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Abstract Background Mesenchymal stem cells (MSCs) are widely used in a variety of tissue regeneration and clinical trials due to their multiple differentiation potency. However, it remains challenging to maintain their replicative capability during in vitro passaging while preventing their premature cellular senescence. Forkhead Box P1 (FOXP1), a FOX family transcription factor, has been revealed to regulate MSC cell fate commitment and self-renewal capacity in our previous study. Methods Mass spectra analysis was performed to identify acetylation sites in FOXP1 protein. Single and double knockout mice of FOXP1 and HDAC7 were generated and analyzed with bone marrow MSCs properties. Gene engineering in human embryonic stem cell (hESC)-derived MSCs was obtained to evaluate the impact of FOXP1 key modification on MSC self-renewal potency. Results FOXP1 is deacetylated and potentiated by histone deacetylase 7 (HDAC7) in MSCs. FOXP1 and HDAC7 cooperatively sustain bone marrow MSC self-renewal potency while attenuating their cellular senescence. A mutation within human FOXP1 at acetylation site (T176G) homologous to murine FOXP1 T172G profoundly augmented MSC expansion capacity during early passages. Conclusion These findings reveal a heretofore unanticipated mechanism by which deacetylation of FOXP1 potentiates self-renewal of MSC and protects them from cellular senescence. Acetylation of FOXP1 residue T172 as a critical modification underlying MSC proliferative capacity. We suggest that in vivo gene editing of FOXP1 may provide a novel avenue for manipulating MSC capability during large-scale expansion in clinical trials.

Beta3-adrenergic receptor (b3-AR) signaling in response to cold activates adipose tissue thermogenesis. Here the authors identify the transcription factor FoxP1 as a direct negative regulator of b3-AR expression and show that loss of FoxP1 leads to enhanced development of thermogenic adipose tissue.

The bone size and quality, acquired during adolescent growth under the influence of anabolic hormones, growth factors, and nutrients, determine the height and bone stability and forecast osteoporosis risks in late life. Yet bone size and quality control mechanisms remain enigmatic. To study the roles of mammalian target of rapamycin (mTOR) signaling, sensor of growth factors and nutrients, in bone size and quality regulation, we ablated Tsc1, a suppressor of mTOR, in mesenchymal stromal cells (MSCs), monocytes, or their progenies osteoblasts and osteoclasts. mTOR activation in MSCs, but much less in osteoblasts, increased bone width and mass due to MSC hyperproliferation, but decreased bone length and mineral contents due to defective MSC differentiation. mTOR activation promotes bone mineral accretion by inhibiting osteoclast differentiation and activity directly or via coupling with MSCs. Tuberous sclerosis complex patient studies confirmed these findings. Thus, mTOR regulates bone size via MSCs and bone quality by suppressing catabolic activities of osteoclasts.

Platelet-derived growth factors (PDGFs) play important roles in skeletal development and bone fracture healing, yet how PDGFs execute their functions remains incompletely understood. Here we show that PDGF-AA, but not -AB or -BB, could activate the BMP-Smad1/5/8 pathway in mesenchymal stem cells (MSCs), which requires BMPRIA as well as PDGFRα. PDGF-AA promotes MSC osteogenic differentiation through the BMP-Smad1/5/8-Runx2/Osx axis and MSC migration via the BMP-Smad1/5/8-Twist1/Atf4 axis. Mechanistic studies show that PDGF-AA activates BMP-Smad1/5/8 signaling by feedback down-regulating PDGFRα, which frees BMPRI and allows for BMPRI-BMPRII complex formation to activate smad1/5/8, using BMP molecules in the microenvironment. This study unravels a physical and functional interaction between PDGFRα and BMPRI, which plays an important role in MSC differentiation and migration, and establishes a link between PDGF-AA and BMPs pathways, two essential regulators of embryonic development and tissue homeostasis.

Abstract Constructing single‐atom catalysts (SACs) and optimizing the electronic structure between metal atoms and support interactions is deemed one of the most effective strategies for boosting the catalytic kinetics of the hydrogen evolution reaction (HER). Herein, a sulfur vacancy defect trapping strategy is developed to anchor tungsten single atoms onto ultrathin V3S4 nanosheets with a high loading of 25.1 wt.%. The obtained W‐V3S4 catalyst exhibits a low overpotential of 54 mV at 10 mA cm−2 and excellent long‐term stability in alkaline electrolytes. Density functional theory calculations reveal that the in situ anchoring of W single atoms triggers the delocalization and redistribution of electron density, which effectively accelerates water dissociation and facilitates hydrogen adsorption/desorption, thus enhancing HER activity. This work provides valuable insights into understanding highly active single‐atom catalysts for large‐scale hydrogen production.

