Efficient bio-remediation of multiple aromatic hydrocarbons using different types of thermotolerant, ring-cleaving dioxygenases derived from Aeribacillus pallidus HB-1.

As toxic contaminants, aromatic compounds are widespread in most environmental matrices, and bioenzymatic catalysis plays a critical role in the degradation of xenobiotics. Here, a thermophillic aromatic hydrocarbon degrader Aeribacillus pallidus HB-1 was found. Bioinformatic analysis of the HB-1 genome revealed two ring-cleaving extradiol dioxygenases (EDOs), among which, EDO-0418 was assigned to a new subfamily of type I.1 EDOs and exhibited a broad substrate specificity, particularly towards biarylic substrate. Both EDOs exhibited optimal activities at elevated temperatures (55 and 65 °C, respectively) and showed remarkable thermostability, pH stability, metal ion resistance and tolerance to chemical reagents. Most importantly, simulated wastewater bioreactor experiments demonstrated efficient and uniform degradation performance of mixed aromatic substrates under harsh environments by the two enzymes combined for potential industrial applications. The unveiling of two thermostable dioxygenases with broad substrate specificities and stress tolerance provides a novel approach for highly efficient environmental bioremediation using composite enzyme systems.

Mesenchymal Stem Cell-Derived Mitochondria Enhance Extracellular Matrix-Derived Grafts for the Repair of Nerve Defect.

Peripheral nerve injuries (PNI) can lead to mitochondrial dysfunction and energy depletion within the affected microenvironment. The objective is to investigate the potential of transplanting mitochondria to reshape the neural regeneration microenvironment. High-purity functional mitochondria with an intact structure are extracted from human umbilical cord-derived mesenchymal stem cells (hUCMSCs) using the Dounce homogenization combined with ultracentrifugation. Results show that when hUCMSC-derived mitochondria (hUCMSC-Mitos) are cocultured with Schwann cells (SCs), they promote the proliferation, migration, and respiratory capacity of SCs. Acellular nerve allografts (ANAs) have shown promise in nerve regeneration, however, their therapeutic effect is not satisfactory enough. The incorporation of hUCMSC-Mitos within ANAs has the potential to remodel the regenerative microenvironment. This approach demonstrates satisfactory outcomes in terms of tissue regeneration and functional recovery. Particularly, the use of metabolomics and bioenergetic profiling is used for the first time to analyze the energy metabolism microenvironment after PNI. This remodeling occurs through the enhancement of the tricarboxylic acid cycle and the regulation of associated metabolites, resulting in increased energy synthesis. Overall, the hUCMSC-Mito-loaded ANAs exhibit high functionality to promote nerve regeneration, providing a novel regenerative strategy based on improving energy metabolism for neural repair.

Stress-responses of microbes in oil reservoir under high tetracycline exposure and their environmental risks.

As the groundwater ecosystem is connected with surface, antibiotics and antibiotic resistance genes (ARGs) in aquatic environments will gradually infiltrate into the deep environment, posing a potential threat to groundwater ecosystem. However, knowledge on the environmental risk of antibiotics and ARGs in groundwater ecosystem and their ecological process still remains unexplored. In this study, lab-scale oil reservoirs under high tetracycline stress were performed to evaluate the dynamics of microbial communities, ARGs and potential functions by using 16S rRNA gene sequencing and metagenomics analysis. Although the presence of antibiotics remarkably reduced the microbial abundance and diversity in a short term, but remain stable or even increased after a long-term incubation. Antibiotic stress caused a greater diversity and abundance of ARGs, and higher numbers of ARGs-related species with the capacity to transfer ARGs to other microbes through horizontal gene transfer. Thus, a much more frequent associations of microbial community at both node- and network-level and a selective pressure on enrichment of antibiotic resistant bacteria related to "anaerobic n-alkane degradation" and "methylotrophic methanogenesis" were observed. It is important to emphasize that high antibiotic stress could also prevent some microbes related to "Sulfate reduction", "Fe(II) oxidation", "Nitrate reduction", and "Xylene and Toluene degradation". This study provides an insight into the long-term stress-responses of microbial communities and functions in oil reservoir under tetracycline exposure, which may help to elucidate the effect of antibiotic stress on biogeochemical cycling with microbial involvement in groundwater ecosystem.

Corrigendum: Developing an immune-related signature for predicting survival rate and the response to immune checkpoint inhibitors in patients with glioma.

[This corrects the article DOI: 10.3389/fgene.2022.899125.].

Spatiotemporally Targeted Polypeptide Nanoantidotes Improve Chemotherapy Tolerance of Cisplatin.

