Single-Center Comparison of Chronic Subdural Hematoma Evacuation Outcomes Under Local Versus General Anesthesia.

BACKGROUND: Chronic subdural hematoma (CSDH) is a neurosurgical pathology of an aged populace. Pathogenetic risk factors include traumatic brain injury, prolonged use of antiplatelet drugs, hypertension, and some inflammatory processes. The incidence increases as patients age. Burr-hole evacuation is the most common approach in management of symptomatic cases. We compared evacuation of chronic subdural hematomas with general or local anesthesia (GA and LA, respectively) and evaluated the safety, economic benefits, effects of comorbidity, benefits, and shortcomings of both techniques. METHODS: We conducted a retrospective study of 67 consecutive patients who had 74 procedures for CSDH in a single neurosurgical center, the Regional Clinic, Centre of Neurosurgery and Neurology, over a 3-year period. They were grouped into the GA group (n = 44) and LA group (n = 23). Mean duration of procedure, length of hospital stay, complications, and preoperative and postoperative neurologic statuses were compared. The distribution of nominal variables between groups was compared using the Fisher exact test. The average duration of operation and length of hospital stay were compared using the Mann-Whitney U-test due to violation of the normality assumption. RESULTS: LA proved to be as effective as GA in CSDH evacuation. Seventy-four surgical procedures were performed on 67 patients due to recurrence in less than 30 days in 7 patients. Fifteen patients had tension pneumocephalus managed with fluid therapy to full recovery. LA was economical and required shorter hospital stays and surgical time. CONCLUSIONS: In our studies, LA proved to be noninferior to GA, time conserving, and less prone to some of the adverse effects of GA on elderly patients with comorbidity, although some patients who are hyperactive or contraindicated to LA will require GA.

COVID-19 DEATHS AND VACCINATION IN NIGERIA: AN APPRAISAL.

Background/Aim: Some estimates indicates that by 2021 ending, more people as a share of the vulnerable population in Africa, Nigeria inclusive, have died than elsewhere due to late and inadequate vaccination. With the pandemic phase of high daily deaths formally declared over, COVID-19 deaths before and after vaccination commenced were compared to observe how vaccination impacted COVID-19 deaths. Method: COVID-19 cases, deaths and vaccination rates in World Health Organization databases up to 07 June 2023 and other variables of interest unavailable there but found in other open- sources were all extracted and examined. Case fatality rate (CFR) per 1,000 for the period prior to vaccination (CFR1) and the period after vaccination commenced (CFR2) was computed. Simple statistics were used in data analysis. Results: Between when the first case was documented and 05 June 2023, Nigeria recorded 3,155 COVID-19 deaths and majority (61.84%) occurred between 19 March 2020 and March 5, 2021 when vaccination commenced. COVID-19 deaths declined to 61.7% of pre-vaccination figure coinciding with vaccination that delivered partial, primary and booster rates of 39.94%, 33.86% and 5.97% respectively. The cumulative COVID-19 deaths by population size was 8.94/106 pre-vaccination while COVID-19 deaths in vaccination era added 5.510/106mortalities to the final mortality figure of 14. 44/106. The calculated CFR1 and CFR2 rebased were 1.24% and 1.04% respectively. Conclusion: More COVID-19 deaths occurred before vaccination commenced than in over two years of ongoing vaccination.

Risk assessment of human exposure to radionuclides and heavy metals in oil-based mud samples used for drilling operation.

