High serum copper as a risk factor of all-cause and cause-specific mortality among US adults, NHANES 2011-2014.

Background: Several studies have shown that serum copper levels are related to coronary heart disease, diabetes, and cancer. However, the association of serum copper levels with all-cause, cause-specific [including cardiovascular disease (CVD) and cancer] mortality remains unclear. Objectives: This study aimed to prospectively examine the association of copper exposure with all-cause, CVD, and cancer mortality among US adults. Methods: The data for this analysis was obtained from the National Health and Nutrition Examination Survey (NHANES) between 2011 and 2014. Mortality from all-causes, CVD, and cancer mortality was linked to US National Death Index mortality data. Cox regression models were used to estimate the association between serum copper levels and all-cause, CVD, and cancer mortality. Results: A total of 2,863 adults were included in the main study. During the mean follow-up time of 81.2 months, 236 deaths were documented, including 68 deaths from cardiovascular disease and 57 deaths from cancer. The weighted mean overall serum copper levels was 117.2 ug/L. After adjusting for all of the covariates, compared with participants with low (1st tertile, <103 µg/L)/medium (2st tertile, 103-124 µg/L) serum copper levels, participants with high serum copper levels (3rd tertile, ≥124 µg/L) had a 1.75-fold (95% CI, 1.05-2.92)/1.78-fold (1.19,2.69) increase in all-cause mortality, a 2.35-fold (95% CI, 1.04-5.31)/3.84-fold (2.09,7.05) increase in CVD mortality and a 0.97-fold (95% CI, 0.28-3.29)/0.86-fold (0.34,2.13) increase in cancer mortality. In addition, there was a linear dose-response association between serum copper concentration with all-cause and CVD mortality (P for nonlinear > 0.05). Conclusions: This prospective study found that serum copper concentrations were linearly associated with all-cause and CVD mortality in US adults. High serum copper levels is a risk factor for all-cause and CVD mortality.

Minocycline alleviates LPS-induced cognitive dysfunction in mice by inhibiting the NLRP3/caspase-1 pathway.

BACKGROUND: Growing experimental evidence indicates that cognitive impairment is linked to neuroinflammation. Minocycline (MINO), an antibiotic known for its anti-inflammatory, has shown promise in alleviating cognitive impairment. Nonetheless, the exact mechanism through which MINO improves cognitive impairment is not yet understood. METHODS: A neuroinflammatory model was establish by utilizing lipopolysaccharide. The assessment of mice's cognitive and learning abilities was conducted through the MWM and Y-maze tests. The evaluation of hippocampal neuronal injury and microglial activation were achieved by performing HE staining and IHC, respectively. To evaluate BV2 cell viability and apoptosis, the CCK-8 and Hoechst 33342/PI staining assays were employed. In order to assess the protein and RNA expression levels of NLRP3, caspase-1, IL-1ß, IL-18, Iba-1, and Bcl2/Bax, WB and RT-qPCR were utilized. Additionally, the inhibitory effect of MINO on apoptosis by targeting the NLRP3/caspase-1 pathway was investigated using Nigericin. RESULTS: MINO was effective in reducing the time it took for mice to escape from the test, increasing the number of platforms they crossed, and mitigating damage to the hippocampus while also suppressing microglial activation and the expression of Iba-1 in a neuroinflammatory model caused by LPS. Furthermore, MINO improved the viability of BV2 cell and reduced apoptosis. It also had the effect of reducing the expression levels of NLRP3/Caspase-1, IL-1ß, IL-18, and BAX, while upregulating the expression of Bcl2. Additionally, MINO was found to downregulate the NLRP3 expression, which is specifically activated by nigericin. CONCLUSION: The protective effect of MINO relies on the crucial involvement of the NLRP3/caspase-1 pathway.

Dexamethasone upregulates macrophage PIEZO1 via SGK1, suppressing inflammation and increasing ROS and apoptosis.

