The N-Myc-responsive lncRNA MILIP promotes DNA double-strand break repair through non-homologous end joining.

The protooncoprotein N-Myc, which is overexpressed in approximately 25% of neuroblastomas as the consequence of MYCN gene amplification, has long been postulated to regulate DNA double-strand break (DSB) repair in neuroblastoma cells, but experimental evidence of this function is presently scant. Here, we show that N-Myc transcriptionally activates the long noncoding RNA MILIP to promote nonhomologous end-joining (NHEJ) DNA repair through facilitating Ku70-Ku80 heterodimerization in neuroblastoma cells. High MILIP expression was associated with poor outcome and appeared as an independent prognostic factor in neuroblastoma patients. Knockdown of MILIP reduced neuroblastoma cell viability through the induction of apoptosis and inhibition of proliferation, retarded neuroblastoma xenograft growth, and sensitized neuroblastoma cells to DNA-damaging therapeutics. The effect of MILIP knockdown was associated with the accumulation of DNA DSBs in neuroblastoma cells largely due to decreased activity of the NHEJ DNA repair pathway. Mechanistical investigations revealed that binding of MILIP to Ku70 and Ku80 increased their heterodimerization, and this was required for MILIP-mediated promotion of NHEJ DNA repair. Disrupting the interaction between MILIP and Ku70 or Ku80 increased DNA DSBs and reduced cell viability with therapeutic potential revealed where targeting MILIP using Gapmers cooperated with the DNA-damaging drug cisplatin to inhibit neuroblastoma growth in vivo. Collectively, our findings identify MILIP as an N-Myc downstream effector critical for activation of the NHEJ DNA repair pathway in neuroblastoma cells, with practical implications of MILIP targeting, alone and in combination with DNA-damaging therapeutics, for neuroblastoma treatment.

Boosting Hydrogen Production of a MOF-based Multicomponent Photocatalyst with Clean Interface via Facile One-pot Electrosynthesis.

Hydrogen production from photocatalysis via the usage of multicomponent photocatalysts represents a promising pathway for carbon peaking and carbon neutrality, owing to their structural advantages in dealing with the three crucial processes in photocatalysis, namely, light harvesting, charge transfer, and surface redox reactions. We demonstrate the fabrication of a MOF-based multicomponent photocatalyst, denoted as semiconductor/MOF/cocatalyst, by a one-pot electrochemical synthetic route. The as-fabricated multicomponent photocatalyst has a clean interface among the components, leading to close connections that contribute to high-quality heterojunction and facilitate photogenerated charge transfer and separation, thereby the efficient hydrogen evolution. The hydrogen production rate of the resultant ZrO2 /Zr-MOF/Pt is 1327 µmol ⋅ g-1 ⋅ h-1 , which is much higher than that of ZrO2 /Zr-MOF (15 µmol ⋅ g-1 ⋅ h-1 ) and pure Zr-MOF (10.1 µmol ⋅ g-1 ⋅ h-1 ), as well as the photodeposited-Pt products ZrO2 /Zr-MOF/PtPD (287 µmol ⋅ g-1 ⋅ h-1 ) and Zr-MOF/PtPD (192 µmol ⋅ g-1 ⋅ h-1 ) obtained by the step-wise synthetic approach. The work gives a good inspiration for the rational design and construction of MOF-based multicomponent photocatalysts through the one-pot electrosynthesis.

Carbon dots with enhanced red emission for ratiometric sensing and encryption applications.