Beige adipocytes have a discrete developmental origin and possess notable plasticity in their thermogenic capacity in response to various environmental cues, but the transcriptionalmachinery controlling beige adipocyte development and thermogenesis remains largely unknown. By analyzing beige adipocyte-specific knockout mice, we identified a transcription factor, forkhead box P4 (FOXP4), that differentially governs beige adipocyte differentiation and activation. Depletion of Foxp4 in progenitor cells impaired beige cell early differentiation. However, we observed that ablation of Foxp4 in differentiated adipocytes profoundly potentiated their thermogenesis capacity upon cold exposure. Of note, the outcome of Foxp4 deficiency on UCP1-mediated thermogenesiswas confined to beige adipocytes, rather than to brown adipocytes. Taken together, we suggest that FOXP4 primes beige adipocyte early differentiation, but attenuates their activation by potent transcriptional repression of the thermogenic program. [ABSTRACT FROM AUTHOR]

Urea shows promise as an alternative substrate to water oxidation in electrolyzers, and replacing OER with the Urea Oxidation Reaction (UOR, theoretical potential of 0.37 V vs. RHE) can significantly increase hydrogen production efficiency. Additionally, the decomposition of urea can help reduce environmental pollution. This paper improves the inherent activity of catalytic materials through morphology and electronic modulation by incorporating tungsten (W), which accelerates electron transfer, enhances the electronic structure of neighboring atoms to create a synergistic effect, and regulates the adsorption process of active sites and intermediates. NiCoW catalytic materials with an ultra-thin nanosheet structure were prepared using an ultrasonic-assisted NaBH4 reduction method. The results show that during the OER process, NiCoW catalytic materials have a potential of only 1.53 V at a current density of 10 mA/cm2, while the UOR process under the same conditions requires a lower potential of 1.31 V, demonstrating superior catalytic performance. In a mixed electrolyte of 1 M KOH and 0.5 M urea, overall water splitting also shows excellent performance. Therefore, the designed NiCoW electrocatalyst, with its high catalytic activity, provides valuable insights for enhancing the efficiency of water electrolysis for hydrogen production and holds practical research significance.

Abstract Background Programmed death ligand 1 (PD‐L1) has been demonstrated to facilitate tumor progression and therapeutic resistance in an immune‐independent manner. Nevertheless, the function and underlying signaling network(s) of cancer cell‐intrinsic PD‐L1 action remain largely unknown. Herein, we sought to better understand how ubiquitin‐specific peptidase 51 (USP51)/PD‐L1/integrin beta‐1 (ITGB1) signaling performs a cell‐intrinsic role in mediating chemotherapeutic resistance in non‐small cell lung cancer (NSCLC). Methods Western blotting and flow cytometry were employed for PD‐L1 detection in NSCLC cell lines. Coimmunoprecipitation and pulldown analyses, protein deubiquitination assay, tissue microarray, bioinformatic analysis and molecular biology methods were then used to determine the significance of PD‐L1 in NSCLC chemoresistance and associated signaling pathways in several different cell lines, mouse models and patient tissue samples. Ubiquitin‐7‐amido‐4‐methylcoumarin (Ub‐AMC)‐based deubiquitinase activity, cellular thermal shift and surface plasmon resonance (SPR) analyses were performed to investigate the activity of USP51 inhibitors. Results We provided evidence that cancer cell‐intrinsic PD‐L1 conferred the development of chemoresistance by directly binding to its membrane‐bound receptor ITGB1 in NSCLC. At the molecular level, PD‐L1/ITGB1 interaction subsequently activated the nuclear factor‐kappa B (NF‐κB) axis to elicit poor response to chemotherapy. We further determined USP51 as a bona fide deubiquitinase that targeted the deubiquitination and stabilization of the PD‐L1 protein in chemoresistant NSCLC cells. Clinically, we found a significant direct relationship between the USP51, PD‐L1 and ITGB1 contents in NSCLC patients with chemoresistant potency. The elevated USP51, PD‐L1 and ITGB1 levels were strongly associated with worse patient prognosis. Of note, we identified that a flavonoid compound dihydromyricetin (DHM) acted as a potential USP51 inhibitor and rendered NSCLC cells more sensitive to chemotherapy by targeting USP51‐dependent PD‐L1 ubiquitination and degradation in vitro and in vivo. Conclusions Together, our results demonstrated that the USP51/PD‐L1/ITGB1 network potentially contributes to the malignant progression and therapeutic resistance in NSCLC. This knowledge is beneficial to the future design of advanced cancer therapy.

