Tartrate-resistant acid phosphatase 5 promotes pulmonary fibrosis by modulating β-catenin signaling

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Tartrate-resistant acid phosphatase 5 (ACP5) performs a variety of functions. However, its role in IPF remains unclear. Here, we demonstrate that the levels of ACP5 are increased in IPF patient samples and mice with bleomycin (BLM)-induced pulmonary fibrosis. In particular, higher levels of ACP5 are present in the sera of IPF patients with a diffusing capacity of the lungs for carbonmonoxide (DLCO) less than 40% of the predicted value. Additionally, Acp5 deficiency protects mice from BLM-induced lung injury and fibrosis coupled with a significant reduction of fibroblast differentiation and proliferation. Mechanistic studies reveal that Acp5 is upregulated by transforming growth factor-β1 (TGF-β1) in a TGF-β receptor 1 (TGFβR1)/Smad family member 3 (Smad3)-dependent manner, after which Acp5 dephosphorylates p-β-catenin at serine 33 and threonine 41, inhibiting the degradation of β-catenin and subsequently enhancing β-catenin signaling in the nucleus, which promotes the differentiation, proliferation and migration of fibroblast. More importantly, the treatment of mice with Acp5 siRNA-loaded liposomes or Acp5 inhibitor reverses established lung fibrosis. In conclusions, Acp5 is involved in the initiation and progression of pulmonary fibrosis and strategies aimed at silencing or suppressing Acp5 could be considered as potential therapeutic approaches against pulmonary fibrosis.

Fibrous Polymer-Based Composites Obtained by Electrospinning for Bone Tissue Engineering

Currently, the significantly developing fields of tissue engineering related to the fabrication of polymer-based materials that possess microenvironments suitable to provide cell attachment and promote cell differentiation and proliferation involve various materials and approaches. Biomimicking approach in tissue engineering is aimed at the development of a highly biocompatible and bioactive material that would most accurately imitate the structural features of the native extracellular matrix consisting of specially arranged fibrous constructions. For this reason, the present research is devoted to the discussion of promising fibrous materials for bone tissue regeneration obtained by electrospinning techniques. In this brief review, we focus on the recently presented natural and synthetic polymers, as well as their combinations with each other and with bioactive inorganic incorporations in order to form composite electrospun scaffolds. The application of several electrospinning techniques in relation to a number of polymers is touched upon. Additionally, the efficiency of nanofibrous composite materials intended for use in bone tissue engineering is discussed based on biological activity and physiochemical characteristics.

BMSCs and Pectin-Based E2-Loaded Microcapsules with Injectable Pectin-Pluronic® F-127 Scaffolds for Mouse Endometrial Regeneration Application

Background Uterine endometrium is a highly dynamic tissue which consists of a basal layer and a functional layer. Bone marrow-derived mesenchymal stem cells (BMSCs) have been recognized as new candidates for the treatment of serious endometrial injuries. However, due to the local microenvironment of damaged endometrium, transplantation of BMSCs yielded disappointing results with respect to survival, attachment, differentiation, and proliferation. Methods Pectin-Pluronic® F-127 scaffolds were fabricated. E2 was encapsulated into the W/O/W microspheres to construct pectin-based E2-loaded microcapsules (E2 MPs). The BMSCs/E2 MPs/scaffolds system was then injected into the uterine cavity of mouse endometrial injury model. Furthermore, the mechanism of E2 in promoting the repair of endometrial injury was also investigated. Result Pectin-Pluronic® F-127 scaffolds could provide three-dimensional architecture for the attachment, growth, and migration of BMSCs. E2 MPs has the potential to serve as a long-term reliable source of E2 for endometrial regeneration. At four weeks after transplantation, it was demonstrated that the system increased proliferative abilities of uterine endometrial cells, facilitated microvasculature regeneration, and restored the ability of endometrium to receive an embryo, suggesting that the BMSCs/E2 MPs/scaffolds system is a promising treatment option for endometrial regeneration. Exosomes are critical paracrine mediators that act as biochemical cues to direct stem cell differentiation. In this study, it was found that the expression of endometrial epithelial cells (EECs) markers was up-regulated in BMSCs treated by exosomes secreted from endometrial stromal cells (ESCs-Exos). Exosomes derived from E2-stimulated ESCs further promoted the expression level of EECs markers in BMSCs, suggesting exosomes released from ESCs by E2 stimulation could enhance the differentiation efficiency of BMSCs. Conclusion The BMSCs/E2 MPs/scaffolds therapeutic strategy may be beneficial in the treatment of severely damaged endometrium. Exosomes derived from ESCs play paracrine roles in endometrial regeneration stimulated by E2, potentially modulating the differentiation of BMSCs.

