Ambient ozone pollution impairs glucose homeostasis and contributes to renal function decline: Population-based evidence.

Particulate matter pollution could increase the risk of kidney disease, while evidence for ozone exposure is less well-established. Here, we aimed to evaluate the effect of ozone pollution on renal function and explore mechanisms. We first conducted a cross-sectional study based on Wuhan Chronic Disease Cohort Study baseline information. We recruited 2699 eligible participants, estimated their residential ozone concentrations, collected fasting peripheral blood samples for biochemical analysis and calculated the estimated glomerular filtration rate (eGFR). The linear regression model was applied to evaluate the long-term association between ozone pollution and eGFR. Then, we recruited another 70 volunteers as a panel with 8 rounds follow-up visits. We calculated the eGFR and measured fasting blood glucose and lipid levels. The linear mixed-effect model along with mediation analysis were performed to confirm the short-term association and explore potential mechanisms, respectively. For the long-term association, a 10.95 µg/m3 increment of 3-year ozone exposure was associated with 2.96 mL/min/1.73 m2 decrease in eGFR (95%CI: -4.85, -1.06). Furthermore, the drinkers exhibited a pronounced declination of eGFR (-7.46 mL/min/1.73 m2, 95%CI: -11.84, -3.08) compared to non-drinkers in relation to ozone exposure. Additionally, a 19.02 µg/m3 increase in 3-day ozone concentrations was related to 2.51 mL/min/1.73 m2 decrease in eGFR (95%CI: -3.78, -1.26). Hyperglycemia and insulin resistance mediated 12.2% and 16.5% of the aforementioned association, respectively. Our findings indicated that higher ozone pollution could affect renal function, and the hyperglycemia and insulin resistance linked to ozone might be the underlying mechanisms.

Purification and activity evaluation of novel anti-inflammatory peptides from pearl oyster (Pinctada martensii) hydrolysates.

Pearl oyster meat, a by-product of pearl production, is rich in protein, but has a low utilization rate. Our previous study showed that pearl oyster meat hydrolysates have potential anti-inflammatory activity. In this study, highly active peptides from pearl oyster meat hydrolysates were purified, identified, and extracted, and their anti-inflammatory activity was further investigated. A total of 206 peptides were identified, and three novel anti-inflammatory peptides, TWP (402.1903 Da), TAMY (484.1992 Da) and FPGA (390.1903 Da), were screened by molecular docking. The molecular docking results showed that TWP, TAMY and FPGA can bind to key regions in the cyclooxygenase-2 (COX-2) active site. Furthermore, the three anti-inflammatory peptides can effectively regulate the release of inflammatory mediators from RAW264.7 macrophages by reducing the levels of nitric oxide (NO) and pro-inflammatory cytokines (such as TNF-α, IL-6 and IL-1ß), and increasing the production of anti-inflammatory cytokine IL-10, showing great anti-inflammatory activity. This study provides a new theoretical reference for the development of functional foods or nutritional supplements with natural anti-inflammatory effects.

The relationship between renal function and diabetic retinopathy in patients with type 2 diabetes: A three-year prospective study.

Objective: To explore the association of diabetic retinopathy (DR) and diabetic macular edema (DME) with renal function in patients with type 2 diabetes mellitus (T2DM). Design: A prospective cohort study. Methods: This single-centre study included patients with no DR, mild non-proliferative DR (NPDR), and no DME at baseline. DR and DME were assessed using 7-field fundus photography and swept-source OCT (SS-OCT). The baseline renal function assessed included the estimated glomerular filtration rate (eGFR) and microalbuminuria (MAU). Cox regression analyses were used to assess the hazard ratio (HR) of renal function with the progression of DR and the development of DME. Results: A total of 1409 patients with T2DM (1409 eyes) were included. During 3 years of follow-up,143 patients had DR progression, and 54 patients developed DME. Low eGFR levels at baseline were associated with the development of DR (HR, 1.044 per 1-SD decrease; 95% CI, 1.035-1.053; P < 0.001). Compared to the participants with eGFRs >90 mL/min/1.73 m2, the participants with eGFRs of 60-90 mL/min/1.73 m2 (HR, 1.649; 95% CI, 1.094-2.485; P = 0.017) or < 60 mL/min/1.73 m2 (HR, 2.106; 95% CI, 1.039-4.269; P = 0.039) had a higher risk of DR progression. Increasing MAU tertiles were associated with progression of DR (Tertile 2: HR, 2.577; 95% CI, 1.561-4.256; P < 0.001; Tertile 3: HR, 3.135; 95% CI, 1.892-5.194; P < 0.001). No significant relationship was found between renal function and the development of DME (P > 0.05). Conclusions: Abnormal renal profiles (i.e., low levels of eGFR and high levels of MAU) were associated with the progression of DR, but not with the development of DME.

