PCNA
Proliferating cell nuclear antigen (PCNA) (Cyclin)
Publications[править]
The aim of this work was to examine the content of aryl hydrocarbon receptor interacting protein (AIP) in fibroblasts of human dermis from 20 weeks of pregnancy until 85 years old, and defining of a role of AIP in age-dependent changes in the number of fibroblasts in the dermis. AIP, proliferating cells nuclear antigen (PCNA) were detected with indirect immunohistochemical technique. Results showed that a portion of fibroblasts with positive staining for AIP in the dermis is gradually increased from 20 weeks of pregnancy until 85 years old. A total number and percent of PCNA positive fibroblasts in dermis decreased with progression of age. Most sufficient age-dependent reduction in a total and PCNA positive number of dermal fibroblast was observed from antenatal until 40 years of life. Correlation analysis showed that both age-dependent decrease in the number of fibroblasts and retardation of their proliferation are significantly associated with age-related increase in the number of AIP positive fibroblasts in dermis. Results allow to suggest that AIP is involved in age-dependent decrease in the number and proliferation of fibroblasts in human dermis.
Keywords
- AIP
- PCNA
- aging
- fibroblasts
- skin
The mechanism underlying the association between age and depletion of the human ovarian follicle reserves remains uncertain. Many identified that impaired DNA polymerase β (Pol β)-mediated DNA base-excision repair (BER) drives to mouse oocyte aging. With aging, DNA lesions accumulate in primordial follicles. However, the expression of most DNA BER genes, including APE1, OGG1, XRCC1, Ligase I, Ligase α, PCNA and FEN1, remains unchanged during aging in mouse oocytes. Also, the reproductive capacity of Pol β /- heterozygote mice was impaired, and the primordial follicle counts were lower than that of wild type (wt) mice. The DNA lesions of heterozygous mice increased. Moreover, the Pol β knockdown leads to increased DNA damage in oocytes and decreased survival rate of oocytes. Oocytes over-expressing Pol β showed that the vitality of senescent cells enhancesis significantly. Furthermore, serum concentrations of anti-Müllerian hormone (AMH) indicated that the ovarian reserves of young mice with Pol β germline mutations were lower than those in wt. These data show that Pol β-related DNA BER efficiency is a major factor governing oocyte aging in mice.
Keywords
- BER
- Pol β
- menopause
- oocytes
- ovarian aging
The aim of this work was to examine the content of arylhydrocarbon receptor nuclear translocator (ARNT) in fibroblasts of human dermis from 20 weeks of pregnancy until 85 years old, and defining of a role of ARNT in age-dependent changes in the number of fibroblasts in the dermis. ARNT, proliferating cells nuclear antigen (PCNA) were detected with indirect immunohistochemical technique. Results showed that a portion of fibroblasts with positive staining for ARNT in the dermis is decreased from 20 weeks of pregnancy to 40 years old. Percent of ARNT positive fibroblasts in dermis is increased sufficiently since 41 year old until 60-85 years old group. A total number and percent of PCNA positive fibroblasts in dermis decreased with progression of age. Most sufficient age-dependent reduction in a total and PCNA positive number of dermal fibroblast was observed from antenatal until 40 years of life. Age-related changes in the content of ARNT in fibroblasts is not associated with an age-related decrease in total number and percent of PCNA positive fibroblasts the dermis.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Aryl Hydrocarbon Receptor Nuclear Translocator
- Child
- Child, Preschool
- Dermis
- Fetus
- Fibroblasts
- Humans
- Infant
- Infant, Newborn
- Skin
- Skin Aging
- Young Adult
Keywords
- ARNT
- PCNA
- aging
- fibroblasts
- skin
Bone marrow mesenchymal stem cells (BMSCs) have been considered to be an important regulator for immune function. We aim to prove the function improvement of aging spleen and thymus induced by BMSCs and unfold the specific mechanisms. Aging animal model was established using D-galactose. The morphological changes of spleen and thymus tissues were observed using hematoxylin-eosin staining and transmission electron microscopy. Key cytokines in the serum were measured with enzyme linked immunosorbent assay. Protein and mRNA levels of P16, P21, and PCNA were detected using western blotting and RT-qPCR. Special markers of BMSCs were identified using flow cytometry, and successful induction of BMSCs to steatoblast and osteoblasts was observed. Compared to aging model, BMSCs significantly increased the spleen and thymus index, improved the histological changes of spleen and thymus tissues. A remarkable increase of ratio between CD4 T cells and CD8 T cells, level of IL-2 was achieved by BMSCs. However, BMSCs markedly inhibited the content of IL-10, TNF-[i]a[/i], P16, and P21 but promoted PCNA. Significant inhibition of oxidative stress by BMSCs was also observed. We demonstrated that BMSCs significantly improved the tissue damage of aging spleen and thymus, BMSCs may improve aging organs through influencing cytokines, oxidative stress, and P21/PCNA.
