Hippo-YAP Signaling Pathway Research Articles

Integrated proteomics and metabolomics analyses reveal new insights into the antitumor effects of valproic acid plus simvastatin combination in a prostate cancer xenograft model associated with downmodulation of YAP/TAZ signaling

BackgroundDespite advancements in therapeutic approaches, including taxane-based chemotherapy and androgen receptor-targeting agents, metastatic castration-resistant prostate cancer (mCRPC) remains an incurable tumor, highlighting the need for novel strategies that can target the complexities of this disease and bypass the development of drug resistance mechanisms. We previously demonstrated the synergistic antitumor interaction of valproic acid (VPA), an antiepileptic agent with histone deacetylase inhibitory activity, with the lipid-lowering drug simvastatin (SIM). This combination sensitizes mCRPC cells to docetaxel treatment both in vitro and in vivo by targeting the cancer stem cell compartment via mevalonate pathway/YAP axis modulation.MethodsHere, using a combined proteomic and metabolomic/lipidomic approach, we characterized tumor samples derived from 22Rv1 mCRPC cell-xenografted mice treated with or without VPA/SIM and performed an in-depth bioinformatics analysis.ResultsWe confirmed the specific impact of VPA/SIM on the Hippo–YAP signaling pathway, which is functionally related to the modulation of cancer-related extracellular matrix biology and metabolic reprogramming, providing further insights into the molecular mechanism of the antitumor effects of VPA/SIM.ConclusionsIn this study, we present an in-depth exploration of the potential to repurpose two generic, safe drugs for mCRPC treatment, valproic acid (VPA) and simvastatin (SIM), which already show antitumor efficacy in combination, primarily affecting the cancer stem cell compartment via MVP/YAP axis modulation. Bioinformatics analysis of the LC‒MS/MS and 1H‒NMR metabolomics/lipidomics results confirmed the specific impact of VPA/SIM on Hippo–YAP.

Effect of the polyphenol flavonoids fisetin and quercetin on the adipogenic differentiation of human mesenchymal stromal cells.

Fisetin and quercetin, polyphenol flavonoids, have been shown to have a wide range of beneficial pharmacological effects including anti-inflammatory, antioxidative, and anti-cancer. Our previous work shows that fisetin also affects the specification of the adipogenic-osteogenic lineage of human mesenchymal stem cells (hMSCs) by modulating the Hippo-YAP signaling pathway. Although quercetin has a structure similar to that of fisetin, its effects on the functional properties of hMSCs have not yet been investigated. The objective of the present study is to determine the effects of quercetin on the various properties of hMSCs, including proliferation, migration, and differentiation capacity toward adipogenic and osteogenic lineages. The results show that while fisetin increases hMSC adipogenic differentiation, quercetin inhibited adipogenic differentiation of hMSCs. The inhibition is mediated, at least in part, by the activation of hippo signaling and up-regulation of miR-27b, which inhibits the expression of genes involved in all critical steps of lipid droplet biogenesis, resulting in a decrease in the number of lipid droplets in hMSCs. It is possible that the lack of hydroxylation of the 5 position on the A ring of quercetin could be responsible for its different effect on the adipogenic-osteogenic lineage specification of hMSCs compared with fisetin. Molecular docking and molecular dynamics simulation suggested that fisetin and quercetin possibly bind to serine / threonine protein kinases 4 (STK4/MST1), which is an upstream kinase responsible for LATS phosphorylation. Taken together, our results demonstrate more insight into the mechanism underlying the role of flavonoid fisetin and quercetin in the regulation of adipogenesis.

Pan-cancer analysis of the prognostic and immunological role of hippo-YAP signaling pathway

