A systematic analysis of the global and regional burden of colon and rectum cancer and the difference between early- and late-onset CRC from 1990 to 2019.

The burden of colorectal cancer (CRC) varies substantially across different geographical locations. However, there was no further quantitative analysis of regional social development and the disease burden of CRC. In addition, the incidence of early- and late-onset CRC has increased rapidly in developed and developing regions. The main purpose of this study was to investigate the trends in CRC burden across different regions, in addition to the epidemiological differences between early and late-onset CRC and their risk factors. In this study, estimated annual percentage change (EAPC) was employed to quantify trends in age-standardized incidence rate (ASIR), mortality rate, and disability-adjusted life-years. Restricted cubic spline models were fitted to quantitatively analyze the relationship between trends in ASIR and Human Development Index (HDI). In addition, the epidemiological characteristics of early- and late-onset CRC were investigated using analyses stratified by age groups and regions. Specifically, meat consumption and antibiotic use were included to explore the differences in the risk factors for early- and late-onset CRC. The quantitative analysis showed that the ASIR of CRC was exponentially and positively correlated with the 2019 HDI in different regions. In addition, the growing trend of ASIR in recent years varied substantially across HDI regions. Specifically, the ASIR of CRC showed a significant increase in developing countries, while it remained stable or decreased in developed countries. Moreover, a linear correlation was found between the ASIR of CRC and meat consumption in different regions, especially in developing countries. Furthermore, a similar correlation was found between the ASIR and antibiotic use in all age groups, with different correlation coefficients for early-onset and late-onset CRC. It is worth mentioning that the early onset of CRC could be attributable to the unrestrained use of antibiotics among young people in developed countries. In summary, for better prevention and control of CRC, governments should pay attention to advocate self-testing and hospital visits among all age groups, especially among young people at high risk of CRC, and strictly control meat consumption and the usage of antibiotics.

Transcriptional profiling and network pharmacology analysis identify the potential biomarkers from Chinese herbal formula Huosu Yangwei Formula treated gastric cancer in vivo.

Huosu Yangwei (HSYW) Formula is a traditioanl Chinese herbal medicine that has been extensively used to treat chronic atrophic gastritis, precancerous lesions of gastric cancer and advanced gastric cancer. However, the effective compounds of HSYW and its related anti-tumor mechanisms are not completely understood. In the current study, 160 ingredients of HSYW were identified and 64 effective compounds were screened by the ADMET evaluation. Furthermore, 64 effective compounds and 2579 potential targets were mapped based on public databases. Animal experiments demonstrated that HSYW significantly inhibited tumor growth in vivo. Transcriptional profiles revealed that 81 mRNAs were differentially expressed in HSYW-treated N87-bearing Balb/c mice. Network pharmacology and PPI network showed that 12 core genes acted as potential markers to evaluate the curative effects of HSYW. Bioinformatics and qRT-PCR results suggested that HSYW might regulate the mRNA expression of DNAJB4, CALD, AKR1C1, CST1, CASP1, PREX1, SOCS3 and PRDM1 against tumor growth in N87-bearing Balb/c mice.

Discovery and Characterization of the Biflavones From Ginkgo biloba as Highly Specific and Potent Inhibitors Against Human Carboxylesterase 2.

Human carboxylesterase 2 (CES2), one of the most abundant hydrolases distributed in the small intestine, has been validated as a key therapeutic target to ameliorate the intestinal toxicity caused by irinotecan. This study aims to discover efficacious CES2 inhibitors from natural products and to characterize the inhibition potentials and inhibitory mechanisms of the newly identified CES2 inhibitors. Following high-throughput screening and evaluation of the inhibition potency of more than 100 natural products against CES2, it was found that the biflavones isolated from Ginkgo biloba displayed extremely potent CES2 inhibition activities and high specificity over CES1 (>1000-fold). Further investigation showed that ginkgetin, bilobetin, sciadopitysin and isoginkgetin potently inhibited CES2-catalyzed hydrolysis of various substrates, including the CES2 substrate-drug irinotecan. Notably, the inhibition potentials of four biflavones against CES2 were more potent than that of loperamide, a marketed anti-diarrhea agent used for alleviating irinotecan-induced intestinal toxicity. Inhibition kinetic analyses demonstrated that ginkgetin, bilobetin, sciadopitysin and isoginkgetin potently inhibited CES2-catalyzed fluorescein diacetate hydrolysis via a reversible and mixed inhibition manner, with K i values of less than 100 nM. Ensemble docking and molecular dynamics revealed that these biflavones could tightly and stably bind on the catalytic cavity of CES2 via hydrogen bonding and π-π stacking interactions, while the interactions with CES1 were awfully poor. Collectively, this study reports that the biflavones isolated from Ginkgo biloba are potent and highly specific CES2 inhibitors, which offers several promising lead compounds for developing novel anti-diarrhea agent to alleviate irinotecan-induced diarrhea.

