Identification of a distal enhancer that determines the expression pattern of acute phase marker C-reactive protein.

C-reactive protein (CRP) is a major acute phase protein and inflammatory marker, the expression of which is largely liver specific and highly inducible. Enhancers are regulatory elements critical for the precise activation of gene expression, yet the contributions of enhancers to the expression pattern of CRP have not been well defined. Here, we identify a constitutively active enhancer (E1) located 37.7 kb upstream of the promoter of human CRP in hepatocytes. By using chromatin immunoprecipitation, luciferase reporter assay, in situ genetic manipulation, CRISPRi, and CRISPRa, we show that E1 is enriched in binding sites for transcription factors STAT3 and C/EBP-ß and is essential for the full induction of human CRP during the acute phase. Moreover, we demonstrate that E1 orchestrates with the promoter of CRP to determine its varied expression across tissues and species through surveying activities of E1-promoter hybrids and the associated epigenetic modifications. These results thus suggest an intriguing mode of molecular evolution wherein expression-changing mutations in distal regulatory elements initiate subsequent functional selection involving coupling among distal/proximal regulatory mutations and activity-changing coding mutations.

[Mechanism of geniposide in improving free fatty acid metabolism in rats with non-alcoholic fatty liver disease].

To observe the effect of geniposide on non-alcoholic fatty liver disease (NAFLD), and discuss the mechanism of geniposide for NAFLD from the aspect of free fatty acid, forty healthy Wistar male rats were randomly divided into normal group, model group, geniposide and Xuezhikang group. The rats in normal group were fed with normal diets, and the rats in other 3 groups were given with high-fat diet for 8 weeks to induce the NAFLD models. From the week 5 to end of week 8, the rats in geniposide and Xuezhikang group were intervened with corresponding medicines. The body weight, liver wet weight, and fat weight of the rats were recorded. Visual and pathological changes in hepatic tissues were observed with HE staining. The contents of TG, FFA, FAS, AMPK, ACCase and Malonyl-CoA in hepatic tissue, contents of CHO and LDL-C in serum and activities of AST and ALT in serum were detected by using corresponding methods. The results showed that the body weight, liver wet weight, and fat weight of the rats, CHO, LDL-C, ALT and AST levels in serum, TG, FFA, FAS, ACCase and Malonyl-CoA levels in hepatic tissues of the rats in model group were significantly higher than those in normal group (P<0.01), while AMPK activity was significantly lower than that of the normal group (P<0.01), with obvious visual and pathological steatosis in hepatic tissues, and inflammatory injury occurred in model group. Compared with the model group, body weight of the rat, fat weight, levels of FFA in hepatic tissues, ALT and AST activities in serum, liver wet weight, TG, FAS, ACCase and Malonyl-CoA levels were significantly decreased in geniposide group (P<0.01), while the AMPK activity in hepatic tissues was significantly increased (P<0.05),with improvement in visual and pathological performance. Compared with the model group, liver wet weight, fat weight, TG and FFA levels in hepatic tissues, and LDL-C level in serum were significantly decreased in Xuezhikang group (P<0.05). Compared with Xuezhikang group, the body weight of rat, fat weight and FFA level in hepatic tissues were significantly lower in geniposide group (P<0.01), but with no significant difference in other aspects. These findings indicated that geniposide was highly effective in improving the pharmacological effect of NAFLD induced by high-fat diet, and the mechanism was achieved through AMPK-ACCase-Malonyl-CoA-FFA axis.

C-reactive protein: structure, function, regulation, and role in clinical diseases.

C-reactive protein (CRP) is a plasma protein that is evolutionarily conserved, found in both vertebrates and many invertebrates. It is a member of the pentraxin superfamily, characterized by its pentameric structure and calcium-dependent binding to ligands like phosphocholine (PC). In humans and various other species, the plasma concentration of this protein is markedly elevated during inflammatory conditions, establishing it as a prototypical acute phase protein that plays a role in innate immune responses. This feature can also be used clinically to evaluate the severity of inflammation in the organism. Human CRP (huCRP) can exhibit contrasting biological functions due to conformational transitions, while CRP in various species retains conserved protective functions in vivo. The focus of this review will be on the structural traits of CRP, the regulation of its expression, activate complement, and its function in related diseases in vivo.

