All-aqueous droplets-templated tailorable core-shell alginate microspheres for constructing vascularized intestinal mucosa in vitro models.

Recently, in vitro models of intestinal mucosa have become important tools for drug screening and studying the physiology and pathology of the intestine. These models enable the examination of cellular behavior in diseased states or in reaction to alterations in the microenvironment, potentially serving as alternatives to animal models. One of the major challenges in constructing physiologically relevant in vitro models of intestinal mucosa is the creation of three-dimensional (3D) microstructures that accurately mimic the integration of intestinal epithelium and vascularized stroma. Here, core-shell alginate (Alg) microspheres were generated to create the compartmentalized extracellular matrix (ECM) microenvironment needed to simulate the epithelial and vascularized stromal compartments of the intestinal mucosa. We demonstrated that NIH-3T3 and human umbilical vein endothelial cells (HUVECs) embedded in the core of the microspheres can proliferate and develop a vascular network, while human colorectal adenocarcinoma cells (Caco-2) can form an epithelial monolayer in the shell. Compared to Caco-2 monolayer encapsulated within the shell, the presence of the vascularized stroma enhances their proliferation and functionality. As such, our core-shell Alg microspheres provide a valuable method for generating in vitro models of vascularized intestinal mucosa with epithelial and vascularized stroma arranged in a spatially relevant manner and demonstrating near-physiological functionality.

Causal effects of gut microbiota on autism spectrum disorder: A two-sample mendelian randomization study.

There is increasing evidence that alterations in gut microbiota (GM) composition are associated with autism spectrum disorder (ASD), but no reliable causal relationship has been established. Therefore, a 2-sample Mendelian randomization (MR) study was conducted to reveal a potential causal relationship between GM and ASD. Instrumental variables for 211 GM taxa were obtained from genome-wide association studies (GWAS) and Mendelian randomization studies to estimate their impact on ASD risk in the iPSYCH-PGC GWAS dataset (18,382 ASD cases and 27,969 controls). Inverse variance weighted (IVW) is the primary method for causality analysis, and several sensitivity analyses validate MR results. Among 211 GM taxa, IVW results confirmed that Tenericutes (P value = .0369), Mollicutes (P value = .0369), Negativicutes (P value = .0374), Bifidobacteriales (P value = .0389), Selenomonadales (P value = .0374), Bifidobacteriaceae (P value = .0389), Family XIII (P value = .0149), Prevotella7 (P value = .0215), Ruminococcaceae NK4A214 group (P value = .0205) were potential protective factors for ASD. Eisenbergiella (P value = .0159) was a possible risk factor for ASD. No evidence of heterogeneous, pleiotropic, or outlier single-nucleotide polymorphism was detected. Additionally, further sensitivity analysis verified the robustness of the above results. We confirm a potential causal relationship between certain gut microbes and ASD, providing new insights into how gut microbes mediate ASD. The association between them needs to be further explored and will provide new ideas for the prevention and treatment of ASD.

