Embryonic stem (ES) cells derived from the inner cell mass (ICM) of blastocysts are characterised by their ability to self-renew and their potential to differentiate into many different cell types. Recent studies have shown that zinc finger proteins are crucial for maintaining pluripotent ES cells. Mouse zinc finger protein 322a (Zfp322a) is expressed in the ICM of early mouse embryos. However, little is known regarding the role of Zfp322a in the pluripotency maintenance of mouse ES cells. Here, we report that Zfp322a is required for mES cell identity since depletion of Zfp322a directs mES cells towards differentiation. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays revealed that Zfp322a binds to Pou5f1 and Nanog promoters and regulates their transcription. These data along with the results obtained from our ChIP-seq experiment showed that Zfp322a is an essential component of mES cell transcription regulatory network. Targets which are directly regulated by Zfp322a were identified by correlating the gene expression profile of Zfp322a RNAi-treated mES cells with the ChIP-seq results. These experiments revealed that Zfp322a inhibits mES cell differentiation by suppressing MAPK pathway. Additionally, Zfp322a is found to be a novel reprogramming factor that can replace Sox2 in the classical Yamanaka's factors (OSKM). It can be even used in combination with Yamanaka's factors and that addition leads to a higher reprogramming efficiency and to acceleration of the onset of the reprogramming process. Together, our results demonstrate that Zfp322a is a novel essential component of the transcription factor network which maintains the identity of mouse ES cells.
Embryonic stem (ES) cells are featured by their ability to self-renew and by their potential to differentiate into many different cell types. Recent studies have revealed that the unique properties of mouse ES cells are governed by a specific transcription regulatory network, including master regulators Oct4/Sox2/Nanog and other pluripotency factors. The importance of these factors was highlighted by the subsequent finding that combination of several transcription factors can reprogram differentiated fibroblasts back to pluripotent stem cells. Here, we report that Zfp322a is a novel factor which is required for mES cell identity. We revealed that Zfp322a can regulate the key pluripotency genes Pou5f1 and Nanog and functions as a repressor of MAPK/ERK pathway in mES cells, therefore preventing mES cell differentiation. Furthermore, we discovered that Zfp332a can promote the generation of induced pluripotent stem cells (iPSCs) from mouse embryonic fibroblasts (MEFs). Our results reveal that Zfp322a is a novel essential transcription factor which not only regulates ES cell pluripotency but also enhances iPSC formation.
The roles of cholecystokinin 2 receptor (CCK2R) in numerous physiologic processes in the gastrointestinal tract and central nervous system are ‘well documented. There has been some evidence that CCK2R alterations play a role in cancers, but the functional significance of these alterations for tumorigenesis is unknown. We have identified six mutations in CCK2R among a panel of 140 colorectal cancers and 44 gastric cancers. We show that these mutations increase receptor activity, activate multiple downstream signaling pathways, increase cell migration, and promote angiogenesis. Our findings suggest that somatic mutations in CCK2R may promote tumorigenesis through deregulated receptor activity and highlight the importance of evaluating CCK2R inhibitors to block both the normal and mutant forms of the receptor.
Background and objective
Transcriptional factor E2A is crucial for the normal development and differentiation of B and T lymphocytes. Dysregulation of E2A leads to leukemia and tumorigenesis of some solid tumors. The expression and clinical significance of E2A as well as its role in colorectal cancer (CRC) are still unknown. This study aims to assess E2A expression in CRC tissues, evaluate its prognosis value, and investigate its role in colon cancer cell growth.
E2A expression in CRC tissues and normal mucosa was detected by immunohistochemical staining; Kaplan-Meier survival curve and Cox regression model were used to evaluate the prognostic value of E2A. Lentivirus was used to construct E2A stably knocked-down cells. MTT assay was employed to detect cell proliferation change; cell cycle was analyzed by flow cytometry; and chromatin immunoprecipitation (ChIP) assay was used to validate the predicted binding target of E2A.
Expression of E2A was lower in CRC tissues than normal mucosa; low E2A expression correlated with advanced TNM stage and larger tumor size, and predicted poor prognosis of CRC patients. E2A knockdown resulted in increased cell proliferation rate and cell cycle acceleration. ChIP assay showed miR-320a was a direct target of E2A and upregulation of miR-320a in E2A downregulated cells could reverse cell proliferation and cell cycle changes caused by E2A deficiency.
