The Role of Paracellular Transport in the Intestinal Absorption and Biopharmaceutical Characterization of Minoxidil
Creator:
Amidon, Gordon L., Zur, Moran, Cvijić, Sandra, Markovic, Milica, Porat, Daniel, Garsiani, Sapir, and Dahan, Arik
Date of publication:
2022
Abstract Tesim:
The purpose of this study was to evaluate mechanisms behind the intestinal permeability of minoxidil, with special emphasis on paracellular transport, and elucidate the suitability of minoxidil to be a reference drug for Biopharmaceutics Classification System (BCS). The permeability of minoxidil (vs. metoprolol) was evaluated in-silico, in-vitro using both the PAMPA assay and across Caco-2 cell monolayers, as well as in-vivo in rats throughout the entire intestine. The permeability was studied in conditions that represent the different segments of the small intestine: upper jejunum (pH 6.5), mid small intestine (pH 7.0), distal ileum (pH 7.5), and colon (pH 6.5). Since we aimed to investigate the paracellular transport of minoxidil, we have also examined its permeability in the presence of quercetin (250 µM), which closes the tight junctions, and sodium decanoate (10 mM), which opens the tight junctions. While metoprolol demonstrated segmental-dependent rat and PAMPA permeability, with higher permeability in higher pH regions, the permeability of minoxidil was pH-independent. Minoxidil PAMPA permeability was significantly lower than its rat permeability, indicating a potential significant role of the paracellular route. In rat intestinal perfusion studies, and across Caco-2 monolayers, tight junction modifiers significantly affected minoxidil permeability; while the presence of quercetin caused decreased permeability, the presence of sodium decanoate caused an increase in minoxidil permeability. In accordance with these in-vitro and in-vivo results, in-silico simulations indicated that approximatelly 15% of minoxidil dose is absorbed paracellularly, mainly in the proximal parts of the intestine. The results of this study indicate that paracellular transport plays a significant role in the intestinal permeability of minoxidil following oral administration. Since this permeation route may lead to higher variability in comparison to transcellular, these findings diminish the suitability of minoxidil to serve as the low/high BSC permeability class benchmark.
Resource type:
Article
Affiliation Label Tesim:
Division of Pharmacotherapy and Experimental Therapeutics
DOI:
https://doi.org/10.17615/a7nx-9066
Edition:
Publisher
Identifier:
https://dx.doi.org/10.3390/pharmaceutics14071360
ISSN:
1999-4923
Journal Issue:
7
Journal Title:
Pharmaceutics
Journal Volume:
14
Keyword:
Biopharmaceutics Classification System (BCS), intestinal absorption, minoxidil, permeability pathways, drug permeability, and paracellular drug transport
Language Label:
English
License Label:
Attribution 3.0 United States
Other Affiliation:
University of Michigan, Ben-Gurion University of the Negev, and University of Belgrade
Page Start:
1360
Person:
Amidon, Gordon L., Zur, Moran, Cvijić, Sandra, Markovic, Milica, Porat, Daniel, Garsiani, Sapir, and Dahan, Arik
Nutritional Quality of Pre-Packaged Foods in China under Various Nutrient Profile Models
Creator:
Pettigrew, Simone, Du, Wenwen, Wang, Huijun, Zhang, Jiguo, Coyle, Daisy H., Li, Yuan, Ding, Jingmin, Popkin, Barry M., Zhang, Puhong, and Dong, Le
Date of publication:
2022
Abstract Tesim:
This study used various nutrient profile models (NPMs) to evaluate the nutritional quality of pre-packaged foods in China to inform future food policy development. Nutrition data for pre-packaged foods were collected through FoodSwitch China in 2017–2020. The analyses included 73,885 pre-packaged foods, including 8236 beverages and 65,649 foods. Processed foods (PFs) and ultra-processed foods (UPFs) accounted for 8222 (11.4%) and 47,003 (63.6%) of all products, respectively. Among the 55,425 PFs and UPFs, the overall proportion of products with an excessive quantity of at least one negative nutrient was 86.0% according to the Chilean NPM (2019), 83.3% for the Pan American Health Organization NPM (PAHO NPM), and 90.6% for the Western Pacific Region NPM for protecting children from food marketing (WPHO NPM), respectively. In all NPMs, 70.4% of PFs and UPFs were identified as containing an excessive quantity of at least one negative nutrient, with higher proportions of UPFs compared to PFs. Food groups exceeding nutrient thresholds in most NPMs included snack foods, meat and meat products, bread and bakery products, non-alcoholic beverages, confectionery, and convenience foods. In conclusion, PFs and UPFs accounted for three-fourths of pre-packaged foods in China, and the majority of PFs and UPFs exceeded the threshold for at least one negative nutrient under all three NPMs. Given the need to prevent obesity and other diet-related chronic diseases, efforts are warranted to improve the healthiness of foods in China through evidence-based food policy.
