbyl groups as substituents at C-4. All isolated compounds were evaluated for their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1-6 showed significant antiproliferative effects against various human cancer cell lines with IC50 values ranging from 0.28 to 12.06 µM. These findings suggest that the discoveries of these novel γ-lactone derivatives and furan derivatives with significant antiproliferative activities isolated from T. heterophyllus could be of great importance to the development of new anticancer agents.

Mucinous Adenocarcinomas Histotype Can Also be a High-Risk Factor for Stage II Colorectal Cancer Patients.

BACKGROUND/AIMS: Colorectal mucinous adenocarcinoma (MA) has been associated with a worse prognosis than adenocarcinoma (AD) in advanced stages. Little is known about the prognostic impact of a mucinous histotype on the early stages of colorectal cancer with negative lymph node (LN) metastasis. In contrast to the established prognostic factors such as T stage and grading, the histological subtype is not thought to contribute to the therapeutic outcome, although different subtypes can potentially represent different entities. In this study, we aimed to define the prognostic value of mucinous histology in colorectal cancer with negative LNs. METHODS: Between 2006 and 2017, a total of 4893 consecutive patients without LN metastasis underwent radical surgery for primary colorectal cancer (MA and AD) in Fudan University Shanghai Cancer Center (FUSCC). Clinical, histopathological, and survival data were analyzed. RESULTS: The incidence of MA was 11% in 4893 colorectal cancer patients without LN metastasis. The MA patients had a higher T category, a greater percentage of LN harvested, larger tumor size and worse grading than the AD patients (p < 0.001 for each). We found that MA histology was correlated with a poor prognosis in terms of relapse in node-negative patients, and MA histology combined with TNM staging may be a feasible method for predicting the relapse rate. Additionally, MA presented as a high-risk factor in patients with negative perineural or vascular invasion and well/moderate-differentiation and showed a more dismal prognosis for stage II patients. Meanwhile, the disease-free survival was identical in MA and AD patients after neo- and adjuvant chemotherapy. CONCLUSION: MA histology is an independent predictor of poor prognosis due to relapse in LN-negative colorectal cancer patients. Mucinous histology can suggest a possible high risk in early-stage colorectal carcinoma.

Osteoglycin (OGN) reverses epithelial to mesenchymal transition and invasiveness in colorectal cancer via EGFR/Akt pathway.

BACKGROUND: Many types of cancers are devoid of the small leucine-rich proteoglycans: osteoglycin (OGN), but its role in tumorigenesis is poorly studied especially in colorectal cancers (CRC). Here we aim to evaluate the relationship between OGN expression patterns and the clinical course of CRC, and the role of OGN in cancer progression. METHODS: The tissue microarray staining was performed and the relevance between OGN expression and oncologic outcomes was performed using Cox regression analysis. The effect of OGN on cell proliferation and tumorigenesis was examined in vitro and in vivo. Immunoprecipitation assay, immunofluorescence analysis and internalization assay were used for mechanistic study. RESULTS: Patients with high expression of OGN were associated with a profound longer survival in CRC and the high serum OGN level was also indicative of fewer recurrences consistently. In colon cancer cells, OGN increased dimerization of EGFR, then triggered EGFR endocytosis and induced the recruitment of downstream components of the EGFR internalization machinery (Eps15 and epsin1). Above all, OGN reduced Zeb-1 expression via EGFR/Akt leading to inhibition of epithelial-mesenchymal transition. As results, in vitro and in vivo, the OGN expression was demonstrated to reduce cell proliferation, inhibit invasion of colon cancer cells then impede cancer progression. CONCLUSIONS: There is a positive association between OGN level and prolonged survival in CRC. OGN plays a restrictive role in colorectal cancer progression by reduced activation of EGFR/AKT/Zeb-1.

Carbazole alkaloids from Clausena hainanensis with their potential antiproliferative activities.