E2A is an independent prognostic factor for CRC patients and targets miR-320a to regulate cell proliferation of colon cancer cells.
Hawthorn (Crataegus oxyacantha) is a widely used Chinese herb for treatment of gastrointestinal ailments and heart problems and consumed as food. In North America, the role of treatment for heart problems dates back to 1800. Currently, evidence is accumulating from various in vivo and in vitro studies that hawthorn extracts exert a wide range of cardiovascular pharmacological properties, including antioxidant activity, positive inotropic effect, anti-inflammatory effect, anticardiac remodeling effect, antiplatelet aggregation effect, vasodilating effect, endothelial protective effect, reduction of smooth muscle cell migration and proliferation, protective effect against ischemia/reperfusion injury, antiarrhythmic effect, lipid-lowering effect and decrease of arterial blood pressure effect. On the other hand, reviews of placebo-controlled trials have reported both subjective and objective improvement in patients with mild forms of heart failure (NYHA I–III), hypertension, and hyperlipidemia. This paper discussed the underlying pharmacology mechanisms in potential cardioprotective effects and elucidated the clinical applications of Crataegus and its various extracts.
E2A gene, which encodes two basic helix–loop–helix (bHLH) transcription factors E12 and E47, has been identified as regulator of B lymphoid hematopoiesis and suppressor of lymphoma. E47 protein was found to decrease E-cadherin expression and induce epithelial-mesenchymal transition (EMT). However, the role of E2A in colorectal cancer (CRC) metastasis is still elusive.
qRT-PCR and semi-qRT-PCR were performed to determine mRNA level of E2A in CRC specimens and colorectal cancer cells. RNAi was employed to downregulate E2A expression and subsequent protein level change was evaluated by immunoblot. Cell invasion and migration capacity were detected by transwell assay using cell culture inserts with or without basement membrane matrix, respectively.
E2A expression was decreased in metastatic CRC tissues. Invasion and migration assays showed downregulation of E2A increased metastatic capacity of CRC cells while forced expression of E12 or E47 could offset this effect. Both E12 and E47 suppressed EMT induced by E2A downregulation. Moreover, Yes-Associated Protein (YAP) was a downstream target of E2A and suppression of YAP inhibited the pro-migration/invasion of E2A deficiency.
Our results suggest that E2A suppresses CRC cell metastasis, at least partially if not all, by inhibiting YAP expression.
Metastasis; E2A; Colorectal cancer; YAP; EMT
Objectives. We aimed to assess the current clinical evidence of Chinese herbal medicine for AMS. Methods. Seven electronic databases were searched until January 2013. We included randomized clinical trials testing Chinese herbal medicine against placebo, no drugs, Western drugs, or a combination of routine treatment drugs against routine treatment drugs. Study selection, data extraction, quality assessment, and data analyses were conducted according to Cochrane standards. Results. Nine randomized trials were included. The methodological quality of the included trials was evaluated as low. Two trials compared prescriptions of Chinese formula used alone with Western drugs. A meta-analysis showed a beneficial effect in decreasing the score of AMS (MD: −2.23 [−3.98, −0.49], P = 0.01). Only one trial compared prescriptions of Chinese formula used alone with no drugs. A meta-analysis showed a significant beneficial effect in decreasing the score of AMS (MD: −6.00 [−6.45, −5.55], P < 0.00001). Four trials compared Chinese formula used alone with placebo. A meta-analysis also showed a significant beneficial effect in decreasing the score of AMS (MD: −1.10 [−1.64, −0.55], P < 0.0001). Two trials compared the combination of Chinese formula plus routine treatment drugs with routine treatment drugs. A meta-analysis showed a beneficial effect in decreasing the score of AMS (MD: −5.99 [−11.11, −0.86], P = 0.02). Conclusions. No firm conclusion on the effectiveness and safety of Chinese herbal medicine for AMS can be made. More rigorous high-quality trials are required to generate a high level of evidence and to confirm the results.
Although numerous clinical trials have evaluated the body weight change achieved using diabetes medications alone or in combinations, the composition of body weight change in these clinical trials has rarely been assessed.
