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BMJ (Clinical Research Ed.) Sep 2023To study the influence of concomitant use of hormonal contraception and non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of venous thromboembolism.
OBJECTIVE
To study the influence of concomitant use of hormonal contraception and non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of venous thromboembolism.
DESIGN
Nationwide cohort study.
SETTING
Denmark through national registries.
PARTICIPANTS
All 15-49 year old women living in Denmark between 1996 and 2017 with no medical history of any venous or arterial thrombotic event, cancer, thrombophilia, hysterectomy, bilateral oophorectomy, sterilisation, or infertility treatment (n=2 029 065).
MAIN OUTCOME MEASURE
A first time discharge diagnosis of lower limb deep venous thrombosis or pulmonary embolism.
RESULTS
Among 2.0 million women followed for 21.0 million person years, 8710 venous thromboembolic events occurred. Compared with non-use of NSAIDs, use of NSAIDs was associated with an adjusted incidence rate ratio of venous thromboembolism of 7.2 (95% confidence interval 6.0 to 8.5) in women not using hormonal contraception, 11.0 (9.6 to 12.6) in women using high risk hormonal contraception, 7.9 (5.9 to 10.6) in those using medium risk hormonal contraception, and 4.5 (2.6 to 8.1) in users of low/no risk hormonal contraception. The corresponding numbers of extra venous thromboembolic events per 100 000 women over the first week of NSAID treatment compared with non-use of NSAIDs were 4 (3 to 5) in women not using hormonal contraception, 23 (19 to 27) in women using high risk hormonal contraception, 11 (7 to 15) in those using medium risk hormonal contraception, and 3 (0 to 5) in users of low/no risk hormonal contraception.
CONCLUSIONS
NSAID use was positively associated with the development of venous thromboembolism in women of reproductive age. The number of extra venous thromboembolic events with NSAID use compared with non-use was significantly larger with concomitant use of high/medium risk hormonal contraception compared with concomitant use of low/no risk hormonal contraception. Women needing both hormonal contraception and regular use of NSAIDs should be advised accordingly.
Topics: Female; Humans; Adolescent; Young Adult; Adult; Middle Aged; Venous Thromboembolism; Cohort Studies; Hormonal Contraception; Anti-Inflammatory Agents, Non-Steroidal; Hysterectomy
PubMed: 37673431
DOI: 10.1136/bmj-2022-074450 -
Bone Research Oct 2023Despite the diverse roles of tripartite motif (Trim)-containing proteins in the regulation of autophagy, the innate immune response, and cell differentiation, their...
Despite the diverse roles of tripartite motif (Trim)-containing proteins in the regulation of autophagy, the innate immune response, and cell differentiation, their roles in skeletal diseases are largely unknown. We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast (OB) differentiation in osteosarcoma. However, how Trim21 contributes to skeletal degenerative disorders, including osteoporosis, remains unknown. First, human and mouse bone specimens were evaluated, and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients. Next, we found that global knockout of the Trim21 gene (KO, Trim21) resulted in higher bone mass compared to that of the control littermates. We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and elevating the activity of OBs; moreover, Trim21 depletion suppressed osteoclast (OC) formation of RAW264.7 cells. In addition, the differentiation of OCs from bone marrow-derived macrophages (BMMs) isolated from Trim21 and Ctsk-cre; Trim21 mice was largely compromised compared to that of the littermate control mice. Mechanistically, YAP1/β-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs. More importantly, the loss of Trim21 prevented ovariectomy (OVX)- and lipopolysaccharide (LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling. Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption, thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.
Topics: Animals; Female; Humans; Mice; beta Catenin; Bone and Bones; Cell Differentiation; Osteogenesis; Osteoporosis
PubMed: 37884520
DOI: 10.1038/s41413-023-00296-3 -
Advanced Science (Weinheim,... Jun 2023Bone undergoes constant remodeling by osteoclast bone resorption coupled with osteoblast bone formation at the bone surface. A third major cell type in the bone is...
Bone undergoes constant remodeling by osteoclast bone resorption coupled with osteoblast bone formation at the bone surface. A third major cell type in the bone is osteocytes, which are embedded in the matrix, are well-connected to the lacunar network, and are believed to act as mechanical sensors. Here, it is reported that sympathetic innervation directly regulates lacunar osteocyte-mediated bone resorption inside cortical bone. It is found that sympathetic activity is elevated in different mouse models of bone loss, including lactation, ovariectomy, and glucocorticoid treatment. Further, during lactation elevated sympathetic outflow induces netrin-1 expression by osteocytes to further promote sympathetic nerve sprouting in the cortical bone endosteum in a feed-forward loop. Depletion of tyrosine hydroxylase-positive (TH ) sympathetic nerves ameliorated osteocyte-mediated perilacunar bone resorption in lactating mice. Moreover, norepinephrine activates β-adrenergic receptor 2 (Adrb2) signaling to promote secretion of extracellular vesicles (EVs) containing bone-degrading enzymes for perilacunar bone resorption and inhibit osteoblast differentiation. Importantly, osteocyte-specific deletion of Adrb2 or treatment with a β-blocker results in lower bone resorption in lactating mice. Together, these findings show that the sympathetic nervous system promotes osteocyte-driven bone loss during lactation, likely as an adaptive response to the increased energy and mineral demands of the nursing mother.
