Cancer is considered one of the primary diseases that cause morbidity and mortality in millions of people worldwide and due to its prevalence, there is undoubtedly an unmet need to discover novel anticancer drugs. However, the traditional process of drug discovery and development is lengthy and expensive, so the application of in silico techniques and optimization algorithms in drug discovery projects can provide a solution, saving time and costs. A set of 617 approved anticancer drugs, constituting the active domain, and a set of 2,892 natural products, constituting the inactive domain, were employed to build predictive models and to index natural products for their anticancer bioactivity. Using the iterative stochastic elimination optimization technique, we obtained a highly discriminative and robust model, with an area under the curve of 0.95. Twelve natural products that scored highly as potential anticancer drug candidates are disclosed. Searching the scientific literature revealed that few of those molecules (Neoechinulin, Colchicine, and Piperolactam) have already been experimentally screened for their anticancer activity and found active. The other phytochemicals await evaluation for their anticancerous activity in wet lab.
The genes for two different 70-kDa heat shock protein (HSP70) homologs have been cloned and sequenced from the protozoan Giardia lambiba. On the basis of their sequence features, one of these genes corresponds to the cytoplasmic form of HSP70. The second gene, on the basis of its characteristic N-terminal hydrophobic signal sequence and C-tenal endoplasmic reticulum (ER) retention sequence (Lys-Asp-Glu-Leu), is the equivalent of ER-resident GRP78 or the Bip family of proteins. To test this hypothesis we undertook to clone HSP70 homologs from the protozoan Giardia lamblia, which lacks mitochondria (6) and which, on the basis of 16S rRNA phylogeny, constitutes the earliest diverging member within the eukaryotic lineage (7). In the present paper we describe the cloning and sequence comparison of two HSP70 homologs from G. lamblia.t One of these homologs apparently corresponds to the cytoplasmic form of the protein, whereas the other bears various characteristics of the form present in the endoplasmic reticulum (ER) (see refs. 3 and 8). Detailed comparison and phylogenetic analyses of these and other eukaryotic and prokaryotic HSP70 sequences presented here provide important insight into the origin of eukaryotic cells and of ER.
The 70-kDa heat shock protein (hsp70) sequences define one of the most conserved proteins known to date. The hsp70 genes from Deinococcus proteolyticus and Thermomicrobium roseum, which were chosen as representatives of two of the most deeply branching divisions in the 16S rRNA trees, were cloned and sequenced. hsp70 from both these species as well as Thermus aquaticus contained a large insert in the N-terminal quadrant, which has been observed before as a unique characteristic of gram-negative eubacteria and eukaryotes and is not found in any gram-positive bacteria or archaebacteria. Phylogenetic analysis of hsp70 sequences shows that all of the gram-negative eubacterial species examined to date (which includes members from the genera Deinococcus and Thermus, green nonsulfur bacteria, cyanobacteria, chlamydiae, spirochetes, and ␣-, -, and ␥-subdivisions of proteobacteria) form a monophyletic group (excluding eukaryotic homologs which are derived from this group via endosybitic means) strongly supported by the bootstrap scores. A closer affinity of the Deinococcus and Thermus species to the cyanobacteria than to the other available gram-negative sequences is also observed in the present work. In the hsp70 trees, D. proteolyticus and T. aquaticus were found to be the most deeply branching species within the gram-negative eubacteria. The hsp70 homologs from gram-positive bacteria branched separately from gram-negative bacteria and exhibited a closer relationship to and shared sequence signatures with the archaebacteria. A polyphyletic branching of archaebacteria within gram-positive bacteria is strongly favored by different phylogenetic methods. These observations differ from the rRNA-based phylogenies where both gram-negative and gram-positive species are indicated to be polyphyletic. While it remains unclear whether parts of the genome may have variant evolutionary histories, these results call into question the general validity of the currently favored three-domain dogma.The classification of prokaryotes has posed a major challenge for biologists for centuries (see references 71 and 79). Given their enormous diversity, which dates back to the beginning of life, the classical taxonomical criteria based on morphology and physiology have generally proven inadequate to satisfactorily define their evolutionary relationships (86). However, in the past few decades, the ability to clone and sequence nucleic acids as well as their products has led to the field of molecular phylogeny, in which the evolutionary relationships among organisms are derived from the extent of similarity in the primary sequences of either protein or nucleic acid homologs (55,84,85,89). These techniques have now become the preferred criteria for bacterial classification (1, 3, 5, 7, 8, 16-18, 22, 40, 44, 55, 56, 75, 77, 78, 80, 81, 84, 85).Most extensive studies with regard to the molecular classification of bacterial species have been based on the smallsubunit rRNA, or 16S rRNA (22,56,84). These studies have led to the concept of division of ...
