Cannabidiol (CBD) and hemp oil use in veterans using a VA Pain Clinic: a cross-sectional survey study.

BACKGROUND: Many United States veterans utilize prescription opioids to treat chronic pain symptoms and are subsequently at risk for opioid and alcohol misuse. As more states legalized the use of cannabis for medical use, increasing numbers of people are using cannabis pharmacotherapy for pain. The veterans Health Administration (VHA) Directive 1315, July 28, 2023 prohibits any medical staff on recommending, making referral to, and complete forms for a state approved program. Also, a veterans medical center does not provide marijuana to veterans. State laws do not change the status of CBD under federal law. CBD is illegal in the federal system. OBJECTIVES: Our aim was to investigate the prevalence of cannabidiol product usage in Veterans and the association with changes in self-reported pain. METHODS: We conducted a cross-sectional descriptive survey offering questionnaires to patients greater than 18 years of age receiving care at the Fargo Veteran Health Administration medical center Pain Clinic (2101 Elm St N, Fargo ND, 58102). RESULTS: A total of 218 veterans participated of which 81.2% were male and 52.3% were in the age range of 60-80 years. Twenty-one participants reported cannabidiol usage (9.6%), with 52.4% using to treat pain symptoms. Average pain scores pre-usage of 6.37 were reduced to 4.05 post-usage indicating a statistically significant reduction in pain (p < 0.001). CONCLUSION: Our study broadened the baseline knowledge of cannabidiol use in the Veteran population. Limitations include results being self-reported and the inability to verify cannabinoid constituents.

The Prevalence and Trends of Instrumental Activities of Daily Living Impairments in the United States from 2008-2018.

Background: Instrumental activities of daily living (IADL) are neuropsychological-driven tasks that are linked to cognitive dysfunction. Examining population-based IADL deficits may reveal insights for the presence of these impairments in the United States. Objective: This investigation sought to evaluate the prevalence and trends of IADL impairments in Americans. Methods: A secondary analysis of data from the 2006-2018 waves of the Health and Retirement Study was conducted. The overall unweighted analytic sample included 29,764 Americans aged≥50 years. Respondents indicated their ability to perform six IADLs: manage money, manage medications, use a telephone, prepare hot meals, shop for groceries, and use a map. Persons reporting difficulty or an inability to complete an individual IADL were considered as having a task-specific impairment. Similarly, those indicating difficulty or an inability to perform any IADL were classified as having an IADL impairment. Sample weights were utilized to generate nationally-representative estimates. Results: Having an impairment in using a map (2018 wave: 15.7% (95% confidence interval (CI): 15.0-16.4) had the highest prevalence in individual IADLs regardless of wave examined. The overall prevalence of IADL impairments declined during the study period (p < 0.001) to 25.4% (CI: 24.5-26.2) in the 2018 wave. Older Americans and women had a consistently higher prevalence of IADL impairments compared to middle-aged Americans and men, respectively. The prevalence of IADL impairments was also highest among Hispanics and non-Hispanic Blacks. Conclusion: IADL impairments have declined over time. Continued surveillance of IADLs may help inform cognitive screening, identify subpopulations at risk of impairment, and guide relevant policy.

Handgrip Strength Asymmetry and Weakness Are Associated With Future Morbidity Accumulation in Americans.