Keywords
- BMSCs
- P21/PCNA
- aging
- immune system
- oxidative stress
Fibroblasts are crucial for supporting normal wound healing. However, the functional state of these cells is impaired in diabetics because of a high-glucose (HG) microenvironment. Small extracellular vesicles (sEVs) have emerged as a promising tool for skin wound treatment. The aim of this study was to investigate the effects of sEVs derived from human decidua-derived mesenchymal stem cells (dMSC-sEVs) on HG-induced human dermal fibroblast (HDF) senescence and diabetic wound healing and explore the underlying mechanism. We first created a HDF senescent model induced by HG in vitro. dMSC-conditioned medium (dMSC-CM) and dMSC-sEVs were collected and applied to treat the HG-induced HDFs. We then examined the proliferation, migration, differentiation, and senescence of these fibroblasts. At the same time, the expressions of RAGE, p21 RAS, Smad2/3, and pSmad2/3 were also analyzed. Furthermore, pSmad2/3 inhibitor (SB431542) was used to block the expression of pSmad2/3 to determine whether dMSC-sEVs improved HDF senescence by activating Smad pathway. Finally, we assessed the effect of dMSC-sEVs on diabetic wound healing. The HG microenvironment impaired the proliferation, migration, and differentiation abilities of the HDFs and accelerated their senescence. dMSC-CM containing sEVs improved the proliferation and migration abilities of the HG-induced fibroblasts. dMSC-sEVs internalized by HG-induced HDFs not only significantly promoted HDF proliferation, migration, and differentiation, but also improved the senescent state. Furthermore, dMSC-sEVs inhibited the expression of RAGE and stimulated the activation of Smad signaling pathway in these cells. However, SB431542 (pSmad2/3 inhibitor) could partially alleviate the anti-senescent effects of dMSC-sEVs on HG-induced HDFs. Moreover, the local application of dMSC-sEVs accelerated collagen deposition and led to enhanced wound healing in diabetic mice. The detection of PCNA, CXCR4, α-SMA, and p21 showed that dMSC-sEVs could enhance HDF proliferation, migration, and differentiation abilities and improve HDF senescent state in vivo. dMSC-sEVs have regenerative and protective effects on HG-induced senescent fibroblasts by suppressing RAGE pathway and activating Smad pathway, thereby accelerating diabetic wound healing. This indicates that dMSC-sEVs may be a promising candidate for diabetic wound treatment.
Keywords
- Diabetic wounds
- Fibroblasts
- High-glucose
- Senescence
- Small extracellular vesicles
The aim of this work was to examine the content of heat shock protein 90 (HSP90) in fibroblasts of human dermis from the development until deep aging (from 20 weeks of pregnancy until 85 years old), and defining of a role of HSP90 in age-dependent changes in the number of fibroblasts in the dermis. HSP90, proliferating cells nuclear antigen (PCNA) were detected with indirect immunohistochemical technique. Results showed that a portion of fibroblasts with positive staining for HSP90 in the dermis is not changed from 20 weeks of development to 20 years old. Percent of HSP90 positive fibroblasts in dermis is decreased from 21 to 60 years old. From 61 year, the number of HSP90 positive fibroblasts in dermis is increased. Age-related changes in the number of HSP90 positive fibroblasts is not statistically associated with an age-related decrease in a total number and percent of PCNA positive fibroblasts the dermis.
MeSH Terms
- Adolescent
- Adult
- Aging
- Child
- Child, Preschool
- Dermis
- Female
- Fibroblasts
- HSP90 Heat-Shock Proteins
- Humans
- Infant
- Infant, Newborn
- Middle Aged
- Pregnancy
- Young Adult
Keywords
- HSP90
- PCNA
- aging
- fibroblasts
- skin
[i]Parthenium argentatum[/i] (Gray), commonly known as guayule, has been used to obtain natural rubber since the beginning of the 20th century. Additionally, the so called "resin" is a waste product derived from the industrial process. The cycloartane-type triterpene Argentatin A (AA) is one of the main constituents of the industrial waste resin. In this study we evaluated the AA anticancer activity both in vitro and in vivo in the HCT116 colon cancer cells. The apoptosis promotion of AA was assessed by the annexin V/propidium iodide (PI) assay. The senescence was evaluated for SA-β-galactosidase, and PCNA was used as a marker of proliferation. Its antitumor activity was evaluated using a xenograft mouse model. The results indicated that AA-induced apoptosis in HCT-116 cells and was positively stained for SA-β-galactosidase. In the xenografted mice test, the administration of AA at the dose of 250 mg/kg three times a week for 21 days reduced tumor growth by 78.1%. A comparable tumor reduction was achieved with cisplatin at the dose of 2 mg/kg administered three times a week for 21 days. However, nude mice treated with AA did not lose weight, as they did remarkably when treated with cisplatin. Furthermore, the animals treated with AA showed similar blood profiles as the healthy control group. These data indicate the low toxicity of AA compared to that shown by cisplatin.