Causal relationships between gut microbiota and dementia: A two-sample, bidirectional, Mendelian randomization study.

BACKGROUND: Existing evidence suggests that gut microbiota represent a significant environmental risk factor for various forms of dementia, including Alzheimer's dementia, vascular dementia, and dementia in other diseases classified elsewhere. However, the exact causal relationships between gut microbiota and the different forms of dementia or their subtypes remain unclear. AIM: To investigate putative causal relationships between gut microbiota and dementia or its subtypes using Mendelian randomization (MR) analysis. METHODS: A bidirectional, two-sample, MR analysis was conducted utilizing publicly available gut microbiota-related genome-wide association study (GWAS) summary data from the MiBioGen consortium alongside GWAS summary statistics for dementia and its subtypes from the FinnGen consortium. Instrumental variables were selected according to the fundamental tenets of MR and their strengths were evaluated using the F-statistic. Five MR methods were employed, and the robustness of our findings was validated. To account for multiple comparisons, we applied the Bonferroni method for P-value adjustment. RESULTS: We identified several gut microbiota taxa exhibiting putative causal relationships with dementia or its subtypes, potentially serving as risk or protective factors for the disease. In addition, reverse MR analysis indicated that the relative abundance of several gut microbiota taxa might be influenced by dementia or its subtypes. An exhaustive sensitivity analysis confirmed the absence of heterogeneity and horizontal pleiotropy. After applying correction for multiple testing, we observed that the order Bacillales (odds ratio: 0.830, 95% confidence interval: 0.740-0.932, P = 0.00155, Padjust = 0.0311) exhibited a strong association with Alzheimer's disease-related dementia. CONCLUSION: The results suggest that gut microbiota is causally associated with dementia. Our findings provide novel insights into the pathophysiology of dementia and have important implications for its treatment and prevention.

A redox switch in C-reactive protein modulates activation of endothelial cells.

C-reactive protein (CRP) has been implicated in the regulation of inflammation underlying coronary artery disease; however, little is known about the molecular mechanisms responsible for the expression of its pro- or anti-inflammatory activities. Here, we have identified the intrasubunit disulfide bond as a conserved switch that controls the structure and functions of CRP. Conformational rearrangement in human pentameric CRP to monomeric CRP (mCRP) is the prerequisite for this switch to be activated by reducing agents, including thioredoxin. Immunohistochemical analysis revealed 36-79% colocalization of thioredoxin and mCRP in human advanced coronary atherosclerotic lesions. Nonreduced mCRP was largely inert in activating human coronary artery endothelial cells (HCAECs), whereas reduced or cysteine-mutated mCRP evoked marked release of IL-8 and monocyte chemoattractant protein-1 from HCAECs, with ~50% increase at a concentration of 1 µg/ml. Reduced mCRP was ~4 to 40-fold more potent than mCRP in up-regulating adhesion molecule expression, promoting U937 monocyte adhesion to HCAECs, and inducing cytokine release from rabbit arteries ex vivo and in mice. These actions were primarily due to unlocking the lipid raft interaction motif. Therefore, expression of proinflammatory properties of CRP on endothelial cells requires sequential conformational changes, i.e., loss of pentameric symmetry followed by reduction of the intrasubunit disulfide bond.

Study on effects of zhi zi (fructus gardeniae) on non-alcoholic fatty liver disease in the rat.

OBJECTIVE: To investigate the effects of Zhi Zi (Fructus Gardeniae) on non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet in the rat. METHODS: A rat model of NAFLD was established using a high-fat diet. Twenty one rats were randomly divided into a normal group, a model group and a Zhi Zi treatment group, 7 rats per group. Drinking water and the drug were intragastrically administrated for 5 weeks. Samples were then taken to observe pathological changes of the liver tissue (HE staining); changes in the fat metabolism pathway e. g. triglyceride (TG) and free fatty acid (FFA) content; alterations in liver function, i.e. serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity; and differences in tumor necrosis factor alpha (TNF-alpha) and P-IkB protein expression in the liver tissue. RESULTS: Fatty degeneration and vacuole-like changes of different degrees occurred in hepatic cells of the model group. Markers for fat metabolism, serum ALT and AST activities, and expression of TNF-alpha and P-IkB proteins in liver tissue significantly increased. Fat metabolism in the Zhi Zi group significantly reduced, as shown by a drop in marker levels. Serum ALT and AST activities, and expression of TNF-alpha, P-IkB proteins in liver tissue were also significantly decreased in this group. CONCLUSION: Zhi Zi has a very strong inhibitory action on lipidosis and inflammatory injury in the rat model of NAFLD. This mechanism may possibly be related to the inhibition of the free fatty acid metabolism pathway.