Developing Toxic Metal Environmental Justice Indices (TM-EJIs) for Arsenic, Cadmium, Lead, and Manganese Contamination in Private Drinking Wells in North Carolina
Creator:
Eaves, Lauren A., Fry, Rebecca C., Enggasser, Adam E., and Gavino-Lopez, Noemi
Date of publication:
2022
Abstract Tesim:
Toxic metal exposure via private drinking wells is an environmental health challenge in North Carolina (NC). Policies tainted by environmental racism shape who has access to public water supplies, with Black People, Indigenous People, and People of Color (BIPOC) often excluded from municipal services. Thus, toxic metal exposure via private wells is an environmental justice (EJ) issue, and it is under-studied in NC. In this study, we developed four Toxic Metal Environmental Justice Indices (TM-EJIs) for inorganic arsenic (iAs), cadmium (Cd), lead (Pb), and manganese (Mn) to quantitatively identify areas of environmental injustice in NC. TM-EJIs were calculated at the census tract level (n = 2038) as the product of the following: (1) number of well water tests with concentrations exceeding national standards, (2) percentage of the low-income and minority population, and (3) population density. Mn had the greatest proportion (25.17%) of positive TM-EJIs, which are indicative of socioeconomically disadvantaged groups exposed to toxic metals. Positive TM-EJIs, particularly for Pb and Mn, were primarily located in eastern NC. These results highlight several new counties of concern and can be used by public health professionals and state environmental agencies to prioritize remediation efforts and efforts to reduce environmental injustices.
Resource type:
Article
Affiliation Label Tesim:
Department of Environmental Sciences and Engineering
DOI:
https://doi.org/10.17615/sy2p-kq82
Edition:
Publisher
Identifier:
https://dx.doi.org/10.3390/w14132088
ISSN:
2073-4441
Journal Issue:
13
Journal Title:
Water
Journal Volume:
14
Keyword:
private wells, toxic metals, and environmental justice
Language Label:
English
License Label:
Attribution 3.0 United States
Page Start:
2088
Person:
Eaves, Lauren A., Fry, Rebecca C., Enggasser, Adam E., and Gavino-Lopez, Noemi
Analyzing the Systems Biology Effects of COVID-19 mRNA Vaccines to Assess Their Safety and Putative Side Effects
Creator:
Hajjo, Rima, Tropsha, Alexander, and Sabbah, Dima A.
Date of publication:
2022
Abstract Tesim:
COVID-19 vaccines have been instrumental tools in reducing the impact of SARS-CoV-2 infections around the world by preventing 80% to 90% of hospitalizations and deaths from reinfection, in addition to preventing 40% to 65% of symptomatic illnesses. However, the simultaneous large-scale vaccination of the global population will indubitably unveil heterogeneity in immune responses as well as in the propensity to developing post-vaccine adverse events, especially in vulnerable individuals. Herein, we applied a systems biology workflow, integrating vaccine transcriptional signatures with chemogenomics, to study the pharmacological effects of mRNA vaccines. First, we derived transcriptional signatures and predicted their biological effects using pathway enrichment and network approaches. Second, we queried the Connectivity Map (CMap) to prioritize adverse events hypotheses. Finally, we accepted higher-confidence hypotheses that have been predicted by independent approaches. Our results reveal that the mRNA-based BNT162b2 vaccine affects immune response pathways related to interferon and cytokine signaling, which should lead to vaccine success, but may also result in some adverse events. Our results emphasize the effects of BNT162b2 on calcium homeostasis, which could be contributing to some frequently encountered adverse events related to mRNA vaccines. Notably, cardiac side effects were signaled in the CMap query results. In summary, our approach has identified mechanisms underlying both the expected protective effects of vaccination as well as possible post-vaccine adverse effects. Our study illustrates the power of systems biology approaches in improving our understanding of the comprehensive biological response to vaccination against COVID-19.
