On the Far Side of Telomeres: The Many Roles of Telomerase in the Acquisition and Retention of Cancer Stemness

It is well recognised that upregulation/reactivation of telomerase, the telomere-lengthening enzyme, is the sine qua non of cellular immortalisation and malignant transformation. But there is also convincing evidence that telomerase stands at a crossroads where several developmental signalling pathways meet and that its upregulation/reactivation has effects beyond maintaining telomere length, such as altering energy metabolism and modulating gene expression. We believe that it is important to realise that, in a pathological context, such extratelomeric effects of telomerase are related to the emergence and persistence of the cancer stem cell (CSC) phenotype. Given the common conception of cancer stemness as a major contributor to therapy resistance and tumour relapse, a more complete annotation of biological mechanisms for its regulation by telomerase will provide the opportunity to develop telomerase-targeted anticancer therapies which kill or differentiate CSCs effectively

Identification of the FGFR3G380R Mutant As a Likely Cause of Psychomotor Delay in an Achondroplastic Child: A Combined Clinical Exome Sequencing and Biomolecular Modeling Approach

Mutations in the gene for fibroblast growth factor receptor 3 (FGFR3) are implicated in achondroplasia, an autosomal-dominant form of short-limbed dwarfism. The present study involves a combination of clinical exome sequencing, targeted resequencing and protein modeling methods to decipher the pathobiology of achondroplasia with psychomotor delay in a two-year-old child. Accordingly, the resulting genetic information establishes the frequent FGFR3 c.1138G > A (p.G380R) mutation as the single hit causing pediatric achondroplasia with psychomotor delay, while the predicted model stresses the importance of a phenylalanyl residue (F384) in enhancing the dimerization potential of the receptor’s transmembrane domain via a cation‒π interaction with the newly introduced arginyl residue. Overall, the likely involvement of FGFR3G380R in psychomotor delay calls for comprehensive clinical assessment in achondroplastic children, although the precise mechanism by which the mutant receptor results in the development of neurological manifestations awaits further investigation

Prediction of molecular phenotypes for novel SCN1A variants from a Turkish genetic epilepsy syndromes cohort and report of two new patients with recessive Dravet syndrome

Abstract Dravet syndrome and genetic epilepsy with febrile seizures plus (GEFS+) are both epilepsy syndromes that can be attributed to deleterious mutations occurring in SCN1A, the gene encoding the pore‐forming α‐subunit of the NaV1.1 voltage‐gated sodium channel predominantly expressed in the central nervous system. In this research endeavor, our goal is to expand our prior cohort of Turkish patients affected by SCN1A‐positive genetic epilepsy disorders. This will be accomplished by incorporating two recently discovered and infrequent index cases who possess a novel biallelic (homozygous) SCN1A missense variant, namely E158G, associated with Dravet syndrome. Furthermore, our intention is to use computational techniques to predict the molecular phenotypes of each distinct SCN1A variant that has been detected to date within our center. The correlation between genotype and phenotype in Dravet syndrome/GEFS+ is intricate and necessitates meticulous clinical investigation as well as advanced scientific exploration. Broadened mechanistic and structural insights into NaV1.1 dysfunction offer significant promise in facilitating the development of targeted and effective therapies, which will ultimately enhance clinical outcomes in the treatment of epilepsy

Isolation, Characterization and In Silico Studies of Secondary Metabolites from the Whole Plant of Polygala inexpectata Peşmen & Erik

