Whole-grain intake and its inverse relationships with fatty acids intake among multiethnic Malaysian schoolchildren.

INTRODUCTION: Little is known about the relationship of whole-grain intake with dietary fatty acids intake. The present study aimed to assess the whole-grain intake and its relationships with dietary fatty acids intake among multiethnic schoolchildren in Kuala Lumpur, Malaysia. METHODS: This cross-sectional study was conducted among 392 schoolchildren aged 9-11 years, cluster sampled from five randomly selected schools in Kuala Lumpur. Whole-grain and fatty acids intakes were assessed by 3-day, 24-h diet recalls. All whole-grain foods were considered irrespective of the amount of whole grain they contained. RESULTS: In total, 55.6% (n = 218) were whole-grain consumers. Mean (SD) daily intake of whole grain in the total sample was 5.13 (9.75) g day-1 . In the whole-grain consumer's only sample, mean (SD) intakes reached 9.23 (11.55) g day-1 . Significant inverse associations were found between whole-grain intake and saturated fatty acid (SAFA) intake (r = -0.357; P < 0.001), monosaturated fatty acid (MUFA) (r = -0.373; P < 0.001) and polyunsaturated fatty acid (PUFA) (r = -0.307; P < 0.001) intake. Furthermore, whole-grain intake was a significant predictor of SAFA (ß = -0.077; P = 0.004), MUFA (ß = -0.112; P = <0.001) and PUFA (ß = -0.202; P = <0.001) intakes, after controlling for sex, age and ethnicity. CONCLUSIONS: Whole-grain intake in Malaysia was well below recommendations. Schoolchildren who consumed higher whole grain tend to reduce fat intake; however, it would also reduce the SAFA, MUFA and PUFA intakes. Future collaboration may be conducted between industry, government and universities to promote unsaturated fatty acids-rich foods and whole-grain food, although not to promote processed whole-grain foods with a high sugar and salt content.

Low-level laser therapy for carpal tunnel syndrome: systematic review and network meta-analysis.

BACKGROUND: Splinting is recommended by various organisations as a non-surgical first-line treatment for carpal tunnel syndrome (CTS), despite the limited evidence supporting its effectiveness. Previous studies on the effectiveness of low-level laser therapy (LLLT) have reported mixed results, and this systematic review aimed to resolve this controversy. OBJECTIVE: To perform a network meta-analysis (NMA) for evaluating the effectiveness of LLLT compared with other conservative treatments for CTS. METHODS: Eighteen electronic databases were searched for potential randomised controlled trials (RCTs). RCTs evaluating LLLT or other non-surgical treatments as an add-on to splinting were included. Included RCTs measured at least one of the following three outcomes with validated instruments: pain, symptom severity and functional status. RESULTS: Six RCTs (418 patients) were included. NMA suggested that LLLT plus splinting has the highest probability (75%) of pain reduction, compared with sham laser plus splinting (61%), ultrasound plus splinting (57%) and splinting alone (8%). However, while LLLT plus splinting is significantly more effective than sham laser plus splinting for pain reduction, the magnitude is not clinically significant (Visual Analogue Scale mean difference -0.53cm, 95% confidence interval -1.01 to -0.05cm; P=0.03, I2=25%). The effect of LLLT plus splinting on symptom severity and functional status was not superior to splinting alone. CONCLUSION: The use of LLLT in addition to splinting for the management of CTS is not recommended, as LLLT offers limited additional benefits over splining alone in terms of pain reduction, reduction of symptom severity or improved functional status. PROSPERO for systematic reviews and meta-analyses registration number CRD42017082650.

Complementary and alternative medicine (CAM) information and support needs of Chinese-speaking cancer patients.

