Compared to other species, little information is available on the xenobiotic-induced regulation of cytochrome P450 enzymes in the beagle dog. Dogs are widely used in the pharmaceutical industry for many study types, including those that will impact decisions on compound progression. The purpose of this study was (1) to determine the temporal kinetics of drug-induced changes in canine CYP1A, CYP2B, and CYP3A mRNA and enzymatic activity, and (2) to characterize concentration-response relationships for CYP1A2, CYP2B11, and CYP3A12 using primary cultures of canine hepatocytes treated with beta-naphthoflavone (BNF), phenobarbital (PB), and rifampin (RIF), respectively. CYP1A1 and CYP1A2 mRNA exhibited maximal expression (12,700-fold and 206-fold, respectively) after 36 h of treatment with BNF. PB treatment, but not RIF treatment, caused maximal induction of CYP2B11 mRNA (149-fold) after 48 h of treatment. CYP3A12 and CYP3A26 mRNA levels were increased maximally after 72 h of treatment with PB and RIF (CYP3A12, 35-fold and 18-fold, and CYP3A26, 72-fold and 22-fold with PB and RIF treatment, respectively). Concentration-response relationships for BNF induced 7-ethoxyresorufin O-dealkylation (EROD) (EC(50) = 7.8 +/- 4.2 microM), PB induced 7-benzyloxyresorufin O-dealkylation (BROD) (EC(50) = 123 +/- 30 microM), and PB and RIF induced testosterone 6beta-hydroxylation (EC(50) = 132 +/- 28 microM and 0.98 +/- 0.16 microM) resembled the relationship for human CYP induction compared to that of rodent. Interestingly, RIF had no effect on CYP2B11 expression, which represents a species difference overlooked in previous investigations. Overall, the induction of dog CYP1A, CYP2B, and CYP3A exhibits characteristics that are intermediate to those of rodent and human.
n-Butyl-p-hydroxybenzoate (n-butylparaben, BPB) is an antioxidant used in foods, pharmaceuticals and cosmetics. This study investigated the disposition of ring-labelled [(14)C]BPB in Harlan Sprague Dawley rats, and in rat and human hepatocytes. BPB was rapidly cleared in hepatocytes from rat (t(1/2) = 3-4 min) and human (t(1/2) = 20-30 min). The major metabolites detected in rat hepatocytes were hydroxybenzoic acid and in human hepatocytes were hydroxybenzoic acid and hydroxyhippuric acid. [(14)C]BPB was administered to male rats orally at 10, 100 or 1000 mg/kg, intravenously at 10 mg/kg and dermally at 10 and 100 mg/kg; female rats were administered oral doses at 10 mg/kg. Oral doses of BPB were well-absorbed (>83%) and eliminated chiefly in urine (83-84%); ≤ 1% of the radioactivity remained in tissues at 24 h or 72 h after dosing. About 4% and 8%, respectively, of 100 mg/kg dermal doses were absorbed in 24 h and 72 h, and about 50% of a 10 mg/kg dose was absorbed in 72 h. Metabolites detected in urine included those previously reported, BPB-glucuronide, BPB-sulfate, hydroxybenzoic acid and hydroxyhippuric acid, but also novel metabolites arising from ring hydroxylation followed by glucuronidation and sulfation.
Aim/Purpose: This paper provides the results of the preliminary analysis of the findings of an ongoing study that seeks to examine the social media use, cultural and political awareness, civic engagement, issue prioritization, and social activism of Gen Z students enrolled at four different institutional types located in the Mid-Atlantic region of the United States. The aim of this study is to look at the group as a whole as well as compare findings across populations. The institutional types under consideration include a mid-sized majority serving or otherwise referred to as a traditionally white institution (TWI) located in a small coastal city on the Atlantic Ocean, a small Historically Black University (HBCU) located in a rural area, a large community college located in a county that is a mixture of rural and suburban and which sits on the border of Maryland and Pennsylvania, and graduating high school students enrolled in career and technical education (CTE) programs in a large urban area. This exploration is purposed to examine the behaviors and expectations of Gen Z students within a representative American region during a time of tremendous turmoil and civil unrest in the United States. Background: Over 74 million strong, Gen Z makes up almost one-quarter of the U.S. population. They already outnumber any current living generation and are the first true digital natives. Born after 1996 and through 2012, they are known for their short attention spans and heightened ability to multi-task. Raised in the age of the smart phone, they have been tethered to digital devices from a young age with most having the preponderance of their childhood milestones commemorated online. Often called Zoomers, they are more racially and ethnically diverse than any previous generation and are on track to be the most well-educated generation in history. Gen Zers in the United States have been found in the research to be progressive and pro-government and viewing increasing racial and ethnic diversity as positive change. Finally, they are less likely to hold xenophobic beliefs such as the notion of American exceptionalism and superiority that have been popular with by prior generations. The United States has been in a period of social and civil unrest in recent years with concerns over systematic racism, rampant inequalities, political polarization, xenophobia, police violence, sexual assault and harassment, and the growing epidemic of gun violence. Anxieties stirred by the COVID-19 pandemic further compounded these issues resulting in a powder keg explosion occurring throughout the summer of 2020 and leading well into 2021. As a result, the United States has deteriorated significantly in the Civil Unrest Index falling from 91st to 34th. The vitriol, polarization, protests, murders, and shootings have all occurred during Gen Z’s formative years, and the limited research available indicates that it has shaped their values and political views. Methodology: The Mid-Atlantic region