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Heliyon May 2024To reveal the role of gut microbiota (GM) in the occurrence and development of idiopathic central precocious puberty (ICPP) using 16S rDNA sequencing and bioinformatics...
To reveal the role of gut microbiota (GM) in the occurrence and development of idiopathic central precocious puberty (ICPP) using 16S rDNA sequencing and bioinformatics analysis. The Danazol-induced ICPP model was successfully constructed in this study. ZBDH and GnRHa treatments could effectively inhibit ICPP in rats, as manifested by the delayed vaginal opening time, reduced weight, decreased uterine organ coefficient, and decreased uterine wall thickness and corpus luteum number, as well as remarkably reduced serum hormone (LH, FSH, and E2) levels. According to 16S rDNA sequencing analysis results, there was no significant difference in the GM community diversity across different groups; however, the composition of the microbial community and the abundance of the dominant microbial community were dramatically different among groups. ZBDH and GnRHa treatments could effectively reduce the abundance of and and promote abundance. ZBDH and GnRHa were effective in treating Danazol-induced ICPP model rats. The therapeutic effects of ZBDH and GnRHa could be related to the changes in GM in rats.
PubMed: 38707434
DOI: 10.1016/j.heliyon.2024.e29723 -
Frontiers in Pharmacology 2024Hypertension, a significant risk factor for cardiovascular diseases, demands proactive management as cardiovascular diseases remain the leading cause of death worldwide....
BACKGROUND
Hypertension, a significant risk factor for cardiovascular diseases, demands proactive management as cardiovascular diseases remain the leading cause of death worldwide. Reducing systolic and diastolic blood pressure levels below recommended reference values of <140/90 mmHg can lead to a significant reduction of the risk of CVD and all-cause mortality. However, treatment of hypertension can be difficult and the presence of comorbidities could further complicate this treatment. Drugs used to manage these comorbidities may inadvertently have an impact on blood pressure, resulting in a phenomenon known as drug-disease interaction. This study aims to assess the safety of medication that can affect blood pressure in patients with hypertension and provide practical recommendations for healthcare professionals.
METHODS
For the development of recommendations for the drug-disease interaction (DDSI) hypertension, a six-step plan that combined literature selection and multidisciplinary expert opinion was used. The process involved (1) defining the scope of the DDSI and selecting relevant drugs, (2) collecting evidence, (3) data-extraction, (4) reaching of expert consensus, (5) publication and implementation of the recommendations in healthcare systems and (6) updating the information.
RESULTS
An increase of 10 mmHg in systolic blood pressure and 5 mmHg in diastolic blood pressure was defined as clinically relevant. Corticosteroids, danazol, and yohimbine caused a clinically relevant DDSI with hypertension. Several other drugs with warnings for hypertension in the official product information were assessed to have no clinically relevant DDSI due to minor influence or lack of data on blood pressure. Drugs with evidence for a relevant change in blood pressure which are prescribed under close monitoring of blood pressure according to clinical guidelines, were deemed to be not clinically relevant for signalling.
CONCLUSION
This study provides specific recommendations that can be implemented directly in clinical practice, for example, in clinical decision support systems, potentially resulting in safer drug use in patients with hypertension and better healthcare by reducing alert fatigue. Future research should focus on evaluating the effectiveness of implementation strategies and their impact on reducing unsafe use of medication in patients with hypertension.
PubMed: 38694908
DOI: 10.3389/fphar.2024.1360146 -
International Journal of Reproductive... Jan 2024Precocious puberty (PP) involves early activation of the hypothalamic gonadotropin-releasing hormone (GnRH) generator. The RFamide-related peptide/G protein-coupled...
Modulating the RFamide-related peptide-3/G protein-coupled receptor 147 signaling pathway with nourishing Yin-removing fire herbal mixture to alleviate precocious puberty in female rats: An experimental study.
