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Journal of Biomedical Research May 2024Previous studies have shown that differentiated embryo-chondrocyte expressed gene 1 (DEC1) promotes osteoblast osteogenesis. To investigate the role of DEC1 in...
Previous studies have shown that differentiated embryo-chondrocyte expressed gene 1 (DEC1) promotes osteoblast osteogenesis. To investigate the role of DEC1 in postmenopausal osteoporosis (PMOP), we utilized the two types (DEC1 , DEC1 ) mice to establish an ovariectomy (OVX) model and found that the bone loss in DEC1 OVX mice were much less than that in DEC1 OVX mice. The expression levels of RUNX2 and OSX significantly increased in DEC1 OVX mice compared with those in DEC1 OVX mice. Whereas, NFATc1, c-Fos, CTSK and RANKL/OPG significantly decreased in DEC1 OVX mice compared with those in DEC1 OVX mice. Likewise, DEC1 deficiency suppressed IL-6 and IL-1β. Further study showed , , and significantly increased in DEC1 OVX BMSCs compared with those in DEC1 OVX BMSCs. And the mRNA levels of , and increased significantly in DEC1 OVX BMMs compared with those in DEC1 sham BMMs, but not in DEC1 OVX BMMs compared with those in DEC1 sham BMMs. Furthermore, the p-IκBα and p-P65 significantly increased in DEC1 OVX BMMs compared with those in DEC1 sham BMMs, but did not increase in DEC1 OVX BMMs compared with those in DEC1 sham BMMs. Taken together, DEC1 deficiency inhibits the NF-κB pathway induced by OVX, thereby decreasing cytokines, and subsequently, inhibits the decrease of osteogenesis and the increase of osteoclastogenesis caused by OVX. The findings provide a novel understanding of postmenopausal osteoporosis development, which offers potential avenues for the intervention strategies.
PubMed: 38807374
DOI: 10.7555/JBR.38.20240069 -
PeerJ 2024We propose a new mouse (C57Bl6/J) model combining several features of heart failure with preserved ejection fraction encountered in older women, including hypertension...
We propose a new mouse (C57Bl6/J) model combining several features of heart failure with preserved ejection fraction encountered in older women, including hypertension from Angiotensin II infusion (AngII), menopause, and advanced age. To mimic menopause, we delayed ovariectomy (Ovx) at 12 months of age. We also studied the effects of AngII infusion for 28 days in younger animals and the impact of losing gonadal steroids earlier in life. We observed that AngII effects on heart morphology were different in younger and adult mice (3- and 12-month-old; 20 and 19% increase in heart weight. < 0.01 for both) than in older animals (24-month-old; 6%; not significant). Ovariectomy at 12 months restored the hypertrophic response to AngII in elderly females (23%, = 0.0001). We performed a bulk RNA sequencing study of the left ventricle (LV) and left atrial gene expression in elderly animals, controls, and Ovx. AngII modulated (|Log fold change| ≥ 1) the LV expression of 170 genes in control females and 179 in Ovx ones, 64 being shared. In the left atrium, AngII modulated 235 genes in control females and 453 in Ovx, 140 shared. We observed many upregulated genes associated with the extracellular matrix regulation in both heart chambers. Many of these upregulated genes were shared between the ventricle and the atrium as well as in control and Ovx animals, namely for the most expressed , and . Several circadian clock LV genes were modulated differently by AngII between control and Ovx females ( and ). In conclusion, sex hormones, even in elderly female mice, modulate the heart's hypertrophic response to AngII. Our study identifies potential new markers of hypertensive disease in aging female mice and possible disturbances of their cardiac circadian clock.
Topics: Animals; Female; Angiotensin II; Disease Models, Animal; Mice; Hypertension; Mice, Inbred C57BL; Ovariectomy; Aging; Heart Ventricles; Menopause; Humans; Connective Tissue Growth Factor; Heart Atria; Collagen Type III
PubMed: 38799057
DOI: 10.7717/peerj.17434 -
Particle and Fibre Toxicology May 2024Rural regions of the western United States have experienced a noticeable surge in both the frequency and severity of acute wildfire events, which brings significant...
