Sensory neurons, neuroimmunity, and pain modulation by sex hormones

Endocrinology ◽  
2021 ◽  
Author(s):  
Melissa E Lenert ◽  
Amanda Avona ◽  
Katherine M Garner ◽  
Luz R Barron ◽  
Michael D Burton
Keyword(s):  
Sex Differences ◽  
Sex Hormones ◽  
Cell Types ◽  
Pain Modulation ◽  
National Institutes Of Health ◽  
Neuron Activity ◽  
Sexually Dimorphic ◽  
Dependent Manner ◽  
Biological Variable ◽  
Different Cell Types

Abstract The inclusion of females in preclinical pain studies has become more commonplace in the last decade, as the National Institutes of Health (NIH) “Sex as a Biological Variable” (SABV) mandate was released. Presumably, basic researchers have not had a comprehensive understanding about neuroimmune interactions in half of the population and how hormones play a role in this. To date, we have learned that sex hormones contribute to sexual differentiation of the nervous system and sex differences in behavior throughout the lifespan; however, the cycling of sex hormones does not always explain these differences. Here, we highlight recent advances in our understanding of sex differences and how hormones and immune interactions influence sensory neuron activity to contribute to physiology and pain. Neuroimmune mechanisms may be mediated by different cell types in each sex, as the actions of immune cells are sexually dimorphic. Unfortunately, the majority of studies assessing neuronal contributions to immune function have been limited to males, so it is unclear if the mechanisms are similar in females. Finally, pathways that control cellular metabolism, like nuclear receptors have been shown to play a regulatory role in both pain and inflammation. Overall, communication between the neuroimmune and endocrine systems modulate pain signaling in a sex-dependent manner, but more research is needed to reveal nuances of these mechanisms.

scholarly journals Profiling of Sexually Dimorphic Genes in Neural Cells to Identify Eif2s3y, Whose Overexpression Causes Autism-Like Behaviors in Male Mice

2021 ◽  
Vol 9 ◽  
Author(s):  
Muxian Zhang ◽  
Yunqiang Zhou ◽  
Yiru Jiang ◽  
Zhancheng Lu ◽  
Xiaoxia Xiao ◽  
...  
Keyword(s):  
Sex Differences ◽  
Y Chromosome ◽  
Neurological Disorders ◽  
Cell Types ◽  
Neural Cells ◽  
Sexually Dimorphic ◽  
Primary Neurons ◽  
Primary Cells ◽  
Male Mice ◽  
Cellular Mechanisms

Many neurological disorders exhibit sex differences and sex-specific therapeutic responses. Unfortunately, significant amounts of studies investigating molecular and cellular mechanisms underlying these neurological disorders use primary cell cultures with undetermined sexes; and this may be a source for contradictory results among different studies and impair the validity of study conclusion. Herein, we comprehensively compared sexual dimorphism of gene expression in primary neurons, astrocytes, and microglia derived from neonatal mouse brains. We found that overall sexually dimorphic gene numbers were relatively low in these primary cells, with microglia possessing the most (264 genes), neurons possessing the medium (69 genes), and astrocytes possessing the least (30 genes). KEGG analysis indicated that sexually dimorphic genes in these three cell types were strongly enriched for the immune system and immune-related diseases. Furthermore, we identified that sexually dimorphic genes shared by these primary cells dominantly located on the Y chromosome, including Ddx3y, Eif2s3y, Kdm5d, and Uty. Finally, we demonstrated that overexpression of Eif2s3y increased synaptic transmission specifically in male neurons and caused autism-like behaviors specifically in male mice. Together, our results demonstrate that the sex of primary cells should be considered when these cells are used for studying the molecular mechanism underlying neurological disorders with sex-biased susceptibility, especially those related to immune dysfunction. Moreover, our findings indicate that dysregulation of sexually dimorphic genes on the Y chromosome may also result in autism and possibly other neurological disorders, providing new insights into the genetic driver of sex differences in neurological disorders.

scholarly journals Reporting and misreporting of sex differences in the biological sciences

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Yesenia Garcia-Sifuentes ◽  
Donna L Maney
Keyword(s):  
Biological Sciences ◽  
Sex Differences ◽  
Biomedical Research ◽  
Specific Effect ◽  
National Institutes Of Health ◽  
Specific Effects ◽  
Biological Variable ◽  
Males And Females ◽  
Increasing Risk ◽  
Do So

As part of an initiative to improve rigor and reproducibility in biomedical research, the U.S. National Institutes of Health now requires the consideration of sex as a biological variable in preclinical studies. This new policy has been interpreted by some as a call to compare males and females with each other. Researchers testing for sex differences may not be trained to do so, however, increasing risk for misinterpretation of results. Using a list of recently published articles curated by Woitowich et al. (eLife, 2020; 9:e56344), we examined reports of sex differences and non-differences across nine biological disciplines. Sex differences were claimed in the majority of the 147 articles we analyzed; however, statistical evidence supporting those differences was often missing. For example, when a sex-specific effect of a manipulation was claimed, authors usually had not tested statistically whether females and males responded differently. Thus, sex-specific effects may be over-reported. In contrast, we also encountered practices that could mask sex differences, such as pooling the sexes without first testing for a difference. Our findings support the need for continuing efforts to train researchers how to test for and report sex differences in order to promote rigor and reproducibility in biomedical research.

