Tranexamic Acid Protects Ovary and Testis Functions and Ameliorates Osteoporosis in Mice

Pharmacology ◽  
2020 ◽  
Vol 105 (11-12) ◽  
pp. 652-661 ◽  
Author(s):  
Keiichi Hiramoto ◽  
Hirotaka Oikawa ◽  
Yurika Yamate ◽  
Eisuke F. Sato
Keyword(s):  
Tranexamic Acid ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Male Mice ◽  
Mineral Density ◽  
Effective Prevention ◽  
Female Mice ◽  
Ameliorative Effect ◽  
17Β Estradiol ◽  
Old Mice

<b><i>Introduction:</i></b> In a rapidly aging society, the number of people suffering from osteoporosis keeps increasing. However, effective prevention strategies for osteoporosis are not yet currently available. <b><i>Objective:</i></b> In this study, we examined the ameliorative effects of tranexamic acid on osteoporosis in 24-month-old mice. <b><i>Methods:</i></b> During the study period, mice were orally administered tranexamic acid 3 times per week. <b><i>Results:</i></b> Bone mineral density, which is a parameter of osteoporosis, was improved following tranexamic acid administration. In addition, female mice evidenced a stronger phenotypic improvement than male mice. In female mice treated with tranexamic acid, ovary abnormalities were reduced. Furthermore, the levels of transforming growth factor-β, hyaluronic acid, CD44, reactive oxygen species, and apoptosis, as well as the number of infiltrated neutrophils and macrophages in the ovary were lower than those in the control or solvent-administered mice. In addition, 17β-estradiol levels in blood increased when compared with the control or solvent-treated mice. In addition, administration of tranexamic acid to 24-month-old male mice decreased the level of apoptosis in the testis. However, the levels of 17β-estradiol and testosterone in blood increased compared with the control or solvent-administered mice. <b><i>Conclusions:</i></b> The use of tranexamic acid had an ameliorative effect on osteoporosis, possibly by protecting ovaries and testes.

Acute regulation of activin A and its binding protein, follistatin, in serum and tissues following lipopolysaccharide treatment of adult male mice

2012 ◽  
Vol 303 (6) ◽  
pp. R665-R675 ◽  
Author(s):  
Hui Wu ◽  
Yi Chen ◽  
Wendy R. Winnall ◽  
David J. Phillips ◽  
Mark P. Hedger
Keyword(s):  
Bone Marrow ◽  
Adult Male ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Protein Translation ◽  
Transforming Growth Factor Β ◽  
Activin A ◽  
Male Mice ◽  
Mrna Transcription ◽  
Bone Marrow Derived Cells

Activin A, a member of the transforming growth factor-β family, increases in the circulation within 1 h after administration of bacterial LPS. To clarify the origins of this rapid increase, the distribution of activin A and its binding protein, follistatin, and their production following LPS treatment, were assessed in adult male mice. In untreated mice, activin A was detectable in all 23 tissues examined, with highest mRNA expression (as measured by quantitative RT-PCR) was found in the liver, and the largest concentration of activin A protein (by ELISA) was found in the bone marrow. Likewise, follistatin mRNA and protein were present in all tissues, with highest expression in the vas deferens. Activin A and follistatin mRNA did not increase significantly in any tissue within the first hour after LPS, but activin A protein decreased by 35% in the bone marrow and increased 5-fold in the lung. No significant changes were observed in any other tissue. Activin A reached a peak in the circulation 1 h following LPS, and then declined. Cycloheximide, an inhibitor of protein translation, reduced this increase of activin A by more than 50%. Actinomycin D, an inhibitor of mRNA transcription, had no effect. Circulating follistatin did not increase until 4 h after LPS and was not affected by either inhibitor. These data indicate that the rapid increase in circulating activin A during LPS-induced inflammation is regulated at the posttranscriptional level, apparently from newly translated and stored protein, and implicate bone marrow-derived cells, and, in particular, neutrophils, as a significant source of this preformed activin A.

scholarly journals Age and sex dimorphisms contribute to the severity of bleomycin-induced lung injury and fibrosis

