Human monocytes produce interferon-gamma upon stimulation with LPS.

Representing a crucial T-helper 1 cytokine, IFN-γ acts as an important bridge between innate and adaptive immunity and is involved in many acute and chronic pathologic states, such as autoimmune diseases and solid organ transplant rejection. At present, debate still prevails about the ability of human monocytes to produce IFN-γ. We aimed to investigate whether human monocytes possess the capacity to produce IFN-γ at mRNA and protein level. Using real time PCR, flow cytometric analysis and ELISA, we investigated the capacity of freshly isolated CD14+ monocytes of healthy individuals and kidney transplant recipients to produce IFN-γ after stimulation with IFN-γ and LPS or LPS alone. We observed increased IFN-γ mRNA levels in CD14+ monocytes after stimulation as compared to the unstimulated controls in both populations. In addition, stimulation with IFN-γ and LPS or LPS alone led to a significant increase in the percentage of CD14+ monocytes producing TNF-α and IFN-γ at protein level (p<0.05). A trend towards increased secreted IFN-γ production in supernatants was also observed after LPS stimulation using ELISA. We conclude that human monocytes from healthy individuals and kidney transplant recipients possess the capacity to produce IFN-γ.

Hedgehog signalling as an antagonist of ageing and its associated diseases.

Hedgehog is an important morphogenic signal that directs pattern formation during embryogenesis, but its activity also remains present through adult life. It is now becoming increasingly clear that during the reproductive phase of life and beyond it continues to direct cell renewal (which is essential to combat the chronic environmental stress to which the body is constantly exposed) and counteracts vascular, osteolytic and sometimes oncological insults to the body. Conversely, down-regulation of hedgehog signalling is associated with ageing-related diseases such as type 2 diabetes, neurodegeneration, atherosclerosis and osteoporosis. Hence, in this essay we argue that hedgehog signalling is not only important at the start of life, but also constitutes an important anti-geriatric influence, and that enhanced understanding of its properties may contribute to developing rational strategies for healthy ageing and prevention of ageing-related diseases.

Biomaterials coated with zwitterionic polymer brush demonstrated significant resistance to bacterial adhesion and biofilm formation in comparison to brush coatings incorporated with antibiotics.

A critical problem with the use of biomaterial implants is associated with bacterial adhesion on the surface of implants and in turn the biofilm formation. Among different strategies that have been reported to resolve this dilemma, surface design combined with both antiadhesive and antimicrobial properties has proven to be highly effective. Physiochemical properties of polymer brush coatings possess non-adhesive capability against bacterial adhesion and create a niche for further functionalization. The current study aims to evaluate the effect of antibiotics incorporated into the polymer brush on bacterial adhesion and biofilm formation. Brushes made of zwitterionic polymers were synthesized, functionalized with vancomycin via both physical and chemical conjugation, and grafted onto the silicon rubber surfaces. Antibacterial and antiadhesive measurements of designed coated biomaterials were mediated through the use of a parallel plate flow chamber against biofilm growth developed by Staphylococcus aureus and Escherichia coli over a period of 24 h. The analysis of biofilm growth on designed coated biomaterials showed that the pristine coated zwitterionic brushes are significantly resistant to bacterial adhesion and biofilm formation but not in the polymer brush coating incorporated with antibiotics.

Dichotomy in Hedgehog signaling between human healthy vessel and atherosclerotic plaques.

The major cause for plaque instability in atherosclerotic disease is neoangiogenic revascularization, but the factors controlling this process remain only partly understood. Hedgehog (HH) is a morphogen with important functions in revascularization, but its function in human healthy vessel biology as well as in atherosclerotic plaques has not been well investigated. Hence, we determined the status of HH pathway activity both in healthy vessels and atherosclerotic plaques. A series of 10 healthy organ donor-derived human vessels, 17 coronary atherosclerotic plaques and 24 atherosclerotic carotid plaques were investigated for HH pathway activity. We show that a healthy vessel is characterized by a high level of HH pathway activity but that atherosclerotic plaques are devoid of HH signaling despite the presence of HH ligand in these pathological structures. Thus, a dichotomy between healthy vessels and atherosclerotic plaques with respect to the activation status of the HH pathway exists, and it is tempting to suggest that downregulation of HH signaling contributes to long-term plaque stability.

