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Acta Medica Philippina 2024Current medical management of endometriosis leads to suppression of ovulation and will not be helpful for women with endometriosis who are desirous of pregnancy. Thus,...
BACKGROUND
Current medical management of endometriosis leads to suppression of ovulation and will not be helpful for women with endometriosis who are desirous of pregnancy. Thus, drugs that can both treat endometriosis and its associated infertility are highly warranted.
OBJECTIVE
Anti-angiogenic agents are potential drugs for patients with endometriosis and infertility. Among these drugs, dopamine agonist (DA) is promising since it does not interfere with ovulation, is safe, and not teratogenic. The aim of the study is to determine the efficacy and safety of DA for improving reproductive outcomes in women with endometriosis and infertility.
METHODS
A qualitative narrative review was done from inception to July 31, 2022 using the appropriate MeSH terms in PubMed, Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, ClinicalTrial.gov, and World Health Organization International Clinical Trials Registry Platform. Date analysis was through qualitative analysis and synthesis of researches and their outcome measures.
RESULTS
No studies used the core outcomes for trials evaluating treatments for infertility associated with endometriosis. All the included articles in the review supported the possible anti-angiogenic effects of DA on the vascular endothelial growth factor [VEGF] /VEGF receptor system. The use of DA does not have an effect on ovulation and menstrual cyclicity. Studies on safety profile of DA were consistent with existing data.
CONCLUSION
Most of studies reviewed demonstrated that DA were effective in reducing endometriotic lesions. However, further research is required to establish whether this anti-angiogenic effect can improve reproductive outcomes in women with endometriosis-associated infertility.
PubMed: 38939420
DOI: 10.47895/amp.vi0.6994 -
JACC. Advances Feb 2024
PubMed: 38939407
DOI: 10.1016/j.jacadv.2023.100812 -
Frontiers in Cellular and Infection... 2024Hand, foot, and mouth disease (HFMD) is a common infectious disease caused by enterovirus 71 (EV71) that frequently affects children, leading to severe infections in...
Hand, foot, and mouth disease (HFMD) is a common infectious disease caused by enterovirus 71 (EV71) that frequently affects children, leading to severe infections in some cases. In general, when infection occurs, the body upregulates inflammatory responses to eliminate pathogenic microorganisms to protect the host from infection. However, EV71 may inhibit host's innate immunity to promote virus infection. At present, it is not fully understood how EV71 hijack the host cells for its own replication. Toll-like receptor 4 (TLR4), a natural immune receptor, historically associated with bacterial endotoxin-induced inflammatory responses. However, it is still unclear whether and how TLR4 is altered during EV71 infection. In this study, we observed a reduction in both TLR4 protein and gene transcript levels in RD, GES-1, and Vero cells following EV71 infection, as detected by RT-qPCR, immunofluorescence staining and western blot. Furthermore, we observed that the TLR4 downstream molecules of MYD88, p-NF-κB p65, p-TBK1 and related inflammatory cytokines were also reduced, suggesting that antiviral innate immune and inflammatory response were suppressed. To determine the impact of TLR4 changes on EV71 infection, we interfered EV71-infected RD cells with TLR4 agonist or inhibitor and the results showed that activation of TLR4 inhibited EV71 replication, while inhibition of TLR4 promote EV71 replication. Besides, EV71 replication was also promoted in TLR4 siRNA-transfected and EV71-infected RD cells. This suggests that down-regulation the expression of TLR4 by EV71 can inhibit host immune defense to promote EV71 self-replication. This novel mechanism may be a strategy for EV71 to evade host immunity.
Topics: Toll-Like Receptor 4; Enterovirus A, Human; Humans; Virus Replication; Signal Transduction; Animals; Vero Cells; Chlorocebus aethiops; Immunity, Innate; Host-Pathogen Interactions; Inflammation; Myeloid Differentiation Factor 88; Cell Line; Protein Serine-Threonine Kinases; Cytokines; NF-kappa B; Hand, Foot and Mouth Disease
PubMed: 38938877
DOI: 10.3389/fcimb.2024.1393680 -
Innovations in Clinical Neuroscience 2024Glucagon-like peptide-1 (GLP-1) receptor agonists have garnered significant attention in diabetes management, and they act by mimicking the effects of GLP-1, a hormone...
Glucagon-like peptide-1 (GLP-1) receptor agonists have garnered significant attention in diabetes management, and they act by mimicking the effects of GLP-1, a hormone that regulates insulin secretion and appetite. While these medications have become increasingly popular, their impact on mood and other psychiatric manifestations remains uncertain because of inconsistent data. It has been shown to affect brain regions involved in emotional regulation. This case report underscores the adverse mood changes possibly linked to semaglutide and the need for further study in this area.
