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Genes Apr 2023Mammalian preimplantation development depends on the interaction between embryonic autocrine and maternal paracrine signaling. Despite the robust independence of...
Mammalian preimplantation development depends on the interaction between embryonic autocrine and maternal paracrine signaling. Despite the robust independence of preimplantation embryos, oviductal factors are thought to be critical to pregnancy success. However, how oviductal factors regulate embryonic development and the underlying mechanism remain unknown. In the present study, focusing on WNT signaling, which has been reported to be essential for developmental reprogramming after fertilization, we analyzed the receptor-ligand repertoire of preimplantation embryonic WNT signaling, and identified that the WNT co-receptor LRP6 is necessary for early cleavage and has a prolonged effect on preimplantation development. LRP6 inhibition significantly impeded zygotic genome activation and disrupted relevant epigenetic reprogramming. Focusing on the potential oviductal WNT ligands, we found WNT2 as the candidate interacting with embryonic LRP6. More importantly, we found that WNT2 supplementation in culture medium significantly promoted zygotic genome activation (ZGA) and improved blastocyst formation and quality following in vitro fertilization (IVF). In addition, WNT2 supplementation significantly improved implantation rate and pregnancy outcomes following embryo transfer. Collectively, our findings not only provide novel insight into how maternal factors regulate preimplantation development through maternal-embryonic communication, but they also propose a promising strategy for improving current IVF systems.
Topics: Pregnancy; Humans; Animals; Female; Ligands; Embryonic Development; Zygote; Embryo Implantation; Oviducts; Mammals; Wnt2 Protein; Low Density Lipoprotein Receptor-Related Protein-6
PubMed: 37107647
DOI: 10.3390/genes14040891 -
Cell Death & Disease Apr 2023Galectin-3 is a galactoside-binding protein that is commonly overexpressed in many epithelial cancers. It is increasingly recognized as a multi-functional, multi-mode...
Galectin-3 is a galactoside-binding protein that is commonly overexpressed in many epithelial cancers. It is increasingly recognized as a multi-functional, multi-mode promoter in cancer development, progression, and metastasis. This study reports that galectin-3 secretion by human colon cancer cells induces cancer cell secretion, in an autocrine/paracrine manner, of a number of proteases including cathepsin-B, MMP-1 and MMP-13. The secretion of these proteases causes disruption of epithelial monolayer integrity, increases its permeability and promotes tumour cell invasion. This effect of galectin-3 is shown to be mediated through induction of cellular PYK2-GSK3α/β signalling and can be prevented by the presence of galectin-3 binding inhibitors. This study thus reveals an important mechanism in galectin-3-mediated promotion of cancer progression and metastasis. It provides further evidence to the increased realization of galectin-3 as a potential therapeutic target for the treatment of cancer.
Topics: Humans; Galectin 3; Peptide Hydrolases; Colonic Neoplasms; Epithelium
PubMed: 37055381
DOI: 10.1038/s41419-023-05789-x -
BioRxiv : the Preprint Server For... Jan 2023Brain metastasis is a dismal cancer complication, hinging on the initial survival and outgrowth of disseminated cancer cells. To understand these crucial early stages of...
Brain metastasis is a dismal cancer complication, hinging on the initial survival and outgrowth of disseminated cancer cells. To understand these crucial early stages of colonization, we investigated two prevalent sources of cerebral relapse, triple-negative (TNBC) and HER2+ breast cancer (HER2BC). We show that these tumor types colonize the brain aggressively, yet with distinct tumor architectures, stromal interfaces, and autocrine growth programs. TNBC forms perivascular sheaths with diffusive contact with astrocytes and microglia. In contrast, HER2BC forms compact spheroids prompted by autonomous extracellular matrix components and segregating stromal cells to their periphery. Single-cell transcriptomic dissection reveals canonical Alzheimer's disease-associated microglia (DAM) responses. Differential engagement of tumor-DAM signaling through the receptor AXL suggests specific pro-metastatic functions of the tumor architecture in both TNBC perivascular and HER2BC spheroidal colonies. The distinct spatial features of these two highly efficient modes of brain colonization have relevance for leveraging the stroma to treat brain metastasis.
