AR
Androgen receptor (Dihydrotestosterone receptor) (Nuclear receptor subfamily 3 group C member 4) [DHTR] [NR3C4]
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The androgen receptor (AR) plays a leading role in the control of prostate cancer (PCa) growth. Interestingly, structurally different AR antagonists with distinct mechanisms of antagonism induce cell senescence, a mechanism that inhibits cell cycle progression, and thus seems to be a key cellular response for the treatment of PCa. Surprisingly, while physiological levels of androgens promote growth, supraphysiological androgen levels (SAL) inhibit PCa growth in an AR-dependent manner by inducing cell senescence in cancer cells. Thus, oppositional acting ligands, AR antagonists, and agonists are able to induce cellular senescence in PCa cells, as shown in cell culture model as well as ex vivo in patient tumor samples. This suggests a dual AR-signaling dependent on androgen levels that leads to the paradox of the rational to keep the AR constantly inactivated in order to treat PCa. These observations however opened the option to treat PCa patients with AR antagonists and/or with androgens at supraphysiological levels. The latter is currently used in clinical trials in so-called bipolar androgen therapy (BAT). Notably, cellular senescence is induced by AR antagonists or agonist in both androgen-dependent and castration-resistant PCa (CRPC). Pathway analysis suggests a crosstalk between AR and the non-receptor tyrosine kinase Src-Akt/PKB and the PI3K-mTOR-autophagy signaling in mediating AR-induced cellular senescence in PCa. In this review, we summarize the current knowledge of therapeutic induction and intracellular pathways of AR-mediated cellular senescence.
Keywords
- PKB/Akt
- Src
- androgen receptor antagonist
- antiandrogen
- bipolar androgen therapy
- cellular senescence
- prostate cancer
- supraphysiological androgen levels
Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer-related deaths of men in Western countries. Androgen deprivation therapy is initially successful, however eventually fails, and tumors progress to the more aggressive castration-resistant PCa (CRPC). Yet, androgen receptor (AR) usually remains as a major regulator of tumor cell proliferation in CRPC. Interleukin-23 (IL-23) was recently shown to promote the development of CRPC by driving AR transcription. Here we used the androgen-sensitive LNCaP, castration-resistant C4-2, and 22Rv1 cells. Interestingly, cellular senescence is induced in these human cell lines by treatment with the AR antagonists enzalutamide (ENZ) or darolutamide (ODM), which might be one underlying mechanism for inhibition of PCa cell proliferation. Treatment with IL-23 alone did not change cellular senescence levels in these cell lines, whereas IL-23 inhibited significantly cellular senescence levels induced by ENZ or ODM in both CRPC cell lines C4-2 and 22Rv1 but not in LNCaP cells. This indicates a response of IL-23 specific in CRPC cells. Generating LNCaP and C4-2 three-dimensional (3D) spheroids and treatment with AR antagonists resulted in the reduced spheroid volume and thus growth inhibition. However, the combination of AR antagonists with IL-23 did not affect the antagonist-mediated reduction of spheroid volumes. This observation was confirmed with proliferation assays using adherent monolayer cell cultures. Taken together, the data indicate that IL-23 treatment reduces the AR antagonists-induced level of cellular senescence of CRPC cells, which could be one possible mechanism for promoting castration resistance.
Keywords
- Androgen receptor antagonists
- Cellular senescence
- Interleukin-23
- Prostate cancer spheroids
Aging is an inevitable process that involves profound physiological changes. Long non-coding RNAs (lncRNAs) are emerging as important regulators in various biological processes but are not systemically studied in aging. To provide an organism-wide lncRNA landscape during aging, we conduct comprehensive RNA sequencing (RNA-seq) analyses across the mouse lifespan. Of the 1,675 aging-regulated lncRNAs (AR-lncRNAs) identified, the majority are connected to inflammation-related biological pathways. AR-lncRNAs exhibit high tissue specificity; conversely, those with higher tissue specificity are preferentially regulated during aging. White adipose tissue (WAT) displays the highest number of AR-lncRNAs and develops the most dynamic crosstalk between AR-lncRNA and AR-mRNA during aging. An adipose-enriched AR-lncRNA, lnc-adipoAR1, is negatively correlated with aging, and knocking it down inhibits adipogenesis, phenocopying the compromised adipogenic capacity of aged fat. Our works together reveal AR-lncRNAs as essential components in aging and suggest that although each tissue ages in a distinct manner, WAT is a leading contributor to aging-related health decline.
Keywords
- adipocyte
- adipose tissue
- aging
- lncRNA
- long non-coding RNA
- non-coding RNA
- transcriptome
The benefit of inducing cellular senescence as a tumor suppressive strategy remains questionable due to the senescence-associated secretory phenotype. Hence, studies and development of senolytic compounds that induce cell death in senescent cells have recently emerged. Senescent cells are hypothesized to exhibit different upregulated pro-survival/anti-apoptotic networks depending on the senescent inducers. This might limit the effect of a particular senolytic compound that targets rather only a specific pathway. Interestingly, cellular senescence in prostate cancer (PCa) cells can be induced by either androgen receptor (AR) agonists at supraphysiological androgen level (SAL) used in bipolar androgen therapy or by AR antagonists. This challenges to define ligand-specific senolytic compounds. Here, we first induced cellular senescence by treating androgen-sensitive PCa LNCaP cells with either SAL or the AR antagonist Enzalutamide (ENZ). Subsequently, cells were incubated with the HSP90 inhibitor Ganetespib (GT), the Bcl-2 family inhibitor ABT263, or the Akt inhibitor MK2206 to analyze senolysis. GT and ABT263 are known senolytic compounds. We observed that GT exhibits senolytic activity specifically in SAL-pretreated PCa cells. Mechanistically, GT treatment results in reduction of AR, Akt, and phospho-S6 (p-S6) protein levels. Surprisingly, ABT263 lacks senolytic effect in both AR agonist- and antagonist-pretreated cells. ABT263 treatment does not affect AR, Akt, or S6 protein levels. Treatment with MK2206 does not reduce AR protein level and, as expected, potently inhibits Akt phosphorylation. However, ENZ-induced cellular senescent cells undergo apoptosis by MK2206, whereas SAL-treated cells are resistant. In line with this, we reveal that the pro-survival p-S6 level is higher in SAL-induced cellular senescent PCa cells compared to ENZ-treated cells. These data indicate a difference in the agonist- or antagonist-induced cellular senescence and suggest a novel role of MK2206 as a senolytic agent preferentially for AR antagonist-treated cells. Taken together, our data suggest that both AR agonist and antagonist induce cellular senescence but differentially upregulate a pro-survival signaling which preferentially sensitize androgen-sensitive PCa LNCaP cells to a specific senolytic compound.
