scholarly journals Inflammatory pathways in female reproductive health and disease

Reproduction ◽  
2009 ◽  
Vol 138 (6) ◽  
pp. 903-919 ◽  
Author(s):  
Henry N Jabbour ◽  
Kurt J Sales ◽  
Rob D Catalano ◽  
Jane E Norman
Keyword(s):  
Reproductive Tract ◽  
Cell Function ◽  
Immune Cell ◽  
Reproductive Function ◽  
The Body ◽  
Inflammatory Pathways ◽  
Female Reproductive Health ◽  
Affected Tissue ◽  
Proper Resolution ◽  
Reproductive Events

Inflammation involves alterations to vascular and immune cell function. It is well recognised that many physiological reproductive events such as ovulation, menstruation, implantation and onset of labour display hallmark signs of inflammation. These are orchestrated by specific molecular pathways involving a host of growth factors, cytokines, chemokines and lipid mediators. Resumption of normal reproductive function involves prompt and proper resolution of these inflammatory pathways. Recent literature confirms that resolution of inflammatory pathways involves specific biochemical events that are activated to re-establish homeostasis in the affected tissue. Moreover, initiation and maintenance of inflammatory pathways are the key components of many pathologies of the reproductive tract and elsewhere in the body. The onset of reproductive disorders or disease may be the result of exacerbated activation and maintenance of inflammatory pathways or their dysregulated resolution. This review will address the role of inflammatory events in normal reproductive function and its pathologies.

scholarly journals Pyruvate dehydrogenase kinase is a negative regulator of interleukin-10 production in macrophages

2020 ◽  
Vol 12 (7) ◽  
pp. 543-555
Author(s):  
Yi Rang Na ◽  
Daun Jung ◽  
Juha Song ◽  
Jong-Wan Park ◽  
Jung Joo Hong ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Pyruvate Dehydrogenase ◽  
Cell Function ◽  
Immune Cell ◽  
Interleukin 10 ◽  
The Body ◽  
Pyruvate Dehydrogenase Kinase ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Inflammatory Phase

Abstract Interleukin-10 (IL-10) is the most potent anti-inflammatory cytokine in the body and plays an essential role in determining outcomes of many inflammatory diseases. Cellular metabolism is a critical determinant of immune cell function; however, it is currently unclear whether metabolic processes are specifically involved in IL-10 production. In this study, we aimed to find the central metabolic molecule regulating IL-10 production of macrophages, which are the main producers of IL-10. Transcriptomic analysis identified that metabolic changes were predominantly enriched in Kupffer cells at the early inflammatory phase of a mouse endotoxemia model. Among them, pyruvate dehydrogenase kinase (PDK)-dependent acute glycolysis was negatively involved in IL-10 production. Inhibition or knockdown of PDK selectively increased macrophage IL-10 expression. Mechanistically, PDK inhibition increased IL-10 production via profound phosphorylation of adenosine monophosphate (AMP)-activated protein kinase alpha 1 (AMPKα1) by restricting glucose uptake in lipopolysaccharide-stimulated macrophages. AMPKα1 consequently activated p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and cyclic AMP-responsive element-binding protein to regulate IL-10 production. Our study uncovers a previously unknown regulatory mechanism of IL-10 in activated macrophages involving an immunometabolic function of PDK.

scholarly journals The Functions of ZIP8, ZIP14, and ZnT10 in the Regulation of Systemic Manganese Homeostasis

2020 ◽  
Vol 21 (9) ◽  
pp. 3304
Author(s):  
James W.W. Winslow ◽  
Kirsten H. Limesand ◽  
Ningning Zhao
Keyword(s):  
Antioxidant Defense ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Immune Cell ◽  
The Body ◽  
Metal Transporters ◽  
Cellular Processes ◽  
The Past ◽  
Genes Encoding ◽  
Essential Nutrient

As an essential nutrient, manganese is required for the regulation of numerous cellular processes, including cell growth, neuronal health, immune cell function, and antioxidant defense. However, excess manganese in the body is toxic and produces symptoms of neurological and behavioral defects, clinically known as manganism. Therefore, manganese balance needs to be tightly controlled. In the past eight years, mutations of genes encoding metal transporters ZIP8 (SLC39A8), ZIP14 (SLC39A14), and ZnT10 (SLC30A10) have been identified to cause dysregulated manganese homeostasis in humans, highlighting the critical roles of these genes in manganese metabolism. This review focuses on the most recent advances in the understanding of physiological functions of these three identified manganese transporters and summarizes the molecular mechanisms underlying how the loss of functions in these genes leads to impaired manganese homeostasis and human diseases.