BACKGROUND
Precocious puberty (PP) involves early activation of the hypothalamic gonadotropin-releasing hormone (GnRH) generator. The RFamide-related peptide/G protein-coupled receptor 147 () signaling pathway is vital in inhibiting GnRH and delaying puberty onset. The nourishing Yin-removing fire (NYRF) herbal mixture has shown promising results in treating PP.
OBJECTIVE
This study aimed to assess the impact of the NYRF herbal mixture on the signaling pathway in the hypothalamus and its potential in alleviating PP in female rats.
MATERIALS AND METHODS
In a controlled experiment, 24 female Sprague-Dawley rats (11.20 0.69 gr, postnatal day [PD5]) were divided into normal, model, normal saline, and NYRF groups (n = 6/each). PP was induced in the model, normal saline, and NYRF groups by subcutaneous injection of danazol at PD5. The NYRF herbal mixture or normal saline was administered from PD15. Serum sex hormone levels and hypothalamic samples were collected for mRNA and protein expression at PD30.
RESULTS
In the model group, hypothalamic GnRH and kisspeptin levels increased, while RFRP3 and GPR147 levels decreased, luteinizing hormone levels elevated, reproductive organ coefficients increased, and the vagina opened earlier compared to the normal group. Conversely, the NYRF group exhibited lower GnRH and kisspeptin levels but higher RFRP3 levels in the hypothalamus. Serum luteinizing hormone levels were reduced, reproductive organ coefficients were reduced, and the vaginal opening was delayed compared to the model and normal saline groups.
CONCLUSION
The NYRF herbal mixture delayed sexual development in rats with PP by hypothalamic upregulating RFRP3 and downregulating GnRH and kisspeptin.
PubMed: 38544669
DOI: 10.18502/ijrm.v22i1.15240 -
Frontiers in Endocrinology 2024Precocious puberty (PP) is a prevalent endocrine disorder affecting the physical and mental wellbeing of children. Identifying the triggering factors of PP has become a...
OBJECTIVE
Precocious puberty (PP) is a prevalent endocrine disorder affecting the physical and mental wellbeing of children. Identifying the triggering factors of PP has become a central issue. This study seeks to investigate the metabolomic and transcriptomic alterations in PP.
MATERIAL AND METHODS
First, 37 school-aged girls diagnosed with PP and 25 age-matched prepubertal control girls were recruited, and the fecal samples were collected for non-targeted metabolomic analysis to screen for differentially expressed metabolites (DEMs). Subsequently, an animal model of PP was constructed by danazol administration to neonatal female rats, and both fecal non-targeted metabolomics and serum next-generation transcriptomic sequencing were performed to screen DEMs and differentially expressed genes (DEGs) in PP. Moreover, the DEM co-existing in clinical and animal models was administrated to PP rats to explore the role of the target metabolite in PP.
RESULTS
A total of 24 DEMs in PP clinical samples and 180 DEMs and 425 DEGs in PP animal samples were identified. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that these DEMs and DEGs were enriched in disease-associated pathways, including fatty acid synthesis, glycerolipid metabolism, pyrimidine metabolism, steroid hormone biosynthesis, progesterone-mediated oocyte maturation, and gonadotropin-releasing hormone (GnRH) signaling pathway, forming a tight DEM-DEG pathway regulatory network. Further DEM validation demonstrated that thymine supplementation delayed the opening of the vagina and development of PP in model rats.
CONCLUSION
This study reveals that the metabolomic and transcriptomic changes, along with enriched pathways, are implicated in PP based on clinical and animal analyses. The findings may provide new strategies and research avenues for PP treatment.
Topics: Humans; Child; Female; Rats; Animals; Puberty, Precocious; Gonadotropin-Releasing Hormone; Multiomics
PubMed: 38487340
DOI: 10.3389/fendo.2024.1285666 -
Molecular Metabolism Jan 2024Non-alcoholic fatty liver disease (NAFLD) involves hepatic accumulation of intracellular lipid droplets via incompletely understood processes. Here, we report distinct...