is a portion of the United States that exists as the overlap between the northeastern and southeastern portions of the country. It includes the nation’s capital, as well as large urban centers, small cities, suburbs, and rural enclaves. It is one of the most socially, economically, racially, and culturally diverse parts of the United States and is often referred to as the “typically American region.” An electronic survey was administered to students from 2019 through 2021 attending a high school dual enrollment program, a minority serving institution, a majority serving institution, and a community college all located within the larger mid-Atlantic region. The survey included a combination of multiple response, Likert scaled, dichotomous, open ended, and ordinal questions. It was developed in the Survey Monkey system and reviewed by several content and methodological experts in order to examine bias, vagueness, or potential semantic problems. Finally, the survey was pilot tested prior to implementation in order to explore the efficacy of the research methodology. It was then modified accordingly prior to widespread distribution to potential participants. The surveys were administered to students enrolled in classes taught by the authors all of whom are educators. Participation was voluntary, optional, and anonymous. Over 800 individuals completed the survey with just over 700 usable results, after partial completes and the responses of individuals outside of the 18-24 age range were removed. Findings: Participants in this study overwhelmingly were users of social media. In descending order, YouTube, Instagram, Snapchat, Twitter, Facebook, Pinterest, WhatsApp, LinkedIn and Tik Tok were the most popular social media services reported as being used. When volume of use was considered, Instagram, Snapchat, YouTube and Twitter were the most cited with most participants reporting using Instagram and Snapchat multiple times a day. When asked to select which social media service they would use if forced to choose just one, the number one choice was YouTube followed by Instagram and Snapchat. Additionally, more than half of participants responded that they have uploaded a video to a video sharing site such as YouTube or Tik Tok. When asked about their familiarity with different technologies, participants overwhelmingly responded that they are “very familiar” with smart phones, searching the Web, social media, and email. About half the respondents said that they were “very familiar” with common computer applications such as the Microsoft Office Suite or Google Suite with another third saying that they were “somewhat familiar.” When asked about Learning Management Systems (LMS) like Blackboard, Course Compass, Canvas, Edmodo, Moodle, Course Sites, Google Classroom, Mindtap, Schoology, Absorb, D2L, itslearning, Otus, PowerSchool, or WizIQ, only 43% said they were “very familiar” with 31% responding that they were “somewhat familiar.” Finally, about half the students were either “very” or “somewhat” familiar with operating systems such as Windows. A few preferences with respect to technology in the teaching and learning process were explored in the survey. Most students (85%) responded that they want course announcements and reminders sent to their phones, 76% expect their courses to incorporate the use of technology, 71% want their courses to have course websites, and 71% said that they would rather watch a video than read a book chapter. When asked to consider the future, over 81% or respondents reported that technology will play a major role in their future career. Most participants considered themselves “informed” or “well informed” about current events although few considered themselves “very informed” or “well informed” about politics. When asked how they get their news, the most common forum reported for getting news and information about current events and politics was social media with 81% of respondents reporting. Gen Z is known to be an engaged generation and the participants in this study were not an exception. As such, it came as no surprise to discover that, in the past year more than 78% of respondents had educated friends or family about an important social or political issue, about half (48%) had donated to a cause of importance to them, more than a quarter (26%) had participated in a march or rally, and a quarter (26%) had actively boycotted a product or company. Further, about 37% consider themselves to be a social activist with another 41% responding that aren’t sure if they would consider themselves an activist and only 22% saying that they would not consider themselves an activist. When asked what issues were important to them, the most frequently cited were Black Lives Matter (75%), human trafficking (68%), sexual assault/harassment/Me Too (66.49%), gun violence (65.82%), women’s rights (65.15%), climate change (55.4%), immigration reform/deferred action for childhood arrivals (DACA) (48.8%), and LGBTQ+ rights (47.39%). When the schools were compared, there were only minor differences in social media use with the high school students indicating slightly more use of Tik Tok than the other participants. All groups were virtually equal when it came to how informed they perceived themselves about current events and politics. Consensus among groups existed with respect to how they get their news, and the community college and high school students were slightly more likely to have participated in a march, protest, or rally in the last 12 months than the university students. The community college and high school students were also slightly more likely to consider themselves social activists than the participants from either of the universities. When the importance of the issues was considered, significant differences based on institutional type were noted. Black Lives Matter (BLM) was identified as important by the largest portion of students attending the HBCU followed by the community college students and