Purification, identification and hypolipidemic activities of three novel hypolipidemic peptides from tea protein.

In this study, hypolipidemic peptides were obtained from tea protein by enzymatic hydrolysis, ultrafiltration and high-performance liquid chromatography. Subsequently, the hypolipidemic peptides were identified by mass spectrometry and screened through molecular docking technology, and the hypolipidemic activities and mechanisms of the active peptides were explored. The results showed that the hydrolysate of hypolipidemic peptides obtained by pepsin hydrolysis for 3 h had good bile salt binding ability. After purification, identification and molecular docking screening, three novel hypolipidemic peptides FLF, IYF and QIF were obtained. FLF, IYF and QIF can interact with the receptor proteins 1LPB and 1F6W through hydrogen bonds, π-π bonds, hydrophobic interactions and van der Waals forces, thus exerting hypolipidemic activities. Activity studies showed that, compared with the positive controls, FLF, IYF and QIF had excellent sodium taurocholate binding abilities, pancreatic lipase inhibitory activities and cholesterol esterase inhibitory activities. Moreover, FLF, IYF and QIF can effectively inhibit lipogenic differentiation of 3T3-L1 preadipocytes, reduce intracellular lipid and low-density lipoprotein content and increase high-density lipoprotein content. These results indicated that the three novel hypolipidemic peptides screened in this study had excellent hypolipidemic activities and were expected to be used as natural-derived hypolipidemic active ingredients for the development and application in functional foods.

Purification, Identification, and Mechanistic Investigation of Novel Selenium-Enriched Antioxidant Peptides from Moringa oleifera Seeds.

In this study, five novel Se-enriched antioxidant peptides (FLSeML, LSeMAAL, LASeMMVL, SeMLLAA, and LSeMAL) were purified and identified from Se-enriched Moringa oleifera (M. oleifera) seed protein hydrolysate. The five peptides showed excellent cellular antioxidant activity, with respective EC50 values of 0.291, 0.383, 0.662, 0.1, and 0.123 µg/mL. The five peptides (0.025 mg/mL) increased the cell viability from 78.72 to 90.71, 89.16, 93.92, 83.68, and 98.29%, respectively, effectively reducing reactive oxygen species accumulation and significantly increasing superoxide dismutase and catalase activities in damaged cells. Molecular docking results revealed that the five novel Se-enriched peptides interacted with the key amino acid of Keap1, thus directly blocking the interaction of Keap1-Nrf2 and activating the antioxidant stress response to enhance the ability of scavenging free radicals in vitro. In conclusion, Se-enriched M. oleifera seed peptides exhibited significant antioxidant activity and can be expected to find widespread use as a highly active natural functional food additive and ingredient.

Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile men and cynomolgus monkey and tree shrew models.

Primate-specific genes (PSGs) tend to be expressed in the brain and testis. This phenomenon is consistent with brain evolution in primates but is seemingly contradictory to the similarity of spermatogenesis among mammals. Here, using whole-exome sequencing, we identified deleterious variants of X-linked SSX1 in six unrelated men with asthenoteratozoospermia. SSX1 is a PSG expressed predominantly in the testis, and the SSX family evolutionarily expanded independently in rodents and primates. As the mouse model could not be used for studying SSX1, we used a non-human primate model and tree shrews, which are phylogenetically similar to primates, to knock down (KD) Ssx1 expression in the testes. Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced sperm motility and abnormal sperm morphology. Further, RNA sequencing indicated that Ssx1 deficiency influenced multiple biological processes during spermatogenesis. Collectively, our experimental observations in humans and cynomolgus monkey and tree shrew models highlight the crucial role of SSX1 in spermatogenesis. Notably, three of the five couples who underwent intra-cytoplasmic sperm injection treatment achieved a successful pregnancy. This study provides important guidance for genetic counseling and clinical diagnosis and, significantly, describes the approaches for elucidating the functions of testis-enriched PSGs in spermatogenesis.

