Multi-omics study of sulfur metabolism affecting functional microbial community succession during aerobic solid-state fermentation.

Microbial-mediated sulfur metabolism is closely related to carbon and nitrogen metabolism in natural biological systems. In this study, the effects of sulfur metabolism on microbial communities and functional enzyme succession were investigated based on integrated multi-omics by adding sulfur-containing compounds to aerobic fermentation systems. Sulfur powder was oxidized to S2O32- and subsequently to SO42- by the microbial sulfur-oxidizing system, which lowered the pH to 7.5 on day 7. The decrease in pH resulted in Planifilum (secreted S8, M17 and M32 proteases) losing its competitive advantage, whereas Novibacillus (secreted M14 and M19 metalloproteases) became dominant. Structural proteomics indicated that the surface of Novibacillus proteases has more negatively charged amino acid residues that help maintain protein stability at low pH. These findings aid understanding of the effects of sulfur metabolism on fermentation and the mechanism of microbial adaptation after pH reduction, providing new perspectives on the optimization of fermentation processes.

SETDB1 tumour suppressor roles in near-haploid mesothelioma involve TP53.

BACKGROUND: Mutational inactivation of the SETDB1 histone methyltransferase is found in a subset of mesothelioma, particularly in cases with near-haploidy and TP53 mutations. However, the tumourigenic consequences of SETDB1 inactivation are poorly understood. METHODS: In this study, we investigated SETDB1 tumour suppressor functions in mesothelioma and explored biologic relationships between SETDB1 and TP53. RESULTS: Immunoblotting of early passage cultures showed that SETDB1 was undetectable in 7 of 8 near-haploid mesotheliomas whereas SETDB1 expression was retained in each of 13 near-diploid mesotheliomas. TP53 aberrations were present in 5 of 8 near-haploid mesotheliomas compared to 2 of 13 near-diploid mesotheliomas, and BAP1 inactivation was demonstrated only in near-diploid mesotheliomas, indicating that near-haploid and near-diploid mesothelioma have distinct molecular and biologic profiles. Lentiviral SETDB1 restoration in near-haploid mesotheliomas (MESO257 and MESO542) reduced cell viability, colony formation, reactive oxygen species levels, proliferative marker cyclin A expression, and inhibited growth of MESO542 xenografts. The combination of SETDB1 restoration with pemetrexed and/or cisplatin treatment additively inhibited tumour growth in vitro and in vivo. Furthermore, SETDB1 restoration upregulated TP53 expression in MESO542 and MESO257, whereas SETDB1 knockdown inhibited mutant TP53 expression in JMN1B near-haploid mesothelioma cells. Likewise, TP53 knockdown inhibited SETDB1 expression. Similarly, immunoblotting evaluations of ten near-diploid mesothelioma biopsies and analysis of TCGA expression profiles showed that SETDB1 expression levels paralleled TP53 expression. CONCLUSION: These findings demonstrate that SETDB1 inactivation in near-haploid mesothelioma is generally associated with complete loss of SETDB1 protein expression and dysregulates TP53 expression. Targeting SETDB1 pathways could be an effective therapeutic strategy in these often untreatable tumours.

Bidirectionally Regulating Viral and Cellular Ferroptosis with Metastable Iron Sulfide Against Influenza Virus.

Influenza virus with numerous subtypes and frequent variation limits the development of high-efficacy and broad-spectrum antiviral strategy. Here, a novel multi-antiviral metastable iron sulfides (mFeS) against various influenza A/B subtype viruses is developed. This work finds that mFeS induces high levels of lipid peroxidation and •OH free radicals in the conservative viral envelope, which depends on Fe2+ . This phenomenon, termed as a viral ferroptosis, results in the loss of viral infectibility and pathogenicity in vitro and in vivo, respectively. Furthermore, the decoction of mFeS (Dc(mFeS)) inhibits cellular ferroptosis-dependent intracellular viral replication by correcting the virus-induced reprogrammed sulfur metabolism, a conserved cellular metabolism. Notably, personal protective equipment (PPE) that is loaded with mFeS provides good antiviral protection. Aerosol administration of mFeS combined with the decoction (mFeS&Dc) has a potential therapeutic effect against H1N1 lethal infection in mice. Collectively, mFeS represents an antiviral alternative with broad-spectrum activity against intracellular and extracellular influenza virus.