The proposed anti-inflammatory model can be utilized for the virtual screening of large chemical databases and for indexing natural products for potential anti-inflammatory activity.
The genes for hsp7O (or dnaK) have been cloned and sequenced from Rhizobium meliloti and Pseudomonas cepacia, two bacterial species belonging to the a-and ,8-subdivisions of gram-negative proteobacteria, respectively. On the basis of global alignment of HSP70 proteins, several sequence signatures have been identified that are distinctive of mitochondrial homologs and gram-negative proteobacteria on the one hand and the chloroplasts and cyanobacteria on the other. Detailed phylogenetic analyses of HSP70 sequences from various eubacteria and eukaryotic organellar and cytosolic homologs support the inference regarding the origin of mitochondria from a member of the a-proteobacteria and of chloroplasts from cyanobacteria. The analysis presented here also suggests a monophyletic origin of the mitochondrial homologs.The members of the 70-kDa heat shock family of proteins (HSP70) are ubiquitously present in all eukaryotic and prokaryotic organisms and constitute one of the most conserved classes of proteins found in all species (1,11,16). Because of their ubiquitous presence and high degree of sequence conservation, HSP70 homologs provide an attractive system for molecular evolutionary studies (1,10,11,13). On the basis of morphological and biochemical similarities between eukaryotic cell organelles such as mitochondria and chloroplasts and certain groups of eubacteria, it has been proposed that the former arose by serial endosymbiotic capture of the latter species (see references 6, 8, 14, and 19). This view has received support from phylogenetic analysis of gene sequences. In the case of mitochondria, studies based on rRNA and cytochrome c sequences indicate that the endosymbionts that gave rise to mitochondria are (or were) related to the a-subdivision of proteobacteria, which have been referred to as purple bacteria in earlier studies (2,6,14,18,21). However, because of the large variation in the sizes of rRNAs in eukaryotic species (see reference 5) and in the cytochrome c sequences in prokaryotic species (see reference 2), it is necessary to confirm this inference using other molecules which show a higher degree of sequence and structural conservation. To examine this question, the cloning and sequencing of hsp7O genes from Rhizobium meliloti and Pseudomonas cepacia, which are members of the a-subdivision and P-subdivision of the proteobacteria (20), were undertaken. Global comparisons and detailed phylogenetic analyses of the organellar, eubacterial, and eukaryotic HSP70 sequences presented here strongly support the endosymbiotic hypothesis for the origin of mitochondria from a member of the a-subdivision of proteobacteria and of chloroplasts from a cyanobacterial species.Cloning of hsp7O (dnaK) genes from R. meliloti and P.cepacia. The approach used for cloning the hsp7O genes is described in earlier work (4, 12 shown; see references 4 and 12). The nucleotide and the deduced amino acid sequences of the amplified fragments were unique; however, they showed extensive similarity to other HSP70 sequences. To isolat...
