Dihydroquercetin alleviates dopamine neuron loss via regulating TREM2 activation.

BACKGROUND: Parkinson's disease (PD) is a prevalent neurodegenerative disorder, marked by the degeneration of dopamine (DA) neurons in the substantia nigra (SN). Current evidence strongly suggests that neuroinflammation, primarily mediated by microglia, contributes to PD pathogenesis. Triggering receptor expressed on myeloid cells 2 (TREM2) might serve as a promising therapeutic target for PD due to its ability to suppress neuroinflammation. Dihydroquercetin (DHQ) is an important natural dihydroflavone and confers apparent anti-inflammatory, antioxidant and anti-fibrotic effects. Recently, DHQ-mediated neuroprotection was exhibited. However, the specific mechanisms of its neuroprotective effects remain incompletely elucidated. METHODS: In this study, rat models were utilized to induce damage to DA neurons using lipopolysaccharide (LPS) and 6-hydroxydopamine (6-OHDA) to assess the impacts of DHQ on the loss of DA neurons. Furthermore, DA neuronal MN9D cells and microglial BV2 cells were employed to investigate the function of TREM2 in DHQ-mediated DA neuroprotection. Finally, TREM2 knockout mice were used to investigate whether the neuroprotective effects mediated by DHQ through a mechanism dependent on TREM2. RESULTS: The main findings demonstrated that DHQ effectively protected DA neurons against neurotoxicity induced by LPS and 6-OHDA and inhibited microglia-elicited neuroinflammation. Meanwhile, DHQ promoted microglial TREM2 signaling activation. Notably, DHQ failed to reduce inflammatory cytokines release and further present neuroprotection from DA neurotoxicity upon TREM2 silencing. Similarly, DHQ didn't exert DA neuroprotection in TREM2 knockout mice. CONCLUSIONS: These findings suggest that DHQ exerted DA neuroprotection by regulating microglia TREM2 activation.

Knowledge, attitudes, practices, and self-efficacy of the Chinese public regarding cardiopulmonary resuscitation: an online cross-sectional survey.

Objective: To evaluate the current status of Chinese public's knowledge, attitudes, practices (KAP) and self-efficacy regarding cardiopulmonary resuscitation (CPR), and to analyze the factors that influence KAP and self-efficacy. Methods: An online cross-sectional survey was conducted from February to June 2022 in Mainland China via a self-designed self-filled questionnaire. Potential participants were recruited through WeChat by convenience sampling and snowball sampling methods. Descriptive and quantitative analyses were used for statistical analysis. Results: The survey included 4,450 participants from 31 provinces, autonomous regions, or municipalities across Mainland China, aged 18 or above. The public's average understanding (clear and very clear) of the knowledge regarding CPR was 67.4% (3,000/4,450), with an average proportion of positive attitudes at 96.8% (4,308/4,450). In practice, the average proportion of good practices was 92.8% (4,130/4,450), while the percentage of good self-efficacy averaged at 58.9% (2,621/4,450), only 42.4% (1,885/4,450) of the participants had confidence in the correct use of automated external defibrillator (AED). Pearson correlation analysis showed a significantly positive correlation among knowledge, attitude, practice, and self-efficacy (p < 0.01). Multiple linear regression analysis revealed that several factors have a significant influence on the public's CPR KAP and self-efficacy, including ever having received CPR training (p < 0.001), hearing about AED (p < 0.001), performing CPR on others (p < 0.001), hearing about CPR (p < 0.001), occupation (p < 0.001), personal health status (p < 0.001), education level (p < 0.001), gender (p < 0.001), and encountering someone in need of CPR (p = 0.021). Conclusion: The Chinese public demonstrates good knowledge of CPR, positive attitude, and high willingness to perform CPR. However, there is still room for improvement in the mastery of some professional knowledge points related to CPR and AED. It should be noted that knowledge, attitude, practice, and self-efficacy are interrelated and influence each other. Factors such as prior CPR training, hearing about AED, having performed CPR before, hearing about CPR, occupation, personal health status, education level, gender, and having encountered someone in need of CPR have a significant impact on the public's KAP and self-efficacy.

Application of the whole-course care model (IWF/C Care) for postintensive care syndrome based on an early warning system in critically ill patients: a randomised controlled trial study protocol.

