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Background

Adaptive properties of the bone-PDL-tooth complex have been identified by changing the magnitude of functional loads using small-scale animal models such as rodents. Reported adaptive responses as a result of lower loads due to softer diet include decreased muscle development, change in structure-function relationship of the cranium, narrowed PDL-space, changes in mineral level of the cortical bone and alveolar jaw bone, and glycosaminoglycans of the alveolar bone. However, the adaptive role of the dynamic bone-PDL-cementum complex due to prolonged reduced loads has not been fully explained to date, especially with regards to concurrent adaptations of bone, PDL and cementum. Hence, the temporal effect of reduced functional loads on physical characteristics such as morphology and mechanical properties, and mineral profiles of the bone-periodontal ligament (PDL)-cementum complex using a rat model was investigated.

Materials and Methods

Two groups of six-week-old male Sprague-Dawley rats were fed nutritionally identical food with a stiffness range of 127–158N/mm for hard pellet or 0.32–0.47N/mm for soft powder forms. Spatio-temporal adaptation of the bone-PDL-cementum complex was identified by mapping changes in: 1) PDL-collagen orientation and birefringence using polarized light microscopy, bone and cementum adaptation using histochemistry, and bone and cementum morphology using micro X-ray computed tomography, 2) mineral profiles of the PDL-cementum and PDL-bone interfaces by X-ray attenuation, and 3) microhardness of bone and cementum by microindentation of specimens at ages six, eight, twelve, and fifteen weeks.

Results

Reduced functional loads over prolonged time resulted in 1) altered PDL orientation and decreased PDL collagen birefringence indicating decreased PDL turnover rate and decreased apical cementum resorption; 2) a gradual increase in X-ray attenuation, owing to mineral differences, at the PDL-bone and PDL-cementum interfaces without significant differences in the gradients for either group; 3) significantly (p<0.05) lower microhardness of alveolar bone (0.93±0.16 GPa) and secondary cementum (0.803±0.13 GPa) compared to the higher load group (1.10±0.17 GPa and 0.940±0.15 GPa respectively) at fifteen weeks indicating a temporal effect of loads on local mineralization of bone and cementum.

Conclusions

Based on the results from this study, the effect of reduced functional loads for a prolonged time could differentially affect morphology and mechanical properties, and mineral variations and of the local load-bearing sites in a bone-PDL-cementum complex. These observed local changes in turn could help explain the overall biomechanical function and adaptations of the tooth-bone joint. From a clinical translation perspective, our study provides an insight into modulation of load on the complex for improved tooth function during periodontal disease, and/or orthodontic and prosthodontic treatments.

New stable cationic organogold(III) complexes containing the ‘pincer’ iminophosphorane ligand (2-C6H4-PPh2=NPh) have been prepared by reaction of the previously described [Au{κ2-C,N-C6H4(PPh2=N(C6H5)-2}Cl2] 1 and a combination of sodium or silver salts and appropriate ligands. The presence of the P atom in the PR3 fragment has been used as a “spectroscopic marker” to study the in vitro stability (and oxidation state) of the new organogold complexes in solvents like DMSO and water. Compounds with dithiocarbamato ligands and water-soluble phosphines of the general type [Au{κ2-C,NC6H4(PPh2=N(C6H5)-2}(S2CN-R2)]PF6 (R = Me 2; Bz 3) and [Au{κ2-C,N-C6H4(PPh2=N(C6H5)-2}(PR3)nCl]PF6 (PR3 = P{Cp(m-C6H4-SO3Na)2} n = 1 4, n = 2 TPA {1,3,5-triaza-7-phosphaadamantane} 5) have been synthesized and characterized in solution and in the solid state (the crystal structure of 2 has been determined by X-ray diffraction studies). Complexes 1–5 have been tested as potential anticancer agents and their cytotoxicity properties were evaluated in vitro against HeLa human cervical carcinoma and Jurkat-T acute lymphoblastic leukemia cells. Compounds 2 and 3 are quite cytotoxic for these two cell lines. There is a preferential induction of apoptosis in HeLa cells after treatment with 1–5. However in the case of the more cytotoxic complex (2), cell death is activated due to both apoptosis and necrosis. The interactions of 1–5 with Calf Thymus DNA have been evaluated by Thermal Denaturation methods. All these complexes show no or little (electrostatic) interaction with DNA. The interaction of 2 with two model proteins (cytochrome c and thioredoxin reductase) has been analyzed by spectroscopic methods (vis-UV and fluorescence). Compound 2 manifests a high reactivity toward both proteins. The mechanistic implications of these results are discussed here.