Erchen decoction alleviates the progression of NAFLD by inhibiting lipid accumulation and iron overload through Caveolin-1 signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: A combination of 6 different Chinese herbs known as Erchen decoction (ECD) has been traditionally used to treat digestive tract diseases and found to have a protective effect against nonalcoholic fatty liver disease (NAFLD). Despite its efficacy in treating NAFLD, the precise molecular mechanism by which Erchen Decoction regulated iron ion metabolism to prevent disease progression remained poorly understood. AIM OF STUDY: Our study attempted to confirm the specific mechanism of ECD in reducing lipid and iron in NAFLD from the perspective of regulating the expression of Caveolin-1 (Cav-1). STUDY DESIGN: In our study, the protective effect of ECD was investigated in Palmitic Acid + Oleic Acid-induced hepatocyte NAFLD model and high-fat diet-induced mice NAFLD model. To investigate the impact of Erchen Decoction (ECD) on lipid metabolism and iron metabolism via mediating Cav-1 in vitro, Cav-1 knockdown cell lines were established using lentivirus-mediated transfection techniques. MATERIALS AND METHODS: We constructed NAFLD model by feeding with high-fat diet for 12 weeks in vivo and Palmitic Acid + Oleic Acid treatment for 24 h in vitro. The regulation of Lipid and iron metabolism results by ECD were detected by serological diagnosis, immunofluorescent and immunohistochemical staining, and western blotting. The binding ability of 6 small molecules of ECD to Cav-1 was analyzed by molecular docking. RESULTS: We demonstrated that ECD alleviated the progression of NAFLD by inhibiting lipid accumulation, nitrogen oxygen stress, and iron accumulation in vivo and in vitro experiments. Furthermore, ECD inhibited lipid and iron accumulation in liver by up-regulating the expression of Cav-1, which indicated that Cav-1 was an important target for ECD to exert its curative effect. CONCLUSIONS: In summary, our study demonstrated that ECD alleviated the accumulation of lipid and iron in NAFLD through promoting the expression of Cav-1, and ECD might serve as a novel Cav-1 agonist to treat NAFLD.

Dynamic alterations of striatal-related functional networks in juvenile absence epilepsy.

PURPOSE: To explore the features of dynamic functional connectivity (dFC) variability of striatal-cortical/subcortical networks in juvenile absence epilepsy (JAE). METHODS: We collected resting-state functional magnetic imaging data from 18 JAE patients and 28 healthy controls. The striatum was divided into six pairs of regions: the inferior-ventral striatum (VSi), superior-ventral striatum (VSs), dorsal-caudal putamen, dorsal-rostral putamen, dorsal-caudate (DC) and ventral-rostral putamen. We assessed the dFC variability of each subdivision in the whole brain using the sliding-window method, and correlated altered circuit with clinical variables in JAE patients. RESULTS: We found altered dFC variability of striatal-cortical/subcortical networks in patients with JAE. The VSs exhibited decreased dFC variability with subcortical regions, and dFC variability between VSs and thalamus was negatively correlated with epilepsy duration. For the striatal-cortical networks, the dFC variability was decreased in VSi-affective network but increased in DC-executive network. The altered dynamics of striatal-cortical networks involved crucial nodes of the default mode network (DMN). CONCLUSION: JAE patients exhibit excessive stability in the striatal-subcortical networks. For striatal-cortical networks in JAE, the striatal-affective circuit was more stable, while the striatal-executive circuit was more variable. Furthermore, crucial nodes of DMN were changed in striatal-cortical networks in JAE.

Distinct brain state dynamics of native and second language processing during narrative listening in late bilinguals.

The process of complex cognition, which includes language processing, is dynamic in nature and involves various network modes or cognitive modes. This dynamic process can be manifested by a set of brain states and transitions between them. Previous neuroimaging studies have shed light on how bilingual brains support native language (L1) and second language (L2) through a shared network. However, the mechanism through which this shared brain network enables L1 and L2 processing remains unknown. This study examined this issue by testing the hypothesis that L1 and L2 processing is associated with distinct brain state dynamics in terms of brain state integration and transition flexibility. A group of late Chinese-English bilinguals was scanned using functional magnetic resonance imaging (fMRI) while listening to eight short narratives in Chinese (L1) and English (L2). Brain state dynamics were modeled using the leading eigenvector dynamic analysis framework. The results show that L1 processing involves more integrated states and frequent transitions between integrated and segregated states, while L2 processing involves more segregated states and fewer transitions. Our work provides insight into the dynamic process of narrative listening comprehension in late bilinguals and sheds new light on the neural representation of language processing and related disorders.

Discovery of potent and selective HPK1 inhibitors based on the 2,4-disubstituted pyrimidine scaffold with immune modulatory properties for ameliorating T cell exhaustion.

