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proliferation - Top 30 Publications

RUNX3 inhibits the proliferation and metastasis of gastric cancer through regulating miR-182/HOXA9.

This study intended to explore the molecular mechanism of RUNX3 in inhibiting the process of migration and proliferation of gastric cancer (GC) cells.

Orexin system in swine ovarian follicles.

Successful reproduction is strictly linked to metabolic cues. The orexins are a family of hypothalamic neurohormones, well known for their key role in the control of food intake and the involvement in several aspects of the reproductive process. The biological actions of both orexins are carried out through binding to the related Orexin 1 (OX1R) and Orexin 2 (OX2R) G-protein-coupled receptors. The purpose of this study was to investigate the presence of orexin system components in the porcine ovaries, to contribute to expand the knowledge about their pleiotropic role. First, we investigated the localization of orexin A (OXA) and its receptors by immunochemistry in different ovarian districts. Thereafter, we evaluated the expression of the prepro-orexin (PPO) gene and OXA effects on granulosa cell functions. Immunohistochemical study revealed the presence of orexinergic system components in porcine ovarian follicles. Moreover, our data show the expression of PPO messenger RNA in swine ovarian follicles >5 mm. In addition, OXA influences proliferation (P < 0.05), steroidogenic activity (P < 0.05), and redox status of granulosa cells (P < 0.05). Therefore, we hypothesize that OXA could exert a local physiological role in swine ovarian follicles even if further studies are required to deeply define the function of this pleiotropic system.

Intermedin reduces neointima formation by regulating vascular smooth muscle cell phenotype via cAMP/PKA pathway.

Vascular smooth muscle cell (VSMC) dedifferentiation contributes to neointima formation, which results in various vascular disorders. Intermedin (IMD), a cardiovascular paracrine/autocrine polypeptide, is involved in maintaining circulatory homeostasis. However, whether IMD protects against neointima formation remains largely unknown. The purpose of this study is to investigate the role of IMD in neointima formation and the possible mechanism.

Propolis supplementation attenuates the negative effects of oxidative stress induced by paraquat injection on productive performance and immune function in turkey poults.

Paraquat (PQ) is used as a herbicide in agriculture and causes oxidative and inflammatory damage to animal tissues. The current study was conducted to investigate the positive effects of dietary propolis (PR), as a potent naturally produced antioxidant, on growth performance and immune function of turkey poults exposed to oxidative stress induced by PQ injection. Native male turkey poults (n = 120, 49-d-old) were randomly assigned into 4 groups: poults received a basal diet with a daily subcutaneous PQ injection of 5 mg/kg BW for 7 consecutive days (PQ group), an experimental diet containing 1 g/kg PR with a daily subcutaneous PQ injection for 7 days (PR+PQ group), or received the experimental PR diet with a daily subcutaneous injection of 0.5 mL sterile saline for 7 days (PR group); while the control poults received a basal diet with a daily subcutaneous saline injection for 7 consecutive days (C group). The productive performance in the PQ group showed a significant (P < 0.05) reduction in the weight gain (WG) and feed intake (FI), and impaired feed conversion ratio (FCR). Propolis supplementation in the PR+PQ group significantly ameliorated the PQ effects on WG and FCR. Turkey poults of the PQ and PR+PQ groups had a significant augmentation in the blood malondialdehyde (MDA), tumor necrosis factor-α (TNFα), and corticosterone levels, and in contrast, a significant reduction in the triiodothyronine (T3), when compared to the C group. While propolis significantly reduced the MDA and corticosterone, and increased the T3 levels in the PR+PQ group compared to the PQ group. Furthermore, the dietary PR supplementation significantly limited the PQ-suppressive effects on cell- and humoral-mediated immunity and lymphocyte proliferation of turkey poults. In addition, propolis supplementation in the PR and PR+PQ groups markedly reversed the PQ-induced DNA fragmentation and heat shock protein 70 (Hsp70) over-expression in blood cells. It can be concluded that PR could improve turkey immunity and performance, particularly under inflammation and oxidative stress induced by PQ exposure.

Meat quality traits and proteome profile of woody broiler breast (pectoralis major) meat.

