Gluconeogenesis is critical in maintaining blood glucose levels in a normal range during fasting. In this study, we investigated the role of Yin Yang 1 (YY1), a key transcription factor involved in cell proliferation and differentiation, in the regulation of hepatic gluconeogenesis. Our data showed that hepatic YY1 expression levels were induced in mice during fasting conditions and in a state of insulin resistance. Overexpression of YY1 in livers augmented gluconeogenesis, raising fasting blood glucose levels in C57BL/6 mice, whereas liver-specific ablation of YY1 using adenoviral shRNA ameliorated hyperglycemia in wild-type and diabetic db/db mice. At the molecular level, we further demonstrated that the major mechanism of YY1 in the regulation of hepatic glucose production is to modulate the expression of glucocorticoid receptor. Therefore, our study uncovered for the first time that YY1 participates in the regulation of hepatic gluconeogenesis, which implies that YY1 might serve as a potential therapeutic target for hyperglycemia in diabetes.
We analyzed the prevalence and characteristics of Vibrio parahaemolyticus among patients with acute infectious diarrhea in the southern coastal region of China. V. parahaemolyticus was the leading cause of bacterial infectious diarrhea in this region during 2007–2012. Serotype O3:K6 strains were most common, followed by serotypes O4:K8 and O3:K29.
Vibrio parahaemolyticus; infectious diarrhea; epidemic; China; bacteria; Vibrio
Schistosomiasis remains a serious public health problem in affected countries, and routine, highly sensitive and cost-effective diagnostic methods are lacking. We evaluated two immunodiagnostic techniques for the detection of Schistosoma japonicum infections: circulating antibody and circulating antigen assays.
A total of 1864 individuals (between 6 and 72 years old) residing in five administrative villages in Hubei province were screened by serum examination with an indirect hemagglutination assay (IHA). The positive individuals (titer ≥20 in IHA) were reconfirmed by stool examination with the Kato-Katz method (three slides from a single stool specimen). Samples of good serum quality and a volume above 0.5 ml were selected for further testing with two immunodiagnostic antibody (DDIA and ELISA) and two antigen (ELISA) assays.
The average antibody positive rate in the five villages was 12.7%, while the average parasitological prevalence was 1.50%; 25 of the 28 egg-positive samples were also circulating antigen-positive. Significant differences were observed between the prevalence according to the Kato-Katz method and all three immunodiagnostic antibody assays (P-value <0.0001). Similar differences were observed between the Kato-Katz method and the two immunodiagnostic antigen assays (P-value <0.0001) and between the antigen and antibody assays (P-value <0.0001).
Both circulating antibody and circulating antigen assays had acceptable performance characteristics. Immunodiagnostic techniques to detect circulating antigens have potential to be deployed for schistosomiasis japonica screening in the endemic areas.
Schistosoma japonicum; Circulating antibody; Circulating antigen; China
Our previous studies have shown that an active fragment of human tachykinins (hHK-1(4-11)) produced an opioid-independent analgesia after intracerebroventricular (i.c.v.) injection in mice, which has been markedly enhanced by a δ OR antagonist, naltrindole hydrochloride (NTI). In this study, we have further characterized the in vivo analgesia after i.c.v. injection of hHK-1(4-11) in mouse model. Our qRT-PCR results showed that the mRNA levels of several ligands and receptors (e.g. PPT-A, PPT-C, KOR, PDYN and PENK) have not changed significantly. Furthermore, neither transcription nor expression of NK1 receptor, MOR and POMC have changed noticeably. In contrast, both mRNA and protein levels of DOR have been up-regulated significantly, indicating that the enhanced expression of δ opioid receptor negatively modulates the analgesia induced by i.c.v. injection of hHK-1(4-11). Additionally, the combinatorial data from our previous and present experiments strongly suggest that the discriminable distribution sites in the central nervous system between hHK-1(4-11) and r/mHK-1 may be attributed to their discriminable analgesic effects. Altogether, our findings will not only contribute to the understanding of the complicated mechanisms regarding the nociceptive modulation of hemokinin-1 as well as its active fragments at supraspinal level, but may also lead to novel pharmacological interventions.
