Nifuroxazide suppresses PD-L1 expression and enhances the efficacy of radiotherapy in hepatocellular carcinoma.

Radiation therapy is a primary treatment for hepatocellular carcinoma (HCC), but its effectiveness can be diminished by various factors. The over-expression of PD-L1 has been identified as a critical reason for radiotherapy resistance. Previous studies have demonstrated that nifuroxazide exerts antitumor activity by damaging the Stat3 pathway, but its efficacy against PD-L1 has remained unclear. In this study, we investigated whether nifuroxazide could enhance the efficacy of radiotherapy in HCC by reducing PD-L1 expression. Our results showed that nifuroxazide significantly increased the sensitivity of tumor cells to radiation therapy by inhibiting cell proliferation and migration while increasing apoptosis in vitro. Additionally, nifuroxazide attenuated the up-regulation of PD-L1 expression induced by irradiation, which may be associated with increased degradation of PD-L1 through the ubiquitination-proteasome pathway. Furthermore, nifuroxazide greatly enhanced the efficacy of radiation therapy in H22-bearing mice by inhibiting tumor growth, improving survival, boosting the activation of T lymphocytes, and decelerating the ratios of Treg cells in spleens. Importantly, nifuroxazide limited the increased expression of PD-L1 in tumor tissues induced by radiation therapy. This study confirms, for the first time, that nifuroxazide can augment PD-L1 degradation to improve the efficacy of radiation therapy in HCC-bearing mice.

Global patterns of human exposure to flame retardants indoors.

To fill the knowledge gaps regarding the global patterns of human exposure to flame retardants (FRs) (i.e., brominated flame retardants (BFRs) and organophosphorus flame retardants (OPFRs)), data on the levels and distributions of FRs in external and internal exposure mediums, including indoor dust, indoor air, skin wipe, serum and urine, were summarized and analysed. Comparatively, FR levels were relatively higher in developed regions in all mediums, and significant positive correlations between FR contamination and economic development level were observed in indoor dust and air. Over time, the concentration of BFRs showed a slightly decreasing trend in all mediums worldwide, whereas OPFRs represented an upward tendency in some regions (e.g., the USA and China). The occurrence levels of FRs and their metabolites in all external and internal media were generally correlated, implying a mutual indicative role among them. Dermal absorption generally contributed >60% of the total exposure of most FR monomers, and dust ingestion was dominant for several low volatile compounds, while inhalation was found to be negligible. The high-risk FR monomers (BDE-47, BDE-99 and TCIPP) identified by external exposure assessment showed similarity to the major FRs or metabolites observed in internal exposure mediums, suggesting the feasibility of using these methods to characterize human exposure and the contribution of indoor exposure to the human burden of FRs. This review highlights the significant importance of exposure assessment based on multiple mediums for future studies.

Quantitative characterization of resident' exposure to typical semi-volatile organic compounds (SVOCs) around a non-ferrous metal smelting plant.

To comprehensively characterize residents' exposure to major semi-volatile organic compounds (SVOCs), samples of indoor floor wipes, size-segregated airborne particles, gaseous air, food, and paired skin wipes were simultaneously collected from residential areas around a large non-ferrous metal smelting plant as compared with the control areas, and three typical SVOCs (including polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), and halogenated PAHs (HPAHs)) were determined. Comparison and correlation analysis among matrices indicated PAHs were the major contaminants emitted from metal smelting activities compared to HPAHs and PCBs, with naphthalene verified as the most important characteristic compound, and their accumulation on skin may be a comprehensive consequence of contact with floor dust and air. While patterns of human exposure pathways for the SVOCs were found to be clearly correlated to their vapor pressure, dermal absorption was the major contributor (51.1-76.3%) to total carcinogenic risk (TCR) of PAHs and HPAHs for surrounding residents, especially for low molecular weight PAHs, but dietary ingestion (98.6%) was the dominant exposure pathway to PCBs. The TCR of PAHs exceeded the acceptable level (1 × 10-4), implying smelting activities obviously elevated the health risk. This study will serve developing pertinent exposure and health risk prevention measures.

