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Biomedical Research (Tokyo, Japan) 2022Selective estrogen receptor modulator (SERM) binds to estrogen receptors (ERs) and acts as both an agonist or an antagonist, depending on the target tissue. Raloxifene...
Selective estrogen receptor modulators, acting as agonists of estrogen receptor α in osteoblasts, reduce the TGF-β-induced synthesis of macrophage colony-stimulating factor via inhibition of JNK signaling pathway.
Selective estrogen receptor modulator (SERM) binds to estrogen receptors (ERs) and acts as both an agonist or an antagonist, depending on the target tissue. Raloxifene and bazedoxifene as SERMs are currently used hormone replacement medicines for postmenopausal osteoporosis. Macrophage colony-stimulating factor (M-CSF) secreted from osteoblasts promotes osteoclastogenesis. We have previously demonstrated that transforming growth factor (TGF)-β induces the synthesis of M-CSF via SMAD2/3, p38 mitogen-activated protein kinase (MAPK), p44/p42 MAPK and c-Jun N-terminal kinase (JNK) in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether SERM affects the M-CSF synthesis by TGF-β in MC3T3-E1 cells. Raloxifene and bazedoxifene significantly suppressed the synthesis of M-CSF. PPT, an ERα agonist, but not ERB041, an ERβ agonist, inhibited the release of M-CSF. MPP, an ERα antagonist, reversed the suppression by raloxifene of the M-CSF release. Raloxifene attenuated the TGF-β-induced phosphorylation of JNK but not SMAD3, p42 MAPK and p38 MAPK. Bazedoxifene and PPT also inhibited the phosphorylation of JNK. Furthermore, MPP, an ERα antagonist, reversed the suppression by both raloxifene and bazedoxifene of the phosphorylation of JNK. Our results strongly indicate that raloxifene and bazedoxifene, SERMs, suppress the TGF-β-induced synthesis of M-CSF through ERα-mediated inhibition of JNK pathway in osteoblasts.
Topics: Selective Estrogen Receptor Modulators; Transforming Growth Factor beta; MAP Kinase Signaling System; Estrogen Receptor alpha; Macrophage Colony-Stimulating Factor; Raloxifene Hydrochloride; Mitogen-Activated Protein Kinase 1; Osteoblasts; JNK Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Phosphorylation
PubMed: 36517023
DOI: 10.2220/biomedres.43.211 -
Medical Oncology (Northwood, London,... Dec 2022Triple-negative breast cancers (TNBCs) are characterized by a lack of approved targeted therapies and remain a challenge in the clinic. Several overexpressed proteins,...
Triple-negative breast cancers (TNBCs) are characterized by a lack of approved targeted therapies and remain a challenge in the clinic. Several overexpressed proteins, including epidermal growth factor receptor (EGFR), have been associated with TNBCs and are considered potential therapeutic targets. However, EGFR inhibitors alone failed to demonstrate a cutting-edge advantage for treating TNBCs over conventional chemotherapies. Studies have shown that selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene also affect TNBC cell viability. The combination of gefitinib and raloxifene was assessed against TNBC cell lines in vitro. Two TNBC cell lines, MDA-MB-231 and MDA-MB-468, were used to investigate the combination of gefitinib and raloxifene on cell viability, DNA synthesis, and apoptosis. The combination was assessed on intracellular signaling pathways, colony formation, migration, and angiogenesis. In the present study, raloxifene, in combination with gefitinib, decreased cell viability. The combination potentiates apoptosis and affects the expression and phosphorylation pattern of proteins involved in cell proliferation, such as NFκB, β-catenin, and EGFR. Furthermore, evidence of apoptosis activation was also observed, along with a decreased cell migration and tumorigenicity of TNBC cells. Moreover, the combined treatment decreased the ability of neovascularization as assessed by tube formation of endothelial cells. These results suggested the potential of the combination of raloxifene and gefitinib for the prevention of TNBC growth and the appearance of metastatic events. Our findings provide the basis for future studies on the mechanism involved in raloxifene-gefitinib inhibition of ER-negative tumor growth.
