The emerging tumor microbe microenvironment: From delineation to multidisciplinary approach-based interventions.

Intratumoral microbiota has become research hotspots, and emerges as a non-negligent new component of tumor microenvironments (TME), due to its powerful influence on tumor initiation, metastasis, immunosurveillance and prognosis despite in low-biomass. The accumulations of microbes, and their related components and metabolites within tumor tissues, endow TME with additional pluralistic features which are distinct from the conventional one. Therefore, it's definitely necessary to comprehensively delineate the sophisticated landscapes of tumor microbe microenvironment, as well as their functions and related underlying mechanisms. Herein, in this review, we focused on the fields of tumor microbe microenvironment, including the heterogeneity of intratumor microbiota in different types of tumors, the controversial roles of intratumoral microbiota, the basic features of tumor microbe microenvironment (i.e., pathogen-associated molecular patterns (PAMPs), typical microbial metabolites, autophagy, inflammation, multi-faceted immunomodulation and chemoresistance), as well as the multidisciplinary approach-based intervention of tumor microbiome for cancer therapy by applying wild-type or engineered live microbes, microbiota metabolites, antibiotics, synthetic biology and rationally designed biomaterials. We hope our work will provide valuable insight to deeply understand the interplay of cancer-immune-microbial, and facilitate the development of microbes-based tumor-specific treatments.

Brain glucose induces tolerance of Cryptococcus neoformans to amphotericin B during meningitis.

Antibiotic tolerance is the ability of a susceptible population to survive high doses of cidal drugs and has been shown to compromise therapeutic outcomes in bacterial infections. In comparison, whether fungicide tolerance can be induced by host-derived factors during fungal diseases remains largely unknown. Here, through a systematic evaluation of metabolite-drug-fungal interactions in the leading fungal meningitis pathogen, Cryptococcus neoformans, we found that brain glucose induces fungal tolerance to amphotericin B (AmB) in mouse brain tissue and patient cerebrospinal fluid via the fungal glucose repression activator Mig1. Mig1-mediated tolerance limits treatment efficacy for cryptococcal meningitis in mice via inhibiting the synthesis of ergosterol, the target of AmB, and promoting the production of inositolphosphorylceramide, which competes with AmB for ergosterol. Furthermore, AmB combined with an inhibitor of fungal-specific inositolphosphorylceramide synthase, aureobasidin A, shows better efficacy against cryptococcal meningitis in mice than do clinically recommended therapies.

Advances in anti-invasive fungal drug delivery systems. / æŠ—ä¾µè¢­æ€§çœŸèŒæ„ŸæŸ“è¯ç‰©é€’é€ç³»ç»Ÿç ”ç©¶è¿›å±•.

Currently, the first-line drugs for invasive fungal infections (IFI), such as amphotericin B, fluconazole and itraconazole, have drawbacks including poor water solubility, low bioavailability, and severe side effects. Using drug delivery systems is a promising strategy to improve the efficacy and safety of traditional antifungal therapy. Synthetic and biomimetic carriers have greatly facilitated the development of targeted delivery systems for antifungal drugs. Synthetic carrier drug delivery systems, such as liposomes, nanoparticles, polymer micelles, and microspheres, can improve the physicochemical properties of antifungal drugs, prolong their circulation time, enhance targeting capabilities, and reduce toxic side effects. Cell membrane biomimetic drug delivery systems, such as macrophage or red blood cell membrane-coated drug delivery systems, retain the membrane structure of somatic cells and confer various biological functions and specific targeting abilities to the loaded antifungal drugs, exhibiting better biocompatibility and lower toxicity. This article reviews the development of antifungal drug delivery systems and their application in the treatment of IFI, and also discusses the prospects of novel biomimetic carriers in antifungal drug delivery.

Simple, additive-free, extra pressure-free process to direct convert lignin into carbon foams.

