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Caroline C Faria Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Leonardo Matta Pereira Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Luiz Gabriel Portilho Moreira Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Kathelinie Celestino Faustino Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Milena Simões Peixoto Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Ariclécio Cunha de Oliveira Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Ceará, Brazil

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Andrea Claudia Freitas Ferreira Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
NUMPEX, Campus Duque de Caxias, UFRJ, Rio de Janeiro, Brazil

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Denise Pires Carvalho Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Rodrigo Soares Fortunato Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Thyroid disorders affect more women than men, but the underlying mechanisms contributing to this disparity remain incompletely understood. Thyrotropin (TSH), the primary regulator of thyroid oxidative hormonogenesis, has been implicated as a risk factor for proliferative thyroid diseases and a predictor of malignancy. In this study, we aimed to evaluate the impact of sustained elevated TSH levels on thyroid redox homeostasis, inflammatory markers, and DNA damage response in both male and female rats. Rats were treated with methimazole for 7 or 21 days, and hormonal measurements were conducted. H2O2 levels were evaluated in thyroid membrane fractions, while enzymatic activities were assessed in total thyroid homogenates. Sex-specific differences emerged, with females displaying higher reactive oxygen species levels – increased transiently NOX and sustained DUOX activities. Lipid peroxidation marker 4-hydroxynonenal (4-HNE) was elevated in females at both time points, contrasting with males just at 21 days. Sexual dimorphism was observed in DNA damage response, with females showing higher γH2AX levels at 21 days. Elevated IL-1β, TNF-α, CD11b mRNA, and phospho-NF-κB levels at 7 days indicated a distinct inflammatory profile in females. Notably, both sexes exhibited upregulated antioxidant enzymes. Our data suggest that females are more susceptible to oxidative damage and inflammation in our goiter model, which may be associated with higher ROS production and a less-efficient antioxidant defense system. These findings provide insights into the sex-specific mechanisms underlying thyroid dysfunction and highlight the importance of considering sex disparities in thyroid disorder research.

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Jonathan D Douros Novo Nordisk Research Center Indianapolis, Indianapolis, Indiana, USA

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Jacek Mokrosinski Novo Nordisk Research Center Indianapolis, Indianapolis, Indiana, USA

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Brian Finan Novo Nordisk Research Center Indianapolis, Indianapolis, Indiana, USA

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The glucagon-like peptide 1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) that emerged as a pharmacologic target in cardiometabolic disease, including diabetes and obesity, over 30 years ago. The subsequent widespread clinical use of GLP-1R agonists, including exenatide, liraglutide, and semaglutide, has made the GLP-1R a preeminent model for understanding basic GPCR biology, including the emergent field of biased agonism. Recent data demonstrate that the dual GLP-1R/glucose dependent insulinotropic polypeptide receptor (GIPR) agonist tirzepatide exhibits a biased signaling profile characterized by preferential Gαs activation over β-arrestin recruitment, which appears to contribute to its insulinotropic and body-weight reducing effects in preclinical models. This constitutes a major finding in which nuanced, mechanistic receptor signaling dynamics in vitro mediate real-world clinical differentiation within a drug class. Because of the striking bench-top-to-bed side relevance of this biased signaling phenomenon, we have undertaken a review of the emerging data detailing biased agonism at the GLP-1R. In this review, we introduce the core concept of biased agonism followed by a detailed consideration of the key mechanisms, including ligand-mediated bias, receptor-mediated bias, and systems/cell-type bias. Current industry programs are largely, if not entirely, focused on developing biased ligands, and so we have dedicated a section of the review to a brief meta-analysis of compounds reported to drive biased signaling, with a consideration of the structural determinants of receptor–ligand interactions. In this work, we aim to assess the current knowledge regarding signaling bias at the GLP-1R and how these ideas might be leveraged in future optimization.

