Geet K Nagar

Central Drug Research Institute, Lakhnau, Uttar Pradesh, India

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Publications (26)73.68 Total impact

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    ABSTRACT: Objective Bone protective effects of withaferin A (WFA) from leaves of Withania somnifera (L.) was evaluated in preventive model of Balb/c mice with 17β-estradiol (E2) and alendronate (ALD). Research Methods and Procedures Adult female Balb/c mice, 7-9 weeks were bilaterally ovariectomized (OVx) to mimic the state of E2 deficiency. Immediately after surgery mice were administrated WFA at doses of 1, 5, 10 mg/kg/day while other two OVx groups received ALD or E2 for two months. Sham and OVx groups with vehicle and no treatment served as controls. Results WFA administration increased new bone formation, improved micro-architecture and biomechanical strength of the bones. It prevented bone loss by reducing expression of osteoclastic genes Tartrate Resistant Acid Phosphatase (TRAP) and Receptor Activator of Nuclear Factor κ B (RANK). Increase in bone turnover marker, Osteocalcin (OCN) and inflammatory cytokine Tumor Necrosis Factor-alpha (TNF-α) due to ovariectomy were reduced with WFA treatment, with effects comparable to E2 administration. Histomorphometric analysis of uterus shows that WFA was not fraught with estrogenic or anti-estrogenic effects. At cellular level, WFA promoted differentiation of Bone Marrow Cells (BMCs) and increased mineralization by inducing expression of osteogenic genes. WFA has bone protective potential as its treatment prevents bone loss that is comparable to ALD and E2. Conclusion It is surmised that WFA in preclinical setting is effective in preserving bone loss by both inhibition of resorption and stimulation of new bone formation before onset of osteoporosis with no uterine hyperplasia
    Nutrition. 01/2014;
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    Dataset: Paper1
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    ABSTRACT: Withania somnifera or Ashwagandha is a medicinal herb of Ayurveda. Though the extract and purified molecules, withanolides, from this plant have been shown to have different pharmacological activities, their effect on bone formation has not been studied. Here, we show that one of the withanolide, withaferin A (WFA) acts as a proteasomal inhibitor (PI) and binds to specific catalytic β subunit of the 20S proteasome. It exerts positive effect on osteoblast by increasing osteoblast proliferation and differentiation. WFA increased expression of osteoblast-specific transcription factor and mineralizing genes, promoted osteoblast survival and suppressed inflammatory cytokines. In osteoclast, WFA treatment decreased osteoclast number directly by decreasing expression of tartarate-resistant acid phosphatase and receptor activator of nuclear factor kappa-B (RANK) and indirectly by decreasing osteoprotegrin/RANK ligand ratio. Our data show that in vitro treatment of WFA to calvarial osteoblast cells decreased expression of E3 ubiquitin ligase, Smad ubiquitin regulatory factor 2 (Smurf2), preventing degradation of Runt-related transcription factor 2 (RunX2) and relevant Smad proteins, which are phosphorylated by bone morphogenetic protein 2. Increased Smurf2 expression due to exogenous treatment of tumor necrosis factor α (TNFα) to primary osteoblast cells was decreased by WFA treatment. This was corroborated by using small interfering RNA against Smurf2. Further, WFA also blocked nuclear factor kappa-B (NF-kB) signaling as assessed by tumor necrosis factor stimulated nuclear translocation of p65-subunit of NF-kB. Overall data show that in vitro proteasome inhibition by WFA simultaneously promoted osteoblastogenesis by stabilizing RunX2 and suppressed osteoclast differentiation, by inhibiting osteoclastogenesis. Oral administration of WFA to osteopenic ovariectomized mice increased osteoprogenitor cells in the bone marrow and increased expression of osteogenic genes. WFA supplementation improved trabecular micro-architecture of the long bones, increased biomechanical strength parameters of the vertebra and femur, decreased bone turnover markers (osteocalcin and TNFα) and expression of skeletal osteoclastogenic genes. It also increased new bone formation and expression of osteogenic genes in the femur bone as compared with vehicle groups (Sham) and ovariectomy (OVx), Bortezomib (known PI), injectible parathyroid hormone and alendronate (FDA approved drugs). WFA promoted the process of cortical bone regeneration at drill-holes site in the femur mid-diaphysis region and cortical gap was bridged with woven bone within 11 days of both estrogen sufficient and deficient (ovariectomized, Ovx) mice. Together our data suggest that WFA stimulates bone formation by abrogating proteasomal machinery and provides knowledge base for its clinical evaluation as a bone anabolic agent.