INTRODUCTION: Critically ill patients are at risk of developing postintensive care syndrome (PICS), which is manifested by physical, psychological and cognitive impairment. Currently, there are no programmes that combine early warning systems with interventions for PICS. We hypothesise that a comprehensive care model for PICS based on an early warning system would reduce medical costs and the incidence of PICS. METHODS AND ANALYSIS: The Intensive Care Unit (ICU) -Ward-Family/Community whole-course care (IWF/C Care) trial will be a unicentric, randomised, controlled trial. A total of 138 ICU patients from two ICUs at a university hospital in Guizhou province, China, will be enrolled in February 2023. The inclusion criteria are an age of 18 years or older, an ICU stay of more than 48 hours, provide informed consent and the ability to communicate normally. Patients will be followed for 12 months and randomised in a 1:1:1 ratio to three groups. INTERVENTIONS: Patients in intervention group 1 will be assessed by the PICS early warning system within 24 hours of ICU discharge, and precise interventions will be carried out according to the results; that is, high-risk patients will receive care based on the IWF/C Care model and low-risk patients will receive routine care. All patients in intervention group 2 will receive care based on the IWF/C Care model. The control group will receive routine care. The primary endpoints are the incidence of PICS and quality of life. The secondary endpoints include the incidence of adverse events: the unplanned readmission rate, cost-effectiveness, and the experiences and feelings of patients receiving care based on the IWF/C Care model. The incidence of PICS will be measured at ICU discharge, general ward discharge, the home/community stage and 1 month and 3, 6, 9, and 12 months after discharge. ETHICS AND DISSEMINATION: Ethics approval was obtained from Biomedical Research Ethics Committee of the Affiliated Hospital of Zunyi Medical University (approval number: KLL-2022-780). The results of this study will be distributed through peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR2300068135.

Activation of neuronal NADPH oxidase NOX2 promotes inflammatory neurodegeneration.

Strong evidence indicates critical roles of NADPH oxidase (a key superoxide-producing enzyme complex during inflammation) in activated microglia for mediating neuroinflammation and neurodegeneration. However, little is known about roles of neuronal NADPH oxidase in neurodegenerative diseases. This study aimed to investigate expression patterns, regulatory mechanisms and pathological roles of neuronal NADPH oxidase in inflammation-associated neurodegeneration. The results showed persistent upregulation of NOX2 (gp91phox; the catalytic subunit of NADPH oxidase) in both microglia and neurons in a chronic mouse model of Parkinson's disease (PD) with intraperitoneal LPS injection and LPS-treated midbrain neuron-glia cultures (a cellular model of PD). Notably, NOX2 was found for the first time to exhibit a progressive and persistent upregulation in neurons during chronic neuroinflammation. While primary neurons and N27 neuronal cells displayed basal expression of NOX1, NOX2 and NOX4, significant upregulation only occurred in NOX2 but not NOX1 or NOX4 under inflammatory conditions. Persistent NOX2 upregulation was associated with functional outcomes of oxidative stress including increased ROS production and lipid peroxidation. Neuronal NOX2 activation displayed membrane translocation of cytosolic p47phox subunit and was inhibited by apocynin and diphenyleneiodonium chloride (two widely-used NADPH oxidase inhibitors). Importantly, neuronal ROS production, mitochondrial dysfunction and degeneration induced by inflammatory mediators in microglia-derived conditional medium were blocked by pharmacological inhibition of neuronal NOX2. Furthermore, specific deletion of neuronal NOX2 prevented LPS-elicited dopaminergic neurodegeneration in neuron-microglia co-cultures separately grown in the transwell system. The attenuation of inflammation-elicited upregulation of NOX2 in neuron-enriched and neuron-glia cultures by ROS scavenger N-acetylcysteine indicated a positive feedback mechanism between excessive ROS production and NOX2 upregulation. Collectively, our findings uncovered crucial contribution of neuronal NOX2 upregulation and activation to chronic neuroinflammation and inflammation-related neurodegeneration. This study reinforced the importance of developing NADPH oxidase-targeting therapeutics for neurodegenerative diseases.

Dysfunction of the noradrenergic system drives inflammation, α-synucleinopathy, and neuronal loss in mouse colon.