Propionic acid affects immune status and metabolism in adipose tissue from overweight subjects.

BACKGROUND: Adipose tissue is a primary site of obesity-induced inflammation, which is emerging as an important contributor to obesity-related diseases such as type 2 diabetes. Dietary fibre consumption appears to be protective. Short-chain fatty acids, e.g. propionic acid, are the principal products of the colonic fermentation of dietary fibre and may have beneficial effects on adipose tissue inflammation. MATERIALS AND METHODS: Human omental adipose tissue explants were obtained from overweight (mean BMI 28·8) gynaecological patients who underwent surgery. Explants were incubated for 24 h with propionic acid. Human THP-1 monocytic cells were differentiated to macrophages and incubated with LPS in the presence and absence of propionic acid. Cytokine and chemokine production were determined by multiplex-ELISA, and mRNA expression of metabolic and macrophages genes was determined by RT-PCR. RESULTS: Treatment of adipose tissue explants with propionic acid results in a significant down-regulation of several inflammatory cytokines and chemokines such as TNF-α and CCL5. In addition, expression of lipoprotein lipase and GLUT4, associated with lipogenesis and glucose uptake, respectively, increased. Similar effects on cytokine and chemokine production by macrophages were observed. CONCLUSION: We show that propionic acid, normally produced in the colon, may have a direct beneficial effect on visceral adipose tissue, reducing obesity-associated inflammation and increasing lipogenesis and glucose uptake. Effects on adipose tissue as a whole are at least partially explained by effects on macrophages but likely also adipocytes are involved. This suggests that, in vivo, propionic acid and dietary fibres may have potential in preventing obesity-related inflammation and associated diseases.

Human plasma very low density lipoprotein carries Indian hedgehog.

Hedgehog is one of the major morphogens and fulfils critical functions in both the development and maintenance of the vasculature. Hedgehog is highly hydrophobic and its diffusion toward target tissues remains only partly understood. In Drosophila, hedgehog transport via lipophorins is relevant for development, but neither the presence nor a function for a mammalian Hedgehog carried by human plasma lipoproteins has been established. We investigated the presence of Hedgehog on lipoprotein particles and determined its importance for maintaining the endothelium. LTQ-Orbitrap XL analysis of defined plasma lipoproteins revealed that Indian Hedgehog (Ihh) is present in the human very low density lipoprotein (VLDL) fraction but not in other plasma lipoprotein fractions (low density lipoprotein (LDL) and high density lipoprotein (HDL)). Using the same approach, neither Sonic Hedgehog nor Desert Hedgehog could be detected in plasma lipoprotein fractions. Most likely, primary white adipocytes are the source of Ihh loading on VLDL as both transcriptome as well as immunofluorescence analysis showed high expression of Ihh in these cells. Additionally, we show that the endothelial compartment is most likely to be affected by the presence of Ihh on VLDL. Indeed, VLDL increased survival of primary endothelial cells, suggesting that Ihh transport by VLDL is important for maintaining the human endothelium. In conclusion, our study shows that VLDL carries Ihh throughout the body in mammals and Hedgehog signaling by human plasma VLDL particles may affect blood vessel pathophysiology. A combination of three state-of-the-art technologies, proteomics, genomics, and confocal microscopy, appeared to be a powerful tool for analyzing plasma lipoprotein-associated proteins.

Regulation of adipokine production in human adipose tissue by propionic acid.

