Aspartate (Asp) can act on liver Kupffer cells, inhibit NOD-like receptor-P 3 (NLRP3) inflammatory bodies, and improve liver inflammation in acute hepatitis. However, the effect of Asp on the role of hepatic stellate cells (HSCs) in the pathogenesis of liver fibrosis in chronic liver injury remains unexplored. This study aimed to investigate the effects of Asp on CCl₄-induced liver fibrosis in mice and HSCs via the NF-κB/NLRP3 signaling pathway. Liver fibrosis was induced in C57BL/6J mice by intraperitoneally (IP) injecting 0.5 mL/kg 2% CCl₄ three times weekly for 8 weeks. Asp was administered to mice by gavage once every morning for 4 weeks. Masson’s trichrome staining, Sirius red staining and hematoxylin and eosin staining were used to detect and analyze the pathological changes in liver tissues. Western blot analysis and immunohistochemistry were applied to determine the protein expression levels of α-smooth muscle actin (α-SMA), collagen Ⅲ (COL III), NLRP3, and IL-1β. In addition, reverse transcription-quantitative PCR was performed to detect the mRNA expression levels. In the liver fibrosis model, the pathological changes in liver tissues improved following treatment with Asp. A marked decrease was observed in protein and mRNA expression levels of α-SMA, COL III, NLRP3, and IL-1β. In addition, HSCs were treated with Asp. The expression levels of α-SMA, COL III, NLRP3, and IL-1β reduced in dose- and time-dependent manners. Furthermore, Asp upregulated the expression of NS3TP1 in vivo and in vitro, and NS3TP1 had a significant inhibitory effect on liver fibrosis. Asp attenuated liver fibrosis and reduced collagen production by suppressing the NF-κB/NLRP3 signaling pathway via upregulating the expression of NS3TP1.

Pulmonary fibrosis is a progressive and irreversible disease for which therapeutic options are currently limited. A recent in vivo study showed that tenofovir, a nucleotide analogue reverse transcriptase inhibitor, had direct antifibrotic effects on skin and liver fibrosis. Another study in vitro revealed that NS5ATP9 inhibited the activation of human hepatic stellate cells. Because of the similarity of fibrotic diseases, we hypothesized that tenofovir alafenamide fumarate (TAF), the prodrug of tenofovir, and NS5ATP9, is related to and plays a role in the suppression of pulmonary fibrosis. We investigated the influence of NS5ATP9 on fibrosis in vitro. Human lung fibroblasts (HFL1) were transfected with short interfering RNAs or overexpression plasmids of NS5ATP9 before stimulation by human recombinant transforming growth factor-β1. The effect of TAF was evaluated in a bleomycin-induced fibrosis murine model. Male C57BL/6 mice were treated with bleomycin on day 0 by intratracheal injection and intragastrically administered TAF or vehicle. Left lung sections were fixed for histological analysis, while homogenates of the right lung sections and HFL1 cells were analyzed by western blotting and quantitative reverse transcription polymerase chain reaction. NS5ATP9 suppressed the activation of lung fibroblasts. Upregulation of collagen type 3 (α 1 chain) and α-smooth muscle actin was observed in HFL1 cells when NS5ATP9 was silenced, and vice-versa. TAF also showed anti-fibrotic effects in mice, as demonstrated by histological analysis of fibrosis and expression of extracellular matrix components in the lung sections. Additionally, TAF inhibited transforming growth factor-β1 and phosphorylated-Smad3 synthesis in HFL1 cells and the murine model, which was accompanied by upregulation of NS5ATP9. Our results suggest that NS5ATP9 forms a negative feedback pathway in pulmonary fibrosis and TAF has anti-fibrotic properties as it upregulates the expression level of NS5ATP9. As TAF has been shown to be safe and well-tolerated in humans, TAF and NS5ATP9 may be useful for developing novel therapeutics for pulmonary fibrosis.

Aspartate (Asp) can act on liver Kupffer cells, inhibit NOD-like receptor-P 3 (NLRP3) inflammatory bodies, and improve liver inflammation in acute hepatitis. However, the effect of Asp on the role of hepatic stellate cells (HSCs) in the pathogenesis of liver fibrosis in chronic liver injury remains unexplored. This study aimed to investigate the effects of Asp on CCl₄‑induced liver fibrosis in mice and HSCs via the NF-κB/ NLRP3 signaling pathway. Liver fibrosis was induced in C57BL/6J mice by intraperitoneally (IP) injecting 0.5 mL/kg 2% CCl₄ three times weekly for 8 weeks. Asp was administered to mice by gavage once every morning for 4 weeks. Masson's trichrome staining, Sirius red staining and hematoxylin and eosin staining were used to detect and analyze the pathological changes in liver tissues. Western blot analysis and immunohistochemistry were applied to determine the protein expression levels of α‑smooth muscle actin (α‑SMA), collagen Ⅲ (COL Ⅲ), NLRP3, and IL-1β. Also, reverse transcription‑quantitative PCR was performed to detect the mRNA expression levels. In the liver fibrosis model, the pathological changes in liver tissues improved following treatment with Asp. A marked decrease was observed in protein and mRNA expression levels of α‑SMA, COL Ⅲ, NLRP3, and IL-1β. In addition, HSCs were treated with Asp. The expression levels of α‑SMA, COL Ⅲ, NLRP3, and IL-1β reduced in dose‑ and time-dependent manners. Furthermore, Asp upregulated the expression of NS3TP1 in vivo and in vitro, and NS3TP1 had a significant inhibitory effect on liver fibrosis. Asp attenuated liver fibrosis and reduced collagen production by suppressing the NF-κB/ NLRP3 signaling pathway via upregulating the expression of NS3TP1.

BACKGROUND:Thyroid storm, or thyrotoxic crisis, is an acute and life-threatening manifestation or complication of hyperthyroidism that may involve sudden multisystem dysfunction. For these reasons, the initial diagnosis can be challenging. This report describes a 73-year-old woman with an atypical presentation of life-threatening thyroid storm. CASE REPORT:A 73-year-old woman with no history of hyperthyroidism experienced 1 month of abdominal distension and palpitations. Upon arrival at the emergency department, she displayed profound, refractory hypoglycemia (capillary glucose 0.24 mmol/L). Within 24 hours, she developed fulminant liver failure (aspartate aminotransferase 3767 U/L, alanine aminotransferase 791 U/L), coagulopathy, and thrombocytopenia (platelets 83 000/μL). Thyroid function tests confirmed severe thyrotoxicosis (free T3 10.30 pg/mL, free T4 6.11 ng/dL, thyroid-stimulating hormone <0.008 μIU/mL), and a Burch-Wartofsky Point Scale score of 70 established the diagnosis of thyroid storm. Additional diagnoses included acute liver failure, disseminated intravascular coagulation, and heart failure (ejection fraction 43%). Conventional antithyroid drugs were contraindicated due to severe hepatic dysfunction; rescue therapies such as plasmapheresis were precluded by a prohibitive bleeding risk. After multidisciplinary counseling, the family chose palliative discharge; the patient died 3 days later. CONCLUSIONS:This case demonstrates that thyroid storm can present with atypical features in patients without known hyperthyroidism, leading to delayed diagnosis and fatal multiorgan failure. Early consideration of thyroid dysfunction is essential to prevent irreversible outcomes.