Clinical and pathological evidence revealed that α-synuclein (α-syn) pathology seen in PD patients starts in the gut and spreads via anatomically connected structures from the gut to the brain. Our previous study demonstrated that depletion of central norepinephrine (NE) disrupted brain immune homeostasis, producing a spatiotemporal order of neurodegeneration in the mouse brain. The purpose of this study was 1) to determine the role of peripheral noradrenergic system in the maintenance of gut immune homeostasis and in the pathogenesis of PD and 2) to investigate whether NE-depletion induced PD-like α-syn pathological changes starts from the gut. For these purposes, we investigated time-dependent changes of α-synucleinopathy and neuronal loss in the gut following a single injection of DSP-4 (a selective noradrenergic neurotoxin) to A53T-SNCA (human mutant α-syn) over-expression mice. We found DPS-4 significantly reduced the tissue level of NE and increased immune activities in gut, characterized by increased number of phagocytes and proinflammatory gene expression. Furthermore, a rapid-onset of α-syn pathology was observed in enteric neurons after 2 weeks and delayed dopaminergic neurodegeneration in the substantia nigra was detected after 3-5 months, associated with the appearance of constipation and impaired motor function, respectively. The increased α-syn pathology was only observed in large, but not in the small, intestine, which is similar to what was observed in PD patients. Mechanistic studies reveal that DSP-4-elicited upregulation of NADPH oxidase (NOX2) initially occurred only in immune cells during the acute intestinal inflammation stage, and then spread to enteric neurons and mucosal epithelial cells during the chronic inflammation stage. The upregulation of neuronal NOX2 correlated well with the extent of α-syn aggregation and subsequent enteric neuronal loss, suggesting that NOX2-generated reactive oxygen species play a key role in α-synucleinopathy. Moreover, inhibiting NOX2 by diphenyleneiodonium or restoring NE function by salmeterol (a ß2-receptor agonist) significantly attenuated colon inflammation, α-syn aggregation/propagation, and enteric neurodegeneration in the colon and ameliorated subsequent behavioral deficits. Taken together, our model of PD shows a progressive pattern of pathological changes from the gut to the brain and suggests a potential role of the noradrenergic dysfunction in the pathogenesis of PD.

Posttranslational S-nitrosylation modification regulates HMGB1 secretion and promotes its proinflammatory and neurodegenerative effects.

Nuclear protein high-mobility group box 1 (HMGB1) can be actively secreted by activated immune cells and functions as a proinflammatory cytokine. Regulation of HMGB1 secretion is critical for treatment of HMGB1-mediated inflammation and related diseases. This study demonstrates that S-nitrosylation (SNO; the covalent binding of nitric oxide [NO] to cysteine thiols) by inducible nitric oxide synthase (iNOS)-derived NO at Cys106 is essential and sufficient for inflammation-elicited HMGB1 secretion. iNOS deletion or inhibition or Cys106Ser mutation prevents lipopolysaccharide (LPS)- and/or poly(I:C)-elicited HMGB1 secretion. NO donors induce SNO of HMGB1 and reproduce inflammogen-triggered HMGB1 secretion. SNO of HMGB1 promotes its proinflammatory and neurodegenerative effects. Intranigral HMGB1 injection induces chronic microglial activation, dopaminergic neurodegeneration, and locomotor deficits, the key features of Parkinson's disease (PD), in wild-type, but not Mac1 (CD11b/CD18)-deficient, mice. This study indicates pivotal roles for SNO modification in HMGB1 secretion and HMGB1-Mac1 interaction for inflammatory neurodegeneration, identifying a mechanistic basis for PD development.

Activation of the MAC1-ERK1/2-NOX2 Pathway Is Required for LPS-Induced Sustaining Reactive Microgliosis, Chronic Neuroinflammation and Neurodegeneration.

