Preclinical Evaluation of JAB-2485, a Potent AURKA Inhibitor with High Selectivity and Favorable Pharmacokinetic Properties.

As a critical mitotic regulator, Aurora kinase A (AURKA) is aberrantly activated in a wide range of cancers. Therapeutic targeting of AUKRA is a promising strategy for the treatment of solid tumors. In this study, we evaluated the preclinical characteristics of JAB-2485, a small-molecule inhibitor of AURKA currently in Phase I/IIa clinical trial in the US (NCT05490472). Biochemical studies demonstrated that JAB-2485 is potent and highly selective on AURKA, with subnanomolar IC50 and around 1500-fold selectivity over AURKB or AURKC. In addition, JAB-2485 exhibited favorable pharmacokinetic properties featured by low clearance and good bioavailability, strong dose-response relationship, as well as low risk for hematotoxicity and off-target liability. As a single agent, JAB-2485 effectively induced G2/M cell cycle arrest and apoptosis and inhibited the proliferation of small cell lung cancer, triple-negative breast cancer, and neuroblastoma cells. Furthermore, JAB-2485 exhibited robust in vivo antitumor activity both as monotherapy and in combination with chemotherapies or the bromodomain inhibitor JAB-8263 in xenograft models of various cancer types. Together, these encouraging preclinical data provide a strong basis for safety and efficacy evaluations of JAB-2485 in the clinical setting.

Magnolol ameliorates fumonisin B1-induced oxidative damage and lipid metabolism dysfunction in astrocyte-like C6 cells.

The neurotoxicity of fumonisin B1 (FB1), a commonly detected mycotoxin in crops and the environment, has attracted considerable attention in recent years. However, no effective method for eliminating FB1 completely exists due to the thermal stability and water solubility of this mycotoxin. Magnolol (MAG) is a neolignane with antioxidative and neuroprotective effects. It has been applied in neurotoxicity treatment. However, the application of MAG to attenuate FB1-induced toxicity has not been reported. This study explored the protective mechanism of MAG against FB1-induced damage in C6 cells through antioxidant and lipid metabolism modulation. Results showed that exposure to 15 µM FB1 caused oxidative stress by changing the levels of malondialdehyde, reactive oxygen species, total superoxide dismutase, catalase, and total glutathione. These changes were reversed by MAG addition, especially at the concentration of 80 µM. The protective effects of MAG were further confirmed by the reduction in the phosphorylation levels of proteins in the MAPK signaling pathway. Lipidomics analysis identified 263 lipids, which belong to 24 lipid classes. Among all of the identified lipids, triglycerides (TGs), diglycerides (DGs), phosphatidylcholines (PCs), wax monoesters (WEs), Cers, and phosphatidylethanolamines (PEs) were major categories. Moreover, nine categories of lipids showed the opposite change trend in the FB1 exposure and MAG 80 groups. A further investigation of the 34 co-occurring differential lipids with remarkable changes (P value < 0.05 and VIP value > 1) in the control, FB1 exposure, and MAG 80 groups was performed. Therein, nine lipids (PCs, LPCs, and SM) were screened out as potential biomarkers to reveal the cytoprotective effects of MAG. This work is the first to investigate the rescue mechanism of MAG in FB1-induced cytotoxicity. The obtained results may expand the application of MAG to alleviate the toxicity of mycotoxins.

In silico prediction aided preparation of antioxidant soybean peptides by enzymatic hydrolysis for ameliorating lead exposure-induced toxicity.

Food derived bioactive peptides are prominent dietary supplements to protect against oxidative stress induced by lead (Pb) exposure. This study aimed to develop a new strategy for rapid preparation of highly active antioxidant soybean polypeptides (ASPs) against Pb toxicity. In silico enzymatic hydrolysis simulation and antioxidant activity prediction showed that pepsin, chymotrypsin and bromelain can produce peptides with the highest activity. The preparation process was then optimized, and the obtained ASP showed good antioxidant and metal-chelating activities in vitro. An in vivo study showed that ASP exerted prominent protective effects against Pb-induced cognitive impairment and tissue damage in mice by reducing Pb deposition and enhancing the antioxidant capacity in tissues and was superior to Vc, DMSA or their combination in some aspects. ASP composition analysis demonstrated that its prominent antioxidant activity might be attributed to the high proportion of amino acid residues E, L, P and V in the peptide sequence and L, V and A at the C- and N-termini. In conclusion, in silico prediction could facilitate the preparation of ASP. And the ASP prepared with the new strategy exerted prominent protective effects against Pb toxicity.

