MST1 inhibitor

We have previously reported that TAZ functions as a tumor suppressor in multiple myeloma. MST1 is a serine-threonine kinase upstream of the Hippo-signaling pathway that functions as a tumor suppressor in many non-haematological malignancies. However, its role in hematological malignancies, including MM is still poorly understood. In this paper, we provide evidence that MST1 expression is higher in MM, and negatively correlates with TAZ expression in both cell lines and patient samples. High MST1 expression was associated with poor clinical outcomes...

Insulin-producing pancreatic β cell death is the fundamental cause of type 1 diabetes (T1D) and a contributing factor to type 2 diabetes (T2D). Moreover, metabolic disorder is another hallmark of T2D. Mammalian sterile 20-like kinase 1 (MST1) contributes to the progression of diabetes mellitus through apoptosis induction and acceleration of pancreatic β cell dysfunction. AMP-activated protein kinase (AMPK) is an energy sensing kinase and its activation has been suggested as a treatment option for metabolic diseases...

BACKGROUND: The conditioned medium from human umbilical cord mesenchymal stem cells (UCMSCs-CM) provides a new cell-free therapy for tumors due to its unique secretome. However, there are many contradictory reports about the effect of UCMSCs-CM on tumor cells. The loss of contact inhibition is a common characteristic of tumor cells. A relationship between the effect of UCMSCs-CM on tumor cells and contact inhibition in tumor cells is rarely concerned. Whether the effect of UCMSCs-CM on tumor cells is affected by cell density? Here, we explored the effect of UCMSCs-CM on granulosa tumor cell line (KGN) cells at low or high density...

This work focused on investigating the effect of A Disintegrin And Metalloproteases 12 (ADAM12) on colorectal cancer (CRC) development. ADAM12 levels within CRC samples were analyzed by using The Cancer Genome Atlas (TCGA) database. Then, altogether 55 CRC patients were enrolled to detect ADAM12 expression. ADAM12 overexpression or knockdown was transfected into CRC cells. Thereafter, this work examined CRC cell viability through cell counting kit-8 (CCK-8) and cell clone forming assays. Meanwhile, nude mice were utilized for in-vivo analysis...

Rationale: Chemotherapy is a common clinical strategy for cancer treatment. However, the accompanied cardiomyopathy renders cancer patients under risk of another life-threatening condition. Whereas Hippo pathway is known to play key roles in both cancerogenesis and heart disease, it remains unclear whether Hippo pathway activation mediates chemotherapy-induced cardiomyopathy. Methods and Results: In human breast cancer cells, doxorubicin (DOX) significantly induced upregulation of Hippo kinase Mst1, inhibitory phosphorylation of YAP, mitochondrial damage, reduced cell viability and increased apoptosis...

Salvianolic acid B (Sal B) is a component obtained from Salvia miltiorrhiza and is empirically used for liver diseases. The TGF-β/Smad and Hippo/YAP pathways may interact with each other in hepatocellular carcinoma (HCC). Previously, we found that Sal B mediates the TGF-β/Smad pathway in mice and delays liver fibrosis-carcinoma progression by promoting the conversion of pSmad3L to pSmad3C, but the effect of Sal B on the Hippo/YAP pathway has not been determined. Therefore, we used a DEN/CCl4 /C2 H5 OH-induced liver cancer model in mice to analyze liver index and tumor incidence, detect AST and ALT serological markers, observe liver pathology and the number of Ki67-positive cells to evaluate the anti-HCC effect of Sal B in vivo...

INTRODUCTION: Mammalian ste20-like kinases-1/2 (MST1/2), the core kinases of the Hippo pathway, play critical roles in the biology of hematopoietic cells via noncanonical mechanisms and contributes to megakaryocyte differentiation, polyploidization, and maturation to produce platelets. However, the role of MST1/2 in platelet functions remains unclear. MATERIALS AND METHODS: In this study, we investigated this topic by determining platelet aggregation and through flow cytometry, ATP release assay, clot retraction assay, and immunoblotting analysis...

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), responsible for the Coronavirus Disease 2019 (COVID-19) pandemic, causes respiratory failure and damage to multiple organ systems. The emergence of viral variants poses a risk of vaccine failures and prolongation of the pandemic. However, our understanding of the molecular basis of SARS-CoV-2 infection and subsequent COVID-19 pathophysiology is limited. In this study, we have uncovered a critical role for the evolutionarily conserved Hippo signaling pathway in COVID-19 pathogenesis...

Osteoarthritis (OA) is the most prevalent type of degenerative joint disease; it is reported to be associated with inflammatory responses, chondrocyte apoptosis, and cartilage degeneration. XMU-MP-1 is a selective MST1/2 inhibitor which activates the downstream effector YAP and promotes cell growth. It has displayed excellent benefits in mouse intestinal repair, as well as liver repair and regeneration. However, the effects of XMU-MP-1 on OA remain unclear. In this study, we investigated the therapeutic role of XMU-MP-1 on interleukin-1β (IL-1β)-induced inflammation in mice chondrocytes and the destabilization of the medial meniscus surgery (DMM)-induced OA model...

Intervertebral disc (IVD) degeneration (IVDD) which is highly prevalent within the elderly population, is a leading cause of chronic low back pain and disability. Nucleus pulposus (NP) cell senescence plays an indispensable role in the pathogenesis of IVDD. Morroniside is a major iridoid glycoside and one of the quality control metrics of Cornus officinalis Siebold & Zucc (CO). An increasing body of evidence suggests that morroniside and CO-containing formulae share many similar biological effects, including anti-inflammatory, anti-oxidative, and anti-apoptotic properties...