This study investigates heavy metals and naturally occurring radionuclide materials (NORM) possible presence and pollution rates in oil-based drilling fluids system used to drill an oil and gas well. It also estimates the health risks of the drilling crew due to their exposure to these substances. Measurements from Atomic Absorption Spectrometry (AAS) revealed that, the concentrations of the metals present in the drilling mud samples varied significantly and decreased in the order of Zn > Al > Ni > Pb > Cr > Cu > As > Hg > Cd. Generally, amongst all the heavy metals considered, mud sample C had the highest heavy metal concentration when compared to samples A and B, respectively. When compared with the recommended maximum allowable limits, Cd and Ni were found to be higher than the International Reference Standard by factors of Cd (3 mg/kg) and Ni (50 mg/kg). The cancer risk obtained from this present study are 1.1 × 10-3 and 7.7 × 10-3 for the drilling crew, which is slightly above the acceptable risk range considered by the environmental and regulatory agencies. The concentrations of radioactive substances as obtained from analysis, show that K-40 is the dominant radionuclide in the samples with the highest value slightly twice the standard reference value. The concentrations of Ra-226 and Th-232 activity in the mud samples were found to be lower when compared with the International Reference Level. Also, the X-ray diffraction analysis helped to identify 16 very important/useful minerals in the three mud samples under consideration. The higher elemental concentrations of potassium and aluminum silicate found in sample C can be credited to the elevated heavy metal-content found in the mud samples. Significantly, these exposure risks found in this present study indicate that the potential health risks due to radiological activities may not pose short - but long-term risks to the drillers.

COVID-19 Pandemic as a mass killer and existential public health emergency in Nigeria remains unproven: A viewpoint

Framing COVID­19 pandemic as mass killer and existential public health emergency/threat in Nigeria with 2,120 COVID­19­related deaths in over 14 months of the pandemic in the country is problematic, especially as other public health conditions kill more Nigerians annually. In 2018, for example, malaria and road traffic accident caused 97,200 and 38,902 deaths, respectively, while HIV/AIDS caused 43,000 deaths in 2019. Therefore, rushing into an extensive vaccination campaign projected to cost 540 billion naira when 76.03 billion naira was allocated for primary health services nationwide including other major immunization programs in the 2021 federal health budget could raise question of priority/effective spending. Especially with COVID-19 deaths relative to reported cases(case fatality ratio) declining to 1.30% by June 30, 2021 from 3.45% in April 2020 and daily mass deaths non-evident. Temporizing to understand how the pandemic evolves especially in jurisdictions with higher need could be cost­effective.

TNFα-Induced LDL Cholesterol Accumulation Involve Elevated LDLR Cell Surface Levels and SR-B1 Downregulation in Human Arterial Endothelial Cells.

Excess lipid droplets are frequently observed in arterial endothelial cells at sites of advanced atherosclerotic plaques. Here, the role of tumor necrosis factor alpha (TNFα) in modulating the low-density lipoprotein (LDL) content in confluent primary human aortic endothelial cells (pHAECs) was investigated. TNFα promoted an up to 2 folds increase in cellular cholesterol, which was resistant to ACAT inhibition. The cholesterol increase was associated with increased 125I-LDL surface binding. Using the non-hydrolysable label, Dil, TNFα could induce a massive increase in Dil-LDL by over 200 folds. The elevated intracellular Dil-LDL was blocked with excess unlabeled LDL and PCSK9, but not oxidized LDL (oxLDL), or apolipoprotein (apoE) depletion. Moreover, the TNFα-induced increase of LDL-derived lipids was elevated through lysosome inhibition. Using specific LDLR antibody, the Dil-LDL accumulation was reduced by over 99%. The effects of TNFα included an LDLR cell surface increase of 138%, and very large increases in ICAM-1 total and surface proteins, respectively. In contrast, that of scavenger receptor B1 (SR-B1) was reduced. Additionally, LDLR antibody bound rapidly in TNFα-treated cells by about 30 folds, inducing a migrating shift in the LDLR protein. The effect of TNFα on Dil-LDL accumulation was inhibited by the antioxidant tetramethythiourea (TMTU) dose-dependently, but not by inhibitors against NF-κB, stress kinases, ASK1, JNK, p38, or apoptosis caspases. Grown on Transwell inserts, TNFα did not enhance apical to basolateral LDL cholesterol or Dil release. It is concluded that TNFα promotes LDLR functions through combined increase at the cell surface and SR-B1 downregulation.

A Review on Polymer Nanocomposites and Their Effective Applications in Membranes and Adsorbents for Water Treatment and Gas Separation.

