PARP1 modulates METTL3 promoter chromatin accessibility and associated LPAR5 RNA m6A methylation to control cancer cell radiosensitivity.

Chromatin remodeling and N6-methyladenosine (m6A) modification are two critical layers in controlling gene expression and DNA damage signaling in most eukaryotic bioprocesses. Here, we report that poly(ADP-ribose) polymerase 1 (PARP1) controls the chromatin accessibility of METTL3 to regulate its transcription and subsequent m6A methylation of poly(A)+ RNA in response to DNA damage induced by radiation. The transcription factors nuclear factor I-C (NFIC) and TATA binding protein (TBP) are dependent on PARP1 to access the METTL3 promoter to activate METTL3 transcription. Upon irradiation or PARP1 inhibitor treatment, PARP1 disassociated from METTL3 promoter chromatin, which resulted in attenuated accessibility of NFIC and TBP and, consequently, suppressed METTL3 expression and RNA m6A methylation. Lysophosphatidic Acid Receptor 5 (LPAR5) mRNA was identified as a target of METTL3, and m6A methylation was located at A1881. The level of m6A methylation of LPAR5 significantly decreased, along with METTL3 depression, in cells after irradiation or PARP1 inhibition. Mutation of the LPAR5 A1881 locus in its 3' UTR results in loss of m6A methylation and, consequently, decreased stability of LPAR5 mRNA. METTL3-targeted small-molecule inhibitors depress murine xenograft tumor growth and exhibit a synergistic effect with radiotherapy in vivo. These findings advance our comprehensive understanding of PARP-related biological roles, which may have implications for developing valuable therapeutic strategies for PARP1 inhibitors in oncology.

Exposure to polystyrene nanoplastics induces abnormal activation of innate immunity via the cGAS-STING pathway.

Endogenous immune defenses provide an intrinsic barrier against external entity invasion. Microplastics in the environment, especially those at the nanoscale (nanoplastics or NPs), may pose latent health risks through direct exposure. While links between nanoplastics and inflammatory processes have been established, detailed insights into how they may perturb the innate immune mechanisms remain uncharted. Employing murine and macrophage (RAW264.7) cellular models subjected to polystyrene nanoplastics (PS-NPs), our investigative approach encompassed an array of techniques: Cell Counting Kit-8 assays, flow cytometric analysis, acridine orange/ethidium bromide (AO/EB) fluorescence staining, cell transfection, cell cycle scrutiny, genetic manipulation, messenger RNA expression profiling via quantitative real-time PCR, and protein expression evaluation through western blotting. The results showed that PS-NPs caused RAW264.7 cell apoptosis, leading to cell cycle arrest, and activated the cGAS-STING pathway. This resulted in NF-κB signaling activation and increased pro-inflammatory mediator expression. Importantly, PS-NPs-induced activation of NF-κB and its downstream inflammatory cascade were markedly diminished after the silencing of the STING gene. Our findings highlight the critical role of the cGAS-STING pathway in the immunotoxic effects induced by PS-NPs. We outline a new mechanism whereby nanoplastics may trigger dysregulated innate immune and inflammatory responses via the cGAS/STING pathway.

Integrin Mac1 mediates paraquat and maneb-induced learning and memory impairments in mice through NADPH oxidase-NLRP3 inflammasome axis-dependent microglial activation.

