3D Nanoprinting of Heterogeneous Metal Oxides with High Shape Fidelity.

3D nanoprinting can significantly enhance the performance of sensors, batteries, optoelectronic/microelectronic devices, etc. However, current 3D nanoprinting methods for metal oxides are suffering from three key issues including limited material applicability, serious shape distortion, and the difficulty of heterogeneous integration. This paper discovers a mechanism in which imidazole and acrylic acid synergistically coordinate with metal ions in water. Using the mechanism, this work develops a series of metal ion synergistic coordination water-soluble (MISCWS) resins for 3D nanoprinting of various metal oxides, including MnO2, Cr2O3, Co3O4, and ZnO, as well as heterogeneous structures of MnO2/NiO, Cr2O3/Al2O3, and ZnO/MgO. Besides, the synergistic coordination effect results in a 2.54-fold increase in inorganic mass fraction within the polymer, compared with previous works, which effectively mitigates the shape distortion of metal oxide microstructures. Based on this method, this work also demonstrates a 3D ZnO microsensor with a high sensitivity (1.113 million at 200 ppm NO2), surpassing the conventional 2D ZnO sensors by tenfold. The method yields high-fidelity 3D structures of heterogeneous metal oxides with nanoscale resolution, paving the way for applications such as sensing, micro-optics, energy storage, and microsystems.

3D Directional Assembly of Liquid Crystal Molecules.

The precise construction of hierarchically long-range ordered structures using molecules as fundamental building blocks can fully harness their anisotropy and potential. However, the 3D, high-precision, and single-step directional assembly of molecules is a long-pending challenge. Here, a 3D directional molecular assembly strategy via femtosecond laser direct writing (FsLDW) is proposed and the feasibility of this approach using liquid crystal (LC) molecules as an illustrative example is demonstrated. The physical mechanism for femtosecond (fs) laser-induced assembly of LC molecules is investigated, and precise 3D arbitrary assembly of LC molecules is achieved by defining the discretized laser scanning pathway. Additionally, an LC-based Fresnel zone plate array with polarization selection and colorization imaging functions is fabricated to further illustrate the potential of this method. This study not only introduces a 3D high-resolution alignment method for LC-based functional devices but also establishes a universal protocol for the precise 3D directional assembly of anisotropic molecules.

Loureirin A Promotes Cell Differentiation and Suppresses Migration and Invasion of Melanoma Cells via WNT and AKT/mTOR Signaling Pathways.

Resina Draconis is a traditional Chinese medicine, with the in-depth research, its medicinal value in anti-tumor has been revealed. Loureirin A is extracted from Resina Draconis, however, research on the anti-tumor efficacy of Loureirin A is rare. Herein, we investigated the function of Loureirin A in melanoma. Our research demonstrated that Loureirin A inhibited the proliferation of and caused G0/G1 cell cycle arrest in melanoma cells in a concentration-dependent manner. Further study showed that the melanin content and tyrosinase activity was enhanced after Loureirin A treatment, demonstrated that Loureirin A promoted melanoma cell differentiation, which was accompanied with the reduce of WNT signaling pathway. Meanwhile, we found that Loureirin A suppressed the migration and invasion of melanoma cells through the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. Taken together, this study demonstrated for the first time the anti-tumor effects of Loureirin A in melanoma cells, which provided a novel therapeutic strategy against melanoma.

DNAJC10 maintains survival and self-renewal of leukemia stem cells through PERK branch of the unfolded protein response.