Glycogen: a carbohydrate source for GLUT-1 glycosylation during glucose deprivation of 3T3-L1 adipocytes

1996 ◽  
Vol 270 (4) ◽  
pp. E640-E645 ◽  
Author(s):  
R. J. McMahon ◽  
S. C. Frost
Keyword(s):  
Cho Cells ◽  
Chinese Hamster ◽  
Glucose Deprivation ◽  
Cell Types ◽  
Protein Glycosylation ◽  
Dependent Manner ◽  
Glycogen Depletion ◽  
Carbohydrate Source ◽  
Glut 1 ◽  
Different Cell Types

In 3T3-L1 adipocytes, the glycosylation of the GLUT-1 transporter is altered beyond 12 h of glucose deprivation. To determine whether glycogen degradation provides substrate for normal protein glycosylation during this delay, we measured the glycogen content of 3T3-L1 adipocytes. From an initial value of 0.537 +/- 0.097 mumol glucose/10(6) cells, glycogen was depleted in a time-dependent manner in response to glucose deprivation, exhibiting a half-time of 6 h. Surprisingly, fructose did not prevent glycogen depletion. However, in such glycogen-depleted adipocytes, the alteration of GLUT-1 glycosylation in response to glucose deprivation was more rapid than in normal adipocytes. Chinese hamster ovary (CHO) cells, which synthesize abbreviated dolichol-linked oligosaccharides within minutes of glucose deprivation (J. I. Rearick, A. Chapman, and S. Kornfeld. J. Biol. Chem. 256: 6255-6261, 1981), contained only 1% of the level of glycogen found in 3T3-L1 adipocytes. Glycosylation of GLUT-1 was altered in CHO cells within 3 h of glucose deprivation. These data demonstrate that, during glucose stress, glycogen may serve as a buffer for oligosaccharide biosynthesis and provide a potential explanation for varying sensitivities of different cell types to glucose deprivation.

scholarly journals A Tutorial of the Effects of Sex Hormones on Laryngeal Senescence and Neuromuscular Response to Exercise

2019 ◽  
Vol 62 (3) ◽  
pp. 602-610 ◽  
Author(s):  
Charles Lenell ◽  
Mary J. Sandage ◽  
Aaron M. Johnson
Keyword(s):  
Sex Differences ◽  
Sexual Dimorphism ◽  
Sex Hormones ◽  
Voice Therapy ◽  
Sexually Dimorphic ◽  
Men And Women ◽  
Women's Voices ◽  
Age Related ◽  
Neuromuscular Response ◽  
Response To Exercise

Purpose The purpose of this tutorial is to summarize how sex hormones affect both laryngeal senescence and neuromuscular response to exercise, highlighting the importance of considering sex differences in developing treatment for the senescent voice. Conclusion Men and women's voices are sexually dimorphic throughout the life span, including during the laryngeal adaptations observed during senescence. Therefore, presbyphonia (age-related dysphonia) likely clinically manifests differently for men and women due to differences in how the male and the female larynx change in response to aging. Because sexual dimorphism is evident in both laryngeal aging and response to exercise, voice therapy programs aimed at treating the typical and disordered aged voice should consider sex differences in their design.

scholarly journals The Modular Adaptive Ribosome

2016 ◽  
Author(s):  
Anupama Yadav ◽  
Aparna Radhakrishnan ◽  
Anshuman Panda ◽  
Amartya Singh ◽  
Himanshu Sinha ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Large Data ◽  
Cell Types ◽  
Ecological Niches ◽  
Environmental Cues ◽  
Dependent Manner ◽  
Yeast Strains ◽  
Specific Manner ◽  
Signatures Of Selection ◽  
Different Cell Types

