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Brazilian Oral Research 2024The aim of this systematic review was to answer the following question: "Does alendronate, a nitrogen-containing bisphosphonate, improve or impair alveolar socket...
The aim of this systematic review was to answer the following question: "Does alendronate, a nitrogen-containing bisphosphonate, improve or impair alveolar socket healing after tooth extraction in animal models"? To this end, a systematic review of the literature was carried out in PubMed, Scopus, LILACS, Web of Science, as well as in the gray literature up to May 2023. Preclinical studies that evaluated alveolar healing after tooth extraction and the intake of sodium alendronate compared with placebo were included. Two investigators were responsible for screening the articles independently, extracting the data, and assessing their quality through the SYRCLE's RoB tool for randomized trials in animal studies. The study selection process, study characteristics, risk of bias in studies, impact of alendronate on bone healing, and certainty of evidence were described in text and table formats. Methodological differences among the studies were restricted to the synthesis methods. The synthesis of qualitative results followed the Synthesis Without Meta-analysis (SWiM) reporting guideline. From the 19 included studies, five were considered to have low risk, three were of unclear risk, and eleven presented a high risk of bias. The studies were considered heterogeneous regarding alendronate posology, including its dosage and route of administration. Furthermore, a variety of animal species, different age ranges, diverse teeth extracted, and exposure or not to ovariectomy contributed to the lack of parity of the selected studies. Our results indicated that alendronate monotherapy negatively affects the early phase of wound healing after tooth extraction in preclinical studies, suggesting that the bone resorption process after tooth extraction in animals treated with alendronate might impair the bone healing process of the extraction socket. In conclusion, alendronate administration restrains bone resorption, thereby delaying alveolar socket healing . Future studies should be conducted to validate these findings and to better understand the effects of alendronate therapy on oral tissues.
Topics: Alendronate; Tooth Extraction; Animals; Wound Healing; Tooth Socket; Bone Density Conservation Agents
PubMed: 38747825
DOI: 10.1590/1807-3107bor-2024.vol38.0038 -
Research Square May 2024Osteoporosis is incurable because there are no dual antiresorptive and anabolic therapeutic agents that can be administered long-term. The most widely used...
Osteoporosis is incurable because there are no dual antiresorptive and anabolic therapeutic agents that can be administered long-term. The most widely used antiresorptive agents, bisphosphonates (BPs), also inhibit bone formation and thus have limited effect in preventing osteoporotic fracture. Hydroxychloroquine (HCQ), which is used to treat rheumatoid arthritis, prevents the lysosomal degradation of TNF receptor-associated factor 3 (TRAF3), an NF-κB adaptor protein that limits bone resorption and maintains bone formation. We attempted to covalently link HCQ to a hydroxyalklyl BP (HABP) with anticipated low antiresorptive activity, to target delivery of HCQ to bone to test if this targeting increases its efficacy to prevent TRAF3 degradation in the bone microenvironment and thus reduce bone resorption and increase bone formation, while reducing its systemic side effects. Unexpectedly, HABP-HCQ was found to exist as a salt in aqueous solution, composed of a protonated HCQ cation and a deprotonated HABP anion. Nevertheless, it inhibited osteoclastogenesis, stimulated osteoblast differentiation, and increased TRAF3 protein levels in vitro. HABP-HCQ significantly inhibited both osteoclast formation and bone marrow fibrosis in mice given multiple daily PTH injections. In contrast, HCQ inhibited fibrosis, but not osteoclast formation, while the HABP alone inhibited osteoclast formation, but not fibrosis, in the mice. HABP-HCQ, but not HCQ, prevented trabecular bone loss following ovariectomy in mice and, importantly, increased bone volume in ovariectomized mice with established bone loss because HABP-HCQ increased bone formation and decreased bone resorption parameters simultaneously. In contrast, HCQ increased bone formation, but did not decrease bone resorption parameters, while HABP also restored the bone lost in ovariectomized mice, but it inhibited parameters of both bone resorption and formation. Our findings suggest that the combination of HABP and HCQ could have dual antiresorptive and anabolic effects to prevent and treat osteoporosis.