Hematopoietic progenitor kinase 1 (HPK1), a member of the mitogen-activated protein kinase (MAP4K) family, is a serine/threonine (SER/THR) kinase and has been demonstrated as a negative regulator of T cell receptor signaling. Targeting HPK1 has been considered as an attractive therapeutic strategy for immune-oncology. Here, we describe the discovery and structure-activity relationship (SAR) of potent HPK1 inhibitors based on the 2,4-disubstituted pyrimidine scaffold. Systematically SAR exploration afforded the desired compound HMC-H8 (F1) with potent HPK1 inhibition (IC50 = 1.11 nM) and highly selectivity profile. Compound HMC-H8 also exhibited robust inhibition of p-SLP 76 (IC50 = 283.0 nM) and promotion IL-2 release (EC50 = 157.08 nM), and INF-γ production in a dose-dependent manner in vitro assays. Strikingly, HMC-H8 shown effective immune reversal response in immunesuppressive condition. Moreover, Compound HMC-H8 displayed acceptable metabolic stability (T1/2 = 56.87 min), along with low CYP450 inhibition in human liver microsomes and good oral bioavailability (F = 15.05%) in rat. Furthermore, HMC-H8 was found to modulate the expression of c-Myc in Western blotting experiments. Taken together, this study provides new potent HPK1 inhibitors for further anticancer drug discovery based on immuno-oncology.

Exploiting Machine Learning Technologies to Study the Compound Effects of Serum Creatinine and Electrolytes on the Risk of Acute Kidney Injury in Intensive Care Units.

Assessing the risk of acute kidney injury (AKI) has been a challenging issue for clinicians in intensive care units (ICUs). In recent years, a number of studies have been conducted to investigate the associations between several serum electrolytes and AKI. Nevertheless, the compound effects of serum creatinine, blood urea nitrogen (BUN), and clinically relevant serum electrolytes have yet to be comprehensively investigated. Accordingly, we initiated this study aiming to develop machine learning models that illustrate how these factors interact with each other. In particular, we focused on ICU patients without a prior history of AKI or AKI-related comorbidities. With this practice, we were able to examine the associations between the levels of serum electrolytes and renal function in a more controlled manner. Our analyses revealed that the levels of serum creatinine, chloride, and magnesium were the three major factors to be monitored for this group of patients. In summary, our results can provide valuable insights for developing early intervention and effective management strategies as well as crucial clues for future investigations of the pathophysiological mechanisms that are involved. In future studies, subgroup analyses based on different causes of AKI should be conducted to further enhance our understanding of AKI.

Plasmon-Mediated Photoelectrochemical Hot-Hole Oxidation Coupling Reactions of Adenine on Nanostructured Silver Electrodes.

Surface-enhanced Raman spectroscopy (SERS) has been widely applied in the identification and characterization of DNA structures with high efficiency. Especially, the SERS signals of the adenine group have exhibited high detection sensitivity in several biomolecular systems. However, there is still no unanimous conclusion regarding the interpretation of some special kinds of SERS signals of adenine and its derivatives on silver colloids and electrodes. This Letter presents a new photochemical azo coupling reaction for adenyl residues, in which the adenine is selectively oxidized to (E)-1,2-di(7H-purin-6-yl) diazene (azopurine) in the presence of silver ions, silver colloids, and electrodes of nanostructures under visible light irradiation. The product, azopurine, is first found to be responsible for the SERS signals. This photoelectrochemical oxidative coupling reaction of adenine and its derivatives is promoted by plasmon-mediated hot holes and is regulated by positive potentials and pH of solutions, which opens up new avenues for studying azo coupling in the photoelectrochemistry of adenine-containing biomolecules on electrode surfaces of plasmonic metal nanostructures.

Exocarpium Citri Grandis alleviates the aggravation of NAFLD by mitigating lipid accumulation and iron metabolism disorders.

