Five-Flavor Sophora flavescens Enteric-Coated Capsules for Ulcerative Colitis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Ulcerative colitis (UC), a chronic inflammatory bowel disease, is characterized by abdominal pain, diarrhea, and mucopurulent bloody stool. In recent years, the incidence and prevalence of UC have been increasing consistently. Five-flavor Sophora falvescens enteric-coated capsule (FSEC), a licensed Chinese patent medicine, was specifically used to treat UC. This review was aimed to assess the effectiveness and safety of FSEC for the treatment of UC. METHODS: Six electronic databases were searched from inception to March 2021. Randomized clinical trials (RCTs) comparing FSEC or FSEC plus conventional Western medicine with conventional Western medicine in participants with UC were included. Two authors screened all references, assessed the risk of bias, and extracted data independently. Binary data were presented as risk ratios (RRs) with 95% confidence intervals (CIs) and metric data as mean difference (MD) with 95% CI. The overall certainty of the evidence was assessed by GRADE. RESULTS: We included 15 RCTs (1194 participants, 763 in the FSEC group and 431 in the control group). The treatment duration ranged from 42 to 64 days. Twelve trials compared FSEC with conventional Western medicine, and two trials compared FSEC plus conventional medicine with conventional medicine. Another trial compared FSEC plus mesalazine with compound glutamine enteric capsules plus mesalazine. FSEC showed a higher clinical effective rate (improved clinical symptoms, colonoscopy results, and stools) (RR 1.12, 95% CI 1.05 to 1.20; 729 participants; 8 trials; low-quality evidence) as well as the effective rate of traditional Chinese medicine (TCM) syndromes (RR 1.10, 95% CI 1.01 to 1.20; 452 participants; 5 trials; low-quality evidence) compared to mesalazine. There was no significant difference in the adverse events between FSEC and control groups. CONCLUSIONS: FSEC may show effectiveness in UC treatment compared to conventional medicine, and the use of FSEC may not increase the risk of adverse events. Due to the limited number of clinical trials and low methodological quality of the included trials, our findings must be interpreted with discretion.

Efficacy and safety of ciprofol for agitation and delirium in the ICU: A multicenter, single-blind, 3-arm parallel randomized controlled trial study protocol.

Background: Agitation is very common in the intensive care unit (ICU). The causes include pain, delirium, underlying disease, withdrawal syndrome, and some drug treatments. The practical goal of ICU treatment is to find an appropriate sedation regimen to reduce pain, restlessness, and delirium. Previous trials have examined the use of dexmedetomidine, but no trials have evaluated the efficacy and safety of ciprofol, a new sedative drug. Methods: This study was a multicenter, single-blind, 3-arm parallel randomized controlled trial. ICU patients aged ≥ 18 years with agitation and delirium who met the eligibility criteria were included. The main outcome was the proportion of patients who needed additional study medication or midazolam due to agitation within 4 h after the first intravenous injection of the study medication. The secondary outcomes included the pass rate as indicated by a Richmond Agitation-Sedation Scale (RASS) score < +1, the effectiveness rate of improving delirium symptoms, the number of recurrences of agitation within 24 h, the incidence of rescue treatment, the dose and cost of analgesic and sedative drugs, the length and cost of ICU stay, and the 30-day survival period. The safety evaluation included the incidence of adverse events (hypotension, bradycardia, hypoxia, etc.) and the rate of endotracheal intubation. The subjects were randomly assigned to receive ciprofol, dexmedetomidine, or normal saline at a ratio of 1:1:1. The rates of additional drug administration within 4 h after the first injection of the study drug in the three groups were 40, 50, and 90%, respectively. A total sample size of 81 subjects was required to reach 90% power and an α of 0.05. Considering a 20% loss rate, 102 patients were enrolled and randomly assigned to the three groups in equal proportions. Ethics and communication: This trial was approved by the Ethics Committee of Dalian Municipal Central Hospital. The communication plan includes presentations at scientific conferences, scientific publications, and presentations to the public through non-professional media. Clinical trial registration: www.ClinicalTrials.gov, identifier ChiCTR220006 2799.