Effect of electroacupuncture on serum copper, zinc, calcium and magnesium levels in the depression rats.

OBJECTIVE: To investigate effect of electroacupuncture (EA) on serum copper, zinc, calcium and magnesium levels in the rat models of depression. METHODS: Forty healthy SD male rats were divided into a normal group, a model group, an EA group, and a maprotiline group, 10 in each with completely random. The depression models were prepared with isolated chronic unpredictable stress method in the latter three groups. EA was given at Baihui (GV 20), Yintang (EX-HN3), Fenglong (ST 40), and Taichong (LR 3) in the EA group from the second day of modeling, once every other day, 15 min each time. The maprotiline group was administered intragastrically suspension of maprotiline (10 mg/kg), once each day. After treatment for 3 weeks, serum copper and zinc levels were detected with atomic absorption method, and the serum calcium with Arsenazo III method and magnesium with MTB method. RESULTS: Compared with the normal group, the serum copper level (3.90 +/- 1.20 mmol/L) significantly increased and the serum zinc level (2.08 +/- 0.44 mmol/L) significantly decreased in the model group (P < 0.05). Compared with the model group, the serum copper level (2.62 +/- 1.03 mmol/L) significantly decreased, the serum zinc level (2.55 +/- 0.38 mmol/L) significantly increased (P < 0.05), but the serum calcium and magnesium levels did not significantly change in the EA group and the maprotiline group. CONCLUSION: EA can regulate the change of copper and zinc levels in the body induced by depression, which is possibly one of mechanisms of effectively improving depression symptoms.

Effects of grape seed proanthocyanidin B2 pretreatment on oxidative stress and renal tubular epithelial cell apoptosis after renal ischemia reperfusion in mice.

PURPOSE: To investigate the effects of grape seed proanthocyanidin B2 (GSPB2) preconditioning on oxidative stress and apoptosis of renal tubular epithelial cells in mice after renal ischemia-reperfusion (RIR). METHODS: Forty male ICR mice were randomly divided into 4 groups: Group A: mice were treated with right nephrectomy. Group B: right kidney was resected and the left renal vessel was clamped for 45 minutes. Group C: mice were intraperitoneally injected with GSPB2 before RIR established. Group D: mice were intraperitoneally injected with GSPB2 plus brusatol before RIR established. Creatinine and urea nitrogen of mice were determined. Pathological and morphological changes of kidney were checked. Expressions of Nrf-2, HO-1, cleaved-caspase3 were detected by Western-blot. RESULTS: Compared to Group B, morphology and pathological damages of renal tissue were less serious in Group C. Western-blot showed that expressions of Nrf-2 and HO-1 in Group C were obviously higher than those in Group B. The expression of cleaved-caspase3 in Group C was significantly lower than that in Group B. CONCLUSION: GSPB2 preconditioning could attenuate renal oxidative stress injury and renal tubular epithelial cell apoptosis by up-regulating expressions of Nrf-2 and HO-1 and down-regulating the expression of cleaved-caspase-3, but the protective effect could be reversed by brusatol.

A Systematic Review and Meta-analysis of the Therapeutic Effect of Acupuncture on Migraine.