Leukemia stem cells (LSC) require frequent adaptation to maintain their self-renewal ability in the face of longer exposure to cell-intrinsic and cell-extrinsic stresses. However, the mechanisms by which LSC maintain their leukemogenic activities, and how individual LSC respond to stress, remain poorly understood. Here, we found that DNAJC10, a member of HSP40 family, was frequently up-regulated in various types of acute myeloid leukemia (AML) and in LSC-enriched cells. Deficiency of DNAJC10 leads to a dramatic increase in the apoptosis of both human leukemia cell lines and LSC-enriched populations. Although DNAJC10 is not required for normal hematopoiesis, deficiency of Dnajc10 significantly abrogated AML development and suppressed self-renewal of LSC in the MLL-AF9-induced murine leukemia model. Mechanistically, inhibition of DNAJC10 specifically induces endoplasmic reticulum stress and promotes activation of PERK-EIF2α-ATF4 branch of unfolded protein response (UPR). Blocking PERK by GSK2606414 (PERKi) or shRNA rescued the loss of function of DNAJC10 both in vitro and in vivo. Importantly, deficiency of DNAJC10 increased sensitivity of AML cells to daunorubicin (DNR) and cytarabine (Ara-C). These data revealed that DNAJC10 functions as an oncogene in MLL-AF9-induced AML via regulation of the PERK branch of the UPR. DNAJC10 may be an ideal therapeutic target for eliminating LSC, and improving the effectiveness of DNR and Ara-C.

Progress of research into the pharmacological effect and clinical application of the traditional Chinese medicine Rehmanniae Radix.

The traditional Chinese medicine (TCM) Rehmanniae Radix (RR) refers to the fresh or dried root tuber of the plant Rehmannia glutinosa Libosch of the family Scrophulariaceae. As a traditional Chinese herbal medicine (CHM), it possesses multiple effects, including analgesia, sedation, anti-inflammation, antioxidation, anti-tumor, immunomodulation, cardiovascular and cerebrovascular regulation, and nerve damage repair, and it has been widely used in clinical practice. In recent years, scientists have extensively studied the active components and pharmacological effects of RR. Active ingredients mainly include iridoid glycosides (such as catalpol and aucuboside), phenylpropanoid glycosides (such as acteoside), other saccharides, and unsaturated fatty acids. In addition, the Chinese patent medicine (CPM) and Chinese decoction related to RR have also become major research subjects for TCM practitioners; one example is the Bolus of Six Drugs, which includes Rehmannia, Lily Bulb and Rehmannia Decoction, and Siwu Decoction. This article reviews recent literature on RR; summarizes the studies on its chemical constituents, pharmacological effects, and clinical applications; and analyzes the progress and limitations of current investigations to provide reference for further exploration and development of RR.

SERPINB1 promotes Senecavirus A replication by degrading IKBKE and regulating the IFN pathway via autophagy.

IMPORTANCE: Senecavirus A (SVA) is an emerging picornavirus associated with vesicular disease, which wide spreads around the world. It has evolved multiple strategies to evade host immune surveillance. The mechanism and pathogenesis of the virus infection remain unclear. In this study, we show that SERPINB1, a member of the SERPINB family, promotes SVA replication, and regulates both innate immunity and the autophagy pathway. SERPINB1 catalyzes K48-linked polyubiquitination of IκB kinase epsilon (IKBKE) and degrades IKBKE through the proteasome pathway. Inhibition of IKBKE expression by SERPINB1 induces autophagy to decrease type I interferon signaling, and ultimately promotes SVA proliferation. These results provide importantly the theoretical basis of SVA replication and pathogenesis. SERPINB1 could be a potential therapeutic target for the control of viral infection.

Targeting HSP90 with picropodophyllin suppresses gastric cancer tumorigenesis by disrupting the association of HSP90 and AKT.

Gastric cancer (GC) is one of the most common malignant tumors worldwide. Thus, the development of safe and effective therapeutic compounds for GC treatment is urgently required. Here, we aimed to examine the role of picropodophyllin (PPP), a compound extracted from the rhizome of Dysosma versipellis (Hance) M. Cheng ex Ying, on the proliferation of GC cells. Our study revealed that PPP inhibits the proliferation of GC cells in a dose-dependent manner by inducing apoptosis. Moreover, our study elucidated that PPP suppresses the growth of GC tumor xenografts with no side effects of observable toxicity. Mechanistically, PPP exerts its effects by blocking the AKT/mammalian target of rapamycin (mTOR) signaling pathway; these effects are markedly abrogated by the overexpression of constitutively active AKT. Furthermore, drug affinity responsive target stability (DARTS) and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) revealed that heat shock protein 90 (HSP90) may be a potential target of PPP. Surface plasmon resonance and immunoprecipitation assay validated that PPP directly targets HSP90 and disrupts the binding of HSP90 to AKT, thereby suppressing GC cell proliferation. Thus, our study revealed that PPP may be a promising therapeutic compound for GC treatment.