OBJECTIVE
Non-alcoholic fatty liver disease (NAFLD) involves hepatic accumulation of intracellular lipid droplets via incompletely understood processes. Here, we report distinct and cooperative NAFLD roles of LysTTT-5'tRF transfer RNA fragments and microRNA miR-194-5p.
METHODS
Combined use of diet induced obese mice with human-derived oleic acid-exposed Hep G2 cells revealed new NAFLD roles of LysTTT-5'tRF and miR-194-5p.
RESULTS
Unlike lean animals, dietary-induced NAFLD mice showed concurrent hepatic decrease of both LysTTT-5'tRF and miR-194-5p levels, which were restored following miR-132 antisense oligonucleotide treatment which suppresses hepatic steatosis. Moreover, exposing human-derived Hep G2 cells to oleic acid for 7 days co-suppressed miR-194-5p and LysTTT-5'tRF levels while increasing lipid accumulation. Inversely, transfecting fattened cells with a synthetic LysTTT-5'tRF mimic elevated mRNA levels of the metabolic regulator β-Klotho while decreasing triglyceride amounts by 30% within 24 h. In contradistinction, antisense suppression of miR-194-5p induced accumulation of its novel target, the NAFLD-implicated lipid droplet-coating PLIN2 protein. Further, two out of 15 steatosis-alleviating screened drug-repurposing compounds, Danazol and Latanoprost, elevated miR-194-5p or LysTTT-5'tRF levels.
CONCLUSION
Our findings highlight the different yet complementary roles of miR-194-5p and LysTTT-5'tRF and offer new insights into the complex roles of small non-coding RNAs and the multiple pathways involved in NAFLD pathogenesis.
Topics: Animals; Humans; Mice; Lysine; MicroRNAs; Non-alcoholic Fatty Liver Disease; Oleic Acid; Perilipin-2
PubMed: 38141848
DOI: 10.1016/j.molmet.2023.101856 -
Oncology (Williston Park, N.Y.) Dec 2023Purpose To study the potential utility of danazol for treating patients with myelodysplastic syndromes, with a focus on efficacy and adverse effects (AEs). Methods... (Review)
Review
Purpose To study the potential utility of danazol for treating patients with myelodysplastic syndromes, with a focus on efficacy and adverse effects (AEs). Methods MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus were searched for relevant publications from inception June 1, 1950, until June 28, 2022. The studies were screened by title and abstract, followed by full-text screening. The quality of the included studies was assessed via a prespecified set of questionnaires. Data on the efficacy measures and adverse outcomes were extracted and included in a descriptive summary. Results Nine studies consisting of 246 participants were included in our review. The overall quality of the included studies was fair. The age of the participants ranged from 61 to 78 years. In all 9 studies, more male patients had been enrolled than female patients. Overall, a proportion of patients in all the studies reported a desired major response to a danazol dose of 400 to 800 mg/day. Few studies did not observe any improvement in the platelet count. Elevated liver enzyme levels, weight gain, headache, dermatitis, and weakness were the most common AEs observed. One study reported a fatal intracerebral hemorrhage in 1 participant. Conclusions Danazol has been effective in increasing platelet count and hemoglobin level. Despite a few AEs, danazol is a safe drug for the treatment of patients with myelodysplastic syndromes.
Topics: Aged; Female; Humans; Male; Middle Aged; Danazol; Myelodysplastic Syndromes
PubMed: 38133562
DOI: 10.46883/2023.25921009 -
Journal of Computer-aided Molecular... Dec 2023Theoretical predictions of the solubilizing capacity of micelles and vesicles present in intestinal fluid are important for the development of new delivery techniques...
