-
Clinical and Translational Science Oct 2023Green tea is a popular beverage worldwide. The abundant green tea catechin (-)-epigallocatechin gallate (EGCG) is a potent in vitro inhibitor of intestinal...
Green tea is a popular beverage worldwide. The abundant green tea catechin (-)-epigallocatechin gallate (EGCG) is a potent in vitro inhibitor of intestinal UDP-glucuronosyltransferase (UGT) activity (K ~2 μM). Co-consuming green tea with intestinal UGT drug substrates, including raloxifene, could increase systemic drug exposure. The effects of a well-characterized green tea on the pharmacokinetics of raloxifene, raloxifene 4'-glucuronide, and raloxifene 6-glucuronide were evaluated in 16 healthy adults via a three-arm crossover, fixed-sequence study. Raloxifene (60 mg) was administered orally with water (baseline), with green tea for 1 day (acute), and on the fifth day after daily green tea administration for 4 days (chronic). Unexpectedly, green tea decreased the geometric mean green tea/baseline raloxifene AUC ratio to ~0.60 after both acute and chronic administration, which is below the predefined no-effect range (0.75-1.33). Lack of change in terminal half-life and glucuronide-to-raloxifene ratios indicated the predominant mechanism was not inhibition of intestinal UGT. One potential mechanism includes inhibition of intestinal transport. Using established transfected cell systems, a green tea extract normalized to EGCG inhibited 10 of 16 transporters tested (IC , 0.37-12 μM). Another potential mechanism, interruption by green tea of gut microbe-mediated raloxifene reabsorption, prompted a follow-up exploratory clinical study to evaluate the potential for a green tea-gut microbiota-drug interaction. No clear mechanisms were identified. Overall, results highlight that improvements in current models and methods used to predict UGT-mediated drug interactions are needed. Informing patients about the risk of co-consuming green tea with raloxifene may be considered.
Topics: Adult; Humans; Catechin; Drug Interactions; Glucuronides; Raloxifene Hydrochloride; Tea; Cross-Over Studies
PubMed: 37639334
DOI: 10.1111/cts.13578 -
Pharmacological Research Jun 2024Neuropsychiatric disorders shorten human life spans through multiple ways and become major threats to human health. Exercise can regulate the estrogen signaling, which... (Review)
Review
Neuropsychiatric disorders shorten human life spans through multiple ways and become major threats to human health. Exercise can regulate the estrogen signaling, which may be involved in depression, Alzheimer's disease (AD) and Parkinson's disease (PD), and other neuropsychiatric disorders as well in their sex differences. In nervous system, estrogen is an important regulator of cell development, synaptic development, and brain connectivity. Therefore, this review aimed to investigate the potential of estrogen system in the exercise intervention of neuropsychiatric disorders to better understand the exercise in neuropsychiatric disorders and its sex specific. Exercise can exert a protective effect in neuropsychiatric disorders through regulating the expression of estrogen and estrogen receptors, which are involved in neuroprotection, neurodevelopment, and neuronal glucose homeostasis. These processes are mediated by the downstream factors of estrogen signaling, including N-myc downstream regulatory gene 2 (Ndrg2), serotonin (5-HT), delta like canonical Notch ligand 1 (DLL1), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), etc. In addition, exercise can act on the estrogen response element (ERE) fragment in the genes of estrogenic downstream factors like β-amyloid precursor protein cleavase 1 (BACE1). However, there are few studies on the relationship between exercise, the estrogen signaling pathway, and neuropsychiatric disorders. Hence, we review how the estrogen signaling mediates the mechanism of exercise intervention in neuropsychiatric disorders. We aim to provide a theoretical perspective for neuropsychiatric disorders affecting female health and provide theoretical support for the design of exercise prescriptions.
Topics: Humans; Estrogens; Animals; Mental Disorders; Exercise; Exercise Therapy; Signal Transduction; Receptors, Estrogen
PubMed: 38704108
DOI: 10.1016/j.phrs.2024.107201 -
Journal of Endocrinological... Mar 2024Selective androgen (ostarine, OST) and estrogen (raloxifene, RAL) receptor modulators with improved tissue selectivity have been developed as alternatives to hormone...
