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The Journal of Pharmacology and... Jun 2024Estrogen receptors are essential pharmacological targets for treating hormonal disorders and estrogen-dependent malignancies. Selective activation of estrogen receptor...
Estrogen receptors are essential pharmacological targets for treating hormonal disorders and estrogen-dependent malignancies. Selective activation of estrogen receptor (ER) β is hypothesized to provide therapeutic benefit with reduced risk of unwanted estrogenic side-effects associated with ERα activity. However, activating ERβ without activating α is challenging due to the high sequence and structural homology between the receptor subtypes. We assessed the impact of structural modifications to the parent compound OSU-ERβ-12 on receptor subtype binding selectivity using cell-free binding assays. Functional selectivity was evaluated by transactivation in HEK-293 cells overexpressing human or murine estrogen receptors. selectivity was examined through the uterotrophic effects of the analogs after oral administration in estrogen-naïve female mice. Furthermore, we evaluated the pharmacokinetics of the analogs following single dose IV and oral administration. Regarding selectivity, a single compound exhibited greater functional selectivity than OSU-ERβ-12 for human ERβ. However, like others in the -carborane series, its poor pharmacokinetics limit its suitability for further development. Surprisingly, and at odds with their pharmacokinetic and human activity data, most analogs potently induced uterotrophic effects in estrogen-naïve female mice. Further investigation of activity in HEK293 cells expressing murine estrogen receptors revealed species-specific differences in the ER-subtype selectivity of these analogs. Our findings highlight species-specific receptor pharmacology and the challenges it poses to characterizing developmental therapeutics in preclinical species. This study investigates - and -substituted carborane analogs targeting estrogen receptors, revealing the greater selectivity of carborane analogs for human ERβ compared to the mouse homolog. These findings shed light on the intricacies of using preclinical species in drug development to predict human pharmacology. The report also provides insights for the refinement and optimization of carborane analogs as potential therapeutic agents for estrogen-related disease states.
PubMed: 38936980
DOI: 10.1124/jpet.123.001874 -
The Journal of Pharmacology and... Jun 2024Endocannabinoids, which are present throughout the central nervous system (CNS), can activate CB1 and CB2 receptors. CB1 and CB2 agonists exhibit broad...
Endocannabinoids, which are present throughout the central nervous system (CNS), can activate CB1 and CB2 receptors. CB1 and CB2 agonists exhibit broad anti-inflammatory properties, suggesting their potential to treat inflammatory diseases. However, careful evaluation of abuse potential is necessary. This study evaluated the abuse potential of lenabasum, a selective CB2 receptor agonist in participants (n=56) endorsing recreational cannabis use. Three doses of lenabasum (20, 60, and 120mg) were compared to placebo, and nabilone (3 and 6mg). The primary endpoint was the peak effect (Emax) on a bipolar Drug Liking visual analog scale (VAS). Secondary VAS and pharmacokinetic (PK) endpoints and adverse events were assessed. : Lenabasum was safe and well tolerated. Compared to placebo, a 20mg dose of lenabasum did not increase ratings of Drug Liking and had no distinguishable effect on other VAS endpoints. Dose-dependent increases in ratings of Drug Liking were observed with 60 and 120mg lenabasum. Drug Liking and all other VAS outcomes were greatest for nabilone 3mg and 6mg, which is a currently FDA-approved medication. : At a target therapeutic dose (20mg), lenabasum did not elicit subjective ratings of Drug Liking. However, supratherapeutic doses of lenabasum (60 and 120mg) did elicit subjective ratings of Drug Liking compared to placebo. Although both doses of lenabasum were associated with lower ratings of Drug Liking compared to 3mg and 6mg of nabilone, suggesting that lenabasum does have abuse potential and should be used cautiously in clinical settings. This work provides evidence that in people with a history of recreational cannabis use, lenabasum was safe and well-tolerated, although it did demonstrate abuse potential. This work supports further development of lenabasum for potential therapeutic indications.
PubMed: 38936978
DOI: 10.1124/jpet.124.002129 -
Global Health, Science and Practice Jun 2024Barriers to achieving and sustaining access to water, sanitation, hygiene, cleaning, and waste management (WASH) in health care facilities include a lack of supportive...
