Impact of chronic kidney disease and end-stage renal disease on the mid-term adverse outcomes in diabetic patients with cardiovascular diseases.

The evidence for the impact of renal dysfunction in patients with diabetes mellitus (DM) and first cardiovascular diseases on mid-term adverse outcomes remain scarce. This study included the data of patients with DM having first atherosclerotic cardiovascular disease (ASCVD) or congestive heart failure (CHF) from the Taipei Medical University Clinical Research Database. A Cox proportional hazards regression model was used to assess the impact of chronic kidney disease (CKD) or end-stage renal disease (ESRD) on the 1-year mortality and recurrent ASCVD/CHF outcomes. We enrolled 21,320 patients with DM hospitalized for ASCVD or CHF; of them, 18,185, 2639, and 496 were assigned to the non-CKD, CKD, and ESRD groups, respectively. After propensity score matching, compared with the non-CKD group, the CKD and ESRD groups had higher mid-term all-cause mortality (adjusted hazard ratio 1.72 [95% confidence interval 1.48-1.99] and 2.77 [2.05-3.73], respectively), cardiovascular death (1.84 [1.44-2.35] and 1.87 [1.08-3.24], respectively), and recurrent hospitalization for ASCVD (1.44 [1.24-1.68] and 2.33 [1.69-3.23], respectively) and CHF (2.08 [1.75-2.47] and 1.50 [1.04-2.17], respectively). The advancing age was associated with mortality in CKD/ESRD groups. In CKD group, male sex was associated with all-cause mortality and recurrent ASCVD risk; the diuretics usage was associated with mortality and recurrent CHF risks. Our findings suggest that CKD and ESRD are significant risk factors for mid-term adverse outcomes in patients with DM and established cardiovascular diseases. Additionally, old age, male sex and diuretics usage requires attention. Further good quality studies are needed in the future.

Nattokinase attenuates endothelial inflammation through the activation of SRF and THBS1.

Natto contains a potent fibrinolytic enzyme called nattokinase (NK), which has thrombolytic, antihypertensive, antiatherosclerotic and lipid-lowering effects. Although NK has been recognized for its beneficial effect on humans with atherosclerotic cardiovascular disease (ASCVD), the underlying mechanisms involved in vascular inflammation-atherosclerosis development remain largely unknown. The current study aimed to explore the effects of NK on gene regulation, autophagy, necroptosis and inflammasome in vascular inflammation. The transcriptional profiles of NK in endothelial cells (ECs) by RNA sequencing (RNA-seq) revealed that NK affected THBS1, SRF and SREBF1 mRNA expression. In Q-PCR analysis, SRF and THBS1 were upregulated but SREBF1 was unaffected in ECs treated with NK. NK treatment induced autophagy and inhibited NLRP3 inflammasome and necroptosis in ECs. Furthermore, the inhibition of SRF or THBS1 by siRNA suppressed autophagy and enhanced the NLRP3 inflammasome and necroptosis. In a mouse model, NK reduced vascular inflammation by activating autophagy and inhibiting NLRP3 inflammasome and necroptosis. Our findings provide the first evidence that NK upregulates SRF and THBS1 genes, subsequently increasing autophagy and decreasing necroptosis and NLRP3 inflammasome formation to reduce vascular inflammation. Therefore, NK could serve as nutraceuticals or adjuvant therapies to reduce vascular inflammation and possible atherosclerosis progression.

Oxidative stress and potential effects of metal nanoparticles: A review of biocompatibility and toxicity concerns.

Metal nanoparticles (M-NPs) have garnered significant attention due to their unique properties, driving diverse applications across packaging, biomedicine, electronics, and environmental remediation. However, the potential health risks associated with M-NPs must not be disregarded. M-NPs' ability to accumulate in organs and traverse the blood-brain barrier poses potential health threats to animals, humans, and the environment. The interaction between M-NPs and various cellular components, including DNA, multiple proteins, and mitochondria, triggers the production of reactive oxygen species (ROS), influencing several cellular activities. These interactions have been linked to various effects, such as protein alterations, the buildup of M-NPs in the Golgi apparatus, heightened lysosomal hydrolases, mitochondrial dysfunction, apoptosis, cell membrane impairment, cytoplasmic disruption, and fluctuations in ATP levels. Despite the evident advantages M-NPs offer in diverse applications, gaps in understanding their biocompatibility and toxicity necessitate further research. This review provides an updated assessment of M-NPs' pros and cons across different applications, emphasizing associated hazards and potential toxicity. To ensure the responsible and safe use of M-NPs, comprehensive research is conducted to fully grasp the potential impact of these nanoparticles on both human health and the environment. By delving into their intricate interactions with biological systems, we can navigate the delicate balance between harnessing the benefits of M-NPs and minimizing potential risks. Further exploration will pave the way for informed decision-making, leading to the conscientious development of these nanomaterials and safeguarding the well-being of society and the environment.