Topics: Humans; Gefitinib; Triple Negative Breast Neoplasms; Raloxifene Hydrochloride; Quinazolines; Endothelial Cells; Protein Kinase Inhibitors; Cell Line, Tumor; Cell Proliferation; Apoptosis
PubMed: 36494506
DOI: 10.1007/s12032-022-01909-3 -
Journal of Chemical Information and... Dec 2022Suicide inhibition of the CYP3A4 enzyme by a drug inactivates the enzyme in the drug biotransformation process and often shows safety concerns about the drug. Despite...
Suicide inhibition of the CYP3A4 enzyme by a drug inactivates the enzyme in the drug biotransformation process and often shows safety concerns about the drug. Despite extensive experimental studies, the abnormal molecular mechanism of a suicide inhibitor that forms a covalent bond with the residue far away from the catalytically active center of CYP3A4 inactivating the enzyme remains elusive. Here, the authors used molecular simulation approaches to study in detail how diquinone methide (DQR), the metabolite product of raloxifene, unbinds from CYP3A4 and inactivates the enzyme at the atomistic level. The results clearly indicate that in one of the intermediate states formed in its unbinding process, DQR covalently binds to Cys239, a residue far away from the catalytically active center of CYP3A4, and hinders the substrate from entering or leaving the enzyme. This work therefore provides an unprecedented way of clarifying the abnormal mechanism of suicide inhibition of the CYP3A4 enzyme.
Topics: Humans; Cytochrome P-450 CYP3A; Raloxifene Hydrochloride
PubMed: 36457253
DOI: 10.1021/acs.jcim.2c01035 -
Antiviral Research Jan 2023To identify potent antiviral compounds, we introduced a high-throughput screen platform that can rapidly classify hit compounds according to their target. In our...
To identify potent antiviral compounds, we introduced a high-throughput screen platform that can rapidly classify hit compounds according to their target. In our platform, we performed a compound screen using a lentivirus-based pseudovirus presenting a spike protein of coronavirus, and we evaluated the hit compounds using an amplified luminescence proximity homogeneous assay (alpha) test with purified host receptor protein and the receptor binding domain of the viral spike. With our screen platform, we were able to identify both spike-specific compounds (class I) and broad-spectrum antiviral compounds (class II). Among the hit compounds, thiosemicarbazide was identified to be selective to the interaction between the viral spike and its host cell receptor, and we further optimized the binding potency of thiosemicarbazide through modification of the pyridine group. Among the class II compounds, we found raloxifene and amiodarone to be highly potent against human coronaviruses including Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV-2. In particular, using analogs of the benzothiophene moiety, which is also present in raloxifene, we have identified benzothiophene as a novel structural scaffold for broad-spectrum antivirals. This work highlights the strong utility of our screen platform using a pseudovirus assay and an alpha test for rapid identification of potential antiviral compounds and their mechanism of action, which can lead to the accelerated development of therapeutics against newly emerging viral infections.
Topics: Humans; Luminescence; Raloxifene Hydrochloride; SARS-CoV-2; COVID-19; Middle East Respiratory Syndrome Coronavirus; Antiviral Agents; Spike Glycoprotein, Coronavirus
PubMed: 36435212
DOI: 10.1016/j.antiviral.2022.105473 -
Calcified Tissue International Mar 2023Thermoneutral housing and Raloxifene (RAL) treatment both have potential for improving mechanical and architectural properties of bone. Housing mice within a 30 to...