ABSTRACT: Klawitter, L, Vincent, BM, Choi, BJ, Smith, J, Hammer, KD, Jurivich, DA, Dahl, LJ, and McGrath, R. Handgrip strength asymmetry and weakness are associated with future morbidity accumulation in americans. J Strength Cond Res 36(1): 106-112, 2022-Identifying strength asymmetries in physically deconditioned populations may help in screening and treating persons at risk for morbidities linked to muscle dysfunction. Our investigation sought to examine the associations between handgrip strength (HGS) asymmetry and weakness on accumulating morbidities in aging Americans. The analytic sample included 18,506 Americans aged ≥50 years from the 2006-2016 Health and Retirement Study. Handgrip strength was measured on each hand with a handgrip dynamometer, and persons with an imbalance in strength >10% between hands had HGS asymmetry. Men with HGS <26 kg and women with HGS <16 kg were considered as weak. Subjects reported the presence of healthcare provider-diagnosed morbidities: hypertension, diabetes, cancer, chronic lung disease, cardiovascular disease, stroke, arthritis, and psychiatric problems. Covariate-adjusted ordinal generalized estimating equations analyzed the associations for each HGS asymmetry and weakness group on future accumulating morbidities. Of those included in our study, subjects at baseline were aged 65.0 ± 10.2 years, 9,570 (51.7%) had asymmetric HGS, and 996 (5.4%) were weak. Asymmetry alone and weakness alone were associated with 1.09 (95% confidence interval [CI]: 1.04-1.14) and 1.27 (CI: 1.11-1.45) greater odds for future accumulating morbidities, respectively. Having both HGS asymmetry and weakness was associated with 1.46 (CI: 1.29-1.65) greater odds for future accumulating morbidities. Handgrip-strength asymmetry, as another potential indicator of impaired muscle function, is associated with future morbidity status during aging. Exercise professionals and related practitioners should consider examining asymmetry and weakness with handgrip dynamometers as a simple and noninvasive screening method for helping to determine muscle dysfunction and future chronic disease risk.

Effect of pulsed-xenon ultraviolet light on environmental contamination and risk of health care worker hand contamination.

In this study, we conducted a prospective survey of a convenience sample of high touch objects using adenosine triphosphate bioluminescence surface sample readings, aerobic cultures, and gloved hand methicillin-resistant Staphylococcus aureus imprint cultures to assess inpatient room cleanliness. We demonstrated that thoroughness of cleaning is improved with housekeeping education and feedback and that the addition of automated decontamination with pulsed UV irradiation provides further benefit in decontamination and subsequent risk for health care worker hand contamination.

Methicillin-resistant Staphylococcus aureus (MRSA) screening upon inpatient hospital admission: Is there concordance between nasal swab results and samples taken from skin and soft tissue?

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) infections are associated with increased mortality and healthcare costs. In 2007, a Veterans' Affairs (VA) hospital implemented a MRSA nasal screening program, following a nationwide VA mandate, in an effort to reduce healthcare-associated MRSA infections. OBJECTIVE: To evaluate the correlation between the nasal screening results for MRSA and culture results of wound and tissue sites. METHODS: This retrospective study was conducted on inpatients at our VA hospital. Patients were included if they had undergone nasal screening for MRSA plus culture of a wound or tissue site within 30 days of hospital admission. RESULTS: In total, 337 patients underwent nasal screening and wound culture and 211 underwent nasal screening and wound and tissue cultures. The prevalence of MRSA nasal colonization was 14.2% for wound samples and 15.2% for tissue samples. The sensitivities of MRSA nasal screening for detecting MRSA were 64.6% for wound cultures and 65.5% for tissue cultures. Specificities were 86.2% and 88.8% for wound and tissue cultures, respectively. The positive predictive values (PPVs) were 43.7% and 51.2% for wound and tissue cultures, respectively, and the negative predictive values (NPVs) were high at 93.6% and 93.5%, respectively. CONCLUSIONS: In cases of wound or tissue samples for which culture results are pending, a negative MRSA nasal swab may be a component of the decision to withhold or discontinue MRSA-active agents.

Longitudinal study on the detection of Clostridioides difficile at the Fargo Veteran Affairs Community Living Center.

Our study used C Diff Banana Broth to evaluate the occurrence of positive Clostridioides difficile spores in new and preexisting hospital rooms. C difficile incidence was 5.5%. Analysis using multiple linear regression found that rooms with contact precautions in place were significant predictors of a positive sample (P ≤ .001). Room occupancy was not a significant predictor (P = .544). Thus it could be interpreted that the environment can be a significant carrier for C difficile.

Factors Impacting Perceived Access to Early Prenatal Care among Pregnant Veterans Enrolled in the Department of Veterans Affairs.