PURPOSE: Complementary and alternative medicine (CAM) is popular among Chinese-speaking cancer patients (CSCPs), but little research examines CAM use by Canadian CSCPs. The use of CAM is controversial because of potential interactions with conventional cancer treatments. The purpose of this study was to explore CSCPs' use of CAM, sources of CAM information, and decision support needs, as well as their experience of making CAM decisions. METHODS: A sequential, multi-method research design was used: a secondary data analysis of a CAM use survey conducted in a Western Canadian regional cancer agency followed by a qualitative interpretive description approach to inquiry using semi-structured interviews with CSPCs and support persons. RESULTS: More than 65% of CSCPs reported using CAM. CSCPs favored biologically-based therapies, including traditional Chinese medicine herbs and other natural health products. Many CSCPs were using CAM without adequate culturally appropriate information and decision support. Those who made decisions spontaneously relied on peers for advice whereas deliberate decision makers sought information from multiple sources, including peers and the Internet, selecting therapies congruent with their cultural health perspectives and previous experiences with CAM. CSCPs rarely spoke with oncology healthcare providers (HCPs) about CAM use. CONCLUSIONS: CSCPs reported using CAM at rates significantly higher than for non-CSCPs. Given the predominance of biological-based therapies and the lack of consultation with oncology HCPs, it is imperative that CAM use be assessed and documented to ensure CSCPs' safety during cancer treatment. Culturally appropriate information and decision support is required to ensure that CSCPs are making safe and informed CAM decisions.

Diversity of pollination ecology in the Schismatoglottis Calyptrata Complex Clade (Araceae).

Field studies integrating pollination investigations with an assessment of floral scent composition and thermogenesis in tropical aroids are rather few. Thus, this study aimed to investigate the pollination biology of nine species belonging to Schismatoglottis Calyptrata Complex Clade. The flowering mechanism, visiting insect activities, reproductive system, thermogenesis and floral scent composition were examined. Anthesis for all species started at dawn and lasted 25-29 h. Colocasiomyia (Diptera, Drosophilidae) are considered the main pollinators for all the investigated species. Cycreon (Coleoptera, Hydrophilidae) are considered secondary pollinators as they are only present in seven of the nine host plants, despite the fact that they are the most effective pollen carrier, carrying up to 15 times more pollen grains than Colocasiomyia flies. However, the number of Colocasiomyia individuals was six times higher than Cycreon beetles. Chaloenus (Chrysomelidae, Galeuricinae) appeared to be an inadvertent pollinator. Atheta (Coleoptera, Staphylinidae) is considered a floral visitor in most investigated species of the Calyptrata Complex Clade in Sarawak, but a possible pollinator in S. muluensis. Chironomidae midges and pteromalid wasps are considered visitors in S. calyptrata. Thermogenesis in a biphasic pattern was observed in inflorescences of S. adducta, S. calyptrata, S. giamensis, S. pseudoniahensis and S. roh. The first peak occurred during pistillate anthesis; the second peak during staminate anthesis. Inflorescences of all investigated species of Calyptrata Complex Clade emitted four types of ester compound, with methyl ester-3-methyl-3-butenoic acid as a single major VOC (volatile organic compound). The appendix, pistillate zone, staminate zone and spathe emitted all these compounds. A mixed fly-beetle pollination system is considered an ancestral trait in the Calyptrata Complex Clade, persisting in Sarawak taxa, whereas the marked reduction of interpistillar staminodes in taxa from Peninsular Malaysia and especially, Ambon, Indonesia, is probably linked to a shift in these taxa to a fly-pollinated system.

Reduced prostate cancer risk with green tea and epigallocatechin 3-gallate intake among Hong Kong Chinese men.

BACKGROUND: In vitro and in vivo studies suggested that polyphenol epigallocatechin 3-gallate (EGCG) in tea may have anti-carcinogenic effect on prostate cells, but this protective effect has less been examined in epidemiology studies. We aimed to investigate the association between prostate cancer (PCA) risk and habitual green tea intake among Chinese men in Hong Kong; meanwhile, the relationship with EGCG was also explored. METHODS: We consecutively recruited 404 PCA cases and 395 controls from the same hospital who had complete data on habitual tea consumption, including green, oolong, black and pu'er tea. We reconstructed the level of EGCG intake according to a standard questionnaire and the analytic values for EGCG extracted from the literature published by Lin et al. in 2003. We calculated odds ratios (ORs) for tea consumption and EGCG intake using unconditional multiple logistic regression, and examined their exposure--response relationships with PCA risk. RESULTS: A total of 32 cases and 50 controls reported habitual green tea drinking, showing an adjusted OR of 0.60 (95% confidence interval (CI): 0.37, 0.98). A moderate excess risk was observed among the habitual pu'er tea drinkers (OR=1.44, 95% CI: 1.02, 1.91). A significantly lower intake of EGCG was observed among cases (54.4 mg) than the controls (72.5 mg), which resulted in an inverse gradient of PCA risk with the increasing intake of EGCG (test for trend, P=0.015). CONCLUSION: PCA risk among Chinese men in Hong Kong was inversely associated with green tea consumption and EGCG intake, but these results need to be replicated in larger studies.