Keywords
- Akt inhibitor
- Antiandrogen
- Bcl-2 family inhibitor
- Bipolar androgen therapy
- Cellular senescence
- HSP90 inhibitor
- Prostate cancer
- Senolytic compounds
To obtain the desired technological properties (pasting, texture, and rheology) of naturally aged rice (AR), the aging process of freshly harvested rice was accelerated by controlled microwave treatment at 540 W for 1-3 min. Similar to AR, the rice microwave treated for 2 min showed increased pasting viscosities (peak, trough, breakdown, final, and setback) and pasting temperature, enhanced gel hardness and strength, and reduced gel adhesiveness. The mechanism by which microwaves accelerated rice aging was illustrated. Microwave treatment promoted the formation of protein disulfide bonds and the release of free phenolic acids, which enhanced protein gel network and cell wall strength. This phenomenon inhibited the swelling of starch granules and consequently modified the technological properties of rice. The crystalline structure and fatty acid content of rice flour was uninvolved in the mechanism, but the microwave-induced micromechanical change (intercellular cleavage to intracellular cleavage) of rice endosperm may be involved.
Keywords
- Chemical composition
- Microwave
- Rice aging
- Rice noodles
- Technological properties
The gut microbiota is involved in metabolic disorders induced by androgen deficiency after sexual maturation in males (late-onset hypogonadism). However, its role in the energy metabolism of congenital androgen deficiency (e.g., androgen-insensitive syndrome) remains elusive. Here, we examined the link between the gut microbiota and metabolic disease symptoms in androgen receptor knockout (ARKO) mouse by administering high-fat diet (HFD) and/or antibiotics. HFD-fed male, but not standard diet-fed male or HFD-fed female, ARKO mice exhibited increased feed efficiency, obesity with increased visceral adipocyte mass and hypertrophy, hepatic steatosis, glucose intolerance, insulin resistance, and loss of thigh muscle. In contrast, subcutaneous fat mass accumulated in ARKO mice irrespective of the diet and sex. Notably, all HFD-dependent metabolic disorders observed in ARKO males were abolished after antibiotics administration. The ratios of fecal weight-to-food weight and cecum weight-to-body weight were specifically reduced by ARKO in HFD-fed males. 16S rRNA sequencing of fecal microbiota from HFD-fed male mice revealed differences in microbiota composition between control and ARKO mice. Several genera or species (e.g., [i]Turicibacter[/i] and [i]Lactobacillus reuteri[/i], respectively) were enriched in ARKO mice, and antibiotics treatment spoiled the changes. Furthermore, the life span of HFD-fed ARKO males was shorter than that of control mice, indicating that androgen deficiency causes metabolic dysfunctions leading to early death. These findings also suggest that AR signaling plays a role in the prevention of metabolic dysfunctions, presumably by influencing the gut microbiome, and improve our understanding of health consequences in subjects with hypogonadism and androgen insensitivity.
MeSH Terms
- Adipocytes
- Adipose Tissue
- Animals
- Anti-Bacterial Agents
- Diet
- Diet, High-Fat
- Feces
- Female
- Gastrointestinal Microbiome
- Lipid Metabolism
- Longevity
- Male
- Metabolic Diseases
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Obesity
- Receptors, Androgen
- Sex Characteristics
Keywords
- androgen-insensitive syndrome
- longevity
- metabolic syndrome
- testosterone
- type 2 diabetes
Aging and overweight are involved in prostatic lesion development, due to their association with cell proliferation, hormonal imbalance and angiogenesis. The jaboticaba fruit is rich in bioactive compounds, showing potential chemopreventive action such as the capacity to modulate hormones and angiogenesis hallmarks. This study aimed to evaluate the jaboticaba extract (PJE) effect on the prostate morphology and on molecules related to hormone signaling and angiogenesis, during aging and/or high-fat diet (HFD) intake. Seventy FVB mice were distributed into experimental groups: YG group (young: 3 month old mice), AG group (aged: 11 month old mice), HfAG group (aged HFD), JAGI group (aged 2.9 g kg-1 PJE), JAGII group (aged 5.8 g kg-1 PJE), HfJAGI group (aged HFD 2.9 g kg-1 PJE) and HfJAGII group (aged HFD 5.8 g kg-1 PJE). The ventral prostate was collected for morphological, immunohistochemistry and western-blotting analysis after 60 days of treatment. All PJE treatments promoted hormonal signaling balance and inhibited angiogenesis in the prostates of aged or HFD-fed aged mice, leading to the maintenance of healthy prostate morphology. A high dose of the PJE (JAGII and HfJAGII groups) led to the best capacity to reduce AR (58.40% and 74.42%; p = 0.0240 and p = 0.0023), ERα (30.29% and 45.12%; p = 0.0004 and p < 0.0001), aromatase (39.54% and 55.94%; p = 0.0038 and p = 0.0020), and VEGF (50.81% and 67.68%; p < 0.0001) and increase endostatin immunoexpression. Moreover, HFD intake intensified the hormonal and angiogenic alterations in the aged mouse prostates, contributing to the increase in premalignant lesion incidence. The PJE exerted a dose-dependent positive effect on aged or HFD-fed aged mouse prostates, contributing to the gland microenvironment recovery, mainly due to the hormonal and angiogenic balance. Therefore, we suggest that the PJE can be a potential candidate for prostatic lesion prevention.
MeSH Terms
- Aging
- Animals
- Cell Proliferation
- Diet, High-Fat
- Male
- Mice
- Myrtaceae
- Plant Extracts
- Prostate
In multiple sclerosis (MS) patients with a progressive form of the disease, spinal cord (SC) functions slowly deteriorate beyond age 40. We previously showed that in the SC of these patients, large areas of incomplete demyelination extend distance away from plaque borders and are characterized by a unique progliotic TGFB1 (Transforming Growth Factor Beta 1) genomic signature. Here, we attempted to determine whether region- and age-specific physiological parameters could promote the progression of SC periplaques in MS patients beyond age 40. An analysis of transcriptomics databases showed that, under physiological conditions, a set of 10 homeobox (HOX) genes are highly significantly overexpressed in the human SC as compared to distinct brain regions. Among these HOX genes, a survey of the human proteome showed that only HOXA5 encodes a protein which interacts with a member of the TGF-beta signaling pathway, namely SMAD1 (SMAD family member 1). Moreover, HOXA5 was previously found to promote the TGF-beta pathway. Interestingly, SMAD1 is also a protein partner of the androgen receptor (AR) and an unsupervised analysis of gene ontology terms indicates that the AR pathway antagonizes the TGF-beta/SMAD pathway. Retrieval of promoter analysis data further confirmed that AR negatively regulates the transcription of several members of the TGF-beta/SMAD pathway. On this basis, we propose that in progressive MS patients, the physiological SC overexpression of HOXA5 combined with the age-dependent decline in AR ligands may favor the slow progression of TGFB1-mediated gliosis. Potential therapeutic implications are discussed.