The Hippo-Yes-associated protein (Hippo-YAP) signaling pathway, a conserved pathway that regulates organ size, participates in tumor progression. However, there are few comprehensive analyses of tumor prognosis and immunity. In the present study, TCGA, GTEx, GEO, TIMER2, STRING, GSCA, ImmuCellAI, and other bioinformatics tools were used to reveal the involvement of the Hippo-YAP signaling pathway in the prognosis and immunity of pan-cancers. The obtained results showed that mRNA expression differences of Hippo-YAP pathway genes between normal samples and tumor samples in pan-cancers and some genes (such as TEAD4, MAP4K4, and STK3) might affect the prognosis of patients with skin cutaneous melanoma (SKCM) and pancreatic adenocarcinoma (PAAD). Furthermore, mutation and methylation of the Hippo-YAP signaling pathway genes in normal and primary tumor tissues differ in various cancers (KIRP, BRCA). Additionally, the relationship between the tumor microenvironment, molecular pathways, and the Hippo-YAP pathway indicated that it might lead to a suppressive immune microenvironment that affects the efficacy of immunotherapy. This is a pan-cancer overview of the Hippo-YAP signaling pathway genes, which explores the aberrant expression or mutation of this pathway that regulates the tumor microenvironment and immunotherapy.

KLF4 activates LATS2 to promote cisplatin sensitivity in ovarian cancer through DNA damage.

We aimed to investigate the role of large tumor suppressor kinase 2 (LATS2) in cisplatin (DDP) sensitivity in ovarian cancer. Bioinformatic analysis explored LATS2 expression, pathways, and regulators. Quantitative reverse transcription-PCR measured LATS2 and KLF4 mRNA levels. Dual-luciferase and chromatin immunoprecipitation assays confirmed their binding relationship. Cell viability, half maximal inhibitory concentration (IC50) values, cell cycle, and DNA damage were assessed using CCK-8, flow cytometry, and comet assays. Western blot analyzed protein expression. The effect of LATS2 on the sensitivity of ovarian cancer to DDP was verified in vivo. LATS2 and KLF4 were downregulated in ovarian cancer, with LATS2 enriched in cell cycle, DNA replication, and mismatch repair pathways. KLF4, an upstream regulator of LATS2, bound to its promoter. Overexpressing LATS2 increased G1-phase cells, reduced cell viability and IC50 values, and induced DNA damage. Silencing KLF4 alone showed the opposite effect on LATS2 overexpression. Knocking out LATS2 reversed the effects of KLF4 overexpression on cell viability, cell cycle, IC50 values, and DNA damage in ovarian cancer cells. Inhibiting LATS2 inactivated the Hippo-YAP signaling pathway. In vivo experiments showed that overexpression of LATS2 enhanced the sensitivity of ovarian cancer to DDP. KLF4 activates LATS2 via DNA damage to enhance DDP sensitivity in ovarian cancer, providing a potential target for improving treatment outcomes.

Activation of VGLL4 Suppresses Cardiomyocyte Maturational Hypertrophic Growth.

From birth to adulthood, the mammalian heart grows primarily through increasing cardiomyocyte (CM) size, which is known as maturational hypertrophic growth. The Hippo-YAP signaling pathway is well known for regulating heart development and regeneration, but its roles in CM maturational hypertrophy have not been clearly addressed. Vestigial-like 4 (VGLL4) is a crucial component of the Hippo-YAP pathway, and it functions as a suppressor of YAP/TAZ, the terminal transcriptional effectors of this signaling pathway. To develop an in vitro model for studying CM maturational hypertrophy, we compared the biological effects of T3 (triiodothyronine), Dex (dexamethasone), and T3/Dex in cultured neonatal rat ventricular myocytes (NRVMs). The T3/Dex combination treatment stimulated greater maturational hypertrophy than either the T3 or Dex single treatment. Using T3/Dex treatment of NRVMs as an in vitro model, we found that activation of VGLL4 suppressed CM maturational hypertrophy. In the postnatal heart, activation of VGLL4 suppressed heart growth, impaired heart function, and decreased CM size. On the molecular level, activation of VGLL4 inhibited the PI3K-AKT pathway, and disrupting VGLL4 and TEAD interaction abolished this inhibition. In conclusion, our data suggest that VGLL4 suppresses CM maturational hypertrophy by inhibiting the YAP/TAZ-TEAD complex and its downstream activation of the PI3K-AKT pathway.