ETHNOPHARMACOLOGICAL RELEVANCE: Exocarpium Citri grandis (ECG, Huajuhong in Chinese), the epicarp of C. grandis 'Tomentosa', has been used for hundreds of years as an anti-inflammatory, expectorant, hypoglycemic, and lipid-lowering medication in China. Nevertheless, there have been few papers that have explored the mechanism behind ECG's hypolipidemic characteristics from the perspective of treating nonalcoholic fatty liver disease (NAFLD). AIM OF STUDY: The purpose of our study was to confirm the therapeutic and preventative effects of ECG in NAFLD by regulating lipid accumulation and iron metabolism, and to explore the specific mechanism of ECG in enhancing hepatic iron transport and excretion capabilities. STUDY DESIGN: We constructed a NAFLD model by feeding male C57BL/6 J mice with a high-fat diet for 12 weeks. Mice were gavaged with ECG beginning in the seventh week of modeling, and three dosage gradients were established: low dose group (2.5 g/kg/d), medium dose group (5 g/kg/d) y, and high dose group (10 g/kg/d) until the end of model construction in week 12. MATERIALS AND METHODS: We used network pharmacology to analyze the relationship between ECG and NAFLD. In addition, we constructed a nonalcoholic fatty liver disease model by feeding male C57BL/6 J mice a high-fat diet for 12 weeks. Finally, lipid accumulation, iron accumulation, inflammation and oxidative stress were evaluated by serological index detection, histological detection, immunofluorescent and immunohistochemical staining, and western blotting. RESULTS: Network pharmacology confirmed the treatment effect of ECG in NAFLD. Three active components of ECG, including Naringenin, Naringin and Neohesperidin, were detected by UHPLC-HRMS analysis. The results of serum TC, TG, LDL concentration, HE staining, Oil red staining and Nile red staining demonstrated that ECG could improve lipid metabolism disorders. The results of serum iron concentration, liver tissue iron concentration, iron metabolism-related proteins Ferritin light chain, Ferroportin1, Transferrin receptor, and Transferrin demonstrated that ECG improved the iron transport and storage capacities of hepatic cells. CONCLUSIONS: Our results demonstrated that ECG relieved liver injury by inhibiting lipid accumulation and iron accumulation in NAFLD.

Protective effect of resveratrol on mitochondrial biogenesis during hyperoxia-induced brain injury in neonatal pups.

BACKGROUND: Neonatal hyperoxic brain injury is caused by exposure to hyperphysiological oxygen content during the period of incomplete development of the oxidative stress defence system, resulting in a large number of reactive oxygen species (ROS) and causing damage to brain tissue. Mitochondrial biogenesis refers to the synthesis of new mitochondria from existing mitochondria, mostly through the PGC-1α/Nrfs/TFAM signalling pathway. Resveratrol (Res), a silencing information regulator 2-related enzyme 1 (Sirt1) agonist, has been shown to upregulate the level of Sirt1 and the expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). We speculate that Res has a protective effect on hyperoxia-induced brain injury through mitochondrial biogenesis. METHODS: Sprague-Dawley (SD) pups were randomly divided into the nonhyperoxia (NN) group, the nonhyperoxia with dimethyl sulfoxide (ND) group, the nonhyperoxia with Res (NR) group, the hyperoxia (HN) group, the hyperoxia with dimethyl sulfoxide (HD) group, and the hyperoxia with Res (HR) group within 12 h after birth. The HN, HD, and HR groups were placed in a high-oxygen environment (80‒85%), and the other three groups were placed in the standard atmosphere. The NR and HR groups were given 60 mg/kg Res every day, the ND and HD groups were given the same dose of dimethyl sulfoxide (DMSO) every day, and the NN and HN groups were given the same dose of normal saline every day. On postnatal day (PN) 1, PN7, and PN14, brain samples were acquired for HE staining to assess pathology, TUNEL to detect apoptosis, and real-time quantitative polymerase chain reaction and immunoblotting to detect the expression levels of Sirt1, PGC-1α, nuclear respiratory factor 1 (Nrf1), nuclear respiratory factor 2 (Nrf2) and mitochondrial transcription factor A (TFAM) in brain tissue. RESULTS: Hyperoxia induced brain tissue injury; increased brain tissue apoptosis; inhibited Sirt1, PGC-1α, Nrf1, Nrf2, TFAM mRNA expression in mitochondria; diminished the ND1 copy number and ND4/ND1 ratio; and decreased Sirt1, PGC-1α, Nrf1, Nrf2, and TFAM protein levels in the brain. In contrast, Res reduced brain injury and attenuated brain tissue apoptosis in neonatal pups and increased the levels of the corresponding indices. CONCLUSION: Res has a protective effect on hyperoxia-induced brain injury in neonatal SD pups by upregulating Sirt1 and stimulating the PGC-1α/Nrfs/TFAM signalling pathway for mitochondrial biogenesis.