To achieve lignin valorization, we reported a simple method to direct covert lignin into carbon foam materials in this work. Unlike multiple steps required to fabricate traditional carbon foams from most of other precursors (often non-renewable), the approach herein required solely heating for carbon production. We found that the intrinsic features of lignin render the formation of lignin block meanwhile generate the porous structure under the invented heating course. Three key factors including glass transition temperature, crosslinking ability, and thermal stability of lignin were identified to determine the successful fabrication of lignin foam (i.e., precursor of carbon foam). Upon tuning the heating profile or fractionating the lignin, lignin foam with different morphologies and properties were obtained. After carbonization, the selected lignin-derived carbon foams possessed well porous structures with bulk densities of 0.52 or 0.62 g cm-3, superior integrity with strength properties of around 10 MPa, BET surface areas of 143.29 or 325.86 m2 g-1, and many other attractive properties. This work is expected to stimulate further seek of lignin valorization in carbon foam production.

Bioresponsive micro-to-nano albumin-based systems for targeted drug delivery against complex fungal infections.

As a typical human pathogenic fungus, Cryptococcus neoformans is a life-threatening invasive fungal pathogen with a worldwide distribution causing ∼700,000 deaths annually. Cryptococcosis is not just an infection with multi-organ involvement, intracellular survival and extracellular multiplication of the fungus also play important roles in the pathogenesis of C. neoformans infections. Because adequate accumulation of drugs at target organs and cells is still difficult to achieve, an effective delivery strategy is desperately required to treat these infections. Here, we report a bioresponsive micro-to-nano (MTN) system that effectively clears the C. neoformans in vivo. This strategy is based on our in-depth study of the overexpression of matrix metalloproteinase 3 (MMP-3) in infectious microenvironments (IMEs) and secreted protein acidic and rich in cysteine (SPARC) in several associated target cells. In this MTN system, bovine serum albumin (BSA, a natural ligand of SPARC) was used for the preparation of nanoparticles (NPs), and then microspheres were constructed by conjugation with a special linker, which mainly consisted of a BSA-binding peptide and an MMP-3-responsive peptide. This MTN system was mechanically captured by the smallest capillaries of the lungs after intravenous injection, and then hydrolyzed into BSA NPs by MMP-3 in the IMEs. The NPs further targeted the lung tissue, brain and infected macrophages based on the overexpression of SPARC, reaching multiple targets and achieving efficient treatment. We have developed a size-tunable strategy where microspheres "shrink" to NPs in IMEs, which effectively combines active and passive targeting and may be especially powerful in the fight against complex fungal infections.

Precise Delivery of Nanomedicines to M2 Macrophages by Combining "Eat Me/Don't Eat Me" Signals and Its Anticancer Application.

Targeted delivery of nanomedicines to M2 tumor-associated macrophages (TAMs) has been proposed to reduce tumor promotion and enhance the efficacy of anticancer therapy. However, upregulated receptors on M2 TAMs are also expressed on M1 TAMs and other macrophages in normal tissues. Therefore, improving targeting specificity remains a key challenge. Here, we developed a precise M2 TAM-targeted delivery system using "eat-me" and "don't-eat-me" signals. A CD47-derived self-peptide ligand (don't-eat-me signal) and galactose ligand (eat-me signal) were introduced on liposomes. Cleavable phospholipid-polyethylene glycol was covered on the surface and could combine with the self-peptide to inhibit macrophage recognition even after immunoglobulin M adsorption and protect galactose from hepatic clearance to prolong the circulation time and promote the accumulation of liposomes in tumors. This detachable polymer can be removed by the redox microenvironment upon transcytosis through the tumor endothelium and re-expose the self-peptide and galactose. The self-peptide highly reduced M1 macrophage phagocytosis, and the galactose ligand enhanced the interaction between the liposomes and M2 macrophages. Thus, the modified liposomes enabled specific recognition of M1/M2 TAMs. In vitro evidence revealed reduced endocytosis of the liposomes by M1 macrophages. Moreover, in vivo studies demonstrated that doxorubicin-loaded liposomes efficiently eliminated M2 TAMs but did not affect M1 TAMs, enhancing the potency of the antitumor therapy. Collectively, our results demonstrate the potential of combining active escape and active targeting for precisely delivering a drug of interest to M2 macrophages and suggest its application in anticancer therapy.

