benzofurans and Osteoporosis

Psoralidin (PSO) is a natural phenolic coumarin that is extracted from the seeds of Psoralea corylifolia L. PSO possesses a variety of pharmacological activities, including anti-oxidative, antibacterial, anti-inflammatory, anti-depressive and estrogenic-like effects. Other studies have indicated that PSO plays a beneficial role in multiple disease, especially cancer and osteoporosis. In this review, we first outline the basic background of PSO. Then we introduced the molecular mechanisms and signaling pathways of PSO in multiple cancers to elucidate its anticancer potential via inducing oxidative stress and apoptosis, inhibiting proliferation, promoting autophagy-dependent cell death, and activating the estrogen receptors (ER)-signaling pathway. Finally, we recommend the direction of future investigations. In general, the information compiled in this paper should serve as a comprehensive repository of information to help design PSO in other research and future efforts.

Topics: Animals; Antineoplastic Agents; Benzofurans; Coumarins; Humans; Neoplasms; Osteoporosis

Most patients with senile osteoporosis (SOP) are severely deficient in bone mass, and treatments using bone resorption inhibitors, such as bisphosphonates, have shown limited efficacy. Small-molecule osteogenesis-promoting drugs are required to improve the treatment for this disease. Previously, we demonstrated that a compound with a benzofuran-like structure promoted bone formation by upregulating BMP-2, and it exhibited a therapeutic effect in SAMP-6 mice, glucocorticoid-induced osteoporosis rats, and ovariectomized rats. In this study, aged C57 and SAMP-6 mice models were used to investigate the therapeutic and preventive effects of compound

Topics: Animals; Benzofurans; Mice; Osteoblasts; Osteogenesis; Osteoporosis; Rats; Structure-Activity Relationship; Zebrafish

Topics: Animals; Apoptosis; Benzofurans; beta Catenin; Cell Differentiation; Glucocorticoids; Male; Mice; Osteoblasts; Osteogenesis; Osteoporosis; Pyrans; Wnt Signaling Pathway

Glucocorticoids (GCs) induce osteoporosis, which results in fractures in the bond, causing significant morbidity. In the conducted study, we examined the antiosteoporosis effect of dieckol against GC-induced osteoporosis in rats.. Sprague-Dawley (SD) rats were used for the current study and dexamethasone (2.5 mg/kg) induced osteoporosis in the rats that received the dieckol (test) and alendronate (standard) for 20 weeks. Bone turnover parameters, microCT, antioxidant, inflammatory cytokines, nutrient, and hormones parameters.. Dieckol noticeably suppressed the body weight and boosted the uterine and vagina weight. Dieckol considerably altered the level of trabecular number (Tb. N), the bone volume to total volume (BV/TV), trabecular separation (Tb.Sp), bone surface to bone volume (BS/BV), and t​r​a​b​e​c​u​l​a​r thickness (Tb.Th). Dieckol noticeably (P < 0.001) elevated the level of osteocalcin (OC) and alleviated the level of bone Gla protein (BGP), acid phosphatase (ACP), alkaline phosphatase (ALP), and β-CTx. Dieckol markedly boosted the level of malondialdehyde (MDA) and suppressed the level of glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) along with the suppression of inflammatory cytokines like TNF-α, IL-1β, and IL-6. Dieckol remarkably increased the level of calcium, potassium, magnesium, and 25 (OH) vitamin D. Dieckol substantially (P < 0.001) boosted the level of estradiol and alleviated the level of parathyroid hormone and tartrate-resistant acid phosphatase (TRAP). Dieckol also suppressed the level of receptor activator of nuclear factor κB ligand (RANKL) and boosted the level of osteoprotegerin (OPG).. Taken together, our data suggest that dieckol demonstrated the anti-osteoporosis effect against GC-induced osteoporosis in rats.

