Keratinocytes present Staphylococcus aureus enterotoxins and promote malignant and non-malignant T cell proliferation in cutaneous T cell lymphoma.

Cutaneous T-cell lymphoma (CTCL) is characterized by malignant T-cells proliferating in a unique tumor microenvironment (TME) dominated by keratinocytes. Skin colonization and infection by Staphylococcus aureus (S. aureus) is a common cause of morbidity and suspected of fueling disease activity. Here we show that expression of HLA-DR, high-affinity receptors for Staphylococcal enterotoxins (SE), by keratinocytes correlates with IFN-γ expression in the TME. Importantly, IFN-γ induces HLA-DR, SE-binding, and SE-presentation by keratinocytes to malignant T-cells from Sézary syndrome (SS) patients, and malignant and non-malignant T-cell lines derived from SS and Mycosis fungoides patients. Likewise, preincubation of keratinocytes with supernatant from patient-derived SE-producing S. aureus triggers proliferation in malignant T-cells and cytokine release (including IL-2), when cultured with non-malignant T-cells. This is inhibited by pre-treatment with engineered bacteriophage S. aureus-specific endolysins. Furthermore, mutations in the HLA-DR binding sites of SE type-A, and siRNA-mediated knockdown of Janus Kinase-3 (JAK3) and IL-2Rγ block induction of malignant T-cell proliferation. In conclusion, we show that, upon exposure to patient-derived S. aureus and SE, keratinocytes stimulate IL-2Rγ/JAK3-dependent proliferation of malignant and non-malignant T-cells in an environment with non-malignant T-cells. These findings suggest that keratinocytes in the TME play a key role in S. aureus mediated disease activity in CTCL.

Multiwalled Carbon Nanotubes-Reprogrammed Macrophages Facilitate Breast Cancer Metastasis via NBR2/TBX1 Axis.

In recent years, carbon nanotubes have emerged as a widely used nanomaterial, but their human exposure has become a significant concern. In our former study, we reported that pulmonary exposure of multiwalled carbon nanotubes (MWCNTs) promoted tumor metastasis of breast cancer; macrophages were key effectors of MWCNTs and contributed to the metastasis-promoting procedure in breast cancer, but the underlying molecular mechanisms remain to be explored. As a follow-up study, we herein demonstrated that MWCNT exposure in breast cancer cells and macrophage coculture systems promoted metastasis of breast cancer cells both in vitro and in vivo; macrophages were skewed into M2 polarization by MWCNT exposure. LncRNA NBR2 was screened out to be significantly decreased in MWCNTs-stimulated macrophages through RNA-seq; depletion of NBR2 led to the acquisition of M2 phenotypes in macrophages by activating multiple M2-related pathways. Specifically, NBR2 was found to positively regulate the downstream gene TBX1 through H3k27ac activation. TBX1 silence rescued NBR2-induced impairment of M2 polarization in IL-4 & IL-13-stimulated macrophages. Moreover, NBR2 overexpression mitigated the enhancing effects of MWCNT-exposed macrophages on breast cancer metastasis. This study uncovered the molecular mechanisms underlying breast cancer metastasis induced by MWCNT exposure.

DNAJA1­knockout alleviates heat stroke­induced endothelial barrier disruption via improving thermal tolerance and suppressing the MLCK­MLC signaling pathway.