NEDD8 enhances Hippo signaling by mediating YAP1 neddylation

The Hippo-YAP signaling pathway plays a central role in many biological processes such as regulating cell fate, organ size and tissue growth, and its key components are spatiotemporally expressed and post-translationally modified during these processes. Neddylation is a post-translational modification that involves the covalent attachment of NEDD8 to target proteins by NEDD8-specific E1-E2-E3 enzymes. Whether neddylation is involved in Hippo-YAP signaling remains poorly understood. Here, we provide evidence supporting the critical role of NEDD8 in facilitating the Hippo-YAP signaling pathway by mediating neddylation of the transcriptional coactivator Yes-associated protein 1 (YAP1). Overexpression of NEDD8 induces YAP1 neddylation and enhances YAP1 transactivity, but inhibition of neddylation suppresses YAP1 transactivity and attenuates YAP1 nuclear accumulation. Furthermore, inhibition of YAP1 signaling promotes MLN4924-induced GCs apoptosis and disruption of nedd8 in zebrafish results in downregulation of yap1-activated genes and upregulation of yap1-repressed genes. Further assays show that the xiap ligase promotes nedd8 conjugates to yap1 and that yap1 neddylation. In addition, we identify lysine 159 as a major neddylation site on YAP1. These findings reveal a novel mechanism for neddylation in the regulation of Hippo-YAP signaling.

FGF2 promotes the proliferation of injured granulosa cells in premature ovarian failure via Hippo-YAP signaling pathway

Young women undergoing anticancer treatment are at risk of premature ovarian failure (POF). Endometrial-derived stem cells (EnSCs) have demonstrated significant therapeutic potential for treating ovarian insufficiency, although the underlying mechanisms remain to be fully understood. This study aims to further investigate the therapeutic effects of EnSCs, particularly through the paracrine action of fibroblast growth factor 2 (FGF2), on POF. The findings show that exogenous FGF2 enhances the survival of ovarian granulosa cells damaged by cisplatin. FGF2 stimulates the proliferation of these damaged cells by suppressing the Hippo signaling pathway and activating YAP expression. In vivo experiments also revealed that FGF2 treatment significantly improves ovarian reserve and endocrine function in mice with POF. These results suggest that FGF2 can boost the proliferative capacity of damaged ovarian granulosa cells through the Hippo-YAP signaling pathway, providing a theoretical foundation for using EnSCs and FGF2 in clinical treatments for POF.

Jisuikang formula promotes spinal cord injury repair in rats by activating the YAP/PKM2 signaling axis in astrocytes

To investigate the effect of Jisuikang formula-medicated serum for promoting spinal cord injury (SCI) repair in rats and explore the possible mechanism. Thirty adult SD rats were randomized into sham-operated group, SCI (induced using a modified Allen method) model group, and Jisuikang formula-medicated serum treatment group. After the operations, the rats were treated with normal saline or Jisuikang by gavage on a daily basis for 14 days, and the changes in hindlimb motor function of the rats was assessed with Basso-Beattie-Bresnahan (BBB) scores and inclined-plate test. The injured spinal cord tissues were sampled from the SCI rat models for single-cell RNA sequencing, and bioinformatics analysis was performed to identify the target genes of Jisuikang, spinal cord injury and glycolysis. In the cell experiment, cultured astrocytes from neonatal SD rat cortex were treated with SOX2 alone or in combination with Jisuikang-medicated serum for 21 days, and the protein expressions of PKM2, p-PKM2 and YAP and colocalization of PKM2 and YAP in the cells were analyzed with Western blotting and immunofluorescence staining, respectively. The SCI rats with Jisuikang treatment showed significantly improved BBB scores and performance in inclined-plate test. At the injury site, high PKM2 expression was detected in various cell types. Bioinformatic analysis identified the HIPPO-YAP signaling pathway as the target pathway of Jisuikang. In cultured astrocytes, SOX2 combined with the mediated serum, as compared with SOX2 alone, significantly increased PKM2, p-PKM2 and YAP expressions and entry of phosphorylated PKM2 into the nucleus, and promoted PKM2 and YAP co-localization in the cells. Jisuikang formula accelerates SCI repair in rats possibly by promoting aerobic glycolysis of the astrocytes via activating the PKM2/YAP axis to induce reprogramming of the astrocytes into neurons.

The mechanisms of exercise improving cardiovascular function by stimulating Piezo1 and TRP ion channels: a systemic review.