Thermoneutral housing and Raloxifene (RAL) treatment both have potential for improving mechanical and architectural properties of bone. Housing mice within a 30 to 32 °C range improves bone quality by reducing the consequences of cold stress, such as shivering and metabolic energy consumption (Chevalier et al. in Cell Metab 32(4):575-590.e7, 2020; Martin et al. in Endocr Connect 8(11):1455-1467, 2019; Hankenson et al. in Comp Med 68(6):425-438, 2018). Previous work suggests that Raloxifene can enhance bone strength and geometry (Ettinger et al. in Jama 282(7):637-645, 1999; Powell et al. in Bone Rep 12:100246, 2020). An earlier study in our lab utilized long bones to examine the effect of thermoneutral housing and Raloxifene treatment in mice, but no significant interactive effects were found. The lack of an impact is hypothesized to be connected to the short 6-week duration of the study and the type of bone analyzed. This study will examine the same question within the axial skeleton, which has a higher proportion of trabecular bone. After 6 weeks of treatment with RAL, vertebrae from female C57BL/6 J mice underwent microcomputed tomography (μCT), architectural analysis, and compression testing. Most of the tested geometric properties (bone volume/tissue volume percent, trabecular thickness, trabecular number, trabecular spacing) improved with both the housing and RAL treatment. The effect sizes suggested an additive effect when treating mice housed under thermoneutral conditions. While ultimate force was enhanced with the treatment and housing, force normalized by bone volume fraction was not significantly different between groups. For longer pre-clinical trials, it may be important to consider the impacts of temperature on mice to improve the accuracy of these models.
Topics: Mice; Female; Animals; Raloxifene Hydrochloride; Cancellous Bone; X-Ray Microtomography; Housing; Mice, Inbred C57BL; Bone Density
PubMed: 36371724
DOI: 10.1007/s00223-022-01038-z -
Drug Research Feb 2023A series of 7 compounds with isoxazole - indole - γ-resorcylic acid scaffold, segregated into B2 & A2 series, wherein, B2 comprises Compounds: 13, 14, 15 & 16 and A2...
A series of 7 compounds with isoxazole - indole - γ-resorcylic acid scaffold, segregated into B2 & A2 series, wherein, B2 comprises Compounds: 13, 14, 15 & 16 and A2 comprises Compounds: 10, 11 & 12, on the basis of the variable substituents at the indole, resorcinol and isoxazole end of the scaffold as in Figure: 1, were designed and docked with human estrogen receptor: 1ERRα. The Binding affinity (BA) and the interacting amino acids compared with reference selective estrogen receptor modulators (SERM's) such as Raloxifene, Estradiol, Bazedoxifene, Bisphenol, Genistein, Daidzein, Ormiloxifene, Tamoxifen, 6-hydroxy-naphthalen-2yl-benzo(D)-isoxazol-6-ol(1) using PyRx software and their ADME properties predicted with SWISS ADME online tool. Significant similarities and minor differences in the binding pattern between the key interacting aminoacids such as Arg 394, Glu 353, Asp 351, Leu 346, Leu 525, Trp 383, Phe 404, Ala 350, Leu 387, Met 421 responsible for ER agonist/antagonist affinity found in the binding cavity of a 1 Errα -Bazedoxifene/1 Errα -raloxifene/1 Errα -estradiol docked complex AND 1 Errα -isoxazole-indole- resorcinol docked complex indicate their promising potential to serve as potent ER agonists in bone or ER antagonists against breast cancer and other cancer diseases. The Compounds with highest BA is of the order: BA (A1series)>B1series>/
/=BA (B2 series) exceptions: compounds: 4, 5 of B1 series & compound:13 of B2 series with identical and least BA values.BA(6)=BA(8)>BA(7)>BA(2)>BA(9)=BA(1)>BA(12)>BA(10)=BA(15)=BA(11)=BA(3)>BA(14)=BA(16)>BA(4)=BA(5)=BA(13). Topics: Humans; Selective Estrogen Receptor Modulators; Raloxifene Hydrochloride; Molecular Docking Simulation; Antineoplastic Agents; Estradiol; Indoles
PubMed: 36302538
DOI: 10.1055/a-1958-3823 -
Journal of Bone Metabolism Aug 2022The impact of osteopenia as a risk factor for fractures is underrecognized. Moreover, the efficacy of selective estrogen receptor modulators (SERMs) in postmenopausal...
BACKGROUND
The impact of osteopenia as a risk factor for fractures is underrecognized. Moreover, the efficacy of selective estrogen receptor modulators (SERMs) in postmenopausal women with osteopenia is limited. This study aimed to evaluate the efficacy of SERMs in postmenopausal women with osteopenia.