PURPOSE
Selective androgen (ostarine, OST) and estrogen (raloxifene, RAL) receptor modulators with improved tissue selectivity have been developed as alternatives to hormone replacement therapy. We investigated the combined effects of OST and RAL on muscle tissue in an estrogen-deficient rat model of postmenopausal conditions.
METHODS
Three-month-old Sprague Dawley rats were divided into groups: (1) untreated non-ovariectomized rats (Non-OVX), (2) untreated ovariectomized rats (OVX), (3) OVX rats treated with OST, (4) OVX rats treated with RAL, (5) OVX rats treated with OST and RAL. Both compounds were administered in the diet. The average dose received was 0.6 ± 0.1 mg for OST and 11.1 ± 1.2 mg for RAL per kg body weight/day. After thirteen weeks, rat activity, muscle weight, structure, gene expression, and serum markers were analyzed.
RESULTS
OST increased muscle weight, capillary ratio, insulin-like growth factor 1 (Igf-1) expression, serum phosphorus, uterine weight. RAL decreased muscle weight, capillary ratio, food intake, serum calcium and increased Igf-1 and Myostatin expression, serum follicle stimulating hormone (FSH). OST + RAL increased muscle nucleus ratio, uterine weight, serum phosphorus, FSH and luteinizing hormone and decreased body and muscle weight, serum calcium. Neither treatment changed muscle fiber size. OVX increased body and muscle weight, decreased uterine weight, serum calcium and magnesium.
CONCLUSION
OST had beneficial effects on muscle in OVX rats. Side effects of OST on the uterus and serum electrolytes should be considered before using it for therapeutic purposes. RAL and RAL + OST had less effect on muscle and showed endocrinological side effects on pituitary-gonadal axis.
Topics: Female; Rats; Animals; Raloxifene Hydrochloride; Insulin-Like Growth Factor I; Calcium; Rats, Sprague-Dawley; Estrogens; Muscle Fibers, Skeletal; Follicle Stimulating Hormone; Phosphorus; Anilides
PubMed: 37672168
DOI: 10.1007/s40618-023-02188-z -
Revista Brasileira de Ortopedia Apr 2024To evaluate the effects of estrogen, raloxifene and genistein on the expression of (kisspeptin), (kisspeptin receptor), (androgen receptor) and (insulin...
To evaluate the effects of estrogen, raloxifene and genistein on the expression of (kisspeptin), (kisspeptin receptor), (androgen receptor) and (insulin receptor) in the bones of ovariectomized rats. Forty-eight adult rats were randomly divided into 6 groups, containing 8 animals each: G1-nonovariectomized control; G2-ovariectomized and treated with conjugated equine estrogens (50 µg/Kg/day); G3-ovariectomized and treated with raloxifene (0.75 mg/kg/day); G4-ovariectomized animal that received soy extract with genistein (300 mg/kg/day); G5-ovariectomized animal that received estrogen and genistein; and G6-ovariectomized animal that received estrogen and raloxifene. Three months after surgery, the castrated animals received the drugs orally daily for 120 days. All animals were sacrificed after this period, by deepening the anesthesia. The left tibia was removed for total RNA extraction and analysis of gene expression of , , and , by quantitative real-time polymerase chain reaction (qRT-PCR). was not detected in any of the treated groups. , and showed higher expression in the G3 group ( < 0.001), while lower levels of transcripts for these genes were observed in G4 and G5. G2 animals showed hypoexpression of the evaluated genes. The results indicate that raloxifene, alone or combined with estrogen, was able to induce the expression of genes associated with the recovery of bone tissue homeostasis in ovariectomized rats.
PubMed: 38606141
DOI: 10.1055/s-0044-1779319 -
Schizophrenia Research May 2024Maternal immune activation (MIA) during pregnancy is known to increase the risk of development of schizophrenia in the offspring. Sex steroid hormone analogues have been...