PubMed: 38938530
DOI: No ID Found -
Alimentary Pharmacology & Therapeutics Jun 2024Glucagon-like peptide-1 receptor agonists (GLP-1RA) show anti-inflammatory properties.
BACKGROUND
Glucagon-like peptide-1 receptor agonists (GLP-1RA) show anti-inflammatory properties.
AIM
To evaluate their clinical impact on inflammatory bowel disease (IBD) outcomes.
METHODS
Retrospective cohort study utilising the TriNetX database comparing IBD-specific outcomes in patients with ulcerative colitis (UC) or Crohn's disease (CD) and type 2 diabetes mellitus (T2DM) on GLP-1RA compared to oral hypoglycaemic agents. The primary outcome was hospitalisation requiring intravenous steroids and IBD-related surgery within 3 years. We performed 1:1 propensity score matching (PSM) for demographics, co-morbid conditions, BMI, laboratory values, HbA1c, and IBD medications including steroids.
RESULTS
We identified 1130 patients in the UC GLP-1RA cohort (mean age: 58.9 ± 11.6 years, 56.3% female, 70.2% White, 57.2% with obesity) and 1140 patients in the CD GLP-1RA cohort (mean age: 56.7 ± 11.5, 61.9% female, 73.6% White, 56.2% with obesity). After PSM, there was no difference in the risk of intravenous steroid use (aHR: 1.21, 95% CI: 0.92-1.59) but a lower risk of colectomy (aHR: 0.37, 95% CI: 0.14-0.97) between the UC GLP-1RA and control cohort. There was no difference in the risk of intravenous steroid use (aHR: 1.04, 95% CI: 0.80-1.34) but a lower risk of surgery (aHR: 0.55, 95% CI: 0.36-0.84) between the CD GLP-1RA and CD control cohort. There was no difference in the risk of oral steroid use or advanced therapy initiation in the UC and CD GLP-1RA than control cohorts.
CONCLUSIONS
We found an association between lower risk of IBD-related surgery and GLP-1RA use for T2DM in patients with UC or CD.
PubMed: 38938071
DOI: 10.1111/apt.18138 -
European Journal of Endocrinology Jun 2024Osteoanabolic agents are used as a first line treatment in patients at high fracture risk. The PTH receptor 1 (PTH1R) agonists teriparatide (TPTD) and abaloparatide...
Osteoanabolic agents are used as a first line treatment in patients at high fracture risk. The PTH receptor 1 (PTH1R) agonists teriparatide (TPTD) and abaloparatide (ABL) increase bone formation, bone mineral density (BMD), and bone strength by activating PTH receptors on osteoblasts. Romosozumab (ROMO), a humanized monoclonal antibody against sclerostin, dramatically but transiently stimulates bone formation and persistently reduces bone resorption. Osteoanabolic agents increase BMD and bone strength while being more effective than antiresorptives in reducing fracture risk in postmenopausal women. However, direct comparisons of the antifracture benefits of osteoanabolic therapies are limited. In a direct comparison of TPTD and ABL, the latter resulted in greater BMD increases at the hip. While no differences in vertebral or non-vertebral fracture risk were observed between the two drugs, ABL led to a greater reduction of major osteoporotic fractures. Adverse event profiles were similar between the two agents except for hypercalcemia, which occurred more often with TPTD. No direct comparisons of fracture risk reduction between ROMO and the PTH1R agonists exist. Individual studies have shown greater increases in BMD and bone strength with ROMO compared to TPTD in treatment-naïve women and in women previously treated with bisphosphonates. Some safety aspects, such as a history of tumor precluding the use of PTH1R agonists, and a history of major cardiovascular events precluding the use of ROMO, should also be considered when choosing between these agents. Lastly, convenience of administration, reimbursement by national health systems and length of clinical experience may influence patient choice.
PubMed: 38938063
DOI: 10.1093/ejendo/lvae076 -
Parasites & Vectors Jun 2024Female Aedes aegypti mosquitoes can spread disease-causing pathogens when they bite humans to obtain blood nutrients required for egg production. Following a complete...
BACKGROUND
Female Aedes aegypti mosquitoes can spread disease-causing pathogens when they bite humans to obtain blood nutrients required for egg production. Following a complete blood meal, host-seeking is suppressed until eggs are laid. Neuropeptide Y-like receptor 7 (NPYLR7) plays a role in endogenous host-seeking suppression and previous work identified small-molecule NPYLR7 agonists that inhibit host-seeking and blood-feeding when fed to mosquitoes at high micromolar doses.
METHODS
Using structure-activity relationship analysis and structure-guided design we synthesized 128 compounds with similarity to known NPYLR7 agonists.