To investigate the effects of intravitreal injection of bevacizumab-chitosan nanoparticles on pathological morphology of retina and the expression of vascular endothelial growth factor (VEGF) protein and VEGF mRNA in the retina of diabetic rats.
Seventy-two 3-month aged diabetic rats were randomly divided into 3 groups, each containing 24 animals and 48 eyes. Both eyes of the rats in group A were injected into the vitreous at the pars plana with 3µL of physiological saline, while in groups B and C were injected with 3µL (75µg) of bevacizumab and 3µL of bevacizumab-chitosan nanoparticles (containing 75µg of bevacizumab), respectively. Immunohistochemistry was used to assess retinal angiogenesis, real-time PCR assay was used to analyse the expression of VEGF mRNA, and light microscopy was used to evaluate the morphology of retinal capillaries.
Real-time PCR assay revealed that the VEGF mRNA expression in the retina before injection was similar to 1 week after injection in group A (P>0.05), while the VEGF mRNA expression before injection significantly differed from those 4 and 8 weeks after injection (P<0.05). Retinal expression of VEGF protein and VEGF mRNA was inhibited 1 week and 4 weeks after injection (P<0.05) in group B, and the expression of VEGF protein and VEGF mRNA was obviously inhibited until 8 weeks after injection (P<0.05) in group C. Using multiple comparisons among group A, group B, and group C, the VEGF expression before injection was higher than at 1, 4 and 8 weeks after injection (P<0.05). The amount of VEGF expression was higher 8 weeks after injection than 1 week or 4 weeks after injection, and also higher 1 week after injection compared with 4 weeks after injection (P<0.05). No toxic effect on SD rats was observed with bevacizumab-chitosan nanoparticles injection alone.
The results offer a new approach for inhibiting angiogenesis of diabetic retinopathy and indicate that the intravitreal injection of bevacizumab inhibits VEGF expression in retina, and bevacizumab-chitosan nanoparticles have a longer duration of action.
bevacizumab; nanoparticles; diabetic retinopathy; intravitreal injection
Background and Aim. It remains challenging to determine the inflammatory activity in Crohn's disease (CD) for lack of specific laboratory markers. Recent studies suggest that serum omentin-1 is associated with inflammatory response. We aimed to assess the potential of serum omentin-1 as a marker of disease activity in CD patients.
Methods. Serum omentin-1 concentrations were determined by enzyme-linked immunosorbent assay (ELISA) in patients with CD (n = 240), functional gastrointestinal disorders (FGDs, n = 120), and healthy controls (HC, n = 60) and evaluated for correlation with disease activity. Expression of omentin-1 in colonic tissues from patients with CD was also analyzed by real-time PCR and Western blotting. Serum omentin-1 levels as an activity index were evaluated using a receiver operating characteristic (ROC) curve.
Results. Serum omentin-1 concentrations were significantly decreased in active CD patients compared with patients in remission, FGDs, and HC (all P < 0.001). Expression of omentin-1 was decreased at mRNA and protein levels in inflamed colonic tissues in active CD than that in noninflamed colonic tissues. Serum omentin-1 levels were negatively correlated with disease activity in CD, better than C-reactive protein (CRP). Conclusion. Our results indicate that serum and colonic omentin-1 expressions are decreased in active CD patients. The correlation of serum omentin-1 with disease activity in CD is superior to that of CRP. Serum omentin-1 is a potential marker for CD disease activity.