Maternal immune activation (MIA) during pregnancy is known to increase the risk of development of schizophrenia in the offspring. Sex steroid hormone analogues have been proposed as potential antipsychotic treatments but the mechanisms of action involved remain unclear. Estrogen has been shown to alter N-methyl-d-aspartate (NMDA) receptor binding in the brain. We therefore studied the effect of chronic treatment with 17β-estradiol, its isomer, 17α-estradiol, and the selective estrogen receptor modulator, raloxifene, on MIA-induced psychosis-like behaviour and the effect of the NMDA receptor antagonist, MK-801. Pregnant rats were treated with saline or the viral mimetic, poly(I:C), on gestational day 15. Adult female offspring were tested for changes in baseline prepulse inhibition (PPI) and the effects of acute treatment with MK-801 on PPI and locomotor activity. Poly(I:C) offspring had significantly lower baseline PPI compared to control offspring, and this effect was prevented by 17β-estradiol and raloxifene, but not 17α-estradiol. MK-801 reduced PPI in control offspring but had no effect in poly(I:C) offspring treated with vehicle. Chronic treatment with 17β-estradiol and raloxifene restored the effect of MK-801 on PPI. There were no effects of MIA or estrogenic treatment on MK-801 induced locomotor hyperactivity. These results show that MIA affects baseline PPI as well as NMDA receptor-mediated regulation of PPI in female rats, and strengthen the view that estrogenic treatment may have antipsychotic effects.
Topics: Animals; Female; Estradiol; Raloxifene Hydrochloride; Schizophrenia; Pregnancy; Prepulse Inhibition; Disease Models, Animal; Dizocilpine Maleate; Poly I-C; Receptors, N-Methyl-D-Aspartate; Prenatal Exposure Delayed Effects; Rats; Excitatory Amino Acid Antagonists; Male; Selective Estrogen Receptor Modulators; Estrogens; Motor Activity
PubMed: 38642484
DOI: 10.1016/j.schres.2024.04.008 -
Journal of Cellular and Molecular... Sep 2023PKN1 (protein kinase N1), a serine/threonine protein kinase family member, is associated with various cancers. However, the role of PKN1 in gliomas has rarely been...
PKN1 (protein kinase N1), a serine/threonine protein kinase family member, is associated with various cancers. However, the role of PKN1 in gliomas has rarely been studied. We suggest that PKN1 expression in glioma specimens is considerably upregulated and positively correlates with the histopathological grading of gliomas. Knocking down PKN1 expression in glioblastoma (GBM) cells inhibits GBM cell proliferation, invasion and migration and promotes apoptosis. In addition, yes-associated protein (YAP) expression, an essential effector of the Hippo pathway contributing to the oncogenic role of gliomagenesis, was also downregulated. In contrast, PKN1 upregulation enhances the malignant characteristics of GBM cells and simultaneously upregulates YAP expression. Therefore, PKN1 is a promising therapeutic target for gliomas. Raloxifene (Ralo), a commonly used selective oestrogen-receptor modulator to treat osteoporosis in postmenopausal women, was predicted to target PKN1 according to the bioinformatics team from the School of Mathematics, Tianjin Nankai University. We showed that Ralo effectively targets PKN1, inhibits GBM cells proliferation and migration and sensitizes GBM cells to the major chemotherapeutic drug, Temozolomide. Ralo also reverses the effect of PKN1 on YAP activation. Thus, we confirm that PKN1 contributes to the pathogenesis of gliomas and may be a potential target for Ralo adjuvant glioma therapy.
Topics: Female; Humans; Raloxifene Hydrochloride; Glioma; Glioblastoma; Apoptosis; Cell Proliferation
PubMed: 37480215
DOI: 10.1111/jcmm.17860 -
Journal of Dental Sciences Oct 2023
PubMed: 37799902
DOI: 10.1016/j.jds.2023.06.015 -
Yakugaku Zasshi : Journal of the... 2024Transdermal drug delivery is a formulation in which the drug is absorbed through the skin for systemic action. Its advantages include avoidance of first-pass effects,... (Review)
Review
Transdermal drug delivery is a formulation in which the drug is absorbed through the skin for systemic action. Its advantages include avoidance of first-pass effects, sustained drug supply, and ease of administration and discontinuation. Drugs administered transdermally transfer into the blood circulation through the stratum corneum, epidermis, and dermis. The stratum corneum on the skin surface plays a barrier function in skin absorption. Therefore, developing of transdermal drug delivery systems requires innovations that overcome the barrier function of the stratum corneum and improve skin permeation. This review examines the usefulness of transdermal formulations based on solid nanoparticles using raloxifene. Milled raloxifene was gelled with (mRal-NPs) or without menthol (Ral-NPs) using Carbopol. The drug release and transdermal penetration were measured using a Franz diffusion cell, and the therapeutic evaluation of osteoporosis was determined in an ovariectomized rat model. Although the raloxifene released from Ral-NPs remained in the nanoparticle state, the skin penetration of raloxifene nanoparticles was prevented by the stratum corneum in rat. The inclusion of menthol in the formulation attenuated the barrier function of the stratum corneum and permitted raloxifene nanoparticles to penetrate through the skin. Moreover, macropinocytosis relates to the formulation's skin penetration, including menthol (mRal-NPs). Applying mRal-NPs attenuated the decreases in calcium level and stiffness of bones of ovariectomized rats. This information can support future studies aimed at designing novel transdermal formulations.
