• Akkermansia muciniphila
• Crohn’s disease
• IL-6
• STAT3
• colitis

• 2023YFS0279 Sichuan Province Science and Technology Support Program

• ER stress
• extracellular CIRP
• hepatectomy
• intracellular CIRP
• liver regeneration

• Animals
• STAT3 Transcription Factor/metabolism
• Liver Regeneration/physiology
• Hepatectomy
• Signal Transduction
• Humans
• Hep G2 Cells
• Mice
• RNA-Binding Proteins/metabolism
• RNA-Binding Proteins/genetics
• Cell Proliferation
• Male
• Mice, Inbred C57BL
• Endoplasmic Reticulum Stress
• Liver/metabolism
• Oxidative Stress

• HIES
• Mendelian disorders
• atopic dermatitis
• elevated serum IgE
• genetic etiology
• immune signaling
• primary immunodeficiency disorders
• recurrent infections

• Humans
• Job Syndrome/genetics
• Job Syndrome/immunology
• Job Syndrome/diagnosis
• Immunoglobulin E/immunology
• Immunoglobulin E/blood
• Genetic Predisposition to Disease
• Mutation
• Animals

• disease model
• ulcerative colitis

• Colitis, Ulcerative/metabolism
• Colitis, Ulcerative/pathology
• Colitis, Ulcerative/chemically induced
• Colitis, Ulcerative/genetics
• Animals
• STAT3 Transcription Factor/metabolism
• Humans
• Ubiquitin Thiolesterase/metabolism
• Ubiquitin Thiolesterase/genetics
• Mice
• Mice, Knockout
• Mice, Inbred C57BL
• Male
• Ubiquitination
• Dextran Sulfate
• Phosphorylation
• Proteolysis
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/pathology

• 81870392 National Natural Science Foundation of China (National Science Foundation of China)

• ARG1
• Acute lung injury
• Fibroblast Growth Factor 10
• Macrophage

• 8200087, 81900007, 81270132 National Natural Science Foundation of China
• 8200087, 81900007, 81270132 National Natural Science Foundation of China
• 20204Y0082 Scientific Research Project of Shanghai Municipal Health Committee Project
• SHXH201838 Shanghai Xuhui District Science Committee Project
• JLY20180016, JLY20180124 Clinical Medicine Foundation of Jiangsu University

• Autoimmune disease
• JAK/STAT signaling
• T cell
• cancer
• dendritic cell

• Humans
• Dendritic Cells/immunology
• Dendritic Cells/metabolism
• Signal Transduction/immunology
• STAT Transcription Factors/metabolism
• Animals
• Immunotherapy/methods
• Neoplasms/immunology
• Neoplasms/therapy
• Neoplasms/metabolism
• Cell Differentiation/immunology
• Antigen Presentation/immunology
• Molecular Targeted Therapy
• Autoimmune Diseases/immunology
• Autoimmune Diseases/therapy
• Autoimmune Diseases/metabolism

• Animal models
• Cytokines
• Granulocyte colony-stimulating factor
• Innate immunity
• Macrophage
• Neutrophil
• STAT3
• Zebrafish

• Animals
• Zebrafish
• STAT3 Transcription Factor/metabolism
• STAT3 Transcription Factor/genetics
• Hematopoiesis/genetics
• Zebrafish Proteins/genetics
• Zebrafish Proteins/metabolism
• Humans
• Myeloid Cells/immunology
• Myeloid Cells/metabolism
• Neutrophils/immunology
• Signal Transduction
• CRISPR-Cas Systems
• Granulocyte Colony-Stimulating Factor/metabolism
• Granulocyte Colony-Stimulating Factor/genetics
• Gene Editing
• Lipopolysaccharides
• Hematopoietic Stem Cells

• inflammatory bowel diseases (IBDs)
• myeloid cells
• neutrophils
• suppressors of cytokine signaling (SOCS)
• ulcerative colitis (uc)

• National Institutes of Health

• DNA damage
• IFN signaling
• STAT3
• cell cycle
• hematopoietic stem cell

• S10 RR029552 NCRR NIH HHS
• R35 CA197566 NCI NIH HHS
• S10 OD024977 NIH HHS
• R01 AI133822 NIAID NIH HHS
• R56 AI109294 NIAID NIH HHS