Keywords
- Argentatin A
- PCNA
- antiproliferative
- antitumor
- apoptosis
- cell senescence
- colon cancer
- xenografts
The aim of this work was to examine the content of transcription coactivator with PZD-binding motif (TAZ) in fibroblasts and blood vessels of human dermis from the development until deep aging (from 20 weeks of pregnancy until 85 years old), and defining of a role of TAZ in age-dependent changes in the number of fibroblasts and blood vessels in the dermis. TAZ, proliferating cells nuclear antigen (PCNA), endothelial cells marker CD31 were detected with indirect immunohistochemical technique. Results showed that portion of fibroblasts with positive staining for TAZ in the dermis is decreased from 20 weeks of pregnancy to 40 years old. Percent of TAZ positive fibroblasts in dermis is increased since 41 years old until 60-85 years old group. The content of TAZ in blood vessels in the human dermis is decreased sufficiently from 20 weeks of pregnancy until 40 years old followed by an increase from 41 years old. From 61 to 85 years of life, content of TAZ in dermal vessels was not differ from those in 41-60 age group. Age-related changes in the content of TAZ in fibroblasts and blood vessels is not associated with an age-related decrease in total number and percent of PCNA positive fibroblasts, the number of blood vessels in the dermis.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Child
- Child, Preschool
- Dermis
- Female
- Fibroblasts
- Humans
- Infant
- Infant, Newborn
- Middle Aged
- Pregnancy
- Protein-Serine-Threonine Kinases
- Skin Aging
- Trans-Activators
- Young Adult
Keywords
- CD31
- PCNA
- TAZ
- aging
- blood vessels
- fibroblasts
- skin
Preeclampsia (PE) is a serious complication of human pregnancy. Women who have had PE, especially early-onset PE (EPE), have an increased risk of cardiovascular disease (CVD) later in life. However, how PE is linked to CVD is not well understood. We previously reported that HtrA4, a placenta-specific protease, is significantly elevated in EPE, and inhibits the proliferation of endothelial cells as well as endothelial progenitor cells (EPCs). This can potentially impair endothelial repair and regeneration, leading to endothelial aging, which is a major risk factor of CVD. In this study, we examined whether HtrA4 can alter endothelial expression of senescence genes. Human umbilical vein endothelial cells (HUVECs) and primary EPCs isolated from cord blood of healthy pregnancies were used as in vitro models. Firstly, HUVECs were treated with HtrA4 at the highest levels detected in EPE for 48h and screened with a senescence PCR array. The results were then validated by RT-PCR and ELISA in HUVECs and EPCs treated with HtrA4 for 24 and 48h. We observed that HtrA4 significantly up-regulated IGFBP3, SERPINE1 and SERPINB2, which all promote senescence. IGFBP-3 protein was also significantly elevated in the media of HtrA4-treated HUVECs. Conversely, a number of genes including CDKN2C, PCNA, CALR, CHEK2 and NOX4 were downregulated by HtrA4. Many of these genes also showed a similar trend of change in EPCs following HtrA4 treatment. Elevation of placenta-derived HtrA4 in PE alters the expression of endothelial genes to promote cellular senescence and may contribute to premature endothelial aging.
Keywords
- Endothelial aging
- Endothelial cells
- HtrA4
- Preeclampsia
- Senescence
The aim of this work was to examine the content of Yes-associated protein (YAP) in fibroblasts and blood microvessels of human dermis from the development until deep aging (from 20 weeks of pregnancy until 85 years old), and defining of a role of YAP in age-dependent changes in the number of fibroblasts and blood microvessels in the dermis. YAP, proliferating cells nuclear antigen (PCNA), endothelial cells marker CD31 were detected with indirect immunohistochemical technique. Results showed that portion of fibroblasts with positive staining for YAP in the dermis is decreased from 20 weeks of pregnancy to 40 years old. Percent of YAP positive fibroblasts in dermis is increased sufficiently since 41 years old until 60-85 years old group. The content of YAP in blood microvessels in the human dermis is decreased sufficiently from 20 weeks of pregnancy until 40 years old. Age-related changes in the content of YAP in fibroblasts and blood microvessels is not statistically associated with an age-related decrease in total number and percent of PCNA positive fibroblasts, the number of blood vessels in the dermis.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Adult
- Aged
- Aged, 80 and over
- Aging
- Dermis
- Endothelial Cells
- Female
- Fibroblasts
- Humans
- Middle Aged
- Pregnancy
- Skin Aging
- Transcription Factors
Keywords
- CD31
- PCNA
- YAP
- aging
- blood vessels
- fibroblasts
- skin
