Synthesis,biological evaluation,and molecular docking investigation of benzhydrol- and indole-based dual PPAR-γ/FFAR1 agonists

Type-2 diabetes mellitus is a progressive cluster of metabolic disorders, representing a global public health burden affecting more than 366?million people worldwide. We recently reported the discovery of three series of novel agents showing balanced activity on two metabolic receptors, peroxisome proliferator activated receptor-γ (PPAR-γ) and free fatty acid receptor 1 (FFAR1), also known as GPCR40. Our designing strategy relied on linking the thiazolidinedione head with known GPCR privilege structures. To further investigate this concept, two new scaffolds, the benzhydrol- and indole-based chemotypes, were introduced here in. Our optimization campaign resulted in three compounds; 15a, 15c, and 15d, with affinities in the low micromolar range on both targets. In vivo study of selected test compounds, revealed that 15c possesses a significant anti-hyperglycemic and anti-hyperlipidemic activities superior to rosiglitazone in fat-fed animal models. Molecular docking analysis was conducted to explain the binding modes of both series. These compounds could lead to the development of the unique antidiabetic agent acting as insulin sensitizer as well as insulin secretagogue.     

Mechanisms Underpinning Increased Plasma Creatinine Levels in Patients Receiving Vemurafenib for Advanced Melanoma

Context

Serum creatinine has been reported to increase in patients receiving Vemurafenib, yet neither the prevalence nor the mechanism of this adverse event are known.

Objective

We aimed to evaluate the frequency and the mechanisms of increases in plasma creatinine level in patients receiving Vemurafenib for advanced melanoma.

Methods

We performed a retrospective monocentric study including consecutive patients treated with Vemurafenib for an advanced melanoma. We collected clinical and biological data concerning renal function before introduction of Vemurafenib and in the course of monthly follow-up visits from March 2013 to December 2014. Cystatin C-derived glomerular filtration rate was evaluated before and after Vemurafenib initiation, as increase in serum cystatin C is specific to a decrease in the glomerular filtration rate. We also performed thorough renal explorations in 3 patients, with measurement of tubular secretion of creatinine before and after Vemurafenib initiation and a renal biopsy in 2 patients.

Results

70 patients were included: 97% of them displayed an immediate, and thereafter stable, increase in creatinine (+22.8%) after Vemurafenib initiation. In 44/52 patients in whom Vemurafenib was discontinued, creatinine levels returned to baseline. Serum cystatin C increased, although proportionally less than serum creatinine, showing that creatinine increase under vemurafenib was indeed partly due to a renal function impairment. In addition, renal explorations demonstrated that Vemurafenib induced an inhibition of creatinine tubular secretion.

Conclusion

Thus, Vemurafenib induces a dual mechanism of increase in plasma creatinine with both an inhibition of creatinine tubular secretion and slight renal function impairment. However, this side effect is mostly reversible when Vemurafenib is discontinued, and should not lead physicians to discontinue the treatment if it is effective.     

Early and Non-Invasive Detection of Chronic Wasting Disease Prions in Elk Feces by Real-Time Quaking Induced Conversion

Chronic wasting disease (CWD) is a fatal prion disease of wild and captive cervids in North America. Prions are infectious agents composed of a misfolded version of a host-encoded protein, termed PrP^Sc. Infected cervids excrete and secrete prions, contributing to lateral transmission. Geographical distribution is expanding and case numbers in wild cervids are increasing. Recently, the first European cases of CWD have been reported in a wild reindeer and two moose from Norway. Therefore, methods to detect the infection early in the incubation time using easily available samples are desirable to facilitate effective disease management. We have adapted the real-time quaking induced conversion (RT-QuIC) assay, a sensitive in vitro prion amplification method, for pre-clinical detection of prion seeding activity in elk feces. Testing fecal samples from orally inoculated elk taken at various time points post infection revealed early shedding and detectable prion seeding activity throughout the disease course. Early shedding was also found in two elk encoding a PrP genotype associated with reduced susceptibility for CWD. In summary, we suggest that detection of CWD prions in feces by RT-QuIC may become a useful tool to support CWD surveillance in wild and captive cervids. The finding of early shedding independent of the elk’s prion protein genotype raises the question whether prolonged survival is beneficial, considering accumulation of environmental prions and its contribution to CWD transmission upon extended duration of shedding.     

A pandemic strain of calicivirus threatens rabbit industries in the Americas

The filoviruses, Ebola (EBOV) and Marburg (MARV), cause a lethal hemorrhagic fever. Human isolates of MARV are not lethal to immmunocompetent adult mice and, to date, there are no reports of a mouse-adapted MARV model. Previously, a uniformly lethal EBOV-Zaire mouse-adapted virus was developed by performing 9 sequential passages in progressively older mice (suckling to adult). Evaluation of this model identified many similarities between infection in mice and nonhuman primates, including viral tropism for antigen-presenting cells, high viral titers in the spleen and liver, and an equivalent mean time to death. Existence of the EBOV mouse model has increased our understanding of host responses to filovirus infections and likely has accelerated the development of countermeasures, as it is one of the only hemorrhagic fever viruses that has multiple candidate vaccines and therapeutics. Here, we demonstrate that serially passaging liver homogenates from MARV-infected severe combined immunodeficient (scid) mice was highly successful in reducing the time to death in scid mice from 50–70 days to 7–10 days after MARV-Ci67, -Musoke, or -Ravn challenge. We performed serial sampling studies to characterize the pathology of these scid mouse-adapted MARV strains. These scid mouse-adapted MARV models appear to have many similar properties as the MARV models previously developed in guinea pigs and nonhuman primates. Also, as shown here, the scid-adapted MARV mouse models can be used to evaluate the efficacy of candidate antiviral therapeutic molecules, such as phosphorodiamidate morpholino oligomers or antibodies.     