Complex roles of Hippo-YAP/TAZ signaling in hepatocellular carcinoma.

BACKGROUND: The Hippo signaling pathway is an evolutionarily conserved signaling module that controls organ size in different species, and the disorder of the Hippo pathway can induce liver cancer in organisms, especially hepatocellular carcinoma (HCC). The exact mechanism that causes cancer is still unknown. Recent studies have shown that it is a classical kinase cascade that phosphorylates the Mst1/2-sav1 complex and activates the phosphorylation of the Lats1/2-mob1A/B complex for inactivating Yap and Taz. These kinases and scaffolds are regarded as primary regulators of the Hippo pathway, and help in activating a variety of carcinogenic processes. Among them, Yap/Taz is seen to be the main effector molecule, which is downstream of the Hippo pathway, and its abnormal activation is related to a variety of human cancers including liver cancer. Currently, since Yap/Taz plays a variety of roles in cancer promotion and tumor regeneration, the Hippo pathway has emerged as an attractive target in recent drug development research. METHODS: We collect and review relevant literature in web of Science and Pubmed. CONCLUSION: This review highlights the important roles of Yap/Taz in activating Hippo pathway in liver cancer. The recent findings on the crosstalks between the Hippo and other cancer associated pathways and moleculars are also discussed. In this review, we summarized and discussed recent breakthroughs in our understanding of how key components of the Hippo-YAP/TAZ pathway influence the hepatocellular carcinoma, including their effects on tumor occurrence and development, their roles in regulating metastasis, and their function in chemotherapy resistance. Further, the molecular mechanism and roles in regulating cross talk between Hippo-YAP/TAZ pathway and other cancer-associated pathways or oncogenes/cancer suppressor genes were summarized and discussed. More, many other inducers and inhibitors of this signaling cascade and available experimental therapies against the YAP/TAZ/TEAD axis were discussed. Targeting this pathway for cancer therapy may have great significance in the treatment of hepatocellular carcinoma. Graphical summary of the complex role of Hippo-YAP/TAZ signaling in hepatocellular carcinoma.

Ambient temperature exposure causes lung function impairment: The evidence from Controlled Temperature Study in Healthy Subjects (CTSHS).

BACKGROUND: The effect of non-optimal ambient temperatures (low and high temperatures) on lung function and the underlying mechanisms remains unclear. METHODS: Forty-three (20 males, 23 females) healthy non-obese volunteers with an average of 23.9 years participated in the controlled temperature study. All volunteers underwent three temperature exposures in a sequence (moderate [18 °C], low [6 °C], and high [30 °C] temperatures) lasting 12 h with air pollutants controlled. lung function parameters (forced vital capacity [FVC], forced expiratory volume in 1 s [FEV1], and peak expiratory flow [PEF]) were determined in each exposure. Blood and urine samples were collected after each exposure and assayed for inflammatory markers [C-reactive protein (CRP), procalcitonin (PCT), platelet-lymphocyte ratio (PLR), and neutrophil-lymphocyte ratio (NLR)] and oxidative damage markers [protein carbonylation (PCO), 4-hydroxy-2-nominal-mercapturic acid (HNE-MA), 8-iso-prostaglandin-F2α (8-isoPGF2α), and 8-hydroxy-2-deoxyguanosine (8-OHdG)]. Mixed-effects models were constructed to assess the changes of the above indexes under low or high temperatures relative to moderate temperature, and then the repeated measures correlation analyses were performed. RESULTS: Compared with moderate temperature, a 2.20% and 2.59% net decrease in FVC, FEV1, and a 5.68% net increase for PEF were observed under low-temperature exposure, while a 1.59% net decrease in FVC and a 7.29% net increase in PEF under high-temperature exposure were found (all P < 0.05). In addition, low temperature elevated inflammatory markers (PCT, PLR, and NLR) and oxidative damage markers (8-isoPGF2α, 8-OHdG), and high temperature elevated HNE-MA. Repeated measures correlation analyses revealed that PCT (r = -0.33) and NLR (r = -0.31) were negatively correlated with FVC and HNE-MA (r = -0.35) and 8-OHdG (r = -0.31) were negatively correlated with the FEV1 under low-temperature exposure (all P < 0.05). CONCLUSION: Non-optimal ambient temperatures exposure alters lung function, inflammation, and oxidative damage. Inflammation and oxidative damage might be involved in low temperature-related lung function reduction.

