Growth Inhibition Rate Research Articles

Effects of Enrofloxacin and Ciprofloxacin on Growth and Toxin Production of Microcystis aeruginosa

Microcystis aeruginosa is a common cyanobacterium found in water blooms and often causes ecological harm. Antibiotics are also increasingly used for the prevention and treatment of bacterial infections in aquaculture. However, since most antibiotics cannot be fully metabolized, they enter the water environment and cause ecological impacts. In this paper, the effects of the two fluoroquinolone antibiotics (enrofloxacin and ciprofloxacin) on the population density and microcystins (MCs) production of M. aeruginosa were studied. It is of great significance for the ecological risk assessment of antibiotics in the water environment. The results showed that the 96h EC50 values of enrofloxacin and ciprofloxacin to M. aeruginosa were 56.10 mg/L and 49.80 mg/L, respectively, and the toxicity of ciprofloxacin to M. aeruginosa was slightly stronger than that of enrofloxacin. With the increase in the two antibiotic concentration, the growth inhibition rate (IR) increased, but when the concentration reached a certain level, the IR would reach its threshold. Long-term exposure to low concentrations of these two antibiotics is not only more likely to lead to the outbreak of M. aeruginosa, but also increase its toxin production capacity. The highest contents of MCs in enrofloxacin and ciprofloxacin groups were 95.539 μg/g and 93.720 μg/g, respectively. The MCs value of these three enrofloxacin treatment groups was more than above 51.8 times that of control group (CK) on the 4th day; from 8th day to 14th day, the MCs value of these three enrofloxacin treatment groups was more than above 3.2 times that of CK group. For ciprofloxacin, the MCs value of the treatment group was more than 64.98 times that of the CK group on the 4th day, and from 8th day to 14th day, the MCs value of the treatment group was more than 2.7 times that of the CK group. These findings provide crucial management rationale.

Discovery of highly potent and selective KRASG12C degraders by VHL-recruiting PROTACs for the treatment of tumors with KRASG12C-Mutation

Although several covalent KRASG12C inhibitors have made great progress in the treatment of KRASG12C-mutant cancer, their clinical applications are limited by adaptive resistance, motivating novel therapeutic strategies. Through drug design and structure optimization, a series of highly potent and selective KRASG12C Proteolysis Targeting Chimeras (PROTACs) were developed by incorporating AMG510 and VHL ligand VH032. Among them, degrader YN14 significantly inhibited KRASG12C-dependent cancer cells growth with nanomolar IC50 and DC50 values, and ＞ 95 % maximum degradation (Dmax). Molecular dynamics (MD) simulation showed that YN14 induced a stable KRASG12C: YN14: VHL ternary complex with low binding free energy (ΔG). Notably, YN14 led to tumor regression with tumor growth inhibition (TGI%) rates more than 100 % in the MIA PaCa-2 xenograft model with well-tolerated dose-schedules. We also found that KRASG12C degradation exhibited advantages in overcoming adaptive KRASG12C feedback resistance over KRASG12C inhibition. Furthermore, combination of RTKs, SHP2, or CDK9 inhibitors with YN14 exhibited synergetic efficacy in KRASG12C-mutant cancer cells. Overall, these results demonstrated that YN14 holds exciting prospects for the treatment of tumors with KRASG12C-mutation and boosted efficacy could be achieved for greater clinical applications via drug combination.

Biological control of Magnaporthe oryzae using natively isolated Bacillus subtilis G5 from Oryza officinalis roots.