• INFLAMMATORY OSTEOLYSIS
• MITOPHAGY
• NLRP3 INFLAMMASOME
• STAT3

• BBB
• STAT3
• cerebral ischemia
• endothelial cell

• Animals
• Mice
• Nitric Oxide/metabolism
• Acetylcholine/metabolism
• Brain Ischemia/metabolism
• Blood-Brain Barrier/metabolism
• Infarction, Middle Cerebral Artery/metabolism
• Glucose/metabolism
• Oxygen/metabolism
• Brain Injuries/metabolism

• R01 NS108501 NINDS NIH HHS
• R56 NS108501 NINDS NIH HHS
• NS108501 NIH HHS

• Dendritic cells ⋅ Mouse models ⋅ Transgenic mice ⋅ cre-loxP ⋅ Intersectional genetics

Neutrophils are key pathogen exterminators of the innate immune system endowed with oxidative and non-oxidative defense mechanisms. More recently, a more complex role for neutrophils as decision shaping cells that instruct other leukocytes to fine-tune innate and adaptive immune responses has come into view. Under homeostatic conditions, neutrophils are short-lived cells that are continuously released from the bone marrow. Their development starts with undifferentiated hematopoietic stem cells that pass through different immature subtypes to eventually become fully equipped, mature neutrophils capable of launching fast and robust immune responses. During severe (systemic) inflammation, there is an increased need for neutrophils. The hematopoietic system rapidly adapts to this increased demand by switching from steady-state blood cell production to emergency granulopoiesis. During emergency granulopoiesis, the de novo production of neutrophils by the bone marrow and at extramedullary sites is augmented, while additional mature neutrophils are rapidly released from the marginated pools. Although neutrophils are indispensable for host protection against microorganisms, excessive activation causes tissue damage in neutrophil-rich diseases. Therefore, tight regulation of neutrophil homeostasis is imperative. In this review, we discuss the kinetics of neutrophil ontogenesis in homeostatic conditions and during emergency myelopoiesis and provide an overview of the different molecular players involved in this regulation. We substantiate this review with the example of an autoinflammatory disease, i.e. systemic juvenile idiopathic arthritis.

• cytokines
• emergency granulopoiesis
• inflammation
• left shift
• neutrophil
• systemic juvenile idiopathic arthritis

The key target and regulatory mechanism of electroacupuncture of Zusanli (ST36) on extensor longus muscle injury in a jumping rat model were investigated. To this end, 24 female SD rats were randomly divided into the following four groups: no-treatment control group (NON), 6-week jumping group (J6O), electroacupuncture group after 6-week jumping (J6A), and natural recovery group after 6-week jumping (J6N). After 6 weeks of jumping, in the electroacupuncture group (J6A), electroacupuncture stimulation was applied at Zusanli(ST36) for 20 min per day over the course of 5 days. In the natural recovery group (J6N), rats were fastened with a special apparatus without electroacupuncture stimulation for 20 min at the same time. Transmission electron microscopy, transcriptome sequencing and analysis, Western blotting assay and immunofluorescence staining were performed at the end of our experiment. The recovery effect of J6A rats was more obvious than that of J6N rats and J6O rats as indicated by changes of infiltration of inflammatory cells and morphological structure. Notably, the morphological structure of J6A rats was closer to NON rats in the observation of transmission electron microscopy. CISH/STAT3 regulation was identified by mRNA-seq. The pro-inflammatory response to STAT3 activation was alleviated through up-regulating the expression of CISH protein in J6A rats relative to J6O rats. The level of BAX was decreased and the level of Bcl-2 level was increased in J6A rats relative to J6O rats. Moreover, when compared to J6N rats, the level of Bcl-2 was significantly up-regulated in J6A rats. Increased caspase-3 expression but decreased CDKN2α expression was shown in J6A rats relative to NON rats. These results indicate that the potential mechanism underlying electroacupuncture stimulation of Zusanli (ST36) in repairing the injured extensor digitorum longus following overused jumping may be attributed to CISH/STAT3 regulation of proteins associated with inflammation, apoptosis, and proliferation.