Effects of exercise on pregnancy and postpartum fatigue: A systematic review and meta-analysis.

OBJECTIVE: Fatigue is a common adverse experience in pregnant and postpartum women and is associated with poor outcomes and can seriously affect maternal and infant health and quality of life. However, data from existing studies are inconsistent, and no studies have examined the effects of exercise on pregnancy and postpartum fatigue. The aim of this review is to evaluate the effects of exercise on pregnancy and postpartum fatigue. STUDY DESIGN: PubMed, EMBASE, Web of Science and the Cochrane Library database were used to retrieve literature. Eligible studies were clinical trials that reported the effects of exercise on pregnancy and postpartum fatigue in women. The methodological quality of the included studies was assessed using the Cochrane Collaboration Risk of Bias Assessment Tool. A fixed-effect model was used to analyse the pooled results. Subgroup analyses were used to explore sources of heterogeneity. Sensitivity analysis was used to validate the robustness of the pooled results. RESULTS: Seven studies were included. The results of meta-analysis of five studies showed that exercise during pregnancy and the postpartum period may have beneficial effects on women's fatigue ([SMD = 0.29, 95 % CI (0.10, 0.47), P = 0.003]). Subgroup analyses reported that compared with the control, long exercise programmes, postpartum exercise and supervised exercise significantly improved fatigue levels. CONCLUSIONS: Postpartum exercise in a supervised programme lasting more than eight weeks may be beneficial for reducing postpartum fatigue. More available data from large-scale and high-quality trials are needed to demonstrate the effects of exercise on pregnant and postpartum fatigue.

The effectiveness of massage on peri-operative anxiety in adults: A meta-analysis of randomized controlled trials and controlled clinical trials.

BACKGROUND AND PURPOSE: and purpose: Massage has gained increasing attention for reducing peri-operative anxiety. We aimed to investigate the effectiveness of massage for peri-operative anxiety in adults. METHODS: Six English electronic databases were comprehensively searched from their inception to February 2020. Subgroup analysis, quality assessment, sensitivity analysis, meta-regression and publication bias assessment were performed. RESULTS: Twenty-five controlled trials comprising 2494 participants were included. The meta-analysis indicated that massage could significantly reduce peri-operative anxiety for most types of surgical patients. Specifically, it was effective for pre-, intra- and post-operative anxiety. Acupoint or specific body reflex area massage showed a larger effect than general massage did. Massage delivered by professionals and non-professionals were both effective. Massage lasting 10-20 min per session was the most worthy of recommendation. Massage was concomitant with the improvement of peri-operative vital signs and post-operative pain. CONCLUSION: Massage is a promising complementary therapy for ameliorating peri-operative anxiety in adults.

Psychometric properties of the Breast Cancer Awareness Measurement among Chinese women: a cross-sectional study.

OBJECTIVES: To perform the cross-cultural adaption of the Breast Cancer Awareness Measurement (BCAM) and to test its psychometric properties among Chinese women. DESIGN: This is a cross-sectional study. SETTINGS: This study was conducted in communities, schools and institutions in Changchun, Jilin Province, China. PARTICIPANTS: A total of 328 women voluntarily participated in and completed the Chinese version of the BCAM (C-BCAM), resulting in an effective response rate of 91.1%. PRIMARY AND SECONDARY OUTCOME MEASURES: Psychometric properties, including item analysis (the extreme group comparison and item-total correlations), content validity (item-level content validity index (I-CVI) and scale-level content validity index (S-CVI)), construct validity (exploratory factor analysis (EFA) and confirmatory factor analysis (CFA)) and internal consistency (Cronbach's α and test-retest reliability), were measured. RESULTS: The C-BCAM has excellent internal consistency (Cronbach's α=0.90), with alpha coefficients of 0.88, 0.84 and 0.94 for its three domains. The test-retest reliability coefficient was 0.72. The I-CVI ranged from 0.86 to 1.00, and the S-CVI was 0.92. CFA showed that the three-factor model explained 51.56% of the total variance, with a good model fit (likelihood ratio χ2/df=1.86, incremental fit index=0.94, comparative fit index=0.94, goodness-of-fit index=0.84, adjusted goodness-of-fit index=0.80, standardised root mean square error of approximation=0.06 and root mean square residual=0.05). CONCLUSIONS: The C-BCAM has satisfactory validity and reliability and is a culturally appropriate and reliable tool for evaluating breast cancer awareness among Chinese women. This reliable instrument can help researchers and health professionals evaluate women's knowledge about the symptoms and risk factors of breast cancer and identify their barriers to seeking medical help. It also helps healthcare providers identify women with poor breast cancer awareness and encourage them to perform screening practice.

