Sex-specific association of serum dehydroepiandrosterone and its sulfate levels with osteoporosis in type 2 diabetes.

INTRODUCTION: This study is to investigate the relation between serum dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) levels and the risk of osteoporosis in patients with T2DM. MATERIALS AND METHODS: This cross-sectional study involved 938 hospitalized patients with T2DM. Linear regression models were used to explore the relationship between DHEA and DHEAS and the BMD at different skeletal sites. Multinominal logistic regression models and the restricted cubic spline (RCS) were used to evaluate the associations of DHEA and DHEAS with the risks of osteopenia and/or osteoporosis. RESULTS: In postmenopausal women with T2DM, after adjustment for confounders including testosterone and estradiol, DHEA showed a significant positive correlation with lumbar spine BMD (P = 0.013). Moreover, DHEAS exhibited significant positive correlations with BMD at three skeletal sites: including femoral neck, total hip, and lumbar spine (all P < 0.05). Low DHEA and DHEAS levels were associated with increased risk of osteopenia and/or osteoporosis (all P < 0.05) and the risk of osteoporosis gradually decreased with increasing DHEAS levels (P overall = 0.018, P-nonlinear = 0.559). However, DHEA and DHEAS levels in men over the age of 50 with T2DM were not associated with any of above outcomes. CONCLUSION: In patients with T2DM, independent of testosterone and estradiol, higher DHEA and DHEAS levels are associated with higher BMD and lower risk of osteopenia/osteoporosis in postmenopausal women but not men over the age of 50.

Associations of four surrogate insulin resistance indexes with non-alcoholic steatohepatitis in Chinese patients with obesity: a cross-sectional study.

OBJECTIVES: This study was designed to evaluate the association of four surrogate indexes of IR with NASH in patients with obesity. METHODS: A total of 270 patients who underwent bariatric surgery, were included in this cross-sectional study. NASH was diagnosed based on liver biopsies. Binary logistics regression analyses were performed to assess the associations of four surrogate indexes of IR (HOMA-IR, Matsuda index, TyG, and TG/HDL-C) with NASH in patients with obesity. The restricted cubic spline was used to assess the dose-response associations of surrogate indexes of IR with NASH after adjusting for confounding factors. RESULTS: NASH was diagnosed in 136 patients, with a prevalence of 50.37%. Compared with tertile 1, the fully adjusted ORs (95% CIs) of NASH for tertile 3 were 2.711(1.113-6.608) and 0.297 (0.152-0.579) for TyG and Matsuda index. Consistently, per SD increment of TyG were still significantly associated with 64% increased risks of NASH, and per SD increment of Matsuda index were still significantly associated with 38% decreased risks of NASH. In contrast, no significant associations were found between HOMA-IR and TG/HDL-C and the risk of NASH in patients with obesity (all P > 0.05). After adjusting covariates in restricted cubic splines, the risk of NASH decreased with the increment of Matsuda Index levels (P-nonlinear = 0.442, P-overall = 0.007) and with the decrement of TyG levels (P-nonlinear = 0.004, P-overall = 0.001). CONCLUSIONS: In patients with obesity, TyG and Matsuda index were independently related to the risk of NASH after adjustment for traditional risk factors. In addition, compared with HOMA-IR and TG/HDL-C, the Matsuda index and TyG may be more suitable for NASH prediction in patients with obesity.

Lowest Glucagon/Highest C-Peptide in Oral Glucose Tolerance Test: Clinical Utility in Monitoring Glucose Control in Type 2 Diabetes Mellitus.

