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Frontiers in Psychology 2023Oxytocin supports reproduction by promoting sexual- and nursing behavior. Moreover, it stimulates reproductive organs by different avenues. Oxytocin is released to the... (Review)
Review
Oxytocin supports reproduction by promoting sexual- and nursing behavior. Moreover, it stimulates reproductive organs by different avenues. Oxytocin is released to the blood from terminals of oxytocinergic neurons which project from the hypothalamus to the pituitary gland. Concomitantly, the dendrites of these neurons discharge oxytocin into neighboring areas of the hypothalamus. At this location it affects other neuroendocrine systems by autocrine and paracrine mechanisms. Moreover, sensory processing, affective functions, and reward circuits are influenced by oxytocinergic neurons that reach different sites in the brain. In addition to its facilitating impact on various aspects of reproduction, oxytocin is revealed to possess significant anti-inflammatory, restoring, and tranquilizing properties. This has been demonstrated both in many and studies. The oxytocin system may therefore have the capacity to alleviate detrimental physiological- and mental stress reactions. Thus, high levels of endogenous oxytocin may counteract inadequate inflammation and malfunctioning of neurons and supportive cells in the brain. A persistent low-grade inflammation increasing with age-referred to as inflammaging-may lead to a cognitive decline but may also predispose to neurodegenerative diseases such as Alzheimer's and Parkinson. Interestingly, animal studies indicate that age-related destructive processes in the body can be postponed by techniques that preserve immune- and stem cell functions in the hypothalamus. It is argued in this article that sexual activity-by its stimulating impact on the oxytocinergic activity in many regions of the brain-has the capacity to delay the onset of age-related cerebral decay. This may also postpone frailty and age-associated diseases in the body. Finally, oxytocin possesses neuroplastic properties that may be applied to expand sexual reward. The release of oxytocin may therefore be further potentiated by learning processes that involves oxytocin itself. It may therefore be profitable to raise the consciousness about the potential health benefits of sexual activity particularly among the seniors.
PubMed: 38222845
DOI: 10.3389/fpsyg.2023.1250745 -
GeroScience Jan 2024Ascites plays a key role in supporting the metastatic potential of ovarian cancer cells. Shear stress and carry-over of cancer cells by ascites flow support...
Ascites plays a key role in supporting the metastatic potential of ovarian cancer cells. Shear stress and carry-over of cancer cells by ascites flow support carcinogenesis and metastasis formation. In addition, soluble factors may participate in the procarcinogenic effects of ascites in ovarian cancer. This study aimed to determine the biological effects of cell-free ascites on carcinogenesis in ovarian cancer cells. Cell-free ascites from ovarian cancer patients (ASC) non-selectively induced cell proliferation in multiple models of ovarian cancer and untransformed primary human dermal fibroblasts. Furthermore, ASC induced a Warburg-type rearrangement of cellular metabolism in A2780 ovarian cancer cells characterized by increases in cellular oxygen consumption and glycolytic flux; increases in glycolytic flux were dominant. ASC induced mitochondrial uncoupling and fundamentally reduced fatty acid oxidation. Ascites-elicited effects were uniform among ascites specimens. ASC-elicited transcriptomic changes in A2780 ovarian cancer cells included induction of the TGFβ-ERK/MEK pathway, which plays a key role in inducing cell proliferation and oncometabolism. ASC-induced gene expression changes, as well as the overexpression of members of the TGFβ signaling system, were associated with poor survival in ovarian cancer patients. We provided evidence that the activation of the autocrine/paracrine of TGFβ signaling system may be present in bladder urothelial carcinoma and stomach adenocarcinoma. Database analysis suggests that the TGFβ system may feed forward bladder urothelial carcinoma and stomach adenocarcinoma. Soluble components of ASC support the progression of ovarian cancer. These results suggest that reducing ascites production may play an essential role in the treatment of ovarian cancer by inhibiting the progression and reducing the severity of the disease.
PubMed: 38196068
DOI: 10.1007/s11357-023-01056-1 -
Nature Cancer Feb 2024The contribution of antitumor immunity to metastatic dormancy is poorly understood. Here we show that the long noncoding RNA Malat1 is required for tumor initiation and...
