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ENeuro Jun 2024Ghrelin is a stomach-derived hormone that increases feeding and is elevated in response to chronic psychosocial stressors. The effects of ghrelin on feeding are mediated...
Ghrelin is a stomach-derived hormone that increases feeding and is elevated in response to chronic psychosocial stressors. The effects of ghrelin on feeding are mediated by the binding of ghrelin to the growth hormone secretagogue receptor (GHSR), a receptor located in hypothalamic and extra-hypothalamic regions important for regulating food intake and metabolic rate. The ability of ghrelin to enter the brain, however, seems to be restricted to circumventricular organs like the median eminence and the brain stem area postrema (AP), whereas ghrelin does not readily enter other GHSR expressing regions like the ventral tegmental area (VTA). Interestingly, social stressors result in increased blood brain barrier permeability, and this could therefore facilitate the entry of ghrelin into the brain. To investigate this, we exposed mice to social defeat stress for 21 days, then peripherally injected a Cy5-labelled biologically active ghrelin analogue. Results demonstrate that chronically stressed mice exhibit higher Cy5-ghrelin fluorescence in several hypothalamic regions in addition to the ARC, including the hippocampus and midbrain. Furthermore, Cy5-ghrelin injections resulted in increased FOS expression in regions associated with the reward system in the chronically stressed mice. Further histologic analyses identified a reduction in branching of hypothalamic astrocytes in the ARC-median eminence junction, suggesting increased blood-brain barrier permeability. These data support the hypothesis that during metabolically challenging conditions like chronic stress, ghrelin may be more able to cross the blood brain barrier and diffuse throughout the brain to target GHSR expressing brain regions away from circumventricular organs. Ghrelin is secreted in response to negative energy balance states including stress and is associated with changes in food intake and energy balance. The receptors for ghrelin are found throughout the brain but ghrelin seems to only reach circumventricular regions where the blood brain barrier is more porous. In this paper we demonstrate that chronic social defeat stress increases brain permeability to ghrelin to allow for entry and activation of target sites in the mesolimbic dopaminergic system that are not accessible to ghrelin under non-stress conditions. Overall, these results provide for an explanation as to how ghrelin can access the mesolimbic dopaminergic system in a state dependent manner.
PubMed: 38937108
DOI: 10.1523/ENEURO.0093-24.2024 -
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 -
PLoS Pathogens Jun 2024The bloodstream form of Trypanosoma brucei expresses large poly-N-acetyllactosamine (pNAL) chains on complex N-glycans of a subset of glycoproteins. It has been...
The bloodstream form of Trypanosoma brucei expresses large poly-N-acetyllactosamine (pNAL) chains on complex N-glycans of a subset of glycoproteins. It has been hypothesised that pNAL may be required for receptor-mediated endocytosis. African trypanosomes contain a unique family of glycosyltransferases, the GT67 family. Two of these, TbGT10 and TbGT8, have been shown to be involved in pNAL biosynthesis in bloodstream form Trypanosoma brucei, raising the possibility that deleting both enzymes simultaneously might abolish pNAL biosynthesis and provide clues to pNAL function and/or essentiality. In this paper, we describe the creation of a TbGT10 null mutant containing a single TbGT8 allele that can be excised upon the addition of rapamycin and, from that, a TbGT10 and TbGT8 double null mutant. These mutants were analysed by lectin blotting, glycopeptide methylation linkage analysis and flow cytometry. The data show that the mutants are defective, but not abrogated, in pNAL synthesis, suggesting that other GT67 family members can compensate to some degree for loss of TbGT10 and TbGT8. Despite there being residual pNAL synthesis in these mutants, certain glycoproteins appear to be particularly affected. These include the lysosomal CBP1B serine carboxypeptidase, cell surface ESAG2 and the ESAG6 subunit of the essential parasite transferrin receptor (TfR). The pNAL deficient TfR in the mutants continued to function normally with respect to protein stability, transferrin binding, receptor mediated endocytosis of transferrin and subcellular localisation. Further the pNAL deficient mutants were as viable as wild type parasites in vitro and in in vivo mouse infection experiments. Although we were able to reproduce the inhibition of transferrin uptake with high concentrations of pNAL structural analogues (N-acetylchito-oligosaccharides), this effect disappeared at lower concentrations that still inhibited tomato lectin uptake, i.e., at concentrations able to outcompete lectin-pNAL binding. Based on these findings, we recommend revision of the pNAL-dependent receptor mediated endocytosis hypothesis.
