Frontotemporal dementia and amyotrophic lateral sclerosis are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1-q12.2 with genome-wide significant linkage in a large European Australian family with autosomal dominant inheritance of frontotemporal dementia and amyotrophic lateral sclerosis and no mutation in known amyotrophic lateral sclerosis or dementia genes. Here we demonstrate the segregation of a novel missense variant in CYLD (c.2155A>G, p.M719V) within the linkage region as the genetic cause of disease in this family. Immunohistochemical analysis of brain tissue from two CYLD p.M719V mutation carriers showed widespread glial CYLD immunoreactivity. Primary mouse neurons transfected with CYLDM719V exhibited increased cytoplasmic localization of TDP-43 and shortened axons. CYLD encodes a lysine 63 deubiquitinase and CYLD cutaneous syndrome, a skin tumour disorder, is caused by mutations that lead to reduced deubiquitinase activity. In contrast with CYLD cutaneous syndrome-causative mutations, CYLDM719V exhibited significantly increased lysine 63 deubiquitinase activity relative to the wild-type enzyme (paired Wilcoxon signed-rank test P = 0.005). Overexpression of CYLDM719V in HEK293 cells led to more potent inhibition of the cell signalling molecule NF-κB and impairment of autophagosome fusion to lysosomes, a key process in autophagy. Although CYLD mutations appear to be rare, CYLD's interaction with at least three other proteins encoded by frontotemporal dementia and/or amyotrophic lateral sclerosis genes (TBK1, OPTN and SQSTM1) suggests that it may play a central role in the pathogenesis of these disorders. Mutations in several frontotemporal dementia and amyotrophic lateral sclerosis genes, including TBK1, OPTN and SQSTM1, result in a loss of autophagy function. We show here that increased CYLD activity also reduces autophagy function, highlighting the importance of autophagy regulation in the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

Estragole, naturally occurring in a variety of herbs and spices, can form DNA adducts after bioactivation. Estragole DNA adduct formation and repair was studied in in vitro liver cell models, and a molecular dynamics simulation was used to investigate the conformation dependent (in)efficiency of N2-(trans-isoestragol-3'-yl)-2'-deoxyguanosine (E-3'-N2-dG) DNA adduct repair. HepG2, HepaRG cells, primary rat hepatocytes and CHO cells (including CHO wild-type and three NER-deficient mutants) were exposed to 50 μM estragole or 1'-hydroxyestragole and DNA adduct formation was quantified by LC-MS immediately following exposure and after a period of repair. Results obtained from CHO cell lines indicated that NER plays a role in repair of E-3'-N2-dG adducts, however, with limited efficiency since in the CHO wt cells 80% DNA adducts remained upon 24 h repair. Inefficiency of DNA repair was also found in HepaRG cells and primary rat hepatocytes. Changes in DNA structure resulting from E-3'-N2-dG adduct formation were investigated by molecular dynamics simulations. Results from molecular dynamics simulations revealed that conformational changes in double-stranded DNA by E-3'-N2-dG adduct formation are small, providing a possible explanation for the restrained repair, which may require larger distortions in the DNA structure. NER-mediated enzymatic repair of E-3'-N2-dG DNA adducts upon exposure to estragole will be limited, providing opportunities for accumulation of damage upon repeated daily exposure. The inability of this enzymatic repair is likely due to a limited distortion of the DNA double-stranded helix resulting in inefficient activation of nucleotide excision repair.

