Wogonin induces apoptosis by suppressing E6 and E7 expressions and activating intrinsic signaling pathways in HPV-16 cervical cancer cells

Wogonin is a flavonoid compound extracted from Scutellaria baicalensis and is well known as a benzodiazepine receptor ligand with anxiolytic effects. Many recent studies have demonstrated that wogonin modulates angiogenesis, proliferation, invasion, and tumor progress in various cancer tissues. We further explored the mechanism of action of wogonin on cervical cancer cells that contain or lack human papillomavirus (HPV) DNA. Wogonin was cytotoxic to HPV 16 (+) cervical cancer cells, SiHa and CaSki, but not to HPV-negative cells. We demonstrated that wogonin induced apoptosis by suppressing the expressions of the E6 and E7 viral oncogenes in HPV-infected cervical cancer CaSki and SiHa cells. The modulation of p53 and protein retinoblastoma (pRb) were also triggered by the suppression of E6 and E7 expressions. However, p53 was not altered in HPV-negative cervical cancer C33A cells. Moreover, wogonin modulated the mitochondrial membrane potential and the expression of pro- and anti-apoptotic factors such as Bax and Bcl-2. Wogonin also provoked the cleavage of caspase-3, caspase-9, and poly ADP ribose polymerase. After transfection of siRNAs to target E6 and E7, additional restoration of p53 and pRb was not induced, but processing of caspases and PARP was increased compared with wogonin treatment alone. Together, our findings demonstrated that wogonin effectively promotes apoptosis by downregulating E6 and E7 expressions and promoting intrinsic apoptosis in human cervical cancer cells.     

Inactivation of Max-interacting Protein 1 Induces Renal Cilia Disassembly through Reduction in Levels of Intraflagellar Transport 20 in Polycystic Kidney

Cilia in ciliated cells consist of protruding structures that sense mechanical and chemical signals from the extracellular environment. Cilia are assembled with variety molecules via a process known as intraflagellar transport (IFT). What controls the length of cilia in ciliated cells is critical to understand ciliary disease such as autosomal dominant polycystic kidney disease, which involves abnormally short cilia. But this control mechanism is not well understood. Previously, multiple tubular cysts have been observed in the kidneys of max-interacting protein 1 (Mxi1)-deficient mice aged 6 months or more. Here, we clarified the relationship between Mxi1 inactivation and cilia disassembly. Cilia phenotypes were observed in kidneys of Mxi1-deficient mice using scanning electron microscopy to elucidate the effect of Mxi1 on renal cilia phenotype, and cilia disassembly was observed in Mxi1-deficient kidney. In addition, genes related to cilia were validated in vitro and in vivo using quantitative PCR, and Ift20 was selected as a candidate gene in this study. The length of cilium decreased, and p-ERK level induced by a cilia defect increased in kidneys of Mxi1-deficient mice. Ciliogenesis of Mxi1-deficient mouse embryonic fibroblasts (MEFs) decreased, and this abnormality was restored by Mxi1 transfection in Mxi1-deficient MEFs. We confirmed that ciliogenesis and Ift20 expression were regulated by Mxi1 in vitro. We also determined that Mxi1 regulates Ift20 promoter activity via Ets-1 binding to the Ift20 promoter. These results indicate that inactivating Mxi1 induces ciliary defects in polycystic kidney.     

Short-term temperature impact on soil heterotrophic respiration in limed agricultural soil samples

This study sought to investigate the hourly and daily timescale responses of soil CO₂ fluxes to temperature in a limed agricultural soil. Observations from different incubation experiments were compared with the results of a model combining biotic (heterotrophic respiration) and abiotic (carbonate weathering) components. Several samples were pre-incubated for 8–9 days at three temperatures (5, 15 and 25 °C) and then submitted to short-term temperature (STT) cycles (where the temperature was increased from 5 to 35 °C in 10 °C stages, with each stage being 3 h long). During the temperature cycles (hourly timescale), the soil CO₂ fluxes increased significantly with temperature under all pre-incubation temperature (PIT) treatments. A hysteresis effect and negative fluxes during cooling phases were also systematically observed. At a given hourly timescale temperature, there was a negative relationship of the CO₂ fluxes with the PIT. Using the combined model allowed the experimental results to be clearly described, including the negative fluxes and the hysteresis effect, showing the potentially large contribution of abiotic fluxes to total fluxes in limed soils, after STT changes. The fairly good agreement between the measured and simulated flux results also suggested that the biotic flux temperature sensitivity was probably unaffected by timescale (hourly or daily) or PIT. The negative relationship of the CO₂ fluxes with the PIT probably derived from very labile soil carbon depletion, as shown in the simulations. This was not, however, confirmed by soil carbon measurements, which leaves open the possibility of adaptation within the microbial community.     

Partitioning of oxygen uptake and cost of surfacing during swimming in the air-breathing catfish Pangasianodon hypophthalmus

Though air-breathing has probably evolved mainly as a response to hypoxia, it may provide an important oxygen supplement when metabolism is elevated, as for example during swimming. Due to the increased travelling distance involved when an air-breathing fish swims to and from the surface, and the increased drag when the surface is breached, it can be proposed that air-breathing results in a rise in the apparent cost of transport. In order to investigate this hypothesis, it is necessary to use a fish that is able to swim equally well with and without access to air. The striped catfish Pangasianodon hypophthalmus has been shown to have a sufficiently high capacity for aquatic oxygen uptake in normoxia, to allow for such a comparison. Here, we measured the partitioning of oxygen uptake ( $ \dot{M}{\text{O}}_{2} $ ) during swimming and recovery, and calculated the apparent cost of transport with and without access to air, under normoxic conditions. Aerial $ \dot{M}{\text{O}}_{2} $ constituted 25–40 % of the total $ \dot{M}{\text{O}}_{2} $ during swimming and less than 15 % during recovery. The net cost of transport was 25 % lower in fish that did not air-breathe compared to fish that did, showing that the cost of surfacing can be substantial. This is the first study to measure partitioning in an air-breathing fish during swimming at velocities close to the critical swimming speed.     