scholarly journals Hypoxia/HIF Modulates Immune Responses

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 260
Author(s):  
Yuling Chen ◽  
Timo Gaber
Keyword(s):  
Immune Response ◽  
Cancer Progression ◽  
Immune Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Adaptive Immune Response ◽  
Oxygen Availability ◽  
The Body ◽  
Low Oxygen ◽  
Adaptive Immune

Oxygen availability varies throughout the human body in health and disease. Under physiological conditions, oxygen availability drops from the lungs over the blood stream towards the different tissues into the cells and the mitochondrial cavities leading to physiological low oxygen conditions or physiological hypoxia in all organs including primary lymphoid organs. Moreover, immune cells travel throughout the body searching for damaged cells and foreign antigens facing a variety of oxygen levels. Consequently, physiological hypoxia impacts immune cell function finally controlling innate and adaptive immune response mainly by transcriptional regulation via hypoxia-inducible factors (HIFs). Under pathophysiological conditions such as found in inflammation, injury, infection, ischemia and cancer, severe hypoxia can alter immune cells leading to dysfunctional immune response finally leading to tissue damage, cancer progression and autoimmunity. Here we summarize the effects of physiological and pathophysiological hypoxia on innate and adaptive immune activity, we provide an overview on the control of immune response by cellular hypoxia-induced pathways with focus on the role of HIFs and discuss the opportunity to target hypoxia-sensitive pathways for the treatment of cancer and autoimmunity.

scholarly journals The Role of microRNA Let-7d in Female Malignancies and Diseases of the Female Reproductive Tract

2021 ◽  
Vol 22 (14) ◽  
pp. 7359
Author(s):  
Chiara De Santis ◽  
Martin Götte
Keyword(s):  
Ovarian Cancer ◽  
Posttranscriptional Regulation ◽  
Reproductive Tract ◽  
Cell Function ◽  
Immune Cell ◽  
Female Reproductive Tract ◽  
Apoptosis Resistance ◽  
Therapeutic Concept ◽  
Mrna Targets ◽  
Wide Range

microRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level. Let-7d is a microRNA of the conserved let-7 family that is dysregulated in female malignancies including breast cancer, ovarian cancer, endometrial cancer, and cervical cancer. Moreover, a dysregulation is observed in endometriosis and pregnancy-associated diseases such as preeclampsia and fetal growth restriction. Let-7d expression is regulated by cytokines and steroids, involving transcriptional regulation by OCT4, MYC and p53, as well as posttranscriptional regulation via LIN28 and ADAR. By downregulating a wide range of relevant mRNA targets, let-7d affects cellular processes that drive disease progression such as cell proliferation, apoptosis (resistance), angiogenesis and immune cell function. In an oncological context, let-7d has a tumor-suppressive function, although some of its functions are context-dependent. Notably, its expression is associated with improved therapeutic responses to chemotherapy in breast and ovarian cancer. Studies in mouse models have furthermore revealed important roles in uterine development and function, with implications for obstetric diseases. Apart from a possible utility as a diagnostic blood-based biomarker, pharmacological modulation of let-7d emerges as a promising therapeutic concept in a variety of female disease conditions.

scholarly journals Ultrasonographic imaging of the reproductive organs of the female bottlenose dolphin, Tursiops truncatus aduncas

Reproduction ◽  
2001 ◽  
pp. 419-428 ◽  
Author(s):  
FM Brook
Keyword(s):  
Tursiops Truncatus ◽  
Reproductive Tract ◽  
Bottlenose Dolphins ◽  
Reproductive Organs ◽  
The Body ◽  
Corpora Lutea ◽  
Age Related ◽  
Close Relationship ◽  
Poorly Differentiated ◽  
Reproductive Events

Routine ultrasonographic examination of the reproductive tract was performed for periods of up to 10 years in ten female bottlenose dolphins (Tursiops truncatus aduncas) in Hong Kong. The ovaries could be reliably and repeatedly identified, lying close to the body surface, in the angle formed by the rectus abdominus and hypaxialis lumborum muscles, and were most easily located by scanning in the transverse plane from the proximal end of the genital slit towards the head. The ovaries are ovoid, with a relatively hypoechoic cortex around a central echogenic mesovarium. The echogenicity of the ovarian parenchyma appeared to increase with increasing age. This may be the result of age-related changes, such as increased fat deposition or fibrosis, or of ovarian 'scars' from multiple ovulations. Small antral follicles, developing follicles and corpora lutea can be identified within the ovarian cortex. Owing to its shape and lack of a definitive border, plus the close relationship to the intestines, the contents of which may obstruct the ultrasound beam, the non-pregnant uterus was not so easily visualized. The endometrium was poorly differentiated and difficult to see. To date, examination of the uterus using ultrasonography has provided little information about endometrial changes during the ovarian cycle in this group of dolphins. Real-time diagnostic ultrasonography provides a means to image the morphology of the reproductive organs in live female dolphins directly and provides a valuable means of assessing reproductive events in this species.

