Silver nanoparticles facilitate phage-borne resistance gene transfer in planktonic and microplastic-attached bacteria.

The spread of bacteriophage-borne antibiotic resistance genes (ARGs) poses a realistic threat to human health. Nanomaterials, as important emerging pollutants, have potential impacts on ARGs dissemination in aquatic environments. However, little is known about its role in transductive transfer of ARGs mediated by bacteriophage in the presence of microplastics. Therefore, this study comprehensively investigated the influence of silver nanoparticles (AgNPs) on the transfer of bacteriophage-encoded ARGs in planktonic Escherichia coli and microplastic-attached biofilm. AgNPs exposure facilitated the phage transduction in planktonic and microplastic-attached bacteria at ambient concentration of 0.1 mg/L. Biological binding mediated by phage-specific recognition, rather than physical aggregation conducted by hydrophilicity and ζ-potential, dominated the bacterial adhesion of AgNPs. The aggregated AgNPs in turn resulted in elevated oxidative stress and membrane destabilization, which promoted the bacteriophage infection to planktonic bacteria. AgNPs exposure could disrupt colanic acid biosynthesis and then reduce the thickness of biofilm on microplastics, contributing to the transfer of phage-encoded ARGs. Moreover, the roughness of microplastics also affected the performance of AgNPs on the transductive transfer of ARGs in biofilms. This study reveals the compound risks of nanomaterials and microplastics in phage-borne ARGs dissemination and highlights the complexity in various environmental scenarios.

Hazards of microplastics exposure to liver function in fishes: A systematic review and meta-analysis.

Microplastics (5 mm - 1 µm) have become one of the major pollutants in the environment. Numerous studies have shown that microplastics can have negative impacts on aquatic organisms, affecting their liver function levels. However, the extent of these effects and their potential toxicological mechanisms are largely unknown. In this study, a meta-analysis and systematic review were conducted to assess the effects of microplastics on fish liver function and summarize the potential toxicological mechanisms of microplastic-induced liver toxicity. The meta-analysis results indicate that compared to the control group, exposure to microplastics significantly affects fish liver indicators: aspartate aminotransferase (AST) (p < 0.001), alanine aminotransferase (ALT) (p < 0.001), alkaline phosphatase (ALP) (p < 0.001), total protein (TP) (p < 0.001), and lactate dehydrogenase (LDH) (p < 0.001), including oxidative stress indicators: superoxide dismutase (SOD) (p < 0.001), glutathione S-transferase (GST) (p < 0.001), glutathione (GSH) (p < 0.001), and malondialdehyde (MDA) (p < 0.001) in fish liver. For fish living in different environments, the potential toxicological mechanisms of microplastics exposure on fish liver may exhibit some differences. For freshwater fish, the mechanism may be that microplastics exposure causes overproduction of reactive oxygen species (ROS) in fish hepatocyte mitochondria. ROS promotes the expression of toll-like receptor 2 (TLR2) and activates downstream molecules myeloid differentiation factor 88 (MyD88) and tumor necrosis factor receptor-associated factor 6 (TRAF6) of the TLR2 signaling pathway, leading to phosphorylation of NF-κB p65. This leads to the release of inflammatory factors and oxidative stress and inflammation in fish liver. In addition, for seawater fish, the mechanism may be that microplastics exposure can cause damage or death of fish hepatocytes, leading to continuous pathological changes, inflammation, lipid and energy metabolism disorders, thereby causing significant changes in liver function indexes.

Extraction, structural characterization and biological activities of polysaccharides from mulberry leaves: A review.

