Graphene quantum dots disturbed the energy homeostasis by influencing lipid metabolism of macrophages.

To investigate the potential factors of graphene quantum dots (GQDs), the assessment impact on the innate immune system is one of the most important. As the innate immune cell, macrophages possess phagocytosis activity and affect immunomodulation. Higher oxygen consumption rates (OCR) are used to gain insight into GQDs' effects on macrophages. Metabolomics profiling also revealed that GQDs exposure provoked an increase in phosphoglycerides, sphingolipids, and oxidized lipids in macrophages. The molecular pathways disrupted by GQDs were associated with lipid and energy metabolisms. Metabolite flux analysis was used to evaluate changes in the lipid metabolism of macrophages exposed to 100 µg mL-1 GQDs for 24 and 48 h. A combination of 13C-flux analysis and metabolomics revealed the regulation of lipid biosynthesis influenced the balance of energy metabolism. Integrated proteomics and metabolomics analyses showed that nicotinic acid adenine dinucleotide and coenzyme Q10 were significantly increased under GQDs treatment, alongside upregulated protein activity (e.g., Cox5b and Cd36). The experimental evidences were expected to be provided in this study to reveal the potential harmful effect from exposure to GQDs.

Functionally integrating nanoparticles alleviate deep vein thrombosis in pregnancy and rescue intrauterine growth restriction.

There is still unmet demand for effective, safe, and patient-friendly anti-thrombotics to treat deep vein thrombosis (DVT) during pregnancy. Here we first engineer a bioactive amphiphile (TLH) by simultaneously conjugating Tempol and linoleic acid onto low molecular weight heparin (LMWH), which can assemble into multifunctional nanoparticles (TLH NP). In pregnant rats with DVT, TLH NP can target and dissolve thrombi, recanalize vessel occlusion, and eradicate the recurrence of thromboembolism, thereby reversing DVT-mediated intrauterine growth restriction and delayed development of fetuses. Mechanistically, therapeutic effects of TLH NP are realized by inhibiting platelet aggregation, facilitating thrombolysis, reducing local inflammation, attenuating oxidative stress, promoting endothelial repair, and increasing bioavailability. By decorating with a fibrin-binding peptide, targeting efficiency and therapeutic benefits of TLH NP are considerably improved. Importantly, LMWH nanotherapies show no toxicities to the mother and fetus at the dose 10-time higher than the examined therapeutic dosage.

Liver X receptor inhibits the growth of hepatocellular carcinoma cells via regulating HULC/miR-134-5p/FOXM1 axis.

Hepatocellular carcinoma (HCC) is one of the most common malignancies with a high rate of mortality. Highly upregulated in liver cancer (HULC), the specifically overexpressed long non-coding RNA in human HCC, plays important roles in promoting the growth and metastasis of HCC cells. So downregulating HULC will be benefit to HCC treatment. The nuclear receptor LXR (liver X receptor), consist of α and ß isoforms, exerts significant anti-HCC effects, but the corresponding mechanisms are not well known, especially, it's unclear whether LXR is involved in the regulation of HULC. In this study, we found that LXR inhibited HCC cell growth by downregulating HULC, and LXRα (but not LXRß) caused HULC downregulation. Luciferase reporter assays showed that LXR suppressed transcriptional activity of HULC gene promoter, and chromatin immunoprecipitation assays revealed that LXRα (but not LXRß) bound to HULC promoter region. Furthermore, LXR increased miR-134-5p while decreased FOXM1 by reducing HULC. Additionally, HULC upregulated FOXM1 via sequestrating miR-134-5p, and miR-134-5p downregulated FOXM1 by targeting 3'-UTR of its mRNA. The in vivo experiments showed that LXR repressed the growth of HCC xenografts, and decreased HULC and FOXM1 while increased miR-134-5p in the xenografts. In summary, these findings for the first time demonstrate that LXR inhibits HCC cell growth by modulating HULC/miR-134-5p/FOXM1 axis, suggesting that the pathway LXR/HULC/miR-134-5p/FOXM1 may serve as a novel target for HCC treatment.

Silk fibroin/carboxymethyl chitosan hydrogel with tunable biomechanical properties has application potential as cartilage scaffold.