Rice blast, caused by Magnaporthe oryzae, is a major threat to global rice production causing significant crop losses and impacting grain quality. The annual loss of rice production due to this disease ranges from 10% to 30%. The use of biologically controlled strains, instead of chemical pesticides, to control plant diseases has become a research hotspot. In this study, an antagonistic endophytic bacterial strain was isolated from the roots of Oryza officinalis using the traditional isolation and culture methods. A phylogenetic tree based on 16S RNA and whole-genome sequencing identified isolate G5 as a strain of Bacillus subtilis. This isolate displayed strong antagonistic effects against different physiological strains of M. oryzae. After co-culture in LB medium for 7 days, the inhibition rates of the mycelial growth of four strains of M. oryzae, ZB15, WH97, Guy11, and T-39800E were 98.07 ± 0.0034%, 98.59 ± 0.0051%, 99.16 ± 0.0012%, and 98.69 ± 0.0065%, respectively. Isolate G5 significantly inhibited the formation of conidia of M. oryzae, with an inhibition rate of 97% at an OD600 of 2. Isolate G5 was able to provide 66.81% protection against rice blast under potted conditions. Whole-genome sequencing revealed that the genome size of isolate G5 was 4,065,878 bp, including 4,182 coding genes. Using the anti-SMASH software, 14 secondary metabolite synthesis gene clusters were predicted to encode antifungal substances, such as fengycin, surfactin, and bacilysin. The G5 isolate also contained genes related to plant growth promotion. These findings provide a theoretical basis for expounding the biocontrol mechanisms of this strain and suggest further development of biogenic agents that could effectively inhibit rice blast pathogen growth and reduce crop damage, while being environmentally friendly, conducive to ecological development, and a sustainable alternative to chemical pesticides. This study also enriches the relevant research on endophytes of wild rice, which proves that wild rice is a valuable microbial resource bank.

Asymmetric A‐DA′D‐A′′ Molecular Configuration Type‐I Photosensitizer with Two Complementary Reactive Oxygen Species for Efficient Imaging and Photodynamic Therapy

AbstractType‐I photosensitizers (PSs) can efficiently generate reactive oxygen species (ROS) in the hypoxia condition of tumors, which show less oxygen dependence and are considered better candidates for photodynamic therapy (PDT). However, relatively few efficient type‐I organic PSs simultaneously generating two or more type‐I ROS under irradiation are reported. Herein, new alternate donor (D)‐acceptor (A) type molecules containing ladder‐type core (DA′D) fused with an electron‐deficient benzothiadiazole core are reported, which show symmetrical A‐DA′D‐A (QY1) and asymmetrical A‐DA′D‐A′′ (QY2) configurations, respectively. As these ROSs possess complementary properties of strong oxidizing ability (•OH) and long radical lifetime (O2•−), in vitro and in vivo experiments demonstrate that QY1 and QY2 show excellent PDT effects for tumor cells under normoxia or hypoxia, and can achieve remarkable tumor growth inhibition (TGI) rate of 90% for the QY2. More importantly, the generation of •OH in these PSs is revealed by experiments both in aqueous and in vitro, including the well‐known transformation of O2•− and direct electron transition from water to excited triplet PS. It thus provides a comprehensive understanding of the O2 dependence property of •OH radical and deep insights into the mechanism of type‐I PS.

The Therapeutic Effects of MUC1-C shRNA@Fe3O4 Magnetic Nanoparticles in Alternating Magnetic Fields on Triple-Negative Breast Cancer.