Globally, environmental challenges have been recognised as a matter of concern. Among these challenges are the reduced availability and quality of drinking water, and greenhouse gases that give rise to change in climate by entrapping heat, which result in respirational illness from smog and air pollution. Globally, the rate of demand for the use of freshwater has outgrown the rate of population increase; as the rapid growth in town and cities place a huge pressure on neighbouring water resources. Besides, the rapid growth in anthropogenic activities, such as the generation of energy and its conveyance, release carbon dioxide and other greenhouse gases, warming the planet. Polymer nanocomposite has played a significant role in finding solutions to current environmental problems. It has found interest due to its high potential for the reduction of gas emission, and elimination of pollutants, heavy metals, dyes, and oil in wastewater. The revolution of integrating developed novel nanomaterials such as nanoparticles, carbon nanotubes, nanofibers and activated carbon, in polymers, have instigated revitalizing and favourable inventive nanotechnologies for the treatment of wastewater and gas separation. This review discusses the effective employment of polymer nanocomposites for environmental utilizations. Polymer nanocomposite membranes for wastewater treatment and gas separation were reviewed together with their mechanisms. The use of polymer nanocomposites as an adsorbent for toxic metals ions removal and an adsorbent for dye removal were also discussed, together with the mechanism of the adsorption process. Patents in the utilization of innovative polymeric nanocomposite membranes for environmental utilizations were discussed.

In-situ remediation of petroleum-contaminated soil by application of plant-based surfactants toward preventing environmental degradation.

Remediation in this study employs the use of green plants and their extracts in enhancing the remediation process of polluted soils. GC-MS & FTIR techniques were employed in determining the constituents of the soil during the investigation. 60 ml of the extracts were applied on 1 by 2 ft segments of hydrocarbon polluted site and observed for two months. The results show that plant extract A significantly reduced the TPHs and PAHs to 5,450 and 126.2 mg/kg, respectively, as compared to those of extract B whose TPH and PAH values are 10,432 and 362.3 mg/kg, respectively. Both plant extracts reduced the total petroleum hydrocarbon compounds significantly when compared to the standard reference PAH and PAHs (4,500 mg/kg and 50 mg/kg respectively). The microbial plate count for the three media shows that the plant based surfactant had a synergy with the identified bacteria in enhancing Phytoremediation of the crude oil polluted site. Novelty statement: This study examined the application of two plant-based surfactants for remediation. These natural surfactants significantly reduced the petroleum hydrocarbon compounds present in the soil within the in-situ observation window. These Herbaceous plant family extracts have a great advantage as an eco-friendly alternative to synthetic surfactants, and they also exhibited an anti-fungi characteristic. The two biodegradable plant-based surfactants also significantly reduced the time that it could have taken for a remediation process.

Porphyromonas gingivalis infection alters Nrf2-phase II enzymes and nitric oxide in primary human aortic endothelial cells.

BACKGROUND: Periodontal disease (PD) is known to be associated with endothelial dysfunction in patients with coronary artery and/or cardiovascular disease. In our study, we sought to explore the virulence of P. gingivalis (Pg) affecting glycogen synthase kinase 3 beta (GSK-3ß)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/tetrahydrobiopterin (BH4 )/ nitric oxide synthase (NOS) expression in primary human aortic endothelial cells (pHAECs). METHODS: pHAECs were infected for 48 hours with Pg in vitro using the Human oxygen-Bacteria anaerobic coculture technique. Cell viability was determined, and target gene expression changes were evaluated by quantitative real-time polymerase chain reaction at the end of each incubation period. RESULTS: Pg impaired pHAEC viability 24 hours post-infection. Pg infection reduced mRNA expression levels of endothelial NOS (eNOS), Nrf2, and Phase II enzymes (heme oxygenase-1, catalase, superoxide dismutase-1) in a time-dependent manner. Significant (P <0.05) increase in the inflammatory markers (interleukin [IL]-1ß, IL-6, and tumor necrosis factor-α) were observed in the medium as well as in the infected cells. Interestingly, inducible NOS mRNA levels showed a significant (P <0.05) increase at 12 hours and 24 hours and were reduced at later time points. BH4 (cofactor of eNOS) biosynthesis enzyme dihydrofolate reductase (DHFR, salvage pathway) mRNA levels showed a significant (P <0.05) decrease, while mRNA levels of GSK-3ß were elevated. CONCLUSIONS: These results suggest that periodontal bacterial infection may cause significant changes in the endothelial GSK-3ß/BH4 /eNOS/Nrf2 pathways, which may lead to impaired vascular relaxation. Greater understanding of the factors that adversely affect endothelial cell function could contribute to the development of new therapeutic compounds to treat PD-induced vascular diseases.

