Pyroptosis, one kind of inflammatory regulated cell death, is involved in various inflammatory diseases, including acute kidney injury (AKI). Besides Gasdermin D (GSDMD), GSDME is a newly identified ...mediator of pyroptosis via the cleavage of caspase-3 generating pyroptotic GSDME-N. Here, we investigated the role of GSDME in renal cellular pyroptosis and AKI pathogenesis employing GSDME-deficient mice and human tubular epithelial cells (TECs) with the interventions of pharmacological and genetic approaches. After cisplatin treatment, GSDME-mediated pyroptosis was induced as shown by the characteristic pyroptotic morphology in TECs, upregulated GSDME-N expression and enhanced release of IL-1β and LDH, and decreased cell viability. Strikingly, silencing GSDME in mice attenuated acute kidney injury and inflammation. The pyroptotic role of GSDME was also verified in human TECs in vitro. Further investigation showed that inhibition of caspase-3 blocked GSDME-N cleavage and attenuated cisplatin-induced pyroptosis and kidney dysfunction. Moreover, deletion of GSDME also protected against kidney injury induced by ischemia-reperfusion. Taken together, the findings from current study demonstrated that caspase-3/GSDME-triggered pyroptosis and inflammation contributes to AKI, providing new insights into the understanding and treatment of this disease.
Long noncoding RNA HULC is highly up-regulation in human hepatocellular carcinoma (HCC). However, the functions of HULC in hepatocarcinogenesis remains unclear.
RT-PCR, Western blotting, Chromatin ...immunoprecipitation (CHIP) assay, RNA Immunoprecipitation (RIP) and tumorignesis test in vitro and in vivo were performed.
HULC is negatively associated with expression of PTEN or miR15a in patients of human liver cancer. Moreover, HULC accelerates malignant progression of liver cancer cells in vitro and in vivo. Mechanistically, HULC increasesthe expression of P62 via decreasing mature miR15a. On the other hand, excessive HULC increases the expression of LC3 on the level of transcription and then activates LC3 through Sirt1 (a deacetylase). Notably, HULC enhanced the interplay between LC3 and ATG3. Furthermore, HULC also increases the expression of becline-1(autophagy related gene). Therefore, HULC increases the cellular autophagy by increasing LC3II dependent on Sirt1.Noteworthy, excessive HULC reduces the expression of PTEN, β-catenin and enhances the expression of SAPK/JUNK, PKM2, CDK2, NOTCH1, C-Jun in liver cancer cells. Of significance, our observations also revealed that HULC inhibited PTEN through ubiquitin-proteasome system mediated by autophagy-P62.Ultimately,HULC activates AKT-PI3K-mTOR pathway through inhibiting PTEN in human liver cancer cells.
This study elucidates a novel mechanism that lncRNA HULC produces a vital function during hepatocarcinogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Candida krusei
attracts attention from medical professionals mainly for its intrinsic resistance to fluconazole and the limited number of drugs available to treat
C. krusei
vulvovaginal candidiasis. ...Miltefosine was demonstrated to have good antifungal activity both
in vitro
and
in vivo
. Here, we determined the susceptibility profiles of 57 clinical
C. krusei
isolates from vulvovaginal candidiasis patients and assessed the antifungal activity of miltefosine against
C. krusei
. All isolates were susceptible to voriconazole and itraconazole, whereas 1.8% of the isolates were of non-wild-type phenotype to amphotericin B. In contrast, miltefosine showed low MICs against all
C. krusei
isolates with fungicidal activity. The checkerboard assay showed that the synergistic effect of miltefosine in combination with amphotericin B was observed in 25% of the tested planktonic
C. krusei
isolates and 18.8% of the tested preformed biofilms, whereas miltefosine in combination with fluconazole showed indifferent interaction for all tested planktonic isolates. The presence of sorbitol in the broth microdilution assay did not influence the MIC values of miltefosine against
C. krusei
, but the presence of ergosterol increased the MIC values. Visible changes in cell content in cells treated with miltefosine were observed. We found that cells treated with miltefosine showed decreased cell viability and chromatin condensation under PI staining, which indicates that miltefosine may induce apoptosis-like cell death in
C. krusei
. In conclusion, we found miltefosine has a good activity against
C. krusei
isolates and exerts its fungicidal effect by binding to ergosterol in the cell membrane and inducing apoptosis.