Polystyrene microplastic-induced extracellular vesicles cause kidney-related effects in the crosstalk between tubular cells and fibroblasts.

Plastic waste accumulation and its degradation into microplastics (MPs) and nanoplastics (NPs) pose environmental concerns. Previous studies have indicated that polystyrene (PS)-MPs harm living animals. Extracellular vesicles (EVs) are associated with metabolic reprogramming and mitochondrial dysfunction in various kidney diseases. In this article, we evaluated how PS-MPs affected tubular cells and fibroblasts. The results demonstrated that PS-MPs increased EV production in human tubular cells and caused endoplasmic reticulum (ER) stress-related proteins without inducing inflammation-related proteins in human tubular cells. The uptake of PS-MPs and incubation with the conditioned medium of PS-MPs induced reactive oxygen species (ROS) production and ER stress-related proteins in fibroblast cells. The fibroblast cells treated with the conditioned medium of PS-MPs also increased the expression of fibrosis-related proteins. Our findings suggested that the expression of EV-related markers increased in tubular cells via Beclin 1 after PS-MP treatment. In addition, PS-MPs induced ROS production in vitro and in vivo. We found that PS-MPs also altered the expression of EV markers in urine, and CD63 expression was also increased in vitro and in vivo after PS-MP treatment. In conclusion, PS-MP-induced EVs lead to ER stress-related proteins, ROS production and fibrosis-related proteins in tubular cells and fibroblasts.

Guanylate binding protein 5 triggers NF-κB activation to foster radioresistance, metastatic progression and PD-L1 expression in oral squamous cell carcinoma.

Radioresistance and metastasis are critical issues in managing oral squamous cell carcinoma (OSCC). Although immune checkpoint inhibitors (ICIs) has been recommended to treat OSCC, lacking useful biomarkers limited their anti-cancer effectiveness. We found that guanylate binding protein 5 (GBP5) is upregulated in primary tumors and associates with radioresistance in OSCC. GBP5 expression causally associated with cellular radioresistance and migration ability in the OSCC cell variants. GBP5 upregulation was examined to be correlated with NF-κB activation and programmed cell death-ligand 1 (PD-L1) elevation in OSCC samples. GBP5 knockdown was mitigated, but overexpression enhanced, NF-κB activity and PD-L1 expression in the OSCC cells. NF-κB inhibition by SN50 dramatically suppressed the GBP5-forested irradiation resistance, cellular migration ability and PD-L1 expression in OSCC cells. Importantly, GBP5 upregulation predicted a favorable outcome in cancer patients received ICI treatment. Our findings provide GBP5 as a useful biomarker to predict the anti-OSCC effectiveness of irradiation and ICIs.

AIM2 promotes irradiation resistance, migration ability and PD-L1 expression through STAT1/NF-κB activation in oral squamous cell carcinoma.

BACKGROUND: Radioresistance and lymph node metastasis are common phenotypes of refractory oral squamous cell carcinoma (OSCC). As a result, understanding the mechanism for radioresistance and metastatic progression is urgently needed for the precise management of refractory OSCC. Recently, immunotherapies, e.g. immune checkpoint inhibitors (ICIs), were employed to treat refractory OSCC; however, the lack of predictive biomarkers still limited their therapeutic effectiveness. METHODS: The Cancer Genome Atlas (TCGA)/Gene Expression Omnibus (GEO) databases and RT-PCR analysis were used to determine absent in melanoma 2 (AIM2) expression in OSCC samples. Colony-forming assay and trans-well cultivation was established for estimating AIM2 function in modulating the irradiation resistance and migration ability of OSCC cells, respectively. RT-PCR, Western blot and flow-cytometric analyses were performed to examine AIM2 effects on the expression of programmed death-ligand 1 (PD-L1) expression. Luciferase-based reporter assay and site-directed mutagenesis were employed to determine the transcriptional regulatory activity of Signal Transducer and Activator of Transcription 1 (STAT1) and NF-κB towards the AIM2-triggered PD-L1 expression. RESULTS: Here, we found that AIM2 is extensively upregulated in primary tumors compared to the normal adjacent tissues and acts as a poor prognostic marker in OSCC. AIM2 knockdown mitigated, but overexpression promoted, radioresistance, migration and PD-L1 expression via modulating the activity of STAT1/NF-κB in OSCC cell variants. AIM2 upregulation significantly predicted a favorable response in patients receiving ICI treatments. CONCLUSIONS: Our data unveil AIM2 as a critical factor for promoting radioresistance, metastasis and PD-L1 expression and as a potential biomarker for predicting ICI effectiveness on the refractory OSCC.