Dysregulation of gap junctional intercellular communication (GJIC) has been associated with different pathologies, including cancer; however, molecular mechanisms regulating GJIC are not fully understood. Mitogen Activated Protein Kinase (MAPK)-dependent mechanisms of GJIC-dysregulation have been well-established, however recent discoveries have implicated phosphatidylcholine-specific phospholipase C (PC-PLC) in the regulation of GJIC. What is not known is how prevalent these two signaling mechanisms are in toxicant/toxin-induced dysregulation of GJIC, and do toxicants/toxins work through either signaling mechanisms or both, or through alternative signaling mechanisms. Different chemical toxicants were used to assess whether they dysregulate GJIC via MEK or PC-PLC, or both Mek and PC-PLC, or through other signaling pathways, using a pluripotent rat liver epithelial oval-cell line, WB-F344. Epidermal growth factor, 12-O-tetradecanoylphorbol-13-acetate, thrombin receptor activating peptide-6 and lindane regulated GJIC through a MEK1/2-dependent mechanism that was independent of PC-PLC; whereas PAHs, DDT, PCB 153, dicumylperoxide and perfluorodecanoic acid inhibited GJIC through PC-PLC independent of Mek. Dysregulation of GJIC by perfluorooctanoic acid and R59022 required both MEK1/2 and PC-PLC; while benzoylperoxide, arachidonic acid, 18β-glycyrrhetinic acid, perfluorooctane sulfonic acid, 1-monolaurin, pentachlorophenol and alachlor required neither MEK1/2 nor PC-PLC. Resveratrol prevented dysregulation of GJIC by toxicants that acted either through MEK1/2 or PC-PLC. Except for alachlor, resveratrol did not prevent dysregulation of GJIC by toxicants that worked through PC-PLC-independent and MEK1/2-independent pathways, which indicated at least two other, yet unidentified, pathways that are involved in the regulation of GJIC. In conclusion: the dysregulation of GJIC is a contributing factor to the cancer process; however the underlying mechanisms by which gap junction channels are closed by toxicants vary. Thus, accurate assessments of risk posed by toxic agents, and the role of dietary phytochemicals play in preventing or reversing the effects of these agents must take into account the specific mechanisms involved in the cancer process.

Methoxychlor (MXC) and vinclozolin (VIN) are well-recognized endocrine disrupting chemicals known to alter epigenetic regulations and transgenerational inheritance; however, non-endocrine disruption endpoints are also important. Thus, we determined the effects of MXC and VIN on the dysregulation of gap junctional intercellular communication (GJIC) and activation of mitogen-activated protein kinases (MAPKs) in WB-F344 rat liver epithelial cells. Both chemicals induced a rapid dysregulation of GJIC at non-cytotoxic doses, with 30 min EC 50 values for GJIC inhibition being 10 mM for MXC and 126 mM for VIN. MXC inhibited GJIC for at least 24 h, while VIN effects were transient and GJIC recovered after 4 h. VIN induced rapid hyperphosphorylation and internalization of gap junction protein connexin43, and both chemicals also activated MAPK ERK1/2 and p38. Effects on GJIC were not prevented by MEK1/2 inhibitor, but by an inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC), resveratrol, and in the case of VIN, also, by a p38 inhibitor. Estrogen (ER) and androgen receptor (AR) modulators (estradiol, ICI 182,780, HPTE, testosterone, flutamide, VIN M2) did not attenuate MXC or VIN effects on GJIC. Our data also indicate that the effects were elicited by the parental compounds of MXC and VIN. Our study provides new evidence that MXC and VIN dysregulate GJIC via mechanisms involving rapid activation of PC-PLC occurring independently of ER-or AR-dependent genomic signaling. Such alterations of rapid intercellular and intracellular signaling events involved in regulations of gene expression, tissue development, function and homeostasis, could also contribute to transgenerational epigenetic effects of endocrine disruptors.