Five new carbazole alkaloids, clausehainanines A-E (1-5), together with seven known analogues (6-12) were isolated from the stems and leaves of C. hainanensis. Their structures were elucidated by extensive spectroscopic methods. Among them, compounds 1-5 were an unusual type of carbazole alkaloids, possessing diverse isopentenyl derivatives as substituents at C-2. All isolated compounds were evaluated for their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Alkaloids 1-12 showed significant antiproliferative effects against various human cancer cell lines with IC50 values ranging from 0.12 to 15.56 µM. These findings suggest that the discoveries of these carbazole alkaloids with significant cytotoxic activities isolated from C. hainanensis could be of great importance to the development of new anticancer agents.

Bioactive furanocoumarins from the stems and leaves of Clausena hainanensis.

A new furanocoumarin, clauhainanin A (1), together with seven known furanocoumarins (2-8), were isolated from the stems and leaves of Clausena hainanensis. The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with data reported in the literature. All known compounds (2-8) were isolated from C. hainanensis for the first time. All isolated compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1-8 exhibited significant inhibitory effects with IC50 values ranging from 1.36 to 18.96 µM.

Radiotherapy for stage IIA rectal cancer may not benefit all.

This study sought to determine whether additional radiotherapy is necessary in patients after optimal surgery for stage IIA rectal cancer and how the different covariates influence the efficacy of radiotherapy. The first primary rectal cancer was identified from the 1988-December 2013 Surveillance, Epidemiology and End Results database. We identified 13647 patients with IIA rectal cancer, in which 39.6% received neo-adjuvant radiotherapy and in another 14.96% patients the adjuvant radiotherapy were performed. Neo-adjuvant or adjuvant radiotherapy group had better survival with 10-Year cancer-specific survival estimates as 75.1% and 73.8% compared to 68.4% of no radiotherapy group (P < 0.01). Adjusted hazard ratio (HR) demonstrated neo-adjuvant and adjuvant radiotherapy (HR: 0.814 and 0.848) were all associated with significantly decreased risk for cancer death. However, radiotherapy did not seem to yield the same survival benefit in selected population. Adjusted stratified analysis demonstrated patients with increasing age, relative large tumor size, and more retrieved regional lymph nodes had no additional benefit for cancer specific survival based on radiation use. In conclusions, unselected patients with stage IIA rectal cancer receiving radiotherapy experienced better survival in comparison to patients without radiation. However, additional radiotherapy is not beneficial for all.

A new monoterpenoid indole alkaloid from Ochrosia elliptica.

A new monoterpenoid indole alkaloid, 10-methoxyakuammidine (1), together with four known alkaloids (2-5), were isolated from the stems and leaves of Ochrosia elliptica. The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with data reported in the literature. New compound 1 was evaluated for its cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. 1 exhibited inhibitory effects with IC50 values comparable to those of cisplatin.

A new indole alkaloid with anti-inflammatory activity from Nauclea officinalis.

A new indole alkaloid, 17-O-methyl-19-(Z)-naucline (1), together with seven known alkaloids (2-8), were isolated from the stems and leaves of Nauclea officinalis. The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons their data with those reported in the literature. 17-O-methyl-19-(Z)-naucline (1) showed significant inhibitory activity on nitric oxide production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells in vitro with an IC50 value of 3.6 µM.

[Effect of salvianolic acid A on anesthetized canine experimental myocardial infarction].

Salvianolic acid A (SAA), one of the major active water-soluble salvianolic acids of traditional Chinese medicine Salvia miltiorrhiza Bunge, has been reported to be effective on anti-myocardial ischemia, anti-oxidation and anti-thrombus. This study aimed to investigate appropriate administration route on dogs with acute myocardial ischemia(AMI). Twenty-four dogs were randomized into four groups (n=6), model, oral administration of SAA (8 mg•kg⁻¹), intravenous administration of SAA (4 mg•kg⁻¹), intravenous administration of Herbesser(0.5 mg•kg⁻¹) as positive drug group. AMI model was established by ligating left anterior descending coronary arteries(LAD) of dogs. Changes of ST segment were determined by epicardial electrocardiogram(ECG), coronary blood flow (CBF) and myocardial oxygen consumption were measured by ultrasonic Doppler flow meter, serum creatine kinase (CK) and lactate dehydrogenase (LDH) were observed by fully automatic biochemical analyser. Myocardial infarct size was assessed by nitro blue tetrazolium (NBT) staining. Both oral and intravenous administration of SAA reduced the myocardial infarct area/left ventricle area significantly [(16.73±6.52)% and (13.19±2.38)%, compared with (24.35±4.89)% in model group, P<0.01). Oral administration of SAA improved the ECG performance of Σ-ST from 30-190 min after ischemia (P<0.05-0.01), while intravenous SAA had a rapid onset (10-190 min after ischemia, P<0.05-0.01). Compared with model group, oral and intravenous SAA both decreased serum CK and LDH significantly (P<0.05-0.01), while the difference of intravenous administration is more significant. SAA protects myocardium in canine experimental myocardial infarction models. Intravenous administration of SAA alleviates myocardial infarction with greater significance than oral route.