Topics: Animals; Benzofurans; Cytokines; Female; Glucocorticoids; Osteocalcin; Osteoporosis; Rats; Rats, Sprague-Dawley

The bone morphogenetic protein (BMP) pathway is a promising new target for the design of therapeutic agents for the treatment of low bone mass. This study optimized the structure of the anti-osteoporosis compound 38 by balancing its lipophilicity and improving its stability. Twenty derivatives which were not reported in the literature were designed and synthesized. The ovariectomized rat model of osteoporosis was selected to evaluate the therapeutic effects. Compound 125 showed better therapeutic efficacy than that of 38. We verified the anti-osteoporosis activity and BMP-2 protein upregulation after treatment with 125 in a zebrafish osteoporosis model. We found that 125 improved the ADME properties, therapeutic efficacy, and pharmacokinetics of the drug. Overall, we evaluated the anti-osteoporosis effects of the compounds of this type, preliminarily determined the target patient population, verified the mechanism of action, clarified the level of toxicity, and provided preliminary ADME data. We believe that these compounds can both correct bone loss that is already occurring in patients and have broad clinical applicability.

Topics: Animals; Benzofurans; Bone Morphogenetic Protein 2; Caco-2 Cells; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Mice; Mice, Inbred BALB C; Molecular Structure; Osteoporosis; Ovariectomy; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Thiophenes; Zebrafish

Sanggenon C (SC), which is a natural flavonoid found in the stem bark of Cortex Mori, has been discovered to have the antioxidant, anti-inflammatory, and antitumor properties. However, its effect in osteoporosis has not yet been reported. In this research, the effect of SC on the proliferation of MC3T3-E1 cells was evaluated by using the MTT assay. Alkaline phosphatase (ALP) activity and the mRNA expression of

Topics: Alkaline Phosphatase; Animals; Benzofurans; Cell Differentiation; Cell Line; Cell Proliferation; Chromones; Collagen; Core Binding Factor alpha Subunits; Disease Models, Animal; Gene Expression Regulation; Mice; Osteoblasts; Osteoclasts; Osteoporosis; Osteoprotegerin; Prednisone; RANK Ligand; Zebrafish

Traditional Chinese medicines (TCM) have been proven to prevent osteoporosis, but their clinical applications are not widely recognized due to their complicated ingredients. Psoralidin, a prenylated coumestan, has been reported to prevent bone loss of ovariectomized rats, but detailed mechanisms are still not clear. In current study, we found that both psoralidin and coumestrol promoted osteoblast proliferation and differentiation, as evidenced by improvements in cell proliferation and alkaline phosphatase activity; increased formation of ALP colonies and calcified nodules; enhanced secretion of collagen-I, BMP-2, osteocalcin and osteopontin; and stimulation of the expression of IGF-1, β-catenin, Runx-2, Osterix, and OPG, as well as the mRNA ratio of OPG/RANKL, while significantly decreasing the expression of RANKL. In addition, both psoralidin and coumestrol inhibited osteoclast formation and osteoclastic bone resorption, as demonstrated by the lower tartrate-resistant acid phosphatase activity and smaller area, with fewer resorption pits formed. Interestingly, psoralidin showed much stronger effects than coumestrol at enhancing osteoblast proliferation/differentiation or inhibiting osteoclast differentiation and bone resorption. Moreover, we found that both psoralidin and coumestrol suppressed COX-2 and ROS production in rat osteoblastic calvarias cells, and psoralidin showed stronger effects than coumestrol. Furthermore, we detected that by blocking estrogen receptors with ICI 182.780 (an estrogen receptor antagonist), the osteoprotective effects of psoralidin and coumestrol were also blocked. Our findings demonstrated that psoralidin and coumestrol exert their bone-protective effects by enhancing bone formation of osteoblasts and inhibiting bone resorption of osteoclasts. These roles might be mediated by their antioxidant activity and transduced through estrogen receptor signaling.

Topics: Alkaline Phosphatase; Animals; Benzofurans; Bone Resorption; Cell Differentiation; Cell Proliferation; Coumarins; Dose-Response Relationship, Drug; Osteoclasts; Osteogenesis; Osteoporosis; Prenylation; Rats; Rats, Sprague-Dawley; Skull

In a search for novel small molecule calcium-sensing receptor (CaSR) antagonists as oral bone anabolic agents, we discovered dihydrobenzofuran cyclopropane carboxylic acid derivatives, such as 12f (IC50=27.6nM), are highly potent calcium-sensing receptor antagonists. Studies in rats established that compound 12f stimulates parathyroid hormone (PTH) release in a fast-acting, pulsatile manner.