PubMed: 38935804
DOI: 10.1371/journal.ppat.1012333 -
PloS One 2024The economic impact of gastrointestinal (GI) nematode infections on livestock production is well documented worldwide. Increasing evidence supports the hypothesis that...
The economic impact of gastrointestinal (GI) nematode infections on livestock production is well documented worldwide. Increasing evidence supports the hypothesis that parasite colonization induces significant changes in the GI tract environment and, therefore, in the landscape where the microbiota and parasites occur. Understanding the interactions between bacterial and parasite populations in the digestive tract of livestock may be useful to design parasite control strategies based on microbiota modification. The aims of this work were to investigate the impact of the oxytetracycline-mediated manipulation of the gut microbial community on the composition of GI nematode populations in naturally infected sheep and to explore changes in the GI microbial communities after nematode population treatment with the anthelmintic compound monepantel. Extensive manipulation of the GI microbiota with a therapeutic dose of the long-acting oxytetracycline formulation did not induce significant changes in the GI nematode burden. The gut microbiota of treated animals returned to control levels 17 days after treatment, suggesting strong resilience of the sheep microbial community to antibiotic-mediated microbiota perturbation. A significant decrease of the bacterial Mycoplasmataceae family (Log2FC = -4, Padj = 0.001) and a marked increase of the Methanobacteriaceae family (Log2FC = 2.9, Padj = 0.018) were observed in the abomasum of sheep receiving the monepantel treatment. While a comprehensive evaluation of the interactions among GI mycoplasma, methanobacteria and nematode populations deserves further assessment, the bacteria-nematode population interactions should be included in future control programs in livestock production. Understanding how bacteria and parasites may influence each other in the GI tract environment may substantially contribute to the knowledge of the role of microbiota composition in nematode parasite establishment and the role of the parasites in the microbiota composition.
Topics: Animals; Sheep; Gastrointestinal Microbiome; Sheep Diseases; Nematode Infections; Nematoda; Oxytetracycline; Gastrointestinal Tract; Aminoacetonitrile; Bacteria
PubMed: 38935803
DOI: 10.1371/journal.pone.0306390 -
PloS One 2024To investigate the therapeutic effect and mechanism of sivelestat sodium on acute lung injury (AIL).
OBJECTIVE
To investigate the therapeutic effect and mechanism of sivelestat sodium on acute lung injury (AIL).
METHODS
A rat model for ALI/acute respiratory distress syndrome (ALI/ARDS) was established. Pathological examination of lung tissue was conducted to assess lung injury. Blood gas in the arteries was measured using a blood analyzer. Changes in PaO2, PaO2/FiO2, and lung wet/dry (W/D) weight ratio were carefully compared. ELISA assay was conducted to estimate cell adhesion and inflammation response. Finally, real-time reverse transcription polymerase chain reaction and western blotting assay was used to determine the activation of PI3K/AKT/mTOR pathway.
RESULTS
ARDS in vivo model was successfully constructed by LPS injection. Compared with the sham group, PaO2 and PaO2/FiO2 were significantly lower in the vehicle group, while the lung W/D ratio, the lung injury score, NE, VCAM-1, IL-8 andTNF-αwere significantly increased. After treatment with different doses of sivelestat sodium, we found PaO2, PaO2/FiO2 were prominently increased, while the lung W/D ratio, the lung injury score, NE, VCAM-1, IL-8, TNF-α levels were decreased in the dose-dependent manner. Meanwhile, compared with the vehicle group, the expression levels of Bax, PI3K, Akt and mTOR were significantly lower, and the expression of Bcl-2 was significantly higher after injection with sivelestat sodium.