The toxicity of drugs causes various adverse effects in patients. While antidotes that neutralize drug toxicity help reduce systemic damage during clinical therapy, these antidotes are generally accompanied by the loss of drug efficacy. Herein, the spatiotemporally targeted polycystine-based nanoantidotes were designed as a neutralizer of cisplatin (CDDP) to decrease its toxicity without affecting its anticancer efficacy. The nanoantidotes administered before CDDP selectively accumulated in the liver and kidney and then firmly bound to CDDP through the highly stable Pt-S bond during subsequent chemotherapy. This two-step administration strategy reduced the level of Pt in normal organs, shortened the half-life of CDDP in plasma, and increased the tolerance to CDDP. More importantly, the nanoantidotes maintained the anticancer efficacy of CDDP after reducing systemic toxicity, indicating its great potential in expanding the clinical application of CDDP.

miR-596-3p suppresses brain metastasis of non-small cell lung cancer by modulating YAP1 and IL-8.

Brain metastasis (BM) frequently occurs in advanced non-small cell lung cancer (NSCLC) and is associated with poor clinical prognosis. Due to the location of metastatic lesions, the surgical resection is limited and the chemotherapy is ineffective because of the existence of the blood brain barrier (BBB). Therefore, it is essential to enhance our understanding about the underlying mechanisms associated with brain metastasis in NSCLC. In the present study, we explored the RNA-Seq data of brain metastasis cells from the GEO database, and extracted RNA collected from primary NSCLC tumors as well as paired brain metastatic lesions followed by microRNA PCR array. Meanwhile, we improved the in vivo model and constructed a cancer stem cell-derived transplantation model of brain metastasis in mice. Our data indicated that the level of miR-596-3p is high in primary NSCLC tumors, but significantly downregulated in the brain metastatic lesion. The prediction target of microRNA suggested that miR-596-3p was considered to modulate two genes essential in the brain invasion process, YAP1 and IL-8 that restrain the invasion of cancer cells and permeability of BBB, respectively. Moreover, in vivo experiments suggested that our model mimics the clinical aspect of NSCLC and improves the success ratio of brain metastasis model. The results demonstrated that miR-596-3p significantly inhibited the capacity of NSCLC cells to metastasize to the brain. Furthermore, these finding elucidated that miR-596-3p exerts a critical role in brain metastasis of NSCLC by modulating the YAP1-IL8 network, and this miRNA axis may provide a potential therapeutic strategy for brain metastasis.

Developing an Immune-Related Signature for Predicting Survival Rate and the Response to Immune Checkpoint Inhibitors in Patients With Glioma.

Background: Glioma is one of the most aggressive cancer types affecting the central nerve system, with poor overall survival (OS) rates. The present study aimed to construct a novel immune-related signature to predict prognosis and the efficiency of immunotherapy in patients with glioma. Methods: The mRNA expression data and other clinical information of patients with glioblastoma multiforme (GBM) and low grade glioma (LGG) were obtained from The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases. The immune-related genes were obtained from the Immunology Database and Analysis Portal database. Subsequently, an immune-related signature was created following the results obtained from the Least Absolute Shrinkage and Selection Operator regression model. To validate the predictability of the signature, Kaplan-Meier survival curves and time-dependent receiver operating characteristic curves were created. Moreover, both univariate and multivariate analyses were carried out using the OS between this signature and other clinicopathologic factors, and a nomogram was constructed. In addition, the association between signature, immune cell infiltration, tumor mutation burden and immunophenoscore were determined. Results: Results of the present study using 118 GBM and LGG samples uncovered 15 immune-related genes that were also differently expressed in glioma samples. These were subsequently used to construct the immune-related signature. This signature exhibits the ability to predict prognosis, the infiltration of immune cells in the tumor microenvironment and the response of patients with glioma to immunotherapy. Conclusion: Results of the present study demonstrated that the aforementioned novel immune-related signature may accurately predict prognosis and the response of patients with glioma to immunotherapy.

Circular RNA circBFAR promotes glioblastoma progression by regulating a miR-548b/FoxM1 axis.