PubMed: 37034672
DOI: 10.1101/2023.01.27.525190 -
Frontiers in Endocrinology 2023With increasing life expectancy, the related disorders of bone loss, metabolic dysregulation and sarcopenia have become major health threats to the elderly. Each of... (Review)
Review
With increasing life expectancy, the related disorders of bone loss, metabolic dysregulation and sarcopenia have become major health threats to the elderly. Each of these conditions is prevalent in patients with chronic kidney disease (CKD), particularly in more advanced stages. Our current understanding of the bone-muscle interaction is beyond mechanical coupling, where bone and muscle have been identified as interrelated secretory organs, and regulation of both bone and muscle metabolism occurs through osteokines and myokines autocrine, paracrine and endocrine systems. This review appraises the current knowledge regarding biochemical crosstalk between bone and muscle, and considers recent progress related to the role of osteokines and myokines in CKD, including modulatory effects of physical exercise and potential therapeutic targets to improve musculoskeletal health in CKD patients.
Topics: Humans; Aged; Muscle, Skeletal; Sarcopenia; Bone and Bones; Cell Physiological Phenomena; Bone Diseases, Metabolic
PubMed: 37033253
DOI: 10.3389/fendo.2023.1146868 -
British Journal of Pharmacology Sep 2023In animal models of sepsis, increased activation of the Nociceptin/Orphanin FQ (N/OFQ) receptor NOP is associated with mortality and NOP antagonists improved survival....
BACKGROUND AND PURPOSE
In animal models of sepsis, increased activation of the Nociceptin/Orphanin FQ (N/OFQ) receptor NOP is associated with mortality and NOP antagonists improved survival. We have explored the role of the N/OFQ-NOP system in freshly isolated volunteer human B- and T-cells incubated with lipopolysaccharide (LPS) and peptidoglycan G (PepG) as a model of in vitro sepsis.
EXPERIMENTAL APPROACH
B- and T-cell NOP expression was measured using the NOP fluorescent probe N/OFQ , N/OFQ content was measured using immunofluorescence, N/OFQ release was tracked using a CHO biosensor assay and NOP function was measured using transwell migration and cytokine/chemokine release using a 25-plex assay format. Cells were challenged with LPS/PepG.
KEY RESULTS
CD19-positive B-cells bound N/OFQ ; they also contain N/OFQ. Stimulation with CXCL13/IL-4 increased N/OFQ release. N/OFQ trended to reduced migration to CXCL13/IL-4. Surface NOP expression was unaffected by LPS/PepG, but this treatment increased GM-CSF release in an N/OFQ sensitive manner. CD3-positive T-cells did not bind N/OFQ ; they did contain N/OFQ. Stimulation with CXCL12/IL-6 increased N/OFQ release. When incubated with LPS/PepG, NOP surface expression was induced leading to N/OFQ binding. In LPS/PepG-treated cells, N/OFQ reduced migration to CXCL12/IL-6. LPS/PepG increased GM-CSF release in an N/OFQ sensitive manner.
CONCLUSIONS AND IMPLICATIONS
We suggest both a constitutive and sepsis-inducible N/OFQ-NOP receptor autocrine regulation of B- and T-cell function, respectively. These NOP receptors variably inhibit migration and reduce GM-CSF release. These data provide mechanistic insights to the detrimental role for increased N/OFQ signalling in sepsis and suggest a potential role for NOP antagonists as treatments.
Topics: Animals; Humans; Receptors, Opioid; Nociceptin Receptor; Granulocyte-Macrophage Colony-Stimulating Factor; Lipopolysaccharides; Interleukin-4; Interleukin-6; Opioid Peptides; Sepsis; Nociceptin
PubMed: 37021779
DOI: 10.1111/bph.16088 -
Frontiers in Cellular Neuroscience 2023Vitamin D (VD) is a potent para/autocrine regulator and neurosteroid that can strongly influence nerve cell function and counteract the negative effects of...
INTRODUCTION
Vitamin D (VD) is a potent para/autocrine regulator and neurosteroid that can strongly influence nerve cell function and counteract the negative effects of glucocorticoid (GC) therapy. The aim of the study was to reveal the relationship between VD status and behavioral, structural-functional and molecular changes associated with GC-induced neurotoxicity.
METHODS
Female Wistar rats received synthetic GC prednisolone (5 mg/kg b.w.) with or without VD (1000 IU/kg b.w.) for 30 days. Behavioral, histological, physiological, biochemical, molecular biological (RT-PCR, Western blotting) methods, and ELISA were used.