The contribution of antitumor immunity to metastatic dormancy is poorly understood. Here we show that the long noncoding RNA Malat1 is required for tumor initiation and metastatic reactivation in mouse models of breast cancer and other tumor types. Malat1 localizes to nuclear speckles to couple transcription, splicing and mRNA maturation. In metastatic cells, Malat1 induces WNT ligands, autocrine loops to promote self-renewal and the expression of Serpin protease inhibitors. Through inhibition of caspase-1 and cathepsin G, SERPINB6B prevents gasdermin D-mediated induction of pyroptosis. In this way, SERPINB6B suppresses immunogenic cell death and confers evasion of T cell-mediated tumor lysis of incipient metastatic cells. On-target inhibition of Malat1 using therapeutic antisense nucleotides suppresses metastasis in a SERPINB6B-dependent manner. These results suggest that Malat1-induced expression of SERPINB6B can titrate pyroptosis and immune recognition at metastatic sites. Thus, Malat1 is at the nexus of tumor initiation, reactivation and immune evasion and represents a tractable and clinically relevant drug target.
Topics: Animals; Mice; Cell Line, Tumor; Pyroptosis; RNA Splicing; RNA, Long Noncoding; T-Lymphocytes
PubMed: 38195932
DOI: 10.1038/s43018-023-00695-9 -
Nature Immunology Feb 2024Melanoma cells, deriving from neuroectodermal melanocytes, may exploit the nervous system's immune privilege for growth. Here we show that nerve growth factor (NGF) has...
Melanoma cells, deriving from neuroectodermal melanocytes, may exploit the nervous system's immune privilege for growth. Here we show that nerve growth factor (NGF) has both melanoma cell intrinsic and extrinsic immunosuppressive functions. Autocrine NGF engages tropomyosin receptor kinase A (TrkA) on melanoma cells to desensitize interferon γ signaling, leading to T and natural killer cell exclusion. In effector T cells that upregulate surface TrkA expression upon T cell receptor activation, paracrine NGF dampens T cell receptor signaling and effector function. Inhibiting NGF, either through genetic modification or with the tropomyosin receptor kinase inhibitor larotrectinib, renders melanomas susceptible to immune checkpoint blockade therapy and fosters long-term immunity by activating memory T cells with low affinity. These results identify the NGF-TrkA axis as an important suppressor of anti-tumor immunity and suggest larotrectinib might be repurposed for immune sensitization. Moreover, by enlisting low-affinity T cells, anti-NGF reduces acquired resistance to immune checkpoint blockade and prevents melanoma recurrence.
Topics: Humans; Receptor, Nerve Growth Factor; Nerve Growth Factor; Tropomyosin; Melanoma; Receptor, trkA; Cytoprotection; Immune Checkpoint Inhibitors; Memory T Cells; Immunosuppression Therapy; Immunotherapy; Receptors, Antigen, T-Cell
PubMed: 38195702
DOI: 10.1038/s41590-023-01723-7 -
Current Cardiology Reviews Jan 2024Heart failure (HF) is the fastest-growing cardiovascular condition worldwide. The immune system may play a role in the development of HF since this condition is...
Heart failure (HF) is the fastest-growing cardiovascular condition worldwide. The immune system may play a role in the development of HF since this condition is associated with elevated pro-inflammatory cytokine levels. HF is a life-threatening disease, and there is an increasing demand for diagnostic biomarkers, prognostic factors, and therapeutic agents that can help treat it. Galectin-1 (Gal-1) is the prototype galectin of the lectin family. Multiple signal transduction pathways are regulated by Ras proteins, which act as a molecular switch in cells. Gal-1 regulates T and B cell activation, differentiation, and survival. Gal-1 has been linked to inflammation. Activated T cells produce Gal-1 through an autocrine apoptotic mechanism involving MEK1/ERK and p38 MAPK. In the cardiovascular system, atherosclerosis is facilitated by Gal-1. Heart disease, myocardial infarction, hypertension, and stroke can be caused by atherosclerotic plaque. HF and heart hypertrophy are caused by decreased cardiac L-type Ca2+ channel activity. Deregulation of Gal-1 and CaV1.2 in pathological cardiac hypertrophy suggests a possible target for anti-hypertrophic therapy. Rat hypertrophic cardiomyocytes express Gal-1 and CaV1.2 channels simultaneously. It has been reported that diastolic dysfunction (DD) is associated with elevated Gal-1 levels. The high Gal-1 level in subjects led to the lowest cumulative survival as a composite endpoint. Incidences of HF, DD, and serum Gal-1 levels correlated significantly. The ejection fraction was negatively correlated with Gal-1 and CRP concentrations. Based on two different approaches in mice and humans, Gal-1 was identified as a potential mediator of HF.