The abrogation of GRP78 sensitizes liver cancer cells to lysionotin by enhancing ER stress-mediated pro-apoptotic pathway.

Glucose-regulated protein 78 (GRP78) is frequently and highly expressed in various human malignancies and protects cancer cells against apoptosis induced by multifarious stresses, particularly endoplasmic reticulum stress (ER stress). The inhibition of GRP78 expression or activity could enhance apoptosis induced by anti-tumor drugs or compounds. Herein, we will evaluate the efficacy of lysionotin in the treatment of human liver cancer as well as the molecular mechanism. Moreover, we will examine whether inhibition of GRP78 enhanced the sensitivity of hepatocellular carcinoma cells to lysionotin. We found that lysionotin significantly suppressed proliferation and induced apoptosis of liver cancer cells. TEM showed that lysionotin-treated liver cancer cells showed an extensively distended and dilated endoplasmic reticulum lumen. Meanwhile, the levels of the ER stress hallmark GRP78 and UPR hallmarks (e.g., IRE1α and CHOP) were significantly increased in response to lysionotin treatment in liver cancer cells. Moreover, the reactive oxygen species (ROS) scavenger NAC and caspase-3 inhibitor Ac-DEVD-CHO visibly attenuated the induction of GRP78 and attenuated the decrease in cell viability induced by lysionotin. More importantly, the knockdown of GRP78 expression by siRNAs or treatment with EGCG, both induced remarkable increase in lysionotin-induced PARP and pro-caspase-3 cleavage and JNK phosphorylation. In addition, knockdown of GRP78 expression by siRNA or suppression GRP78 activity by EGCG both significantly improved the effectiveness of lysionotin. These data indicated that pro-survival GRP78 induction may contribute to lysionotin resistance. The combination of EGCG and lysionotin is suggested to represent a novel approach in cancer chemo-prevention and therapeutics.

Activating the Hippo pathway by nevadensin overcomes Yap-drived resistance to sorafenib in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly malignant type of tumor that is insensitive to cytotoxic chemotherapy and often develops drug resistance. Nevadensin, a bioflavonoid, exhibits anti-cancer properties in some cancers. However, the precise underlying mechanism of nevadensin against liver cancer are poorly understood. We aim to evaluate the efficacy as well as the molecular mechanism of nevadensin in the treatment of liver cancer. METHODS: Effects of nevadensin on HCC cell proliferation and apoptosis were detected using EdU labeling and flow cytometry assays. The molecular mechanism of nevadensin on HCC was determined using RNAseq. The effects of nevadensin on hippo-Yap signaling were verified using western blot and RT-PCR. RESULTS: In this study, we show that nevadensin significantly inhibits growth of HCC cells via inducing cell cycle arrest and apoptosis. RNAseq analysis showed that nevadensin regulates multiple functional signaling pathways associated with cancer including Hippo signaling. Western Blot analysis revealed that nevadensin notably induces activation of the MST1/2- LATS1/2 kinase in HCC cells, further resulting in the primary effector molecule YAP phosphorylation and subsequent degradation. These results indicated that nevadensin might exert its anti-HCC activity through the Hippo-ON mechanism. Moreover, nevadensin could increase the sensitivity of HCC cells to sorafenib by down-regulating YAP and its downstream targets. CONCLUSIONS: The present study indicates that nevadensin could be a potential effective approach to treating HCC, and overcoming sorafeni resistance via inducing activation of Hippo signaling.

