Liquid-Phase Adsorption Behavior of ß-D-Glucooligosaccharides When Using Activated Carbon for Separation, and the Antioxidant Stress Activity of Purified Fractions.

The adsorption characteristics of ß-glucooligosaccharides on activated carbon and the purification were systematically investigated. The maximum adsorption capacity of activated carbon reached 0.419 g/g in the optimal conditions. The adsorption behavior was described to be monolayer, spontaneous, and exothermic based on several models' fitting results. Five fractions with different degrees of polymerization (DPs) and structures of ß-glucooligosaccharides were obtained by gradient ethanol elution. 10E mainly contained disaccharides with dp2a (G1→6G) and dp2b (G1→3G). 20E possessed trisaccharides with dp3a (G1→6G1→3G) and dp3b (G1→3G1→3G). 30E mainly consisted of dp3a and dp4a (G1→3G1→3(G1→6)G), dp4b (G1→6G1→3G1→3G), and dp4c (G1→3G1→3G1→3G). In addition to tetrasaccharides, 40E and 50E also contained pentasaccharides and hexasaccharides with ß-(1→3)-linked or ß-(1→6)-linked glucose residues. All fractions could inhibit the accumulation of intracellular reactive oxygen species (ROS) in H2O2-induced Caco-2 cells, and they could improve oxidative stress damage by increasing the activity of superoxide dismutase (SOD) and reduced glutathione (GSH), which were related to their DPs and structures. 50E with high DPs showed better anti-oxidative stress activity.

Dimethyl fumarate ameliorates chronic stress-induced anxiety-like behaviors by decreasing neuroinflammation and neuronal activity in the amygdala.

BACKGROUND: Chronic stress-induced neuroinflammation plays a pivotal role in the development and exacerbation of mental disorders, such as anxiety and depression. Dimethyl Fumarate (DMF), an effective therapeutic agent approved for the treatment of multiple sclerosis, has been widely reported to display anti-inflammatory and anti-oxidative effects. However, the impact of DMF on chronic stress-induced anxiety disorders and the exact underlying mechanisms remain largely unknown. METHODS: We established a mouse model of chronic social defeat stress (CSDS). DMF was administered orally 1 h before daily stress session for 10 days in CSDS + DMF group. qRT-PCR and western blotting were used to analyze mRNA and protein expression of NLRP3, Caspase-1 and IL-1ß. Immunofluorescence staining was carried out to detect the expression of Iba 1 and c-fos positive cells as well as morphological change of Iba 1+ microglia. Whole-cell patch-clamp recording was applied to evaluate synaptic transmission and intrinsic excitability of neurons. RESULTS: DMF treatment significantly alleviated CSDS-induced anxiety-like behaviors in mice. Mechanistically, DMF treatment prevented CSDS-induced neuroinflammation by inhibiting the activation of microglia and NLRP3/Caspase-1/IL-1ß signaling pathway in basolateral amygdala (BLA), a brain region important for emotional processing. Furthermore, DMF treatment effectively reversed the CSDS-caused disruption of excitatory and inhibitory synaptic transmission balance, as well as the increased intrinsic excitability of BLA neurons. CONCLUSIONS: Our findings provide new evidence that DMF may exert anxiolytic effect by preventing CSDS-induced activation of NLRP3/Caspase-1/IL-1ß signaling pathway and alleviating hyperactivity of BLA neurons.

T7 peptide-mediated co-delivery platform overcoming multidrug-resistant breast cancer: In vitro and in vivo evaluation.