Two Novel Angiotensin I-Converting Enzyme (ACE) Inhibitory Peptides from Rice (Oryza sativa L.) Bran Protein.

To realize the high-value utilization of rice byproducts, the rice bran protein hydrolysate was separated and purified by ultrafiltration and reversed-phase high-performance liquid chromatography (RP-HPLC), then the sequences of peptides were identified by liquid chromatography with tandem mass spectrometry (LC-MS/MS), and their molecular docking analysis and activities in vitro and in the cell were carried out. Two novel peptides FDGSPVGY (840.3654 Da) and VFDGVLRPGQ (1086.582 Da) were obtained with IC50 values of 0.079 mg/mL (94.05 µM) and 0.093 mg/mL (85.59 µM) on angiotensin I-converting enzyme (ACE) inhibitory activity in vitro, respectively. Molecular docking results showed that two peptides interacted with ACE receptor protein through hydrogen bonding, hydrophobic interactions, etc. Through the EA.hy926 cells, it was found that FDGSPVGY and VFDGVLRPGQ could promote the release of nitric oxide (NO) and reduce the content of ET-1 to achieve the effect of antihypertension. In conclusion, the peptides from rice bran protein exhibited significant antihypertension activity and may be expected to realize the high-value utilization of rice byproducts.

Rapid screening of novel tyrosinase inhibitory peptides from a pearl shell meat hydrolysate by molecular docking and the anti-melanin mechanism.

Pearls are an edible and medicinal resource with whitening activity and nutritional value in China. In the previous study, we found that the pearl shell meat hydrolysate showed dual activities of antioxidation and tyrosinase inhibition, which were similar to the activities of pearls. In this research, a pearl shell meat hydrolysate was isolated, identified and screened by molecular docking, and three peptides FLF, SPSSS and WLL with high tyrosinase inhibitory activities were obtained. The results indicated that FLF, SPSSS and WLL could effectively inhibit tyrosinase activities and the inhibition rates (1.0 mg mL-1) were 54.32%, 65.26% and 57.50%, respectively. The results of a zebrafish whitening experiment showed that the tyrosinase activities of zebrafish treated with FLF, SPSSS and WLL decreased by 75.41%, 62.87% and 64.99% (p < 0.05), respectively, and the melanin content decreased by 37.34%, 38.52% and 40.39% (p < 0.05), respectively. In a B16F10 cell whitening experiment, compared with a control group, FLF, SPSSS and WLL also showed a significant whitening effect, the tyrosinase activities decreased by 84.08%, 79.08% and 77.45% (p < 0.05), respectively, and the melanin content decreased by 42.23%, 34.37% and 34.02% (p < 0.05), respectively. Moreover, the active peptides could act on three signal pathways including Wnt/ß-catenin, MAPK and MC1R/α-MSH and significantly downregulated the expressions of the signaling factors WNT4, MITF, ß-catenin, ERK, JNK, TRP1 and TRP2 (p < 0.05). The results demonstrated that the whitening active peptides were edible natural antioxidants, tyrosinase inhibitors and skin anti-melanin agents, which could be added to functional foods as food ingredients.

Graphene Infrared Radiation Management Targeting Photothermal Conversion for Electric-Energy-Free Crude Oil Collection.