Resource type:
Article
Affiliation Label Tesim:
Division of Chemical Biology and Medicinal Chemistry
DOI:
https://doi.org/10.17615/e2mw-t208
Edition:
Publisher
Identifier:
https://dx.doi.org/10.3390/pathogens11070743
ISSN:
2076-0817
Journal Issue:
7
Journal Title:
Pathogens
Journal Volume:
11
Keyword:
COVID-19, SARS-CoV-2, vaccine adverse events, systems biology, VAERS, mRNA vaccine, and informatics workflow
Language Label:
English
License Label:
Attribution 3.0 United States
Other Affiliation:
Al‐Zaytoonah University of Jordan
Page Start:
743
Person:
Hajjo, Rima, Tropsha, Alexander, and Sabbah, Dima A.
Prenatal Exposure to Organophosphorus Pesticides and Preschool ADHD in the Norwegian Mother, Father and Child Cohort Study
Creator:
Thomsen, Cathrine, Kamai, Elizabeth M., Øvergaard, Kristin R., Engel, Lawrence S., Cequier, Enrique, Zeiner, Pal, Thistle, Jake, Engel, Stephanie M., Hall, Amber, Sakhi, Amrit K., Reichborn-Kjennerud, Ted, Manley, Cherrel K., Herring, Amy H., Aase, Heidi, Villanger, Gro D., and Roell, Kyle R.
Date of publication:
2022
Abstract Tesim:
Prenatal organophosphorus pesticide (OPP) exposure has been associated with child attention-deficit/hyperactivity disorder (ADHD) in agricultural communities and those that are exposed to residentially applied insecticides. To examine this association in populations that are exposed primarily through diet, we estimate the associations between prenatal OPP exposure and preschool ADHD in the Norwegian Mother, Father and Child Cohort Study (MoBa), and describe modification by paraoxonase 1 (PON1) gene variants. We used participants from the MoBa Preschool ADHD Sub-study (n = 259 cases) and a random sample of MoBa sub-cohort participants (n = 547) with birth years from 2004 to 2008. Prenatal urinary dialkylphosphate (DAP) metabolites (total diethylphosphate [∑DEP] and total dimethylphosphate [∑DMP]) were measured by an ultra-performance liquid chromatography-time-of-flight system and summed by molar concentration. Maternal DNA was genotyped for coding variants of PON1 (Q192R and L55M). We used a multivariable logistic regression to calculate the odds ratios (OR) and 95% confidence intervals, adjusted for maternal education, parity, income dependency, age, marital status, ADHD-like symptoms, pesticide use, produce consumption, and season. We found no associations between DAP metabolite concentrations and preschool ADHD. The adjusted ORs for exposure quartiles 2–4 relative to 1 were slightly inverse. No monotonic trends were observed, and the estimates lacked precision, likely due to the small sample size and variation in the population. We found no evidence of modification by PON1 SNP variation or child sex. Maternal urinary DAP concentrations were not associated with preschool ADHD.
