Cr(VI) removal from wastewater using nano zero-valent iron and chromium-reducing bacteria.

Significant global efforts are currently underway to alleviate the presence of toxic metals in water bodies, aiming to encourage a sustainable environment. Nevertheless, the scientific community has yet to methodically inspect the performance and mechanisms underlying the interaction between nanomaterials and microorganisms in this context. Therefore, this study seeks to address this knowledge gap by developing a novel system that integrates nano zero-valent iron (nZVI) with chromium-reducing bacteria (CrRB) to efficiently remove Cr(VI) from water sources. The combined use of RBC600 and CrRB resulted in a Cr(VI) removal rate of 77.73%, displaying a substantial improvement of 17.61% compared to the use of CrRB alone. The efficacy of Cr(VI) elimination was observed to be affected by several factors within the system, such as the pH value, the quantity of nZVI added, the degree of CrRB inoculation, and the initial concentration of Cr(VI) at the onset of the experiment. When the pH was adjusted to 5, the complete removal of 200 mg/L Cr(VI) was achieved within 36 h. Increasing the dosage of nZVI to above 2 g/L resulted in the complete elimination of Cr(VI) from the solution within 72 h. This can be attributed to the availability of more reaction sites for the reduction of Cr(VI), facilitated by the higher nZVI dose. Additionally, the increased dose of nZVI allowed for the dissolution of more reactive Fe(II) ions. The characterization analysis, high-throughput sequencing, and fluorescence quantitative PCR results have established that CrRB and its extracellular polymer effectively reduce and complex Cr(VI). This process facilitated the dissolution of the passivated layer on the surface of nZVI, thus significantly enhancing the efficiency of nZVI in responding to Cr(VI). Additionally, the presence of nZVI created a favorable living environment for CrRB, resulting in increased richness and diversity within the CrRB community. These findings provide valuable preliminary insights into the mechanism underlying Cr(VI) elimination by the synergistic interaction between nZVI and CrRB. Therefore, this study establishes a solid theoretical foundations for the application of nano-bio synergy in the remediation of Cr(VI).

AMIGO2 attenuates innate cisplatin sensitivity by suppression of GSDME-conferred pyroptosis in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer. Cisplatin is commonly used in the treatment of many malignant tumours including NSCLC. The innate drug sensitivity greatly affects the clinical efficacy of cisplatin-based chemotherapy. As a plasma membrane adhesion molecule, amphoterin-induced gene and ORF-2 (AMIGO2) initially identified as a neurite outgrowth factor has been recently found to play a crucial role in cancer occurrence and progression. However, it is still unclear whether AMIGO2 is involved in innate cisplatin sensitivity. In the present study, we provided the in vitro and in vivo evidences indicating that the alteration of AMIGO2 expression triggered changes of innate cisplatin sensitivity as well as cisplatin-induced pyroptosis in NSCLC. Further results revealed that AMIGO2 might inhibit cisplatin-induced activation of (caspase-8 and caspase-9)/caspase-3 via stimulating PDK1/Akt (T308) signalling axis, resulting in suppression of GSDME cleavage and the subsequent cell pyroptosis, thereby decreasing the sensitivity of NSCLC cells to cisplatin treatment. The results provided a new insight that AMIGO2 regulated the innate cisplatin sensitivity of NSCLC through GSDME-mediated pyroptosis.

Genome-wide CRISPR/Cas9 screening identifies a targetable MEST-PURA interaction in cancer metastasis.

BACKGROUND: Metastasis is one of the most lethal hallmarks of esophageal squamous cell carcinoma (ESCC), yet the mechanisms remain unclear due to a lack of reliable experimental models and systematic identification of key drivers. There is urgent need to develop useful therapies for this lethal disease. METHODS: A genome-wide CRISPR/Cas9 screening, in combination with gene profiling of highly invasive and metastatic ESCC sublines, as well as PDX models, was performed to identify key regulators of cancer metastasis. The Gain- and loss-of-function experiments were taken to examine gene function. Protein interactome, RNA-seq, and whole genome methylation sequencing were used to investigate gene regulation and molecular mechanisms. Clinical significance was analyzed in tumor tissue microarray and TCGA databases. Homology modeling, modified ELISA, surface plasmon resonance and functional assays were performed to identify lead compound which targets MEST to suppress cancer metastasis. FINDINGS: High MEST expression was associated with poor patient survival and promoted cancer invasion and metastasis in ESCC. Mechanistically, MEST activates SRCIN1/RASAL1-ERK-snail signaling by interacting with PURA. miR-449a was identified as a direct regulator of MEST, and hypermethylation of its promoter led to MEST upregulation, whereas systemically delivered miR-449a mimic could suppress tumor metastasis without overt toxicity. Furthermore, molecular docking and computational screening in a small-molecule library of 1,500,000 compounds and functional assays showed that G699-0288 targets the MEST-PURA interaction and significantly inhibits cancer metastasis. INTERPRETATION: We identified the MEST-PURA-SRCIN1/RASAL1-ERK-snail signaling cascade as an important mechanism underlying cancer metastasis. Blockade of MEST-PURA interaction has therapeutic potential in management of cancer metastasis. FUNDING: This work was supported by National Key Research and Development Program of China (2021YFC2501000, 2021YFC2501900, 2017YFA0505100); National Natural Science Foundation of China (31961160727, 82073196, 81973339, 81803551); NSFC/RGC Joint Research Scheme (N_HKU727/19); Natural Science Foundation of Guangdong Province (2021A1515011158, 2021A0505030035); Key Laboratory of Guangdong Higher Education Institutes of China (2021KSYS009).