Purslane (Portulacae oleracea L.) polysaccharide relieves cadmium-induced colonic impairments by restricting Cd accumulation and inhibiting inflammatory responses.

This study aimed to assess the protective effects of purslane polysaccharide (PP) on colonic impairments in mice exposed to cadmium (Cd). C57BL/6 mice were administered with PP (200-800 mg/kg/day) by gavage for 4 weeks after treatment with 100 mg·L-1 CdCl2. PP significantly reduced Cd accumulation in the colon tissue and promoted the excretion of Cd in the feces. PP could reduce the expression levels of inflammatory factors (tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6) and inhibit the activation of the TLR4/MyD88/NF-κB signaling pathway. In addition, the results of 16S rRNA analysis revealed that PP significantly increased the abundance of probiotics (Lactobacillus), while decreased the abundance of pathogenic bacteria (Lachnospiraceae_NK4A136_group). Following the augmentation of beneficial intestinal bacteria, the treatment with PP led to an increase in the levels of intestinal microbial metabolites, specifically short-chain fatty acids (SCFAs). The SCFAs are known for their anti-inflammatory properties, immune-regulatory effects, and promotion of intestinal barrier function. Additionally, the results suggested that PP effectively impeded the enterohepatic circulation by inhibiting the FXR-FGF15 axis in the intestines of Cd-exposed mice. In summary, PP mitigated the toxic effects of Cd by limiting its accumulation and suppressing inflammatory responses in colon.

Aluminum-maltol induced oxidative stress and reduced AMPK activity via BCK-related energy supply failure in C6 cell.

Aluminum (Al) exposure significantly interferes with the energy supply in astrocytes, which may be a potential mechanism of Al-induced neurotoxicity. This study was designed to explore the mechanisms of Al-induced energy supply impairment in rat C6 astroglioma cell line. Aluminum-maltolate (Al(mal)3) (0.1 mM, 24 h) exposure significantly decreased brain-type creatine kinase (BCK) co-localization with the endoplasmic reticulum (ER) and resulted in mitochondrial dysfunctions, accompanied by a decrease in AMPK phosphorylation. The results of molecular docking showed that Al(mal)3 increased BCK's hydrophobicity and hindered the localization movement of BCK between subcells·H2O2 co-administration was found to exacerbate mitochondrial dysfunction, Ca2+ dyshomeostasis, and apoptosis. After treated with Al(mal)3, additional oxidative stress contributed to BCK activity inhibition but did not promote a further decrease in AMPK phosphorylation. The activation of p-AMPK by its agonist can partially restore mitochondrial function, BCK activity, and ER-localized-BCK levels in Al(mal)3-treated astrocytes. In summary, Al exposure resulted in a sustained depletion of the mitochondrial and antioxidant systems, which was associated with reduced p-AMPK activity and decreased ER-localized-BCK levels in astrocytes. This study provides a theoretical basis for exploring the mechanisms of neurotoxicity induced by Al exposure.

Segmentation of pancreatic tumors based on multi-scale convolution and channel attention mechanism in the encoder-decoder scheme.