Kaempferol inhibits non-homologous end joining repair via regulating Ku80 stability in glioma cancer.

BACKGROUND: Targeting DNA damage response and DNA repair proficiency of cancers is an important anticancer strategy. Kaempferol (Kae), a natural flavonoid, displays potent antitumor properties in some cancers. However, the precise underlying mechanism of Kae regulates DNA repair system are poorly understood. PURPOSE: We aim to evaluate the efficacy of Kae in the treatment of human glioma as well as the molecular mechanism regarding DNA repair. STUDY DESIGN: Effects of Kae on glioma cells were detected using CCK-8 and EdU labeling assays. The molecular mechanism of Kae on glioma was determined using RNAseq. The inhibition effects of Kae on DNA repair were verified using Immunoprecipitation, immunofluorescence, and pimEJ5-GFP report assays. For in vivo study, orthotopic xenograft models were established and treated with Kae or vehicle. Glioma development was monitored by bioluminescence imaging, Magnetic Resonance Imaging (MRI), and brain sections Hematoxylin/Eosin (HE) staining. Immunohistochemical (IHC) analysis was used to detect expression of Ku80, Ki67 and γH2AX in engrafted glioma tissue. RESULTS: We found that Kae remarkably inhibits viability of glioma cells and decreases its proliferation. Mechanistically, Kae regulates multiple functional pathways associated with cancer, including non-homologous end joining (NHEJ) repair. Further studies revealed that Kae inhibits release of Ku80 from the double-strand breaks (DSBs) sites via reducing ubiquitylation and degradation of Ku80. Therefore, Kae significantly suppresses NHEJ repair and induces accumulation of DSBs in glioma cells. Moreover, Kae displays a dramatic inhibition effects on glioma growth in an orthotopic transplantation model. These data demonstrate that Kae can induce deubiquitination of Ku80, suppress NHEJ repair and inhibit glioma growth. CONCLUSION: Our findings indicate that inhibiting release of Ku80 from the DSBs by Kae may be a potential effective approach for glioma treatment.

Triazine herbicides exposure, natural immunoglobulin M antibodies, and fasting plasma glucose changes: Association and mediation analyses in general Chinese urban adults.

The effects of triazine herbicides on glucose metabolism remain unclear. In this study, we aimed to assess the associations between serum triazine herbicides and glycemia-related risk indicators in general adults, and to evaluate the mediating role of natural immunoglobulin M antibodies (IgM) in the above associations among uninfected participants. We measured the concentrations of atrazine, cyanazine, and IgM in serum, as well as fasting plasma glucose (FPG), and fasting plasma insulin in 4423 adult participants from the Wuhan-Zhuhai cohort baseline population, enrolled in 2011-2012. Generalized linear models were used to evaluate the associations of serum triazine herbicides with glycemia-related risk indicators, and mediation analyses were performed to evaluate the mediating role of serum IgM in the above associations. The median levels of serum atrazine and cyanazine were 0.0237 µg/L and 0.0786 µg/L, respectively. Our study found significant positive associations of serum atrazine, cyanazine, and Σtriazine with FPG levels, risk of impaired fasting glucose (IFG), abnormal glucose regulation (AGR), and type 2 diabetes (T2D). Additionally, serum cyanazine and Σtriazine were found to be significant positive associated with the homeostatic model assessment of insulin resistance (HOMA-IR) levels. Significant negative linear relationships were observed in associations of serum IgM with serum triazine herbicides, FPG, HOMA-IR levels, the prevalence of T2D, and AGR (P < 0.05). Furthermore, we observed a significant mediating role by IgM in the associations of serum triazine herbicides with FPG, HOMA-IR, and AGR, with the proportions ranging from 2.96% to 7.71%. To ensure the stability of our findings, we conducted sensitivity analyses in normoglycemic participants and found that the association of serum IgM with FPG and the mediating role by IgM remained stable. Our results suggest that triazine herbicides exposure is positively associated with abnormal glucose metabolism, and decreasing serum IgM may partly mediate these associations.