Background-independent (BI) and stably expressed (SE) quantitative trait loci (QTLs) were identified using two sets of introgression lines across multiple environments. Genetic background more greatly affected fiber quality traits than environmental factors. Sixty-one SE-QTLs, including two BI-QTLs, were novel and 48 SE-QTLs, including seven BI-QTLs, were previously reported. Cotton fiber quality traits are controlled by QTLs and are susceptible to environmental influence. Fiber quality improvement is an essential goal in cotton breeding but is hindered by limited knowledge of the genetic basis of fiber quality traits. In this study, two sets of introgression lines of Gossypium hirsutum × G. barbadense were used to dissect the QTL stability of three fiber quality traits (fiber length, strength and micronaire) across environments using 551 simple sequence repeat markers selected from our high-density genetic map. A total of 76 and 120 QTLs were detected in the CCRI36 and CCRI45 backgrounds, respectively. Nine BI-QTLs were found, and 78 (41.71%) of the detected QTLs were reported previously. Thirty-nine and 79 QTLs were SE-QTLs in at least two environments in the CCRI36 and CCRI45 backgrounds, respectively. Forty-eight SE-QTLs, including seven BI-QTLs, were confirmed in previous reports, and 61 SE-QTLs, including two BI-QTLs, were considered novel. These results indicate that genetic background more strongly impacts on fiber quality traits than environmental factors. Twenty-three clusters with BI- and/or SE-QTLs were identified, 19 of which harbored favorable alleles from G. barbadense for two or three fiber quality traits. This study is the first report using two sets of introgression lines to identify fiber quality QTLs across environments in cotton, providing insights into the effect of genetic backgrounds and environments on the QTL expression of fiber quality and important information for the genetic basis underlying fiber quality traits toward QTL cloning and molecular breeding.

Anyone who has ever found themselves lost while driving in an unfamiliar neighborhood or forgotten where they parked their car can appreciate the importance of being able to navigate their environment. Navigation, or wayfinding, is a large-scale spatial ability that involves keeping track of the relative positions of objects and features in space, which allows for determining the path to a goal location. Early experiences shape spatial skill development, and research finds sex differences in spatial behaviors from preschool through adulthood, with males consistently outperforming females. The basis for sex differences in spatial aptitude is still debated, but explanations include differences in childhood spatial experience, the use of strategies for solving large-scale spatial problems, and spatial anxiety. The current study seeks to understand childhood wayfinding factors that may influence sex and individual differences in wayfinding strategies and wayfinding anxiety in adulthood.

Co-delivery of two different therapeutics (miRNA-1284 and cisplatin (CDDP)) into the cancer cells in a single nanocarrier provides new dimension to the cancer treatment. In this study, we have designed the CD59sp-conjugated miRNA-1284/cisplatin(CDDP)-loaded liposomes for the enhanced therapeutic effect against cervical cancers. Compared with miRNA-1284/CDDP-loaded liposomes (LP-miCDDP), CD59 antibody-conjugated LP-miCDDP (CD/LP-miCDDP) showed a significantly higher cytotoxicity in HeLa cells. Notably, MiR-1284 showed a typical concentration-dependent cell killing effect in the cervical cancer cells owing to the downregulation of HMGB1. Flow cytometer analysis showed that CD/LP-miCDDP resulted in maximum apoptosis effect (~ 60%) compared to CDDP (~ 20%) or miR-1284 (~ 12%) treated cells indicating the superior anticancer effect in the cancer cells. Importantly, CD/LP-miCDDP significantly prolonged the blood circulation of encapsulated drug in rats with AUC(o-t) of CD/LP-miCDDP showed a 6.9 fold higher value than that of free CDDP. Similarly, CD/LP-miCDDP showed an eightfold decrease in the clearance (CL) and 3.6-fold higher t1/2 compared to that of free CDDP. Overall, results demonstrated that targeted and synergistic co-delivery of therapeutic components could be promising in cervical cancer therapy.

Evaluate the physical performance of the VERITON CzT camera (Spectrum Dynamics, Caesarea, Israel) that benefits from new detection architecture enabling whole-body imaging compared to that of a conventional dual-head Anger camera.

The burden of nontuberculous mycobacterial (NTM) pulmonary disease (PD) is increasing globally. To understand the treatment outcomes and prognosis of NTM-PD, a unified registry is needed. In this project, we aim to construct a multicenter prospective observational cohort with NTM-PD in South Korea (NTM-KOREA).