Glioblastoma multiforme (GBM) is the most common and aggressive type of tumor of the primary nervous system. Treatment options for GBM include surgery, chemotherapy, and radiation therapy; however, the clinical outcomes are poor, with a high rate of recurrence. An increasing number of studies have shown that circular RNAs (circRNAs) serve important roles in several types of cancer. Gene Expression Omnibus (GEO) database was utilized to identify the differentially expressed circRNAs and their biological functions. Then, we detected the circular RNA bifunctional apoptosis regulator (circBFAR) was significantly increased in three GEO datasets. However, the role of circBFAR has not been reported in GBM. In this study, the expression of circBFAR was significantly increased both in GBM tissues or cell lines and was negatively correlated with overall survival in patients with GBM. Knockdown of circBFAR inhibited proliferation and invasion both in vitro and in vivo. Increased expression of circBFAR resulted in a reduction of miR-548b expression in glioma cells. A luciferase reporter and RIP assay indicated that miR-548b was a direct target of circBFAR, and miR-548b may negatively regulate the expression of FoxM1. Rescue experiments showed that overexpression of FoxM1 could counter the effect of circBFAR silencing on the proliferation and invasion of glioma cell lines. Moreover, we identified that circBFAR regulates FoxM1 by interacting with miR-548b in glioma cells. In conclusion, the present study demonstrated that a circBFAR/miR-548b/FoxM1 axis regulates the development of GBM and highlights potentially novel therapeutic targets for the treatment of GBM.

Deep mining decreases the microbial taxonomic and functional diversity of subsurface oil reservoirs.

Microbes in subsurface oil reservoirs play important roles in elemental cycles and biogeochemical processes. However, the community assembly pattern of indigenous microbiome and their succession under long-term human activity remain poorly understood. Here we studied the microbial community assembly in underground sandstone cores from 190 to 2050 m in northeast China and their response to long-term oil recovery (10-50 years). Indigenous microbiome in subsurface petroleum reservoirs were dominated by Gammaproteobacteria, Firmicutes, Alphaproteobacteria, Bacteroidetes, and Actinobacteria, which exhibited a higher contribution of homogenizing dispersal assembly and different taxonomy distinct ecological modules when compared with perturbed samples. Specifically, the long-term oil recovery reduced the bacterial taxonomic- and functional-diversity, and increased the community co-occurrence associations in subsurface oil reservoirs. Moreover, distinguished from the perturbed samples, both variation partition analysis and structural equation model revealed that the contents of quartz, NO3- and Cl- significantly structured the α- and ß-diversity in indigenous subsurface bacterial communities. These findings first provide the holistic picture of microbiome in the deep oil reservoirs, which demonstrate the significant impact of human activity on microbiome in deep continental subsurface.

Polymer nanotherapeutics to correct autoimmunity.

The immune system maintains homeostasis and protects the body from pathogens, mutated cells, and other harmful substances. When immune homeostasis is disrupted, excessive autoimmunity will lead to diseases. To inhibit the unexpected immune responses and reduce the impact of treatment on immunoprotective functions, polymer nanotherapeutics, such as nanomedicines, nanovaccines, and nanodecoys, were developed as part of an advanced strategy for precise immunomodulation. Nanomedicines transport cytotoxic drugs to target sites to reduce the occurrence of side effects and increase the stability and bioactivity of various immunomodulating agents, especially nucleic acids and cytokines. In addition, polymer nanomaterials carrying autoantigens used as nanovaccines can induce antigen-specific immune tolerance without interfering with protective immune responses. The precise immunomodulatory function of nanovaccines has broad prospects for the treatment of immune related-diseases. Besides, nanodecoys, which are designed to protect the body from various pathogenic substances by intravenous administration, are simple and relatively noninvasive treatments. Herein, we have discussed and predicted the application of polymer nanotherapeutics in the correction of autoimmunity, including treating autoimmune diseases, controlling hypersensitivity, and avoiding transplant rejection.

Circular RNA circHECTD1 facilitates glioma progression by regulating the miR-296-3p/SLC10A7 axis.

Glioma is the most common type of primary brain tumor. Treatment options for recurrent gliomas include surgery, chemotherapy, and radiation therapy, but the clinical outcome is usually limited. In recent years, circular RNAs have been found to play a vital role in several human cancers. Gene Expression Omnibus database was utilized to verify the differentially expressed circRNAs. Then we detected that the expression of circular RNA circHECTD1 was significantly increased. The expression and function of circHECDT1 has not yet been reported in glioma. Then we confirmed that the level of circHECTD1 was significantly increased both in glioma tissues and cell lines, which is negatively correlated with the overall survival of patients. Knockdown of circHECTD1 inhibited proliferation and invasion in vitro, and also reduced the growth of tumor and prolonged the prognosis in vivo. Knockdown of circHECTD1 significantly elevated the miR-296-3p expression in LN229 and T98G cells. Luciferase reports and RNA immunoprecipitation data indicated that miR-296-3p was a direct target of circHECTD1 and that the miR-296-3p expression negatively regulated SLC10A7. Rescue experiments showed that the overexpression of SLC10A7 could impede the effects of circHECTD1 silencing on the proliferation and invasion of glioma cells. In this study, we identified that circHECTD1 regulates SLC10A7 by interacting with miR-296-3p in glioma cells. In conclusion, this study investigated a novel biomarker panel consisting of the circHECTD1/miR-296-3p/SLC10A7 axis, which is critical for glioma tumorigenesis and invasiveness and may represent a novel therapeutic target for intervening in glioma progression.