In recent years, plant polysaccharides have garnered attention for their impressive biological activity. Mulberry leaves have a long history of medicinal and edible use in China, polysaccharide is one of the main active components of mulberry leaves, mainly consist of xylose, arabinose, fructose, galactose, glucose and mannose, etc. The extraction methods of mulberry leaves polysaccharides (MLPs) mainly include hot water extraction, microwave-assisted extraction, ultrasonic extraction, enzyme-assisted extraction, and co-extraction. The separation and purification of MLPs involve core steps such as decolorization, protein removal, and chromatographic separation. In terms of pharmacological effects, MLPs exhibit excellent activity in reducing blood glucose, anti-oxidation, immune regulation, anti-tumor, antibacterial, anti-coagulation, and regulation of gut microbiota. Currently, there is a considerable amount of research on MLPs, however, there is a lack of systematic summarization. This review summarizes the research progress on the extraction, structural characterization, and pharmacological activities of MLPs, and points out existing shortcomings and suggests reference solutions, aiming to provide a basis for further research and development of MLPs.

Abnormal functional connectivity of the reward network is associated with social communication impairments in autism spectrum disorder: A large-scale multi-site resting-state fMRI study.

BACKGROUND: The social motivation hypothesis proposes that the social deficits of autism spectrum disorder (ASD) are related to reward system dysfunction. However, functional connectivity (FC) patterns of the reward network in ASD have not been systematically explored yet. METHODS: The reward network was defined as eight regions of interest (ROIs) per hemisphere, including the nucleus accumbens (NAc), caudate, putamen, anterior cingulate cortex (ACC), ventromedial prefrontal cortex (vmPFC), orbitofrontal cortex (OFC), amygdala, and insula. We computed both the ROI-wise resting-state FC and seed-based whole-brain FC in 298 ASD participants and 348 typically developing (TD) controls from the Autism Brain Imaging Data Exchange I dataset. Two-sample t-tests were applied to obtain the aberrant FCs. Then, the association between aberrant FCs and clinical symptoms was assessed with Pearson's correlation or Spearman's correlation. In addition, Neurosynth Image Decoder was used to generate word clouds verifying the cognitive functions of the aberrant pathways. Furthermore, a three-way multivariate analysis of variance (MANOVA) was conducted to examine the effects of gender, subtype and age on the atypical FCs. RESULTS: For the within network analysis, the left ACC showed weaker FCs with both the right amygdala and left NAc in ASD compared with TD, which were negatively correlated with the Autism Diagnostic Observation Schedule (ADOS) total scores and Social Responsiveness Scale (SRS) total scores respectively. For the whole-brain analysis, weaker FC (i.e., FC between the left vmPFC and left calcarine gyrus, and between the right vmPFC and left precuneus) accompanied by stronger FC (i.e., FC between the left caudate and right insula) were exhibited in ASD relative to TD, which were positively associated with the SRS motivation scores. Additionally, we detected the main effect of age on FC between the left vmPFC and left calcarine gyrus, of subtype on FC between the right vmPFC and left precuneus, of age and age-by-gender interaction on FC between the left caudate and right insula. CONCLUSIONS: Our findings highlight the crucial role of abnormal FC patterns of the reward network in the core social deficits of ASD, which have the potential to reveal new biomarkers for ASD.

Discovery of small molecule c-Maf inhibitors using molecular docking-based virtual screening, molecular dynamics simulation, and biological evaluation.

Multiple myeloma (MM) is a prevalent plasma cell malignancy in the blood system that remains incurable. Given the abnormally high expression of c-Maf in most MM patients, targeting c-Maf presents an attractive therapeutic approach for treating MM malignancies. In this study, we employed a combined strategy involving molecular docking-based virtual screening, molecular dynamics (MD) simulation, and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation on existing FDA-approved drugs. Six compounds were selected for further experimental assay: vemurafenib, sorafenib, sildenafil, fluvastatin, erlotinib, and glimepiride. Among these compounds, sorafenib and glimepiride exhibited significant inhibition of myeloma cell proliferation in the RPMI-8226 cell line. Moreover, both compounds simultaneously downregulated c-Maf protein expression to induce G1 phase arrest and apoptosis in myeloma cells. Collectively, sorafenib and glimepiride may be considered promising candidates for developing more potent c-Maf inhibitors in the future.

Impaired segregation of the attention deficit hyperactivity disorder related pattern in children.