Chaetoglobosin A Contributes to the Antagonistic Action of Chaetomium globosum Strain 61239 Toward the Apple Valsa Canker Pathogen Cytospora mali.

Apple Valsa canker (AVC) weakens apple trees and significantly reduces apple production in China and other East Asian countries. Thus far, very few AVC-targeting biocontrol resources have been described. Here, we present a thorough description of a fungal isolate (Chaetomium globosum, 61239) that has strong antagonistic action toward the AVC causal agent Cytospora mali. Potato dextrose broth culture filtrate of strain 61239 completely suppressed the mycelial growth of C. mali on potato dextrose agar, and strongly constrained the development of AVC lesions in in vitro infection assays. ultra-performance liquid chromatography (UPLC) and HPLC-MS/MS investigations supported the conclusion that strain 61239 produces chaetoglobosin A, an antimicrobial metabolite that inhibits C. mali. Using genome sequencing, we discovered a gene cluster in strain 61239 that may be responsible for chaetoglobosin A production. Two of the cluster's genes-cheA, a PKS-NRPS hybrid enzyme, and cheB, an enoyl reductase-were individually silenced, which significantly decreased chaetoglobosin A accumulation as well as the strain's antagonistic activity against C. mali. Together, the findings of our investigation illustrate the potential use of Chaetomium globosum for the management of AVC disease and emphasize the significant contribution of chaetoglobosin A to the antagonistic action of strain 61239.

Constructing Defective Heterojunctions of BiOBr Nanosheets and Hollow NH2 -functionalized MOFs for Visible-light-driven CO2 Reduction with Nearly 100% CO Selectivity by Pure H2 O.

To rationally design photocatalysts with high generation rate and selectivity of target product remains an ongoing challenge for CO2 conversion in pure H2 O. Herein, from the viewpoint of enhancing the separation efficiency of photoinduced electron-hole pairs and the adsorption ability of CO2 molecule, we have constructed a series of Z-scheme defective heterojunctions of BiOBr nanosheets and hollow NH2 -functionalized metal-organic framework (MOF) MIL-125 with Ti ions as metal centers (noted as NH2 -MIL-125(Ti)). Systematic characterization demonstrates that the BiOBr nanosheets are anchored on the surface of hollow NH2 -MIL-125(Ti), which facilitates the efficient visible-light-driven catalytic reduction of CO2 to CO with nearly 100% selectivity by pure H2 O. Especially, the CO generation rate of optimized catalyst with oxygen vacancies reaches 459.7 µmol g-1 h-1 , which is higher than those of all the previously reported photocatalysts without sacrificial reagents. This approach provides a new insight for using inorganic semiconductors to fabricate semiconducting MOFs for high-efficiency photocatalytic reduction CO2 into value-added chemicals by pure H2 O.

Trace elements in outdoor and indoor PM2.5 in urban schools in Xi'an, Western China: characteristics, sources identification and health risk assessment.