P-glycoprotein (P-gp) overexpressed mutidrug resistance (MDR) is currently a key factor limiting the effectiveness of breast cancer chemotherapy. Systemic administration based on P-gp-associated mechanism leads to severe toxic side effects. Here, we designed a T7 peptide-modified mixed liposome (T7-MLP@DTX/SchB) that, by active targeting co-delivering chemotherapeutic agents and P-gp inhibitors, harnessed synergistic effects to improve the treatment of MDR breast cancer. This study established drug-resistant cell models and animal models. Subsequently, comprehensive evaluations involving cell uptake, cell apoptosis, cellular toxicity assays, in vivo tumor-targeting capability, and anti-tumor activity assays were conducted to assess the drug resistance reversal effects of T7-MLP@DTX/SchB. Additionally, a systematic assessment of the biosafety profile of T7-MLP@DTX/SchB was executed, including blood profiles, biochemical markers, and histopathological examination. It was found that this co-delivery strategy successfully exerted the synergistic effects, since there was a significant tumor growth inhibitory effect on multidrug-resistant breast cancer. Targeted modification with T7 peptide enhanced the therapeutic efficacy remarkably, while vastly ameliorating the biocompatibility compared to free drugs. The intriguing results supported the promising potential use of T7-MLP@DTX/SchB in overcoming MDR breast cancer treatment.

Substance Addiction Rehabilitation Drugs.

The relapse rate of substance abusers is high, and addiction rehabilitation adjunct drugs need to be developed urgently. There have been numerous reports on blocking the formation of substance addiction, but studies on drugs that can alleviate withdrawal symptoms are very limited. Both the dopamine transporter (DAT) hypothesis and D3 dopamine receptor (D3R) hypothesis are proposed. DAT activators reduce the extracellular dopamine level, and D3R antagonists reduce the neuron's sensitivity to dopamine, both of which may exacerbate the withdrawal symptoms subsequently. The D3R partial agonist SK608 has biased signaling properties via the G-protein-dependent pathway but did not induce D3R desensitization and, thus, may be a promising drug for the withdrawal symptoms. Drugs for serotoninergic neurons or GABAergic neurons and anti-inflammatory drugs may have auxiliary effects to addiction treatments. Drugs that promote structural synaptic plasticity are also discussed.

Mixed crushing and competitive leaching of all electrode material components and metal collector fluid in the spent lithium battery.

Hydrometallurgy is a primary method for recovering cathode electrode materials from spent lithium-ion batteries (LIBs). Most of the current research materials are pure cathode electrode materials obtained through manual disassembly. However, the spent LIBs are typically broken as a whole during the actual industrial recycling which makes the electrode materials combined with the collector fluid. Therefore, the competitive leaching between metal collector fluid and electrode material was examined. The pyrolysis characteristics of the electrode materials were analyzed to determine the pyrolysis temperature. The electrode sheet was pyrolyzed and then crushed for competitive leaching. The effect of pyrolysis was analyzed by XPS. The competitive leaching behavior was studied based on leaching agent concentration, leaching time and leaching temperature. The composition and morphology of the residue were determined to prove the competitive leaching results by XRD-SEM. TG results showed that 500 °C was the suitable pyrolysis temperature. XPS analysis demonstrated that pyrolysis can completely remove PVDF. Li and Co were preferentially leached during the competitive leaching while the leaching rates were 90.10% and 93.40% with 50 min leaching at 70 °C. The Al and Cu had weak competitive leachability and the leaching rate was 29.10% and 0.00%. XRD-SEM analysis showed that Li and Co can be fully leached with residual Al and Cu remaining. The results showed that the mixed leaching of electrode materials is feasible based on its excellent selective leaching properties.

Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson's disease through Mfn2-cGAS signaling.

BACKGROUND: Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson's disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined. METHODS: Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD. RESULTS: We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration. CONCLUSIONS: This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.

Vagus nerve stimulation as a promising neuroprotection for ischemic stroke via α7nAchR-dependent inactivation of microglial NLRP3 inflammasome.