Resource type:
Article
Affiliation Label Tesim:
Department of Epidemiology
DOI:
https://doi.org/10.17615/z2fz-4405
Edition:
Publisher
Identifier:
https://dx.doi.org/10.3390/ijerph19138148
ISSN:
1660-4601
Journal Issue:
13
Journal Title:
International Journal of Environmental Research and Public Health
Journal Volume:
19
Keyword:
preschool attention-deficit hyperactivity disorder, medical birth registry of Norway, the Norwegian Mother, prenatal exposure, Father and Child Cohort Study, and organophosphorus pesticide
Language Label:
English
License Label:
Attribution 3.0 United States
Other Affiliation:
Norwegian Institute of Public Health, University of Southern California, Oslo University Hospital, and Duke University
Page Start:
8148
Person:
Thomsen, Cathrine, Kamai, Elizabeth M., Øvergaard, Kristin R., Engel, Lawrence S., Cequier, Enrique, Zeiner, Pal, Thistle, Jake, Engel, Stephanie M., Hall, Amber, Sakhi, Amrit K., Reichborn-Kjennerud, Ted, Manley, Cherrel K., Herring, Amy H., Aase, Heidi, Villanger, Gro D., and Roell, Kyle R.
G-Protein Phosphorylation: Aspects of Binding Specificity and Function in the Plant Kingdom
Creator:
Braga dos Reis, Pedro A. , Jones, Alan M., Pacheco Batista Fontes, Elizabeth, and Oliveira, Celio Cabral
Date of publication:
2022
Abstract Tesim:
Plant survival depends on adaptive mechanisms that constantly rely on signal recognition and transduction. The predominant class of signal discriminators is receptor kinases, with a vast member composition in plants. The transduction of signals occurs in part by a simple repertoire of heterotrimeric G proteins, with a core composed of α-, β-, and γ-subunits, together with a 7-transmembrane Regulator G Signaling (RGS) protein. With a small repertoire of G proteins in plants, phosphorylation by receptor kinases is critical in regulating the active state of the G-protein complex. This review describes the in vivo detected phosphosites in plant G proteins and conservation scores, and their in vitro corresponding kinases. Furthermore, recently described outcomes, including novel arrestin-like internalization of RGS and a non-canonical phosphorylation switching mechanism that drives G-protein plasticity, are discussed.
Resource type:
Article
Affiliation Label Tesim:
Department of Biology
DOI:
https://doi.org/10.17615/e6kn-7r58
Edition:
Publisher
Identifier:
https://dx.doi.org/10.3390/ijms23126544
ISSN:
1422-0067
Journal Issue:
12
Journal Title:
International Journal of Molecular Sciences
Journal Volume:
23
Keyword:
GPA1, regulation, kinase, XLG, structure, phosphorylation, AGB1, RGS, G protein, and AGG
Language Label:
English
License Label:
Attribution 3.0 United States
Other Affiliation:
Universidade Federal de Viçosa
Page Start:
6544
Person:
Braga dos Reis, Pedro A. , Jones, Alan M., Pacheco Batista Fontes, Elizabeth, and Oliveira, Celio Cabral
Trends and Insights from Transportation Congestion Pricing Policy Research: A Bibliometric Analysis
Creator:
Dodd, Adam, Sabounchi, Nasim S., Singichetti, Bhavna, Conklin, Jamie L., Hassmiller Lich, Kristen, and Naumann, Rebecca B.
Date of publication:
2022
Abstract Tesim:
Toll-based congestion pricing (CP) policies are increasingly implemented globally for alleviating road traffic congestion. Several interconnected factors affecting or induced by CP implementation include air quality/emissions, travel time, and road user safety. We sought to examine and characterize research output and patterns across several domains (e.g., health, policy acceptability) surrounding toll-based CP policies, in order to identify where research has focused and where gaps exist. We conducted a structured review and identified 2333 relevant publications, using semi-supervised and machine learning strategies combined with manual review. Annual publication counts peaked in 2015 (n = 122). Themes identified from title and abstract terms included policy implementation characteristics, advanced transportation modeling methods and approaches, and public perception and acceptability. Authorship networks indicated a lack of interdisciplinary research. Country analyses identified the US, China, and the UK as the most frequently represented countries, and underrepresentation from low-income countries. Findings indicate that research focused on specific road user types (e.g., pedestrians) and safety impacts, and equity considerations were relatively sparse compared to other topics (e.g., policy economics, public perception). Additional research on these critical topics is necessary to ensure that such policies are designed to promote positive and equitable effects on road user health and safety.