ABSTRACTThe ribosome is an ancient machine, performing the same function across organisms. Although functionally unitary, recent experiments suggest specialized roles for some ribosomal proteins. Our central thesis is that ribosomal proteins function in a modular fashion to decode genetic information in a context dependent manner. We show through large data analyses that although many ribosomal proteins are essential with consistent effect on growth in different conditions in yeast and similar expression across cell and tissue types in mice and humans, some ribosomal proteins are used in an environment specific manner. The latter set of variable ribosomal proteins further function in a coordinated manner forming modules, which are adapted to different environmental cues in different organisms. We show that these environment specific modules of ribosomal proteins in yeast have differential genetic interactions with other pathways and their 5’UTRs show differential signatures of selection in yeast strains, presumably to facilitate adaptation. Similarly, we show that in higher metazoans such as mice and humans, different modules of ribosomal proteins are expressed in different cell types and tissues. A clear example is nervous tissue that uses a ribosomal protein module distinct from the rest of the tissues in both mice and humans. Our results suggest a novel stratification of ribosomal proteins that could have played a role in adaptation, presumably to optimize translation for adaptation to diverse ecological niches and tissue microenvironments.

scholarly journals KRAS-related long noncoding RNAs in human cancers

2021 ◽  
Author(s):  
Mahsa Saliani ◽  
Amin Mirzaiebadizi ◽  
Ali Javadmanesh ◽  
Akram Siavoshi ◽  
Mohammad Reza Ahmadian
Keyword(s):  
Mapk Pathway ◽  
Noncoding Rnas ◽  
Cell Types ◽  
Review Article ◽  
Long Noncoding Rnas ◽  
Dependent Manner ◽  
Clinical Tool ◽  
Human Cancers ◽  
Tumor Onset ◽  
Different Cell Types

AbstractKRAS is one of the most widely prevalent proto-oncogenes in human cancers. The constitutively active KRAS oncoprotein contributes to both tumor onset and cancer development by promoting cell proliferation and anchorage-independent growth in a MAPK pathway-dependent manner. The expression of microRNAs (miRNAs) and the KRAS oncogene are known to be dysregulated in various cancers, while long noncoding RNAs (lncRNAs) can act as regulators of the miRNAs targeting KRAS oncogene in different cancers and have gradually become a focus of research in recent years. In this review article, we summarize recent advances in the research on lncRNAs that have sponging effects on KRAS-targeting miRNAs as crucial mediators of KRAS expression in different cell types and organs. A deeper understanding of lncRNA function in KRAS-driven cancers is of major fundamental importance and will provide a valuable clinical tool for the diagnosis, prognosis, and eventual treatment of cancers.

scholarly journals Restricted epithelial proliferation by lacritin via PKCα-dependent NFAT and mTOR pathways

2006 ◽  
Vol 174 (5) ◽  
pp. 689-700 ◽  
Author(s):  
Jiahu Wang ◽  
Ningning Wang ◽  
Jinling Xie ◽  
Staci C. Walton ◽  
Robert L. McKown ◽  
...  
Keyword(s):  
Phospholipase D ◽  
Cell Types ◽  
Secretory Cells ◽  
Dependent Manner ◽  
The Novel ◽  
Receptor Binding Domain ◽  
Epithelial Proliferation ◽  
Α Helix ◽  
Different Cell Types ◽  
Dose Dependent

Renewal of nongermative epithelia is poorly understood. The novel mitogen “lacritin” is apically secreted by several nongermative epithelia. We tested 17 different cell types and discovered that lacritin is preferentially mitogenic or prosecretory for those types that normally contact lacritin during its glandular outward flow. Mitogenesis is dependent on lacritin's C-terminal domain, which can form an α-helix with a hydrophobic face, as per VEGF's and PTHLP's respective dimerization or receptor-binding domain. Lacritin targets downstream NFATC1 and mTOR. The use of inhibitors or siRNA suggests that lacritin mitogenic signaling involves Gαi or Gαo–PKCα-PLC–Ca2+–calcineurin–NFATC1 and Gαi or Gαo–PKCα-PLC–phospholipase D (PLD)–mTOR in a bell-shaped, dose-dependent manner requiring the Ca2+ sensor STIM1, but not TRPC1. This pathway suggests the placement of transiently dephosphorylated and perinuclear Golgi–translocated PKCα upstream of both Ca2+ mobilization and PLD activation in a complex with PLCγ2. Outward flow of lacritin from secretory cells through ducts may generate a proliferative/secretory field as a different unit of cellular renewal in nongermative epithelia where luminal structures predominate.

scholarly journals Mechanisms for sex differences in energy homeostasis

2019 ◽  
Vol 62 (2) ◽  
pp. R129-R143 ◽  
Author(s):  
Chunmei Wang ◽  
Yong Xu
Keyword(s):  
Sex Differences ◽  
Energy Balance ◽  
Sex Hormones ◽  
Sex Chromosomes ◽  
Energy Homeostasis ◽  
Liver Fat ◽  
Sexually Dimorphic ◽  
Multiple Organs ◽  
Specific Regulation ◽  
Underlying Mechanisms