We aimed to evaluate the effects of gliclazide, metformin, and acarbose monotherapy on body composition, fat distribution, and other cardiometabolic risk factors in patients with newly diagnosed type 2 diabetes.
A total of 86 patients with newly diagnosed type 2 diabetes mellitus were randomly assigned to receive gliclazide, metformin, or acarbose for 6 months. Dual-energy x-ray absorptiometry; abdominal computed tomography scans; and measurements of adiponectin, leptin, and lipid levels were performed before and after 6-month monodrug therapy.
Blood glucose and glycosylated hemoglobin levels significantly improved after 6 months of monodrug therapy. During the 6 months of use of the 3 antidiabetes medications, the majority of participants experienced fat mass loss and lean mass gain. Metformin monotherapy in patients with newly diagnosed type 2 diabetes led to a significant decrease in percent body fat (P = 0.029) and body fat mass (P = 0.038). Levels of serum total cholesterol (P = 0.004), triglycerides (P = 0.014), and adiponectin (P = 0.001) took a favorable turn after metformin treatment. The 3 antidiabetes medications caused no significant change in abdominal fat distribution, waist circumstance, and blood pressure during the 6 months.
Our results suggest metformin therapy in patients with newly diagnosed type 2 diabetes can improve cardiometabolic risk markers. Moreover, body composition change induced by gliclazide and acarbose was not likely to be simple fat deposition.
body composition; fat distribution; monodrug therapy; newly diagnosed type 2 diabetes
We examined the clinical value of two serum markers of low-grade inflammation, C-reactive protein (CRP) and receptor of advanced glycation products (RAGE), as prognostic indices for cognitive decline.
Patients with cognitive impairment (n = 377) and controls (n = 66) were examined by blood biochemistry tests, including ELISAs of serum CRP and RAGE, the Mini-mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), and STEAM 1H-MRS of the left hippocampus and thalamus.
Compared to the control group, the cognitive impairment group was older (63.10 ± 9.70 years vs. 55.09 ± 10.77 years, P = 0.000) and had fewer years of formal education (9.01 ± 4.01 vs. 12.94 ± 3.0, P = 0.000). There were no significant differences in the frequencies of type 2 diabetes, hypertension, or hyperlipidemia between groups. Serum CRP and RAGE were higher in the cognitive impairment group (CRP: 2.08 mg/L, range 1.07 − 3.36 mg/L vs. 0.21 mg/L, range 0.18 − 0.42 mg/L; RAGE: 4.01, range 2.49 − 5.71, vs. 2.28, range 1.84 − 3.03; P < 0.05 for both). In patients with cognitive impairment, there were negative correlations between cognitive function (as measured by MMSE and MoCA) and both CRP and RAGE levels (P < 0.05). Patients over 55 years exhibited a positive correlation between CRP and myo-inositol peak area in the left hippocampus (P < 0.05), while there was no relationship between RAGE and any metabolite (P > 0.05). Multiple linear regression revealed that CRP was influenced by hypertension (P = 0.026) and cognitive impairment (P = 0.042).
Chronic low-grade inflammation is present in patients with cognitive impairment. Serum CRP, RAGE, and left hippocampal myo-inositol may provide prognostic information on cognitive decline.
Objectives. To assess the current clinical evidence of Tai Chi for essential hypertension (EH). Search Strategy. 7 electronic databases were searched until 20 April, 2013.
Inclusion Criteria. We included randomized trials testing Tai Chi versus routine care or antihypertensive drugs. Trials testing Tai Chi combined with antihypertensive drugs versus antihypertensive drugs were also included.
Data Extraction and Analyses. Study selection, data extraction, quality assessment, and data analyses were conducted according to the Cochrane standards. Results. 18 trials were included. Methodological quality of the trials was low. 14 trials compared Tai Chi with routine care. 1 trial compared Tai Chi with antihypertensive drugs. Meta-analysis all showed significant effect of TaiChi in lowering blood pressure (BP). 3 trials compared Tai Chi plus antihypertensive drugs with antihypertensive drugs. Positive results in BP were found in the other 2 combination groups. Most of the trials did not report adverse events, and the safety of Tai Chi is still uncertain. Conclusions. There is some encouraging evidence of Tai Chi for EH. However, due to poor methodological quality of included studies, the evidence remains weak. Rigorously designed trials are needed to confirm the evidence.