Strategies of Drug Delivery for Deep Fungal Infection: A Review.

The deep fungal infection poses serious threats to human health, mainly due to the increase in the number of immunocompromised individuals. Current first-line antifungal agents such as Amphotericin B, Fluconazole and Itraconazole, may decrease the severity of fungal infection to some extent, but the poor drug bioavailability, drug toxicity and poor water solubility seriously restrict their clinical utility. This review focuses on the study of drug delivery strategies for the treatment of deep fungal infections. We summarize the drug delivery strategies recently reported for the treatment of deep fungal infection, and explain each part with research examples. We discuss the use of pharmaceutical approaches to improve the physicochemical properties of the antifungal drugs to provide a basis for the clinical application of antifungal drugs. We then highlight the strategies for targeting drug delivery to the infection sites of fungi and fungal surface moieties, which have the potential to get developed as clinically relevant targeted therapies against deep fungal infections. It is worth noting that the current research on fungal infections still lags behind the research on other pathogens, and the drug delivery strategy for the treatment of deep fungal infections is far from meeting the treatment needs. Therefore, we envision the potential strategies inspired by the treatment of diseases with referential pathology or pathophysiology, further enriching the delivery of antifungal agents, providing references for basic research of fungal infections. Lay Summary: The deep fungal infections pose serious threats to the health of immunodeficiency patients. It is worth noting that the current research on fungi is still lagging behind that on other pathogens. The drug delivery strategies for the treatment of deep fungal infections are far from meeting the treatment needs. We summarize the recently reported drug delivery strategies for treating deep fungal infection, and envision the potential strategies to further enrich the delivery of antifungal agents.

miR-9 inhibition of neuronal apoptosis and expression levels of apoptosis genes Bcl-2 and Bax in depression model rats through Notch pathway.

Effects of micro ribonucleic acid (miR)-9 on neuronal apoptosis and expression levels of apoptosis genes B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax) in depression model rats, as well as its regulatory mechanism, were investigated. Thirty Sprague-Dawley rats were randomly divided into control group (n=10), model group (n=10) and miR-9 inhibitor group (n=10). The rat model of depression was established using the chronic stress method. The learning and memory abilities of rats were detected via water maze test, the neuronal morphology of the brain was detected using hematoxylin and eosin (H&E) staining, and the levels of serum Bcl-2 and Bax were determined using the enzyme-linked immunosorbent assay (ELISA) kits. Moreover, the neuronal apoptosis in the brain was determined through terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, and the protein levels of Notch1 and Hes1 in brain tissues were measured via western blot analysis. Compared with the control group, the rats in the model group presented significantly decreased learning and memory abilities, poor neuronal morphology of the brain, significantly higher neuronal apoptosis rate in the brain, decreased level of serum Bcl-2, increased level of serum Bax, and significantly decreased protein levels of Notch1 and Hes1 in brain tissues. Compared with the model group, the rats in miR-9 inhibitor group showed obviously improved learning and memory abilities, improved neuronal morphology of the brain, an obviously lower neuronal apoptosis rate in the brain, increased level of serum Bcl-2, decreased level of serum Bax, and obviously increased protein levels of Notch1 and Hes1 in brain tissues. In conclusion, miR-9 inhibitor can promote the neurological function recovery and inhibit the neuronal apoptosis of depression model rats through activating the Notch signaling pathway, suggesting that miR-9 can be an important therapeutic target for depression.

Stabilizing Optimal Crystalline Facet of Cobalt Catalysts for Fischer-Tropsch Synthesis.

