Interference in the nutrient-sensing and inflammatory signaling pathways by renal autophagy activation in mice with late stage diabetic nephropathy.

PURPOSE: Disturbance in metabolism and inflammation are the main causes of kidney injury in patients with late stage diabetic nephropathy (DN). Here, we explored whether autophagy was activated in mice with late stage DN and whether it was associated with disturbance in metabolism and inflammation. METHODS: In total, mice were divided into the control group (db/m) and DN group (db/db). Mice were raised for 7 months, and their biochemical indices were measured. Subsequently, their kidneys were collected to detect autophagy and the related nutrient-sensing and inflammatory signaling pathways in late stage DN. RESULTS: The expression levels of autophagy markers LC3-I and LC3-II were significantly increased in mice with late stage DN, whereas that of autophagy flux marker P62 was significantly decreased, indicating activation of autophagy. Concurrently, mechanistic target of rapamycin was highly expressed as a cellular nutrient-sensing and energy regulator in mice with late stage DN. Additionally, the expression levels of markers of nutrient-sensing signaling pathways adenosine monophosphate-activated protein kinase (AMPK) were increased markedly in mice with late stage DN. Additionally, the expression levels of the marker of nutrient-sensing signaling pathways silent information regulator T1 (SIRT1), the marker of inflammatory signaling pathways high mobility group box protein 1 (HMGB1), and interferon regulatory factor 3 (IRF3) were significantly increased in mice with late stage DN. CONCLUSIONS: The findings of our study indicate that autophagy activation in late stage DN may interfere with nutrient-sensing and inflammatory signaling pathways involving AMPK, SIRT1, HMGB1, and IRF3.

Bacterial dynamic of flue-cured tobacco leaf surface caused by change of environmental conditions.

Microorganisms present on the surface of tobacco leaves play a significant role in shaping the composition of the tobacco microbial ecosystem, which undergoes continuous changes throughout the curing process. In the present study, a total of four distinct tobacco curing periods were selected for sampling, namely the fresh, yellowing, leaf-drying, and stem-drying stages. The bacterial 16S rRNA gene sequences of the collected samples were subsequently analyzed to identify operational taxonomic units (OTUs). The findings indicated that the complete dataset of leaf microbial samples was clustered, resulting in the identification of 1,783 operational taxonomic units (OTUs). Furthermore, the analysis of diversity revealed a pattern of initially increasing and subsequently decreasing community diversity. Redundancy Analysis (RDA) and weighted gene correlation networks for analysis (WGCNA) were employed in conjunction with environmental factors to assign OTUs to 22 modules for functional analysis. Additionally, a classification model utilizing the random forest algorithm was utilized to identify seven marker microorganisms (Escherichia coli, Faecalibacterium prausnitzii, Faecalibacterium, Escherichia-Shigella, Peptostreptococcaceae, Peptostreptococcales-Tissierellales, and Proteobacteria) that exhibited discriminative characteristics across different time periods. This study aimed to investigate the dynamic changes in the bacterial community throughout the curing process and their impact on the community's function. Additionally, certain bacteria were identified as potential markers for detecting changes in the curing stage. These findings offer a novel opportunity to accurately regulate the curing environment, thereby enhancing the overall quality of tobacco leaf curing.

The dysregulation of immune cells induced by uric acid: mechanisms of inflammation associated with hyperuricemia and its complications.

Changes in lifestyle induce an increase in patients with hyperuricemia (HUA), leading to gout, gouty arthritis, renal damage, and cardiovascular injury. There is a strong inflammatory response in the process of HUA, while dysregulation of immune cells, including monocytes, macrophages, and T cells, plays a crucial role in the inflammatory response. Recent studies have indicated that urate has a direct impact on immune cell populations, changes in cytokine expression, modifications in chemotaxis and differentiation, and the provocation of immune cells by intrinsic cells to cause the aforementioned conditions. Here we conducted a detailed review of the relationship among uric acid, immune response, and inflammatory status in hyperuricemia and its complications, providing new therapeutic targets and strategies.

TGF-ß1 peptide-based inhibitor P144 ameliorates renal fibrosis after ischemia-reperfusion injury by modulating alternatively activated macrophages.