Stroke has severe consequences in postmenopausal women. As replacement therapy of estrogen have various adverse effects and the undermined outcomes. Genistein, a natural phytoestrogen, has been suggested to be a potential neuroprotective agent for such stroke patients. However, the role of genistein and its underlying mechanism in ovariectomized mice has not yet been evaluated. In the present study, ovariectomized mice were treated with genistein (10 mg/kg) or vehicle daily for two weeks before developing transient cerebral ischemia (middle cerebral artery occlusion). The neurological manifestation was evaluated, and infarct volumes were demonstrated by 2,3,5-triphenyltetrazolium chloride staining at 24 h after reperfusion. In addition, phosphorylation of extracellular signal-regulated kinase (ERK) was detected by Western blotting and immunofluorescence staining, and cellular apoptosis was evaluated in the ischemic penumbra. We found that treatment with genistein reduced infarct volumes, improved neurological outcomes and attenuated cellular apoptosis at 24 h after reperfusion. ERK1/2 showed increased phosphorylation by genistein treatment after reperfusion, and an ERK1/2 inhibitor U0126 abolished this protective effect of genistein in terms of infarct volumes, neurological scores and cellular apoptosis. Our findings indicate that treatment with genistein can reduce the severity of subsequent stroke episodes, and that this beneficial function is associated with ERK activation.
cerebral ischemia; extracellular signal-regulated protein kinase; genistein; phytoestrogen; postmenopausal stroke.
Fatsia polycarpa, a plant endemic to Taiwan, is an herbal medicine known for treating several inflammation-related diseases, but its biological function needs scientific support. Thus, the anti-inflammatory effects and mechanisms of the methanolic crude extract (MCE) of F. polycarpa and its feature constituents, that is, brassicasterol (a phytosterol), triterpenoids 3α-hydroxyolean-11,13(18)-dien-28-oic acid (HODA), 3α-hydroxyolean-11-en-28,13β-olide (HOEO), fatsicarpain D, and fatsicarpain F, were investigated. MCE and HOEO, but not brassicasterol, dose-dependently inhibited lipopolysaccharide- (LPS-)induced expression of inducible nitric oxide synthase and cyclooxygenase-2 in RAW 264.7 macrophage line, whereas HODA, fatsicarpain D and fatsicarpain F were toxic to RAW cells. Additionally, MCE and HOEO suppressed LPS-induced production of nitric oxide, prostaglandin E2, and interleukin-1β and interfered with LPS-promoted activation of the inhibitor kappa B kinase (IKK)/nuclear factor-κB (NF-κB) pathway, and that of the mitogen-activated protein kinases (MAPKs) extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. In animal tests, MCE and HOEO effectively ameliorated 12-O-tetradecanoylphorobol-13 acetate- (TPA-)induced ear edema of mice. Thus, MCE of F. polycarpa exhibited an obvious anti-inflammatory activity in vivo and in vitro that likely involved the inhibition of the IKK/NF-κB pathway and the MAPKs, which may be attributed by triterpenoids such as HOEO.
Obesity is becoming one of the global epidemics of the 21st century. In this study, the effects of citrange (Citrus sinensis × Poncirus trifoliata) fruit extracts in high-fat (HF) diet-induced obesity mice were studied. Female C57BL/6 mice were fed respectively a chow diet (control), an HF diet, HF diet supplemented with 1% w/w citrange peel extract (CPE) or 1% w/w citrange flesh and seed extract (CFSE) for 8 weeks. Our results showed that both CPE and CFSE regulated the glucose metabolic disorders of obese mice. In CPE and CFSE-treated groups, the body weight gain, blood glucose, serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-c) levels were significantly (p < 0.05) reduced relative to those in the HF group. To explore the mechanisms of action of CPE and CFSE on the metabolism of glucose and lipid, related genes’ expressions in liver were assayed. In liver tissue, the expression level of peroxisome proliferator-activated receptor γ (PPARγ) and its target genes were down-regulated by CPE and CFSE supplementation as revealed by qPCR tests. In addition, both CPE and CFSE decreased the expression level of liver X receptor (LXR) α and β, which are involved in lipid and glucose metabolism. Taken together, these results suggest that CPE and CFSE administration could ameliorate obesity and related metabolic disorders in HF diet-induced obesity mice probably through the inhibition of PPARγ and LXRs gene expressions.
citrange fruit extracts; obesity mice; metabolic disorder; regulation
To evaluate the long-term effects of thrombolysis on patients with submassive pulmonary embolism (PE).