MeSH Terms
- Age Factors
- Aged
- Aging
- Brain
- Data Mining
- Databases, Genetic
- Disease Progression
- Female
- Gene Expression Profiling
- Gliosis
- Homeodomain Proteins
- Humans
- Ligands
- Male
- Middle Aged
- Multiple Sclerosis
- Proteomics
- Receptors, Androgen
- Sequence Analysis, RNA
- Signal Transduction
- Smad1 Protein
- Spinal Cord
- Transforming Growth Factor beta1
- Up-Regulation
Keywords
- androgen receptor
- astrocytes
- homeobox A5
- multiple sclerosis
- spinal cord
- transforming growth factor beta 1
The past decade has seen rapid development in DNA methylation (DNAm) microarrays, including the Illumina HumanMethylation27 and HumanMethylation450 (450K) chips, which have played an essential role in identifying and evaluating age-related (AR) DNAm markers in different tissues. Recently, a new array, the Illumina MethylationEPIC (EPIC) was introduced, with nearly double the number of probes as the 450K (∼850,000 probes). In this study, we test these newly added probes for age association using a large cohort of 754 DNAm profiles from blood samples assayed on the EPIC BeadChip, for individuals aged 0-88 years old. 52 AR CpG sites (Spearman's abs(rho) >0.6 and P-value <10 ) were identified, 21 of which were novel sites and mapped to 18 genes, nine of which (LHFPL4, SLC12A8, EGFEM1P, GPR158, TAL1, KIAA1755, LOC730668, DUSP16, and FAM65C) have never previously been reported to be associated with age. The data were subsequently split into a 527-sample training set and a 227-sample testing set to build and validate two age prediction models using elastic net regression and multivariate regression. Elastic net regression selected 425 CpG markers with a mean absolute deviation (MAD) of 2.6 years based on the testing set. To build a multivariate linear regression model, AR CpG sites with R > 0.5 at FDR < 0.05 were input into stepwise regression to select the best subset for age prediction. The resulting six CpG markers were linearly modelled with age and explained 81% of age-correlated variation in DNAm levels. Age estimation accuracy using bootstrap analysis was 4.5 years, with 95% confidence intervals of 4.56 to 4.57 years based on the testing set. These results suggest that EPIC BeadChip probes for age estimation fall within the range of probes found on the previous Illumina HumanMethylation platforms in terms of their age-prediction ability.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Child
- Child, Preschool
- Cohort Studies
- CpG Islands
- DNA Methylation
- Forensic Genetics
- Genetic Markers
- Humans
- Infant
- Infant, Newborn
- Linear Models
- Middle Aged
- Oligonucleotide Array Sequence Analysis
- Young Adult
Keywords
- Age
- CpG sites
- DNA methylation
- Forensic age estimation
- Forensic epigenetics
- Illumina MethylationEPIC
Hematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and -extrinsic aging mechanisms remains debated. Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological/natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the BM microenvironment promotes myelopoiesis in premature/physiological aging. During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased BM noradrenergic innervation promotes β -adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced β -AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with β -AR agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal/premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment.
MeSH Terms
- Adrenergic Agonists
- Aging
- Aging, Premature
- Animals
- Bone Marrow
- Cell Differentiation
- Cell Encapsulation
- Cell Proliferation
- Disease Models, Animal
- Hematopoietic Stem Cells
- Humans
- Interleukin-6
- Megakaryocytes
- Mice
- Myeloid Cells
- Nitric Oxide Synthase Type I
- Progeria
- Receptors, Adrenergic, beta-2
- Signal Transduction
- Stem Cell Niche
Keywords
- Hutchinson-Gilford progeria
- aging
- hematopoietic stem cell
- lymphoid
- microenvironment
- myeloid
- niche
Androgens are known to be an essential regulator of male health. Androgen receptor (AR) is widely expressed throughout the adrenal cortex, yet the wider role for androgen signalling in the adrenal remains underexplored. To investigate AR-dependent and AR-independent androgen signalling in the adrenal, we used a novel mouse model with a specific ablation of androgen receptor in the adrenal cortex with or without reduction of circulating androgen levels by castration. Our results describe AR expression in the human and mouse adrenal and highlight that the mouse is a viable model to investigate androgen signalling in the adrenal cortex. We show androgen signalling via AR is required for X-zone regression during puberty. Furthermore, cortex measurements define differences in X-zone morphology depending on whether circulating androgens or AR have been removed. We show androgens promote both cortical cell differentiation and apoptosis but are dispensable for the formation of the definitive cortex. Additionally, investigation of aged mice with AR ablation reveals severe cortex disruption, spindle cell hyperplasia and X-zone expansion. The data described herein demonstrates AR-signalling is required to facilitate X-zone regression, cell clearance and to protect against adrenal degeneration during ageing.
MeSH Terms
- Adrenal Cortex
- Aging
- Androgens
- Animals
- Apoptosis
- Castration
- Humans
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Protective Agents
- Receptors, Androgen
- Signal Transduction
Our past study showed that a single tail vein injection of adipose-derived stromal vascular fraction (SVF) into old rats was associated with improved dobutamine-mediated coronary flow reserve. We hypothesize that i.v. injection of SVF improves coronary microvascular function in aged rats via alterations in beta adrenergic microvascular signaling. Female Fischer-344 rats aged young (3 months, n=32) and old (24 months, n=30) were utilized, along with two cell therapies intravenously injected in old rats four weeks prior to sacrifice: 1x10 green fluorescent protein (GFP ) SVF cells (O SVF, n=21), and 5x10 GFP bone-marrow mesenchymal stromal cells (O BM, n=6), both harvested from young donors. Cardiac ultrasound and pressure-volume measurements were obtained, and coronary arterioles were isolated from each group for microvessel reactivity studies and immunofluorescence staining. Coronary flow reserve decreased with advancing age, but this effect was rescued by the SVF treatment in the O SVF group. Echocardiography showed an age-related diastolic dysfunction that was improved with SVF to a greater extent than with BM treatment. Coronary arterioles isolated from SVF-treated rats showed amelioration of the age-related decrease in vasodilation to a non-selective β-AR agonist. I.v. injected SVF cells improved β-adrenergic receptor-dependent coronary flow and microvascular function in a model of advanced age.