Barriers to achieving and sustaining access to water, sanitation, hygiene, cleaning, and waste management (WASH) in health care facilities include a lack of supportive policy environment and adequate funding. While guidelines exist for assessing needs and making initial infrastructure improvements, there is little guidance on how to develop budgets and policies to sustain WASH services. We conducted costing and advocacy activities in Thakurbaba municipality, Nepal, to develop a budget and operations and maintenance policy for WASH in health care facilities in partnership with the municipal government. Our objectives for this study were to (1) describe the process and methods used for costing and advocacy, (2) report the costs to achieve and maintain basic WASH services in the 8 health care facilities of Thakurbaba municipality, and (3) report the outcomes of advocacy activities and policy development. We applied bottom-up costing to enumerate the resources necessary to achieve and maintain basic WASH services and their costs. The annual costs to achieve, operate, and maintain basic access to WASH services ranged from US$4881-US$9695 per facility. Cost findings were used to prepare annual budgets recommended to achieve, operate, and maintain basic services, which were presented to the municipal government and incorporated into an operations and maintenance policy. To date, the municipality has adopted the policy and established a recovery fund of US$3831 for repair and maintenance of infrastructure and an additional US$153 per facility for discretionary WASH spending, which were to be replenished as they were spent. Advocacy at the national level for WASH in health care facilities is currently being championed by the municipality, and findings from this project have informed the development of a nationally costed plan for universal access. This study is intended to provide a roadmap for how cost data can be collected and applied to inform policy.
Topics: Nepal; Sanitation; Humans; Hygiene; Health Facilities; Budgets; Water Supply; Waste Management
PubMed: 38936959
DOI: 10.9745/GHSP-D-23-00491 -
Ultrasonics Sonochemistry Jun 2024In the current study, a novel crude polysaccharide (cNCEP) was extracted from N. commune Vaucher utilizing ultrasonic-assisted extraction (UAE) with 60 % ethanol,...
In the current study, a novel crude polysaccharide (cNCEP) was extracted from N. commune Vaucher utilizing ultrasonic-assisted extraction (UAE) with 60 % ethanol, employing response surface methodology. The optimal yield of cNCEP was determined to be 8.07 ± 0.08 mg/g, achieved through ultrasonic-assisted extraction under the conditions of a material-to-liquid ratio of 1:22, temperature of 56 °C, power of 570 W, and duration of 147 min. Subsequent purification of NCEP via Sephadex G75 resulted in a novel polysaccharide with a molecular weight of 20.466 kDa. NCEP exhibited significant scavenging activites against DPPH and hydroxyl radicals, as well as notable in vitro immunomodulatory properties. Furthermore, the mechanisms underlying the immunomodulatory effects of NCEP, involving enhancement of immunity, were investigated, revealing potential regulation of MAPK and TLR4-IRF7-NF-κB signaling pathways through RNA-Seq and Western blot analyses. These findings highlight the promising potential of NCEP as an organic immunomodulatory agent and functional food ingredient.
PubMed: 38936294
DOI: 10.1016/j.ultsonch.2024.106961 -
Ultrasonics Sonochemistry Jun 2024In this study, corn starch was used as the raw material, and modified starch was prepared using a method combining plasma-activated water and ultrasound treatment (PUL)....
In this study, corn starch was used as the raw material, and modified starch was prepared using a method combining plasma-activated water and ultrasound treatment (PUL). This method was compared with treatments using plasma-activated water (PAW) and ultrasound (UL) alone. The structure, thermal, physicochemical, pasting, and functional properties of the native and treated starches were evaluated. The results indicated that PAW and UL treatments did not alter the shape of the starch granules but caused some surface damage. The PUL treatment increased the starch gelatinization temperature and enthalpy (from 11.22 J/g to 13.13 J/g), as well as its relative crystallinity (increased by 0.51 %), gel hardness (increased by 16.19 %) compared to untreated starch, without inducing a crystalline transition. The PUL treatment resulted in a whitening of the samples. The dual treatment enhanced the thermal stability of the starch paste, which can be attributed to the synergistic effect between PAW and ultrasound (PAW can modify the starch structure at a molecular level, while ultrasound can further disrupt the granule weak crystalline structures, leading to improved thermal properties). Furthermore, FTIR results suggested significant changes in the functional groups related to the water-binding capacity of starch, and the order of the double-helical structure was disrupted. The findings of this study suggest that PUL treatment is a promising new green modification technique for improving the starch structure and enhancing starch properties. However, further research is needed to tailor the approach based on the specific properties of the raw material.
PubMed: 38936293
DOI: 10.1016/j.ultsonch.2024.106963 -
Redox Biology Jun 2024GPCR-G protein signaling from endosomes plays a crucial role in various physiological and pathological processes. However, the mechanism by which endosomal G protein...
