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Life (Basel, Switzerland) Aug 2022Insulin-like growth factors (IGFs) are peptides which exert mitogenic, endocrine and cytokine activities. Together with their receptors, binding proteins and associated... (Review)
Review
Insulin-like growth factors (IGFs) are peptides which exert mitogenic, endocrine and cytokine activities. Together with their receptors, binding proteins and associated molecules, they participate in numerous pathophysiological processes, including cancer development. Colorectal cancer (CRC) is a disease with high incidence and mortality rates worldwide, whose etiology usually represents a combination of the environmental and genetic factors. IGFs are most often increased in CRC, enabling excessive autocrine/paracrine stimulation of the cell growth. Overexpression or increased activation/accessibility of IGF receptors is a coinciding step which transmits IGF-related signals. A number of molecules and biochemical mechanisms exert modulatory effects shaping the final outcome of the IGF-stimulated processes, frequently leading to neoplastic transformation in the case of irreparable disbalance. The IGF system and related molecules and pathways which participate in the development of CRC are the focus of this review.
PubMed: 36013453
DOI: 10.3390/life12081274 -
International Journal of Molecular... Dec 2023Steroid hormone production via the adrenal cortex, gonads, and placenta (so-called glandular steroidogenesis) is responsible for the endocrine control of the body's... (Review)
Review
Steroid hormone production via the adrenal cortex, gonads, and placenta (so-called glandular steroidogenesis) is responsible for the endocrine control of the body's homeostasis and is organized by a feedback regulatory mechanism based on the hypothalamus-pituitary-steroidogenic gland axis. On the other hand, recently discovered extraglandular steroidogenesis occurring locally in different tissues is instead linked to paracrine or autocrine signaling, and it is independent of the control by the hypothalamus and pituitary glands. Bone cells, such as bone-forming osteoblasts, osteoblast-derived osteocytes, and bone-resorbing osteoclasts, respond to steroid hormones produced by both glandular and extraglandular steroidogenesis. Recently, new techniques to identify steroid hormones, as well as synthetic steroids and steroidogenesis inhibitors, have been introduced, which greatly empowered steroid hormone research. Based on recent literature and new advances in the field, here we review the local role of steroid hormones in regulating bone homeostasis and skeletal lesion formation. The novel idea of extraglandular steroidogenesis occurring within the skeletal system raises the possibility of the development of new therapies for the treatment of bone diseases.
Topics: Pregnancy; Female; Humans; Steroids; Adrenal Cortex Hormones; Gonads; Adrenal Cortex; Bone and Bones
PubMed: 38139309
DOI: 10.3390/ijms242417482 -
Aging Mar 2023Sarcopenia is progressive loss of muscle mass and strength, occurring during normal aging with significant consequences on the quality of life for elderly. Neurotrophin...
Sarcopenia is progressive loss of muscle mass and strength, occurring during normal aging with significant consequences on the quality of life for elderly. Neurotrophin 3 (NT-3) is an important autocrine factor supporting Schwann cell survival and differentiation and stimulating axon regeneration and myelination. NT-3 is involved in the maintenance of neuromuscular junction (NMJ) integrity, restoration of impaired radial growth of muscle fibers through activation of the Akt/mTOR pathway. We tested the efficacy of NT-3 gene transfer therapy in wild type (WT)-aged C57BL/6 mice, a model for natural aging and sarcopenia, via intramuscular injection 1 × 1011 vg AAV1.tMCK.NT-3, at 18 months of age. The treatment efficacy was assessed at 6 months post-injection using run to exhaustion and rotarod tests, muscle contractility assay, and histopathological studies of the peripheral nervous system, including NMJ connectivity and muscle. AAV1.NT-3 gene therapy in WT-aged C57BL/6 mice resulted in functional and muscle physiology improvements, supported by quantitative histology from muscle, peripheral nerves and NMJ. Hindlimb and forelimb muscles in the untreated cohort showed the presence of a muscle- and sex-dependent remodeling and fiber size decrease with aging, which was normalized toward values obtained from 10 months old WT mice with treatment. The molecular studies assessing the NT-3 effect on the oxidative state of distal hindlimb muscles, accompanied by western blot analyses for mTORC1 activation were in accordance with the histological findings. Considering the cost and quality of life to the individual, we believe our study has important implications for management of age-related sarcopenia.