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Eugenie Macfarlane Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia

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Hong Zhou Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia

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Markus J Seibel Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia
Department of Endocrinology and Metabolism, Concord Repatriation General Hospital, Sydney, Australia

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Glucocorticoids are steroid hormones, secreted by the adrenals to regulate a range of metabolic, immunologic, and homeostatic functions. Due to their potent anti-inflammatory effects, synthetic glucocorticoids are widely used to treat inflammatory disorders. However, their use especially at high doses and over the long-term is associated with several unwanted side effects that compromises their intended use (e.g. glucocorticoid-induced osteoporosis and/or diabetes, myopathy, and skin atrophy). Both endogenous and synthetic glucocorticoids exert their effects through the glucocorticoid receptor, a transcription factor present in nearly all nucleated cells. Glucocorticoid receptor knockout mouse models have proved to be valuable tools in understanding how glucocorticoids contribute to skeletal health and disease. These models, described in this review, have helped to establish that the effects of glucocorticoids on the skeleton are multifaceted, cell specific and concentration dependent. Intriguingly, while endogenous glucocorticoids are essential for bone formation, high-dose exogenous glucocorticoids may induce bone loss. Additionally, the actions of endogenous glucocorticoids vary greatly depending on the disease microenvironment. For example, endogenous glucocorticoids have predominately beneficial anti-inflammatory effects in rheumatoid arthritis, but detrimental actions in osteoarthritis by driving cartilage loss and abnormal bone formation. Studies in tissue-specific knockout models provide important insights that will aid the development of new glucocorticoid therapeutics that can specifically target certain cell types to minimise unwanted effects from current glucocorticoid therapy.

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Sonu Khanka Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India

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Charul Somani Department of Chemistry, Mohanlal Sukhadia University, Udaipur-Rajasthan, India

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Kriti Sharma Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India

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Shivani Sharma Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India

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Akhilesh Kumar Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
Sophisticated Analytical Instrument Facility & Research, Division, CSIR-Central Drug Research Institute, Lucknow, India

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Naibedya Chattopadhyay Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India

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Sanjeev K Kanojiya Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
Sophisticated Analytical Instrument Facility & Research, Division, CSIR-Central Drug Research Institute, Lucknow, India

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Dinesh Kumar Yadav Department of Chemistry, Mohanlal Sukhadia University, Udaipur-Rajasthan, India

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Divya Singh Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India

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Estrogen deficiency is one of the main causes for postmenopausal osteoporosis. Current osteoporotic therapies are of high cost and associated with serious side effects. So there is an urgent need for cost-effective anti-osteoporotic agents. Anti-osteoporotic activity of Litsea glutinosa extract (LGE) is less explored. Moreover, its role in fracture healing and mechanism of action is still unknown. In the present study we explore the osteoprotective potential of LGE in osteoblast cells and fractured and ovariectomized (Ovx) mice models. Alkaline phosphatase (ALP), MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and mineralization assays revealed that LGE treatment increased osteoblast cell differentiation, viability and mineralization. LGE treatment at 0.01 μg increased the expression of BMP2, PSMAD, RUNX2 and type 1 col. LGE also mitigated RANKL-induced osteoclastogenesis. Next, drill hole injury Balb/C mice model was treated with LGE for 12 days. Micro-CT analysis and Calcein labeling at the fracture site showed that LGE (20 mg/kg) enhanced new bone formation and bone regeneration, also increased expression of BMP2/SMAD1 signaling genes at fracture site. Ovx mice were treated with LGE for 1 month. μCT analysis indicated that the treatment of LGE at 20 mg/kg dose prevented the alteration in bone microarchitecture and maintained bone mineral density and bone mineral content. Treatment also increased bone strength and restored the bone turnover markers. Furthermore, in bone samples, LGE increased osteogenesis by enhancing the expression of BMP2/SMAD1 signaling components and decreased osteoclast number and surface. We conclude that LGE promotes osteogenesis via modulating the BMP2/SMAD1 signaling pathway. The study advocates the therapeutic potential of LGE in osteoporosis treatment.