Silence behavior is a common and influential phenomenon in organizations. Scholars have explored a lot of antecedents for silence behavior, but rarely from the perspective of colleagues. Based on the ...conservation of resources theory and self-regulation theory, the study constructs a double-moderated mediating model to explore the relationship between workplace suspicion and silence behavior as well as its mechanism. This study conducts a three-wave questionnaire survey and adopts 303 valid pairs of samples from 23 companies in China to validate the research hypotheses. A confirmatory factor analysis in the AMOS software and the PROCESS bootstrapping program in SPSS is used in this study. Our findings indicate that workplace suspicion is positively correlated with silence behavior; knowledge hiding mediates the relationship between workplace suspicion and silence behavior; knowledge-based psychological ownership moderates this mediating effect by strengthening the negative impact of workplace suspicion on knowledge hiding; and face consciousness moderates the mediating effect by weakening the positive impact of workplace suspicion on knowledge hiding. Managerial and practical implications, limitations, and future research directions are discussed and offered.
Atomic-level structure engineering can substantially change the chemical and physical properties of materials. However, the effects of structure engineering on the capacitive properties of electrode ...materials at the atomic scale are poorly understood. Fast transport of ions and electrons to all active sites of electrode materials remains a grand challenge. Here, we report the radical modification of the pseudocapacitive properties of an oxide material, Zn
Co
O, via atomic-level structure engineering, which changes its dominant charge storage mechanism from surface redox reactions to ion intercalation into bulk material. Fast ion and electron transports are simultaneously achieved in this mixed oxide, increasing its capacity almost to the theoretical limit. The resultant Zn
Co
O exhibits high-rate performance with capacitance up to 450 F g
at a scan rate of 1 V s
, competing with the state-of-the-art transition metal carbides. A symmetric device assembled with Zn
Co
O achieves an energy density of 67.3 watt-hour kg
at a power density of 1.67 kW kg
, which is the highest value ever reported for symmetric pseudocapacitors. Our finding suggests that the rational design of electrode materials at the atomic scale opens a new opportunity for achieving high power/energy density electrode materials for advanced energy storage devices.
Cisplatin is extensively used and is highly effective in clinical oncology; nevertheless, nephrotoxicity has severely limited its widespread utility. Isoquercitrin (IQC), a natural flavonoid widely ...found in herbage, is well known and recognized for its antioxidant, anti-inflammatory, and anti-apoptotic properties. However, the potential effects and mechanism of IQC in cisplatin-induced acute kidney diseases remain unknown. In this study, we postulated the potential effects and mechanism of IQC upon cisplatin exposure
and
. For the
study, C57BL/6J mice were pretreated with IQC or saline (50 mg/kg/day) by gavage for 3 days before cisplatin single injection (25 mg/kg). Renal function, apoptosis, inflammation, oxidative stress and p-ERK were measured to evaluate kidney injury.
, mouse proximal tubular cells (mPTCs) and human proximal tubule epithelial cell line (HK2) were pretreated with or without IQC (80 μM for mPTCs and 120 μM for HK2) for 2 h and then co-administrated with cisplatin for another 24 h. Apoptosis, inflammation, ROS and p-ERK of cells were also measured.
, IQC administration strikingly reduced cisplatin-induced nephrotoxicity as evidenced by the improvement in renal function (serum creatinine and blood urea nitrogen), kidney histology (PAS staining), apoptotic molecules (cleaved caspase-3, caspase-8, Bax and Bcl-2), inflammatory cytokines (IL-1β, IL-6, TNF-α, and COX-2), oxidative stress (MDA and total glutathione) and p-ERK. In line with
findings, IQC markedly protected against cisplatin-induced cell injury in mPTCs and HK2 cells. Collectively, these findings demonstrated that IQC administration could significantly protect against cisplatin nephrotoxicity possibly through ameliorating apoptosis, inflammation and oxidative stress accompanied by cross talk with p-ERK. Furthermore, IQC may have potential therapeutic uses in the treatment of cisplatin-induced acute kidney injury.
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•A total of 50 chemical compounds were identified from the aqueous decoction of oven-dried (DCF) and shade-dried Chrysanthemi Flos (SCF).•Chrysanthemi Flos showed hypotensive, ...lipid-regulating, and liver and kidney damage-reducing effects in MetS disease.•The eight metabolites considered as potential biomarkers for the treatment of MetS.•No significant difference between DCF and SCF for the treatment of MetS.