2011 ◽  
Vol 301 (4) ◽  
pp. L510-L518 ◽  
Author(s):  
Elizabeth F. Redente ◽  
Kristen M. Jacobsen ◽  
Joshua J. Solomon ◽  
Abigail R. Lara ◽  
Sarah Faubel ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Bronchoalveolar Lavage ◽  
Lung Disease ◽  
Bronchoalveolar Lavage Fluid ◽  
Transforming Growth Factor ◽  
Young Male ◽  
Lavage Fluid ◽  
Male Mice ◽  
Female Mice ◽  
Age And Sex

Fibrotic interstitial pneumonias are more prevalent in males of advancing age, although little is known about the underlying mechanisms. To evaluate the contributions of age and sex to the development of pulmonary fibrosis, we intratracheally instilled young (8–12 wk) and aged (52–54 wk) male and female mice with bleomycin and assessed the development and severity of fibrotic lung disease by measurements of lung collagen levels, static compliance, leukocyte infiltration, and stereological quantification of fibrotic areas in histological sections. We also quantified proinflammatory and profibrotic chemokine and cytokine levels in the bronchoalveolar lavage fluid. Aged male mice developed more severe lung disease, indicated by increased mortality, increased collagen deposition, and neutrophilic alveolitis compared with aged female mice or young mice of either sex. Aged male mice also exhibited increased levels of transforming growth factor-β, IL-17A, and CXCL1 in their bronchoalveolar lavage fluid. Young male mice developed a more fibrotic disease after bleomycin instillation compared with female mice, regardless of age. There was no difference in fibrosis between young and aged female mice. Taken together, these findings suggest that the variables of advanced age and male sex contribute to the severity of pulmonary fibrosis in this model. Our findings also emphasize the importance of stratifying experimental groups on the basis of age and sex in experimental and epidemiological studies of this nature.

scholarly journals Local versus systemic control of bone and skeletal muscle mass by components of the transforming growth factor-β signaling pathway

2021 ◽  
Vol 118 (33) ◽  
pp. e2111401118
Author(s):  
Yewei Liu ◽  
Adam Lehar ◽  
Renata Rydzik ◽  
Harshpreet Chandok ◽  
Yun-Sil Lee ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Muscle Mass ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
The Body ◽  
Dependent Manner ◽  
Bone Homeostasis ◽  
Mineral Density

Skeletal muscle and bone homeostasis are regulated by members of the myostatin/GDF-11/activin branch of the transforming growth factor-β superfamily, which share many regulatory components, including inhibitory extracellular binding proteins and receptors that mediate signaling. Here, we present the results of genetic studies demonstrating a critical role for the binding protein follistatin (FST) in regulating both skeletal muscle and bone. Using an allelic series corresponding to varying expression levels of endogenous Fst, we show that FST acts in an exquisitely dose-dependent manner to regulate both muscle mass and bone density. Moreover, by employing a genetic strategy to target Fst expression only in the posterior (caudal) region of the animal, we show that the effects of Fst loss are mostly restricted to the posterior region, implying that locally produced FST plays a much more important role than circulating FST with respect to regulation of muscle and bone. Finally, we show that targeting receptors for these ligands specifically in osteoblasts leads to dramatic increases in bone mass, with trabecular bone volume fraction being increased by 12- to 13-fold and bone mineral density being increased by 8- to 9-fold in humeri, femurs, and lumbar vertebrae. These findings demonstrate that bone, like muscle, has an enormous inherent capacity for growth that is normally kept in check by this signaling system and suggest that the extent to which this regulatory mechanism may be used throughout the body to regulate tissue mass may be more significant than previously appreciated.

scholarly journals Cortical bone gain following loading is site-specifically enhanced by prior and concurrent disuse in aged male mice

2019 ◽  
Author(s):  
Gabriel Galea ◽  
Peter J Delisser ◽  
Lee Meakin ◽  
Lance E Lanyon ◽  
Joanna S Price ◽  
...  
Keyword(s):  
Bone Mass ◽  
Cortical Bone ◽  
List Type ◽  
Male Mice ◽  
Site Specific ◽  
Female Mice ◽  
Age Related ◽  
Sciatic Neurectomy ◽  
Bone Gain ◽  
Old Mice