Developing efficient catalysts with a stable optimal crystalline facet is highly promising yet challenging for the Fischer-Tropsch synthesis (FTS). Here, we demonstrate a coating strategy to fabricate a stable optimal cobalt-facet catalyst. The catalyst (Co@C-SiO2) is composed of a single crystalline core, a wrapped carbon layer, and an amorphous silica shell. The moderate metal-support interaction endowed by carbon, combining the confined effect of the silica shell, protects and maintains the single-crystal structure and optimal crystalline facet of the core, that is, Co(10-11). Due to the unique core-shell nanostructure and optimal cobalt facets, our Co@C-SiO2 catalyst shows a remarkable low methane selectivity (5.3%), high activity (TOF = 4.0 × 10-2 s-1), C5+ selectivity (88.9%), and more importantly, excellent stability (TOS = 168 h) in FTS.

[Development of genetically stable recombinant Saccharomyces cerevisiae strains using combinational chromosomal integration].

Chromosomal integration enables stable phenotype and therefore has become an important strategy for breeding of industrial Saccharomyces cerevisiae strains. pAUR135 is a plasmid that enables recycling use of antibiotic selection marker, and once attached with designated homologous sequences, integration vector for stable expression can be constructed. Development of S. cerevisiae strains by metabolic engineering normally demands overexpression of multiple genes, and employing pAUR135 plasmid, it is possible to construct S. cerevisiae strains by combinational integration of multiple genes in multiple sites, which results in different ratios of expressions of these genes. Xylose utilization pathway was taken as an example, with three pAUR135-based plasmids carrying three xylose assimilation genes constructed in this study. The three genes were sequentially integrated on the chromosome of S. cerevisiae by combinational integration. Xylose utilization rate was improved 24.4%-35.5% in the combinational integration strain comparing with that of the control strain with all the three genes integrated in one location. Strain improvement achieved by combinational integration is a novel method to manipulate multiple genes for genetic engineering of S. cerevisiae, and the recombinant strains are free of foreign sequences and selection markers. In addition, stable phenotype can be maintained, which is important for breeding of industrial strains. Therefore, combinational integration employing pAUR135 is a novel method for metabolic engineering of industrial S. cerevisiae strains.

Fine-tuning of xylose metabolism in genetically engineered Saccharomyces cerevisiae by scattered integration of xylose assimilation genes.

Manipulation of multiple genes is a common experience in metabolic engineering and synthetic biology studies. Chromosome integration of multiple genes in one single position is always performed, however, there is so far no study on the integration of multiple genes separately in various positions (here in after referred to as "scattered integration") and its effect on fine-tuning of cellular metabolism. In this study, scattered integration of the xylose assimilation genes PsXR, PsXDH and ScXK was investigated in Saccharomyces cerevisiae, and transcription analysis of these genes as well as their enzyme activities were compared with those observed when the genes were integrated into one single site (defined as "tandem integration" here). Not only notable differences in transcription levels and enzyme activities were observed when the genes were integrated by the two strategies, but also change of the cofactor preference of PsXR gene was validated. Xylose fermentation was further studied with the strains developed with these strategies, and elevated xylose utilization rate was obtained in the scattered integration strain. These results proved that by positioning multiple genes on different chromosomes, fine-tuning of cellular metabolism could be achieved in recombinant S. cerevisiae.

[Study of methanol adsorption on zirconia polymorphs by FTIR].

The influence of zirconia polymorphs on methanol adsorption was investigated by FTIR technique. One terminal and two types of bridged methoxyl were formed on the am-ZrO2 and t-ZrO2 samples, while another tribridged methoxyl species was detected on the m-ZrO2 sample. During the formation of methoxyl, bridged hydroxyl species on the am-ZrO2 and m-ZrO2 was more active, while the terminal one on the t-ZrO2 sample was more active. The methoxyl was oxygenated by surface oxygen ions to be formate and further to be carbonate on the m-ZrO2 and am-ZrO2 samples. But for t-ZrO2, methoxyl could be directly oxygenated to be carbonate at RT, which implied that the surface oxygen ions on t-ZrO2 were more active than those on the two other samples.