• cytokine-inducible SH2 containing protein (CISH)
• electroacupuncture stimulation
• inflammation
• longitudinal jump training
• transcriptomic

Hematopoiesis is the production of blood cells from hematopoietic stem cells (HSCs) that reside in the bone marrow. Cyclophosphamide (CTX) is a chemotherapy drug that suppresses the immune system. Korean Red Ginseng (KRG) and Colla corii asini (CCA) have been traditionally used for boosting the immune system.

HSCs in the bone marrow, and immune cell subtype in splenocytes, PBMCs, and thymocytes were investigated. Serum levels of hematopoietic-related markers were analyzed using ELISA. Protein expression in spleen tissue was analyzed using western blot analysis. Hematoxylin & eosin staining in the femurs of mice were also conducted.

The combination of KRG and CCA with a ratio of 3:2 increased HSCs, CD3 and CD8⁺ T cells in the circulation, and CD3 T cells in the spleen. A ratio of 2:3 (KRG:CCA) increased the thymic regulatory T cells and recovered the CD3 T cells in the spleen and circulation while recovering proteins in the JAK-STAT pathway in the spleen. Overall, blood cell population and differentiating factors vital for cell differentiation were also significantly recovered by all combinations especially in ratios of 3:2 and 2:3.

A ratio of 3:2 (KRG:CCA) is the most ideal combination as it recovered the HSC population in the bone marrow of mice.

• Colla corii asini
• Panax ginseng
• cyclophosphamide
• hematopoiesis
• immunosuppression

Vascular permeability triggered by inflammation or ischemia promotes edema, exacerbates disease progression and impairs tissue recovery. Vascular endothelial growth factor (VEGF) is a potent inducer of vascular permeability. VEGF plays an integral role in regulating vascular barrier function physiologically and in pathologies, including cancer, stroke, cardiovascular disease, retinal conditions and COVID-19-associated pulmonary edema, sepsis and acute lung injury. Understanding temporal molecular regulation of VEGF-induced vascular permeability will facilitate developing therapeutics to inhibit vascular permeability, while preserving tissue-restorative angiogenesis. Here, we demonstrate that VEGF signals through signal transducer and activator of transcription 3 (STAT3) to promote vascular permeability. We show that genetic STAT3 ablation reduces vascular permeability in STAT3-deficient endothelium of mice and VEGF-inducible zebrafish crossed with CRISPR/Cas9-generated Stat3 knockout zebrafish. Intercellular adhesion molecule 1 (ICAM-1) expression is transcriptionally regulated by STAT3, and VEGF-dependent STAT3 activation is regulated by JAK2. Pyrimethamine, an FDA-approved antimicrobial agent that inhibits STAT3-dependent transcription, substantially reduces VEGF-induced vascular permeability in zebrafish, mouse and human endothelium. Collectively, our findings suggest that VEGF/VEGFR-2/JAK2/STAT3 signaling regulates vascular barrier integrity, and inhibition of STAT3-dependent activity reduces VEGF-induced vascular permeability.

This article has an associated First Person interview with the first author of the paper.

Summary: Genetic STAT3 ablation in mice and VEGF-inducible zebrafish reveals that VEGF signals through STAT3 to promote vascular permeability. Pyrimethamine reduces VEGF-induced permeability in animal models.

• COVID-19
• Pyrimethamine
• STAT3
• VEGF
• Vascular permeability
• Zebrafish

Heritability accounts for over 80% of adult human height, indicating that genetic variability is the main determinant of stature. The rapid technological development of Next-Generation Sequencing (NGS), particularly Whole Exome Sequencing (WES), has resulted in the characterization of several genetic conditions affecting growth and development. The greatest challenge of NGS remains the high number of candidate variants identified. In silico bioinformatic tools represent the first approach for classifying these variants. However, solving the complicated problem of variant interpretation requires the use of experimental approaches such as in vitro and, when needed, in vivo functional assays. In this review, we will discuss a rational approach to apply to the gene variants identified in children with growth and developmental defects including: (i) bioinformatic tools; (ii) in silico modeling tools; (iii) in vitro functional assays; and (iv) the development of in vivo models. While bioinformatic tools are useful for a preliminary selection of potentially pathogenic variants, in vitro—and sometimes also in vivo—functional assays are further required to unequivocally determine the pathogenicity of a novel genetic variant. This long, time-consuming, and expensive process is the only scientifically proven method to determine causality between a genetic variant and a human genetic disease.