[Recognizing signs of sexual abuse]. / Signalen van seksueel misbruik herkennen.

Sexual abuse is very common. In the Netherlands 42% of women and 13% of men aged over 25 years have experienced unacceptable sexual behaviour. Most victims do not seek professional help nor do they report the abuse to the police, and most of the victims who do seek medical help do not mention the abuse. Doctors often do not recognize the signs of sexual abuse. Most victims of rape have symptoms that may develop into posttraumatic stress disorder (PTSD) if they persist for more than 4 weeks, such as sleep problems or panic attacks. Victims of sexual abuse also more often develop a psychiatric disorder or medically unexplained symptoms (MUS). Doctors should ask about sexual abuse in cases of MUS or unexplained mental problems. The complications of abuse can be treated with eye movement desensitization and reprocessing (EMDR) or cognitive processing therapy (CPT).

Floral diversity and pollination strategies of three rheophytic Schismatoglottideae (Araceae).

Homoplastic evolution of 'unique' morphological characteristics in the Schismatoglottideae - many previously used to define genera - prompted this study to compare morphology and function in connection with pollination biology for Aridarum nicolsonii, Phymatarum borneense and Schottarum sarikeense. Aridarum nicolsonii and P. borneense extrude pollen through a pair of horned thecae while S. sarikeense sheds pollen through a pair of pores on the thecae. Floral traits of spathe constriction, presence and movement of sterile structures on the spadix, the comparable role of horned thecae and thecae pores, the presence of stamen-associated calcium oxalate packages, and the timing of odour emission are discussed in the context of their roles in pollinator management. Pollinators for all investigated species were determined to be species of Colocasiomyia (Diptera: Drosophilidae).

Treating cancer with infection: a review on bacterial cancer therapy.

There is an increasing need for new cancer therapies. The antitumour effect of bacterial infection has been well observed and practiced throughout history. Bacteria are well-suited to serve as anticancer agents due to their intrinsic mobility, cell toxicity, immunogenicity, and preferential accumulation within the anoxic tumour environment. Furthermore, advances in biotechnology and molecular techniques have made it easier than ever to engineer bacteria as both therapeutic agents themselves and as therapeutic vectors. Here, we review bacteriolytic therapy and immunotherapy strategies, and examine the development of bacteria as vehicles for cell- and tissue-targeted delivery of genetic cancer therapeutics.

Effects of beverages with variable nutrients on rehydration and cognitive function.

The purpose of the present study was to investigate the effect of carbohydrate-electrolyte solution (CE), lemon tea (LT), and distilled water (DW) on rehydration and cognitive performance after 60 min of moderate exercise. 9 healthy males and 10 eumenorrheic females completed 3 runs in a randomized crossover study design. During the 4-h recovery (REC) period, they consumed either a volume of CE, LT or DW equal to 150% of their body mass (BM) loss during the previous run. The 3 beverages vary in carbohydrate and electrolyte content. A battery of cognitive tests was performed upon arrival, immediately after exercise, and at the end of REC. After the REC, the restoration of BM loss was lower in the DW and LT trials than that in the CE trial in the female participants (CE vs. LT vs. DW: 59.3±2.8 vs. 41.7±5.7 vs. 45.6±2.2%). When compared with the DW, the accuracy of performances during a working memory task in both males and females was higher in the CE and LT trials. The results suggested that during a short-term recovery, both LT and CE show certain beneficial effect in maintaining cognitive performance. However, CE appears to be more effective than LT and DW in rehydrating female participants.