scholarly journals OP0013 SEX DIFFERENCES IN AUTOIMMUNE DISEASE SUSCEPTIBILITY; A MULTI-OMIC APPROACH

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 8.1-8
Author(s):  
G. Robinson ◽  
K. Waddington ◽  
J. Peng ◽  
A. Radziszewska ◽  
H. Peckham ◽  
...  
Keyword(s):  
Sex Differences ◽  
Lipid Metabolism ◽  
Sex Hormones ◽  
Cell Function ◽  
Immune Cell ◽  
Density Lipoprotein ◽  
Hormone Treatment ◽  
Immune Cell Function ◽  
Immune Cell Subsets ◽  
Males And Females

Background:Males and females have altered immune responses resulting in variation in autoimmune and cardiovascular disease risk (CVR). Recently, these differences have played a role in the inflammatory response to COVID-19. Sex differences exist in the frequency and activity of immune-cell subsets but mechanisms underlying sexual dimorphism remain unknown. Juvenile-onset systemic lupus erythematosus (JSLE) is an autoimmune disorder that commonly emerges during puberty, has a strong female prevalence (female:male ratio, 4.5:1) and results in an increased CVR. JSLE is characterised by chronic inflammation and dyslipidaemia, where cardiovascular disease is a leading cause of mortality for patients. Our previous work identified a link between immune cell function and lipid metabolism in adult-onset SLE. We hypothesised that sex hormones could influence both lipid metabolism and immune cell function and this could determine sex-specific susceptibility to JSLE and associated CVR.Objectives:We investigated the role of sex hormones in modifying systemic lipid metabolism and inflammation.Methods:Nuclear magnetic resonance spectroscopy based serum metabolomics measuring over 130 lipoproteins (14-subsets with lipid compositions), flow cytometry measuring immune-cells, and RNA-sequencing were used to assess the metabolic and immune profile in young, pre/post-pubertal males (n=10/17) and females (n=10/23) and in individuals with gender-dysphoria (GD) under cross-hormone treatment (trans-male/female, n=26/25). This analysis was also performed on a cohort of post-pubertal male (n=12) and female (n=23) JSLE patients. Data was analysed by logistic regression, balanced random forest machine learning (BRF-ML), differential gene expression (DEG) and pathway analysis.Results:Post-pubertal males had significantly reduced cardio-protective high-density lipoprotein (HDL) subsets (p<0.0001) and increased cardio-pathogenic very-low-density lipoprotein subsets (p<0.0001) compared to females. These differences were not observed pre-puberty and were reversed significantly by cross-hormone treatment in GD individuals, suggesting that sex hormones regulate lipid metabolism in-vivo.BRF-ML (28 immune-cell subsets) identified an increased frequency of anti-inflammatory regulatory T-cells (Tregs) in post-pubertal males compared to females (p=0.0097). These Tregs were also more suppressive in males compared to females. Differences in Treg frequency were seen pre-puberty and were not altered by sex hormone treatment in GD individuals. However, Treg DEGs and functional transcriptomic pathways altered between post-pubertal males and females, including those involved in inflammatory signalling, overlapped with those altered by hormones in GD, suggesting hormones may also drive Treg functional changes. In addition, HDL metabolites modified by hormones showed differential associations with Treg phenotypes between post-pubertal males and females.Strikingly, sex differences in lipoproteins and Tregs were lost in JSLE, suggesting hormone signalling could be dysregulated in the pathogenesis of autoimmunity and could increase CVR for patients.Conclusion:Sex hormones drive altered lipoprotein metabolism and functional transcriptomic pathways in Tregs. Males have a lipoprotein profile associated with increased CVR, but a more anti-inflammatory immune profile compared to females. Together, this could explain sex differences in inflammatory disease susceptibilities and inform future sex-specific therapeutic strategies for the management of both JSLE and CVR.Acknowledgements:Lupus UKRosetrees TrustVersus ArthritisNIHR UCLH Biomedical Research CentreDisclosure of Interests:None declared

scholarly journals Pre-Transplant Immune Cell Function Assay as a Predictor of Early Cardiac Allograft Rejection