METHODS
Thirty-two postmenopausal women with osteopenia were treated with 3 types of SERMs medication: raloxifene (group I, N=15), bazedoxifene (group II, N=8), and raloxifene with cholecalciferol (group III, N=9). Bone mineral density (BMD) was measured using dual energy X-ray absorptiometry scans before treatment to after 3 years of treatment once a year.
RESULTS
Patients in group I showed significant increases in hip BMD, -1.93 to -1.73 and spine BMD, -1.85 to -1.67. In addition, patients in groups II and III showed significant increases in hip BMD, -1.93 to -1.69 and -2.22 to -1.86, respectively and spine BMD, -2.1 to -1.3 and -2.22 to -1.37, respectively. The BMD increased in the hip and spine by 9.7% and 10.3%, respectively in group I, 38.0% and 12.4%, respectively in group II, and 38.2% and 16.2%, respectively in group III.
CONCLUSIONS
In this study, we found that SERMs could improve spine and hip BMD. In conclusion, preemptive treatment using SERMs is necessary for postmenopausal women with osteopenia. None of the patients experienced fractures during the follow-up period.
PubMed: 36153854
DOI: 10.11005/jbm.2022.29.3.185 -
Journal of Bone Metabolism Aug 2022We compared the efficacy of a fixed dose combination of raloxifene 60 mg/vitamin D 800 IU to raloxifene 60 mg alone on vitamin D status, as indicated by change in serum...
Raloxifene/Vitamin D Combination Therapy vs. Raloxifene Monotherapy on Serum 25-Hydroxy-Vitamin D Level among Postmenopausal Women with Osteoporosis or Osteopenia: A Randomized Controlled Trial.
BACKGROUND
We compared the efficacy of a fixed dose combination of raloxifene 60 mg/vitamin D 800 IU to raloxifene 60 mg alone on vitamin D status, as indicated by change in serum 25-hydroxy-vitamin D (25[OH]D) levels.
METHODS
In this 16-week, open-label, randomized, active controlled, multicenter clinical trial conducted in 4 university-affiliated hospitals in Korea, postmenopausal women aged 55 to 70 years with osteoporosis or osteopenia were randomly assigned in a 1:1 ratio to receive raloxifene 60 mg/cholecalciferol 800 IU combination therapy or raloxifene 60 mg monotherapy. Primary endpoint was change in serum 25(OH)D level from baseline to 16 weeks after the intervention.
RESULTS
A total of 96 participants were randomly assigned to raloxifene/vitamin D combination therapy (N=49) and raloxifene monotherapy (N=47) groups. At week 16, serum 25(OH)D level increased from baseline, only in the raloxifene/vitamin D combination therapy group. Change in serum 25(OH)D level from baseline to week 16 was higher in the raloxifene/vitamin D combination therapy group (2.7±6.5 ng/mL) than in the raloxifene monotherapy (-1.7±6.2 ng/mL; P=0.0034) group. Proportions and number of adverse events (AEs) categorized by the System-Organ Class were not different between the groups. There was only one severe AE case (spondylolisthesis; raloxifene/vitamin D group), unlikely to be related to trial intervention.
CONCLUSIONS
Among postmenopausal women with osteoporosis or osteopenia, a fixed dose combination of raloxifene 60 mg/vitamin D 800 IU showed superior efficacy in elevating serum 25(OH)D levels compared with raloxifene 60 mg alone during 16 weeks of follow-up. The safety of raloxifene/vitamin D combination was comparable to raloxifene alone.
PubMed: 36153851
DOI: 10.11005/jbm.2022.29.3.155 -
Microbiology Spectrum Oct 2022Pseudomonas aeruginosa is an opportunistic pathogen that has been declared by the World Health Organization as a "priority 1 critical pathogen" needing immediate new...