Structural analysis of raw and commercial farm edible bird nests.

Edible bird nests (EBNs) are consumed worldwide for various health benefits. EBNs are nests built from the saliva of swiftlets of Aerodramus species. The global market for EBNs is on the rise, especially from Hong Kong and mainland China. In the past, EBNs were harvested mainly from natural caves; however in the recent years, there has been a rapid growth of swiftlet farming. Little is known about the actual composition of EBNs except for protein, carbohydrate, ash and lipid contents, amino acids, vitamins and macro/ micronutrients. Besides the biochemical components of EBNs, are there any other structures that are associated with EBNs? This paper reports on the structural analysis of raw unprocessed farm and processed commercial EBNs. The raw EBNs were purchased from swiftlet farms in five locations in Peninsula Malaysia: Kuala Sanglang (Perlis; 6° 16' 0"N, 100° 12' 0"E), Pantai Remis (Perak; 4º 27' 0" N, 100º 38' 0" E), Kluang (Johor; 02º 012 303N 103º 192 583E), Kajang (Selangor; 2º 59' 0"N, 101º 47' 0"E) and Kota Bharu (Kelantan; 6º 8' 0"N, 102º 15' 0"E). The commercial nests were purchased from five different Chinese traditional medicinal shops (Companies A-E). A portion of each EBN was randomly broken into small fragments, attached to carbon tape and coated with gold and palladium particles for examination and photography under a scanning electron microscope. Structural analysis revealed the presence of mites, fungi, bacteria and feather strands on both the raw and commercial nests. Mite eggshells and faecal pellets, and body parts of other arthropods were seen only in the raw nests. The commercial nests had a variety of unidentified structures and substances coated on the nests' surfaces that were not found on the raw nests. The presence of these contaminants may jeopardise the quality of EBNs and pose health risks to consumers. Further identification of the mites and their allergens, fungi and bacteria are on-going and will be reported separately.

The impact of dietary calcium intake and vitamin D status on the effects of zoledronate.

UNLABELLED: We investigated whether baseline dietary calcium intake or vitamin D status modified the effects of zoledronate. Neither variable influenced the effect of zoledronate on bone mineral density, bone turnover, or risk of acute phase reaction, suggesting that co-administration of calcium and vitamin D supplements with zoledronate may not always be necessary. INTRODUCTION: Calcium and vitamin D supplements are often co-administered with bisphosphonates, but it is unclear whether they are necessary for therapeutic efficacy or minimizing side effects of bisphosphonates. We investigated whether baseline dietary calcium intake or vitamin D status modified the effect of zoledronate on bone mineral density (BMD) or bone turnover at 1 year, or the risk of acute phase reactions (APR). METHODS: Data were pooled from two trials of zoledronate in postmenopausal women without vitamin D deficiency in which calcium and vitamin D were not routinely administered. The cohort (zoledronate n = 154, placebo n = 68) was divided into subgroups by baseline dietary calcium intake (<800 vs. ≥800 mg/day) and vitamin D status [25-hydroxyvitamin D (25OHD) <50 vs. ≥50 nmol/L, and <75 nmol/L vs. ≥75 nmol/L] and treatment × subgroup interactions tested. RESULTS: There were 52, 86, and 36 % of the zoledronate group and 64, 94, and 46 % of the placebo group that had dietary calcium intake ≥800 mg/day, 25OHD ≥50 nmol/L, and 25OHD ≥75 nmol/L, respectively. There were no significant interactions between treatment and either baseline dietary calcium or baseline vitamin D status for lumbar spine BMD, total hip BMD, the bone turnover markers P1NP and ß-CTx, or the risk of an APR. There was also no three-way interaction between baseline dietary calcium intake, baseline vitamin D status, and treatment for any of these variables. CONCLUSIONS: Baseline dietary calcium intake and vitamin D status did not alter the effects of zoledronate, suggesting that co-administration of calcium and vitamin D with zoledronate may not be necessary for individuals not at risk of marked vitamin D deficiency.

Meal provision in a UK National Spinal Injury Centre: a qualitative audit of service users and stakeholders.

