Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members

Unique among fibroblast growth factors (FGFs), FGF19, -21, and -23 act in an endocrine fashion to regulate energy, bile acid, glucose, lipid, phosphate, and vitamin D homeostasis. These FGFs require the presence of Klotho/betaKlotho in their target tissues. Here, we present the crystal structures of FGF19 alone and FGF23 in complex with sucrose octasulfate, a disaccharide chemically related to heparin. The conformation of the heparin-binding region between beta strands 10 and 12 in FGF19 and FGF23 diverges completely from the common conformation adopted by paracrine-acting FGFs. A cleft between this region and the beta1-beta2 loop, the other heparin-binding region, precludes direct interaction between heparin/heparan sulfate and backbone atoms of FGF19/23. This reduces the heparin-binding affinity of these ligands and confers endocrine function. Klotho/betaKlotho have evolved as a compensatory mechanism for the poor ability of heparin/heparan sulfate to promote binding of FGF19, -21, and -23 to their cognate receptors.     

F.t.-i.r. and laser-Raman spectra of thymine and thymidine

F.t.-i.r. and laser-Raman spectra of thymine and thymidine in the solid state were recorded. Assignments were proposed for the frequencies observed. The influence of the deoxy sugar on the vibrations of the nucleoside are discussed as a function of its particular puckering. The aim of this work is to elucidate the differences between the molecules constituting the nucleic acids, in order the better to comprehend their biological functions.     

New pyrazolylpyrazoline derivatives as dual acting antimalarial-antileishamanial agents: synthesis,biological evaluation and molecular modelling simulations

Promising inhibitory activities of the parasite multiplication were obtained upon evaluation of in vivo antimalarial activities of new pyrazolylpyrazoline derivatives against Plasmodium berghei infected mice. Further evaluation of 5b and 6a against chloroquine-resistant strain (RKL9) of P. falciparum showed higher potency than chloroquine. In vitro antileishmanial activity testing against Leishmania aethiopica promastigote and amastigote forms indicated that 5b, 6a and 7b possessed promising activity compared to miltefosine and amphotericin B deoxycholate. Moreover, antileishmanial activity reversal of the active compounds via folic and folinic acids showed comparable results to the positive control trimethoprim, indicating an antifolate mechanism via targeting leishmanial DHFR and PTR1. The compounds were non-toxic at 125, 250 and 500 mg/kg. In addition, docking of the most active compound against putative malarial target Pf-DHFR-TS and leishmanial PTR1 rationalised the observed activities. Molecular dynamics simulations confirmed a stable and high potential binding of 7a against leishmanial PTR1.     

Biochemical and hematological findings and risk factors associated with kidney impairment in patients with COVID-19

BackgroundCOVID-19 is a new pandemic that has infected millions of people worldwide and caused a high morbidity and mortality rate. COVID-19 may have a harmful effect on organs, especially the kidneys. Aims: The main aim of our research is to study the association between the severity of COVID-19 disease and biochemical parameters related to kidney function and to investigate certain risk factors of COVID-19-associated kidney disease.MethodsA total of 174 individuals, 121 COVID-19 positive and 53 COVID-19 negative, were enrolled in this study. The relation between COVID-19 infection, severity, kidney function test, and hematological indicators were examined.ResultsThe most prominent symptoms among COVID-19 were fever (95% ) and fatigue (92%). Regarding biochemical parameters, median creatinine, MPV, and CRP were significantly higher in COVID-19 patients, whereas median eGFR, Na+, WBC, MCH, MCHC, and eosinophil percentages were significantly lower in this group. Severely infected patients were observed to have higher urea, creatinine, neutrophils, and NLR. However, median sodium, eGFR, hemoglobin, hematocrit, RBC, lymphocytes, and platelet count were significantly lower in the severe group. Urine examination of the severe group showed a significantly lower specific gravity, while urine pH, protein, and glucose were significantly higher.ConclusionsOur analysis indicates that COVID-19 infection affects kidney function, mainly creatinine level, urea, eGFR, Na+ and urine protein. Additionally, comorbidities such as older age (>65), hypertension, taking medications, and CRP (>33.55 mg/L) are considered risk factors that are more likely to contribute to kidney impairment in COVID-19 positive patients.     

The Sl TPL3–Sl WUS module regulates multi-locule formation in tomato by modulating auxin and gibberellin levels in the shoot apical meristem

Malformed fruits depreciate a plant’s market value.In tomato(Solanum lycopersicum),fruit malformation is associated with the multi-locule trait,which involves genes regulating shoot apical meristem(SAM) development.The expression pattern of TOPLESS3(SITPL3) throughout SAM development prompted us to investigate its functional significance via RNA interference(RNAi) and clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9(Cas9)-mediated gene editing.Lower SITPL3 t...     

Design and synthesis of thiazolidine-2,4-diones hybrids with 1,2-dihydroquinolones and 2-oxindoles as potential VEGFR-2 inhibitors: in-vitro anticancer evaluation and in-silico studies

A thiazolidine-2,4-dione nucleus was molecularly hybridised with the effective antitumor moieties; 2-oxo-1,2-dihydroquinoline and 2-oxoindoline to obtain new hybrids with potential activity against VEGFR-2. The cytotoxic effects of the synthesised derivatives against Caco-2, HepG-2, and MDA-MB-231 cell lines were investigated. Compound 12a was found to be the most potent candidate against the investigated cell lines with IC₅₀ values of 2, 10, and 40 µM, respectively. Furthermore, the synthesised derivatives were tested in vitro for their VEGFR-2 inhibitory activity showing strong inhibition. Moreover, an in vitro viability study against Vero non-cancerous cell line was investigated and the results reflected a high safety profile of all tested compounds. Compound 12a was further investigated for its apoptotic behaviour by assessing the gene expression of four genes (Bcl2, Bcl-xl, TGF, and Survivin). Molecular dynamic simulations authenticated the high affinity, accurate binding, and perfect dynamics of compound 12a against VEGFR-2.     

Association of long non-coding RNAs NEAT1, and MALAT1 expression and pathogenesis of Behçet's disease among Egyptian patients

Behçet''s disease (BD) is a chronic inflammatory disease. Immunological defects have been shown to play a significant role in the progression of BD. The serum levels of two long non-coding RNAs (lncRNAs), NEAT1 and MALAT1, were examined in patients with BD to identify their role in the disease pathogenesis. Both lncRNAs were mentioned as essential regulators of innate immune responses and have a crucial role in inflammatory diseases. Fifty patients with BD and a similar number of control individuals were involved in our study. At enrollment, data was collected from patients and controls, and the disease severity in active cases was determined using the Behçet''s Disease Current Activity Form (BDCAF). Levels of the two studied biomarkers in the serum, NEAT1 and MALAT1, were investigated by quantitative RT-PCR (qRT-PCR). NEAT1 levels were significantly turned down in BD patients (fold changes = 0.77, p = 0.0001) and correlated negatively with the BDCAF (r = −0.41; p = 0.003). On the other hand, the MALAT1 levels were significantly up-regulated in BD patients (fold changes = 2.65, p = 0.003). Serum levels of NEAT1 were significantly decreased in patients with active states than in stationary cases (0.387 versus 1.99, respectively; p = 0.01) and compared with controls (p = 0.001). Also, NEAT1 levels were significantly increased in patients with stationary states compared to controls (p = 0.03). There was a positive association between NEAT1 and MALAT1 levels among BD patients (r = 0.29, p = 0.04). Our findings demonstrate a possible role of NEAT1 and MALAT1 in the pathogenesis of BD.