Endothelial barrier disruption plays a key role in the pathophysiology of heat stroke (HS). Knockout of DNAJA1 (DNAJA1­KO) is thought to be protective against HS based on a genome­wide CRISPR­Cas9 screen experiment. The present study aimed to illustrate the function of DNAJA1­KO against HS in human umbilical vein endothelial cells. DNAJA1­KO cells were infected using a lentivirus to investigate the role of DNAJA1­KO in HS­induced endothelial barrier disruption. It was shown that DNAJA1­KO could ameliorate decreased cell viability and increased cell injury, according to the results of Cell Counting Kit­8 and lactate dehydrogenase assays. Moreover, HS­induced endothelial cell apoptosis was inhibited by DNAJA1­KO, as indicated by Annexin V­FITC/PI staining and cleaved­caspase­3 expression using flow cytometry and western blotting, respectively. Furthermore, the endothelial barrier function, as measured by transepithelial electrical resistance and FITC­Dextran, was sustained during HS. DNAJA1­KO was not found to have a significant effect on the expression and distribution of cell junction proteins under normal conditions without HS. However, DNAJA1­KO could effectively protect the HS­induced decrease in the expression and distribution of cell junction proteins, including zonula occludens­1, claudin­5, junctional adhesion molecule A and occludin. A total of 4,394 proteins were identified using proteomic analysis, of which 102 differentially expressed proteins (DEPs) were activated in HS­induced wild­type cells and inhibited by DNAJA1­KO. DEPs were investigated by enrichment analysis, which demonstrated significant enrichment in the 'calcium signaling pathway' and associations with vascular­barrier regulation. Furthermore, the 'myosin light­chain kinase (MLCK)­MLC signaling pathway' was proven to be activated by HS and inhibited by DNAJA1­KO, as expected. Moreover, DNAJA1­KO mice and a HS mouse model were established to demonstrate the protective effects on endothelial barrier in vivo. In conclusion, the results of the present study suggested that DNAJA1­KO alleviates HS­induced endothelial barrier disruption by improving thermal tolerance and suppressing the MLCK­MLC signaling pathway.

Tumour microenvironment-responded Fe-doped carbon dots-sensitized cubic Cu2O for Z-scheme heterojunction-enhanced sono-chemodynamic synergistic tumor therapy.

The efficacy of electron-hole separation in a single sonosensitizer and the complexities of the tumor microenvironment (TME) present significant challenges to the effectiveness of sonodynamic therapy (SDT). Designing efficient sonosensitizers to enhance electron-hole separation and alleviate TME resistance is crucial yet challenging. Herein, we introduce a novel Z-scheme heterojunctions (HJs) sonosensitizer using Fe-doped carbon dots (CDs) as auxiliary semiconductors to sensitize cubic Cu2O (Fe-CDs@Cu2O) for the first time. Fe-CDs@Cu2O demonstrated enhanced SDT effects due to improved electron-hole separation. Additionally, the introduction of Fe ions in CDs synergistically enhances Fenton-like reactions with Cu ions in Cu2O, resulting in enhanced chemodynamic therapy (CDT) effects. Moreover, Fe-CDs@Cu2O exhibited rapid glutathione (GSH) depletion, effectively mitigating TME resistance. With high rates of 1O2 and OH generated by Fe-CDs@Cu2O, coupled with strong GSH depletion, single drug injection and ultrasound (US) irradiation effectively eliminate tumors. This innovative heterojunction sonosensitizer offers a promising pathway for clinical anti-tumor treatment.

RtNAC055 promotes drought tolerance via a stomatal closure pathway linked to methyl jasmonate/hydrogen peroxide signaling in Reaumuria trigyna.

The stomata regulate CO2 uptake and efficient water usage, thereby promoting drought stress tolerance. NAC proteins (NAM, ATAF1/2, and CUC2) participate in plant reactions following drought stress, but the molecular mechanisms underlying NAC-mediated regulation of stomatal movement are unclear. In this study, a novel NAC gene from Reaumuria trigyna, RtNAC055, was found to enhance drought tolerance via a stomatal closure pathway. It was regulated by RtMYC2 and integrated with jasmonic acid signaling and was predominantly expressed in stomata and root. The suppression of RtNAC055 could improve jasmonic acid and H2O2 production and increase the drought tolerance of transgenic R. trigyna callus. Ectopic expression of RtNAC055 in the Arabidopsis atnac055 mutant rescued its drought-sensitive phenotype by decreasing stomatal aperture. Under drought stress, overexpression of RtNAC055 in poplar promoted ROS (H2O2) accumulation in stomata, which accelerated stomatal closure and maintained a high photosynthetic rate. Drought upregulated the expression of PtRbohD/F, PtP5CS2, and PtDREB1.1, as well as antioxidant enzyme activities in heterologous expression poplars. RtNAC055 promoted H2O2 production in guard cells by directly binding to the promoter of RtRbohE, thus regulating stomatal closure. The stress-related genes RtDREB1.1/P5CS1 were directly regulated by RtNAC055. These results indicate that RtNAC055 regulates stomatal closure by maintaining the balance between the antioxidant system and H2O2 level, reducing the transpiration rate and water loss, and improving photosynthetic efficiency and drought resistance.