IntroductionIn recent years, massive studies have examined sport from the standpoint of cultural capital. However, these studies have not examined cultural capital in relation to habitus within specific fields.MethodsThis article utilized a multivariate latent growth curve model to analyze changes of participants’ physical habitus. Hypotheses concerning the form of growth in physical habitus, individual perceived capital influence differences in the common trajectory over time, and covariates influencing the growth of PH were tested.ResultsSignificant linear increases existed for perceived influence from family and school, while significant linear decreases existed for perceived influence from community. The second-order alternative format of the latent growth curve model indicated that associations among individual perceived influence differences could be adequately explained by a higher order physical habitus construct. Gender, personal health condition, family socio-economic status, and weekly time spent on physical activities significantly predicted initial levels of physical habitus, whereas family social economic status significantly predicted the rate of change in physical habitus simultaneously.DiscussionThese findings not only support the participation in sport is constructed socially but also that individual efforts and contextual influences contribute to physical habitus. Furthermore, three types of perceived influences intertwined so much in simultaneity, instead of contributing to physical habitus across time.

Abstract Lung adenocarcinoma is the major subtype of lung cancer, accounting for approximately 40% of lung cancers. During clinical treatment, the emergence of chemotherapy resistance seriously affects the effectiveness of treatment. Thus, finding new chemotherapeutic sensitizers is considered to be one of the effective solutions. Biochanin A, as a naturally occurring isoflavone, has been demonstrated to exhibit anticancer effects in various tumors. However, the potential mechanisms of Biochanin A to inhibit tumor development have not been clarified. In the present study, we found that the combinational treatment of cisplatin and Biochanin A exhibited strong synergistic repression on lung adenocarcinoma growth and progression in vitro and in vivo. Considering that epithelial–mesenchymal transition (EMT) is recognized to be associated with both chemoresistance and metastasis, we examined the EMT-related markers and found that Biochanin A could specifically inhibit the expression of ZEB1. Importantly, Biochanin A chemosensitizes lung adenocarcinoma and inhibits cancer cell metastasis by suppressing ZEB1. At the molecular level, Biochanin A affects the stability of ZEB1 protein through the deubiquitination pathway and thereby influences the progression of lung adenocarcinoma. In conclusion, our finding elucidates the potential efficacy of Bichanin A as a chemosensitizer and provides new strategy for the chemotherapy of advanced lung adenocarcinoma.

Abstract In the aging process and central nervous system (CNS) diseases, the functions of the meningeal lymphatic vessels (MLVs) are impaired. Alterations in MLVs have been observed in aging-related neurodegenerative diseases, brain tumors, and even cerebrovascular disease. These findings reveal a new perspective on aging and CNS disorders and provide a promising therapeutic target. Additionally, recent neuropathological studies have shown that MLVs exchange soluble components between the cerebrospinal fluid (CSF) and interstitial fluid (ISF) and drain metabolites, cellular debris, misfolded proteins, and immune cells from the CSF into the deep cervical lymph nodes (dCLNs), directly connecting the brain with the peripheral circulation. Impairment and dysfunction of meningeal lymphatics can lead to the accumulation of toxic proteins in the brain, exacerbating the progression of neurological disorders. However, for many CNS diseases, the causal relationship between MLVs and neuropathological changes is not fully clear. Here, after a brief historical retrospection, we review recent discoveries about the hallmarks of MLVs and their roles in the aging and CNS diseases, as well as potential therapeutic targets for the treatment of neurologic diseases.

SnO2 has been extensively used in the detection of various gases. As a gas sensing material, SnO2 has excellent physical-chemical properties, high reliability, and short adsorption-desorption time. The application of the traditional SnO2 gas sensor is limited due to its higher work-temperature, low gas response, and poor selectivity. Nanomaterials can significantly impact gas-sensitive properties due to the quantum size, surface, and small size effects of nanomaterials. By applying nanotechnology to the preparation of SnO2, the SnO2 nanomaterial-based sensors could show better performance, which greatly expands the application of SnO2 gas sensors. In this review, the preparation method of the SnO2 nanostructure, the types of gas detected, and the improvements of SnO2 gas-sensing performances via elemental modification are introduced as well as the future development of SnO2 is discussed.