Blockade of NMT1 enzymatic activity inhibits N-myristoylation of VILIP3 protein and suppresses liver cancer progression.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Identification of the underlying mechanism of HCC progression and exploration of new therapeutic drugs are urgently needed. Here, a compound library consisting of 419 FDA-approved drugs was taken to screen potential anticancer drugs. A series of functional assays showed that desloratadine, an antiallergic drug, can repress proliferation in HCC cell lines, cell-derived xenograft (CDX), patient-derived organoid (PDO) and patient-derived xenograft (PDX) models. N-myristoyl transferase 1 (NMT1) was identified as a target protein of desloratadine by drug affinity responsive target stability (DARTS) and surface plasmon resonance (SPR) assays. Upregulation of NMT1 expression enhanced but NMT1 knockdown suppressed tumor growth in vitro and in vivo. Metabolic labeling and mass spectrometry analyses revealed that Visinin-like protein 3 (VILIP3) was a new substrate of NMT1 in protein N-myristoylation modification, and high NMT1 or VILIP3 expression was associated with advanced stages and poor survival in HCC. Mechanistically, desloratadine binds to Asn-246 in NMT1 and inhibits its enzymatic activity, disrupting the NMT1-mediated myristoylation of the VILIP3 protein and subsequent NFκB/Bcl-2 signaling. Conclusively, this study demonstrates that desloratadine may be a novel anticancer drug and that NMT1-mediated myristoylation contributes to HCC progression and is a potential biomarker and therapeutic target in HCC.

Remediation of Cr(VI)-Contaminated Soil by Biochar-Supported Nanoscale Zero-Valent Iron and the Consequences for Indigenous Microbial Communities.

Biochar/nano-zero-valent iron (BC-nZVI) composites are currently of great interest as an efficient remediation material for contaminated soil, but their potential to remediate Cr-contaminated soils and effect on soil microecology is unclear. The purpose of this study was to investigate the effect of BC-nZVI composites on the removal of Cr(VI) from soil, and indigenous microbial diversity and community composition. The results showed that after 15 days of remediation with 10 g/kg of BC-nZVI, 86.55% of Cr(VI) was removed from the soil. The remediation of the Cr-contaminated soil with BC-nZVI resulted in a significant increase in OTUs and α-diversity index, and even a significant increase in the abundance and diversity of indigenous bacteria and unique bacterial species in the community by reducing the toxic concentration of Cr, changing soil properties, and providing habitat for survival. These results confirm that BC-nZVI is effective in removing Cr(VI) and stabilizing Cr in soil with no significant adverse effects on soil quality or soil microorganisms.

FXYD5 promotes sorafenib resistance through the Akt/mTOR signaling pathway in hepatocellular carcinoma.

Tumor chemoresistance is often a major cause for the failure of chemotherapy. The resistance of hepatocellular carcinoma (HCC) cells to sorafenib significantly limits its therapeutic effect in HCC patients. For the first time, we found that FXYD domain-containing ion transport regulator 5 (FXYD5) is highly expressed in sorafenib-resistant HCC cells. In addition, the protein expression level of FXYD5 was markedly higher in HCC tissues than in paracancerous tissues. Remarkably, downregulation of FXYD5 expression in Huh7/sora cells reversed their resistance to sorafenib. Moreover, overexpression of FXYD5 reduced the sensitivity of HCC cells to sorafenib, while the downregulation of its expression in HCC cells had the opposite effect. We also found abnormal activation of the Akt/mTOR signaling pathway in Huh7/sora cells. Furthermore, MK2206, an Akt inhibitor, was found to significantly increase the sensitivity of HCC cells to sorafenib. More importantly, the expression level of p-Akt was positively correlated with the expression of FXYD5 in HCC tissues. Therefore, mechanistically, FXYD5 enhances the resistance of HCC cells to sorafenib by activating the Akt/mTOR signaling pathway. In conclusion, this study showed that the activation of the FXYD5/Akt/mTOR signaling axis plays key role in the resistance of HCC cells to sorafenib, and FXYD5 may represent a new potential target for HCC therapy.