Complementary and alternative medicine for natural and treatment-induced vasomotor symptoms: An overview of systematic reviews and meta-analyses.

BACKGROUND AND PURPOSE: Vasomotor symptoms (VMS) are very common in menopausal populations and cancer patients and can cause physical and mental discomfort. We aim to summarize the findings of systematic reviews and meta-analyses (SRs/MAs) that assessed the effectiveness of complementary and alternative medicines(CAMs)on VMS to provide solid evidence for future practice. METHODS: PubMed, Embase, the Cochrane Library, and Web of Science were searched from inception to May 2019 to identify relevant SRs/MAs. The methodological quality of SRs/MAs and evidence levels of the outcomes were assessed. RESULTS: A total of 29 SRs/MAs were reviewed. Evidence has shown that acupuncture, hypnosis, paced respiration, cognitive behavioural therapy, genistein, soy isoflavones, S-equol, combined preparations of black cohosh, and omega-3 supplements could significantly reduce VMS. The methodological quality of the SRs/MAs was moderate or high. CONCLUSION: CAMs might be beneficial for reducing VMS, but the evidence levels were not high. Several priorities for future practice were identified.

Tools for the assessment of breast cancer screening beliefs in women: a literature review.

Aim: This review aims to compare the development, characteristics and validity of three widely used breast cancer screening belief tools (the Champion's Health Belief Model Scale [CHBMS], the Breast Module of a Cancer Awareness Measures [BCAM] and the Breast Cancer Screening Beliefs Questionnaire [BCSBQ]). Materials & methods: Literature reports were retrieved from electronic databases, including PubMed, EMBASE, Web of Science and the Cochrane Library, and other references. All three tools had good reliability and validity. Certain significant differences between these tools should be noted. Results: CHBMS, BCAM and BCSBQ are valid and reliable instruments within certain populations. Due to the high heterogeneity among the targeted population, their characteristics and those of the instruments should be fully considered for clinical decision-making. Conclusion: The conclusion of this review contributes to the development of a more comprehensive and objective instruments based on the deficiencies of the existing studies.

Effects of exercise on pregnant women's quality of life: A systematic review.

OBJECTIVES: Exercise is a promising approach to improve the health of pregnant women. However, data from studies investigating exercise and the quality of life of pregnant women are inconsistent and, to date, no systematic review on this topic has been published. The aim of this review was to comprehensively assess the effects of exercise on pregnant women's quality of life, and to determine whether exercise positively affects quality of life in this population. STUDY DESIGN: Literature was retrieved from electronic databases, namely PubMed, EMBASE, Web of Science and the Cochrane Library, from inception to 30 October 2018. Clinical trials published in English evaluating the effects of exercise on pregnant women's quality of life were included. The authors assessed the risk of bias in all eligible studies using the Effective Public Health Practice Project, and used a qualitative synthesis method to identify the effects of exercise on pregnant women's quality of life. RESULTS: Thirteen studies were included. Exercise was divided into the following four modes: aerobic exercise, resistance exercise, a combination (aerobic and resistance exercises), and yoga or physical activity. Aerobic and resistance training had a mixed effect on pregnant women's quality of life, while the combination of aerobic and resistance exercises and yoga or physical activity resulted in significant improvements. CONCLUSIONS: This systematic review is the first to suggest that group-based combined exercise and yoga or physical activity are associated with significant benefits related to improvements in pregnant women's quality of life. Furthermore, aerobic or resistance exercise could potentially improve pregnant women's quality of life. Therefore, it is recommended that medical service providers should pay more attention to the importance of exercise, and develop tailored exercise programmes to promote improvements in pregnant women's quality of life.