Improving the treatment of triple-negative breast cancer (TNBC) is a serious challenge today. The primary objective of this study was to construct MUC1-C shRNA@ Fe3O4 magnetic nanoparticles (MNPs) and investigate their potential therapeutic benefits in alternating magnetic fields (AMF) on TNBC. Firstly, we verified the high expression of MUC1 in TNBC and synthesized specific MUC1-C shRNA plasmids (MUC1-C shRNA). Then, we prepared and characterized MUC1-C shRNA@Fe3O4 MNPs and confirmed their MUC1-C gene silencing effect and magneto-thermal conversion ability in AMF. Moreover, the inhibitory effects on TNBC in vitro and in vivo were observed as well as biosafety. Finally, the protein levels of BCL-2-associated X protein (Bax), cleaved-caspase3, glutathione peroxidase inhibitor 4 (GPX4), nuclear factor erythroid 2-related factor 2 (NRF2), and ferritin heavy chain 1 (FTH1) in TNBC cells and tissues were examined, and it was speculated that apoptosis and ferroptosis were involved in the synergistic treatment. MUC1-C shRNA@ Fe3O4 MNPs have a size of ~75 nm, with an encapsulation rate of (29.78±0.63) %, showing excellent gene therapy and magnetic hyperthermia functions. Under a constant AMF (3Kw) and a set concentration (200µg mL-1), the nanoparticles could be rapidly warmed up within 20 minutes and stabilized at about 43 °C. It could be uptaken by TNBC cells through endocytosis and significantly inhibit their proliferation and migration, with a growth inhibition rate of 79.22% for TNBC tumors. After treatment, GPX4, NRF2, and FTH1 expression levels in TNBC cells and tumor tissues were suppressed, while Bax and cleaved-caspase3 were increased. As key therapeutic measures, gene therapy, and magnetic hyperthermia have shown a synergistic effect in this treatment strategy, with a combined index (q index) of 1.23. In conclusion, we developed MUC1-C shRNA@Fe3O4 MNPs with magnetic hyperthermia and gene therapy functions, which have shown satisfactory therapeutic effects on TNBC without significant side effects. This study provides a potential option for the precision treatment of TNBC.

Dual-function β-cyclodextrin/starch-based intelligent film with reversible responsiveness and sustained bacteriostat-releasing for food preservation and monitoring

The full combination of high sensitivity indication and long-lasting bacteriostatic function is an innovative need to meet the practicality of intelligent film packaging systems for food products. Hence, Blueberry anthocyanins (BA) copigmentated by ferulic acid (FA) was used as an indicator, and cinnamon essential oil (CO) encapsulated by β-cyclodextrin (β-CD) as a bacteriostat, potato starch (PS) as a film-forming substrate to prepared a dual-function starch-based intelligent active packaging film with pH indicator and antibacterial function. FA had the best copigmentation effect with a threefold increase in a value compared to other phenolic acids. The ΔE value increased from 3.24 to 5.13 at pH 2–8, and the change was still prominent in acid-base alternating test, indicating a high response sensitivity. Notably, the yellow gamut of indicating terminus increased its visibility to the naked eye. The release behavior of CO from film was in line with Fick's diffusion. Meanwhile, the release of CO delayed to about 90 h through β-cyclodextrin encapsulation, showing a high growth-inhibition rate in E. coli and S. aureus of almost 100 %. In this study, a dual-function film with indication and bacteriostasis was prepared and enhanced with both, expanding its wide application in intelligent packaging of fresh food.

Proteasome inhibitors reduce CD73 expression partly via decreasing p-ERK in NSCLC cells

Ecto-5'-nucleotidase (CD73), encoded by the NT5E gene, mediates tumor immunosuppression and has been targeted for the development of new anticancer drugs. Proteasome inhibitors impair protein degradation by inhibiting proteasome and have been used in the clinic for cancer therapy. Here we report that proteasome inhibitors reduce the protein and mRNA levels of CD73. Among 127 tested small-molecule drugs, proteasome inhibitors were found to consistently decrease the protein and mRNA levels of CD73 in NSCLC NCI-H1299 cells. This effect was further confirmed in different NSCLC cells exposed to different proteasome inhibitors. In those treated cells, the protein levels of ERK and its active form p-ERK, the vital components in the MAPK pathway, were reduced. Consistently, inhibitors of MEK and ERK, another two members of the MAPK pathway, also lowered the protein and mRNA levels of CD73. Correspondingly, treatments with fibroblast growth factor 2 (FGF2), an activator of the MAPK pathway, enhanced the levels of p-ERK and partly rescued the proteasome inhibitor-driven reduction of CD73 mRNA and protein in NSCLC cells. However, exogenous CD73 overexpression in murine Lewis lung carcinoma (LLC) cells was not lowered either in vitro or in vivo, by the treatments with proteasome inhibitors and basically, did not affect their in vitro proliferative inhibition either. In contrast, CD73 overexpression dramatically reduced the in vivo anticancer activity of Bortezomib in immunocompetent mice, with tumor growth inhibition rates from 52.18 % for LLC/vector down to 8.75 % for LLC/NT5E homografts. These findings give new insights into the anticancer mechanisms of proteasome inhibitors.