STUDY DESIGN: A single centre survey. OBJECTIVES: The objective of this study is to (1) assess patients' food intake and (2) measure satisfaction with current food provision, as judged by patients and by stakeholders (medical and nursing staff, managers and catering staff). METHODS: Standardised questionnaires were used to record food intake over a 24-h period, and to evaluate the quality, ordering, delivery and overall acceptability of food provided. RESULTS: The food intake of 67 patients with spinal cord injury (SCI) was recorded (64% response rate) and 166 evaluations (50% response rate) were returned. Twenty-nine patients (48%) consumed three full meals a day, 17 (26%) received oral nutritional supplements, 22 (34%) received vitamin/mineral supplements, and 23 (35%) required assistance to eat. Some patients and stakeholders expressed satisfaction with the current food provision: taste good: 25 versus 17% (for patients and stakeholders, respectively); appropriate texture: 22 versus 21%; appropriate temperature: 55 versus 72% (P = 0.002); well presented: 43 versus 28%; good choice: 49 versus 59%; received meal ordered: 65 versus 37% (P < 0.001); meal served on time: 71 versus 58%; and no interruption during mealtimes: 62 versus 46%. Principal component analyses of item scores identified three main factors (food quality, food presentation and food delivery (logistics). CONCLUSION: The present study identified some areas where there appeared to have been improvement in SCI hospital catering, but with much still to be achieved. Hospital-catering systems should be tailored to meet the demands of the different patient groups to optimise nutritional intake. Periodic quality control is essential to meet recommendations and patients' expectations.

Pharmacological characterization of 2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242), a high-affinity antagonist selective for κ-opioid receptors.

2-Methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242) is a novel κ-opioid receptor (KOR) antagonist with high affinity for human (3 nM), rat (21 nM), and mouse (22 nM) KOR, a ∼ 20-fold reduced affinity for human µ-opioid receptors (MORs; K(i) = 64 nM), and negligible affinity for δ-opioid receptors (K(i) > 4 µM). PF-04455242 also showed selectivity for KORs in vivo. In rats, PF-04455242 blocked KOR and MOR agonist-induced analgesia with ID(50) values of 1.5 and 9.8 mg/kg, respectively, and inhibited ex vivo [(3)H](2-(benzofuran-4-yl)-N-methyl-N-((5S,7R,8R)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]decan-8-yl)acetamide ([(3)H]CI977) and [(3)H](2S)-2-[[2-[[(2R)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl) propanoyl]amino]propanoyl]amino]acetyl]-methylamino]-N-(2-hydroxyethyl)-3-phenylpropanamide ([(3)H]DAMGO) binding to KOR and MOR receptors with ID(50) values of 2.0 and 8.6 mg/kg, respectively. An in vivo binding assay was developed using (-)-4-[(3)H]methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine ([(3)H]PF-04767135), a tritiated version of the KOR positron emission tomography ligand (-)-4-[(11)C]methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine ([(11)C]GR103545) in which PF-04455242 had an ID(50) of 5.2 mg/kg. PF-04455242 demonstrated antidepressant-like efficacy (mouse forced-swim test), attenuated the behavioral effects of stress (mouse social defeat stress assay), and showed therapeutic potential in treating reinstatement of extinguished cocaine-seeking behavior (mouse conditioned place preference). KOR agonist-induced plasma prolactin was investigated as a translatable mechanism biomarker. Spiradoline (0.32 mg/kg) significantly increased rat plasma prolactin levels from 1.9 ± 0.4 to 41.9 ± 4.9 ng/ml. PF-04455242 dose-dependently reduced the elevation of spiradoline-induced plasma prolactin with an ID(50) of 2.3 ± 0.1 mg/kg, which aligned well with the ED(50) values obtained from the rat in vivo binding and efficacy assays. These data provide further evidence that KOR antagonists have potential for the treatment of depression and addiction disorders.

Daily ciprofloxacin treatment for patients with advanced liver disease awaiting liver transplantation reduces hospitalizations.