Tissue engineering is a promising strategy for cartilage repair and regeneration. However, an ideal scaffolding material that not only mimics the biomechanical properties of the native cartilage, but also supports the chondrogenic phenotype of the seeding cells is in need. In this study, we developed a silk fibroin (SF) and carboxymethyl chitosan (CMCS) composite hydrogel with enzymatic cross-links (horseradish peroxidase and hydrogen peroxide) and ß-sheet cross-links (ethanol treatment). Results of Fourier transform infrared (FTIR), thermal gravimetric analysis (TGA), and X-ray diffraction (XRD) verified that SF/CMCS composite hydrogels had a tunable ß-sheet structure. Therefore, by increasing the time of ethanol treatment from 0 h to 8 h, a series of parameters including pore size (from 50 to 300 µm), equilibrium swelling (from 78.1 ±â€¯2.6% to 91.9 ±â€¯0.9%), degradation (from 100% to 9% reduction in mass over 56 days), rheological properties (storage modulus from 177 Pa to 88,904 Pa), and mechanical properties (compressive modulus from 13 to 829 kPa) of the hydrogels were adjusted. In particular, the material parameters of the hydrogels with 2 h ethanol treatment appeared most suitable for engineered cartilage. Furthermore, the in vitro cellular experiments showed that the hydrogels supported the adhesion, proliferation, glycosaminoglycan synthesis, and chondrogenic phenotype of rabbit articular chondrocytes. Finally, subcutaneous implantation of the hydrogels in mice showed no infections or local inflammatory responses, indicating a good biocompatibility in vivo. In conclusion, the chemical-physical cross-linking SF/CMCS composite hydrogels, with tunable material properties and degradation rate, good biocompatibility, are promising scaffolds for cartilage tissue engineering.

Analysis of the Rab GTPase Interactome in Dendritic Cells Reveals Anti-microbial Functions of the Rab32 Complex in Bacterial Containment.

Dendritic cells (DCs) orchestrate complex membrane trafficking through an interconnected transportation network linked together by Rab GTPases. Through a tandem affinity purification strategy and mass spectrometry, we depicted an interactomic landscape of major members of the mammalian Rab GTPase family. When complemented with imaging tools, this proteomic analysis provided a global view of intracellular membrane organization. Driven by this analysis, we investigated dynamic changes to the Rab32 subnetwork in DCs induced by L. monocytogenes infection and uncovered an essential role of this subnetwork in controlling the intracellular proliferation of L. monocytogenes. Mechanistically, Rab32 formed a persistent complex with two interacting proteins, PHB and PHB2, to encompass bacteria both during early phagosome formation and after L. monocytogenes escaped the original containment vacuole. Collectively, we have provided a functional compartmentalization overview and an organizational framework of intracellular Rab-mediated vesicle trafficking that can serve as a resource for future investigations.

Post-translational modifications of proliferating cell nuclear antigen: A key signal integrator for DNA damage response (Review).

Previous studies have shown that the post-translational modifications of proliferating cell nuclear antigen (PCNA) may be crucial in influencing the cellular choice between different pathways, such as the cell cycle checkpoint, DNA repair or apoptosis pathways, in order to maintain genomic stability. DNA damage leads to replication stress and the subsequent induction of PCNA modification by small ubiquitin (Ub)-related modifiers and Ub, which has been identified to affect multiple biological processes of genomic DNA. Thus far, much has been learned concerning the behavior of modified PCNA as a key signal integrator in response to DNA damage. In humans and yeast, modified PCNA activates DNA damage bypass via an error-prone or error-free pathway to prevent the breakage of DNA replication forks, which may potentially induce double-strand breaks and subsequent chromosomal rearrangements. However, the exact mechanisms by which these pathways work and by what means the modified PCNA is involved in these processes remain elusive. Thus, the improved understanding of PCNA modification and its implications for DNA damage response may provide us with more insight into the mechanisms by which human cells regulate aberrant recombination events, and cancer initiation and development. The present review focuses on the post-translational modifications of PCNA and its important functions in mediating mammalian cellular response to different types of DNA damage.

Overexpressed DNA polymerase iota regulated by JNK/c-Jun contributes to hypermutagenesis in bladder cancer.

Human DNA polymerase iota (pol ι) possesses high error-prone DNA replication features and performs translesion DNA synthesis. It may be specialized and strictly regulated in normal mammalian cells. Dysregulation of pol ι may contribute to the acquisition of a mutator phenotype. However, there are few reports describing the transcription regulatory mechanism of pol ι, and there is controversy regarding its role in carcinogenesis. In this study, we performed the deletion and point-mutation experiment, EMSA, ChIP, RNA interference and western blot assay to prove that c-Jun activated by c-Jun N-terminal kinase (JNK) regulates the transcription of pol ι in normal and cancer cells. Xeroderma pigmentosum group C protein (XPC) and ataxia-telangiectasia mutated related protein (ATR) promote early JNK activation in response to DNA damage and consequently enhance the expression of pol ι, indicating that the novel role of JNK signal pathway is involved in DNA damage response. Furthermore, associated with elevated c-Jun activity, the overexpression of pol ι is positively correlated with the clinical tumor grade in 97 bladder cancer samples and may contribute to the hypermutagenesis. The overexpressed pol ι-involved mutagenesis is dependent on JNK/c-Jun pathway in bladder cancer cells identifying by the special mutation spectra. Our results support the conclusion that dysregulation of pol ι by JNK/c-Jun is involved in carcinogenesis and offer a novel understanding of the role of pol ι or c-Jun in mutagenesis.