Woody breast meat has recently become prevalent in the broiler industry in both the United States and European Union. Recent publications have described the meat quality characteristics of woody breast meat as having hardened areas and pale ridge-like bulges at both the caudal and cranial regions of the breast. The present study investigated the meat quality (pH, color, cooking loss, and shear force) and protein quality characteristics (protein and salt-soluble protein content) in woody breast meat as compared to normal breast meat. In addition, the differences in the muscle proteome profiles of woody and normal breast meat were characterized. Results indicated that woody breast meat had a greater average pH (P < 0.0001) and cooking loss (P = 0.001) than normal breast meat, but woody breast meat did not differ in shear force (P > 0.05) in comparison to normal breast meat samples. The L*, a*, and b* values of woody breast fillets were greater than normal breast fillets (P < 0.0001 to L*; P = 0.002 to a*; P = 0.016 to b*). The woody breast meat had more fat (P < 0.0001) and moisture (P < 0.021) and less protein (P < 0.0001) and salt-soluble protein (P < 0.0001) when compared with normal breast fillets. Whole muscle proteome analysis indicated 8 proteins that were differentially expressed (P < 0.05) between normal and woody breast meat samples. The differences in muscle proteome between normal and woody breast meat indicated an increased oxidative stress in woody breast meat when compared to normal meat. In addition, the abundance of some glycolytic enzymes, which are critical to the regeneration of adenosine triphosphate (ATP) in postmortem muscles, was lower in woody breast meat than in normal breast meat. Proteomic differences provide additional information on the biochemical pathways and genetic variations that lead to woody breast meat. Further research should be conducted to elucidate the genetic and nutritional contributions to the proliferation of woody breast meat in the United States.

Effect of radiation on sucrose detection thresholds of mice.

Radiotherapy is one of the most common treatments for head and neck cancers, with an almost obligate side effect of altered taste (Conger 1973). In mice, targeted irradiation of the head and neck causes transient repression of proliferation of basal epithelial cells responsible for taste cell replacement, leading to a temporary depletion of taste sensory cells within taste buds, including Type II taste cells involved in detection of sweet stimuli (Nguyen et al. 2012). These findings suggest that irradiation may elevate sucrose detection thresholds, peaking at 7 days post-irradiation when loss of Type II cells is greatest. To test this hypothesis, sucrose detection thresholds (concentration detected in 50% of presentations) were measured in mice for 15 days after treatment of: 1) irradiation while anesthetized, 2) anesthetic alone, or 3) saline. Mice were trained to distinguish water from several concentrations of sucrose. Mice were irradiated with one 8 Gy dose (RADSOURCE-2000 X-ray Irradiator) to the nose and mouth while under 2,2,2-tribromethanol anesthesia (Avertin). Unexpectedly, mice given anesthesia showed a small elevation in sucrose thresholds compared to saline-injected mice, but irradiated mice show significantly elevated sucrose thresholds compared to either control group, an effect that peaked at 6-8 days post-irradiation. The timing of loss and recovery of sucrose sensitivity generally coincides with the reported maximal reduction and recovery of Type II taste cells (Nguyen et al. 2012). Thus, even a single dose of irradiation can significantly alter detection of carbohydrates, an important consideration for patients undergoing radiotherapy.

The Hippo signaling pathway in pancreatic β-cells: functions and regulations.

Hippo signaling is an evolutionarily conserved pathway that critically regulates development and homeostasis of various tissues in response to a wide range of extracellular and intracellular signals. As an emerging significant player in many diseases, the Hippo pathway is also involved in the pathophysiology of diabetes on the level of the pancreatic islets. Multiple lines of evidence uncover the importance of Hippo signaling in pancreas development as well as in the regulation of β-cell survival, proliferation and regeneration. Hippo therefore represents a potential target for therapeutic agents designed to improve β-cell function and survival in diabetes. In this review, we summarize recent data on the regulation of the Hippo signaling pathway in the pancreas/ in pancreatic islets, its functions on β-cell homeostasis in physiology and pathophysiology and its contribution towards diabetes progression. The current knowledge related to general mechanisms of action and the possibility of exploiting the Hippo pathway for therapeutic approaches to block β-cell failure in diabetes is highlighted.

The importance of propolis in alleviating the negative physiological effects of heat stress in quail chicks.