PubMed: 38192129
DOI: 10.2174/011573403X274886231227111902 -
Journal of Controlled Release :... Feb 2024Vascular endothelial growth factor (VEGF) not only serves as an autocrine survival factor for tumor cells themselves, but also stimulates angiogenesis by paracrine...
Vascular endothelial growth factor (VEGF) not only serves as an autocrine survival factor for tumor cells themselves, but also stimulates angiogenesis by paracrine pathway. Strategies targeting VEGF holds tremendous potential for tumor therapy, however, agents targeting VEGF are limited by intolerable side effects, together with incomplete and temporary blocking of VEGF, resulting in unsatisfactory and unsustained therapeutic outcomes. Herein, hierarchical-unlocking virus-esque NanoCRISPR (HUNGER) is constructed for complete, permanent and efficient intracellular disruption of autocrine and paracrine pathway of VEGF, thereby eliciting notable tumor inhibition and antiangiogenesis. After intravenous administration, HUNGER exhibits prolonged blood circulation and hyaluronic acid-CD44 mediated tumor-targeting capability. Subsequently, when matrix metalloproteinase-2 is overexpressed in the tumor microenvironment, the PEG layer will be removed. The cell-penetrating peptide R8 endows HUNGER deep tumor penetration and specific cellular uptake. Upon cellular internalization, HUNGER undergoes hyaluronidase-triggered deshielding in lysosome, lysosomal escape is realized swiftly, and then the loaded CRISPR/Cas9 plasmid (>8 kb) is transported to nucleus efficiently. Consequentially, complete, permanent and efficient intracellular disruption of autocrine and paracrine pathway of VEGF ensures inhibition of angiogenesis and tumor growth with inappreciable toxicity. Overall, this work opens a brand-new avenue for anti-VEGF therapy and presents a feasible strategy for in vivo delivery of CRISPR/Cas9 system.
Topics: Humans; Biological Transport; Immunotherapy; Matrix Metalloproteinase 2; Neoplasms; Tumor Microenvironment; Vascular Endothelial Growth Factor A; Neovascularization, Pathologic
PubMed: 38184233
DOI: 10.1016/j.jconrel.2024.01.001 -
Scientific Reports Jan 2024Glioblastoma (GBM) is one of the most aggressive and deadly brain tumors; however, its current therapeutic strategies are limited. Selenoprotein P (SeP; SELENOP, encoded...
Glioblastoma (GBM) is one of the most aggressive and deadly brain tumors; however, its current therapeutic strategies are limited. Selenoprotein P (SeP; SELENOP, encoded by the SELENOP gene) is a unique selenium-containing protein that exhibits high expression levels in astroglia. SeP is thought to be associated with ferroptosis sensitivity through the induction of glutathione peroxidase 4 (GPX4) via selenium supplementation. In this study, to elucidate the role of SeP in GBM, we analyzed its expression in GBM patients and found that SeP expression levels were significantly higher when compared to healthy subjects. Knock down of SeP in cultured GBM cells resulted in a decrease in GPX1 and GPX4 protein levels. Under the same conditions, cell death caused by RSL3, a ferroptosis inducer, was enhanced, however this enhancement was canceled by supplementation of selenite. These results indicate that SeP expression contributes to preserving GPX and selenium levels in an autocrine/paracrine manner, i.e., SeP regulates a dynamic cycling-selenium storage system in GBM. We also confirmed the role of SeP expression in ferroptosis sensitivity using patient-derived primary GBM cells. These findings indicate that expression of SeP in GBM can be a significant therapeutic target to overcome anticancer drug resistance.
Topics: Humans; Ferroptosis; Glioblastoma; Phospholipid Hydroperoxide Glutathione Peroxidase; Selenium; Selenoprotein P
PubMed: 38182643
DOI: 10.1038/s41598-024-51259-5 -
Frontiers in Bioscience (Landmark... Dec 2023Alzheimer's disease is widely regarded as poorly treated due to poor conceptualization. For 40 years, Alzheimer's disease pathophysiology has focused on two culprits,... (Review)
Review
A More Holistic Perspective of Alzheimer's Disease: Roles of Gut Microbiome, Adipocytes, HPA Axis, Melatonergic Pathway and Astrocyte Mitochondria in the Emergence of Autoimmunity.