Relationship between 25(OH)D and Colorectal Cancer Prevalence at Dr. Moewardi Hospital Surakarta-Indonesia: A Cross-Sectional Study

Background: Colorectal cancer is a malignancy of the colon and / or rectum. Vitamin D has a role as an inhibitor of tumor progression, namely through the process of influencing cellular differentiation and proliferation. (VDR) Vitamin D Receptor affects cell differentiation by upregulating brush boundary enzymes and improving morphological microvilli. This study seeks to determine the relationship between 25(OH)D levels and colorectal cancer in dr. Moewardi Hospital, Surakarta, Indonesia. Methods: A cross-sectional design study with quantitative-analytical observation was conducted. All patients had symptoms of colorectal cancer, either undiagnosed or previously diagnosed. 25(OH)D samples were taken from a total of 50 patients at dr. Moewardi Surakarta and subsequent diagnostic measures from the results of histopathology were assessed. The parameters assessed were 25(OH)D level and a diagnosis of colorectal malignancy. Statistical analysis of 25(OH)D levels and colorectal diagnosis using the Chi Square test. Results: The prevalence of colorectal cancer is higher in respondents with 25(OH)D deficiency and insufficiency compared to respondents with normal 25(OH)D concentrations who tend to have non-colorectal cancer. Based on the Chi-Square test result, the significance value was 0.004, marking a statistically significant association. Conclusion: This study shows a significant relationship between deficiency and insufficiency of 25(OH)D concentrations with the occurrence of colorectal malignancy

Metformin Inhibits Mitochondrial Complex I To Promote Health

The major function of mitochondria in cellular homeostasis has been the generation of ATP through oxidative phosphorylation. However, we have previously demonstrated that mitochondria can serve as signaling organelles by releasing low levels of reactive oxygen species (ROS) and TCA cycle metabolites that are essential for hypoxic activation of HIF, antigen activation of T cells, cellular differentiation and proliferation of cancer cells. The anti-diabetic drug metformin has been proposed to inhibit mitochondrial complex I. We will present data indicating that metformin inhibits mitochondrial complex I to exert it’s biological effects through controlling ROS, ATP, and NAD+.

Identification of a new regulation pathway of EGFR and E-cadherin dynamics

E-cadherin and EGFR are known to be closely associated hence regulating differentiation and proliferation notably in epithelia. We have previously shown that galectin-7 binds to E-cadherin and favors its retention at the plasma membrane. In this study, we shed in light that galectin-7 establishes a physical link between E-cadherin and EGFR. Indeed, our results demonstrate that galectin-7 also binds to EGFR, but unlike the binding to E-cadherin this binding is sugar dependent. The establishment of E-cadherin/EGFR complex and the binding of galectin-7 to EGFR thus lead to a regulation of its signaling and intracellular trafficking allowing cell proliferation and migration control. In vivo observations further support these results since an epidermal thickening is observed in galectin-7 deficient mice. This study therefore reveals that galectin-7 controls epidermal homeostasis through the regulation of E-cadherin/EGFR balance.

IFNγ suppresses the expression of GFI1 and thereby inhibits Th2 cell proliferation

While IFNγ is a well-known cytokine that actively promotes the type I immune response, it is also known to suppress the type II response by inhibiting the differentiation and proliferation of Th2 cells. However, the mechanism by which IFNγ suppresses Th2 cell proliferation is still not fully understood. We found that IFNγ decreases the expression of growth factor independent-1 transcriptional repressor (GFI1) in Th2 cells, resulting in the inhibition of Th2 cell proliferation. The deletion of the Gfi1 gene in Th2 cells results in the failure of their proliferation, accompanied by an impaired cell cycle progression. In contrast, the enforced expression of GFI1 restores the defective Th2 cell proliferation, even in the presence of IFNγ. These results demonstrate that GFI1 is a key molecule in the IFNγ-mediated inhibition of Th2 cell proliferation.

Osteoblast-specific inactivation of p53 results in locally increased bone formation

Inactivation of the tumor suppressor p53 (encoded by the Trp53 gene) is relevant for development and growth of different cancers, including osteosarcoma, a primary bone tumor mostly affecting children and young adolescents. We have previously shown that deficiency of the ribosomal S6 kinase 2 (Rsk2) limits osteosarcoma growth in a transgenic mouse model overexpressing the proto-oncogene c-Fos. Our initial aim for the present study was to address the question, if Rsk2 deficiency would also influence osteosarcoma growth in another mouse model. For that purpose, we took advantage of Trp53fl/fl mice, which were crossed with Runx2Cre transgenic mice in order to inactivate p53 specifically in osteoblast lineage cells. However, since we unexpectedly identified Runx2Cre-mediated recombination also in the thymus, the majority of 6-month-old Trp53fl/fl;Runx2-Cre (thereafter termed Trp53Cre) animals displayed thymic lymphomas, similar to what has been described for Trp53-deficient mice. Since we did not detect osteosarcoma formation at that age, we could not follow our initial aim, but we studied the skeletal phenotype of Trp53Cre mice, with or without additional Rsk2 deficiency. Here we unexpectedly observed that Trp53Cre mice display a unique accumulation of trabecular bone in the midshaft region of the femur and the humerus, consistent with its previously established role as a negative regulator of osteoblastogenesis. Since this local bone mass increase in Trp53Cre mice was significantly reduced by Rsk2 deficiency, we isolated bone marrow cells from the different groups of mice and analyzed their behavior ex vivo. Here we observed a remarkable increase of colony formation, osteogenic differentiation and proliferation in Trp53Cre cultures, which was unaffected by Rsk2 deficiency. Our data thereby confirm a critical and tumorigenesis-independent function of p53 as a key regulator of mesenchymal cell differentiation.