Interaction between polymorphisms of DNA repair genes significantly modulated bladder cancer risk.

DNA repair is a primary defense mechanism against damage caused by exogenous and endogenous sources. We examined the associations between bladder cancer and 7 polymorphisms from 5 genes involved in the maintenance of genetic stability (MMR: MLH1-93G>A; BER: XRCC1--77T>C and Arg399Gln; NER:XPC Lys939Gln and PAT +/-; DSBR:ATM G5557A and XRCC7 G6721T) in 302 incident bladder cancer cases and 311 hospital controls. Genotyping was done using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. The homozygous variant of XRCC7 G6721T (Odds Ratio [OR]: 2.36; 95% Confidence Interval [CI]: 1.13-4.92) was associated with increased bladder cancer risk. In an analysis of combined genotypes, the combination of XRCC1Arg399Gln (Gln allele) with XRCC1-77 T/T led to an increase in risk (OR: 1.61; 95% CI: 1.10-2.36). Moreover, when the XPCLys939Gln (Gln allele) (nucleotide excision repair [NER]) was present together with XRCC7 (T allele) (double strand break repair [DSBR]), the bladder cancer risk dramatically increased (OR: 4.42; 95% CI: 1.23-15.87). Our results suggest that there are multigenic variations in the DNA repair pathway involved in bladder cancer susceptibility, despite the existence of ethnic group differences.

Poly (AT) polymorphism in the XPC gene and smoking enhance the risk of prostate cancer in a low-risk Chinese population.

We investigated two polymorphisms of xeroderma pigmentosum complementary group C (XPC) in 202 subjects with prostate cancer (PCa) and 221 healthy controls in a Chinese Han population. Genotyping was performed using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. Our results indicated that smoking is associated with an increased risk for PCa (odds ratio [OR]: 1.51; 95% confidence interval [CI]: 1.02-2.22). Subjects carrying the XPC-PAT+/+ genotype exhibited a significantly increased risk for PCa (OR: 2.11; 95% CI: 1.12-3.99). The combined subjects with either the PAT+/+ or PAT+/- genotype also exhibited a 1.54-fold increased risk associated with PCa (OR: 1.54; 95% CI: 1.04-2.26). Moreover, smokers with PAT+/- or PAT+/+ had a higher risk for PCa (OR: 1.98; 95% CI: 1.08-3.64; P = 0.026 and OR: 3.56; 95% CI: 1.45-8.76; P = 0.004, respectively) compared with never smokers with the PAT-/- genotype. Analyses of the XPC Lys939Gln polymorphism did not show an association with PCa risk. Our findings support the hypothesis that XPC-PAT polymorphisms may contribute to the risk of developing PCa. More important, an elevated risk of PCa associated with a gene-environment (smoking) interaction was determined in a Chinese population.

Interactions between cigarette smoking and XPC-PAT genetic polymorphism enhance bladder cancer risk.

Inherited polymorphisms in the XPC gene that lead to a reduction in DNA repair capacity may increase susceptibility to bladder cancer. We investigated three polymorphisms of the XPC gene (PAT, Ala499Val and Lys939Gln) in 600 subjects with bladder cancer and in 609 healthy controls by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in a Chinese Han population. Smoking was associated with a significant increase in the risk for bladder cancer (OR, 2.48; 95% CI, 1.91-3.21). The risk was greater among heavy smokers (OR, 3.09, 95% CI, 2.24-4.25) compared to light smokers (OR, 1.91, 95% CI, 1.37-2.68). In three polymorphisms of XPC, only the XPC-PAT variant genotype exhibited a significantly increased risk for bladder cancer. When the total smoking exposure-gene interaction was examined, the three polymorphisms did not exhibit any significant effect in never smokers but a significant dose-response association in light or heavy smokers. Especially, the bladder cancer risk was significantly elevated among the polymorphisms of XPC-PAT(+/-) (OR, 2.56, 95% CI, 1.56-4.21, p<0.001; OR, 3.41, 95% CI, 2.19-5.29, p<0.001) and XPC-PAT(+/+) (OR, 3. 00, 95% CI, 1.31-6.88, p=0.009; OR, 6. 78, 95% CI, 3.00-15.54, p<0.001) with either light or heavy smoking exposure, respectively. XPC-PAT polymorphisms contribute to the risk for developing bladder cancer and an elevated risk of bladder cancer was significantly associated with the gene-environment (smoking) interaction in a Chinese Han population.