Metastasis remains to be one of the most prevalent causes leading to poor long-term survival of colorectal cancer (CRC) patients. The clinical significances of tumor metastatic suppressor, N-myc downregulated gene 1 (NDRG1), have been inconsistently reported in a variety of cancerous diseases. In this study with 240 CRC clinical specimens, we showed that NDRG1 expression was significantly decreased in most of CRC tissues compared to the paired non-tumor counterparts. Statistical analysis revealed a significant inverse correlation of NDRG1 expression with tumor stage, differentiation status and metastasis. Compared with NDRG1-negative group, NDRG1-positve group had better disease-free/overall survival (p = 0.000) over 5 years’ follow-up. Furthermore, NDRG1 was considered to be an independent prognostic factor for overall survival (p = 0.001) and recurrence (p = 0.003). Our study concludes that NDRG1 is a novel favorable predictor for the prognosis in CRC patients.
Objectives. To assess the current clinical evidence of Chinese herbal medicine (CHM) for prehypertension. Search Strategy. Electronic databases were searched until May, 2013. Inclusion Criteria. We included randomized clinical trials testing CHM against life style intervention and no treatment, or combined with life style intervention against life style intervention. Data Extraction and Analyses. Study selection, data extraction, quality assessment, and data analyses were conducted according to Cochrane standards. Results. Five trials were included. Methodological quality of the trials was evaluated as generally low. Only 1 trial reported allocation sequence. No trial reported the allocation concealment, double blinding, placebo control, presample size estimation, intention to treat analysis, and drop-out. All the included trials were not multicenter and large scale. Although meta-analysis showed that CHM is superior to either life style intervention group or no treatment group in decreasing blood pressure, we are unable to draw a definite conclusion on the effect of CHM due to the poor research methods used in the reviewed trials. The safety of CHM is still uncertain. Conclusions. There is no evidence to show that CHM is effective and safe for prehypertension due to serious methodological flaw of the reviewed trials. Rigorously designed trials are warranted to confirm these results.
Reduction of glutamine synthetase (GS) function is closely related to established epilepsy, but little is known regarding its role in epileptogenesis. The present study aimed to elucidate the functional changes of GS in the brain and its involvement in epileptogenesis using the amygdala kindling model of epilepsy induced by daily electrical stimulation of basolateral amygdala in rats. Both expression and activity of GS in the ipsilateral dentate gyrus (DG) were upregulated when kindled seizures progressed to stage 4. A single dose of L-methionine sulfoximine (MSO, in 2 µl), a selective GS inhibitor, was administered into the ipsilateral DG on the third day following the first stage 3 seizure (just before GS was upregulated). It was found that low doses of MSO (5 or 10 µg) significantly and dose-dependently reduced the severity of and susceptibility to evoked seizures, whereas MSO at a high dose (20 µg) aggravated kindled seizures. In animals that seizure acquisition had been successfully suppressed with 10 µg MSO, GS upregulation reoccurred when seizures re-progressed to stage 4 and re-administration of 10 µg MSO consistently reduced the seizures. GLN at a dose of 1.5 µg abolished the alleviative effect of 10 µg MSO and deleterious effect of 20 µg MSO on kindled seizures. Moreover, appropriate artificial microRNA interference (1 and 1.5×106 TU/2 µl) of GS expression in the ipsilateral DG also inhibited seizure progression. In addition, a transient increase of GS expression and activity in the cortex was also observed during epileptogenesis evoked by pentylenetetrazole kindling. These results strongly suggest that a transient and region-specific upregulation of GS function occurs when epilepsy develops into a certain stage and eventually promotes the process of epileptogenesis. Inhibition of GS to an adequate degree and at an appropriate timing may be a potential therapeutic approach to interrupting epileptogenesis.