Background: Migraine is an intractable headache disorder, manifesting as periodic attacks. It is highly burdensome for patients and society. Acupuncture treatment can be beneficial as a supplementary and preventive therapy for migraine. Objectives: This systematic review and meta-analysis aimed to investigate the efficacy and safety of acupuncture for migraine, and to examine transcranial doppler changes after acupuncture. Methods: Reports, conference, and academic papers published before March 15, 2019 in databases including PubMed, Cochrane library, Embase, China National Knowledge Infrastructure, WANFANG Database, Chinese journal of Science and Technology, and China Biomedical were searched. Randomized controlled trials (RCTs) involving acupuncture, sham acupuncture, and medication in migraine were included. The Cochrane Collaboration software, RevMan 5.3, was used for data processing and migration risk analysis. Results: Twenty-eight RCTs were included. 15 RCTs included medication only, 10 RCTs included sham acupuncture only, and 3 RCTs included both. The study included 2874 patients, split into 3 groups: acupuncture treatment group (n = 1396), medication control group (n = 865), and sham acupuncture control group (n = 613). The results showed that treatment was more effective in the acupuncture group than in the sham acupuncture group (MD = 1.88, 95% CI [1.61, 2.20], P < 0.00001) and medication group (MD = 1.16, 95% CI [1.12, 1.21], P < 0.00001). Improvement in visual analog scale (VAS) score was greater in the acupuncture group than in the sham acupuncture group (MD = -1.00, 95% CI [-1.27,-0.46], P < 0.00001; MD = -0.59, 95% CI [-0.81,-0.38], P < 0.00001), and their adverse reaction rate was lower than that of the medication group (RR = 0.16, 95% CI [0.05, 0.52], P = 0.002). The improvement of intracranial blood flow velocity by acupuncture is better than that by medication, but the heterogeneity makes the result unreliable. Conclusions: Acupuncture reduced the frequency of migraine attacks, lowered VAS scores, and increased therapeutic efficiency compared with sham acupuncture. Compared with medication, acupuncture showed higher effectiveness with less adverse reactions and improved intracranial blood circulation. However, owing to inter-study heterogeneity, a prospective, multicenter RCT with a large sample is required to verify these results.

A Functional Genetic Variant at the C-Reactive Protein Promoter (rs3091244) Is Not Associated With Cancer Risk in a Chinese Population.

Background: The association of genetically elevated levels of circulating C-reactive protein (CRP) with cancer risk has been extensively investigated in European populations; however, there are conflicting conclusions. The tri-allelic rs3091244 is a functionally validated genetic variant, and its allelic frequencies differ significantly between European and Asian populations. Here, we examined the association of rs3091244 with cancer risk in a Chinese population. Methods: rs3091244 was genotyped by Sanger sequencing in 4,971 cancer cases and 2,485 controls. The rs1205 and rs2794521 gene variants were also genotyped using TaqMan assays in subgroups. Results: No association was detected between the genotyped CRP variants and cancer risk, with or without distinguishing cancer types, suggesting that circulating CRP is not causally involved in tumorigenesis in Chinese populations.

Intra-subunit Disulfide Determines the Conversion and Structural Stability of CRP Isoforms.

C-reactive protein (CRP) is a major human acute-phase reactant that is composed of five identical subunits. CRP dissociates into subunits at inflammatory loci forming monomeric CRP (mCRP) with substantially enhanced activities, which can be further activated by reducing the intra-subunit disulfide bond. However, conformational changes underlying the activation process of CRP are less well understood. Conformational changes accompanying the conversion of CRP to mCRP with or without reduction were examined with circular dichroism spectroscopy, fluorescence spectroscopy, electron microscopy, size-exclusion chromatography, and neoepitope expression. The conversion of CRP to mCRP follows a two-stage process. In the first stage, CRP dissociates into molten globular subunits characterized by intact secondary structure elements with greatly impaired tertiary packing. In the second stage, these intermediates completely lose their native subunit conformation and assemble into high-order aggregates. The inclusion of reductant accelerates the formation of molten globular subunits in the first step and promotes the formation of more compact aggregates in the second stage. We further show a significant contribution of electrostatic interactions to the stabilization of native CRP. The conformational features of dissociated subunits and the aggregation of mCRP may have a key impact on their activities.

Survivin Promotes Piperlongumine Resistance in Ovarian Cancer.