Staphylococcus aureus induces drug resistance in cancer T cells in Sézary syndrome.

ABSTRACT: Patients with Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), are prone to Staphylococcus aureus infections and have a poor prognosis due to treatment resistance. Here, we report that S aureus and staphylococcal enterotoxins (SE) induce drug resistance in malignant T cells against therapeutics commonly used in CTCL. Supernatant from patient-derived, SE-producing S aureus and recombinant SE significantly inhibit cell death induced by histone deacetylase (HDAC) inhibitor romidepsin in primary malignant T cells from patients with SS. Bacterial killing by engineered, bacteriophage-derived, S aureus-specific endolysin (XZ.700) abrogates the effect of S aureus supernatant. Similarly, mutations in major histocompatibility complex (MHC) class II binding sites of SE type A (SEA) and anti-SEA antibody block induction of resistance. Importantly, SE also triggers resistance to other HDAC inhibitors (vorinostat and resminostat) and chemotherapeutic drugs (doxorubicin and etoposide). Multimodal single-cell sequencing indicates T-cell receptor (TCR), NF-κB, and JAK/STAT signaling pathways (previously associated with drug resistance) as putative mediators of SE-induced drug resistance. In support, inhibition of TCR-signaling and Protein kinase C (upstream of NF-κB) counteracts SE-induced rescue from drug-induced cell death. Inversely, SE cannot rescue from cell death induced by the proteasome/NF-κB inhibitor bortezomib. Inhibition of JAK/STAT only blocks rescue in patients whose malignant T-cell survival is dependent on SE-induced cytokines, suggesting 2 distinct ways SE can induce drug resistance. In conclusion, we show that S aureus enterotoxins induce drug resistance in primary malignant T cells. These findings suggest that S aureus enterotoxins cause clinical treatment resistance in patients with SS, and antibacterial measures may improve the outcome of cancer-directed therapy in patients harboring S aureus.

An NIR-II-photoresponsive CoSnO3 nanozyme for mild photothermally augmented nanocatalytic cancer therapy.

The main challenges of nanozyme-based tumor catalytic therapy (NCT) lie in the unsatisfactory catalytic activity accompanied by a complex tumor microenvironment (TME). A few nanozymes have been designed to possess both enzyme-like catalytic activities and photothermal properties; however, the previously reported nanozymes mainly utilize the inefficient and unsafe NIR-I laser, which has a low maximum permissible exposure limit and a limited penetration depth. Herein, we report for the first time an all-in-one strategy to realize mild NIR-II photothermally amplified NCT by synthesizing amorphous CoSnO3 nanocubes with efficient triple enzyme-like catalytic activities and photothermal conversion properties. The presence of Co2+ and Sn4+ endows CoSnO3 nanocubes with the triple enzyme-like catalytic activities, not only achieving enhanced reactive oxygen species (ROS) generation through the Co2+-mediated peroxidase-like catalytic reaction to generate ˙OH and Sn4+-mediated depletion of overexpressed GSH, but also realizing the catalytic decomposition of endogenous H2O2 for relieving tumor hypoxia. More importantly, the obtained CoSnO3 nanocubes with a high photothermal conversion efficiency of 82.1% at 1064 nm could achieve mild hyperthermia (43 °C), which further improves the triple enzyme-like catalytic activities of the CoSnO3 nanozyme. The synergetic therapeutic efficacy of the NIR-II-responsive CoSnO3 nanozyme through mild NIR-II PTT-enhanced NCT could realize all-in-one multimodal tumor therapy to completely eliminate tumors without recurrence. This study will open a new avenue to explore NIR-II-photoresponsive nanozymes for efficient tumor therapy.