BACKGROUND: Despite the relatively recent Department of Veterans Affairs (VA) policy advances in providing care for veterans and their infants during the perinatal period, little information exists regarding access to prenatal care for women veterans. Currently, VA medical centers do not provide onsite pregnancy care for veterans, but pay for care from community obstetricians through the Veterans Choice Program (VCP) and related non-VA care programs. The VCP is subcontracted to two large contractors, Health Net and TriWest, to assist the VA in administering the VCP. To date, no studies have evaluated women's perceived access to prenatal care under the VCP. OBJECTIVE: The purpose of this study was to understand pregnant veterans' perceived access to community prenatal care through the VCP. DESIGN: The Center for Maternal and Infant Outcomes Research in Translation (COMFORT) study is a longitudinal, prospective multisite observational cohort study of pregnant and postpartum veterans at 15 VA facilities nationwide. Telephone surveys were conducted with women veterans at 20 weeks of pregnancy. We used multivariable logistic regression to examine the odds of receiving care early enough adjusted for these key factors. Measures included perceived access to early prenatal care by race, age, marital status, history of mental health conditions, urban/rural residence, and the VCP contractor (Health Net vs. TriWest). RESULTS: Overall, 519 women veterans completed the baseline pregnancy survey. A sizeable proportion of participants reported a history of mental health conditions, including depression (56.7%), anxiety disorder (45.5%), and posttraumatic stress disorder (40.5%). White veterans were more likely to report perceived timely access to prenatal care than minority veterans (66% vs. 52%; p = .0038). Veterans receiving care at Health Net facilities were more likely to report receiving prenatal care as early as desired in comparison to veterans at TriWest facilities (adjusted odds ratio, 0.48; 95% CI, 0.32-0.73), whereas veterans with a history of depression were 1.7 times more likely to report perceived delays in desired prenatal care compared with veterans without a history of depression (adjusted odds ratio, 1.65; 95% CI, 1.08-2.53). CONCLUSIONS: We found that nearly one-third of women reported problems receiving early prenatal care as soon as they would have liked. Women with histories of depression and racial minorities may require additional maternity care coordination services to ensure they receive timely prenatal care. Community-based provider networks under the VCP should continue to be expanded so that pregnant veterans are able to access high-quality prenatal care in a timely manner.

Risky Driving Behaviors for Older Adults: Differences by Veteran's Status.

Veterans are at an increased risk of being injured or killed in motor vehicle crashes, potentially due to their proclivity to engage in risky driving behaviors. However, most research in this area has focused on driving behaviors of veterans who have recently returned home after deployment. No research has focused on risky driving behaviors of older veterans (aged 65 or older) and if risky driving behaviors extend beyond the time period immediately following return from deployment. The purpose of this research is to determine if differences exist in risky driving behaviors of veterans and non-veterans aged 65 or older. This study used data from the 2011 National Health and Aging Trend Study (NHATS), a nationally representative, longitudinal survey of community-dwelling, Medicare beneficiaries aged 65 or older. Binary logistic regression analyses were conducted in 2017 to determine if veteran's status was predictive of specific risky driving behaviors. Veteran's status was found to be predictive of specific driving behaviors for adults aged 65 and older, with non-veterans significantly more likely than veterans to: not currently drive; avoid driving at night; avoid driving alone; avoid driving on busy roads or highways; and avoid driving in bad weather. The results of this study highlight the need to further understand the effects of veteran's status on risky driving behaviors among older adults, specifically, whether veteran's status compounds driving-related risks associated with aging-related physical and mental changes.

The cholesterol metabolite 27-hydroxycholesterol stimulates cell proliferation via ERß in prostate cancer cells.