Dual-acidity-labile polysaccharide-di-drugs conjugate for targeted cancer chemotherapy.

Polymer-drug conjugates synthesized by binding therapeutic agents to functional polymers have long been a mainstay of prodrugs, while the slow drug release, insufficient efficacy of a single drug, and low selectivity hamper the clinical translation. By rational prodrug design, a targeted dual-acidity-labile polysaccharide-di-drugs conjugate was synthesized by one-pot simultaneous Schiff base and boronic esterification reactions between oxidized dextran (Dex-CHO) and cyclo-(Arg-Gly-Asp-D-Phe-Lys) (c(RGDfK)), doxorubicin (DOX), and bortezomib (BTZ). The polysaccharide-di-drugs conjugate (Dex-g-(DOX+BTZ)/cRGD) self-assembled into micelle with a diameter at around 80 nm and released the drugs simultaneously triggered by the acidic conditions. Dex-g-(DOX+BTZ)/cRGD specifically recognized and entered the cancer cells through the RGD-αvß3 integrin interplay, selectively released DOX and BTZ in the acidic intracellular microenvironment, and efficiently inhibited the cell proliferation in vitro. More importantly, Dex-DOX/BTZ/cRGD showed higher intratumoral accumulation and better antitumor efficacy in vivo compared with free drugs and non-targeted control prodrug Dex-g-(DOX+BTZ). The findings indicated that this study provided a facile strategy to develop smart polymer-multi-drugs conjugates for targeted cancer chemotherapy.

Polymer nanoparticle-assisted chemotherapy of pancreatic cancer.

Pancreatic cancer is a lethal disease characterized by highly dense stroma fibrosis. Only 15-20% of patients with pancreatic cancer have resectable tumors, and only around 20% of them survive to 5 years. Traditional cancer treatments have little effect on their prognosis, and successful surgical resection combined with effective perioperative therapy is the main method for maximizing long-term survival. For this reason, chemotherapy is an adjunct treatment for resectable cancer and is the main therapy for incurable pancreatic cancer, including metastatic pancreatic adenocarcinoma. However, there are various side effects of chemotherapeutic medicine and low drug penetration because the complex tumor microenvironment limits the application of chemotherapy. As a novel strategy, polymer nanoparticles make it possible to target the tumor microenvironment, release cytotoxic agents through various responsive reactions, and thus overcome the treatment barrier. As drug carriers, polymer nanoparticles show marked advantages, such as increased drug delivery and efficiency, controlled drug release, decreased side effects, prolonged half-life, and evasion of immunogenic blockade. In this review, we discuss the factors that cause chemotherapy obstacles in pancreatic cancer, and introduce the application of polymer nanoparticles to treat pancreatic cancer.

A novel engineered interferon-α hybrid molecule increases anticancer efficacy of doxorubicin in breast cancer chemotherapy.

Breast cancer is the most common carcinoma among Chinese women. Interferon α (IFNα) has been used to treat various types of cancer, including breast cancer, but its antitumor activity is relative low, which significantly hinders its clinical application. In this study, we utilized a Ph.D.-12 peptide library screening system to identify a short peptide that specifically binds to MCF-7 breast cancer cells. By fusing the MCF-7 binding peptide (MBP) to the C-terminus of IFNα, we constructed an engineered IFNα-MBP fusion molecule (IMBP), and applied this novel fusion protein to the treatment of breast cancer. We found that IMBP exhibited significantly higher activity than wild-type IFNα in inhibiting cell growth and inducing cell apoptosis. Additionally, IMBP potentiated the therapeutic efficacy of doxorubicin-based breast cancer chemotherapy via the activation of cell cycle arrest and cell apoptosis pathway genes including p53, p21, CDK2, cyclin A, caspase 9, Bcl-2 and Bax. The enhanced activity of the synthetic IMBP was also associated with the activation of signal transducer and activation of transcription 1 (STAT1) pathway target genes (STAT1, IFIT1, IFITM1 and MX1). This study evaluated the potential value of the synthetic IMBP as a novel anti-breast cancer agent.