BACKGROUND: Dietary fibre (DF) has been shown to be protective for the development of obesity, insulin resistance and type 2 diabetes. Short-chain fatty acids, produced by colonic fermentation of DF might mediate this beneficial effect. Adipose tissue plays a key role in the regulation of energy homeostasis, therefore, we investigated the influence of the short-chain fatty acid propionic acid (PA) on leptin, adiponectin and resistin production by human omental (OAT) and subcutaneous adipose tissue (SAT). As PA has been shown to be a ligand for G-protein coupled receptor (GPCR) 41 and 43, we investigated the role of GPCR's in PA signalling. MATERIALS AND METHODS: Human OAT and SAT explants were obtained from gynaecological patients who underwent surgery. Explants were incubated for 24 h with PA. Adipokine secretion and mRNA expression were determined using ELISA and RT-PCR respectively. RESULTS: We found that PA significantly stimulated leptin mRNA expression and secretion by OAT and SAT, whereas it had no effect on adiponectin. Furthermore, PA reduced resistin mRNA expression. Leptin induction, but not resistin reduction, was abolished by inhibition of Gi/o-coupled GPCR signalling. Moreover, GPCR41 and GPCR43 mRNA levels were considerably higher in SAT than in OAT. CONCLUSIONS: We demonstrate that PA stimulates expression of the anorexigenic hormone leptin and reduces the pro-inflammatory factor resistin in human adipose tissue depots. This suggests that PA is involved in regulation of human energy metabolism and inflammation and in this way may influence the development of obesity and type 2 diabetes.

Administration of Nicotine Exacerbates the Quinine-induced Structural and Functional Alterations of Testicular Tissue in Adult Rats: An Experimental Study.

PURPOSE: In this study the role of nicotine (NCT) administration on the intensity of rat testicular tissue alterations induced by quinine (QU) was evaluated. MATERIALS AND METHODS: Forty adult Wistar rats were divided into four groups. Control (CON), NCT administrated (4 mg/kg) (NCT), QU treated (25 mg/kg for 7 days) (QU), and nicotine with quinine received (NCT+QU). After 28 days, serum testosterone and malondialdehyde (MDA) levels were measured. Testes and epididymides samples were prepared for determining tissue MDA levels, histomorphometry, microscopic indices of spermatogenesis, immunohistochemistry of p53 and sperm analysis. RESULTS: Testosterone levels were decreased significantly (P = .0004) in treated groups compared to CON group. Serum MDA levels were increased significantly (P = .0004) in NCT and QU groups compared to CON group. Tissue MDA levels were increased significantly (P = .0012) in NCT+QU group in comparison to CON group. These parameters were changed significantly in NCT+QU group compared to QU group. Seminiferous tubules diameter decreased significantly (P < .0001) in treated groups compared to CON group and in NCT+QU group compared to QU group. The height of germinal epithelium decreased significantly (P = .0001) in NCT and NCT+QU groups compared to CON and QU groups. The number of Sertoli cells, spermatocytes, and spermatids decreased significantly in treated groups compared to CON group. The number of spermatogonia decreased significantly (P = .0017) in NCT and NCT+QU groups compared to CON group. The number of Sertoli cells, spermatogonia, and spermatocytes decreased significantly in NCT+QU group compared to QU group. All indices of spermatogenesis decreased in treated groups compared to CON group. The lowest mean of these indices was observed in NCT+QU group. The sperm viability decreased significantly (P < .0001) in treated groups compared to CON group. Sperm count and motility decreased significantly in NCT and NCT+QU groups compared to CON group. All experimental groups showed the over-expression of p53 compared to CON group. CONCLUSION: The administration of nicotine could be involved in the exacerbation of testicular tissue alterations related to quinine therapy.

Cannabinoids as anti-ROS in aged pancreatic islet cells.