The side effects of high-dose dexamethasone in anti-infection include increased ROS production and immune cell apoptosis. Dexamethasone effectively activates serum/glucocorticoid-regulated kinase 1 (SGK1), which upregulates various ion channels by activating store-operated calcium entry (SOCE), leading to Ca2+ oscillations. PIEZO1 plays a crucial role in macrophages' immune activity and function, but whether dexamethasone can regulate PIEZO1 by enhancing SOCE via SGK1 activation remains unclear. The effects of dexamethasone were assessed in a mouse model of sepsis, and primary BMDMs and the RAW264.7 were treated with overexpression plasmids, siRNAs, or specific activators or inhibitors to examine the relationships between SGK1, SOCE, and PIEZO1. The functional and phenotypic changes of mouse and macrophage models were detected. The results indicate that high-dose dexamethasone upregulated SGK1 by activating the macrophage glucocorticoid receptor, which enhanced SOCE and subsequently activated PIEZO1. Activation of PIEZO1 resulted in Ca2+ influx and cytoskeletal remodelling. The increase in intracellular Ca2+ mediated by PIEZO1 further increased the activation of SGK1 and ORAI1/STIM1, leading to intracellular Ca2+ peaks. In the context of inflammation, activation of PIEZO1 suppressed the activation of TLR4/NFκB p65 in macrophages. In RAW264.7 cells, PIEZO1 continuous activation inhibited the change in mitochondrial membrane potential, accelerated ROS accumulation, and induced autophagic damage and cell apoptosis in the late stage. CaMK2α was identified as a downstream mediator of TLR4 and PIEZO1, facilitating high-dose dexamethasone-induced macrophage immunosuppression and apoptosis. PIEZO1 is a new glucocorticoid target to regulate macrophage function and activity. This study provides a theoretical basis for the rational use of dexamethasone.

ω3-PUFA alleviates neuroinflammation by upregulating miR-107 targeting PIEZO1/NFκB p65.

BACKGROUND: MiR-107 is reduced in sepsis and associated with inflammation regulation. Dietary supplementation with polyunsaturated fatty acids (ω3-PUFA) can increase the expression of miR-107; this study investigated whether the ω3-PUFA can effectively inhibit neuroinflammation and improve cognitive function by regulating miR-107 in the brain. METHODS: The LPS-induced mouse model of neuroinflammation and the BV2 cell inflammatory model were used to evaluate the effects of ω3-PUFA on miR-107 expression and inflammation. Intraventricular injection of Agomir and Antagomir was used to modulate miR-107 expression. HE and Nissl staining for analyzing hippocampal neuronal damage, immunofluorescence analysis for glial activation, RT-qPCR, and Western blot were conducted to examine miR-107 expression and inflammation signalling. RESULTS: The result shows that LPS successfully induced the mouse neuroinflammation model and BV2 cell inflammation model. Supplementation of ω3-PUFA effectively reduced the secretion of pro-inflammatory factors TNFα, IL1ß, and IL6 induced by LPS, improved cognitive function impairment, and increased miR-107 expression in the brain. Overexpression of miR-107 in the brain inhibited the nuclear factor κB (NFκB) pro-inflammatory signalling pathway by targeting PIEZO1, thus suppressing microglial and astrocyte activation and reducing the release of inflammatory mediators, which alleviated neuroinflammatory damage and improved cognitive function in mice. miR-107, as an intron of PANK1, PANK1 is subject to PPAR α Adjust. ω3-PUFA can activate PPARα, but ω3-PUFA upregulates brain miR-107, and PPARα/PANK1-related pathways may not be synchronized, and further research is needed to confirm the specific mechanism by which ω3-PUFA upregulates miR-107. CONCLUSION: The miR-107/PIEZO1/NFκB p65 pathway represents a novel mechanism underlying the improvement of neuroinflammation by ω3-PUFA.

PIEZO1 as a new target for hyperglycemic stress-induced neuropathic injury: The potential therapeutic role of bezafibrate.