Ovarian cancer is one of the most fatal female malignancies while targeting apoptosis is critical for improving ovarian cancer patients' lives. Survivin is regarded as the most robust anti-apoptosis protein, and its overexpression in ovarian cancer is related to poor survival and apoptosis resistance. Piperlongumine (PL) extracted from peppers is defined as an active alkaloid/amide and exhibits a broad spectrum of antitumor effects. Here, we demonstrate that PL induces the rapid depletion of survivin protein levels via reactive oxygen species (ROS)-mediated proteasome-dependent pathway in vitro, while exerting a remarkable inhibitory influence on the proliferation of ovarian cancer cells. Overexpression of survivin raises the survival rate of ovarian cancer cells to PL. Moreover, PL inhibits ovarian cancer cells xenograft tumor growth and downregulates survivin in vivo. Our findings reveal a previously unrecognized mechanism of PL in suppressing survivin expression as well as survivin promotes piperlongumine resistance in ovarian cancer and suggest that ROS-mediated proteasome-dependent pathway can be exploited to overcome apoptosis resistance triggered by aberrant expression of survivin.

Erastin Reverses ABCB1-Mediated Docetaxel Resistance in Ovarian Cancer.

Overexpression of drug efflux transport ABCB1 is correlated with multidrug resistance (MDR) among cancer cells. Upregulation of ABCB1 accounts for the recurrence of resistance to docetaxel therapy in ovarian cancer with poor survival. Erastin is a novel and specific small molecule that targets SLC7A11 to induce ferroptosis. In the present research, we explored the synergistic effect of erastin and docetaxel in ovarian cancer. We confirmed that the co-delivery of erastin with docetaxel significantly decreased cell viability, promoted cell apoptosis, and induced cell cycle arrest at G2/M in ovarian cancer cells with ABCB1 overexpression. Mechanistically, erastin dominantly elevated the intracellular ABCB1 substrate levels by restricting the drug-efflux activity of ABCB1 without alteration of the expression of ABCB1. Consequently, erastin can reverse ABCB1-mediated docetaxel resistance in ovarian cancer, revealing that the combination of erastin and docetaxel may potentially offer an effective administration for chemo-resistant patients suffering from ovarian cancers.

Celastrol Inhibits the Growth of Ovarian Cancer Cells in vitro and in vivo.

Celastrol is a natural triterpene isolated from the Chinese plant Thunder God Vine with potent antitumor activity. However, the effect of celastrol on the growth of ovarian cancer cells in vitro and in vivo is still unclear. In this study, we found that celastrol induced cell growth inhibition, cell cycle arrest in G2/M phase and apoptosis with the increased intracellular reactive oxygen species (ROS) accumulation in ovarian cancer cells. Pretreatment with ROS scavenger N-acetyl-cysteine totally blocked the apoptosis induced by celastrol. Additionally, celastrol inhibited the growth of ovarian cancer xenografts in nude mice. Altogether, these findings suggest celastrol is a potential therapeutic agent for treating ovarian cancer.

Association between parity and the risk for urinary incontinence in women: A meta-analysis of case-control and cohort studies.

Urinary incontinence (UI) is a common complaint for adult female. Cross-sectional studies suggested parity may link with UI, but the association between them was not well-established. We conducted a meta-analysis to investigate the association between parity and UI.Medline and Embase were searched for eligible case-control and cohort studies about parity and UI. Two authors screened the literature and extracted the data independently. Odds ratio (OR) was used as the measure of the effect of parity on UI. We pooled the ORs of different number of parity by a random-effect model. Subgroup analysis was conducted by a subtype of UI. Sensitivity analysis was conducted to see whether the results were stable.Thirteen studies (8 cohorts and 5 case-controls) were included in our meta-analysis, with a total of 74,883 adult females. Our meta-analysis showed that compared with nulliparity, ORs of women with 1, 2, and ≥3 parity were 1.43 [95% confidence interval (95% CI): 0.90-2.28; I = 81.4%; n = 4], 1.50 (95% CI: 1.02-2.20; I = 82.5%; n = 4), and 1.58 (95% CI: 1.22-2.03; I = 70.1%; n = 7) compared with nulliparity. The OR for any multiparity to nulliparity was 1.68 (95% CI: 1.39-2.03; I = 0%; n = 4). Subgroup analysis showed that parity was associated with an increased risk of stress UI (OR = 2.32, 95% CI: 1.41-3.81; I = 0%; n = 2; 1 compared with null parity) but not urgent UI; However, the definition of parity varies across studies and studies defined parity as delivery times showed higher pooled OR than those not. Sensitivity analysis showed our results were stable.Current evidence suggested that parity was associated with an increased risk of overall and stress UI but not urgency UI, though the definition of parity may differ. Higher parity may have a more significant effect on overall UI. Standardized definition of parity is needed.