INTRODUCTION: The mechanisms of cognitive impairments in Parkinson's disease (PD) remain unknown. Accumulating evidence revealed that brain neuroinflammatory response mediated by microglial cells contributes to cognitive deficits in neuropathological conditions and macrophage antigen complex-1 (Mac1) is a key factor in controlling microglial activation. OBJECTIVES: To explore whether Mac1-mediated microglial activation participates in cognitive dysfunction in PD using paraquat and maneb-generated mouse PD model. METHODS: Cognitive performance was measured in wild type and Mac1-/- mice using Morris water maze test. The role and mechanisms of NADPH oxidase (NOX)-NLRP3 inflammasome axis in Mac1-mediated microglial dysfunction, neuronal damage, synaptic degeneration and phosphorylation (Ser129) of α-synuclein were explored by immunohistochemistry, Western blot and RT-PCR. RESULTS: Genetic deletion of Mac1 significantly ameliorated learning and memory impairments, neuronal damage, synaptic loss and α-synuclein phosphorylation (Ser129) caused by paraquat and maneb in mice. Subsequently, blocking Mac1 activation was found to mitigate paraquat and maneb-elicited microglial NLRP3 inflammasome activation in both in vivo and in vitro. Interestingly, stimulating activation of NOX by phorbol myristate acetate abolished the inhibitory effects of Mac1 blocking peptide RGD on paraquat and maneb-provoked NLRP3 inflammasome activation, indicating a key role of NOX in Mac1-mediated NLRP3 inflammasome activation. Furthermore, NOX1 and NOX2, two members of NOX family, and downstream PAK1 and MAPK pathways were recognized to be essential for NOX to regulate NLRP3 inflammasome activation. Finally, a NLRP3 inflammasome inhibitor glybenclamide abrogated microglial M1 activation, neurodegeneration and phosphorylation (Ser129) of α-synuclein elicited by paraquat and maneb, which were accompanied by improved cognitive capacity in mice. CONCLUSIONS: Mac1 was involved in cognitive dysfunction in a mouse PD model through NOX-NLRP3 inflammasome axis-dependent microglial activation, providing a novel mechanistic basis of cognitive decline in PD.

Association between per- and polyfluoroalkyl substances (PFAS) and depression in U.S. adults: A cross-sectional study of NHANES from 2005 to 2018.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are widespread persistent organic pollutants (POPs) associated with diseases including osteoporosis, altered immune function and cancer. However, few studies have investigated the association between PFAS mixture exposure and Depression in general populations. METHODS: Nationally representative data from the National Health and Nutrition Examination Survey (NHANES) (2005-2018) were used to analyze the association between PFAS and Depression in U.S. adults. Total 12,239 adults aged 20 years or older who had serum PFAS measured and answered Patient Health Questionnaire-9 (PHQ-9) were enrolled in this study. PFAS monomers detected in all 7 investigation cycles were included in the study. Generalized additive model (GAM) was used to fit smooth curves and threshold effect analysis was carried out to find the turning point of smooth curves. Generalized linear model (GLM) was used to describe the non-linear relationship between PFAS and depression and unconditioned logistic regression was used to risk analysis. RESULTS: The median of total serum PFAS concentration was 14.54 ng/mL. The curve fitting results indicated a U-shaped relationship between total serum PFAS and depression: PFAS< 39.66 ng/mL, A negative correlation between PHQ-9 score and serum PFAS concentration was observed (ß 0.047,95%CI -0.059, -0.036). The depression PHQ-9 score decreased with the increase of serum PFAS concentration. PFAS ≥ 39.66 ng/mL, A positive correlation was observed between PFAS and PHQ-9 score (ß 0.010,95% CI 0.003, 0.017). The depression PHQ-9 score increased with the increase of serum PFAS concentration. CONCLUSIONS: Our study provides new clues to the association of PFAS with depression, and large population-based cohort studies that can validate the causal association as well as toxicological mechanism studies are needed for validation.