Purpose: Understanding factors that influence blood glucose levels in patients with type 2 diabetes mellitus (T2DM) is crucial for managing hyperglycemia. Currently, there is no standardized interpretation method for glucagon levels in oral glucose tolerance test (OGTT). This study aims to assess the relationship between the lowest glucagon/highest C-peptide ratio (Lglc/Hcp) in OGTT and glucose control levels in T2DM. Patients and Methods: Clinical data from 120 patients with T2DM were examined to compare the correlations of Lglc/Hcp and other pancreatic islet function-associated indices with fasting blood glucose (G0), glucose at 120 minutes in OGTT (G120), hemoglobin A1c (HbA1c), and the area under the glucose curve in OGTT (AUCglu). Additionally, the study investigated difference in Lglc/Hcp between patient groups based on the highest blood glucose levels (Hglu) in OGTT (Hglu ≥ 16.7 mmol/L vs Hglu < 16.7 mmol/L). Results: The generalized linear model suggested that Lglc/Hcp significantly correlated with G0 (B = 0.85, P < 0.001), G120(B = 1.46, P < 0.001), HbA1c (B = 0.67, P < 0.001), and AUCglu (B = 3.46, P < 0.001). This correlation surpassed C-peptide and glucagon-related parameters, even after adjusting for confounding factors. Furthermore, Lglc/Hcp was notably higher in patients with Hglu ≥ 16.7 mmol/L compared to those with Hglu < 16.7 mmol/L (Z = -3.71, p < 0.001). Conclusion: Lglc/Hcp in OGTT closely relates to blood glucose control in patients with T2DM, potentially reflecting the overall pancreatic islet function in regulating glucose levels. Moreover, inhibiting glucagon secretion may be a crucial consideration for patients requiring insulin treatment.

Central hyperthyroidism due to an ectopic TSH-secreting pituitary tumor: a case report and literature review.

Ectopic thyroid-stimulating hormone (TSH)-secreting tumors are extremely rare, with only 15 reported cases in the literature. Herein, we described a 60-year-old female patient with thyrotoxicosis and elevated or unsuppressed levels of TSH. Family history and laboratory and genetic tests did not support a diagnosis of resistance to thyroid hormone (RTH). Given the unsuppressed TSH, TSH-secreting tumor was suspected, and magnetic resonance imaging (MRI) of the pituitary gland was performed. Surprisingly, the MRI scans revealed a nodule in the nasopharynx rather than a pituitary tumor in the sella region. Further evaluation using Gallium-68 DOTATATE positron emission tomography/computed tomography (68Ga-DOTATATE PET/CT) demonstrated increased DOTATATE uptake in the nasopharyngeal nodule. Additionally, an octreotide suppression test (OST) revealed an obvious reduction in TSH levels, further supporting the suspicion of the nasopharyngeal mass as the cause of inappropriate TSH secretion. To prepare for surgery, the patient received preoperative administration of octreotide, resulting in the normalization of TSH and thyroid hormone levels. The patient subsequently underwent successful surgical removal of the nasopharyngeal mass. Following the procedure, the patient experienced complete resolution of hyperthyroidism symptoms, with TSH declined and thyroid hormone levels returned to normal. Histochemistry analysis of the tumor revealed positive staining for TSH, growth hormone (GH), prolactin (PRL), luteinizing hormone (LH), and somatostatin receptor 2 (SSTR2). We discussed differential diagnosis of hyperthyroidism due to inappropriate TSH secretion, with a particular emphasis on the importance of 68Ga-DOTATATE PET/CT in combination with OST for identifying ectopic pituitary tumors.

A family case report of parathyroid carcinoma associated with CDC73 mutation in hyperparathyroidism-jaw tumor syndrome.

Background: Hereditary primary hyperparathyroidism (PHPT) accounts for 5-10% of all PHPT cases, necessitating genetic testing for diagnosis and management. Among these, hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant disorder caused by CDC73 mutations with variable clinical presentations and incomplete symptoms. Case summary: The proband, diagnosed with PHPT, underwent parathyroidectomy at the age of 41 with pathological examination of parathyroid carcinoma (PC). Hereditary PHPT was initially suspected due to the early-onset PHPT and family history. Genetic testing identified a heterozygous CDC73 mutation, NM_024529.4: c. 687_688delAG (p. Arg229Serfs*37). Even in the absence of jaw tumors, the diagnosis of HPT-JT was confirmed based on the discovery of renal cysts. A secondary thyroidectomy was performed to reduce the risk of recurrence. Conclusion: Genetic testing is strongly recommended in cases of early-onset PHPT, family history, jaw tumors, renal and uterine involvement, atypical parathyroid tumors, and PC. This testing provides valuable information for personalized management, and counseling is available for affected families.