BACKGROUND Doxorubicin-induced myocardial toxicity is associated with oxidative stress, cardiomyocyte, apoptosis, and loss of contractile function. Previous studies showed that microRNA-375 (miR-375) expression was increased in mouse models of heart failure and clinically, and that inhibition of miR-375 reduced inflammation and increased survival of cardiomyocytes. This study aimed to investigate the effects and mechanisms of inhibition of miR-375 in a mouse model of doxorubicin-induced cardiac toxicity in vivo and in doxorubicin-treated rat and mouse cardiomyocytes in vitro. MATERIAL AND METHODS The mouse model of doxorubicin-induced cardiac toxicity was developed using an intraperitoneal injection of doxorubicin (15 mg/kg diluted in 0.9% saline) for eight days. Treatment was followed by a single subcutaneous injection of miR-375 inhibitor. H9c2 rat cardiac myocytes and adult murine cardiomyocytes (AMCs) were cultured in vitro and treated with doxorubicin, with and without pretreatment with miR-375 inhibitor. RESULTS Doxorubicin significantly upregulated miR-375 expression in vitro and in vivo, and inhibition of miR-375 re-established myocardial redox homeostasis, prevented doxorubicin-induced oxidative stress and cardiomyocyte apoptosis, and activated the PDK1/AKT axis by reducing the direct binding of miR-375 to 3' UTR of the PDK1 gene. Inhibition of PDK1 and AKT abolished the protective role of miR-375 inhibition on doxorubicin-induced oxidative damage. CONCLUSIONS Inhibition of miR-375 prevented oxidative damage in a mouse model of doxorubicin-induced cardiac toxicity in vivo and in doxorubicin-treated rat and mouse cardiomyocytes in vitro through the PDK1/AKT signaling pathway.

Shigellosis outbreaks caused by Shigella with decreased susceptibility to azithromycin (DSA-Shigella) among men who have sex with men (MSM) have been reported worldwide. We describe sexual health indicators and antimicrobial drug resistance for shigellosis cases in Minnesota, USA. We analyzed a sample of isolates received during 2012-2015 and cross-referenced cases with the Minnesota Department of Health Sexually Transmitted Disease Database to ascertain patients' HIV status and recent chlamydia, gonorrhea, and syphilis infections. Of 691 Shigella isolates, 46 (7%) were DSA-Shigella; 91% of DSA-Shigella patients were men, of whom 60% were living with HIV. Among men, those with DSA-Shigella infection had greater odds of living with HIV, identifying as MSM, or having a recent diagnosis of a sexually transmitted disease. DSA-Shigella was associated with MSM, HIV infection, and recent sexually transmitted disease. To decrease spread of DSA-Shigella, interventions targeted at communities at high risk are needed.

Pancreatic cancer (PaCa) is a common malignant tumor of the digestive system with poor prognosis and no ideal treatment for inoperable patients, which is partly due to delayed diagnoses. It is recently reported that the protein histidine phosphatase LHPP is a tumor suppressor in hepatocellular carcinoma, cervical cancer, and bladder cancer. So far, there is no study on the expression level of LHPP in PaCa, and its mechanism of action on tumors is unclear. In this experiment, LHPP expression was lower in cancer tissues than that in normal pancreatic tissue, and clinicopathological results showed that LHPP expression was correlated with the degree of differentiation and lymphatic metastasis of pancreatic carcinoma. The biological characteristics of LHPP in PaCa cells were examined by the cell counting kit-8 assay, transwell assay, and monoclonal formation test. The inhibitory mechanism of LHPP in PaCa cells was determined using Western blotting and flow cytometry. The results showed that LHPP restrained PaCa cell proliferation, migration, and invasion. Increased LHPP expression promoted the apoptosis of PaCa cells through higher activation of cleaved-PARP and cleaved-Casp3 and lower activation of cIAP1. Importantly, the increase in LHPP enhanced PTEN expression and decreased the phosphorylated AKT level. Moreover, LHPP-induced apoptosis was diminished by SC79 (AKT activator) in PaCa cells. In conclusion, LHPP blocks proliferation, migration, and invasion and enhances apoptosis in PaCa cells through the PTEN/AKT signaling pathway.