BACKGROUND
Rural regions of the western United States have experienced a noticeable surge in both the frequency and severity of acute wildfire events, which brings significant challenges to both public safety and environmental conservation efforts, with impacts felt globally. Identifying factors contributing to immune dysfunction, including endocrinological phenotypes, is essential to understanding how hormones may influence toxicological susceptibility.
METHODS
This exploratory study utilized male and female C57BL/6 mice as in vivo models to investigate distinct responses to acute woodsmoke (WS) exposure with a focus on sex-based differences. In a second set of investigations, two groups were established within the female mouse cohort. In one group, mice experienced ovariectomy (OVX) to simulate an ovarian hormone-deficient state similar to surgical menopause, while the other group received Sham surgery as controls, to investigate the mechanistic role of ovarian hormone presence in driving immune dysregulation following acute WS exposure. Each experimental cohort followed a consecutive 2-day protocol with daily 4-h exposure intervals under two conditions: control HEPA-filtered air (FA) and acute WS to simulate an acute wildfire episode.
RESULTS
Metals analysis of WS particulate matter (PM) revealed significantly increased levels of Cu, W, Pb, and U, compared to filtered air (FA) controls, providing insights into the specific metal components most impacted by the changing dynamics of wildfire occurrences in the region. Male and female mice exhibited diverse patterns in lung mRNA cytokine expression following WS exposure, with males showing downregulation and females displaying upregulation, notably for IL-1β, TNF-α, CXCL-1, CCL-5, TGF-β, and IL-6. After acute WS exposure, there were notable differences in the responses of macrophages, neutrophils, and bronchoalveolar lavage (BAL) cytokines IL-10, IL-6, IL-1β, and TNF-α. Significant diverse alterations were observed in BAL cytokines, specifically IL-1β, IL-10, IL-6, and TNF-α, as well as in the populations of immune cells, such as macrophages and polymorphonuclear leukocytes, in both Sham and OVX mice, following acute WS exposure. These findings elucidated the profound influence of hormonal changes on inflammatory outcomes, delineating substantial sex-related differences in immune activation and revealing altered immune responses in OVX mice due to ovarian hormone deficiency. In addition, the flow cytometry analysis highlighted the complex interaction between OVX surgery, acute WS exposure, and their collective impact on immune cell populations within the hematopoietic bone marrow niche.
CONCLUSIONS
In summary, both male and female mice, alongside females subjected to OVX and those who had sham surgery, exhibit significant variations in the expression of proinflammatory cytokines, chemokines, lung mRNA gene expression, and related functional networks linked to signaling pathways. These differences potentially act as mediators of sex-specific and hormonal influences in the systemic inflammatory response to acute WS exposure during a wildfire event. Understanding the regulatory roles of genes expressed differentially under environmental stressors holds considerable implications, aiding in identifying sex-specific therapeutic targets for addressing acute lung inflammation and injury.
Topics: Animals; Female; Male; Mice, Inbred C57BL; Inhalation Exposure; Wildfires; Particulate Matter; Sex Factors; Cytokines; Lung; Smoke; Air Pollutants; Bronchoalveolar Lavage Fluid; Ovariectomy; Mice; Ovary
PubMed: 38797836
DOI: 10.1186/s12989-024-00587-5 -
Nutrients May 2024Recent interest in preventing the development of osteoporosis has focused on the regulation of redox homeostasis. However, the action of lycopene (LYC), a strong natural...
Recent interest in preventing the development of osteoporosis has focused on the regulation of redox homeostasis. However, the action of lycopene (LYC), a strong natural antioxidant compound, on osteoporotic bone loss remains largely unknown. Here, we show that oral administration of LYC to OVX rats for 12 weeks reduced body weight gain, improved lipid metabolism, and preserved bone quality. In addition, LYC treatment inhibited ROS overgeneration in serum and bone marrow in OVX rats, and in BMSCs upon HO stimulation, leading to inhibiting adipogenesis and promoting osteogenesis during bone remodeling. At the molecular level, LYC improved bone quality via an increase in the expressions of FoxO1 and Runx2 and a decrease in the expressions of PPARγ and C/EBPα in OVX rats and BMSCs. Collectively, these findings suggest that LYC attenuates osteoporotic bone loss through promoting osteogenesis and inhibiting adipogenesis via regulation of the FoxO1/PPARγ pathway driven by oxidative stress, presenting a novel strategy for osteoporosis management.