RESULTS
Although in vitro potency (EC) was not strictly predictive of in vivo effect, we identified three compounds that reduced blood-feeding from a live host when fed to mosquitoes at a dose of 1 μM-a 100-fold improvement over the original reference compound.
CONCLUSIONS
Exogenous activation of NPYLR7 represents an innovative vector control strategy to block mosquito biting behavior and prevent mosquito-human host interactions that lead to pathogen transmission.
Topics: Animals; Aedes; Female; Feeding Behavior; Receptors, Neuropeptide Y; Mosquito Vectors; Structure-Activity Relationship; Humans
PubMed: 38937807
DOI: 10.1186/s13071-024-06347-w -
Diabetes, Obesity & Metabolism Jun 2024Weight loss induced by glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucagon-like peptide-1 receptor (GLP-1R)/glucose-dependent insulinotropic...
Weight loss induced by glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucagon-like peptide-1 receptor (GLP-1R)/glucose-dependent insulinotropic polypeptide receptor agonists is coming closer to the magnitudes achieved with surgery. However, with greater weight loss there is concern about potential side effects on muscle quantity (mass), health and function. There is heterogeneity in the reported effects of GLP-1-based therapies on lean mass changes in clinical trials: in some studies, reductions in lean mass range between 40% and 60% as a proportion of total weight lost, while other studies show lean mass reductions of approximately 15% or less of total weight lost. There are several potential reasons underlying this heterogeneity, including population, drug-specific/molecular, and comorbidity effects. Furthermore, changes in lean mass may not always reflect changes in muscle mass as the former measure includes not only muscle but also organs, bone, fluids, and water in fat tissue. Based on contemporary evidence with the addition of magnetic resonance imaging-based studies, skeletal muscle changes with GLP-1RA treatments appear to be adaptive: reductions in muscle volume seem to be commensurate with what is expected given ageing, disease status, and weight loss achieved, and the improvement in insulin sensitivity and muscle fat infiltration likely contributes to an adaptive process with improved muscle quality, lowering the probability for loss in strength and function. Nevertheless, factors such as older age and severity of disease may influence the selection of appropriate candidates for these therapies due to risk of sarcopenia. To further improve muscle health during weight loss, several pharmacological treatments to maintain or improve muscle mass designed in combination with GLP-1-based therapies are under development. Future research on GLP-1-based and other therapies designed for weight loss should focus on more accurate and meaningful assessments of muscle mass, composition, as well as function, mobility or strength, to better define their impact on muscle health for the substantial number of patients who will likely be taking these medications well into the future.
PubMed: 38937282
DOI: 10.1111/dom.15728 -
Seminars in Oncology May 2024We examined data from US Veterans with prostate cancer (PC) to assess disease response to immune checkpoint inhibitors (ICI) as monotherapy or combined with abiraterone...
We examined data from US Veterans with prostate cancer (PC) to assess disease response to immune checkpoint inhibitors (ICI) as monotherapy or combined with abiraterone or enzalutamide to assess ICI efficacy in the real-world. We queried the VA corporate data warehouse (CDW) to identify Veterans with a diagnosis of PC who received ICI for any malignancy and had ≥1 PSA measurement while receiving ICI. To evaluate ICI monotherapy, we restricted analysis to Veterans who had not received LHRH agonists/antagonists, PC-directed medical therapy, or radiation/extirpative surgery of the bladder/prostate within and preceding the duration of ICI administration. For ICI combination analysis, we identified Veterans who received abiraterone or enzalutamide for PC while on ICI. We calculated rates of tumor (PSA) growth (g-rates), comparing them to a 1:2 matched reference cohort. We identified 787 Veterans with PC and ≥1 PSA measurement while receiving an ICI. Median duration of ICI therapy was 155 days. 223 Veterans received ICI monotherapy, with only 17(8%) having a reduction in PSA (median decline = 43%). 12 (5%) had PSA declines >30% (PSA30) which included 6 (3%) who had PSA reductions greater than 50% (PSA50). Median g-rates for ICI plus abiraterone (n = 20) or enzalutamide (n = 31) were 0.000689/d and 0.002819/d, respectively, and were statistically insignificant compared to g-rates of matched cohorts receiving abiraterone (g = 0.000925/d, P = 0.73) or enzalutamide (g = 0.001929/d, P = 0.58) alone. Our data align with clinical trial data in PC, demonstrating limited benefit from ICI monotherapy and predicting no survival benefit from simultaneous abiraterone or enzalutamide with an ICI using g-rate.
PubMed: 38937152
DOI: 10.1053/j.seminoncol.2024.04.002 -
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