Exosomes are nanoscale membrane vesicles secreted from many types of cells. Carrying functional molecules, exosomes transfer information between cells and mediate many physiological and pathological ...processes. In this report, utilizing selective inhibitors, molecular tools, and specific endocytosis markers, the cellular uptake of PC12 cell-derived exosomes was imaged by high-throughput microscopy and statistically analyzed. It was found that the uptake was through clathrin-mediated endocytosis and macropinocytosis. Furthermore, PC12 cell-derived exosomes can enter and deliver microRNAs (miRNAs) into bone marrow-derived mesenchymal stromal cells (BMSCs), and decrease the expression level of transforming growth factor β receptor II (TGFβRII) and tropomyosin-1 (TPM1) through miR-21. These results show the pathway of exosome internalization and demonstrate that tumor cell-derived exosomes regulate target gene expression in normal cells.
The mud cellar creates a unique microenvironment for the fermentation of strong-flavor baijiu (SFB). Recent research and long-term practice have highlighted the key roles of microbes inhabiting pit ...mud in the formation of SFB’s characteristic flavor. A positive correlation between the quality of SFB and cellar age was extracted from practice; however, the evolutionary patterns of pit mud microbiome and driving factors remain unclear. Here, based on the variation regularity analysis of microbial community structure and metabolites of samples from cellars of different ages (∼30/100/300 years), we further investigated the effects of lactate and acetate (main microbial metabolites in fermented grains) on modulating the pit mud microbiome. Esters (50.3% to 64.5%) dominated the volatile compounds identified in pit mud, and contents of the four typical acids (lactate, hexanoate, acetate, and butyrate) increased with cellar age. Bacteria (9.5 to 10.4 log10 lg copies/g) and archaea (8.3 to 9.1 lg copies/g) mainly constituted pit mud microbiota, respectively dominated by Clostridia (39.7% to 81.2%) and Methanomicrobia (32.8% to 92.9%). An upward trend with cellar age characterized the relative and absolute abundance of the most predominant bacterial and archaeal genera, Caproiciproducens and Methanosarcina. Correlation analysis revealed significantly (P < 0.05) positive relationships between the two genera and major metabolites. Anaerobic fermentation with acetate and lactate as carbon sources enhanced the enrichment of Clostridia, and furthermore, the relative abundance of Caproiciproducens (40.9%) significantly increased after 15-day fed-batch fermentation with lactate compared with the initial pit mud (0.22%). This work presents a directional evolutionary pattern of pit mud microbial consortia and provides an alternative way to accelerate the enrichment of functional microbes. IMPORTANCE The solid-state anaerobic fermentation in a mud cellar is the most typical feature of strong-flavor baijiu (SFB). Metabolites produced by microbes inhabiting pit mud are crucial to create the unique flavor of SFB. Accordingly, craftspeople have always highlighted the importance of the pit mud microbiome and concluded by centuries of practice that the production rate of high-quality baijiu increases with cellar age. To deepen the understanding of the pit mud microbiome, we determined the microbial community and metabolites of different-aged pit mud, inferred the main functional groups, and explored the forces driving the microbial community evolution through metagenomic, metabolomic, and multivariate statistical analyses. The results showed that the microbial consortia of pit mud presented a regular and directional evolutionary pattern under the impact of continuous batch-to-batch brewing activities. This work provides insight into the key roles of the pit mud microbiome in SFB production and supports the production optimization of high-quality pit mud.
•Aerobic composting of distilled grain waste (DGW) was investigated.•Composting of DGW without pH adjustment yielded an unsuccessful start-up.•Initial pH of 5–6 in raw DGW allowed successful ...composting.•The occurrence of nitrification was attributed to the activity of ammonia-oxidizing bacteria.
Aerobic composting of distilled grain waste (DGW) at different initial pH values adjusted by CaO addition was investigated. Three pH-adjusted treatments with initial pH values of 4 (R1), 5 (R2) and 6 (R3) and a control treatment (R0) with a pH value of 3.5 were conducted simultaneously. The results showed that R0 had an unsuccessful start-up of composting. However, the pH-adjusted treatments produced remarkable results, with a relatively high initial pH being beneficial for the start-up. Within 65days of composting, the degradation of volatile solids (VS) and the physicochemical properties of R2 and R3 displayed similar tendencies, and both produced a mature end-product, while R1 exhibited a lower VS degradation rate, and some of its physicochemical properties indicated the end-product was immature. Quantitative PCR analysis of ammonia oxidizers indicated that the occurrence of nitrification during the composting of DGW could be attributed to the activity of ammonia-oxidizing bacteria.
NOD‐like receptor (NLR) family CARD domain containing 3 (NLRC3), an intracellular member of NLR family, is a negative regulator of inflammatory signaling pathways in innate and adaptive immune cells. ...Previous reports have shown that NLRC3 is expressed in dendritic cells (DCs). However, the role of NLRC3 in DC activation and immunogenicity is unclear. In the present study, we find that NLRC3 attenuates the antigen‐presenting function of DCs and their ability to activate and polarize CD4+ T cells into Th1 and Th17 subsets. Loss of NLRC3 promotes pathogenic Th1 and Th17 responses and enhanced experimental autoimmune encephalomyelitis (EAE) development. NLRC3 negatively regulates the antigen‐presenting function of DCs via p38 signaling pathway. Vaccination with NLRC3‐overexpressed DCs reduces EAE progression. Our findings support that NLRC3 serves as a potential target for treating adaptive immune responses driving multiple sclerosis and other autoimmune disorders.
Synopsis
The innate immune sensor NLRC3 negatively regulates dendritic cell activation to affect Th1 and Th17 cell differentiation and experimental autoimmune encephalomyelitis.