The study explores the role of neddylation in early trophoblast development and its alteration during the pathogenesis of recurrent spontaneous abortion (RSA). Immunofluorescence and western blot were conducted to evaluate the expression pattern of NEDD8 protein in the first-trimester placentas of healthy control and RSA patients. Neddylated-cullins, especially neddylated-cullin1, were downregulated and their substrate, p21, was accumulated in RSA samples. NEDD8 cytoplasmic recruitment was observed in extravillous trophoblast (EVT) progenitors of RSA placentas. Consistent with the results of clinical samples, neddylation inhibition using MLN4924 in trophoblast cell lines caused obvious p21 accumulation and free NEDD8 cytoplasmic recruitment. Further in vitro study demonstrated neddylation inhibition attenuated proliferation of Jeg-3 cells via p21 accumulation. Moreover, when trophoblast stem (TS) cells derived from first-trimester placentas were cultured for differentiation analyses. MLN4924 impaired the differentiation of TS cells towards EVTs by downregulating HLA-G and GATA3. p21 knockdown could partly rescue MLN4924-suppressed HLA-G and GATA3 expression. In conclusion, cullin1 neddylation-mediated p21 degradation is required for trophoblast proliferation and can affect trophoblast plasticity by affecting HLA-G and GATA3 expression. The results provide insights into the pathological mechanism of RSA and the biological regulation of trophoblast development.

One of the major risk factors for asthma development is exposure to environmental allergens. House dust mites (HDM) can induce DNA damage, resulting in asthma. Resveratrol (RES) produced by several plants, has anti‑apoptotic properties and may affect a variety of biological processes. The aim of the present study was to investigate the protective role of RES against apoptosis in bronchial epithelial cells. C57BL/6J mice treated with HDM exhibited high levels of cell apoptosis, while RES significantly reversed this process. Induced DNA damage was more severe in the HDM group vs. the HDM combined with RES group. This result was confirmed by immunostaining and western blot analysis of the protein expression of the DNA damage‑related gene γH2AX, which was highly induced by HDM. In addition, treatment with RES protected bronchial epithelial cells exposed to HDM from DNA damage. RES decreases reactive oxygen species levels to inhibit oxidative DNA damage in bronchial epithelial cells. Furthermore, compared with the HDM group, induced cell apoptosis could be attenuated by RES in the group of combined treatment with RES and HDM. A DNA repair inhibitor augmented DNA damage and apoptosis in bronchial epithelial cells, whereas RES significantly attenuated cell apoptosis through inhibiting DNA damage.

Periodontitis is a common inflammatory disorder affecting the tissues surrounding the teeth, which can lead to the destruction of periodontal tissue and tooth loss. Resveratrol, a natural phytoalexin, exerts multiple biological effects. For example, its anti‑inflammatory activity has been widely studied for the treatment of inflammatory bowel disease for a number of years. However, its effect on bone repair and new bone formation in an inflammatory microenvironment is not well understood. Accordingly, the effect of resveratrol on inflammation‑affected human periodontal ligament stem cells (hPDLSCs) requires further investigation. In the present study, the effect of tumor necrosis factor‑α (TNF‑α), resveratrol, or the combination of both on the osteogenic differentiation of hPDLSCs, as well as the underlying mechanisms involved, were investigated. Cell Counting Kit‑8 assay, alkaline phosphatase staining, Alizarin red staining, Oil Red O staining, reverse transcription‑quantitative PCR and western blotting were used in the present study. It was demonstrated that resveratrol enhanced hPDLSC osteogenesis and reversed the inhibitory effects of TNF‑α on this process. Further mechanistic studies indicated that resveratrol exerted anti‑inflammatory activity by activating the ERK1/2 pathway, decreasing the secretion of interleukin (IL)‑6 and IL‑8 induced by TNF‑α, and enhancing hPDLSCs osteogenesis. The present study suggested that resveratrol may be a novel and promising therapeutic choice for periodontitis.