PubMed: 38746138
DOI: 10.21203/rs.3.rs-4237258/v1 -
Chinese Medicine May 2024Postmenopausal osteoporosis is a chronic metabolic bone disease caused by excessive osteoclast formation and function. Targeting osteoclast differentiation and activity...
BACKGROUND
Postmenopausal osteoporosis is a chronic metabolic bone disease caused by excessive osteoclast formation and function. Targeting osteoclast differentiation and activity can modulate bone resorption and alleviate osteoporosis. Cirsilineol, an active constituent of Vestita Wall, has shown numerous biological activities and has been used to treat many metabolic diseases. However, whether cirsilineol inhibits osteoclast activity and prevents postmenopausal osteoporosis still remain unknown.
MATERIALS AND METHODS
Primary bone marrow macrophages (BMMs) and RAW264.7 cells were used. Osteoclast activity was measured by TRAP staining, F-actin staining, and bone resorption assay after BMMs were treated with cirsilineol at concentrations of 0, 1, 2.5 and 5 µM. RT-PCR and western blotting were performed to evaluate the expression of osteoclast-related genes. In addition, female C57BL/6 mice underwent OVX surgery and were treated with cirsilineol (20 mg/kg) to demonstrate the effect of cirsilineol on osteoporosis.
RESULTS
Cirsilineol significantly inhibited receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclast differentiation in a concentration- and time-dependent manner, respectively. Additionally, cirsilineol inhibited F-actin ring formation, thus reducing the activation of bone resorption ability. Cirsilineol suppressed the expression of osteoclast-related genes and proteins via blocking nuclear factor (NF)-κb, ERK, and p38 signaling cascades. More importantly, cirsilineol treatment in mice with osteoporosis alleviated osteoclasts hyperactivation and bone mass loss caused by estrogen depletion.
CONCLUSION
In this study, the protective effect of cirsilineol on osteoporosis has been investigated for the first time. In conclusion, our findings prove the inhibitory effect of cirsilineol on osteoclast activity via NF-κb/ERK/p38 signaling pathways and strongapplication of cirsilineol can be proposed as a potential therapeutic strategy.
PubMed: 38745234
DOI: 10.1186/s13020-024-00938-6 -
Bone Research May 2024Mature osteoclasts degrade bone matrix by exocytosis of active proteases from secretory lysosomes through a ruffled border. However, the molecular mechanisms underlying...
Mature osteoclasts degrade bone matrix by exocytosis of active proteases from secretory lysosomes through a ruffled border. However, the molecular mechanisms underlying lysosomal trafficking and secretion in osteoclasts remain largely unknown. Here, we show with GeneChip analysis that RUN and FYVE domain-containing protein 4 (RUFY4) is strongly upregulated during osteoclastogenesis. Mice lacking Rufy4 exhibited a high trabecular bone mass phenotype with abnormalities in osteoclast function in vivo. Furthermore, deleting Rufy4 did not affect osteoclast differentiation, but inhibited bone-resorbing activity due to disruption in the acidic maturation of secondary lysosomes, their trafficking to the membrane, and their secretion of cathepsin K into the extracellular space. Mechanistically, RUFY4 promotes late endosome-lysosome fusion by acting as an adaptor protein between Rab7 on late endosomes and LAMP2 on primary lysosomes. Consequently, Rufy4-deficient mice were highly protected from lipopolysaccharide- and ovariectomy-induced bone loss. Thus, RUFY4 plays as a new regulator in osteoclast activity by mediating endo-lysosomal trafficking and have a potential to be specific target for therapies against bone-loss diseases such as osteoporosis.