Newly identified adverse events for gemcitabine using the Food and Drug Administration Adverse Event Reporting System.

BACKGROUND: Our research aimed to identify previously undocumented adverse events (AEs) in the gemcitabine drug insert with the goal of informing clinical practice. METHODS: We extracted adverse events associated with gemcitabine use through 2023 using the Food and Drug Administration Adverse Event Reporting System (FAERS) database. Four algorithms (Reporting Odds Ratio, Proportional Reporting Ratio, Bayesian Confidence Propagation Neural Network, and Empirical Bayesian Geometric Mean) were employed to detect new AE signals. AEs were considered positive signals only if they were detected by all four algorithms. RESULTS: From 2014 to 2023, a total of 42,360 AEs were reported in 14,905 individuals following gemcitabine use. These AEs totaled 437 preferred terms (PTs) across 20 system organ classes (SOCs). We identified unexpected AEs related to the ocular disorders, the nervous system, and the ear and the labyrinth. The ocular organ system will present with retinopathy, purtscher retinopathy, choroidal effusion, amaurosis, necrotizing scleritis, etc. The nervous system may experience reversible posterior encephalopathy syndrome, cerebellar syndrome, cauda equina syndrome, athetosis, transverse myelitis, etc. The ears and labyrinth may exhibit ototoxicity. CONCLUSION: Our study identified previously undetected signals following gemcitabine treatment, thereby providing new insights for future medication guidance.

Newly identified adverse events of enzalutamide using the food and drug administration adverse event reporting system.

OBJECTIVES: Enzalutamide, a second-generation anti-androgen drug, is an androgen receptor inhibitor developed to overcome resistance to first-generation anti-androgens, such as bicalutamide. This study aimed to identify previously undisclosed adverse events associated with enzalutamide. METHODS: Adverse reactions following enzalutamide administration were extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS) database, and the data obtained were from 2014 to 2023. Four algorithms, namely ROR, PRR, BCPNN, and EBGM, were used to detect signs of adverse reactions associated with enzalutamide use. RESULTS: This study determined several adverse reactions in the nervous system, including hypogeusia, ageusia, dysgeusia, normal-pressure hydrocephalus, dementia, amnesia, balance disorders, and seizure-like phenomena. The mental aspects manifested as laziness, confusion, and eating disorders. Gastrointestinal system-related adverse reactions included dysphagia, constipation, fecal hardening, and abdominal discomfort. We identified several previously unreported adverse reactions, including normal-pressure hydrocephalus, dementia, balance disorders, eating disorders, and dysphagia. CONCLUSION: Our study revealed novel adverse events associated with enzalutamide, particularly in the nervous system, that have not been previously documented. These findings have important implications for future clinical medication guidelines.

The comparison of three different molecular imaging methods in localization and grading of insulinoma.