CONCLUSION
Sivelestat sodium has an interventional effect on ALI in sepsis by inhibiting the PI3K/AKT/mTOR signalling pathway.
Topics: Animals; TOR Serine-Threonine Kinases; Acute Lung Injury; Signal Transduction; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Rats; Male; Glycine; Sulfonamides; Rats, Sprague-Dawley; Lung; Disease Models, Animal
PubMed: 38935660
DOI: 10.1371/journal.pone.0302721 -
Cell Reports Jun 2024Kisspeptin signaling through its G protein-coupled receptor, KISS1R, plays an indispensable role in regulating reproduction via the hypothalamic-pituitary-gonadal axis....
Kisspeptin signaling through its G protein-coupled receptor, KISS1R, plays an indispensable role in regulating reproduction via the hypothalamic-pituitary-gonadal axis. Dysregulation of this pathway underlies severe disorders like infertility and precocious puberty. Here, we present cryo-EM structures of KISS1R bound to the endogenous agonist kisspeptin-10 and a synthetic analog TAK-448. These structures reveal pivotal interactions between peptide ligands and KISS1R extracellular loops for receptor activation. Both peptides exhibit a conserved binding mode, unveiling their common activation mechanism. Intriguingly, KISS1R displays a distinct 40° angular deviation in its intracellular TM6 region compared to other G-coupled receptors, enabling distinct interactions with G. This study reveals the molecular intricacies governing ligand binding and activation of KISS1R, while highlighting its exceptional ability to couple with G. Our findings pave the way for structure-guided design of therapeutics targeting this physiologically indispensable receptor.
PubMed: 38935498
DOI: 10.1016/j.celrep.2024.114389 -
Indian Journal of Dental Research :... Jan 2024Dental radiography is an integral part of intraoral evaluation. Children are often uncomfortable during the placement of film or sensor due to the impingement of the...
BACKGROUND
Dental radiography is an integral part of intraoral evaluation. Children are often uncomfortable during the placement of film or sensor due to the impingement of the soft tissues. Thus, the perception of pain with three intraoral radiographic methods in children was evaluated using three subjective pain rating scales.
AIM
To evaluate the discomfort with three different techniques, that is, intraoral periapical (IOPA) radiograph, charge-coupled device (CCD), and photostimulable phosphor (PSP) luminescence (PSPL), using the Wong-Baker Faces Pain Rating Scale (WBFPRS), numerical rating scale, and visual analog scale (VAS).
MATERIALS AND METHODS
A sample of 35 children aged 6-12 years were divided into two groups: group 1 (6-8 years) and group 2 (9-12 years). For each child, simulations of the three radiological methods (IOPA, CCD, and PSPL) were performed. The meaning of each facial expression on the WBFPRS, VAS, and the numbers on the numerical rating scale was explained to each child before the procedure.
STATISTICAL ANALYSIS USED
A one-way analysis of variance (ANOVA) test and paired-samples t-test are used.
RESULTS
The results revealed that the CCD sensors elicited higher pain scores than those obtained with IOPA and PSPL, whereas the IOPA film showed the least pain score. Higher score values were obtained in group 1 than in group 2, indicating that children aged 6-8 years felt higher discomfort than the 9- to 12-year age group for the same procedure. This difference was statistically significant (P < 0.001).
CONCLUSION
It was concluded that conventional IOPA films were tolerated better by children when compared to PSP plates and CCD sensors.
Topics: Humans; Child; Pain Measurement; Male; Female; Radiography, Dental, Digital; Pain Perception; Radiography, Dental
PubMed: 38934750
DOI: 10.4103/ijdr.ijdr_78_23 -
Indian Journal of Dental Research :... Jan 2024Compare the efficacy of 2% lidocaine with adrenaline (1:200,000) and 4% articaine with adrenaline (1:100,000) in inferior alveolar nerve block prior to extraction of... (Comparative Study)
Comparative Study Randomized Controlled Trial
AIMS
Compare the efficacy of 2% lidocaine with adrenaline (1:200,000) and 4% articaine with adrenaline (1:100,000) in inferior alveolar nerve block prior to extraction of bilateral teeth posterior to canine in interval of one week.