Daidzein stimulates osteogenesis facilitating proliferation, differentiation, and antiapoptosis in human osteoblast-like MG-63 cells via estrogen receptor-dependent MEK/ERK and PI3K/Akt activation.

Daidzein, a natural soy isoflavone, has a structure similar to estradiol and exhibiting bone-sparing effects against osteoporosis. However, the molecular mechanisms of osteogenesis remain unclear. We hypothesized that daidzein stimulates osteogenesis through estrogen receptor (ER)-dependent signal pathways. To test this hypothesis, we investigated the effects of daidzein compared with 17ß-estradiol on proliferation, differentiation, and cisplatin-induced apoptosis in human osteoblast-like MG-63 cells containing 2 ER isoforms. The results showed that daidzein stimulated cell proliferation by altering cell cycle distribution, promoted cell differentiation by increasing the alkaline phosphatase activity and collagen content, and reduced cell apoptosis associated by up-regulating the expression of Bcl-xL. The above actions of daidzein were prevented by cotreatment with the ER antagonist ICI 182780. Using small interfering RNA technology, we further demonstrated that the effects of daidzein on alkaline phosphatase activity, collagen content, and cell apoptosis are mediated by both ERα and ERß, whereas the effects on cell proliferation are primarily mediated by ERα. However, the effects of 17ß-estradiol on osteoblastic proliferation and survival are mediated by both ER isotypes, and the effects on osteoblastic differentiation are primarily mediated by ERα. The use of specific inhibitors indicated that activation of the mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK/ERK) and phosphoinositide 3-kinase/protein kinase B or PKB (PI3K/Akt) signaling pathway at least partially accounts for these effects of daidzein. Taken together, the results indicate that daidzein stimulates osteogenesis through facilitating proliferation, differentiation, and antiapoptosis in human osteoblast-like MG-63 cells via activation of MEK/ERK and PI3K/Akt in an ER-dependent manner.

Daidzein increases OPG/RANKL ratio and suppresses IL-6 in MG-63 osteoblast cells.

Daidzein is a major dietary source of isoflavones found in Leguminosae, and belongs to the family of diphenolic compounds. The estrogenic effects of daidzein to prompt bone formation and prevent bone resorption have been observed in animal models and cultured cells. In our study, we studied the effects of daidzein, raloxifene and E2 on expression of the osteoblast-produced bone regulatory factors OPG, RANKL and IL-6 in human osteoblastic MG-63 cells. Results suggest that treatment with daidzein, raloxifene and E2 increased the levels of OPG and decreased those of RANKL and IL-6. The effects of daidzein on OPG and RANKL expression are mediated by both ERα and ERß but those on IL-6 production primarily by ERα. Moreover, daidzein may promote activation of the classic estrogen response element (ERE) pathway through increasing ERα, ERß and steroid hormone receptor coactivator (SRC)-1 expression. E2 was also able to enhance transcription derived from the ERE, while raloxifene has no effect on it. Raloxifene increased ERα protein and gene expression levels but had no effect on ERß protein and gene expression at 0.1µM. E2 was found significantly increased the protein and mRNA levels of SRC-1, while raloxifene has no effect on it compared with control. This ability of daidzein to affect osteoblastic cells makes it a good candidate for the treatment of bone loss in postmenopausal women.

Identification of C-type lectin-domain proteins (CTLDPs) in silkworm Bombyx mori.