Mechanosensitive ion channels are widely distributed in the heart, lung, bladder and other tissues, and plays an important role in exercise-induced cardiovascular function promotion. By reviewing the PubMed databases, the results were summarized using the terms "Exercise/Sport", "Piezo1", "Transient receptor potential (TRP)" and "Cardiovascular" as the keywords, 124-related papers screened were sorted and reviewed. The results showed that: (1) Piezo1 and TRP channels play an important role in regulating blood pressure and the development of cardiovascular diseases such as atherosclerosis, myocardial infarction, and cardiac fibrosis; (2) Exercise promotes cardiac health, inhibits the development of pathological heart to heart failure, regulating the changes in the characterization of Piezo1 and TRP channels; (3) Piezo1 activates downstream signaling pathways with very broad pathways, such as AKT/eNOS, NF-κB, p38MAPK and HIPPO-YAP signaling pathways. Piezo1 and Irisin regulate nuclear localization of YAP and are hypothesized to act synergistically to regulate tissue mechanical properties of the cardiovascular system and (4) The cardioprotective effects of exercise through the TRP family are mostly accomplished through Ca2+ and involve many signaling pathways. TRP channels exert their important cardioprotective effects by reducing the TRPC3-Nox2 complex and mediating Irisin-induced Ca2+ influx through TRPV4. It is proposed that exercise stimulates the mechanosensitive cation channel Piezo1 and TRP channels, which exerts cardioprotective effects. The activation of Piezo1 and TRP channels and their downstream targets to exert cardioprotective function by exercise may provide a theoretical basis for the prevention of cardiovascular diseases and the rehabilitation of clinical patients.

Reversal of cisplatin resistance in oral squamous cell carcinoma by piperlongumine loaded smart nanoparticles through inhibition of Hippo-YAP signaling pathway

Cisplatin alone or in combination with 5FU and docetaxel is the preferred chemotherapy regimen for advanced-stage OSCC patients. However, its use has been linked to recurrence and metastasis due to the development of drug resistance. Therefore, sensitization of cancer cells to conventional chemotherapeutics can be an effective strategy to overcome drug resistance. Piperlongumine (PL), an alkaloid, have shown anticancer properties and sensitizes numerous neoplasms, but its effect on OSCC has not been explored. However, low aqueous solubility and poor pharmacokinetics limit its clinical application. Therefore, to improve its therapeutic efficacy, we developed piperlongumine-loaded PLGA-based smart nanoparticles (smart PL-NPs) that can rapidly release PL in an acidic environment of cancer cells and provide optimum drug concentrations to overcome chemoresistance. Our results revealed that smart PL-NPs has high cellular uptake in acidic environment, facilitating the intracellular delivery of PL and sensitizing cancer cells to cisplatin, resulting in synergistic anticancer activity in vitro by increasing DNA damage, apoptosis, and inhibiting drug efflux. Further, we have mechanistically explored the Hippo-YAP signaling pathway, which is the critical mediator of chemoresistance, and investigated the chemosensitizing effect of PL in OSCC. We observed that PL alone and in combination with cisplatin significantly inhibits the activation of YAP and its downstream target genes and proteins. In addition, the combination of cisplatin with smart PL-NPs significantly inhibited tumor growth in two preclinical models (patient-derived cell based nude mice and zebrafish xenograft). Taken together, our findings suggest that smart PL-NPs with cisplatin will be a novel formulation to reverse cisplatin resistance in patients with advanced OSCC.

The Hippo-YAP Signaling Pathway in Osteoarthritis and Rheumatoid Arthritis.

Arthritis is the most prevalent joint disease and is characterized by articular cartilage degradation, synovial inflammation, and changes in periarticular and subchondral bone. Recent studies have reported that Yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) have significant effects on the proliferation, migration, and survival of chondrocytes and fibroblast-like synovial cells (FLSs). YAP/TAZ signaling pathway, as well as the related Hippo-YAP signaling pathway, are responsible for the condition of cells and articular cartilage in joints. They are tightly regulated to maintain metabolism in chondrocytes and FLSs because abnormal expression may result in cartilage damage. However, the roles and mechanisms of the Hippo-YAP pathway in arthritis remain largely unknown. This review summarizes the roles and key functions of YAP/TAZ and the Hippo-YAP signaling pathway in FLSs and chondrocytes for the induction of proliferation, migration, survival, and differentiation in rheumatoid arthritis (RA) and osteoarthritis (OA) research. We also discuss the therapeutic strategies involving YAP/TAZ and the related Hippo-YAP signaling pathway involved in OA.