Lomerizine 2HCl inhibits cell proliferation and induces protective autophagy in colorectal cancer via the PI3K/Akt/mTOR signaling pathway.

Colorectal cancer (CRC) is one of the most common malignancies currently. Despite advances in drug development, the survival and response rates in CRC patients are still poor. In our previous study, a library comprised of 1056 bioactive compounds was used for screening of drugs that could suppress CRC. Lomerizine 2HCl, which is an approved prophylactic drug for migraines, was selected for our studies. The results of in vitro and in vivo assays suggested that lomerizine 2HCl suppresses cell growth and promotes apoptosis in CRC cells. Moreover, lomerizine 2HCl inhibits cell migration and invasion of CRC. RNA sequencing analysis and Western blotting confirmed that lomerizine 2HCl can inhibit cell growth, migration, and invasion through PI3K/AKT/mTOR signaling pathway and induces protective autophagy in CRC. Meanwhile, autophagy inhibition by 3-methyladenine (3-MA) increases lomerizine 2HCl-induced cell apoptosis. Taken together, these results imply that lomerizine 2HCl is a potential anticancer agent, and the combination of lomerizine 2HCl and autophagy inhibitors may serve as a novel strategy to increase the antitumor efficacy of agents in the treatment of CRC.

Efficient Removal of Hexavalent Chromium from an Aquatic System Using Nanoscale Zero-Valent Iron Supported by Ramie Biochar.

In this study, ramie biochar (RBC) was used to activate nano zero-valent iron (nZVI) to enhance hexavalent chromium (Cr(VI)) removal. The best results were obtained at a pyrolysis temperature of 600 °C, a biochar particle size of < 150 µm, and an iron to carbon ratio = 1:1. Under the optimal conditions, the removal of Cr(VI) by RBC600-nZVI (98.69%) was much greater than that of RBC600 (12.42%) and nZVI (58.26%). Scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and X-ray photoelectron spectroscopy (XPS) revealed that the reaction mechanism at the Fe and Cr interface was a multiple interaction mechanism with reduction dominated, adsorption, and co-precipitation simultaneously. The enhanced performance of RBC600-nZVI resulted from the effective dispersion of nZVI on the surface of RBC600, therefore increasing the adsorption activity sites. At the same time, RBC600 and nZVI exerted a synergistic influence on the composite structure, which jointly promoted the reduction reaction of Cr(VI) and removed more Cr(VI). This study shows that RBC-nZVI is a potentially valuable remediation material that not only provides a new idea for the utilization of ramie waste, but also effectively overcomes the limitations of nZVI, thus, achieving efficient and rapid remediation of Cr(VI).

Identification of cofilin-1 as a novel mediator for the metastatic potentials and chemoresistance of the prostate cancer cells.

Prostate cancer (PCa) is the most common malignancy among men. Tumor metastasis and chemoresistance contribute to the major cause of the mortality. In this study, we compared the protein profiles of two prostate cancer cell lines with different metastatic potentials, and identified cofilin-1 (CFL1) was one of the most differentially expressed proteins between two cell lines. Further results suggested that cofilin-1 promoted the remodeling of F-actin cytoskeleton, and enhanced the proliferation, migration and invasion of the prostate cancer cells via activation of P38 MAPK signaling pathway. In addition, cofilin-1 elevated the expression and drug efflux activity of multidrug resistance protein 1 (MDR1) by P38 MAPK signaling pathway, resulting in decrease of the adriamycin-induced apoptosis as well as the lytic cell death, and the subsequent resistance against adriamycin. Collectively, cofilin-1 might serve as a novel target candidate for both inhibiting the metastasis and reversing the chemoresistance of PCa.

Synthesis, X-Ray Crystal Structure of Oxidovanadium(V) Complex Derived from 4-Bromo-N’-(2-hydroxybenzylidene) benzohydrazide with Catalytic Epoxidation Property.

