Microglial hyperactivation of the NOD‐, LRR‐, and pyrin domain‐containing 3 (NLRP3) inflammasome contributes to the pathogenesis of Parkinson's disease (PD). Recently, neuronally expressed NLRP3 was ...demonstrated to be a Parkin polyubiquitination substrate and a driver of neurodegeneration in PD. However, the role of Parkin in NLRP3 inflammasome activation in microglia remains unclear. Thus, we aimed to investigate whether Parkin regulates NLRP3 in microglia. We investigated the role of Parkin in NLRP3 inflammasome activation through the overexpression of Parkin in BV2 microglial cells and knockout of Parkin in primary microglia after lipopolysaccharide (LPS) treatment. Immunoprecipitation experiments were conducted to quantify the ubiquitination levels of NLRP3 under various conditions and to assess the interaction between Parkin and NLRP3. In vivo experiments were conducted by administering intraperitoneal injections of LPS in wild‐type and Parkin knockout mice. The Rotarod test, pole test, and open field test were performed to evaluate motor functions. Immunofluorescence was performed for pathological detection of key proteins. Overexpression of Parkin mediated NLRP3 degradation via K48‐linked polyubiquitination in microglia. The loss of Parkin activity in LPS‐induced mice resulted in excessive microglial NLRP3 inflammasome assembly, facilitating motor impairment, and dopaminergic neuron loss in the substantia nigra. Accelerating Parkin‐induced NLRP3 degradation by administration of a heat shock protein (HSP90) inhibitor reduced the inflammatory response. Parkin regulates microglial NLRP3 inflammasome activation through polyubiquitination and alleviates neurodegeneration in PD. These results suggest that targeting Parkin‐mediated microglial NLRP3 inflammasome activity could be a potential therapeutic strategy for PD.
Parkin regulates microglial NLRP3 inflammasome activation through polyubiquitination and alleviates neurodegeneration in PD. Combined genetic deletion of Parkin and stimulation by LPS created a PD phenotype that more accurately modeled that of humans. Targeting Parkin‐mediated microglial NLRP3 inflammasome activity using HSP90 inhibitor could be a potential therapeutic strategy for PD.
This article presents a design method for broadband digital phase shifter (PS). In this design, the phase-slope tuning properties of microstrip to slotline transition and <inline-formula> <tex-math ...notation="LaTeX">\lambda </tex-math></inline-formula>/4 short-circuit microstrip-loaded slotline structure are researched and exposed. Equivalent transmission line models and a set of closed-form equations for both structures are presented for the purpose of revealing the mechanism of phase-slope tuning properties while predicting their transmission and matching characteristics. Design methods and specific design parameters for 11.25°, 22.5°, and 45° PSs are provided, for the case where two structures are used independently. Combining two structures for PS designs with larger phase shift range (PSR), such as 90° PS, has likewise been investigated to improve the flexibility of the proposed design method. In order to verify the correctness and practicality of the theoretical analysis, 11.25°, 22.5°, 45°, 90°, and 180° single-bit PSs and a 5-bit 360° broadband digital PS are designed and fabricated. From measurement, the operating bandwidth, return loss (RL), maximum root mean square (rms) phase error, and maximum rms amplitude error of this 5-bit PS are 2.55-4.5 GHz (55%), 10 dB, 4.5°, and 0.35 dB, respectively. The average insertion loss (IL) at the center frequency is 5.7 dB. The measured results demonstrate the usefulness of the proposed two structures with phase-slope tuning property for broadband PS design.
Little is known about the changes in soil microbial phosphorus (P) cycling potential during terrestrial ecosystem management and restoration, although much research aims to enhance soil P cycling. ...Here, we used metagenomic sequencing to analyse 18 soil microbial communities at a P-deficient degraded mine site in southern China where ecological restoration was implemented using two soil ameliorants and eight plant species. Our results show that the relative abundances of key genes governing soil microbial P-cycling potential were higher at the restored site than at the unrestored site, indicating enhancement of soil P cycling following restoration. The gcd gene, encoding an enzyme that mediates inorganic P solubilization, was predominant across soil samples and was a major determinant of bioavailable soil P. We reconstructed 39 near-complete bacterial genomes harboring gcd, which represented diverse novel phosphate-solubilizing microbial taxa. Strong correlations were found between the relative abundance of these genomes and bioavailable soil P, suggesting their contributions to the enhancement of soil P cycling. Moreover, 84 mobile genetic elements were detected in the scaffolds containing gcd in the 39 genomes, providing evidence for the role of phage-related horizontal gene transfer in assisting soil microbes to acquire new metabolic potential related to P cycling.