A Two-Generation Reproductive Toxicity Study of Cerium Nitrate in Sprague-Dawley Rats.

A two-generation reproductive toxicity study was performed to evaluate the effects of cerium nitrate on the development of the parent, offspring, and third generation of Sprague-Dawley (SD) rats. A total of 240 SD rats (30 rats/sex/group) were randomly divided into four dosage groups according to body weight: 0 mg/kg, 30 mg/kg, 90 mg/kg, and 270 mg/kg. The rats were administered different dosages of cerium nitrate by oral gavage. There were no observed changes related to cerium nitrate in body weight, food consumption, sperm survival rate, motility, mating rate, conception rate, abortion rate, uterine plus fetal weight, uterine weight, corpus luteum number, implantation rate, live fetus number (rate), stillbirth number (rate), absorbed fetus number (rate), appearance, visceral, and skeletal in rats of each generation dosage group. In addition, the pathological findings showed no significant lesions associated with cerium nitrate toxicity in all tissues and organs, including reproductive organs. In conclusion, the present study showed that long-term oral gavage of cerium nitrate at 30 mg/kg, 90 mg/kg, and 270 mg/kg had no significant effect on reproduction and the developmental ability of their offspring in rats. The no-observed-adverse-effect level (NOAEL) of cerium nitrate in SD rats was higher than 270 mg/kg.

A Sonoresponsive and NIR-II-Photoresponsive Nanozyme for Heterojunction-Enhanced "Three-in-One" Multimodal Oncotherapy.

Although low-cost nanozymes with excellent stability have demonstrated the potential to be highly beneficial for nanocatalytic therapy (NCT), their unsatisfactory catalytic activity accompanied by intricate tumor microenvironment (TME) significantly hinders the therapeutic effect of NCT. Herein, for the first time, a heterojunction (HJ)-fabricated sonoresponsive and NIR-II-photoresponsive nanozyme is reported by assembling carbon dots (CDs) onto TiCN nanosheets. The narrow bandgap and mixed valences of Ti3+ and Ti4+ endow TiCN with the capability to generate reactive oxygen species (ROS) when exposed to ultrasound (US), as well as the dual enzyme-like activities of peroxidase and glutathione peroxidase. Moreover, the catalytic activities and sonodynamic properties of the TiCN nanosheets are boosted by the formation of HJs owing to the increased speed of carrier transfer and the enhanced electron-hole separation. More importantly, the introduction of CDs with excellent NIR-II photothermal properties could achieve mild hyperthermia (43 °C) and thereby further improve the NCT and sonodynamic therapy (SDT) performances of CD/TiCN. The synergetic therapeutic efficacy of CD/TiCN through mild hyperthermia-amplified NCT and SDT could realize "three-in-one" multimodal oncotherapy to completely eliminate tumors without recurrence. This study opens a new avenue for exploring sonoresponsive and NIR-II-photoresponsive nanozymes for efficient tumor therapy based on semiconductor HJs.

In Situ Synthesis of Ru/TiO2- x @TiCN Ternary Heterojunctions for Enhanced Sonodynamic and Nanocatalytic Cancer Therapy.

