Activated AMPK by metformin protects against fibroblast proliferation during pulmonary fibrosis by suppressing FOXM1.

A new animal model of congestive heart failure that mimics failure of coronary heart diseasL with hypertension was established in rabbits 6-9 d after gradual aortic constriction superimposed on myocardial infarction. The model resulted in significant hypertrophy of the left ventricle and whole heart. an increase of LVEDP (1.7+0.6 vs 0.4+0.3 kPa, p<0.01) and especially significant decreasc of ventricular segmental contraction within the non-infarct area (AL. 0.8+0.4 vs l.4+0.5 mm, p<0.01) as monitored by a sonomicrometer. Comparative evaluation of captopril. nitroprusside, dopaminc and lanatoside C was performed on this model. It was demonstrated that captopril and nitroprus-side significantly lowered the dP/dtmax left ventricular pressure (LVP), and enhanced the segmental contraction; dopamine predominantly increascd dP/dtmax, while lanatoside C manifested significant positive effect on both dP/dtmax and segmental contraction. Vasodilators captopril and nitroprusside were also characterized by a significant reduction of the tension-timc index (TTI). while dopamine increased it.

Comparative effects of captopril, nitroprusside, dopamine and lanatoside C on a new model of rabbit congestive heart failure.

Identifying new molecular signatures and potential therapeutics for idiopathic pulmonary fibrosis: a network medicine approach

Cervical cancer is one of the leading causes of cancer-associated mortality in gynecological diseases and ranks third among female cancers worldwide. Although early detection and vaccination have reduced incidence rates, cancer recurrence and metastasis lead to high mortality due to the lack of effective medicines. The present study aimed to identify novel drug candidates to treat cervical cancer. In the present study, lanatoside C, an FDA-approved cardiac glycoside used for the treatment of heart failure, was demonstrated to have anti-proliferative and cytotoxic effects on cervical cancer cells, with abrogation of cell migration in a dose-dependent manner. Lanatoside C also triggered cell apoptosis by enhancing reactive oxygen species production and reducing the mitochondrial membrane potential, which induced cell cycle arrest at the S and G2/M phases. Furthermore, lanatoside C inhibited the phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 6 (STAT6), while inducing the expression of suppressor of cytokine signaling 2, a negative regulator of JAK2-STAT6 signaling. Taken together, the results of the present study suggest that lanatoside C suppresses cell proliferation and induces cell apoptosis by inhibiting JAK2-STAT6 signaling, indicating that lanatoside C is a promising agent for the treatment of cervical cancer.

Lanatoside C inhibits human cervical cancer cell proliferation and induces cell apoptosis by a reduction of the JAK2/STAT6/SOCS2 signaling pathway

Background and Aim: Genome-wide association studies revealed a strong association between cardiovascular diseases (CVD) and clonal hematopoiesis of indeterminate potential (CHIP), highlighting one of its most common CHIP-driving mutations-TET2 (ten-eleven translocation 2), as a target for CHIP related CVD research. Our lab has established the generation of self-organizing cardiac organoids (SCO), which demonstrate the cellular composition and organization of the native human heart, and mimics human myocardial responses to stress stimulation. This project aims to examine whether SCOs would be an appropriate CHIP model and decipher promising drugs for cardiovascular CHIP treatment. Methods: To study TET2-mutant cardiovascular CHIP, we set up the TET2 cardiac-CHIP model through a knockdown (KD) of TET2 in myeloid cells that infiltrated our lab-made SCO. Immunofluorescence and qPCR were performed to ascertain TET2-KD myeloid cell infiltration, SCO fibrosis, and apoptosis assessments. SCO fibrosis was further analyzed by immunofluorescence staining, and cardiac contractile frequency and amplitude were determined by calcium flux analysis. Finally, RNAseq was performed to analyze transcriptomic changes in drug/vehicle-treated TET2-KD myeloid cells and the TET2 cardiac-CHIP model. Results: The TET2 cardiac-CHIP model resulted in significantly increased inflammation in SCO, accompanied by fibrosis and more cleaved Caspase-3, causing cardiomyocytes apoptosis and promoting the release of cTNT. The shortlisted drugs revealed a reduction of proliferation in TET2-KD myeloid cells, decreased pro-inflammatory cytokines, and a higher apoptosis level. Furthermore, the TET2 cardiac-CHIP model treated with selected drugs showed a remarkable decline in TET2-KD myeloid cell infiltration and pro-inflammation cytokines, cardiomyocyte apoptosis, fibrosis, and lowered cTNT levels, while drug control groups were not affected. Moreover, the drug treatment groups improved the heartbeat frequency and amplitude accessed by the calcium transient assay. RNAseq data also validated the above findings. Conclusions &amp; Discussion: Our results indicate that SCOs are an efficient pre-clinical model for studying and validating CHIP genes and drug interactions. Our data revealed that TET2-KD myeloid cells invade SCO and secrete pro-inflammatory cytokines, which promote apoptosis of cardiomyocytes and the release of cTNT. In this regard, our TET2 cardiac-CHIP model matches the inflammatory phenotype previously characterized in CHIP patients. Nevertheless, this phenotype could be rescued using positive drug candidates (Clopidogrel, R406, and Lanatoside C) selected by this project, emphasizing the significant value of our TET2 cardiac-CHIP model for drug screens and pre-clinical validation studies. Furthermore, among these three drug candidates, we found Lancatoside C, as proved by FDA/EMA, showed an unmet possibility for clinical therapeutic demand, insinuating potential benefit in repurposing Lanatoside C for the treatment of TET2-mutant cardiovascular CHIP. 

pdf/modeling-and-drug-discovery-of-clonal-hematopoiesis-of-167ce0zv1s.pdf

Modeling and drug discovery of clonal hematopoiesis of indeterminate potential (CHIP) - driven cardiovascular disease in self-organizing cardiac organoids (SCO)

It has been established that lanatoside C, a FDA-approved cardiac glycoside, reduces proliferation of cancer cell lines. The proliferation of fibroblasts is critical to the pathogenesis of pulmonary fibrosis (PF), a progressive and fatal fibrotic lung disease lacking effective treatment. In this study we have investigated the impact of lanatoside C on a bleomycin (BLM)-induced mouse model of PF and through the evaluation of fibroblast proliferation and activation in vitro. We evaluated explanted lung tissue by histological staining, western blot analysis, qRT-PCR and survival analysis, demonstrating that lanatoside C was able to protect mice against BLM-induced pulmonary fibrosis. The proliferation of cultured pulmonary fibroblasts isolated from BLM-induced PF mice was suppressed by lanatoside C, as hypothesized, through the induction of cell apoptosis and cell cycle arrest at the G2/M phase. The Akt signalling pathway was involved in this process. Interestingly, the production of α-SMA, fibronectin, and collagen I and III in response to TGF-β1 in healthy mouse fibroblasts was suppressed following lanatoside C administration by inhibition of TGF-β1/Smad signalling. In addition, TGF-β1-induced migration in lung fibroblasts was also impeded after lanatoside C treatment. Together, our data revealed that lanatoside C alleviated BLM-induced pulmonary fibrosis in mice via attenuation of growth and differentiation of fibroblasts, suggesting that it has potential as a candidate therapy for PF patients.

Lanatoside C protects mice against bleomycin-induced pulmonary fibrosis through suppression of fibroblast proliferation and differentiation

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Lanatoside C protects mice against bleomycin-induced pulmonary fibrosis through suppression of fibroblast proliferation and differentiation