Graphene has been widely used as a solar absorber for its broad-band absorption. However, targeting a higher photothermal efficiency, the intrinsic infrared radiation loss of graphene requires to be further reduced. Herein, band structure engineering is performed to modulate graphene infrared radiation. Nitrogen-doped vertical graphene is grown on quartz foam (NVGQF) by the plasma-enhanced chemical vapor deposition method. Under the premise of keeping high solar absorption (250-2500 nm), graphitic nitrogen doping effectively modulates the infrared emissivity (2.5-25 µm) of NVGQF from 0.96 to 0.68, reducing the radiation loss by ∼31%. Based on the excellent photothermal properties of NVGQF, a temperature-gradient-driven crude oil collecting raft is designed, where the crude oil flows along the collecting path driven by the viscosity gradient without any external electric energy input. Compared with a nondoped vertical graphene quartz foam raft, the NVGQF raft with a superior photothermal efficiency shows a significantly enhanced crude oil collecting efficiency by three times. The advances in this work suggest broad radiation-managed application platforms for graphene materials, such as seawater desalination and personal or building thermal management.

Cryopreservation did not affect sperm DNA methylation levels of genes related to fertilization and embryonic development of cynomolgus macaque (Macaca fascicularis).

DNA methylation alters gene expression in numerous biological processes, including embryonic development. It is little known about the effect of cryopreservation on sperm DNA methylation. The present study has investigated whether cryopreservation causes abnormal DNA methylation in cynomolgus macaque sperm for five critical genes that includes the maternally imprinted gene (SNRPN), genes associated with male infertility (HSPA1L, MTHFR) and genes involved in embryonic development (TET3, LZTR1). Our results showed that sperm motility, the percentage of acrosomal integrity, DNA integrity and mitochondrial membrane potential were decreased after cryopreservation either being frozen with penetrating cryoprotectant, glycerol (Gly) or ethylene glycol (EG), compared to fresh sperm (p = 0.000), but the methylation patterns of the five target genes from cynomolgus macaque sperm samples were not affected after cryopreservation as evaluated by the Bisulfite Sequencing PCR (BSP) method. The data indicates that the current protocol for sperm cryopreservation of cynomolgus macaque is safe in terms of DNA methylation levels in these genes related to critical sperm functions.

Design and Modeling of a Microfluidic Coral Polyps Culture Chip with Concentration and Temperature Gradients.

Traditional methods of cultivating polyps are costly and time-consuming. Microfluidic chip technology makes it possible to study coral polyps at the single-cell level, but most chips can only be analyzed for a single environmental variable. In this work, we addressed these issues by designing a microfluidic coral polyp culture chip with a multi-physical field for multivariable analyses and verifying the feasibility of the chip through numerical simulation. This chip used multiple serpentine structures to generate the concentration gradient and used a circuit to form the Joule effect for the temperature gradient. It could generate different temperature gradients at different voltages for studying the growth of polyps in different solutes or at different temperatures. The simulation of flow field and temperature showed that the solute and heat could be transferred evenly and efficiently in the chambers, and that the temperature of the chamber remained unchanged after 24 h of continuous heating. The thermal expansion of the microfluidic chip was low at the optimal culture temperature of coral polyps, which proves the feasibility of the use of the multivariable microfluidic model for polyp culture and provides a theoretical basis for the actual chip processing.

Purification, identification, and antioxidative mechanism of three novel selenium-enriched oyster antioxidant peptides.

Natural organic selenium (Se) has multiple physiological health benefits and has become a hotspot of research in recent years. In this study, the Se-enriched antioxidant peptides were purified from Se-enriched oyster hydrolysate. Three novel Se-enriched antioxidant peptides LLVSeMY (685.2953 Da), MMDSeML (687.1875 Da) and VSeMDSeML (703.1599 Da) were identified from fraction F6-4, which all exhibited strong cellular antioxidant activity (CAA) with EC50 values of 0.739, 0.423, and 0.395 µg/mL, respectively. These three Se-enriched antioxidant peptides (0.025 mg/mL) could significantly enhanced cell viability to 84.60 ± 3.32% âˆ¼ 86.18 ± 1.36% compared with the AAPH injury group (75.99 ± 0.79%), and the cytoprotective effects were even better than that of GSH (80.47 ± 2.78%). Moreover, these three Se-enriched peptides also significantly protected HepG2 cells from AAPH-induced oxidative injury by inhibiting ROS production and enhancing the activities of antioxidant enzymes. The molecular docking results showed that these three Se-enriched peptides can form stable hydrogen and hydrophobic bonds with key amino acid residues of Keap1 protein, thereby potentially regulating the Keap1-Nrf2 pathway. In conclusion, the three novel Se-enriched oyster antioxidant peptides are expected to be used in medicine or functional food, providing a new theoretical basis for the high-value utilization of natural organic Se.