As an important medicinal and dietary flower tea, Chrysanthemi Flos has hypotensive, hypolipidemic and hypoglycaemic benefits. This study investigated the effects of two types of processed Chrysanthemi Flos products—oven-dried Chrysanthemi Flos (DCF) and shade-dried Chrysanthemi Flos (SCF)—on rats with metabolic syndrome (MetS) and their potential mechanisms of action. The pharmacodynamic analysis showed that DCF and SCF improved hypertension, regulated lipid profiles, and reduced liver and kidney damage. Metabolomics analysis revealed eight metabolites, including L-serine, oxaloacetate and succinate as potential biomarkers for mitigating metabolic disorders in MetS rats. Our findings provide scientific evidence for the integration of Chrysanthemi Flos-based products into clinical dietary interventions, offering insights into the mechanisms through which these products can ameliorate MetS. These results have important implications for the development of functional foods that can improve metabolic health.
Exposure to particulate matter (PM) from agricultural environments has been extensively reported to cause respiratory health concerns in both animals and agricultural workers. Furthermore, PM from ...agricultural environments, containing fungal spores, has emerged as a significant threat to public health and the environment. Despite its potential toxicity, the impact of fungal spores present in PM from agricultural environments on the lung microbiome and metabolic profile is not well understood. To address this gap in knowledge, we developed a mice model of immunodeficiency using cyclophosphamide and subsequently exposed the mice to fungal spores via the trachea. By utilizing metabolomics techniques and 16 S rRNA sequencing, we conducted a comprehensive investigation into the alterations in the lung microbiome and metabolic profile of mice exposed to fungal spores. Our study uncovered significant modifications in both the lung microbiome and metabolic profile post-exposure to fungal spores. Additionally, fungal spore exposure elicited noticeable changes in α and β diversity, with these microorganisms being closely associated with inflammatory factors. Employing non-targeted metabolomics analysis via GC-TOF-MS, a total of 215 metabolites were identified, among which 42 exhibited significant differences. These metabolites are linked to various metabolic pathways, with amino sugar and nucleotide sugar metabolism, as well as galactose metabolism, standing out as the most notable pathways. Cysteine and methionine metabolism, along with glycine, serine and threonine metabolism, emerged as particularly crucial pathways. Moreover, these metabolites demonstrated a strong correlation with inflammatory factors and exhibited significant associations with microbial production. Overall, our findings suggest that disruptions to the microbiome and metabolome may hold substantial relevance in the mechanism underlying fungal spore-induced lung damage in mice.
•Metabolomics and 16 S rRNA studied fungal exposure impact on mouse lungs.•Fungal spore exposure alters the lung microbiome and its metabolites.•Fungal spore exposure disrupts a variety of metabolic pathways.•Lung metabolites showed notable correlations with microbial or inflammatory factors.
Enhanced mitochondrial respiration in vascular smooth muscle cells (VSMCs) is involved in neointima formation in response to vascular injury. In the present study, we investigated the effect of ...rotenone (ROT), a mitochondrial respiratory chain complex I inhibitor, on VSMC proliferation and migration in vitro, and on femoral artery neointimal hyperplasia induced by wire injury. ROT treatment remarkably ameliorated neointima formation after vascular injury in line with the reduced collagen deposition and significantly restored α-smooth muscle actin (SMA) expression in the neointima. In vitro, ROT markedly suppressed platelet-derived growth factor (PDGF)-BB-induced mouse aorta smooth muscle (MOVA) cell proliferation, migration, and adenosine triphosphate (ATP) production, while the cell viability of MOVA cells was not affected by ROT at concentrations of 10–100 nM. Meanwhile, ROT blocked PDGF-BB-induced cell cycle progression by arresting cell cycle in G0/G1 phase. Interestingly, ROT inhibited the phosphorylation of protein kinase B (AKT), but not extracellular signal-regulated kinase (ERK) 1/2, in response to PDGF-BB, accompanied with the blockade of matrix metalloproteinase-9 (MMP-9) upregulation and reactive oxygen species (ROS) production. These findings indicated that ROT could block neointima formation by preventing the proliferation and migration of MOVA cells, possibly by inhibiting the mitochondrial respiratory chain activity, ATP production, AKT phosphorylation, MMP-9 activation, and ROS production. Thus, inhibiting mitochondrial respiratory chain activity might represent a new strategy to treat neointima formation-associated vascular diseases.
•Rotenone attenuated neointima formation induced by wire injury.•Rotenone prevented the proliferation and migration of MOVA cells.•Rotenone blocked AKT phosphorylation and ROS production in MOVA cells.
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