METHODS AND MATERIAL
Thirty-five patients were selected for the study. Patients were divided into two different groups: Group 1 - (2% lignocaine with adrenaline (1:200,000)) and Group 2 - (4% articaine with adrenaline (1:100,000)) solution. The study variables for each anaesthetic agent were: onset of action and depth of anaesthesia. A pulp tester was used to demonstrate quantitative values and a visual analogue scale (VAS) was used for qualitative evaluation of the two anaesthetic drugs in 2 min cycle for 10 min with respect to test canine. Anaesthesia was considered successful when pulp tester value 64 was achieved in 10 min for both the anaesthetic agent.
STATISTICAL ANALYSIS USED
The difference in the efficacy of lignocaine and articaine was analysed using Student's t test. Within group comparison of the response to the pulp vitality test and VAS over various time periods was analysed using repeated measures Analysis of Variance (ANOVA) with post-hoc Bonferroni test.
RESULTS
Data analysis showed statistical differences in onset and depth of anaesthesia between the two groups (P < 0.05).
CONCLUSIONS
4% Articaine with adrenaline (1:100,000) onset of action is faster and depth of anaesthesia is better compared to 2% lignocaine with adrenaline (1:200,000). Many previous studies reported onset of anaesthesia, but this study evaluates onset and depth of both the anaesthetic agent quantitatively and qualitatively.
Topics: Humans; Carticaine; Lidocaine; Anesthetics, Local; Nerve Block; Mandibular Nerve; Epinephrine; Adult; Anesthesia, Dental; Young Adult; Male; Dental Pulp Test; Dental Pulp; Pain Measurement; Female; Tooth Extraction; Vasoconstrictor Agents; Adolescent; Cuspid; Time Factors; Treatment Outcome
PubMed: 38934747
DOI: 10.4103/ijdr.ijdr_678_23 -
Indian Journal of Dental Research :... Jan 2024To comparatively evaluate the effect of normal saline gel and ozonated saline-ozonated gel (ozone therapy) on pain, inflammation, soft tissue, and crestal bone loss in... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
AIMS
To comparatively evaluate the effect of normal saline gel and ozonated saline-ozonated gel (ozone therapy) on pain, inflammation, soft tissue, and crestal bone loss in dental implant surgery.
METHODS AND MATERIAL
Forty adult patients scheduled to undergo implant were randomized into two groups: Twenty patients (n = 20) received ozone therapy and controls (n = 20) received normal saline and gel during implant placement. Inflammation and pain were noted at days 1 and 7 and 3 month intervals by estimating C-reactive protein (CRP) levels and assessing visual analogue scale (VAS) scores. At 3 months, soft tissue outcomes were noted in terms of plaque index, gingival index, and pocket depth, while crestal bone loss was noted via a radiograph.
RESULTS
Mean CRP levels were significantly higher in the control group as compared to that in the case group on day 1 and day 7 follow-ups (P < 0.05). Mean VAS scores for pain were also lower in the case group as compared to the control group at all follow-ups, but the difference was significant statistically only at day 1 (P = 0.061). The plaque index was significantly lower in the case group as compared to the control group (P = 0.011) at final follow-up. No significant difference between two groups was observed for crestal bone loss.
CONCLUSIONS
Ozone therapy during implant placement was effective in reduction of pain, systemic inflammation, and plaque deposition in dental implant patients.
Topics: Humans; Ozone; Gels; Male; Female; Adult; Middle Aged; C-Reactive Protein; Saline Solution; Dental Implants; Dental Plaque Index; Alveolar Bone Loss; Periodontal Index; Pain Measurement; Dental Implantation; Inflammation
PubMed: 38934740
DOI: 10.4103/ijdr.ijdr_591_23