Topics: Animals; Osteogenesis; Adipogenesis; Lycopene; PPAR gamma; Mesenchymal Stem Cells; Female; Ovariectomy; Signal Transduction; Rats; Rats, Sprague-Dawley; Osteoporosis; Oxidative Stress; Forkhead Box Protein O1; Antioxidants; Reactive Oxygen Species
PubMed: 38794681
DOI: 10.3390/nu16101443 -
Medicina (Kaunas, Lithuania) Apr 2024: The hormonal state of hypoestrogenism is associated with the accumulation of white adipose tissue, which can induce an increase in pro-inflammatory markers, leading to...
: The hormonal state of hypoestrogenism is associated with the accumulation of white adipose tissue, which can induce an increase in pro-inflammatory markers, leading to progressive health complications. Melatonin can act on adipose tissue mass, promoting its reduction and influencing inflammation, reducing IL-6 and releasing IL-10, pro- and anti-inflammatory markers, respectively. However, the role of melatonin regarding such parameters under the context of hypoestrogenism remains unknown. The aim of this study was to determine the effect of 12 weeks of hypoestrogenism and melatonin on white adipose tissue mass and circulating levels of IL-6, IL-10, TGF-β-1, and leukotriene C4 (LTC4). : The animals (Wistar rats with sixteen weeks of age at the beginning of the experiment) under hypoestrogenism were submitted to the surgical technique of bilateral ovariectomy. The animals received melatonin (10 mg·kg) or vehicles by orogastric gavage every day for 12 weeks and administration occurred systematically 1 h after the beginning of the dark period. White adipose tissue (perigonadal, peritoneal, and subcutaneous) was collected for mass recording, while blood was collected for the serum determination of IL-6, IL-10, TGF-β-1, and LTC4. : Hypoestrogenism increased the perigonadal and subcutaneous mass and IL-6 levels. Melatonin kept hypoestrogenic animals in physiological conditions similar to the control group and increased thymus tissue mass. : Hypoestrogenism appears to have a negative impact on white adipose tissue mass and IL-6 and although melatonin commonly exerts a significant effect in preventing these changes, this study did not have a sufficiently negative impact caused by hypoestrogenism for melatonin to promote certain benefits.
Topics: Animals; Melatonin; Rats, Wistar; Rats; Female; Interleukin-6; Biomarkers; Adipose Tissue; Interleukin-10; Ovariectomy; Inflammation; Transforming Growth Factor beta1; Estrogens; Adipose Tissue, White
PubMed: 38792922
DOI: 10.3390/medicina60050740 -
International Journal of Molecular... May 2024Heart failure with preserved ejection fraction (HFpEF) is more prevalent in post- compared to pre-menopausal women. The underlying mechanisms are not fully understood....
Cardiac Left Ventricular miRNA-26a Is Downregulated in Ovariectomized Mice, Upregulated upon 17-Beta Estradiol Replacement, and Inversely Correlated with Collagen Type 1 Gene Expression.
Heart failure with preserved ejection fraction (HFpEF) is more prevalent in post- compared to pre-menopausal women. The underlying mechanisms are not fully understood. Data in humans is confounded by age and co-morbidities. We investigated the effects of ovariectomy and estrogen replacement on the left ventricular (LV) gene expression of pro-inflammatory and pro-fibrotic factors involved in HFpEF and putative regulating miRNAs. Nine-week-old C57BL/6 female mice were subjected to ovariectomy (OVX) or SHAM operation. OVX and SHAM groups were sacrificed 1-, 6-, and 12-weeks post-surgery (T1/SHAM; T1/OVX; T6/SHAM; T6/OVX, T12/SHAM). 17β-estradiol (E) or vehicle (VEH) was then administered to the OVX groups for 6 weeks (T12/OVX/E2; T12/OVX/VEH). Another SHAM group was sacrificed 12-weeks post-surgery. RNA and miRNAs were extracted from the LV apex. An early 3-fold increase in the gene expression of , , , , , and was observed one-week post-surgery in T1/OVX vs. T1/SHAM, but not at later time points. miRNA-26a was lower in T1/OVX vs. T1/SHAM and was inversely correlated with and expression 1-week post-surgery (r = -0.79 < 0.001; r = -0.6 = 0.007). miRNAs-26a, 29b, and 133a were significantly higher, while , , , , , , and gene expression was significantly lower in E- compared to vehicle-treated OVX mice. miRNA-26a was inversely correlated with in T12/OVX/ E (r = -0.56 = 0.02). OVX triggered an early increase in the gene expression of pro-inflammatory and pro-fibrotic factors, highlighting the importance of the early phase post-cessation of ovarian function. E replacement therapy, even if it was not immediately initiated after OVX, reversed these unfavorable changes and upregulated cardiac miRNA-26a, previously unknown to be affected by menopausal status.
