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International Journal of Molecular... Jan 2024Since its initial discovery in 1994, the adipokine leptin has received extensive interest as an important satiety factor and regulator of energy expenditure. Although... (Review)
Review
Since its initial discovery in 1994, the adipokine leptin has received extensive interest as an important satiety factor and regulator of energy expenditure. Although produced primarily by white adipocytes, leptin can be synthesized by numerous tissues including those comprising the cardiovascular system. Cardiovascular function can thus be affected by locally produced leptin via an autocrine or paracrine manner but also by circulating leptin. Leptin exerts its effects by binding to and activating specific receptors, termed ObRs or LepRs, belonging to the Class I cytokine family of receptors of which six isoforms have been identified. Although all ObRs have identical intracellular domains, they differ substantially in length in terms of their extracellular domains, which determine their ability to activate cell signalling pathways. The most important of these receptors in terms of biological effects of leptin is the so-called long form (ObRb), which possesses the complete intracellular domain linked to full cell signalling processes. The heart has been shown to express ObRb as well as to produce leptin. Leptin exerts numerous cardiac effects including the development of hypertrophy likely through a number of cell signaling processes as well as mitochondrial dynamics, thus demonstrating substantial complex underlying mechanisms. Here, we discuss mechanisms that potentially mediate leptin-induced cardiac pathological hypertrophy, which may contribute to the development of heart failure.
Topics: Humans; Cardiomegaly; Heart; Heart Failure; Leptin; Signal Transduction; Vascular Remodeling
PubMed: 38256208
DOI: 10.3390/ijms25021137 -
Biomedicines Dec 2023The paraneoplastic syndrome referred in the literature as non-islet-cell tumor hypoglycemia (NICTH) and extra-pancreatic tumor hypoglycemia (EPTH) was first reported...
The paraneoplastic syndrome referred in the literature as non-islet-cell tumor hypoglycemia (NICTH) and extra-pancreatic tumor hypoglycemia (EPTH) was first reported almost a century ago, and the role of cancer-secreted IGF-II in causing this blood glucose-lowering condition has been widely established. The landscape emerging in the last few decades, based on molecular and cellular findings, supports a broader role for IGF-II in cancer biology beyond its involvement in the paraneoplastic syndrome. In particular, a few key findings are constantly observed during tumorigenesis, (a) a relative and absolute increase in fetal insulin receptor isoform (IR) content, with (b) an increase in IGF-II high-molecular weight cancer-variants (big-IGF-II), and (c) a stage-progressive increase in the IGF-II autocrine signal in the cancer cell, mostly during the transition from benign to malignant growth. An increasing and still under-exploited combinatorial pattern of the IGF-II signal in cancer is shaping up in the literature with respect to its transducing receptorial system and effector intracellular network. Interestingly, while surgical and clinical reports have traditionally restricted IGF-II secretion to a small number of solid malignancies displaying paraneoplastic hypoglycemia, a retrospective literature analysis, along with publicly available expression data from patient-derived cancer cell lines conveyed in the present perspective, clearly suggests that IGF-II expression in cancer is a much more common event, especially in overt malignancy. These findings strengthen the view that (1) IGF-II expression/secretion in solid tumor-derived cancer cell lines and tissues is a broader and more common event compared to the reported IGF-II association to paraneoplastic hypoglycemia, and (2) IGF-II associates to the commonly observed autocrine loops in cancer cells while IGF-I cancer-promoting effects may be linked to its paracrine effects in the tumor microenvironment. Based on these evidence-centered considerations, making the autocrine IGF-II loop a hallmark for malignant cancer growth, we here propose the functional name of IGF-II secreting tumors (IGF-IIsT) to overcome the view that IGF-II secretion and pro-tumorigenic actions affect only a clinical sub-group of rare tumors with associated hypoglycemic symptoms. The proposed scenario provides an updated logical frame towards biologically sound therapeutic strategies and personalized therapeutic interventions for currently unaccounted IGF-II-producing cancers.
PubMed: 38255147
DOI: 10.3390/biomedicines12010040 -
Chinese Medical Journal May 2024Liver metastases (LMs) are common in lung cancer. Despite substantial advances in diagnosis and treatment, the survival rate of patients with LM remains low as the... (Review)
Review
Liver metastases (LMs) are common in lung cancer. Despite substantial advances in diagnosis and treatment, the survival rate of patients with LM remains low as the immune-suppressive microenvironment of the liver allows tumor cells to evade the immune system. The impact of LMs on the outcomes of immune checkpoint inhibitors in patients with solid tumors has been the main focus of recent translational and clinical research. Growing evidence indicates that the hepatic microenvironment delivers paracrine and autocrine signals from non-parenchymal and parenchymal cells. Overall, these microenvironments create pre- and post-metastatic conditions for the progression of LMs. Herein, we reviewed the epidemiology, physiology, pathology and immunology, of LMs associated with non-small cell lung cancer and the role and potential targets of the liver microenvironment in LM in each phase of metastasis. Additionally, we reviewed the current treatment strategies and challenges that should be overcome in preclinical and clinical investigations. These approaches target liver elements as the basis for future clinical trials, including combinatorial interventions reported to resolve hepatic immune suppression, such as immunotherapy plus chemotherapy, immunotherapy plus radiotherapy, immunotherapy plus anti-angiogenesis therapy, and surgical resection.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Tumor Microenvironment; Liver Neoplasms; Lung Neoplasms; Immunotherapy; Immune Checkpoint Inhibitors
PubMed: 38251678
DOI: 10.1097/CM9.0000000000002981 -
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 -
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 -
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 -
Nature Communications Dec 2023Insulin secretion from pancreatic β cells is regulated by multiple stimuli, including nutrients, hormones, neuronal inputs, and local signalling. Amino acids modulate...