Antischistosomal and liver protective effects of Curcuma longa extract in Schistosoma mansoni infected mice

With a view to clarify the induction of the "Crabtree consequence" in liver cells of S. mansoni infected mice, the curative effect of oil extract of C. longa was tested and compared to praziquantel (PZQ) the effective drug against all schistosome species occurring in man. Protein, glucose, glucose-6-phopsphatase, AMP-deaminase, adensoine deaminase, urea concentration, pyravate kinase (PK), phosphoenol pyruvate carboxykinase (PEPCK) and PK/PEPCK ratio were estimated. In addition, worm burden and ova count in mice infected with S. mansoni were elucidated. The result showed that C. longa normalized the concentration of protein, glucose, AMP-deaminase and adenosine deaminase, which were changed by infection. Moreover, it lowered pyruvate kinase level, while PZQ-treatment induced more elevation of this enzyme. PZQ was more effective in lowering worm burden while C. longa extract was more potent in reducing egg count.     

Mitochondrial DNA and Alzheimer’s disease: a first case–control study of the Tunisian population

Molecular Biology Reports - Alzheimer’s disease (AD) is the most common neurodegenerative disorder in humans and presents a major health problem throughout the world. The etiology of AD is...     

Stability and reproducibility of proteomic profiles in epidemiological studies: comparing the Olink and SOMAscan platforms

Limited data exist on the performance of high-throughput proteomics profiling in epidemiological settings, including the impact of specimen collection and within-person variability over time. Thus, the Olink (972 proteins) and SOMAscan7Kv4.1 (7322 proteoforms of 6596 proteins) assays were utilized to measure protein concentrations in archived plasma samples from the Nurses’ Health Studies and Health Professionals Follow-Up Study. Spearman's correlation coefficients (r) and intraclass correlation coefficients (ICCs) were used to assess agreement between (1) 42 triplicate samples processed immediately, 24-h or 48-h after blood collection from 14 participants; and (2) 80 plasma samples from 40 participants collected 1-year apart. When comparing samples processed immediately, 24-h, and 48-h later, 55% of assays had an ICC/r ≥ 0.75 and 87% had an ICC/r ≥ 0.40 in Olink compared to 44% with an ICC/r ≥ 0.75 and 72% with an ICC/r ≥ 0.40 in SOMAscan7K. For both platforms, >90% of the assays were stable (ICC/r ≥ 0.40) in samples collected 1-year apart. Among 817 proteins measured with both platforms, Spearman's correlations were high (r > 0.75) for 14.7% and poor (r < 0.40) for 44.8% of proteins. High-throughput proteomics profiling demonstrated reproducibility in archived plasma samples and stability after delayed processing in epidemiological studies, yet correlations between proteins measured with the Olink and SOMAscan7K platforms were highly variable.     

Content of Fatty Acids and Phenolics in Coratina Olive Oil from Tunisia: Influence of Irrigation and Ripening

The quality indices and chemical composition of Coratina olive oil produced in the northern region of Tunisia were evaluated, to determine the effect of three different irrigation regimes of the trees on the olive oils. The olives were sampled at two different stages of maturity, the oils were extracted, and standard methods were used to analyze the composition and quality of the oils. The fatty‐acid contents and quality parameters were only slightly affected by the irrigation regime. The contents of palmitic, oleic, and linoleic acids were above 12, 72, and 8%, respectively, for the second harvest, regardless of the irrigation level of the olive trees. Parameters such as the α‐tocopherol content and the phenolic profile were found to be significantly affected by the harvesting time; however, inconsistent changes were observed for the irrigation regimes, especially for the oil of the second harvest. It was shown that the irrigation conditions of the olive trees as well as the harvesting time of the fruits gave rise to a diverse range of olive oils in Tunisia.     

NGF and P75NTR Gene Expression Is Associated with the Hepatic Fibrosis Stage Due to Viral and Non-Viral Causes

This study evaluated the relative mRNA expression levels of nerve growth factor (NGF) and the p75 neurothrophin receptor (p75^NTR) in different histological stages of human liver disease. Fifty-one liver biopsy specimens obtained from patients with hepatitis B virus (n = 6), hepatitis C virus (n = 28), and non-viral hepatitis – (n = 9) and standard histological liver (n = 8) as controls (CT) were subjected to qPCR and histopathological exams. Our data revealed a significant difference in the NGF expression levels between the three patient groups and the Control group. p75^NTR expression levels in the HCV and NVH groups were higher than those observed in the HBV and Control groups. In cases of liver cirrhosis, higher p75^NTR mRNA expression was observed, whereas NGF was expressed at higher levels in patients with hepatic fibrosis. NGF expression was lower in the F1 liver fibrosis stage, and p75^NTR receptor expression continuously and proportionately increased compared to the increase in the degree of fibrosis and was significantly higher in livers in fibrosis stages 3 and 4. The hepatic levels of NGF and p75^NTR were decreased and increased, respectively, relative to the stage of inflammatory activity. A positive correlation between p75^NTR and NGF gene expression was observed in livers with mild to moderate fibrosis, though not in cases of severe fibrosis and cirrhosis.

Conclusion

Our results demonstrate that the course of chronic liver disease can be regulated by NGF and p75^NTR, which function by decreasing or inhibiting hepatocyte regeneration and proliferation.