Attenuated Salmonella carrying siRNA-PD-L1 and radiation combinatorial therapy induces tumor regression on HCC through T cell-mediated immuno-enhancement.

Hepatocellular carcinoma (HCC), the most prevalent type of aggressive liver cancer, accounts for the majority of liver cancer diagnoses and fatalities. Despite recent advancements in HCC treatment, it remains one of the deadliest cancers. Radiation therapy (RT) is among the locoregional therapy modalities employed to treat unresectable or medically inoperable HCC. However, radioresistance poses a significant challenge. It has been demonstrated that RT induced the upregulation of programmed death ligand 1 (PD-L1) on tumor cells, which may affect response to PD-1-based immunotherapy, providing a rationale for combining PD-1/PD-L1 inhibitors with radiation. Here, we utilized attenuated Salmonella as a carrier to explore whether attenuated Salmonella carrying siRNA-PD-L1 could effectively enhance the antitumor effect of radiotherapy on HCC-bearing mice. Our results showed that a combination of siRNA-PD-L1 and radiotherapy had a synergistic antitumor effect by inhibiting the expression of PD-L1 induced by radiation therapy. Mechanistic insights indicated that the combination treatment significantly suppressed tumor cell proliferation, promoted cell apoptosis, and stimulated immune cell infiltration and activation in tumor tissues. Additionally, the combination treatment increased the ratios of CD4+ T, CD8+ T, and NK cells from the spleen in tumor-bearing mice. This study presents a novel therapeutic strategy for HCC treatment, especially for patients with RT resistance.

A systematic characterization of soil/dust ingestion for typical subpopulations in China.

An accurate assessment of human exposure to pollutants through the ingestion of dust and/or soil particles depends on a thorough understanding their rate of human ingestion. To this end, we investigated the load and size distribution patterns of dust/soil particles on the hands of three typical subpopulations, including preschoolers, college students, and security guards (outdoor workers). The geometric mean diameter of dust/soil particles on hands was observed to be 38.7 ± 11.2, 40.0 ± 12.1, and 36.8 ± 10.4 µm for preschoolers, college students, and security guards, respectively. The particle size distribution differed between subpopulations: Preschoolers were more exposed to fine particles, whereas security guards were exposed to more coarse particles. The geometric means of dust/soil particle loading on the hands were 0.126, 0.0163, and 0.0377 mg/cm2 for preschoolers, college students, and security guards, respectively. Males had statistically higher dust/soil particle loadings on hands than females, notably for preschoolers and college students; preschoolers with frequent hand contact with the bare ground had higher dust/soil particle loadings compared to those of peers in contact with commercial and residential grounds. The mean total dust/soil particle ingestion rate was estimated to be 245, 19.7, and 33.1 mg/day for preschoolers, college students, and security guards, respectively. Our estimates for college students and security guards are close to the consensus central-tendency values recommended by the U.S. EPA's Exposure Factor Handbook for American adults, whereas the estimates for children are much higher than the upper percentile values recommended for American children.

Distribution, sources and health risks of heavy metals in indoor dust across China.

The potential effects of heavy metals on human health have attracted increasing attention as most people spend up to 90% of their time indoors. Human exposure to heavy metals in indoor dust have only been characterised for limited regions in China, and full-scale data for different functional areas are not available. Therefore, this review analysed the concentrations, contamination characteristics, and potential health risks of seven heavy metals (including zinc (Zn), lead (Pb), copper (Cu), chromium (Cr), nickel (Ni), arsenic (As), and cadmium (Cd)) in indoor dust at 3392 sampling sites in 55 cities across 27 provincial regions of China based on literature data. Results revealed that the median heavy metal concentrations in indoor dust throughout China decreased in the following order: Zn > Pb > Cu > Cr > Ni > As > Cd. Traffic emissions and decorative materials are the primary sources of heavy metal pollution in indoor dust. No considerable non-carcinogenic risk was found for Zn, Cu, Cr, Ni, and Cd in indoor dust, while Pb and As exhibited potential non-carcinogenic risks to children, primarily distributed in cities across Southern China. Meanwhile, the carcinogenic risks posed by Cr and Ni were higher than those posed by As and Cd, especially in Southern China. Therefore, effective measures in Southern China should prioritised for controlling Pb, Cr, Ni and As pollution in indoor dust to reduce human health risk. This review is useful for policy decision-making and protecting human from exposure to heavy metals in indoor dust across China.

