Translational research : the journal of laboratory and clinical medicine
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Artificial Intelligence Assisted Repurposing of Lubiprostone Alleviates Tubulointerstitial Fibrosis.
Tubulointerstitial fibrosis (TIF) is the most prominent cause which leads to chronic kidney disease (CKD) and end-stage renal failure. Despite extensive research, there have been many clinical trial failures, and there is currently no effective treatment to cure renal fibrosis. This demonstrates the necessity of more effective therapies and better preclinical models to screen potential drugs for TIF. ⋯ These findings suggest that the proximal tubule on a chip model is a more physiologically relevant model for studying and identifying potential biomarkers for fibrosis compared to conventional in vitro 2D culture and alternative of an animal model. In conclusion, the high throughput Proximal tubule-on-chip system shows improved in vivo-like function and indicates the potential utility for renal fibrosis drug screening. Additionally, repurposed Lubiprostone shows an effective potency to treat TIF via inhibiting 3 major profibrotic signaling pathways such as TGFβ/Smad, JAK/STAT, and epithelial-mesenchymal transition (EMT), and restores kidney function.
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Liver transplantation is the ultimate treatment option for end-stage liver failure. However, liver graft injury remains a challenge. This study aimed to investigate the role of connexin32 (Cx32) in liver graft injury and elucidate its mechanism of action. ⋯ Simultaneously, mass-produced ROS were transferred to neighboring cells through Cx32 channels, for which oxidative stress and the inflammatory response were aggravated indirectly. Finally, Bak/Bax-related apoptosis was activated, thereby worsening liver graft injury. Our findings propose Cx32 as a dual mechanistic factor for oxidative stress and inflammatory signaling pathways in regulating cell apoptosis on liver graft injury, which suggests a promising therapeutic targets for liver graft injury.
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Chronic heart failure (CHF) as a long-term disease is highly prevalent in elder people worldwide. Early diagnosis and treatments are crucial for preventing the development of CHF. Herein, we aimed to identify novel diagnostic biomarker, therapeutic target and drug for CHF. ⋯ What's more, RUS can effectively improve cardiac function, myocardial fibrosis and morphological damage. Collectively, this study provided a potential metabolic marker CMPF and novel target OAT1/3 for CHF, which were demonstrated to be involved in FAO. And RUS was identified as a potential anti-FAO drug for CHF by regulating OAT1/3.
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Lack of retinoblastoma (Rb) protein causes aggressive intraocular retinal tumors in children. Recently, Rb tumors have been shown to have a distinctly altered metabolic phenotype, such as reduced expression of glycolytic pathway proteins alongside altered pyruvate and fatty acid levels. In this study, we demonstrate that loss of hexokinase 1(HK1) in tumor cells rewires their metabolism allowing enhanced oxidative phosphorylation-dependent energy production. ⋯ HK1 overexpression reduced tumor burden in an intraocular tumor xenograft model. AMPKα activation by AICAR also enhanced the tumoricidal effects of the chemotherapeutic drug topotecan in vivo. Therefore, enhancing HK1 or AMPKα activity can reprogram cancer metabolism and sensitize Rb tumors to lower doses of existing treatments, a potential therapeutic modality for Rb.
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Mitochondrial fission has been noted in the pathogenesis of dilated cardiomyopathy (DCM), but the underlying specific regulatory mechanism, especially in the development of doxorubicin (DOX)-induced cardiomyopathy remains unclear. In the present study, we explore whether the aspartate-glutamate carrier1 (AGC1) interacts with the fission protein dynamin-related protein 1 (Drp1) and reveal the functional and molecular mechanisms contributing to DOX-induced cardiomyopathy. Results of co-immunoprecipitation mass spectrometry (CO-IP MS) analysis based on heart tissue of DCM patients revealed that AGC1 expression was significantly upregulated in DCM-induced injury and AGC1 level was closely correlated with mitochondrial morphogenesis and function. ⋯ Mechanistically, AGC1 overexpression could upregulate Drp1 expression and contribute to subsequent excessive mitochondrial fission. Specifically, AGC1 knockdown or the use of Drp1-specific inhibitor Mdivi-1 alleviated cardiomyocyte apoptosis and inhibited impairment of mitochondrial function induced by DOX exposure. In summary, our data illustrate that AGC1, as a novel contributor to DCM, regulates cardiac function via Drp1-mediated mitochondrial fission, indicating that targeting AGC1-Drp1 axis could be a potential therapeutic strategy for DOX-induced cardiomyopathy.