Toxicology of Heavy Metals to Subsurface Lithofacies and Drillers during Drilling of Hydrocarbon Wells.

This study investigates the toxicological effects of heavy metals on lithofacies of the subsurface in a drilled hydrocarbon well as well as, to the drilling crew and people in an environment. The pollution levels of selected heavy metals were considered alongside their ecological effects during dry and wet seasons. The health hazard potential of human exposures to the metals, were estimated in terms of intensity and time using the USEPA recommended model. The heavy metal concentration for each layer decreased across the lithofacies as follows; Layer 5> Layer 4> Layer 3> Layer 2> Layer 1. The average concentrations of the heavy metals present in the samples obtained from the formation zone, varied significantly and decreased in the order of Al> Zn> Ni> Pb> Cr> Cu> Cd> As> Hg. The highest concentration of Al, Cu, and Zn in this present study were within the maximum allowable limits whereas, those of As, Cd, Hg and Ni were all above their maximum allowable limits. Among the transition metals analysed, the maximum mean daily dose of Pb (9.18 × 10-6 mg/kg/d) and Cr (1.42 × 10-6 mg/kg/d) were confirmed susceptible to human carcinogens and environmental toxins. The estimated hazard quotient shows that the dermal pathway is the most likely route via which the drilling crew and people in the environment can get contaminated. The cancer risk values for the Pb (7.72 × 10-4), Cd (1.35 × 10-1), Ni (9.97 × 10-3), As (1.50 × 10-1) and Cr (3.16 × 10-3) are all above the acceptable values. The cancer risk contribution for each metal was in the order of As> Cd> Ni> Cr> Pb. Layer 5 had the maximum Geo-accumulation index for the heavy metals considered. This higher Geo-accumulation index noted at the depth in Layer 5 may be attributed to the effect of water basin with turbidity currents, deltas, and shallow marine sediment deposits with storm impacted conditions. Also, the pollution from lead (Pb) in the dry season was maximum with an Igeo value> 5 for all the lithofacies considered because of the low background concentration of the metal. During the wet season, the heavy metal pollution rate was moderate for Zn whereas, it was extremely polluted with respect to Pb. The ecological risk potential of Pb shows that the associated ecological risks range from 536 - 664 in the wet season (i.e. extremely strong) and 2810 - 3480 in dry season (extremely strong). The high level of Pb pollution found in the area at such shallow depth may be due to the sedimentary folds possibly caused by the full spectrum of metamorphic rocks and primary flow structures at shallow depths. This was used to identify the environmental sensitivities of the heavy metals during the dry and wet seasons.

Assessment of naturally occurring radiation in lithofacies of oil field in Niger Delta region and its possible health implications.

The accumulation and increase in radionuclide activities of NORMs beyond permissible levels, will lead to health hazards and environmental damages if proper measures are not taken to control their occurrence as well as protect the lives of drillers and the environment. Therefore, evaluations and risk assessments of subsurface lithofacies is inevitable in order to protect people and the environment. Lack of existing Federal environmental regulations to address the presence of NORMs in oil and gas exploration activities in Nigeria, gives credence to this study. However, before these regulations can be developed, adequate research knowledge is needed to better understand the occurrence and distribution of Norms in subsurface lithofacies, as well as quantify the hazards posed by these NORMs to the people in the environment. This study then investigates the occurrence of natural radiation in lithofacies of an oil field region in Niger-Delta area using Hyper Germanium (HPGe) detector. Six (6) samples of different subsurface layers of lithofacies were collected during drilling, and analyzed. The results showed that the measured activity concentration of 238U decreased as the depth increased; the activity concentration of 232Th ranged between 11.8 ± 9.29 Bq/kg and 23.1 ± 8.43 Bq/kg, while the activity concentration of 4 K ranged from 161.8 Bq/kg to 245.4 Bq/kg. The estimated radiological risks such as absorbed dose rates, annual effective dose rates, radium equivalent index, external hazard index and internal hazard index were determined. The mean values for the estimated radiological parameters were 12.32 nGyh-1, 15.1049 Svy-1, 44.7720 Bqkg-1, 0.1209 and 0.1318 respectively. The gamma index estimated for the samples used were within the standard values recommended by Unscear, 2000. Significantly, this study reveals a distinctive decrease in 232Th activity with depth within the area under consideration. Based on the compared results, the measured radioactive concentrations and estimated radiological risks were below international reference values.