The title compound, C14H13BrN2OS, was synthesized from the multicomponent reaction between thio­urea, 4-bromo­benzaldehyde and cyclo­hexane-1,3-dione. The crystal packing is stabilized by inter­molecular N—H⋯O, N—H⋯S, C—H⋯O and C—H⋯S hydrogen bonds. Br⋯O inter­actions [3.183 (3) Å] are also observed in the crystal structure.

In the title complex, [PdBr2(C13H18N2)2], the PdII atom is situated on an inversion center. The tetra­hydro­pyrimidine group of the N-(2,4,6-trimethyl­phen­yl)-1,4,5,6-tetra­hydro­pyrimidine ligand is twisted from the square (PdN2Br2) coordination plane with a C—N—Pd—Br torsion angle of 81.8 (4)°; this is different from the angle of 43.47 (14)°, reported in a closely related structure, dichloridobis(1-methyl-1,4,5,6-tetra­hydro­pyrimidine)­palladium(II).

In the title mol­ecule, C11H16O2S5, the two S atoms from the macrocycle are situated on opposite sides of the mean plane of the five-membered ring, deviating from it by 1.288 (3) and 1.728 (3) Å. In the crystal, weak inter­molecular C—H⋯S and C—H⋯O hydrogen bonds link the mol­ecules into layers parallel to (100). The crystal studied was a racemic twin.

The relative motion between the tooth and alveolar bone is facilitated by the soft-hard tissue interfaces which include periodontal ligament-bone (PDL-bone) and periodontal ligament-cementum (PDL-cementum). The soft-hard tissue interfaces are responsible for attachment and are critical to the overall biomechanical efficiency of the bone-tooth complex. In this study, the PDL-bone and PDL-cementum attachment sites in human molars were investigated to identify the structural orientation and integration of the PDL with bone and cementum. These attachment sites were characterized from a combined materials and mechanics perspective and were related to macro-scale function.

High resolution complimentary imaging techniques including atomic force microscopy, scanning electron microscopy and micro-scale X-ray computed tomography (Micro XCT™) illustrated two distinct orientations of PDL; circumferential-PDL (cir-PDL) and radial-PDL (rad-PDL). Within the PDL-space, the primary orientation of the ligament was radial (rad-PDL) as is well known. Interestingly, circumferential orientation of PDL continuous with rad-PDL was observed adjacent to alveolar bone and cementum. The integration of the cir-PDL was identified by 1 to 2 μm diameter PDL-inserts or Sharpey’s fibers in alveolar bone and cementum. Chemically and biochemically the cir-PDL adjacent to bone and cementum was identified by relatively higher carbon and lower calcium including the localization of small leucine rich proteins responsible for maintaining soft-hard tissue cohesion, stiffness and hygroscopic nature of PDL-bone and PDL-cementum attachment sites. The combined structural and chemical properties provided graded stiffness characteristics of PDL-bone (Er range for PDL: 10 – 50 MPa; bone: 0.2 – 9.6 GPa) and PDL-cementum (Er range for cementum: 1.1 – 8.3 GPa), which was related to the macro-scale function of the bone-tooth complex.

The mean survival of patients with severe primary pulmonary hypertension (PPH) is < 3 years without appropriate treatment. There are no long term reports on the spontaneous course of mild PPH over a longer period. Stable long term follow up is described of a 39 year old patient with PPH without treatment over a 30 year period. PPH had been diagnosed 30 years previously after right heart catheterisation (mean pulmonary artery pressure 35 mm Hg) and 30 years later, repeated measurements showed nearly unchanged haemodynamic parameters. Further examinations confirmed the diagnosis of PPH. It is suggested that PPH with modestly limited physical activity (New York Heart Association functional class II) does not always seem to coincide with progression of the disease and, therefore, it may be feasible to withhold treatment while closely monitoring these patients.

The title compound, C21H17ClO6, is optically pure and adopts an R configuration. It was obtained by an organocatalytic asymmetric Michael addition of 4-hydroxy­coumarin with (E)-ethyl 4-(4-chloro­phen­yl)-2-oxobut-3-enoate. The structure consists of a tetra­hydro­pyran unit fused to the coumarin ring ring system. The hydroxyl and phenyl groups are on the same side of the tetra­hydro­pyrane ring. The benzene ring is almost perpendicular to the coumarin ring [dihedral angle of 72.89 (3)°]. In the crystal structure, inter­molecular O—H⋯O hydrogen bonds are observed. An intra­molecular O—H⋯O contact also occurs.

