No abstract

MAT is characterized with high heterogeneity which may suggest both that marrow adipocytes originate from multiple different progenitors and/or their phenotype is determined by skeletal location and environmental cues. Close relationship to osteoblasts and heterogeneity suggests that MAT consists of cells representing spectrum of phenotypes ranging from lipid-filled adipocytes to pre-osteoblasts. We propose a term of adiposteoblast for describing phenotypic spectrum of MAT. Manipulating with MAT activity in diseases where impairment in energy metabolism correlates with bone functional deficit, such as aging and diabetes, may be beneficial for both. Paracrine activities of MAT might be considered for treatment of bone diseases. MAT has unrecognized potential, either beneficial or detrimental, to regulate bone homeostasis in physiological and pathological conditions. More research is required to harness this potential for therapeutic purposes.

Bone and energy metabolism are integrated by common regulatory mechanisms. Carboxypeptidase E (CPE), also known as obesity susceptibility protein or neurotrophic factor‐α1, is recognized for its function in processing prohormones, including proinsulin and pro‐opiomelanocortin polypeptide. Independent of its enzymatic activity, CPE may also act as a secreted factor with divergent roles in neuroprotection and cancer growth; however, its role in the regulation of bone mass and skeletal cell differentiation is unknown. Male mice with global deficiency in CPE are characterized with profound visceral obesity, low bone mass in both appendicular and axial skeleton, and high volume of marrow fat. Interestingly, although metabolic deficit of CPE KO mice develops early in life, bone deficit develops in older age, suggesting that CPE bone‐specific activities differ from its enzymatic activities. Indeed, mutated CPE knockin (mCPE KI) mice ectopically expressing CPE‐E342Q, a mutated protein lacking enzymatic activity, develop the same obese phenotype and accumulate the same volume of marrow fat as CPE KO mice, but their bone mass is normal. In addition, differentiation of marrow hematopoietic cells toward tartrate‐resistant acid phosphatase‐positive multinucleated osteoclasts is highly increased in CPE KO mice, but normal in mCPE KI mice. Moreover, in murine skeletal stem cells, nonenzymatic trophic CPE has activated ERK signaling, increased cell proliferation and increased mitochondrial activity. Treatment of preosteoblastic cells with intact or mutated recombinant CPE led to a transient accumulation of small lipid droplets, increased oxidative phosphorylation, and increased cellular dependence on fatty acids as fuel for energy production. In human marrow aspirates, CPE expression increases up to 30‐fold in osteogenic conditions. These findings suggest that nonenzymatic and trophic activities of CPE regulate bone mass, whereas marrow adiposity is controlled by CPE enzymatic activity. Thus, CPE can be positioned as a factor regulating simultaneously bone and energy metabolism through a combination of shared and distinct mechanisms. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

No abstract

Inhibition of aromatase (CYTP450), a key enzyme in the estrogen biosynthesis, could result in regression of estrogen-dependent tumors and even prevent the promotion of breast cancer. The present research has been designed for searching a potent chemical moiety from natural sources to inhibit aromatase enzyme, the overfunctionality of which causes the breast cancer. Cannabis sativa contains a very much promising group of cannabinoids with more than 66 compounds with reported anticancer property and for the search of a target specific potent aromatase inhibitor, 61 cannabinoids from C. sativa were selected. The Structures Data File (SDF) of these ligand molecules were subjected to docking studies at the binding site of aromatase X-ray crystallographic structure based on lower resolution of the protein crystal structure and higher docking accuracy, predicted by calculating the correlation between experimental activities and Glide dock scores and compared with the standard aromatase ligand androstenedione and aromatase inhibitor fadrozole with existing drug for breast cancer treatment. The best docked pose of each ligand was selected on the basis of the highest dock score related to the binding free energies of the internal dataset compounds as compared to their observed activities. Apart from the hydrogen bond formation with the oxygen present on the aromatic ring system, the other parts of the molecules are stabilized by hydrophobic interactions with non-polar amino acid residues (Ile133, Phe134, Phe221, Trp224, Ile305, Ala306, Ala307, Val369, Val370, Leu372, Val373, Met374 and Leu477). From the screening results of the cannabinoid analogs, 21 out of 61 were found to have an acceptable docking score in comparison to the standards, androstenedione and fadrozole. The pharmacokinetic filters like absorption, distribution, metabolism and excretion and toxicity (ADMET) property determination were applied to select drug-like compounds. Among them three compounds were found to reveal the most promising drug like activity, which were cannabidiorcol (CN 17, CBD-C1), cannabitriol (CN 43, CBT) and cannabiripsol (CN 55, CBR). The ani-cancer activity of the target compounds was performed against brine shrimp lethality biassay, where cannabidiorcol exhibited significant LC50 value of 0.348 ±0.002 μg/ml (R² = 0.9853) which is almost similar to vincristine sulfate (LC50 = 0.316±0.003 μg/ml, R² = 0.9882). Compound cannabitriol also showed promisimg cytotoxicity 0.650±0.004 μg/ml (R² = 0.9882) in comparison to the reference standard. But cannabiripsol demostrated relatively weaker activity 12.95±1.234 μg/ml (R²=0.9897). It can be concluded that the lead compounds may be developed as potent aromatase inhibitor performing their further biological evaluation. Dhaka Univ. J. Pharm. Sci. 19(1): 47-58, 2020 (June)