    Cell Death & Disease 08/2013; 4:e778. · 6.04 Impact Factor
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    Dataset: Paper 1
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    ABSTRACT: Arsenic (As), lead (Pb) and cadmium (Cd) are the major metal contaminants of ground water in India. We have reported the toxic effect of their mixture (metal mixture, MM), at human relevant doses, on developing rat astrocytes. Astrocyte damage has been shown to be associated with myelin disintegration in CNS. We, therefore, hypothesized that the MM would perturb myelinating white matter in cerebral cortex, optic nerve (O. N.) and retina. We observed modulation in the levels of myelin and axon proteins, such as myelin basic protein (MBP), proteolipid protein, 2'-, 3'-cyclic-nucleotide-3'-phosphodiesterase, myelin-associated glycoprotein and neurofilament (NF) in the brain of developing rats. Dose and time-dependent synergistic toxic effect was noted. The MBP- and NF- immunolabeling, as well as luxol-fast blue (LFB) staining demonstrated a reduction in the area of intact myelin-fibre, and an increase in vacuolated axons, especially in the corpus-callosum. Transmission electron microscopy (TEM) of O. N. revealed a reduction in myelin thickness and axon-density. The immunolabeling with MBP, NF, and LFB staining in O.N. supported the TEM data. The Hematoxylin and eosin staining of retina displayed a decrease in the thickness of nerve-fibre, plexiform-layer, and retinal ganglion cell (RGC) count. Investigating the mechanism revealed a loss in glutamine synthetase activity in the cerebral cortex and O.N., and a fall in the brain derived neurotrophic factor in retina. An enhanced apoptosis in MBP, NF and Brn3b-containing cells justified the diminution in myelinating axons in CNS. Our findings for the first time indicate white matter damage by MM, which may have significance in neurodevelopmental-pediatrics, neurotoxicology and retinal-cell biology.
    Toxicology and Applied Pharmacology 05/2013; · 3.98 Impact Factor
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    ABSTRACT: Arsenic (As), lead (Pb) and cadmium (Cd) are the major metal contaminants of ground water in India. We have reported the toxic effect of their mixture (metal mixture, MM), at human relevant doses, on developing rat astrocytes. Astrocyte damage has been shown to be associated with myelin disintegration in CNS. We, therefore, hypothesized that the MM would perturb myelinating white matter in cerebral cortex, optic nerve (O. N.) and retina. We observed modulation in the levels of myelin and axon proteins, such as myelin basic protein (MBP), proteolipid protein, 2'-, 3'-cyclic-nucleotide-3'-phosphodiesterase, myelin-associated glycoprotein and neurofilament (NF) in the brain of developing rats. Dose and time-dependent synergistic toxic effect was noted. The MBP- and NF- immunolabeling, as well as luxol-fast blue (LFB) staining demonstrated a reduction in the area of intact myelin-fibre, and an increase in vacuolated axons, especially in the corpus-callosum. Transmission electron microscopy (TEM) of O. N. revealed a reduction in myelin thickness and axon-density. The immunolabeling with MBP, NF, and LFB staining in O.N. supported the TEM data. The Hematoxylin and eosin staining of retina displayed a decrease in the thickness of nerve-fibre, plexiform-layer, and retinal ganglion cell (RGC) count. Investigating the mechanism revealed a loss in glutamine synthetase activity in the cerebral cortex and O.N., and a fall in the brain derived neurotrophic factor in retina. An enhanced apoptosis in MBP, NF and Brn3b-containing cells justified the diminution in myelinating axons in CNS. Our findings for the first time indicate white matter damage by MM, which may have significance in neurodevelopmental-pediatrics, neurotoxicology and retinal-cell biology.