Recent studies suggest that improper resolution of acute neuroinflammation may lead to long-lasting low-grade chronic neuroinflammation and drive progressive neurodegeneration. However, the molecular mechanism underlying the transition from acute to chronic neuroinflammation remains unclear. The main purpose of this study was to search for potential pathways mediating LPS-elicited chronic neuroinflammation and resultant neurodegeneration. Using microglia cultures prepared from C57BL/6J, MAC1-deficient, and MyD88-deficient mice, the initial study showed that activation of TLR-4 is not sufficient for maintaining chronic neuroinflammation despite its essential role in LPS-initiated acute neuroinflammation. Opposite to TLR-4, our studies showed significantly reduced intensity of chronic neuroinflammation, oxidative stress, and progressive loss of nigral dopaminergic neurons in MAC1-deficient neuron/glial cultures or mice stimulated with LPS. Mechanistic studies revealed the essential role ERK1/2 activation in chronic neuroinflammation-elicited neurodegeneration, which was demonstrated by using an ERK1/2 inhibitor in neuron-glial cultures. Taken together, we propose a key role of the MAC1-NOX2-ERK1/2 signaling pathway in the initiation and maintenance of low-grade chronic neuroinflammation. Continuing ERK1/2 phosphorylation and NOX2 activation form a vicious feedforward cycle in microglia to maintain the low-grade neuroinflammation and drive neurodegeneration.

Identification of the Powdery Mildew Resistance in Chinese Wheat Cultivar Heng 4568 and its Evaluation in Marker-Assisted Selection.

Powdery mildew induced by Blumeria graminis f. sp. Tritici (Bgt) has a devastating impact on global wheat yield and quality. Host resistance is the most effective and economical means to control this disease. In this study, Heng 4568, an elite wheat cultivar, shows high resistance to 12 Bgt isolates from different regions in China at the seedling stage. Genetic analysis demonstrates that the powdery mildew resistance in Heng 4568 is conferred by a single dominant locus, temporarily designated PmH4568. Furthermore, PmH4568 is mapped to the reported Pm2 interval on chromosome 5DS with five Pm2 linked markers and flanked by the markers Bwm20 and Bwm21 with a genetic distance of 0.3 and 0.6 cM, respectively. To further investigate the relationship between PmH4568 and Pm2, the diagnostic marker Pm2b-map-3 of Pm2 is used to genotype the F2:3 population derived from the cross Heng 4568 × Daimai 2173. Notably, there is no recombination found, indicating that PmH4568 is also probably a Pm2 allele. In addition, five closely linked markers as well as one diagnostic marker are successfully developed and tested in 16 wheat cultivars from different agro-ecological areas in China, which have potential applications in molecular breeding by marker-assisted selection.

Macrophages Are Dispensable for Postnatal Pruning of the Cochlear Ribbon Synapses.

Ribbon synapses of cochlear hair cells undergo pruning and maturation before the hearing onset. In the central nervous system (CNS), synaptic pruning was mediated by microglia, the brain-resident macrophages, via activation of the complement system. Whether a similar mechanism regulates ribbon synapse pruning is currently unknown. In this study, we report that the densities of cochlear macrophages surrounding hair cells were highest at around P8, corresponding well to the completion of ribbon synaptic pruning by P8-P9. Surprisingly, using multiple genetic mouse models, we found that postnatal pruning of the ribbon synapses and auditory functions were unaffected by the knockout of the complement receptor 3 (CR3) or by ablations of macrophages expressing either LysM or Cx3cr1. Our results suggest that unlike microglia in the CNS, macrophages in the cochlea do not mediate pruning of the cochlear ribbon synapses.

Characterization of the Powdery Mildew Resistance Gene in Wheat Breeding Line KN0816 and Its Evaluation in Marker-Assisted Selection.

Wheat powdery mildew, caused by Blumeria graminis (DC.) Speer f. sp. tritici is a destructive disease seriously threatening yield and quality of common wheat (Triticum aestivum L., 2n=6x=42, AABBDD). Characterization of resistance genes against powdery mildew is useful in parental selection and for developing disease-resistant cultivars. Chinese wheat breeding line KN0816 has superior agronomic performance and resistance to powdery mildew at all growth stages. Genetic analysis using populations of KN0816 crossed with different susceptible parents indicated that a single dominant gene, tentatively designated PmKN0816, conferred seedling resistance to different B. graminis f. sp. tritici isolates. Using a bulked segregant analysis, PmKN0816 was mapped to the Pm6 interval on chromosome arm 2BL using polymorphic markers linked to the cataloged genes Pm6, Pm52, and Pm64, and flanked by the markers CISSR02g-6 and CIT02g-2, both with genetic distances of 0.7 cM. Analysis of closely linked molecular markers indicated that the marker alleles of PmKN0816 differed from those of other powdery mildew resistance genes on 2BL, including Pm6, Pm33, Pm51, Pm64, and PmQ. Based on the genetic and physical locations and response pattern to different B. graminis f. sp. tritici isolates, PmKN0816 is most likely a new powdery mildew resistance gene and possesses effective resistance to all the 14 tested B. graminis f. sp. tritici isolates. In view of the elite agronomic performance of KN0816 combined with the resistance, PmKN0816 is expected to become a valuable resistance gene in wheat breeding. To transfer PmKN0816 to different genetic backgrounds using marker-assisted selection (MAS), closely linked markers of PmKN0816 were evaluated, and four of them (CIT02g-2, CISSR02g-6, CIT02g-10, and CIT02g-17) were confirmed to be applicable for MAS in different genetic backgrounds.