The aim of this work was to examine the content of Piezo1 in fibroblasts and blood vessels of human dermis from the development until deep aging (from 20 weeks of pregnancy until 85 years old), and defining of a role of Piezo1 in age-dependent changes in the number of fibroblasts and blood vessels in the dermis. Piezo1, proliferating cells nuclear antigen (PCNA), endothelial cells marker CD31 were detected with indirect immunohistochemical technique. Results showed that a portion of fibroblasts with positive staining for Piezo1 in the dermis is decreased from 20 weeks of pregnancy to 40 years old. Percent of Piezo1 positive fibroblasts in dermis is increased sufficiently since 41 years old until 60-85 years old group. The content of Piezo1 in blood vessels in the human dermis is decreased sufficiently from 20 weeks of pregnancy until 40 years old. Age-related changes in the content of Piezo1 in fibroblasts and blood vessels is not associated with an age-related decrease in total number and percent of PCNA positive fibroblasts, the number of blood vessels in the dermis.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Blood Vessels
- Child
- Child, Preschool
- Dermis
- Female
- Fibroblasts
- Humans
- Infant
- Ion Channels
- Male
- Middle Aged
- Platelet Endothelial Cell Adhesion Molecule-1
- Pregnancy
- Proliferating Cell Nuclear Antigen
- Skin Aging
Keywords
- CD31
- PCNA
- Piezo1
- aging
- blood vessels
- fibroblasts
- skin
Ageing in men is believed to be associated with fertility decline and elevated risk of congenital disorders for the offspring. The previous studies also reported reduced germ and Sertoli cell numbers in older men. However, it is not clear whether ageing in men with normal spermatogenesis affects the testis and germ cell population dynamics in a way sufficient for transmitting adverse age effects to the offspring. We examined men with normal spermatogenesis at different ages concerning effects on persisting testicular cell types, that is the germ line and Sertoli cells, as these cell populations are prone to be exposed to age effects. Ageing was assessed in testicular biopsies of 32 patients assigned to three age groups: (i) 28.8 ± 2.7 years; (ii) 48.1 ± 1 years; and (iii) 70.9 ± 6.2 years, n = 8 each, with normal spermatogenesis according to the Bergmann-Kliesch score, and in a group of meiotic arrest patients (29.9 ± 3.8 years, n = 8) to decipher potential links between different germ cell types. Besides morphometry of seminiferous tubules and Sertoli cell nuclei, we investigated spermatogenic output/efficiency, and dynamics of spermatogonial populations via immunohistochemistry for MAGE A4, PCNA, CREM and quantified A-pale/A-dark spermatogonia. We found a constant spermatogenic output (CREM-positive round spermatids) in all age groups studied. In men beyond their mid-40s (group 2), we detected increased nuclear and nucleolar size in Sertoli cells, indirectly indicating an elevated protein turnover. From the 7th decade (group 3) of life onwards, testes showed increased proliferation of undifferentiated spermatogonia, decreased spermatogenic efficiency and elevated numbers of proliferating A-dark spermatogonia. Maintaining normal sperm output seems to be an intrinsic determinant of spermatogenesis. Ageing appears to affect this output and might provoke compensatory proliferation increase in A spermatogonia which, in turn, might hamper germ cell integrity.
MeSH Terms
- Adult
- Aged
- Aging
- Congenital Abnormalities
- Genetic Diseases, Inborn
- Humans
- Male
- Middle Aged
- Seminiferous Tubules
- Sertoli Cells
- Spermatogenesis
- Spermatogonia
- Spermatozoa
Keywords
- A-dark
- Sertoli cell nuclei
- ageing
- proliferation
- spermatogenesis
- spermatogonia
Heavy ion radiation, prevalent in outer space and relevant for radiotherapy, is densely ionizing and poses risk to stem cells that are key to intestinal homeostasis. Currently, the molecular spectrum of heavy ion radiation-induced perturbations in intestinal stem cells (ISCs), that could trigger intestinal pathologies, remains largely unexplored. The Lgr5-EGFP-IRES-creERT mice were exposed to 50 cGy of iron radiation. Mice were euthanized 60 d after exposure and ISCs were sorted using fluorescence activated cell sorting. Reactive oxygen species (ROS) and mitochondrial superoxide were measured using fluorescent probes. Since DNA damage is linked to senescence and senescent cells acquire senescence-associated secretory phenotype (SASP), we stained ISCs for both senescence markers p16, p21, and p19 as well as SASP markers IL6, IL8, and VEGF. Due to potential positive effects of SASP on proliferation, we also stained for PCNA. Data show increased ROS and ongoing DNA damage, by staining for γH2AX, and 53BP1, along with accumulation of senescence markers. Results also showed increased SASP markers in senescent cells. Collectively, our data suggest that heavy-ion-induced chronic stress and ongoing DNA damage is promoting SASP in a fraction of the ISCs, which has implications for gastrointestinal function, inflammation, and carcinogenesis in astronauts and patients.