Heat stress is one of the most detrimental confrontations in tropical and subtropical regions of the world, causing considerable economic losses in poultry production. Propolis, a resinous product of worker honeybees, possesses several biological activities that could be used to alleviate the deleterious effects of high environmental temperature on poultry production. The current study was aimed at evaluating the effects of propolis supplementation to Japanese quail (Coturnix coturnix japonica) diets on the production performance, intestinal histomorphology, relative physiological and immunological parameters, and selected gene expression under heat stress conditions. Three hundred one-day-old Japanese quail chicks were randomly distributed into 20 wired-cages. At 28 d of age, the birds were divided into 2 temperature treatment groups; a normal at 24°C (C group) and a heat stress at 35°C (HS group). The birds in each group were further assigned to 2 subgroups; one of them was fed on a basal diet without propolis supplementation (-Pr subgroup) while the other was supplemented with propolis (+Pr subgroup). Production performance including body weight gain, feed intake and feed conversion ratio were measured. The intestinal histomorphological measurements were also performed for all treatment groups. Relative physiological parameters including body temperature, corticosterone hormone level, malondialdehyde (MDA) and free triiodothyronine hormone (fT3), as well as the relative immunological parameters including the total white blood cells count (TWBC's), heterophil/lymphocyte (H/L) ratio and lymphocyte proliferation index, were also measured. Furthermore, the mRNA expression for toll like receptor 5 (TLR5), cysteine-aspartic protease-6 (CASP6) and heat shock proteins 70 and 90 (Hsp70 and Hsp90) genes was quantified in this study. The quail production performance was significantly (P<0.05) impaired by HS treatment, while Pr treatment significantly improved the quail production performance. The villus width and area were significantly (P<0.05) lower in the HS compared to the C group, while Pr treatment significantly increased crypts depth of quail. A negative impact of HS treatment was observed on the physiological status of quail; however, propolis significantly alleviated this negative effect. Moreover, quail of the HS group expressed lower immunological parameters than C group, while propolis enhanced the immune status of the quail. The relative mRNA expression of TLR5 gene was down-regulated by HS treatment while it was up-regulated by the Pr treatment. Furthermore, the positive effects of propolis in HS-quail were evidenced by normalizing the high expressions of CASP6 and Hsp70 genes when compared to the C group. Based on these results, the addition of propolis to quail diets as a potential nutritional strategy in order to improve their performance, especially under heat stress conditions, is recommended.

Assay for Phosphorylation and Microtubule Binding Along with Localization of Tau Protein in Colorectal Cancer Cells.

The microtubule-associated protein tau is a neuronal protein that localizes mostly in axons. Generally tau is essential for normal neuronal functioning because it is involved in microtubule assembly and stabilization. Besides neurons, tau is expressed in human breast, prostate, gastric, colorectal, and pancreatic cancers where it shows nearly similar structure and exerts similar functions as the neuronal tau. The amount of tau and its phosphorylation can change its function as a stabilizer of microtubules, and lead to the development of paired helical filaments in different neurodegenerative disorders, such as Alzheimer's disease. Determining the phosphorylation state of tau and its microtubule-binding characteristics is important. In addition, examining the intracellular localization of tau is important in different diseases. This manuscript details standard protocols for measuring tau phosphorylation and tau binding to microtubules in colorectal cancer cells with or without curcumin and LiCl treatment. These treatments can be used to stop cancer cell proliferation and development. Intracellular localization of tau is examined by using immunohistochemistry and confocal microscopy while using low amounts of antibodies. These assays can be used repetitively for screening compounds that affect tau hyperphosphorylation or microtubule binding. Novel therapeutics used for different tauopathies or related anticancer agents can potentially be characterized using these protocols.

Cellulase-Assisted Extraction of Polysaccharides from White Hyacinth Bean: Characterization of Antioxidant Activity and Promotion for Probiotics Proliferation.

Food-derived polysaccharides have advantages over synthetical compounds and have attracted interest globally for decades. In this study, we optimized the cellulase-assisted extraction of polysaccharides from white hyacinth bean (PWBs) with the aid of response surface methodology (RSM). The optimum extraction parameters were a pH of 7.79, a cellulase of 2.73%, and a ratio of water to material of 61.39, producing a high polysaccharide yield (3.32 ± 0.03)%. The scavenging ability of PWBs varied on three radicals (hydroxyl > 2,2-diphenyl-1-picrylhydrazyl (DPPH) > superoxide). Furthermore, PWBs contributed to the proliferation of three probiotic bacteria (Lactobacillus acidophilus LA5, Bifidobacterium bifidum BB01, and Lactobacillus bulgaricus LB6). These investigations of PWBs provide a novel bioresource for the exploitation of antioxidant and probiotic bacterial proliferation.

Chronic Exposure to the Fusarium Mycotoxin Deoxynivalenol: Impact on Performance, Immune Organ, and Intestinal Integrity of Slow-Growing Chickens.