C-type lectins (CTLs) represent a large family of proteins that can bind carbohydrate moieties normally in a calcium-dependent manner. CTLs play important roles in mediating cell adhesion and the recognition of pathogens in the immune system. In the present study, we have identified 23 CTL genes in domestic silkworm Bombyx mori. CTL-domain proteins (CTLDPs) are classified into three groups based on the number of carbohydrate-recognition domains (CRDs) and the domain architectures. These include twelve CTL-S (Single-CRD), six immulectins (Dual-CRD) and five CTL-X (CRD with other domains). We studied their phylogenetic features, analyzed the conserved residues, predicted tertiary structures, and examined the tissue expression profile and immune inducibility. Through bioinformatics analysis, we have putatively identified ten secretory and two cytoplasmic CTL-S; four secretory and two cytoplasmic immulectins; one secretory, one cytoplasmic and three transmembrane forms of CTL-X. Most B. mori CTLDPs form monophyletic groups with orthologs from Lepidoptera, Diptera, Coleoptera and Hymenoptera species. Immulectins of B. mori and Manduca sexta evolved from common ancestor genes perhaps due to gene duplication events of CTL-S ancestor genes. Homology modeling revealed that the overall structures of B. mori CTL domains are analogous to those of humans with a variable loop region. We examined the expression profile of CTLDP genes in naïve and immune-stimulated tissues. The expression and induction of CTLDP genes were related to the tissues and microorganisms. Together, our gene identification, sequence comparison, phylogenetic analysis, homology modeling and expression analysis laid a good foundation for the further studies of B. mori CTLDPs and comparative genomics.

Puerarin concurrently stimulates osteoprotegerin and inhibits receptor activator of NF-κB ligand (RANKL) and interleukin-6 production in human osteoblastic MG-63 cells.

Puerarin, a daidzein-8-C-glucoside, is the major isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.) Ohwi, and has received increasing attention because of its possible role in the prevention of osteoporosis. In our previous studies, puerarin reduced the bone resorption of osteoclasts and promoted long bone growth in fetal mouse in vitro. Further study confirmed that puerarin stimulated proliferation and differentiation of osteoblasts in rat. However, the mechanisms underlying its actions on human bone cells have remained largely unknown. Here we show that puerarin concurrently stimulates osteoprotegerin (OPG) and inhibits receptor activator of nuclear factor-κB ligand (RANKL) and Interleukin-6 (IL-6) production by human osteoblastic MG-63 cells containing two estrogen receptor (ER) isotypes. Treatment with the ER antagonist ICI 182,780 abrogates the above actions of puerarin on osteoblast-derived cells. Using small interfering double-stranded RNAs technology, we further demonstrate that the effects of puerarin on OPG and RANKL expression are mediated by both ERα and ERß but those on IL-6 production primarily by ERα. Moreover, we demonstrate that puerarin may promote activation of the classic estrogen response element (ERE) pathway through increasing ERα, ERß and steroid hormone receptor coactivator (SRC)-1 expression. Therefore, puerarin will be a promising agent that prevents or retards osteoporosis.

Puerarin stimulates proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells via ER-dependent MEK/ERK and PI3K/Akt activation.

Puerarin, the main isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.) Ohwi, has received increasing attention because of its possible role in the prevention of osteoporosis. Previously, we showed that puerarin could inhibit the bone absorption of osteoclasts and promote long bone growth in fetal mouse in vitro. Further study confirmed that puerarin stimulated proliferation and differentiation of osteoblasts in rat. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that puerarin increases proliferation and differentiation and opposes cisplatin-induced apoptosis in human osteoblastic MG-63 cells containing two estrogen receptor (ER) isoforms. Puerarin promotes proliferation by altering cell cycle distribution whereas puerarin-mediated survival may be associated with up-regulation of Bcl-xL expression. Treatment with the ER antagonist ICI 182,780 abolishes the above actions of puerarin on osteoblast-derived cells. Using small interfering double-stranded RNA technology, we further demonstrate that the effects of puerarin on proliferation, differentiation and survival are mediated by both ERα and ERß. Moreover, we also demonstrate that puerarin functions at least partially through activation of MEK/ERK and PI3K/Akt signaling. This agent also shows much weaker effect on breast epithelial cell growth than that of estrogen. Therefore, puerarin will be a promising agent that prevents or retards osteoporosis.