Objectives. To assess the clinical evidence of Chinese herbal medicine (CHM) for obesity-related hypertension. Search Strategy. Electronic databases were searched until January, 2013. Inclusion Criteria. We included randomized clinical trials (RCTs) testing CHM against nondrug therapy and conventional western medicine, or combined with conventional western medicine against conventional western medicine. Data Extraction and Analyses. Study selection, data extraction, quality assessment, and data analyses were conducted according to Cochrane standards. Results. 11 trials were included. Methodological quality was evaluated as low. 1 trial investigated the efficacy of CHM plus nondrug therapy versus nondrug therapy. Positive results in diastolic blood pressure (DBP) (WMD: −5.40 [−5.88, −4.92]; P < 0.00001) were found in combination group. 1 trial investigated the efficacy of CHM versus conventional western medicine. Positive results in systolic blood pressure (SBP) (WMD: −1.39 [−2.11, −0.67]; P = 0.0002) were found in CHM. 9 trials investigated the efficacy of CHM plus conventional western medicine versus conventional western medicine. Positive results in SBP (WMD: -6.71 [−11.08, −1.25]; P = 0.02) were found in combination group. The safety of CHM is unknown. Conclusions. No definite conclusion could be got due to poor methodological quality. Rigorously designed trials are warranted to confirm these results.
The aim of this study was to optimize the extraction parameters of Fomes officinalis Ames polysaccharides (FOAPs) and evaluate their antitumor activity. FOAPs were extracted using the hot water extraction, acid extraction and alkali extraction methods, respectively. Alcohol precipitation and acetone washes were conducted to separate and purify the FOAPs. The FOAP content was determined using the phenol-sulfuric acid method. The effects of raw material particle size, extraction time and material-liquid ratio on the yield of FOAPs were investigated, and the effects of FOAPs on the immune function of S180 tumor-bearing mice and their antitumor activity were evaluated. The yield of FOAPs obtained with the hot water extraction method was higher compared with the yields of the other methods. The optimum extraction conditions were as follows: a raw material particle size of 24 mesh; an extraction time of 2.5 h; and a material-liquid ratio of 1 g:12 ml. Under these conditions, the yield of FOAPs was 1.13%. FOAPs significantly inhibited tumor growth and enhanced the immune function in S180 tumor-bearing mice. FOAPs extracted using the hot water extraction method have antitumor activity.
Fomes officinalis Ames; polysaccharide; extraction; S180 tumor-bearing mice; immune function
Salvianolic acid B (SAB, Sal B) is the representative component of phenolic acids derived from the dried root and rhizome of Salvia miltiorrhiza Bge (Labiatae) which has been used widely and successfully in Asian countries for clinical therapy of various vascular disturbance-related diseases for hundreds of years. However, its exact cardioprotective components and the underlying mechanism for therapeutic basis are still poorly understood. This paper discussed and elucidated the underlying biological mechanisms and pharmacology of Sal B and their potential cardioprotective effects.
Background. Tianma Gouteng Yin (TGY) is widely used for essential hypertension (EH) as adjunctive treatment. Many randomized clinical trials (RCTs) of TGY for EH have been published. However, it has not been evaluated to justify their clinical use and recommendation based on TCM zheng classification. Objectives. To assess the current clinical evidence of TGY as adjunctive treatment for EH with liver yang hyperactivity syndrome (LYHS) and liver-kidney yin deficiency syndrome (LKYDS). Search Strategy. 7 electronic databases were searched until November 20, 2012. Inclusion Criteria. RCTs testing TGY combined with antihypertensive drugs versus antihypertensive drugs were included. Data Extraction and Analyses. Study selection, data extraction, quality assessment, and data analyses were conducted according to the Cochrane standards. Results. 22 RCTs were included. Methodological quality was generally low. Except diuretics treatment group, blood pressure was improved in the other 5 subgroups; zheng was improved in angiotensin converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), and “CCB + ACEI” treatment groups. The safety of TGY is still uncertain. Conclusions. No confirmed conclusion about the effectiveness and safety of TGY as adjunctive treatment for EH with LYHS and LKYDS could be made. More rigorous trials are needed to confirm the results.