Resource type:
Article
Affiliation Label Tesim:
University of North Carolina at Chapel Hill. Health Sciences Library, Injury Prevention Research Center, Department of Health Policy and Management, and Department of Epidemiology
DOI:
https://doi.org/10.17615/gpxv-d592
Edition:
Publisher
Identifier:
https://dx.doi.org/10.3390/ijerph19127189
ISSN:
1660-4601
Journal Issue:
12
Journal Title:
International Journal of Environmental Research and Public Health
Journal Volume:
19
Keyword:
transportation systems, transportation policy, congestion pricing, traffic congestion, travel demand management, cordon pricing, and zone pricing
Language Label:
English
License Label:
Attribution 3.0 United States
Other Affiliation:
City University New York
Page Start:
7189
Person:
Dodd, Adam, Sabounchi, Nasim S., Singichetti, Bhavna, Conklin, Jamie L., Hassmiller Lich, Kristen, and Naumann, Rebecca B.
HIV and Substance Use in Latin America: A Scoping Review
Creator:
Garcia, Patricia J., Aponte, Rocio, Diaz, Monica M., Huff, Hanalise V., Conklin, Jamie L., Salvatierra, Justina, and Carcamo, Paloma M.
Date of publication:
2022
Abstract Tesim:
This scoping review aims to explore the interplay between substance use (SU) and HIV in Latin America (LA). Database searches yielded 3481 references; 196 were included. HIV prevalence among people who used substances (PWUS) ranged from 2.8–15.2%. SU definitions were variable throughout studies, and thus data were not easily comparable. In 2019, only 2% of new HIV infections were attributed to injection drug use (IDU) in LA. Factors associated with HIV among PWUS included being female, IDU and homelessness, and PWUS were likely to engage in risky sexual behaviors, start antiretroviral treatment late, have poor adherence, have treatment failure, be lost to follow-up, have comorbidities, and experience higher mortality rates and lower quality of life, as has been reported in PLWH with SU in other regions. Five intervention studies were identified, and only one was effective at reducing HIV incidence in PWUS. Interventions in other regions have varying success depending on context-specific characteristics, highlighting the need to conduct more research in the LA region. Though progress has been made in establishing SU as a major concern in people living with HIV (PLWH), much more is yet to be done to reduce the burden of HIV and SU in LA.
Resource type:
Article
Affiliation Label Tesim:
Department of Neurology and University of North Carolina at Chapel Hill. Health Sciences Library
DOI:
https://doi.org/10.17615/v9jy-7t19
Edition:
Publisher
Identifier:
https://dx.doi.org/10.3390/ijerph19127198
ISSN:
1660-4601
Journal Issue:
12
Journal Title:
International Journal of Environmental Research and Public Health
Journal Volume:
19
Keyword:
HIV/AIDS, Latin America, and substance use
Language Label:
English
License Label:
Attribution 3.0 United States
Other Affiliation:
Universidad Peruana Cayetano Heredia and Harvard T. H. Chan School of Public Health
Page Start:
7198
Person:
Garcia, Patricia J., Aponte, Rocio, Diaz, Monica M., Huff, Hanalise V., Conklin, Jamie L., Salvatierra, Justina, and Carcamo, Paloma M.
Antigenic Site Immunodominance Redirection Following Repeat Variant Exposure
Creator:
Williams, Rachel, Mallory, Michael L., Becker-Dreps, Sylvia, Zweigart, Mark R., May, Samantha R., Breuer, Judith, Lindesmith, Lisa C., Baric, Ralph S., Bucardo, Filemón, Allen, David J., Kelly, Daniel, and Brewer-Jensen, Paul D.