Discovery of hCES2A inhibitors from Glycyrrhiza inflata via combination of docking-based virtual screening and fluorescence-based inhibition assays.

Human carboxylesterase 2 (hCES2A) is a key target to ameliorate the intestinal toxicity triggered by irinotecan that causes severe diarrhea in 50%-80% of patients receiving this anticancer agent. Herbal medicines are frequently used for the prevention and treatment of the intestinal toxicity of irinotecan, but it is very hard to find strong hCES2A inhibitors from herbal medicines in an efficient way. Herein, an integrated strategy via combination of chemical profiling, docking-based virtual screening and fluorescence-based high-throughput inhibitor screening assays was utilized. Following the screening of a total of 73 herbal products, licorice (the dried root of Glycyrrhiza species) was found with the most potent hCES2A inhibition activity. Further investigation revealed that the chalcones and several flavonols in licorice displayed strong hCES2A inhibition activities, while isoliquiritigenin, echinatin, naringenin, gancaonin I and glycycoumarin exhibited moderate inhibition of hCES2A. Inhibition kinetic analysis demonstrated that licochalcone A, licochalcone C, licochalcone D and isolicoflavonol potently inhibited hCES2A-mediated fluorescein diacetate hydrolysis in a reversible and mixed inhibition manner, with Ki values less than 1.0 µM. Further investigations demonstrated that licochalcone C, the most potent hCES2A inhibitor identified from licorice, dose-dependently inhibited intracellular hCES2A in living HepG2 cells. In summary, this study proposed an integrated strategy to find hCES2A inhibitors from herbal medicines, and our findings suggested that the chalcones and isolicoflavonol in licorice were the key ingredients responsible for hCES2A inhibition, which would be very helpful to develop new herbal remedies or drugs for ameliorating hCES2A-associated drug toxicity.

Herb-drug interaction between Styrax and warfarin: Molecular basis and mechanism.

BACKGROUND: Styrax, one of the most famous folk medicines, has been frequently used for the treatment of cardiovascular diseases and skin problems in Asia and Africa. It is unclear whether Styrax or Styrax-related herbal medicines may trigger clinically relevant herb-drug interactions. PURPOSE: This study was carried out to investigate the inhibitory effects of Styrax on human cytochrome P450 enzymes (CYPs) and to clarify whether this herb may modulate the pharmacokinetic behavior of the CYP-substrate drug warfarin when co-administered. STUDY DESIGN: The inhibitory effects of Styrax on CYPs were assayed in human liver microsomes (HLM), while the pharmacokinetic interactions between Styrax and warfarin were investigated in rats. The bioactive constituents in Styrax with strong CYP3A inhibitory activity were identified and their inhibitory mechanisms were carefully investigated. METHODS: The inhibitory effects of Styrax on human CYPs were assayed in vitro, while the pharmacokinetic interactions between Styrax and warfarin were studied in rats. Fingerprinting analysis of Styrax coupled with LC-TOF-MS/MS profiling and CYP inhibition assays were used to identify the constituents with strong CYP3A inhibitory activity. The inhibitory mechanism of oleanonic acid (the most potent CYP3A inhibitor occurring in Styrax) against CYP3A4 was investigated by a panel of inhibition kinetics analyses and in silico analysis. RESULTS: In vitro assays demonstrated that Styrax extract strongly inhibited human CYP3A and moderately inhibited six other tested human CYPs, as well as potently inhibited warfarin 10-hydroxylation in liver microsomes from both humans and rats. In vivo assays demonstrated that compared with warfarin given individually in rats, Styrax (100 mg/kg) significantly prolonged the plasma half-life of warfarin by 2.3-fold and increased the AUC(0-inf) of warfarin by 2.7-fold when this herb was co-administrated with warfarin (2 mg/kg) in rats. Two LC fractions were found with strong CYP3A inhibitory activity and the major constituents in these fractions were characterized by LC-TOF-MS/MS. Five pentacyclic triterpenoid acids (including epibetulinic acid, betulinic acid, betulonic acid, oleanonic acid and maslinic acid) present in Styrax were potent CYP3A inhibitors, and oleanonic acid was a competitive inhibitor against CYP3A-mediated testosterone 6ß-hydroxylation. CONCLUSION: Styrax and the pentacyclic triterpenoid acids occurring in this herb strongly modulate the pharmacokinetic behavior of warfarin via inhibition of CYP3A.