Insulin secretion from pancreatic β cells is regulated by multiple stimuli, including nutrients, hormones, neuronal inputs, and local signalling. Amino acids modulate insulin secretion via amino acid transporters expressed on β cells. The granin protein VGF has dual roles in β cells: regulating secretory granule formation and functioning as a multiple peptide precursor. A VGF-derived peptide, neuroendocrine regulatory peptide-4 (NERP-4), increases Ca influx in the pancreata of transgenic mice expressing apoaequorin, a Ca-induced bioluminescent protein complex. NERP-4 enhances glucose-stimulated insulin secretion from isolated human and mouse islets and β-cell-derived MIN6-K8 cells. NERP-4 administration reverses the impairment of β-cell maintenance and function in db/db mice by enhancing mitochondrial function and reducing metabolic stress. NERP-4 acts on sodium-coupled neutral amino acid transporter 2 (SNAT2), thereby increasing glutamine, alanine, and proline uptake into β cells and stimulating insulin secretion. SNAT2 deletion and inhibition abolish the protective effects of NERP-4 on β-cell maintenance. These findings demonstrate a novel autocrine mechanism of β-cell maintenance and function that is mediated by the peptide-amino acid transporter axis.
Topics: Animals; Humans; Mice; Glucose; Insulin; Insulin Secretion; Insulin-Secreting Cells; Nerve Tissue Proteins; Neurosecretory Systems; Peptides; Amino Acid Transport System A
PubMed: 38071217
DOI: 10.1038/s41467-023-43976-8 -
International Journal of Molecular... Nov 2023The insulin-like growth factor 2 (IGF2) promotes cell growth by overactivating the IGF system in an autocrine loop in adrenocortical carcinomas (ACCs). The cytoskeleton...
The insulin-like growth factor 2 (IGF2) promotes cell growth by overactivating the IGF system in an autocrine loop in adrenocortical carcinomas (ACCs). The cytoskeleton protein filamin A (FLNA) acts as a repressor of IGF2 mitogenic signalling in ACC cells. The aims of this study were to test FLNA expression by immunohistochemistry in 119 ACCs and 26 adrenocortical adenomas (ACAs) and to evaluate its relationship with clinicopathological features and outcome in ACCs. We found that 71.4% of ACCs did not express FLNA, whereas FLNA absence was a rare event in ACAs (15.4%, < 0.001 vs. ACCs). In addition, the expression of FLNA was associated with a less aggressive tumour behaviour in ACCs. Indeed, the subgroup of ACCs with high FLNA showed a lower ENSAT stage, Weiss score, and S-GRAS score compared to ACCs with low FLNA expression ( < 0.05). Moreover, patients with high FLNA had a longer overall survival than those with low FLNA ( < 0.05). In conclusion, our data suggest that FLNA may represent a "protective" factor in ACCs, and the integration of FLNA immunohistochemical expression in ACC tissues along with other clinical and molecular markers could be helpful to improve diagnostic accuracy and prognosis prediction in ACCs.
Topics: Humans; Adrenal Cortex Neoplasms; Adrenocortical Adenoma; Adrenocortical Carcinoma; Filamins; Signal Transduction; Prognosis
PubMed: 38068896
DOI: 10.3390/ijms242316573 -
Reviews in Endocrine & Metabolic... Apr 2024Adipose tissue, including white adipose tissue (WAT), brown adipose tissue (BAT), and beige adipose tissue, is vital in modulating whole-body energy metabolism. While... (Review)
Review
Adipose tissue, including white adipose tissue (WAT), brown adipose tissue (BAT), and beige adipose tissue, is vital in modulating whole-body energy metabolism. While WAT primarily stores energy, BAT dissipates energy as heat for thermoregulation. Beige adipose tissue is a hybrid form of adipose tissue that shares characteristics with WAT and BAT. Dysregulation of adipose tissue metabolism is linked to various disorders, including obesity, type 2 diabetes, cardiovascular diseases, cancer, and infertility. Both brown and beige adipocytes secrete multiple molecules, such as batokines, packaged in extracellular vesicles or as soluble signaling molecules that play autocrine, paracrine, and endocrine roles. A greater understanding of the adipocyte secretome is essential for identifying novel molecular targets in treating metabolic disorders. Additionally, microRNAs show crucial roles in regulating adipose tissue differentiation and function, highlighting their potential as biomarkers for metabolic disorders. The browning of WAT has emerged as a promising therapeutic approach in treating obesity and associated metabolic disorders. Many browning agents have been identified, and nanotechnology-based drug delivery systems have been developed to enhance their efficacy. This review scrutinizes the characteristics of and differences between white, brown, and beige adipose tissues, the molecular mechanisms involved in the development of the adipocytes, the significant roles of batokines, and regulatory microRNAs active in different adipose tissues. Finally, the potential of WAT browning in treating obesity and atherosclerosis, the relationship of BAT with cancer and fertility disorders, and the crosstalk between adipose tissue with circadian system and circadian disorders are also investigated.
Topics: Humans; Diabetes Mellitus, Type 2; Adipose Tissue, Brown; Obesity; Adipose Tissue, White; MicroRNAs; Adipose Tissue, Beige; Energy Metabolism; Thermogenesis; Neoplasms
PubMed: 38051471
DOI: 10.1007/s11154-023-09850-0