BACKGROUND: Progressive deterioration in liver function is a common cause of hepatic decompensation and indication for liver transplantation in patients with advanced liver disease. Previous studies in animal models of acute and chronic liver disease revealed that daily ciprofloxacin improves biochemical parameters of hepatic function. AIMS: The primary objective of this study was to determine whether hepatic function improves in patients with advanced liver disease after 1 month of daily ciprofloxacin therapy. A secondary objective was to determine whether ciprofloxacin treatment for 1 or 3 months results in fewer hospitalizations for decompensated liver disease. METHODS: Forty-four patients with advanced liver disease awaiting liver transplantation received oral ciprofloxacin (250 or 500 mg twice daily) or placebo for 1 (n=22/group) or 3 (n=10 ciprofloxacin, 14 placebo) months. RESULTS: Compared to placebo recipients, ciprofloxacin-treated patients had mild improvements in serum albumin levels (+1.5 versus -3.4%, p=0.026) while bilirubin and international normalized ratios (INR) of prothrombin times remained unchanged. Overall, fewer hospitalizations occurred in ciprofloxacin-treated patients (1/22, 5% versus 7/22, 32%, respectively, p=0.02) during the study period. Treatment was well tolerated and no resistant infections occurred in either cohort. CONCLUSIONS: The results of this study suggest that daily ciprofloxacin may result in fewer hospitalizations for patients with advanced liver diseases awaiting liver transplantation but not by enhancing hepatic function.

Electroacupuncture versus celecoxib for neuropathic pain in rat SNL model.

Though acupuncture has long been used to treat various kinds of pain, its mechanisms remain partly understood. Our recent study has shown that it may inhibit cyclooxygenase-2 (COX-2) in the spinal dorsal horn where COX-2 is upregulated after the development of neuropathic pain following spinal nerve ligation (SNL). The current study directly compared the effect of acupuncture with COX-2 inhibitor celecoxib in the spinal cord after SNL in rats. After L5 SNL, the rats were treated either with acupuncture applied to Zusanli (ST36) and Sanyinjiao (SP6) bilaterally with or without electrical stimulation (2 Hz, 0.5-1-2 mA) four times over 22 days, and/or celecoxib fed daily. Paw-withdrawal-threshold to mechanical stimulation and paw-withdrawal-latency to thermal test were tested for neuropathic pain at four intervals following the treatments in comparison with the pre-treatment and non-treatment controls. The results demonstrate that electroacupuncture (EA) had a long lasting and better analgesic effect than celecoxib in reducing neuropathic hypersensitivity. Though COX-2 expression in the spinal L4-L6 dorsal horn by immunostaining was significantly reduced by acupuncture just as well as by celecoxib, the superior analgesic mechanism of acupuncture appears well beyond COX-2 inhibition alone.

Influence of polyhydramnios on perinatal outcome in pregestational diabetic pregnancies.

OBJECTIVE: This study was carried out to evaluate the perinatal outcomes of pregnancy with pregestational diabetes mellitus complicated by polyhydramnios. METHODS: This was a retrospective study of singleton pregnancies, with an antepartum diagnosis of polyhydramnios, seen at the maternal fetal medicine department of Mater Mothers' Hospital, a tertiary-level facility. All pregnancies in women with pregestational diabetes with a singleton pregnancy beyond 24 weeks of gestation, from 1996 to 2006, were reviewed (n = 314), and pregnancies complicated by polyhydramnios were identified (n = 59). Pregnancy outcomes of women whose pregnancy was complicated with polyhydramnios were compared to those without this complication. RESULTS: The incidence of polyhydramnios in the study population was 18.8%. Women with polyhydramnios had increased hemoglobin A1c (HbA1c) levels throughout the pregnancy, and the difference was significant during the prepregnancy period and in the third trimester (P = 0.003 and P = 0.025, respectively). Significantly more mothers in the polyhydramnios group delivered preterm (54.2% vs. 33.3%, P = 0.004), the majority of which were iatrogenic preterm deliveries (44.1%). More pregnancies with polyhydramnios were delivered by Cesarean section (83.0% vs. 62%; P = 0.006), with the majority being performed electively in both groups (79.6% and 70.3%, respectively). Regardless, there were no significant differences in perinatal mortality rates, congenital abnormality rates, the incidences of low Apgar score, acidemia, hypoglycemia requiring intravenous therapy, phototherapy and ventilatory needs between the babies of the two groups. CONCLUSION: Pregestational diabetic pregnancy with polyhydramnios is associated with poor diabetic control. Despite this, there is no significant increase in adverse perinatal outcome in these pregnancies, apart from a higher iatrogenic preterm birth rate.