BACKGROUND: Computer-aided diagnosis is of great significance to improve the diagnostic accuracy of pancreatic cancer that has an insidious course and does not have obvious symptoms at first. However, segmentation of pancreatic cancer is challenging because the tumors vary in size with the smallest tumor having a size of about 0.5 c m $cm$ in diameter, and most of them have irregular shapes and unclear boundaries. PURPOSE: In this study, we developed a deep learning architecture Multi-Scale Channel Attention Unet (MSCA-Unet) for pancreatic tumor segmentation and collected CT images of 419 patients from The Affiliated Hospital of Qingdao University and a public dataset. We embedded the multi-scale network into the encoder to extract semantic information at different scales and the decoder to provide supplemental information to overcome the loss of information in the upsampling and the drift of the localized tumor due to the upsampling and skip connections. METHODS: We adopted the channel attention unit after the multi-scale convolution to emphasize the informative channels, which was observed to have the effects of accelerating the positioning process, reducing false positives, and improving the accuracy of outlining very small, irregular pancreatic tumors. RESULTS: Our results show that our network outperformed the other current mainstream segmentation networks and achieved a Dice index of 68.03%, a Jaccard of 59.31%, and an FPR of 1.36% on the private dataset Task-01 without data pre-processing. Compared with the other pancreatic tumor segmentation networks on the public dataset Task-02, our network produced the best Dice index, 80.12%, with the assistance of the data pre-processing scheme. CONCLUSIONS: This study strategically utilizes the multi-scale convolution and channel attention mechanism of the architecture to provide a dedicated network for segmentation of small and irregular pancreatic tumors.

Comparative study of aluminum speciation on brain-type creatine kinase: Enzyme kinetic, molecular docking, cellular experiment, and mouse model study.

Brain-type Creatine kinase (CK-BB), which has a high affinity for Aluminum (Al), and its abnormality is closely related to neurodegenerative diseases. In this study, the comparative effect of Al speciation on the bioactivity of CK-BB has been studied by the inhibition kinetics method, molecular docking, cellular experiment, and mouse model study. Results showed that the half-inhibitory concentration of AlCl3 was 0.67 mM, while Al(mal)3 was 3.81 mM. Fluorescence spectra showed that Al(mal)3 had a more substantial effect on the endogenous fluorescence of CK-BB than AlCl3. Molecular docking showed that AlCl3 was closer to the active site of CK-BB. C6 cells were used to explore the enzyme activity and intracellular distribution of CK-BB by AlCl3 or Al(mal)3. AlCl3 treatment may directly affect CK-BB activity and cause insufficient local ATP supply in cells which affected the formation of F-actin and cell morphology. The change in the hydrophobicity of CK-BB induced by Al(mal)3 affected the movement of CK-BB, which subsequently activated thecytochrome C (Cyt C)/Caspase 9/Caspase 3 pathway. Similar results have been found in vivo experiments. This study demonstrated that interaction between Al and CK-BB might be related to the process of Al-induced energy metabolism disorders, in which the Al speciation revealed differentiated toxicity mechanisms.

Rice hull insoluble dietary fiber alleviated experimental colitis induced by low dose of dextran sulfate sodium in cadmium-exposed mice.

Cadmium (Cd), an important toxic environmental pollutant, can invade the gastrointestinal tract and induce the occurrence of gastrointestinal diseases. This study aimed to investigate the protective effect of rice hull insoluble dietary fiber (RHF) on Cd-promoted colitis induced by low dose of dextran sulfate sodium. Administration of RHF attenuated inflammation by limiting Cd accumulation and regulating intestinal immune homeostasis in colitis mice with Cd exposure. RHF could maintain the structure of the gut barrier by increasing mucin secretion and intestinal tight connectivity in mice. Subsequently, RHF repressed the colonic inflammation mediated by the TLR4/MyD88/NF-κB pathway, and inhibited the transcription regulation of inflammatory cytokines. Furthermore, RHF showed an enhancement of a variety of probiotics, such as Eubacterium and Faecalibaculum. RHF also inhibited the growth of pathogenic bacteria, including Erysipelatoclostridium, Helicobacter and Bacteroides. The growth of beneficial bacteria was also accompanied by reversing the decline in short-chain fatty acids, supporting the initial potentiality of RHF as a prebiotic in cases of damage by Cd exposure in colitis mice. Importantly, RHF also remained resistant to Cd toxicity in colitis mice when the gut microbiota was depleted by antibiotics. We suggest that RHF could be used as a novel dietary supplement strategy against Cd-exacerbated colitis.

Comparative study of aluminum (Al) speciation on apoptosis-promoting process in PC12 cells: Correlations between morphological characteristics and mitochondrial kinetic disorder.

