Nonalcoholic fatty liver disease (NAFLD) is strongly linked to the global epidemic of obesity and type 2 diabetes mellitus (T2DM). Notably, NAFLD can progress from the mildest form of simple ...steatosis to nonalcoholic steatohepatitis (NASH) that increases the risk for hepatocellular carcinoma (HCC), which is a malignancy with a dismal prognosis and rising incidence in the United States and other developed counties, possibly due to the epidemic of NAFLD. Metformin, the first-line drug for T2DM, has been suggested to reduce risks for several types of cancers including HCC and protect against NASH-related HCC, as revealed by epidemical studies on humans and preclinical studies on animal models. This review focuses on the pathogenesis of NASH-related HCC and the mechanisms by which metformin inhibits the initiation and progression of NASH-related HCC. Since the functional role of immune cells in liver homeostasis and pathogenesis is increasingly appreciated in developing anti-cancer therapies on liver malignancies, we discuss both the traditional targets of metformin in hepatocytes and the recently defined effects of metformin on immune cells.
Mitochondrial damage is involved in the pathogenesis of osteoarthritis. Metformin, one of the most common prescriptions for patients with type 2 diabetes, can reportedly activate Sirtuin 3 (SIRT3) ...expression which protects mitochondria from oxidative stress. In this study, we investigated the inhibitory property of metformin on mitochondrial damage by focusing on the interleukin-1 beta (IL-1β)-stimulated osteoarthritis model by using primary murine chondrocytes. Our results demonstrated that SIRT3 was downregulated in chondrocytes under IL-1β stimulation, where its expression was positively correlated with mitochondrial damage and reactive oxygen species (ROS) production. Metformin treatment upregulated SIRT3 expression and mitigated loss of cell viability and decreased the generation of mitochondria-induced ROS in chondrocytes stimulated with IL-1β. Metformin also attenuated IL-1β-induced expressions of catabolic genes such as matrix metalloproteinase-3 (MMP3) and MMP13 and enhanced the anabolic indicator Collagen Ⅱ. These effects were mediated by phosphatase and tensin homolog (PTEN)-induced putative kinase protein 1 (PINK1)/Parkin-dependent mitophagy and the autophagic elimination of damaged mitochondria. Further, the SIRT3 inhibitor 3-TYP effectively inhibited the initiation of mitophagy, as decreased expression of PINK1 and Parkin, decreased the LC3II/LC3I, enhanced the expression of MMP3 and MMP13, and decreased the expression of Collagen Ⅱ. Overall, our findings provide evidence that metformin suppresses IL-1β-induced oxidative and osteoarthritis-like inflammatory changes by enhancing the SIRT3/PINK1/Parkin signaling pathway, thereby indicating metformin's potential in prevention and treatment of osteoarthritic joint disease.
The cool skin effect refers to the phenomenon where the surface skin temperature of the ocean is always slightly cooler than the temperature of the water directly underneath due to the ubiquitous ...cooling processes at the ocean surface, especially in the absence of solar radiation. The cool skin effect plays a critical role in the estimation of heat, momentum, and gas exchange between the air and the sea. However, the scarcity of observational data greatly hinders the accurate assessment of the cool skin effect. Here, the matchup data from the new generation geostationary satellite Himawari-8 and in situ sea surface temperature (SST) observations are used to evaluate the performance and dependence on the cool skin effect in the low/mid-latitude oceans. Results show that the intensity of the cool skin effect as revealed by Himawari-8 (−0.16 K) is found to be relatively weaker than previously published cool skin models based on in situ concurrent observations. A considerable amount of warm skin signals has been detected in the high-latitude oceans (e.g., Southern Ocean) under the circumstances of positive air–sea temperature difference and high wind, which may be the main cause of discrepancies with previous thoughts on the cool skin effect.
Owing to the growing infectious diseases caused by eukaryotic and prokaryotic pathogens, it is urgent to develop novel antimicrobial agents against clinical pathogenic infections. Biofilm formation ...and invasion into the host cells are vital processes during pathogenic colonization and infection. In this study, we tested the inhibitory effect of Au nanoparticles (AuNPs) on pathogenic growth, biofilm formation and invasion. Interestingly, although the synthesized AuNPs had no significant toxicity to the tested pathogens, Candida albicans and Pseudomonas aeruginosa, the nanoparticles strongly inhibited pathogenic biofilm formation and invasion to dental pulp stem cells (DPSCs). Further investigations revealed that AuNPs abundantly bound to the pathogen cells, which likely contributed to their inhibitory effect on biofilm formation and invasion. Moreover, treatment of AuNPs led to activation of immune response-related genes in DPSCs, which may enhance the activity of host immune system against the pathogens. Zeta potential analysis and polyethylene glycol (PEG)/polyethyleneimine (PEI) coating tests further showed that the interaction between pathogen cells and AuNPs is associated with electrostatic attractions. Our findings shed novel light on the application of nanomaterials in fighting against clinical pathogens, and imply that the traditional growth inhibition test is not the only way to evaluate the drug effect during the screening of antimicrobial agents.