    Toxicology and Applied Pharmacology 05/2013; · 3.98 Impact Factor
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    ABSTRACT: We studied the effect of metal mixture (MM), comprising of As, Cd and Pb, in developing female rat skeleton from gestation day-5 until postnatal day-60 (P-60). MM resulted in synergistic inhibition in viability and differentiation of osteoblasts in vitro, likely induced by reactive oxygen species. MM, administered at their most frequently occurring concentrations present in the ground-water of India, i.e. As: 0.38ppm, Pb: 0.22 ppm and Cd: 0.098 ppm or 10× of the ratio to developing rats exhibited a synergistic decrease in ex vivo mineralization of bone marrow stromal (osteoprogenitor) cells. MM group showed a dose-dependent attenuation in weight and axial lengths, and shortening of tibias at P-60. Furthermore, the growth plate was shortened, which was associated with shorter proliferative- and hypertrophic zones, decreased parathyroid hormone-related protein and Indian hedgehog expression in the chondrocytes, reduced primary- and secondary spongiosa, and hypomineralized osteoids - a major characteristic of osteomalacia. In addition, compared to the control, MM treated rats were clearly osteopenic based on BMD, micro-architecture, biomechanical strength, and particularly the biochemical profile, that suggested high turnover bone loss. Finally, in comparison to the control, the fracture healing ability of MM group was delayed and accompanied by inferior quality of the healed bone. Together, these data demonstrated that the mixture of As, Cd and Pb induced synergistic toxicity to developing skeleton thereby diminishing modeling-directed bone accrual, inducing osteopenia and dampening fracture healing.
    Toxicological Sciences 04/2013; · 4.33 Impact Factor
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    ABSTRACT: PURPOSE: Daidzein (Daid) has been implicated in bone health for its estrogen-'like' effects but low bioavailability, unfavorable metabolism and uterine estrogenicity impede its clinical potential. This study was aimed at assessing isoformononetin (Isoformo), a naturally occurring methoxydaidzein, for bone anabolic effect by overcoming the pitfalls associated with Daid. METHODS: Sprague-Dawley ovariectomized (OVx) rats with established osteopenia were administered Isoformo, 17β-oestradiol (E2) or human parathyroid hormone. Efficacy was evaluated by bone microarchitecture using microcomputed tomography and determination of new bone formation by fluorescent labeling of bone. Osteoblast apoptosis was measured by co-labeling of bone sections with Runx-2 and TUNEL. Biochemical markers of bone metabolism were measured by ELISA. Plasma and bone marrow levels of Isoformo and Daid were determined by LC-MS-MS. Rat bone marrow stromal cells were harvested to study osteoblastic differentiation by Isoformo and Daid. New born rat pups were injected with Isoformo and Daid to study the effect of the compounds on the expression of osteogenic genes in the calvaria by real time PCR. RESULTS: In osteopenic rats, Isoformo treatment restored trabecular microarchitecture, increased new bone formation, increased the serum osteogenic marker (procollagen N-terminal propeptide), decreased resorptive marker (urinary C-terminal teleopeptide of type I collagen) and diminished osteoblast apoptosis in bone. At the most effective osteogenic dose of Isoformo, plasma and bone marrow levels were comprised of ∼90% Isoformo and the rest, Daid. Isoformo at the concentration reaching the bone marrow achieved out of its most effective oral dosing induced stromal cell mineralization and osteogenic gene expression in the calvaria of neonatal rats. Isoformo exhibited uterine safety. CONCLUSIONS: Our study demonstrates that Isoformo reverses established osteopenia in adult OVx rats likely via its pro-survival effect on osteoblasts. Given its bone anabolic and anti-catabolic effects accompanied with safety at uterine level we propose its potential in the management of postmenopausal osteoporosis.
