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Deep-sea mineral water (DSW) consists of different compositions and properties. The composition can be varied in different seas all around the world. However, previous studies have investigated that DSW is a potential candidate that can be used to prevent different inflammatory diseases. Even though inflammation is an important protective mechanism in an animal, excessive inflammation causes organ failure and ultimate death. Therefore, the present study was carried out to investigate the anti-inflammatory effect of DSW extracted from the South Korean Sea to unveil its potential as an anti-inflammatory drug. To perform this, first, we have compared the cytotoxic effect of DSW on RAW 264.7 murine macrophage cells with NaCl and normal-sea water (NSW). Results reveal that DSW enhances cell survival while other treatments negatively affect cell survival. Furthermore, we have investigated that DSW reduces the LPS-induced cell apoptosis compared to the NaCl- and NSW-treated cells. Moreover, DSW has the ability to suppress the pro-inflammatory cytokine transcription (TNF-α, IL-1β, and IL-6) and NO production upon LPS treatment. In-vivo survival assay in zebrafish larvae shows a more than 50% survival rate in 10, 20, 30, 40, or 50% concentrations of DSW-treated larvae compared to NaCl- or NSW-treated larvae. Further investigations unveiled that DSW can negatively regulate the neutrophil and macrophage recruitment to the inflammatory site, which was induced by fin-fold amputation in zebrafish larvae and pro-inflammatory cytokine (tnf-α, il-1β, and il-6) secretion. Taken together, the present study concluded that DSW may have the ability to act as an anti-inflammatory drug to suppress excessive inflammation and subsequent consequences. [ABSTRACT FROM AUTHOR]

Erythropoietic protoporphyria (EPP1) results in painful photosensitivity and severe liver damage in humans due to the accumulation of fluorescent protoporphyrin IX (PPIX). While zebrafish (Danio rerio) models for porphyria exist, the utility of ferrochelatase (fech) knockout zebrafish, which exhibit EPP, for therapeutic screening and biological studies remains unexplored. This study investigated the use of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated fech-knockout zebrafish larvae as a model of EPP1 for drug screening. CRISPR/Cas9 was employed to generate fech-knockout zebrafish larvae exhibiting morphological defects without lethality prior to 9 days post-fertilization (dpf). To assess the suitability of this model for drug screening, ursodeoxycholic acid (UDCA), a common treatment for cholestatic liver disease, was employed. This treatment significantly reduced PPIX fluorescence and enhanced bile-secretion-related gene expression (abcb11a and abcc2), indicating the release of PPIX. Acridine orange staining and quantitative reverse transcription polymerase chain reaction analysis of the bax/bcl2 ratio revealed apoptosis in fech−/− larvae, and this was reduced by UDCA treatment, indicating suppression of the intrinsic apoptosis pathway. Neutral red and Sudan black staining revealed increased macrophage and neutrophil production, potentially in response to PPIX-induced cell damage. UDCA treatment effectively reduced macrophage and neutrophil production, suggesting its potential to alleviate cell damage and liver injury in EPP1. In conclusion, CRISPR/Cas9-mediated fech−/− zebrafish larvae represent a promising model for screening drugs against EPP1. [ABSTRACT FROM AUTHOR]

Exploiting the setting of staggered adoption of the Inevitable Disclosure Doctrine (IDD) in U.S. state courts, we examine how quasi-exogenous restrictions of outside employment opportunities affect CEO compensation structure. The IDD adoption constrains executives' ability to work for competitors, which likely decreases CEOs' tendency to take risks by increasing the cost of job loss and reducing the reward to risk taking. We expect the board to respond by increasing the sensitivity of CEO wealth to stock volatility (vega) to encourage risk taking. We find a significant increase in vega post-IDD adoption. The effect is stronger among CEOs with greater career concerns. The effect also increases with the ex ante CEO mobility and the importance of trade secrets, suggesting the board increases vega more when there is a greater reduction in CEO outside opportunities. Overall, we provide new evidence on how external labor market frictions affect the convexity of CEO compensation. JEL Classifications: G32; M12; J60. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-alpha (TNF-α) is a pleiotropic cytokine with critical roles in inflammation, cell survival, and defense. As a member of the TNF superfamily, it exerts its effects by binding to transmembrane receptors and triggering various downstream signaling pathways. Although TNF-α's involvement in antiviral responses in mammals is well-established, its role in teleost remains poorly understood. This study investigated the contribution of TNF-α1 to antiviral immunity in zebrafish using a tnf-α1 (-/-) knockout (KO) line. We challenged both wild-type and tnf-α1 (-/-) zebrafish with viral hemorrhagic septicemia virus (VHSV) at both embryonic and adult stages. Mortality was observed at 4 days post-infection (dpi) in tnf-α1-deficient adult fish challenged with 5 × 10 6 TCID 50 (VHSV) and at 5 dpi in adult wild fish challenged with the same concentration. In addition, tnf-α1 (-/-) KO adult fish reached the maximum mortality of 100 % at 20 dpi, whereas wild adult fish reached 54 % mortality at the same time point. This increased susceptibility to early mortality was associated with a higher viral burden and altered expression of key immune genes, including the pro-inflammatory cytokines il-6 and il-1β, the anti-inflammatory cytokine il-10, and interferon-related genes such as irf1 and ifn-γ. Our findings demonstrate the crucial role of TNF-α1 in antiviral defense mechanisms in zebrafish and provide valuable insights into the functional conservation of TNF-α signaling across vertebrate species. This knowledge may contribute to the development of strategies to combat viral diseases in fish., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The tripartite motif-containing (TRIM) superfamily is the largest family of RING-type E3 ubiquitin ligases that is conserved across the metazoan kingdom. Previous studies in mammals have demonstrated that TRIM59 possesses ubiquitin-protein ligase activity and acts as a negative regulator of NF-κB signaling. However, TRIM59 has rarely been characterized in fish. This study aimed to characterize TRIM59 from Epinephelus akaara (Eatrim59) and elucidate its structural features, expression patterns, and functional properties in innate immune responses and in the regulation of apoptosis. Eatrim59 is composed of 406 amino acids with a molecular weight of 45.84 kDa and a theoretical isoelectric point of 5.25. It comprises a conserved RING domain, a B-box motif, and a coiled-coil region. Subcellular localization analysis revealed that Eatrim59 was localized in the endoplasmic reticulum. Eatrim59 was ubiquitously expressed in all tissues examined, with the highest relative expression detected in the blood, followed by the brain and spleen. Temporal expression of Eatrim59 was dynamically regulated in response to in vivo immune stimulation by Toll-like receptor ligands and nervous necrosis virus infection. In FHM cells overexpressing Eatrim59, an increase in viral replication was observed upon infection with the Viral hemorrhagic septicemia virus. This phenomenon is attributed to Eatrim59-mediated downregulation of interferon, pro-inflammatory cytokines, and other antiviral pathways. Moreover, macrophages stably overexpressing Eatrim59 exhibited a decrease in nitric oxide production and the formation of a filamentous actin structure upon lipopolysaccharide stimulation, indicating dampened M1 polarization. Furthermore, a decrease in apoptosis was observed in Eatrim59-overexpressing FHM cells under oxidative stress induced by H 2 O 2 . In conclusion, these findings demonstrate the multifaceted role of Eatrim59 as a regulator of innate immune response and apoptosis in E. akaara., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cisplatin is a well-known chemotherapy medication used to treat numerous cancers. However, treatment with cisplatin in cancer therapy has major side effects, such as nephrotoxic acute kidney injury. Adult vertebrate kidneys are commonly used as models of cisplatin-induced nephrotoxic acute kidney injury. Embryonic zebrafish kidney is more simplified and is composed simply of two nephrons and thus is an excellent model for the investigation of cisplatin nephrotoxicity. Here, we developed a novel model to induce cisplatin nephrotoxicity in adult zebrafish and demonstrated that intraperitoneal injection of cisplatin caused a decline in kidney proximal tubular function based on fluorescein-labeled dextran uptake and alkaline phosphatase staining. We also showed that cisplatin induced histological injury of the kidney tubules, quantified by tubular injury scores on the periodic acid-Schiff-stained kidney sections. As shown in a mouse model of cisplatin-induced nephrotoxicity, the activation of poly(ADP-ribose) polymerase (PARP), an enzyme implicated in cisplatin-induced cell death, was markedly increased after cisplatin injection in adult zebrafish. Furthermore, pharmacological inhibition of PARP using a specific PARP inhibitor PJ 34 hydrochloride (PJ34) or 3-aminobenzamide ameliorated kidney proximal tubular functional and histological damages in cisplatin-injected adult zebrafish kidneys. Administration of a combination of PARP inhibitors PJ34 and 3-aminobenzamide additively protected renal function and histology in zebrafish and mouse models of cisplatin nephrotoxicity. In conclusion, these data suggest that adult zebrafish are not only suitable for drug screening and genetic manipulation but also useful as a simplified but powerful model to study the pathophysiology of cisplatin nephrotoxicity and establish new therapies for treating human kidney diseases.