MeSH Terms
- Adipose Tissue
- Age Factors
- Animals
- Arterioles
- Female
- Fractional Flow Reserve, Myocardial
- Green Fluorescent Proteins
- Injections, Intravenous
- Luminescent Agents
- Mesenchymal Stem Cells
- Rats
- Rats, Inbred F344
- Receptors, Adrenergic, beta-1
- Signal Transduction
- Stromal Cells
- Vasodilation
Keywords
- adrenergic
- aging
- cell therapy
- coronary
- vasodilation
Recent evidence indicates that inhibition within the visual cortex is greater in older than young adults. Increased inhibition has been associated with reduced visual cortex plasticity in animal models. We investigated whether age-related increases in human visual cortex inhibition occur in conjunction with reduced visual cortex plasticity. Visual cortex inhibition was measured psychophysically using binocular rivalry alternation rates (AR) for dichoptic gratings. Slower ARs are associated with a greater concentration of the inhibitory neurotransmitter GABA within the human visual cortex. Visual cortex plasticity was measured using an established paradigm for induction of long-term potentiation (LTP) -like increases in visually evoked potential (VEP) amplitude. Following rapid visual stimulation, greater increases in VEP amplitude indicate greater visual cortex plasticity. The study involved two groups; young (18-40 years, [i]n[/i] = 29) and older adults (60-80 years, [i]n[/i] = 18). VEPs were recorded for a 1 Hz onset/offset checkerboard stimulus before and after 9 Hz visual stimulation with the same stimulus. ARs were slower in older than young adults. In contrast to most previous studies, VEP amplitudes were significantly reduced following the rapid visual stimulation for young adults; older adult VEP amplitudes were unaffected. Our AR results replicate previous observations of increased visual cortex inhibition in the older adults. Rapid visual stimulation significantly altered VEP amplitude in young adults, albeit in the opposite direction than predicted. VEP amplitudes did not change in older adults suggesting an association between increased inhibition and reduced plasticity within the human visual cortex.
Keywords
- aging
- binocular rivalry
- cortical potentiation
- visual cortex plasticity
- visual evoked potential
The newly evolved prefrontal cortex (PFC) generates goals for "top-down" control of behavior, thought, and emotion. However, these circuits are especially vulnerable to uncontrollable stress, with powerful, intracellular mechanisms that rapidly take the PFC "off-line." High levels of norepinephrine and dopamine released during stress engage α1-AR and D1R, which activate feedforward calcium-cAMP signaling pathways that open nearby potassium channels to weaken connectivity and reduce PFC cell firing. Sustained weakening with chronic stress leads to atrophy of dendrites and spines. Understanding these signaling events helps to explain the increased susceptibility of the PFC to stress pathology during adolescence, when dopamine expression is increased in the PFC, and with advanced age, when the molecular "brakes" on stress signaling are diminished by loss of phosphodiesterases. These mechanisms have also led to pharmacological treatments for stress-related disorders, including guanfacine treatment of childhood trauma, and prazosin treatment of veterans and civilians with post-traumatic stress disorder.
Keywords
- aging
- cAMP
- calcium
- dopamine
- norepinephrine
- prefrontal cortex
- stress adolescence
Desertliving Cistanche herb was first recorded in "Shen Nong'Herbal Classic" and listed as the top grade herbal medicine in it. Phenylethanoid glycosides are indicative components for identification and content determination of Desertliving Cistanche herb in Chinese pharmacopoeia, which is also one of the main active components. In this research, we explored the mechanism of phenylethanoid glycosides of Desertliving Cistanche herb to the perimenopausal model rats. The purpose of this study is to research the effects of phenylethanoid glycosides of Desertliving Cistanche herb (PGC) on the neuroendocrine-immune function of perimenopausal syndrome by perimenopausal model rats. Wistar female rats were selected. The left ovaries for all rats except in the blank control group(BC) were removed, and the right ovaries were removed in 80%. The vaginal smear showed irregular estrous cycle changes for the perimenopausal model rats. And the perimenopausal model rats were gavaged Gengnian'an, Phenylethanoid Glycosides of Desertliving Cistanche herb high, medium, low suspension which is 450mg/(kg day), 133.33mg/(kg day), 66.67mg/(kg day), 33.33mg/(kg day); the group of BC and model group (MC)were given distilled water in the same volume as the drugs group for 30 consecutive days. Horizontal-vertical exercise scores were measured at 29 days of dosing. After the last administration, the blood was taken from the abdominal aorta, and levels of E , LH, FSH, GnRH, BGP in serum, and the levels β-EP in plasma were measured respective. Organ indexes of thymus, spleen, and uterus were calculated. The content of estrogen receptor (ER) in the hypothalamic, pituitary and uterus tissues and the content of androgen receptor (AR) in the hypothalamic homogenate were measured. The pathological changes of the thymus, spleen, uterus, ovary were observed by HE staining. Compared with MC, PGC increase the activity, the organ index (thymus, spleen, uterus), E , T, BGP level in serum, β-EP level in plasma, AR level in hypothalamus, ER level in hypothalamus, pituitary, uterus in perimenopausal model rats. And it also reduced FSH, LH, GnRH level in serum, and improved uterine and ovarian lesions in perimenopausal model rats. Each dose of PCG could counteract the disorder of sex hormone in perimenopausal model rats, correct the imbalance of ER and AR level, enhance and restore the effect of uterus and the nerve cells of hypothalamic, and improve immune function.
MeSH Terms
- Aging
- Animals
- Cistanche
- Female
- Glycosides
- Plants, Medicinal
- Rats
- Rats, Wistar
- Reproductive Physiological Phenomena
Keywords
- Neuroendocrine-immune function
- Perimenopausal model rats
- Phenylethanoid glycosides of desertliving cistanche herb
Testicular aging leads to a decrease in spermatogenesis and steroidogenesis. Vitamin D plays an important role in reproduction by modulating testicular steroidogenesis. As the role of vitamin D3 in testicular steroidogenesis during aging has not been explored, the aim of this study was to evaluate the effects of vitamin D3 on testicular functions in d-gal-induced aged rats. Vitamin D3 treatment on d-gal-induced aged rats resulted in significant improvement in sperm parameters, histoarchitecture, serum testosterone, and rostenedione and estrogen levels. The results of both in vivo and in vitro studies showed that vitamin D3 directly regulates testicular steroidogenic markers. Vitamin D3 treatment also increased CYP19A1 and decreased AR expression in the testes of d-gal-induced aged and normal rats. These results suggest that estrogen-mediated action may be responsible for an improvement in spermatogenesis in aged testis. Furthermore, it may be suggested vitamin D3 has a protective role in the aged testis and unaffected spermatogenesis in normal rats treated with vitamin D3 could be due to a balance between estrogen and androgen action.