Synergistic Effect of L-cycloserine and Capecitabine on Human Colon Cancer Cell Line

Introduction: Colon cancer comes in second place in the list of cancers in developed countries. Drug resistance is one of the causes of colorectal cancer therapeutic failure that usually occurs in most patients in advanced stage of colon cancer. This study investigates the effect of adding L-cycloserine to capecitabine in the HCT-116 colon cancer cell line. Materials and methods: We compared the combined L-cycloserine-capecitabine effect with each of the two drugs alone on the HCT-116 colon cancer cell line as a positive control group. The growth rate inhibition was examined by crystal violet assay. Results: The growth inhibition effect of L-cycloserine-capecitabine, L-cycloserine and capecitabine on HCT-116 cells was assessed with crystal violet assay, different concentrations including 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL were used for L-cycloserine-capecitabine combination, and for both L-cycloserine and capecitabine. After incubation for 24 hours, results appeared that the combination of L-cycloserine and capecitabine increased the effect of both drugs alone as seen by a significant increase (p <0.05) of the growth inhibition percentages in the L-cycloserine-capecitabine combination as compared with the positive control groups. Conclusion: From the result, we can conclude that the L-cycloserine combination with capecitabine has a synergistic effect for colon cancer treatment that could be a more effective regimen.

Nano Ag/PPy Biocomposites Based on Graphene Oxide Modified Bacterial Cellulose from the Juice of Xinhui Citrus and Its Antibacterial Activity.

Bacterial cellulose (BC) is a green, natural biopolymer with excellent biocompatibility and a film-forming ability. However, its lack of inherent antibacterial activity restricts its application in medical materials and food preservation. In this study, BC derived from the juice of discarded Xinhui citrus was obtained through fermentation and further modified in situ with graphene oxide (GO) to obtain BC(GO). Subsequently, BC(GO) was loaded with cell-compatible polypyrrole (PPy) and antibacterial agent silver nanoparticles (AgNPs) to prepare Ag-PPy/BC(GO) composite films. Composite films were characterized using Fourier-transform infrared spectroscopy (FTIR) and scanning electron microscopy-energy-dispersive X-ray spectroscopy (SEM-EDS) to evaluate their chemical structure and morphology. The results demonstrate effective adsorption of PPy and AgNPs onto the surface of BC nanofibers modified with GO. Antibacterial experiments reveal synergistic antibacterial effects of PPy and AgNPs. The Ag-PPy/BC(GO) membranes exhibit strong antibacterial activity against both Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), with 48-h growth inhibition rates of 75-84% and 82-84%, respectively.

Rational design of β-carboline as an efficient type I/II photosensitizer to enable hypoxia-tolerant chemo-photodynamic therapy

Photodynamic therapy (PDT) is a clinically approved treatment for cancer due to its high spatiotemporal selectivity and non-invasive modality. However, its therapeutic outcomes are always limited to the severe hypoxia environment of the solid tumor. Herein, two novel photosensitizers HY and HYM based on naturally antitumor alkaloids β-carboline were designed and synthesized. Through a series of experiments, we found HY and HYM can produce type II ROS (singlet oxygen) after light irradiation. HYM had higher singlet oxygen quantum yield and molar extinction coefficient than HY, as well as type I PDT behavior, which further let us find that HYM could exhibit robust phototoxicity activities in both normoxia and hypoxia. Meanwhile, HYM showed tumor-selective cytotoxicity with minimal toxicity toward normal cells. Notably, thanks to HYM's hypoxia-tolerant type I/II PDT and tumor selective chemotherapy, HYM showed synergistic inhibitory effect on tumor growth (inhibition rate > 91%). Our research provides a promising photosensitizer for hypoxia-tolerant chemo-photodynamic therapy, and may also give a novel molecular skeleton for photosensitizer design.