This study investigates the long-term effects of deoxynivalenol (DON) consumption on avian growth performance, on the proliferation, apoptosis, and DNA damage of spleen cells, and on intestinal integrity. Two hundred and eight 5-day-old black-feathered Taiwan country chickens were fed diets containing 0, 2, 5, and 10 mg/kg of DON for 16 weeks. Body weight gain of male birds in the 2 mg/kg group was significantly lower than that in the 5 mg/kg group. At the end of trial, feeding DON-contaminated diets of 5 mg/kg resulted in heavier spleens. Moreover, the increase in DON induced cellular proliferation, apoptosis, and DNA damage signals in the spleen, the exception being female birds fed 10 mg/kg of DON showing reduced proliferation. Expression of claudin-5 was increased in jejunum of female birds fed 2 and 5 mg/kg of DON, whereas decreased expression levels were found in male birds. In conclusion, our results verified that DON may cause a disturbance to the immune system and alter the intestinal barrier in Taiwan country chickens, and may also lead to discrepancies in growth performances in a dose- and sex-dependent manner.

Different Levels of Skin Whitening Activity among 3,6-Anhydro-l-galactose, Agarooligosaccharides, and Neoagarooligosaccharides.

3,6-Anhydro-l-galactose (AHG), a major monomeric constituent of red macroalgae (Rhodophyta), was recently reported to possess skin whitening activity. Moreover, AHG-containing oligosaccharides, such as agarooligosaccharides (AOSs) and neoagarooligosaccharides (NAOSs), have various physiological activities, including anti-inflammatory, antioxidant, and skin moisturizing effects. In this study, AHG and NAOSs were produced from agarose by enzymatic reactions catalyzed by an endo-type β-agarase, an exo-type β-agarase, and a neoagarobiose hydrolase. In a cell proliferation assay, AHG, AOSs, and NAOSs at 12.5, 25, and 50 μg/mL concentrations did not exhibit cytotoxicity toward murine B16 melanoma cells or human epidermal melanocytes. In an in vitro skin whitening activity assay of AHG, AOSs, and NAOSs at 50 μg/mL, AHG showed the highest skin whitening activity in both murine B16 melanoma cells and human epidermal melanocytes; this activity was mediated by the inhibition of melanogenesis. Neoagarotetraose and neoagarohexaose also exhibited in vitro skin whitening activity, whereas neoagarobiose and AOSs with degrees of polymerization of 3 (agarotriose), 5 (agaropentaose), and 7 (agaroheptaose) did not. Therefore, AHG is responsible for the skin whitening activity of agar-derived sugars, and the structural differences among the AHG-containing oligosaccharides may be responsible for their different skin whitening activities.

Functional Role of Lacrimal Gland Fibroblasts in a Mouse Model of Chronic Graft-Versus-Host Disease.

This study aimed to clarify the mechanisms and assess the characteristics of the chronic graft-versus-host disease (cGVHD) fibrosis in the lacrimal gland (LG) of mice.

Comparison of Moderate and High Energy of a Nano-Fractional Radiofrequency Treatment on a Photoaging Hairless Mice Model.

Fractional radiofrequency (FRF) has been widely used in skin rejuvenation. To explore optimal settings, it is important to compare different treatment parameters.

Induction of Desmoplastic Trichoepithelioma in a Dermatofibroma.

Induction of follicular germinative structures above a dermatofibroma (DF) is a common finding. Rarely, induction of a trichoblastoma in a DF has been observed. Here, we report the case of a desmoplastic trichoepithelioma induced by a DF. The lesion with clinical and histological appearance of a DF situated on the left dorsal foot showed an associated adnexal proliferation that fulfilled histopathological criteria of desmoplastic trichoepithelioma. Immunohistochemistry (Ber-EP4, Bcl-2, CK17, CK20, CK7, EMA, and Ki67) helped to confirm the diagnosis and to exclude possible differential diagnoses.

An Overview of Unfolded Protein Response Signaling and Its Role in Cancer.