AIMS: Cannabinoids are the chemical compounds with a high affinity for cannabinoid receptors affecting the central nervous system through the release of neurotransmitters. However, the current knowledge related to the role of such compounds in the regulation of cellular aging is limited. This study aimed to investigate the effect of cannabidiol and tetrahydrocannabinol on the function of aged pancreatic islets. MAIN METHODS: The expression of p53, p38, p21, p16, and Glut2 genes and ß-galactosidase activity were measured as hallmarks of cell aging applying real-time PCR, ELISA, and immunocytochemistry techniques. Pdx1 protein expression, insulin release, and oxidative stress markers were compared between young and aged rat pancreatic islet cells. KEY FINDINGS: Upon the treatment of aged pancreatic islets cells with cannabidiol and tetrahydrocannabinol, the expression of p53, p38, p21 and the activity of ß-galactosidase were reduced. Cannabidiol and tetrahydrocannabinol increase insulin release, Pdx1, Glut2, and thiol molecules expression, while the oxidative stress parameters were decreased. The enhanced expression of Pdx1 and insulin release in aged pancreatic islet cells reflects the extension of cell healthy aging due to the significant reduction of ROS. SIGNIFICANCE: This study provides evidence for the involvement of cannabidiol and tetrahydrocannabinol in the oxidation process of cellular aging.

Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion.

The developmentally important hedgehog (Hh) pathway is activated by binding of Hh to patched (Ptch1), releasing smoothened (Smo) and the downstream transcription factor glioma associated (Gli) from inhibition. The mechanism behind Ptch1-dependent Smo inhibition remains unresolved. We now show that by mixing Ptch1-transfected and Ptch1 small interfering RNA-transfected cells with Gli reporter cells, Ptch1 is capable of non-cell autonomous repression of Smo. The magnitude of this non-cell autonomous repression of Smo activity was comparable to the fusion of Ptch1-transfected cell lines and Gli reporter cell lines, suggesting that it is the predominant mode of action. CHOD-PAP analysis of medium conditioned by Ptch1-transfected cells showed an elevated 3beta-hydroxysteroid content, which we hypothesized to mediate the Smo inhibition. Indeed, the inhibition of 3beta-hydroxysteroid synthesis impaired Ptch1 action on Smo, whereas adding the 3beta-hydroxysteroid (pro-)vitamin D3 to the medium effectively inhibited Gli activity. Vitamin D3 bound to Smo with high affinity in a cyclopamine-sensitive manner. Treating zebrafish embryos with vitamin D3 mimicked the smo(-/-) phenotype, confirming the inhibitory action in vivo. Hh activates its signalling cascade by inhibiting Ptch1-dependent secretion of the 3beta-hydroxysteroid (pro-)vitamin D3. This action not only explains the seemingly contradictory cause of Smith-Lemli-Opitz syndrome (SLOS), but also establishes Hh as a unique morphogen, because binding of Hh on one cell is capable of activating Hh-dependent signalling cascades on other cells.

Propionic acid counteracts the inflammation of human subcutaneous adipose tissue: a new avenue for drug development.

Adipose tissue is a primary site of obesity-induced inflammation, which has been emerging as an important contributor to obesity associated disorders. The factors influencing adipose tissue-induced inflammation and the resulting pathophysiological events remain poorly understood. However, dietary fiber consumptions appear to be protective. Short-chain fatty acids such as propionic acid (PA) are the principal products of the dietary fiber fermentation by microbiota. Therefore, we aim to investigate the influence of PA on inflammation, lipogenesis and glucose uptake markers from human subcutaneous adipose tissue (SAT). We showed that the treatment of SAT with PA resulted in a significant downregulation of inflammatory parameters (e.g. TNF-α and IP-10) and macrophage markers (e.g. CD163 and MMP-9). The expression levels of PA receptors (i.e. G protein coupled receptor-41 and -43) in human primary adipocytes were very low in comparison with SAT and macrophages. Upon PA treatment, no anti-inflammatory effect was observed in human adipocytes. PA significantly upregulated the expression of lipoprotein lipase (LPL), sterol regulatory-element-binding protein-1c (SREBP-1c) and glucose transporter 4 (GLUT-4), which are associated with lipogenesis and glucose uptake. We also showed that the observed anti-inflammatory effects of PA on SAT were partly mediated by Gi/o protein coupled receptor. Our data suggests that PA anti-inflammatory effects on SAT are mediated partly via Gi/o proteins, leading to the improved expression of factors associated with lipogenesis and glucose uptake. These responses appeared to be not mediated by adipocytes; but most probably by macrophages. The current study provides new knowledge, which can be used as a potential new avenue for drug development in preventing obesity-related inflammation and metabolic disorders in future. Graphical abstract Schematic presentation of study flow and the components of the investigation. In this study the effect of propionic acid (PA) on inflammation investigated in human subcutaneous adipose tissue (SAT), human primary adipocytes and the expression of a few hallmark inflammatory components produced by SAT and human adipocytes.