In the title compound, C13H15ClN2S, the dihydro­pyrimidine ring is essentially planar, with a maximum deviation from the least-squares plane of 0.122 (3) Å for the unsubstitued olefinic C atom. The dihedral angle between the dihydro­pyrimidine and benzene rings is 86.62 (13)°. The crystal structure is stabilized by inter­molecular N—H⋯S hydrogen bonds, which form centrosymmetric dimers arranged along the c axis.

In the title compound, C13H15FN2S, the dihydro­pyrimidine ring is essentially planar, with a maximum deviation of 0.086 (3) Å from the mean plane of the rest of the ring for the dimethyl­ated C atom. The benzene ring is almost perpendicular to the dihydro­pyrimidine ring, with a dihedral angle of 83.97 (14)°. The crystal packing is characterized by centrosymmetric dimers resulting from pairs of inter­molecular N—H⋯S hydrogen bonds. There are also C—H⋯π inter­actions.

Purpose

Under different culture conditions, periodontal ligament (PDL) stem cells are capable of differentiating into cementoblast-like cells, adipocytes, and collagen-forming cells. Several previous studies reported that because of the stem cells in the PDL, the PDL have a regenerative capacity which, when appropriately triggered, participates in restoring connective tissues and mineralized tissues. Therefore, this study analyzed the genes involved in mineralization during differentiation of human PDL (hPDL) cells, and searched for candidate genes possibly associated with the mineralization of hPDL cells.

Methods

To analyze the gene expression pattern of hPDL cells during differentiation, the hPDL cells were cultured in two conditions, with or without osteogenic cocktails (β-glycerophosphate, ascorbic acid and dexamethasone), and a DNA microarray analysis of the cells cultured on days 7 and 14 was performed. Reverse transcription-polymerase chain reaction was performed to validate the DNA microarray data.

Results

The up-regulated genes on day 7 by hPDL cells cultured in osteogenic medium were thought to be associated with calcium/iron/metal ion binding or homeostasis (PDE1A, HFE and PCDH9) and cell viability (PCDH9), and the down-regulated genes were thought to be associated with proliferation (PHGDH and PSAT1). Also, the up-regulated genes on day 14 by hPDL cells cultured in osteogenic medium were thought to be associated with apoptosis, angiogenesis (ANGPTL4 and FOXO1A), and adipogenesis (ANGPTL4 and SEC14L2), and the down-regulated genes were thought to be associated with cell migration (SLC16A4).

Conclusions

This study suggests that when appropriately triggered, the stem cells in the hPDL differentiate into osteoblasts/cementoblasts, and the genes related to calcium binding (PDE1A and PCDH9), which were strongly expressed at the stage of matrix maturation, may be associated with differentiation of the hPDL cells into osteoblasts/cementoblasts.

The title compound, C17H20N2O6, belongs to the monastrol-type of anti­cancer agents and was selected for crystal structure determination in order to confirm its mol­ecular structure and explore some aspects of its structure–activity relationships. The central tetra­hydro­pyrimidine ring has a flat-envelope conformation. The 4-hydroxy­phenyl group occupies a pseudo-axial position and is inclined at an angle of 87.7 (2)° to the mean plane of the heterocyclic ring. Of the two ethyl ester groups, one (in the 5-position) is in a coplanar and the other (in the 6-position) is in a perpendicular orientation with respect to the heterocyclic plane. There is a three-dimensional hydrogen-bonding network in which all hydrogen-bond donors and acceptors are involved.

In the title compound, C14H16N2O4·H2O, the dihedral angles between the planes of the 4-hydroxy­phenyl and ester groups with the plane of the six-membered tetra­hydro­pyrimidine ring are 87.3 (1) and 75.9 (1)°, respectively. The crystal structure is stabilized by O—H⋯O and N—H⋯O hydrogen bonding between the water mol­ecule and the organic functionalities.

The dihydro­pyrimidine ring of the title compound, C13H15ClN2S, adopts an envelope conformation with five almost coplanar atoms (r.m.s. deviation = 0.054 Å) and the C atom bearing the two methyl substituents deviating from this plane by 0.441 (2) Å. The best plane through the five almost coplanar atoms forms a dihedral angle of 89.56 (5)° with the benzene ring. The crystal packing is characterized by centrosymmetric dimers connected by pairs of N—H⋯S hydrogen bonds.

The asymmetric unit of the title compound, C14H18N2S, contains two independent and conformationally similar mol­ecules, which form cyclic dimers via inter­molecular hydrogen bonds of the type N—H⋯S [graph set R 2 2(8)]. The structure is iso­morphous with that of one of the polymorphs of 4,4,6-tri­methyl-1-phenyl-3,4-dihydro­pyrimidine-2(1H)-thione [Yam­in et al. (2005 ▶). Acta Cryst. E61, o55–o57].