GPCR-G protein signaling from endosomes plays a crucial role in various physiological and pathological processes. However, the mechanism by which endosomal G protein signaling is terminated remains largely unknown. In this study, we aimed to investigate the regulatory mechanisms involved in terminating the signaling of Gα subunits from endosomes. Through structural analysis and cell-based assays, we have discovered that SNX25, a protein that targets endosomes via its PXA or PXC domain, interacts with regulator of G protein signaling (RGS) proteins (including RGS2, RGS4, RGS8, and RGS17) in a redox-regulated manner. The interaction between SNX25 and these RGS proteins enhances their GTPase-accelerating activity towards Gα and their ability to bind GDP-bound (inactive form) Gα. As a result, SNX25 recruits these RGS proteins to endosomes, leading to the termination of endosomal Gα signaling. Furthermore, we have found that the SNX25/RGS complex also exerts a negative regulatory effect on Gα signaling from the plasma membrane. This is achieved by recruiting Gα to endosomes and preventing its activation on the plasma membrane. Our findings shed light on the previously unknown role of redox-modulated SNX25 in inhibiting Gα signaling, thereby uncovering a novel mechanism for terminating Gα signaling from endosomes. Importantly, this study expands our understanding of the regulation of GPCR-Gα signaling beyond the plasma membrane.
PubMed: 38936254
DOI: 10.1016/j.redox.2024.103253 -
Developmental Cognitive Neuroscience Jun 2024Adolescent risk-taking has been attributed to earlier-developing motivational neurocircuitry that is poorly controlled by immature executive-control neurocircuitry....
Adolescent risk-taking has been attributed to earlier-developing motivational neurocircuitry that is poorly controlled by immature executive-control neurocircuitry. Functional magnetic resonance imaging findings of increased ventral striatum (VS) recruitment by reward prospects in adolescents compared to adults support this theory. Other studies found blunted VS recruitment by reward-predictive cues in adolescents compared to adults. Task features may explain this discrepancy but have never been systematically explored. Adolescents and adults performed a novel reward task that holds constant the expected value of all rewards but varies whether rewards are dependent on vigilance-intensive responding versus making a lucky choice during a relaxed response window. We examined group by sub-task contrast differences in activation of VS and more motoric regions of striatum in response to anticipatory cues. Reward anticipation in both task conditions activated portions of striatum in both groups. In voxel-wise comparison, adults showed greater anticipatory recruitment of VS in trials involving choice during a relaxed time window, not in the more vigilance-demanding trials as hypothesized. In accord with our hypotheses, however, adults showed greater activation in dorsal striatum and putamen volumes of interest during reward anticipation under vigilance-demanding conditions. Following trial outcome notifications, adolescents showed greater activation of the VS during reward notification but lower activation during loss notification. These data extend findings of cross-sectional age-group differences in incentive-anticipatory recruitment of striatum, by demonstrating in adults relatively greater recruitment of motor effector regions of striatum by attentional and motor demands.
PubMed: 38936253
DOI: 10.1016/j.dcn.2024.101412 -
Poultry Science Jun 2024This study aimed to explore the impact of dietary Bacillus subtilis fmbj (BS) supplementation on acute intestinal dysfunction induced by lipopolysaccharide (LPS) in...
This study aimed to explore the impact of dietary Bacillus subtilis fmbj (BS) supplementation on acute intestinal dysfunction induced by lipopolysaccharide (LPS) in broilers. One hundred and eighty 1-day-old male Arbor Acres broilers were randomly divided into three treatment groups, each comprising ten replicates of 6 birds. On d 20, LPS-challenged (LPS group and LPS-BS group) and LPS-unchallenged (CON group) broilers received intraperitoneal injections of 1 mg/kg body weight LPS solution and an equivalent volume of sterile saline, respectively. Compared to the CON group, LPS disrupted (P < 0.05) the morphology of the small intestine (jejunum or ileum), exacerbated (P < 0.05) serum, small intestinal, and small intestinal mitochondrial antioxidant capacity, induced (P < 0.05) small intestinal oxidative damage, and altered (P < 0.05) the expression of genes and proteins related to antioxidants, cell adhesion, and mitochondrial function in the jejunum. The LPS-BS group exhibited a tendency towards improvement in small intestinal morphology, serum, small intestinal, and small intestinal mitochondrial antioxidant capacity, small intestinal oxidative damage, and the expression of genes and proteins related to antioxidants, cell adhesion, and mitochondrial function in the jejunum when compared to the LPS group. In conclusion, BS supplementation may confer protection against LPS-induced acute intestinal dysfunction in broilers by enhancing the activation of SIRT1/PGC1α, suggesting its potential as a valuable additive for the poultry industry.