Protein corona variation in nanoparticles revisited: A dynamic grouping strategy.

Bio-nano interface investigation models are mainly based on the type of proteins present on corona, bio-nano interaction responses and the evaluation of final outcomes. Due to the extensive diversity in correlative models for investigation of nanoparticles biological responses, a comprehensive model considering different aspects of bio-nano interface from nanoparticles properties to protein corona fingerprints appeared to be essential and cannot be ignored. In order to minimize divergence in studies in the era of bio-nano interface and protein corona with following therapeutic implications, a useful investigation model on the basis of RADAR concept is suggested. The contents of RADAR concept consist of five modules: 1- Reshape of our strategy for synthesis of nanoparticles (NPs), 2- Application of NPs selected based on human fluid, 3- Delivery strategy of NPs selected based on target tissue, 4- Analysis of proteins present on corona using correct procedures and 5- Risk assessment and risk reduction upon the collection and analysis of results to increase drug delivery efficiency and drug efficacy. RADAR grouping strategy for revisiting protein corona phenomenon as a key of success will be discussed with respect to the current state of knowledge.

Synthetic and biological identities of polymeric nanoparticles influencing the cellular delivery: An immunological link.

Enhanced understanding of bio-nano interaction requires recognition of hidden factors such as protein corona, a layer of adsorbed protein around nano-systems. This study compares the biological identity and fingerprint profile of adsorbed proteins on PLGA-based nanoparticles through nano-liquid chromatography-tandem mass spectrometry. The total proteins identified in the corona of nanoparticles (NPs) with different in size, charge and compositions were classified based on molecular mass, isoelectric point and protein function. A higher abundance of complement proteins was observed in modified NPs with an increased size, while NPs with a positive surface charge exhibited the minimum adsorption for immunoglobulin proteins. A correlation of dysopsonin/opsonin ratio was found with cellular uptake of NPs exposed to two positive and negative Fc receptor cell lines. Although the higher abundance of dysopsonins such as apolipoproteins may cover the active sites of opsonins causing a lower uptake, the correlation of adsorbed dysopsonin/opsonin proteins on the NPs surface has an opposite trend with the intensity of cell uptake. Despite the reduced uptake of corona-coated NPs in comparison with pristine NPs, the dysopsonin/opsonin ratio controlled by the physicochemistry properties of NPs could potentially be used to tune up the cellular delivery of polymeric NPs.

Increased plasma macrophage inflammatory protein (MIP)-1alpha and MIP-1beta levels in type 1 Gaucher disease.

Pancytopenia, hepatosplenomegaly and skeletal complications are hallmarks of Gaucher disease. Monitoring of the outcome of therapy on skeletal status of Gaucher patients is problematic since currently available imaging techniques are expensive and not widely accessible. The availability of a blood test that relates to skeletal manifestations would be very valuable. We here report that macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, both implicated in skeletal complications in multiple myeloma (MM), are significantly elevated in plasma of Gaucher patients. Plasma MIP-1alpha of patients (median 78 pg/ml, range 21-550 pg/ml, n=48) is elevated (normal median 9 pg/ml, range 0-208 pg/ml, n=39). Plasma MIP-1beta of patients (median 201 pg/ml, range 59-647 pg/ml, n=49) is even more pronouncedly increased (normal median 17 pg/ml, range 1-41 pg/ml, n=39; one outlier: 122 pg/ml). The increase in plasma MIP-1beta levels of Gaucher patients is associated with skeletal disease. The plasma levels of both chemokines decrease upon effective therapy. Lack of reduction of plasma MIP-1beta below 85 pg/ml during 5 years of therapy was observed in patients with ongoing skeletal disease. In conclusion, MIP-1alpha and MIP-1beta are elevated in plasma of Gaucher patients and remaining high levels of MIP-1beta during therapy seem associated with ongoing skeletal disease.