The Establishment and Application of Indirect 3AB-ELISA for the Detection of Antibodies against Senecavirus A.

Senecavirus A (SVA) is an emerging pathogen that negatively affects the pig industry in China. Affected animals present vesicular lesions which are indistinguishable from other vesicular diseases. To date, there is no commercial vaccine that can be used to control SVA infection in China. In this study, recombinant SVA 3AB, 2C, 3C, 3D, L and VP1 proteins are expressed by using a prokaryotic expression system. The kinetics of the presence and levels of SVA antibodies with SVA-inoculated pig serum show that 3AB has the best antigenicity. An indirect enzyme-linked immunosorbent assay (ELISA) is developed with the 3AB protein, exhibiting a sensitivity of 91.3% and no cross-reaction with serum antibodies against PRRSV, CSFV, PRV, PCV2 or O-type FMDV. Given the high sensitivity and specificity of this approach, a nine-year (2014-2022) retrospective and prospective serological study is conducted to determine the epidemiological profile and dynamics of SVA in East China. Although SVA seropositivity declined markedly from 2016 (98.85%) to 2022 (62.40%), SVA transmission continues in China. Consequently, the SVA 3AB-based indirect ELISA has good sensitivity and specificity and is suitable for viral detection, field surveillance and epidemiological studies.

TRIM7 inhibits encephalomyocarditis virus replication by activating interferon-ß signaling pathway.

Tripartite motif-containing protein 7 (TRIM7), the member of tripartite motif (TRIM) family, plays an important role in innate immune responses against viral infection. Among them, the function of TRIM7 in Encephalomyocarditis virus (EMCV) infection has not been reported. Here, we found that TRIM7 inhibited the replication of EMCV through the type I interferon (IFN) signaling pathway. Interestingly, TRIM7 was down-regulated after EMCV infection in HEK293T cells. Further, overexpression of TRIM7 suppressed the replication of EMCV in HEK293T cells and enhanced the activity of IFN-ß promoter. On the other hand, knockdown of the endogenous TRIM7 promoted EMCV infection and impaired the activity of IFN-ß promoter. TRIM7 could regulate retinoic acid-inducible gene I (RIG-I)/ melanoma differentiation-associated gene 5 (MDA5)/ mitochondrial antiviral-signaling protein (MAVS) mediated IFN-ß signaling pathway. Moreover, TRIM7 interacted with MAVS and they were co-located in HEK293T cells. We demonstrate that TRIM7 plays a positive role in IFN-ß signaling pathway during EMCV infection and suppresses EMCV replication. Taken together, the presented results suggest that TRIM7 has a pivotal function in anti-EMCV infection, thereby providing a potential target for further development of anti-EMCV inhibitors.

Gamabufotalin Induces Apoptosis and Cytoprotective Autophagy through the mTOR Signaling Pathway in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a malignant tumor with a high rate of recurrence and a poor prognosis. Here, we investigated the effect and the potential antitumor mechanism of Gamabufotalin (CS-6) against HCC. Our results show that CS-6 strikingly reduced cell viability, inhibited colony formation, and promoted apoptosis in Hep3B and Huh7 cells. In vivo, CS-6 inhibited HCC xenograft tumor growth with no toxicity to normal tissues. Mechanistically, we found that CS-6 could induce cytoprotective autophagy through the mTOR-ULK1 signaling pathway through downregulation of p62 and upregulation of LC3 II/LC3 I. Meanwhile, CS-6 activated caspase-3 and PARP mediated apoptosis, and the caspase inhibitor Z-VAD-FMK blocked the CS-6-induced cell death in HCC cells. Moreover, autophagy and apoptosis were found to have antagonistic effects in Hep3B and Huh7 cells. Both the autophagy inhibitor chloroquine (CQ) and the mTOR activator MHY1485 blocked autophagy and further enhanced CS-6-induced apoptosis. Taken together, we demonstrated for the first time that CS-6 promotes apoptosis and cytoprotective autophagy through the mTOR signaling pathway in HCC, which proposes a novel strategy for HCC therapy.