Data of 136 patients with acute submassive PE and low risk of bleeding were prospectively collected from January 2005 to October 2011 in a single medical center. Patients received recombinant tissue plasminogen activator (r-tPA) plus low molecular weight heparin (LMWH, TT group, n = 79) or LMWH alone (AT group, n = 57), depending on treating physician's recommendation and patient's preference. Echocardiography was performed at admission, 24 h, 6 and 12 months to evaluate right ventricular function. Computed tomography pulmonary angiography (CTPA) and lung perfusion scan were performed on admission, at 7 days, 6 and 12 months to evaluate clot burden.
Seventy-nine patients received r-tPA plus LMWH (TT group) while 57 received LMWH alone (AT group). The baseline characteristics and risk factors did not differ between the two groups. Respiratory rate, heart rate, and systolic blood pressure improved within two hours in both groups. Systolic pulmonary arterial pressure and tricuspid regurgitation improved to a greater extent in the TT group at 24 h, and at 12 months (P < 0.001), as compared to those in the AT group. At one week, and 12 months, clot burden decreased more in AT group, as compared to that in AT group (P < 0.001). There was no death due to bleeding in both groups. Recurrent PE were similar in both groups (2.5% in TT vs. 1.8% in AT). The rates of minor hemorrhages were 6.3% in TT group and 1.8% in AT group (P < 0.05).
In submassive PE patient who has low risk of bleeding, thrombolysis plus anticoagulation can lead to greater improvement of right ventricular dysfunction and clot burden reduction as compared to anticoagulation therapy alone.
Pulmonary embolism; Right ventricle dysfunction; Thrombolysis; Anticoagulation; Bleeding
The tumor suppressor protein p53 regulates numerous signaling pathways by specifically recognizing diverse p53 response elements (REs). Understanding the mechanisms of p53-DNA interaction requires structural information on p53 REs. However, such information is limited as a 3D structure of any RE in the unbound form is not available yet. Here, site-directed spin labeling was used to probe the solution structures of REs involved in p53 regulation of the p21 and Bax genes. Multiple nanometer distances in the p21-RE and BAX-RE, measured using a nucleotide-independent nitroxide probe and double-electron-electron-resonance spectroscopy, were used to derive molecular models of unbound REs from pools of all-atom structures generated by Monte-Carlo simulations, thus enabling analyses to reveal sequence-dependent DNA shape features of unbound REs in solution. The data revealed distinct RE conformational changes on binding to the p53 core domain, and support the hypothesis that sequence-dependent properties encoded in REs are exploited by p53 to achieve the energetically most favorable mode of deformation, consequently enhancing binding specificity. This work reveals mechanisms of p53-DNA recognition, and establishes a new experimental/computational approach for studying DNA shape in solution that has far-reaching implications for studying protein–DNA interactions.
Tight junctions (TJs) are mainly composed of claudins, occludin, and tight junction adhesion molecules (JAM). The invasive and metastatic phenotype of highly invasive cancer cells has been related to abnormal structure and function of TJs, and with expression of activated matrix metalloproteinases (MMPs). The relevance of these mechanisms responsible for the invasion and metastasis of ovarian carcinoma is unclear. Similarly, it is not known if the expression of claudin-6, occludin and MMP2 is related with the clinical properties of these tumors.
Expression of claudin-6, occludin, and MMP2 was detected in samples of human ovarian cancer tissues by immunohistochemistry and correlated with the clinical properties of the tumors.
The positive expression rates of claudin-6 and MMP-2 were higher in ovarian papillary serous carcinomas than n ovarian serous adenomas (P < 0.05). There were no differences in the expression of occludin (P > 0.05). The expression of claudin-6 and occludin in ovarian cancer was not correlated with patient age, pathological grade, clinical stage, and metastasis (P > 0.05). MMP-2 expression was enhanced with increased clinical stage and metastasis (P < 0.05), but was unrelated to patient age or tumor grade (P > 0.05). There were no apparent correlations between expression of claudin-6, occludin and MMP-2 in ovarian cancer tissue (P > 0.05).