Secretory and transmembrane proteins undergo post-translational modifications and folding in the subcellular organelle, that is, endoplasmic reticulum (ER) to become functionally active. Various factors such as high oxidative stress, low glucose, calcium imbalance, and viral infections interfere with the ER protein folding functions, leading to accumulation of unfolded and misfolded proteins that activate downstream signal transduction pathways, termed as unfolded protein response (UPR). This UPR signaling is adaptive and restored the normal function of cells by decreasing protein synthesis, increasing the folding capacity of ER and degradation of misfolded proteins. If the stress condition is overwhelmed, then UPR signaling shifts to apoptotic pathways. However, cancer cells utilized these UPR signaling for their survival and progression as an adaptive mechanism. In this review, the authors discuss about the overview of ER stress and subsequent UPR signaling and various aspects of cancer as survival, proliferation, and angiogenesis in relation to UPR. Understanding the UPR signaling in relation to cancer will be further helpful in designing therapeutics against cancer.

HIF-1α Promotes Breast Cancer Cell MCF-7 Proliferation and Invasion Through Regulating miR-210.

Many malignant tumors grow in hypoxic condition, which is associated with tumor growth, invasion, and metastasis. MicroRNAs are of great significance in the development of multiple malignant tumors. This study cultured breast cancer cell MCF-7 under the condition of different concentrations of oxygen, to test cell proliferation and invasion, and detect miR-210 expression, aiming to analyze the influence of hypoxia on breast cancer cell behaviors as well as miR-210 expressions.

Imaging of Integrin αvβ3 Expression in Lung Cancers and Brain Tumors Using Single-Photon Emission Computed Tomography with a Novel Radiotracer (99m)Tc-IDA-D-c(RGDfK)2.

Integrin αvβ3 is a molecular marker for the estimation of tumor angiogenesis and is an imaging target for radiolabeled Arg-Gly-Asp (RGD) peptides. In this study, the authors investigated the clinical efficacy and safety of a novel radiolabeled RGD peptide, (99m)Tc-IDA-D-[c(RGDfK)]2, for the imaging of integrin αvβ3 expression, as a measure of tumor angiogenesis in lung cancers and brain tumors. Five patients with lung cancers and seven with brain tumors underwent (99m)Tc-IDA-D-[c(RGDfK)]2 single-photon emission computed tomography (SPECT) imaging. Tumors were also assessed using (18)F-fluorodeoxyglucose positron emission tomography/computed tomography. Uptake of the radiotracer was expressed as the tumor-to-normal uptake ratio (TNR). All the lung cancers and brain tumors were well visualized on (99m)Tc-IDA-D-[c(RGDfK)]2 SPECT. TNR for (99m)Tc-IDA-D-[c(RGDfK)]2 was significantly higher than that for (18)F-FDG in brain tumors (6.4 ± 4.1 vs. 0.9 ± 0.4). Proliferation index of brain tumors showed a significant positive correlation with TNR for (99m)Tc-IDA-D-[c(RGDfK)]2 and (18)F-FDG. No laboratory and clinical adverse events were reported after (99m)Tc-IDA-D-[c(RGDfK)]2 injection. Their results suggest that (99m)Tc-IDA-D-[c(RGDfK)]2 is an efficacious and safe radiotracer for imaging integrin αvβ3 expression with potential application to monitoring the clinical efficacy of antiangiogenic agents in malignant tumors. In addition, this is the first clinical application of radiolabeled RGD peptides for SPECT imaging of brain tumors.

The involvement of lncRNAs in the development and progression of pancreatic cancer.

Pancreatic cancer is one of the most malignant tumors that are difficult to diagnose at its early stage and there is no effective therapy. Recent studies uncovered that many non-protein-coding RNAs including the class of long noncoding RNAs (lncRNAs) are differentially expressed in various types of tumors and they are potent regulators of tumor progression and metastasis. LncRNA can mediate tumor initiation, proliferation, migration and metastasis through modulating epigenetic modification, alternative splicing, transcription, and protein translation. In this review, we discuss the molecular mechanism of lncRNAs in the involvement of tumor growth, survival, epithelial-mesenchymal transition, tumor microenvironment, cancer stem cells and chemoresistance in pancreatic ductal adenocarcinoma (PDAC).

Embryonic Stem Cell Secreted Factors Decrease Invasiveness of Triple-Negative Breast Cancer Cells Through Regulome Modulation.