Pseudomonas aeruginosa is an opportunistic pathogen that has been declared by the World Health Organization as a "priority 1 critical pathogen" needing immediate new strategies for chemotherapy. During infection, P. aeruginosa uses redundant mechanisms to acquire ferric, heme (Hm), or ferrous iron from the host to survive and colonize. Significant efforts have been undertaken to develop siderophore blockers to inhibit ferric iron acquisition by P. aeruginosa, but there is a lack of inhibitors that can block Hm or ferrous iron acquisition by P. aeruginosa. We developed and employed a targeted high-throughput screen (HTS) and identified a molecule(s) that can specifically inhibit the Hm and ferrous iron acquisition systems of P. aeruginosa. Our targeted approach relies on screening a small-molecule library against P. aeruginosa under three growth conditions, where the only variable was the iron source (ferric, Hm, or ferrous iron). Each condition served as a counterscreen for the other, and we identified molecules that inhibit the growth of P. aeruginosa in the presence of only Hm or ferrous iron. Our data indicate that econazole, bithionate, and raloxifene inhibit the growth of P. aeruginosa in the presence of Hm and that oxyquinoline inhibits the growth of P. aeruginosa in the presence of ferrous iron. These iron-specific inhibitors do not interfere with the activity of meropenem, a commercial antipseudomonal, and can also increase meropenem activity. In conclusion, we present a proof of concept of a successful targeted conditional screening method by which we can identify specific iron acquisition inhibitors. This approach is highly adaptable and can easily be extended to any other pathogen. Since acquiring iron is paramount to P. aeruginosa's survival and colonization in the human host, developing novel strategies to block the access of P. aeruginosa to host iron will allow us to starve it of an essential nutrient. P. aeruginosa uses siderophore, heme, or ferrous iron uptake systems to acquire iron in the human host. We have developed a novel approach through which we can directly identify molecules that can prevent P. aeruginosa from utilizing heme or ferrous iron. This approach overcomes the need for the design of molecules and identifies structurally diverse biologically active inhibitor molecules. This screening approach is adaptable and can be extended to any pathogen. Since Gram-negative pathogens share many similarities in iron acquisition at both the mechanistic and molecular levels, our screening approach presents a significant opportunity to develop novel broad-spectrum iron acquisition inhibitors of Gram-negative pathogens.
Topics: Bacterial Proteins; Econazole; Heme; Iron; Meropenem; Oxyquinoline; Pseudomonas aeruginosa; Raloxifene Hydrochloride; Siderophores
PubMed: 36098531
DOI: 10.1128/spectrum.02437-22 -
Cancer Medicine Feb 2023The aim of this cross-sectional study was to examine whether a history of selective estrogen receptor modifiers (SERMs), tamoxifen and raloxifene, use was associated...
The aim of this cross-sectional study was to examine whether a history of selective estrogen receptor modifiers (SERMs), tamoxifen and raloxifene, use was associated with cognitive performance, odds of mild cognitive impairment (MCI), or magnetic resonance imaging (MRI) markers of neurodegeneration associated with Alzheimer's disease. We included women with prior history of breast cancer or no prior history of any cancer at enrollment in the Mayo Clinic Study of Aging (MCSA). This information was abstracted using the Rochester Epidemiology Project medical-linkage system. Logistic regression was used to examine associations of SERMs with odds of MCI. Linear regression models were used to examine associations of SERMs with cognitive z-scores (Memory, Executive Function, Language, Visuospatial Skills, Global Cognition), and MRI markers. Among 2840 women aged 50 and older in the MCSA, 151 had a history of breast cancer, and 42 (28%) of these had a history of tamoxifen treatment. A total of 2235 women had no prior history of any cancer, and 76 (3%) of these had a history of raloxifene use. No significant associations between tamoxifen use and cognition, or odds of MCI were observed among women with a history of breast cancer after adjusting for confounders. Similarly, raloxifene use was not significantly associated with cognition, or odds of MCI in women without a history of cancer after adjusting for confounders. We did not find significant associations between the use of either SERM and MRI markers. Use of tamoxifen or raloxifene was not significantly associated with cognition in postmenopausal women.
Topics: Female; Humans; Middle Aged; Aged; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Cross-Sectional Studies; Tamoxifen; Breast Neoplasms; Cognition; Cognitive Dysfunction; Receptors, Estrogen; Brain
PubMed: 36040183
DOI: 10.1002/cam4.5175