Our data suggest, for the first time, that the claudin-6 and MMP-2 are up-regulated in ovarian papillary serous carcinomas, MMP-2 expression was enhanced with increased clinical stage and metastasis. Claudin-6 and MMP-2 may play a positive role in the invasion and metastasis of ovarian cancer.
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1775628454106511.
Tight junctions; Ovarian cancer; Claudin-6; Occludin; MMP-2
Since our newly synthesized potent 5-indolyl derivative, (2-(1 H-Indol-5-yl) thiazol-4-yl) 3, 4, 5-trimethoxyphenyl methanone (LY293), to treat resistant melanoma was hydrophobic, our objective was to synthesize a biodegradable copolymer for formulating this drug into nanoparticles and to determine its anticancer activity and mechanism of action.
Methoxy poly (ethylene glycol)-b-poly (carbonate-colactide) [mPEG-b-P (CB-co-LA)] was synthesized for formulating LY293 into nanoparticles by o/w emulsification and stabilization by solvent evaporation. Particle size, drug release profile, in vitro efficacy in multiple melanoma cells, and mechanism of action of drug-loaded nanoparticles were determined.
LY293-loaded nanoparticles with 170 nm mean size and 2.2 and 4.16% drug loading efficiently inhibited proliferation of A375 and B16F10 cells with IC50 of 12.5 nM and 25 nM, respectively. LY293 circumvented multidrug resistance and inhibited proliferation of Pgp overexpressing MDA-MB435/LCC6 MDR1 melanoma cells. Upon treatment with LY293-loaded nanoparticles, A375 cells underwent cell cycle arrest in G2/M phase and apoptotic cell death. Immunofluorescence images showed inhibition of tubulin polymerization after treatment with LY293.
LY293-loaded mPEG-b-P (CB-co-LA) nanoparticles showed excellent efficacy and induced apoptosis in melanoma cells. These polyester/polycarbonate-based nanoparticles provided an excellent platform to deliver different poorly soluble drugs to melanoma.
LY293; melanoma; polymeric nanoparticles; tubulin polymerization
To evaluate the efficacy and oral activity of two promising indoles, (2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone [compound II] and (2-(1H-indol-5-ylamino)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone [compound IAT], in paclitaxel- and docetaxel-resistant tumor models in vitro and in vivo.
The in vitro drug-like properties, including potency, solubility, metabolic stability, and drug-drug interactions were examined for our two active compounds. An in vivo pharmacokinetic study and antitumor efficacy study were also completed to compare their efficacy with docetaxel.
Both compounds bound to the colchicine-binding site on tubulin, and inhibited tubulin polymerization, resulting in highly potent cytotoxic activity in vitro. While the potency of paclitaxel and docetaxel was compromised in a multidrug-resistant cell line that overexpresses P-glycoprotein, the potency of compounds II and IATwas maintained. Both compounds had favorable drug-like properties, and acceptable oral bioavailability (21–50%) in mice, rats, and dogs. Tumor growth inhibition of greater than 100% was achieved when immunodeficient mice with rapidly growing paclitaxel-resistant prostate cancer cells were treated orally at doses of 3–30 mg/kg of II or IAT.
These studies highlight the potent and broad anticancer activity of two orally bioavailable compounds, offering significant pharmacologic advantage over existing drugs of this class for multidrug resistant or taxane-refractory cancers.
paclitaxel resistant cancer; P-glycoprotein; pharmacokinetics; tubulin; xenograft
To evaluate abilities of 2-aryl-4-benzoyl-imidazoles (ABI) to overcome multidrug resistance (MDR), define their cellular target, and assess in vivo antimelanoma efficacy.
MDR cell lines that overexpressed P-glycoprotein, MDR-associated proteins, and breast cancer resistance protein were used to evaluate ABI ability to overcome MDR. Cell cycle analysis, molecular modeling, and microtubule imaging were used to define ABI cellular target. SHO mice bearing A375 human melanoma xenograft were used to evaluate ABI in vivo antitumor activity. B16-F10/C57BL mouse melanoma lung metastasis model was used to test ABI efficacy to inhibit tumor lung metastasis.