Abstract Aerobic glycolysis (the Warburg effect) has been demonstrated to facilitate tumor progression by producing lactate, which has important roles as a proinflammatory and immunosuppressive mediator. However, how aerobic glycolysis is directly regulated is largely unknown. Here, we show that ectopic Zeb1 directly increases the transcriptional expression of HK2, PFKP, and PKM2, which are glycolytic rate-determining enzymes, thus promoting the Warburg effect and breast cancer proliferation, migration, and chemoresistance in vitro and in vivo. In addition, Zeb1 exerts its biological effects to induce glycolytic activity in response to hypoxia via the PI3K/Akt/HIF-1α signaling axis, which contributes to fostering an immunosuppressive tumor microenvironment (TME). Mechanistically, breast cancer cells with ectopic Zeb1 expression produce lactate in the acidic tumor milieu to induce the alternatively activated (M2) macrophage phenotype through stimulation of the PKA/CREB signaling pathway. Clinically, the expression of Zeb1 is positively correlated with dysregulation of aerobic glycolysis, accumulation of M2-like tumor-associated macrophages (TAMs) and a poor prognosis in breast cancer patients. In conclusion, these findings identify a Zeb1-dependent mechanism as a driver of breast cancer progression that acts by stimulating tumor–macrophage interplay, which could be a viable therapeutic target for the treatment of advanced human cancers.

Hazardous gases have been strongly associated with being a detriment to human life within the environment. The development of a reliable gas sensor with high response and selectivity is of great significance for detecting different hazardous gases. TiO2 nanomaterials are promising candidates with great potential and excellent performance in gas sensor applications, such as hydrogen, acetone, ammonia, and ethanol detection. This review begins with a detailed discussion of the different dimensional morphologies of TiO2, which affect the gas sensing performance of TiO2 sensors. The diverse morphologies of TiO2 can easily be tuned by regulating the manufacturing conditions. Meanwhile, they exhibit unique characteristics for detecting gases, including large specific surface area, superior electron transport rates, extraordinary permeability, and active reaction sites, which offer new opportunities to improve the gas sensing properties. In addition, a variety of efforts have been made to functional TiO2 nanomaterials to further enhance sensing properties, including TiO2-based composites and light-assisted gas sensors. The enhanced gas sensing mechanisms of multi-component composite nanomaterials based on TiO2 include loaded noble metals, doped elements, constructed heterojunctions, and compounded with other functional materials. Finally, several studies have been summarized to demonstrate the comparative sensing properties of TiO2-based gas sensors.

The Dual–Vector model predictive control (DV–MPC) method can improve the steady–state control performance of motor drives compared to using the single–vector method in one switching cycle. However, this performance enhancement generally increases the computational burden due to the exponential increase in the number of vector selections, lowering the system’s dynamic response. Alternatively, limiting the vector combinations will sacrifice system steady–state performance. To address this issue, this paper proposes an enhanced DV–MPC method that can determine the optimal vector combinations along with their duration time within minimized calculation times. Compared to the existing DV–MPC methods, the proposed enhanced technique can achieve excellent steady–state performance while maintaining a low computational burden. These benefits have been demonstrated in the results from a 2.5k rpm permanent magnet synchronous motor drive.

The global objective of achieving net-zero emissions drives a significant electrified trend by replacing fuel-mechanical systems with onboard microgrid (OBMG) systems for transportation applications. Energy management strategies (EMS) for OBMG systems require complicated optimization algorithms and high computation capabilities, while traditional control techniques may not meet these requirements. Driven by the ability to achieve intelligent decision-making by exploring data, artificial intelligence (AI) and digital twins (DT) have gained much interest within the transportation sector. Currently, research on EMS for OBMGs primarily focuses on AI technology, while overlooking the DT. This article provides a comprehensive overview of both information technology, particularly elucidating the role of DT technology. The evaluation and analysis of those emerging information technologies are explicitly summarized. Moreover, this article explores potential challenges in the implementation of AI and DT technologies and subsequently offers insights into future trends.