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Qin Yin Department of Orthopedics, Wuxi Ninth People’s Hospital Affiliated to Soochow University, Wuxi, Jiangsu, China

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Jun Gu Department of Orthopedics, Wuxi Ninth People’s Hospital Affiliated to Soochow University, Wuxi, Jiangsu, China

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Pengju Ren Department of Orthopedics, The Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China

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Zhiqiang Guan Department of Dermatology, Xuzhou Municipal Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, China

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Yongxiang Wang Department of Orthopedics, Clinical Medical College, Yangzhou University, Yangzhou, China
Department of Orthopedics, Northern Jiangsu People’s Hospital, Yangzhou, China

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Ruijun Bai Department of Orthopedics, Wuxi Ninth People’s Hospital Affiliated to Soochow University, Wuxi, Jiangsu, China

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Yu Liu Department of Orthopedics, Wuxi Ninth People’s Hospital Affiliated to Soochow University, Wuxi, Jiangsu, China

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The role of this study was to evaluate the impact of gut microbiota depletion on the progression of osteoarthritis (OA) and osteoporosis (OP). We conducted an experimental mouse model of OA and OP over an 8-week period. The model involved destabilization of the medial meniscus and bilateral ovariectomy (OVX). To deplete the gut microbiota, we administered a course of antibiotics for 8 weeks. The severity of OA was assessed through micro-CT scanning, X-rays, and immunohistochemical staining. Microbiome analysis was performed using PCR of 16S DNA on fecal samples, and the levels of serum lipopolysaccharide, interleukin 6, tumor necrosis factor-α (TNF-α), osteocalcin, and estrogen were measured using enzyme-linked immunosorbent assay. We found that in comparison to the OVX+OA group, the OVX+OA+ABT group exhibited increased bone mineral density (P < 0.0001), bone volume fraction (P = 0.0051), and trabecular number (P = 0.0023) in the metaphyseal bone. Additionally, cartilage injury and levels of matrix metalloproteinase 13 were reduced in the OVX+OA+ABT group compared to the OVX+OA group. Moreover, the OVX+OA+ABT group demonstrated decreased relative abundance of Bacteroidetes, serum lipopolysaccharide (P = 0.0005), TNF-α (P < 0.0001), CTX-1 (P = 0.0002), and increased expression of bone formation markers. These findings were further supported by correlation network analyses. Depletion of gut microbiota was shown to protect against bone loss and cartilage degradation by modulating the composition of the gut microbiota in osteoporosis and osteoarthritis.

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Thomas Willmott Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

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Elizabeth C Cottrell Maternal and Fetal Health Research Centre, Division of Developmental Biology & Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

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During pregnancy, all major physiological systems undergo remarkable changes, driven largely by alterations in the maternal hormonal milieu. In healthy pregnancies, maternal cardiovascular and metabolic adaptation to pregnancy occurs to support fetal growth and maternal well-being. Impaired maternal adaptation to pregnancy is associated with a range of pregnancy complications, including gestational diabetes and preeclampsia. There is growing recognition of the importance of different maternal microbiota, including in the gut, vagina and oral cavity, in supporting normal maternal adaptations to pregnancy as well as evidence for microbial disturbances associating with pregnancy pathologies. Here, we aim to summarise emerging evidence demonstrating that differences in maternal microbiota associate with pregnancy outcomes and discuss potential therapeutic approaches under development that might restore an ‘optimal’ microbiome. In particular, we highlight recent work by ourselves and others exploring the role of the oral microbiome in pregnancy, given established links between poor oral health (e.g. periodontitis) and adverse pregnancy outcomes. Our research has focussed on specific nitrate-reducing oral bacteria which play a role in the generation of nitric oxide (NO) and other bioactive nitrogen oxides associated with cardiovascular health and maternal cardiovascular adaption to pregnancy. Ongoing research aims to define whether altered microbial profiles have clinical utility in the prediction of pregnancy pathologies, and whether interventions designed to optimise specific maternal microbiota could help prevent future complications.