Diagnostic Kompetitive Allele-Specific PCR Markers of Wheat Broad-Spectrum Powdery Mildew Resistance Genes Pm21, PmV, and Pm12 Developed for High-Throughput Marker-Assisted Selection.

Wheat powdery mildew is a devastating disease that seriously threatens yield worldwide. Utilization of host resistance is considered an effective strategy to minimize powdery mildew damage. Pm21, PmV, and Pm12 confer broad-spectrum resistance to wheat powdery mildew in China, of which Pm21 and PmV are allelic genes derived from the 6VS chromosome of Dasypyrum villosum, and Pm12 is derived from the 6SS chromosome of Aegilops speltoides and most likely orthologous to the former two genes. To accurately and efficiently transfer and pyramid these genes using marker-assisted selection (MAS), distinctive single-nucleotide polymorphisms (SNPs) among the exon sequences of Pm21, PmV, and Pm12 and their homologous sequences in the common wheat genome were identified and then used for developing diagnostic Kompetitive Allele-Specific PCR (KASP) markers. The markers were validated in different genotypes including transgenic vectors, transgenic lines, translocation lines, resistance stocks with documented Pm genes, and in multiple susceptible cultivars without Pm genes. As a result, we initially developed a KASP marker that can simultaneously diagnose Pm21, Pm12, and PmV. Subsequently, we obtained a highly diagnostic KASP marker for each of the three genes that could distinguish among the three genes and also accurately distinguish them from other resistant stocks with documented Pm genes and from multiple susceptible genotypes. Compared with previously reported markers, the highly diagnostic KASP markers developed in this study have the advantages of low cost, easy assay, accuracy, and potentially high throughput for MAS.

[Optimization of determination of astragaloside â £ in Astragali Radix by continuous single-factor method].

This paper aims to solve the problems of complicated-unstable test solution preparation process and insufficient extraction of the active ingredient astragaloside Ⅳ in the legal method for the determination of astragaloside Ⅳ in Astragali Radix. The continuous single-factor analysis of seven main factors affecting the content of astragaloside Ⅳ was carried out by HPLC-ELSD, and then the pre-paration method of test solution was optimized. This optimized method exhibited excellent performance in precision, repeatability and stability. The average recovery rate of astragaloside Ⅳ was 99.65% with RSD 2.2%. Astragaloside Ⅳ showed a good linearity between the logarithm of peak area and the logarithm of injection quantity in the range of 0.46-9.1 µg(r=0.999 6). The contents of astragaloside Ⅳ in 29 batches of Astragali Radix were determined by the new and the legal methods. The results showed that the average content of astragaloside Ⅳ in these Astragali Radix samples determined by the former method was 1.458 times than that of the latter one, indicating the new method was simple, reliable and more adequate to extract target compound. According to the results, it is suggested to improve the content standard of astragaloside Ⅳ in Astragali Radix in the new edition of Chinese Pharmacopeia.

Knowledge, attitudes and practices of the Chinese public with respect to coronavirus disease (COVID-19): an online cross-sectional survey.