Aims: This cross-sectional study compared the value of molecular imaging (Exendin-4 positron emission tomography/computed tomography [PET/CT], 68Ga-DOTATATE PET/CT, 18F- fluorodeoxyglucose [FDG] PET/CT) in insulinoma localization by stratified tumor size and grading, and explored the correlation of the related the maximum standardized uptake value (SUVmax) with insulinoma grading, Ki-67, maximum tumor diameter, and glucose metabolism. Methods: In 28 insulinoma patients, the sensitivity of three types of PET/CT for localizing insulinoma was calculated according to tumor size and grade. We compared the SUVmax for different insulinoma grades and analyzed the correlation of SUVmax with Ki-67, maximum tumor diameter, and glucose metabolism indicators. Results: The study included 12 grade (G) 1 and 16 G2 cases, with maximum tumor diameters ranging from 9 to 40 mm. Without differentiation by size and grade, the sensitivity of Exendin-4 PET/CT to localize insulinoma was 100%, which significantly exceeded that of 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT (75% and 57%, respectively). In tumors with a maximum diameter ≤ 20 mm and ≤ 15 mm, the sensitivity of Exendin-4 (both 100%) significantly exceeded that of 68Ga-DOTATATE PET/CT (74% and 64%, respectively) and 18F-FDG PET/CT (54% and 50%, respectively). In G1 tumors, the sensitivity of Exendin-4 PET/CT was significantly higher than that of 18F-FDG PET/CT, but not that of 68Ga-DOTATATE PET/CT, while in G2 tumors, the sensitivity of Exendin-4 PET/CT was significantly higher than that of both other types. However, all three PET/CT types missed a metastatic lymph node in one patient. The 18F-FDG PET/CT SUVmax was significantly lower than that of the other PET/CT types and that of 68Ga-DOTATATE PET/CT was significantly lower in G2 than in G1. 68Ga-DOTATATE PET/CT SUVmax correlated negatively with Ki-67. A receiver operating characteristic (ROC) curve suggested that 68Ga-DOTATATE PET/CT SUVmax > 19.9 could predict G1 tumors. Conclusion: Exendin-4 PET/CT was superior to 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT for insulinoma localization, particularly small and G2 tumors, but its diagnostic value in small metastatic lymph nodes requires further exploration. 68Ga-DOTATATE PET/CT SUVmax could be used as an adjunct to pathology, and a value > 19.9 could predict G1 tumors. No PET/CT SUVmax could predict tumor maximum diameter and glucose metabolism.

Differential regulation of lipopolysaccharide-induced IL-1ß and TNF-α production in macrophages by palmitate via modulating TLR4 downstream signaling.

Diabetic patients are susceptible to infectious diseases. Bacterial invasion activates immune cells such as macrophages through interaction between LPS and TLR4, and induces the expression of inflammatory mediators, including IL-1ß and TNF-α, which play key roles in the elimination of infections. Unregulated overproduction or underproduction of these cytokines has been reported as a major factor in the development of septic shock, immune deficiency, and autoimmunity. Recent studies found that metabolic abnormalities of diabetes, such as hyperglycemia and dyslipidemia, played a major role in modulating the immune response. In this study, we studied the effects of palmitic acid (PA) pretreatment on LPS-induced IL-1ß and TNF-α production and LPS-TLR4 signaling in macrophages. Compared with control, PA pretreatment significantly increased LPS-induced TNF-α production and secretion in macrophages. In contrast, LPS-induced IL-1ß production and secretion was significantly suppressed by PA pretreatment. PA pretreatment did not affect the expression levels of TLR4 or Myd88, or the endocytosis of TLR4 in macrophages. However, PA pretreatment significantly suppressed the phosphorylation level and nuclear translocation of NF-κB, and the phosphorylation level of ERK1/2, whereas increased the phosphorylation levels of p38 and JNK. The activation of IKK which was upstream of NF-κB and ERK1/2 was attenuated, while the activation of TAK1 which was upstream of JNK and p38 was augmented by PA pretreatment. Inhibitors of NF-κB, MEK1/2, and p38 significantly decreased IL-1ß expression, while JNK and p38 pathway inhibitors significantly inhibited TNF-α expression. The differential regulation of LPS-induced TNF-α and IL-1ß production by PA was associated with cellular metabolism of PA, because inhibiting metabolism of PA with etomoxir or pretreatment with Br-PA which cannot be metabolized reversed these effects. We also showed that PA treatment increased acetylated IKK level which might contribute to the suppressed activation of IKK. The present study showed that LPS-induced production of TNF-α and IL-1ß was regulated by different TLR4 downstream pathways in macrophages. PA differentially affected LPS-induced production of TNF-α and IL-1ß in macrophages through differentially modulating these pathways. Further experiments will be needed to determine how these phenomena lead to the impaired immune response in patients with diabetes.

Hypertension With High Homocysteine Is Associated With Default Network Gray Matter Loss.