OBJECTIVES: Ischemia-reperfusion injury (IRI) is a major cause of chronic renal fibrosis. Currently, numerous therapies have shown a minimal effect on the blockade of fibrosis progression. Here, the therapeutic potential of peptide-based TGF-ß1 inhibitor P144 in IRI-induced renal fibrosis and the underlying mechanism were analyzed. MATERIALS AND METHODS: The unilateral ischemia-reperfusion injury with the contralateral nephrectomy model was established, and the P144 was administered intravenously 1d/14d after the onset of IRI. The histopathology and immunofluorescence staining were used to detect renal fibrosis and macrophage infiltration. The in vivo fluorescence imaging was used to measure the bio-distribution of P144. The transwell assays were used to observe the migration of macrophages. RT-qPCR and western blot were used to analyze TGF-ß1 signaling. RESULTS: P144 ameliorated the accumulation of extracellular matrix in the kidney and improved the renal function in the unilateral ischemia-reperfusion injury plus contralateral nephrectomy model. Mechanistically, P144 downregulated the TGF-ß1-Smad3 signaling at both the transcriptional and translational levels and further reduced the TGF-ß1-dependent infiltration of macrophages to the injured kidney. Additionally, P144 blocked the polarization of macrophages to an M2-like phenotype induced by TGF-ß1 in vitro, but showed no effect on their proliferation. CONCLUSIONS: Our study showed that the TGF-ß1 peptide-based inhibitor P144 decreased renal fibrosis through the blockade of the TGF-ß1-Smad3 signaling pathway and the modulation of macrophage polarization, suggesting its potential therapeutic use in IRI-induced renal fibrosis.

Expression characteristics of interferon-stimulated genes and possible regulatory mechanisms in lupus patients using transcriptomics analyses.

BACKGROUND: Type I interferon signature is one of the most important features of systemic lupus erythematosus (SLE), which indicates an active immune response to antigen invasion. Characteristics of type I interferon-stimulated genes (ISGs) in SLE patients have not been well described thus far. METHODS: We analyzed 35,842 cells of PBMC single-cell RNA sequencing data of five SLE patients and three healthy controls. Thereafter, 178 type I ISGs among DEGs of all cell clusters were screened based on the Interferome Database and AUCell package was used for ISGs activity calculation. To determine whether common ISG features exist in PBMCs and kidneys of patients with SLE, we analyzed kidney transcriptomic data from patients with lupus nephritis (LN) from the GEO database. MRL/lpr mice model were used to verify our findings. FINDINGS: We found that monocytes, B cells, dendritic cells, and granulocytes were significantly increased in SLE patients, while subsets of T cells were significantly decreased. Neutrophils and low-density granulocytes (LDGs) exhibited the highest ISG activity. GO and pathway enrichment analyses showed that DEGs focused on leukocyte activation, cell secretion, and pathogen infection. Thirty-one common ISGs were found expressed in both PBMCs and kidneys; these ISGs were also most active in neutrophils and LDGs. Transcription factors including PLSCR1, TCF4, IRF9 and STAT1 were found to be associated to ISGs expression. Consistently, we found granulocyte infiltration in the kidneys of MRL/lpr mice. Granulocyte inhibitor Avacopan reduced granulocyte infiltration and reversed renal conditions in MRL/lpr mice. INTERPRETATION: This study shows for the first time, the use of the AUCell method to describe ISG activity of granulocytes in SLE patients. Moreover, Avacopan may serve as a granulocyte inhibitor for treatment of lupus patients in the future. FUNDING: None.

Estimation of Vibration Characteristics of a Space Manipulator From Air Bearing Supported Test Data.

Space manipulators have attracted much attention due to their implications in on-orbit servicing in recent years. Air bearing based support equipment is widely used for ground test to offset the effect of gravity. However, an air bearing support introduces a new problem caused by additional inertial and mass properties. Additional mass and inertial load will influence the dynamics behavior, especially stiffness information and vibration response of the whole ground test system. In this paper, a set of procedures are presented to remove the influence of air bearings and identify the true equivalent joint stiffness and damping from the test data of a motor-braked space manipulator with an air bearing support. First, inertia parameters are identified. Then, the equivalent joint stiffness and damping are determined by using a genetic algorithm (GA) method. Finally, true vibration characteristics of the manipulator are estimated by removing the additional inertia caused by the air bearings. Moreover, simulations and experiments are carried out to validate the presented procedures.

Advancements in Tobacco (Nicotiana tabacum L.) Seed Oils for Biodiesel Production.

With the increasing demand for fossil fuels, decreasing fossil fuel reserves and deteriorating global environment, humanity urgently need to explore new clean and renewable energy to replace fossil fuel resources. Biodiesel, as an environmentally friendly fuel that has attracted considerable attention because of its renewable, biodegradable, and non-toxic superiority, seems to be a solution for future fuel production. Tobacco (Nicotiana tabacum L.), an industrial crop, is traditionally used for manufacturing cigarettes. More importantly, tobacco seed is also widely being deemed as a typical inedible oilseed crop for the production of second-generation biodiesel. Advancements in raw material and enhanced production methods are currently needed for the large-scale and sustainable production of biodiesel. To this end, this study reviews various aspects of extraction and transesterification methods, genetic and agricultural modification, and properties and application of tobacco biodiesel, while discussing the key problems in tobacco biodiesel production and application. Besides, the proposals of new ways or methods for producing biodiesel from tobacco crops are presented. Based on this review, we anticipate that this can further promote the development and application of biodiesel from tobacco seed oil by increasing the availability and reducing the costs of extraction, transesterification, and purification methods, cultivating new varieties or transgenic lines with high oilseed contents, formulating scientific agricultural norms and policies, and improving the environmental properties of biodiesel.