The excitation-dependent emission properties of carbon dots (Cdots) are extensively reported, but their red emission is often weak, limiting their wider application. Here we introduce ethidium bromide, as a functional precursor with red emission, to enhance the red emission for Cdots, with comparable intensity at a broad wavelength range to multi-emission Cdots (M-Cdots). We found that Cdots prepared with ethidium bromide/ethylenediamine exhibited strong blue and red emission at 440 and 615 nm, with optimal excitation at 360 and 470 nm as M-Cdots, respectively, but the Cdots from single ethidium bromide (EB-Cdots) possessed weak red emission. M-Cdots exhibited a broad absorption band at 478 nm, but a band blue-shifted to 425 nm was observed for EB-Cdots, while no absorption was observed at 478-425 nm for the Cdots prepared with citric acid and ethylenediamine. Thus, we proposed that C=O and C=N formed a π-conjugation structure as the absorption band at 478 nm for the red emission of M-Cdots, as also confirmed with the excitation at 470 nm. Moreover, the π-conjugation structure is fragile and sensitive to harsh conditions, so red emission was difficult to observe for the Cdots prepared with citric acid/ethylenediamine or single ethidium bromide. M-Cdots possess two centers for blue and red emission with different structures. The dual emission was therefore used for ratiometric sensing with dichromate (Cr2O72-) and formaldehyde (HCHO) as the targets using the intensity ratio of the emissions at 615 and 440 nm. Due to the comparable intensity at a broad wavelength range, we designed encryption codes with five excitations at 360, 400, 420, 450, and 470 nm as the inputs, and the emission colors were used for information decoding. Thus, we determined why red emission was difficult to realize for Cdots, and our results could motivate the design of red-emission Cdots for extensive applications.

ß-arrestin2 deficiency ameliorates S-100-induced autoimmune hepatitis in mice by inhibiting infiltration of monocyte-derived macrophage and attenuating hepatocyte apoptosis.

Autoimmune hepatitis (AIH) is a progressive hepatitis syndrome characterized by high transaminase levels, interface hepatitis, hypergammaglobulinemia, and the presence of autoantibodies. Misdiagnosis or delayed treatment of AIH can lead to cirrhosis or liver failure, which poses a major risk to human health. ß-Arrestin2, a key scaffold protein for intracellular signaling pathways, has been found to be involved in many autoimmune diseases such as Sjogren's syndrome and rheumatoid arthritis. However, whether ß-arrestin2 plays a role in AIH remains unknown. In the present study, S-100-induced AIH was established in both wild-type mice and ß-arrestin2 knockout (Arrb2 KO) mice, and the experiments identified that liver ß-arrestin2 expression was gradually increased, and positively correlated to serum ANA, ALT and AST levels during AIH progression. Furthermore, ß-arrestin2 deficiency ameliorated hepatic pathological damage, decreased serum autoantibody and inflammatory cytokine levels. ß-arrestin2 deficiency also inhibited hepatocyte apoptosis and prevented the infiltration of monocyte-derived macrophages into the damaged liver. In vitro experiments revealed that ß-arrestin2 knockdown suppressed the migration and differentiation of THP-1 cells, whereas ß-arrestin2 overexpression promoted the migration of THP-1 cells, which was regulated by the activation of the ERK and p38 MAPK pathways. In addition, ß-arrestin2 deficiency attenuated TNF-α-induced primary hepatocyte apoptosis by activating the Akt/GSK-3ß pathway. These results suggest that ß-arrestin2 deficiency ameliorates AIH by inhibiting the migration and differentiation of monocytes, decreasing the infiltration of monocyte-derived macrophages into the liver, thereby reducing inflammatory cytokines-induced hepatocytes apoptosis. Therefore, ß-arrestin2 may act as an effective therapeutic target for AIH.

Synthesis, biological evaluation and molecular docking studies of novel diosgenin derivatives as anti-inflammatory agents.

Thirty-two novel DG F-spiroacetal ring-opening derivatives, including 24 acetylated derivatives and 8 nitrogenous derivatives, were designed and synthesized from diosgenin (DG). The cytotoxicity of the novel derivatives was evaluated by MTT assay, except for compounds 4a, 4e, 4i, 4 l, 5a and 5 h, which were potentially cytotoxic to RAW264.7 cells, all the other derivatives had no significant cytotoxicity. The NO release inhibitory activities of novel derivatives were screened by Griess method. The results showed that the anti-inflammatory activity of the DG acetylated derivatives was stronger than the nitrogenous derivatives, and 4a-4 m containing acetyl groups at the 3-position may have better anti-inflammatory effects than 5a-5 k containing free hydroxyl groups. In ELISA assay, compound 4 m exhibited potent anti-inflammatory activity by inhibiting the production of NO in RAW264.7 cells activated by LPS with IC50 values 0.449 ± 0.050 µM. The results of docking experiments showed that 4 m has a good affinity for p65 protein.