Glycyrrhizin mitigates acute lung injury by inhibiting the NLRP3 inflammasome in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Glycyrrhiza glabra L. is a widely used traditional Chinese medicine with antipyretic, detoxification, antibacterial and therapeutic effects against various diseases, including liver diseases. Glycyrrhizin (GL), the most significant active ingredient of Glycyrrhiza glabra L., exerts anti-inflammatory activity. However, the anti-inflammatory effect of GL remains to be determined. AIM OF THIS STUDY: Consequently, this research was carried out to discover the effects and mechanism of action of GL on ALI. MATERIALS AND METHODS: Cell experiments established an in vitro model of LPS-induced RAW 264.7 macrophages to verify the mechanism. The levels of NO, PEG2, and inflammatory cytokines were estimated by ELISA. The expression levels of proteins related to the NF-κB signalling pathway and NLRP3 inflammasome were determined by Western blotting. The nuclear translocation of NF-κB p65 and ASC was tested through immunofluorescence analysis. The inhibitory effect of NLRP3 inhibitor MCC950 on macrophage was evaluated. Male BALB/C mice were selected to establish the ALI model. The experiment was randomly divided into five groups: control, ALI, GLL, GLH, and DEX. Pathological alterations were explored by H&E staining. The weight ratios of lung W/D, MPO, and inflammatory cytokines were evaluated by ELISA. The expression levels of proteins related to the NF-κB signalling pathway or NLRP3 inflammasome were analysed by Western blotting. RESULTS: Here, we demonstrate that GL attenuates inflammation, nitric oxide, IL-18, IL-1ß, TNF-α, IL-6, and PGE2 levels and alveolar epithelial barrier permeability in macrophages and mice challenged with LPS. In addition, GL inhibits NLRP3 inflammasome initiation and activation and NF-κB signalling pathway activation. CONCLUSION: This research demonstrates that GL may alleviate ALI inflammation by interfering with the NF-κB/NLRP3 inflammasome signalling pathway.

SALL4 Oncogenic Function in Cancers: Mechanisms and Therapeutic Relevance.

SALL4, a member of the SALL family, is an embryonic stem cell regulator involved in self-renewal and pluripotency. Recently, SALL4 overexpression was found in malignant cancers, including lung cancer, hepatocellular carcinoma, breast cancer, gastric cancer, colorectal cancer, osteosarcoma, acute myeloid leukemia, ovarian cancer, and glioma. This review updates recent advances of our knowledge of the biology of SALL4 with a focus on its mechanisms and regulatory functions in tumors and human hematopoiesis. SALL4 overexpression promotes proliferation, development, invasion, and migration in cancers through activation of the Wnt/ß-catenin, PI3K/AKT, and Notch signaling pathways; expression of mitochondrial oxidative phosphorylation genes; and inhibition of the expression of the Bcl-2 family, caspase-related proteins, and death receptors. Additionally, SALL4 regulates tumor progression correlated with the immune microenvironment involved in the TNF family and gene expression through epigenetic mechanisms, consequently affecting hematopoiesis. Therefore, SALL4 plays a critical oncogenic role in gene transcription and tumor growth. However, there are still some scientific hypotheses to be tested regarding whether SALL4 is a therapeutic target, such as different tumor microenvironments and drug resistance. Thus, an in-depth understanding and study of the functions and mechanisms of SALL4 in cancer may help develop novel strategies for cancer therapy.

Dynamics and removal mechanisms of antibiotic and antibiotic resistance genes during the fermentation process of spectinomycin mycelial dregs: An integrated meta-omics study.

Antibiotic mycelial dregs (AMDs) have been listed as industrial hazardous wastes. With the aim of reducing the environmental risk, the integrated-omics and qPCR approaches were used to reveal the dynamics and removal mechanisms of antibiotic and antibiotic resistance genes (ARGs) during the fermentation of different spectinomycin mycelial dregs (SMDs). The results showed that the removal efficiency of antibiotic in the fermentation of high moisture SMDs reached up to 98%. The high abundance of aadA1 gene encoded by Streptomyces, Lactobacillus, and Pseudomonas was associated with the efficient degradation of spectinomycin, and the inactivating enzymes secreted by degradative bacteria were identified. Furthermore, the dominant microbiota was impacted by moisture content significantly under high temperature environments. In the fermentation of low moisture SMDs, Saccharopolyspora was the dominant microbiota which secreted S8 endopeptidase, M14, M15, S10, S13 carboxypeptidases, M1, M28, S15 aminopeptidases, and antioxidant enzymes, while in the fermentation of high moisture SMDs, Bacillus and Cerasibacillus were dominant genera which mainly secreted S8 endopeptidase and antioxidant enzymes. The abundance of ARGs and mobile genetic elements decreased significantly at thermophilic phase, with maximum drops of 93.7% and 99.9%, respectively. Maintaining moisture content below 30% at the end phase could prevent the transmission of ARGs effectively.