AbstractThe primary aim of bone anabolic therapies is to strategically increase bone mass in skeletal regions likely to experience high strains. This is naturally achieved by mechanical loading of the young healthy skeleton. However, these bone anabolic responses fail with age. Here, we applied site specificity analysis to map regional differences in bone anabolic responses to axial loading of the tibia (tri-weekly, for two weeks) between young (19-week-old) and aged (19-month-old), male and female mice. Loading increased bone mass specifically in the proximal tibia in both sexes and ages. Young female mice gained more cortical bone than young males in specific regions of the tibia. However, these site-specific sex difference were lost with age such that bone gain following loading was not significantly different between old males and females. Having previously demonstrated that prior and concurrent disuse enhances bone gain following loading in old females, we established whether this “rescue” is sex-specific. Old male mice were subjected to sciatic neurectomy or sham surgery, and tri-weekly loading was initiated four days after surgery. Disuse augmented cortical bone gain in response to loading in old male mice, but only in the regions of the tibia which were load-responsive in the young. Increased understanding of how locally-activated load-responsive processes lead to site-specific bone formation, and how the age-related diminution of these processes can be site-specifically enhanced by disuse, may lead to the next generation of strategic bone anabolic therapies.HighlightsSex differences in cortical tissue area of young and old mice are not site-specificThe loading response in young, but not old, mice is sex- and site-specificThe cortical loading response is site-specifically enhanced by disuse in old mice of both sexesThe trabecular loading response can be rescued by disuse in old male, but not female, mice

Selected Contribution: Effects of gender on reduced-size liver ischemia and reperfusion injury

2001 ◽  
Vol 91 (6) ◽  
pp. 2816-2822 ◽  
Author(s):  
Hirohisa Harada ◽  
Kevin P. Pavlick ◽  
Ian N. Hines ◽  
Jason M. Hoffman ◽  
Sulaiman Bharwani ◽  
...  
Keyword(s):  
Liver Injury ◽  
Ischemia And Reperfusion ◽  
Male Mice ◽  
Hepatocellular Injury ◽  
Ischemia And Reperfusion Injury ◽  
Female Mice ◽  
Hepatocellular Damage ◽  
Living Donor Transplantation ◽  
Split Liver ◽  
17Β Estradiol

Hepatic resection with concomitant periods of ischemia and reperfusion (I/R) is a common occurrence in resectional surgery as well as reduced-size liver transplantation (e.g., split liver or living donor transplantation). However, the I/R induced by these types of surgical manipulations may impair liver regeneration, ultimately leading to liver failure. The objectives of the study were to develop a murine model of reduced-size liver I/R and assess the role of gender in this model of hepatocellular injury. We found that 100% of female mice survived the surgery indefinitely, whereas all male mice had greater initial liver injury and died within 5 days after surgery. The protective effect observed in females appeared to be due to ovarian 17β-estradiol, as ovariectomy of females or administration of a selective estrogen antagonist to female mice resulted in enhanced liver injury and greater mortality following reduced-size liver I/R. Conversely, 17β-estradiol-treated male mice exhibited less hepatocellular damage and survived indefinitely. Taken together, these data demonstrate an estrogen-mediated protective pathway(s) that limits or attenuates hepatocellular injury induced by reduced-size liver I/R.

17β-Estradiol replacement improves renal function and pathology associated with diabetic nephropathy

2005 ◽  
Vol 288 (2) ◽  
pp. F399-F405 ◽  
Author(s):  
Richard W. Mankhey ◽  
Faizah Bhatti ◽  
Christine Maric
Keyword(s):  
Renal Function ◽  
Diabetic Nephropathy ◽  
Protective Factor ◽  
Transforming Growth Factor ◽  
Female Gender ◽  
Transforming Growth Factor Β ◽  
Diabetic Animal ◽  
Urine Albumin ◽  
Β Protein ◽  
17Β Estradiol