MeSH Terms
- Aging
- Animals
- Cholecalciferol
- Estrogens
- Male
- Rats, Wistar
- Spermatogenesis
- Spermatozoa
- Steroids
- Testis
- Testosterone
- Vitamins
Keywords
- Aging
- Estrogen
- Testis
- Testosterone
- VDR
- d-Galactose
There is abundant evidence that low circulating testosterone levels in older men are associated with adverse cardiovascular outcomes; however, the direction of causality is unclear. Although there is burgeoning interest in the potential of androgen therapy in older men, the effect of androgens on cardiovascular regeneration in aging males remains poorly defined. We investigated the role of androgens in age-related impairment in ischemia-induced neovascularization. Castrated young (2 months) and old (24 months) male mice were subjected to unilateral hindlimb ischemia and treated with subdermal DHT or placebo Silastic implants. Blood flow recovery was enhanced by DHT treatment in young and old mice compared with age-matched placebo controls. DHT augmented angiogenesis in young mice and ameliorated age-related impairment in neovascularization in old mice. Administration of DHT was associated with increased hypoxia inducible factor-1α (HIF-1α) and stromal cell‒derived factor-1 expression in young mice, but not in old mice. In vitro, DHT-induced HIF-1α transcriptional activation was attenuated in fibroblasts from old mice. Interaction between androgen receptor (AR) and importins, key proteins that facilitate nuclear translocation of AR, was impaired with age. In contrast, DHT treatment stimulated the production and mobilization of Sca1 /CXCR4 circulating progenitor cells in both young and old mice. DHT stimulated the migration and proangiogenic paracrine effect of ex vivo cultured bone marrow‒derived angiogenic cells from young and old mice. In conclusion, androgens ameliorated age-related impairment in ischemia-induced neovascularization. Although age-dependent dysfunction in androgen signaling attenuated some androgen effects on angiogenesis, provasculogenic effects of androgens were partially preserved with age.
MeSH Terms
- Age Factors
- Aging
- Androgens
- Animals
- Cells, Cultured
- Chemokine CXCL12
- Dihydrotestosterone
- Gene Expression
- Hindlimb
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit
- Ischemia
- Male
- Mice, Inbred C57BL
- Neovascularization, Physiologic
Androgen receptor (AR) antagonists are used for hormone therapy of prostate cancer (PCa). However resistance to the treatment occurs eventually. One possible reason is the occurrence of AR mutations that prevent inhibition of AR-mediated transactivation by antagonists. To offer in future more options to inhibit AR signaling, novel chemical lead structures for new AR antagonists would be beneficial. Here we analyzed structure-activity relationships of a battery of 36 non-steroidal structural variants of methyl anthranilate including 23 synthesized compounds. We identified structural requirements that lead to more potent AR antagonists. Specific compounds inhibit the transactivation of wild-type AR as well as AR mutants that render treatment resistance to hydroxyflutamide, bicalutamide and the second-generation AR antagonist enzalutamide. This suggests a distinct mode of inhibiting the AR compared to the clinically used compounds. Competition assays suggest binding of these compounds to the AR ligand binding domain and inhibit PCa cell proliferation. Moreover, active compounds induce cellular senescence despite inhibition of AR-mediated transactivation indicating a transactivation-independent AR-pathway. In line with this, fluorescence resonance after photobleaching (FRAP) - assays reveal higher mobility of the AR in the cell nuclei. Mechanistically, fluorescence resonance energy transfer (FRET) - assays indicate that the amino-carboxy (N/C)-interaction of the AR is not affected, which is in contrast to known AR-antagonists. This suggests a mechanistically novel mode of AR-antagonism. Together, these findings indicate the identification of a novel chemical platform as a new lead structure that extends the diversity of known AR antagonists and possesses a distinct mode of antagonizing AR-function.
MeSH Terms
- Androgen Receptor Antagonists
- Animals
- COS Cells
- Cell Line, Tumor
- Cell Proliferation
- Chlorocebus aethiops
- Halogenation
- Humans
- Male
- Mutation
- Pancreatic Neoplasms
- Receptors, Androgen
- ortho-Aminobenzoates
Keywords
- Androgen receptor
- Antiandrogens
- Antihormone
- Cellular senescence
- Methyl anthranilate derivatives
- Prostate cancer
G protein-coupled receptors that signal through Gαq (GqPCRs), like α1-adrenergic and angiotensin receptors (α1-AR, AT-R), are traditionally thought to mediate pathologic remodeling in heart failure, including cardiac myocyte death. However, we previously demonstrated that α1- ARs are cardioprotective and identified an α1A-subtype-ERK survival-signaling pathway in adult cardiac myocytes. Recently, we demonstrated that α1-ARs localize to and signal from the nucleus, whereas AT-R localize to and signal from the sarcolemma in adult cardiac myocytes. Thus, we proposed a novel paradigm, predicated on compartmentalization of GqPCR signaling, to explain the phenotypic diversity of GqPCRs. Here, we tested the hypothesis that differential subcellular compartmentalization of α1-AR and AT-R mediated activation of ERK might explain the differential effects of these receptors on cardiac myocyte survival. Using a fluorescent ERK activity FRET-based biosensor, EKAR, to measure subcellular localization and extent of receptor-mediated ERK activation in single adult cardiac myocytes, we found that α1-ARs induced ERK activity at the nucleus and in the cytosol in 60% of cardiac myocytes, whereas AT-Rs showed no consistent ERK activation. The cell-specific α1-mediated activation of ERK in 60% of adult cardiac myocytes showed concordance with previous studies indicating that the α1A-subtype is expressed in only 60% of cardiac myocytes. Consistent with the ability to activate ERK, we found that only α1-ARs induced phosphorylation of Bcl-2 family member Bad, improved mitochondrial membrane stability, and promoted cardiac myocyte survival. In summary, our results suggest that compartmentalization of GqPCRs dictate activation of ERK and cardiac myocyte survival in adult cardiac myocytes.