Topics: Administration, Oral; Animals; Benzofurans; Cyclopropanes; Drug Evaluation, Preclinical; Female; Half-Life; Osteoporosis; Parathyroid Hormone; Protein Binding; Rats; Rats, Sprague-Dawley; Receptors, Calcium-Sensing; Structure-Activity Relationship

The BMP pathway is a promising new target for the design of therapeutic agents for the treatment of low bone mass. To enrich our understanding of SAR and based on our previously concluded structure-effect relationship, 23 derivatives were prepared in this work. The synthesis, up-regulating activities on BMP-2 expression, and bone loss prevention efficacies of these compounds in rats with glucocorticoid-induced osteoporosis are presented. The bone histology of the tested rats assessed through light microscopy showed that compounds 1, 21, 35, and 38 significantly increased the trabecula compared with the model group, and the trabecula of the groups treated with 8a was similar to that obtained with raloxifene and alfacalcidol. The compounds exhibited potential for development as anabolic agents.

Topics: Animals; Benzofurans; Bone Morphogenetic Protein 2; Cell Line; Female; Glucocorticoids; Male; Mice; Mice, Inbred Strains; Osteoporosis; Rats; Rats, Wistar; Thiophenes; Up-Regulation

Salvianolic acid B, a major bioactive component of Chinese medicine herb, Salvia miltiorrhiza, is widely used for treatment of cardiovascular diseases. Our recent studies have shown that Salvianolic acid B can prevent development of osteoporosis. However, the underlying mechanisms are still not clarified clearly. In the present study, we aim to investigate the effects of Salvianolic acid B on viability and osteogenic differentiation of human mesenchymal stem cells (hMSCs). The results showed Salvianolic acid B (Sal B) had no obvious toxic effects on hMSCs, whereas Sal B supplementation (5μM) increased the alkaline phosphatase activity, osteopontin, Runx2 and osterix expression in hMSCs. Under osteogenic induction condition, Sal B (5μM) significantly promoted mineralization; and when the extracellular-signal-regulated kinases signaling (ERK) pathway was blocked, the anabolic effects of Sal B were diminished, indicating that Sal B promoted osteogenesis of hMSCs through activating ERK signaling pathway. The current study confirms that Sal B promotes osteogenesis of hMSCs with no cytotoxicity, and it may be used as a potential therapeutic agent for the management of osteoporosis.

Topics: Benzofurans; Cell Differentiation; Cell Survival; Drugs, Chinese Herbal; Humans; MAP Kinase Signaling System; Mesenchymal Stem Cells; Osteogenesis; Osteoporosis; Transfection

Glucocorticoid (GC) induced osteoporosis (GIO) is caused by the long-term use of GC for treatment of autoimmune and inflammatory diseases. The GC related disruption of bone marrow microcirculation and increased adipogenesis contribute to GIO development. However, neither currently available anti-osteoporosis agent is completely addressed to microcirculation and bone marrow adipogenesis. Salvianolic acid B (Sal B) is a polyphenolic compound from a Chinese herbal medicine, Salvia miltiorrhiza Bunge. The aim of this study was to determine the effects of Sal B on osteoblast bone formation, angiogenesis and adipogenesis-associated GIO by performing marrow adipogenesis and microcirculation dilation and bone histomorphometry analyses. (1) In vivo study: Bone loss in GC treated rats was confirmed by significantly decreased BMD, bone strength, cancellous bone mass and architecture, osteoblast distribution, bone formation, marrow microvessel density and diameter along with down-regulation of marrow BMPs expression and increased adipogenesis. Daily treatment with Sal B (40 mg/kg/d) for 12 weeks in GC male rats prevented GC-induced cancellous bone loss and increased adipogenesis while increasing cancellous bone formation rate with improved local microcirculation by capillary dilation. Treatment with Sal B at a higher dose (80 mg/kg/d) not only prevented GC-induced osteopenia, but also increased cancellous bone mass and thickness, associated with increase of marrow BMPs expression, inhibited adipogenesis and further increased microvessel diameters. (2) In vitro study: In concentration from 10(-6) mol/L to 10(-7) mol/L, Sal B stimulated bone marrow stromal cell (MSC) differentiation to osteoblast and increased osteoblast activities, decreased GC associated adipogenic differentiation by down-regulation of PPARγ mRNA expression, increased Runx2 mRNA expression without osteoblast inducement, and, furthermore, Sal B decreased Dickkopf-1 and increased β-catenin mRNA expression with or without adipocyte inducement in MSC. We conclude that Sal B prevented bone loss in GC-treated rats through stimulation of osteogenesis, bone marrow angiogenesis and inhibition of adipogenesis.