Metal 3D nanoprinting with coupled fields Liu, Bingyan; Liu, Shirong; Devaraj, Vasanthan ...
Nature communications,
08/2023, Letnik:
14, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Abstract
Metallized arrays of three-dimensional (3D) nanoarchitectures offer new and exciting prospects in nanophotonics and nanoelectronics. Engineering these repeating nanoarchitectures, which have ...dimensions smaller than the wavelength of the light source, enables in-depth investigation of unprecedented light–matter interactions. Conventional metal nanomanufacturing relies largely on lithographic methods that are limited regarding the choice of materials and machine write time and are restricted to flat patterns and rigid structures. Herein, we present a 3D nanoprinter devised to fabricate flexible arrays of 3D metallic nanoarchitectures over areas up to 4 × 4 mm
2
within 20 min. By suitably adjusting the electric and flow fields, metal lines as narrow as 14 nm were printed. We also demonstrate the key ability to print a wide variety of materials ranging from single metals, alloys to multimaterials. In addition, the optical properties of the as-printed 3D nanoarchitectures can be tailored by varying the material, geometry, feature size, and periodic arrangement. The custom-designed and custom-built 3D nanoprinter not only combines metal 3D printing with nanoscale precision but also decouples the materials from the printing process, thereby yielding opportunities to advance future nanophotonics and semiconductor devices.
Chondrocyte dysfunction is a key mechanism underlying osteoarthritis. Metformin has shown protective effects in many diseases. The present study aimed to investigate the effects of metformin on ...autophagy and apoptosis in the process of osteoarthritis. A mouse osteoarthritis model was set up by surgically destabilizing medial meniscus in the knee. Intraarticular injection of metformin or vehicle was applied in the right knee for eight weeks. Mouse articular chondrocytes were isolated and passaged for
in vitro
experiments. Small interfering RNA (siRNA) transfection was used to silence target genes. Western blotting, immunohistochemistry, transmission electron microscopy were used. After eight weeks, metformin restored surgery-induced upregulation of MMP13 and downregulation of type II collagen in the joint cartilage. In cultured primary murine chondrocytes, IL-1β aggravated apoptosis and catabolic response in a dose-dependent manner. In the presence of IL-1β, metformin increased phosphorylated levels of AMPKα and upregulated SIRT1 protein expression, leading to an increase in autophagy as well as a decrease in catabolism and apoptosis. Inactivating AMPKα or inhibiting SIRT1 prevented the augmented autophagy in the presence of metformin. Silencing AMPKα2, but not AMPKα1, reduced SIRT1 expression and downregulated autophagy in cultured chondrocytes. Metformin protects against IL-1β-induced extracellular matrix (ECM) degradation in cultured chondrocytes and in mouse osteoarthritis model through activating AMPKα/SIRT1 signaling. Metformin shed light on the treatment of osteoarthritis.
Although diabetic cognitive impairment is one of the most common complications of type 2 diabetes mellitus (T2DM), optimized therapeutic strategies are not available yet. Astragalosides IV (AS-IV) is ...a traditional Chinese medicine possessing diverse pharmacological properties including anti-inflammatory and antioxidant effects. However, the effects of AS-IV on diabetes-related cognitive impairment and its precise mechanisms remain largely unknown. T2DM mice, induced by a high-fat diet (HFD) and an intraperitoneal injection of low-dose streptozotocin (STZ) were administrated with AS-IV every other day for eight consecutive weeks. Learning and memory abilities were assessed subsequently using the Ymaze test and the anxious behavior was evaluated using an open field test. Then, the morphology and number of neurons and microglia were observed by HE staining or immunohistochemistry. Oxidative stress biomarkers and pro-inflammatory cytokines were determined using relevant kits. In addition, the expression levels of Nrf2, Keap1, HO-1, and NQO1 were determined by Western blot analyses. The results indicated that AS-IV administration significantly improved neuronal damage and cognitive deficit in T2DM mice. Meanwhile, oxidative stress and neuroinflammation were also ameliorated in T2DM mice, which might be attributed to the regulation of Nrf2/Keap1/HO-1/NQO1 pathway in T2DM mice. Taken together, these data suggested that AS-IV ameliorates cognitive impairment in T2DM mice by attenuating oxidative stress and neuroinflammation, possibly through modulating the Nrf2/Keap1/HO1/NQO1 pathway.