Radiological and toxicity risk exposures of oil based mud: health implication on drilling crew in Niger Delta.

Naturally occurring radioactive materials (NORMs) and the presence of toxic metals in drilling fluids/their additives have raised research interests in recent times owing to the risks associated with the exposure times for drillers of petroleum wells. In this study, two drilling fluids A and B were formulated, while two other Mud Samples C and D were obtained from drilled shale and shale-sand formation zones. All four fluids were collected and analyzed for the presence of radioactive and heavy metals. Lead (Pb), mercury (Hg), cadmium Cd), zinc (Zn), chromium (Cr), aluminum (Al), arsenic (As), nickel (Ni), and copper (Cu) were detected in the mud samples. The heavy metal contents of the mud samples are in the following decreasing order of magnitude Hg > Pb > Cd > Cr. In Samples A-D, Hg, Pb, Cr, and Cd were found to have significant concentrations, and the concentrations of these metals increased in the mud samples after they were used for drilling. The concentration of Hg was above the permissible limit. Also, the concentrations of Pb, Cu, As, and Al found in Mud Samples A and B can cause skin irritations over long-term exposures, while Cd, Hg, Zn, and Ni present in the samples were within levels that can cause lung infections or immune breakdown when ingested over long periods. The quantities of Cd, Hg, and Cu detected in Mud Samples C and D can cause skin irritations over long-term exposures, while those of As, Zn, Ni, and Al were seen to have the potential to cause dermal infections/diseases. Based on the results obtained, the cancer risk for the drilling crew lies within 1.1 × 10-3 - 7.7 × 10-3 HQ. The highest dose rate, radium release, and external hazard index were obtained for Mud Sample C whose radium equivalent was judged to be far below the critical safe limit for the drillers. The radium equivalent activity for the two field mud samples (C and D) were estimated to be 27.467 and 22.978 Bq kg-1, respectively, which is the maximum activity obtained for the analyzed samples. The maximum radium equivalent activity for Mud Sample C was estimated as 27.48 Bq kg-1 with a corresponding external hazard index of 0.7. Based on the analysis, there is a significant correlation between the concentration of heavy metals and the radionuclides found in the mud samples.

Transport of Apolipoprotein B-Containing Lipoproteins through Endothelial Cells Is Associated with Apolipoprotein E-Carrying HDL-Like Particle Formation.

Passage of apolipoprotein B-containing lipoproteins (apoB-LPs), i.e., triglyceride-rich lipoproteins (TRLs), intermediate-density lipoproteins (IDLs), and low-density lipoproteins (LDLs), through the endothelial monolayer occurs in normal and atherosclerotic arteries. Among these lipoproteins, TRLs and IDLs are apoE-rich apoB-LPs (E/B-LPs). Recycling of TRL-associated apoE has been shown to form apoE-carrying high-density lipoprotein (HDL)-like (HDLE) particles in many types of cells. The current report studied the formation of HDLE particles by transcytosis of apoB-LPs through mouse aortic endothelial cells (MAECs). Our data indicated that passage of radiolabeled apoB-LPs, rich or poor in apoE, through the MAEC monolayer is inhibited by filipin and unlabeled competitor lipoproteins, suggesting that MAECs transport apoB-LPs via a caveolae-mediated pathway. The cholesterol and apoE in the cell-untreated E/B-LPs, TRLs, IDLs, and LDLs distributed primarily in the low-density (LD) fractions (d ≤ 1.063). A substantial portion of the cholesterol and apoE that passed through the MAEC monolayer was allotted into the high-density (HD) (d > 1.063) fractions. In contrast, apoB was detectable only in the LD fractions before or after apoB-LPs were incubated with the MAEC monolayer, suggesting that apoB-LPs pass through the MAEC monolayer in the forms of apoB-containing LD particles and apoE-containing HD particles.