Topics: Adipocytes; Adipogenesis; Animals; Benzofurans; beta Catenin; Bone and Bones; Bone Marrow Cells; Bone Morphogenetic Proteins; Cell Differentiation; Core Binding Factor Alpha 1 Subunit; Gene Expression; Intercellular Signaling Peptides and Proteins; Male; Neovascularization, Physiologic; Osteoblasts; Osteogenesis; Osteoporosis; PPAR gamma; Prednisone; Rats; Rats, Sprague-Dawley; Stromal Cells

The benzo[b]furan derivative MU314 inhibits in vitro bone resorption as potently as β-estradiol (E(2)). Here, we examined the point of action on the anti-osteoporotic effects of MU314. MU314 (10 nM) suppressed lacunae formation by osteoclastic cells and ICI-182,780, a pure E(2) antagonist, inhibited this effect. Specifically, we ovariectomized (OVX) Wistar female rats and subcutaneously injected them with either MU314 (30 or 100 µg/kg) or E(2) (100 µg/kg) over an 8-week period. Bone mineral content (BMC) in the proximal end of the tibia was significantly decreased (14%) in OVX rats, and MU314 (100 µg/kg) and E(2) significantly suppressed the decline in BMC. OVX rats exhibited decreased cancellous bone in the proximal end of the tibia and induced destruction of its trabecular structure. MU314 suppressed these changes. OVX also reduced the mechanical strength of the femoral neck, which was also recovered by MU314 and E(2). E(2) completely protected against OVX-induced uterine atrophy, but MU314 had no effect. These results strongly indicate that MU314 acts as a selective estrogen receptor modulator.

Topics: Animals; Benzofurans; Female; Osteoporosis; Rats; Rats, Wistar; Selective Estrogen Receptor Modulators

In this work, substituted benzothiophene and benzofuran compounds were found to be a new class of potential anabolic agents by enhancing BMP-2 expression. A series of benzothiophene and benzofuran derivatives have been synthesized, and their activities of up-regulating BMP-2 and bone loss prevention efficacies in SAMP6 mice and OVX rats have been studied. Benzothiophenes 1, 3, 14, 4a, 7a, 8a, and benzofuran analogue 2 showed higher BMP-2 up-regulation rates in vitro. Compound 8a was found to significantly affect the bone formation rate of tested SAMP6 mice. Compound 1 showed an improved bone quality in SAMP6 mice and also showed activity in OVX rats. We have demonstrated that substituted benzothiophene and benzofuran derivatives, especially compounds 1 and 8a, enhance BMP-2 expression in vitro and in vivo and stimulate bone formation and trabecular connectivity restoration in vivo. The compounds represent potential leads in the development of a new class of anabolic agents.