Sex differences exist in the regulation of energy homeostasis. Better understanding of the underlying mechanisms for sexual dimorphism in energy balance may facilitate development of gender-specific therapies for human diseases, e.g. obesity. Multiple organs, including the brain, liver, fat and muscle, play important roles in the regulations of feeding behavior, energy expenditure and physical activity, which therefore contribute to the maintenance of energy balance. It has been increasingly appreciated that this multi-organ system is under different regulations in male vs female animals. Much of effort has been focused on roles of sex hormones (including androgens, estrogens and progesterone) and sex chromosomes in this sex-specific regulation of energy balance. Emerging evidence also indicates that other factors (not sex hormones/receptors and not encoded by the sex chromosomes) exist to regulate energy homeostasis differentially in males vs females. In this review, we summarize factors and signals that have been shown to regulate energy homeostasis in a sexually dimorphic fashion and propose a framework where these factors and signals may be integrated to mediate sex differences in energy homeostasis.

scholarly journals Mechanosensitive calcium signaling in filopodia

2020 ◽  
Author(s):  
Artem K. Efremov ◽  
Mingxi Yao ◽  
Michael P. Sheetz ◽  
Alexander D. Bershadsky ◽  
Boris Martinac ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Crucial Role ◽  
Cell Types ◽  
Molecular Pathways ◽  
Mechanical Forces ◽  
Dependent Manner ◽  
Tensile Forces ◽  
Channel Dependent ◽  
Different Cell Types

AbstractFilopodia are ubiquitous membrane projections that play crucial role in guiding cell migration on rigid substrates and through extracellular matrix by utilizing yet unknown mechanosensing molecular pathways. As recent studies show that Ca2+ channels localized to filopodia play an important role in regulation of their formation and since some Ca2+ channels are known to possess mechanosensing properties, activity of filopodial Ca2+ channels might be tightly interlinked with the filopodia mechanosensing function. We tested this hypothesis by monitoring changes in the intra-filopodial Ca2+ level in response to application of stretching force to individual filopodia of several cell types. It has been found that stretching forces of tens of pN strongly promote Ca2+ influx into filopodia, causing persistent Ca2+ oscillations that last for minutes even after the force is released. Most of the known mechanosensitive Ca2+ channels, such as Piezo 1, Piezo 2 and TRPV4, were found to be dispensable for the observed force-dependent Ca2+ influx. In contrast, L-type Ca2+ channels appear to be a key component in the discovered phenomenon. Since previous studies have shown that intra-filopodial transient Ca2+ signals play an important role in guidance of cell migration, our results suggest that the force-dependent activation of L-type Ca2+ channels may contribute to this process. Overall, our study reveals an intricate interplay between mechanical forces and Ca2+ signaling in filopodia, providing novel mechanistic insights for the force-dependent filopodia functions in guidance of cell migration.Significance statementWe found that tensile forces of tens of pN applied to individual filopodia trigger Ca2+ influx through L-type Ca2+ channels, producing persistent Ca2+ oscillations inside mechanically stretched filopodia. Resulting elevation of the intra-filopodial Ca2+ level in turn leads to downstream activation of calpain protease, which is known to play a crucial role in regulation of the cell adhesion dynamics. Thus, our work suggests that L-type channel-dependent Ca2+ signaling and the mechanosensing function of filopodia are coupled to each other, synergistically governing cell adhesion and motion in a force-dependent manner. Since L-type Ca2+ channels have been previously found in many different cell types, such as neural or cancer cells, the above mechanism is likely to be widespread among various cell lines.

scholarly journals Reporting and Misreporting of Sex Differences in the Biological Sciences

2021 ◽  
Author(s):  
Yesenia Garcia-Sifuentes ◽  
Donna L Maney
Keyword(s):  
Biological Sciences ◽  
Sex Differences ◽  
Biomedical Research ◽  
Specific Effect ◽  
National Institutes Of Health ◽  
Specific Effects ◽  
Biological Variable ◽  
Males And Females ◽  
Increasing Risk ◽  
Do So

As part of an initiative to improve rigor and reproducibility in biomedical research, the U. S. National Institutes of Health now requires the consideration of sex as a biological variable in preclinical studies. This new policy has been interpreted by some as a call to compare males and females with each other. Researchers testing for sex differences may not be trained to do so, however, increasing risk for misinterpretation of results. Using a list of recently published articles curated by Woitowich et al. (eLife, 2020; 9:e56344), we examined reports of sex differences and non-differences across nine biological disciplines. Sex differences were claimed in the majority of the 147 articles we analyzed; however, statistical evidence supporting those differences was often missing. For example, when a sex-specific effect of a manipulation was claimed, authors usually had not tested statistically whether females and males responded differently. Thus, sex-specific effects may be over-reported. In contrast, we also encountered practices that could mask sex differences, such as pooling the sexes without first testing for a difference. Our findings support the need for continuing efforts to train researchers how to test for and report sex differences in order to promote rigor and reproducibility in biomedical research.

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