• GH-IGF axis
• bioinformatics
• functional assays
• growth and development
• next-generation sequencing
• short stature

• Job syndrome
• Sost
• Stat3
• Wnt/beta-catenin signaling
• bone development

• Alleles
• Animals
• Bone and Bones/pathology
• Cartilage/pathology
• Cell Differentiation
• Embryo, Mammalian/pathology
• Extremities/pathology
• Gene Deletion
• Humans
• Integrases/metabolism
• Job Syndrome/metabolism
• Job Syndrome/pathology
• Low Density Lipoprotein Receptor-Related Protein-5/metabolism
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cells/pathology
• Mesoderm/embryology
• Mice, Transgenic
• Osteoblasts/pathology
• Osteogenesis
• STAT3 Transcription Factor/deficiency
• Wnt Signaling Pathway

• R01 AR070877 NIAMS NIH HHS
• R01 CA222571 NCI NIH HHS
• R01 DE025866 NIDCR NIH HHS

Protein inhibitors of activated STAT (PIAS) are involved in the regulation of the JAK/STAT signaling pathway and have interactions with NF-κB, p73 and p53. These proteins regulate immune responses; therefore dysregulation in their expression leads to several immune-mediated disorders. In the present study, we examined expression of PIAS1-4 in peripheral blood of patients with acute/chronic inflammatory demyelinating polyradiculoneuropathy (AIDP/CIDP) compared with healthy subjects. We demonstrated down-regulation of all PIAS genes in both AIDP and CIDP cases compared with controls. Similarly, comparisons in gender-based groups revealed down-regulation of these gene0s in patients of each gender compared with gender-matched controls. There was no significant difference in expression of PIAS genes between AIDP and CIDP cases. Based on the area under the receiver operating characteristic curves, PIAS1-4 genes could distinguish between inflammatory demyelinating polyradiculoneuropathy and healthy status with accuracy values of 0.87, 0.87, 0.79 and 0.80, respectively. In differentiation between AIDP cases and healthy controls, these values were 0.92, 0.92, 0.83 and 0.86, respectively. Finally, PIAS1-4 genes could discriminate CIDP from healthy status with accuracy values of 0.82, 0.83, 0.75 and 0.75, respectively. The current study underscores the role of PIAS genes in the pathogenesis of inflammatory demyelinating polyradiculoneuropathy and their potential usage as biomarkers.

• AIDP
• CIDP
• PIAS
• inflammatory demyelinating polyradiculoneuropathy
• protein inhibitor of activated STAT

• Colitis-associated colorectal cancer
• Dysplasia
• Inflammation
• Inflammatory bowel disease
• Tumorigenesis

JAK/STAT signaling pathway is involved in many diseases, including autoimmune diseases, which are characterized by a close interconnection between immune and bone system. JAK/STAT pathway is involved in bone homeostasis and plays an important role in proliferation and differentiation of some cell types, including osteoblasts and osteoclasts. Different molecules, such as cytokines, hormones, and growth factors are responsible for the activation of the JAK/STAT pathway, which leads, at the nuclear level, to start DNA transcription of target genes. Bone cells and remodeling process are often influenced by many cytokines, which act as strong stimulators of bone formation and resorption. Our aim, through careful research in literature, has been to provide an overview of the role of the JAK/STAT pathway in bone remodeling and on bone cells, with a focus on cytokines involved in bone turnover through this signal cascade. The JAK/STAT pathway, through the signal cascade activation mediated by the interaction with many cytokines, acts on bone cells and appears to be involved in bone remodeling process. However, many other studies are needed to completely understand the molecular mechanism underlying these bone process.