Stem cell microenvironments decrease the invasiveness of cancer cells, and elucidating the mechanisms associated with disease regression could further the development of targeted therapies for aggressive cancer subtypes. To this end, we applied an emerging technology, TRanscriptional Activity CEll aRray (TRACER), to investigate the reprogramming of triple-negative breast cancer (TNBC) cells in conditions that promoted a less aggressive phenotype. The repressive environment was established through exposure to mouse embryonic stem cell conditioned media (mESC CM). Assessment of carcinogenic phenotypes indicated that mESC CM exposure decreased proliferation, invasion, migration, and stemness in TNBC cells. Protein expression analysis revealed that mESC CM exposure increased expression of the epithelial protein E-cadherin and decreased the mesenchymal protein MMP9. Gene expression analysis showed that mESC CM decreased epithelial to mesenchymal transition (EMT) markers fibronectin, vimentin, and Snail. Over a period of 6 days, TRACER quantified changes in activity of 11 transcription factors (TFs) associated with oncogenic progression. The EMT profile was decreased in association with the activity of 7 TFs (Smad3, NF-κΒ, MEF2, GATA, Hif1, Sp1, and RXR). Further examination of Smad3 and GATA expression and phosphorylation revealed that mESC CM exposure decreased noncanonical Smad3 phosphorylation and Smad3-mediated gene expression, increased GATA3 expression and phosphorylation, and resulted in a synergistic decrease in migration of GATA3 overexpressing MDA-MB-231 cells. Collectively, the application of TRACER to examine TF activity associated with the transition of cancer cells to a less aggressive phenotype, as directed by mESC CM, identified novel mechanistic events linking the embryonic microenvironment to both favorable changes and cellular plasticity in TNBC cell phenotypes.

Overexpression of HN1L promotes cell malignant proliferation in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a progressive malignant disease, involving the activation of oncogenes and inactivation of tumor suppressors. In this study, we identified and characterized a novel oncogene hematopoietic- and neurologic-expressed sequence 1-like (HN1L) in human NSCLC. Overexpression of HN1L was frequently detected in primary NSCLC compared with their non-tumor counterparts (P < 0.001), which was significantly associated with tumor size (P = 0.022). In addition, Kaplan-Meier analysis showed that upregulation of HN1L correlated with worse overall survival (P = 0.029) and disease-free survival (P = 0.011) for NSCLC patients. Both in vitro and in vivo studies demonstrated that inhibition of HN1L expression with shRNA dramatically inhibited cell growth, adherent and non-adherent colony formation, and tumorigenicity in nude mice. The positive correlation of HN1L expression and Ki67 level in a large NSCLC samples further suggested the key role of HN1L in the regulation of cell growth. Further study showed that knockdown of HN1L resulted in dramatic cell cycle arrest by interfering with MAPK pathway via interacting with RASA4 protein. In conclusion, HN1L plays a crucial role in the progression of NSCLC by contributing to malignant proliferation, with possible use as a new intervention point for therapeutic strategies.

ECM Crosslinking Enhances Fibroblast Growth and Protects Against Matrix Proteolysis in Lung Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterised by accumulation of extra cellular matrix (ECM) proteins and fibroblast proliferation. ECM cross-linking enzymes have been implicated in fibrotic diseases and we hypothesised that the ECM in IPF is abnormally cross-linked which enhances fibroblast growth and resistance to normal ECM turnover. We used a combination of in vitro ECM preparations and in vivo assays to examine the expression of cross-linking enzymes and the effect of their inhibitors on fibroblast growth and ECM turnover. Lysyl oxidase like 1, 2, 3 and 4 were expressed equally in control and IPF derived fibroblasts. Transglutaminase 2 was more strongly expressed in IPF fibroblasts. Lysyl oxidase like 2, transglutaminase 2 and transglutaminase generated cross-links were strongly expressed in IPF lung tissue. Fibroblasts grown on IPF ECM had higher LOXL3 protein expression and transglutaminase activity compared with those grown on control ECM. IPF derived ECM also enhanced fibroblast adhesion and proliferation compared with control ECM. Inhibition of lysyl oxidase and transglutaminse activity during ECM formation affected ECM structure as visualised by electron microscopy and reduced the enhanced fibroblast adhesion and proliferation of IPF ECM to control levels. Inhibition of transglutaminase, but not lysyl oxidase activity, enhanced the turnover of ECM in vitro. In bleomycin treated mice, during the post-inflammatory fibrotic phase, inhibition of transglutaminases was associated with a reduction in whole lung collagen. Our findings suggest that the ECM in IPF may enhance pathological cross-linking which contributes to increased fibroblast growth, resistance to normal ECM turnover to drive lung fibrosis.

miR-31a-5p promotes postnatal cardiomyocyte proliferation by targeting RhoBTB1.