Effects of lifestyle intervention and meal replacement on glycaemic and body-weight control in Chinese subjects with impaired glucose regulation: a 1-year randomised controlled trial.

The purpose of the present study was to evaluate the impact of a lifestyle intervention programme, combined with a daily low-glycaemic index meal replacement, on body-weight and glycaemic control in subjects with impaired glucose regulation (IGR). Subjects with IGR were randomly assigned to an intervention group (n 46) and a control group (n 42). Both groups received health counselling at baseline. The intervention group also received a daily meal replacement and intensive lifestyle intervention to promote healthy eating habits during the first 3 months of the study, and follow-up visits performed monthly until the end of the 1-year study. Outcome measurements included changes in plasma glucose, glycated Hb (HbA1c), plasma lipids, body weight, blood pressure and body composition (such as body fat mass and visceral fat area). The results showed that body-weight loss after 1 year was significant in the intervention group compared with the control group (-1·8 (SEM 0·35) v. -0·6 (SEM 0·40) 2·5 kg, P<0·05). The 2 h plasma glucose concentration decreased 1·24 mmol/l in the intervention group and increased 0·85 mmol/l in the control group (P<0·05) compared with their baseline, respectively. A 5 kg body-weight loss at 1 year was associated with a decrease of 1·49 mmol/l in 2 h plasma glucose (P<0·01). The incidence of normal glucose regulation (NGR) in the two groups was significantly different (P=0·001). In conclusion, the combination of regular contact, lifestyle advice and meal replacement is beneficial in promoting IGR to NGR.

The antitumor activity of recombinant antitumor antiviral protein and the associated molecular mechanism in pancreatic tumor cells.

BACKGROUND: Pancreatic cancer has poor prognosis and high mortality. Currently, the therapy of pancreatic cancer remains a challenge. In this study, we compared the antitumor activity of the recombinant antitumor antiviral protein (RAAP), an improved interferon, with gemcitabine, a classic chemotherapy agent used for pancreatic cancer treatment. METHODS: The proliferation of Bx-PC3 pancreatic cancer cells was evaluated by an MTT assay. Cell cycle arrest and apoptosis were evaluated by flow cytometry and annexin V-FITC/propidium iodide double staining, respectively. The expressions of matrix metalloproteinase (MMP)-2, MMP-9, caspase-3, caspase-8, and caspase-9 genes were evaluated by reverse transcription-polymerase chain reaction and the Western blot analysis. A xenograft pancreatic cancer model was established by inoculating Bx-PC3 cells into athymic nude mice. The antitumor activity of RAAP and gemcitabine was tested in the xenograft tumor model. RESULTS: RAAP significantly inhibited proliferation, induced cell cycle arrest, and induced apoptosis in Bx-PC3 cells in vitro and delayed tumor growth in vivo. The antitumor activity of 20 ng/mL of RAAP was a little more effective than 10 µM of gemcitabine. The antitumor activity of RAAP was associated with its role in inducing caspase-3 and caspase-8 expression as well as downregulating MMP-2 expression. CONCLUSIONS: RAAP can effectively suppress human pancreatic cancer cell growth in vitro and in vivo. The antitumor efficacy of RAAP is similar to gemcitabine.

[Meta-analysis of the efficacy between gemcitabine-alone and gemcitabine-based chemotherapy applied in advanced pancreatic cancer].