Serum irisin levels in patients with myasthenia gravis.

OBJECTIVE: Myasthenia gravis (MG) is an autoimmune disorder whose main symptoms are muscle weakness and fatigue. Irisin is a novel skeletal muscle-derived myokine participating in several physiological and pathological processes. The initial objective of the project was to explore serum levels of irisin in patients with MG, as well as its correlation with disease severity. METHODS: We retrospectively evaluated serum levels of irisin in 77 MG patients and 57 healthy controls (HCs) by enzyme-linked immunosorbent assay. Further, clinical parameters were measured properly. RESULTS: Serum irisin levels were significantly elevated in MG patients compared with HCs (p < 0.001). Furthermore, serum irisin levels were associated with the myasthenia gravis activities of daily living score in ocular myasthenia gravis (OMG) patients (r = 0.476, p = 0.004), but there was no relationship to be considered of any relevant value in generalized myasthenia gravis (GMG) patients. Acetylcholine receptor antibody-positive MG patients had higher serum irisin levels compared with HCs. Thymoma, endotracheal intubation, or intensive care unit treatments subsequently were not found to have effect on serum levels of irisin, but tendencies of increase were observed in negative ones. CONCLUSIONS: Serum irisin levels were elevated in patients with MG, suggesting its possible involvement in MG. And irisin is expected to be a signal to evaluate the activities of daily living of OMG patients, while its effect needs further study.

Irisin levels in the serum and cerebrospinal fluid of patients with multiple sclerosis and the expression and distribution of irisin in experimental autoimmune encephalomyelitis.

Irisin is a novel hormone-like myokine that plays an important role in central nervous system (CNS) diseases, such as cerebral ischaemia and Alzheimer's disease. However, irisin is rarely investigated in multiple sclerosis (MS), a typical inflammatory demyelinating disease of the CNS, and in experimental autoimmune encephalomyelitis (EAE), a typical model of MS. We determined the levels of irisin in the serum and cerebrospinal fluid in patients with MS. The expression and histological distribution of irisin were determined in EAE. Serum irisin levels in patients with MS and in EAE mice were increased, and the levels of FNDC5/irisin mRNA were decreased in the spinal cord and brain regardless of the onset, peak or chronic phase of EAE. Immunofluorescence staining showed co-localization of irisin and neurones. The levels of irisin fluctuated with disease progression in MS and EAE. Irisin may be involved in the pathological process of MS/EAE.

OncoPDSS: an evidence-based clinical decision support system for oncology pharmacotherapy at the individual level.

BACKGROUND: Precision oncology pharmacotherapy relies on precise patient-specific alterations that impact drug responses. Due to rapid advances in clinical tumor sequencing, an urgent need exists for a clinical support tool that automatically interprets sequencing results based on a structured knowledge base of alteration events associated with clinical implications. RESULTS: Here, we introduced the Oncology Pharmacotherapy Decision Support System (OncoPDSS), a web server that systematically annotates the effects of alterations on drug responses. The platform integrates actionable evidence from several well-known resources, distills drug indications from anti-cancer drug labels, and extracts cancer clinical trial data from the ClinicalTrials.gov database. A therapy-centric classification strategy was used to identify potentially effective and non-effective pharmacotherapies from user-uploaded alterations of multi-omics based on integrative evidence. For each potentially effective therapy, clinical trials with faculty information were listed to help patients and their health care providers find the most suitable one. CONCLUSIONS: OncoPDSS can serve as both an integrative knowledge base on cancer precision medicine, as well as a clinical decision support system for cancer researchers and clinical oncologists. It receives multi-omics alterations as input and interprets them into pharmacotherapy-centered information, thus helping clinicians to make clinical pharmacotherapy decisions. The OncoPDSS web server is freely accessible at https://oncopdss.capitalbiobigdata.com .

3α,19-Dihydroxyl-ent-pimara-8(14),15-diene, a new diterpenoid from the rhizomes of Ricinus communis.