Distribution and risk assessment of antibiotics under water level fluctuation in the riparian zone of the Hanjiang River.

The riparian zone (RZ) is an important region connecting surface water and groundwater, and it has widely been acknowledged for its pollutant buffering capacity. However, the decontaminating effect of RZ on trace organic compounds such as antibiotics has received little attention. This study explored the distribution of 21 antibiotics and 4 sulfonamide metabolites in river water and groundwater in the lower reaches of the Hanjiang River. The diffusion and exchange of contaminants between the river and riverbanks under the influence of water conservancy projects (Xinglong Dam and the Yangtze-Hanjiang Water Diversion Project) were investigated. Macrolide antibiotics were prevalent in river water (62.5-100%) and groundwater samples (42.9-80.4%). Ofloxacin and chlortetracycline were detected with the highest concentrations in river water (12.2 ng L-1) and groundwater (9.3 ng L-1) respectively. Higher levels of antibiotics were observed in spring and winter than in other seasons. The river-groundwater interaction has a certain interception effect on antibiotics, especially near riverbanks. Redox sensitive element Fe2+ showed significantly positive correlations with some tetracycline and macrolide antibiotics (p < 0.05), and thus the migration mechanism between Fe2+ and antibiotics under the condition of redox change should be investigated further. Environmental risks posed by antibiotics were assessed for algae, daphnids, and fish in surface water and groundwater. Only clarithromycin and chlortetracycline presented a medium risk to algae (0.1 < RQ < 1), and the rest presented low risk (RQ < 0.1). Nevertheless, the risk range may be further extended by interactions between groundwater and surface water. Accurate understanding of antibiotic transport in RZ is critical for developing management strategies aimed at reducing the pollution load on the watershed.

EGFR-TKI Combined with Pemetrexed versus EGFR-TKI Monotherapy in Advanced EGFR-mutated NSCLC: A Prospective, Randomized, Exploratory Study.

PURPOSE: We aimed to evaluate whether the addition of pemetrexed is effective in improving progression-free survival (PFS) in epidermal growth factor receptor (EGFR)-mutated patients with or without concomitant alterations. Materials and Methods: This multicenter clinical trial was conducted in China from June 15, 2018, to May 31, 2019. A total of 92 non-small cell lung cancer (NSCLC) patients harboring EGFR-sensitive mutations were included and divided into concomitant and non-concomitant groups. Patients in each group were randomly treated with EGFR-tyrosine kinase inhibitor (TKI) monotherapy or EGFR-TKI combined with pemetrexed in a ratio of 1:1. PFS was recorded as the primary endpoint. RESULTS: The overall median PFS of this cohort was 10.1 months. There were no significant differences in PFS between patients with and without concomitant and between patients received TKI monotherapy and TKI combined with pemetrexed (p=0.210 and p=0.085, respectively). Stratification analysis indicated that patients received TKI monotherapy had a significantly longer PFS in non-concomitant group than that in concomitant group (p=0.002). In concomitant group, patients received TKI combined with pemetrexed had a significantly longer PFS than patients received TKI monotherapy (p=0.013). Molecular dynamic analysis showed rapidly emerging EGFR T790M in patients received TKI monotherapy. EGFR mutation abundance decreased in patients received TKI combined chemotherapy, which supports better efficacy for a TKI combined chemotherapy as compared to TKI monotherapy. A good correlation between therapeutic efficacy and a change in circulating tumor DNA (ctDNA) status was found in 66% of patients, supporting the guiding role of ctDNA minimal residual disease (MRD) in NSCLC treatment. CONCLUSION: EGFR-TKI monotherapy is applicable to EGFR-sensitive patients without concomitant alterations, while a TKI combined chemotherapy is applicable to EGFR-sensitive patients with concomitant alterations. CtDNA MRD may be a potential biomarker for predicting therapeutic efficacy.