Association of Perfluoroalkyl and polyfluoroalkyl substances (PFASs) exposures and the risk of systemic lupus erythematosus: a case-control study in China.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) may have a role in impaired health. However, the data on the association between PFASs and Systemic lupus erythematosus (SLE) have been limited. We designed a population-based case-control study in China and evaluated the association. 100 normal persons (Control) and 100 SLE patients (Case) were obtained from 113 controls and 125 cases according to matching conditions. Serum samples were collected by venipuncture for UHPLC-MRM-MS Analysis to obtain the concentration of five PFASs in participants. Demographic characterization description was performed for the two groups of participants, the PFASs concentration distribution of the two groups was described and compared, then divided into three tiers (< 50th, 50th ~ 75th, > 75th) for subsequent analysis. Conditional logistic regression models were utilized to calculate the odds ratios (ORs) and 95% CIs for SLE. Relationship between changes in the concentration of PFASs and the risk of SLE assessed by restricted cubic spline. As the highest serum levels of the five PFASs tested in this study population, the highest perfluoroundecanoic acid (PFUnA) quartile had a 2.78-fold (95%CI: 1.270, 6.10) compared with the lowest quartile of PFUnA exposure, other types of PFASs also showed high association with SLE as well as PFASs mixture. Additionally, the exposure of PFASs exist a dose-response relationship (ptrend < 0.05). This risk association remained be found after adjusting the covariates in model 1 (adjustment of BMI) and in model 2(adjustment of BMI, smoking, drinking, hypertension and leukocyte). The restricted cubic spline illustrated a gradual increase in the possible risk of SLE with the increasing exposure of PFASs components levels. Our study firstly revealed that PFASs are risk factors for SLE and PFASs exposures are associated with SLE risk in a dose - response manner. Evidence from larger and more adequately powered cohort studies is needed to confirm our results.

Long-term LDR exposure may induce cognitive impairments: A possible association through targeting gut microbiota-gut-brain axis.

Environmental and occupational low-dose radiation (LDR) exposure may be harmful for health but the previous reports regarding effect of LDR on cognition are contradictory. Here we investigated the effect of long-term LDR exposure on cognition. In this study, male Balb/c mice' cognitive functions were tested at 15 weeks after being exposed to 0.5 Gy LDR in 10 fractions at each dose of 0.05 Gy. The results demonstrated that long-term LDR exposure increases escape latency and the time spent in finding exits in mice compared with non LDR exposure. Meanwhile, the inflammation-related proteins including NFκB and p38 also increased. Lipopolysaccharide (LPS) increased and short-chain fatty acid (SCFA) levels decreased following long term LDR exposure. Treatment with microbiota-derived LPS and SCFAs reversed these effects in mice. Furthermore, the gut barrier integrity was damaged in a time-dependent manner with the decreased expression of intestinal epithelial-related biomarkers such as ZO-1 and occludin. Mechanistically, long after exposure to LDR, increased LPS levels may cause cognitive impairment through the regulation of Akt/mTOR signaling in the mouse hippocampus. These findings provide new insight into the clinical applications of LDR and suggest that the gut microbiota-plasma LPS and SCFAs-brain axis may underlie long-term LDR-induced cognition effects.

Association of urinary arsenic with insulin resistance: Cross-sectional analysis of the National Health and Nutrition Examination Survey, 2015-2016.

BACKGROUND: Long-term arsenic exposure is associated with diabetes in adults, the mechanism of which involves insulin resistance. The relationship between arsenic and insulin resistance in adults is unclear. We analyzed the relationship between urinary arsenic and insulin resistance in US adults. RESULTS: We identified 815 adults aged 20-79 years who participated in the 2015-2016 National Health and Nutrition Examination Survey (NHANES). Urinary arsenic, fasting glucose, serum insulin, and other key covariates were obtained from the NHANES data. The association between urinary arsenic and insulin resistance was evaluated by analyzing the urinary arsenic level and homeostasis model assessment-insulin resistance. The median total urinary arsenic level was 6.82 µg/L. After adjusting for possible confounding factors (gender, age, and body mass index), the 80th and 20th percentile odds ratio (OR) was 1.41 (95% confidence interval [CI] 1.07, 1.87); the OR of the 70th and 30th percentiles was 1.41 (95% CI 1.08, 1.84). CONCLUSIONS: In most subgroups, after similar adjustment, the relationship between urine total arsenic and insulin resistance remained. Total arsenic exposure in urine may be associated with insulin resistance. Evidence from larger and more adequately powered cohort studies is needed to confirm our results.

Aptamer-AuNP-conjugated carboxymethyl chitosan-functionalized graphene oxide for colorimetric identification of Salmonella typhimurium.