Pancreatic lipase inhibitory constituents from Fructus Psoraleae.

Pancreatic lipase (PL), a crucial enzyme in the digestive system of mammals, has been proven as a therapeutic target to prevent and treat obesity. The purpose of this study is to evaluate and characterize the PL inhibition activities of the major constituents from Fructus Psoraleae (FP), one of the most frequently used Chinese herbs with lipid-lowering activity. To this end, a total of eleven major constituents isolated from Fructus Psoraleae have been obtained and their inhibition potentials against PL have been assayed by a fluorescence-based assay. Among all tested compounds, isobavachalcone, bavachalcone and corylifol A displayed strong inhibition on PL (IC50 < 10 µmol·L-1). Inhibition kinetic analyses demonstrated that isobavachalcone, bavachalcone and corylifol A acted as mixed inhibitors against PL-mediated 4-methylumbelliferyl oleate (4-MUO) hydrolysis, with the Ki values of 1.61, 3.77 and 10.16 µmol·L-1, respectively. Furthermore, docking simulations indicated that two chalcones (isobavachalcone and bavachalcone) could interact with the key residues located in the catalytic cavity of PL via hydrogen binding and hydrophobic interactions. Collectively, these finding provided solid evidence to support that Fructus Psoraleae contained bioactive compounds with lipid-lowering effects via targeting PL, and also suggested that the chalcones in Fructus Psoraleae could be used as ideal leading compounds to develop novel PL inhibitors.

Pharmacokinetic interaction between a Chinese herbal formula Huosu Yangwei oral liquid and apatinib in vitro and in vivo.

OBJECTIVES: This study aimed to evaluate the inhibitory effects of Huosu Yangwei oral liquid (HSYW) on cytochrome P450 enzymes (CYPs) and to investigate whether this herbal medicine could modulate the pharmacokinetic behaviour of the co-administered CYP-substrate drug apatinib. METHODS: Cytochrome P450 enzymes inhibition assays were conducted in human liver microsomes (HLM) by a LC-MS/MS method for simultaneous determination of the oxidative metabolites of eight probe substrates for hepatic CYPs. The modulatory effects of HSYW on the oxidative metabolism of apatinib were investigated in both HLM and rat liver microsomes (RLM). The influences of HSYW on the pharmacokinetic behaviour of apatinib were investigated in rats. KEY FINDINGS: Huosu Yangwei oral liquid inhibited all tested CYPs in human liver preparations, with the IC50 values ranged from 0.3148 to 2.642 mg/ml. HSYW could also inhibit the formation of two major oxidative metabolites of apatinib in liver microsomes from both human and rat. In-vivo assays demonstrated that HSYW could significantly prolong the plasma half-life of apatinib by 7.4-fold and increase the AUC0-inf (nm·h) of apatinib by 43%, when HSYW (10 ml/kg) was co-administered with apatinib (10 mg/kg) in rats. CONCLUSIONS: Huosu Yangwei oral liquid could inhibit mammalian CYPs and modulated the metabolic half-life of apatinib both in vitro and in vivo.

Interspecies variation of clopidogrel hydrolysis in liver microsomes from various mammals.