BACKGROUND: Inattention is a key characteristic of attention deficit hyperactivity disorder (ADHD). Specific brain abnormalities associated with this symptom form a discernible pattern related with ADHD in children (i.e., ADHD related pattern) in our earlier research. The developmental processes of segregation and integration may be crucial to ADHD. However, how brains reconfigure these processes of the ADHD related pattern in different subtypes of ADHD and across sexes remain unclear. METHODS: Nested-spectral partition method was applied to identify effects of subtype and sex on segregation and integration of the ADHD related pattern, using 145 ADHD patients and 135 typically developing controls (TDC) aged 7-14. Relationships between the measures and inattention symptoms were also investigated. RESULTS: Children with ADHD exhibited lower segregation of the ADHD related pattern (p = 1.17 × 10-8) than TDCs. Only the main effect of subtype was significant (p = 1.14 × 10-5). Both ADHD-C (p = 2.16 × 10-6) and ADHD-I (p = 2.87 × 10-6) patients had lower segregation components relative to the TDC. Moreover, segregation components were negatively correlated with inattention scores. CONCLUSIONS: This study identified impaired segregation in the ADHD related pattern of children with ADHD and found shared neural bases among different subtypes and sexes.

Effect of natural polysaccharides on alcoholic liver disease: A review.

In this study, we systematically collected relevant literature in the past five years on the intervention of natural polysaccharides in alcoholic liver disease (ALD) and reviewed the pharmacological activities and potential mechanisms of action. Natural polysaccharides are effective in preventing liver tissue degeneration, inhibiting the alcohol-induced expression of inflammatory factors, inactivation of antioxidant enzymes, and abnormal hepatic lipid deposition. Natural polysaccharides regulate the expression of proteins, such as tight junction proteins, production of small molecule metabolites, and balance of intestinal flora in the intestinal tract to alleviate ALD. Natural polysaccharides also exert therapeutic effects by modulating inflammatory, oxidative, lipid metabolism, and other pathways in the liver. Natural polysaccharides also inhibit alcohol-induced intestinal abnormalities by regulating intestinal flora and feeding back into the liver via the gut-liver axis. However, existing research on natural polysaccharides has many shortcomings: for example, most of the natural polysaccharides for testing are total polysaccharides or crude polysaccharides, progress in research on in vivo metabolic processes and mechanisms is slow, and the degree of industrialisation is insufficient. Finally, we discuss the difficulties in studying natural polysaccharides and future directions to provide a theoretical basis for their development and application.

The role of lncRNAs and exosomal lncRNAs in cancer metastasis.

Tumor metastasis is the main reason for cancer-related death, but there is still a lack of effective therapeutic to inhibit tumor metastasis. Therefore, the discovery and study of new tumor metastasis regulators is a prominent measure for cancer diagnosis and treatment. Long non-coding RNA (lncRNA) is a type of non-coding RNAs over 200 bp in length. It has been shown that the abnormally expressed lncRNAs promote tumor metastasis by participating in the epithelial-to-mesenchymal transition (EMT) process, altering the metastatic tumor microenvironment, or changing the extracellular matrix. It is,thus, critical to explore the regulation of lncRNAs expression in cells and the molecular mechanism of lncRNA-mediated cancer metastasis. Simultaneously, it has been shown that lncRNA is one kind of the main components of exosomes, which protects lncRNAs from being rapidly degraded. Meanwhile, the components of exosomes are parent-specific, making exosomal lncRNAs to be potential tumor metastasis markers and therapeutic targets. In view of this, we also summarized the aberrant enrichment of lncRNAs in exosomes and their role in metastatic cancer. The aberrant lncRNAs and exosomal lncRNAs gradually become biomarkers and therapeutic targets for tumor metastatic, and the potential of lncRNAs in therapeutics are studied here. Besides, the lncRNA-related databases, which could greatly facilitate in the study of lncRNAs and exosomal lncRNAs in metastatic of cancer are included in this review.

Design, synthesis and biological evaluation of nitric oxide-releasing 5-cyano-6-phenyl-2, 4-disubstituted pyrimidine derivatives.