Alzheimer's disease is widely regarded as poorly treated due to poor conceptualization. For 40 years, Alzheimer's disease pathophysiology has focused on two culprits, amyloid-β induced plaques and hyperphosphorylated tau associated tangles, with no significant treatment advance. This is confounded by data showing amyloid-β to be an endogenous antimicrobial that is increased in a wide array of diverse medical conditions associated with heightened inflammation. This article reviews the wider bodies of data pertaining to Alzheimer's disease pathophysiology, highlighting the role of suppressed astrocyte mitochondrial function and mitochondrial melatonergic pathway as a core hub in driving neuronal loss in dementia. It is proposed that astrocyte function over aging becomes dysregulated, at least partly mediated by systemic processes involving the 10-fold decrease in pineal melatonin leading to the attenuated capacity of night-time melatonin to dampen residual daytime inflammation. Suppressed pineal melatonin also attenuates melatonin's inhibition of glucocorticoid receptor nuclear translocation, thereby changing not only stress/hypothalamus-pituitary-adrenal (HPA) axis consequences but also the consequences of the cortisol awakening response, which 'primes the body for the coming day'. Gut microbiome-derived butyrate also inhibits glucocorticoid receptor nuclear translocation, as well as inducing the mitochondrial melatonergic pathway. It is proposed that the loss of astrocyte melatonin prevents the autocrine and paracrine effects of melatonin in limiting amyloid-β levels and effects. Suppressed astrocyte melatonin production also attenuates the melatonin induction of astrocyte lactate, thereby decreasing neuronal mitochondrial metabolism and the neuronal mitochondrial melatonergic pathway. The loss of astrocyte lactate and melatonin, coupled to the suppression of neuronal mitochondrial metabolism and melatonin production decreases mitophagy, leading to the induction of the major histocompatibility complex (MHC)-1. MHC-1 initiates the chemoattraction of CD8+ t cells, leading to neuronal destruction in Alzheimer's disease being driven by 'autoimmune'/'immune-mediated' processes. Alzheimer's disease may therefore be conceptualized as being initiated by systemic processes that act on astrocytes as a core hub, with the suppression of the astrocyte melatonergic pathway leaving neurons deplete of appropriate metabolic substrates and co-ordinated antioxidants. This culminates in an 'immune-mediated' cell death. Future research and treatment/prevention implications are indicated.
Topics: Humans; Astrocytes; Melatonin; Alzheimer Disease; Autoimmunity; Gastrointestinal Microbiome; Hypothalamo-Hypophyseal System; Receptors, Glucocorticoid; Pituitary-Adrenal System; Inflammation; Mitochondria; Adipocytes; Lactates
PubMed: 38179773
DOI: 10.31083/j.fbl2812355 -
Sleep Medicine Feb 2024Obstructive Sleep Apnea Syndrome (OSAS) affects approximately 1-5% of children and is linked to cardiovascular, metabolic, and neurobehavioral complications....
Reduction of IL-6, IL-8 and β2-ADRENOCEPTOR mRNA levels in circulating polymorphonuclear leukocytes after adenotonsillectomy in children with Obstructive Sleep Apnea Syndrome.
BACKGROUND
Obstructive Sleep Apnea Syndrome (OSAS) affects approximately 1-5% of children and is linked to cardiovascular, metabolic, and neurobehavioral complications. Dysregulation of inflammatory process and sympathetic nervous system overstimulation leading to increased catecholamine production may contribute to OSAS pathogenesis. Polymorphonuclear Neutrophils (PMN), key cells in the inflammatory process, express adrenergic receptors, including β2-adrenergic receptor (ADRB2), which modulate their functions through an autocrine/paracrine loop. In this pilot study, we aimed to investigate the relationship between OSAS severity, ADRB2 expression in PMN and patient's inflammatory profile before and after adenotonsillectomy.
PATIENTS/METHODS
In this pilot study we enrolled OSAS pediatric patients in which ADRB2, IL-6 and IL-8 mRNA expression levels were evaluated in circulating PMN by RT-PCR.
RESULTS
9 OSAS pediatric patients, ranged from 3 to 8 years of age, were enrolled in the study. We found that adenotonsillectomy significantly reduced ADRB2 as well as IL-6, IL-8 mRNA expression levels in PMN.
CONCLUSIONS
These findings offer valuable insights into the underlying immune and inflammatory mechanisms of OSAS and open the way for the development of novel therapeutic approaches.
Topics: Child; Humans; Adenoidectomy; Interleukin-6; Interleukin-8; Neutrophils; Pilot Projects; Sleep Apnea, Obstructive
PubMed: 38157624
DOI: 10.1016/j.sleep.2023.12.017 -
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