[Mechanism of Huanglian Wendan Decoction in improving impaired glucose tolerance based on skeletal muscle NLRP3/caspase-1/IL-1ß, IL-18 pathway].

This study investigated the mechanism of improving impaired glucose tolerance(IGT) of rats by Huanglian Wendan Decoction from the perspective of the skeletal muscle Nod-like receptor protein 3(NLRP3)/cysteinyl aspartate specific proteinase-1(caspase-1)/interleukin-1ß(IL-1ß), interleukin-18(IL-18) pathway. Healthy male SD rats were fed with the diet containing 45% fat for 20 weeks, accompanied by a high-temperature and high-humidity environment and an inactive lifestyle, for the establishment of the IGT rat model. The rats were divided into the blank control group, model control group, metformin hydrochloride group(positive drug group, 0.05 g·kg~(-1)·d~(-1)) and Huanglian Wendan Decoction group(7.8 g·kg~(-1)·d~(-1)). After continuous intragastric administration for 4 weeks, the obesity and glycemic indexes of all the rats were measured. The fasting serum insulin(FINS) level was determined by ELISA, with the insulin sensitivity index(ISI) and insulin resistance index(IRI) calculated. The mRNA and protein expression le-vels of nuclear factor kappaB(NF-κB), NLRP3, caspase-1, IL-1ß and IL-18 in skeletal muscle tissue were detected by real-time polymerase chain reaction(PCR), Western blot and immunofluorescence. Compared with the blank control group, the model control group witnessed significantly increased mRNA and protein expression of NF-κB, NLRP3, caspase-1, IL-1ß and IL-18. As revealed by the comparison with the model control group, Huanglian Wendan Decoction could effectively regulate the obesity status, reduce body weight, correct the abnormal levels of 2-hour plasma glucose(2 hPG), insulin resistance index(IRI), insulin sensitivity index(ISI), and lower the mRNA and protein expression of NF-κB, NLRP3, caspase-1, IL-1ß and IL-18 in the skeletal muscle tissue of IGT rats. Combined with previous studies, the above results showed that the occurrence and development of IGT was closely related to inflammatory response and the classic pyroptosis pathway in skeletal muscle, such as NLRP3/caspase-1/IL-1ß, IL-18. It is inferred that the mechanism of Huanglian Wendan Decoction was to alleviate insulin resistance(IR) and then reverse the course of IGT lies in the regulation of the abnormal insulin receptor signaling pathway based on the NLRP3 inflammasome pathway.

Cyclometalated iridium(III) complexes as mitochondria-targeted anticancer and antibacterial agents to induce both autophagy and apoptosis.

Mitochondrial damage will hinder the energy production of cells and produce excessive ROS (reactive oxygen species), resulting in cell death through autophagy or apoptosis. In this paper, four cyclometalated iridium(III) complexes (Ir1: [Ir(piq)2L]PF6; Ir2: [Ir(bzq)2L]PF6; Ir3: [Ir(dfppy)2L]PF6; Ir4: [Ir(thpy)2L]PF6; piq = 1-phenylisoquinoline; bzq = benzo[h]quinoline; dfppy = 2-(2,4-difluorophenyl)pyridine;thpy = 2-(2-thienyl)pyridine; L = 1,10-phenanthroline-5-amine) were synthesized and characterized. Cytotoxicity tests show that these complexes have excellent cytotoxicity to cancer cells, and mechanism studies indicatethat these complexes can specifically target mitochondria. Complexes Ir1 and Ir2 can damage the function of mitochondria, subsequently increasing intracellular levels of ROS, decreasing MMP (mitochondrial membrane potential), and interfering with ATP energy production, which leads to autophagy and apoptosis. Furthermore, autophagy induced by Ir1 and Ir2 can promote cell death in coordination with apoptosis. Surprisingly, these four complexes also showed moderate antibacterial activity to S. aureusand P. aeruginosa.