MeSH Terms
- Animals
- Cellular Senescence
- DNA Damage
- Epithelial Cells
- Flow Cytometry
- Green Fluorescent Proteins
- Heavy Ions
- Humans
- Intestinal Mucosa
- Iron
- Male
- Mice
- Reactive Oxygen Species
- Receptors, G-Protein-Coupled
- Stem Cells
Keywords
- SASP
- heavy ion radiation
- intestinal stem cell
- premature aging
- radiotherapy
- senescence
- space radiation
The aim of this work was to examine the content of transforming growth factor-β (TGF-β) in fibroblasts and blood microvessels of human dermis from the development until deep aging (from 20 weeks of pregnancy until 85 years old), and defining of a role of TGF-β in age-dependent changes in the number of fibroblasts and blood microvessels in the dermis. TGF-β, proliferating cells nuclear antigen (PCNA), endothelial cells marker CD 31 were detected with indirect immunohistochemical technique. Results showed that portion of fibroblasts with positive staining for TGF-β in the dermis is increased from 20 weeks of pregnancy until 85 years old. More expressed growth in percent of TGF-β positive fibroblasts in the human dermis is observed after birth and after 40 years old. The content of TGF-β in blood microvessels in the human dermis is decreased sufficiently from 41 years old. Age-related increase in a portion of fibroblasts with positive staining on TGF-β is associated with an age-related decrease in total number and percent of PCNA positive fibroblasts in human dermis. Age-related decrease in the content of TGF-β in blood microvessels is accompanied with an age-related decrease in their number in the dermis. Age-related increase in the content of TGF-β in fibroblasts is involved in an age-dependent decrease in their total number and proliferation in the dermis. Age-related decrease in the content of TGF-β in blood microvessels in dermis takes part in the age-related diminishing of blood microvessels number in the dermis.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Dermis
- Female
- Fibroblasts
- Humans
- Middle Aged
- Pregnancy
- Skin
- Transforming Growth Factor beta
- Transforming Growth Factors
Keywords
- CD31
- PCNA
- TGF-β
- aging
- blood vessels
- fibroblasts
- skin
Whether hippocampal neurogenesis persists throughout life in the human brain is not fully resolved. Here, we demonstrate that hippocampal neurogenesis is persistent through the tenth decade of life and is detectable in patients with mild cognitive impairments and Alzheimer's disease. In a cohort of 18 participants with a mean age of 90.6 years, Nestin Sox2 neural progenitor cells (NPCs) and DCX neuroblasts and immature neurons were detected, but their numbers greatly varied between participants. Nestin cells localize in the anterior hippocampus, and NPCs, neuroblasts, and immature neurons are evenly distributed along the anterior to posterior axis. The number of DCX PCNA cells is reduced in mild cognitive impairments, and higher numbers of neuroblasts are associated with better cognitive status. The number of DCX PCNA cells correlates with functional interactions between presynaptic SNARE proteins. Our results suggest that hippocampal neurogenesis persists in the aged and diseased human brain and that it is possibly associated with cognition.
MeSH Terms
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Cells, Cultured
- Cognition
- Cohort Studies
- Female
- Hippocampus
- Humans
- Male
- Microtubule-Associated Proteins
- Nestin
- Neural Stem Cells
- Neurogenesis
- Neurons
- Neuropeptides
- Proliferating Cell Nuclear Antigen
- SNARE Proteins
- SOXB1 Transcription Factors
Keywords
- Alzheimer’s disease
- adult neurogenesis
- aging
- cognitive dysfunction
- human neurogenesis
- neural stem cells
- neurogenesis in aging
Environmental factors during perinatal life can lead to changes in the mammary gland, making it susceptible to cancer in adulthood. Breastfeeding has a special importance since it takes place at a critical period of growth and development of the newborn. We aimed to analyze if an appropriate lactation protects the offspring against mammary carcinogenesis during adult life and explore the mechanisms involved in the protective effect. One-day-old Sprague-Dawley female rats were randomly distributed in litters of three (L3), eight (L8) or 12 (L12) pups per dam, to induce a differential consumption of breast milk. At 55 days of age, the animals were treated with a single dose of dimethylbenzanthracene to study tumor latency, incidence and progression. Histological, immunohistochemical and Western blot studies were performed. We observed lower incidence and higher latency in L3 compared to the other groups. The mitotic index and expression of proliferating cell nuclear antigen (PCNA) was significantly augmented in tumors of L12 rats compared to L3 and L8, while the apoptotic index was augmented in tumors of L3 v. L12. Cleaved caspase 8 was significantly higher in tumors from L3 compared to L12. Tumors developed in L3 have a greater number of apoptotic bodies and a greater expression of caspase 8. These results demonstrate that the animals that maintained a higher intake of maternal milk (L3) presented lower incidence and greater tumor latency. Lower consumption of breast milk (L12) would increase tumor mitosis and the expression of PCNA, explaining the higher tumor incidence observed in this group.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Breast Feeding
- Female
- Incidence
- Lactation
- Mammary Neoplasms, Animal
- Milk
- Mitosis
- Pregnancy
- Rats
- Rats, Sprague-Dawley
Keywords
- PCNA
- caspase 8
- dimethylbenz(a)anthracene
- mammary gland
- tumor
Perfluoroalkyl acids (PFAAs) are widely used in industrial and commercial products and possess endocrine disrupting properties. Perfluorononanoic acid (PFNA), one of PFAAs, has been mainly reported to produce testicular toxicity in adult animals. The objective of the present study was to examine the effect of acute exposure of PFNA to prepubertal male Parkes (P) mice on spermatogenesis and testicular steroidogenesis, and to study the possible mechanism(s) of its action. PFNA (2 and 5 mg/kg) was orally administered to male P mice for 14 days from postnatal day 25-38. Histologically, testis in PFNA-treated mice showed non-uniform diverse degenerative changes in the seminiferous tubules; both normal and affected tubules were seen in the same testicular sections. The treatment caused a reduction in intra-testicular and serum testosterone levels accompanied by a decrease in testicular expression of SF1, StAR, CYP11A1, and 3β- and17β-HSD. Further, the activity of antioxidant enzymes and expression of Nrf2 and HO-1 in the testis were markedly decreased, while the level of lipid peroxidation and expression of IKKβ, NF-κB and caspase-3 were significantly increased in testis of PFNA-treated mice. There was also a decrease in PCNA expression and in PCNA-index and an increase in TUNEL-positive germ cells in testes of PFNA-treated mice. In conclusion, the results suggest that PFNA exposure to prepubertal male mice altered antioxidant enzymes activity and Nrf2-HO-1 signaling, leading to oxidative stress and a decrease in testosterone biosynthesis in the testis; these changes, in turn, caused increased apoptosis and decreased proliferation of germ cells, thereby suppression of spermatogenesis.