A new natural product, 3α,19-dihydroxyl-ent-pimara-8(14),15-diene (1), which possesses an α-orientation hydroxymethyl at C-4 and ∆8,14 groups, as well as eight known compounds, was isolated from the rhizomes of Ricinus communis. The structure of 1 was elucidated by extensive spectroscopic methods and its absolute configurations were confirmed by X-ray crystallographic analysis. The inhibitory rate of 1 against protein tyrosine phosphatase 1B (PTP1B) was 49.49% at the concentration of 6.58 × 10-5 mol/L.

[Effects of Shenmai injection on afterdepolarization and triggered activities in left ventricular papillary muscle in rat cardiac hypertrophy].

This study is to evaluate the effects of Shenmai injection on the temporal alterations of action potential (AP), early afterdepolarization (EAD) and delayed afterdepolarization (DAD) in papillary muscles. The action potentials were recorded by a glass electrode. APD at 90% repolarization (APD9 ) was measured, and spontaneous EAD and DAD were observed. The results show APD90 was significantly prolonged in model group compared with sham-operated group, whereas it was remained unchanged in Shenmai injec- tion treatment group and amiodarone group. The spontaneous EADs and DADs were frequently visible in model group. In conclusion, EAD, DAD and trigger activities increase gradually during pathological progression of rat cardiac hypertrophy, and Shenmai injection could improve the action potential change in rat cardiac hypertrophy.

A sequency match filtering algorithm based on the generalized Walsh transform for processing rectangular wave signals.

The conventional Walsh function just takes values of +1 and -1 and can only track limited signal states. However, based on the characteristics of Walsh functions that can capture the frequency of square wave signals, this article proposes a generalized Walsh transform algorithm to process multi-valued rectangular wave signals. As an extension of the traditional Walsh functions, generalized Walsh functions have advantages in signal frequency matching and sequency spectrum amplitude extraction, which makes them well suited to express the valuable signal. First, we infer the invariance displacement theory in the time and sequency domains, limiting the value of a circular time shift to ensure the concentrated distribution of the signal sequency energy. This limitation lays a good foundation for constructing generalized Walsh functions. Then, two types of generalized Walsh functions are built by combining the characteristics of different periodic rectangular waves. We deduce two properties of orthogonality and completeness to prove the ability of the constructed functions to match the frequency and the extracted energy. Finally, we compare multiple filtering methods to verify the reliability of the proposed method.

[Effect of TLK2 Expression Regulated by MiR-21 on Proliferation and Apoptosis of Acute Myeloid Leukemia Cells].

OBJECTIVE: To investigate the effect of TLK2 expression regulated by miR-21 on proliferation and apoptosis of acute myeloid leukemia cells. METHODS: Seventy patients with AML admitted to our hospital from January 2019 to July 2022 were selected, while 30 patients with iron deficiency anemia were selected as the control group. Bone marrow mononuclear cells (BMMNCs) of the patients were obtained using Ficoll density gradient centrifugation. RT-qPCR was used to determine the expression levels of miR-21 and TLK2 mRNA in BMMNCs. Mimics-miR-21, mimics-NC, inhibitor-miR-21, inhibitor-NC and NC were transfected into HL-60 cells using liposome-mediated transfection technology. CCK-8 method was used to determine the activity of transfected HL-60 cells after treatment with cytarabine. The apoptosis rate of HL-60 transfected cells was determined by TUNEL method. The expression of TLK2 mRNA in HL-60 cells transfected with inhibitor-miR-21 was determined by RT-qPCR. RESULTS: The relative expression levels of miR-21 and TLK2 mRNA in BMMNCs of AML patients were significantly higher than those of controls (both P < 0.05). After HL-60 cells were treated with cytarabine, both the cell activity of inhibitor-miR-21 group and mimics-miR-21 group decreased significantly with the increase of cytarabine concentration (both P < 0.05). However, at each concentration point of cytarabine, the cell activity of inhibitor-miR-21 group was lower than that of control group (P < 0.05), while mimics-miR-21 group was higher than control group (P < 0.05). After HL-60 cells were treated with cytarabine, the apoptosis rate of inhibitor-miR-21 group was significantly increased (P < 0.05), while that of mimics-miR-21 group was significantly decreased (P < 0.05). After HL-60 cells were treated with inhibitor-miR-21, the relative expression of TLK2 mRNA decreased significantly (P < 0.05). CONCLUSION: miR-21 is highly expressed in AML patients, which may promote the apoptosis of AML cells by inhibiting the expression of TLK2.