Overexpression of Catalase Enhances Benzo(a)pyrene Detoxification in Endothelial Microsomes.

We previously reported that overexpression of catalase upregulated xenobiotic- metabolizing enzyme (XME) expression and diminished benzo(a)pyrene (BaP) intermediate accumulation in mouse aortic endothelial cells (MAECs). Endoplasmic reticulum (ER) is the most active organelle involved in BaP metabolism. To examine the involvement of ER in catalase-induced BaP detoxification, we compared the level and distribution of XMEs, and the profile of BaP intermediates in the microsomes of wild-type and catalase transgenic endothelial cells. Our data showed that endothelial microsomes were enriched in cytochrome P450 (CYP) 1A1, CYP1B1 and epoxide hydrolase 1 (EH1), and contained considerable levels of NAD(P)H: quinone oxidoreductase-1 (NQO1) and glutathione S-transferase-pi (GSTP). Treatment of wild-type MAECs with 1µM BaP for 2 h increased the expression of microsomal CYP1A1, 1B1 and NQO1 by ~300, 64 and 116%, respectively. However, the same treatment did not significantly alter the expression of EH1 and GSTP. Overexpression of catalase did not significantly increase EH1, but upregulated BaP-induced expression of microsomal CYP1A1, 1B1, NQO1 and GSTP in the following order: 1A1>NQO1>GSTP>1B1. Overexpression of catalase did not alter the distribution of each of these enzymes in the microsomes. In contrast to our previous report showing lower level of BaP phenols versus BaP diols/diones in the whole-cell, this report demonstrated that the sum of microsomal BaP phenolic metabolites were ~60% greater than that of the BaP diols/diones after exposure of microsomes to BaP. Overexpression of catalase reduced the concentrations of microsomal BaP phenols and diols/diones by ~45 and 95%, respectively. This process enhanced the ratio of BaP phenol versus diol/dione metabolites in a potent manner. Taken together, upregulation of phase II XMEs and CYP1 proteins, but not EH1 in the ER might be the mechanism by which overexpression of catalase reduces the levels of all the BaP metabolites, and enhances the ratio of BaP phenolic metabolites versus diol/diones in endothelial microsomes.

Akt isoform-dependent regulation of ATP-Binding cassette A1 expression by apolipoprotein E.

We previously reported that apolipoprotein E (apoE) upregulates ATP-binding cassette transporter A1 (ABCA1) transcription through phosphatidylinositol 3-kinase (PI3K). Here we demonstrate that treatment of murine macrophages with human apoE3 enhanced Akt phosphorylation, and upregulated ABCA1 protein and mRNA expression. Inhibition of PI3K weakened apoE3-induced Akt phosphorylation, and ABCA1 protein and mRNA increase. In contrast, inhibition of Akt only diminished apoE-induced ABCA1 protein but not the mRNA level. Suppression of protein synthesis did not erase the ability of apoE3 to increase ABCA1 protein level. Further, apoE3 increased the resistance of ABCA1 protein to calpain-mediated degradation without affecting calpain activity. Treatment of macrophages with apoE3 selectively enhanced the phosphorylation of Akt1 and Akt2, but not Akt3. Knockdown of Akt1 or Akt2 increased and decreased ABCA1 protein level, respectively; while overexpression of these Akt isoenzymes caused changes in ABCA1 protein level opposite to those induced by knockdown of the corresponding Akt. These data imply that apoE3 guards against calpain-mediated ABCA1 degradation through Akt2.

Western diet enhances benzo(a)pyrene-induced colon tumorigenesis in a polyposis in rat coli (PIRC) rat model of colon cancer.