MeSH Terms
- Aging
- Animals
- Antioxidants
- Endocrine Disruptors
- Fluorocarbons
- Male
- Mice
- Oxidative Stress
- Signal Transduction
- Spermatogenesis
- Testis
- Testosterone
Keywords
- Oxidative stress
- Perfluorononanoic acid
- Prepuberty
- Spermatogenesis
- Steroidogenesis
Multiple sclerosis (MS) is a chronic inflammatory CNS disease, which causes demyelinated lesions and damages white and gray matter regions. Aging is a significant factor in the progression of MS, and microglia, the immune cells of the CNS tissue, play an important role in all disease stages. During aging, microglia are functionally altered. These age-related changes probably already begin early and might influence the progression of CNS pathologies. The aim of the present study was to investigate whether microglia in the middle-aged CNS already react differently to demyelination. For this purpose, several microglia markers (ionized calcium binding adaptor molecule 1 (Iba-1), P2RY12, F4/80, CD68, major histocompatibility complex II (MHCII), macrophage receptor with collagenous structure (Marco), Translocator protein 18 kD ([[TSPO]]), CD206, and CD163) were analyzed in the acute cuprizone demyelination model in young (2-month-old) and middle-aged (10-month-old) mice. In addition, microglial proliferation was quantified using double-labeling with proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine (BrdU), which was injected with the onset of remyelination. To compare age-related microglial changes during de- and remyelination in both gray and white matter, the hilus of the dorsal hippocampal dentate gyrus (DG) and the splenium of the corpus callosum (CC) were analyzed in parallel. Age-related changes in microglia of healthy controls were more pronounced in the analyzed gray matter region (higher levels of F4/80 and Marco as well as lower expression of CD68 in middle-aged mice). During de- and remyelination, a stronger increase of the microglial markers Iba-1, CD68 and [[TSPO]] was observed in the splenium of the younger groups. There was a significant reduction of P2RY12 during demyelination, however, this was age- and region-dependent. The induction of the anti-inflammatory markers CD206 and CD163 was stronger in the middle-aged group, but also differed between the two analyzed regions. De- and remyelination led to a significant increase in PCNA microglia only in young groups within the white matter region. The number of BrdU microglia was not changed during de- or remyelination. These results clearly show that microglia are already altered during middle-age and also react differently to CNS demyelination, however, this is highly region-dependent.
Keywords
- P2RY12
- TSPO
- aging
- corpus callosum
- cuprizone
- demyelination
- hippocampus
- microglia
Cells expend a large amount of energy to maintain their DNA sequence. DNA repair pathways, cell cycle checkpoint activation, proofreading polymerases, and chromatin structure are ways in which the cell minimizes changes to the genome. During replication, the DNA-damage tolerance pathway allows the replication forks to bypass damage on the template strand. This avoids prolonged replication fork stalling, which can contribute to genome instability. The DNA-damage tolerance pathway includes two subpathways: translesion synthesis and template switch. Post-translational modification of PCNA and the histone tails, cell cycle phase, and local DNA structure have all been shown to influence subpathway choice. Chromatin architecture contributes to maintaining genome stability by providing physical protection of the DNA and by regulating DNA-processing pathways. As such, chromatin-binding factors have been implicated in maintaining genome stability. Using [i]Saccharomyces cerevisiae[/i], we examined the role of Spn1 (Suppresses postrecruitment gene number 1), a chromatin-binding and transcription elongation factor, in DNA-damage tolerance. Expression of a mutant allele of [i]SPN1[/i] results in increased resistance to the DNA-damaging agent methyl methanesulfonate, lower spontaneous and damage-induced mutation rates, along with increased chronological life span. We attribute these effects to an increased usage of the template switch branch of the DNA-damage tolerance pathway in the [i]spn1[/i] strain. This provides evidence for a role of wild-type Spn1 in promoting genome instability, as well as having ties to overcoming replication stress and contributing to chronological aging.