The expression levels of chemotaxis-related molecules CXC chemokine receptor 1, interleukin-8, and pro-platelet basic protein in gingival tissues.

Background/purpose: Excessive host immune response is thought to be an important cause of periodontal tissue damage during periodontitis. The potent chemotaxis produced by locally released chemokines is the key signal to trigger this response. Here, we aimed to investigate the expression of CXC chemokine receptor 1 (CXCR1), and chemokines interleukin-8 (IL-8) and pro-platelet basic protein (PPBP) in human inflammatory gingival tissues compared with healthy tissues. Materials and methods: A total of 54 human gingival tissues, 27 healthy and 27 inflammatory samples, were collected. Fifteen specimens of each group were employed for quantitative reverse transcription polymerase chain reaction to determine the mRNA levels of CXCR1, IL-8, and PPBP. Six samples of each group were used for Western blotting to investigate the protein expression of CXCR1 and for enzyme-linked immunosorbent assay to evaluate the protein levels of IL-8 and PPBP, respectively. Results: The mRNA levels of chemokine receptor CXCR1, chemokine IL-8, and PPBP in inflammatory gingival tissues were significantly higher than those in healthy controls (P < 0.05). The protein levels of CXCR1, IL-8, and PPBP in inflammatory gingival tissues were also significantly higher than those in healthy gingival tissues (P < 0.05). Conclusion: When compared to healthy gingival tissues, the expression of CXCR1, IL-8, and PPBP in inflammatory gingival tissues is higher.

Combined inhibitory effects of microcystin-LR and microcystin-RR on growth and development in zebrafish larvae.

Microcystins (MCs) are the most widespread, frequently found, and seriously toxic cyanobacterial toxins in aquatic environments. Microcystin-leucine-arginine (MCLR) and microcystin-arginine-arginine (MCRR) are the most studied MCs. Normally, their levels are low and they coexist in the environment; however, they may also interact with each other. The developmental toxicity of MCLR in the presence of MCRR in the early life stage of zebrafish (from 2 to 120 h post fertilization) was investigated for the first time in this study. Our findings revealed that MCRR treatment marginally elevated thyroxine (T4) and 3,5,3'-triiodothyronine (T3) levels, whereas MCLR treatment alone resulted in a significant increase in T3 and T4 levels, indicating a cooperative effect. Furthermore, clear changes in the expression levels of genes involved in growth and development, accompanied by growth inhibition, were observed after co-treatment with MCRR and MCLR. In addition, zebrafish larvae subjected to MCRR and/or MCLR treatment showed increased levels of superoxide dismutase, glutathione, and malondialdehyde, and decreased levels of catalase in the MCRR + MCLR group, indicating oxidative stress and lipid peroxidation. Thus, we investigated the synergistic developmental toxicity of MCRR and MCLR during the early life stages of zebrafish development.

Combined effects of cadmium and sulfamethoxazole on Eisenia fetida: Insights into accumulation, subcellular partitioning, biomarkers and toxicological responses.

Cadmium (Cd) and sulfamethoxazole (SMX) frequently coexist in farmlands, yet their synergistic toxicological impacts on terrestrial invertebrates remain unexplored. In this study, earthworms were exposed to artificial soils percolated with Cd (5 mg/kg), SMX (5 mg/kg) or combination of them for 7 days, followed by a 12-day elimination phase in uncontaminated soil. The uptake of Cd and SMX by the earthworms, along with their subcellular distribution, was meticulously analyzed. Additionally, a suite of biomarkers-including superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and weight loss-were evaluated to assess the health status of the earthworms and the toxicological effects of the Cd and SMX mixture. Notably, the cotreatment with Cd and SMX resulted in a significantly higher weight loss in Eisenia fetida (41.25 %) compared to exposure to Cd alone (26.84 %). Moreover, the cotreatment group exhibited substantially higher concentrations of Cd in the total internal body, fraction C (cytosol), and fraction E (tissue fragments and cell membranes) in Eisenia fetida compared to Cd alone counterparts. The combined exposure also significantly elevated the SMX levels in the total body and fraction C compared with the SMX-only treated earthworms. Additionally, Eisenia fetida subjected to the combined treatment showed markedly increased activities of SOD, CAT, and MDA compared to those treated with Cd alone. The effect addition indices (EAIs), ranging from 1.00 to 2.23, unequivocally demonstrated a synergistic effect of the combined treatments. Interestingly, relocating the earthworms to clean soil did not mitigate the observed adverse effects. These findings underscore the increased risk posed by the Cd-SMX complex to terrestrial invertebrates in agricultural areas.