The Hippo-YAP signaling pathway drives CD24-mediated immune evasion in esophageal squamous cell carcinoma via macrophage phagocytosis.

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies in the world with poor prognosis. Despite the promising applications of immunotherapy, the objective response rate is still unsatisfactory. We have previously shown that Hippo/YAP signaling acts as a powerful tumor promoter in ESCC. However, whether Hippo/YAP signaling is involved in tumor immune escape in ESCC remains largely unknown. Here, we show that YAP directly activates transcription of the "don't eat me" signal CD24, and plays a crucial role in driving tumor cells to avoid phagocytosis by macrophages. Mechanistically, YAP regulates CD24 expression by interacting with TEAD and binding the CD24 promoter to initiate transcription, which facilitates tumor cell escape from macrophage-mediated immune attack. Our animal model data and clinical data show that YAP combined with CD24 in tumor microenvironment redefines the impact of TAMs on the prognosis of ESCC patients which will provide a valuable basis for precision medicine. Moreover, treatment with YAP inhibitor altered the distribution of macrophages and suppressed tumorigenesis and progression of ESCC in vivo. Together, our study provides a novel link between Hippo/YAP signaling and macrophage-mediated immune escape, which suggests that the Hippo-YAP-CD24 axis may act as a promising target to improve the prognosis of ESCC patients. A proposed model for the regulatory mechanism of Hippo-YAP-CD24-signaling axis in the tumor-associated macrophages mediated immune escape.

Efficacy and mechanism of Shenqi Compound in inhibiting diabetic vascular calcification

BackgroundShenqi Compound (SQC) has been used in clinic for several decades in the prevention and treatment of diabetes and its complications. But this is merely a heritage of experience. The primary aim of this study is to scientifically validate the therapeutic effects of SQC on diabetic vascular calcification (DVC) in an animal model and, simultaneously, uncover its potential underlying mechanisms.MethodSpontaneous diabetic rat- Goto Kakizaki (GK) rats were selected for rat modeling. We meticulously designed three distinct groups: a control group, a model group, and an SQC treatment group to rigorously evaluate the influence of SQC. Utilizing a comprehensive approach that encompassed methods such as pathological staining, western blot analysis, qRT-PCR, and RNA sequencing, we thoroughly investigated the therapeutic advantages and the underlying mechanistic pathways associated with SQC in the treatment of DVC.ResultThe findings from this investigation have unveiled the extraordinary efficacy of SQC treatment in significantly mitigating DVC. The underlying mechanisms driving this effect encompass multifaceted facets, including the restoration of aberrant glucose and lipid metabolism, the prevention of phenotypic transformation of vascular smooth muscle cells (VSMCs) into osteogenic-like states, the subsequent inhibition of cell apoptosis, the modulation of inflammation responses, the remodeling of the extracellular matrix (ECM), and the activation of the Hippo-YAP signaling pathway. Collectively, these mechanisms lead to the dissolution of deposited calcium salts, ultimately achieving the desired inhibition of DVC.ConclusionOur study has provided compelling and robust evidence of the remarkable efficacy of SQC treatment in significantly reducing DVC. This reduction is attributed to a multifaceted interplay of mechanisms, each playing a crucial role in the observed therapeutic effects. Notably, our findings illuminate prospective directions for further research and potential clinical applications in the field of cardiovascular health.Graphical

EP300 promotes lung cancer cell proliferation by regulating the oncogenic transcription of Hippo-YAP signaling pathway

The transcriptional activation function of YAP in cancer development has been widely studied. However, the underlying regulatory mechanisms remain largely unknown. In this study, we found that EP300, one histone acetyltransferase, interacted with YAP and was recruited into the phase separated condensates of YAP. Transcriptomic analysis revealed substantial alterations in gene expression upon EP300 depletion, with downregulated genes associated with cancer progression and Hippo-YAP pathway. Notably, disruption of EP300 inhibited the transcriptional activation of YAP and reduced the binding of H3K27ac on YAP target oncogenes in Hippo pathway. Moreover, depletion of EP300 effectively inhibited YAP-driven tumor growth. Taken together, these results indicate that EP300 contributes to lung cancer progression by promoting the oncogenic transcription of YAP through H3K27ac, which suggests that YAP-EP300 axis may be potential therapeutic targets for lung cancer treatment.