Ischemic stroke is a major cause of disability and death worldwide, and its management requires urgent attention. Previous studies have shown that vagus nerve stimulation (VNS) exerts neuroprotection in ischemic stroke by inhibiting neuroinflammation and apoptosis. In this study, we evaluated the timing for VNS intervention in ischemic stroke, and the underlying mechanisms  of VNS-induced neuroprotection. Mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60 min. The left vagus nerve at cervical level was exposed and attached to an electrode connected to a low-frequency electrical stimulator. Vagus nerve stimulation (VNS) was given for 60 min before, during and after tMCAO (Pre-VNS, Dur-VNS, Post-VNS). Neurological function was assessed 24 h after reperfusion. We found that all the three VNS significantly protected against the tMCAO-induced injury evidenced by improved neurological function and reduced infarct volume. Moreover, the Pre-VNS was the most effective against the ischemic injury. We found that tMCAO activated microglia in the ischemic core and penumbra regions of the brain, followed by the NLRP3 inflammasome activation-induced neuroinflammation, which finally triggered neuronal death. VNS treatment preserved α7nAChR expression in the penumbra regions, inhibited NLRP3 inflammasome activation and ensuing neuroinflammation, rescuing cerebral neurons. The role of α7nAChR in microglial NLRP3 inflammasome activation in ischemic stroke was further validated using genetic manipulations, including Chrna7 knockout mice and microglial Chrna7 overexpression mice, as well as pharmacological interventions using the α7nAChR inhibitor methyllycaconitine and agonist PNU-282987. Collectively, this study demonstrates the potential of VNS as a safe and effective strategy to treat ischemic stroke, and presents a new approach targeting microglial NLRP3 inflammasome, which might be therapeutic for other inflammation-related diseases.

[A case of neonatal Netherton syndrome]. / 新生儿Netherton综合征1例.

A male infant, aged 6 days, was admitted to the hospital due to respiratory distress and systemic desquamative rash after birth. The infant presented with erythema and desquamative rash, respiratory failure, recurrent infections, chronic diarrhea, hypernatremic dehydration, and growth retardation. Comprehensive treatment, including anti-infection therapy, intravenous immunoglobulin administration, and skin care, resulted in improvement of the rash, but recurrent infections persisted. Second-generation sequencing revealed a homozygous mutation in the SPINK5 gene, consistent with the pathogenic variation of Netherton syndrome. The family opted for palliative care, and the infant died at the age of 2 months after discharge. This report documents a case of Netherton syndrome caused by the SPINK5 gene mutation in the neonatal period, and highlights multidisciplinary diagnosis and therapy for this condition.

Oligo/polysaccharides from Cyathula officinalis and Achyranthes bidentata: a review of structures and bioactivities.

OBJECTIVES: Oligo-/polysaccharides from Cyathula officinalis Kuan (COPs) and Achyranthes bidentata Blume (ABPs) have attracted researchers' attention in the fields of healthy food supplements and traditional Chinese medicine (Niúxi) due to their multiple bioactivities combined with their nontoxic and highly biocompatible nature. The purpose of this paper was to provide a systematic and comprehensive overview of the extraction, purification, and structural analysis methods, chemical characteristics, biological activities, and structure bioactivity relationship. Furthermore, the possible development trends and perspectives for future research, and traditional uses of Niúxi are also summarized. METHODS: All the information was gathered from a library search and scientific databases. KEY FINDINGS: Although COPs and ABPs are derived from different plants, they have similar structural features in type, structure, and glycosidic linkage patterns and biological activities in vivo and in vitro. However, there are differences in monosaccharide compositions, which can be used as an identification mark. CONCLUSIONS: As traditional Chinese herbal medicine, C. officinalis and A. bidentata have similar pharmacological activities. The COPs and ABP possess wide pharmacological effects such as antitumor, antioxidant, anti-osteoporosis, and anti-inflammatory. Meanwhile, the biological activity and structure-activity relationship of purified COPs and ABPs are less studied, future research should focus on them.

Antibodies against SARS-CoV-2 non-structural protein 3 cross-react with human muscle cells and neuroglial cells.