To evaluate the protective effects of α-lipoic acid on the kidneys of Goto-Kakisaki (GK) diabetic rats, ten GK diabetic rats were randomly divided into a diabetic control group and a lipoic acid-treated diabetic group with α-lipoic acid 35 mg·Kg−1 intraperitoneal injections. Four healthy Wistar rats served as normal controls. Malonaldehyde (MDA), ascorbic acid (vitamin C), vitamin E, glutathione (GSH) and superoxide dismutase (SOD) levels in renal homogenate, and urine protein excretion were measured. The expression of mRNA for NF-κB, NADPH oxidase subunits p22phox and p47phox in renal tissue was examined by realtime PCR. Pathological changes in renal tissue were evaluated by light and electron microscopy. There were significant increases in urine protein excretion, MDA levels and the expression of mRNA of NF-κB, p22phox and p47phox, and significant decreases in GSH, SOD, vitamin C and vitamin E levels in the diabetic control group compared with the normal control group. Pathological changes of renal tissue were more progressive in the diabetic control group than in the normal control group. All the parameters above were improved in the α-lipoic acid-treated diabetic group. Oxidative stress is increased in the kidney of type 2 diabetic GK rats. It is associated with the progression of diabetic nephropathy. α-lipoic acid can protect renal function in diabetic rats via its antioxidant activity.
antioxidant; α-lipoic acid; diabetic nephropathy; oxidative stress
Patients with diabetes mellitus exhibit peripheral arterioles lesions that is associated with reduced blood flow. Here, we intended to assess the acral arterioles lesion in patients with type 2 diabetes based on the rate of blood flow by multigate spectral Doppler ultrasonography. Fifty-two patients with type 2 DM were divided into two groups. Group 1 included 13 men and 12 women with an average age of 60.60 ± 14.03 years and a duration of type 2 diabetes for 2.44 ± 1.50 years. Group 2 included 17 men and 11 women with an average age of 64.25 ± 10.84 years and type 2 diabetes for 12.57 ± 6.26 years. Age-matched control subjects (n = 52) were recruited (30 men and 22 woman, mean age of 61.19 ± 10.38 years). A multigate spectral Doppler algorithm was applied to the acral finger of the thumb of the right hand to test the arteriole diameter and hemodynamic parameters, including diameter of the acral finger arterioles (D), area of the blood flow profile of the acral finger arterioles (Amax) and hemodynamic parameters. Patients with diabetes exhibited a significant reduction in the arteriole diameter (1.63 ± 0.18 and 1.57 ± 0.22 mm, respectively, P < 0.001 for both) compared to control subjects (2.09 ± 0.17 mm). Amax were significantly reduced in patients with diabetes (61.35 ± 10.66 mm2/s for group 1 and 46.50 ± 6.59 mm2/s for group 2, P < 0.001 for both) compared to that in control subjects (77.93 ± 12.37 mm2/s). Furthermore, a significant difference in Amax was found between group 1 and group 2 (P < 0.001). The vascular resistance index (RI) was significantly higher in both patient groups 0.58 ± 0.06 for group 1 (P < 0.001) and 0.64 ± 0.07 for group 2 (P < 0.001) than that in control subjects (0.48 ± 0.04). The RI value of the acral finger arterioles differed significantly between group 1 and group 2 (P < 0.01). Diabetic patients exhibited a weak blood flow in the acral finger arterioles. The multigate spectral Doppler technology can be used to test blood flow in the acral finger arterioles and provide hemodynamic data for systematic analyses of the peripheral arteriole lesions in diabetes.
Ultrasound; Diabetes mellitus, type 2; Complications; Finger; Arterioles
Objectives. To assess the clinical effectiveness and adverse effects of Zhen Gan Xi Feng Decoction (ZGXFD) for essential hypertension (EH). Methods. Five major electronic databases were searched up to August 2012 to retrieve any potential randomized controlled trials designed to evaluate the clinical effectiveness of ZGXFD for EH reported in any language, with main outcome measure as blood pressure (BP). Results. Six randomized trials were included. Methodological quality of the trials was evaluated as generally low. Four trials compared prescriptions based on ZGXFD with antihypertensive drugs. Meta-analysis showed that ZGXFD was more effective in BP control and TCM syndrome and symptom differentiation (TCM-SSD) scores than antihypertensive drugs. Two trials compared the combination of modified ZGXFD plus antihypertensive drugs with antihypertensive drugs. Meta-analysis showed that there is significant beneficial effect on TCM-SSD scores. However, no significant effect on BP was found. The safety of ZGXFD is still uncertain. Conclusions. ZGXFD appears to be effective in improving blood pressure and hypertension-related symptoms for EH. However, the evidence remains weak due to poor methodological quality of the included studies. More rigorous trials are warranted to support their clinical use.
The phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) controls phosphate homeostasis by regulating renal expression of sodium-dependent phosphate co-transporters and cytochrome P450 enzymes involved in vitamin D catabolism. Multiple FGF Receptors (FGFRs) can act as receptors for FGF23 when bound by the co-receptor Klotho expressed in the renal tubular epithelium. FGFRs also regulate skeletal FGF23 secretion; ectopic FGFR activation is implicated in genetic conditions associated with FGF23 overproduction and hypophosphatemia. The identity of FGFRs that mediate the activity of FGF23 or that regulate skeletal FGF23 secretion remains ill defined. Here we report that pharmacological activation of FGFR1 with monoclonal anti-FGFR1 antibodies (R1MAb) in adult mice is sufficient to cause an elevation in serum FGF23 and mild hypophosphatemia. In cultured rat calvariae osteoblasts, R1MAb induces FGF23 mRNA expression and FGF23 protein secretion into the culture medium. In a cultured kidney epithelial cell line, R1MAb acts as a functional FGF23 mimetic and activates the FGF23 program. siRNA-mediated Fgfr1 knockdown induced the opposite effects. Taken together, our work reveals the central role of FGFR1 in the regulation of FGF23 production and signal transduction, and has implications in the pathogenesis of FGF23-related hypophosphatemic disorders.
Background. Yangxue Qingnao granule (YQG) combined with antihypertensive drugs, a new integrative medicine therapy, has been widely used for essential hypertension (EH) in China. This study aims to assess the current clinical evidence of YQG combined with antihypertensive drugs for EH. Methods. Randomized controlled trials(RCTs) published between 1996 and 2012 on YQG combined with antihypertensive drugs versus antihypertensive drugs in treating EH were retrieved from six major electronic databases, including The Cochrane Library, PubMed, Chinese National Knowledge Infrastructure, Chinese Scientific Journal Database, Chinese Biomedical Literature Database, and Wanfang Data. Meta-analysis was performed on the overall effects on blood pressure. Results. Twelve randomized trials were included. Methodological quality of the trials was evaluated as generally low. Meta-analysis showed that YQG combined with antihypertensive drugs demonstrated potential effect for lowing either SBP (MD: −7.31 [−11.75, −2.87]; P = 0.001) or DBP (MD: −5.21 [−8.19, −2.24]; P = 0.0006) compared to antihypertensive drugs alone. Conclusions. It indicated that YQG combined with antihypertensive drugs is more effective than antihypertensive drugs alone in treating EH. However, more RCTs of larger scale, multicentre/country, longer follow-up periods, and higher quality are required to verify the efficacy of integrative medicine therapy over all antihypertensive therapies.
Objectives. To assess the current clinical evidence of Banxia Baizhu Tianma Decoction (BBTD) for essential hypertension (EH). Search Strategy. Electronic databases were searched until July 2012. Inclusion Criteria. We included randomized clinical trials testing BBTD against placebo, antihypertensive drugs, or combined with antihypertensive drugs against antihypertensive drugs. Data Extraction and Analyses. Study selection, data extraction, quality assessment, and data analyses were conducted according to Cochrane standards. Results. 16 randomized trials were included. Methodological quality of the included trials was evaluated as generally low. 2 trials compared prescriptions based on BBTD using alone with antihypertensive drugs. Meta-analysis showed no significant effect of modified BBTD compared with captopril in systolic blood pressure (MD: −0.75 (−5.77, 4.27); P = 0.77) and diastolic blood pressure (MD: −0.75 (−2.89, 1.39); P = 0.49). 14 trials compared the combination of BBTD or modified BBTD plus antihypertensive drugs with antihypertensive drugs. Meta-analysis showed there are significant beneficial effect on systolic blood pressure in the combination group compare to the antihypertensive drugs (MD: −4.33 (−8.44, −0.22); P = 0.04). The safety of BBTD is uncertain. Conclusions. There is encouraging evidence of BBTD for lowering SBP, but evidence remains weak. Rigorously designed trials are warranted to confirm these results.