Fluvoxamine prompts the antitumor immune effect via inhibiting the PD-L1 expression on mice-burdened colon tumor.

A colon tumor, one of the digestive tract malignant tumors, is harmful to human health. A potential new treatment still deserves attention. The development of a new drug needs more resources, including time and expense. Therefore, the old drug with new targets has become a current research hotspot. Fluvoxamine, as an antidepressant, could play an effect on inhibiting 5-hydroxytryptamine reuptake. In the present research, the antitumor effects and possible mechanisms of fluvoxamine are validated. The results showed that fluvoxamine significantly suppressed the migration and proliferation of tumor cells, and increased the apoptosis in vitro. Additionally, fluvoxamine significantly delays tumor development, and prompts the apoptosis in tumor tissues of mice-burdened colon tumors in vivo. The tumor suppression might be related with that fluvoxamine inhibits the expression of phosphorylated signal transducer and activator of transcription 3, matrix metalloproteinase 2, and cleaved-caspase 3. Importantly, fluvoxamine significantly reduces the expression level of programmed cell death ligand 1. This could be a possible reason that treatment with fluvoxamine drives the infiltration of T lymphocytes and M1-type macrophages in tumor tissues. Taken together, this research suggests that fluvoxamine might be a promising drug to treat colon cancer by inhibiting the proliferation and migration, inducing apoptosis, and even increasing the immune response of antitumor.

siRNA targeting PD-L1 delivered with attenuated Salmonella enhanced the anti-tumor effect of lenvatinib on mice bearing Hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a primary liver cancer representing serious harm to human health. The effective treatment of HCC is challenging. Lenvatinib is an inhibitor of polytyrosine kinase that exerts an effect against HCC by blocking the VEGF signaling pathway. However, its efficacy in most patients remains unsatisfactory. The factors influencing tumorigenesis are diverse; thus, combined treatment is an important strategy against tumors. Programmed death ligand-1 (PD-L1), which binds to programmed death-1 (PD-1), significantly compromises the anti-tumor effect of T cells. Therefore, we designed a siRNA-PD-L1 and delivered it using attenuated Salmonella, and its synergistic effects with Lenvatinib against HCC were evaluated. The results showed that the combination of Lenvatinib and siRNA-PD-L1 inhibited tumor growth in H22 tumor-bearing mice, arrested cell proliferation, and increased cell apoptosis in the tumor. The combination treatment synergistically inhibited the expression of VEGF and PD-L1 and contributed to the increase in T-cell infiltration in the tumor tissues and the ratio of T cells in the spleen. Furthermore, the combination treatment increased the number of granzyme B+ T cells, indicating a significantly improved anti-tumor immunity in mice. Therefore, this combination might be a potential novel strategy for HCC treatment.

Taraxasterol prompted the anti-tumor effect in mice burden hepatocellular carcinoma by regulating T lymphocytes.

Hepatocellular carcinoma (HCC) is a common digestive malignant tumor with high morbidity and mortality worldwide, however, the treatment of HCC and prognosis of patients are not optimistic, finding more effective treatments are imperative. Taraxacum officinale (L.) Weber ex F.H.Wigg is a perennial herb of compositae, and our study has demonstrated that Taraxacum officinale polysaccharide has certain anti-tumor effect on HCC cells. Taraxasterol (TS) is a natural product extracted from Taraxacum officinale with strong physiological, pharmacological and biological activities, but the effect of TS on HCC is yet to be determined. Therefore, the aim of this study is to explore the effect of dandelion sterol on HCC in vivo and in vitro. The results showed that TS significantly inhibited the proliferation, induced apoptosis and blocked cell cycle in HCC cell lines HepG2 and Huh7 cells in vitro. TS inhibited the tumor growth of H22 bearing mice and the expression of Ki67 in vivo. More importantly, TS regulated the immunity of H22 bearing mice by elevating the ratio of CD4+ T cells in spleen, and increasing the number of T cell infiltration in tumor tissue. Except immunomodulation, the mechanism of tumor growth inhibition may be related to the regulation of apoptosis related proteins and IL-6/STAT3 pathway. TS significantly inhibited the growth of HCC cells both in vitro and in vivo. The study would provide a theoretical basis for the new application of TS and the adjuvant treatment of malignant tumor with traditional Chinese medicine.