Coronavirus Disease 2019 (COVID-19) vaccines protect the public and limit viral spread. However, inactivated viral vaccines use the whole virus particle, which contains many non-capsid proteins that may cause adverse immune responses. A report has found that the ADP-ribose-binding domains of SARS-CoV-2 non-structural protein 3 (NSP3) and human poly(ADP-ribose) polymerase family member 14 (PARP14) share a significant degree of homology. Here, we further show that antibodies against 2019 novel SARS-like coronavirus (SARS-CoV-2) NSP3 can bind human PARP14 protein. However, when G159R + G162R mutations were introduced into NSP3, the antibody titer against human PARP14 decreased 14-fold. Antibodies against SARS-CoV-2 NSP3 can cross-react with human skeletal muscle cells and astrocytes, but not human embryonic kidney 293T cells. However, when G159R + G162R mutations were introduced into NSP3, the cross-reaction was largely inhibited. The results imply that COVID-19 patients with high antibody titers against NSP3 may have high risks of muscular and/or neurological complications. And the possible strategies to improve the safety of inactivated viral vaccines are also discussed.

Multifunctional Interlayer Engineering for Silkworm Excrement-Derived Porous Carbon Enabling High-Energy Lithium Sulfur Batteries.

Lithium-sulfur (Li-S) batteries show advantage of high theoretical capacity. However, the shuttle effect of polysulfides and sluggish sulfur redox kinetics seriously reduce their service life. Inspired by the porous structural features of biomass materials, herein, a functional interlayer is fabricated by silkworm excrement-derived three-dimensional porous carbon accommodating nano sized CoS2 particles (SC@CoS2 ). The porous carbon delivers a high specific surface area, which provides adequate adsorption sites, being responsible for suppressing the shuttle effect of polysulfides. Meanwhile, the porous carbon is favorable for hindering the aggregation of CoS2 and maintaining its high activity during extended cycles, which effectively accelerates the polysulfides conversion kinetics. Moreover, the SC@CoS2 functional interlayer effectively limits the formation of Li dendrites and promotes the uniform deposition of Li on the Li electrode surface. As a result, the CMK-3/S cathode achieves a high initial capacity of 1599.1 mAh g-1 at 0.2 C rate assisted by the polypropylene separator coated with the functional interlayer and 1208.3 mAh g-1 is maintained after the long cycling test. This work provides an insight into the designing of long-lasting catalysts for stable functional interlayer, which encourages the application of biomass-derived porous carbon in high-energy Li-S batteries.

Delivery room resuscitation intensity and associated neonatal outcomes of 24+0-31+6 weeks' preterm infants in China: a retrospective cross-sectional study.

BACKGROUND: The aim of this study was to review current delivery room (DR) resuscitation intensity in Chinese tertiary neonatal intensive care units and to investigate the association between DR resuscitation intensity and short-term outcomes in preterm infants born at 24+0-31+6 weeks' gestation age (GA). METHODS: This was a retrospective cross-sectional study. The source population was infants born at 24+0-31+6 weeks' GA who were enrolled in the Chinese Neonatal Network 2019 cohort. Eligible infants were categorized into five groups: (1) regular care; (2) oxygen supplementation and/or continuous positive airway pressure (O2/CPAP); (3) mask ventilation; (4) endotracheal intubation; and (5) cardiopulmonary resuscitation (CPR). The association between DR resuscitation and short-term outcomes was evaluated by inverse propensity score-weighted logistic regression. RESULTS: Of 7939 infants included in this cohort, 2419 (30.5%) received regular care, 1994 (25.1%) received O2/CPAP, 1436 (18.1%) received mask ventilation, 1769 (22.3%) received endotracheal intubation, and 321 (4.0%) received CPR in the DR. Advanced maternal age and maternal hypertension correlated with a higher need for resuscitation, and antenatal steroid use tended to be associated with a lower need for resuscitation (P < 0.001). Severe brain impairment increased significantly with increasing amounts of resuscitation in DR after adjusting for perinatal factors. Resuscitation strategies vary widely between centers, with over 50% of preterm infants in eight centers requiring higher intensity resuscitation. CONCLUSIONS: Increased intensity of DR interventions was associated with increased mortality and morbidities in very preterm infants in China. There is wide variation in resuscitative approaches across delivery centers, and ongoing quality improvement to standardize resuscitation practices is needed.