BACKGROUND: For every six men, one will be diagnosed with prostate cancer (PCa) in their lifetime. Estrogen receptors (ERs) are known to play a role in prostate carcinogenesis. However, it is unclear whether the estrogenic effects are mediated by estrogen receptor α (ERα) or estrogen receptor ß (ERß). Although it is speculated that ERα is associated with harmful effects on PCa, the role of ERß in PCa is still ill-defined. The cholesterol oxidized metabolite 27-hydroxycholesterol (27-OHC) has been found to bind to ERs and act as a selective ER modulator (SERM). Increased 27-OHC levels are found in individuals with hypercholesterolemia, a condition that is suggested to be a risk factor for PCa. METHODS: In the present study, we determined the extent to which 27-OHC causes deleterious effects in the non-tumorigenic RWPE-1, the low tumorigenic LNCaP, and the highly tumorigenic PC3 prostate cancer cells. We conducted cell metabolic activity and proliferation assays using MTS and CyQUANT dyes, protein expression analyses via immunoblots and gene expression analyses via RT-PCR. Additionally, immunocytochemistry and invasion assays were performed to analyze intracellular protein distribution and quantify transepithelial cell motility. RESULTS: We found that incubation of LNCaP and PC3 cells with 27-OHC significantly increased cell proliferation. We also demonstrate that the ER inhibitor ICI 182,780 (fulvestrant) significantly reduced 27-OH-induced cell proliferation, indicating the involvement of ERs in proliferation. Interestingly, ERß levels, and to a lesser extent ERα, were significantly increased following incubation of PCa cells with 27-OHC. Furthermore, in the presence of the ERß specific inhibitor, PHTPP, 27-OHC-induced proliferation is attenuated. CONCLUSIONS: Altogether, our results show for the first time that 27-OHC, through ER activation, triggers deleterious effect in prostate cancer cell lines. We propose that dysregulated levels of 27-OHC may trigger or exacerbate prostate cancer via acting on ERß.

27-Hydroxycholesterol stimulates cell proliferation and resistance to docetaxel-induced apoptosis in prostate epithelial cells.

Although the causes of prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are not known, the role of oxidative stress, aging, and diet are suspected to increase the incidence of prostate complications. The cholesterol oxidation derivative (oxysterol) 27-hydroxycholesterol (27-OHC) is the most prevalent cholesterol metabolite in the blood. As aging, oxidative stress, and hypercholesterolemia are associated with increased risk of PCa and BPH, and because 27-OHC levels are also increased with aging, hypercholesterolemia, and oxidative stress, determining the role of 27-OHC in the progression of PCas and BPH is warranted. In this study, we determined the effect of 27-OHC in human prostate epithelial cells RWPE-1. We found that 27-OHC stimulates proliferation and increases androgen receptor (AR) transcriptional activity. 27-OHC also increased prostate-specific antigen expression and enhanced AR binding to the androgen response element compared to controls. Silencing AR expression with siRNA markedly reduced the 27-OHC-induced proliferation. Furthermore, 27-OHC blocked docetaxel-induced apoptosis. Altogether, our results suggest that 27-OHC may play an important role in PCa and BPH progression by promoting proliferation and suppressing apoptosis.

The cholesterol metabolite 27-hydroxycholesterol regulates p53 activity and increases cell proliferation via MDM2 in breast cancer cells.

Estrogen is synthesized from cholesterol and high cholesterol levels are suggested to be associated with increased risk of estrogen receptor(ER)-positive breast cancer. The cholesterol metabolite 27-hydroxycholesterol (27-OHC) was recently identified as a selective estrogen receptor modulator (SERM) and may therefore impact breast cancer progression. However, the mechanisms by which 27-OHC may contribute to breast cancer are not all known. We determined the extent to which 27-OHC regulates cell proliferation in MCF7 ER-positive breast cancer cell line involving the tumor suppressor protein p53. We found that treatment of MCF7 cells with 27-OHC resulted reduced p53 transcriptional activity. Conversely, treatment of the ER-negative MDA-MB 231 cells with 27-OHC induced no significant change in p53 activity. Exposure of MCF7 cells to 27-OHC was also associated with increased protein levels of the E3 ubiquitin protein ligase MDM2 and decreased levels of p53. Moreover, 27-OHC also enhanced physical interaction between p53 and MDM2. Furthermore, 27-OHC-induced proliferation was attenuated using either the p53 activator Tenovin-1 or the MDM2 inhibitor Nutlin-3 and Mdm2 siRNA. Taken together, our results indicate that 27-OHC may contribute to ER-positive breast cancer progression by disrupting constitutive p53 signaling in an MDM2-dependent manner.

Phosphodiesterase 4D inhibitors limit prostate cancer growth potential.