Mitochondria-targeted Re(I) complexes bearing guanidinium as ligands and their anticancer activity.

As the "powerhouse" of a cell, mitochondria maintain energy homeostasis, synthesize ATP via oxidative phosphorylation, generate ROS signaling molecules, and modulate cell apoptosis. Herein, three Re(I) complexes bearing guanidinium derivatives have been synthesized and characterized. All of these complexes exhibit moderate anticancer activity in HepG2, HeLa, MCF-7, and A549 cancer cells. Mechanism studies indicate that complex 3, [Re(CO)3(L)(Im)](PF6)2, can selectively localize in the mitochondria and induce cancer cell death through mitochondria-associated pathways. In addition, complex 3 can effectively depress the ability of cell migration, cell invasion, and colony formation.

Interactions between iron and α-synuclein pathology in Parkinson's disease.

Both iron deposition and α-synuclein aggregation are neuropathological hallmarks of Parkinson's disease (PD). We aimed to summarize the extensive interactions between these two factors. The direct structural links between iron and α-synuclein suggest that structural reorganization provokes α-synuclein conformational change. Iron post-transcriptionally regulates α-synuclein synthesis in the presence of iron-responsive element. Increased oxidative/nitrative stress induced by iron is believed to be involved in the post-translational modulation of α-synuclein. Iron modulates proteolytic pathways and therefore participates in the regulation of α-synuclein levels. Meanwhile, the recycling of iron through ferritin degradation suggests a link from the aspects of the degradation signaling pathway. Finally, α-synuclein might regulate iron metabolism through its ferrireductase activity. A prominent role of α-synuclein in iron homeostasis is involved in the uptake of transferrin-Fe. These findings suggest that intracellular iron and α-synuclein are closely related to each other, contributing to the vulnerability of dopaminergic neurons or even to a vicious cycle of toxicity in the pathology of PD.

Guanidine-modified cyclometalated iridium(III) complexes for mitochondria-targeted imaging and photodynamic therapy.

PDT is a well-established therapeutic modality for many types of cancer. Photoluminescent cyclometalated iridium(III) complexes are one of the most commonly used classes of organometallic compounds with potential beneficial applications in bioimaging and as promising anticancer agents. In the present study, three new cyclometalated iridium(III) complexes (Ir1-Ir3) containing guanidinium ligands were found to exert excellent cytotoxic effects on different types of cancer cells upon light irradiation at 425 nm. Notably, Ir1 conferred almost no dark toxicity (IC50 > 100 µM) to HepG2 cells, but the value decreased by 387-fold to 0.36 µM following 10 min of light irradiation (425 nm). Further mechanistic investigation revealed that complex Ir1 could induce apoptosis via the activation of reactive oxygen species (ROS)-mediated mitochondrial signaling pathways in the presence or absence of light irradiation. In vivo studies demonstrated that Ir1 significantly inhibited tumor growth in HepG2 xenograft-bearing mice under light irradiation at 425 nm. Taken together, these findings indicate that designing PDT-based Ir(III) complexes may hold a great deal of promise for anticancer drug development.

Circulating Iron Levels Interaction with Central Obesity on the Risk of Nonalcoholic Fatty Liver Disease: A Case-Control Study in Southeast China.

OBJECTIVES: We aimed to evaluate the associations between body iron stores and the risk of nonalcoholic fatty liver disease (NAFLD) in a Chinese population and explore whether this effect may be modified by other factors. METHODS: A 1: 1 frequency-matched case-control study was conducted, including 482 NAFLD cases and 490 gender- and age-matched controls. Serum levels of ferritin, hepcidin, and C-reactive protein were measured. RESULTS: Multivariate logistic regression analysis showed that hepcidin was not associated with NAFLD risk; however, elevated serum ferritin was significantly associated with increased risk of NAFLD (adjusted OR 1.619, 95% CI 1.158-2.267), and hepcidin:ferritin ratio was significantly associated with decreased risk of NAFLD -(OR-adjusted 0.702, 95% CI 0.501-0.984). When stratified by gender, a significant association was found between elevated serum ferritin and hepcidin:ferritin ratio and NAFLD only for women (ORadjusted 2.131, 95% CI 1.151-3.944 and ORadjusted 0.414, 95% CI 0.219-0.781, respectively). A significant multiplicative interaction between central obesity and elevated serum hepcidin was observed (p < 0.05). CONCLUSIONS: Elevated serum ferritin and hepcidin:ferritin ratio are associated with NAFLD in a Chinese population. Although serum hepcidin is not associated with NAFLD, it may augment the risk effect of central obesity on NAFLD.