Consumption of Western diet (WD), contaminated with environmental toxicants, has been implicated as one of the risk factors for sporadic colon cancer. Our earlier studies using a mouse model revealed that compared to unsaturated dietary fat, the saturated dietary fat exacerbated the development of colon tumors caused by B(a)P. The objective of this study was to study how WD potentiates B(a)P-induced colon carcinogenesis in the adult male rats that carry a mutation in the Apc locus - the polyposis in the rat colon (PIRC) rats. Groups of PIRC rats were fed with AIN-76A standard diet (RD) or Western diet (WD) and received 25, 50, or 100 µg B(a)P/kg body weight (wt) via oral gavage for 60 days. Subsequent to exposure, rats were euthanized; colons were retrieved and preserved in 10% formalin for counting the polyp numbers, measuring the polyp size, and histological analyses. Blood samples were collected and concentrations of cholesterol, triglycerides, glucose, insulin and leptin were measured. Rats that received WD + B(a)P showed increased levels of cholesterol, triglycerides, and leptin in comparison to RD + B(a)P groups or controls. The colon tumor numbers showed a B(a)P dose-response relationship. Adenomas with high grade dysplasia were prominent in B(a)P + WD rats compared to B(a)P + RD rats and controls (p < 0.05). The larger rat model system used in this study allows for studying more advanced tumor phenotypes over a longer duration and delineating the role of diet - toxicant interactions in sporadic colon tumor development.

High-density lipoprotein-mediated transcellular cholesterol transport in mouse aortic endothelial cells.

Accumulation of unesterified cholesterol-rich lipid vesicles in the subendothelial space contributes to atherogenesis. Transport of cholesterol from the subendothelial intima back to the circulating blood inhibits atherosclerosis development; however, the mechanism for this process has not been fully defined. Using cultured mouse aortic endothelial cells (MAECs), we observed that unesterified cholesterol can be transported across the endothelial cell monolayer from the basolateral to the apical compartment. Administration of high-density lipoprotein (HDL) or apolipoprotein AI (apoAI) to the apical compartment enhanced transendothelial cholesterol transport in a concentration-dependent manner. Knockdown of ATP-binding cassette transporter G1 (ABCG1) or scavenger receptor class B type I (SR-B1), or inhibition of SR-B1 diminished HDL-induced transendothelial cholesterol transport; while knockdown of ABCA1 reduced apoAI-mediated cholesterol transport. HDL enhanced phosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt in MAECs. However, inhibition of PI3K or Akt did not reduce HDL-induced transendothelial cholesterol transport. These results suggest that HDL enhances transendothelial cholesterol transport by activation of a mechanism involving ABCA1, ABCG1 and SR-B1 but not involving PI3K and Akt.

A Subregion of Reelin Suppresses Lipoprotein-Induced Cholesterol Accumulation in Macrophages.

Activation of apolipoprotein E receptor-2 (apoER2) and very low density lipoprotein receptor (VLDLR) inhibits foam cell formation. Reelin is a ligand of these receptors. Here we generated two reelin subregions containing the receptor binding domain with or without its C-terminal region (R5-6C and R5-6, respectively) and studied the impact of these peptides on macrophage cholesterol metabolism. We found that both R5-6C and R5-6 can be secreted by cells. Purified R5-6 protein can bind apoER2 and VLDLR. Overexpression of apoER2 in macrophages increased the amount of R5-6 bound to the cell surface. Treatment of macrophages with 0.2 µg/ml R5-6 elevated ATP binding cassette A1 (ABCA1) protein level by ~72% and apoAI-mediated cholesterol efflux by ~39%. In addition, the medium harvested from cells overexpressing R5-6 or R5-6C (R5-6- and R5-6C-conditioned media, respectively) also up-regulated ABCA1 protein expression, which was associated with accelerated cholesterol efflux and enhanced phosphorylation of phosphatidylinositol 3 kinase (PI3K) and specificity protein-1 (Sp1) in macrophages. The increased ABCA1 expression and cholesterol efflux by R5-6- and R5-6C-conditioned media were diminished by Sp1 or PI3K inhibitors mithramycin A and LY294002. Further, the cholesterol accumulation induced by apoB-containing, apoE-free lipoproteins was significantly less in macrophages incubated with R5-6- or R5-6C-conditioned medium than in those incubated with control conditioned medium. Knockdown of apoER2 or VLDLR attenuated the inhibitory role of R5-6-conditioned medium against lipoprotein-induced cholesterol accumulation. These results suggest that the reelin subregion R5-6 can serve as a tool for studying the role of apoER2 and VLDLR in atherogenesis.