Effect of trichostatin A on biological characteristics of side population cells of cervical cancer cell line (HeLa)

Purpose: To investigate the effect of trichostatin A (TSA) on biological characteristics of side population (SP) cells of cervical cancer cell line (HeLa)Methods: Side population (SP) and NSP cells were obtained from 6th generation of primary cervical cancer cells and cervical cancer cell line (HeLa). Cell surface markers (ATP-binding membrane transporter superfamily G member 2 (ABCG2), CD133, CD43, p63, Ki67, multidrug resistance (MDR) as well as cell cycle phase distribution and apoptosis, were determined. SP cells in HeLa were divided into 3 groups that received TSA at doses of 0.01, 0.05, and 0.2 μM. Untreated cells served as control. Cell growth inhibition rates of different dose groups were compared. SP cells in HeLa were divided into simple irradiation group and combined irradiation group TSA (10 % inhibition concentration (IC10) + irradiation, and values of SP cell survival fraction (SF) of the two groups under different irradiation conditions were compared.Results: The content of SP in HeLa cell line was significantly higher than in cervical cancer tissue (p > 0.05). There were no significant differences in expression levels of ABCG2, CD133, CD43, p63, Ki67, and MDR, as well as G0/G1, S, and G2/M phase distributions and apoptosis rate between HeLa cell line and cervical cancer tissue (p > 0.05). On the 3rd, 5th, and 7th day, SF value of SP cells was significantly higher in NSP cells (p > 0.05). With increasing concentration of TSA, SF value of NSP cells gradually decreased, while that of SP cells did not change significantly.Conclusion: Cervical cancer cell line (HeLa) contains SP cells which have biological characteristics of tumor stem cells. Moreover, TSA exerts good cytotoxicity and radio-sensitization effect on SP cells.

Exploring the toxicity of biodegradable microplastics and imidacloprid to earthworms (Eisenia fetida) from morphological and gut microbial perspectives

Biodegradable microplastics (BMPs) pose serious environmental problems to soil organisms, and their adsorption capacity might make pesticides more dangerous for soil organisms. Therefore, in this study, polylactic acid (PLA) BMPs and imidacloprid (IMI) were used as a representative of BMPs and pesticides, respectively. Eisenia fetida was used as a test animal to investigate the effects of environmentally relevant concentrations of single and compound contaminated PLA BMPs and IMI on mortality, growth, number of offspring, tissue damage, and gut microorganisms of E.fetida. Exposure to PLA BMPs treatment and PLA BMPs + IMI treatment resulted in a sustained increase in E.fetida mortality, reaching 16.7% and 26.7%, respectively. The growth inhibition rate of single treatments was significantly increased. The compound contamination had the greatest effect on E.fetida offspring compared to the control. PLA BMPs and IMI cause histological damage to E.fetida, with the compound treatment causing the most severe damage. Based on the results of 16S sequencing, the bacterial communities in E.fetida gut and soil treated to PLA BMPs and IMI were significantly different. PLA BMPs + IMI treatment suppresses the abundance and diversity of E.fetida gut microorganisms, disrupting the homeostasis of bacterial communities and causing immune and metabolic dysfunction. These findings highlight the more severe damage of combined PLA BMPs and IMI pollution to E.fetida, and help to assess the risk of earthworm exposure to environmentally relevant concentrations of PLA BMPs and IMI.

Evidence for Suppression of Structure Growth in the Concordance Cosmological Model.