•The role of NLRP3 inflammasome in Parkinson’s disease pathogenesis.•Parkin may regulate neuron inflammation in both mitochondria dependent and mitochondria independent manner.•Targeting chronic ...inflammation is the future for Parkinson’s disease treatment.
Chronic inflammation might correlate with the formation of α-synuclein oligomers, subsequently leading to dopaminergic (DA) neuronal death in Parkinson’s disease (PD). As major components of chronic inflammation, NOD-like receptor protein 3 (NLRP3) inflammasomes play a crucial role in PD via caspase 1 activation, primarily induced by mitochondrial damage. NLRP3 binds to apoptosis-associated speck-like protein containing a CARD (PYCARD/ASC), and forms inflammasomes in the brain. Inflammasomes act as a platform for caspase 1 to induce interleukin 1 Beta (IL1β) maturation, leading to neuronal pyroptosis. Furthermore, alpha-synuclein, whose abnormal aggregation is the main pathogenesis of PD, also activates NLRP3 inflammasomes. Mutations to PRKN (encoding Parkin) are the most common cause of autosomal recessive familial and sporadic early-onset PD. Evidence has confirmed a relationship between Parkin and NLRP3 inflammasomes. In this review, we summarize the current understanding of NLRP3 inflammasomes and their role in PD progression, and discuss their regulation by Parkin.
Population-wide reductions in cardiovascular disease incidence and mortality have not been shared equally by African Americans. The burden of cardiovascular disease in the African American community ...remains high and is a primary cause of disparities in life expectancy between African Americans and whites. The objectives of the present scientific statement are to describe cardiovascular health in African Americans and to highlight unique considerations for disease prevention and management.
The primary sources of information were identified with PubMed/Medline and online sources from the Centers for Disease Control and Prevention.
The higher prevalence of traditional cardiovascular risk factors (eg, hypertension, diabetes mellitus, obesity, and atherosclerotic cardiovascular risk) underlies the relatively earlier age of onset of cardiovascular diseases among African Americans. Hypertension in particular is highly prevalent among African Americans and contributes directly to the notable disparities in stroke, heart failure, and peripheral artery disease among African Americans. Despite the availability of effective pharmacotherapies and indications for some tailored pharmacotherapies for African Americans (eg, heart failure medications), disease management is less effective among African Americans, yielding higher mortality. Explanations for these persistent disparities in cardiovascular disease are multifactorial and span from the individual level to the social environment.
The strategies needed to promote equity in the cardiovascular health of African Americans require input from a broad set of stakeholders, including clinicians and researchers from across multiple disciplines.
Ferroptosis, a novel form of regulated cell death, is caused by accumulation of lipid peroxides and excessive iron deposition. This process has been linked to the death of dopaminergic neurons in ...substantia nigra compacta (SNc) of Parkinson’s disease (PD) patients. Quercetin (QCT), a natural flavonoid, has multiple pharmacological activities. However, it has not been established whether QCT can protect against dopaminergic neuron death by inhibiting ferroptosis. In this study, we investigated the potential antiferroptotic effects of QCT in cellular models established using specific ferroptosis inducers (Erastin and RSL-3) and MPP+. The effects were also explored using MPTP-induced PD mouse models. The cell counting kit-8 (CCK-8) assay was performed to assess cell viability. Variations in mitochondrial morphology were evaluated by transmission electron microscopy (TEM) while the mitochondrial membrane potential, mass, and ROS were measured by fluorescent probes. Lipid peroxidation levels were assayed through measurement of lipid ROS, MDA, GSH, and SOD levels. The effects of QCT on MPTP-induced behavioral disorders were examined by rotarod and open field tests. In vitro and in vivo, QCT significantly inhibited ferroptosis by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) protein. Additionally, QCT ameliorated motor behavioral impairments and protected against the loss of dopaminergic neurons in MPTP-induced PD models. Interestingly, Nrf2 knockdown alleviated the protective effects of QCT against ferroptosis. In conclusion, these results demonstrate that ferroptosis is involved in MPP+/MPTP-induced PD, and QCT inhibits ferroptosis by activating the Nrf2 protein. Therefore, QCT is a potential agent for preventing the loss of dopaminergic neurons by targeting ferroptosis.