ABIs showed similar potency to MDR cells compared to matching parent cells. ABIs were identified to target tubulin on the colchicine binding site. After 31 days of treatment, ABI-288 dosed at 25 mg/kg inhibited melanoma tumor growth by 69%; dacarbazine at 60 mg/kg inhibited growth by 52%. ABI-274 dosed at 25 mg/kg showed better lung metastasis inhibition than dacarbazine at 60 mg/kg.
This new class of antimitotic compounds can overcome several clinically important drug resistant mechanisms in vitro and are effective in inhibiting melanoma lung metastasis in vivo, supporting their further development.
2-aryl-4-benzoyl-imidazoles (ABI); antimelanoma; melanoma lung metastasis; multidrug resistance; tubulin polymerization inhibitor
Tubulin dynamics is a promising target for new chemotherapeutic agents. The colchicine binding site is one of the most important pockets for potential tubulin polymerization destabilizers. Colchicine binding site inhibitors (CBSI) exert their biological effects by inhibiting tubulin assembly and suppressing microtubule formation. A large number of molecules interacting with the colchicine binding site have been designed and synthesized with significant structural diversity. CBSIs have been modified as to chemical structure as well as pharmacokinetic properties, and tested in order to find a highly potent, low toxicity agent for treatment of cancers. CBSIs are believed to act by a common mechanism via binding to the colchicine site on tubulin. The present review is a synopsis of compounds that have been reported in the past decade that have provided an increase in our understanding of the actions of CBSIs.
antimitotic; cancer; colchicine; multidrug resistance; tubulin polymerization inhibitor
Scrub typhus is endemic to a 13,000,000-km2 area of the Asia-Pacific region, and causes an annual incidence of 1 million people. The mortality rate of scrub typhus ranges from 6.1% to 25% in Southeast Asia. Natural infection of Orientia tsutsugamushi has been identified in domestic rodents in Shandong Province. However, infestation of chiggers and ticks on the domestic rodents and prevalence and genotypes of O. tsutsugamushi in these Acarina remain unclear.
During September 2010 to March 2012, 3134 chiggers and 89 ticks were collected from domestic rodents captured in three counties of Shandong Province. We amplified and sequenced the 56-kDa type-specific antigen gene of O. tsutsugamushi from DNA samples of these Acarina and designated to genotype according to sequence analysis.
Overall, the infestation rate of chiggers on domestic rodents was 17.0%, and the chigger index was 5.38. The infestation rate of ticks on rodents was 3.1%. Natural infection of O. tsutsugamushi was found in Leptotrombidium taishanicum, L. linhuaikongense, L. intermedium, L. scutellare, L. palpale, and Ixodes spp., the minimum positive rates of which were 5.9%, 3.2%, 1.2%, 0.8%, 0.8%, and 2.2%, respectively. Kawasaki-like genotypes were predominant in chiggers and ticks on domestic rodents, which were detected from L. taishanicum, L. intermedium, L. scutellare, L. palpale, and Ixodes spp. Shimokoshi-like genotype was detected from L. palpale.
In the present study we investigated the infestation of chiggers and ticks on domestic rodents in Shandong Province, and identified the prevalence and genotypes of O. tsutsugamushi in the Acarina. Infestation of vector chiggers in domestic rodents, prevalence of O. tsutsugamushi in infested chiggers, and high nucleotide homologies among the O. tsutsugamushi sequences from the Acarina, their animal hosts and scrub typhus patients, implied that domestic rodents may play an important role in the transmission of scrub typhus in Shandong, China. Further studies are needed to verify the vector significance of chiggers and ticks that tested positive for O. tsutsugamushi, and to assess the risk of human exposure to chiggers and ticks on domestic rodents.