In vitro inhalation bioaccessibility and health risk assessment of difenoconazole in the atmosphere.

BACKGROUND: Assessment of the risk of pesticide inhalation in populations around farmland is necessary because inhalation is one of the ways in which pesticides can risk human health. This study aimed to identify the inhalation risk of difenoconazole on humans by using dose-response and exposure assessments. RESULTS: In the field simulation application, respiratory exposure in populations around farmland ranged from 71 to 430 ng/m3 . Using response surface methodology, the maximum bioaccessibility of difenoconazole in three simulated lung fluids was 35.33% in Gamble's solution (GS), 34.12% in artificial lysosomal fluid (ALF), and 42.06% in simulated interstitial lung fluid (SLF). Taking the proliferation activity of the A549 cell model as the endpoint, the benchmark dose limit and benchmark dose of difenoconazole on A549 cells were 16.36 and 5.60 mg/kg, respectively. The margin of exposure to difenoconazole in GS, ALF and SLF were, respectively, 8.66 × 105 to 5.28 × 106 , 8.97 × 105 to 5.47 × 106 and 7.28 × 105 to 4.44 × 106 . CONCLUSION: The risk assessment results indicate that under all circumstances, applying difenoconazole is safe for populations around farmland. However, a fan-shaped nozzle, suspension concentrate and greater inhalation height increase the risk of inhalation. © 2023 Society of Chemical Industry.

Review on the gentle hydrometallurgical treatment of WPCBs: Sustainable and selective gradient process for multiple valuable metals recovery.

The metal resource crisis and the inherent need for a low-carbon circular economy have driven the rapid development of e-waste recycling technology. High-value waste printed circuit boards (WPCBs) are an essential component of e-waste. However, WPCBs are considered hazardous to the ecosystem due to the presence of heavy metals and brominated organic polymers. Therefore, achieving the recycling of metals in WPCBs is not only a strategic requirement for building a green ecological civilization but also an essential guarantee for achieving a safe supply of mineral resources. This review systematically analyzes the hydrometallurgical technology of metals in WPCBs in recent years. Firstly, the different unit operations of pretreatment in the hydrometallurgical process, which contain disassembly, crushing, and pre-enrichment, were analyzed. Secondly, environmentally friendly hydrometallurgical leaching systems and high-value product regeneration technologies used in recent years to recover metals from WPCBs were evaluated. The leaching techniques, including cyanidation, halide, thiourea, and thiosulfate for precious metals, and inorganic acid, organic acid, and other leaching methods for base metals such as copper and nickel in WPCBs, were outlined, and the leaching performance and greenness of each leaching system were summarized and analyzed. Eventually, based on the advantages of each leaching system and the differences in chemical properties of metals in WPCBs, an integrated and multi-gradient green process for the recovery of WPCBs was proposed, which provides a sustainable pathway for the recovery of metals in WPCBs. This paper provides a reference for realizing the gradient hydrometallurgical recovery of metals from WPCBs to promote the recycling metal resources.

Eco-friendly approach for enhancing the floatability of non-metallic components in waste printed circuit boards: Adding gutter oil during dry grinding.