Albeit nanozymes-based tumor catalytic therapy (NCT) relies on endogenous chemical reactions that could achieve tumor microenvironment (TME)-specialized reactive oxygen species (ROS) production, the unsatisfactory catalytic activity of nanozymes accompanied by complex TME poses a barrier to the therapeutic effect of NCT. Herein, a one-step in situ synthesis strategy is reported to construct ternary Ru/TiO2- x @TiCN heterojunctions through oxidative conversion of TiCN nanosheets (NSs) to TiO2- x NSs and reductive deposition of Ru3+ to Ru nanoparticles. The narrow bandgap and existence of heterojunctions enhance the ultrasound-activated ROS generation of Ru/TiO2- x @TiCN because of the accelerated electron transfer and inhibits electron-hole pair recombination. The augmented ROS production efficiency is achieved by Ru/TiO2- x @TiCN with triple enzyme-like activities, which amplifies the ROS levels in a cascade manner through the catalytic decomposition of endogenous H2 O2 to relieve hypoxia and heterojunction-mediated NCT, as well as depletion of overexpressed glutathione. The satisfactory therapeutic effects of Ru/TiO2- x @TiCN heterojunctions are achieved through synergetic sonodynamic therapy and NCT, which achieve the complete elimination of tumors without recurrence. This strategy highlights the potential of in situ synthesis of semiconductor heterojunctions as enhanced sonosensitizers and nanozymes for efficient tumor therapy.

Exploring the differences between sole silages of gramineous forages and mixed silages with forage legumes using 16S/ITS full-length sequencing.

Background/Objective: Silage characteristics of grass materials directly affect their silage qualities. To expand the source of silage raw materials and develop mixed silages underlined by exploring the positive interactions between forage grasses and legumes, three gramineous grasses, Napier grass (Pennisetum purpureum), king grass (Pennisetum sinese), and forage maize (Zea mays) were separately mixed ensiled with a combination of four forage legumes including Medicago sativa, Vicia villosa, Vicia sativa, and Trifolium repens. Methods: The chemical composition and fermentation quality of the mixed silages were analyzed and compared with those of the sole silages of these three grasses, as well as the diversity of microbial communities, through the 16S/ITS full-length sequencing. Results: The results showed that the inclusion of forage legumes could somewhat improve the fermentation quality, as indicated by significantly (p < 0.05) higher crude protein and lactic acid contents while lower neutral detergent fiber, acid detergent fiber contents and pH values, compared with the sole silages. Among the three types of mixed silages, the mixed king grass had the highest dry matter and crude protein content as well as lowest neutral detergent fiber and acid detergent fiber content. Meanwhile, the bacterial and fungal communities in the mixed silages were influenced by increased the relative abundance of lactic acid bacteria, which inhibited the proliferation of undesirable bacteria, such as Hafnia alvei, Enterobacter cloacae, and Serratia proteamaculanss. Co-occurrence networks identified 32 nodes with 164 positive and 18 negative correlations in bacteria and 80 nodes with two negative and 76 positive correlations in fungi during fermentation. Conclusion: Inclusion of forage legume to grasses can improve the fermentation quality and optimize the structure of microbial community, which appears to be a feasible strategy to enhance the forage resource utilization.

Subchronic toxicity study of ferric oxide nanoparticles through intragastric administration: A 94-d, repeated dose study in Sprague Dawley rats.

In this study, the toxicity of ferric oxide nanoparticles (Fe2O3 NPs) administered through gavage to Sprague Dawley (SD) rats for 94 d, consecutively and the recovery after Fe2O3 NPs withdrawal for 30 d were evaluated. The vehicle control group, low-, medium-, and high-dose groups were administered with the vehicle (0.5% sodium carboxymethyl cellulose [CMC-Na]), 125, 250, and 500 mg/kg of Fe2O3 NPs, respectively, administered every morning for 94 d. There was no significant difference in the body weight, food intake, hematological, blood biochemical, and urine indices of SD rats in each administration group and the control group (P > 0.05). There was no significant difference in organ weight, organ indices, and the coefficient of the visceral brain between the SD rats in the different dosage groups and the SD rats in the vehicle control group (P > 0.05). Histopathological observations showed that there was no correlation between the pathological lesions of the organs observed in this study and the dose of Fe2O3 NPs (P > 0.05). The no-observed-adverse-effect level (NOAEL) dose of Fe2O3 NPs was initially determined to be 500 mg/kg administered to SD rats through oral gavage for 94 d, consecutively, followed by recovery after Fe2O3 NPs withdrawal for 30 d.