Scrub typhus; Orientia tsutsugamushi; Chigger; Tick; Rodents
Endometrial carcinoma with a germ cell tumor component is a rare event. Here we report a uterine neoplasm with a unique combination of endometrioid adenocarcinoma and mixed germ cell malignant elements. A 28-year-old woman with abnormal vaginal bleeding, an abdominal mass, and elevated alfa-fetoprotein and beta-human chorionic gonadotropin (β-hCG) levels had a history of biopsy of an omental mass and chemotherapy in another hospital one month before her referral to our department. Histologic examination of the mass removed from the omentum revealed an endometrioid adenocarcinoma with yolk sac tumor-like differentiation. Total abdominal hysterectomy, bilateral salpingo-oophorectomy, infracolic omentectomy, and removal of metastatic disease were then undertaken at our hospital. Postoperative chemotherapy was given. Eight months postoperatively, serum alfa-fetoprotein and β-hCG rose again. Cases with primary yolk sac tumors of the endometrium or endometrial carcinoma with trophoblastic differentiation in the literature were reviewed.
endometrial carcinoma; yolk sac tumor; trophoblastic differentiation
Metabolic syndrome is a serious health problem in both developed and developing countries. The present study investigated the anti-metabolic disorder effects of different pomelo varieties on obese C57BL/6 mice induced by high-fat (HF) diet.
The peels of four pomelo varieties were extracted with ethanol and the total phenols and flavonoids content of these extracts were measured. For the animal experiment, the female C57BL/6 mice were fed with a Chow diet or a HF diet alone or supplemented with 1% (w/w) different pomelo peel extracts for 8 weeks. Body weight and food intake were measured every other day. At the end of the treatment, the fasting blood glucose, glucose tolerance and insulin (INS) tolerance test, serum lipid profile and insulin levels, and liver lipid contents were analyzed. The gene expression analysis was performed with a quantitative real-time PCR assay.
The present study showed that the Citrus grandis liangpinyou (LP) and beibeiyou (BB) extracts were more potent in anti-metabolic disorder effects than the duanshiyou (DS) and wubuyou (WB) extracts. Both LP and BB extracts blocked the body weight gain, lowered fasting blood glucose, serum TC, liver lipid levels, and improved glucose tolerance and insulin resistance, and lowered serum insulin levels in HF diet-fed mice. Compared with the HF group, LP and BB peel extracts increased the mRNA expression of PPARα and its target genes, such as FAS, PGC-1α and PGC-1β, and GLUT4 in the liver and white adipocyte tissue (WAT).
We found that that pomelo peel extracts could prevent high-fat diet-induced metabolic disorders in C57BL/6 mice through the activation of the PPARα and GLUT4 signaling. Our results indicate that pomelo peels could be used as a dietary therapy and the potential source of drug for metabolic disorders.
The vascular endothelial growth factor (VEGFA) gene has been suggested to play an important role in the pathogenesis of diabetic retinopathy (DR). However, the results have been inconsistent. In this study, we performed a meta-analysis to clarify the associations between VEGFA polymorphisms and DR risk.
Published literature from PubMed, EMBASE, Web of Science and Google Scholar were retrieved. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed- or random-effects model.
A total of eight studies (1204 cases and 1198 controls) for rs699947 polymorphism and ten studies (1666 cases and 1782 controls) for rs2010963 polymorphism were included in the meta-analysis. The results suggested that rs699947 polymorphism was marginally associated with DR under a homogeneous co-dominant model (AA vs. CC: OR = 1.69, 95% CI = 1.03-2.77, p = 0.040) and a dominant model (AA + AC vs. CC: OR = 1.38, 95% CI = 1.01-1.90, p = 0.040), whereas the association between rs2010963 polymorphism and DR was not significant under all genetic models (all p > 0.05). In the subgroup analysis, the effect size for rs699947 polymorphism was only marginally significant among European populations under a dominant model (OR = 1.47, 95% CI = 1.07–2.02, p = 0.018), but not among East Asians. After exclusion of outliers which were the source of between-study heterogeneity, there was significant association between rs699947 polymorphism and DR under a homogeneous co-dominant model (OR = 1.64, 95% CI = 1.18-2.28, p = 0.003), even after multiple comparison correction.
Our meta-analysis confirmed the significant association between rs699947 polymorphism and DR after exclusion of outliers, and rs2010963 polymorphism might be not associated with DR.