FAM111A Mutations Result in Hypoparathyroidism and Impaired Skeletal Development

Kenny-Caffey syndrome (KCS) and the similar but more severe osteocraniostenosis (OCS) are genetic conditions characterized by impaired skeletal development with small and dense bones, short stature, and primary hypoparathyroidism with hypocalcemia. We studied five individuals with KCS and five with OCS and found that all of them had heterozygous mutations in FAM111A. One mutation was identified in four unrelated individuals with KCS, and another one was identified in two unrelated individuals with OCS; all occurred de novo. Thus, OCS and KCS are allelic disorders of different severity. FAM111A codes for a 611 amino acid protein with homology to trypsin-like peptidases. Although FAM111A has been found to bind to the large T-antigen of SV40 and restrict viral replication, its native function is unknown. Molecular modeling of FAM111A shows that residues affected by KCS and OCS mutations do not map close to the active site but are clustered on a segment of the protein and are at, or close to, its outer surface, suggesting that the pathogenesis involves the interaction with as yet unidentified partner proteins rather than impaired catalysis. FAM111A appears to be crucial to a pathway that governs parathyroid hormone production, calcium homeostasis, and skeletal development and growth.     

Dating the “red beds” of the Eastern Moroccan High Plateaus: Evidence from late Late Cretaceous charophytes and dinosaur eggshells

A new locality in the poorly known “red beds” of Tendrara (High Plateaus, Morocco) has yielded four charophytes species (Feistiella anluensis, Lamprothamnium stipitatum, Peckisphaera portezueloensis, Platychara caudata) and dinosaur eggshells (Pseudomegaloolithus atlasi). These red beds, which overly the Cenomanian-Turonian marine deposits, generally assigned to “Senonian” based on geometric position, are directly dated by these fossils: the charophytes species and dinosaur oospecies association indicates a Campano-Maastrichtian or Maastrichtian age for these calm floodplain deposits.     

Modulation of adipose tissue inflammation by bioactive food compounds

Adipose tissue has an important endocrine function in the regulation of whole-body metabolism. Obesity leads to a chronic low-grade inflammation of the adipose tissue, which disrupts this endocrine function and results in metabolic derangements, such as type-2 diabetes. Dietary bioactive compounds, such as polyphenols and certain fatty acids, are known to suppress both systemic and adipose tissue inflammation and have the potential to improve these obesity-associated metabolic disorders. Mechanistically, polyphenolic compounds including non-flavonoids, such as curcumin and resveratrol, and flavonoids, such as catechins (tea-polyphenols), quercetin and isoflavones, suppress nuclear factor-κB (NF-κB) and mitogen-activated protein (MAP) kinases (MAPK) pathways while activating the 5′ adenosine monophosphate-activated protein kinase (AMPK) pathway in adipose tissue. Dietary polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), conjugated linoleic acid (CLA) and monounsaturated fatty acids (MUFA), such as oleic acid, also impart anti-inflammatory effects through several mechanisms. These include activation of AMPK and peroxisome proliferator-activated receptor gamma (PPAR-γ), as well as suppression of toll-like receptors (TLRs) and NF-κB pathway. This review discusses the major molecular mechanisms of dietary polyphenols and fatty acids, alone or in combination, which are responsible for adipose tissue-associated anti-inflammatory effects.     

Anoctamin 1 dysregulation alters bronchial epithelial repair in cystic fibrosis

Cystic fibrosis (CF) airway epithelium is constantly subjected to injury events due to chronic infection and inflammation. Moreover, abnormalities in CF airway epithelium repair have been described and contribute to the lung function decline seen in CF patients. In the last past years, it has been proposed that anoctamin 1 (ANO1), a Ca^2 +-activated Cl^? channel, might offset the CFTR deficiency but this protein has not been characterized in CF airways. Interestingly, recent evidence indicates a role for ANO1 in cell proliferation and tumor growth. Our aims were to study non-CF and CF bronchial epithelial repair and to determine whether ANO1 is involved in airway epithelial repair. Here, we showed, with human bronchial epithelial cell lines and primary cells, that both cell proliferation and migration during epithelial repair are delayed in CF compared to non-CF cells. We then demonstrated that ANO1 Cl^? channel activity was significantly decreased in CF versus non-CF cells. To explain this decreased Cl^? channel activity in CF context, we compared ANO1 expression in non-CF vs. CF bronchial epithelial cell lines and primary cells, in lung explants from wild-type vs. F508del mice and non-CF vs. CF patients. In all these models, ANO1 expression was markedly lower in CF compared to non-CF. Finally, we established that ANO1 inhibition or overexpression was associated respectively with decreases and increases in cell proliferation and migration. In summary, our study demonstrates involvement of ANO1 decreased activity and expression in abnormal CF airway epithelial repair and suggests that ANO1 correction may improve this process.