Objectives. To assess the beneficial and adverse effects of Liu Wei Di Huang Wan (LWDHW), combined with antihypertensive drugs, for essential hypertension. Methods. Five major electronic databases were searched up to August 2012 to retrieve any potential randomized controlled trials designed to evaluate the clinical effectiveness of LWDHW combined with antihypertensive drugs for essential hypertension reported in any language, with main outcome measures as blood pressure. The quality of the included studies was assessed with the Jadad scale and a customized standard quality assessment scale. Results. 6 randomized trials were included. The methodological quality of the trials was evaluated as generally low. The pooled results showed that LWDHW combined with antihypertensive drugs was more effective in blood pressure and the scale for TCM syndrome and symptom differentiation scores compared with antihypertensive drugs alone. Most of the trials did not report adverse events, and the safety is still uncertain. Conclusions. LWDHW combined with antihypertensive drugs appears to be effective in improving blood pressure and symptoms in patients with essential hypertension. However, the evidence remains weak due to the poor methodological quality of the included studies.
Circulating endothelial progenitor cells (EPCs) capture technology improves endothelialization rates of sirolimus-eluting stents (SES), but the problem of delayed re-endothelialization, as well as endothelial dysfunction, has still not been overcome. Therefore, we investigated whether the combination coating of hyaluronan-chitosan (HC) and anti-CD34 antibody applied on an SES (HCASES) can promote endothelialization, while reducing neointimal formation and inflammation.
Sirolimus-eluting stents(SES), anti-CD34 antibody stents (GS) and HC-anti-CD34 antibody combined with sirolimus-eluting stents (HCASES) were deployed in 54 normal porcine arteries and harvested for scanning electron microscopy (SEM) and histological analysis. The ratio of endothelial coverage above the stents was evaluated by SEM analysis at 7, 14 and 28 days. The percentage of in-stent stenosis was histologically analyzed at 14 and 28 days.
SEM analysis at 7 days showed that endothelial strut coverage was increased in the HCASES group (68±7%) compared with that in the SES group (31±4%, p=0.02). At 14 days, stent surface endothelialization, evaluated by SEM, showed a significantly higher extent of endothelial coverage above struts in the GS (95 ± 2%) and the HCASES groups (87±4%) compared with that in the SES group (51±6%, p=0.02). Histological examination showed that the percentage of stenosis in the HCASES group was not significantly different to that of the SES and GS groups (both p> 0.05). At 28 days, there was no difference in the rates of endothelial coverage between the HCASES and GS groups. The HCASES group showed less stenosis than that in the GS group (P < 0.05), but it was not significantly different from the SES group (P=0.068).
SEM and histology demonstrated that HCASESs can promote re-endothelialization while enhancing antiproliferative effects.
Anti-CD34 antibody; Endothelial progenitor cells; Hyaluronan and chitosan coating; Scanning electron microscopy
Toll-like receptors (TLRs) are pivotal components of the innate immune response. Activation of the innate immune system and subsequent chronic low-grade inflammation are thought to be involved in the pathogenesis of atherosclerosis and type 2 diabetes. In the study, we genotyped TLRs gene polymorphisms, including TLR2 Arg677Trp and Arg753Gln, TLR4 Asp299Gly and Thr399Ile, TLR9-1486T/C and -1237T/C. The frequencies of TT, TC and CC genotype of TLR9-1486T/C mutation were 39.6%, 45.8% and 14.6%, respectively; the frequencies of T allele and C allele were 62.5% and 37.5%. However, neither of these parameters was statistically significant among study groups. In addition, we were surprised to find that the commonly reported TLR SNPs in the Western countries, like TLR2 Arg677Trp or Arg753Gln, TLR4 Asp299Gly or Thr399Ile and TLR9-1237T/C, were not polymorphic at all in all study subjects. In conclusion, our data suggests that TLR2 Arg677Trp or Arg753Gln, TLR4 Asp299Gly or Thr399Ile and TLR9-1237T/C polymorphisms have low frequency and TLR9-1486T/C polymorphism may not be a suitable marker in predicting the susceptibility to type 2 diabetes or coronary artery disease in the Chinese Han population.