Topics: Mice; Animals; Sarcopenia; Muscle, Skeletal; Axons; Quality of Life; Mice, Inbred C57BL; Nerve Regeneration; Aging; Genetic Therapy
PubMed: 36897179
DOI: 10.18632/aging.204577 -
Proceedings of the National Academy of... Jan 2022Immune cells infiltrate the peripheral nervous system (PNS) after injury and with autoimmunity, but their net effect is divergent. After injury, immune cells are...
Immune cells infiltrate the peripheral nervous system (PNS) after injury and with autoimmunity, but their net effect is divergent. After injury, immune cells are reparative, while in inflammatory neuropathies (e.g., Guillain Barré Syndrome and chronic inflammatory demyelinating polyneuropathy), immune cells are proinflammatory and promote autoimmune demyelination. An understanding of immune cell phenotypes that distinguish these conditions may, therefore, reveal new therapeutic targets for switching immune cells from an inflammatory role to a reparative state. In an autoimmune regulator (Aire)-deficient mouse model of inflammatory neuropathy, we used single-cell RNA sequencing of sciatic nerves to discover a transcriptionally heterogeneous cellular landscape, including multiple myeloid, innate lymphoid, and lymphoid cell types. Analysis of cell-cell ligand-receptor interactions uncovered a macrophage-mediated tumor necrosis factor-α (TNF-α) signaling axis that is induced by interferon-γ and required for initiation of autoimmune demyelination. Developmental trajectory visualization suggested that TNF-α signaling is associated with metabolic reprogramming of macrophages and polarization of macrophages from a reparative state in injury to a pathogenic, inflammatory state in autoimmunity. Autocrine TNF-α signaling induced macrophage expression of multiple genes (, , , and ) important in immune cell activation and recruitment. Genetic and antibody-based blockade of TNF-α/TNF-α signaling ameliorated clinical neuropathy, peripheral nerve infiltration, and demyelination, which provides preclinical evidence that the TNF-α axis may be effectively targeted to resolve inflammatory neuropathies.
Topics: Adoptive Transfer; Animals; Antibodies, Monoclonal; Autocrine Communication; Biomarkers; Cytokines; Disease Models, Animal; Disease Susceptibility; Gene Expression Profiling; Inflammation Mediators; Macrophages; Mice; Mice, Transgenic; Neuroinflammatory Diseases; Paracrine Communication; Peripheral Nervous System Diseases; Polyendocrinopathies, Autoimmune; Receptors, Tumor Necrosis Factor; Sciatic Nerve; Signal Transduction; Tumor Necrosis Factor-alpha
PubMed: 35058362
DOI: 10.1073/pnas.2114406119 -
Proceedings of the National Academy of... Feb 2021Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to...
Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I-dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I-expressing tumors by reinvigorated CD8 CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had "epigenetically down-regulated," but had not permanently lost MHC-I AgPP activity.
Topics: Animals; Antigen Presentation; Antineoplastic Agents; Apoptosis; B7-H1 Antigen; Biomarkers, Tumor; CD8-Positive T-Lymphocytes; Cell Proliferation; Drug Therapy, Combination; Gene Expression Regulation, Neoplastic; Histocompatibility Antigens Class I; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Mice; NF-kappa B; Neoplasms; Oxaliplatin; Prognosis; Survival Rate; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; p300-CBP Transcription Factors
PubMed: 33602823
DOI: 10.1073/pnas.2025840118 -
Journal of Cellular and Molecular... Sep 2020There are many different types of cardiovascular diseases, which impose a huge economic burden due to their extremely high mortality rates, so it is necessary to explore... (Review)
Review
There are many different types of cardiovascular diseases, which impose a huge economic burden due to their extremely high mortality rates, so it is necessary to explore the underlying mechanisms to achieve better supportive and curative care outcomes. Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator with paracrine and autocrine activities that acts through its cell surface S1P receptors (S1PRs) and intracellular signals. In the circulatory system, S1P is indispensable for both normal and disease conditions; however, there are very different views on its diverse roles, and its specific relevance to cardiovascular pathogenesis remains elusive. Here, we review the synthesis, release and functions of S1P, specifically detail the roles of S1P and S1PRs in some common cardiovascular diseases, and then address several controversial points, finally, we focus on the development of S1P-based therapeutic approaches in cardiovascular diseases, such as the selective S1PR1 modulator amiselimod (MT-1303) and the non-selective S1PR1 and S1PR3 agonist fingolimod, which may provide valuable insights into potential therapeutic strategies for cardiovascular diseases.