    Phytomedicine: international journal of phytotherapy and phytopharmacology 02/2013; · 2.97 Impact Factor
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    ABSTRACT: Aim: A layer-by-layer matrix (LBL) comprising kaempferol (LBL-KEM) was prepared for improved osteogenic action. Materials & methods: The LBL-KEM consisted of alternate layers of sodium alginate and protamine sulfate, which were sequentially deposited on the preformed kaempferol (KEM)-loaded CaCO(3) core (CaCO(3)-KEM) by LBL self-assembly. The LBL matrix developed was evaluated for layer growth by ζ-potential and size alterations after self-assembly of each layer. Its physicochemical properties and intestinal absorption pattern were characterized and its pharmacokinetic behavior, mineralization of bone marrow cells, bone mineral density, bone strength, microcrack formation and estrogenicity were evaluated after oral administration. Results: The entrapment efficiency of KEM was 94 ± 2% and the cumulative %KEM released from LBL-KEM was 19.2 and 63.5% at pH 1.4 and 7.4, respectively, after 24 h. Stepwise polyelectrolyte assembly onto initially positively charged particles (+21.2 mV) resulted in alterations between -28.5 and +10.9 mV. A final ζ-potential of -8.9 mV was obtained after terminal surface modification with sodium deoxycholate. Fluorescein isothiocyanate-labeled LBL matrix was diffused into the basolateral lacteal region upon oral administration to rats. The area under the KEM serum concentration curve following oral administration of LBL-KEM to rats was 2479 ± 682 ng h/ml, nearly twofold higher than free KEM. The concentration-time profile in bone marrow indicated improved penetration and retention of KEM on administration of LBL-KEM. Treatment with LBL-KEM restored bone mineralization, bone mineral density, microcrack formation and empty osteocyte lacunae density in ovariectomized (OVx) rats, which was significantly (p < 0.05) improved in femoral diaphysea, tibial head and vertebrae compared with free KEM treatment. Administration of LBL-KEM to growing female rats for 4 weeks resulted in no estrogenicity when compared with OVx rats. Conclusions: The data suggests that LBL matrix enhanced drug delivery, improved pharmacokinetics and maintained better bone quality under OVx conditions. Original submitted 30 November 2011; Revised submitted 17 May 2012.
    Nanomedicine 01/2013; · 5.26 Impact Factor
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    Dataset: Paper 2
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    Cell Death & Disease 01/2013; 01/2013; 4:e778. · 6.04 Impact Factor
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    Menopause. 12/2012;
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    ABSTRACT: Effects of cladrin treatment and withdrawal in osteopenic rats were studied. Cladrin improved trabecular microarchitecture, increased lumbar vertebral compressive strength, augmented coupled remodeling, and increased bone osteogenic genes. A significant skeletal gain was maintained 4 weeks after cladrin withdrawal. Findings suggest that cladrin has significant positive skeletal effects. INTRODUCTION: We showed that a standardized extract of Butea monosperma preserved trabecular bone mass in ovariectomized (OVx) rats. Cladrin, the most abundant bioactive compound of the extract, promoted peak bone mass achievement in growing rats by stimulating osteoblast function. Here, we studied the effects of cladrin treatment and withdrawal on the osteopenic bones. METHODS: Adult female Sprague-Dawley rats were OVx and left untreated for 12 weeks to allow for significant estrogen deficiency-induced bone loss, at which point cladrin (1 and 10 mg/kg/day) was administered orally for another 12 weeks. Half of the rats were killed at the end of the treatments and the other half at 4 weeks after treatment withdrawal. Sham-operated rats and OVx rats treated with PTH or 17β-estradiol (E2) served as various controls. Efficacy was evaluated by bone microarchitecture using microcomputed tomographic analysis and fluorescent labeling of bone. qPCR and western blotting measured mRNA and protein levels in bone and uterus. Specific ELISA was used for measuring levels of serum PINP and urinary CTx. RESULTS: In osteopenic rats, cladrin treatment dose dependently improved trabecular microarchitecture, increased lumbar vertebral compression strength, bone formation rate (BFR), cortical thickness (Cs.Th), serum PINP levels, and expression of osteogenic genes in bones; and reduced expression of bone osteoclastogenic genes and urinary CTx levels. Cladrin had no uterine estrogenicity. Cladrin at 10 mg/kg maintained acquired skeletal gains 4 weeks after withdrawal. CONCLUSION: Cladrin had positive skeletal effects in osteopenic rats that were maintained after treatment withdrawal.
