ALKBH5 decreases SLC7A11 expression by erasing m6A modification and promotes the ferroptosis of colorectal cancer cells

Background Colorectal cancer (CRC) is the major subtype of gastrointestinal malignancy and involves cancer-related genes and signaling pathways to regulate ferroptosis. The present study was conducted to analyze the role of alkB homolog 5 (ALKBH5) in the ferroptosis of CRC cells and provide novel targets for CRC treatment. Methods The transcriptional and protein levels of ALKBH5 and solute carrier family 7 members 11 (SLC7A11) in tissues and cells were determined by qRT-PCR and Western blot assay. HCT116 and SW620 cells were transfected with ALKBH5 overexpression vectors to determine cell viability and levels of reactive oxygen species (ROS), Fe+, glutathione, and glutathione peroxidase 4 using cell counting kit-8, colony formation, fluorescence probe, assay kits, and Western blot assay. The N6-methyladenosine (m6A) level and the enrichment of m6A on SLC7A11 mRNA were measured by m6A quantitative analysis and m6A methylated RNA immunoprecipitation-qPCR, and the mRNA stability was determined after actinomycin D treatment. CRC cells were treated with the combination of SLC7A11 and ALKBH5 overexpression vectors to confirm the mechanism. Nude mice were subcutaneously injected with CRC cells overexpressing ALKBH5. Results ALKBH5 was downregulated in CRC and ALKBH5 overexpression promoted ROS release and ferroptosis. ALKBH5 erased the m6A modification on SLC7A11 mRNA to reduce the mRNA stability of SLC7A11, further reducing SLC7A11 expression. SLC7A11 overexpression reversed the promotive role of ALKBH5 overexpression in ferroptosis. ALKBH5 upregulation mitigated tumor growth in vivo. Conclusions ALKBH5 reduced SLC7A11 transcription by erasing m6A modification, thus promoting the ferroptosis of CRC cells (AU)

Relationship between peritoneal solute transport and dialysate inflammatory markers in peritoneal dialysis patients: A cross-sectional study / Relación entre el transporte de soluto peritoneal y los marcadores inflamatorios del diálisis peritoneal en pacientes en diálisis peritoneal: un estudio transversal

Background: The associated factors of peritoneal small solute transport was not fully understood. This research aimed to investigate the connection between dialysate inflammatory markers (e.g. macrophage migration inhibitory factor, MIF) in peritoneal dialysis (PD) effluent and peritoneal solute transport rate (PSTR) properties. Subjects and design: A total of 80 stable PD patients in the First ShaoYang Hospital were enrolled in present study. Overnight PD effluent and serum inflammatory markers including MIF, MCP-1, VEGF, IL-6, TNFα and TGFβ were detected. Pearson correlation analysis and Logistic regression was performed to determine the risk factors for the increased PSTR. Results: A trend toward increased values of MIF, MCP-1 and IL-6 in PD effluent was observed in subjects with high PSTR when compared with those with low PSTR. The Pearson correlation test showed that D/P Cr exhibited positive correlations with dialysis effluent MIF (r=0.32, p=0.01), MCP-1 (r=0.47, p=0.01), IL-6 (r=0.48, p=0.01). Conversely, no significant correlation was found between D/P Cr and TGF-β (r=0.04, p=0.70), TNF-ɑ (r=0.22, p=0.05), VEGF (r=0.02, p=0.86) and serum inflammatory markers. In the unadjusted regression analysis, dialysis effluent MIF (OR 2.41), MCP-1 (OR 1.72), IL-6 (OR 1.55) were associated with high PSTR condition. Multivariate logistic regression analysis showed that the adjusted odds ratios (OR) of dialysis effluent MIF for high PSTR were 2.47 in all subjects (p=0.03). Conclusion: Elevated MIF, MCP-1 and IL-6 levels in PD effluent were associated with increased PSTR. Elevated dialysis effluent MIF levels was an independent risk factor for high PSTR in subjects with PD treatment. (AU)