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Ana Fernanda Castillo Departamento de Bioquímica Humana, Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina
CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina

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Cecilia Poderoso Departamento de Bioquímica Humana, Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina
CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina

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Paula Mariana Maloberti Departamento de Bioquímica Humana, Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina
CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina

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Fabiana Cornejo Maciel Departamento de Bioquímica Humana, Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina
CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina

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María Mercedes Mori Sequeiros Garcia Departamento de Bioquímica Humana, Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina
CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina

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Ulises Daniel Orlando CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina

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Pablo Mele Departamento de Bioquímica Humana, Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina
CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina

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Yanina Benzo Departamento de Bioquímica Humana, Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina
CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina

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Melina Andrea Dattilo Departamento de Bioquímica Humana, Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina
CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina

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Jesica Prada CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina

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Luciano Quevedo CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina

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Matías Belluno CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina

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Cristina Paz Departamento de Bioquímica Humana, Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina
CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina

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Ernesto Jorge Podesta Departamento de Bioquímica Humana, Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina
CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina

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For many years, research in the field of steroid synthesis has aimed to understand the regulation of the rate-limiting step of steroid synthesis, i.e. the transport of cholesterol from the outer to the inner mitochondrial membrane, and identify the protein involved in the conversion of cholesterol into pregnenolone. The extraordinary work by B Clark, J Wells, S R King, and D M Stocco eventually identified this protein and named it steroidogenic acute regulatory protein (StAR). The group’s finding was also one of the milestones in understanding the mechanism of nonvesicular lipid transport between organelles. A notable feature of StAR is its high degree of phosphorylation. In fact, StAR phosphorylation in the acute phase is required for full steroid biosynthesis. As a contribution to this subject, our work has led to the characterization of StAR as a substrate of kinases and phosphatases and as an integral part of a mitochondrion-associated multiprotein complex, essential for StAR function and cholesterol binding and mitochondrial transport to yield maximum steroid production. Results allow us to postulate the existence of a specific cellular microenvironment where StAR protein synthesis and activation, along with steroid synthesis and secretion, are performed in a compartmentalized manner, at the site of hormone receptor stimulation, and involving the compartmentalized formation of the steroid molecule-synthesizing complex.

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Rebecca J Ainslie R Ainslie, Institute for Regeneration and Repair , The University of Edinburgh, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Ioannis Simitsidellis I Simitsidellis, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Phoebe M Kirkwood P Kirkwood, Institute for Regeneration and Repair , The University of Edinburgh, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Douglas A Gibson D Gibson, Institute for Regeneration and Repair , The University of Edinburgh, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Androgens can modulate immune cell function and may contribute to differences in the prevalence and severity of common inflammatory conditions. Although most immune cells are androgen targets, our understanding of how changes in androgen bioavailability can affect immune responses is incomplete. Androgens alter immune cell composition, phenotype and activation by modulating expression and secretion of inflammatory mediators or by altering development and maturation of immune cell precursors. Androgens are generally associated with having suppressive effects on the immune system but their impacts are cell and tissue context dependent and can be highly nuanced even within immune cell subsets. In response to androgens, innate immune cells such as neutrophils, monocytes, and macrophages increase production of the anti-inflammatory cytokine IL10 and decrease nitric oxide production. Androgens promote differentiation of T cell subsets and reduce production of inflammatory mediators, such as IFNG, IL4 and IL5. Additionally, androgens/AR can promote maturation of B cells. Thus, androgens can be considered as immunomodulatory agents but further work is required to understand the precise molecular pathways that are regulated at the intersection between endocrine and inflammatory signals. This narrative review focusses on summarising our current understanding of how androgens can alter immune cell function and how this might affect inflammatory responses in health and disease.