INTRODUCTION: Maternal vitamin D deficiency (VDD) is associated with intrauterine growth restriction (IUGR), but the exact mechanism remains unclear. Here we explored the mechanism through which VDD induced IUGR. METHODS: Female SD rats were fed a control normal diet (VD > 800 IU/Kg) or VDD diet (VD: 0 IU/Kg) for 8 weeks. Then, females were mated with 12-week-old male SD rats, and fetal and placental tissue were collected on the gestational day 13 (GD13) or 18 (GD18) to analyze the effects of VDD on pregnancy outcome and embryonic development...

Among pulmonary arterial hypertension (PAH) patients, right ventricular (RV) functioning has been considered a major determining factor for cardiac capacity and survival. However, despite the recognition of the clinical importance for preserving RV functioning, no effective treatments are currently available for RV failure. This study aims to suggest one such possible treatment, through investigating the cardio-protective capabilities of the anti-oxidant, melatonin (Mel), for treating adverse RV remodeling in PAH, along with its underlying mechanisms...

The critical pathogenesis of type 1 diabetes (T1D)/type 2 diabetes (T2D) is the physical status, mass, and function of pancreatic β cells. Mammalian STE20-like protein 1 kinase (MST1) plays vital roles in the apoptosis and insulin secretion of β cells. Here, we discovered a novel, potent, and selective MST1 inhibitor 19 (IC50 = 23 nM), which inhibited the phosphorylation of MST1-protected β cells from the damage of inflammatory cytokines in vitro. In vivo, it displayed acceptable pharmacokinetic properties in different species...

BACKGROUND: CCR2 is involved in maintaining immune homeostasis and regulating immune function. This study aims to elucidate the mechanism by which CCR2 regulates B-cell signalling. METHODS: In Ccr2-knockout mice, the development and differentiation of B cells, BCR proximal signals, actin movement and B-cell immune response were determined. Besides, the level of CCR2 in PBMC of SLE patients was analysed by bioinformatics. RESULTS: CCR2 deficiency reduces the proportion and number of follicular B cells, upregulates BCR proximal signalling and enhances the oxidative phosphorylation of B cells...

Following spinal cord injury (SCI), microglia gradually migrate to the edge of the lesion, interweaving around the border of the lesion to form the microglial scar, which performs inflammatory limiting and neuroprotective functions. Recent reports showed that Yes-associated protein (YAP) was expressed in astrocytes and promoted the formation of astrocytic scars, while YAP was not expressed in microglia after SCI. YAP and its paralogue transcriptional coactivator with PDZ-binding motif (TAZ) are transcriptional coactivators, which have a similar functional role as both are negatively regulated by the Hippo signalling pathway...

PURPOSE: Ischemic postconditioning (IPostC) alleviates myocardial ischemia/reperfusion (IR) injury, but the protective effect is lost during diabetes. PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) is able to inactivate Akt. Our previous study found that PHLPP1 expression was upregulated in diabetic hearts. We presumed that the attenuation of myocardial injury by IPostC might be hindered by PHLPP1 overexpression in diabetic animals. METHODS AND RESULTS: Nondiabetic and diabetic mice were subjected to 45 min of ischemia followed by 2 h of reperfusion with or without IPostC...

BACKGROUND: Colorectal cancer (CRC) is one of the three major cancers in the world and is the cancer with the most liver metastasis. The present study aimed to investigate the role of metallothionein 2A (MT2A) in the modulation of CRC cell proliferation and liver metastasis, as well as its molecular mechanisms. METHODS: The expression profile of metallothionein 2A (MT2A) in colorectal cancer retrieved from TCGA, GEO and Oncomine database. The biological effect of MT2A overexpression was investigated mainly involving cell proliferation and migration in CRC cells as well as growth and metastasis in CRC animal models...

AIM: To reveal whether and how Yes-associated protein (YAP) promotes the occurrence of subretinal fibrosis in age-related macular degeneration (AMD). METHODS: Cobalt chloride (CoCl2 ) was used in primary human umbilical vein endothelial cells (HUVECs) to induce hypoxia in vitro . Eight-week-old male C57BL/6J mice weighing 19-25 g were used for a choroidal neovascularization (CNV) model induced by laser photocoagulation in vivo . Expression levels of YAP, phosphorylated YAP, mesenchymal markers [α smooth muscle actin (α-SMA), vimentin, and Snail], and endothelial cell markers (CD31 and zonula occludens 1) were measured by Western blotting, quantitative real-time PCR, and immunofluorescence microscopy...

Arterial stiffness (AS) results from the progressive loss of elasticity of large vessels due to aging and is correlated with hypertension and other cardiovascular co-morbidities. Increased collagen deposition and contractile protein loss are key contributors to diminished flexibility. The histone 3 lysine demethylase 6a (Kdm6a) transcriptionally activates target genes via removal of tri-methyl residues on lysine 27 of histone 3 (H3K27me3). The Hippo signaling pathway is crucial for regulating cell proliferation, cell survival, and organ size...

SARS-CoV-2 is responsible for the ongoing COVID-19 pandemic, which causes respiratory failure and damage to multiple organ systems. Emergence of new variants of concern (VOCs), including Omicron can potentially render the current vaccines ineffective. However, our understanding of COVID-19 pathophysiology and molecular basis of SARS-CoV-2 infection is very limited. The role of the Hippo signaling pathway, an evolutionarily conserved organogenesis circuitry, in tissue inflammation and innate immune response is beginning to be understood...