• Bone
• Cytokine
• JAK/STAT pathway
• Osteoblast
• Osteoclast

• Akt
• COX-2
• NF-κB
• STAT3
• TLR4
• iNOS
• inflammation
• macrophages

• bronchopulmonary dysplasia
• hyperoxia
• inflammation
• lipopolysaccharide
• pulmonary hypertension

• Janus Kinase
• Key-words: inflammatory bowel disease
• efficacy
• safety
• selectivity

Bone growth and the maintenance of bone structure are controlled by multiple endocrine and paracrine factors, including cytokines expressed locally within the bone microenvironment and those that are elevated, both locally and systemically, under inflammatory conditions. This review focuses on those bone-active cytokines that initiate JAK–STAT signaling, and outlines the discoveries made from studying skeletal defects caused by induced or spontaneous modifications in this pathway. Specifically, this review describes defects in JAK1, STAT3, and SOCS3 signaling in mouse models and in humans, including mutations designed to modify these pathways downstream of the gp130 coreceptor. It is shown that osteoclast formation is generally stimulated indirectly by these pathways through JAK1 and STAT3 actions in inflammatory and other accessory cells, including osteoblasts. In addition, in bone remodeling, osteoblast differentiation is increased secondary to stimulated osteoclast formation through an IL-6-dependent pathway. In growth plate chondrocytes, STAT3 signaling promotes the normal differentiation process that leads to bone lengthening. Within the osteoblast lineage, STAT3 signaling promotes bone formation in normal physiology and in response to mechanical loading through direct signaling in osteocytes. This activity, particularly that of the IL-6/gp130 family of cytokines, must be suppressed by SOCS3 for the normal formation of cortical bone.

Maintaining normal bone structure and strength depends on a group of signaling proteins called cytokines that bind to receptor molecules on cell surfaces. Natalie Sims at St. Vincent’s Institute of Medical Research and The University of Melbourne in Australia reviews the role of cytokines in a specific signaling pathway in bone development and disease. Two of the proteins in this pathway respond to cytokine activity, whereas the third inhibits the cytokines’ effects. Studies in mice and humans have identified links between specific bone defects and spontaneous or experimentally induced mutations in the genes that code for the three proteins. The review covers the significance of recent findings to several types of cells that form new bone, degrade bone as part of normal bone turnover, and sustain the structure of bone and cartilage.

• CD163
• antibody-drug conjugate
• cancer
• glucocorticoid
• inflammation
• macrophage
• targeting

• Antigens, CD/genetics
• Antigens, Differentiation, Myelomonocytic/genetics
• Humans
• Inflammation/genetics
• Inflammation/pathology
• Inflammation/therapy
• Macrophages/metabolism
• Macrophages/pathology
• Molecular Targeted Therapy
• Neoplasms/genetics
• Neoplasms/pathology
• Neoplasms/therapy
• Receptors, Cell Surface/genetics
• Tumor Microenvironment/genetics

• DNRF141 Danmarks Grundforskningsfond
• NNF14OC0011537 Novo Nordisk Fonden
• 7017-00126B Det Frie Forskningsråd
• NNF20OC0062163 Novo Nordisk Fonden

• Crohn’s disease
• Inflammatory bowel disease
• JAK/STAT inhibition
• JAK/STAT pathway
• Janus kinase
• Signal transducer and activator of transcription
• Tofacitinib
• Ulcerative colitis

• Colitis, Ulcerative/drug therapy
• Crohn Disease/drug therapy
• Humans
• Janus Kinase Inhibitors/pharmacology
• Janus Kinase Inhibitors/therapeutic use
• Janus Kinases
• Transducers

• C1EIP
• ENO1
• Notch signal
• chicken PGCs
• germ cell differentiation

The proliferation and differentiation of neural progenitor lay the foundation for brain development. In neural progenitors, activation of Signal Transducer and Activator of Transcription 3 (STAT3) has been found to promote proliferation and astrocytogenesis while suppressing neurogenesis. However, our study found that Stat3 conditional knockout in neural progenitors (Stat3 cKO) also results in increased proliferation and suppressed neurogenesis. To investigate how STAT3 regulates these processes, we attempted to identify potential STAT3 target genes by RNA-seq profiling of the control (CTL) and Stat3 cKO neural progenitors. We found that STAT3 promotes the expression of genes involved in the mitochondrial oxidative phosphorylation (OXPHOS), and thereby promotes mitochondrial respiration and negatively regulates reactive oxygen species (ROS) production. In addition, we demonstrated that Stat3 loss-of-function promotes proliferation via regulation of mitochondrial metabolism and downstream signaling pathways. Our study provides novel insights into the relation between STAT3, mitochondrial metabolism and the process of embryonic neurogenesis.