MeSH Terms
- Aging
- Animals
- Cell Death
- Cell Nucleus
- Cell Survival
- Cytosol
- Female
- GTP-Binding Protein alpha Subunits, Gq-G11
- MAP Kinase Signaling System
- Membrane Potential, Mitochondrial
- Mice, Inbred C57BL
- Myocytes, Cardiac
- Phosphorylation
- Receptors, G-Protein-Coupled
- Subcellular Fractions
- bcl-Associated Death Protein
Keywords
- Angiotensin receptors
- Cardiac myocytes
- Cell signaling
- ERK
- Fluorescent lifetime imaging microscopy
- α1-adrenergic receptors
It is not known whether aging alters the enzymatic reactive aldehyde- and lipid hydroperoxide-detoxifying capacity of the human arterial tissue favoring vascular oxidative stress. To address this issue, we studied the specific enzymatic activities of class 1, 2 and 3 aldehyde dehydrogenase (ALDH1, ALDH2 and ALDH3), glutathione S‑transferase (isozyme A4-4, GSTA4-4) and aldose reductase (AR), namely the major reactive aldehyde-scavenging enzymes, together with the activity of the lipid hydroperoxide-removing enzyme glutathione peroxidase (GSH-Px), in superior thyroid arteries (STA) specimens obtained in the thyroid surgery setting in aged subjects (age 72.3 ± 3.6 years) and young adult controls (age 31.9 ± 3.5 years). Vascular lipid peroxidation was also studied by assessing in STA fluorescent damage products of lipid peroxidation (FDPL), which reflect oxidant-induced 4‑hydroxynonenal and lipid hydroperoxide formation. Remarkably, the activities of ALDH1, ALDH2, ALDH3, GSTA4-4, AR and GSH-Px were significantly lower, and FDPL levels higher, in the arterial tissue of the aged subjects than in that of the young adult controls. Moreover, the enzymatic activities were inversely and significantly correlated with the levels of FDPL in the arterial tissue of both the aged and young subjects, highlighting their vascular antioxidant/antilipoperoxidative role in vivo. Thus, aging impairs the enzymatic reactive aldehyde-detoxifying capacity and GSH-Px activity of the human arterial tissue eventually favoring vascular oxidative stress.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Aldehyde Dehydrogenase
- Aldehyde Reductase
- Arteries
- Case-Control Studies
- Female
- Glutathione Peroxidase
- Glutathione Transferase
- Humans
- Lipid Peroxidation
- Male
- Oxidative Stress
Keywords
- Aging
- Aldehyde dehydrogenase
- Aldose reductase
- Glutathione S‑transferase
- Glutathione peroxidase
- Lipid peroxidation
- Oxidative stress
- Reactive aldehydes
Androgens via the androgen receptor (AR) are required for optimal male bone health. The target cell(s) for the effects of androgens on cortical bone remain(s) incompletely understood. In females, estrogen receptor alpha in neurons is a negative regulator of cortical and trabecular bone. Whether neuronal AR regulates bone mass in males remains unexplored. Here, we inactivated AR in neurons using a tamoxifen-inducible CreERT2 under the control of the neuronal promoter Thy1. Tamoxifen induced a 70% to 80% reduction of AR mRNA levels in Thy1-CreERT2-positive brain regions cerebral cortex and brainstem as well as in the peripheral nervous tissue of male neuronal AR knockout (N-ARKO) mice. Hypothalamic AR mRNA levels were only marginally reduced and the hypothalamic-pituitary-gonadal axis remained unaffected, as determined by normal levels of serum testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). In contrast to orchidectomy, deletion of neuronal AR did not alter body weight, body composition, hindlimb muscle mass, grip strength, or wheel running. MicroCT analysis of the femur revealed no changes in bone accrual during growth in N-ARKO mice. However, 36- and 46-week-old N-ARKO mice displayed an accelerated age-related cortical involution, namely a more pronounced loss of cortical thickness and strength, which occurred in the setting of androgen sufficiency. Neuronal AR inactivation decreased the cancellous bone volume fraction in L vertebra but not in the appendicular skeleton of aging mice. MicroCT findings were corroborated in the tibia and after normalization of hormonal levels. Serum markers of bone turnover and histomorphometry parameters were comparable between genotypes, except for a 30% increase in osteoclast surface in the trabecular compartment of 36-week-old N-ARKO mice. Cortical bone loss in N-ARKO mice was associated with an upregulation of Ucp1 expression in brown adipose tissue, a widely used readout for sympathetic tone. We conclude that androgens preserve cortical integrity in aging male mice via AR in neurons. © 2018 American Society for Bone and Mineral Research.
MeSH Terms
- Aging
- Animals
- Body Composition
- Body Weight
- Bone Resorption
- Cancellous Bone
- Cortical Bone
- Femur
- Gene Deletion
- Gonads
- Hypothalamo-Hypophyseal System
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Muscles
- Neurons
- Osteogenesis
- Receptors, Androgen
- Uncoupling Protein 1
Keywords
- AGING
- BONE-BRAIN-NERVOUS SYSTEM INTERACTIONS
- GENETIC ANIMAL MODELS
- NEUROENDOCRINE AND SEX STEROIDS
Nonagenarians (NON) are a growing segment of the population and have a high prevalence of cardiac disease. Many findings encountered on their echocardiograms are also found in younger individuals with valvular or myocardial disease. Therefore, the purpose of this study was to describe this distinct echocardiographic phenotype. We identified our study population by querying our echo database to identify unique septuagenarians (SEPT) and nonagenarians (NON) who underwent a transthoracic echocardiogram (TTE) from January 1, 2010 to December 31, 2014. Exclusion criteria were LVEF < 50%, any akinetic wall segment, aortic stenosis, moderate-severe AR and/or severe MR, coronary revascularization within 60 days of study echo, and prior valve surgery. The mean age of SEPT was 73.0 ± 2.0 and NON was 92.0 ± 2.1 (P < 0.001). There was no gender difference between groups. NON had significantly smaller LV end-diastolic diameters than SEPT (41.6 ± 5.7 mm vs 48.0 ± 7.0 mm, P < 0.001). NON had a greater relative wall thickness (0.51 ± 0.10 vs 0.40 ± 0.08, P < 0.001) and more frequently had concentric remodeling or hypertrophy. NON had higher E/Ea ratios and estimated LA pressures (P < 0.01). 48% of NON had moderate-severe mitral annular calcification compared to 25.0% of SEPT (P < 0.01). Herein, we provide the first comprehensive echocardiographic description of 'presbycardia'; concentric LVH, asymmetric septal hypertrophy, mitral and aortic valve calcification, and increased epicardial fat thickness. This pattern of findings may be increasingly seen as the population ages.