In this study, a series of nitric oxide (NO) -releasing 5-cyano-6-phenyl-2, 4-disubstituted pyrimidine derivatives were designed and synthesized. In the in vitro biological evaluation, compound 24l exhibited optimal antiproliferative activity against MGC-803 cells with the IC50 value of 0.95 µM, significantly better than that of the positive control 5-FU. In addition, preliminary mechanistic studies indicated that 24l inhibited colony formation and blocked MGC-803 cells in the G0/G1 phase. DAPI staining, reactive oxygen species and apoptosis assays demonstrated that 24l induced apoptosis of MGC-803 cells. Particularly, the most potent compound 24l produced the highest level of NO, and the antiproliferative activity was significantly reduced after preincubation with NO scavengers. In conclusion, compound 24l may be considered as a potential candidate antitumor agent.

Metal-based nanomaterials as antimicrobial agents: A novel driveway to accelerate the aggravation of antibiotic resistance.

The consequences of antibiotic tolerance directly affect human health and result in socioeconomic loss. Nanomaterials as antimicrobial agents are considered a promising alternative to antibiotics and have been blended with various medical applications. However, with increasing evidence that metal-based nanomaterials may induce antibiotic tolerance, there is an urgent need to scrutinize how nanomaterial-induced microbial adaption affects the evolution and spread of antibiotic tolerance. Accordingly, within this investigation, we summarized the principal factors influencing the resistance development exposed to metal-based nanomaterials, including physicochemical properties, exposure scenario, as well as bacterial response. Furthermore, the mechanisms of metal-based nanomaterial-induced antibiotic resistance development were comprehensively elucidated from acquired resistance by horizontal transfer of antibiotic resistance genes (ARGs), intrinsic resistance by genetic mutation or upregulated resistance-related gene expression, and adaptive resistance by global evolution. Overall, our review raises concerns about the safety of nanomaterials as antimicrobial agents, which will facilitate assistance in the safe development of antibiotic-free antibacterial strategies.

BP@Au undergoes rapid degradation and releases singlet oxygen under dark conditions: Doping effect and detrimental effects on superoxide-producing marine algae.

Black phosphorus (BP) shows encouraging utility in many fields, and metal doping has been suggested as an efficient way to improve stability. However, controversial results and inconsistent mechanisms have been reported for doping modulation and stability change. We observed the unforeseen evolution of singlet oxygen (1O2) from BP integrated with gold nanoparticles (BP@Au) under dark conditions, and this led to rapid BP deterioration, even though enhanced stability is commonly thought via surface doping. Briefly, the BP reacted with oxygen and water to yield superoxide (O2•-) and hydrogen peroxide. Au0 acted as an enzyme mimic and catalyzed the conversion of these derivatives, and Au0 was converted to a mixture of Au3+ and Au+. The O2•- was converted to 1O2 via direct donation of electrons to the Au3+/+. The Au-catalyzed redox reactions accelerated the degradation of the BP nanosheets. BP@Au showed significant toxicity toward marine alga that produce O2•- in the dark, as indicated by a more than 30% reduction in cell viability after 12 h of incubation with 7.56 mg/L BP@Au. The novelty of this work lies in the demonstration of a dopant-related degradation pathway of BP that shows unrevealed toxicity toward O2•--producing marine algae.

Annual review of KRAS inhibitors in 2022.

Kirsten rat sarcoma viral (KRAS) oncogene is the most commonly mutated isoform of RAS, accounting for 85% of RAS-driven human cancers. KRAS functioning as a signaling hub participates in multiple cellular signaling pathways and regulates a variety of critical processes such as cell proliferation, differentiation, growth, metabolism and migration. Over the past decades, KRAS oncoprotein has been considered as an "undruggable" target due to its smooth surface and high GTP/GDP affinity. The breakthrough in directly targeting G12C mutated-KRAS and recently approved covalent KRASG12C inhibitors sotorasib and adagrasib broke the myth of KRAS undruggable and confirmed the directly targeting KRAS as one of the most promising strategies for the treatment of cancers. Targeting KRASG12C successfully enriched the understanding of KRAS and brought opportunities for the development of inhibitors to directly target other KRAS mutations. With the stage now set for a new era in the treatment of KRAS-driven cancers, the development of KRAS inhibitors also enters a booming epoch. In this review, we overviewed the research progress of KRAS inhibitors with the potential to treat cancers covering articles published in 2022. The design strategies, discovery processes, structure-activity relationship (SAR) studies, cocrystal structure analysis as well as in vitro and in vivo activity were highlighted with the aim of providing updated sight to accelerate the further development of more potent inhibitors targeting various mutated-KRAS with favorable drug-like properties.