Topics: Animals; MicroRNAs; Ovariectomy; Female; Estradiol; Mice; Collagen Type I; Heart Ventricles; Mice, Inbred C57BL; Collagen Type III; Gene Expression Regulation; Down-Regulation; Heart Failure; Collagen Type I, alpha 1 Chain; Up-Regulation; Interleukin-6; Interleukin-1alpha; Estrogen Replacement Therapy
PubMed: 38791190
DOI: 10.3390/ijms25105153 -
International Journal of Molecular... May 2024Menopause is characterized by a reduction in sex hormones in women and is associated with metabolic changes, including fatty liver and insulin resistance. Lifestyle...
Menopause is characterized by a reduction in sex hormones in women and is associated with metabolic changes, including fatty liver and insulin resistance. Lifestyle changes, including a balanced diet and physical exercise, are necessary to prevent these undesirable changes. Strength training (ST) has been widely used because of the muscle and metabolic benefits it provides. Our study aims to evaluate the effects of ST on hepatic steatosis and insulin resistance in ovariectomized mice fed a high-fat diet (HFD) divided into four groups as follows: simulated sedentary surgery (SHAM-SED), trained simulated surgery (SHAM-EXE), sedentary ovariectomy (OVX-SED), and trained ovariectomy (OVX-EXE). They were fed an HFD for 9 weeks. ST was performed thrice a week. ST efficiently reduced body weight and fat percentage and increased lean mass in OVX mice. Furthermore, ST reduced the accumulation of ectopic hepatic lipids, increased AMPK phosphorylation, and inhibited the de novo lipogenesis pathway. OVX-EXE mice also showed a better glycemic profile, associated with greater insulin sensitivity identified by the euglycemic-hyperinsulinemic clamp, and reduced markers of hepatic oxidative stress compared with sedentary animals. Our data support the idea that ST can be indicated as a non-pharmacological treatment approach to mitigate metabolic changes resulting from menopause.
Topics: Animals; Insulin Resistance; Female; Ovariectomy; Diet, High-Fat; Mice; Resistance Training; Fatty Liver; Physical Conditioning, Animal; Oxidative Stress; Liver; Mice, Inbred C57BL; Body Weight; Lipogenesis
PubMed: 38791103
DOI: 10.3390/ijms25105066 -
Biomedicine & Pharmacotherapy =... May 2024Obesity is a multifaceted medical condition characterized by the pathological accumulation of excessive lipids in the body. We investigated the effects of morroniside, a...
Obesity is a multifaceted medical condition characterized by the pathological accumulation of excessive lipids in the body. We investigated the effects of morroniside, a bioactive compound derived from Cornus officinalis, on adipogenesis. We used a preadipocyte 3T3-L1 stable cell line and primary cultured adipose-derived stem cells (ADSCs) in vitro and ovariectomized (OVX) and a high-fat diet (HFD)-fed obese mouse model in vivo. Preadipocyte 3T3-L1 cells and ADSCs incubated with morroniside during adipocyte differentiation and obese mice subjected to OVX and HFD received oral morroniside treatment for 12 weeks. Morroniside treatment significantly reduced adipocyte differentiation and fatty acid accumulation and downregulated adipogenesis-related gene expression, concomitant with a decrease in triglyceride content and an increase in glycerol release in cells. The results of the in vivo study showed that morroniside ameliorated obesity-related phenotypes by reducing body weight gain, hepatic steatosis, and adipose tissue in obese mice. These findings suggest that morroniside is a promising compound for preventing and treating obesity.