Aluminum contamination in environment is very serious and the central nervous system is the main target of aluminum toxicity. The neurotoxic of aluminum is closely related to its speciation. PC12 cells were taken as the cell model to compare the morphological characteristics and mitochondrial kinetic disorder of two speciation of aluminum compounds (AlCl3 and aluminum-maltolate (Al(mal)3)). When the concentration of AlCl3 was 3 mM, the intracellular aluminum ion content was 3.87 times that of the 0.5 mM Al(mal)3 treatment group. At the 3 mM AlCl3 treatment group, intracellular ion homeostasis was disrupted. Abnormally elevated Ca2+ levels inhibited protein kinase B (AKT) phosphorylation, resulting in impaired cell morphology. At the 0.5 mM Al(mal)3 treatment group, abnormally high levels of Ca2+ caused mitochondrial kinetic disorder, which led to impaired cellular energy metabolism. Al(mal)3 had shown more cytotoxic in PC12 than AlCl3 at the same concentration. AlCl3 tended to inhibit the phosphorylation of AKT and damages cell morphology. Al(mal)3 mainly affected mitochondrial kinetic disorder, which led to impaired cellular energy metabolism. These findings provided experimental evidence for in-depth research on aluminum-induced neurotoxicity.

Purslane (Portulacae oleracea L.) attenuates cadmium-induced hepatorenal and colonic damage in mice: Role of chelation, antioxidant and intestinal microecological regulation.

BACKGROUND: Cadmium (Cd) is a representative pernicious metal, which has high biological toxicity. Its precaution through dietary administration is considered an important strategy. Considering that Portulaca oleracea L. (Por.L) has antioxidant, anti-inflammatory and other high medicinal value, and purslane insoluble dietary fiber (PIDF) has good binding property to metal ions, they could be good methods for Cd-induced biotoxicity therapy. PURPOSE: To investigate the beneficial effects of Por.L or PIDF against Cd-induced subchronic toxicity and identify its underlying mechanisms. STUDY DESIGN AND METHODS: C57BL/6 male mice (n = 12) were received 100 mg l-1 CdCl2 in water for 8 weeks. Mice were divided into four groups: Control, Cd-treated, 8% Por.L + Cd, and 8% PIDF + Cd. Histological evaluation, inductively coupled plasma-mass spectrometry, western blotting analysis, quantitative real time-PCR, gas chromatography-mass spectrometry and 16S rDNA analysis were used in the study. RESULTS: Por.L treatment was able to inhibit inflammation and accumulation of Cd, enhance the activity of antioxidant enzymes, increase beneficial bacterial species of Akkermansia and Faecalibaculum and suppress the production of inflammatory cytokines in the colon, such as TNF-α, IL-6, IL-1ß and IFN-γ. PIDF mainly relieved the toxicity of Cd by increasing the production of short chain fatty acids with anti-inflammatory functions and repressing the liver and kidney inflammation mediated by the TLR4/ MyD88/NF-κB pathway. CONCLUSION: Our study has demonstrated that the antagonistic-Cd effects of Por.L might be mediated via chelation, antioxidation, regulation of intestinal microecology. Thus, our study provides a novel insight into Por.L as a promising function food for the anti-Cd biotoxicity. Por.L supplement could be considered as a potential coping strategy to alleviate hazardous effects in Cd-exposed humans.

Comparative Study on the Protective Effect of Chlorogenic Acid and 3-(3-Hydroxyphenyl) Propionic Acid against Cadmium-Induced Erythrocyte Cytotoxicity: In Vitro and In Vivo Evaluation.

The metabolism of chlorogenic acid (CGA) through the intestinal tract was studied. As cadmium is a well-known toxic heavy metal, this study was carried out to investigate the comparative protective effect of CGA and its representative intestinal metabolite (3-(3-hydroxyphenyl) propionic acid, HPPA) against Cd-induced erythrocyte cytotoxicity in vitro and in vivo. We found that CGA and its intestinal metabolite appreciably prevented erythrocyte hemolysis, osmotic fragility, and oxidative stress induced by Cd. Also, we found that HPPA had a stronger protective ability than CGA against Cd-induced erythrocyte injury in vivo, such as increasing the ratio of protein kinase C from 7.7% (CGA) to 12.0% (HPPA). Therefore, we hypothesized that CGA and its microbial metabolite had protective effects against Cd-induced erythrocyte damage via multiple actions including antioxidation and chelation. For humans, CGA supplementation may be favorable for avoiding Cd-induced biotoxicity.