A novel aptamer-AuNP-conjugated carboxymethyl chitosan-functionalized graphene oxide (CMC/GO@Apt-Au NP) probe was for the first time developed for the determination of Salmonella typhimurium (S. typhimurium). Owing to the conformational change of the aptamers in the presence of S. typhimurium, the Au NPs, which were pre-adsorbed on the aptamers through van der Waals forces, were released into the solution phase and induced the color change of the solution. As a result, S. typhimurium ranging from 102 to 107 CFU/mL was successfully identified using the designed assay with a limit of detection (LOD) of 10 CFU/mL. This low detection level allowed the sensitive recognition of S. typhimurium in milk samples within 40 min without sample pretreatment, a conclusion that agreed well with the traditional plate counting method. The developed method not only provides a rapid way for the determination of S. typhimurium with simplicity and sensitivity but also shows potential universality in the quantification of other pathogenic microorganisms.

Microglial Activation Damages Dopaminergic Neurons through MMP-2/-9-Mediated Increase of Blood-Brain Barrier Permeability in a Parkinson's Disease Mouse Model.

Chronic neuroinflammation has been considered to be involved in the progressive dopaminergic neurodegeneration in Parkinson's disease (PD). However, the mechanisms remain unknown. Accumulating evidence indicated a key role of the blood-brain barrier (BBB) dysfunction in neurological disorders. This study is designed to elucidate whether chronic neuroinflammation damages dopaminergic neurons through BBB dysfunction by using a rotenone-induced mouse PD model. Results showed that rotenone dose-dependently induced nigral dopaminergic neurodegeneration, which was associated with increased Evans blue content and fibrinogen accumulation as well as reduced expressions of zonula occludens-1 (ZO-1), claudin-5 and occludin, three tight junction proteins for maintaining BBB permeability, in mice, indicating BBB disruption. Rotenone also induced nigral microglial activation. Depletion of microglia or inhibition of microglial activation by PLX3397 or minocycline, respectively, greatly attenuated BBB dysfunction in rotenone-lesioned mice. Mechanistic inquiry revealed that microglia-mediated activation of matrix metalloproteinases-2 and 9 (MMP-2/-9) contributed to rotenone-induced BBB disruption and dopaminergic neurodegeneration. Rotenone-induced activation of MMP-2/-9 was significantly attenuated by microglial depletion and inactivation. Furthermore, inhibition of MMP-2/-9 by a wide-range inhibitor, SB-3CT, abrogated elevation of BBB permeability and simultaneously increased tight junctions expression. Finally, we found that microglial depletion and inactivation as well as inhibition of MMP-2/-9 significantly ameliorated rotenone-elicited nigrostriatal dopaminergic neurodegeneration and motor dysfunction in mice. Altogether, our findings suggested that microglial MMP-2/-9 activation-mediated BBB dysfunction contributed to dopaminergic neurodegeneration in rotenone-induced mouse PD model, providing a novel view for the mechanisms of Parkinsonism.

Potential liver damage due to co-exposure to As, Cd, and Pb in mining areas: Association analysis and research trends from a Chinese perspective.

There is global concern regarding the public health hazards of environmental exposure to multiple toxic heavy metals. The effects of toxic heavy metals on liver function have been suggested in previous reports, but the association between exposure to multiple toxic heavy metals and liver function has not been elucidated. The aim of this study was to investigate the effects of exposure to multiple toxic heavy metals, arsenic(As), lead(Pb), and cadmium(Cd), on liver function through population-based and animal studies. A total of 3590 participants were enrolled from the mining areas in Western Hunan Province. The concentrations of As, Pb, and Cd in the urine and plasma samples were determined using quadrupole inductively coupled plasma mass spectrometry (ICP-MS). Bayesian kernel machine regression (BKMR) was employed for the joint association assay. An animal study was conducted to further verify the cumulative effects of metals on liver damage-related parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) levels. Research trends regarding toxic metals were also explored to obtain in-depth understanding of the current knowledge in this field. Typically, for single-exposure analysis, in most mines, Pb exhibited a significantly negative association with ALT levels, whereas for cumulative effects analysis, when As, Pb, and Cd concentrations were at the 50thpercentile, a significantly negative effect on liver ALT levels was observed. Furthermore, animal studies have shown that co-exposure to As, Pb, and Cd could aggravate liver dysfunction in mice compared to that in the single-metal treated group (p < 0.05). From 1990 to 2019, 1965 projects relating to As, Pb, and Cd research have been initiated, and the total RMB(RenMingBi) funded was approximately 800 million in China, as opposed to 2500 projects in the US with an approximate amount of US$ 1 billion, which is substantially greater than that of China. Finally, from a global viewpoint, scientists should continue to substantially contribute to the field of heavy metal contamination through more extensive academic investigation, global cooperation, and the development of novel control methods. Overall, this study identified that elevated combined concentrations of As, Pb, and Cd were significantly negatively associated with liver function.