A limited number of microRNAs (miRNAs, miRs) have been reported to control postnatal cardiomyocyte proliferation, but their strong regulatory effects suggest a possible therapeutic approach to stimulate regenerative capacity in the diseased myocardium. This study aimed to investigate the miRNAs responsible for postnatal cardiomyocyte proliferation and their downstream targets. Here, we compared miRNA profiles in cardiomyocytes between postnatal day 0 (P0) and day 10 (P10) using miRNA arrays, and found that 21 miRNAs were upregulated at P10, whereas 11 were downregulated. Among them, miR-31a-5p was identified as being able to promote cardiomyocyte proliferation as determined by proliferating cell nuclear antigen (PCNA) expression, double immunofluorescent labeling for α-actinin and 5-ethynyl-2-deoxyuridine (EdU) or Ki-67, and cell number counting, whereas miR-31a-5p inhibition could reduce their levels. RhoBTB1 was identified as a target gene of miR-31a-5p, mediating the regulatory effect of miR-31a-5p in cardiomyocyte proliferation. Importantly, neonatal rats injected with a miR-31a-5p antagomir at day 0 for three consecutive days exhibited reduced expression of markers of cardiomyocyte proliferation including PCNA expression and double immunofluorescent labeling for α-actinin and EdU, Ki-67 or phospho-histone-H3. In conclusion, miR-31a-5p controls postnatal cardiomyocyte proliferation by targeting RhoBTB1, and increasing miR-31a-5p level might be a novel therapeutic strategy for enhancing cardiac reparative processes.

Force induced calpain cleavage of talin is critical for growth, adhesion development and rigidity sensing.

Cell growth depends upon formation of cell-matrix adhesions, but mechanisms detailing the transmission of signals from adhesions to control proliferation are still lacking. Here, we find that the scaffold protein talin undergoes force-induced cleavage in early adhesions to produce the talin rod fragment that is needed for cell cycle progression. Expression of non-cleavable talin blocks cell growth, adhesion maturation, proper mechanosensing, and the related property of EGF activation of motility. Further, the expression of talin rod in the presence of non-cleavable full-length talin rescues cell growth and other functions. The cleavage of talin is found in early adhesions where there is also rapid turnover of talin that depends upon calpain and TRPM4 activity as well as the generation of force on talin. Thus, we suggest that an important function of talin is its control over cell cycle progression through its cleavage in early adhesions.

Deficiency of p38α in macrophage ameliorates D-galactosamine/TNF-α-induced acute liver injury in mice.

Growing evidence suggests that hepatic macrophages play an important role in tissue repair after liver injury by coordinating the induction and resolution of inflammation, removing apoptotic cells and promoting hepatocyte proliferation. Understanding the role of macrophage in the pathogenesis of liver injury will help pave the way to future therapeutics. Here we investigated whether macrophage p38α plays a regulatory role in the tissue repair following a GalN/TNF-α-induced acute liver injury. We found that macrophage p38α deficient mice displayed decreased mortality and relieved liver injury as evident from less apoptosis, accelerated regeneration, decreased granulocytes recruitment, monocytes infiltration, and cytokine production after GalN/TNF-α treatment. Mechanistically, we found that p38 signaling was activated by LPS/IFN-γ treatment but not by IL-4 stimulation, while pharmaceutical inhibition of p38α induced a shift in polarization from M1 macrophages to M2 macrophages. Together, our results indicated that macrophage p38α signaling is involved in the pathogenesis of liver injury induced by GalN/TNF-α and inhibition of p38α signaling in macrophage could ameliorate liver injury and accelerate regeneration, probably by promoting the polarization of macrophages from M1 phenotype to M2 phenotype. This article is protected by copyright. All rights reserved.

OAMDP, a novel podophyllotoxin derivative, induces apoptosis, cell cycle arrest and autophagy in hepatoma HepG2 cells.

4β-(1,3,4-oxadiazole-2-amino-5-methyl)-4-deoxypodophyllotoxin (OAMDP), a novel podophyllotoxin derivative, has demonstrated potent anti-tumor activity with significant cytotoxic effect. Here we report the anti-proliferative effect of OAMDP, for which OAMDP could suppress the proliferation of HepG2 cells (human hepatoma cell line) in a dose- and time-dependent manner. After treating with OAMDP, cell apoptosis was confirmed by Annexin V-FITC/PI double staining assay. Furthermore, flow cytometry analysis revealed the loss of mitochondrial membrane potential and the increase of intracellular reactive oxygen species in HepG2 cells. OAMDP increased apoptotic cell population with induction of Bax, cytochrome c (cyt-c), caspase-9, caspase-3, PARP1 and the reduction of Bcl-2 and p-Akt protein expressions. The MAPK family, JNK, ERK, p38, p-JNK, p-ERK, p-p38, were also regulated by OAMDP in HepG2 cells. Moreover, cell cycle analysis showed that OAMDP induced S or G2/M phase arrest through modulation of cycle regulatory proteins. In addition, MDC staining and LC3 protein expression indicated that autophagy was induced by OAMDP in HepG2 cells. To sum up, our results suggested that OAMDP, with the ability to induce autophagy, causing cell cycle arrest and apoptosis, has potential to become a novel antitumor agent.

