Small-Molecule-Mediated Suppression of BMP Signaling by Selective Inhibition of BMP1-Dependent Chordin Cleavage.

BMP signaling is critical for many biological processes. Therefore, small molecules that modulate BMP signaling are useful for elucidating the function of BMP signaling and treating BMP signaling-related diseases. Here, we performed a phenotypic screening in zebrafish to examine the in vivo effects of N-substituted-2-amino-benzoic acid analogs NPL1010 and NPL3008 and found that they affect BMP signaling-dependent dorsal-ventral (D-V) patterning and bone formation in zebrafish embryos. Furthermore, NPL1010 and NPL3008 suppressed BMP signaling upstream of BMP receptors. BMP1 cleaves Chordin, an antagonist of BMP, and negatively regulates BMP signaling. Docking simulations demonstrated that NPL1010 and NPL3008 bind BMP1. We found that NPL1010 and NPL3008 partially rescued the disruptions in the D-V phenotype caused by bmp1 overexpression and selectively inhibited BMP1-dependent Chordin cleavage. Therefore, NPL1010 and NPL3008 are potentially valuable inhibitors of BMP signaling that act through selective inhibition of Chordin cleavage.

The Pathophysiology of Sepsis-Associated AKI.

Sepsis-associated AKI is a life-threatening complication that is associated with high morbidity and mortality in patients who are critically ill. Although it is clear early supportive interventions in sepsis reduce mortality, it is less clear that they prevent or ameliorate sepsis-associated AKI. This is likely because specific mechanisms underlying AKI attributable to sepsis are not fully understood. Understanding these mechanisms will form the foundation for the development of strategies for early diagnosis and treatment of sepsis-associated AKI. Here, we summarize recent laboratory and clinical studies, focusing on critical factors in the pathophysiology of sepsis-associated AKI: microcirculatory dysfunction, inflammation, NOD-like receptor protein 3 inflammasome, microRNAs, extracellular vesicles, autophagy and efferocytosis, inflammatory reflex pathway, vitamin D, and metabolic reprogramming. Lastly, identifying these molecular targets and defining clinical subphenotypes will permit precision approaches in the prevention and treatment of sepsis-associated AKI.

Neuroimmune Circuits Activated by Vagus Nerve Stimulation.

The interaction between the nervous system and the immune system has recently been well-recognized. Vagus nerve stimulation (VNS) presents potential as an anti-inflammatory therapy through activation of neuroimmune pathways. Detailed understanding of the neuroimmune pathways VNS evokes is critical in order to successfully use it in the clinic for the treatment of acute kidney injury, in which inflammation plays an important role. In this review, we describe recent findings regarding VNS-induced neuroimmune pathways responsible for anti-inflammation and tissue protection.

Transient activation of the Notch-her15.1 axis plays an important role in the maturation of V2b interneurons.

In the vertebrate ventral spinal cord, p2 progenitors give rise to two interneuron subtypes: excitatory V2a interneurons and inhibitory V2b interneurons. In the differentiation of V2a and V2b cells, Notch signaling promotes V2b fate at the expense of V2a fate. Later, V2b cells extend axons along the ipsilateral side of the spinal cord and express the inhibitory transmitter GABA. Notch signaling has been reported to inhibit the axonal outgrowth of mature neurons of the central nervous system; however, it remains unknown how Notch signaling modulates V2b neurite outgrowth and maturation into GABAergic neurons. Here, we have investigated neuron-specific Notch functions regarding V2b axon growth and maturation into zebrafish GABAergic neurons. We found that continuous neuron-specific Notch activation enhanced V2b fate determination but inhibited V2b axonal outgrowth and maturation into GABAergic neurons. These results suggest that Notch signaling activation is required for V2b fate determination, whereas its downregulation at a later stage is essential for V2b maturation. Accordingly, we found that a Notch signaling downstream gene, her15.1, showed biased expression in V2 linage cells and downregulated expression during the maturation of V2b cells, and continuous expression of her15.1 repressed V2b axogenesis. Our data suggest that spatiotemporal control of Notch signaling activity is required for V2b fate determination, maturation and axogenesis.

A newly developed feeder and oxygen measurement system reveals the effects of aging and obesity on the metabolic rate of zebrafish.

Metabolic alterations are relevant for the aging process. Declining metabolic rate with age is a common future of many animals, but it is not well understood how it does so. Here, we used zebrafish as a model for understanding how metabolic changes occur during aging and the interaction between aging and obesity on the metabolic rate. The oxygen consumption rate (OCR) has been used as an index of metabolic processes; however, it is difficult to accurately evaluate OCR with movement being considered because zebrafish need to move freely during the OCR measurement. To measure metabolic rate with high accuracy and efficiency, we developed a method for simultaneously collecting data on sequential oxygen consumption and distance moved by zebrafish using optical dissolved-oxygen sensors and the EthoVision video-tracking system as well as an automatic feeding system for zebrafish whereby obese zebrafish were produced by short-term overfeeding treatment. Using these systems, we examined metabolic changes during aging and overfeeding. First, we used 1- to 22-month-old zebrafish to evaluate changes in metabolism during the aging process. Measurements of body mass and length showed that the growth of the body rarely continued beyond 6 months, at which point zebrafish reach adulthood. Spontaneous swimming activity peaked at approximately 6-10 months and declined thereafter. Metabolic rates at low movement dramatically dropped during the first 4 months and gradually decreased with age after 10 months. These data suggest that metabolic aging becomes evident at approximately 10-14 months and that the metabolic rate (low movement) is useful for the detection of age-related metabolic changes in zebrafish. Second, by short-term overfeeding treatment using the automatic feeding system, we found that overweight is a strong risk factor for the development of metabolic disorders in zebrafish, but there was no interaction between obesity and aging on the metabolic rate. Therefore, our data suggest that the aging-related decline in metabolic-rate may be mostly programmed rather than being affected by energy balance disorder.

Notch signaling regulates the expression of glycolysis-related genes in a context-dependent manner during embryonic development.

Glycolysis, the classic pathway for producing energy, has been known to be involved in neural development. Notch signaling also contributes to neural development and regulation of glycolysis in various tissues. However, the role of Notch signaling in glycolysis-related gene regulation during neural development is poorly understood. Here, we analyzed mRNA expression patterns and levels of glucose transporters (GLUT) as well as rate-limiting enzymes in glycolysis using zebrafish mib1ta52b mutants, in which Notch signaling was deficient at the early embryonic and larval stages. Our results indicated that in neural tissues, Notch signaling positively regulates glut1a and glut3a expression and negatively regulates hk2 expression at the larval stage but may not regulate them during early embryonic stages. Therefore, these results suggest that Notch signaling regulates glycolysis-related gene expression in a context-dependent manner in neural tissues at different developmental stages.