Topics: Animals; Administration, Cutaneous; Skin Absorption; Raloxifene Hydrochloride; Menthol; Nanoparticles; Drug Delivery Systems; Rats; Humans; Skin; Nanotechnology; Drug Liberation; Osteoporosis; Female; Drug Development
PubMed: 38692925
DOI: 10.1248/yakushi.23-00178-1 -
Pharmaceutics Jan 2024The journal retracts the article "Lipidic Nano-Sized Emulsomes Potentiates the Cytotoxic and Apoptotic Effects of Raloxifene Hydrochloride in MCF-7 Human Breast Cancer...
RETRACTED: Aldawsari et al. Lipidic Nano-Sized Emulsomes Potentiates the Cytotoxic and Apoptotic Effects of Raloxifene Hydrochloride in MCF-7 Human Breast Cancer Cells: Factorial Analysis and In Vitro Anti-Tumor Activity Assessment. 2021, , 783.
The journal retracts the article "Lipidic Nano-Sized Emulsomes Potentiates the Cytotoxic and Apoptotic Effects of Raloxifene Hydrochloride in MCF-7 Human Breast Cancer Cells: Factorial Analysis and In Vitro Anti-Tumor Activity Assessment" [...].
PubMed: 38399356
DOI: 10.3390/pharmaceutics16020195 -
Biomedicine & Pharmacotherapy =... Sep 2023Raloxifene belongs to the family of Selective Estrogen Receptor Modulators (SERMs), which are drugs widely prescribed for Estrogen Receptor alpha (ERα)-related...
Raloxifene belongs to the family of Selective Estrogen Receptor Modulators (SERMs), which are drugs widely prescribed for Estrogen Receptor alpha (ERα)-related pathologies. Recently, SERMs are being tested in repurposing strategies for ERα-independent clinical indications, including a wide range of microbial infections. Macrophages are central in the fight against pathogen invasion. Despite estrogens have been shown to regulate macrophage phenotype, SERMs activity in these cells is still poorly defined. We investigated the activity of Raloxifene in comparison with another widely used SERM, Tamoxifen, on immune gene expression in macrophages obtained from mouse and human tissues, including mouse peritoneal macrophages, bone marrow-derived macrophages, microglia or human blood-derived macrophages, assaying for the involvement of the ERα, PI3K and NRF2 pathways also under inflammatory conditions. Our data demonstrate that Raloxifene acts by a dual mechanism, which entails ERα antagonism and off-target mediators. Moreover, micromolar concentrations of Raloxifene increase the expression of immune metabolic genes, such as Vegfa and Hmox1, through PI3K and NRF2 activation selectively in peritoneal macrophages. Conversely, Il1b mRNA down-regulation by SERMs is consistently observed in all macrophage subtypes and unrelated to the PI3K/NRF2 system. Importantly, the production of the inflammatory cytokine TNFα induced by the bacterial endotoxin, LPS, is potentiated by SERMs and paralleled by the cell subtype-specific increase in IL1β secretion. This work extends our knowledge on the biological and molecular mechanisms of SERMs immune activity and indicate macrophages as a pharmacological target for the exploitation of the antimicrobial potential of these drugs.
Topics: Mice; Humans; Animals; Selective Estrogen Receptor Modulators; Raloxifene Hydrochloride; Estrogen Receptor alpha; Down-Regulation; NF-E2-Related Factor 2; Tamoxifen; Macrophages; Phosphatidylinositol 3-Kinases
PubMed: 37442065
DOI: 10.1016/j.biopha.2023.115008