Cell density-dependent regulation of microcystin synthetase genes (mcy) expression and microcystin-LR production in Microcystis aeruginosa that mimics quorum sensing.

As the secondary metabolites of cyanobacterial harmful algal blooms (Cyano-HABs), microcystins (MCs) were generated under various environmental and cellular conditions. The understanding of the causes of MCs generation is of great interest in the field of water treatment and environmental science. In this work, we studied how Microcystis aeruginosa (FACHB-905) cell densities affect the MCs synthetase genes (mcy) expression, microcystin-LR (MC-LR) and quorum sensing molecules (Acyl-homoserine lactones (AHLs)) production. An electrochemical sensor was developed here for sensitive and quantitative detection of MC-LR that cultured at different cell densities. The results showed that mcy expression and MC-LR concentration started to increase when the cell density reached ca. 22 × 106 cells/mL, and was significantly increased with increasing cell densities. Moreover, the up-regulation of AHLs with increasing cell densities revealed that MC-LR is quorum sensing-mediated. Our results undoubtedly confirmed that MC-LR was produced in a cell density-dependent way that mimics quorum sensing, and the minimum cell density (ca. 22 × 106 cells/mL) that was required to produce MC-LR was provided and offered a reference standard for the prevention and control of MCs pollution in the actual water environment.

Integrin CD11b mediates locus coeruleus noradrenergic neurodegeneration in a mouse Parkinson's disease model.

BACKGROUND: The loss of locus coeruleus noradrenergic (LC/NE) neurons in the brainstem is reported in multiple neurodegenerative disorders, including Parkinson's disease (PD). However, the mechanisms remain unclear. Strong evidence suggested that microglia-mediated neuroinflammation contributes to neurodegeneration in PD. We recently recognized integrin CD11b, the α-chain of macrophage antigen complex-1 (Mac-1, also called CR3), as a key regulator for microglial activation. However, whether CD11b is involved in LC/NE neurodegeneration in PD remains to be investigated. METHODS: LC/NE neurodegeneration and microglial activation were compared between wild type (WT) and CD11b KO mice after treated with paraquat and maneb, two pesticides that widely used to create PD model. The role of NLRP3 inflammasome in CD11b-mediated microglial dysfunction and LC/NE neurodegeneration was further explored. LC/NE neurodegeneration, microglial phenotype, and NLRP3 inflammasome activation were determined by using Western blot, immunohistochemistry, and RT-PCR technologies. RESULTS: Paraquat and maneb co-exposure elevated the expressions of CD11b in the brainstem of mice, and CD11b knockout significantly reduced LC/NE neurodegeneration induced by paraquat and maneb. Mitigated microglial activation and gene expressions of proinflammatory cytokines were also observed in paraquat and maneb-treated CD11b-/- mice. Mechanistically, CD11b-mediated NLRP3 inflammasome activation contributes to paraquat and maneb-induced LC/NE neurodegeneration. Compared with WT controls, CD11b deficiency reduced paraquat and maneb-induced NLRP3 expression, caspase-1 activation, and interleukin-1ß production in mice. Furthermore, inhibition of NLRP3 inflammasome by glybenclamide, a sulfonylurea inhibitor of NLRP3 inflammasome, was found to be able to suppress microglial proinflammatory activation and nuclear factor-κB activation induced by paraquat and maneb. Moreover, reduced reactive oxygen species production, NADPH oxidase, and inducible nitric oxide synthase expressions as well as 4-hydroxynonenal and malondialdehyde levels were detected in combined glybenclamide and paraquat and maneb-treated mice compared with paraquat and maneb alone group. Finally, we found that glybenclamide treatment ameliorated LC/NE neurodegeneration and α-synuclein aggregation in paraquat and maneb-treated mice. CONCLUSION: Our findings suggested that CD11b mediates LC/NE neurodegeneration through NLRP3 inflammation-dependent microglial proinflammatory activation in a two pesticide-induced mouse PD model, providing a novel insight into the immune pathogenesis of LC/NE neuronal damage in related disorders.