Topics: Animals; Osteoclasts; Lysosomes; Endosomes; Mice; Mice, Knockout; Bone Resorption; Protein Transport; Mice, Inbred C57BL; rab GTP-Binding Proteins; Cell Differentiation; Gene Deletion; Cathepsin K; Female; rab7 GTP-Binding Proteins
PubMed: 38744829
DOI: 10.1038/s41413-024-00326-8 -
Aging May 2024After menopause, the incidence of cardiovascular disease rapidly rises in women. The disappearing protection provided by sex steroids is a consequence of the development...
After menopause, the incidence of cardiovascular disease rapidly rises in women. The disappearing protection provided by sex steroids is a consequence of the development of many risk factors. Preclinical studies are necessary to understand better the effects of ovarian hormones loss cardiac aging. To mimic menopause in mice and study its consequences, we delayed ovariectomy at 12 months and followed animals for 12 months. Using RNA sequencing, we investigated changes in the myocardial exome with aging. In addition, with four-core genotypes (FCG) transgenic mice, we studied sex chromosome effects on cardiac aging. Heart weight increased from 3 to 24 months (males + 35%, females + 29%). In males, 75% of this increase had occurred at 12 months; in females, only 30%. Gonadectomy of mice at 12 months blocked cardiac hypertrophy in both sexes during the second year of life. The dosage of the X chromosomes did not influence cardiac growth in young and older mice. We performed an RNA sequencing study in young and old mice. We identified new highly expressed genes modulated during aging (, , and ). The myocardial exome in older animals displayed few differences related to the animal's sex or the presence or absence of sex steroids for a year. We show that the morphological evolution of the heart depends on the biological sex via gonadal sex hormone actions. The myocardial exome of old male and female mice is relatively similar. Our study emphasizes the need to consider sex steroid effects in studying cardiac aging.
PubMed: 38742935
DOI: 10.18632/aging.205822 -
Frontiers in Endocrinology 2024Increasing evidence suggests that female individuals have a higher Alzheimer's disease (AD) risk associated with post-menopausal loss of circulating estradiol (E)....
Increasing evidence suggests that female individuals have a higher Alzheimer's disease (AD) risk associated with post-menopausal loss of circulating estradiol (E). However, clinical data are conflicting on whether E lowers AD risk. One potential contributing factor is . The greatest genetic risk factor for AD is , a factor that is pronounced in female individuals post-menopause. Clinical data suggests that impacts the response of AD patients to E replacement therapy. However, whether prevents, is neutral, or promotes any positive effects of E is unclear. Therefore, our goal was to determine whether modulates the impact of E on behavior and AD pathology . To that end, mice that express human (E3FAD) or (E4FAD) and overproduce Aβ42 were ovariectomized at either 4 months (early) or 8 months (late) and treated with vehicle or E for 4 months. In E3FAD mice, we found that E mitigated the detrimental effect of ovariectomy on memory, with no effect on Aβ in the early paradigm and only improved learning in the late paradigm. Although E lowered Aβ in E4FAD mice in the early paradigm, there was no impact on learning or memory, possibly due to higher Aβ pathology compared to E3FAD mice. In the late paradigm, there was no effect on learning/memory and Aβ pathology in E4FAD mice. Collectively, these data support the idea that, in the presence of Aβ pathology, impacts the response to E supplementation post-menopause.
Topics: Animals; Estradiol; Ovariectomy; Female; Apolipoprotein E3; Mice, Transgenic; Mice; Apolipoprotein E4; Alzheimer Disease; Humans; Behavior, Animal; Amyloid beta-Peptides; Disease Models, Animal
PubMed: 38742194
DOI: 10.3389/fendo.2024.1374825 -
Cureus Apr 2024Struma ovarii is a monodermal teratoma characterized by the presence of >50% thyroid tissue. It is mostly benign; therefore, preoperative diagnosis is important. It...