The vascular endothelial growth factor gene; Polymorphism; Diabetic retinopathy; Meta-analysis
The light-harvesting chlorophyll a/b-binding (LHCB) proteins are the apoproteins of the light-harvesting complex of photosystem II. In the present study, we observed that downregulation of any of the six LHCB genes resulted in abscisic acid (ABA)-insensitive phenotypes in seed germination and post-germination growth, demonstrating that LHCB proteins are positively involved in these developmental processes in response to ABA. ABA was required for full expression of different LHCB members and physiologically high levels of ABA enhanced LHCB expression. The LHCB members were shown to be targets of an ABA-responsive WRKY-domain transcription factor, WRKY40, which represses LHCB expression to balance the positive function of the LHCBs in ABA signalling. These findings revealed that ABA is an inducer that fine-tunes LHCB expression at least partly through repressing the WRKY40 transcription repressor in stressful conditions in co-operation with light, which allows plants to adapt to environmental challenges.
Abscisic acid signalling; Arabidopsis thaliana; light-harvesting chlorophyll a/b-binding protein; post-germination growth; seed germination; WRKY40 transcription factor.
Sleep duration has been shown to play an important role in the development of cancer. However, the results have been inconsistent. A meta-analysis with prospective cohort studies was performed to clarify the association between short or long sleep duration and cancer risk.
PubMed and Embase databases were searched for eligible publications. Pooled relative risk (RR) with 95% confidence interval (CI) was calculated using random- or fixed- model.
A total of 10 prospective studies (8392 incident cases and 555678 participants) were included in the meta-analysis. Neither short nor long sleep duration was statistically associated with increased risk of cancer (short sleep duration: RR=1.05, 95%CI=0.90-1.24, p=0.523; long sleep duration: RR=0.92, 95%CI=0.76-1.12, p=0.415). In the subgroup by cancer type, long sleep duration was positively associated with colorectal cancer (RR=1.29, 95%CI=1.09-1.52, p=0.003).
The present meta-analysis suggested that neither short nor long sleep duration was significantly associated with risk of cancer, although long sleep duration increased risk of with colorectal cancer. Large-scale well-design prospective studies are required to be conducted to further investigate the observed association.
Novel ABI–III compounds were designed and synthesized based on our previously reported ABI-I and ABI–II analogs. ABI–III compounds are highly potent against a panel of melanoma and prostate cancer cell lines, with the best compound having an average IC50 value of 3.8 nM. They are not substrate of Pgp and thus may effectively overcome Pgp mediated multidrug resistance. ABI–III analogs maintain their mechanisms of action by inhibition of tubulin polymerization.
Melanoma; prostate cancer; multidrug resistance; tubulin polymerization inhibitor; antiproliferative activity
Cancers have a multifactorial etiology a part of which is genetic. Recent data indicate that expression of the tight junction claudin proteins is involved in the etiology and progression of cancer.
To explore the correlations of the tight junction proteins claudin-2,-6, and −11 in the pathogenesis and clinical behavior of gastric cancer, 40 gastric cancer tissues and 28 samples of non-neoplastic tissues adjacent to the tumors were examined for expression of claudin-2,-6, and −11 by streptavidin-perosidase immunohistochemical staining method.
The positive expression rates of claudin-2 in gastric cancer tissues and adjacent tissues were 25% and 68% respectively (P < 0.001). The positive expression rates of claudin-6 in gastric cancer tissues and adjacent tissues were 55% and 79% respectively (P = 0.045 < 0.05). In contrast, the positive expression rates of claudin-11 in gastric cancer tissues and gastric cancer adjacent tissues were 80% and 46% (P = 0.004 < 0.01). Thus in our study, the expression of claudin-2, and claudin-6 was down regulated in gastric cancer tissue while the expression of claudin-11 was up regulated. Correlations between claudin expression and clinical behavior were not observed.
Our study provides the first evidence that claudin-2,-6, and −11 protein expression varies between human gastric cancers and adjacent non-neoplastic tissues.
The virtual slide(s) for this article can be found here:
Gastric cancer; Tight junctions; Claudin-2; Claudin-6; Claudin-11; Immunohistochemistry