Celastrol alleviates oxidative stress induced by multi-walled carbon nanotubes through the Keap1/Nrf2/HO-1 signaling pathway.

Multi-walled carbon nanotubes (MWCNTs) mainly induce oxidative stress through the overproduction of reactive oxygen species (ROS), which can lead to cytotoxicity. Celastrol, a plant-derived compound, can exert antioxidant effects by reducing ROS production. Our results indicated that exposure to MWCNTs decreased cell viability and increased ROS production. Nrf2 knockdown (kd) led to increased ROS production and enhanced MWCNT-induced cytotoxicity. Keap1-kd led to decreased ROS production and attenuated cytotoxicity. Treatment with celastrol significantly decreased ROS production and promoted Keap1 protein degradation through the lysosomal pathway, thereby enhancing the translocation of Nrf2 from the cytoplasm to the nucleus and increasing HO-1 expression. The in vivo results showed that celastrol could alleviate the inflammatory damage of lung tissues, increase the levels of the antioxidants, GSH and SOD, as well as promote the expression of the antioxidant protein, HO-1 in MWCNT-treated mice. Celastrol can alleviate MWCNT-induced oxidative stress through the Keap1/Nrf2/HO-1 signaling pathway.

The reproductive toxicity of yttrium nitrate in a two-generation study in Sprague-Dawley rats.

OBJECTIVE: To evaluate the effects of yttrium nitrate on the development of the parent, offspring and third generation of Sprague-Dawley (SD) rats by using a two-generation reproductive toxicity test. METHODS: The SD rats were randomly divided into 0 mg/kg group, 10.0 mg/kg group, 30.0 mg/kg group and 90.0 mg/kg group according to the different doses of yttrium nitrate administration. The reproductive toxicity of parent, offspring and third generation SD rats were compared. RESULTS: The weight gains of F1a female rats and F2a female rats in the low-dose groups were significantly lower than those of the control groups (p < 0.05), the weight gains of F1a male rats in the medium-dose and high-dose groups were significantly lower than those of the control groups (p < 0.05), and the weight gains of F2a male rats in the low-dose, medium-dose and high-dose groups were significantly lower than those of the control groups (p < 0.05). In F0 male rats, the absolute weight and relative weight of the liver in the low-dose, middle-dose, and high-dose groups were significantly lower than those of the control group (p < 0.05). In F1b male rats, the absolute and relative weights of the liver in the medium-dose and high-dose groups were significantly lower than those of the control group (p < 0.05). In F2b male rats, the absolute and relative weights of the liver and spleen of the medium-dose and high-dose groups were significantly lower than those of the control group (p < 0.05). In F2a female rats, the absolute weight and relative weight of oviduct in the high-dose group were significantly lower than those in the control group (p < 0.05). The absolute and relative weights of lung, spleen, brain and uterus of F2b female rats in the high-dose group were higher than those of the control group (p < 0.05). But the pathological test results showed no hepatotoxicity. There was no statistically significant difference in sperm count and sperm motility between male rats in the yttrium nitrate administration groups and the control group (p > 0.05). There was no significant correlation between F0, F1a, F1b, F2a, F2b SD rats' reproductive organ lesions and the dose of yttrium nitrate. CONCLUSION: Yttrium nitrate at a dose of 90 mg/kg has no reproductive toxicity to two generations of SD rats, but 30.0 mg/kg dose of yttrium nitrate is toxic to the liver weight of male two generations of SD rats, but no hepatotoxicity.