Struma ovarii is a monodermal teratoma characterized by the presence of >50% thyroid tissue. It is mostly benign; therefore, preoperative diagnosis is important. It usually manifests as a multilocular cystic mass but rarely as a predominantly solid mass. On magnetic resonance imaging (MRI), solid-appearing struma ovarii showed early signal intensity enhancement on dynamic gadolinium-enhanced T1-weighted images, which histopathologically indicates the presence of thyroid tissue with abundant blood vessels. The Ovarian-Adnexal Reporting and Data System (O-RADS) MRI score is a validated classification worldwide for characterizing adnexal lesions. Based on the morphology, signal intensity, and enhancement of any solid tissue on the MRI, the scoring system can be used to classify adnexal lesions into five categories from score one (no adnexal mass) to score five (high risk of malignancy). An adnexal solid mass with a higher signal intensity than that of the myometrium 30-40 seconds after gadolinium (Gd) injection on non-dynamic contrast-enhanced (non-DCE) MRI was assigned a score of 5 (high risk of malignancy). We present a case of solid-appearing struma ovarii with a higher signal intensity than that of the myometrium 30 seconds after Gd injection on non-DCE MRI, and it was classified as score five preoperatively. Therefore, a total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed despite the presence of a benign ovarian mass. When an adnexal mass with a higher signal intensity than that of the myometrium 30-40 seconds after Gd injection on non-DCE MRI is encountered, struma ovarii should be included in the differential diagnosis, despite the O-RADS MRI score of five and management of the situation should be discussed.
PubMed: 38741801
DOI: 10.7759/cureus.58176 -
Biochimica Et Biophysica Acta.... May 2024Olanzapine (OLA) is a highly obesogenic second-generation antipsychotic (SGA). Recently we demonstrated that, contrarily to OLA oral treatment, intraperitoneal (i.p.)...
Olanzapine (OLA) is a highly obesogenic second-generation antipsychotic (SGA). Recently we demonstrated that, contrarily to OLA oral treatment, intraperitoneal (i.p.) administration resulted in weight loss and absence of hepatic steatosis in wild-type (WT) and protein tyrosine phosphatase 1B (PTP1B)-deficient (KO) male mice. This protection relied on two central-peripheral axes connecting hypothalamic AMPK with brown/inguinal white adipose tissue (BAT/iWAT) uncoupling protein-1 (UCP-1) and hypothalamic JNK with hepatic fatty acid synthase (FAS). Herein, we addressed OLA i.p. treatment effects in WT and PTP1B-KO female mice. Contrarily to our previous results in WT females receiving OLA orally, the i.p. treatment did not induce weight gain or hyperphagia. Molecularly, in females OLA failed to diminish hypothalamic phospho-AMPK or elevate BAT UCP-1 and energy expenditure (EE) despite the preservation of iWAT browning. Conversely, OLA i.p. treatment in ovariectomized mice reduced hypothalamic phospho-AMPK, increased BAT/iWAT UCP-1 and EE, and induced weight loss as occurred in males. Pretreatment of hypothalamic neurons with 17β-estradiol (E) abolished OLA effects on AMPK. Moreover, neither hypothalamic JNK activation nor hepatic FAS upregulation were found in WT and PTP1B-KO females receiving OLA via i.p. Importantly, this axis was reestablished upon ovariectomy. In this line, E prevented OLA-induced phospho-JNK in hypothalamic neurons. These results support the role of estrogens in sex-related dimorphism in OLA treatment. This study evidenced the benefit of OLA i.p. administration in preventing its obesogenic effects in female mice that could offer clinical value.
PubMed: 38733774
DOI: 10.1016/j.bbadis.2024.167227 -
International Journal of Molecular... Apr 2024This study explores low-intensity extracorporeal shock wave therapy (LiESWT)'s efficacy in alleviating detrusor hyperactivity with impaired contractility (DHIC) induced...
Low-Intensity Extracorporeal Shock Wave Therapy Ameliorates Detrusor Hyperactivity with Impaired Contractility via Transient Potential Vanilloid Channels: A Rat Model for Ovarian Hormone Deficiency.