Prostaglandin E receptor subtype 4 (EP4) is widely distributed in the heart, but its role in hepatic ischemia/reperfusion (I/R), particularly in mitochondrial permeability transition pore (MPTP) modulation, is yet to be elucidated. In the present study, an EP4 agonist (CAY10598) was used in a rat model to evaluate the effects of EP4 activation on liver I/R and the mechanisms underlying this. I/R insult upregulated hepatic EP4 expression during early reperfusion. In addition, subcutaneous CAY10598 injection prior to the onset of reperfusion significantly increased hepatocyte cAMP concentrations and decreased serum ALT and AST levels and necrotic and apoptotic cell percentages, after 6 h of reperfusion. Moreover, CAY10598 protected mitochondrial morphology, markedly inhibited mitochondrial permeability transition pore (MPTP) opening and decreased liver reactive oxygen species levels. This occurred via activation of the ERK1/2‑GSK3β pathway rather than the janus kinase (JAK)2‑signal transducers and activators of transcription (STAT)3 pathway, and resulted in prevention of mitochondria‑associated cell injury. The MPTP opener carboxyatractyloside (CATR) and the ERK1/2 inhibitor PD98059 also partially reversed the protective effects of CAY10598 on the liver and mitochondria. The current findings indicate that EP4 activation induces ERK1/2‑GSK3β signaling and subsequent MPTP inhibition to provide hepatoprotection, and these observations are informative for developing new molecular targets and preventative therapies for I/R in a clinical setting.

Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly population. Autophagy is a well‑known regulator of neurodegenerative diseases and β‑asarone has been discovered to have certain neuropharmacological effects. Thus, the present study aimed to analyze the potential effects of β‑asarone in AD and its possible mechanism of action in relation to autophagy. The present study investigated the effects of β‑asarone on the number of senile plaques and amyloid β(Aβ)40, Aβ42, amyloid precursor protein (APP) and Beclin‑1 mRNA levels in the hippocampus of APP/presenilin‑1 (PS1) transgenic mice. The possible mechanism of β‑asarone on autophagy‑related proteins, including Beclin‑1, light chain (LC)3A, LC3B and p62 levels, and the number of autophagosomes was also investigated. Mice were divided into a normal control group, a model group, a β‑asarone‑treated group, a 3‑MA‑treated group and a rapamycin‑treated group. Treatments were continuously administered to all mice for 30 days by intragastric administration. The mice, including those in the normal and model control groups, were given equal volumes of saline. It was demonstrated that β‑asarone treatment reduced the number of senile plaques and autophagosomes, and decreased Aβ40, Aβ42, APP and Beclin‑1 expression in the hippocampus of model mice compared with untreated model mice. β‑asarone also inhibited LC3A/B expression levels, but increased p62 expression. It was deduced that the neuroprotective effects of β‑asarone in APP/PS1 transgenic mice resulted from its inhibition of autophagy. In conclusion, the data suggested that β‑asarone should be explored further as a potential therapeutic agent in AD.