To obtain structural and spectroscopic models for the diiron(II,III) centers in the active sites of diiron enzymes, the (μ-alkoxo)(μ-carboxylato)diiron(II,III) complexes [FeIIFeIII(N-Et-HPTB)(O2CPh)(NCCH3)2](ClO4)3 (1) and [FeIIFeIII(N-Et-HPTB)(O2CPh) (Cl)(HOCH3)](ClO4)2 (2) (N-Et-HPTB = N,N,N′,N′-tetrakis(2-(1-ethyl-benzimidazolylmethyl))-2-hydroxy-1,3-diamino propane), have been prepared and characterized by X-ray crystallography, EPR, and Mössbauer spectroscopy. The Fe1-Fe2 separations are 3.60 Å and 3.63 Å and the Fe1-O1-Fe2 bond angles are 128.0° and 129.4° for 1 and 2, respectively. Mössbauer and EPR studies of 1 show that the FeIII (SA = 5/2) and FeII (SB = 2) sites are antiferromagnetically coupled to yield a ground state with S = 1/2 (g = 1.75, 1.88, 1.96); Mössbauer analysis of solid 1 yields J = 22.5 ± 2 cm−1 for the exchange coupling constant ( = JSA•SB convention). In addition to the S = 1/2 ground state spectrum of 1, the EPR signal for the S = 3/2 excited state of the spin ladder can also be observed, the first time such a signal has been detected for an antiferromagnetically coupled diiron(II,III) complex. The anisotropy of the 57Fe magnetic hyperfine interactions at the FeIII site is larger than normally observed in mononuclear complexes and arises from admixing S > 1/2 excited states into the S = 1/2 ground state by zero-field splittings at the two Fe sites. Analysis of the “D/J” mixing has allowed us to extract the zero-field splitting parameters, local g values, and magnetic hyperfine structural parameters for the individual Fe sites. The methodology developed and followed in this analysis is presented in detail. The spin Hamiltonian parameters of 1 are related to the molecular structure with the help of DFT calculations. Contrary to what was assumed in previous studies, our analysis demonstrates that the deviations of the g-values from the free electron value (g = 2) for the antiferromagnetically coupled diiron(II,III) core in complex 1 are predominantly determined by the anisotropy of the effective g-values of the ferrous ion, and only to a lesser extent by the admixture of excited states into ground state ZFS terms (D/J mixing). The results for 1 are discussed in the context of the data available for diiron(II,III) clusters in proteins and synthetic diiron(II,III) complexes.

The title compound, C16H20F3N3O4, was prepared by reaction of 4-(dimethyl­amino)benzaldehyde, ethyl 4,4,4-trifluoro-3-oxo­butanoate and urea. In the title mol­ecule, the pyrimidine ring adopts a half-chair conformation and there is an intra­molecular hydrogen bond (O—H⋯O). The crystal structure is stabilized by two types inter­molecular hydrogen bonds (N—H⋯O and N—H⋯N).

In the title compound, C14H15F3N2O5, prepared by reaction of 2-hy­droxy­benzaldehyde, ethyl 4,4,4-trifluoro-3-oxobutano­ate and urea, the tetra­pyrimidine ring adopts a half-chair conformation. The crystal structure is stabilized by five inter­molecular hydrogen bonds, three O—H⋯O and two N—H⋯O, giving cyclic dimers (through three hydrogen bonds) which are further extended into a two-dimensional network.

The title compound, C16H12F3N3O5S·H2O, was prepared by reaction of 4-nitro­benzaldehyde, 4,4,4-trifluoro-1-(thio­phen-2-yl)butane-1,3-dione and urea. The asymmetric unit contains two independent mol­ecules, with essentially identical geom­etries and conformations. The dihydro­pyrimidine rings adopt a half-chair conformation. The dihedral angles between the benzene ring and the thio­phene ring are 54.82 (8) and 58.72 (8)° in the two mol­ecules. The mol­ecular conformation of one of the mol­ecules is stabilized by two intra­molecular O—H⋯O hydrogen bonds, generating an S(6) ring. The crystal structure is stabilized by inter­molecular O—H⋯O and N—H⋯O hydrogen bonds.

In the title compound, C17H18N2O4S, where one of the N-4-methoxy­phenyl fragments is disordered over two sets of sites, the five-membered ring exhibits a nearly half-chair conformation and the two hydroxyl groups lie on opposite sides of the five-membered ring. In the crystal, the mol­ecules are linked into sheets parallel to (100) via O—H⋯O and O—H⋯S hydrogen bonds.