High expression of CD28 enhanced the anti-cancer effect of siRNA-PD-1 through prompting the immune response of melanoma-bearing mice.

Immune checkpoint blockade is considered to be an effective method of tumor immunotherapy. As one of the main immune checkpoints, blocking PD-1/PD-L1 pathway has been proved to be effective in the treatment of many cancers via activating T cells; however, many patients still do not respond to the blocking PD-1/PD-L1 treatment with satisfying results. Related research demonstrated that the activation of T cells required a co-stimulatory signal generated by the interaction between CD28 and CD80/CD86, whereas in many patients, CD28 on the T cell surface was lost. Thus, in this study, we constructed the co-expression plasmid of CD28-siRNA-PD-1 and explored the anti-tumor mechanism of the co-expression plasmid on mouse model. The results showed that the expression of PD-1 was inhibited and the expression of CD28 was increased significantly in tumor tissues after the mice were treated with the co-expression plasmid. The survival rate of the tumor-bearing mice was recorded every day. PD-1 expression and tumor-infiltrating lymphocytes in cancer tissues were detected by immunofluorescence staining and the ratios of different immune cells in spleens were detected by flow cytometry. We found that treatment with the co-expression plasmid significantly prolonged the survival of melanoma-bearing mice, induced the cell apoptosis, increased the infiltration of T cells in tumor tissues, and altered the ratios of different immune cells in the spleens. These results also laid the foundation for reducing the resistance of PD-1 blockade in the clinic.

Identifying dermal exposure as the dominant pathway of children's exposure to flame retardants in kindergartens.

Exploration of multiple sources of brominated (BFRs) and organophosphate flame retardants (OPFRs) for children promotes the understanding of exposure pathways and health risk. 10 BFRs and 9 OPFRs were measured in skin wipes from hands, forehead, and arms of 30 children, and surface wipe samples from sills, toys, desks and floors, and indoor air samples of kindergartens from Xinxiang, China. Higher ∑9OPFRs concentrations were observed in the forehead (1840 ng/m2), followed by hand (1420 ng/m2) and arm wipes (1130 ng/m2), and the ∑8BFRs concentrations in forehead, hand and arm wipes were 116, 315 and 165 ng/m2, respectively. The total concentration of OPFRs and BFRs in floor wipes (66.1 and 24.5 ng/m2) were lower than those in toy (205 and 535 ng/m2), sill (227 and 30.1 ng/m2) and desk (84.4 and 139 ng/m2) wipes. Concentrations of FRs in forehead wipes were significantly correlated with those in gaseous air (p < 0.05), moderate correlations were found between the hand wipes and surface wipes (p = 0.054). We estimated the daily average dosages (DADs) of children exposure to FRs via multiple pathways. Compared to DADs via inhalation and hand-to-mouth transfer, dermal exposure was determined to be the predominant exposure pathway to ∑9OPFRs and ∑8BFRs.

Gas-particle partition and size-segregated distribution of flame retardants in indoor and outdoor air: Reevaluation on the role of fine particles in human exposure.