Penehyclidine hydrochloride (PHC) suppresses renal ischemia and reperfusion (I/R) injury (IRI); however, the underlying mechanism of action that achieves this function remains largely unknown. The present study aimed to investigate the potential role of autophagy in PHC‑induced suppression of renal IRI, as well as the involvement of cell proliferation and apoptosis. A rat IRI model and a cellular hypoxia/oxygenation (H/R) model were established; PHC, 3‑methyladenine (3‑MA) and rapamycin (Rapa) were administered to the IRI model rats prior to I/R induction and to H/R cells following reperfusion. Serum creatinine was measured using a biochemistry analyzer, whereas aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) expression levels were detected using ELISA kits. Renal tissue injury was evaluated by histological examination. In addition, microtubule‑associated protein light chain 3B (LC3B) expression, autophagosome formation, cell proliferation and apoptosis were detected in the cellular H/R model. The results demonstrated that I/R induced renal injury in IRI model rats, upregulated serum creatinine, ALAT and ASAT expression levels, and increased autophagic processes. In contrast, pretreatment with PHC or Rapa significantly prevented these I/R‑induced changes, whereas the administration of 3‑MA enhanced I/R‑induced injuries through suppressing autophagy. PHC and Rapa increased LC3B and Beclin‑1 expression levels, but decreased sequestome 1 (p62) expression in the cellular H/R model, whereas 3‑MA prevented these PHC‑induced changes. PHC and Rapa promoted proliferation and autophagy in the cellular H/R model; these effects were accompanied by increased expression levels of LC3B and Beclin‑1, and reduced p62 expression levels, whereas these levels were inhibited by 3‑MA. Furthermore, PHC and Rapa inhibited apoptosis in the cellular H/R model through increasing Bcl‑2 expression levels, and suppressing Bax and caspase‑3 expression levels; the opposite effect was induced by 3‑MA. In conclusion, PHC suppressed renal IRI through the induction of autophagy, which in turn promoted proliferation and suppressed apoptosis in renal cells.

lncRNA cancer susceptibility candidate 2 (CASC2) is a recently identified oncogenic lncRNA in different types of cancers. Our preliminary microarray data showed that lncRNA CASC2 was downregulated in the plasma of patients with rheumatoid arthritis (RA), indicating the involvement of this lncRNA in RA. In the present study, lncRNA CASC2 and IL‑17 in plasma were detected by reverse transcription‑-quantitative PCR and ELISA, respectively. Diagnostic analyses were performed using receiver operating characteristic curves. Flow cytometry was performed to evaluate cell apoptosis. The effects of lncRNA CASC2 on IL‑17 expression were determined via western blotting. lncRNA CASC2 was found to be downregulated, while IL‑17 was upregulated in the plasma of RA patients when compared with these levels in the plasma of healthy controls. Plasma levels of lncRNA CASC2 and IL‑17 were significantly and inversely correlated in both RA patients and healthy controls. Altered plasma levels of lncRNA CASC2 and IL‑17 were able to differentiate RA patients from healthy controls. Overexpression of lncRNA CASC2 promoted, while treatment with IL‑17 inhibited the apoptosis of human fibroblast‑like synoviocytes (HFLSs) isolated from RA patients. Overexpression of lncRNA CASC2 inhibited IL‑17 expression in HFLS, while treatment with IL‑17 did not significantly affect the expression of lncRNA CASC2. Therefore, downregulation of lncRNA CASC2 is involved in RA and lncRNA CASC2 overexpression may promote the apoptosis of HFLS by downregulating IL‑17.

Glial cells are the resident immune cells of the central nervous system. Reactive glial cells release inflammatory mediators that induce neurotoxicity or aggravate neurodegeneration. Regulation of glial activation is crucial for the initiation and progression of neuropathological conditions. Constituents of the peach tree (Prunus persica L. Batsch), which has a global distribution, have been found to exert therapeutic effects in pathological conditions, such as rashes, eczema and allergies. However, the therapeutic potential of its aerial parts (leaves, fruits and twigs) remains to be elucidated. The present study aimed to evaluate the anti‑inflammatory role of P. persica methanol extract (PPB) on lipopolysaccharide (LPS)‑stimulated glial cells. High‑performance liquid chromatography coupled with tandem mass spectrometry analysis showed that PPB contained chlorogenic acid and catechin, which have antioxidant properties. Western blot and reverse transcription polymerase chain reaction results indicated that PPB reduced the transcription of various proinflammatory enzymes (nitric oxide synthase and cyclooxygenase‑2) and cytokines [tumor necrosis factor‑α, interleukin (IL)‑1β and IL‑6] in LPS‑stimulated BV2 cells. In addition, PPB inhibited the activation of NF‑κB and various mitogen‑activated protein kinases required for proinflammatory mediator transcription. Finally, nitrite measurement and immunocytochemistry results indicated that PPB also suppressed nitrite production and NF‑κB translocation in LPS‑stimulated primary astrocytes. Thus, PPB may be used as a potential therapeutic agent for neurodegenerative diseases and neurotoxicity via the suppression of glial cell activation.