The overview of Mitogen-activated extracellular signal-regulated kinase (MEK)-based dual inhibitor in the treatment of cancers.

Mitogen-activated extracellular signal-regulated kinase 1 and 2 (MEK1/2) are the critical components of the mitogen-activated protein kinase/extracellular signal-regulated kinase 1 and 2 (MAPK/ERK1/2) signaling pathway which is one of the well-characterized kinase cascades regulating cell proliferation, differentiation, growth, metabolism, survival and mobility both in normal and cancer cells. The aberrant activation of MAPK/ERK1/2 pathway is a hallmark of numerous human cancers, therefore targeting the components of this pathway to inhibit its dysregulation is a promising strategy for cancer treatment. Enormous efforts have been done in the development of MEK1/2 inhibitors and encouraging advancements have been made, including four inhibitors approved for clinical use. However, due to the multifactorial property of cancer and rapidly arising drug resistance, the clinical efficacy of these MEK1/2 inhibitors as monotherapy are far from ideal. Several alternative strategies have been developed to improve the limited clinical efficacy, including the dual inhibitor which is a single drug molecule able to simultaneously inhibit two targets. In this review, we first introduced the activation and function of the MAPK/ERK1/2 components and discussed the advantages of MEK1/2-based dual inhibitors compared with the single inhibitors and combination therapy in the treatment of cancers. Then, we overviewed the MEK1/2-based dual inhibitors for the treatment of cancers and highlighted the theoretical basis of concurrent inhibition of MEK1/2 and other targets for development of these dual inhibitors. Besides, the status and results of these dual inhibitors in both preclinical and clinical studies were also the focus of this review.

Characterization of erm(B)-carrying Campylobacter Spp. of retail chicken meat origin.

OBJECTIVES: The erm(B) gene in Campylobacter Spp., conferring resistance to macrolides, is of great concern worldwide. In this study, the prevalence of erm(B) in Campylobacter of retail chicken meat origin was investigated and the characterization of erm(B)-harboring Campylobacter isolates was analyzed. METHODS: Antimicrobial susceptibility testing was performed to determine the susceptibility of Campylobacter isolates. Whole-genome sequencing and analysis were used to characterize sequence type (ST) and genetic context of erm(B). Natural transformation was conducted to evaluate transferability of the erm(B) gene. RESULTS: A total of 16 (11.8%) Campylobacter isolates were obtained from 136 samples collected from retail chicken meat, amongst which five erm(B)-positive isolates were identified as Campylobacter coli belonging to ST3753 (n = 4) and ST825 (n = 1). A total of 22 Campylobacter Spp. were erm(B)-positive in GenBank database; all isolates were collected in China except for one Campylobacter jejuni isolate. Diverse STs were involved in these erm(B)-carrying isolates. Comparison analysis indicated that 11 types of genetic environment for erm(B) were identified, mostly associated with multidrug-resistance genomic islands (MDRGIs). The genetic context of erm(B) in C. coli of retail chicken meat origin showed high nucleotide sequence similarity with that of C. coli from humans. CONCLUSION: This is the first report of prevalence and characterization for erm(B) in Campylobacter of retail chicken meat origin. The genetic context of erm(B) in C. coli isolates from retail chicken meat is highly homologous with that of C. coli from humans; this impies the possibility of zoonotic transmission of erm(B) in Campylobacter, which presents a threat to public health.

[Effect of Dimethyl Fumarate (DMF) on T-cell Acute Lymphoblastic Leukemia].