Antecedentes: Los factores asociados del transporte peritoneal de pequeños solutos no se conocen completamente. Esta investigación tuvo como objetivo investigar la conexión entre los marcadores inflamatorios del dializado (por ejemplo, el factor inhibidor de la migración de macrófagos [MIF]) en el efluente de diálisis peritoneal (DP) y las propiedades de la tasa de transporte de solutos peritoneal (PSTR). Sujetos y diseño: Se incluyó un total de 80 pacientes con DP estable en el primer Hospital de Shaoyang. Se detectaron efluentes de DP nocturnos y marcadores inflamatorios séricos, incluyendo MIF, MCP-1, VEGF, IL-6, TNF -ɑ, TGF -β. Se realizó un análisis de correlación de Pearson y regresión logística para determinar los factores de riesgo para la PSTR aumentada. Resultados: Se observó una tendencia hacia valores incrementados de MIF, MCP-1 e IL-6 en el efluente de DP en sujetos con PSTR alta, en comparación con aquellos con PSTR baja. La prueba de correlación de Pearson mostró que D/Pcr exhibe correlaciones positivas con el MIF del efluente diálisis (r = 0,32, p = 0,01), MCP-1 (r = 0,47, p = 0,01), IL-6 (r = 0,48, p = 0,01). Por el contrario, no se encontró una correlación significativa entre D/Pcr y TGF-β (r = 0,04, p = 0,70), TNF-ɑ (r = 0,22, p = 0,05), VEGF (r = 0,02, p = 0,86) y marcadores séricos de inflamación. En el análisis de regresión no ajustado, el MIF del efluente diálisis (OR 2,41), la MCP-1 (OR 1,72), la IL-6 (OR 1,55) se asociaron con una PSTR elevada. El análisis de regresión logística multivariante mostró que las odds ratios (OR) ajustadas del MIF del efluente diálisis para PSTR alta fueron de 2,47 en todos los sujetos (p = 0,03). Conclusión: Los niveles elevados de MIF, MCP-1 y IL-6 en el efluente de DP se asociaron con un aumento de la PSTR. Los niveles elevados del MIF del efluente diálisis fueron un factor de riesgo independiente para PSTR elevada en sujetos tratados con DP. (AU)

Identification of novel halophilic/halotolerant bacterial species producing compatible solutes / Identificación de nuevas especies bacterianas halófilas/halotolerantes que producen solutos compatibles

Ectoine and hydroxyectoine are compatible solutes with enormous potential for use in the medical and cosmetic industries. Considering the excellent osmoprotective properties of these compatible solutes, we investigate the presence of four compatible solutes (ectoine, hydroxyectoine, proline, and glutamic acid) quantitatively by liquid chromatography-tandem mass spectrometry (LC–MS/MS) in forty-five halophilic/halotolerant bacterial isolates. We determined ectoine production by Marinibacillus sp., Nesterenkonia xinjiangensis, Halobacillus sp., Bacillus patagoniensis, Virgibacillus picturae, Halomonas neptunia, Bacillus patagoniensis, Gracilibacillus sp., Thalassobacillus devorans, Microbacterium sp., Nesterenkonia sp., and Bacillus agaradhaerens, and this production was NaCl dependent. Additionally, the production of hydroxyectoine was observed in six bacterial isolates (Nesterenkonia xinjiangensis, Halobacillus sp., Halomonas neptunia, Thalassobacillus devorans, Nesterenkonia sp., and Bacillus agaradhaerens) which was NaCl and temperature dependent. The study identified new bacterial isolates producing ectoine or hydroxyectoine. While the ectoine production in many different Bacillus members and a few Nesterenkonia have been documented before, ectoine production by Bacillus patagoniensis and Nesterenkonia xinjiangensis has not been shown so far. Further, ectoine production by a member of the genus Thalassobacillus (Thalassobacillus devorans) was demonstrated experimentally for the first time. The findings reported in the study may serve as a basis for the large-scale production of ectoine and hydroxyectoine in the future.(AU)

Interacción entre Valsartán y Repaglinida mediada por transportadores hepáticos OATPs (Organic Anion Transporting Polypeptides): a propósito de un caso / Interaction between Valsartan and Repaglinide mediated for hepatic transporters OATPs (Organic Anion Transporting Polypeptides): report of a case

Paciente de 69 años que acude a la farmacia a retirar su medicación. Recientemente ha sido diagnosticado de hipertensión y lleva 20 días en tratamiento con valsartán 160mg. Refiere que no quiere retirar uno de sus tratamientos para la diabetes porque sufre hipoglucemias al tomar el tratamiento con la comida, por lo que no toma la medicación al mediodía. El paciente tiene pautado: sitagliptina 100mg (0/1/0), Repaglinida 1mg (1/2/1), Tamsulosina 0.4mg (0/0/1) y Valsartán 160mg (1/0/0). El valsartán es sustrato del OATP1B1 a la vez que un inhibidor de éste y la repaglinida también. Esto causa una elevación plasmática de la repaglinida, ya que no puede ser metabolizada al tener bloqueado el transportador, lo que explicaría la hipoglucemia. Se le comunica al médico la sospecha de interacción y procede al cambio de medicación del paciente. Sustituye la repaglinida por metformina, lo que lleva al paciente a normalizar su glucemia y a seguir con la tensión controlada

A 69-year-old patient comes to the pharmacist to get his medication. He was recently diagnosed with hypertension and has been taken Valsartan 160mg during the last 20 days. He explains that he does not want to get one of his medicines for his diabetes because he suffers hypoglycemia when he takes the treatment while eating so he does not take it at noon. The patient is prescribed: sitagliptina 100mg (0/1/0), Repaglinida 1mg (1/2/1), Tamsulosina 0.4mg (0/0/1) and Valsartan 160mg (1/0/0). Valsartan is an OATP1B1 substrate and an inhibitor of it too, just as repaglinide. This causes a repaglinide plasma elevation because the transporter is blocked and the repaglinide can not be metabolized. Thus, there is a hypoglycemia. Repaglinide is replaced by Metformina. As a result, the glycaemia’s patient is stabilized and the blood pressure keeps controlled