Safety and Feasibility of Primary Closure Following Laparoscopic Common Bile Duct Exploration for Treatment of Choledocholithiasis.

BACKGROUND: T-tube drainage following laparoscopic common bile duct (CBD) exploration may lead to T-tube displacement and water-electrolyte disorders, affecting patients' quality of life. In particular, biliary peritonitis may develop in a small number of patients after T-tube removal, requiring reoperation. This prospective cohort study was performed to investigate the safety and feasibility of primary closure following laparoscopic CBD exploration for the treatment of choledocholithiasis. METHODS: Patients who were treated for choledocholithiasis by laparoscopic CBD exploration with primary closure from January 2019 to March 2022 comprised the PC group (n = 145). Patients who were treated for choledocholithiasis by laparoscopic CBD exploration with T-tube drainage during this period comprised the TD group (n = 153). Perioperative and follow-up outcomes were collected and statistically analyzed. RESULTS: The TD and PC groups showed significant differences in the operation time (124.6 ± 40.8 vs. 106 ± 36.4 min, P = 0.000) and postoperative hospital stay (7.1 ± 2.6 vs. 5.9 ± 2.0 days, P = 0.000). No significant difference was observed in terms of blood loss, the ratio of conversion to laparotomy, and postoperative parameters. Preoperative albumin and total bilirubin levels were the risk factors of bile leakage after surgery. No patients developed CBD stricture or carcinogenesis, The rates of residual and recurrent stones in the TD and PC groups were 1.97% vs. 1.40% and 1.31% vs. 1.40%, respectively, with no significant difference (P = 1.000 for both). CONCLUSIONS: Primary closure following laparoscopic CBD exploration is safe and feasible for selected patients with choledocholithiasis.

Carbon Dot@MXene Nanozymes with Triple Enzyme-Mimic Activities for Mild NIR-II Photothermal-Amplified Nanocatalytic Therapy.

Nanozymes have shown promising potential in disease treatment owing to the advantages of low-cost, facile fabrication, and high stability. However, the highly complex tumor microenvironment (TME) and inherent low catalytic activity severely restrict the clinical applications of nanozymes. Herein, a novel mild hyperthermia-enhanced nanocatalytic therapy platform based on Z-scheme heterojunction nanozymes by depositing N-doped carbon dots (CDs) onto Nb2 C nanosheets is constructed. CD@Nb2 C nanozymes not only display outstanding photothermal effects in the safe and efficient NIR-II window but also possess triple enzyme-mimic activities to obtain amplified ROS levels. The triple enzyme-mimic activities and NIR-II photothermal properties of CD nanozymes are enhanced by the construction of Z-scheme heterojunctions owing to the accelerated carrier transfer process. More importantly, the introduction of mild hyperthermia can further improve the peroxidase-mimic and catalase-mimic activities as well as the glGSH depletion abilities of CD@Nb2 C nanozymes, thereby producing more ROS to efficiently inhibit tumor growth. The combined therapy effect of CD@Nb2 C nanozymes through mild NIR-II photothermal-enhanced nanocatalytic therapy can achieve complete tumor eradication. This work highlights the efficient tumor therapy potential of heterojunction nanozymes.

Evaluation of subchronic toxicity of the compound of diphenhydramine hydrochloride and caffeine after 28 days of repeated oral administration in Sprague-Dawley rats and beagle dogs.