In this study, we investigated the distribution of brominated and organophosphate flame retardants (BFRs and OPFRs) in the paired gaseous and nine size-segregated particulate samples collected from 8 typical indoor compartments and monthly outdoor in Xinxiang, China, respectively. For the indoor environments, total concentrations of FRs (Σ19FRs) in bulk air ranged from 3.9 ng/m3 to 37.5 ng/m3, with that in children recreation center (37.5 ng/m3) and furniture store (28.7 ng/m3) showing highest levels. In the outdoor air, Σ19FRs ranged from 3.1 ng/m3 to 13.6 ng/m3 among the 12 months, with that from late spring and summer being the highest. OPFRs had higher concentration than BFRs, with the total concentration of OPFRs accounting for 77%-99% of ∑19FRs. TCIPP (tris(chloroiso-propyl) phosphate), TCEP (tris(2-chloroethyl) phosphate), TEP (triethyl phosphate) and DBDPE (decabromodiphenyl ethane), BDE-209 (decabromodiphenyl ether) were the predominant analogs. Specifically, BFRs tended to enrich in gas phase indoors and coarse particles (aerodynamic diameters >3.3 µm) outdoors, but OPFRs mainly distributed in coarse particles both indoors and outdoors. The size distribution patterns varied among FRs, with the higher volatile FRs (e.g., TCEP, TCIPP) distributed more uniformly across particulate size. Although the distribution patterns of FRs in air were driven by multiple factors, organic carbon and element carbon in particulate matter had an influence to a certain extent. Health risks from exposure to FRs were characterized via the hazard quotient approaches. The total noncarcinogenic risks of ∑16FRs from inhalation were higher than that from air to skin transport, and the risks resulted from coarse particle-bound ∑16FRs (>3.3 µm) and gas phase were both significantly higher than that from fine fraction (<3.3 µm) in all scenarios, implying that FRs in coarse particles should not be underestimated.

Less is more: biological effects of NiSe2/rGO nanocomposites with low dose provide new insight for risk assessment.

Nickel selenide nanomaterials (NiSe2 NMs) with different vacancies demonstrated high catalytic activity as electrocatalyst in oxygen evolution reaction. As the growing needs of the industrial applications in electrocatalyst, the increased occupational exposure and environmental releasing of NMs would be unavoidable. While, much efforts have been made to evaluate the ecological safety of such engineered NMs at unrealistically high concentrations, failed to provide the comprehensively guideline for exposure thresholds. To supplement the current knowledge gap, we testified the cytotoxicity of NiSe2/rGO nanocomposites with different surface defects under more realistic exposure mode. Compared with the short-term exposure and repetitive exposure, rat lung macrophages exhibited the augmented oxidative stress, dysfunction of mitochondria, damage of DNA and disorder of calcium homeostasis under the long-term NiSe2/rGO exposure. Noteworthily, no significant differences could be found between the NiSe2/rGO with different surface defects, indicated that the defect type of NMs were not the accurate predictor for real risk assessment. Collectively, the study provided the real potential toxic effects and exposure thresholds of NMs that might be highly possible industrial produced, and appealed the new insight for risk assessments of engineered NMs under the long-term exposure, which exhibited difference from the traditional evaluation of short-term and repetitive exposure.

Nickel cobalt oxide nanowires with iron incorporation realizing a promising electrocatalytic oxygen evolution reaction.

Developing cost-effective electrocatalysts for water electrolysis is a promising strategy to enhance conversion and storage efficiency of sustainable energy. Transition metal oxides have been considered as alternative oxygen evolution reaction (OER) catalysts to replace noble metal-based catalysts. Here, we report a series of Fe-doped NiCo2O4 (NCO) nanowires with different Fe-doped concentrations, synthesized by a facile solvothermal and calcinations process, as high-efficiency electrocatalysts for OER. Due to abundant catalytically active sites, high-charge transport capability and specific surface area, these as-obtained NCO nanowires exhibit low overpotential and small Tafel slope. Specifically, NCO-0.1 shows the outstanding OER performance with a low overpotential of 297 mV at a current density of 10 mA cm-2 and a small Tafel slope of about 68 mV dec-1 in 1.0 M KOH. This study offers a promising electrocatalyst for the OER in water splitting.

Controllable Synthesis of Fe-Doped NiCo2 O4 Nanobelts as Superior Catalysts for Oxygen Evolution Reaction.