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Leena Strauss L Strauss, Institution of Biomedicine, University of Turku, Turku, 20014, Finland

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Arttu Junnila A Junnila, Institute of Biomedicine, University of Turku, Turku, Finland

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Anni Wärri A Wärri, Institute of Biomedicine, University of Turku, Turku, Finland

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Maria Manti M Manti, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden

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Yiwen Jiang Y Jiang, Sahlgreska Osteoporosis Centre, Centre for Bone and Arthritis Research at Institute of Medicine, University of Gothenburg Sahlgrenska Academy, Gothenburg, Sweden

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Eliisa Löyttyniemi E Löyttyniemi, Department of Biostatistics, University of Turku, Helsinki, Finland

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Elisabet Stener-Victorin E Stener-Victorin, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, 17176, Sweden

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Marie K Lagerquist M Lagerquist, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy, Goteborg, Sweden

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Krisztina Kukoricza K Kukoricza, Institute of Biomedicine, University of Turku, Turku, Finland

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Taija Heinosalo T Heinosalo, Department of Physiology, University of Turku, Institute of Biomedicine, Turku, Finland

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Sami Blom S Blom, Aiforia Technologies Oyj, Aiforia Technologies Oyj, Helsinki, United Kingdom of Great Britain and Northern Ireland

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Matti Poutanen M Poutanen, University of Turku, Institute of Biomedicine and Turku Center for Disease Modeling, Turku, Finland

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The mouse estrous cycle is divided into four stages: proestrus (P), estrus (E), metestrus (M) and diestrus (D). The estrous cycle affects reproductive hormone levels in a wide variety of tissues. Therefore, to obtain reliable results from female mice, it is important to know the estrous cycle stage during sampling. The stage can be analyzed from a vaginal smear under a microscope. However, it is time-consuming, and the results vary between evaluators. Here, we present an accurate and reproducible method for staging the mouse estrous cycle in digital whole slide images (WSIs) of vaginal smears. We developed a model using a deep convolutional neural network (CNN) in a cloud-based platform, Aiforia Create. The CNN was trained by supervised pixel-level multiclass semantic segmentation of image features from 171 hematoxylin-stained samples. The model was validated by comparing the results obtained by CNN with those of four independent researchers. The validation data included three separate studies comprising altogether 148 slides. The total agreement attested by the Fleiss kappa value between the validators and the CNN was excellent (0.75), and when D, E and P were analyzed separately, the kappa values were 0.89, 0.79 and 0.74, respectively. The M stage is short and not well defined by the researchers. Thus, identification of the M stage by the CNN was challenging due to the lack of proper ground truth, and the kappa value was 0.26. We conclude that our model is reliable and effective for classifying the estrous cycle stages in female mice.

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Se-Min Kim S Kim, Mount Sinai Bone Program, Mount Sinai Health System, New York, United States

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Farthath Sultana F Sultana, Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States

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Steven Sims S Sims, Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States

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Judit Gimenez-Roig J Gimenez-Roig, Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States

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Victoria Laurencin V Laurencin, Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States

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Anusha Pallapati A Pallapati, Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States

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Satish Rojekar S Rojekar, Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States

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Vitaly Ryu V Ryu, Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States

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Daria Lizneva D Lizneva, Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States

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Funda Korkmaz F Korkmaz, Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States

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Tony Yuen T Yuen, Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States

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Mone Zaidi M Zaidi, Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States

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The pituitary gland, often called the “master gland”, orchestrates multiple effector hormonal organs and other glands by secreting various tropic hormones, which play a significant role in a myriad of physiological processes including skeletal modeling and remodeling, fat and glucose metabolism, and cognitive and psychological processes. The findings of the expression of receptors for each pituitary hormone and the hormone itself in skeleton, fat and immune cells suggested that their role is much broader than the traditional or classic role. Follicle-stimulating hormone (FSH), once believed to regulate gonadal function – gonadal development and maturation at puberty and gamete production during the fertile phase – is also found to involve in fat and bone metabolism as well as cognition, which provides us a better understanding of complex physiology. This emerging understanding of the non-reproductive role of FSH opens potential therapeutic opportunity to address detrimental health burden during and after menopause, namely osteoporosis, obesity and dementia. In this Review, we outline the current understanding of crosstalk between the pituitary, bone, adipose tissue and brain through FSH. The pre-clinical evidence from genetic and pharmacologic intervention in rodent models, and human data from population-based observation, genetic studies, and a small number of studies with interventional nature support an independent skeletal, lipogenic and cognitive effect of FSH and more.

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