    Osteoporosis International 08/2012; · 4.04 Impact Factor
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    ABSTRACT: Our earlier study has demonstrated that EGb 761 (standardized extract of Ginkgo) has the bone sparing effect on the estrogen deficiency induced bone loss model. In the present study, we have addressed the question whether treatment of osteoporosis benefits arterial calcification or vice versa, because both adipocyte and osteoblast originate from the same mesenchymal cell of the bone marrow cell (BMC) population. Bone marrow cells were isolated to study the effect of EGb 761 on osteoblast and adipocytes. For in vivo effect hamsters were fed high fat diet and the effect of EGb 761 studied on atherosclerotic plaque formation and endothelial function. BMC's undergoing induced osteogenic or adipogenic differentiations in the presence of EGb 761 show increase and decrease in mineralization and adipogenesis respectively. Osteogenic and adipogenic mRNAs, reveal lineage dependent expression patterns. Runx-2 (osteoblast transcription factor) showed a progressive increase, whereas PPAR-γ (adipogenic regulator) was attenuated, with same pattern of expression being for late osteogenic and adipogenic genes. EGb 761 led to increase in apoptotic cells and ROS, an important upstream signal. In vivo experiments in hamsters after induction with high cholesterol diet (HCD) show improvement in endothelial function by EGb 761 with lowering in total plasma cholesterol levels. EGb 761 led to vascular preservation of the aortic lumen with impairment of the endothelium dependent relaxation which was corroborated by micro-CT and histological sections of the thoracic region of the aorta. From this data, it can be implied that EGb 761 controls bone loss, adiposity and lowers atherogenic risk factor after HCD induction.
    Phytomedicine: international journal of phytotherapy and phytopharmacology 08/2012; 19(12):1134-42. · 2.97 Impact Factor
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    ABSTRACT: A prototype formulation based on layer-by-layer (LbL) nano-matrix was developed to increase bioavailability of kaempferol with improved retention in bone marrow to achieve enhanced bone formation. The layer-by-layer nano-matrix was prepared by sequential adsorption of biocompatible polyelectrolytes over the preformed kaempferol-loaded CaCO(3) template. The system was pharmaceutically characterized and evaluated for osteogenic activity in ovariectomized (OVx) rats. Data have been compared to the standard osteogenic agent parathyroid hormone (PTH). Single oral dose of kaempferol loaded LbL nano-matrix formulation increased bioavailability significantly compared to unformulated kaempferol. Three months of Formulated kaempferol administration to osteopenic rats increased plasma and bone marrow Kaempferol levels by 2.8- and 1.75-fold, respectively, compared to free Kaempferol. Formulated Kaempferol increased bone marrow osteoprogenitor cells, osteogenic genes in femur, bone formation rate, and improved trabecular micro-architecture. Withdrawal of Formulated kaempferol-in OVx rats resulted in the maintenance of bone micro-architecture up to 30days, whereas micro-architectural deterioration was readily observed in OVx rats treated with unformulated kaempferol-within 15days of withdrawal. The developed novel formulation has enhanced anabolic effect in osteopenic rats through increased stimulatory effect in osteoblasts. Treatment post-withdrawal sustenance of formulated kaempferol could become a strategy to enhance bioavailability of flavanoids.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 08/2012; · 3.15 Impact Factor
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    ABSTRACT: OBJECTIVE: The aim of this study was to evaluate the skeletal effects of an extract made from the leaves and pods of Dalbergia sissoo (butanol-soluble standardized fraction [BSSF]) on ovariectomized rats, a model for postmenopausal osteopenia. METHODS: Adult Sprague-Dawley rats were ovariectomized and administered BSSF (50 and 100 mg/kg per day) or 17β-estradiol orally for 12 weeks. The sham-operated group and the ovariectomy + vehicle group served as controls. Bone microarchitecture, bone turnover markers (serum osteocalcin and C-telopeptide fragment of collagen type I), biomechanical strength, new bone formation (based on mineral apposition rate and bone formation rate), and skeletal expressions of osteogenic and resorptive gene markers were studied. Uterine histomorphometry was used to assess estrogenicity. Bioactive marker compounds in BSSF were analyzed by high-performance liquid chromatography. One-way analysis of variance was used to test the significance of effects. RESULTS: In comparison with ovariectomized rats treated with vehicle, BSSF treatment in ovariectomized rats resulted in an improved trabecular microarchitecture of the long bones, increased biomechanical strength parameters of the vertebra and femur, decreased bone turnover markers (osteocalcin and type I collagen) and expression of skeletal osteoclastogenic genes, and increased new bone formation and expression of osteogenic genes in the femur. Overall, the osteoprotective effects of BSSF were comparable to those of 17β-estradiol. BSSF did not exhibit uterine estrogenicity. Analysis of marker compounds revealed the presence of osteogenic methoxyisoflavones, including caviunin 7-O-[β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside] (a novel compound), biochanin A, and pratensin. CONCLUSIONS: Oral doses of BSSF in the preclinical setting are effective in preventing estrogen deficiency-induced bone loss by dual action: inhibition of bone resorption and stimulation of new bone formation.