SELDI-TOF mass spectrometry of High-Density Lipoprotein.

BACKGROUND: High-Density Lipoprotein (HDL), one of the main plasma lipoproteins, serves as a docking station for proteins involved in inflammation, coagulation, and lipid metabolism. METHODS: To elucidate the protein composition of HDL, we employed SELDI-TOF mass spectrometry as a potential high-throughput proteomic candidate for protein profiling of HDL. HDL derived from normolipemic individuals was captured on PS20 protein-chips using covalently bound antibodies against apo A-I or A-II. RESULTS: After optimisation, on-chip capture of HDL particles directly from plasma or from pre-purified HDL resulted in comparable fingerprints confirming specific capture of HDL. Depending on the capture antibody some differences in the fingerprint were observed. The most detailed fingerprint was observed up to 50 kDa; approximately 95 peaks were detected in the 3-50 kDa molecular mass range. Between 50 and 160 kDa, 27 more peaks were detected. CONCLUSION: Based on these results, SELDI-TOF MS may be a suitable high-throughput candidate for HDL protein profiling and marker search. This approach may be used to i) investigate the underlying mechanisms that lead to increased atherothrombotic risk and ii) to investigate the atherothrombotic state of an individual.

Lifestyle alters GUT-bacteria function: Linking immune response and host.

Microbiota in human is a "mixture society" of different species (i.e. bacteria, viruses, funguses) populations with a different way of relationship classification to Human. Human GUT serves as the host of the majority of different bacterial populations (GUT flora, more than 500 species), which are with us ("from the beginning") in an innate manner known as the commensal (no harm to each other) and symbiotic (mutual benefit) relationship. A homeostatic balance of host-bacteria relationship is very important and vital for a normal health process. However, this beneficial relationship and delicate homeostatic state can be disrupted by the imbalance of microbiome-composition of gut microbiota, expressing a pathogenic state. A strict homeostatic balance of microbiome-composition strongly depends on several factors; 1- lifestyle, 2- geography, 3- ethnicities, 4- "mom" as prime of the type of bacterial colonization in infant and 5- the disease. With such diversity in individuals combined with huge number of different bacterial species and their interactions, it is wise to perform an in-depth systems biology (e.g. genomics, proteomics, glycomics, and etcetera) analysis of personalized microbiome. Only in this way, we are able to generate a map of complete GUT microbiota and, in turn, to determine its interaction with host and intra-interaction with pathogenic bacteria. A specific microbiome analysis provides us the knowledge to decipher the nature of interactions between the GUT microbiota and the host and its response to the invading bacteria in a pathogenic state. The GUT-bacteria composition is independent of geography and ethnicity but lifestyle well affects GUT-bacteria composition and function. Microbiome knowledge obtained by systems biology also helps us to change the behavior of GUT microbiota in response to the pathogenic microbes as protection. Functional microbiome changes in response to environmental factors will be discussed in this review.

Advances in Alzheimer's Diagnosis and Therapy: The Implications of Nanotechnology.

Alzheimer's disease (AD) is a type of dementia that causes major issues for patients' memory, thinking, and behavior. Despite efforts to advance AD diagnostic and therapeutic tools, AD remains incurable due to its complex and multifactorial nature and lack of effective diagnostics/therapeutics. Nanoparticles (NPs) have demonstrated the potential to overcome the challenges and limitations associated with traditional diagnostics/therapeutics. Nanotechnology is now offering new tools and insights to advance our understanding of AD and eventually may offer new hope to AD patients. Here, we review the key roles of nanotechnologies in the recent literature, in both diagnostic and therapeutic aspects of AD, and discuss how these achievements may improve patient prognosis and quality of life.