RESULTS AND DISCUSSION
There was no difference in open field test (OFT), while forced swim test (FST) showed an increase in immobility time and a decrease in active behavior in prednisolone-treated rats, indicative of depressive changes. GC increased the perikaryon area, enlarged the size of the nuclei, and caused a slight reduction of cell density in CA1-CA3 hippocampal sections. We established a GC-induced decrease in the long-term potentiation (LTP) in CA1-CA3 hippocampal synapses, the amplitude of high K-stimulated exocytosis, and the rate of Ca-dependent fusion of synaptic vesicles with synaptic plasma membranes. These changes were accompanied by an increase in nitration and poly(ADP)-ribosylation of cerebral proteins, suggesting the development of oxidative-nitrosative stress. Prednisolone upregulated the expression and phosphorylation of NF-κB p65 subunit at Ser311, whereas downregulating IκB. GC loading depleted the circulating pool of 25OHD in serum and CSF, elevated VDR mRNA and protein levels but had an inhibitory effect on CYP24A1 and VDBP expression. Vitamin D supplementation had an antidepressant-like effect, decreasing the immobility time and stimulating active behavior. VD caused a decrease in the size of the perikaryon and nucleus in CA1 hippocampal area. We found a recovery in depolarization-induced fusion of synaptic vesicles and long-term synaptic plasticity after VD treatment. VD diminished the intensity of oxidative-nitrosative stress, and suppressed the NF-κB activation. Its ameliorative effect on GC-induced neuroanatomical and behavioral abnormalities was accompanied by the 25OHD3 repletion and partial restoration of the VD-auto/paracrine system.
CONCLUSION
GC-induced neurotoxicity and behavioral disturbances are associated with increased oxidative-nitrosative stress and impairments of VD metabolism. Thus, VD can be effective in preventing structural and functional abnormalities in the brain and behavior changes caused by long-term GC administration.
PubMed: 37020845
DOI: 10.3389/fncel.2023.1133400 -
Cell Death & Disease Apr 2023Female subfertility is an increasing reproductive issue worldwide, which is partially related to abnormal ovarian follicular development. Granulosa cells (GCs), by...
Female subfertility is an increasing reproductive issue worldwide, which is partially related to abnormal ovarian follicular development. Granulosa cells (GCs), by providing the necessary physical support and microenvironment for follicular development, play critical roles in maintaining female fertility. We previously showed that ectopic expression of four and a half LIM domains 2 (FHL2) promoted ovarian granulosa cell tumor progression. However, its function in follicular development and fertility remains unknown. Here, we confirmed that FHL2 is highly expressed in human and mouse ovaries. FHL2 immunosignals were predominantly expressed in ovarian GCs. A Fhl2 knockout (KO) mouse model was generated to examine its roles in follicular development and fertility. Compared with wildtype, knockout of Fhl2 significantly decreased female litter size and offspring number. Furthermore, Fhl2 deficiency reduced ovarian size and impaired follicular development. RNA-sequencing analysis of GCs isolated from either KO or WT mice revealed that, Fhl2 deletion impaired multiple biological functions and signaling pathways, such as Ovarian Putative Early Atresia Granulosa Cell, ErbB, Hippo/YAP, etc. In vitro studies confirmed that FHL2 silencing suppressed GCs growth and EGF-induced GCs proliferation, while its overexpression promoted GC proliferation and decreased apoptosis. Mechanistic studies indicated that FHL2, via forming complexes with transcriptional factors AP-1 or NF-κB, regulated Egf and Egfr expression, respectively. Besides, FHL2 depletion decreased YAP1 expression, especially the active form of YAP1 (nuclear YAP1) in GCs of growing follicles. EGF, serving as an autocrine/paracrine factor, not only induced FHL2 expression and nuclear accumulation, but also stimulated YAP1 expression and activation. Collectively, our study suggests that FHL2 interacts with EGFR and Hippo/YAP signaling to regulate follicular development and maintain fertility. This study illuminates a novel mechanism for follicular development and a potential therapeutic target to address subfertility.