Topics: Anabolic Agents; Animals; Benzofurans; Bone Density; Bone Density Conservation Agents; Bone Morphogenetic Protein 2; Cell Line; Female; Lethal Dose 50; Male; Mice; Osteoporosis; Ovariectomy; Rats; Stereoisomerism; Structure-Activity Relationship; Thiophenes; Up-Regulation

We measured bone mineral density of the distal end of radius with dual energy X-ray absorptiometry, serum cross-linked N-telopeptides of type I collagen, serum bone-specific alkaline phosphatase, serum Ca, serum P, blood PCB level, blood PCQ level and blood PCDF level in Yusho. As a result, the osteoporosis group (< 70% of the young adult mean [YAM] bone mineral density [BMD]) was observed in 7.1% of the studied male subjects. And, the moderate group (> or = 70% and < 80% of YAM BMD), 16.1%, the normal (> or = 80% of YAM BMD) group was 76.8%. Also, 42.3% of all female tested subjects observed in osteoporosis group. The moderate group, 19.2%, the normal group was 38.5%. There was no difference in PCB blood level, PCQ, PCDF for men and women in osteoporosis group, moderate group, and in the normal group. Serum cross-linked N-telopeptides of type I collagen increased in the male osteoporosis group, but serum bone-specific alkaline phosphatase did not change. This study was inconclusive since the results did not determine the influence that PCB, PCQ, PCDF gave to bone density and bone metabolism.

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Bone Density; Chlorobenzenes; Dibenzofurans, Polychlorinated; Dioxins; Environmental Pollutants; Female; Food Contamination; Humans; Male; Middle Aged; Osteoporosis; Polychlorinated Biphenyls

FR167356, a novel inhibitor of vacuolar ATPase, has high potency against osteoclast V-ATPase and low potency against lysosomal V-ATPase. FR167356 is the first compound of this nature to be tested. It has the potential to be useful for clinical application.. It has been suggested that the key issue regarding the therapeutic usefulness of V-ATPase inhibitors is their selectivity.. In in vitro and in vivo studies, we compared FR167356 with other vacuolar ATPase (V-ATPase) inhibitors, bafilomycin A1 and SB242784. H+ transport by various membrane vesicles was assayed by measuring uptake of acridine orange. Inhibitory activity against in vitro bone resorption was examined by measuring the Ca2+ release from cultured calvariae. In vivo, hypercalcemia was induced by retinoic acid in thyroparathyroidectomized-ovariectomized rats, and the effect on serum Ca2+ level was assessed. Ovariectomized rats were treated with FR167356 or SB242784. One week after surgery, free deoxypyridinoline levels in 24-h urine samples, which were collected from 6 h after administration of FR167356, were measured by ELISA. After 4 weeks of treatment, plasma biochemical parameters were analyzed. BMD of the distal femur metaphysis was measured with pQCT. Histomorphometric analysis of the proximal tibias was performed. Blood gases of rats treated with FR167356 were measured with a blood gas analyzer for estimating the effect of FR167356 on in vivo function of renal V-ATPase.. FR167356, which is distinctly different from other V-ATPase inhibitors, has a high potency against osteoclast V-ATPase and low potency against lysosomal V-ATPase. Similarly, FR167356 inhibited bone resorption in vitro when stimulated by PTH, IL-1, and IL-6. FR167356 reduced retinoic acid-induced hypercalcemia in thyroparathyroidectomized-ovariectomized rats in a dose-dependent manner. Moreover, FR167356 was shown to restore BMD of ovariectomized rats caused by the inhibition of bone resorption. Ovariectomized rats treated with FR167356 did not show adverse symptoms, whereas SB242784 caused a decrease in body weight gain and significant changes in two plasma biochemical parameters. Interestingly, FR167356 treatment did not affect blood acid-base balance; however, FR167356 inhibited renal V-ATPase with a similar potency as for osteoclast V-ATPase inhibition.. Comparison of FR167356 with SB242784 implies that the characteristics of FR167356 may be more appropriate for clinical application as a V-ATPase inhibitor.

Topics: Animals; Benzamides; Benzofurans; Biological Transport; Bone and Bones; Bone Density; Bone Resorption; Calcium; Cell Membrane; Drug Evaluation, Preclinical; Enzyme-Linked Immunosorbent Assay; Female; Femur; Inhibitory Concentration 50; Kidney; Lysosomes; Macrolides; Male; Mice; Models, Chemical; Osteoclasts; Osteoporosis; Protons; Rabbits; Rats; Rats, Wistar; Time Factors; Vacuolar Proton-Translocating ATPases