• OXPHOS
• STAT3
• mitochondria
• neural progenitor
• neurogenesis
• proliferation

• Animals
• Basic-Leucine Zipper Transcription Factors/genetics
• Basic-Leucine Zipper Transcription Factors/metabolism
• Carbon Tetrachloride/toxicity
• Cell Cycle/genetics
• Gene Deletion
• Gene Expression Regulation
• Hepatocytes/drug effects
• Hepatocytes/physiology
• Liver/drug effects
• Liver/injuries
• Liver/physiology
• Liver Regeneration/genetics
• Metabolic Networks and Pathways
• Mice
• Mice, Knockout
• STAT3 Transcription Factor/genetics

• Animals
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Clinical Trials, Phase II as Topic
• Fibrosis/drug therapy
• Fibrosis/metabolism
• Humans
• Inflammation/drug therapy
• Inflammation/metabolism
• Janus Kinases/antagonists & inhibitors
• Janus Kinases/genetics
• Janus Kinases/metabolism
• Molecular Targeted Therapy
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Phosphorylation
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• STAT3 Transcription Factor/antagonists & inhibitors
• STAT3 Transcription Factor/genetics
• STAT3 Transcription Factor/metabolism

• P50 CA221707 NCI NIH HHS

Epidemiological investigations have shown that smoking ameliorates ulcerative colitis (UC) but exacerbates Crohn's disease (CD), diseases that feature a Th2-mediated and Th1-mediated response, respectively. Cigarette extracts, especially nicotine, affect the Th1/Th2 balance. We previously reported that nicotine protects against mouse DSS colitis (similar to UC) by enhancing microRNA-124 (miR-124) expression. Intriguingly, elevation of miR-124 in CD is reported to aggravate the disease. Here we investigate the dual regulation of miR-124 in inflammatory bowel diseases (IBDs), which may explain the similar bidirectional regulation of tobacco. We found that overexpressed miR-124 protected against mouse DSS-induced colitis with a Th1 polarization in peripheral blood lymphocytes and colon tissues, which was also found in human peripheral blood lymphocytes. Conversely, miR-124 knockdown worsened DSS murine colitis with a Th2 polarization. Moreover, knockdown of miR-124 could eliminate the polarization toward Th1 after nicotine treatment, suggesting that miR-124 mediates the effect of nicotine on the Th1/Th2 balance. In addition, interference of IL-6R, which is a downstream target of miR-124, could remarkably weaken the Th1 polarization induced by miR-124. Taken together, these results suggest that nicotine shifts the balance of Th1/Th2 toward Th1 via a miR-124-mediated IL-6R pathway, which might explain its dual role in IBDs.

• Crohn's disease
• IL-6R
• Th1/Th2 balance
• miR-124
• nicotine
• ulcerative colitis

Patients with gastrointestinal diseases frequently suffer from skeletal abnormality, characterized by reduced bone mineral density, increased fracture risk, and/or joint inflammation. This pathological process is characterized by altered immune cell activity and elevated inflammatory cytokines in the bone marrow microenvironment due to disrupted gut immune response. Gastrointestinal disease is recognized as an immune malfunction driven by multiple factors, including cytokines and signaling molecules. However, the mechanism by which intestinal inflammation magnified by gut-residing actors stimulates bone loss remains to be elucidated. In this article, we discuss the main risk factors potentially contributing to intestinal disease-associated bone loss, and summarize current animal models, illustrating gut-bone axis to bridge the gap between intestinal inflammation and skeletal disease.

• animal models
• bone loss
• gut inflammation
• mucosal immunity
• osteoclasts
• risk factors

Hypoxia in the vicinity of bone defects triggers the osteogenic differentiation of precursor cells and promotes healing. The activation of STAT3 signaling in mesenchymal stem cells (MSCs) has similarly been reported to mediate bone regeneration. However, the interaction between hypoxia and STAT3 signaling in the osteogenic differentiation of precursor cells during bone defect healing is still unknown.

In this study, we assessed the impact of different durations of CoCl₂-induced cellular hypoxia on the osteogenic differentiation of MSCs. Role of STAT3 signaling on hypoxia induced osteogenic differentiation was analyzed both in vitro and in vivo. The interaction between cellular hypoxia and STAT3 signaling in vivo was investigated in a mouse femoral bone defect model.