OBJECTIVE: To compare the efficacy of gemcitabine (GEM) alone and gemcitabine based combination chemotherapy (GEMCOM) on advanced pancreatic cancer. METHODS: Keywords Phase III, gemcitabine and pancreatic cancer were used to search and collect Phase III-randomized references about gemcitabine and gemcitabine-based combination chemotherapy applied on advanced pancreatic cancer. A references-based meta-analysis was made to compare the efficacy between GEM and GEMCOM. Before that, test for heterogeneity was committed. Fixed effect model was used if the I(2) ≤ 50%, and random effect model was used if not. The evaluating indicators were overall response rate and 1-year survival rate. RESULTS: There were 14 randomized controlled trial (RCT) and 10 RCT enrolled in overall response rate analysis and 1-year survival rate analysis, respectively. Results of meta-analysis showed that, arm GEMCOM's overall response rate and 1-year survival rate were higher than arm GEM's (z = 2.190, P = 0.028 vs. z = 4.400, P = 0.000). The differences were significant. The biases of the results were tested by Egger-test. The tests showed that no bias exists in both of two meta-analysis (t = 0.070, P = 0.946 and t = -0.740, P = 0.483) respectively. CONCLUSION: There is a possibility that the gemcitabine-combination is more effective than the gemcitabine on overall response rate and 1-year survival rate.

Autocrine production of interleukin-8 confers cisplatin and paclitaxel resistance in ovarian cancer cells.

It has been widely reported that interleukin-8 (IL-8) is overexpressed in ovarian cyst fluid, ascites, serum, and tumor tissue from ovarian cancer (OVCA) patients, and elevated IL-8 expression correlates with a poor final outcome and chemosensitivity. However, the role of IL-8 expression in the acquisition of the chemoresistance phenotype and the underlining mechanisms of drug resistance in OVCA cells are not yet fully understood. Here we show that both exogenous (a relatively short period of treatment with recombination IL-8) and endogenous IL-8 (by transfecting with plasmid encoding for sense IL-8) induce cisplatin and paclitaxel resistance in non-IL-8-expressing A2780 cells, while deleting of endogenous IL-8 expression in IL-8-overexpressing SKOV-3 cells (by transfecting with plasmid encoding for antisense IL-8) promotes the sensitivity of these cells to anticancer drugs. IL-8-mediated resistance of OVCA cells exhibits decreased proteolytic activation of caspase-3. Meanwhile, the further study demonstrates that the chemoresistance caused by IL-8 is associated with increased expression of both multidrug resistance-related genes (MDR1) and apoptosis inhibitory proteins (Bcl-2, Bcl-xL, and XIAP), as well as activation of PI3K/Akt and Ras/MEK/ERK signaling. Therefore, modulation of IL-8 expression or its related signaling pathway may be a promising strategy of treatment for drug-resistant OVCA.

LC, a novel estrone-rhein hybrid compound, promotes proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells.

Estrogen analogs are promising drugs for postmenopausal osteoporosis, but because of their possible side effects, estrogens which exert their estrogenic effects selectively on bone are desired. Based on our previous studies that rhein had high affinity for the bone mineral, we synthesized estrone-rhein hybrid compounds and confirmed that one of these hybrid compounds, LC, exhibited a selective profile in the bone and prevented bone loss but had no effect on endometrium growth in ovariectomized rats. However, the mechanisms underlying its actions on human bone cells have remained largely unknown. Here we show that LC increases proliferation and differentiation and opposes cisplatin-induced apoptosis in human osteoblastic MG-63 cells containing two estrogen receptor (ER) isoforms. LC promotes proliferation by altering cell cycle distribution whereas LC-mediated survival may be associated with up-regulation of X-linked inhibitor of apoptosis (XIAP) expression. Treatment with the ER antagonist ICI 182,780 abolishes the above actions of LC on osteoblast-derived cells. Using small interfering double-stranded RNAs technology, we further demonstrate that the effects of LC on proliferation and survival are mediated by both ERα and ERß but those on differentiation primarily by ERα. Moreover, we demonstrate that LC may promote activation of the classic estrogen response element (ERE) pathway through increasing steroid receptor coactivator (SRC)-3 expression. Meanwhile, we find that regulation of osteoblastic proliferation and survival by LC involves Ras/MEK/ERK and PI3K/Akt signaling. Therefore, using rhein for conjugating compounds is a promising method of effectively targeting estrogens to the bone.