BACKGROUND: Coronavirus disease (COVID-19) has become a pandemic. The knowledge, attitudes, and practices (KAP) of the public play a major role in the prevention and control of infectious diseases. The objective of the present study was to evaluate the KAP of the Chinese public and to assess potential influencing factors related to practices. METHODS: A cross-sectional online survey was conducted in China in February 2020 via a self-designed questionnaire comprising 33 questions assessing KAP. RESULTS: For the 2136 respondents from 30 provinces or municipalities in China, the accurate response rate for the knowledge section ranged from 72.7 to 99.5%, and the average was 91.2%. Regarding attitude section, the percentage of positive attitudes ("strongly agree" and "agree") ranged from 94.7 to 99.7%, and the average value was 98.0%. The good practices ("always" and "often") results ranged from 76.1 to 99.5%, and the average value was 96.8%. The independent samples t-test revealed that gender and ethnic differences had no effect on knowledge, attitude or behaviour (P > 0.05). However, knowledge was associated with age (t = 4.842, p < 0.001), marital status (t = - 5.323, p < 0.001), education level (t = 8.441, p < 0.001), occupation (t = - 10.858, p < 0.001), and place of residence (t = 7.929, p < 0.001). Similarly, attitude was associated with marital status (t = - 2.383, p = 0.017), education level (t = 2.106, p = 0.035), occupation (t = - 4.834, p < 0.001), and place of residence (t = 4.242, p < 0.001). The multiple linear regression analysis results showed that the factors influencing practices were knowledge (t = - 3.281, p = 0.001), attitude (t = 18.756, p < 0.001), occupation (t = - 3.860, p < 0.001), education level (t = 3.136, p = 0.002), and place of residence (t = 3.257, p = 0.001). CONCLUSIONS: The Chinese public exhibited a good level of knowledge of COVID-19, a positive attitude, and high adherence to good practices. COVID-19-related knowledge, attitudes and practices were affected by age, marital status, education level, occupation, and place of residence to varying degrees. In addition, practices were affected by knowledge and attitudes towards COVID-19.

Double-stranded RNA-induced dopaminergic neuronal loss in the substantia nigra in the presence of Mac1 receptor.

BACKGROUND: The underlying mechanism of viral infection as a risk factor for Parkinson's disease (PD), the second most common neurodegenerative disease, remains unclear. OBJECTIVE: We used Mac-1-/- and gp91phox-/- transgene animal models to investigate the mechanisms by which poly I:C, a mimic of virus double-stranded RNA, induces PD neurodegeneration. METHOD: Poly I:C was stereotaxically injected into the substantia nigra (SN) of wild-type (WT), Mac-1-knockout (Mac-1-/-) and gp91 phox-knockout (gp91 phox-/-) mice (10 µg/µl), and nigral dopaminergic neurodegeneration, α-synuclein accumulation and neuroinflammation were evaluated. RESULT: Dopaminergic neurons in the nigra and striatum were markedly reduced in WT mice after administration of poly I:C together with abundant microglial activation in the SN, and the expression of α-synuclein was also elevated. However, these pathological changes were greatly dampened in Mac-1-/- and gp91 phox-/- mice. CONCLUSIONS: Our findings demonstrated that viral infection could result in the activation of microglia as well as NADPH oxidase, which may lead to neuron loss and the development of Parkinson's-like symptoms. Mac-1 is a key receptor during this process.

Benzo(a)pyrene exposure induced neuronal loss, plaque deposition, and cognitive decline in APP/PS1 mice.

BACKGROUND: Exposure to benzo(a)pyrene (BaP) was associated with cognitive impairments and some Alzheimer's disease (AD)-like pathological changes. However, it is largely unknown whether BaP exposure participates in the disease progression of AD. OBJECTIVES: To investigate the effect of BaP exposure on AD progression and its underlying mechanisms. METHODS: BaP or vehicle was administered to 4-month-old APPswe/PS1dE9 transgenic (APP/PS1) mice and wildtype (WT) mice for 2 months. Learning and memory ability and exploratory behaviors were evaluated 1 month after the initiation/termination of BaP exposure. AD-like pathological and biochemical alterations were examined 1 month after 2-month BaP exposure. Levels of soluble beta-amyloid (Aß) oligomers and the number of Aß plaques in the cortex and the hippocampus were quantified. Gene expression profiling was used to evaluate alternation of genes/pathways associated with AD onset and progression. Immunohistochemistry and Western blot were used to demonstrate neuronal loss and neuroinflammation in the cortex and the hippocampus. Treatment of primary neuron-glia cultures with aged Aß (a mixture of monomers, oligomers, and fibrils) and/or BaP was used to investigate mechanisms by which BaP enhanced Aß-induced neurodegeneration. RESULTS: BaP exposure induced progressive decline in spatial learning/memory and exploratory behaviors in APP/PS1 mice and WT mice, and APP/PS1 mice showed severer behavioral deficits than WT mice. Moreover, BaP exposure promoted neuronal loss, Aß burden and Aß plaque formation in APP/PS1 mice, but not in WT mice. Gene expression profiling showed most robust alteration in genes and pathways related to inflammation and immunoregulatory process, Aß secretion and degradation, and synaptic formation in WT and APP/PS1 mice after BaP exposure. Consistently, the cortex and the hippocampus of WT and APP/PS1 mice displayed activation of microglia and astroglia and upregulation of inducible nitric oxide synthase (iNOS), glial fibrillary acidic protein (GFAP), and NADPH oxidase (three widely used neuroinflammatory markers) after BaP exposure. Furthermore, BaP exposure aggravated neurodegeneration induced by aged Aß peptide in primary neuron-glia cultures through enhancing NADPH oxidase-derived oxidative stress. CONCLUSION: Our study showed that chronic exposure to environmental pollutant BaP induced, accelerated, and exacerbated the progression of AD, in which elevated neuroinflammation and NADPH oxidase-derived oxidative insults were key pathogenic events.