A new Biginelli compound, C18H25BN2O4S2, containing a boronate ester group was synthesized from a lithium bromide-catalysed reaction. The compound crystallizes with two independent mol­ecules in the asymmetric unit that differ mainly in the conformation of the ester functionality. The crystal structure is stabilized by inter­molecular N—H⋯O and N—H⋯S hydrogen bonds involving the 3,4-dihydro­pyrimidine-2(1H)-thione NH groups as donors and the carbonyl O and thio­phene S atoms as acceptors.

The asymmetric unit of the title compound, C16H12ClF3N2O3S·H2O, contains two crystallographically independent organic mol­ecules and two water mol­ecules. The organic species are linked by an inter­molecular O—H⋯O hydrogen bond, while the water mol­ecules are connected to them through inter­molecular O—H⋯N hydrogen bonds. The thio­phene and phenyl rings are oriented at dihedral angles of 62.35 (4) in the first independent mol­ecule and 60.74 (5)° in the second, while the pyrimidine rings adopt twisted conformations in both molecules. Intra­molecular N—H⋯F inter­actions result in the formation of two five-membered rings having envelope conformations. In the crystal structure, further inter­molecular O—H⋯O and N—H⋯O hydrogen bonds link the mol­ecules into chains.

The title compound, C19H15NO2S3, is the first example of a dithia analogue of pyrano[3,4-b]indolone. The almost planar thio­pyrano­indole­thione ring system (r.m.s. deviation for all non-H atoms = 0.030 Å) makes a dihedral angle of 80.70 (8)° with the p-tolyl ring. In the crystal, mol­ecules are connected via C—H⋯O hydrogen bonds into two chains along the b axis. These chains are connected via π–π inter­actions between symmetry-related thio­pyrano­indole­thione ring systems [centroid–centroid distance = 3.588 (1) Å].

The tooth root cementum is a thin, mineralized tissue covering the root dentin that is present primarily as acellular cementum on the cervical root and cellular cementum covering the apical root. While cementum shares many properties in common with bone and dentin, it is a unique mineralized tissue and acellular cementum is critical for attachment of the tooth to the surrounding periodontal ligament (PDL). Resources for methodologies for hard tissues often overlook cementum and approaches that may be of value for studying this tissue. To address this issue, this report offers detailed methodology, as well as comparisons of several histological and immunohistochemical stains available for imaging the cementum–PDL complex by light microscopy. Notably, the infrequently used Alcian blue stain with nuclear fast red counterstain provided utility in imaging cementum in mouse, porcine and human teeth. While no truly unique extracellular matrix markers have been identified to differentiate cementum from the other hard tissues, immunohistochemistry for detection of bone sialoprotein (BSP), osteopontin (OPN), and dentin matrix protein 1 (DMP1) is a reliable approach for studying both acellular and cellular cementum and providing insight into developmental biology of these tissues. Histological and immunohistochemical approaches provide insight on developmental biology of cementum.

Four new metal complexes {M = Pd(II) or Pt(II)} containing the ligand 9-aminoacridine (9AA) were prepared. The compounds were characterized by FT-IR and 1H, 13C, and 195Pt NMR spectroscopies. Crystal structure of the palladium complex of formulae [Pd(9AA)(μ-Cl)]2 · 2DMF was determined by X-ray diffraction. Two 9-acridine molecules in the imine form bind symmetrically to the metal ions in a bidentate fashion through the imine nitrogen atom and the C(1) atom of the aminoacridine closing a new five-membered ring. By reaction with phosphine or pyridine, the Cl bridges broke and compounds with general formulae [Pd(9AA)Cl(L)] (where L = PPh3 or py) were formed. A mononuclear complex of platinum of formulae [Pt(9AA)Cl(DMSO)] was also obtained by direct reaction of 9-aminoacridine and the complex [PtCl2(DMSO2]. The capacity of the compounds to modify the secondary and tertiary structures of DNA was evaluated by means of circular dichroism and electrophoretic mobility. Both palladium and platinum compounds proved active in the modification of both the secondary and tertiary DNA structures. AFM images showed noticeable modifications of the morphology of the plasmid pBR322 DNA by the compounds probably due to the intercalation of the complexes between base pairs of the DNA molecule. Finally, the palladium complex was tested for antiproliferative activity against three different human tumor cell lines. The results suggest that the palladium complex of formula [Pd(9AA)(μ-Cl)]2 has significant antiproliferative activity, although it is less active than cisplatin.