We present evidence for a suppressed growth rate of large-scale structure during the dark-energy-dominated era. Modeling the growth rate of perturbations with the "growth index" γ, we find that current cosmological data strongly prefer a higher growth index than the value γ=0.55 predicted by general relativity in a flat Lambda cold dark matter cosmology. Both the cosmic microwave background data from Planck and the large-scale structure data from weak lensing, galaxy clustering, and cosmic velocities separately favor growth suppression. When combined, they yield γ=0.633_{-0.024}^{+0.025}, excluding γ=0.55 at a statistical significance of 3.7σ. The combination of fσ_{8} and Planck measurements prefers an even higher growth index of γ=0.639_{-0.025}^{+0.024}, corresponding to a 4.2σ tension with the concordance model. In Planck data, the suppressed growth rate offsets the preference for nonzero curvature and fits the data equally well as the latter model. A higher γ leads to a higher matter fluctuation amplitude S_{8} inferred from galaxy clustering and weak lensing measurements, and a lower S_{8} from Planck data, effectively resolving the S_{8} tension.

Preparation and activity of sodium carboxymethyl cellulose (CMC-Na) and Metarhizium rileyi ZHKUMR1 composite membrane

Improving the adhesion capability of Metarhizium rileyi ZHKUMR1 on leaves enabled by the combination with Carboxymethyl Cellulose (CMCNa) materials is feasible to improve the utilization rate of Metarhizium rileyi. Herein, the CMC-Na-ZHKUMR1 membrane was prepared by simply mixing Carboxymethyl Cellulose (CMCNa) with Metarhizium rileyi. Through compatibility test, it was found that the inhibition rates of spore germination and mycelial growth of ZHKUMR1 were only 1.51 % and 3.13 % when the concentration of Carboxymethyl Cellulose (CMCNa) was 0.5 %. By adding 2 % of Carboxymethyl Cellulose (CMCNa) under UV irradiation for 30 min, the protective rate of spore germination of ZHKUMR1 was up to ~12.44 %, where the wettability on corn leaves was achieved and the retention of ZHKUMR1 spores on corn leaves was increased. After indoor activity determination, it was found that after 3 min of simulated rain washing, the lethal rate of corn leaves pretreated with CMC-Na-ZHKUMR1 on the 2nd instar larvae of Spodoptera frugiperda was 46.67 %, which was much higher than that of ZHKUMR1 spore suspension alone. This work clearly showed that Carboxymethyl Cellulose (CMCNa) effectively improved the field application effect of Metarhizium rileyi ZHKUMR1, and this strategy provided guidance for improving the field efficacy of Metarhizium rileyi ZHKUMR1.

Effect of Structurally Related Compounds on Desupersaturation Kinetics of Indomethacin.

The pharmaceutical literature contains examples wherein desupersaturation from high concentrations does not proceed to equilibrium concentration of the thermodynamically most stable form but remains above equilibrium. The purpose of the current research was to investigate the effect of structurally related compounds on desupersaturation kinetics as a possible explanation for a higher than equilibrium solubility after crystal growth of γ-indomethacin (γ-IMC). Three structurally related compounds (SRC) - cis-sulindac (c-SUL), trans-sulindac (t-SUL) and indomethacin-related compound-A (IMC-A) -were investigated. Desupersaturation kinetics to the most stable γ-IMC, in the presence of c-SUL, t-SUL or IMC-A, was measured at pH 2.0. The SRCs c-SUL and t-SUL were effective crystallization inhibitors of IMC, while IMC-A was not a potent crystallization inhibitor of IMC. Among the sulindac isomers, t-SUL was a stronger crystallization inhibitor. The apparent solubility of γ-IMC crystals grown from supersaturated solutions in the presence of SRCs matched the equilibrium solubility of γ-IMC. During crystallization of IMC in the presence of IMC-A, the concentration of IMC-A declined initially but rebounded as supersaturation and crystallization rate of IMC declined, suggesting that IMC-A itself became incorporated in the IMC crystal lattice at higher degrees of IMC supersaturation. The results suggest that high apparent solubility after crystallization of IMC reported by several authors is not related to the presence of IMC-A impurity. The greater IMC crystal growth rate inhibition by t-SUL than by c-SUL was consistent with the proposed orientation of SUL molecules adsorbed on the IMC crystal, providing a mechanistic understanding of the inhibition.