Theoretical predictions of the solubilizing capacity of micelles and vesicles present in intestinal fluid are important for the development of new delivery techniques and bioavailability improvement. A balance between accuracy and computational cost is a key factor for an extensive study of numerous compounds in diverse environments. In this study, we aimed to determine an optimal molecular dynamics (MD) protocol to evaluate small-molecule interactions with micelles composed of bile salts and phospholipids. MD simulations were used to produce free energy profiles for three drug molecules (danazol, probucol, and prednisolone) and one surfactant molecule (sodium caprate) as a function of the distance from the colloid center of mass. To address the challenges associated with such tasks, we compared different simulation setups, including freely assembled colloids versus pre-organized spherical micelles, full free energy profiles versus only a few points of interest, and a coarse-grained model versus an all-atom model. Our findings demonstrate that combining these techniques is advantageous for achieving optimal performance and accuracy when evaluating the solubilization capacity of micelles. All-atom (AA) and coarse-grained (CG) umbrella sampling (US) simulations and point-wise free energy (FE) calculations were compared to their efficiency to computationally analyze the solubilization of active pharmaceutical ingredients in intestinal fluid colloids.
Topics: Micelles; Molecular Dynamics Simulation; Colloids; Surface-Active Agents
PubMed: 38103089
DOI: 10.1007/s10822-023-00541-1 -
Psychological Assessment and Treatment Effectiveness in Mastalgia: Developing a Treatment Algorithm.Cureus Oct 2023Background Mastalgia often impairs the physical, social, and sexual lives of women. It may manifest in both cyclical or acyclical patterns. The psychoneurotic...
Background Mastalgia often impairs the physical, social, and sexual lives of women. It may manifest in both cyclical or acyclical patterns. The psychoneurotic association of mastalgia has been claimed for a long time in various available literature. Several treatment options have been used and are available in the market for mastalgia, but no specific guidelines are currently in place at the global or local levels. This study aims to evaluate the psychological status and effectiveness of various treatment options in women presenting with mastalgia. Methods This study was conducted in the General Surgery outpatient department from February 1 to November 30, 2021, at King George's Medical University, Lucknow, India. Females of all age groups presenting to the General Surgery outpatient department with unilateral/bilateral breast pain and/or chest wall pain were considered for this study. Pregnant patients, those with a history of allergy to drugs, or those who were lost to follow-up were excluded from the study. The psychological status of patients was assessed using the Depression Anxiety and Stress Scale (DASS-42) scale. Pain assessment was performed using a visual analog scale (VAS). Patients were divided into five categories: (i) isolated chest wall pain, (ii) isolated breast pain, (iii) both chest wall and breast pain, (iv) pain with an associated lump(s), and (v) pain and tenderness isolated over the lump, and two groups: Group-A: VAS≤4, and Group-B: VAS>4. Group B patients in Category iv were randomized into two groups: topical non-steroidal anti-inflammatory drugs (NSAIDs) or evening primrose oil+vitamin E. The next line of treatment was tamoxifen 10mg followed by danazol 100mg followed by ormeloxifene 30mg. Results The mean age of 106 participants enrolled was 31.59±10.52 years. The mean scores, using the DASS-42 scale, for depression, anxiety, and stress were 7.31±8.53, 7.08±6.57, and 11.15±8.07, respectively. The depression, anxiety, and stress scores had no significant correlation with pain scores (p =0.84, 0.99, and 0.97 for depression, anxiety, and stress, respectively), or duration (p=0.69, 0.66, and 0.85 for depression, anxiety, and stress, respectively). Twenty-nine of 43 patients (67.44%) responded to topical NSAIDs as first-line treatment, and out of the remaining, 6.98% responded to evening primrose oil + vitamin E, 18.60% to tamoxifen, and 4.65% to danazol. Twenty-nine of 32 patients (90.63%) responded to evening primrose oil+vitamin E as first-line treatment, while 6.25% and 3.12% responded to tamoxifen and danazol, respectively. Conclusions Both topical NSAIDs and evening primrose oil + vitamin E were found effective first-line treatment options in the majority of patients. Hence, it is always advisable to start such patients on topical NSAIDs, or evening primrose oil + vitamin E, before switching over (if no resolution of pain is reported with these drugs) to higher and more severe treatment options. The duration or severity of pain did not correlate with the psychological condition of the patient.
PubMed: 38021953
DOI: 10.7759/cureus.46838