Comparative analysis of denitrification performance, denitrifying community and functional genes to oxytetracycline exposure between single and hybrid biodegradable polymers supported solid-phase denitrification systems.

Biodegradable carrier are vital for the solid-phase denitrification (SPD) systems for treating nitrate-rich water. Two solid-phase denitrification reactors were developed with both 200 g L-1 of single (polycaprolactone, PCL) (R1) and hybrid solid carbon sources (PCL/polylactic acid (PLA) /polyhydroxyalkanoates (PHA)) (R2) to examine the denitrification performance, denitrifying community and functional genes to various oxytetracycline (OTC) exposure in this study, respectively. Complete denitrification performance was achieved in the both SPD systems at low stress of OTC (1 mg L-1), but then dramatically reduced to less than 20% of nitrate reduction efficiency after one-month high OTC stress (10 mg L-1), and rapidly recovered to stable nitrate removal rates of 76.77 ± 5.48% (R1) and 40.68 ± 4.40% (R2) after the next day of no OTC stress. However, the reactor R1 with single PCL carriers acquired more efficient nitrate removal rate than that of reactor R2 at the high OTC stress and recovery phase with OTC stress, mainly due to the more organics availability from the single PCL carriers. The richness and diversity of nirK and nirS deintrifiers significantly declined at high OTC stress, and much more of those occurred in biofilm R1 with more organics availability. Besides, biofilm R1 achieved much more abundant periplasmic nitrate reductase, nitrite reductase genes and tetracycline resistance genes after high OTC stress, which explained the potential resistance to OTC and rapid recovery efficiency after no stress of OTC. Thus, the organics availability played an important role in assuring SPD system to be efficient under high OTC stress.

Successful blood glucose management of a severe COVID-19 patient with diabetes: A case report.

RATIONALE: Coronavirus disease 2019 (COVID-19) has emerged as a rapidly spreading communicable disease affecting individuals worldwide. Patients with diabetes are more vulnerable to the disease, and the mortality is higher than in those without diabetes. We reported a severe COVID-19 patient with diabetes and shared our experience with blood glucose management. PATIENT CONCERNS: A 64-year-old female diabetes patient was admitted to the intensive care unit due to productive coughing for 8 days without any obvious cause. The results of blood gas analysis indicated that the partial pressure of oxygen was 84 mm Hg with oxygen 8 L/min, and the oxygenation index was less than 200 mm Hg. In addition, postprandial blood glucose levels were abnormal (29.9 mmol/L). DIAGNOSES: The patient was diagnosed with COVID-19 (severe type) and type 2 diabetes. INTERVENTIONS: Comprehensive interventions including establishing a multidisciplinary team, closely monitoring her blood glucose level, an individualized diabetes diet, early activities, psychological care, etc, were performed to control blood glucose while actively treating COVID-19 infection. OUTCOMES: After the comprehensive measures, the patient's blood glucose level gradually became stable, and the patient was discharged after 20 days of hospitalization. LESSONS: This case indicated that the comprehensive measures performed by a multidisciplinary team achieved good treatment effects on a COVID-19 patient with diabetes. Targeted treatment and nursing methods should be performed based on patients' actual situations in clinical practice.

Through Reducing ROS Production, IL-10 Suppresses Caspase-1-Dependent IL-1ß Maturation, thereby Preventing Chronic Neuroinflammation and Neurodegeneration.