This study was designed to evaluate the subchronic toxicity of the compound of diphenhydramine hydrochloride (DH) and caffeine in Sprague-Dawley (SD) rats and beagle dogs. A total of 180 SD rats (15/sex/group) were randomly divided into the compound low-, medium- and high-dose groups (51, 102, 204 mg/kg), DH group (60 mg/kg), caffeine group (144 mg/kg) and the vehicle control group. Sixty beagle dogs (5/sex/group) were randomly divided into the compound low-, medium- and high-dose groups (male: 14.20, 28.30, 56.60 mg/kg, female: 5.66, 14.20, 28.30 mg/kg), DH group (male: 16.60 mg/kg, female: 8.30 mg/kg), caffeine group (male: 40.00 mg/kg, female: 20.00 mg/kg) and the vehicle control group. Rats and dogs were given continuous oral administration for 28 days following a 28-day recovery period. The adverse effects of the compound on rats and beagle dogs mainly included anorexia and liver function impairment. Most adverse effects induced by administration were reversible. Under the experimental conditions, the no-observed-adverse-effect level (NOAEL) of the compound of DH and caffeine was 51 mg/kg/day for SD rats and 28.30 mg/kg/day (male) and 5.66 mg/kg/day (female) for beagle dogs.

Vascular toxicity of multi-walled carbon nanotubes targeting vascular endothelial growth factor.

Multiwalled carbon nanotubes (MWCNTs) are currently widely used and are expected to be used as drug carriers and contrast agents in clinical practice. Previous studies mainly focused on their lung toxicity; therefore, their effects on the vascular endothelium are unclear. In this study, a human angiogenesis array was used to determine the effect of MWCNTs on the expression profile of angiogenic factors in endothelial cells and to clarify the role of vascular endothelial growth factor (VEGF) in MWCNT-induced endothelial cell injury at the cellular and animal levels. The results indicated that MWCNTs (20-30 nm and 30-50 nm) could enter endothelial cells and disrupt human umbilical vein endothelial cell (HUVECs) activity in a concentration-dependent manner. MWCNTs disrupted the tube formation ability and cell migration function of HUVECs. The results from a Matrigel Plug experiment in mice showed that angiogenesis in the MWCNT experimental group was significantly reduced. The results of a protein chip analysis indicated that VEGF expression in the MWCNT treatment group was decreased, a finding that was validated by ELISA results. The protein expression levels of AKT and eNOS in the MWCNT treatment group were significantly decreased; the administration of recombinant VEGF significantly alleviated the migration ability and tube formation ability of endothelial cells injured by MWCNTs, upregulated the protein expression of AKT and eNOS, and increased the number of neovascularization in mice in the MWCNT treatment group. This study demonstrated that MWCNTs affect angiogenesis via the VEGF-Akt-eNOS axis which can be rescued by VEGF endothelial treatment.

Integrative Analysis of Genes Involved in the Global Response to Potato Wart Formation.

Synchytrium endobioticum, the causal agent of potato wart disease, poses a major threat to commercial potato production. Understanding the roles of transcriptionally regulated genes following pathogen infection is necessary for understanding the system-level host response to pathogen. Although some understanding of defense mechanisms against S. endobioticum infection has been gained for incompatible interactions, the genes and signaling pathways involved in the compatible interaction remain unclear. Based on the collection of wart diseased tubers of a susceptible cultivar, we performed phenotypic and dual RNA-Seq analyses of wart lesions in seven stages of disease progression. We totally detected 5,052 differentially expressed genes (DEGs) by comparing the different stages of infection to uninfected controls. The tendency toward differential gene expression was active rather than suppressed under attack by the pathogen. The number of DEGs step-up along with the development of the disease and the first, third and seventh of the disease stages showed substantially increase of DEGs in comparison of the previous stage. The important functional groups identified via Gene ontology (GO) and KEGG enrichment were those responsible for plant-pathogen interaction, fatty acid elongation and phenylpropanoid biosynthesis. Gene coexpression networks, composed of 17 distinct gene modules that contained between 25 and 813 genes, revealed high interconnectivity of the induced response and led to the identification of a number of hub genes enriched at different stages of infection. These results provide a comprehensive perspective on the global response of potato to S. endobioticum infection and identify a potential transcriptional regulatory network underlying this susceptible response, which contribute to a better understanding of the potato-S. endobioticum pathosystem.