Polygala species are frequently used worldwide in the treatment of various diseases, such as inflammatory and autoimmune disorders as well as metabolic and neurodegenerative diseases, due to the large number of secondary metabolites they contain. The present study was performed on Polygala inexpectata, which is a narrow endemic species for the flora of Turkey, and resulted in the isolation of nine known compounds, 6,3′-disinapoyl-sucrose (1), 6-O-sinapoyl,3′-O-trimethoxy-cinnamoyl-sucrose (tenuifoliside C) (2), 3′-O-(O-methyl-feruloyl)-sucrose (3), 3′-O-(sinapoyl)-sucrose (4), 3′-O-trimethoxy-cinnamoyl-sucrose (glomeratose) (5), 3′-O-feruloyl-sucrose (sibiricose A5) (6), sinapyl alcohol 4-O-glucoside (syringin or eleutheroside B) (7), liriodendrin (8), and 7,4′-di-O-methylquercetin-3-O-β-rutinoside (ombuin 3-O-rutinoside or ombuoside) (9). The structures of the compounds were determined by the spectroscopic methods including 1D-NMR (1H NMR, 13C NMR, DEPT-135), 2D-NMR (COSY, NOESY, HSQC, HMBC), and HRMS. The isolated compounds were shown in an in silico setting to be accommodated well within the inhibitor-binding pockets of myeloperoxidase and inducible nitric oxide synthase and anchored mainly through hydrogen-bonding interactions and π-effects. It is therefore plausible to suggest that the previously established anti-inflammatory properties of some Polygala-derived phytochemicals may be due, in part, to the modulation of pro-inflammatory enzyme activities

Investigation of the Possible Protective Effect of <i>N</i>-Acetylcysteine (NAC) against Irinotecan (CPT-11)-Induced Toxicity in Rats

Irinotecan (CPT-11) is a chemotherapeutic agent involved in the treatment regimens for several malignancies such as colorectal cancer. N-acetylcysteine (NAC) is a strong antioxidant and anti-inflammatory agent used in the treatment of several diseases related to oxidative stress and inflammation. This study aimed at investigating whether NAC provides protection against hepatorenal and gastrointestinal tissue damage induced by CPT-11. Thirty-two Wistar albino rats were divided into four groups as control, NAC, CPT-11, and CPT-11+NAC. Following the experimental period, blood, and tissue samples (liver, kidney, stomach, and small intestine) were collected, and biochemical indicators, together with pro-inflammatory cytokines (TNF-α and IL-1β), matrix metalloproteinases (MMPs), malondialdehyde (MDA), glutathione peroxidase (GPx) and superoxide dismutase (SOD) levels were evaluated. Both the biochemical indicators and the pro-inflammatory cytokines, MMP, and MDA levels increased in animals treated with CPT-11, while SOD and GPx activities decreased. Histopathological evaluation revealed structural damage in all examined tissues. With NAC administration, significant improvements were observed, both biochemically and histologically. In conclusion, the results of the present study suggest that NAC treatment together with CPT-11 may have a beneficial effect on reducing CPT-11 toxicity in rats, by modulating inflammation and the oxidant–antioxidant balance. These results strongly promote further investigative studies

Protective Effects of Alpha-Lipoic Acid against 5-Fluorouracil-Induced Gastrointestinal Mucositis in Rats

Alpha-lipoic acid (ALA) is extensively utilized in multivitamin formulas and anti-aging products. The purpose of this study was to investigate the potential protective benefits of ALA on 5-fluorouracil (5-FU)-induced gastrointestinal mucositis in Wistar albino rats. Tissues from the stomach, small intestine, and large intestine were excised, and blood sera were obtained to identify biochemical indices such as TNF-α, IL-1β, MDA, GPx, SOD, MMP-1, -2, -8, and TIMP-1. A histopathological study was also performed. The results revealed mucositis-elevated TNF-, IL-1, MDA, MMP-1, -2, -8, and TIMP-1 levels in both tissues and sera, and these values dropped dramatically following ALA treatment. Reduced SOD and GPx activities in mucositis groups were reversed in ALA-treated groups. The damage produced by mucositis in the stomach and small intestine regressed in the ALA-treated group, according to histopathological evaluation. Consequently, the implementation of ALA supplementation in 5-FU therapy may act as a protective intervention for cancer patients with gastrointestinal mucositis. In light of the findings, ALA, a food-derived antioxidant with pleiotropic properties, may be an effective treatment for 5-FU-induced gastrointestinal mucositus, and prevent oxidative stress, inflammation, and tissue damage in cancer patients receiving 5-FU therapy

Assessing the Molecular Targets and Mode of Action of Furanone C-30 on Pseudomonas aeruginosa Quorum Sensing