Associations between ambient air pollution and daily incidence of pediatric hand, foot and mouth disease in Ningbo, 2014-2016: a distributed lag nonlinear model.

Hand, foot and mouth disease (HFMD) has high prevalence around the world, with serious consequences for children. Due to the long survival period of HFMD virus in ambient air, air pollutants may play a critical role in HFMD epidemics. We collected data on daily cases of HFMD among children aged 0-14 years in Ningbo City between 2014 and 2016. Distributed lag nonlinear models were used to assess the effects of particulate matter (PM2.5), sulphur dioxide (SO2), nitrogen dioxide (NO2) and ozone (O3) on the daily incidence of HFMD among children, with analyses stratified by gender and age. Compared with moderate levels of air pollution, high SO2 levels had a relative risk (RR) of 2.32 (95% CI 1.42-3.79) and high NO2 levels had a RR of 2.01 (95% CI 1.22-3.31). The RR of O3 was 2.12 (95% CI 1.47-3.05) and that of PM2.5 was 0.77 (95% CI 0.64-0.92) at moderate levels of air pollution. Specifically, high levels of SO2 and NO2 had RRs of 2.39 (95% CI 1.44-3.96) and 2.02 (95% CI 1.21-3.39), respectively, among 0-4-year-old children, while high O3 had an RR of 2.31 (95% CI 1.09-4.89) among 5-14-year-old children. Our findings suggest significant associations of high SO2 and NO2 levels and moderate O3 levels in HFMD epidemics, and also indicate that air pollution causes lagged effects on HFMD epidemics. Our study provides practical and useful data for targeted prevention and control of HMFD based on environmental evidence.

Exosome-packaged miR-1246 contributes to bystander DNA damage by targeting LIG4.

BACKGROUND: An increasing number of studies have recently reported that microRNAs packaged in exosomes contribute to multiple biological processes such as cancer progression; however, little is known about their role in the development of radiation-induced bystander effects. METHODS: The exosomes were isolated from the culture medium of BEP2D cells with or without γ-ray irradiation by ultracentrifugation. To monitor DNA damage and repair efficiency, the DNA double-strand break biomarker 53BP1 foci, comet, micronuclei, expression of DNA repair genes and NHEJ repair activity were detected. The miR-1246 targeting sequence of the DNA ligase 4 (LIG4) mRNA 3'UTR was assessed by luciferase reporter vectors. RESULTS: miR-1246 was increased in exosomes secreted from 2 Gy-irradiated BEP2D cells and inhibited the proliferation of nonirradiated cells. The miR-1246 mimic, exosomes from irradiated cells, and radiation-conditioned cell culture medium increased the yields of 53BP1 foci, comet tail and micronuclei in nonirradiated cells, and decreased NHEJ efficiency. miR-1246 downregulated LIG4 expression by directly targeting its 3'UTR. CONCLUSIONS: Our findings demonstrate that miR-1246 packaged in exosomes could act as a transfer messenger and contribute to DNA damage by directly repressing the LIG4 gene. Exosomal miR-1246 may be a critical predictor of and player in radiation-induced bystander DNA damage.