After a sinus lifting procedure, the compartment around the implants under the sinus mucosal lining in the sinus floor is filled with a blood clot from surrounding bleeding. The aim of this study was to evaluate the feasibility of bone formation following graftless sinus lifting with the simultaneous placement of dental implants. Thirty graftless sinus lifting procedures were performed and 72 dental implants placed in 18 consecutive patients, using the lateral window approach. Clinical and radiological follow-up was conducted throughout the 6-month healing period. Biopsies of 30 cases were collected at 6 months post-treatment: 15 biopsies were taken from the newly formed bone near the basal floor and 15 from the newly formed bone near the elevated membrane. New bone consolidation in the maxillary sinus was apparent radiologically and histologically at 6 months after sinus augmentation, providing an average 6.14±1.34mm of bone-gain. Based on histological analysis and histomorphometric data, the consolidated bone in the augmented sinus comprised 56.7±11.9% to 59.9±13.4% vital bone tissue. Out of the 72 implants placed, only four failed, indicating a 94% overall implant survival rate. Based on this case series, blood clot can be considered autologous osteogenic graft material, to which osteoprogenitors can migrate, differentiate, and regenerate bone.
This study aimed to test the effectiveness of ethyl gallate (EG) against S. mutans biofilm formation on solid surfaces (polystyrene, glass) and acidogenicity, and to examine the effect on expression of related genes. The biofilm that is formed by S. mutans bacteria was evaluated using colorimetric assay and optical profilometry, while the pH of the biofilm growth medium was measured with microelectrode. The expression of genes encoding glucan binding protein B (gbpB), glucosyltranferases B, -C, -D (gtfB, -C, -D) and F-ATPase (atpD, atpF) was assessed using a quantitative reverse transcription-polymerase chain reaction (RT-qPCR). It was revealed that all of the EG concentrations significantly suppressed S. mutans biofilm build-up on polystyrene and glass surfaces, and inhibited acidogenicity, in a dose-dependent manner, compared to the activity of untreated bacteria (p < 0.05). The highest concentration of EG (3.53 mM) reduced biofilm formation on polystyrene and glass surfaces by 68% and more than 91%, respectively, and prevented a decrease in pH levels by 95%. The RT-qPCR data demonstrate that the biofilm-producing bacteria treated with EG underwent significant gene expression changes involving the gtfC (a 98.6 increase in fold change), gtfB gene (a 47.5 increase in fold change) and the gbpB gene (a 13.8 increase in fold change). However, for the other genes tested (gtfD, atpD and atpF), the EG treatments did not produce significant expression change compared to the control. EG produced significant gene expression change in three genes—gtfC, gtfB, and gbpB; it has the capacity to inhibit S. mutans biofilm formation on solid surfaces (polystyrene, glass), as well as acidogenicity. Therefore, EG might be used as an antibiofilm and/or anticaries agent for oral formulations in order to reduce the prevalence of dental caries.
Cancer is a complex interaction among multiple signaling pathways involving a variety of target molecules. Cancer causes morbidity and mortality in millions of people worldwide, and due to its prevalence, the discovery of novel anticancer drugs is urgently required. Nature is considered an important source of the discovery of anticancer treatments, and many of the cytotoxic medicines in clinics today are derived from plants and other natural sources. Reactive oxygen species (ROS) induce a variety of human cancers, and antioxidants or scavengers are used to counteract them. The current study reports on the screening of extracts from 57 plants that are used in the galilee district as a food and/or for traditional medicine. Investigating the free radical scavenging capacity and these plants, and their cytotoxicity, may prove helpful to high-throughput screening projects that use antioxidants and cytotoxic natural products. The current study assessed the correlation between free radical scavenging and cytotoxicity. Correlational analysis is important for increasing the efficiency of the screening process. In the present study, free radical scavenging was assessed using a DPPH assay, while cytotoxicity was measured using a XTT assay. A total of 9 extracts were indicated to exhibit EC50 values <250 µg/ml, and 4 others exhibited a high antioxidant content, with EC50 values, for free radical scavenging, of <0.5 µg/ml. An in-depth analysis of the results revealed that the extracts of plants that exhibit an EC50 of free radical scavenging ≤10 µg/ml show a degree of enrichment toward increased cytotoxicity. It is recommended that future studies test the validity of the conclusions of the current study on other cancer cell-lines, and isolate and identify the bioactive agents that are found in the most cytotoxic extracts of plants.
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