MeSH Terms
- Aging
- Chromatin
- DNA Damage
- DNA Repair
- DNA Replication
- Gene Expression Regulation, Fungal
- Genome, Fungal
- Genomic Instability
- Saccharomyces cerevisiae
- Saccharomyces cerevisiae Proteins
Keywords
- DNA-damage tolerance
- genome instability
- methyl methanesulfonate
- yeast
MicroRNAs (miRs) play an important role in many cancers and can affect cancer cell behavior, including glioma. This study aims at investigating the effects of miR-338-5p on the senescence, migration, invasion, and apoptosis of glioma cells via MAPK-signaling pathway by binding to FOXD1. Gene expression microarray analysis was performed to screen differentially expressed miRNAs associated with glioma. Glioma tissues and adjacent tissues were collected. siRNA, mimic, and inhibitor were introduced for investigating the tumor suppressor role of miR-338-5p in glioma. Proliferation, migration, invasion, senescence, cell-cycle distribution, and apoptosis after transfection were detected by MTT assay, scratch test, Transwell assay, β-galactosidase staining, and flow cytometry, respectively. FOXD1 was identified as the up-regulated gene in glioma based on microarray data of GSE65626. FOXD1 was the target gene of miR-338-5p. Glioma tissues had increased expression of FOXD1, MEK-2, ERK-1, DAF, PCNA, and Bcl-2, and decreased expression of miR-338-5p and Bax. In cell experiments, after transfected with overexpressed miR-338-5p, higher expression of miR-338-5p, Bax, CD133, ZEB1, SOX2, SNAI1, and MMP2, but lower expression of FOXD1, MEK-2, ERK-1, Bcl-2, DAF, and PCNA were found accompanied with weaker proliferation, migration and invasion as well as stemness abilities but stronger senescence and higher apoptosis rate. We found that overexpression of miR-338-5p suppresses glioma cell proliferation, migration, and invasion and accelerates its senescence and apoptosis by decreasing FOXD1 expression via inhibition of activation of MAPK-signaling pathway.
MeSH Terms
- Apoptosis
- Biomarkers
- Brain Neoplasms
- Cell Line, Tumor
- Cell Movement
- Cell Proliferation
- Cell Survival
- Computational Biology
- Forkhead Transcription Factors
- Gene Expression
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Genes, Reporter
- Genes, Tumor Suppressor
- Glioma
- Humans
- MicroRNAs
- Mitogen-Activated Protein Kinases
- Neoplastic Stem Cells
- RNA Interference
- Signal Transduction
Keywords
- FOXD1
- Glioma cells
- Invasion
- MAPK-signaling pathway
- MicroRNA-338-5p
- Migration
- Proliferation
- Senescence
Disparate roles exist for tumor-associated macrophages in breast cancer growth and progression. The aim of this study was to explore the influence of induced macrophages on the growth of breast cancer cells. THP-1 monocytes were differentiated to macrophages using phorbol 12-myristate 13-acetate. The effect of the medium from THP-1 monocytes or macrophage-conditioned medium (MφCM) on MCF-7 (estrogen receptor and progesterone-positive positive) and MDA-MB-231 (MB; triple-negative) breast cancer cells was determined at 24 h, 48 h and 72 h. Assays were conducted for cell viability, apoptosis, proliferation and cell phenotype, and quantitative real-time polymerase chain reaction (qRT-PCR) for expression of associated genes. MφCM inhibited proliferation of MCF-7 and MB cells in a time-dependent manner and, in particular, decreased viability of MCF-7 cells. MφCM induced a markedly vacuolated phenotype in MCF-7 increased apoptosis in MCF-7 cells, but correlative changes in Bcl-2 or Bax were absent. A multifold and significant reduction in anti-apoptotic Bcl-2 in MB cells was not matched by increased apoptosis. The cell cycle inhibitor CDKN1A was increased in both cell lines, but PCNA decreased only in MB cells. Senescence-associated galactosidase beta-1 (GLB1) mRNA was decreased in MCF-7 cells (48 and 72 h) but increased in MB cells (72 h). Increased expression of interleukin-6 (IL-6) and IL-8 was seen in both cell lines, and increased tumor necrosis factor- α was seen at 24 h for MB and 72 h for MCF-7 indicating increased inflammatory responses of the cancer cells. The two breast cancer celllines had different responses to MφCM, mainly involving inhibition rather than stimulation of growth of the cells, stimulation of senescence (MB cells) and increased inflammatory cytokine expression. The estrogen and progesterone receptor status of the cell lines may determine their response to MφCM. The function of the inflammatory cytokines in breast cancer growth remains to be identified.