Optimization of Synthesis and Modification of ZnSe/ZnS Quantum Dots for Fluorescence Detection of Escherichia coil.

This study prepared an innovative 3-mercaptopropionic acid modified ZnSe/ZnS core/shell quantum dots (MPA-ZnSe/ZnS QDs), and established a rapid fluorescence method to detect the E. coli cells count by using MPA-ZnSe/ZnS QDs as fluorescence probe. The formulation variables and process were optimized using the response surface methodology (RSM). Fluorescence microscopy was used to obtain fluorescence microscope images of MPA-ZnSe/ZnS QDs that bind to bacteria. The fluorescence peak intensity increases with increasing cells count in the range of 101-108 CFU/mL. Compared with the traditional based on fluorescent detection methods, this method is more convenient and useful in the bacterial count determination.

"What do you know?"--knowledge among village doctors of lead poisoning in children in rural China.

BACKGROUND: This study evaluates the extent of village doctors' knowledge of lead poisoning in children in rural China and assesses the characteristics associated with possessing accurate knowledge. METHODS: A cross-sectional, questionnaire-based survey of 297 village doctors in Fenghuang County, Hunan Province, China was conducted. All village doctors were interviewed face-to-face using a "What do you know" test questionnaire focusing on prevention strategies and lead sources in rural children. RESULTS: A total of 287 (96.6%) village doctors completed the survey in full. Most village doctors had an appropriate degree of general knowledge of lead poisoning; however, they had relatively poor knowledge of lead sources and prevention measures. Village doctors with an undergraduate level education scored an average of 2.7 points higher than those who had a junior college level education (p = 0.033). Village doctors with an annual income ≤ 10,000 RMB yuan scored 1.03 points lower than those whose income was >10,001 RMB yuan. Ethnic Han village doctors scored 1.12 points higher, on average, than ethnic Tujia village doctors (p = 0.027). CONCLUSIONS: This study identified important gaps in knowledge concerning lead poisoning in children among a rural population of village doctors. There is a clear need for multifaceted interventions that target village doctors to improve their knowledge regarding lead poisoning in children. The "What do you know" questionnaire is a new tool to evaluate lead poisoning knowledge and education projects.

[Preparation and characterization of salvianolic acids-tanshinones composite powder for inhalation via co-micronized method].

Salvianolic acids and tanshinones are main hydrophilic and lipophilic extracts from Salvia Miltiorrhiza with significant anti-pulmonary fibrosis effects. The aim of this study was to prepare a co-micronized salvianolic acids-tanshinones composite powder for inhalation using a planetary ball mill. The micronization process parameters were optimized by central composite design (CCD) and response surface methodology (RSM). Treatment time, rotation speed and the ball/sample weight ratio were selected as the independent variables, and the volume fraction of particle size in 1-5 µm was taken as the dependent variable. The powder properties were evaluated by scanning electron microscopy (SEM), laser diffraction and X-ray powder diffraction (XRPD). The powder flow and hygroscopicity were determined with repose angle, compressibility index and critical relative humidity(CRH). According to the results, the salvianolic acids-tanshinones composite powder produced in optimal conditions had a narrow and unimodal particle size distribution and a smaller D50 of 2.33 µm. The volume fraction of particle size in 1-5 µm was 80.82%. The repose angle was (50.60±1.13) °, and the critical relative humidity is about 77%. After being micronized, the particle size significantly reduced, and the number of amorphous substances slightly increased, with no significant changes in powder flow and hygroscopicity. These findings indicate that the grinding method with a planetary ball mill can be used to co-micronize various components with different properties and prepare composite drug powders for dry powder inhalation.

Overexpression of HMGA1 correlates with the malignant status and prognosis of breast cancer.