Topics: Animals; Cardiovascular Diseases; Humans; Lysophospholipids; Models, Biological; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors
PubMed: 32803879
DOI: 10.1111/jcmm.15744 -
Entropy (Basel, Switzerland) Jan 2023Early embryonic development involves forming all specialized cells from a fluid-like mass of identical stem cells. The differentiation process consists of a series of...
Early embryonic development involves forming all specialized cells from a fluid-like mass of identical stem cells. The differentiation process consists of a series of symmetry-breaking events, starting from a high-symmetry state (stem cells) to a low-symmetry state (specialized cells). This scenario closely resembles phase transitions in statistical mechanics. To theoretically study this hypothesis, we model embryonic stem cell (ESC) populations through a coupled Boolean network (BN) model. The interaction is applied using a multilayer Ising model that considers paracrine and autocrine signaling, along with external interventions. It is demonstrated that cell-to-cell variability can be interpreted as a mixture of steady-state probability distributions. Simulations have revealed that such models can undergo a series of first- and second-order phase transitions as a function of the system parameters that describe gene expression noise and interaction strengths. These phase transitions result in spontaneous symmetry-breaking events that generate new types of cells characterized by various steady-state distributions. Coupled BNs have also been shown to self-organize in states that allow spontaneous cell differentiation.
PubMed: 36832602
DOI: 10.3390/e25020235 -
Journal of Hematology & Oncology Oct 2022Metastatic prostate cancer (PC) is a leading cause of cancer death in men worldwide. Targeting of the culprits of disease progression is an unmet need. Interleukin...
BACKGROUND
Metastatic prostate cancer (PC) is a leading cause of cancer death in men worldwide. Targeting of the culprits of disease progression is an unmet need. Interleukin (IL)-30 promotes PC onset and development, but whether it can be a suitable therapeutic target remains to be investigated. Here, we shed light on the relationship between IL30 and canonical PC driver genes and explored the anti-tumor potential of CRISPR/Cas9-mediated deletion of IL30.
METHODS
PC cell production of, and response to, IL30 was tested by flow cytometry, immunoelectron microscopy, invasion and migration assays and PCR arrays. Syngeneic and xenograft models were used to investigate the effects of IL30, and its deletion by CRISPR/Cas9 genome editing, on tumor growth. Bioinformatics of transcriptional data and immunopathology of PC samples were used to assess the translational value of the experimental findings.
RESULTS
Human membrane-bound IL30 promoted PC cell proliferation, invasion and migration in association with STAT1/STAT3 phosphorylation, similarly to its murine, but secreted, counterpart. Both human and murine IL30 regulated PC driver and immunity genes and shared the upregulation of oncogenes, BCL2 and NFKB1, immunoregulatory mediators, IL1A, TNF, TLR4, PTGS2, PD-L1, STAT3, and chemokine receptors, CCR2, CCR4, CXCR5. In human PC cells, IL30 improved the release of IGF1 and CXCL5, which mediated, via autocrine loops, its potent proliferative effect. Deletion of IL30 dramatically downregulated BCL2, NFKB1, STAT3, IGF1 and CXCL5, whereas tumor suppressors, primarily SOCS3, were upregulated. Syngeneic and xenograft PC models demonstrated IL30's ability to boost cancer proliferation, vascularization and myeloid-derived cell infiltration, which were hindered, along with tumor growth and metastasis, by IL30 deletion, with improved host survival. RNA-Seq data from the PanCancer collection and immunohistochemistry of high-grade locally advanced PCs demonstrated an inverse association (chi-squared test, p = 0.0242) between IL30 and SOCS3 expression and a longer progression-free survival of patients with IL30SOCS3PC, when compared to patients with IL30SOCS3PC.