Identification of topoisomerase 2A as a novel bone metastasis-related gene in liver hepatocellular carcinoma.

Bone is the second most frequent site of metastasis for Liver hepatocellular carcinoma (LIHC), which leads to an extremely poor prognosis. Identifying novel biomarkers and therapeutic targets for LIHC patients with bone metastasis is urgently needed. In this study, we used multiple databases for comprehensive bioinformatics analysis, including TCGA, GEO, ICGC, GTEx, TISIDB, and TIMER, to identify key genes related to bone metastasis of LIHC. Clinical tissues and tissue microarray were adopted to assess the expression of TOP2A through qRT-PCR and immunohistochemistry analyses in LIHC. Gene enrichment analysis, DNA methylation, gene mutation, prognosis, and tumor immunity associated with TOP2A in LIHC were investigated. In vitro and in vivo experiments were performed to explore the functional role of TOP2A in LIHC bone metastasis. We identified that TOP2A was involved in LIHC bone metastasis. Clinically, TOP2A was highly expressed in LIHC tumoral specimens, with the highest level in the bone metastasis lesions. TOP2A was an independent prognostic factor that higher expression of TOP2A was markedly associated with poorer prognosis in LIHC. Moreover, the abnormal expression of TOP2A might be related to DNA hypomethylation, often accompanied by TP53 mutation, immune escape and immunotherapy failure. Enrichment analysis and validation experiments unveiled that TOP2A stimulated the Hippo-YAP signaling pathway in LIHC. Functional assays confirmed that TOP2A could promote bone-specific metastatic potential and tumor-induced osteolysis in LIHC. These findings unveil that TOP2A might be a novel prognostic biomarker and therapeutic target for LIHC bone metastasis.

SHOX2 promotes prostate cancer proliferation and metastasis through disruption of the Hippo-YAP pathway

The transcription factor SHOX2 gene is critical in regulating gene expression and the development of tumors, but its biological role in prostate cancer (PCa) remains unclear. In this study, we found that SHOX2 expression was significantly raised in PCa tissues and was associated with clinicopathological features as well as disease-free survival (DFS) of PCa patients. Phenotypic tests showed that the absence of SHOX2 inhibited PCa growth and invasion, while SHOX2 overexpression promoted these effects. Mechanistically, SHOX2 was found to activate the transcription of nephronophthisis type 4 (NPHP4), a gene located downstream of SHOX2. Further analysis revealed that SHOX2 could potentially interfere with the Hippo-YAP signaling pathway through NPHP4 activation, facilitating the oncogenic behavior of PCa cells. These findings highlight SHOX2 as an oncogene in PCa and provide a basis for developing potential therapeutic approaches against this disease.

GPR81-mediated reprogramming of glucose metabolism contributes to the immune landscape in breast cancer

BackgroundLocal tumor microenvironment (TME) plays a crucial role in immunotherapy for breast cancer (BC). Whereas, the molecular mechanism responsible for the crosstalk between BC cells and surrounding immune cells remains unclear. The present study aimed to determine the interplay between GPR81-mediated glucometabolic reprogramming of BC and the immune landscape in TME.Materials and MethodsImmunohistochemistry (IHC) assay was first performed to evaluate the association between GPR81 and the immune landscape. Then, several stable BC cell lines with down-regulated GPR81 expression were established to directly identify the role of GPR81 in glucometabolic reprogramming, and western blotting assay was used to detect the underlying molecular mechanism. Finally, a transwell co-culture system confirmed the crosstalk between glucometabolic regulation mediated by GPR81 in BC and induced immune attenuation.ResultsIHC analysis demonstrated that the representation of infiltrating CD8+ T cells and FOXP3+ T cells were dramatically higher in BC with a triple negative (TN) subtype in comparison with that with a non-TN subtype (P < 0.001). Additionally, the ratio of infiltrating CD8+ to FOXP3+ T cells was significantly negatively associated with GPR81 expression in BC with a TN subtype (P < 0.001). Furthermore, GPR81 was found to be substantially correlated with the glycolytic capability (P < 0.001) of BC cells depending on a Hippo-YAP signaling pathway (P < 0.001). In the transwell co-culture system, GPR81-mediated reprogramming of glucose metabolism in BC significantly contributed to a decreased proportion of CD8+ T (P < 0.001) and an increased percentage of FOXP3+ T (P < 0.001) in the co-cultured lymphocytes.ConclusionGlucometabolic reprogramming through a GPR81-mediated Hippo-YAP signaling pathway was responsible for the distinct immune landscape in BC. GPR81 was a potential biomarker to stratify patients before immunotherapy to improve BC’s clinical prospect.