Study of bioaccumulation of Cr, Ni and Zn by the green alga Desmodesmus subspicatus and assessment of the toxic effect of selected elements and their mixtures on algae cells

Toxicity assessment of K2Cr2O7, ZnCl2 and NiCl2.6H2O focusing on the green unicellular alga Desmodesmus subspicatus showed that Ni was the most toxic (EC50 = 0.121 mg L−1), followed by Cr (EC50 = 0.357 mg L−1) and Zn (EC50 = 0.968 mg L−1). The alga was exposed to solutions of the individual metals and their mixtures (Zn + Ni, Zn + Ni + Cr). After 48, 72 and 96 h of exposure, the accumulation of Zn, Ni and Cr in algal cells was assessed. Moreover, the change in toxicity of the metals, the concentration of selected biogenic elements (Ca, Na, Mg, S, K, P, Mn) in algal cells and the rate of metal removal from the solutions were also analysed. In the case of single-metal solutions, for Zn and Cr, the toxicity and accumulation in algal cells decreased over the 96 h of the experiment, whereas for Ni as well as for the binary and ternary mixtures the toxicity and accumulation increased. Significant correlations between the amount of metals accumulated in the cells and the inhibition of growth rates were observed. The content of selected biogenic elements in algal cells decreased over time in all treatments with added metals as well as in the control group, and after 96 h was higher in all treatments with addition of Ni compared to the control group and single-metal solutions of Zn and Cr. The highest removal of the metal from the solution occurred in the case of the single metal solution of Zn, where 83.4% of Zn was removed from the solution in 96 h.

The improved size distribution and NIR luminescence of ZGGO:Cr3+ nanoparticles induced by Y3+ doping

Zn2Ga2.98-xYxCr0.02Ge0.75O8 (ZGGO:Cr0.02,Yx) persistent luminescent nanoparticles (PLNPs) with different concentrations were synthesized by a hydrothermal method combined with a vacuum heat treatment. With increasing Y3+ concentration from 0 to 0.05, the average size reduces from 53 to 28 nm and the particle shape changes from irregular to nearly spherical due to Y3+ doping leading to the suppressed growth rate of nanocrystals via surface charge modification. On the basis of spectral analyses and the first-principles calculation, the near infrared (NIR) emission peaks at 703 and 743 nm originate from the 4T2→4A2 transition of Cr3+ occupying octahedral Ga3+ sites and the 4A2→4T1 transition of Cr3+ occupying tetrahedral Ga3+ sites, respectively. Meanwhile, it is found that Y3+ ions are more likely to occupy tetrahedral Ga3+ sites and it leads to not only the creation of more anti-site defect pairs and the enhanced afterglow intensity but also the increased rigidity and the improved dispersibility of PLNPs in different simulated body fluids induced by complete surface modification (i.e. SiO2 coating). The above results indicate that ZGGO: Cr0.02,Y0.03@SiO2 PLNPs have potential applications in bioimaging.

Positive Chemotaxis of CREKA-Modified Ceria@Polydopamine Biomimetic Nanoswimmers for Enhanced Penetration and Chemo-photothermal Tumor Therapy.