High mobility group A1 (HMGA1), as a major member of HMGA family, plays an important part in promotion of cell proliferation and motility, induction of epithelial-mesenchymal transition, and maintenance of stemness, but little is known about the pathological role of HMGA1 in breast cancer patients. The aim of this study was to identify the pathological roles of HMGA1 in breast cancer. In our results, we found that mRNA and protein expression levels of HMGA1 were markedly higher in breast cancer tissues than in normal breast tissues. Using immunohistochemistry, high levels of HMGA1 protein were positively correlated with the status of histological grade (I-II vs. III-IV; P = 0.023), clinical stage (I-II vs. III-IV; P = 0.008), tumor size (T1-T2 vs. T3-T4; P = 0.015), lymph node metastasis (N0-N1 vs. N2-N3; P = 0.002), distant metastasis (M0 vs. M1; P < 0.001), and triple-negative breast cancer (No vs. Yes; P = 0.014) of breast cancer patients. Patients with higher HMGA1 expression had a significantly shorter overall survival time than did patients with low HMGA1 expression. Multivariate analysis indicated that the level of HMGA1 expression was an independent prognostic indicator (P < 0.001) for the survival of patients with breast cancer. In conclusion, HMGA1 plays an important role on breast cancer aggressiveness and prognosis and may act as a promising target for prognostic prediction.

Preparation of etoposide liposomes for enhancing antitumor efficacy on small cell lung cancer and reducing hematotoxicity of drugs.

Etoposide (VP16) is commonly used in the treatment of small cell lung cancer (SCLC) in clinical practice. However, severe adverse reactions such as bone marrow suppression toxicity limit its clinical application. Although several studies on VP16 liposomes were reported, no significant improvement in bone marrow suppression toxicity has been found, and there was a lack of validation of animal models for in vivo antitumor effects. Therefore, we attempted to develop a PEGylated liposomal formulation that effectively encapsulated VP16 (VP16-LPs) and evaluated its therapeutic effect and toxicity at the cellular level and in animal models. First, we optimized the preparation process of VP16-LPs using an orthogonal experimental design and further prepared them into freeze-dried powder to improve storage stability of the product. Results showed that VP16-LPs freeze-dried powder exhibited good dispersibility and stability after redispersion. In addition, compared to marketed VP16 injection, VP16-LPs exhibited sustained drug release characteristics. At the cellular level, VP16-LPs enhanced the cellular uptake of drugs and exhibited strong cytotoxic activity. In animal models, VP16-LPs could target and aggregate in tumors and exhibit a higher anti-tumor effect than VP16-injection after intravenous injection. Most importantly, hematological analysis results showed that VP16-LPs significantly alleviated the bone marrow suppression toxicity of drug. In summary, our study confirmed that PEGylated liposomes could enhance therapeutic efficacy and reduce toxicity of VP16, which demonstrated that VP16-LPs had enormous clinical application potential.

Radiation-targeted immunotherapy: A new perspective in cancer radiotherapy.

In contemporary oncology, radiation therapy and immunotherapy stand as critical treatments, each with distinct mechanisms and outcomes. Radiation therapy, a key player in cancer management, targets cancer cells by damaging their DNA with ionizing radiation. Its effectiveness is heightened when used alongside other treatments like surgery and chemotherapy. Employing varied radiation types like X-rays, gamma rays, and proton beams, this approach aims to minimize damage to healthy tissue. However, it is not without risks, including potential damage to surrounding normal cells and side effects ranging from skin inflammation to serious long-term complications. Conversely, immunotherapy marks a revolutionary step in cancer treatment, leveraging the body's immune system to target and destroy cancer cells. It manipulates the immune system's specificity and memory, offering a versatile approach either alone or in combination with other treatments. Immunotherapy is known for its targeted action, long-lasting responses, and fewer side effects compared to traditional therapies. The interaction between radiation therapy and immunotherapy is intricate, with potential for both synergistic and antagonistic effects. Their combined use can be more effective than either treatment alone, but careful consideration of timing and sequence is essential. This review explores the impact of various radiation therapy regimens on immunotherapy, focusing on changes in the immune microenvironment, immune protein expression, and epigenetic factors, emphasizing the need for personalized treatment strategies and ongoing research to enhance the efficacy of these combined therapies in cancer care.