Although patients with chronic kidney disease (CKD) have a higher risk of colorectal cancer (CRC) aggravation, the connection between these two diseases is not well understood. Recent studies have shown that both CKD and CRC aggravation are closely related to an increased abundance of indole-producing Fusobacterium nucleatum in the gut. The indole absorbed from the gut is eventually metabolized to indoxyl sulfate in the liver. Since indoxyl sulfate is involved not only in accelerating CKD progression but also in the initiation and development of its associated complications, the present study aimed to clarify whether indoxyl sulfate induces the proliferation of CRC cells. This study found that indoxyl sulfate induced the proliferation of CRC-derived HCT-116 cells by activating the aryl hydrocarbon receptor (AhR) and the proto-oncogene Akt. The AhR antagonist CH223191 and Akt inhibitor MK2206 suppressed indoxyl sulfate-induced proliferation of HCT-116 cells. We also found that indoxyl sulfate upregulated epidermal growth factor receptor (EGFR) expression, which is associated with poor prognosis of CRC, whereas CH223191 and MK2206 repressed EGFR expression. Furthermore, indoxyl sulfate increased the sensitivity of CRC cells to EGF by upregulating EGFR expression. These findings suggest that indoxyl sulfate may be an important link between CKD and CRC aggravation.

We previously reported that tenascin-X (Tnxb) aggravates hepatic fibrosis in mice fed a high-fat and high-cholesterol diet with high levels of phosphorus and calcium (HFCD). In this study, we investigated Tnxb expression in livers with fibrosis caused by administration of a methionine-chorine-deficient (MCD) diet in mice. Whole transcriptome analysis showed that Tnxb was one of the genes with increased expression in livers of MCD diet-fed mice compared with that in livers of normal diet (ND)-fed mice. In microarray and subsequent microRNA (miRNA) network analyses, miR-378a-5p and miR-486-5p were identified in livers of MCD diet-fed mice as downregulated miRNAs, which have their predicted target sites in the 3’ untranslated region of Tnxb mRNA and might suppress the translation of Tnxb mRNA. RT-qPCR analyses of livers of MCD diet-fed mice compared with livers of ND-fed mice verified the upregulation of Tnxb and fibrosis-triggering genes and conversely the downregulation of miR-378a-5p and miR-486-5p. Overexpression of miR-378a-5p and miR-486-5p resulted in decreased level not only of the FLAG-tagged fibrinogen-like domain of Tnxb protein (FLAG-mTNX-FG) but also of endogenous Tnxb protein in murine cultured cells. These results indicate that expression of Tnxb is regulated by miR-378a-5p and miR-486-5p in hepatic fibrosis following MCD diet feeding.

Distribution of endomorphin-1 (EM-1) was immunohistochemically investigated in the rat cranial sensory ganglia. Small to medium-sized neurons in the trigeminal (TG), petrosal (PG), and jugular ganglia (JG) expressed EM-1-immunoreactivity. However, EM-1-immunoreactive (-ir) neurons were infrequent in the nodose ganglion. In the brainstem, EM-1-ir varicose fibers were detected in the superficial layer of the medullary dorsal horn and the caudal part of the nucleus tractus solitarius. By trichrome immunofluorescence analysis, approximately 70% of EM-1-ir neurons were also immunoreactive for transient receptor potential vanilloid 1 (TRPV1) in all the examined ganglia. Additionally, 56.8% of EM1-ir TG neurons and approximately 30% of EM-1-ir PG and JG neurons showed calcitonin gene-related peptide (CGRP)-immunoreactivity. By a retrograde tracing method, several TG, PG, and JG neurons innervating the facial and external ear canal skin expressed EM-1-immunoreactivity. However, EM-1-ir neurons innervating the tooth pulp, circumvallate papilla, and pharynx were relatively rare. Thus, EM-1 expression and its coexistence with TRPV1 and CGRP in the cranial sensory neurons may depend on their various peripheral targets. EM1-ir neurons probably project to the superficial layer of the medullary dorsal horn and caudal part of the nucleus tractus solitarius. EM-1 may be involved in nociceptive transmission from the skin.

Hemoglobin vesicles (HbVs), considered as red blood cell substitutes, are liposomes encapsulating purified hemoglobin, with a phospholipid bilayer membrane (diameter: 250 nm; P50, 28 Torr). In this study, we aimed to investigate HbV function during hemorrhagic shock in lung resection and analyze the details of oxygen delivery. Left pneumonectomy was performed in dogs under mechanical ventilation, followed by rapid exsanguination of approximately 30% of the total circulating blood volume, which led to shock, reducing the mean arterial pressure (MAP) by approximately 60% of baseline. Subsequently, either 5% human serum albumin (HSA) or HbVs suspended in 5% HSA were infused for resuscitation. The MAP only recovered to 75% of baseline after HSA administration, but fully recovered (100%) after HbV administration, with significant differences between the groups (P < 0.005). Oxygen delivery was restored in the HbV group and was significantly higher than that in the HSA group (P < 0.0001). The infusion of HbVs dispersed in a 5% HSA solution compensated for the rapid loss of approximately 30% of the total circulating blood volume in a dog pneumonectomy model, even with impaired lung function. Thus, HbVs can be used for resuscitation from hemorrhagic shock during thoracic surgery.