Iron-induced oxidative stress contributes to α-synuclein phosphorylation and up-regulation via polo-like kinase 2 and casein kinase 2.

α-Synuclein plays a central role in synucleinopathies pathogenesis such as Parkinson's disease (PD). Phosphorylation is the most common and important protein modification linked to α-synuclein pathologies. There is mounting evidence suggested iron and α-synuclein are closely related in PD. We previously reported iron up-regulated α-synuclein mRNA levels and induced α-synuclein aggregation. In the present study, we aimed to investigate whether and how phosphorylation was involved in iron-induced α-synuclein regulations. The results showed that iron could induce pS129 α-synuclein (phosphorylation at Ser129) and α-synuclein upregulation in the substantia nigra of iron-overloaded rats and iron-treated SH-SY5Y cells, accompanied by the elevated levels of polo-like kinase 2 (PLK2) and casein kinase 2 (CK2). Over-expression of CK2 or PLK2 induced pS129 α-synuclein up-regulation and inhibitors of CK2 or PLK2 could suppress iron-induced α-synuclein phosphorylation. Antioxidant NAC could fully block iron-induced upregulation of CK2, PLK2 and pS129 α-synuclein levels, indicating oxidative stress plays a critical role in iron-induced α-synuclein phosphorylation. However, iron-induced α-synuclein up-regulation could only be partially blocked by CK2/PLK2 inhibitor or NAC. These findings demonstrate that iron-induced oxidative stress is largely responsible for α-synuclein phosphorylation and upregulation via CK2 and PLK2, and α-synuclein upregulation is not fully phosphorylation-dependent.

Heterogenic transplantation of bone marrow-derived rhesus macaque mesenchymal stem cells ameliorates liver fibrosis induced by carbon tetrachloride in mouse.

Liver fibrosis is a disease that causes high morbidity and has become a major health problem. Liver fibrosis can lead to the end stage of liver diseases (livercirrhosisand hepatocellularcarcinoma). Currently, liver transplantation is the only effective treatment for end-stage liver disease. However, the shortage of organ donors, high cost of medical surgery, immunological rejection and transplantation complications severely hamper liver transplantation therapy. Mesenchymal stem cells (MSCs) have been regarded as promising cells for clinical applications in stem cell therapy in the treatment of liver diseases due to their unique multipotent differentiation capacity, immunoregulation and paracrine effects. Although liver fibrosis improvements by MSC transplantation in preclinical experiments as well as clinical trials have been reported, the in vivo fate of MSCs after transportation and their therapeutic mechanisms remain unclear. In this present study, we isolated MSCs from the bone marrow of rhesus macaques. The cells exhibited typical MSC markers and could differentiate into chondrocytes, osteocytes, and adipocytes, which were not affected by labeling with enhanced green fluorescent protein (EGFP). The harvested MSCs respond to interferon-γ stimulation and have the ability to inhibit lymphocyte proliferation in vitro. EGFP-labeled MSCs (1 × 106 cells) were transplanted into mice with carbon tetrachloride-induced liver fibrosis via tail vein injection. The ability of the heterogenic MSC infusion to ameliorate liver fibrosis in mice was evaluated by a blood plasma chemistry index, pathological examination and liver fibrosis-associated gene expression. Additionally, a small number of MSCs that homed and engrafted in the mouse liver tissues were evaluated by immunofluorescence analysis. Our results showed that the transplantation of heterogenic MSCs derived from monkey bone marrow can be used to treat liver fibrosis in the mouse model and that the paracrine effects of MSCs may play an important role in the improvement of liver fibrosis.