NLRC3 attenuates the antigen‐presenting function of DCs and their ability to activate and polarize CD4+ T cells into Th1 and Th17 subsets.
Loss of NLRC3 promotes pathogenic Th1 and Th17 responses and enhanced EAE development.
NLRC3 negatively regulates the antigen‐presenting function of DCs via p38 signaling pathway.
The innate immune sensor NLRC3 negatively regulates dendritic cell activation to affect Th1 and Th17 cell differentiation and experimental autoimmune encephalomyelitis.
Azvudine (FNC) is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp). Recently, we discovered FNC an agent against SARS-CoV-2, and have taken it into Phase III trial for ...COVID-19 patients. FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC
between 1.2 and 4.3 μM, depending on viruses or cells, and selective index (SI) in 15-83 range. Oral administration of FNC in rats revealed a substantial thymus-homing feature, with FNC triphosphate (the active form) concentrated in the thymus and peripheral blood mononuclear cells (PBMC). Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray. Single-cell sequencing suggested the promotion of thymus function by FNC. A randomized, single-arm clinical trial of FNC on compassionate use (n = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range: 1-9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2-25 days). The side-effect of FNC is minor and transient dizziness and nausea in 16.12% (5/31) patients. Thus, FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus, followed by promoted immunity.
The chronic rejection responses and side effects of the systematic administration of immunosuppressants are the main obstacles to heart allograft and patient survival. The development of ...xenotransplantation also urgently requires more efficient immune regulation strategies. Herein, it is demonstrated that lymph‐node (LN)‐targeted drug delivery can realize LN‐specific immunomodulation with attenuated immune suppression on distant peripheral immune organs to effectively prolong long‐term survival after heart transplantation in a chronic murine heart transplantation model. A chemokine C‐C motif ligand 21 (CCL21) specific aptamer for LN targeting is decorated onto the surface of the hybrid nanoparticular delivery vector mainly composed of CaCO3/CaP/heparin. The targeting delivery system can dramatically enhance accumulation of the loaded immunosuppressant, fingolimod hydrochloride (FTY720), in draining lymph nodes (dLNs) for inducing powerful immune suppression. By promoting the generation of endogenous regulatory T cells (Tregs) and decreasing the proportion of effector T cells (Teffs) in dLNs after heart transplantation, the LN‐targeting strategy can effectively regulate local immune responses instead of systemic immunity, which reduces the incidence of long‐term complications. This study provides an efficient strategy to improve the survival rate after organ transplantation by precise and localized immunoregulation with minimized side effects of immunosuppression.
A targeting drug delivery system decorated by a chemokine C‐C motif ligand 21 (CCL21) specific aptamer can realize lymph‐node‐targeted immunomodulation with attenuated immune suppression on distant peripheral immune organs, resulting in effectively prolonged long‐term survival after heart transplantation. This study provides an efficient strategy to achieve precise and localized immunoregulation with minimized side effects of immunosuppression.
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic worldwide. Currently, however, no effective drug or vaccine is available to treat or prevent the ...resulting coronavirus disease 2019 (COVID-19). Here, we report our discovery of a promising anti-COVID-19 drug candidate, the lipoglycopeptide antibiotic dalbavancin, based on virtual screening of the FDA-approved peptide drug library combined with in vitro and in vivo functional antiviral assays. Our results showed that dalbavancin directly binds to human angiotensin-converting enzyme 2 (ACE2) with high affinity, thereby blocking its interaction with the SARS-CoV-2 spike protein. Furthermore, dalbavancin effectively prevents SARS-CoV-2 replication in Vero E6 cells with an EC
of ~12 nM. In both mouse and rhesus macaque models, viral replication and histopathological injuries caused by SARS-CoV-2 infection are significantly inhibited by dalbavancin administration. Given its high safety and long plasma half-life (8-10 days) shown in previous clinical trials, our data indicate that dalbavancin is a promising anti-COVID-19 drug candidate.
Isoniazid(INH) is highly effective for the management of tuberculosis.However,it can cause liver injury and even liver failure.INH metabolism has been thought to be associated with INH-induced liver ...injury.This review summarized the metabolic pathways of INH and discussed their associations with INH-induced liver injury.
Biogas can be produced from distilled grain waste by dry anaerobic digestion, however, digested residue was eluted and needs further treatment. To develop a zero-emission process and achieve ...efficient resource recovery, the compostability of the digested residue was studied. Composting of the digested residue by adding a mature compost and bulking agent was performed using a lab-scale composting reactor. The composting process showed that the degradation of organic matters was mainly occurred during the first 30 days, and the final volatile solid (VS) degradation efficiency was about 15.2%. The digested residue was not suitable as a fertilizer as revealed by the lower germination index (GI) value. However, the composting process produced remarkable results; the physico-chemical parameters indicated that a highly mature end product was obtained 65 days after beginning the composting process. The final nitrogen content, NO3− concentration, and GI value in the final product were 1.7%, 11,128.8 mg·kg−1-TS, and 110.0%, respectively. A highly statically significant correlation was found among the GI, pH, soluble total organic carbon (S-TOC), inorganic carbon (IC), and concentrations of NH4+ and NO3−. The numbers of ammonia oxidizing bacteria (AOB) and archaea (AOA) decreased during the first 12 days, but significant increases occurred during the maturation phase, indicating that AOB and AOA were responsible for nitrification during the composting of digested residue.
•Composting digested residue eluted from dry anaerobic digestion.•The NO3− content in the end product was 11,128.8 mg·kg−1-TS and GI reached 110.0%.•Occurrence of nitrification was attributed to AOB and AOA activity.
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