Developing an efficient method for chloramphenicol (CAP) detection is of great significance for food safety. Arginine (Arg) was selected as a functional monomer. Benefiting from its excellent electrochemical performance, which is different from traditional functional monomers, it can be combined with CAP to form a highly selective molecularly imprinted polymer (MIP) material. It overcomes the shortcoming of poor MIP sensitivity faced by traditional functional monomers, and achieves high sensitivity detection without compounding other nanomaterials, greatly reducing the preparation difficulty and cost investment of the sensor. The possible binding sites between CAP and Arg molecules were calculated by molecular electrostatic potential (MEP). A low-cost, non-modified MIP electrochemical sensor was developed for the high-performance detection of CAP. The prepared sensor has a wide linear range from 1 × 10−12 mol L−1 to 5 × 10−4 mol L−1, achieves a very low concentration CAP detection, and the detection limit is 1.36 × 10−13 mol L−1. It also exhibits excellent selectivity, anti-interference, repeatability, and reproducibility. The detection of CAP in actual honey samples was achieved, which has important practical value in food safety.

Low spectral utilization and charge carrier compounding limit the application of photocatalysis in energy conversion and environmental purification, and the rational construction of heterojunction is a promising strategy to break this bottleneck. Herein, we prepared surface-engineered plasma Ag-modified α-Fe2O3/g-C3N4 S-Scheme heterojunction photothermal catalysts by electrostatic self-assembly and light deposition strategy. The local surface plasmon resonance effect induced by Ag nanoparticles broadens the spectral response region and produces significant photothermal effects. The temperature of Ag/α-Fe2O3/g-C3N4 powder is increased to 173 °C with irradiation for 90 s, ~3.2 times higher than that of the original g-C3N4. The formation of 2D/2D structured S-Scheme heterojunction promotes rapid electron-hole transfer and spatial separation. Ternary heterojunction construction leads to significant enhancement of photocatalytic performance of Ag/α-Fe2O3/g-C3N4, the H2 photocatalytic generation rate up to 3125.62 µmol g−1 h−1, which is eight times higher than original g-C3N4, and the photocatalytic degradation rate of tetracycline to reach 93.6%. This thermally assisted photocatalysis strategy improves the spectral utilization of conventional photocatalytic processes and provides new ideas for the practical application of photocatalysis in energy conversion and environmental purification.

The purpose of this study was to investigate whether dietary lactose supplementation relieves rotavirus (RV)-induced diarrhea and gut dysfunction. Thirty-six crossbred weaned piglets were randomly allocated into three groups and fed diets containing 0, 4%, and 6% lactose for 20 days. On Day 15, half of the piglets in each group were orally infused with RV. RV infection impaired growth performance; induced severe diarrhea; decreased serum D-xylose concentration and morphology and sIgA level of jejunal mucosa; downregulated MUC1, MUC2, occludin, Bcl-2, IL-4, pBD3, pBD2, and pBD1 mRNA expression of jejunal mucosa and/or mesenteric lymph nodes; upregulated Bax, caspase-3, IL-2, IFN-γ, and IFN-β mRNA expression of jejunal mucosa and/or mesenteric lymph nodes; and damaged microbiota and metabolites of cecal digesta in weaned piglets (p < 0.05). Dietary lactose supplementation improved nutrient digestibility and growth performance and relieved the negative influence of RV challenge on intestinal barrier function, mRNA expression of cytokines, and host defense peptides of jejunal mucosa and/or mesenteric lymph nodes in weaned piglets (p < 0.05). Dietary administration of 6% lactose tended to relieve diarrhea (p = 0.07). These results suggest that lactose in feed increases growth performance and has a tendency to alleviate RV-induced diarrhea, derived from the improvement of nutrient utilization, gut barrier function, and immunity.

The DNA damage response helps to maintain genome integrity, suppress tumorigenesis, and mediate the effects of radiotherapy and chemotherapy. Our previous studies have shown that Smad1 is upregulated and activated by Atm in DNA damage response, which can further bind to p53 and promote p53 stabilization. Here we report another aspect of the interplay between p53 and Smad1. Comparison of rectal tumor against paired paraneoplastic specimens and analysis of >500 colorectal tumors revealed that Smad1 was upregulated in tumor samples, which was attributable to p53 defects. Using MEFs as a model, we found that knockdown of the elevated Smad1 in p53 -/- MEFs promoted cell proliferation, E1A/Ras-induced cell transformation, and tumorigenesis. Mechanistic studies suggest that elevated Smad1 and momentary activation inhibit cell proliferation by upregulating p57Kip2 and enhancing Atm-Chk2 activation. Surprisingly, elevated Smad1 appears to have a negative effect on chemotherapy, as colorectal tumors, primary cancer cells, and cell lines with Smad1 knockdown all showed an increase in chemosensitivity, which could be attributable to elevated p57Kip2. These findings underscore the significance of Smad1-p53 interaction in tumor suppression and reveal an unexpected role for Smad1 in chemoresistance of colorectal cancers. [ABSTRACT FROM AUTHOR]