Andrographolide regulates epidermal growth factor receptor and transferrin receptor trafficking in epidermoid carcinoma (A-431) cells.

BACKGROUND AND PURPOSE: Andrographolide is the active component of Andrographis paniculata, a plant used in both Indian and Chinese traditional medicine, and it has been demonstrated to induce apoptosis in different cancer cell lines. However, not much is known about how it may affect the key receptors implicated in cancer. Knowledge of how andrographolide affects receptor trafficking will allow us to better understand new mechanisms by which andrographolide may cause death in cancer cells. EXPERIMENTAL APPROACH: We utilized the well-characterized epidermal growth factor receptor (EGFR) and transferrin receptor (TfR) expressed in epidermoid carcinoma (A-431) cells as a model to study the effect of andrographolide on receptor trafficking. Receptor distribution, the total number of receptors and surface receptors were analysed by immunofluorescence, Western blot as well as flow-cytometry respectively. KEY RESULTS: Andrographolide treatment inhibited cell growth, down-regulated EGFRs on the cell surface and affected the degradation of EGFRs and TfRs. The EGFR was internalized into the cell at an increased rate, and accumulated in a compartment that co-localizes with the lysosomal-associated membrane protein in the late endosomes. CONCLUSION AND IMPLICATIONS: This study sheds light on how andrographolide may affect receptor trafficking by inhibiting receptor movement from the late endosomes to lysosomes. The down-regulation of EGFR from the cell surface also indicates a new mechanism by which andrographolide may induce cancer cell death.

Preclinical assessment of the absorption, distribution, metabolism and excretion of GDC-0449 (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide), an orally bioavailable systemic Hedgehog signalling pathway inhibitor.

GDC-0449 (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide) is a potent, selective Hedgehog (Hh) signalling pathway inhibitor being developed for the treatment of various cancers. The in vivo clearance of GDC-0449 was estimated to be 23.0, 4.65, 0.338, and 19.3 ml min(-1) kg(-1) in mouse, rat, dog and monkeys, respectively. The volume of distribution ranged from 0.490 in rats to 1.68 l kg(-1) in mice. Oral bioavailability ranged from 13% in monkeys to 53% in dogs. Predicted human clearance using allometry was 0.096-0.649 ml min(-1) kg(-1) and the predicted volume of distribution was 0.766 l kg(-1). Protein binding was extensive with an unbound fraction less than or equal to 6%, and the blood-to-plasma partition ratio ranged from 0.6 to 0.8 in all species tested. GDC-0449 was metabolically stable in mouse, rat, dog and human hepatocytes and had a more rapid turnover in monkey hepatocytes. Proposed metabolites from exploratory metabolite identification in vitro (rat, dog and human liver microsomes) and in vivo (dog and rat urine) include three primary oxidative metabolites (M1-M3) and three sequential glucuronides (M4-M6). Oxidative metabolites identified in microsomes M1 and M3 were formed primarily by P4503A4/5 (M1) and P4502C9 (M3). GDC-0449 was not a potent inhibitor of P4501A2, P4502B6, P4502D6, and P4503A4/5 with IC50 estimates greater than 20 microM. K(i)'s estimated for P4502C8, P4502C9 and P4502C19 and were 6.0, 5.4 and 24 microM, respectively. An evaluation with Simcyp suggests that GDC-0449 has a low potential of inhibiting P4502C8 and P4502C9. Furthermore, GDC-0449 (15 microM) was not a potent P-glycoprotein/ABCB1 inhibitor in MDR1-MDCK cells. Overall, GDC-0449 has an attractive preclinical profile and is currently in Phase II clinical trials.