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Bone Regeneration Effect of Cassia occidentalis Linn. Extract and Its Isolated Compounds
Published in Brijesh Kumar, Vikas Bajpai, Vikaskumar Gond, Subhashis Pal, Naibedya Chattopadhyay, Phytochemistry of Plants of Genus Cassia, 2021
Brijesh Kumar, Vikas Bajpai, Vikaskumar Gond, Subhashis Pal, Naibedya Chattopadhyay
Self-nano emulsifying drug delivery system (SEDDS) is an efficient mode for improving the bioavailability of poorly absorbed compounds often present in phytoextracts. A lipid-based SEDDS of CBE was found to enhance the bioavailabilities of apigenin, isovitexin, THF, luteolin and emodin along with the increase in the skeletal effect. However, CBE at 100 mg/kg dose increased osteogenic effect, the SEDDS formulated CBE achieved the same effect at 50 mg/kg (Pal et al., 2020). The study also found that MP treatment significantly suppressed osteocyte markers including dentin matrix acidic phosphoprotein 1 (DMP-1) and matrix extracellular phosphoglycoprotein (MEPE), and SEDDS formulated CBE maintained their expression (Pal et al., 2020). Muscle atrophy is another signature of GC treatment and we found that SEDDS-formulated CBE significantly improved muscle structure and prevented muscle atrophy. Reports also showed that SEDDS-formulated CBE did not alter the anti-inflammatory effect of MP (Pal et al., 2020). These studies established CO extract and its related formulation as an effective pharmacotherapy for the treatment of GC-induced osteo-sarcopenia.
Metabolic and endocrine bone disorders
Published in Ashley W. Blom, David Warwick, Michael R. Whitehouse, Apley and Solomon’s System of Orthopaedics and Trauma, 2017
For example, in autosomal dominant hypophosphataemic rickets (ADHR), FGF23 levels are elevated due to a gain of function mutation causing resistance to enzymatic cleavage. Similarly, sex-linked hypophosphataemic rickets (XLH), autosomal recessive hypophosphataemic rickets type I (ARHR1) and autosomal recessive hypophosphataemic rickets type 2 (ARHR2) are associated with overproduction of FGF23 in osteocytes due to loss of function mutations in other genes, namely PHEX, DMP1 and ENPP1 respectively (Ruppe and Jan de Beur, 2013). Conversely, a number of mutations have been identified leading to decreased FGF23 levels, resulting in familial tumoural calcinosis in which hyperphosphataemia occurs, leading to soft-tissue calcification.
The Nature of Renal Function
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
The activity of NPT IIa is inhibited by not only PTH, but also a recently described protein of the fibroblast growth factor family, FGF23(73), produced in osteocytes. FGF23 is also secreted by some tumors that cause tumor-induced osteomalacia, a paraneoplastic syndrome leading to renal phosphate wasting, hypophosphatemia, and rickets/osteomalacia (74). FGF23 is inactivated by a yet unidentified peptidase that cleaves it into two inactive fragments. Mutations in FGF23 that render it resistant to enzymatic cleavage but do not inhibit its activity cause a rare, autosomal dominant, form of hypophosphatemic rickets (75). Two other proteins are also expressed in osteocytes, and are believed to be involved in the regulation of expression of the gene for FGF23. The gene for the first of these to be described is called PHEX (a phosphate-regulating gene with homologies to genes for endopeptidases on the X chromosome), and is mutated in patients with the relatively common X-linked hypo-phosphatemic rickets (76). The second is called DMP-1 (dentin matrix protein-1) and the gene for it is mutated in the very rare autosomal recessive hypophosphatemic rickets (77). The phenotypes of all these forms of hereditary hypophosphatemia are similar, and are caused by inhibition of NPT IIa either by the uncontrolled release of FGF23 or by failure of its enzymatic degradation, leading to inhibition of P reabsorption by NPT IIa, phosphaturia, and hypophosphatemic rickets. Yet another gene, rather quaintly called klotho in honor of the Greek goddess who spins the thread of life, is mutated in transgenic mice with a premature aging syndrome. Further studies have shown that klotho is expressed in the renal tubule and is an essential coreceptor for FGF23. Klotho-deficient mice and FGF-deficient mice develop identical phenotypes, indicating that klotho expression in the renal tubules is necessary for the renal effect of FGF23. These interrelationships are reviewed at greater length by Kurosu and Kuro-o (78).
Bioactive molecule carrier systems in endodontics
Published in Expert Opinion on Drug Delivery, 2020
Anil Kishen, Hebatullah Hussein
Collagen, the major macromolecule component of the ECM, is one of the most studied natural polymers for tissue-engineering scaffolds [77,78]. Collagen scaffolds loaded with several BM have been tested in regenerative endodontic procedures. It was demonstrated that when BMP-2 was delivered using a collagen sponge in a canine tooth, a mineralized osteodentin-like tissue containing embedded osteodentinocytes was formed [79]. Other studies have applied collagen as a carrier of BMP-7 in exposed teeth to achieve reparative dentin, complete bridging of defects, and maintaining radicular pulp vitality [63,80,81]. Application of collagen membrane to deliver dentin matrix protein-1 (DMP-1) at the site of pulp exposure in rat molars showed that undifferentiated mesenchymal cells have the potential to regenerate dentin-like tissue [64]. Previous studies employed collagen scaffold for the delivery of DMP-1 along with dental pulp stem cells (DPSCs) in a subcutaneous implantation model in nude mice for the regeneration of new pulp tissue [65]. Basic fibroblast growth factor (bFGF) was also delivered with collagen gel to induce re-cellularization and re-vascularization in endodontically treated human teeth, implanted on the dorsum of rats [69].