Chronic neuroinflammation contributes to the pathogenesis of Parkinson's disease (PD). However, cellular and molecular mechanisms by which chronic neuroinflammation is formed and maintained remain elusive. This study aimed to explore detailed mechanisms by which anti-inflammatory cytokine interleukin-10 (IL-10) prevented chronic neuroinflammation and neurodegeneration. At 24 h after an intranigral injection of lipopolysaccharide (LPS), levels of NLRP3, pro-caspase-1, pro-IL-1ß, active caspase-1, and mature IL-1ß in the midbrain were much higher in IL-10-/- mice than wildtype mice. Mechanistically, IL-10-/- microglia produced more intracellular reactive oxygen species (iROS) and showed more profound activation of NADPH oxidase (NOX2) than wildtype microglia. Meanwhile, suppression of NOX2-derived iROS production blocked LPS-elicited caspase-1 activation and IL-1ß maturation in IL-10-/- microglia in vitro and in vivo. One month after intranigral LPS injection, IL-10-/- mice revealed more profound microglial activation and dopaminergic neurodegeneration in the substantia nigra than wildtype mice. Importantly, such PD-like pathological changes were prevented by IL-1ß neutralization. Collectively, IL-10 inhibited LPS-elicited production of NOX2-derived iROS thereby suppressing synthesis of NLRP3, pro-caspase-1 and pro-IL-1ß and their activation and cleavage. By this mechanism, IL-10 prevented chronic neuroinflammation and neurodegeneration. This study suggested boosting anti-inflammatory effects of IL-10 and suppressing NLRP3 inflammasome activation could be beneficial for PD treatment.

The pentose phosphate pathway regulates chronic neuroinflammation and dopaminergic neurodegeneration.

BACKGROUND: Metabolic dysfunction and neuroinflammation are increasingly implicated in Parkinson's disease (PD). The pentose phosphate pathway (PPP, a metabolic pathway parallel to glycolysis) converts glucose-6-phosphate into pentoses and generates ribose-5-phosphate and NADPH thereby governing anabolic biosynthesis and redox homeostasis. Brains and immune cells display high activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP. A postmortem study reveals dysregulation of G6PD enzyme in brains of PD patients. However, spatial and temporal changes in activity/expression of G6PD in PD remain undetermined. More importantly, it is unclear how dysfunction of G6PD and the PPP affects neuroinflammation and neurodegeneration in PD. METHODS: We examined expression/activity of G6PD and its association with microglial activation and dopaminergic neurodegeneration in multiple chronic PD models generated by an intranigral/intraperitoneal injection of LPS, daily subcutaneous injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 6 days, or transgenic expression of A53T α-synuclein. Primary microglia were transfected with G6PD siRNAs and treated with lipopolysaccharide (LPS) to examine effects of G6PD knockdown on microglial activation and death of co-cultured neurons. LPS alone or with G6PD inhibitor(s) was administrated to mouse substantia nigra or midbrain neuron-glia cultures. While histological and biochemical analyses were conducted to examine microglial activation and dopaminergic neurodegeneration in vitro and in vivo, rotarod behavior test was performed to evaluate locomotor impairment in mice. RESULTS: Expression and activity of G6PD were elevated in LPS-treated midbrain neuron-glia cultures (an in vitro PD model) and the substantia nigra of four in vivo PD models. Such elevation was positively associated with microglial activation and dopaminergic neurodegeneration. Furthermore, inhibition of G6PD by 6-aminonicotinamide and dehydroepiandrosterone and knockdown of microglial G6PD attenuated LPS-elicited chronic dopaminergic neurodegeneration. Mechanistically, microglia with elevated G6PD activity/expression produced excessive NADPH and provided abundant substrate to over-activated NADPH oxidase (NOX2) leading to production of excessive reactive oxygen species (ROS). Knockdown and inhibition of G6PD ameliorated LPS-triggered production of ROS and activation of NF-кB thereby dampening microglial activation. CONCLUSIONS: Our findings indicated that G6PD-mediated PPP dysfunction and neuroinflammation exacerbated each other mediating chronic dopaminergic neurodegeneration and locomotor impairment. Insight into metabolic-inflammatory interface suggests that G6PD and NOX2 are potential therapeutic targets for PD.