OBJECTIVE: To explore the effect and possible mechanism of dimethyl fumarate (DMF) on T-cell acute lymphoblastic leukemia (T-ALL), and provide experimental and theoretical basis for the clinical treatment of T-ALL. METHODS: Jurkat cells were treated with different concentrations of DMF for 24 hours, and then the proportion and absolute count of Ki67-positive Jurkat cells were analyzed by flow cytometry. Meanwhile, the protein levels of nuclear factor-erythroid 2-related factor 2 (Nrf2) and E3 ubiquitin ligase HACE1 in Jurkat cells treated with DMF for 24 hours were evaluated by Western blot. Nrf2 proteins were co-immunoprecipitated in Jurkat cells, and then HACE1 protein was assessed by Western blot. Plasmids of Flag-Nrf2 and different gradients of Flag-HACE1 were transfected into HEK293T cells, and the levels of Flag-Nrf2 were detected by Western blot after 48 hours. RESULTS: DMF could significantly inhibit the proportion and absolute count of Ki67-positive Jurkat cells, and DMF inhibited the proliferation of Jurkat cells in a dose-dependent manner (r=0.9595, r=0.9054). DMF could significantly up-regulate the protein levels of Nrf2 and E3 ubiquitin ligase HACE1 in Jurkat cells (P<0.01, P<0.01). HACE1 physically interacted with Nrf2 in Jurkat cells. Overexpression of Flag-HACE1 significantly increased the protein level of Flag-Nrf2 in a dose-dependent manner (r=0.9771). CONCLUSION: DMF inhibits the proliferation of T-cell acute lymphoblastic leukemia cell. The mechanism may be that, DMF significantly up-regulates the protein levels of Nrf2 and E3 ubiquitin ligase HACE1, and HACE1 interacts with Nrf2 and positively regulates Nrf2 protein level.

Progress in the development of small molecular inhibitors of the Bruton's tyrosine kinase (BTK) as a promising cancer therapy.

Bruton tyrosine kinase (BTK) is a key kinase in the B cell antigen receptor signal transduction pathway, which is involved in the regulation of the proliferation, differentiation and apoptosis of B cells. BTK has become a significant target for the treatment of hematological malignancies and autoimmune diseases. Ibrutinib, the first-generation BTK inhibitor, has made a great contribution to the treatment of B cell malignant tumors, but there are still some problems such as resistance or miss target of site mutation. Therefore, there is an imperative need to develop novel BTK inhibitors to overcome these problems. Besides, proteolysis targeting chimera (PROTAC) technology has been successfully applied to the development of BTK degradation agents, which has opened a fresh way for the BTK targeted treatment. This paper reviews the biological function of BTK, the discovery and development of BTK targeted drugs as a promising cancer therapy. It mainly reviews the binding sites and structural characteristics of BTK, structure-activity relationships, activity and drug resistance of BTK inhibitors, as well as potential treatment strategies to overcome the resistance of BTK, which provides a reference for the rational design and development of new powerful BTK inhibitors.

Design, synthesis and antitumor activity evaluation of trifluoromethyl-substituted pyrimidine derivatives.

In order to find efficient new antitumor drugs, a series of novel trifluoromethyl-substituted pyrimidine derivatives were designed and synthesized, and the bioactivity against four human tumor cells (PC-3, MGC-803, MCF-7 and H1975) was evaluated by MTT assay. Compound 17v displayed potent anti-proliferative activity on H1975 (IC50 = 2.27 µΜ), which was better than the positive control 5-FU (IC50 = 9.37 µΜ). Further biological evaluation studies showed that compound 17v induced apoptosis of H1975 cells and arrested the cell cycle at G2/M phase. Furthermore, compound 17v induced H1975 cells apoptosis through increasing the expression of pro-apoptotic proteins Bax and p53 and down-regulating the anti-apoptotic protein Bcl-2. In addition, compound 17v was able to be tightly embedded in the active pocket of EGFR. In summary, these results demonstrated that compound 17v has a potential as a lead compound for further investigation.

Design, synthesis and biological evaluation of novel 2,4-disubstituted quinazoline derivatives targeting H1975 cells via EGFR-PI3K signaling pathway.