Bone marrow mesenchymal stem cells (BM‑MSCs) regulate the balance between regulatory T cells (Tregs) and T helper 17 (Th17) cells. However, the role of different factors on BM‑MSCs‑mediated regulation of the Treg/Th17 balance is unknown. BM‑MSCs and CD4+ T lymphocytes were co‑cultured with various treatments. The ratio of Treg/Th17 cells was calculated and the expression of different cytokines was measured. BM‑MSCs were found to have a proliferative effect on Th17 cells at a basal concentration and at a 2‑fold increase in the number of BM‑MSCs. However, when the number of BM‑MSCs used was increased 4‑fold, they had an inhibitory effect on the Th17 cells. The effect of BM‑MSCs on Tregs was inhibited by the addition of tacrolimus but not rapamycin. The effect of BM‑MSCs on Th17 cells was inhibited by rapamycin. Additionally, the effect of BM‑MSCs on Tregs were inhibited by the addition of a transforming growth factor‑β (TGF‑β) blocker, whereas these TGF‑β‑blockers had no effect on Th17 cells. Addition of an interleukin (IL)‑2 blocker reduced the proportion of Th17 cells when co‑cultured with a high number of MSCs compared with the low concentration group and the proportion of Treg cells was significantly decreased when cells were treated with an IL‑2 blocker compared with the control group. Together, these results showed the varying effects of MSCs on the ratio of Treg/Th17, its dependence on the number of MSCs and the effects of cytokines in inducing these changes in the balance.

Mesenchymal stem cells (MSCs) affect diverse aspects of tumor progression, such as angiogenesis, tumor growth and metastasis. Bone marrow MSCs (BM‑MSCs) are fibroblast‑like cells with multipotent differentiation ability, that localize to areas of tissue damage, including wounds and solid tumors. The tumor suppressor gene, p53, is functionally involved in cell cycle control, apoptosis and genomic stability, and is mutated and inactivated in most human cancers. The present study aimed to investigate the role of p53 in the biology of BM‑MSCs. In the present study, p53 wild‑type (p53+/+), knockdown (p53+/‑) and knockout (p53‑/‑) mouse BM‑MSCs (mBM‑MSCs) were observed to be similar in appearance and in the expression of cell surface biomarkers, but expressed differential p53 protein levels. The p53+/‑ and p53‑/‑ mBM‑MSCs demonstrated an increased proliferation rate compared with mBM‑MSCs derived from p53+/+ mice. mBM‑MSCs from all three groups, representing distinct p53 statuses, were unable to form tumors over a 3‑month period in vivo. The adipogenic and osteogenic differentiation of mBM‑MSCs was increased in the absence of p53. The colony formation and migratory abilities of p53+/‑ and p53‑/‑ mBM‑MSCs were markedly enhanced, and the expression levels of stem cell‑associated proteins were significantly increased compared with p53+/+. The expression levels of microRNA (miR)‑3152 and miR‑337 were significantly increased in p53+/‑ and p53‑/‑ mBM‑MSCs, whereas the expression levels of miR‑221, miR‑155, miR‑1288 and miR‑4669 were significantly decreased. The expression levels of tumor necrosis factor‑α and interferon‑γ‑inducible protein‑10 were significantly upregulated in the supernatant of p53+/‑ and p53‑/‑ mBM‑MSCs. Ubiquitin protein ligase E3 component n‑recognin 2, RING‑finger protein 31 and matrix metalloproteinase 19 were highly expressed in p53+/‑ and p53‑/‑ mBM‑MSCs. The results of the present study indicated that p53 may serve an important role in the biology of mBM‑MSCs, and may provide novel insights into the role of cells with different p53 statuses in cancer progression.