Clopidogrel, a clinically used antiplatelet agent, can be readily hydrolyzed by human carboxylesterase 1A (CES1A) to release an inactive metabolite clopidogrel carboxylic acid (CCA). In this study, clopidogrel was used as a tool substrate to investigate the interspecies variation of clopidogrel hydrolysis in hepatic microsomes from various mammals including human and six laboratory animals (such as mouse, rat, rabbit, beagle dog, minipig and cynomolgus monkey). The results demonstrated that clopidogrel could be hydrolyzed into CCA by all tested hepatic microsomes from human or other mammals, but the hydrolytic rates greatly varied among species. Inhibition assays demonstrated that BNPP (an inactivator of mammalian CES) strongly inactivated clopidogrel hydrolytic activity in all tested hepatic microsomes, suggested that mammalian CES were major contributor(s) responsible for clopidogrel hydrolysis in hepatic preparations from all above-mentioned species. By contrast, the response of a reversible inhibitor of human CES1A on clopidogrel hydrolysis in these liver preparations varied significantly among different species. Moreover, the enzymatic kinetics and the apparent kinetic parameters of clopidogrel hydrolysis in hepatic microsomes from various animal species were evaluated and compared to each other. These findings provide crucial information for deeply understanding the differences in catalytic behaviors of mammalian CES, which will be very helpful for choosing suitable laboratory animal(s) for whole tests of CES1A substrate-drugs.

Interactions of drug-metabolizing enzymes with the Chinese herb Psoraleae Fructus.

Psoraleae Fructus (the dried fruits of Psoralea corylifolia), one of the most frequently used Chinese herbs in Asian countries, has a variety of biological activities. In clinical settings, Psoraleae Fructus or Psoraleae Fructus-related herbal medicines frequently have been used in combination with a number of therapeutic drugs for the treatment of various human diseases, such as leukoderma, rheumatism and dysentery. The use of Psoraleae Fructus in combination with drugs has aroused concern of the potential risks of herb-drug interactions (HDI) or herb-endobiotic interactions (HEI). This article reviews the interactions between human drug-metabolizing enzymes and the constituents of Psoraleae Fructus; the major constituents in Psoraleae Fructus, along with their chemical structures and metabolic pathways are summarized, and the inhibitory and inductive effects of the constituents in Psoraleae Fructus on human drug-metabolizing enzymes (DMEs), including target enzyme(s), its modulatory potency, and mechanisms of action are presented. Collectively, this review summarizes current knowledge of the interactions between the Chinese herb Psoraleae Fructus and therapeutic drugs in an effort to facilitate its rational use in clinical settings, and especially to avoid the potential risks of HDI or HEI through human DMEs.

Discovery of a highly specific and efficacious inhibitor of human carboxylesterase 2 by large-scale screening.

Human carboxylesterase 2 (CES2A), one of the most abundant hydrolases distributed in human small intestine and colon, play key roles in the hydrolysis of a wide range of prodrugs and other esters. Recent studies have demonstrated that CES2A inhibitors may ameliorate irinotecan-induced severe diarrhea, but the specific and efficacious inhibitors targeting intracellular CES2A are rarely reported. Herein, a large-scale screening campaign was conducted for discovery of potent and specific CES2A inhibitor(s). Following screening of more than one hundred of natural products, glabridin (a bioactive compound of Glycyrrhiza glabra L.) was found displaying potent inhibition on CES2A and high specificity over CES1A (>500-fold) and other serine hydrolases. Further investigation showed that glabridin was cell permeable and low cytotoxic, as well as capable of inhibiting intracellular CES2A in living cells, with the IC50 value of 0.52 µM. Molecular dynamics simulations showed that glabridin formed strong and stable interactions with both the catalytic cavity and Z site of CES2A via hydrophobic interactions. In summary, glabridin was a potent and specific inhibitor targeting intracellular CES2A, which could be used as an ideal lead compound to develop more efficacious CES2A inhibitors for modulating the pharmacokinetic behaviors of CES2A-substrate drugs and alleviating irinotecan-induced diarrhea.

Inhibition of human carboxylesterases by magnolol: Kinetic analyses and mechanism.