Disulfide-induced self-assembled targets: A novel strategy for the label free colorimetric detection of DNAs/RNAs via unmodified gold nanoparticles.

A modified non-cross-linking gold-nanoparticles (Au-NPs) aggregation strategy has been developed for the label free colorimetric detection of DNAs/RNAs based on self-assembling target species in the presence of thiolated probes. Two complementary thiol- modified probes, each of which specifically binds at one half of the target introduced SH groups at both ends of dsDNA. Continuous disulfide bond formation at 3' and 5' terminals of targets leads to the self-assembly of dsDNAs into the sulfur- rich and flexible products with different lengths. These products have a high affinity for the surface of Au-NPs and efficiently protect the surface from salt induced aggregation. To evaluate the assay efficacy, a small part of the citrus tristeza virus (CTV) genome was targeted, leading to a detection limit of about 5 × 10-9 mol.L-1 over a linear ranged from 20 × 10-9 to 10 × 10-7 mol.L-1. This approach also exhibits good reproducibility and recovery levels in the presence of plant total RNA or human plasma total circulating RNA extracts. Self-assembled targets can be then sensitively distinguished from non-assembled or mismatched targets after gel electrophoresis. The disulfide reaction method and integrating self-assembled DNAs/RNAs targets with bare AuNPs as a sensitive indicator provide us a powerful and simple visual detection tool for a wide range of applications.

Regulation of Macrophage Recognition through the Interplay of Nanoparticle Surface Functionality and Protein Corona.

Using a family of cationic gold nanoparticles (NPs) with similar size and charge, we demonstrate that proper surface engineering can control the nature and identity of protein corona in physiological serum conditions. The protein coronas were highly dependent on the hydrophobicity and arrangement of chemical motifs on NP surface. The NPs were uptaken in macrophages in a corona-dependent manner, predominantly through recognition of specific complement proteins in the NP corona. Taken together, this study shows that surface functionality can be used to tune the protein corona formed on NP surface, dictating the interaction of NPs with macrophages.

DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression.

Aging is a major risk factor for progression of liver diseases to hepatocellular carcinoma (HCC). Cellular senescence contributes to age-related tissue dysfunction, but the epigenetic basis underlying drug-induced senescence remains unclear. macroH2A1, a variant of histone H2A, is a marker of senescence-associated heterochromatic foci that synergizes with DNA methylation to silence tumor-suppressor genes in human fibroblasts. In this study, we investigated the relationship between macroH2A1 splice variants, macroH2A1.1 and macroH2A1.2, and liver carcinogenesis. We found that protein levels of both macroH2A1 isoforms were increased in the livers of very elderly rodents and humans, and were robust immunohistochemical markers of human cirrhosis and HCC. In response to the chemotherapeutic and DNA-demethylating agent 5-aza-deoxycytidine (5-aza-dC), transgenic expression of macroH2A1 isoforms in HCC cell lines prevented the emergence of a senescent-like phenotype and induced synergistic global DNA hypomethylation. Conversely, macroH2A1 depletion amplified the antiproliferative effects of 5-aza-dC in HCC cells, but failed to enhance senescence. Senescence-associated secretory phenotype and whole-transcriptome analyses implicated the p38 MAPK/IL8 pathway in mediating macroH2A1-dependent escape of HCC cells from chemotherapy-induced senescence. Furthermore, chromatin immunoprecipitation sequencing revealed that this hepatic antisenescence state also required active transcription that could not be attributed to genomic occupancy of these histones. Collectively, our findings reveal a new mechanism by which drug-induced senescence is epigenetically regulated by macroH2A1 and DNA methylation and suggest macroH2A1 as a novel biomarker of hepatic senescence that could potentially predict prognosis and disease progression.