Increase in Blood Glutathione and Erythrocyte Proteins Related to Glutathione Generation, Reduction and Utilization in African-American Old Women with Diabetes.

Data from this report demonstrate that the plasma and erythrocyte levels of total glutathione (TGSH) are significantly lower in nondiabetic old women than in their young counterparts, and significantly higher in diabetic patients than in age-matched nondiabetic controls. The ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) declines with age and diabetes, and shows an order as follows: nondiabetic young > nondiabetic old > diabetic old women. In addition, advanced glycation end-products (AGEs) accumulates in RBCs obtained from diabetic patients but not in those from young and old nondiabetic controls. The erythrocyte levels of glutamate cysteine ligase catalytic subunit (GCLC), glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase (GR), glutathione peroxidase-1 (GPx1), glutathione S-transferase-ρ1 (GST-ρ1) and glyoxalase I (Glo1) are comparable in nondiabetic young and old women, but significantly higher in diabetic patients than in age-matched nondiabetic controls. Oxidative stress has been suggested to upregulate the expression of these proteins. It is possible that increase in oxidative stress in diabetes, reflected by reduced GSH/GSSG ratio and accumulation of AGEs, upregulates the expression of proteins involved in glutathione synthesis, reduction and utilization in erythrocyte precursor cells, and that overexpression of GCLC is, at least partially, responsible for the increased TGSH in diabetes.

Up-regulation of cholesterol absorption is a mechanism for cholecystokinin-induced hypercholesterolemia.

Excessive absorption of intestinal cholesterol is a risk factor for atherosclerosis. This report examines the effect of cholecystokinin (CCK) on plasma cholesterol level and intestinal cholesterol absorption using the in vivo models of C57BL/6 wild-type and low density lipoprotein receptor knock-out (LDLR(-/-)) mice. These data were supported by in vitro studies involving mouse primary intestinal epithelial cells and human Caco-2 cells; both express CCK receptor 1 and 2 (CCK1R and CCK2R). We found that intravenous injection of [Thr(28),Nle(31)]CCK increased plasma cholesterol levels and intestinal cholesterol absorption in both wild-type and LDLR(-/-) mice. Treatment of mouse primary intestinal epithelial cells with [Thr(28),Nle(31)]CCK increased cholesterol absorption, whereas selective inhibition of CCK1R and CCK2R with antagonists attenuated CCK-induced cholesterol absorption. In Caco-2 cells, CCK enhanced CCK1R/CCK2R heterodimerization. Knockdown of both CCK1R and CCK2 or either one of them diminished CCK-induced cholesterol absorption to the same extent. CCK also increased cell surface-associated NPC1L1 (Niemann-Pick C1-like 1) transporters but did not alter their total protein expression. Inhibition or knockdown of NPC1L1 attenuated CCK-induced cholesterol absorption. CCK enhanced phosphatidylinositide 3-kinase (PI3K) and Akt phosphorylation and augmented the interaction between NPC1L1 and Rab11a (Rab-GTPase-11a), whereas knockdown of CCK receptors or inhibition of G protein ßγ dimer (Gßγ) diminished CCK-induced PI3K and Akt phosphorylation. Inhibition of PI3K and Akt or knockdown of PI3K diminished CCK-induced NPC1L1-Rab11a interaction and cholesterol absorption. Knockdown of Rab11a suppressed CCK-induced NPC1L1 translocation and cholesterol absorption. These data imply that CCK enhances cholesterol absorption by activation of a pathway involving CCK1R/CCK2R, Gßγ, PI3K, Akt, Rab11a, and NPC1L.