Protection Mechanisms Underlying Oral Administration of Chlorogenic Acid against Cadmium-Induced Hepatorenal Injury Related to Regulating Intestinal Flora Balance.

Cadmium (Cd) is a heavy metal, which is widely used in the industry and daily life. It has a long half-life, so large amounts of Cd can accumulate in humans and become toxic. Chlorogenic acid (CGA) can eliminate free radicals and inhibit lipid peroxidation and is mainly used to prevent metal toxicity. In the present study, mice are given CGA by intraperitoneal injection or gavage, respectively, to explore the mechanism of preventing Cd toxicity. In acute Cd-exposed mice, CGA treatment (ip) alleviated Cd-induced oxidative damage and reduced the production of NO and MPO in the liver and kidney tissues, while TLR4 expression levels did not change significantly. After 8 weeks of Cd exposure, CGA administration (gavage) significantly alleviated gut dysbiosis by decreasing the Firmicutes to Bacteroidetes ratio, enhancing the relative abundances of bacteria, including Ruminiclostridium_9, Alloprevotella, and Rikenella, and inhibiting the activation of the TLR4/MyD88/NF-κB signaling pathway. These findings suggested that protection mechanisms underlying the oral administration of CGA against the Cd-induced hepatorenal injury was related to the regulation of the intestinal flora balance. CGA can be used as an effective component in daily diet to prevent Cd toxicity.

Malus micromalus Makino phenolic extract preserves hepatorenal function by regulating PKC-α signaling pathway and attenuating endoplasmic reticulum stress in lead (II) exposure mice.

Lead (Pb), which widely recognized as a nonessential heavy metal and a major environmental contamination, is a growing threat to the ecosystem and human body. In the present study, Malus micromalus Makino cv. 'Dong Hong' phenolic extract (MMPE) has been used to antagonise Pb-induced erythrocyte injury, hepatic and renal dysfunction in mice. Six-week-old male Kunming mice were gavaged with PbCl2 (20 mg/kg mouse/day) and/or MMPE (100 mg/kg mouse/day) by gavage administration for 10 days. We evaluated erythrocyte fragility, relative organ mass, biochemical parameters and histopathological changes to evaluate the protection effect of MMPE on the injury of liver and kidney in Pb-treated mice. MMPE significantly inhibited the increase of protein kinase C-α, B-cell lymphoma-2-associated X, cytochrome C and Caspase-3 protein levels and decreased calreticulin protein expression level in Pb-exposed mice. MMPE supplementation could maintain the integrity of erythrocyte membranes and ameliorate the endoplasmic reticulum stress in Pb-treated mice. It suggested MMPE as a natural nutritional supplement to alleviate Pb-induced hazardous effects in Pb-exposed humans.

Characterization of the binding mechanism and conformational changes of bovine serum albumin upon interaction with aluminum-maltol: a spectroscopic and molecular docking study.

The widespread use of aluminum in the treatment of drinking water, food, agriculture and pharmaceuticals has greatly increased the risk of human exposure to excess aluminum, which is a serious health hazard to human beings. In our previous work, serum albumin was reported to have a specific affinity for aluminum. However, the mechanism of binding of aluminum to serum albumin was unclear. In this work, the interaction between bovine serum albumin (BSA) and aluminum-maltol (Al-Mal) was studied by molecular docking and spectroscopic analysis. The results show that the combination of Al-Mal and BSA is a spontaneous endothermic reaction. The binding force is mainly related to the hydrophobic force and hydrogen bonding; when the ratio of BSA to Al-Mal was 1 : 10, the random coils of BSA increased by 47.6%. In addition, the hydrophobicity of BSA was enhanced after combining with Al-Mal. This study can provide a theoretical evidence for the binding mechanism of food-borne aluminum and serum albumin.

Water-soluble polysaccharides from Grifola Frondosa fruiting bodies protect against immunosuppression in cyclophosphamide-induced mice via JAK2/STAT3/SOCS signal transduction pathways.