MILIP Binding to tRNAs Promotes Protein Synthesis to Drive Triple-Negative Breast Cancer.

Patients with triple-negative breast cancer (TNBC) have a poor prognosis due to the lack of effective molecular targets for therapeutic intervention. Here we found that the long noncoding RNA (lncRNA) MILIP supports TNBC cell survival, proliferation, and tumorigenicity by complexing with transfer RNAs (tRNA) to promote protein production, thus representing a potential therapeutic target in TNBC. MILIP was expressed at high levels in TNBC cells that commonly harbor loss-of-function mutations of the tumor suppressor p53, and MILIP silencing suppressed TNBC cell viability and xenograft growth, indicating that MILIP functions distinctively in TNBC beyond its established role in repressing p53 in other types of cancers. Mechanistic investigations revealed that MILIP interacted with eukaryotic translation elongation factor 1 alpha 1 (eEF1α1) and formed an RNA-RNA duplex with the type II tRNAs tRNALeu and tRNASer through their variable loops, which facilitated the binding of eEF1α1 to these tRNAs. Disrupting the interaction between MILIP and eEF1α1 or tRNAs diminished protein synthesis and cell viability. Targeting MILIP inhibited TNBC growth and cooperated with the clinically available protein synthesis inhibitor omacetaxine mepesuccinate in vivo. Collectively, these results identify MILIP as an RNA translation elongation factor that promotes protein production in TNBC cells and reveal the therapeutic potential of targeting MILIP, alone and in combination with other types of protein synthesis inhibitors, for TNBC treatment. SIGNIFICANCE: LncRNA MILIP plays a key role in supporting protein production in TNBC by forming complexes with tRNAs and eEF1α1, which confers sensitivity to combined MILIP targeting and protein synthesis inhibitors.

Strongly exclusive distribution with putative character displacement in two flying stag beetles.

Character displacement is considered a key driver of evolutionary divergence and adaptation. Few examples of reproductive character displacement with a narrow contact zone have been identified. We examined the genetic structure, body length variation, and genital morphology in the contact and allopatric areas of Platycerus takakuwai and P. viridicuprus to investigate character displacement and gene flow. In the contact area, the species identifications based on endophallic morphology and nuclear genes were identical, whereas mitochondrial gene did not exhibit a perfect match. This incongruence suggests that interspecific hybridization followed by the mitochondrial introgression has likely occurred during historical secondary contact. The species are essentially parapatric in contact area, co-occurring at only one of 28 adjacent sampling sites despite being flying species, and no hybrids based on morphology have been found, which indicates a strongly exclusive distribution. The results showed that the body length variation was consistent with character displacement after controlling for variation along geographic and environmental gradients. Interspecific body size differentiation may have evolved to reduce incorrect mating between the species. Moreover, selective pressure caused by reproductive interference between the two species may act on body size that have likely resulted in strongly exclusive distribution at the edge of their ranges.

Additions to Bambusicolous Fungi of Savoryellaceae from Southwest China.