Cell proliferation is associated with intensity of tumor budding in oral squamous cell carcinoma.

Tumor budding is a morphological marker of cancer invasion, defined as the presence of isolated or small clusters of neoplastic cells at the tumor invasive front. This study aimed to evaluate the association between intensity of tumor budding and cell proliferation in oral squamous cell carcinoma (OSCC).

Androgen Signaling in Esophageal Adenocarcinoma Cell Lines In Vitro.

We showed previously that nuclear localization of the androgen receptor (AR) and expression of the androgen-responsive gene FK506-binding protein 5 (FKBP5) in esophageal adenocarcinoma (EAC) tissues were associated with decreased patient survival, suggesting a role for androgens in this cancer.

Effects of glutamine, taurine and their association on inflammatory pathway markers in macrophages.

The immune system is essential for the control and elimination of infections, and macrophages are cells that act as important players in orchestrating the various parts of the inflammatory/immune response. Amino acids play important role in mediating functionality of the inflammatory response, especially mediating macrophages functions and cytokines production. We investigated the influence of glutamine, taurine and their association on the modulation of inflammatory pathway markers in macrophages. The RAW 264.7 macrophage cell line was cultivated in the presence of glutamine and taurine and proliferation rates, cell viability, cell cycle phases, IL-1α, IL-6, IL-10 and TNF-α as well as H2O2 production and the expression of the transcription factor, NFκB, and its inhibitor, IκBα, were evaluated. Our results showed an increase in viable cells and increased proliferation rates of cells treated with glutamine concentrations over 2 mM, as well as cells treated with both glutamine and taurine. The cell cycle showed a higher percentage of cells in the phases S, G2 and M when they were treated with 2 or 10 mM glutamine, or with glutamine and taurine in cells stimulated with lipopolysaccharide. The pNFκB/NFκB showed reduced ratio expression when cells were treated with 10 mM of glutamine or with glutamine in association with taurine. These conditions also resulted in reduced TNF-α, IL-1α and H2O2 production, and higher production of IL-10. These findings demonstrate that glutamine and taurine are able to modulate macrophages inflammatory pathways, and that taurine can potentiate the effects of glutamine, illustrating their immunomodulatory properties.

Effects of Alcohol Abuse on Proliferating Cells, Stem/Progenitor Cells and Immature Neurons in the Adult Human Hippocampus.

In animal studies, impaired adult hippocampal neurogenesis is associated with behavioral pathologies including addiction to alcohol. We hypothesize that alcohol abuse may have a detrimental effect on the neurogenic pool of the dentate gyrus in the human hippocampus. In this study we investigate whether alcohol abuse affects the number of proliferating cells, stem/progenitor cells and immature neurons in samples from postmortem human hippocampus. The specimens were isolated from deceased donors with an on-going alcohol abuse, and from controls with no alcohol overconsumption. Mid-hippocampal sections were immunostained for Ki67, a marker for cell proliferation, Sox2, a stem/progenitor cell marker and DCX, a marker for immature neurons. Immunoreactivity was counted in alcoholic subjects and compared to controls. Counting was performed in the three layers of dentate gyrus; the subgranular zone, the granular cell layer and the molecular layer. Our data showed reduced numbers of all three markers in the dentate gyrus in subjects with an on-going alcohol abuse. This reduction was most prominent in the subgranular zone, and uniformly distributed across the distances from the granular cell layer. Further, alcohol abusers showed a more pronounced reduction of Sox2-IR cells than DCX-IR cells, suggesting that alcohol primarily causes a depletion of the stem/progenitor cell pool and that immature neurons are secondarily affected. These results are in agreement with observations of impaired adult hippocampal neurogenesis in animal studies and lend further support for the association between hippocampal dysfunction and alcohol abuse.Neuropsychopharmacology accepted article preview online, 20 October 2017. doi:10.1038/npp.2017.251.