Glioma, especially its most malignant type, Glioblastoma (GBM), is the most common and the most aggressive malignant tumour in the central nervous system. Currently, we have no specific therapies ...that can significantly improve its dismal prognosis. Recent studies have reported promising in vitro experimental results of several novel glioma-targeting drugs; these studies are encouraging to both researchers and patients. However, clinical trials have revealed that novel compounds that focus on a single, clear glioma genetic alteration may not achieve a satisfactory outcome or have side effects that are unbearable. Based on this consensus, phytochemicals that exhibit multiple bioactivities have recently attracted much attention. Traditional Chinese medicine and traditional Indian medicine (Ayurveda) have shown that phytocompounds inhibit glioma angiogenesis, cancer stem cells and tumour proliferation; these results suggest a novel drug therapeutic strategy. However, single phytocompounds or their direct usage may not reverse comprehensive malignancy due to poor histological penetrability or relatively unsatisfactory in vivo efficiency. Recent research that has employed temozolomide combination treatment and Nanoparticles (NPs) with phytocompounds has revealed a powerful dual-target therapy and a high blood-brain barrier penetrability, which is accompanied by low side effects and strong specific targeting. This review is focused on major phytocompounds that have contributed to glioma-targeting treatment in recent years and their role in drug resistance inhibition, as well as novel drug delivery systems for clinical strategies. Lastly, we summarize a possible research strategy for the future.
The
genus contains abundant economically important vegetable and oilseed crops, which are under threat of diseases caused by fungal, bacterial and viral pathogens. Resistance gene analogues (RGAs) ...are associated with quantitative and qualitative disease resistance and the identification of candidate RGAs associated with disease resistance is crucial for understanding the mechanism and management of diseases through breeding. The availability of
genome assemblies has greatly facilitated reference-based quantitative trait loci (QTL) mapping for disease resistance. In addition, pangenomes, which characterise both core and variable genes, have been constructed for
,
and
. Genome-wide characterisation of RGAs using conserved domains and motifs in reference genomes and pangenomes reveals their clustered arrangements and presence of structural variations. Here, we comprehensively review RGA identification in important
genome and pangenome assemblies. Comparison of the RGAs in QTL between resistant and susceptible individuals allows for efficient identification of candidate disease resistance genes. However, the reference-based QTL mapping and RGA candidate identification approach is restricted by the under-represented RGA diversity characterised in the limited number of
assemblies. The species-wide repertoire of RGAs make up the pan-resistance gene analogue genome (pan-RGAome). Building a pan-RGAome, through either whole genome resequencing or resistance gene enrichment sequencing, would effectively capture RGA diversity, greatly expanding breeding resources that can be utilised for crop improvement.
Neuroinflammation plays critical roles in vascular dementia (VaD), the second leading cause of dementia, which can be induced by chronic cerebral hypoperfusion (CCH). NLRP3 inflammasome-induced ...pyroptosis, the inflammatory programmed cell death, has been reported to contribute to the development of VaD. ChemR23 is a G protein-coupled receptor that has emerging roles in regulating inflammation. However, the role of ChemR23 signalling in NLRP3 inflammasome-induced pyroptosis in CCH remains elusive. In this study, a CCH rat model was established by permanent bilateral common carotid artery occlusion (BCCAO) surgery. Eight weeks after the surgery, the rats were intraperitoneally injected with the ChemR23 agonist Resolvin E1 (RvE1) or chemerin-9 (C-9). Additionally, primary rat hippocampal neurons and SH-SY5Y cells were adopted to mimic CCH injury in vitro. Our results showed that the levels of ChemR23 expression were decreased from the 8th week after BCCAO, accompanied by significant cognitive impairment. Further analysis revealed that CCH induced neuronal damage, synaptic injury and NLRP3-related pyroptosis activation in hippocampal neurons. However, pharmacologic activation of ChemR23 with RvE1 or C-9 counteracted these changes. In vitro experiments also showed that ChemR23 activation prevented primary neuron pyroptosis induced by chronic hypoxia. In addition, manipulating ChemR23 expression markedly regulated NLRP3 inflammasome-induced neuronal pyroptosis through PI3K/AKT/Nrf2 signalling in SH-SY5Y cells under hypoglycaemic and hypoxic conditions. Collectively, our data demonstrated that ChemR23 activation inhibits NLRP3 inflammasome-induced neuronal pyroptosis and improves cognitive function via the PI3K/AKT/Nrf2 signalling pathway in CCH models. ChemR23 may serve as a potential novel therapeutic target to treat CCH-induced cognitive impairment.
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