The circHMGCS1-miR-205-5p-ErBB3 axis mediated the Sanggenon C-induced anti-proliferation effects on human prostate cancer.

Prostate cancer (PCa) is associated with a high incidence and metastasis rate globally, resulting in an unsatisfactory prognosis and a huge economic burden due to the current deficient of therapeutic strategies. As the most abundant component of Cortex Mori, Sanggenon C (SC) is well known to possess bioactivities in tumors, but its mechanism is poorly understood. Consequently, we attempted to investigate whether SC could modulate circular RNA(s) levels and hence anti-PCa development. We found that SC dramatically promoted cell apoptosis and induced G0/G1 phase arrest in PCa cell lines via the circHMGCS1-miR-205-5p-ErBB3 axis. In brief, circHMGCS1 is highly expressed in PCa and is positively correlated with the degree of malignancy. Over-expression of circHMGCS1 is not only associated with the proliferation of PCa cells but also blocks SC-induced pro-apoptotic effects. As a verified sponge of circHMGCS1, miR-205-5p is down-regulated in PCa tumors, which negatively regulates PCa cell proliferation by modulating ErBB3 expression. After miR-205-5p mimics or inhibitors were used to transfect PCa cells, the effects of circHMGCS1 OE and SC on PCa cells were completely diminished. Similar to miR-205-5p inhibitors, siErBB3 could oppose SC-triggered pro-apoptotic effects on PCa cells. All these results were confirmed in vivo. Together, SC exerts its anti-tumor effects on PCa by inhibiting circHMGCS1 expression and results in the latter losing the ability to sponge miR-205-5p. Subsequently, unfettered miR-205-5p could mostly down-regulate ErBB3 expression by binding to the 5'UTR of ErBB3 mRNA, which eventually resulted in PCa cell cycle arrest and pro-apoptosis.

Wenshen Yiqi Keli Mitigates the Proliferation and Migration of Cigarette Smoke Extract-Induced Human Airway Smooth Muscle Cells through miR-155/FoxO3a Axis.

Some domestic scholars revealed the effectiveness of Wenshen Yiqi Keli (WSYQKL) on chronic obstructive pulmonary disease (COPD). However, the exact mechanism of WSYQKL on COPD is fuzzy and needs further research. We adopted UPLC-Q/TOF-MS to analyze the chemical components of WSYQKL. In in vitro experiments, human airway smooth muscle cells (hASMCs) were intervened with 2.5% cigarette smoke extract (CSE), medicine serum of WSYQKL, miR-155 mimic, and FoxO3a silencing. Cell viability, proliferation, migration, and the expressions of miR-155, PCNA, Ki67, p21, p27, and FoxO3a were examined by cell counting kit-8, EdU staining, Transwell assay, scarification assay, qRT-PCR, immunol cytochemistry, and western blot, respectively. The association between miR-155 and FoxO3a was assessed by database and luciferase reporter gene analysis. We identified 47 kinds of chemical compositions of WSYQKL in ESI+ mode and 42 kinds of components of WSYQKL in ESI- mode. The medicine serum of WSYQKL strongly alleviated the proliferation and migration of hASMCs induced by CSE in a concentration-dependent manner. The medicine serum of WSYQKL enhanced the levels of p21, p27, and FoxO3a and weakened PCNA and Ki67 levels in hASMCs induced by CSE with the increase of concentration. MiR-155 mimic or FoxO3a silencing notably advanced CSE-treated HASMC viability, proliferation, migration, and the levels of PCNA and Ki67 and downregulated the levels of p21, p27, and FoxO3a in CSE-triggered hASMCs, which was reversed by WSYQKL-containing serum. Our results described that WSYQKL alleviated the proliferation and migration of hASMCs induced by CSE by modulating the miR-155/FoxO3a axis.