The burden of cardiovascular disease (CVD) among minority and low-income populations is well documented. This study aimed to assess the impact of patient activation and shared decision-making (SDM) on medication use through the Office-Guidelines Applied to Practice (Office-GAP) intervention in Federally Qualified Healthcare Centers (FQHCs).Patients (243) with diabetes and CHD participated in Office-GAP between October 2010 and March 2014. Two-site (FQHCs) intervention/control design. Office-GAP integrates health literacy, communication skills education for patients and physicians, decision support tools, and SDM into routine care. Main measures: 1) implementation rates, 2) medication use at baseline, 3, 6, and 12 months, and 3) predictors of medication use. Logistic regression with propensity scoring assessed impact on medication use. Intervention arm had 120 and control arm had 123 patients. We found that program elements were consistently used. Compared to control, the Office-GAP program significantly improved medications use from baseline: ACEIs or ARBs at 3 months (OR 1.88, 95% CI = 1.07; 3.30, p < 0.03), 6 months (OR 2.68, 95% CI = 1.58;4.54; p < 0.01); statin at 3 months (OR 2.00, 95% CI = 0.1.22; 3.27; p < 0.05), 6 months (OR 3.05, 95% CI = 1.72; 5.43; p < 0.01), Aspirin and/or clopidogrel at 3 months OR 1.59, 95% CI = 1.02, 2.48; p < 0.05), 6 months (OR 3.67, 95% CI = 1.67; 8.08; p < 0.01). Global medication adherence was predicted only by Office-GAP intervention presence and hypertension.Office-GAP resulted in increased use of guideline-based medications for secondary CVD prevention in underserved populations. The Office-GAP program could serve as a model for implementing guideline-based care for other chronic diseases.

Introduction: Cardiovascular disease and not hyperglycemia is the major cause of mortality in patients with diabetes mellitus (DM). Hypertension is particularly burdensome in low income groups, where the prevalence of uncontrolled hypertension is higher than the general population. Federally Qualified Health Centers (FQHCs) provide care for low income and medically underserved populations (both immigrant and non-immigrant population). Objectives: 1) to determine the rate and predictors of Blood Pressure (BP) control in patients with diabetes and hypertension. 2) to identify differences by immigration status in BP control among patients attending FQHCs. Methods: The Office Guidelines Applied to Practice (Office-GAP) study is a cluster randomized trial designed to improve cardiovascular care for minority and low income populations in outpatient clinical settings. Office-GAP intervention included: provider training, patient education in a group visit, and use of Office-GAP checklist and patient decision aids during office visits. We describe baseline patient characteristics (prior to any intervention) in the FQHC sites. Retrospective review was performed of charts of all patients with hypertension, coronary artery disease and or, diabetes mellitus (DM) from September 2010 to December 2012. Hypertension was defined as Systolic BP>140 mmHg (>130 mm Hg in DM patients) and diastolic BP > 90 mmHg (>80 mm Hg in DM patients). A multivariable logistic regression was used to assess the effects of potential predicators on BP control. Results: Of 242 patients identified, 169 had DM, and 166 had hypertension. The mean age was 54.47 ± 11.91 years and 44.39 % were men (99 of 223). Of the total sample, 178 (73.55%, 178 of 242) were non-immigrants, 23.87 % (53 of 222) were covered by Medicaid, 40.99% (91 of 222) by Medicare, 39.19 % (87 of 222) by county outpatient insurance; 33.06% (70 of 242) were Black, 34.71 % (84 of 242) White and 32.23% (78 of 242) formed other races (Hispanics, Somalis, Nepalese). BP control was 36.73% (83 of 226) 95% CI = [30.44, 43.02] and 27.22% (46 of 169) 95% CI = [20.51, 33.93] in total sample and DM patients respectively. BP control among immigrants was 32.2% (19 of 59) 95% CI = [20.28, 44.12] vs. 38.32% (64 of 167) 95% CI = [30.95, 45.69] in non-immigrants. A logistic regression model identify the DM status as the sole significant predictor associated with BP control, with patients without DM having the best BP control (p-value<0.0001). This effect of DM on BP control remained significant even after adjusted for other predictors. Conclusions: We found that significant number of patients attending FQHCs do not have their BP controlled. Immigration status did not play any role in BP control; however BP control among patients with DM was substantially lower than the whole sample. This underscores the urgent need for strategies to improve BP control in FQHCs, particularly among diabetic patients.