The PM2.5-bounded elements were measured in outdoor and indoor from two urban middle schools in Xi'an. The PM2.5 mass was from 42.4 to 283.7 µg/m3 with bounded element from 3.4 to 41.7 µg/m3. Both the particle mass and the bounded elements displayed higher levels compared with previous studies in school environments. The most abundant elements were Ca, K, Fe, S, Zn and Cl both indoor and outdoor in two schools, which accounted for about 90% of the total elements. Strong correlations between indoor and outdoor were obtained along with relative effect from students' and teachers' activities on the indoor distributions between workdays and weekends. There had different indoor/outdoor (I/O) distributions for the two schools. It revealed the main outdoor sources for elements in JT and predominance of indoor sources in HT. The principal component analysis investigated main sources of elements in this study were coal combustion, geogenic dust and industrial emission, even though there displayed differences in the two school classrooms. The health risk assessment showed that the cancer risk for Ni and Pb was below the safe value while As and Cr might pose acceptable potential threat to both students' and teachers' health. The total non-cancer risks of accumulative multi-metals in JT exhibited to be higher than 1, indicating that there existed the potential non-carcinogenic health risks of exposure metals.

RAGE promotes dysregulation of iron and lipid metabolism in alcoholic liver disease.

Alcoholic liver disease (ALD) is associated with hepatic inflammatory activation and iron overload. The receptor for advanced glycation end products (RAGE) is an important metabolic mediator during the development of ALD. The aim of this study was to determine the effect of RAGE on iron homeostasis in ALD. We found increased circulating transferrin, hepcidin and ferritin in ALD patients and positively correlated with RAGE level. RAGE knockout (RAGE-/-) and wild-type mice were subjected to chronic alcoholic feeding for 6 weeks to induce ALD, and RAGE inhibitor, iron chelator or lipid peroxidation inhibitor were administered. We showed that chronic alcohol administration triggered hepatic steatosis, inflammation, and oxidative stress, which were eliminated by deficiency or inhibition of RAGE. Surprisingly, pathways of hepatic iron metabolism were significantly altered, including increased iron uptake (Tf/TfR) and storage (Ferritin), as well as decreased iron export (FPN1/Hepcidin). In vitro experiments confirmed that RAGE had different effects on the mechanism of iron metabolism of hepatocytes and macrophages respectively. In conclusion, our data revealed preclinical evidence for RAGE inhibition as an effective intervention for alleviating alcohol-induced liver injury.

Brain fingerprints along the language hierarchy.

Recent studies have shown that the brain functional connectome constitutes a unique fingerprint that allows the identification of individuals from a group. However, what information encoded in the brain that makes us unique remains elusive. Here, we addressed this issue by examining how individual identifiability changed along the language hierarchy. Subjects underwent fMRI scanning during rest and when listening to short stories played backward, scrambled at the sentence level, and played forward. Identification for individuals was performed between two scan sessions for each task as well as between the rest and task sessions. We found that individual identifiability tends to increase along the language hierarchy: the more complex the task is, the better subjects can be distinguished from each other based on their whole-brain functional connectivity profiles. A similar principle is found at the functional network level: compared to the low-order network (the auditory network), the high-order network is more individualized (the frontoparietal network). Moreover, in both cases, the increase in individual identifiability is accompanied by the increase in inter-subject variability of functional connectivities. These findings advance the understanding of the source of brain individualization and have potential implications for developing robust connectivity-based biomarkers.

Altered dynamic functional connectivity of striatal-cortical circuits in Juvenile Myoclonic Epilepsy.

OBJECTIVE: To investigate whether the dynamic functional connectivity (dFC) of striatal-cortical circuits changes in juvenile myoclonic epilepsy (JME). METHODS: The resting-state EEG-fMRI and the sliding-window approach were adopted to explore the dynamic striatal-cortical circuitry in thirty JME patients compared with 30 well-matched health controls (HCs). Six pairs of striatal seeds were selected as regions of interests. The correlation analysis was performed to reveal the relationship between the altered dFC variability and clinical variables in JME group. RESULTS: JME patients exhibited increased dFC variability mainly involved in fronto-striatal and striatal-thalamic networks; decreased dFC variability between striatum subdivisions and default mode network (DMN) regions compared with HCs (p<0.05, GRF corrected). In addition, the hypervariability between left ventral-rostral putamen and left medial superior frontal gyrus was positively (r= 0.493, p=0.008) correlated with the mean frequency score of myoclonic seizures in JME group. CONCLUSION: JME presented altered dFC variability in striatal-cortical circuits. The pattern of altered circuits showed increased variability in fronto-striatal and striatal-thalamic networks and decreased variability in striatal-DMN. These results provide novel information about the dynamic neural striatal-cortical circuitry of JME.