Parkinson's disease (PD) is the second most common neurodegenerative disease around the world; however, its pathogenesis remains unclear so far. Recent advances have shown that DNA damage and repair ...deficiency play an important role in the pathophysiology of PD. There is growing evidence suggesting that DNA damage is involved in the propagation of cellular damage in PD, leading to neuropathology under different conditions. Here, we reviewed the current work on DNA damage repair in PD. First, we outlined the evidence and causes of DNA damage in PD. Second, we described the potential pathways by which DNA damage mediates neurotoxicity in PD and discussed the precise mechanisms that drive these processes by DNA damage. In addition, we looked ahead to the potential interventions targeting DNA damage and repair. Finally, based on the current status of research, key problems that need to be addressed in future research were proposed.
Sarcopenia and diabetes are both prevalent health problems worldwide. However, little is known about the relationship between prediabetes and the prevalence and severity of sarcopenia. Therefore, the ...current study aimed to explore the association between glucose status and the components of sarcopenia, including low muscle mass (LMM), low muscle strength (LMS) and low gait speed (LGS) in US adults.
Data from the 1999 to 2002 National Health and Nutrition Examination Survey (NHANES) were analyzed. A total of 4002 participants aged ≥ 50 years with available information on glucose status (NGR: 1939 cases; prediabetes: 1172 cases; diabetes: 891 cases) and sarcopenia were included in this study. Sarcopenia was defined according to the Foundation for National Institute of Health criteria. Muscle mass, muscle strength and gait speed were used to evaluate sarcopenia and its severity. Weighed multivariable logistic regression were used to explore the association between glucose status and the components of sarcopenia. The hypothetical population attributable fraction (PAF) for the glucose status was also calculated.
The mean age of the cohort was 63.01 ± 9.89 years, with 49.4% being male. Multiple logistic regression analysis suggested that diabetes was an independent risk factor for sarcopenia (OR = 5.470, 95% CI 1.551-19.296) and showed a marginal association with severe sarcopenia (OR = 10.693, 95% CI 0.955-119.73) compared to NGR in men, but not in women. Additionally, prediabetes was independently associated with severe sarcopenia (OR = 3.647, 95% CI 1.532-8.697), LMS (OR = 1.472, 95% CI 1.018-2.127) and LGS (OR = 1.673, 95% CI 1.054-2.655) in the entire cohort. When stratifying by gender, we further observed that prediabetes was significantly associated with LMS in men (OR = 1.897, 95% CI 1.019-3.543) and related to LMM (OR = 3.174, 95% CI 1.287-7.829) and LGS (OR = 2.075, 95% CI 1.155-3.727) in women. HbA1c was positively associated with the prevalence of sarcopenia in men (OR = 1.993, 95% CI 1.511-2.629). PAF showed that diabetes accounted for 16.3% of observed sarcopenia cases. Maintaining NGR in the entire population could have prevented 38.5% of sarcopenia cases and 50.9% of severe sarcopenia cases.
Prediabetes and diabetes were independently associated with the prevalence and severity of sarcopenia in US population. Slowing down the progression of hyperglycemia could have prevented a significant proportion of sarcopenia cases.
Background
Oxidative stress-induced endothelial dysfunction and pyroptosis play an important role during chronic kidney disease (CKD) progression. Neferine, which is an alkaloid ingredient from the ...lotus seed embryo, has many biological actions such as anti-inflammatory, anticancer and antioxidant. However, the role of neferine in endothelial cell pyroptosis and the involved mechanism remain obscure. The aim is to probe the protective effects of neferine on cell pyroptosis and the involved underlying mechanism.
Methods
After the HUVECs were primed with neferine treatment for 2 h prior to LPS and ATP exposure for 24 h, the cell proliferation was determined by BrdU; the cell LDH release was detected by LDH kits; the levels of intracellular ROS, MDA and SOD were tested by detection kits; Caspase-1 activity kit was used to determine caspase-1 activity; the contents of NLRP3, ASC, caspase-1, IL-1β, IL-18 and GSDMD were tested by RT-PCR and western blot.
Results
We found that neferine could inhibit LPS-ATP-induced oxidative stress and the activation of NLRP3 inflammasome signaling, and increased the endothelial cell viability and SOD production. siRNA which mediated the knockdown of NLRP3 promoted the neferine-induced inhibition effects of cell pyroptosis. Furthermore, these neferine-induced effects were reversed by the over-expression of NLRP3.
Conclusions
Our findings indicated neferine may reduce ROS by anti-oxidation and inhibit LPS-ATP-induced endothelial cell pyroptosis via blocking ROS/NLRP3/Caspase-1 signaling pathway, which provides the evidence for therapeutic effect in CKD.
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