Tumor interstitial pressure represents the greatest barrier against drug diffusion into the depth of the tumor. Biometric nanomotors highlight the possibility of enhanced deep penetration and improve cellular uptake. However, control of their directionality remains difficult to achieve. Herein, we report cysteine-arginine-glutamic acid-lysine-alanine (CREKA)-modified ceria@polydopamine nanobowls as tumor microenvironment-fueled nanoscale motors for positive chemotaxis into the tumor depth or toward tumor cells. Upon laser irradiation, this nanoswimmer rapidly depletes the tumor microenvironment-specific hydrogen peroxide (H2O2) in the nanobowl, contributing to a self-generated gradient and subsequently propulsion (9.5 μm/s at 46 °C). Moreover, the asymmetrical modification of CREKA on nanobowls could automatically reconfigure the motion direction toward tumor depth or tumor cells in response to receptor-ligand interaction, leading to a deep penetration (70 μm in multicellular spheroids) and enhanced antitumor effects over conventional nanomedicine-induced chemo-photothermal therapy (tumor growth inhibition rate: 84.2% versus 56.9%). Thus, controlling the direction of nanomotors holds considerable potential for improved antitumor responses, especially in solid tumors with high tumor interstitial pressure.

Discovery, Optimization, and Evaluation of Novel N-(Benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine Analogues as Potent STAT3 Inhibitors for Cancer Treatment.

Signal transducer and activator of transcription 3 (STAT3) is an attractive target for cancer therapy. However, identifying potent and selective STAT3 small-molecule inhibitors with drug-like properties remains challenging. Based on a scaffold combination strategy, compounds with a novel N-(benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine scaffold were designed and their inhibition of the interleukin-6 (IL-6)/JAK/STAT3 pathway was tested in HEK-Blue IL-6 reporter cells. After optimization of lead compound 12, compound 40 was identified as a selective STAT3 inhibitor that directly binds the SH2 domain to inhibit STAT3 phosphorylation, translocation, and downstream gene transcription. Compound 40 exhibited antiproliferative activities against STAT3-overactivated DU145 (IC50 value = 2.97 μM) and MDA-MB-231 (IC50 value = 3.26 μM) cancer cells and induced cell cycle arrest and apoptosis. In the DU145 xenograft model, compound 40 showed in vivo antitumor efficacy following intraperitoneal administration, with a tumor growth inhibition rate of 65.3% at 50 mg/kg, indicating promise for further development.

A critical examination of the protection level for primary producers in the first tier of the aquatic risk assessment for plant protection products

BackgroundThe aim of environmental risk assessment (ERA) for pesticides is to protect ecosystems by ensuring that specific protection goals (SPGs) are met. The ERA follows a prospective tiered approach, starting with the most conservative and simple step in risk assessment (RA) (so-called tier 1) using the lowest available appropriate endpoint derived from ecotoxicological tests. In 2015, for the tier 1 RA of aquatic primary producers, the recommendation was changed from using the lowest of the 50% inhibition (EC50) values based on biomass (area under the curve—EbC50), increase in biomass (yield- EyC50) or growth rate (ErC50) to only using the growth rate inhibition endpoint (ErC50) because it is independent of the test design and thus more robust. This study examines the implications of this such on the level of conservatism provided by the tier 1 RA and evaluates whether it ensures a suitable minimum protection level.ResultsOur analysis shows that replacing the lowest endpoint with the growth rate inhibition endpoint while maintaining the assessment factor (AF) of 10 significantly reduces the conservatism in the tier 1 RA. Comparing protection levels achieved with different endpoints reveals that the current assessment is less protective. To maintain the previous level of protection, and since the protection goals have not changed, we recommend to multiply the default AF of 10 by an extra factor of minimum 2.4 in the tier 1 RA based on ErC50. Independently of the endpoint selected in tier 1 RA, several issues in the general RA of pesticides contribute to uncertainties when assessing the protection levels, e.g., lack of appropriate comparison of the higher tier experimental studies (i.e., best achievable approximation of field situation, so-called surrogate reference tier) with field conditions or the regulatory framework's failure to consider realistic conditions in agricultural landscapes with multiple stressors and pesticide mixtures.ConclusionsWe advise to consider adjusting the risk assessment in order to reach at least the previous protection level for aquatic primary producers. Indeed continuing using an endpoint with a higher value and without adjustment of the assessment factor is likely to jeopardize the need of halting biodiversity loss in surface waters.