As one of the promising clean and renewable technologies, water splitting has been a hot topic, especially the half-reaction of oxygen evolution reaction (OER) due to its sluggish and complex kinetics. Hence, Fe-doped NiCo2 O4 nanobelts were designed and prepared as catalysts toward OER. By increasing the Fe amount, the catalytic performances of the as-synthesized products went up and then decreased. Profiting from the synergistic effect between Fe atom and NiCo2 O4 , all the Fe-NiCo2 O4 catalysts exhibited superior catalytic activities to the corresponding NiCo2 O4 . In addition, the characteristic nanobelt architecture facilitates the conduction of electrons and the exposure of active sites. With the optimal Fe content, the 9.1 % Fe-NiCo2 O4 yielded the smallest overpotential and Tafel slope among the catalysts, distinctly lower than that of RuO2 .

Adjustable Ternary FeCoNi Nanohybrids for Enhanced Oxygen Evolution Reaction.

Water splitting as a greatly desired technology to produce clean renewable energy, but is hampered by the sluggish oxygen evolution reaction. So, the development of highly active and durable water oxidation electrocatalysts is of primarily significance for energy conversion. Here, a facial strategy to synthesize FeCoNi nanohybrids with adjustable morphological structures by using fluorine is introduced. The morphology and electrocatalytic activity of the sample is determined by the innovative introduction of fluorine. Among them, the overpotential at 10 mA cm-2 of the best sample is approximately 97 mV lower than the commercial RuO2 toward the oxygen evolution reaction in 1 m KOH. Additionally, the catalysts also have low Tafel slopes and remarkable stability.

Enhancement of Photocatalytic Activity of Bi2 O3 -BiOI Composite Nanosheets through Vacancy Engineering.

Vacancy engineering is an effective strategy to enhance solar-driven photocatalytic performance of semiconductors. It is highly desirable to improve the photocatalytic performance of composite nanomaterials by the introduction of vacancies, but the role of vacancies and the heterostructure in the photocatalytic process is elusive to the composite nanomaterials. Herein, the introduction of I vacancies can significantly enhance the photocatalytic activity of Bi2 O3 -BiOI composite nanosheets in a synergistic manner. The excellent photocatalytic performance of the Bi2 O3 -BiOI composites is attributed to the combination of Bi2 O3 and BiOI and the existence of I vacancies in Bi2 O3 -BiOI composites. Specifically, density functional theory calculation shows that the existence of I vacancies would create a new electric states vacancy band below the conduction band of BiOI and thus can reduce the bandgap of BiOI nanosheets. This greatly facilitates the scavenging of the photogenerated electron on the surface of BiOI by Bi2 O3 , therefore, enhancing the overall photocatalytic activity of the composites. The enhanced photocatalytic efficiency is demonstrated by the degradation of tetracycline (TC), which reaches 96% after 180 min and by the high total organic carbon (TOC) removal (89% after 10 h visible light irradiation). This study provides a novel approach for the design of high-performance composite catalysts.

A Facile Synthesis of Ternary Nickel Iron Sulfide Nanospheres as Counter Electrode in Dye-Sensitized Solar Cells.

The incorporation of a foreign metal into a material may adjust the surface electronic structure and promote charge transfer, which then ultimately improves electrical conductivity and electrocatalytic performance because of the possible charge delocalization between the metal cations. As a result, for the first time, ternary nickel iron sulfide nanospheres have been successfully fabricated through a two-step solvothermal approach with the help of glucose (Ni0.5 Fe0.5 S2 /C). Subsequently, the electrochemical performance and electrocatalytic activity of Ni0.5 Fe0.5 S2 /C were evaluated by electrochemical impedance spectroscopy, Tafel polarization and cyclic voltammetry, indicating high electrical conductivity and great electrocatalytic activity. Ni0.5 Fe0.5 S2 /C was employed as a counter electrode for dye-sensitized solar cells, and exhibited higher power conversion efficiency (6.79 %) than the device with Pt CE (6.31 %) under full sunlight illumination (100 mW cm-2 , AM 1.5G).