Waste printed circuit boards (WPCBs) are an attractive secondary resource that is challenging to dispose of due to its complexity. Reverse flotation is an effective method to remove non-metallic particles (NMPs) to obtain metals from WPCBs. Nevertheless, the removal of NMPs is usually inadequate in the present flotation practice. Thus, to provide a clean approach to improve the removal efficiency of NMPs, the method of adding gutter oil during dry grinding process was adopted to enhance the hydrophobic sites on the surface of NMPs to improve the floatability. The surface morphology of NMPs was analyzed by SEM, the results show that the rough morphology inhibited the adhesion of bubbles, while water occupied the cracks and pores, making it challenging for collector adsorption, which result in unstable particle-bubble adhesion. The results of FTIR indicate that both NMPs and gutter oil have -CH3, -CH2, -C = O, -C-O functional groups, which promotes the adsorption of gutter oil on the surface of NMPs. The contact angle (CA) results show that the adsorption of gutter oil on the particle surface is conducive to the formation of enhanced CA. Furthermore, the flotation enhancement effect was verified by flotation kinetic experiments. The accumulated floats yield of NMPs conditioned by gutter oil during grinding is increased from 67.05% (NMPs without conditioning) to 95.02%, and the resin recovery is increased by 31.10%. It is demonstrated that dry grinding with gutter oil can strengthen the floatability of NMPs, which provides a potential approach to increase the flotation efficiency of WPCBs.

Reliability and validation of the Chinese version of the epilepsy surgery satisfaction questionnaire.

OBJECTIVE: To evaluate the reliability and validity the Chinese version of 19-item Epilepsy Surgery Satisfaction Questionnaire (C-ESSQ-19) in Chinese mainland patients. METHODS: Patients with epilepsy who had epilepsy surgery in our hospital one year earlier were included. Internal consistency and test-retest reliability were assessed by using Cronbach alpha and intraclass correlation coefficient (ICC). Confirmatory factor analysis was used for construct validity. Discriminant validity was assessed using receiver operating characteristic curve analysis. RESULTS: A total of 132 patients participated in our study, consisting of 59 females and 73 males. The C-ESSQ-19 yielded a median summary score of 86.5 (IQR=72.7-98.0). The Cronbach's alpha of the four domains of the C-ESSQ-19 ranged from 0.746 to 0.973. The test-retest reliability evaluated by ICC were good to excellent, ranging from 0.71 to 0.90 (P < 0.001). The C-ESSQ-19 demonstrated excellent construct validity, as indicated by the satisfactory goodness-of-fit of the data (SRMR = 0.046; CFI = 1.000). It exhibited acceptable discriminant validity for differentiating between patients excised or not (AUC = 0.72; 95% CI = 0.59-0.86) and self-rated severity of epilepsy (AUC = 0.76, 95% CI = 0.67-0.86), but poor discriminant validity for other factors, such as being seizure-free or not (AUC = 0.66, CI = 0.56-0.75), depressed or not (AUC = 0.66, 95% CI = 0.54-0.79), and self-rated disability related to seizures (AUC = 0.65, 95% CI = 0.50-0.80). CONCLUSIONS: The C-ESSQ-19 has proven to be a reliable and valid self-rated questionnaire for assessing the satisfaction of Chinese mainland epilepsy patients with surgery.

Influence of green biomass composition on the urban thermal environment in hot summer and warm winter regions: The example of Fuzhou residential area.

The aim of this study was to investigate the relationship between green biomass composition and thermal environment, as well as their optimal composition pattern. We decomposed total green biomass in a certain spatial range into two categories: trees and shrubs-grasses, with urban residential areas as sampling sites and based on aerial photography and field research data of green biomass and optimized green biomass measurement method. We analyzed the correlation between the green biomass composition indicators (shrub and grass biomass, tree canopy biomass, green biomass, mean tree canopy biomass, number of trees) and ambient temperature and humidity in different spatial ranges. The results showed that the most significant cooling and humidifying effect of different green biomass composition indicators was at 50 m below the building scale. The mean tree canopy biomass and tree canopy biomass were the key factors affecting ambient temperature and humidity, respectively, in different time periods during the day. With an average canopy biomass of about 211 m3 and 62 trees in a 50 m space, the regulation effects of trees on ambient temperature and humidity were closer to the thermal comfort requirements of human body.