Acidic pH promotes oxidation-induced dissociation of C-reactive protein.

BACKGROUND: Circulating levels of the systemic inflammation marker C-reactive protein (CRP) have been associated with increased risk and poor outcomes of many diseases, such as cardiovascular events and cancer. Accumulating evidence has indicated that the conformational rearrangement of human pentameric CRP (pCRP) to monomeric CRP (mCRP) is a prerequisite for participation in the pathogenesis. Therefore, determining the mechanism of the dissociation of pCRP into pro-inflammatory mCRP under physiological/pathological circumstances has been intriguing. METHODS: The effects of oxidative and acidic stress occurring in inflammation on pCRP were examined by electrophoresis, electron microscopy, protein fluorescence, neoepitope expression and endothelial cell responses. RESULTS: Reactive oxygen species (ROS) generated by the copper-hydrogen peroxide system could rapidly induce the dissociation of CRP at mild acidic pH within four hours, but not at physiological pH of 7.4. Meanwhile, mannitol, a ROS scavenger, could not protect against dissociation, which implied that local ROS from accessible histidine residues may be crucially beneficial to the formation of mCRP in a redox-balanced microenvironment. Furthermore, mCRP generated by ROS could be reduced by DTT, which indicated the exposure of functional motif aa35-47, and showed potent proinflammatory actions on endothelial cells, comparable to mCRP generated by urea. CONCLUSION: dissociation of pCRP to mCRP could be rapidly induced by ROS from copper- hydrogen peroxide system in dependence on mildly acidic stress regardless of a redox-balanced microenvironment.

Effects of grape seed proanthocyanidin B2 pretreatment on oxidative stress and renal tubular epithelial cell apoptosis after renal ischemia reperfusion in mice

Abstract Purpose To investigate the effects of grape seed proanthocyanidin B2 (GSPB2) preconditioning on oxidative stress and apoptosis of renal tubular epithelial cells in mice after renal ischemia-reperfusion (RIR). Methods Forty male ICR mice were randomly divided into 4 groups: Group A: mice were treated with right nephrectomy. Group B: right kidney was resected and the left renal vessel was clamped for 45 minutes. Group C: mice were intraperitoneally injected with GSPB2 before RIR established. Group D: mice were intraperitoneally injected with GSPB2 plus brusatol before RIR established. Creatinine and urea nitrogen of mice were determined. Pathological and morphological changes of kidney were checked. Expressions of Nrf-2, HO-1, cleaved-caspase3 were detected by Western-blot. Results Compared to Group B, morphology and pathological damages of renal tissue were less serious in Group C. Western-blot showed that expressions of Nrf-2 and HO-1 in Group C were obviously higher than those in Group B. The expression of cleaved-caspase3 in Group C was significantly lower than that in Group B. Conclusion GSPB2 preconditioning could attenuate renal oxidative stress injury and renal tubular epithelial cell apoptosis by up-regulating expressions of Nrf-2 and HO-1 and down-regulating the expression of cleaved-caspase-3, but the protective effect could be reversed by brusatol.

Mutations of C-reactive protein (CRP) -286 SNP, APC and p53 in colorectal cancer: implication for a CRP-Wnt crosstalk.

C-reactive protein (CRP) is an established marker of inflammation with pattern-recognition receptor-like activities. Despite the close association of the serum level of CRP with the risk and prognosis of several types of cancer, it remains elusive whether CRP contributes directly to tumorigenesis or just represents a bystander marker. We have recently identified recurrent mutations at the SNP position -286 (rs3091244) in the promoter of CRP gene in several tumor types, instead suggesting that locally produced CRP is a potential driver of tumorigenesis. However, it is unknown whether the -286 site is the sole SNP position of CRP gene targeted for mutation and whether there is any association between CRP SNP mutations and other frequently mutated genes in tumors. Herein, we have examined the genotypes of three common CRP non-coding SNPs (rs7553007, rs1205, rs3093077) in tumor/normal sample pairs of 5 cancer types (n = 141). No recurrent somatic mutations are found at these SNP positions, indicating that the -286 SNP mutations are preferentially selected during the development of cancer. Further analysis reveals that the -286 SNP mutations of CRP tend to co-occur with mutated APC particularly in rectal cancer (p = 0.04; n = 67). By contrast, mutations of CRP and p53 or K-ras appear to be unrelated. There results thus underscore the functional importance of the -286 mutation of CRP in tumorigenesis and imply an interaction between CRP and Wnt signaling pathway.