    Menopause (New York, N.Y.) 07/2012; · 3.08 Impact Factor
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    ABSTRACT: OBJECTIVE: The aim of this study was to evaluate the skeletal effects of an extract made from the leaves and pods of Dalbergia sissoo (butanol-soluble standardized fraction [BSSF]) on ovariectomized rats, a model for postmenopausal osteopenia. METHODS: Adult Sprague-Dawley rats were ovariectomized and administered BSSF (50 and 100 mg/kg per day) or 17β-estradiol orally for 12 weeks. The sham-operated group and the ovariectomy + vehicle group served as controls. Bone microarchitecture, bone turnover markers (serum osteocalcin and C-telopeptide fragment of collagen type I), biomechanical strength, new bone formation (based on mineral apposition rate and bone formation rate), and skeletal expressions of osteogenic and resorptive gene markers were studied. Uterine histomorphometry was used to assess estrogenicity. Bioactive marker compounds in BSSF were analyzed by high-performance liquid chromatography. One-way analysis of variance was used to test the significance of effects. RESULTS: In comparison with ovariectomized rats treated with vehicle, BSSF treatment in ovariectomized rats resulted in an improved trabecular microarchitecture of the long bones, increased biomechanical strength parameters of the vertebra and femur, decreased bone turnover markers (osteocalcin and type I collagen) and expression of skeletal osteoclastogenic genes, and increased new bone formation and expression of osteogenic genes in the femur. Overall, the osteoprotective effects of BSSF were comparable to those of 17β-estradiol. BSSF did not exhibit uterine estrogenicity. Analysis of marker compounds revealed the presence of osteogenic methoxyisoflavones, including caviunin 7-O-[β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside] (a novel compound), biochanin A, and pratensin. CONCLUSIONS: Oral doses of BSSF in the preclinical setting are effective in preventing estrogen deficiency-induced bone loss by dual action: inhibition of bone resorption and stimulation of new bone formation.
    Menopause (New York, N.Y.) 07/2012; · 3.08 Impact Factor
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    ABSTRACT: Formononetin (Formo) prevents ovariectomy (Ovx)-induced bone loss in rats. However, there are no reports on the curative effects of Formo. The objective of this study was to investigate the ability of Formo in restoring trabecular microarchitecture and promoting new bone formation in osteopenic rats. Adult Sprague-Dawley rats were ovariectomized and left for 90 days for osteopenia to develop. After 90 days, Formo (10.0 mg kg d) was given orally for the next 12 weeks to Ovx rats in a therapeutic protocol. Sham-operated, Ovx + vehicle, and Ovx + parathyroid hormone (PTH) groups served as controls. Trabecular microarchitecture, osteoid formation, bone turnover/resorption markers, and bone osteoprotegerin-to-receptor activator for nuclear κB ligand ratio were studied. One-way analysis of variance was used to test significance of effects. Formo treatment significantly restored the lost trabecular microarchitecture in the femurs and tibia of osteopenic Ovx rats and promoted new bone formation. Formo was devoid of any uterine estrogenicity. Serum levels of type I collagen N-terminal propeptide, which is a reliable marker of bone formation, were increased in Ovx rats treated with Formo compared with Ovx + vehicle group, and the levels were comparable with those in the sham group. Formo prevented the Ovx-induced increase in bone turnover markers, including serum osteocalcin and urinary type I collagen degradation product. Furthermore, Formo-treated Ovx rats had an increased bone osteoprotegerin-to-receptor activator for nuclear κB ligand ratio compared with the Ovx + vehicle group. Daily oral administration of Formo for 12 weeks has a substantial anabolic effect, thus raising the possibility of its use in postmenopausal osteoporosis.
