Diosmin, a citrus fruit-derived phlebotonic bioflavonoid protects rats from chronic kidney disease-induced loss of bone mass and strength without deteriorating the renal function

Sharma, Shivani; Porwal, Konica; Kulkarni, Chirag; Pal, Subhashis; Sihota, Praveer; Kumar, Saroj; Tiwari, Mahesh Chandra; Katekar, Roshan; Kumar, Ashish; Singh, Prati Pal; Rajput, Swati; Guha, Rajdeep; Kumar, Navin; Gayen, Jiaur R.; Chattopadhyay, Naibedya

doi:10.1039/d1fo03867b

Cited by 17 publications

(15 citation statements)

References 80 publications

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“…Different parameters, viz. C max (ng/mL) - maximum plasma concentration; T max (h) - time to reach C max ; AUC0-∞ (ng h/mL) - area under concentration vs. time curve extrapolated to infinity; t½ (h) - elimination half-life; V d (l) - volume of distribution; and Cl r (L/h) - total clearance, were calculated ( 18 , 24 ).…”

Section: Methodsmentioning

confidence: 99%

A novel extraction method enhanced the osteogenic and anti-osteoporosis effect of tea extract without any hepatotoxicity in ovariectomized rats

et al. 2022

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Tea (Camellia sinensis) has several reported health benefits, including that on bone health attributed to catechins of which the most abundant is epigallocatechin-3-gallate (EGCG). However, several preclinical and clinical studies raise safety concerns about EGCG in tea extract causing acute liver failure. Tea also contains kaempferol, albeit scanty, and it has hepatoprotective and osteogenic effects. Here, we utilized a novel extraction procedure of acid hydrolysis to enhance the osteogenic effect of tea extract while reducing its hepatotoxicity. The resultant extract (USKECSE) has a ~40-fold increase in kaempferol and a 2.5-fold reduction in EGCG content compared with the hydroethanolic extract (USCSE). In a female Sprague Dawley (SD) rat femur osteotomy model, USKECSE (100 mg/kg) but not USCSE promoted bone regeneration. In a rat postmenopausal osteoporosis model induced by bilateral ovariectomy (OVX), USKECSE through an osteogenic mechanism maintained bone mass, strength, and microarchitecture to the levels of ovary-intact rats with no hepatotoxic effect. After a single oral dose (100 mg/kg) of USKECSE to adult rats, kaempferol was detectable for 48 hours, suggesting its significant absorption and distribution in plasma. Peak kaempferol concentration in plasma (Cmax) was 483 ng/ml (2 μM), and at this concentration, kaempferol induces osteoblast differentiation. USKECSE had no genotoxicity, and its safety index assessed by preclinical toxicity studies, including safety pharmacology, was >20-fold. Taken together, we report a novel extraction process that enhanced the osteogenicity and concomitantly reduced hepatotoxicity of tea extract with significant kaempferol bioavailability and a favorable systemic safety profile. Based on these data, we propose assessing the USKECSE effect for postmenopausal osteoporosis treatment.

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Section: Methodsmentioning

confidence: 99%

A novel extraction method enhanced the osteogenic and anti-osteoporosis effect of tea extract without any hepatotoxicity in ovariectomized rats

et al. 2022

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“…Western blot analysis was performed as previously described (Mishra et al, 2021;S. Sharma, Porwal, et al, 2022).…”

Section: Western Blot Analysismentioning

confidence: 99%

RING finger E3 ligase, RNF138 inhibits osteoblast differentiation by negatively regulating Runx2 protein turnover

Upadhyay,

Singh,

Sharma

et al. 2024

Journal Cellular Physiology

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A few ubiquitin ligases have been shown to target Runx2, the key osteogenic transcription factor and thereby regulate bone formation. The regulation of Runx2 expression and function are controlled both at the transcriptional and posttranslational levels. Really interesting new gene (RING) finger ubiquitin ligases of which RNF138 is a member are important players in the ubiquitin‐proteasome system, contributing to the regulation of protein turnover and cellular processes. Here, we demonstrated that RNF138 negatively correlated with Runx2 protein levels in osteopenic ovariectomized rats which implied its role in bone loss. Accordingly, RNF138 overexpression potently inhibited osteoblast differentiation of mesenchyme‐like C3H10T1/2 as well primary rat calvarial osteoblast (RCO) cells in vitro, whereas overexpression of catalytically inactive mutant RNF138Δ18‐58 (lacks RING finger domain) had mild to no effect. Contrarily, RNF138 depletion copiously enhanced endogenous Runx2 levels and augmented osteogenic differentiation of C3H10T1/2 as well as RCOs. Mechanistically, RNF138 physically associates within multiple regions of Runx2 and ubiquitinates it leading to its reduced protein stability in a proteasome‐dependent manner. Moreover, catalytically active RNF138 destabilized Runx2 which resulted in inhibition of its transactivation potential and physiological function of promoting osteoblast differentiation leading to bone loss. These findings underscore the functional involvement of RNF138 in bone formation which is primarily achieved through its modulation of Runx2 by stimulating ubiquitin‐mediated proteasomal degradation. Thus, our findings indicate that RNF138 could be a promising novel target for therapeutic intervention in postmenopausal osteoporosis.

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“…In addition to having an intramuscular injection of isotonic saline, once a week for five weeks, DIO 100 group received diosmin 100 mg/kg/day orally for four weeks. The given doses of DEX and diosmin were selected based on published work [34,36].…”

Section: Experimental Designmentioning

confidence: 99%

“…To this end, the antiosteoporotic effect of diosmin has been previously investigated. For instance, Sharma et al [34] and Hu et al [35] showed that diosmin could protect rats from bone loss induced by chronic kidney disease and ovariectomy, respectively. Besides, a composition containing diosmin and hesperidin demonstrated the ability to enhance bone regeneration in a rat femur osteotomy model [29].…”

Section: Introductionmentioning

confidence: 99%

Diosmin mitigates dexamethasone-induced osteoporosis in vivo: Role of Runx2, RANKL/OPG, and oxidative stress

Arafa¹,

Elgendy²,

Elhemely³

et al. 2023

Biomedicine & Pharmacotherapy

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Diosmin, a citrus fruit-derived phlebotonic bioflavonoid protects rats from chronic kidney disease-induced loss of bone mass and strength without deteriorating the renal function

Abstract: Kidney Disease: Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline recommended treatment decisions for patients with chronic kidney disease (CKD) with osteoporosis and/or high risk of fracture. Bisphosphonates, the first-line...

Cited by 17 publications

References 80 publications

A novel extraction method enhanced the osteogenic and anti-osteoporosis effect of tea extract without any hepatotoxicity in ovariectomized rats

A novel extraction method enhanced the osteogenic and anti-osteoporosis effect of tea extract without any hepatotoxicity in ovariectomized rats

RING finger E3 ligase, RNF138 inhibits osteoblast differentiation by negatively regulating Runx2 protein turnover

Diosmin mitigates dexamethasone-induced osteoporosis in vivo: Role of Runx2, RANKL/OPG, and oxidative stress

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