Magnolol, the most abundant bioactive constituent of the Chinese herb Magnolia officinalis, has been found with multiple biological activities, including anti-oxidative, anti-inflammatory and enzyme-regulatory activities. In this study, the inhibitory effects and inhibition mechanism of magnolol on human carboxylesterases (hCEs), the key enzymes responsible for the hydrolytic metabolism of a variety of endogenous esters as well as ester-bearing drugs, have been well-investigated. The results demonstrate that magnolol strongly inhibits hCE1-mediated hydrolysis of various substrates, whereas the inhibition of hCE2 by magnolol is substrate-dependent, ranging from strong to moderate. Inhibition of intracellular hCE1 and hCE2 by magnolol was also investigated in living HepG2 cells, and the results showed that magnolol could strongly inhibit intracellular hCE1, while the inhibition of intracellular hCE2 was weak. Inhibition kinetic analyses and docking simulations revealed that magnolol inhibited both hCE1 and hCE2 in a mixed manner, which could be partially attributed to its binding at two distinct ligand-binding sites in each carboxylesterase, including the catalytic cavity and the regulatory domain. In addition, the potential risk of the metabolic interactions of magnolol via hCE1 inhibition was predicted on the basis of a series of available pharmacokinetic data and the inhibition constants. All these findings are very helpful in deciphering the metabolic interactions between magnolol and hCEs, and also very useful for avoiding deleterious interactions via inhibition of hCEs.

Combining differential expression and differential coexpression analysis identifies optimal gene and gene set in cervical cancer.

OBJECTIVE: The objective of this study is to investigate the optimal gene and functional-related gene set in cervical cancer through combing the differential expression (DE) and differential coexpression (DC) analysis. MATERIALS AND METHODS: To achieve this, we first measured expression data of cervical cancer by incorporating DE and DC effects utilizing absolute t-value in t-statistic and Z-test, respectively. Then, we selected the optimal threshold pair to determine both high DE and high DC (HDE_HDC) partition on the basis of Chi-square maximization, and the best threshold pair divided all genes into four parts, including HDE_HDC, high DE and low DC (HDE_LDC), low DE and high DC (LDE_HDC), and low DE and low DC (LDE_LDC). Using the known functional gene sets, functional relevance of partition genes was explored to determine the best-associated gene set based on the functional information (FI) conception. RESULTS: Under the optimal threshold pair of 3.629 and 1.108 for DE and DC, respectively genes were divided into four partitions: HDE_HDC (311 genes), HDE_LDC (2072 genes), LDE_HDC (seventy genes), and LDE_LDC (1623 genes). Meanwhile, the gene set epidermis development was the best-associated gene set with the largest △G* = 10.496. Among the genes of epidermis development, zinc finger protein 135 (ZNF135) attained highest minimum FI gain of 41.226. CONCLUSION: The combination of DE and DC analysis showed higher mean FI relative to individual DE and DC analyses. We successfully exhibited the optimal gene set epidermis development and gene ZNF135, which might be crucial for the prevention and treatment of cervical cancer.

Understanding the role of CD44V6 in ovarian cancer.

This study examined the association of CD44V6 expression in ovarian cancer. We recruited 38 patients with ovarian cancer, 23 with benign ovarian tumor, and 20 with normal ovaries using RT-PCR and western block analysis. Compared with normal ovaries, the expression of CD44V6 mRNA was significantly elevated in benign ovarian tumor and ovarian cancer. At the protein level, we found no significant differences in CD44V6 expression between normal ovarian tissue and benign ovarian tumor. However, the expression of CD44V6 in ovarian cancer was significantly elevated compared to normal ovaries and benign ovarian tumor. These results were supported by ELISA and western blot analysis. Immunohistochemistry showed that CD44V6 protein in ovarian cancer cells accumulated at high levels on the membrane of ovarian cancer cells. CD44V6 expression is closely associated with the tumorous transformation of ovarian tissue, suggesting that CD44V6 can promote the occurrence and progression of ovarian cancer.