In order to find new and highly effective anti-tumor drugs with targeted therapeutic effects, a series of novel 4-aminoquinazoline derivatives containing N-phenylacetamide structure were designed, synthesized and evaluated for antitumor activity against four human cancer cell lines (H1975, PC-3, MDA-MB-231 and MGC-803) using MTT assay. The results showed that the compound 19e had the most potent antiproliferative activity against H1975, PC-3, MDA-MB-231 and MGC-803 cell lines. At the same time, compound 19e could significantly inhibit the colony formation and migration of H1975 cells. Compound 19e also arrested the H1975 cell cycle in the G1 phase and mediated cell apoptosis, promoted the accumulation of ROS in H1975 cells. Furthermore, compound 19e exerted antitumor effect in vitro by reducing the expression of anti-apoptotic protein Bcl-2 and increasing the pro-apoptotic protein Bax and p53. Mechanistically, compound 19e could significantly decreased the phosphorylation of EGFR and its downstream protein PI3K in H1975 cells. Which indicated that compound 19e targeted H1975 cell via interfering with EGFR-PI3K signaling pathway. Molecular docking showed that compound 19e could bind into the active pocket of EGFR. Those work suggested that compound 19e would have remarkable implications for further design of anti-tumor agents.

Biotransformation of androst-4-ene-3,17-dione by three fungal species Fusarium solani BH1031, Aspergillus awamori MH18 and Mucor circinelloides W12.

The microbial transformation of androst-4-ene-3,17-dione (4-AD; I) by three fungal species, involved Fusarium solani BH1031, Aspergillus awamori MH18 and Mucor circinelloides W12, has been studied. The latter two fungi were studied for the first time on biotransformation of 4-AD. The main product obtained by Fusarium solani BH1031 was 17α-oxa-D-homo-androst-1,4-diene-3,17-dione (testolactone; IV), which can be used as an anticancer agent. The main derivative yielded by Aspergillus awamori MH18 was 11α-hydroxyandrost-4-ene-3,17-dione (11α-OH-4-AD; VI), which was an important intermediate to produce Eplerenone. Meanwhile, the microbial transformation of 4-AD by Mucor circinelloides W12 produced three derivatives. Possible metabolic pathway of 4-AD via Fusarium solani BH1031 was proposed. Furthermore, the optimization for the production of 11α-OH-4-AD was carried out and the conversion rate reached to 84.0%. In this process, the dextrin and corn flour showed significant effects by response surface analysis.

Chronic Exposure to Low Concentration of Graphene Oxide Increases Bacterial Pathogenicity via the Envelope Stress Response.

Graphene oxide (GO), which has diverse antimicrobial mechanisms, is a promising material to address antibiotic resistance. Considering the emergence of antibiotic tolerance/resistance due to prolonged exposure to sublethal antibiotics, it is imperative to assess the microbiological effects and related adaptive mechanisms under chronic exposure to sublethal levels of GO, which have rarely been explored. After repetitive exposure to 5 mg/L GO for 200 subcultures (400 days), evolved Escherichia coli (E. coli) cells (EGO) differed significantly from their ancestor cells according to transcriptomic and metabolomic analyses. Contact with GO surfaces transformed E. coli by activating the Cpx envelope stress response (ESR), resulting in more than twofold greater extracellular protease release and biofilm formation. The ESR also modulated the envelope structure and function via increases in membrane fluidity, permeation, and lipopolysaccharide content to fulfill growth requirements and combat envelope stress. As a consequence of metabolic adjustment, EGO cells showed advantages of surviving in an acidic and oxidative environment, which resembles the cytosol of host cells. With these adaptive features, EGO cells exhibited higher pathogenicity than ancestor E. coli cells as evidenced by increased bacterial invasion and intracellular survival and a more severe inflammatory response in macrophage cells. To conclude, we seek to raise awareness of the possible occurrence of microbial adaptation to antimicrobial nanomaterials, which may be implicated in cross-adaptation to harsh environments and eventually the prevalence of virulence.