UNLABELLED: Phosphodiesterase 4D (PDE4D) has recently been implicated as a proliferation-promoting factor in prostate cancer and is overexpressed in human prostate carcinoma. However, the effects of PDE4D inhibition using pharmacologic inhibitors have not been examined in prostate cancer. These studies examined the effects of selective PDE4D inhibitors, NVP-ABE171 and cilomilast, as anti-prostate cancer therapies in both in vitro and in vivo models. The effects of PDE4D inhibitors on pathways that are critical in prostate cancer and/or downstream of cyclic AMP (cAMP) were examined. Both NVP-ABE171 and cilomilast decreased cell growth. In vitro, PDE4D inhibitors lead to decreased signaling of the sonic hedgehog (SHH), androgen receptor (AR), and MAPK pathways, but growth inhibition was best correlated to the SHH pathway. PDE4D inhibition also reduced proliferation of epithelial cells induced by paracrine signaling from cocultured stromal cells that had activated hedgehog signaling. In addition, PDE4D inhibitors decreased the weight of the prostate in wild-type mice. Prostate cancer xenografts grown in nude mice that were treated with cilomilast or NVP-ABE171 had decreased wet weight and increased apoptosis compared with vehicle-treated controls. These studies suggest the pharmacologic inhibition of PDE4D using small-molecule inhibitors is an effective option for prostate cancer therapy. IMPLICATIONS: PDE4D inhibitors decrease the growth of prostate cancer cells in vivo and in vitro, and PDE4D inhibition has therapeutic potential in prostate cancer.

Methenamine: a forgotten drug for preventing recurrent urinary tract infection in a multidrug resistance era.

In the era of multidrug resistance, it is critical to utilize antibiotics in an appropriate manner and to identify new treatments or revisit the use of 'forgotten' drugs. Because urinary tract infections (UTIs) are common, particularly in an increasing elderly population, the 'forgotten' drug, methenamine, may become important as a preventive therapy for recurrent UTIs. Methenamine, a urinary antibacterial agent, can be used as methenamine hippurate or methenamine mandelate preparations and is United States Food and Drug Administration-approved. This article discusses the place of preventive therapy for recurrent UTIs, chemistry, mechanism of action, pharmacology, clinical uses, dosage, adverse reactions and safety, and drug interactions of methenamine. Because of its unique antiseptic property, the authors suggest that methenamine should be considered when more commonly used antibiotics fail to suppress recurrent UTIs.

A novel method for somatic transgenesis of the mouse prostate using the Sleeping Beauty transposon system.

BACKGROUND: In vivo ectopic gene expression is a common approach for prostate research through the use of transgenes in germline transgenic mice. For some other organs, somatic transgenesis with the Sleeping Beauty transposon system has allowed in vivo ectopic gene expression with higher throughput and lower cost than germline transgenic approaches. METHODS: Mouse e16 urogenital sinuses (UGSs) were co-injected with plasmids expressing the Sleeping Beauty transposase and plasmids with control or activated BRAF expressing transposons. Following electroporation, the transduced UGSs were grown as allografts in mouse hosts for 8 weeks, and the resulting allografts were evaluated for several endpoints. RESULTS: Transposon-transduced UGS allografts developed into prostatic tissue with normal tissue structure and cellular differentiation. Integration of transposon vectors into the genomes of transduced allografts was confirmed using linker-mediated PCR, sequencing, and in situ PCR. Transduction of UGS allografts with transposons expressing activated BRAF resulted in ectopic BRAF expression that was detectable at both the mRNA and protein levels. Prostatic ducts over-expressing activated BRAF also had ectopic activation of the ERK1/2 mitogen activated kinases and increased epithelial cell proliferation. CONCLUSIONS: The Sleeping Beauty transposon system can be used to achieve somatic transgenesis of prostatic allografts. This new method for achieving ectopic gene expression in the prostate will complement other existing approaches such as ectopic gene expression in cell lines and in germline transgenic mice. Advantages of this new approach include preservation of stromal-epithelial interactions not possible with cell lines, and higher throughput and lower cost than traditional germline transgenic approaches.

Evidence for contributions of interactions of constituents to the anti-inflammatory activity of Hypericum perforatum.