CONCLUSIONS
Membrane-anchored IL30 expressed by human PC cells shares a tumor progression programs with its murine homolog and, via juxtacrine signals, steers a complex network of PC driver and immunity genes promoting prostate oncogenesis. The efficacy of CRISPR/Cas9-mediated targeting of IL30 in curbing PC progression paves the way for its clinical use.
Topics: Animals; B7-H1 Antigen; CRISPR-Cas Systems; Cell Line, Tumor; Cell Proliferation; Chemokine CXCL5; Cyclooxygenase 2; Humans; Insulin-Like Growth Factor I; Interleukins; Male; Mice; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Receptors, Chemokine; Suppressor of Cytokine Signaling 3 Protein; Toll-Like Receptor 4
PubMed: 36224639
DOI: 10.1186/s13045-022-01357-6 -
Molecular Nutrition & Food Research Feb 2020Lipoxins (LXs) are autacoids, specialized proresolving lipid mediators (SPMs) acting locally in a paracrine or autocrine fashion. They belong to a complex superfamily of... (Review)
Review
Lipoxins (LXs) are autacoids, specialized proresolving lipid mediators (SPMs) acting locally in a paracrine or autocrine fashion. They belong to a complex superfamily of dietary small polyunsaturated fatty acid (PUFA)-metabolites, which direct potent cellular responses to resolve inflammation and restore tissue homeostasis. Together, these SPM activities have been intensely studied in systemic inflammation and acute injury or infection, but less is known about LX signaling and activities in the central nervous system. LXs are derived from arachidonic acid, an omega-6 PUFA. In addition to well-established roles in systemic inflammation resolution, they have increasingly become implicated in regulating neuroinflammatory and neurodegenerative processes. In particular, chronic inflammation plays a central role in Alzheimer's disease (AD) etiology, and dysregulated LX production and activities have been reported in a variety of AD rodent models and clinical tissue samples, yet with complex and sometimes conflicting results. In addition, reduced LX production following retinal injury has been reported recently by the authors, and an intriguing direct neuronal activity promoting survival and homeostasis in retinal and cortical neurons is demonstrated. Here, the authors review and clarify this growing literature and suggest new research directions to further elaborate the role of lipoxins in neurodegeneration.
Topics: Animals; Humans; Inflammation; Lipoxins; Neurodegenerative Diseases; Neurons; Protein-Lysine 6-Oxidase
PubMed: 31797529
DOI: 10.1002/mnfr.201801076 -
Frontiers in Molecular Neuroscience 2022Since the discovery of STING in 2008, numerous studies have investigated its functions in immunity, inflammation, and cancer. STING activates downstream molecules... (Review)
Review
Since the discovery of STING in 2008, numerous studies have investigated its functions in immunity, inflammation, and cancer. STING activates downstream molecules including IFN-I, NLRP3, and NF-κB. The STING-IFN-I pathway plays a vital role in nociception. After receiving the upstream signal, STING is activated and induces the expression of IFN-I, and after paracrine and autocrine signaling, IFN-I binds to IFN receptors. Subsequently, the activity of ion channels is inhibited by TYK2, which induces an acute antinociceptive effect. JAK activates PIK3 and MAPK-MNK-eIF4E pathways, which sensitize nociceptors in the peripheral nervous system. In the mid-late stage, the STING-IFN-I pathway activates STAT, increases pro-inflammatory and anti-inflammatory cytokines, inhibits ER-phagy, and promotes microglial M1-polarization in the central nervous system, leading to central sensitization. Thus, the STING-IFN-I pathway may exert complex effects on nociception at various stages, and these effects require further comprehensive elucidation. Therefore, in this review, we systematically summarized the mechanisms of the STING-IFN-I pathway and discussed its function in nociception.
PubMed: 36683857
DOI: 10.3389/fnmol.2022.1081288