Grifola Frondosa, the king of mushrooms, is one of the most valued traditional medicines and has been used as a health food for a long time in China, Japan, and other Asian countries. The present study was designed to evaluate the immune-modulating effects of water-soluble polysaccharides from the Grifola Frondosa fruiting body (GFP) by using mouse peritoneal macrophage and cytoxan (CTX) induced immunosuppression models. Compared with CTX-induced immunosuppressive mice, the spleen and thymus indexes in mice with GFP orally administrated were significantly increased, body weight loss was alleviated, and the natural killer (NK) cytotoxicity and the proliferative activities of lymphocytes were elevated. Furthermore, levels of interleukin-2 (IL-2), interferon-6 (IL-6) and tumor necrosis factor-α (TNF-α) were notably reduced by CTX, while GFP abolished these effects. GFP also effectively increased total antioxidant capacity and superoxidase dismutase, catalase and glutathione peroxidase activities, and inhibited an increase in the malondialdehyde level. Histopathological analysis of spleens revealed the protective effect of GFP against CTX-induced immunosuppression. Western blotting results showed that GFP possessed immunomodulatory activity by up-regulating transcription factors (p-JAK2/JAK2, p-STAT3/STAT3 and SOCS3) in JAK2/STAT3/SOCS signaling pathways. This study suggested that GFP may provide an alternative strategy for lessening chemotherapy-induced immunosuppression.

Study on the mechanism underlying Al-induced hepatotoxicity based on the identification of the Al-binding proteins in liver.

Aluminum (Al) is the most abundant metal element in the earth's crust, and is implicated in the pathogenesis of liver lesions. However, the mechanisms underlying Al3+-induced hepatotoxicity are still largely elusive. Based on analysis with native gel electrophoresis, Al3+ plus 8-hydroxyquinoline staining and LC-MS/MS, the proteins with high Al3+ affinity were identified to be carbamoyl-phosphate synthase, adenosylhomocysteinase, heat shock protein 90-alpha, carbonic anhydrase 3, serum albumin and calreticulin. These proteins are involved in physiological processes such as the urea cycle, redox reactions, apoptosis and so on. Then we established an Al3+-treated rat model for biochemical tests, morphology observation and Ca2+ homeostasis analysis, in order to evaluate the extent of oxidative damage, hepatic histopathology and specific indicators of Al3+-related proteins in liver. Our findings indicated the high-affinity interactions with Al3+ perturbed the normal function of the above proteins, which could account for the mechanism underlying Al3+-induced hepatotoxicity.

Chlorogenic acid protects against aluminum toxicity via MAPK/Akt signaling pathway in murine RAW264.7 macrophages.

Aluminum (Al), which may bring about damage to the macrophages, has been implicated in the development of immunological diseases. It has been reported that chlorogenic acid (CGA, 5­caffeoylquinic acid, chemical formula: C16H18O9) is a natural antioxidant and chelating agent with the capacity against Al (III)-induced biotoxicity. The present study was carried out to investigate whether CGA could reduce AlCl3-induced cellular damage in RAW264.7 cells. After treatment with AlCl3, the inhibition rate of viability and phagocytic activity of RAW264.7 cells was 54.5% and 27.6%, respectively. Administration of CGA significantly improved the integrity and phagocytic activity, and attenuated the accumulation of intracellular Al(III) level and oxidative stress in Al(III)-treated cells. Furthermore, CGA significantly inhibited Al(III)-induced increase of phospho-Jun N-terminal kinase (p-JNK), a pro-apoptotic Bcl-2 family protein (Bad), cytochrome c and decrease of extracellular regulated protein kinases (ERK1/2), protein kinase B (Akt) protein expressions. These results showed that CGA has a protective effect against Al(III)-induced cytotoxicity through mitogen-activated protein kinase (MAPK)/Akt-mediated caspase pathways in RAW264.7 cells.

Immunomodulatory activity of a water-soluble polysaccharide obtained from highland barley on immunosuppressive mice models.