The peak osteogenic differentiation and expression of vascular endothelial growth factor (VEGF) occurred after 3 days of hypoxia. Inhibiting STAT3 reversed this effect. Hypoxia enhanced the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and STAT3 phosphorylation in MSCs. Histology and μ-CT results showed that CoCl₂ treatment enhanced bone defect healing. Inhibiting STAT3 reduced this effect. Immunohistochemistry results showed that CoCl₂ treatment enhanced Hif-1α, ALP and pSTAT3 expression in cells present in the bone defect area and that inhibiting STAT3 reduced this effect.

The in vitro study revealed that the duration of hypoxia is crucial for osteogenic differentiation of precursor cells. The results from both the in vitro and in vivo studies show the role of STAT3 signaling in hypoxia-induced osteogenic differentiation of precursor cells and bone defect healing.

• Bone defect healing
• Cellular hypoxia
• Mesenchymal stem cells, STAT3-signaling
• Osteogenic differentiation

• Long non-coding RNA
• Multiple sclerosis
• STAT3
• THRIL
• lnc-DC

In spite of the latest therapeutic developments, no effective treatments for handling critical conditions such as acute lung injuries have yet been found. Such conditions, which may result from lung infections, sepsis, multiple trauma, or shock, represent a significant challenge in intensive care medicine. Seeking ways to better deal with this challenge, the scientific community has recently devoted much attention to small molecules derived from natural products with anti-inflammatory and immunomodulatory effects.

In this context, we investigated the anti-inflammatory effect of Rubiadin-1-methyl ether isolated from Pentas schimperi, using an in vitro model of RAW 264.7 macrophages induced by LPS and an in vivo model of acute lung injury (ALI) induced by LPS.

The macrophages were pretreated with the compound and induced by LPS (1 μg/mL). After 24 h, using the supernatant, we evaluated the cytotoxicity, NOx, and IL-6, IL-1β, and TNF-α levels, as well as the effect of the compound on macrophage apoptosis. Next, the compound was administered in mice with acute lung injury (ALI) induced by LPS (5 mg/kg), and the pro- and anti-inflammatory parameters were analyzed after 12 h using the bronchoalveolar lavage fluid (BALF).

Rubiadin-1-methyl ether was able to inhibit the pro-inflammatory parameters studied in the in vitro assays (NOx, IL-6, and IL-1β) and, at the same time, increased the macrophage apoptosis rate. In the in vivo experiments, this compound was capable of decreasing leukocyte infiltration; fluid leakage; NOx; IL-6, IL-12p70, IFN-γ, TNF-α, and MCP-1 levels; and MPO activity. In addition, Rubiadin-1-methyl ether increased the IL-10 levels in the bronchoalveolar lavage fluid (BALF).

These findings support the evidence that Rubiadin-1-methyl ether has important anti-inflammatory activity, with evidence of an immunomodulatory effect.

• ACDMPV
• FOXF1 transcription factor
• STAT3
• alveolar capillary dysplasia with misalignment of pulmonary veins
• neonatal pulmonary angiogenesis

• Animals
• Forkhead Transcription Factors/genetics
• Gene Expression Regulation
• Humans
• Mice
• Models, Animal
• Mutation
• Persistent Fetal Circulation Syndrome/genetics
• Persistent Fetal Circulation Syndrome/physiopathology
• Pulmonary Alveoli/abnormalities
• Pulmonary Alveoli/physiopathology
• Signal Transduction/genetics

• R01 HL152973 NHLBI NIH HHS
• U01 HL148856 NHLBI NIH HHS
• R01 HL132849 NHLBI NIH HHS
• R01 HL084151 NHLBI NIH HHS
• R01 HL123490 NHLBI NIH HHS
• R01 HL137203 NHLBI NIH HHS
• R01 HL141174 NHLBI NIH HHS

• Cre/loxP
• bacterial artificial chromosome
• embryonic stem cells
• gene targeting
• liver steatosis
• recombineering

• P29222 Austrian Science Fund
• P 25599 Austrian Science Fund
• P 25925 Austrian Science Fund FWF
• P 25599 Austrian Science Fund FWF
• P25925 Austrian Science Fund
• P26908 Austrian Science Fund

• ATP
• Bone formation
• Mechanotransduction
• Osteocyte
• ROS
• Signal transducers and activators of transcription 3 (Stat3)