PubMed: 38936217
DOI: 10.1016/j.psj.2024.103964 -
Animal : An International Journal of... Jun 2024Feed efficiency is an important trait of dairy production. However, assessing feed efficiency is constrained by the associated cost and difficulty in measuring...
Feed efficiency is an important trait of dairy production. However, assessing feed efficiency is constrained by the associated cost and difficulty in measuring individual feed intake, especially on pastures. The objective of this study was to investigate short-term feed efficiency traits of herbage-fed dairy cows and screening of potential biomarkers (n = 238). Derived feed efficiency traits were ratio-based (i.e., feed conversion ratio (FCR) and N use efficiency (NUE)) or residual-based (i.e., residual feed intake (RFI), residual energy intake (REI), and residual N intake (RNI)). Thirty-eight Holstein and 16 Swiss Fleckvieh dairy cows underwent a 7-d measurement period during mid- and/or late-lactation. The experimental data (n = 100 measurement points) covered different lactational and herbage-fed system situations: mid-lactation grazing (n = 56), late-lactation grazing (n = 28), and late-lactation barn feeding (n = 16). During each measuring period, the individual herbage intake of each cow was estimated using the n-alkane marker technique. For each cow, biomarkers representing milk constituents (n = 109), animal characteristics (n = 13), behaviour, and activity (n = 46), breath emissions (n = 3), blood constituents (n = 35), surface, and rectal temperature (n = 29), hair cortisol (n = 1), and near-infrared (NIR) spectra of faeces and milk (n = 2) were obtained. The relationships between biomarkers and efficiency traits were statistically analysed with univariate linear regression and for NIR spectra using partial least squares regression with feed efficiency traits. The feed efficiency traits were interrelated with each other (r: -0.57 to -0.86 and 0.49-0.81). The biomarkers showed varying R values in explaining the variability of feed efficiency traits (FCR: 0.00-0.66, NUE: 0.00-0.74, RFI: 0.00-0.56, REI: 0.00-0.69, RNI: 0.00-0.89). Overall, the feed efficiency traits were best explained by NIR spectral characteristics of milk and faeces (R: 0.25-0.89). Biomarkers show potential for predicting feed efficiency in herbage-fed dairy cows. NIR spectra data analysis of milk and faeces presents a promising method for estimating individual feed efficiency upon further validation of prediction models. Future applications will depend on the ability to improve the robustness of biomarkers to predict feed efficiency in a greater variety of environments (locations), managing conditions, feeding systems, production intensities, and other aspects.
PubMed: 38935984
DOI: 10.1016/j.animal.2024.101211 -
PloS One 2024The elderly is commonly susceptible to depression, the symptoms for which may overlap with natural aging or other illnesses, and therefore miss being captured by routine...
BACKGROUND
The elderly is commonly susceptible to depression, the symptoms for which may overlap with natural aging or other illnesses, and therefore miss being captured by routine screening questionnaires. Passive sensing data have been promoted as a tool for depressive symptoms detection though there is still limited evidence on its usage in the elderly. Therefore, this study aims to review current knowledge on the use of passive sensing data via smartphones and smartwatches in depressive symptom screening for the elderly.
METHOD
The search of literature was performed in PubMed, IEEE Xplore digital library, and PsycINFO. Literature investigating the use of passive sensing data to screen, monitor, and/or predict depressive symptoms in the elderly (aged 60 and above) via smartphones and/or wrist-worn wearables was included for initial screening. Studies in English from international journals published between January 2012 to September 2022 were included. The reviewed studies were further analyzed by a narrative analysis.
RESULTS
The majority of 21 included studies were conducted in Western countries with a few in Asia and Australia. Most studies adopted a cohort study design (n = 12), followed by cross-sectional design (n = 7) and a case-control design (n = 2). The most popular passive sensing data was related to sleep and physical activity using an actigraphy. Sleep characteristics, such as prolonged wakefulness after sleep onset, along with lower levels of physical activity, exhibited a significant association with depression. However, cohort studies expressed concerns regarding data quality stemming from incomplete follow-up and potential confounding effects.
CONCLUSION
Passive sensing data, such as sleep, and physical activity parameters should be promoted for depressive symptoms detection. However, the validity, reliability, feasibility, and privacy concerns still need further exploration.
Topics: Humans; Smartphone; Depression; Aged; Mass Screening; Wearable Electronic Devices; Sleep; Middle Aged; Exercise; Female
PubMed: 38935797
DOI: 10.1371/journal.pone.0304845