A water-soluble polysaccharide (BP-1) was extracted and purified from highland barley (Hordeum vulgare L.) and its average molecular weight was about 6.7 × 104 Da. In this study, the immunomodulatory activity of BP-1 on the immunosuppressive BALB/c mice model and its molecular mechanism were elucidated. It was found that the weight indexes of spleen and thymus were significantly increased by BP-1 (80 mg kg-1 and 160 mg kg-1) treatment in the immunosuppressive mice model. The results showed that BP-1 (80 mg kg-1 and 160 mg kg-1) could significantly increase the number of bone marrow cells (BMC) and peripheral blood white blood cells (WBC) in the immunosuppressive mice model. In addition, the result further confirmed that BP-1 could increase the serum levels of IL-2, TNF-α and IFN-γ, so as to improve the immune function of immunosuppressive mice. The results showed that BP-1 (80 mg kg-1 and 160 mg kg-1) could promote the proliferation of spleen cells and the natural killer (NK) cell activity in vivo. The quantitative real-time polymerase chain reaction (qRT-PCR) and ELISA results revealed that BP-1 (80 mg kg-1 and 160 mg kg-1) could enhance the production of IL-2, TNF-α, IFN-γ, IgG and IgM in the spleen of immunosuppressive mice. The HE (hematoxylin and eosin) stained histopathological images showed that BP-1 (80 mg kg-1 and 160 mg kg-1) could repair the damage induced by CTX in the spleen cells of immunosuppressive mice. The result of macrophages showed that BP-1 (80 mg kg-1 and 160 mg kg-1) could promote the proliferation and phagocytosis activity of macrophages in immunosuppressive mice. Furthermore, BP-1 could activate macrophages by the TLR-4, TRAF6, TAK1 and nuclear factor κB (NF-κB) p65 pathways in vivo. These results suggested that BP-1 has a remarkable immunomodulatory activity on the immunosuppressive mice model.

Identification of the Al-binding proteins that account for aluminum neurotoxicity and transport in vivo.

Studies have shown that aluminum (Al) is the most abundant neurotoxic element on Earth, and is implicated in the pathogenesis of Alzheimer's disease (AD). However, the mechanisms underlying Al-induced neurotoxicity are still largely elusive. Based on affinity analyses with Al and LC-LTQ-MS, we have found that serum albumin, brain CK-B and 14-3-3ζ protein have a high affinity for Al3+, and albumin has a much stronger affinity for Al than transferrin. The normal activity of CK-B, and physiological combination of 14-3-3ζ with tau can be severely perturbed by Al. We anticipate that our assay will provide a new focus concerning the mechanism underlying Al-induced neurotoxicity, and aid the design of strategies to prevent AD and other human diseases related to Al overload.

The immunomodulatory activity and mechanism of docosahexenoic acid (DHA) on immunosuppressive mice models.

In this study, the immunomodulatory activity of docosahexaenoic acid (DHA) on the immunosuppressive BALB/c mice model and its molecular mechanism are elucidated. It was found that the weight indexes of the spleen and thymus were significantly increased by DHA (44.0 mg kg-1 and 88.0 mg kg-1) treatment in the prevention or cure groups. The result of macrophages showed that DHA (44.0 mg kg-1 and 88.0 mg kg-1) could promote the proliferation and phagocytosis activity of macrophages in the prevention or cure groups. In addition, DHA could activate macrophages by the G-protein coupled cell membrane receptor GPR120- Mitogen-Activated Protein Kinases (MAPKs)-nuclear factor κB (NF-κB) p65 pathway in vivo. The result of the spleen showed that DHA (44.0 mg kg-1 and 88.0 mg kg-1) could promote the proliferation of spleen cells and the natural killer (NK) cells activity in vivo. In the prevention or cure groups, the quantitative real-time polymerase chain reaction (qRT-PCR) results revealed that DHA (44.0 mg kg-1 and 88.0 mg kg-1) could enhance the production of cytokines IL-1ß, IL-2, TNF-α and IFN-γ in the spleen of immunosuppressive mice. The HE (hematoxylin and eosin) stained histopathological images showed that DHA could repair the damage induced by CTX in the spleen cells of the prevention or cure groups. These results suggested that DHA has a remarkable immunomodulatory activity on the immunosuppressive mice model in the prevention or cure groups.