Hypertension with high homocysteine (Hcy, ≥10 µmol/L) is also known as H-type hypertension (HHT) and proposed as an independent risk factor for stroke and cognitive impairment. Although previous studies have established the relationships among hypertension, Hcy levels, and cognitive impairment, how they affect brain neuroanatomy remains unclear. Thus, we aimed to investigate whether and to what extent hypertension and high Hcy may affect gray matter volume in 52 middle-aged HHT patients and 51 demographically matched normotensive subjects. Voxel-based morphological analysis suggested that HHT patients experienced significant gray matter loss in the default network. The default network atrophy was significantly correlated with Hcy level and global cognitive function. These findings provide, to our knowledge, novel insights into how HHT affects brain gray matter morphology through blood pressure and Hcy.

Root Physiological Traits and Transcriptome Analyses Reveal that Root Zone Water Retention Confers Drought Tolerance to Opisthopappus taihangensis.

Opisthopappus taihangensis (Ling) Shih, as a relative of chrysanthemum, mainly survives on the cracks of steep slopes and cliffs. Due to the harsh environment in which O. taihangensis lives, it has evolved strong adaptive traits to drought stress. The root system first perceives soil water deficiency, triggering a multi-pronged response mechanism to maintain water potential; however, the drought tolerance mechanism of O. taihangensis roots remains unclear. Therefore, roots were selected as materials to explore the physiological and molecular responsive mechanisms. We found that the roots had a stronger water retention capacity than the leaves. This result was attributed to ABA accumulation, which promoted an increased accumulation of proline and trehalose to maintain cell osmotic pressure, activated SOD and POD to scavenge ROS to protect root cell membrane structure and induced suberin depositions to minimize water backflow to dry soil. Transcriptome sequencing analyses further confirmed that O. taihangensis strongly activated genes involved in the ABA signalling pathway, osmolyte metabolism, antioxidant enzyme activity and biosynthesis of suberin monomer. Overall, these results not only will provide new insights into the drought response mechanisms of O. taihangensis but also will be helpful for future drought breeding programmes of chrysanthemum.

Azepinoindole Synthesis via a N-Bromosuccinimide-Induced Cycloisomerization of Enaminoester/Enaminone.

A protocol based on a newly developed N-bromosuccinimide (NBS)-induced cycloisomerization was described to prepare tricyclic azepino[4,5-b]indoles from simple ß-enaminoesters or ß-enaminones containing an indole unit. A mechanism involving a Pictet-Spengler cyclization, an aziridine ring formation, and a regioselective C-N bond cleavage was proposed to account for the medium-sized ring formation and the migration of electron-withdrawing group (ester, ketone).

Controllable Encapsulation of "Clean" Metal Clusters within MOFs through Kinetic Modulation: Towards Advanced Heterogeneous Nanocatalysts.

Surfactant-free tiny Pt clusters were successfully encapsulated within MOFs with controllable size and spatial distribution by a novel kinetically modulated one-step strategy. Our synthesis relies on the rational manipulation of the reduction rate of Pt ions and/or the growth rate of MOFs by using H2 as assistant reducing agent and/or acetic acid as MOF-formation modulator. The as-prepared Pt@MOF core-shell composites exhibited exceedingly high activity and excellent selectivity in the oxidation of alcohols as a result of the ultrafine "clean" Pt clusters, as well as interesting molecular-sieving effects derived from the outer platinum-free MOF shell.

Azocinoindole synthesis by a gold(I)-catalyzed ring expansion of 2-propargyl-ß-tetrahydrocarboline.

A new methodology taking advantage of gold(I)-catalyzed ring expansion has been developed to assemble tricyclic 1H-azocino[5,4-b]indoles from 2-propargyl-ß-tetrahydrocarbolines. The azocinoindoles were obtained in moderate to excellent yields; the structure of which was established by X-ray crystallographic analysis. A mechanism involving regioselective intramolecular hydroarylation, [1,2]-alkenyl migration and carbon-carbon bond-fragmentation was proposed.

Data extraction from machine-translated versus original language randomized trial reports: a comparative study.