Mefloquine targets NLRP3 to reduce lipopolysaccharide-induced systemic inflammation and neural injury.

The NLR family pyrin domain containing 3 (NLRP3) inflammasome plays an important role in the pathogenesis of a wide variety of human diseases. So far, drugs directly and specifically targeting the NLRP3 inflammasome are not available for clinical use since the safety and efficacy of new compounds are often unclear. A promising approach is thus to identify NLRP3 inhibitors from existing drugs that are already in clinical use. Here, we show that mefloquine, a well-known antimalarial drug, is a highly selective and potent NLRP3 inhibitor by screening a FDA-approved drug library. Mechanistically, mefloquine directly binds to the NLRP3 NACHT and LRR domains to prevent NLRP3 inflammasome activation. More importantly, mefloquine treatment attenuates the symptoms of lipopolysaccharide-induced systemic inflammation and Parkinson's disease-like neural damage in mice. Our findings identify mefloquine as a potential therapeutic agent for NLRP3-driven diseases and migth expand its clinical use considerably.

The cGAS-STING-YY1 axis accelerates progression of neurodegeneration in a mouse model of Parkinson's disease via LCN2-dependent astrocyte senescence.

Recent studies provide clues that astrocyte senescence is correlated with Parkinson's disease (PD) progression, while little is known about the molecular basis for astrocyte senescence in PD. Here, we found that cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) was upregulated in senescent astrocytes of PD and aged mice. Strikingly, deletion of astrocytic cGAS significantly prevented senescence of astrocytes and neurodegeneration. Furthermore, we identified LCN2 as the effector of cGAS-STING signal by RNA-Seq analysis. Genetic manipulation of LCN2 expression proved the regulation of cGAS-STING-LCN2 axis in astrocyte senescence. Additionally, YY1 was discovered as the transcription factor of LCN2 by chromatin immunoprecipitation. Binding of STING to YY1 impedes nuclear translocation of YY1. Herein, we determine the involvement of the cGAS-STING-YY1-LCN2 signaling cascade in the control of astrocyte senescence and PD progression. Together, this work fills the gap in our understanding of astrocyte senescence, and provides potential targets for delaying PD progression.

Cytokine and chemokine map of peripheral specific immune cell subsets in Parkinson's disease.

Peripheral immune cells play a vital role in the development of Parkinson's disease (PD). However, their cytokine and chemokine secretion functions remain unclear. Therefore, we aimed to explore the cytokine and chemokine secretion functions of specific immune cell subtypes in drug-naïve patients with PD at different ages of onset. We included 10 early-onset and 10 late-onset patients with PD and age-matched healthy controls (HCs). We used mass cytometry to select specific immune cell subsets and evaluate intracellular cytokine and chemokine expression. Statistical tests included t-tests, analysis of variance, bivariate correlation analysis, and linear regression analysis. Compared with HCs, patients with PD exhibited significantly decreased intracellular pro-inflammatory cytokines and chemokines in selected clusters (e.g., tumor necrosis factor (TNF)-α, interleukin (IL)-8, IL-1ß, and CC-chemokine ligand (CCL)17). Specific cytokines and cell clusters were associated with clinical symptoms. TNF-α played an important role in cognitive impairment. Intracellular TNF-α levels in the naïve CD8+ T-cell cluster C16 (CD57- naïve CD8+ T) and natural killer (NK) cell cluster C32 (CD57- CD28- NK) were negatively correlated with Montreal Cognitive Assessment scores. The C16 cluster affected cognitive function and motor symptoms. Increased TNF-α and decreased interferon-γ expression in C16 correlated with increased Unified Parkinson's Disease Rating Scale III scores in patients with PD. In summary, we developed a more detailed cytokine and chemokine map of peripheral specific CD8+ T cell and NK cell subsets, which revealed disrupted secretory function in patients with PD and provided unique clues for further mechanistic exploration.