Date of publication:
2022
Abstract Tesim:
Human norovirus is a leading cause of acute gastroenteritis, driven by antigenic variants within the GII.4 genotype. Antibody responses to GII.4 vaccination in adults are shaped by immune memory. How children without extensive immune memory will respond to GII.4 vaccination has not been reported. Here, we characterized the GII.4 neutralizing antibody (nAb) landscape following natural infection using a surrogate assay and antigenic site chimera virus-like particles. We demonstrate that the nAb landscape changes with age and virus exposure. Among sites A, C, and G, nAbs from first infections are focused on sites A and C. As immunity develops with age/exposure, site A is supplemented with antibodies that bridge site A to sites C and G. Cross-site nAbs continue to develop into adulthood, accompanied by an increase in nAb to site G. Continued exposure to GII.4 2012 Sydney correlated with a shift to co-dominance of sites A and G. Furthermore, site G nAbs correlated with the broadening of nAb titer across antigenically divergent variants. These data describe fundamental steps in the development of immunity to GII.4 over a lifetime, and illustrate how the antigenicity of one pandemic variant could influence the pandemic potential of another variant through the redirection of immunodominant epitopes.
Resource type:
Article
Affiliation Label Tesim:
Department of Epidemiology
DOI:
https://doi.org/10.17615/1en4-ze36
Edition:
Publisher
Identifier:
https://dx.doi.org/10.3390/v14061293
ISSN:
1999-4915
Journal Issue:
6
Journal Title:
Viruses
Journal Volume:
14
Keyword:
variant persistence, neutralizing antibody, blockade antibody, norovirus, antigenic seniority, immune imprinting, immunodominance, and variants of concern
Language Label:
English
License Label:
Attribution 3.0 United States
Other Affiliation:
University College London, National Autonomous University of Nicaragua-León, and London School of Hygiene and Tropical Medicine
Page Start:
1293
Person:
Williams, Rachel, Mallory, Michael L., Becker-Dreps, Sylvia, Zweigart, Mark R., May, Samantha R., Breuer, Judith, Lindesmith, Lisa C., Baric, Ralph S., Bucardo, Filemón, Allen, David J., Kelly, Daniel, and Brewer-Jensen, Paul D.
Effects of Housing Aid on Psychosocial Health after a Disaster
Creator:
Thomas, Duncan, Frankenberg, Elizabeth, and Laurito, Maria M.
Date of publication:
2022
Abstract Tesim:
Little is known about whether the provision of aid in the aftermath of a large-scale natural disaster affects psychological well-being. We investigate the effects of housing assistance, a key element of the reconstruction program implemented after the 2004 Indian Ocean tsunami. Population-representative individual-level longitudinal data collected in Aceh, Indonesia, during the decade after the tsunami as part of the Study of the Tsunami Aftermath and Recovery (STAR) are used. Housing aid was targeted to people whose homes were destroyed and, to a lesser extent, damaged by the tsunami and to those who lived, at the time of the tsunami, in communities that sustained the greatest damage. The effects of receipt of aid on post-traumatic stress reactivity (PTSR) are examined using panel data models that take into account observed and unobserved individual-specific fixed characteristics that affect both PTSR and aid receipt, drawing comparisons in each survey wave between individuals who had been living in the same kecamatan when the tsunami hit. Those who received aid have better psychological health; the effects increase with time since aid receipt and are the greatest at two years or longer after the receipt. The effects are concentrated among those whose homes were destroyed in the tsunami.
Resource type:
Article
Affiliation Label Tesim:
Department of Sociology
DOI:
https://doi.org/10.17615/5rf3-qj86
Edition:
Publisher
Identifier:
https://dx.doi.org/10.3390/ijerph19127302
ISSN:
1660-4601
Journal Issue:
12
Journal Title:
International Journal of Environmental Research and Public Health
Journal Volume:
19
Keyword:
natural disaster, housing aid, Indonesia, psychological well-being, and reconstruction
Language Label:
English
License Label:
Attribution 3.0 United States
Other Affiliation:
Duke University and Analysis Group, Inc.
Page Start:
7302
Person:
Thomas, Duncan, Frankenberg, Elizabeth, and Laurito, Maria M.