Tumor suppression by the EGR1, DMP1, ARF, p53, and PTEN Network
Published in Cancer Investigation, 2018
Kazushi Inoue, Elizabeth A. Fry
A cyclin D binding myb-like protein 1 (also called Dmtf1), was originally isolated in a yeast two-hybrid screen of a murine T-lymphocyte library with cyclin D2 as bait (22, 23; 24–28 for reviews). Dmp1 physically interacts with any of the three D-type cyclins, each of which can inhibit its ability to bind to DNA (22, 23). Biological studies indicated that overexpression of Dmp1 causes cell cycle arrest in NIH 3T3 cells, the activity of which was attenuated by D-type cyclins independent of Cdks (23). Dmp1 (Dmp1α) shows its activity as a tumor suppressor by directly binding to the Arf promoter to activate its gene expression, and thereby induces Arf- and p53-dependent cell cycle arrest (19, 29, 30; 31–35 for Arf/Ink4a reviews). Other transcriptional targets for Dmp1 include CD13/APN (36), Areg, Thbs1, JunB, and Egr1 (20), suggesting that it is involved in signal transduction, cell proliferation, apoptosis, and angiogenesis. The activity of the Arf-53 pathway is significantly subverted in Dmp1-deficient cells since they can easily give rise to immortalized cell lines that retain wild type p19Arf and wild type p53 and are transformed by oncogenic Ras alone (37, 38). The murine Dmp1 promoter is activated by oncogenic Ras as well as by constitutively active MEK1/2 and ERK1/2 in primary culture cells (19). Thus, Dmp1 is a key mediator between Ras-Raf-MEK-ERK mitogenic signaling and the Arf-p53 tumor suppressor pathway. Both Dmp1 and Arf mRNA levels decrease at S-G2/M phase of the cell cycle since promoters are repressed by mitogenic signals mediated by E2Fs (39). Both promoters are repressed by and genotoxic signals mediated mainly the p65 subunit of by NF-κB (40). Dmp1 (Dmp1α) physically interacts with p53 to neutralize all the activities of Mdm2 on p53, indicating that this is the secondary mechanism of tumor surveillance in Arf-deficient cells (41, 42). Recent studies show that Dmp1 also transactivates p16Ink4a although the effect is less than stimulation of Arf (43, 44).
Osteogenic and odontogenic differentiation potential of dental pulp stem cells isolated from inflamed dental pulp tissues (I-DPSCs) by two different methods
Published in Acta Odontologica Scandinavica, 2020
Vellore Kannan Gopinath, S. Soumya, Manju Nidagodu Jayakumar
The osteo/odontoblastic differentiation analysed semi quantitatively by qPCR demonstrated an upregulated expression of all the genes at day 21 compared to day 1. Herein, we have checked the gene expression of four potential genes, which are mainly involved in osteogenic and odontogenic differentiation of DPSCs. As discussed earlier, ALP is a phosphatase enzyme, which helps in the deposition of calcium phosphate in bone and dentine. A higher ALP activity could be found during the differentiation phase of bone and dentine. During the odontoblastic differentiation, a higher mineralized dentine matrix is deposited and the main non-collagenous proteins present are DMP1 and DSPP. We have used DMP1 and DSPP in our experiment as this protein is existent in odontoblasts, dentinal tubules and its presence are known during dentine matrix mineralization [45–48]. The upregulated mRNA level expression of DMP1 and DSPP is indicative of odontogenic differentiation and was found to be higher in cells cultured in COL osteogenic media compared to OG at day 21. In a study similar to ours, compared the expression of Dentine Sialophosphoprotein (DSPP) in dental pulp stem cells isolated by outgrowth and enzyme digestion methods, no significant difference was observed in the DSPP expression by the DPSC differentiated odontoblasts between the methods [38]. However, in our study we found that the expression of DMP1, which is considered to regulate the DSPP gene transcription was higher in IDPSC isolated by COL method, compared to the OG method. The expression of other genes such as ALP and BGLAP were enhanced by day 21 in both the cell groups but no significant difference were observed between the groups. These finding were contradictory to the ALP activity and Alizarin Red S staining analysed biochemically wherein, the cells isolated by COL method showed better activity and mineral deposition compared to OG method. Despite the fact that the isolated cells were negative for STRO-1, the stem cell specific marker, the differentiation ability of the cells were not compromised in our case. The cells isolated by both the methods were able to differentiate into osteoblastic and odontogenic lineages, with the COL method showed better differentiation ability than OG method. Our study also favoured the concept that the inflamed dental pulp tissue, which is discarded as a waste in the endodontic procedure, contains putative stem cell population, which retains similar stem cell characteristics as that of the cells isolated from healthy tissues. Comparable to the present work it is interesting to note that human periapical cyst-mesenchymal stem cells (hPcy-MSCs) derived from excised periapical cyst, showed characteristics similar to DPSC [49]. However, it should be noted that hPcy-MSCs cells favoured osteogenic lineages whereas I-DPSCs isolated in the present study favoured odontogenic differentiation [50].