The protective factor of female gender appears to be lost in diabetes; the incidence of diabetes and its complications, including diabetic nephropathy, are equal in women and men. This study examined the effects of estrogen deficiency by ovariectomy (OVX) and replacement with 17β-estradiol (OVX+E2) on renal function and pathology in the nondiabetic (ND) and streptozotocin (STZ)-induced diabetic (D) rat kidneys for 12 wk. Diabetes was associated with an increase in urine albumin excretion (UAE; ND, 0.39 ± 0.03; D, 5.9 ± 0.8 mg/day; P < 0.001), decrease in creatinine clearance (CrCl; ND, 0.69 ± 0.03; D, 0.43 ± 0.09 mg·min−1·100 g body wt−1; P < 0.05), increase in the index of glomerulosclerosis [GSI; ND, 0.01 ± 0.01; D, 0.15 ± 0.04 arbitrary units (AU); P < 0.01], tubulointerstitial fibrosis (TIFI; ND, 0.04 ± 0.04; D, 0.68 ± 0.2 AU; P < 0.01), and transforming growth factor-β (TGF-β) protein expression (ND, 0.61 ± 0.02; D, 1.25 ± 0.07 AU; P < 0.01). In the D group, the severity of these changes was augmented with OVX (UAE, 8.1 ± 0.6 mg/day; CrCl, 0.40 ± 0.04 mg·min−1·100 g body wt−1; GSI, 0.29 ± 0.04 AU; TIFI, 0.90 ± 0.06 AU; TGF-β, 1.26 ± 0.10 AU), whereas E2 replacement attenuated these changes (UAE, 6.3 ± 0.8 mg/day; CrCl, 0.66 ± 0.03 mg·min−1·100 g body wt−1; GSI, 0.06 ± 0.02 AU; TIFI, 0.36 ± 0.08 AU; TGF-β, 0.57 ± 0.08 AU). We conclude that E2 deficiency increases the severity of renal disease in a diabetic animal model and that E2 replacement is renoprotective by attenuating the decline in renal function and pathology associated with diabetes.

scholarly journals Crosstalk between 17β-Estradiol and TGF-β Signaling Modulates Glioblastoma Progression

2021 ◽  
Vol 11 (5) ◽  
pp. 564
Author(s):  
Ana M. Hernández-Vega ◽  
Ignacio Camacho-Arroyo
Keyword(s):  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Morphological Changes ◽  
Transforming Growth Factor Β ◽  
Vimentin Expression ◽  
Mesenchymal Transition ◽  
17Β Estradiol ◽  
Human Gbm

Epithelial–mesenchymal transition (EMT) is an essential mechanism contributing to glioblastoma multiforme (GBM) progression, the most common and malignant brain tumor. EMT is induced by signaling pathways that crosstalk and regulate an intricate regulatory network of transcription factors. It has been shown that downstream components of 17β-estradiol (E2) and transforming growth factor β (TGF-β) signaling pathways crosstalk in estrogen-sensitive tumors. However, little is known about the interaction between the E2 and TGF-β signaling components in brain tumors. We have investigated the relationship between E2 and TGF-β signaling pathways and their effects on EMT induction in human GBM-derived cells. Here, we showed that E2 and TGF-β negatively regulated the expression of estrogen receptor α (ER-α) and Smad2/3. TGF-β induced Smad2 phosphorylation and its subsequent nuclear translocation, which E2 inhibited. Both TGF-β and E2 induced cellular processes related to EMT, such as morphological changes, actin filament reorganization, and mesenchymal markers (N-cadherin and vimentin) expression. Interestingly, we found that the co-treatment of E2 and TGF-β blocked EMT activation. Our results suggest that E2 and TGF-β signaling pathways interact through ER-α and Smad2/3 mediators in cells derived from human GBM and inhibit EMT activation induced by both factors alone.

scholarly journals Differences in fracture healing between female and male C57BL/6J mice

2020 ◽  
Author(s):  
Melanie Haffner-Luntzer ◽  
Verena Fischer ◽  
Anita Ignatius
Keyword(s):  
Fracture Healing ◽  
Callus Formation ◽  
Fibrous Tissue ◽  
Biomechanical Testing ◽  
Transgenic Animals ◽  
Male Mice ◽  
Mineral Density ◽  
Fracture Callus ◽  
Female Mice ◽  
Tissue Mineral Density