Multiple pharmacological actions of Yiqi Huatan Decoction in a model of depression in rats.

OBJECTIVE: To investigate the influence of Yiqi Huatan Decoction (, YHD) on a model of depression in rats under different pathological conditions. METHODS: Thirty-two male SD rats were randomly divided into 4 groups of 8: normal, model, YHD, and maprotiline. The model group, YHD group and maprotiline group used separate feeding and rats were exposed to chronic and unpredictable stress to build the depression model. From day 2, the YHD group and maprotiline group were respectively given YHD (7 g/kg) and maprotiline (10 mg/kg) by gastrogavage once daily. The normal and model groups were given the same volume of drinking water. The medication duration were 21 days. At the end of the experiment, the serum levels of copper and zinc were determined by atomic absorption spectroscopy, plasma concentrations of adrenocorticotropic hormone (ACTH) and cortisol (COR) were detected by radioimmunoassay, and levels of norepinephrine (NE), dopamine (DA), and 5-hydroxytryptamine (5-HT) in the hypothalamus were analysed by high performance liquid chromatography-eletricochemistry. RESULTS: Compared with the content of copper and zinc in the serum of rats in the normal group, serum copper levels in model rats were significantly increased and zinc content was significantly reduced (both P<0.05). Plasma concentrations of ACTH and COR in the model group were significantly increased compared with those in the normal group (P<0.05, P<0.01). The contents of NE, DA, and 5-HT in the hypothalamus of rats in the model group were significantly reduced compared with those of the normal group (P<0.05 or P<0.01). Compared with those in the model group, the serum copper content and plasma concentrations of ACTH and COR were significantly decreased (all P<0.05); meanwhile, serum zinc content and hypothalamic contents of NE, DA, and 5-HT were significantly increased in rats of the YHD group (all P<0.05). The same effects were also shown in the maprotiline group except for 5-HT (all P<0.05) CONCLUSION: The pharmacological actions of YHD for depression might be related to improving trace-element anomalies, reversing endocrine dysfunction, and modulating the disorders of monoaminergic neurotransmitters.

An association study on ADAM10 promoter polymorphisms and atherosclerotic cerebral infarction in a Chinese population.

AIM: Dysregulation of the activity of the disintegrin/metalloproteinase ADAM10 could contribute to the development of atherosclerosis. Although a number of genetic studies have focused on the association of ADAM10 gene polymorphisms with susceptibility to diseases, no genetic association studies of ADAM10 gene variability with atherosclerotic cerebral infarction (ACI) have been conducted. The aim of this study was to analyze the potential association between ADAM10 promoter polymorphisms and ACI. METHODS: The associations between rs653765 and rs514049 polymorphisms of the ADAM10 promoter and the possible risk of ACI were assessed among 347 patients with ACI and 299 matched healthy individuals in a case-control study. RESULTS: Overall, there was a significant difference in the genotypes frequencies of rs653765 (P = 0.04) between the ACI and control subjects. In addition, the rs653765 mutated allele of ADAM10 was significantly associated with increased ADAM10 expression in patients with ACI (P = 0.032). In contrast, the allele frequency of rs514049 was not statistically associated with ACI, and the rs514049 variant A > C did not affect the expression of ADAM10 either. CONCLUSION: Our findings indicate a positive association between the rs653765 polymorphism of ADAM10 and ACI, as well as a negative result for rs514049. In addition, a significant increase in ADAM10 expression was observed in patients with ACI carrying the rs653765 C > T mutation. This new knowledge about ADAM10 might be clinically important and confirm a role for ADAM10 in the pathophysiology of ACI, with potentially important therapeutic implications.