MeSH Terms
- Apoptosis
- Apoptosis Regulatory Proteins
- Breast Neoplasms
- Cell Cycle Proteins
- Cell Proliferation
- Cell Survival
- Cellular Senescence
- Culture Media, Conditioned
- Cytokines
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Inflammation Mediators
- MCF-7 Cells
- Macrophage Activation
- Macrophages
- Paracrine Communication
- Phenotype
- Signal Transduction
- THP-1 Cells
- Tetradecanoylphorbol Acetate
- Time Factors
- Triple Negative Breast Neoplasms
Keywords
- Apoptosis
- Autophagy
- Breast cancer
- Inflammation
- Macrophage
- Senescence
This work was aimed to study levels of thyroid hormone receptors in human dermal fibroblasts from the development to deep aging. Skin specimens from human fetuses died antenatally from 20 to 40 weeks of pregnancy, humans died from different causes from birth to 85 years of life were used for the study. Total number of fibroblasts, percent of proliferating cells nuclear antigen (PCNA) positive dermal fibroblasts, expression of thyroid hormone receptors-α and -β in dermal fibroblasts were examined. PCNA and thyroid hormone receptors were viewed immunohistochemically. A total number of fibroblasts in dermis were counting in sections stained with haematoxylin and eosin. Results showed that maximal levels of thyroid hormone receptors-α and -β were observed from 20 to 40 weeks of pregnancy. The levels of thyroid hormone receptors-α and -β were decreased from birth to 40 years of life. From 41 to 85 years, the levels of thyroid hormone receptors were approximately the same. A total number and percent of PCNA positive fibroblasts in dermis decreased with progression of age. Most sufficient age-dependent reduction in a total and PCNA positive number of dermal fibroblast was observed from antenatal until 40 years of life. Correlation analysis and one-way ANOVA showed that age-dependent decrease in the number of fibroblasts and retardation of their proliferation in human dermis is significantly associated with age-related decrease in the level of thyroid hormone receptors-α and -β in dermal fibroblasts. Results allow to suggest that thyroid hormone receptors are involved in age-dependent decrease in the number and proliferation of fibroblasts in human dermis.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Child
- Child, Preschool
- Dermis
- Female
- Fibroblasts
- Humans
- Infant
- Infant, Newborn
- Male
- Middle Aged
- Pregnancy
- Receptors, Thyroid Hormone
- Young Adult
Keywords
- PCNA
- aging
- fibroblasts
- ontogenesis
- skin
- thyroid hormone receptors
Aging is associated with a deregulation of biological systems that lead to an increase in oxidative stress, inflammation, and apoptosis, among other effects. Xanthohumol is the main preylated chalcone present in hops (Humulus lupulus L.) whose antioxidant, anti-inflammatory and chemopreventive properties have been shown in recent years. In the present study, the possible protective effects of xanthohumol on liver alterations associated with aging were evaluated. Male young and old senescence-accelerated prone mice (SAMP8), aged 2 and 10 months, respectively, were divided into four groups: non-treated young, non-treated old, old treated with 1 mg/kg/day xanthohumol, and old treated with 5 mg/kg/day xanthohumol. Male senescence-accelerated resistant mice (SAMR1) were used as controls. After 30 days of treatment, animals were sacrificed and livers were collected. mRNA (AIF, BAD, BAX, Bcl-2, eNOS, HO-1, IL-1β, NF-κB2, PCNA, sirtuin 1 and TNF-α) and protein expressions (BAD, BAX, AIF, caspase-3, Blc-2, eNOS, iNOS, TNF-α, IL1β, NF-κB2, and IL10) were measured by RT-PCR and Western blotting, respectively. Mean values were analyzed using ANOVA. A significant increase in mRNA and protein levels of oxidative stress, pro-inflammatory and proliferative markers, as well as pro-apoptotic parameters was shown in old non-treated SAMP8 mice compared to the young SAMP8 group and SAMR1 mice. In general, age-related oxidative stress, inflammation and apoptosis were significantly decreased (p < 0.05) after XN treatment. In most cases, this effect was dose-dependent. XN was shown to modulate inflammation, apoptosis, and oxidative stress in aged livers, exerting a protective effect in hepatic alterations.
MeSH Terms
- Aging
- Animals
- Antioxidants
- Apoptosis
- Blotting, Western
- Disease Models, Animal
- Flavonoids
- Inflammation
- Liver
- Male
- Mice
- Oxidative Stress
- Polymerase Chain Reaction
- Propiophenones
Keywords
- Aging
- Inflammation
- Liver
- Senescence-accelerated mouse
- Xanthohumol
{{medline-entry |title=Comparison of naturally aging and D-galactose induced aging model in beagle dogs. |pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29285136 |abstract=Animal models have been used to study aging for decades. In numerous aging studies, beagles are the most commonly used breed of dog. However, few studies have compared between naturally aging models and experimentally induced aging models in beagle dogs. In the present study, a D-galactose induced aging model was compared with a naturally aging model, and young adult dogs were considered as the young control group. The level of malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in serum, and brain tissue were measured. Histopathological comparisons of the liver, kidneys, heart, lungs and spleen were evaluated using hematoxylin and eosin (H