BACKGROUND: Google Translate offers free Web-based translation, but it is unknown whether its translation accuracy is sufficient to use in systematic reviews to mitigate concerns about language bias. METHODS: We compared data extraction from non-English language studies with extraction from translations by Google Translate of 10 studies in each of five languages (Chinese, French, German, Japanese and Spanish). Fluent speakers double-extracted original-language articles. Researchers who did not speak the given language double-extracted translated articles along with 10 additional English language trials. Using the original language extractions as a gold standard, we estimated the probability and odds ratio of correctly extracting items from translated articles compared with English, adjusting for reviewer and language. RESULTS: Translation required about 30 minutes per article and extraction of translated articles required additional extraction time. The likelihood of correct extractions was greater for study design and intervention domain items than for outcome descriptions and, particularly, study results. Translated Spanish articles yielded the highest percentage of items (93%) that were correctly extracted more than half the time (followed by German and Japanese 89%, French 85%, and Chinese 78%) but Chinese articles yielded the highest percentage of items (41%) that were correctly extracted >98% of the time (followed by Spanish 30%, French 26%, German 22%, and Japanese 19%). In general, extractors' confidence in translations was not associated with their accuracy. CONCLUSIONS: Translation by Google Translate generally required few resources. Based on our analysis of translations from five languages, using machine translation has the potential to reduce language bias in systematic reviews; however, pending additional empirical data, reviewers should be cautious about using translated data. There remains a trade-off between completeness of systematic reviews (including all available studies) and risk of error (due to poor translation).

Liver-X-receptor activator prevents homocysteine-induced production of IgG antibodies from murine B lymphocytes via the ROS-NF-kappaB pathway.

Our previous study showed that homosysteine (Hcy) promotes proliferation of mouse splenic B lymphocytes. In this study, we investigated whether Hcy could stimulate the production of IgG antibodies. Hcy significantly increased the production of IgG antibodies from resting B lymphocytes. B lymphocytes from ApoE-knockout mice with hyperhomocysteinemia showed elevated IgG secretion at either the basal Hcy level or in response to lipopolysaccharide. Hcy promoted reactive oxygen species (ROS) formation, and free radical scavengers, MnTMPyP decreased Hcy-induced IgG secretion. The inhibitor of NF-kappaB (MG132) also significantly reduced Hcy-induced IgG secretion. Furthermore, Hcy-induced formation of ROS, activation of NF-kappaB, and secretion of IgG could be inhibited by the liver-X-receptor (LXR) agonist T0901317. Thus, our data provide strong evidence that HHcy induces IgG production from murine splenic B lymphocytes both in vitro and in vivo. The mechanism might be through the ROS-NF-kappaB pathway and can be attenuated by the activation of LXR.

Dna damage and external lesions in brown bullheads (Ameiurus Nebulosus) from contaminated habitats.

The Comet assay was used to compare levels of DNA damage in brown bullheads (Ameiurus nebulosus) collected from three known contaminated locations, the Cuyahoga River (OH, U.S.A.), Ashtabula River (OH, U.S.A.; both tributaries to Lake Erie, USA), and Ashumet Pond (Cape Cod, MA, U.S.A.), with brown bullheads collected from three paired reference sites, Old Woman Creek (OH, U.S.A.), Conneaut River (OH, U.S.A.; both tributaries to Lake Erie), and Great Herring Pond (mainland MA, U.S.A.), respectively. Blood was sampled from each fish, and the Comet assay was conducted on erythrocytes. The assay results demonstrate that fish from the three contaminated sites each suffered higher DNA damage compared with fish from their respective reference sites. The results also show that the genetic damage was associated with the occurrence of external lesions and deformities in fish. The Comet assay is sufficiently sensitive to detect exposure of natural fish populations to environmental levels of genotoxic contaminants.

Role of redox factor-1 in hyperhomocysteinemia-accelerated atherosclerosis.

Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis. We have previously shown that homocysteine can induce monocyte chemoattractant protein-1 (MCP-1) secretion via reactive oxygen species (ROS) in human monocytes in vitro. In the present study, we investigated whether redox factor-1 (Ref-1) is involved in HHcy-accelerated atherosclerosis. We used a mild HHcy animal model, aortic roots and peritoneal macrophages were isolated for immunohistochemistry and Western blotting, from apoE-/- and C57BL/6J mice fed a high Hcy diet (1.8 g/L) for 4 or 12 weeks. Four-week HHcy apoE-/- mice showed more plaques and significantly increased immunostaining of Ref-1 and MCP-1 in foam cells, and HHcy mice showed enhanced Ref-1 expression in peritoneal macrophages. To explore the mediating mechanism, incubation with Hcy (100 microM) increased Ref-1 protein level and translocation in human monocytes in vitro. In addition, Hcy-induced NADPH oxidase activity mediated the upregulation of Ref-1. Furthermore, overexpressed Ref-1 upregulated NF-kappaB and MCP-1 promoter activity, and antisense Ref-1 reduced Hcy-induced NF-kappaB DNA-binding activity and MCP-1 secretion. These data indicate that Hcy-induced ROS upregulate the expression and translocation of Ref-1 via NADPH oxidase, and then Ref-1 increases NF-kappaB activity and MCP-1 secretion in human monocytes/macrophages, which may accelerate the development of atherosclerosis.

C-reactive protein augments interleukin-8 secretion in human peripheral blood monocytes.

C-reactive protein (CRP) is a powerful predictor and risk factor for cardiovascular diseases. The CXC- and CC-type chemokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) are important chemokines for leukocyte trafficking identified in atheromatous plaque expressed mainly by macrophages in humans. We assessed whether C-reactive protein could induce MCP-1 and IL-8 secretion. In human peripheral blood monocytes, C-reactive protein (12.5-50 microg/mL) increased IL-8, but not MCP-1 secretion in a time- (6-24 hours) and dose-dependent manner as detected by ELISA. C-reactive protein could augment the production of reactive oxygen species (ROS) as measured by chemiluminescence and inhibitors of NAD(P)H oxidase (DPI and PAO) and ROS scavengers (superoxide dismutase, catalase, and 1% dimethyl sulphoxide) abolished C-reactive protein-induced IL-8 secretion. Furthermore, relative quantity of IL-8 mRNA was significantly increased by C-reactive protein 50 microg/mLfor 12 hours, which could be inhibited by DPI 1 microM or superoxide dismutase (SOD) 250 U/mL. The inhibitors of ERK 1/2 (PD98059), p38 (SB203580) MAPK, and NF-kappaB (PDTC and MG132) significantly decreased C-reactive protein-induced IL-8 secretion in human monocytes. Also, agonists of peroxisome proliferator-activated receptor (PPAR) alpha (WY14643) and PPARgamma (troglitazone) could largely inhibit C-reactive protein responses. Thus, our data indicate that C-reactive protein at pathologic levels increases IL-8 secretion and mRNA via enhancing ROS derived mainly from NAD(P)H oxidase and the subsequent activation of ERK1/2, p38 MAPK, and NF-kappaB. The activation of PPARalpha/gamma can negatively regulate C-reactive protein-induced IL-8 production in human monocytes.

Responses of molecular indicators of exposure in mesocosms: common carp (Cyprinus carpio) exposed to the herbicides alachlor and atrazine.

Common carp (Cyprinus carpio) were treated in aquatic mesocosms with a single pulse of the herbicides atrazine or alachlor to study the bioavailability and biological activity of these herbicides using molecular indicators: Liver vitellogenin gene expression in male fish for estrogenic activity, liver cytochrome P4501A1 gene expression, and DNA damage in blood cells using the single-cell gel electrophoresis method. Both alachlor and atrazine showed dose-related increases in DNA strand breaks at environmentally relevant concentrations (<100 ppb). Gene expression indicators showed that neither herbicide had estrogenic activity in the carp, whereas atrazine at concentrations as low as 7 ppb induced cytochrome P4501A1. These results support the study of molecular indicators for exposure in surrogate ecosystems to gauge relevant environmental changes following herbicide treatments.