    Menopause (New York, N.Y.) 07/2012; 19(8):856-63. · 3.08 Impact Factor
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    ABSTRACT: Objective: Formononetin (Formo) prevents ovariectomy (Ovx)-induced bone loss in rats. However, there are no reports on the curative effects of formononetin. The objective of this study was to investigate the ability of Formo in restoring trabecular microarchitecture and promoting new bone formation in osteopenic rats. Methods: Adult Sprague-Dawley rats were Ovx and left for 90 days for osteopenia to develop. After 90 days, Formo (10.0 mg.kg-1.day-1) was given orally for the next 12 weeks to Ovx rats in therapeutic protocol. Sham-operated, Ovx + vehicle and Ovx + PTH groups served as controls. Tabecular microarchitecture, osteoid formation, bone turnover/resorption markers and bone osteoprotegerin (OPG) to receptor activator of nuclear kappa B ligand (RANKL) ratio were studied. One-way ANOVA was used to test significance of effects. Results: Formo treatment significantly restored the lost trabecular microarchitecture in the femurs and tibiea of osteopenic Ovx rats and promoted new bone formation. Formo was devoid of any uterine estrogenicity. Serum levels of type I collagen N-terminal propeptide, which is a reliable marker of bone formation was increased in Ovx rats treated with Formo compared to Ovx + vehicle group and the levels were comparable to the sham group. Formo prevented the Ovx-induced increase in bone turnover markers including serum osteocalcin and urinary type I collagen degradation product. Fruthermore, Formo treated Ovx rats had increased OPG/RANKL ratio compared to Ovx + vehicle group. Conclusion: Daily oral administration of Formo for 12 weeks has substantial anabolic effect, thus, raising the possibility of its use in postmenopausal osteoporosis
    Menopause. 06/2012;
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    ABSTRACT: Elephantopus mollis, Spilanthes africana, Urena lobata, Momordica multiflora, Asystasia gangetica and Brillantaisia ovariensis are used in Cameroonian traditional medicine for the treatment of bone diseases and fracture repair. The aim of this study was to evaluate the effect of ethanolic extracts of six Cameroonian medicinal plants on bone regeneration following bone and marrow injury. Ethanol extract of Cameroonian medicinal plants were administered (each extract at 250, 500 and 750mg/kg doses) orally to adult female Sprague-Dawley rats having a drill hole injury (0.8mm) in the femur diaphysis. Vehicle (gum-acacia in distilled water) was given to the control group. After 12 days of treatment, animals were euthanized and femur bones collected. Confocal microscopy of fractured bone was performed to evaluate bone regeneration (calcein labeling). Only active plant extracts were used for further experiments. Thus, callus was analyzed by microcomputed tomography. Osteogenic effects of the extracts were evaluated by assessing mineralized nodules formation of bone marrow stromal cells and osteoblast recruitment at drill hole site by immunohistochemistry. Ethanolic extract of the leaves and twigs of Elephantopus mollis (EM) and whole plant of Spilanthes africana (SA) dose-dependently stimulated bone regeneration at the drill hole site. EM at 250 and 750mg/kg doses and SA at 750mg/kg dose significantly increased mineral deposition compared to controls. Both extracts at 500 and 750mg/kg doses improved microarchitecture of the regenerating bone evident from increased bone volume fraction, trabecular thickness, trabecular number, and decreased trabecular separation and structure model index. EM and SA extracts increased the formation of mineralized nodules from the bone marrow stromal cells. In addition, EM and SA extracts increased osteoblast recruitment at the drill hole site evident from increased Runx-2 positive cells following their treatments compared to control. Ethanolic extracts of EM and SA accelerate fracture repair in rats via stimulatory effects on osteoblast differentiation and mineralization, thereby justifying their traditional use.
    Journal of ethnopharmacology 03/2012; 141(1):331-7. · 2.32 Impact Factor

Publication Stats

149 Citations
73.68 Total Impact Points

Institutions

  • 2009–2014
    • Central Drug Research Institute
      • • Medicinal and Process Chemistry Division (CDRI)
      • • Endocrinology Division (CDRI)
      Lakhnau, Uttar Pradesh, India
  • 2013
    • Council of Scientific and Industrial Research (CSIR), New Delhi
      New Dilli, NCT, India
    • Indian Institute of Toxicology Research
      • Division of Developmental Toxicology
      Lucknow, Uttar Pradesh, India
  • 2012
    • University of Yaoundé II
      Jaúnde, Centre Region, Cameroon