Hypericum perforatum (Hp) extracts contain many different classes of constituents including flavonoids and biflavonoids, phloroglucinols, naphthodianthrones, caffeic acid derivatives, and unknown and/or unidentified compounds. Many constituents may be responsible for the anti-inflammatory activity of Hp including quercetin and derivatives, hyperforin, pseudohypericin, and amentoflavone. In line with antidepressant data, it appears that the interactions of constituents may be important for the anti-inflammatory activity of Hp. Interactions of constituents, tested in bioavailability models, may explain why synergistic mechanisms have been found to be important for antidepressant and antiproliferative bioactivities. This review highlights the relationship among individual constituents and the anti-inflammatory activity of Hp extracts and proposes that interactions of constituents may be important for the anti-inflammatory activity of botanical extracts, although the exact mechanisms of the interactions are still unclear.

Identification of JAK-STAT pathways as important for the anti-inflammatory activity of a Hypericum perforatum fraction and bioactive constituents in RAW 264.7 mouse macrophages.

Hypericum perforatum extracts have been used to treat diseases, including mild-to-moderate depression and inflammatory conditions. It is particularly important to identify which constituents present in the H. perforatum extracts are responsible for its anti-inflammatory activity since consumers are taking H. perforatum preparations to treat inflammation. We used a combination of four putative bioactive constituents, called the 4-component-system that interacted synergistically to explain the light-activated anti-inflammatory activity of an H. perforatum fraction in RAW 264.7 mouse macrophages. We also combined the constituents at concentrations detected in the fraction to identify key molecular targets. LPS was used to model an inflammatory response, and the 4-component-system and H. perforatum fraction were used as treatments that inhibited LPS-induced prostaglandin E(2) (PGE(2)) production in RAW 264.7 mouse macrophages in the studies of gene expression profiles. We used Affymetrix genechips, statistical analysis, and quantitative real-time PCR to identify key gene targets of the 4-component-system and the sub-fraction from an H. perforatum ethanol extract. The H. perforatum sub-fraction, with or without LPS stimulation, affected far more genes than the 4-component-system with and without LPS. Genes involved in Janus kinase, as well as a signal transducer and activator of transcription (JAK-STAT) and eicosanoid pathways were identified that could account for the reduction in PGE(2) observed with both treatments in LPS-stimulated macrophages. Ten genes may be particularly important targets for activity of the 4-component-system and the fraction with LPS stimulation and these genes were involved in inflammatory signaling pathways, namely the JAK-STAT and eicosanoid pathways.

Endogenous levels of Echinacea alkylamides and ketones are important contributors to the inhibition of prostaglandin E2 and nitric oxide production in cultured macrophages.

Because of the popularity of Echinacea as a dietary supplement, researchers have been actively investigating which Echinacea constituent or groups of constituents are necessary for immune-modulating bioactivities. Our prior studies indicate that alkylamides may play an important role in the inhibition of prostaglandin E2 (PGE(2)) production. High-performance liquid chromatography fractionation, employed to elucidate interacting anti-inflammatory constituents from ethanol extracts of Echinacea purpurea, Echinacea angustifolia, Echinacea pallida, and Echinacea tennesseensis, identified fractions containing alkylamides and ketones as key anti-inflammatory contributors using lipopolysaccharide-induced PGE(2) production in RAW264.7 mouse macrophage cells. Nitric oxide (NO) production and parallel cytotoxicity screens were also employed to substantiate an anti-inflammatory response. E. pallida showed significant inhibition of PGE(2) with a first round fraction, containing gas chromatography-mass spectrometry (GC-MS) peaks for Bauer ketones 20, 21, 22, 23, and 24, with 23 and 24 identified as significant contributors to this PGE(2) inhibition. Chemically synthesized Bauer ketones 21 and 23 at 1 microM each significantly inhibited both PGE(2) and NO production. Three rounds of fractionation were produced from an E. angustifolia extract. GC-MS analysis identified the presence of Bauer ketone 23 in third round fraction 3D32 and Bauer alkylamide 11 making up 96% of third round fraction 3E40. Synthetic Bauer ketone 23 inhibited PGE(2) production to 83% of control, and synthetic Bauer alkylamide 11 significantly inhibited PGE(2) and NO production at the endogenous concentrations determined to be present in their respective fraction; thus, each constituent partially explained the in vitro anti-inflammatory activity of their respective fraction. From this study, two key contributors to the anti-inflammatory properties of E. angustifolia were identified as Bauer alkylamide 11 and Bauer ketone 23.