MeSH Terms
- Aged
- Aged, 80 and over
- Echocardiography, Doppler
- Female
- Heart Valve Diseases
- Heart Valves
- Heart Ventricles
- Humans
- Male
- Retrospective Studies
- Stroke Volume
- Ventricular Function, Left
- Ventricular Remodeling
Keywords
- aging
- diastolic function
- left ventricular hypertrophy
- valvular calcification
Previous studies evaluating the role of the androgen receptor (AR) for bone mass have used mouse models with global or tissue-specific lifelong inactivation of the AR. However, these mouse models have the AR inactivated already early in life and the relative roles of the AR during development, sexual maturation and in adult mice cannot be evaluated separately. The aim of the present study was to determine the specific roles of the AR in bone during sexual maturation and in adult mice. The AR was conditionally ablated at four (pre-pubertal) or ten (post-pubertal) weeks of age in male mice using tamoxifen-inducible Cre-mediated recombination. Both the pre-pubertal and the post-pubertal AR inactivation were efficient demonstrated by substantially lower AR mRNA levels in seminal vesicle, bone and white adipose tissue as well as markedly reduced weights of reproductive tissues when comparing inducible ARKO mice and control mice at 14 weeks of age. Total body BMD, as analyzed by DXA, as well as tibia diaphyseal cortical bone thickness and proximal metaphyseal trabecular bone volume fraction, as analyzed by μCT, were significantly reduced by both pre-pubertal and post-pubertal AR inactivation. These bone effects were associated with an increased bone turnover, indicating a high bone turnover osteoporosis. Pre-pubertal but not post-pubertal AR inactivation resulted in substantially increased fat mass. In conclusion, the AR is required for maintenance of both trabecular and cortical bone in adult male mice while AR expression during puberty is crucial for normal fat mass homeostasis in adult male mice.
MeSH Terms
- Adiposity
- Aging
- Animals
- Bone Remodeling
- Bone and Bones
- Cancellous Bone
- Cortical Bone
- Dihydrotestosterone
- Female
- Male
- Mice, Knockout
- Organ Size
- Organ Specificity
- Receptors, Androgen
- Sexual Maturation
- Testosterone
- Thymus Gland
Keywords
- Androgen receptor
- Bone
- Fat
- Inducible
Senescence of innate and adaptive responses and low-grade inflammation (inflammaging) hallmarks normal aging, which increases vulnerability to infectious diseases, autoimmunity and cancer. In normal aging, sympathetic dysregulation contributes to the dysregulation of innate and adaptive immunity and inflammaging. Sympathetic innervation of immune cells in secondary immune organs regulates immune responses. Previously in Fischer 344 (F344) rats, we reported an age-related increase in sympathetic tone and sympathetic dysfunction in beta-adrenergic receptor (AR) signaling of splenic lymphocytes that contributes to immune senescence, although the responsible mechanisms remains unexplored. In this study, we extend our previous findings using the much longer-lived Brown-Norway (BN) rats, whose behavior and immune response profile differ strikingly from F344 rats. Here, we investigated whether increased sympathetic nerve activity (SNA) in the aging spleen contributes to age-related sympathetic neuropathy and altered neurotransmission in splenic lymphocytes in BN rats. Fifteen-month male BN rats received 0, 0.5 or 1.5 μg/kg/day rilmenidine intraperitoneally for 90 days to lower sympathetic tone. Untreated young and age-matched rats controlled for effects of age. We found that elevated SNA in the aging BN rat spleen does not contribute significantly to sympathetic neuropathy or the aging-induced impairment of canonical β-AR signal transduction. Despite the rilmenidine-induced increase in β-AR expression, splenocyte c-AMP production was comparable with age-matched controls, thus dampening nerve activity had no effect on receptor coupling to adenylate cyclase. Understanding how aging affects neuroimmune regulation in healthy aging rodent models may eventually lead to strategies that improve health in aging populations vulnerable to immunosenescence and low-grade systemic inflammation.
MeSH Terms
- Adrenergic beta-Agonists
- Aging
- Animals
- Male
- Norepinephrine
- Organ Size
- Rats
- Rats, Inbred BN
- Receptors, Adrenergic, beta
- Spleen
- Sympathetic Nervous System
- Sympatholytics
- Synaptic Transmission
Keywords
- Imidazoline-1 receptor agonist
- Neurotransmission
- Norepinephrine turnover
- Sympathetic innervation
- β-AR-stimulated cAMP production
Brown adipose tissue (BAT) is an important energy metabolic organ that is highly implicated in obesity, type 2 diabetes, and atherosclerosis. Aging is one of the most important determinants of BAT activity. In this study, we used F-FDG PET/CT imaging to assess BAT aging in Lmna mice. The maximum standardized uptake value (SUV ) of the BAT was measured, and the target/nontarget (T/NT) values of BAT were calculated. The transcription and the protein expression levels of the uncoupling protein 1 (UCP1), beta3-adrenergic receptor ([i]β[/i]3-AR), and the PR domain-containing 16 (PRDM16) were measured by quantitative real-time polymerase chain reaction (RT-PCR) and Western blotting or immunohistochemical analysis. Apoptosis and cell senescence rates in the BAT of WT and Lmna mice were determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and by CDKN2A/p16INK4a immunohistochemical staining, respectively. At 14 weeks of age, the BAT SUV and the expression levels of UCP1, [i]β[/i]3-AR, and PRDM16 in Lmna mice were significantly reduced relative to WT mice. At the same time, the number of p16INK4a and TUNEL positively stained cells (%) increased in Lmna mice. Collectively, our results indicate that the aging characteristics and the aging regulatory mechanism in the BAT of Lmna mice can mimic the normal BAT aging process.
MeSH Terms
- Adipose Tissue, Brown
- Aging
- Animals
- Body Weight
- DNA-Binding Proteins
- Disease Models, Animal
- Fluorodeoxyglucose F18
- Lamin Type A
- Positron Emission Tomography Computed Tomography
- Progeria
- Receptors, Adrenergic, beta-3
- Transcription Factors
- Uncoupling Protein 1
Current models posit a sequence of amyloid β (Aβ), tau, atrophy, and cognitive change leading to Alzheimer's disease, but ambiguities remain. We examined these sequences via serial mediations. We studied normal controls, early mild cognitive impairment, and late mild cognitive impairment individuals from the Alzheimer's Disease Neuroimaging Initiative 2 database for the mediation of baseline cerebrospinal fluid Aβ effects on 2-year cognitive change via regional longitudinal atrophy rate (AR) alone or AR and tau. In normal controls, Aβ correlated directly with regional ARs and memory loss, with no mediations. In early mild cognitive impairment, tau and lateral temporal ARs serially mediated the influence of Aβ on memory while Aβ affected memory via hippocampal AR. Late mild cognitive impairment consistently showed serial mediations of tau followed by atrophy. However, Aβ effects on memory also continued to be specifically mediated by medial temporal ARs without intermediate tau. Biomarker sequences vary by region and disease state, suggesting the need to refine current cascade models.