This study explores low-intensity extracorporeal shock wave therapy (LiESWT)'s efficacy in alleviating detrusor hyperactivity with impaired contractility (DHIC) induced by ovarian hormone deficiency (OHD) in ovariectomized rats. The rats were categorized into the following four groups: sham group; OVX group, subjected to bilateral ovariectomy (OVX) for 12 months to induce OHD; OVX + SW4 group, underwent OHD for 12 months followed by 4 weeks of weekly LiESWT; and OVX + SW8 group, underwent OHD for 12 months followed by 8 weeks of weekly LiESWT. Cystometrogram studies and voiding behavior tracing were used to identify the symptoms of DHIC. Muscle strip contractility was evaluated through electrical-field, carbachol, ATP, and KCl stimulations. Western blot and immunofluorescence analyses were performed to assess the expressions of various markers related to bladder dysfunction. The OVX rats exhibited significant bladder deterioration and overactivity, alleviated by LiESWT. LiESWT modified transient receptor potential vanilloid (TRPV) channel expression, regulating calcium concentration and enhancing bladder capacity. It also elevated endoplasmic reticulum (ER) stress proteins, influencing ER-related Ca channels and receptors to modulate detrusor muscle contractility. OHD after 12 months led to neuronal degeneration and reduced TRPV1 and TRPV4 channel activation. LiESWT demonstrated potential in enhancing angiogenic remodeling, neurogenesis, and receptor response, ameliorating DHIC via TRPV channels and cellular signaling in the OHD-induced DHIC rat model.
Topics: Animals; Female; Rats; TRPV Cation Channels; Extracorporeal Shockwave Therapy; Disease Models, Animal; Muscle Contraction; Urinary Bladder; Urinary Bladder, Overactive; Ovariectomy; Rats, Sprague-Dawley; Ovary
PubMed: 38732143
DOI: 10.3390/ijms25094927 -
Animals : An Open Access Journal From... May 2024The purpose of this study was to evaluate the quality of recovery from general anesthesia with the administration of two low doses of dexmedetomidine in canine patients....
The purpose of this study was to evaluate the quality of recovery from general anesthesia with the administration of two low doses of dexmedetomidine in canine patients. For this blind randomized clinical trial study, 30 dogs undergoing general anesthesia for diagnostic procedures or elective surgery (ovariectomy/castration) were included. The patients were randomly divided into three groups, and at the end of anesthesia, they received a bolus of dexmedetomidine at 1 mcg/kg IV (D1), or a bolus of dexmedetomidine at 0.5 mcg/kg (D0.5), or a bolus of NaCl, in a total of 0.5 mL of solution for all three groups. After administration of the bolus, the anesthetist monitored the patients every 5 min by measuring heart rate, systolic and mean blood pressure, respiratory rate, and oxygen saturation. The quality of recovery was also assessed using 4 different scales. The extubation time, time of headlift, and standing position were also recorded. Both groups receiving dexmedetomidine had better awakening and a lower incidence of delirium when compared to saline administration. The heart rate was lower, while the systolic pressure was higher in the two groups D1 and D0.5 compared to the NaCl with a low presence of atrioventricular blocks. The extubation time resulted significantly higher in the D1 (17 ± 6 min) compared to the D0.5 (10 ± 4 min) and NaCl (8 ± 3 min) ( < 0.0001); the headlift time D1 (25 ± 10 min) resulted significantly longer than the NaCl group (11 ± 5 min) ( = 0.0023) but not than the D0.5 (18 ± 9 min). No significant differences were found among the three groups for standing positioning (D1 50 ± 18 min, D0.5 39 ± 22 min, NaCl 28 ± 17 min). The preventive administration of a bolus of dexmedetomidine at a dosage of 0.5 mcg/kg or 1 mcg/kg IV during the recovery phase improves the quality of recovery in patients undergoing general anesthesia.
PubMed: 38731387
DOI: 10.3390/ani14091383