Hyperglycemic stress can directly lead to neuronal damage. The mechanosensitive ion channel PIEZO1 can be activated in response to hyperglycemia, but its role in hyperglycemic neurotoxicity is unclear. The role of PIEZO1 in hyperglycemic neurotoxicity was explored by constructing a hyperglycemic mouse model and a high-glucose HT22 cell model. The results showed that PIEZO1 was significantly upregulated in response to high glucose stress. In vitro experiments have shown that high glucose stress induces changes in neuronal cell morphology and membrane tension, a key mechanism for PIEZO1 activation. In addition, high glucose stress upregulates serum/glucocorticoid-regulated kinase-1 (SGK1) and activates PIEZO1 through the Ca2+ pool and store-operated calcium entry (SOCE). PIEZO1-mediated Ca2+ influx further enhances SGK1 and SOCE, inducing intracellular Ca2+ peaks in neurons. PIEZO1 mediated intracellular Ca2+ elevation leads to calcium/calmodulin-dependent protein kinase 2α (CaMK2α) overactivation, which promotes oxidative stress and apoptosis signalling through p-CaMK2α/ERK/CREB and ox-CaMK2α/MAPK p38/NFκB p65 pathways, subsequently inducing synaptic damage and cognitive impairment in mice. The intron miR-107 of pantothenic kinase 1 (PANK1) is highly expressed in the brain and has been found to target PIEZO1 and SGK1. The PANK1 receptor is activated by peroxisome proliferator-activated receptor α (PPARα), an activator known to upregulate miR-107 levels in the brain. The clinically used lipid-lowering drug bezafibrate, a known PPARα activator, may upregulate miR-107 through the PPARɑ/PANK1 pathway, thereby inhibiting PIEZO1 and improving hyperglycemia-induced neuronal cell damage. This study provides a new idea for the pathogenesis and drug treatment of hyperglycemic neurotoxicity and diabetes-related cognitive dysfunction.

Prevalence of Chronic Kidney Disease Among US Adults With Hypertension, 1999 to 2018.

BACKGROUND: Hypertension is a major cause of end-stage renal disease. Assessing temporal trends in the prevalence of chronic kidney disease (CKD) in hypertension could provide information for public health policies and plans. METHODS: From the National Health and Nutrition Examination Survey from 1999 to 2018, a probability sample of adults aged ≥20 years was collected. The primary outcomes were classified according to the estimated glomerular filtration rate and urinary albumin. Trend tests were performed to assess age-standardized prevalence trends of CKD, albuminuria, and macroalbuminuria in US adults with hypertension. RESULTS: A total of 23 120 US adults with hypertension were included in this study. The prevalence of any CKD, albuminuria, or macroalbuminuria in hypertension remained relatively stable. However, the age-standardized prevalence of stage 1 CKD in hypertension increased from 4.9% in 2003 to 2006 to 7.0% in 2015 to 2018 (P=0.0077 for trend). The age-standardized prevalence of stage 3b CKD in hypertension decreased from 2.9% in 2011 to 2014 to 2.1% in 2015 to 2018 (P=0.0350 for trend). A similar trend was observed for the age-standardized prevalence of stages 3 to 5 CKD in hypertension, which declined from 10.9% in 2011 to 2014 to 8.9% in 2015 to 2018 (P=0.0160 for trend). CONCLUSIONS: Among US adults with hypertension, the prevalence of any CKD, albuminuria, and macroalbuminuria remained relatively stable from 1999 to 2018, whereas the hypertensive population showed an increasing trend in stage 1 CKD from 2003 to 2006 to 2015 to 2018 and a decreasing trend in the prevalence of stages 3 to 5 and 3b CKD from 2011 to 2014 to 2015 to 2018.

Mechanical properties of the brain: Focus on the essential role of Piezo1-mediated mechanotransduction in the CNS.

BACKGROUND: The brain is a highly mechanosensitive organ, and changes in the mechanical properties of brain tissue influence many physiological and pathological processes. Piezo type mechanosensitive ion channel component 1 (Piezo1), a protein found in metazoans, is highly expressed in the brain and involved in sensing changes of the mechanical microenvironment. Numerous studies have shown that Piezo1-mediated mechanotransduction is closely related to glial cell activation and neuronal function. However, the precise role of Piezo1 in the brain requires further elucidation. OBJECTIVE: This review first discusses the roles of Piezo1-mediated mechanotransduction in regulating the functions of a variety of brain cells, and then briefly assesses the impact of Piezo1-mediated mechanotransduction on the progression of brain dysfunctional disorders. CONCLUSIONS: Mechanical signaling contributes significantly to brain function. Piezo1-mediated mechanotransduction regulates processes such as neuronal differentiation, cell migration, axon guidance, neural regeneration, and oligodendrocyte axon myelination. Additionally, Piezo1-mediated mechanotransduction plays significant roles in normal aging and brain injury, as well as the development of various brain diseases, including demyelinating diseases, Alzheimer's disease, and brain tumors. Investigating the pathophysiological mechanisms through which Piezo1-mediated mechanotransduction affects brain function will give us a novel entry point for the diagnosis and treatment of numerous brain diseases.