Influence of two kinds of preoperative examinations methods on detection rate of peritoneal cytology and the survival rate of patients with endometrial carcinoma / 中国内镜杂志

Objective To investigate the influence of curettage of uterine cavity and hysteroscopy detection before operation on detection rate of abdominal cavity and the survival rate of patients with endometrial carcinoma. Methods 120 patients with endometrial carcinoma were chosen in the period from March 2011 to December 2013 were divided into 2 groups including curettage of uterine cavity group (64 patients) with curettage of uterine cavity and hysteroscopy group (56 patients) with hysteroscopy detection according to preoperative examinations methods; and the eligible rate of specimens, the concordance rate of pathological diagnosis, the detection rate of peritoneal cytology, the overall survival rate and progression free survival rate in 3 years with follow-up of both groups were compared. Results There was no significant difference in the eligible rate of specimens and the concordance rate of pathological diagnosis between the two groups (P > 0.05). The detection rate of ascites cytology of hysteroscopy group were significantly higher than curettage of uterine cavity group (P < 0.05). There was no significant difference in the overall survival rate and progression free survival rate in 3 years with follow-up between the two groups (P > 0.05). Conclusion Curettage of uterine cavity and hysteroscopy detection before operation on patients with endometrial carcinoma posses the same diagnosis value; And hysteroscopy detection maybe peritoneal metastasis risk, but have no effect on long-term survival and larger randomized controlled trials should be necessary.

Influence of two kinds of preoperative examinations methods on detection rate of peritoneal cytology and the survival rate of patients with endometrial carcinoma / 中国内镜杂志

Objective To investigate the influence of curettage of uterine cavity and hysteroscopy detection before operation on detection rate of abdominal cavity and the survival rate of patients with endometrial carcinoma. Methods 120 patients with endometrial carcinoma were chosen in the period from March 2011 to December 2013 were divided into 2 groups including curettage of uterine cavity group (64 patients) with curettage of uterine cavity and hysteroscopy group (56 patients) with hysteroscopy detection according to preoperative examinations methods; and the eligible rate of specimens, the concordance rate of pathological diagnosis, the detection rate of peritoneal cytology, the overall survival rate and progression free survival rate in 3 years with follow-up of both groups were compared. Results There was no significant difference in the eligible rate of specimens and the concordance rate of pathological diagnosis between the two groups (P > 0.05). The detection rate of ascites cytology of hysteroscopy group were significantly higher than curettage of uterine cavity group (P < 0.05). There was no significant difference in the overall survival rate and progression free survival rate in 3 years with follow-up between the two groups (P > 0.05). Conclusion Curettage of uterine cavity and hysteroscopy detection before operation on patients with endometrial carcinoma posses the same diagnosis value; And hysteroscopy detection maybe peritoneal metastasis risk, but have no effect on long-term survival and larger randomized controlled trials should be necessary.

Angelica sinensis suppresses human lung adenocarcinoma A549 cell metastasis by regulating MMPs/TIMPs and TGF-ß1.

In this study we investigated the potential effects of Angelica sinensis on the growth and metastasis in human lung adenocarcinoma A549 cells. In vitro the Cck-8 assays showed that Angelica sinensis had weak antiproliferative effect on A549 cells only at high concentration. The cell adhesion assay showed that Angelica sinensis decreased the adhesive ability of A549 cells in a dose- and time-dependent manner. Transwell invasion and migration assay showed that Angelica sinensis reduced the invasive and migratory abilities of A549 cells in a dose-dependent manner. In vivo the animal experiments showed that Angelica sinensis suppressed lung metastasis of nude mice at high concentration. Then, we attempted to clarify the mechanisms of anti-metastatic activities of Angelica sinensis. The results showed Angelica sinensis inhibited the enzymatic activity of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), it involved the down-regulation of the expressions of MMP-2 and MMP-9 at both the protein and mRNA levels, which may be associated with Angelica sinensis suppressing the expression of TGF-ß1. It also involved the increase of the tissue inhibitors of metalloproteinases TIMP-2, but TIMP-1 decreased upon incubation of A549 cells with Angelica sinensis. The results suggest that Angelica sinensis might exert anti-growth and anti-metastasis activity against lung cancer cells through the decrease of MMP-2, MMP-9, TGF-ß1 and TIMP-1 and increase of TIMP-2.