Asexual and sexual morphs of saprobic bambusicolous fungi were collected from freshwater and terrestrial habitats in Sichuan Province, China. Taxonomic identification of these fungi was carried out on the basis of morphological comparison, culture characteristics, and molecular phylogeny. Multi-gene phylogeny based on combined SSU, ITS, LSU, rpb2, and tef1α sequence data was performed to determine their phylogenetic placement, and the result showed that these fungi belong to Savoryellaceae. Morphologically, four asexual morphs are similar to Canalisporium and Dematiosporium, while a sexual morph well-fits to Savoryella. Three new species, Canalisporium sichuanense, Dematiosporium bambusicola, and Savoryella bambusicola are identified and described. Two new records, C. dehongense and D. aquaticum, were recovered from the bamboo hosts in terrestrial and freshwater habitats, respectively. In addition, the nomenclatural confusion of C. dehongense and C. thailandense is discussed.

Dietary intake of household cadmium-contaminated rice caused genome-wide DNA methylation changes on gene/hubs related to metabolic disorders and cancers.

Cadmium (Cd) contamination in food has raised broad concerns in food safety and human health. The toxicity of Cd to animals/humans have been widely reported, yet little is known about the health risk of dietary Cd intake at the epigenetic level. Here, we investigated the effect of a household Cd-contaminated rice (Cd-rice) on genome-wide DNA methylation (DNAm) changes in the model mouse. Feeding Cd-rice increased kidney Cd and urinary Cd concentrations compared with the Control rice (low-Cd rice), whereas supplementation of ethylenediamine tetraacetic acid iron sodium salt (NaFeEDTA) in the diet significantly increased urinary Cd and consequently decreased kidney Cd concentrations. Genome-wide DNAm sequencing revealed that dietary Cd-rice exposure caused the differentially methylated sites (DMSs), which were mainly located in the promoter (32.5%), downstream (32.5%), and intron (26.1%) regions of genes. Notably, Cd-rice exposure induced hypermethylation at the promoter sites of genes Caspase-8 and interleukin-1ß (Il-1ß), and consequently, their expressions were down-regulated. The two genes are critical in apoptosis and inflammation, respectively. In contrast, Cd-rice induced hypomethylation of the gene midline 1 (Mid1), which is vital to neurodevelopment. Furthermore, 'pathways in cancer' was significantly enriched as the leading canonical pathway. Supplementation of NaFeEDTA partly alleviated the toxic symptoms and DNAm alternations induced by Cd-rice exposure. These results highlight the broad effects of elevated dietary Cd intake on the level of DNAm, providing epigenetic evidence on the specific endpoints of health risks induced by Cd-rice exposure.

The relationship among amyloid-ß deposition, sphingomyelin level, and the expression and function of P-glycoprotein in Alzheimer's disease pathological process.

In Alzheimer's disease, the transporter P-glycoprotein is responsible for the clearance of amyloid-ß in the brain. Amyloid-ß correlates with the sphingomyelin metabolism, and sphingomyelin participates in the regulation of P-glycoprotein. The amyloid cascade hypothesis describes amyloid-ß as the central cause of Alzheimer's disease neuropathology. Better understanding of the change of P-glycoprotein and sphingomyelin along with amyloid-ß and their potential association in the pathological process of Alzheimer's disease is critical. Herein, we found that the expression of P-glycoprotein in APP/PS1 mice tended to increase with age and was significantly higher at 9 and 12 months of age than that in wild-type mice at comparable age. The functionality of P-glycoprotein of APP/PS1 mice did not change with age but was significantly lower than that of wild-type mice at 12 months of age. Decreased sphingomyelin levels, increased ceramide levels, and the increased expression and activity of neutral sphingomyelinase 1 were observed in APP/PS1 mice at 9 and 12 months of age compared with the levels in wild-type mice. Similar results were observed in the Alzheimer's disease mouse model induced by intracerebroventricular injection of amyloid-ß1-42 and human cerebral microvascular endothelial cells treated with amyloid-ß1-42. In human cerebral microvascular endothelial cells, neutral sphingomyelinase 1 inhibitor interfered with the changes of sphingomyelin metabolism and P-glycoprotein expression and functionality caused by amyloid-ß1-42 treatment. Neutral sphingomyelinase 1 regulated the expression and functionality of P-glycoprotein and the levels of sphingomyelin and ceramide. Together, these findings indicate that neutral sphingomyelinase 1 regulates the expression and function of P-glycoprotein via the sphingomyelin/ceramide pathway. These studies may serve as new pursuits for the development of anti-Alzheimer's disease drugs.