PubMed: 38788597
DOI: 10.1016/j.biopha.2024.116762 -
Journal of Functional Biomaterials May 2024The aim of this study was to evaluate the effect of local administration of melatonin (MLT) on molecular biomarkers and calvaria bone critical defects in female rats...
The aim of this study was to evaluate the effect of local administration of melatonin (MLT) on molecular biomarkers and calvaria bone critical defects in female rats with or without osteoporosis, associated or not with a xenogeneic biomaterial. Forty-eight female rats were randomly divided into two groups: (O) ovariectomized and (S) placebo groups. After 45 days of osteoporosis induction, two critical-size defects (5 mm diameter) were created on the calvaria. The groups were subdivided according to the following treatment: (C) Clot, MLT, MLT associated with Bio-Oss (MLTBO), and Bio-Oss (BO). After 45 days, the defect samples were collected and processed for microtomography, histomorphometry, and biomolecular analysis (Col-I, BMP-2, and OPN). All animals had one femur harvested to confirm the osteoporosis. Microtomography analysis demonstrated a bone mineral density reduction in the O group. Regarding bone healing, the S group presented greater filling of the defects than the O group; however, in the O group, the defects treated with MLT showed higher mineral filling than the other treatments. There was no difference between the treatments performed in the S group ( = 0.05). Otherwise, O-MLT had neoformed bone higher than in the other groups ( = 0.05). The groups that did not receive biomaterial demonstrated lower levels of Col-I secretion; S-MLT and S-MLTBO presented higher levels of OPN, while O-C presented statistically lower results ( < 0.05); O-BO showed greater BMP-2 secretion ( < 0.05). In the presence of ovariectomy-induced osteoporosis, MLT treatment increased the newly formed bone area, regulated the inflammatory response, and increased OPN expression.
PubMed: 38786635
DOI: 10.3390/jfb15050124 -
Journal of Orthopaedic Surgery and... May 2024Elderly patients suffering from osteoporotic fractures are more susceptible to delayed union or nonunion, and their bodies then are in a state of low-grade chronic...
BACKGROUND
Elderly patients suffering from osteoporotic fractures are more susceptible to delayed union or nonunion, and their bodies then are in a state of low-grade chronic inflammation with decreased antioxidant capacity. Tanshinone IIA is widely used in treating cardiovascular and cerebrovascular diseases in China and has anti-inflammatory and antioxidant effects. We aimed to observe the antioxidant effects of Tanshinone IIA on mesenchymal stem cells (MSCs), which play important roles in bone repair, and the effects of local application of Tanshinone IIA using an injectable biodegradable hydrogel on osteoporotic fracture healing.
METHODS
MSCs were pretreated with or without different concentrations of Tanshinone IIA followed by HO treatment. Ovariectomized (OVX) C57BL/6 mice received a mid-shaft transverse osteotomy fracture on the left tibia, and Tanshinone IIA was applied to the fracture site using an injectable hydrogel.
RESULTS
Tanshinone IIA pretreatment promoted the expression of nuclear factor erythroid 2-related factor 2 and antioxidant enzymes, and inhibited HO-induced reactive oxygen species accumulation in MSCs. Furthermore, Tanshinone IIA reversed HO-induced apoptosis and decrease in osteogenic differentiation in MSCs. After 4 weeks of treatment with Tanshinone IIA in OVX mice, the bone mineral density of the callus was significantly increased and the biomechanical properties of the healed tibias were improved. Cell apoptosis was decreased and Nrf2 expression was increased in the early stage of callus formation.
CONCLUSIONS
Taken together, these results indicate that Tanshinone IIA can activate antioxidant enzymes to protect MSCs from HO-induced cell apoptosis and osteogenic differentiation inhibition. Local application of Tanshinone IIA accelerates fracture healing in ovariectomized mice.
Topics: Animals; Abietanes; Female; Mesenchymal Stem Cells; Apoptosis; Mice, Inbred C57BL; Fracture Healing; Ovariectomy; Mice; Antioxidants; Hydrogen Peroxide; Osteogenesis; Osteoporotic Fractures
PubMed: 38783358
DOI: 10.1186/s13018-024-04793-x