Quorum sensing (QS), a sophisticated system of bacterial communication that depends on population density, is employed by many pathogenic bacteria to regulate virulence. In view of the current reality of antibiotic resistance, it is expected that interfering with QS can address bacterial pathogenicity without stimulating the incidence of resistance. Thus, harnessing QS inhibitors has been considered a promising approach to overriding bacterial infections and combating antibiotic resistance that has become a major threat to public healthcare around the globe. Pseudomonas aeruginosa is one of the most frequent multidrug-resistant bacteria that utilize QS to control virulence. Many natural compounds, including furanones, have demonstrated strong inhibitory effects on several pathogens via blocking or attenuating QS. While the natural furanones show no activity against P. aeruginosa, furanone C-30, a brominated derivative of natural furanone compounds, has been reported to be a potent inhibitor of the QS system of the notorious opportunistic pathogen. In the present study, we assess the molecular targets and mode of action of furanone C-30 on P. aeruginosa QS system. Our results suggest that furanone C-30 binds to LasR at the ligand-binding site but fails to establish interactions with the residues crucial for the protein’s productive conformational changes and folding, thus rendering the protein dysfunctional. We also show that furanone C-30 inhibits RhlR, independent of LasR, suggesting a complex mechanism for the agent beyond what is known to date

In vitro and in silico evaluation of ACE2 and LOX inhibitory activity of eucalyptus essential oils, 1,8-cineole, and citronellal

Eucalyptus essential oils are well-known and used especially in upper respiratory tract pathologies or diseases as herbal drug preparations. In the present study, the in vitro angiotensin-converting enzyme 2 (ACE2) and lipoxygenase (LOX) enzyme inhibitory potentials of commercial Eucalyptus globulus Labill. and Eucalyptus citriodora Hook. essential oils were evaluated for their potential anti-coronavirus disease 2019 (COVID-19), and anti-inflammatory effects. In addition, the major components, 1,8-cineole and citronellal, were evaluated for their ability to bind at the active site of either human ACE2 or human 5-LOX using an in silico setting. Before activity evaluation, Eucalyptus globulus and E citriodora essential oils were analysed by GC/FID and GC/MS, where 1,8-cineole (30%), and citronellal (80%) were identified as the major components, respectively. The in vitro ACE2 inhibition was calculated as 94.9% for E globulus, and that of E citriodora essential oil as 83.4%. In vitro LOX inhibition experiments for essential oils in the same order showed inhibitions of 71.3 and 91.4%, respectively, at 20 µg/mL test concentrations in microplate-based fluorometric assays. In addition, protein–ligand docking, and interaction profiling was used to gain structural and mechanistic insights into the in silico ACE2 and LOX inhibitory potentials of the major Eucalyptus essential oil constituents, 1,8-cineole as well as citronellal. The resulting data supported the in vitro findings; however, further in vivo studies are needed to confirm the activity.Anadolu Universit

In vitro and in silico evaluation of ACE2 and LOX inhibitory activity of origanum essential oils and carvacrol

Origanum spp. are used both for culinary purposes and for their biological activities. In this study, commercial Origanum majorana, Origanum minutiflorum, Origanum vulgare, and Origanum onites essential oils and their prominent constituent carvacrol were evaluated for their in vitro and in silico angiotensin-converting enzyme 2 and lipoxygenase enzyme inhibitory potentials. The essential oils were analysed by gas chromatography-flame ionisation detection and gas chromatography-mass spectrometry, where carvacrol was identified as the major component (62 - 81%), confirming the quality. In vitro enzyme inhibition assays were conducted both with the essential oils (20 µg/mL) and with carvacrol (5 µg/mL). The comparative values of angiotensin-converting enzyme 2 percent inhibition for O. majorana, O. minutiflorum, O. vulgare, and O. onites essential oils were determined as 85.5, 79.1, 74.3, and 42.8%, respectively. As a result of the enzyme assays, carvacrol showed 90.7% in vitro angiotensin-converting enzyme 2 inhibitory activity. The in vitro lipoxygenase inhibition of the essential oils (in the same order) was 89.4, 78.9, 81.1, and 73.5%, respectively, where carvacrol showed 74.8% inhibition. In addition, protein-ligand docking and interaction profiling was used to gain structural and mechanistic insights into the angiotensin-converting enzyme 2 and lipoxygenase inhibitory potentials of major Origanum essential oil constituents. The in silico findings agreed with the significant enzyme inhibition activity observed in vitro. Further in vivo studies are suggested to confirm the safety and efficacy of the oils