high school students. Less than half of the students attending the TWI considered BLM an important issue. Human trafficking was cited as important by a higher percentage of students attending the HBCU and urban high school than at the suburban and rural community college or the TWI. Sexual assault was considered important by the majority of students at all the schools with the percentage a bit smaller from the majority serving institution. About two thirds of the students at the high school, community college, and HBCU considered gun violence important versus about half the students at the majority serving institution. Women’s rights were reported as being important by more of the high school and HBCU participants than the community college or TWI. Climate change was considered important by about half the students at all schools with a slightly smaller portion reporting out the HBCU. Immigration reform/DACA was reported as important by half the high school, community college, and HBCU participants with only a third of the students from the majority serving institution citing it as an important issue. With respect to LGBTQ rights approximately half of the high school and community college participants cited it as important, 44.53% of the HBCU students, and only about a quarter of the students attending the majority serving institution. Contribution and Conclusion: This paper provides a timely investigation into the mindset of generation Z students living in the United States during a period of heightened civic unrest. This insight is useful to educators who should be informed about the generation of students that is currently populating higher education. The findings of this study are consistent with public opinion polls by Pew Research Center. According to the findings, the Gen Z students participating in this study are heavy users of multiple social media, expect technology to be integrated into teaching and learning, anticipate a future career where technology will play an important role, informed about current and political events, use social media as their main source for getting news and information, and fairly engaged in social activism. When institutional type was compared the students from the university with the more affluent and less diverse population were less likely to find social justice issues important than the other groups. Recommendations for Practitioners: During disruptive and contentious times, it is negligent to think that the abounding issues plaguing society are not important to our students. Gauging the issues of importance and levels of civic engagement provides us crucial information towards understanding the attitudes of students. Further, knowing how our students gain information, their social media usage, as well as how informed they are about current events and political issues can be used to more effectively communicate and educate. Recommendations for Researchers: As social media continues to proliferate daily life and become a vital means of news and information gathering, additional studies such as the one presented here are needed. Additionally, in other countries facing similarly turbulent times, measuring student interest, awareness, and engagement is highly informative. Impact on Society: During a highly contentious period replete with a large volume of civil unrest and compounded by a global pandemic, understanding the behaviors and attitudes of students can help us as higher education faculty be more attuned when it comes to the design and delivery of curriculum. Future Research This presentation presents preliminary findings. Data is still being collected and much more extensive statistical analyses will be performed.
Centella asiatica (CA) shows considerable promise for development as a botanical drug for cognitive decline. Its primary bioactive components include triterpene glycosides asiaticoside and madecassoside and their corresponding aglycones asiatic acid and madecassic acid. Exploration of the bioactivity of CA's caffeoylquinic acids is ongoing. In this study, an aqueous extract of CA (CAW-R61J) was evaluated for drug interaction potential through inhibition or induction of P450 enzymes, as required by the US Food and Drug Administration. CAW-R61J was assessed for induction potential of CYP1A2, CYP2B6, and CYP3A4 using transporter-certified cryopreserved human hepatocytes in sandwich culture. Gene expression of these target P450s was quantified, and enzyme activities were determined to confirm gene expression results. No induction was observed up to 16.7 mg/ml CAW-R61J (equivalent to 1.1 mM asiaticoside, 0.8 mM madecassoside, 0.09 mM asiatic acid, and 0.12 mM madecassic acid). Reversible and time-dependent inhibitory effects of CAW-R61J on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 were evaluated using human liver microsomes. CAW-R61J showed weak reversible inhibition of most of the P450 forms tested, with the strongest being CYP2C9 (IC 50 of 330 mg/ml). CAW-R61J (£1000 mg/ml) was not a time-dependent inhibitor of any of these P450 enzymes. In summary, CAW-R61J had no, or only a weak impact, on P450 induction and inhibition in vitro. The clinical relevance of these results will depend on the in vivo concentration of CAW-R61J components achieved in humans. Plasma triterpene concentrations measured in our recent clinical studies suggest minimal risk of P450-mediated drug interactions by these components. SIGNIFICANCE STATEMENT A preparation of Centella asiatica is currently under clinical development for the prevention or treatment of cognitive decline. The US Food and Drug Administration required an evaluation of its potential for drug interactions mediated through drug-metabolizing enzymes. This in vitro study revealed minimal induction or inhibition of a range of P450 enzymes, including CYP3A4, by the C. asiatica extract, suggesting a low potential for drug interactions modulated by P450 metabolism.
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