Keywords
- Alzheimer's disease
- Amyloid β
- Cognitive aging
- Longitudinal atrophy
- MCI
- Tau
Alpha rhythm (AR) changes are the most pronounced electroencephalogram phenomenon in the aging brain. We analyzed them based on the inherent AR structure obtained by parallel factor analysis decomposition in the cortical source space. AR showed a stable multicomponent structure in 78% of sixty 20- to 81-year-old healthy adults. Typically, it consists of 2 components. The distribution of the higher frequency occipito-parietal component widens with age, with its maximum moving from BA18/19 to BA37. The low-frequency component originating from the occipito-temporal regions in young adults also moves anteriorly with age, while maintaining its maximum within BA37. Both components slow down by 1 Hz over the adult lifespan. The multicomponent AR is more common in younger subjects, whereas a single-component AR in older subjects. This uneven occurrence as well as the increasing spatial and frequency overlaps between components suggest transformation of the multicomponent AR into the single-component AR with age. A detailed knowledge of AR component structure would be useful to monitor age-related neurodegenerative processes in humans.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Alpha Rhythm
- Brain
- Data Interpretation, Statistical
- Female
- Humans
- Male
- Middle Aged
- Signal Processing, Computer-Assisted
- Young Adult
Keywords
- Alpha rhythm slowing
- Component structure of alpha rhythm
- Oscillations
- PARAFAC
- Resting state
- Source localization
Skeletal muscle has emerged as a critical, disease-relevant target tissue in spinal and bulbar muscular atrophy, a degenerative disorder of the neuromuscular system caused by a CAG/polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. Here, we used RNA-sequencing (RNA-Seq) to identify pathways that are disrupted in diseased muscle using AR113Q knockin mice. This analysis unexpectedly identified substantially diminished expression of numerous ubiquitin/proteasome pathway genes in AR113Q muscle, encoding approximately 30% of proteasome subunits and 20% of E2 ubiquitin conjugases. These changes were age, hormone, and glutamine length dependent and arose due to a toxic gain of function conferred by the mutation. Moreover, altered gene expression was associated with decreased levels of the proteasome transcription factor NRF1 and its activator DDI2 and resulted in diminished proteasome activity. Ubiquitinated ADRM1 was detected in AR113Q muscle, indicating the occurrence of stalled proteasomes in mutant mice. Finally, diminished expression of Drosophila orthologues of NRF1 or ADRM1 promoted the accumulation of polyQ AR protein and increased toxicity. Collectively, these data indicate that AR113Q muscle develops progressive proteasome dysfunction that leads to the impairment of quality control and the accumulation of polyQ AR protein, key features that contribute to the age-dependent onset and progression of this disorder.
MeSH Terms
- Aging
- Animals
- Cell Adhesion Molecules
- Intracellular Signaling Peptides and Proteins
- Male
- Mice
- Mice, Transgenic
- Muscle, Skeletal
- Muscular Atrophy, Spinal
- Nuclear Respiratory Factor 1
- Peptides
- Proteasome Endopeptidase Complex
- Receptors, Androgen
- Trinucleotide Repeat Expansion
Keywords
- Muscle Biology
- Neuromuscular disease
- Neuroscience
- Protein misfolding
- Ubiquitin-proteosome system
Renal ischemia/reperfusion (IR) can induce acute kidney injury (AKI), which often progresses to chronic kidney disease (CKD). Dexmedetomidine (Dex), a highly selective α2 adrenergic receptor (α2-AR) agonist, protects against acute renal IR-induced injury. However, the effects of Dex on the transition of AKI to CKD remain unclear. Therefore, we investigated the mechanisms of Dex on renal fibrosis. Adult male C57BL/6 mice were pretreated with Dex, a specific α2A-adrenergic receptor (AR) blocker (BRL-44408), or a cell senescence inhibitor (rapamycin) in a surgical bilateral renal IR model. The diagnoses of AKI and chronic renal fibrosis were performed by histopathological staining and western blotting. Histopathological changes, cell senescence, tubular fibrotic markers, and the expression of inflammatory factors were studied. Pretreatment with Dex alleviated renal IR-induced AKI and chronic tubulointerstitial fibrosis in later stages. Similar to the effects of rapamycin, pretreatment with Dex also decreased the number of senescent tubular cells and weakened the protein expression of senescence-associated markers such as p53, p21, and p16. Furthermore, the expression of inflammatory markers was also decreased in Dex-treated IR mice; and these protective effects of Dex could be abolished by treatment with the specific α2A-AR blocker, BRL-44408. The administration of a single dose of Dex protects against AKI and CKD. Dex inhibits tubular cell senescence and inflammation as well as improves renal fibrosis to moderate the AKI-to-CKD transition. The renal protective potential of Dex may provide a novel treatment strategy for high-risk renal injury patients.
MeSH Terms
- Acute Kidney Injury
- Adrenergic alpha-2 Receptor Agonists
- Animals
- Cellular Senescence
- Dexmedetomidine
- Fibrosis
- Imidazoles
- Inflammation
- Isoindoles
- Kidney
- Male
- Mice
- Mice, Inbred C57BL
- Receptors, Adrenergic, alpha-2
- Reperfusion Injury
- Signal Transduction
- Sirolimus
Keywords
- Dexmedetomidine
- Fibrosis
- Inflammation
- Renal ischemia reperfusion
- Senescence
{{medline-entry |title=Cross talk between androgen and Wnt signaling potentially contributes to age-related skeletal muscle atrophy in rats. |pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29722624 |abstract=We sought to determine whether age-related gastrocnemius muscle mass loss was associated with parallel decrements in androgen receptor (AR) or select Wnt signaling markers. To test this hypothesis, serum-free and total testosterone (TEST) and gastrocnemius AR and Wnt signaling markers were analyzed in male Fischer 344 rats that were 3, 6, 12, 18, and 24 mo (mo) old ( n = 9 per group). Free and total TEST was greatest in 6 mo rats, and AR protein and Wnt5 protein levels linearly declined with aging. There were associations between Wnt5 protein levels and relative gastrocnemius mass ( r = 0.395, P = 0.007) as well as AR and Wnt5 protein levels (r = 0.670, P < 0.001). We next tested the hypothesis that Wnt5 affects muscle fiber size by treating C C -derived myotubes with lower (75 ng/ml) and higher (150 ng/ml) concentrations of recombinant Wnt5a protein. Both treatments increased myotube size ( P < 0.05) suggesting this ligand may affect muscle fiber size in vivo. We next tested if Wnt5a protein levels were androgen-modulated by examining 10-mo-old male Fischer 344 rats ( n = 10-11 per group) that were orchiectomized and treated with testosterone-enanthate (TEST-E); trenbolone enanthate (TREN), a nonaromatizable synthetic testosterone analogue; or a vehicle (ORX only) for 4 wk. Interestingly, TEST-E and TREN treatments increased Wnt5a protein in the androgen-sensitive levator ani/bulbocavernosus muscle compared with ORX only ( P < 0.05). To summarize, aromatizable and nonaromatizable androgens increase Wnt5a protein expression in skeletal muscle, age-related decrements in muscle AR may contribute Wnt5a protein decrements, and our in vitro data imply this mechanism may contribute to age-related muscle loss. NEW