Topics: Female; Humans; Mice; Animals; Epidermal Growth Factor; Granulosa Cells; ErbB Receptors; Transcription Factor AP-1; Fertility; Muscle Proteins; Transcription Factors; LIM-Homeodomain Proteins
PubMed: 37015904
DOI: 10.1038/s41419-023-05759-3 -
The Journal of Physiology May 2023During recent years chemosensory cells in extraoral tissues have been established as mediators for the detection and regulation of innate immune processes in response to... (Review)
Review
During recent years chemosensory cells in extraoral tissues have been established as mediators for the detection and regulation of innate immune processes in response to pathogens. Under physiological conditions, chemosensory cells are present throughout the respiratory epithelium of the upper and lower airways as well as in the main olfactory epithelium. Additionally, they emerge in the alveolar region of the lung upon viral infections. Chemosensory cells in the upper and the lower airways detect signalling molecules from gram-positive and gram-negative bacteria as well as aeroallergens and fungi. Upon stimulation they release multiple molecules, such as the transmitter acetylcholine, the cysteinyl leukotriene E4 and the cytokine interleukin-25, which act as autocrine and paracrine signals and thereby orchestrate the innate immune responses in the respiratory system. Activation of chemosensory cells stimulates various immune cells, e.g. type 2 innate lymphoid cells, modulates mucociliary clearance and induces a protective neurogenic inflammation. This review compiles and discusses recent findings regarding chemosensory cell function in the respiratory tract.
Topics: Immunity, Innate; Anti-Bacterial Agents; Gram-Negative Bacteria; Gram-Positive Bacteria; Lymphocytes; Respiratory Mucosa
PubMed: 37009787
DOI: 10.1113/JP282307 -
Biomedicine & Pharmacotherapy =... May 2023Numerous cancers express platelet-derived growth factors (PDGFs) and PDGF receptors (PDGFRs). By directly stimulating tumour cells in an autocrine manner or by... (Review)
Review
Numerous cancers express platelet-derived growth factors (PDGFs) and PDGF receptors (PDGFRs). By directly stimulating tumour cells in an autocrine manner or by stimulating tumour stromal cells in a paracrine manner, the platelet-derived growth factor (PDGF)/platelet-derived growth factor receptor (PDGFR) pathway is crucial in the growth and spread of several cancers. To combat hypoxia in the tumour microenvironment, it encourages angiogenesis. A growing body of experimental data shows that PDGFs target malignant cells, vascular cells, and stromal cells to modulate tumour growth, metastasis, and the tumour microenvironment. To combat medication resistance and enhance patient outcomes in cancers, targeting the PDGF/PDGFR pathway is a viable therapeutic approach. There have been reports of anomalies in the PDGF pathway, including the gain of function point mutations, activating chromosomal translocations, or overexpression or amplification of PDGF receptors (PDGFRs). As a result, it has been shown that targeting the PDGF/PDGFR signaling pathway is an effective method for treating cancer. As a result, this study will concentrate on the regulation of the PDGF/PDGFR signaling system, in particular the current methods and inhibitors used in cancer treatment, as well as the associated therapeutic advantages and side effects.
Topics: Humans; Platelet-Derived Growth Factor; Neoplasms; Receptors, Platelet-Derived Growth Factor; Signal Transduction; Tumor Microenvironment
PubMed: 37002577
DOI: 10.1016/j.biopha.2023.114491 -
PloS One 2023Axl, a member of the TAM receptor family has been broadly suggested to play a key role in tumor metastasis. However, the function of Axl in the invasion and metastasis...
Axl, a member of the TAM receptor family has been broadly suggested to play a key role in tumor metastasis. However, the function of Axl in the invasion and metastasis of melanoma, the most lethal skin cancer, remains largely unknown. In the present study, we found that melanoma cell lines present variable protein levels of Axl and Tyro3; interestingly, MerTK is not noted at detectable levels in any of tested MGP (metastatic growth phase) cell lines. Treatment with recombinant human Gas6 significantly activates Akt in the Axl-expressing WM852 and IgR3 lines but just slightly in WM1158. IgR3, WM852 and WM1158 demonstrate different autocrine signaling. Knockdown of Axl by siRNA or the treatment with Axl-specific inhibitor R428 dramatically inhibits the migration and invasion of both IgR3 and WM852 in vitro. These findings suggest that Axl enhances the invasion of melanoma cells.
Topics: Cell Line, Tumor; Melanoma; Skin Neoplasms; Humans; Axl Receptor Tyrosine Kinase; Neoplasm Invasiveness; Recombinant Proteins; Receptor Protein-Tyrosine Kinases; c-Mer Tyrosine Kinase; Signal Transduction; Phosphorylation
PubMed: 36989239
DOI: 10.1371/journal.pone.0283749