A new oxidovanadium(V) complex, [VOL(OCH3)(CH3OH)], where H2L = 4-bromo-N'-(2-hydroxybenzylidene)benzohydrazide, has been synthesized and fully characterized on the basis of CHN elemental analysis, FT-IR, UV-Vis, 1H and 13C NMR spectroscopy. Structures of the free hydrazone and the complex were further characterized by single crystal X-ray diffraction, which indicates that the V atom in the complex adopts octahedral coordination, and the hydrazone ligand behaves as a tridentate ligand. The catalytic epoxidation property of the complex was investigated.

N’-(2-Hydroxybenzylidene)-3-Methylbenzohydrazide and its Copper(II) Complex: Syntheses, Characterization, Crystal Structures and Biological Activity.

The hydrazone compound N'-(2-hydroxybenzylidene)-3-methylbenzohydrazide (H2L) was prepared. With H2L and copper acetate a new copper complex [Cu(HL)(NCS)]·CH3OH was synthesized. Both the hydrazone and the copper complex were characterized by physico-chemical methods and single crystal X-ray diffraction techniques. The complex is a thiocyanato-coordinated copper(II) species. The Cu atom in the complex is in square planar geometry. The complex is a promising urease inhibitor.

FGF9 inhibition by a novel binding peptide has efficacy in gastric and bladder cancer per se and reverses resistance to cisplatin.

Aberrant over-expressions of FGF9 in gastric cancer (GC) and its high-affinity receptor FGFR3c in bladder cancer (BC) provide possibilities for the treatment of GC and BC via targeting FGF9. In this study, we isolated a novel FGF9-binding peptide (P4) by screening a phage display random heptapeptide library. Sequence comparison showed that P4 shared high homology with the conserved motif in the immunoglobulin-like (Ig-like) domain II∼III (D2-D3) linker of the FGF9 high-affinity receptor (FGFR3c). The interaction between P4 and FGF9 was confirmed by the surface plasmon resonance (SPR) assay. Functional analysis indicated that P4 counteracted FGF9-induced aggressive phenotype, including cell proliferation, migration, and invasion in vitro, as well as suppressed tumor growth in vivovia down-regulation of the MAPKs and Akt cascades. More importantly, we found that FGF9 served as an underlying mechanism of the chemoresistance in GC and BC cells, and P4 could increase the sensitivity to the chemical agent via antagonizing the suppression effects of FGF9 on cell apoptosis. Taken together, our study identified a novel binding peptide for FGF9, which may serve as a potential therapeutic agent for malignant tumors featured by abnormally up-regulation of FGF9.

Loss of GCN5 leads to increased neuronal apoptosis by upregulating E2F1- and Egr-1-dependent BH3-only protein Bim.

Cellular acetylation homeostasis is a kinetic balance precisely controlled by histone acetyl-transferase (HAT) and histone deacetylase (HDAC) activities. The loss of the counterbalancing function of basal HAT activity alters the precious HAT:HDAC balance towards enhanced histone deacetylation, resulting in a loss of acetylation homeostasis, which is closely associated with neuronal apoptosis. However, the critical HAT member whose activity loss contributes to neuronal apoptosis remains to be identified. In this study, we found that inactivation of GCN5 by either pharmacological inhibitors, such as CPTH2 and MB-3, or by inactivation with siRNAs leads to a typical apoptosis in cultured cerebellar granule neurons. Mechanistically, the BH3-only protein Bim is transcriptionally upregulated by activated Egr-1 and E2F1 and mediates apoptosis following GCN5 inhibition. Furthermore, in the activity withdrawal- or glutamate-evoked neuronal apoptosis models, GCN5 loses its activity, in contrast to Bim induction. Adenovirus-mediated overexpression of GCN5 suppresses Bim induction and apoptosis. Interestingly, the loss of GCN5 activity and the induction of Egr-1, E2F1 and Bim are involved in the early brain injury (EBI) following subarachnoid haemorrhage (SAH) in rats. HDAC inhibition not only significantly rescues Bim expression and apoptosis induced by either potassium deprivation or GCN5 inactivation but also ameliorates these events and EBI in SAH rats. Taken together, our results highlight a new mechanism by which the loss of GCN5 activity promotes neuronal apoptosis through the transcriptional upregulation of Bim, which is probably a critical event in triggering neuronal death when cellular acetylation homeostasis is impaired.

Inhibition of autophagy promotes apoptosis and enhances anticancer efficacy of adriamycin via augmented ROS generation in prostate cancer cells.