Effect of ultraviolet B radiation on activator protein 1 constituent proteins and modulation by dietary energy restriction in SKH-1 mouse skin.

The study examined the timing of modulation of activator protein 1(AP-1):DNA binding and production of AP-1 constituent proteins by ultraviolet B (UVB) radiation and effect of dietary energy restriction [DER, 40% calorie reduction from fat and carbohydrate compared to control ad libitum (AL) diet] in SKH-1 mouse epidermis. AP-1:DNA binding by electromobility shift assay (EMSA) was increased in a biphasic manner after treatment with a tumor-promoting suberythemal dose (750 mJ/cm(2)) of UVB light (311-313 nm) with peaks at 3 and 18 h postirradiation. DER overall reduced AP-1:DNA binding in mock-treated and UVB-treated skin at 3 and 18 h after UVB treatment. The timing of modulation of production of AP-1 constituent proteins by Western blot analysis was examined at 0 h (mock treatment), 3, 9, 18, and 24 h. We found that c-jun (9 h), jun-B (9 and 18 h), phosphorylated c-jun (3 h), and fra-1 (18 h) protein levels were increased after UVB treatment compared to mock controls. In a follow-up diet experiment, animals were placed on DER or AL diet for 10-12 wk and treated with UVB as before. DER was found to completely block the UVB-induced increase in phosphorylated c-jun protein levels and decrease in fra-2 protein levels at 18 h. In addition, DER enhanced UVB-induced increase in jun B levels and lowered basal levels of c-fos seen 18 h after UVB. These data suggest that DER may be able to assist in the prevention of UVB-induced skin carcinogenesis by modulating AP-1:DNA binding and AP-1 constituent protein levels.

Pseudohypericin is necessary for the light-activated inhibition of prostaglandin E2 pathways by a 4 component system mimicking an Hypericum perforatum fraction.

Hypericum perforatum (Hp) has been used medicinally to treat a variety of conditions including mild-to-moderate depression. Recently, several anti-inflammatory activities of Hp have been reported. An ethanol extract of Hp was fractionated with the guidance of an anti-inflammatory bioassay (lipopolysaccharide (LPS)-induced prostaglandin E2 production (PGE2)), and four constituents were identified. When combined together at concentrations detected in the Hp fraction to make a 4 component system, these constituents (0.1microM chlorogenic acid (compound 1), 0.08microM amentoflavone (compound 2), 0.07microM quercetin (compound 3), and 0.03microM pseudohypericin (compound 4)) explained the majority of the activity of the fraction when activated by light, but only partially explained the activity of this Hp fraction in dark conditions. One of the constituents, light-activated pseudohypericin, was necessary, but not sufficient to explain the reduction in LPS-induced PGE2 of the 4 component system. The Hp fraction and the 4 component system inhibited lipoxygenase and cytosolic phospholipase A2, two enzymes in the PGE2-mediated inflammatory response. The 4 component system inhibited the production of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), and the Hp fraction inhibited the anti-inflammatory cytokine interleukin-10 (IL-10). Thus, the Hp fraction and selected constituents from this fraction showed evidence of blocking pro-inflammatory mediators but not enhancing inflammation-suppressing mediators.

Characterizing the metabolic fingerprint and anti-inflammatory activity of Hypericum gentianoides.

In this paper we characterize the metabolic fingerprint and first reported anti-inflammatory activity of Hypericum gentianoides. H. gentianoides has a history of medical use by Native Americans, but it has been studied very little for biological activity. High-performance liquid chromatography (HPLC) and liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) analyses of a methanol extract show that H. gentianoides contains a family of over nine related compounds that have retention times, mass spectra, and a distinctive UV absorption spectra characteristic of certain acyl-phloroglucinols. These metabolites are abundant relative to other secondary products present in H. gentianoides, accounting for approximately 0.2 g per gram of dry plant tissue. H. gentianoides methanol extracts and a specific semipreparative HPLC fraction from these extracts containing the putative acyl-phloroglucinols reduce prostaglandin E 2 synthesis in mammalian macrophages.