Photobiomodulation therapy activates YAP and triggers proliferation and dedifferentiation of Müller glia in mammalian retina

Photobiomodulation therapy has been proposed as a promising therapeutic approach for retinal degenerative diseases. However, its effect on the regenerative capacity in mammalian retina and its intracellular signaling mechanisms remain unknown. Here, we showed that photobiomodulation with 670 nm light stimulates Müller glia cell cycle re-entry and dedifferentiation into a progenitor-like state in both uninjured and injured retina. We also found that 670 nm light treatment inhibits the Hippo pathway, which is activated in Müller glia following NaIO3-induced retinal injury. YAP, a major downstream effector of the Hippo signaling pathway was translocated into nucleus of Müller glia along with YAP dephosphorylation in retina treated with 670 nm light. Deficiency of YAP attenuated Müller glia cell cycle re-entry and dedifferentiation. Our data reveal the Hippo-YAP signaling pathway is associated with the photostimulatory effect on regenerative response in mammalian retina and suggest a potential therapeutic strategy for retinal degenerative diseases.

AcrAB-TolC, a major efflux pump in Gram negative bacteria: toward understanding its operation mechanism

Photobiomodulation therapy has been proposed as a promising therapeutic approach for retinal degenerative diseases. However, its effect on the regenerative capacity in mammalian retina and its intracellular signaling mechanisms remain unknown. Here, we showed that photobiomodulation with 670 nm light stimulates Müller glia cell cycle re-entry and dedifferentiation into a progenitor-like state in both uninjured and injured retina. We also found that 670 nm light treatment inhibits the Hippo pathway, which is activated in Müller glia following NaIO3-induced retinal injury. YAP, a major downstream effector of the Hippo signaling pathway was translocated into nucleus of Müller glia along with YAP dephosphorylation in retina treated with 670 nm light. Deficiency of YAP attenuated Müller glia cell cycle re-entry and dedifferentiation. Our data reveal the Hippo-YAP signaling pathway is associated with the photostimulatory effect on regenerative response in mammalian retina and suggest a potential therapeutic strategy for retinal degenerative diseases.

Hippo-YAP signaling pathway regulates autophagy of human periodontal ligament cells under cyclic tensile stress.

This work aimed to investigate the molecular mechanism of cyclic tensile stress (CTS) stimulating autophagy in human periodontal ligament cells (hPDLCs). hPDLCs were isolated and cultured from normal periodontal tissues. hPDLCs were loaded with tensile stress by force four-point bending extender to simulate the autophagy of hPDLCs induced by orthodontic force du-ring orthodontic tooth movement. XMU-MP-1 was used to inhibit the Hippo signaling pathway to explore the role of the Hippo-YAP signaling pathway in activating hPDLC autophagy by tensile stress. The expression levels of autophagy-related genes (Beclin-1, LC3, and p62) in hPDLCs were detected by real-time quantitative polymerase chain reaction. Western blot was used to detect the expression levels of autophagy-related proteins (Beclin-1, LC3-Ⅱ/LC3-Ⅰ, and p62) and Hippo-YAP pathway proteins (active-YAP and p-YAP) in hPDLCs. Immunofluorescence was used to locate autophagy-related proteins (LC3-Ⅱand p62) and Hippo-YAP pathway proteins (active-YAP) of hPDLCs. CTS-activated autophagy in hPDLCs and expression of autophagy-related proteins initially increased and then decreased; it began to increase at 30 min, peaked at 3 h, and decreased (P<0.05). CTS increased the expression of active-YAP protein and decreased the expression of p-YAP protein (P<0.05). When XMU-MP-1 inhibited the Hippo-YAP signaling pathway (P<0.05), active-YAP protein was promoted to enter the nucleus and autophagy expression was enhanced (P<0.05). The Hippo-YAP signaling pathway is involved in the regulation of autophagy activation in hPDLCs under CTS.