The connexin 43 (Cx43) hemichannel (HC) in the mechanosensory osteocytes is a major portal for the release of factors responsible for the anabolic effects of mechanical loading on bone formation and remodeling. However, little is known about how the Cx43 molecule responds to mechanical stimulation leading to the opening of the HC. Here, we demonstrate that integrin α5β1 interacts directly with Cx43 and that this interaction is required for mechanical stimulation-induced opening of the Cx43 HC. Direct mechanical perturbation via magnetic beads or conformational activation of integrin α5β1 leads to the opening of the Cx43 HC, and this role of the integrin is independent of its association with an extracellular fibronectin substrate. PI3K signaling is responsible for the shear stress-induced conformational activation of integrin α5β1 leading to the opening of the HC. These results identify an unconventional function of integrin that acts as a mechanical tether to induce opening of the HC and provide a mechanism connecting the effect of mechanical forces directly to anabolic function of the bone. [ABSTRACT FROM AUTHOR]

The article discusses research on the treatment of glucocorticoid (GC) that can induce the development of autophagy in osteocytes. The study determined the increase in the accumulation of autophagosome vacuoles in vitro and in vivo by expression of authophagy markers in the GC-induced osteoporosis of an animal model. The study indicated that autophagy inhibitor can reverse the protective effects of GC and that GCs can affect osteocytes in contrast to the manner in which GCs affect tumor necrosis factorλ(TNF-λ) which induces apoptosis.

Bone is progressively lost with advancing age. Therapies are limited and the only effective proanabolic regimen presently available to restore bone is intermittent treatment with teriparatide (parathyroid hormone 1-34). Recent evidence suggests that dietary supplementation with dried plum (DP) can prevent bone loss due to estrogen deficiency. To determine whether dietary DP supplementation can prevent the loss of bone with aging and whether bone that has already been lost can be restored, adult (6 mo) and old (18 mo) male mice were fed a normal diet or isoenergetic, isonitrogenous diets supplemented with DP (0, 15, and 25% DP by weight) for 6 mo. MicroCT analysis and bone histomorphometry were used to assess bone volume, structure, and metabolic activity before, during, and after dietary supplementation. Mice fed the 0% DP diet (control diet) lost bone, whereas both adult and old mice fed the 25% DP- supplemented diet gained bone. Adult but not old mice fed the 15% diet also gained bone. Cancellous bone volume in mice receiving 25% DP exceeded baseline levels by 40-50%. Trabecular structure varied with diet and age and responses in old mice were generally blunted. Trabecular, but not cortical, mineral density varied with age and measures of bone anabolic activity were lower in aged mice. Our findings suggest that DP contains proanabolic factors that can dramatically increase bone volume and restore bone that has already been lost due to aging. In turn, DP may provide effective prophylactic and therapeutic agents for the treatment of osteoporosis. [ABSTRACT FROM AUTHOR]

Gap junction intercellular communication in osteocytes plays an important role in bone remodeling in response to mechanical loading; however, the responsible molecular mechanisms remain largely unknown. Here, we show that phosphoinositide-3 kinase (PI3K)/Akt signaling activated by fluid flow shear stress and prostaglandin E2 (PGE2) had a stimulatory effect on both connexin 43 (Cx43) mRNA and protein expression. PGE2 inactivated glycogen synthase kinase 3 (GSK-3) and promoted nuclear localization and accumulation of β-catenin. Knockdown of β-catenin expression resulted in a reduction in Cx43 protein. Furthermore, the chromatin immunoprecipitation (ChIP) assay demonstrated an association of β-catenin with the Cx43 promoter, suggesting that β-catenin could regulate Cx43 expression at the level of gene transcription. We have previously reported that PGE2 activates cyclic AMP (cAMP)-protein kinase A (PKA) signaling and increases Cx43 and gap junctions. Interestingly, the activation of PI3K/Akt appeared to be independent of the activation of PKA, whereas both PI3K/Akt and PKA signaling inactivated GSK-3 and increased β-catenin translocation. Together, these results suggest that shear stress, through PGE2 release, activates both PI3K/Akt and cAMP-PKA signaling, which converge through the inactivation of GSK-3, leading to the increase in nuclear accumulation of β-catenin. β-Catenin binds to the Cx43 promoter, stimulating Cx43 expression and functional gap junctions between osteocytes. [ABSTRACT FROM AUTHOR]