Suppression of experimental abdominal aortic aneurysm in a rat model by the phosphodiesterase 3 inhibitor cilostazol.

BACKGROUND: The present experiments sought to determine whether cilostazol, a selective inhibitor of cyclic adenosine monophosphate (cAMP) phosphodiesterase 3 (PDE3), suppressed elastase-induced abdominal aortic aneurysm (AAA) development in a rat model. METHODS: Male Sprague-Dawley rats (n = 16/each group) were randomly distributed into three groups: sham-, saline-, and cilostazol-. Rats of saline and cilostazol groups underwent intra-aortic elastase perfusion to induce AAAs, while rats of sham-group were perfused with saline. Rats of cilostazol-group received cilostazol treatment (100 mgkg(-1)d(-1)) for the entire experimental period. The areas of the lumen of the aortas at the segment with maximum diameter were measured preperfusion and on d 7, 14 after perfusion. Systolic blood pressure was measured by tail-cuff technique. Aortic tissue samples were harvested on d 14 after intra-aortic perfusion and evaluated by reverse transcription-polymerase chain reaction and Western blot for matrix metalloproteinase-2, 9 (MMP-2, 9), by immunohistochemistry for nuclear factor kappa B (NF-κB), and by Gomori aldehyde fuchsin for elastin. Activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and level of reactive oxygen species (ROS) in these samples were also measured. RESULTS: On d 14, rats of saline-group had significantly increased aortic sizes compared with sham-group (P < 0.01), while, cilostazol treatment significantly reduced this increase (cilostazol- versus saline-, P < 0.01) without affecting blood pressure (P > 0.05). The expression of both MMP-2 and MMP-9 and the destruction of elastic fibers in aortic tissues were significantly decreased by cilostazol treatment (P < 0.05), probably through the suppression of NF-κB activation (P < 0.01). Consistently, cilostazol significantly inhibited NADPH oxidase activity (P < 0.01), accompanied by a reduced level of ROS (P < 0.01). CONCLUSION: Cilostazol retards experimental AAAs development independently of blood pressure reduction possibly by inhibiting proteolysis, inflammation, and oxidative stress. Selective PDE3 inhibition may offer an additional method to pharmacologically inhibit AAAs.

LC, a novel estrone-rhein hybrid compound, concurrently stimulates osteoprotegerin and inhibits receptor activator of NF-κB ligand (RANKL) and interleukin-6 production by human osteoblastic cells.

Estrogen analogues are promising drugs for postmenopausal osteoporosis, but because of their possible side effects such as increased risk of cancer, estrogens which exert their estrogenic effects selectively on bone are desired. It has been shown that rhein inhibits osteoclast formation and bone resorption activity and has an antitumor role in several types of cancers. Having found that rhein had high affinity for the bone mineral, we synthesized estrone-rhein hybrid compounds and confirmed that one of these hybrid compounds, LC, exhibited a selective profile in the bone and prevented bone loss but had no effect on endometrium growth in ovariectomized rats. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that LC concurrently stimulates osteoprotegerin (OPG) and inhibits receptor activator of nuclear factor-κB ligand (RANKL) and Interleukin-6 (IL-6) production by human osteoblastic MG-63 cells containing two estrogen receptor (ER) isotypes. Treatment with the ER antagonist ICI 182,780 abrogates the above actions of LC on osteoblast-derived cells. Using small interfering double-stranded RNAs (siRNA) technology, we further demonstrate that the effects of LC on IL-6 production are mediated by both ERα and ERß but those on OPG and RANKL expression primarily by ERα. Furthermore, we also demonstrate that LC functions at least partially through activation of the classic estrogen response element (ERE) pathway as well as Ras/MEK/ERK and PI3K/Akt signaling. The effect of LC on bone is due to not only its estrogenic activity but also action of its rhein moiety. Also, this compound shows much weaker effect on breast epithelial cell growth than that of estrone. Therefore, using rhein for conjugating compounds is a promising method of effectively targeting estrogens to the bone.