[Effect of formula of removing both phlegm and blood stasis in improving cardiac function of Chinese mini-swine with coronary heart disease of phlegm-stasis cementation syndrome].

OBJECTIVE: To evaluate that the effect of formula of removing both phlegm and blood stasis in improving cardiac function of Chinese mini-swine with coronary heart disease of phlegm-stasis cementation syndrome. METHOD: Totally 36 Chinese mini-swine were randomly divided to six groups: the normal control group, the model group, the Danlou tablet group, and Tanyu Tonzhi Fang(TYTZ) groups with doses of 2. 0, 1. 0 and 0. 5 g kg-1, with six in each group. Except for the normal control group, all of other groups were fed with high-fat diet for 2 weeks. Interventional balloons are adopted to injure their left anterior descending artery endothelium. After the operation, they were fed with high-fat diet for 8 weeks to prepare the coronary heart disease model of phlegm-stasis cementation syndrome. After the operation, they were administered with drugs for 8 weeks. The changes in the myocardial ischemia were observed. The changes in the cardiac function and structure were detected by cardiac ultrasound and noninvasive hemodynamic method. RESULT: Compared with the normal control group, the model group showed significant increase in myocardial ischemia and SVR and obvious decrease in CO, SV and LCW in noninvasive hemodynamic parameters (P <0.05 or P <0.01). The ultrasonic cardiogram indicated notable decrease in IVSd, LVPWs, EF and FS, and remarkable increase in LVIDs (P<0. 05 orP<0.01). Compared with the model group, TYTZ could reduce the myocardial ischemia, strengthen cardiac function, and improve the abnormal cardiac structure and function induced by ischemia (P <0. 05 or P <0. 01). CONCLUSION: TYTZ shows a significant effect in improving cardiac function of Chinese mini-swine with coronary heart disease of phlegm-stasis cementation syndrome. The clinical cardiac function detection method could be adopted to correctly evaluate the changes in the post-myocardial ischemia cardiac function, and narrow the gap between clinical application and basic experimental studies.

Long-term effect of stent coating with zedoary essential components on neointimal formation in the porcine coronary artery.

OBJECTIVE: To examine the effect of the zedoary essential component-eluting stent (ZES) on a porcine coronary neointimal formation. METHODS: ZES, sirolimus-eluting stents (SES), and bare metal stents (BMS) were randomly implanted in three different major epicardial vessels in 36 balloon-injured pigs. Coronary angiography, optical coherence tomography, and histomorphological analysis were used to determine antihyperplasia effects. RESULTS: ZES and SES had a significantly larger lumen diameter and area, and reduced diameter and area of stenosis in arteries at 30 and 90 days compared with arteries implanted with BMS (P<0.01). Histomorphometric analysis showed moderate inflammatory responses, such as infiltration of mononuclear cells, lymphocytes, and multinucleated giant cells in some arteries with SES compared with ZES (P<0.05). Injury scores were not different among the three groups at 30 and 90 days. The endothelialization score in the SES group was 2.69 ± 0.42 at 30 days and 2.83 ± 0.39 at 90 days compared with the ZES and BMS groups (both were 3.00 ± 0.00 at either 30 or 90 days, P<0.05). Well developed endothelium was observed in the ZES group, while incomplete endothelium and inflammatory cells were observed with stent struts partly naked at the vessel lumen in the SES group. CONCLUSION: The ZES inhibits neointimal hyperplasia with good endothelia coverage in the porcine balloon injury coronary model.