Abstract Background: Mice are increasingly used in fracture healing research because of the opportunity to use transgenic animals. While both, male and female mice are employed, there is no consensus in the literature whether fracture healing differs between both sexes. Therefore, the aim of the present study was to analyse diaphyseal fracture healing in female and male C57BL/6J mice, a commonly used mouse strain in bone research. Methods: For that purpose, 12-week-old female (17–20 g) and male mice (22–26 g) received a standardised femur midshaft osteotomy stabilised by an external fixator. Mice were euthanized 10 and 21 days after fracture and bone healing was analysed by biomechanical testing, µCT, histology, immunohistochemistry and qPCR. Results: Ten days after fracture, male mice displayed significantly more cartilage but less fibrous tissue in the fracture callus compared to female mice, whereas the amount of bone did not differ. At day 21, male mice showed a significantly larger fracture callus compared to female mice. The relative amount of bone in the fracture callus did not significantly differ between both sexes, whereas its tissue mineral density was significantly higher in male mice on day 21, indicating more mature bone and slightly more rapid fracture healing. These results were confirmed by a significantly greater absolute bending stiffness of the fractured femurs of male mice on day 21. On the molecular level, male mice displayed increased active β-catenin expression in the fracture callus, whereas oestrogen receptor α (ERα) expression was lower. Conclusions: These results suggest that male mice display more rapid fracture healing with more prominent cartilaginous callus formation. This might be due to the higher weight of male mice, resulting in increased mechanical loading of the fracture. Furthermore, male mice displayed significantly greater activation of osteoanabolic Wnt/β-catenin signalling, which might also contribute to more rapid bone regeneration.

scholarly journals Local Sympathectomy Promotes Anti-inflammatory Responses and Relief of Paclitaxel-induced Mechanical and Cold Allodynia in Mice

2020 ◽  
Vol 132 (6) ◽  
pp. 1540-1553
Author(s):  
Raquel Tonello ◽  
Wenrui Xie ◽  
Sang Hoon Lee ◽  
Min Wang ◽  
Xiaojuan Liu ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Growth Factor ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Mechanical Allodynia ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Sympathetic Blockade ◽  
Male Mice ◽  
Cold Allodynia

Abstract Background Patients undergoing cancer treatment often experience chemotherapy-induced neuropathic pain at their extremities, for which there is no U.S. Food and Drug Administration–approved drug. The authors hypothesized that local sympathetic blockade, which is used in the clinic to treat various pain conditions, can also be effective to treat chemotherapy-induced neuropathic pain. Methods A local sympathectomy (i.e., cutting the ipsilateral gray rami entering the spinal nerves near the L3 and L4 dorsal root ganglia) was performed in mice receiving intraperitoneal injections every other day of the chemotherapeutic drug paclitaxel. Sympathectomy effects were then assessed in chemotherapy-induced pain-like behaviors (i.e., mechanical and cold allodynia) and neuroimmune and electrophysiologic responses. Results Local microsympathectomy produced a fast recovery from mechanical allodynia (mean ± SD: sympathectomy vs. sham at day 5, 1.07 ± 0.34 g vs. 0.51 ± 0.17g, n = 5, P = 0.030 in male mice, and 1.08 ± 0.28 g vs. 0.62 ± 0.16 g, n = 5, P = 0.036 in female mice) and prevented the development of cold allodynia in both male and female mice after paclitaxel. Mechanistically, microsympathectomy induced transcriptional increases in dorsal root ganglia of macrophage markers and anti-inflammatory cytokines, such as the transforming growth factor-β. Accordingly, depletion of monocytes/macrophages and blockade of transforming growth factor-β signaling reversed the relief of mechanical allodynia by microsympathectomy. In particular, exogenous transforming growth factor-β was sufficient to relieve mechanical allodynia after paclitaxel (transforming growth factor-β 100 ng/site vs. vehicle at 3 h, 1.21 ± 0.34g vs. 0.53 ± 0.14 g, n = 5, P = 0.001 in male mice), and transforming growth factor-β signaling regulated neuronal activity in dorsal root ganglia. Conclusions Local sympathetic nerves control the progression of immune responses in dorsal root ganglia and pain-like behaviors in mice after paclitaxel, raising the possibility that clinical strategies already in use for local sympathetic blockade may also offer an effective treatment for patients experiencing chemotherapy-induced neuropathic pain. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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