2021 ◽  
Vol 40 (4) ◽  
pp. S232-S233
Author(s):  
S.D. Maidman ◽  
C. Gidea ◽  
A. Reyentovich ◽  
S. Rao ◽  
T. Saraon ◽  
...  
Keyword(s):  
Allograft Rejection ◽  
Cell Function ◽  
Immune Cell ◽  
Cardiac Allograft ◽  
Immune Cell Function ◽  
Cardiac Allograft Rejection

scholarly journals Cellular and metabolic mechanisms of nutrient actions in immune function

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Philip Newsholme
Keyword(s):  
Amino Acids ◽  
Fatty Acids ◽  
Vitamin D ◽  
Immune System ◽  
Cell Function ◽  
Immune Cell ◽  
Cell Structure ◽  
Nutritional Intervention ◽  
Immune Cell Function ◽  
And Function

AbstractVarious nutrients can change cell structure, cellular metabolism, and cell function which is particularly important for cells of the immune system as nutrient availability is associated with the activation and function of diverse immune subsets. The most important nutrients for immune cell function and fate appear to be glucose, amino acids, fatty acids, and vitamin D. This perspective will describe recently published information describing the mechanism of action of prominent nutritional intervention agents where evidence exists as to their action and potency.

scholarly journals NF-κB and Human Cancer: What Have We Learned over the Past 35 Years?

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 889
Author(s):  
Thomas D. Gilmore
Keyword(s):  
Cell Cycle Progression ◽  
Cell Function ◽  
Immune Cell ◽  
Human Cancer ◽  
Cancer Prognosis ◽  
Cycle Progression ◽  
The Past ◽  
Human Cancers ◽  
Limited Success ◽  
Upstream Regulators

Transcription factor NF-κB has been extensively studied for its varied roles in cancer development since its initial characterization as a potent retroviral oncogene. It is now clear that NF-κB also plays a major role in a large variety of human cancers, including especially ones of immune cell origin. NF-κB is generally constitutively or aberrantly activated in human cancers where it is involved. These activations can occur due to mutations in the NF-κB transcription factors themselves, in upstream regulators of NF-κB, or in pathways that impact NF-κB. In addition, NF-κB can be activated by tumor-assisting processes such as inflammation, stromal effects, and genetic or epigenetic changes in chromatin. Aberrant NF-κB activity can affect many tumor-associated processes, including cell survival, cell cycle progression, inflammation, metastasis, angiogenesis, and regulatory T cell function. As such, inhibition of NF-κB has often been investigated as an anticancer strategy. Nevertheless, with a few exceptions, NF-κB inhibition has had limited success in human cancer treatment. This review covers general themes that have emerged regarding the biological roles and mechanisms by which NF-κB contributes to human cancers and new thoughts on how NF-κB may be targeted for cancer prognosis or therapy.

Seasonal changes in pancreatic B-cell function in euthermic yellow-bellied marmots

1985 ◽  
Vol 249 (2) ◽  
pp. R159-R165 ◽  
Author(s):  
G. L. Florant ◽  
A. K. Lawrence ◽  
K. Williams ◽  
W. A. Bauman
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
B Cell ◽  
Cell Function ◽  
Peripheral Resistance ◽  
The Body ◽  
Pancreatic B Cell ◽  
Peripheral Insulin Resistance ◽  
Body Weights ◽  
System Input

Fasting plasma insulin (PI) and glucose (PG) concentrations were measured throughout the body weight cycle of marmots. Animals gained weight during summer, and in late fall body weight peaked, after which they ceased feeding. Each month euthermic animals were injected intra-arterially with either dextrose (500 mg/kg) or porcine insulin (0.1 U/kg), and blood samples were collected over the subsequent 2 h. During weight gain fasting PI concentration and pancreatic B-cell response to injected dextrose increased markedly. Maximal insulin release to a dextrose challenge was measured during peak body weight or when body weight initially began to decline. The PG concentration after exogenous insulin administration was slight (less than 10%) in the fall but increased approximately 25% in the spring after marmots lost weight. Basal PG levels were not significantly different throughout the year. Basal fasting PI concentrations were significantly higher during the fall (P less than 0.01). It is suggested that in the fall, when marmots are obese, hyperinsulinemia and peripheral insulin resistance appear. Furthermore, in two animals with an increase in body weight of approximately 30% or less over the summer, peripheral resistance was demonstrable, albeit not as marked as in animals that appropriately doubled their body weights when given food ad libitum. Thus we hypothesize that factors other than adiposity, i.e., food intake, central nervous system input to the pancreatic B-cell, and/or changes in B-cell sensitivity to PG, may contribute to the observed peripheral insulin resistance and may be involved in body weight regulation.

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