The interplay between autophagy and apoptosis response to chemotherapy is still a subject of intense debate in recent years. More efforts have focused on the regulation effects of apoptosis on autophagy, whereas how autophagy affects apoptosis remains poorly understood. In this study performed on prostate cancer cells, we investigated the role of autophagy in adriamycin-induced apoptosis, as well as the mechanisms mediating the effects of autophagy on apoptosis response to adriamycin (ADM). The results show that ADM not only inhibited cell viability and enhanced apoptosis, but also promoted autophagy via PI3K/Akt(T308)/mTOR signal pathway. Inhibition of autophagy by either pharmacological inhibitor chloroquine (CQ) or RNA interference of Atg5 increased ADM-induced apoptosis and enhanced the chemosensitivity of prostate cancer cells. Moreover, blockade of autophagy augmented reactive oxygen species (ROS) generation induced by ADM. Scavenging of ROS by antioxidant N-acetyl-cysteine (NAC) reversed the strengthened effects of CQ on ADM-induced apoptosis and rescued the cells from apoptosis. The results identified ROS as a potential mediator directing the modulation effects of the protective autophagy on apoptosis response to ADM. Suppression of the protective autophagy might provide a promising strategy to increase the anticancer efficacy of agents in the treatment of prostate cancer.

Identification of galectin-1 as a novel mediator for chemoresistance in chronic myeloid leukemia cells.

Multidrug resistance protein-1 (MDR1) has been proven to be associated with the development of chemoresistance to imatinib (Glivec, STI571) which displays high efficacy in treatment of BCR-ABL-positive chronic myelogenous leukemia (CML). However, the possible mechanisms of MDR1 modulation in the process of the resistance development remain to be defined. Herein, galectin-1 was identified as a candidate modulator of MDR1 by proteomic analysis of a model system of leukemia cell lines with a gradual increase of MDR1 expression and drug resistance. Coincidently, alteration of galectin-1 expression triggers the change of MDR1 expression as well as the resistance to the cytotoxic drugs, suggesting that augment of MDR1 expression engages in galectin-1-mediated chemoresistance. Moreover, we provided the first data showing that NF-κB translocation induced by P38 MAPK activation was responsible for the modulation effect of galectin-1 on MDR1 in the chronic myelogenous leukemia cells. Galectin-1 might be considered as a novel target for combined modality therapy for enhancing the efficacy of CML treatment with imatinib.

Selection of a novel FGF23-binding peptide antagonizing the inhibitory effect of FGF23 on phosphate uptake.

Fibroblast growth factor 23 (FGF23) is a bone-derived endocrine regulator of phosphate homeostasis and has been considered as a potential therapeutic target for hypophosphatemic disorders. Herein, we isolated a novel FGF23-binding peptide by screening a phage display library with FGF23180-205, the minimal epitope of FGF23 binding to the binary fibroblast growth factor receptor (FGFR)-Klotho complex. The corresponding peptide (referred to as 23-b6) showed high homology to the immunoglobulin-like (Ig-like) domain III (D3) of FGFR1c, the predominant receptor mediating the phosphaturic activity of FGF23. The 23-b6 peptide and panning target FGF23180-205 carried opposite charges and shared similar hydrophilic profiles. Functional analysis indicated that synthetic 23-b6 peptide exhibited antagonistic effect on the inhibition of phosphate uptake by FGF23 in opossum kidney cells (OK cells). The mechanisms of 23-b6 peptide impairing the bioactivity of FGF23 involved blockade of the activation of Erk cascade and up-regulation of NaPi-2a and NaPi-2c expression in OK cells. Our results demonstrate that the 23-b6 peptide is a potent FGF23 antagonist with increased effect on phosphate uptake in kidney cells and might have therapeutic potentials in hypophosphatemic disorders characterized by an abnormally high level of FGF23.

P7 peptides targeting bFGF sensitize colorectal cancer cells to CPT-11.

The low survival rate of patients with colorectal cancer (CRC) is mainly due to the drug resistance of tumor cells to chemotherapeutic agents. It has been reported that basic fibroblast growth factor (bFGF) is an essential factor involved in the epigenetic mechanisms of drug resistance, which provides a novel potential target for improving the sensitivity of tumor cells to chemotherapeutic agents. In this study, we first demonstrate that a novel bFGF antagonist, peptide P7, previously isolated by phage display technology, reversed bFGF-induced resistance to irinotecan hydrochloride (CPT-11), and counteracted the anti-apoptotic effects of bFGF on CPT-11-treated HT-29 cells. Further experiments indicated that the inhibition of Akt activation, the suppression of bFGF internalization, the increase in the Bax to Bcl-2 ratio and the downregulation of cytokeratin 8 (CK8) by P7 may contribute to the counteracting of the anti-apoptotic effects of bFGF, and further reversal of bFGF-induced resistance to CPT-11. Our results suggest that peptide P7 may have therapeutic potential in CRC as a sensitizer to chemotherapeutic agents by targeting bFGF.