Topics: Female; Animals; Mice; Osteocytes; Lactation; Bone and Bones; Cortical Bone; Bone Resorption; Bone Diseases, Metabolic
PubMed: 37186379
DOI: 10.1002/advs.202207602 -
Redox Biology Jun 2023Ovariectomy (OVX) conducted before the onset of natural menopause is considered to bringing forward and accelerate the process of ageing-associated neurodegeneration....
Ovariectomy (OVX) conducted before the onset of natural menopause is considered to bringing forward and accelerate the process of ageing-associated neurodegeneration. However, the mechanisms underlying memory decline and other cognitive dysfunctions following OVX are unclear. Given that iron accumulates during ageing and after OVX, we hypothesized that excess iron accumulation in the hippocampus would cause ferroptosis-induced increased neuronal degeneration and death associated with memory decline. In the current study, female rats that underwent OVX showed decreased dihydroorotate dehydrogenase (DHODH) expression and reduced performance in the Morris water maze (MWM). We used primary cultured hippocampal cells to explore the ferroptosis resistance-inducing effect of 17β-oestradiol (E). The data supported a vital role of DHODH in neuronal ferroptosis. Specifically, E alleviated ferroptosis induced by erastin and ferric ammonium citrate (FAC), which can be blocked by brequinar (BQR). Further in vitro studies showed that E reduced lipid peroxidation levels and improved the behavioural performance of OVX rats. Our research interprets OVX-related neurodegeneration with respect to ferroptosis, and both our in vivo and in vitro data show that E supplementation exerts beneficial antiferroptotic effects by upregulating DHODH. Our data demonstrate the utility of E supplementation after OVX and provide a potential target, DHODH, for which hormone therapy has not been available.
Topics: Animals; Female; Rats; Dihydroorotate Dehydrogenase; Estradiol; Ferroptosis; Hippocampus; Memory Disorders; Ovariectomy
PubMed: 37116254
DOI: 10.1016/j.redox.2023.102708 -
Autopsy & Case Reports 2024Neuroendocrine breast cancer (NEBC) is a rare and heterogeneous entity. It most commonly presents a luminal phenotype and a worse prognosis. When diagnosed in an...
Neuroendocrine breast cancer (NEBC) is a rare and heterogeneous entity. It most commonly presents a luminal phenotype and a worse prognosis. When diagnosed in an advanced stage, metastasis from another neuroendocrine tumor should be excluded. This case features a premenopausal woman with an oligometastatic breast large cell neuroendocrine carcinoma, estrogen receptor (ER) positive, and human epidermal growth factor receptor 2 (HER2) negative. Since the patient was very symptomatic at the presentation of the disease, chemotherapy was started. Complete radiological response of the metastatic disease was achieved, and the patient was then submitted to radical breast surgery and bilateral oophorectomy. She subsequently underwent radiation therapy. Since then and to date, she has been under endocrine therapy (ET) and a CDK4/6 inhibitor (CDK4/6i), with no evidence of malignant disease. Evidence to guide the choice of treatment for these tumors is currently scarce. In cases with oligometastatic disease, radical treatment should be considered. Given that this entity is rare, its reporting should be encouraged.
PubMed: 38562645
DOI: 10.4322/acr.2024.484 -
Advanced Science (Weinheim,... Jun 2023Osteoblasts play an important role in the regulation of bone homeostasis throughout life. Thus, the damage of osteoblasts can lead to serious skeletal diseases,...
Osteoblasts play an important role in the regulation of bone homeostasis throughout life. Thus, the damage of osteoblasts can lead to serious skeletal diseases, highlighting the urgent need for novel pharmacological targets. This study introduces chemical genetics strategy by using small molecule forskolin (FSK) as a probe to explore the druggable targets for osteoporosis. Here, this work reveals that transglutaminase 2 (TGM2) served as a major cellular target of FSK to obviously induce osteoblast differentiation. Then, this work identifies a previously undisclosed allosteric site in the catalytic core of TGM2. In particular, FSK formed multiple hydrogen bonds in a saddle-like domain to induce an "open" conformation of the β-sandwich domain in TGM2, thereby promoting the substrate protein crosslinks by incorporating polyamine. Furthermore, this work finds that TGM2 interacted with several mitochondrial homeostasis-associated proteins to improve mitochondrial dynamics and ATP production for osteoblast differentiation. Finally, this work observes that FSK effectively ameliorated osteoporosis in the ovariectomy mice model. Taken together, these findings show a previously undescribed pharmacological allosteric site on TGM2 for osteoporosis treatment, and also provide an available chemical tool for interrogating TGM2 biology and developing bone anabolic agent.
Topics: Mice; Animals; Female; Protein Glutamine gamma Glutamyltransferase 2; Allosteric Regulation; Osteogenesis; Osteoblasts; Osteoporosis
PubMed: 37088726
DOI: 10.1002/advs.202206533