Poria cocos polysaccharides rescue pyroptosis-driven gut vascular barrier disruption in order to alleviates non-alcoholic steatohepatitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Poria cocos polysaccharides (PCP) are abundant in Poria cocos (Schw.) Wolf (Poria). This is a common traditional Chinese medicine used to treat gastrointestinal and liver diseases. Poria cocos dispel dampness and enhance gastrointestinal functions, strongly affecting the treatment of non-alcoholic fatty liver disease. Still, the mechanism is not yet clear. AIM OF THE STUDY: The latest research found that protecting the integrity of the intestinal barrier can slow down the progression of non-alcoholic fatty liver disease (NAFLD). Hence, our research ought to explore the protective mechanism of PCP on the intestinal barrier under a high-fat diet and to clarify the relationship between intestinal barrier damage and steatohepatitis. MATERIALS AND METHODS: H&E staining was done to evaluate pathological damage, whereas Nile red and oil red O staining was conducted to evaluate hepatic fat infiltration. Immunofluorescence staining and immunohistochemical staining were used to detect protein expression and locations. Bone marrow-derived macrophages were isolated for in vitro experiments. ONOO- and ROS fluorescent probes and MDA, SOD, and GSH kits assessed the levels of nitrogen and oxidative stress. LPS levels were detected with a Limulus Amebocyte Lysate assay. The Western blot analysis and reverse transcription-quantitative PCR detected the expression of related proteins and genes. The Elisa kit detected the level of the inflammatory factors in the cell supernatant. For the vivo NAFLD experiments, in briefly, mice were randomly chosen to receive either a High-fat diet or control diet for 12 weeks. Drug treatments started after 4 weeks of feeding. Zebrafish larvae were raised separately in fish water or 7 mM thioacetamide as the control or model group for approximately 72 h. In the therapy groups, different concentrations of PCP were added to the culture environment at the same time. RESULTS: In zebrafish, we determined the safe concentration of PCP and found that PCP could effectively reduce the pathological damage in the liver and intestines induced by the NAFLD model. In mice, PCP could slow down weight gain, hyperlipidemia, and liver steatosis caused by a high-fat diet. More importantly, PCP could reduce the destruction of the gut-vascular barrier and the translocation of endotoxins caused by a high-fat diet. Further, we found that PCP could inhibit intestinal pyroptosis by regulating PARP-1. Pyroptosis inhibitors, such as MCC950, could effectively protect the intestinal and liver damage induced by a high-fat diet. We also found that pyroptosis mainly occurred in intestinal macrophages. PCP could effectively improve the survival rate of bone marrow-derived macrophages in a high-fat environment and inhibit pyroptosis. CONCLUSIONS: These results indicated that PCP inhibited the pyroptosis of small intestinal macrophages to protect the intestinal barrier integrity under a high-fat diet. This resulted in decreased endotoxin translocation and progression of steatohepatitis.

Anti-GAD65 Antibody-Associated Autoimmune Encephalitis With Predominant Cerebellar Involvement Following Toripalimab Treatment: A Case Report of a Novel irAE of Toripalimab.

Toripalimab (Junshi Bioscience Co., Ltd) is a new immune checkpoint inhibitor (ICI) that targets programmed cell death protein 1 (PD-1) in various cancers, including metastatic melanoma. No neurological immune-related adverse events (n-irAEs) of toripalimab have been reported, except for neuromuscular involvement. We report a case of a 63-year-old woman who presented with severe vertigo, vomiting, nystagmus, cerebellar ataxia, and cognitive impairment after toripalimab treatment for metastatic melanoma. Compared with the concomitant cognitive dysfunction and a pathological reflex involving the cerebral cortex, the signs and symptoms of cerebellar involvement were much more prominent. Anti-glutamic acid decarboxylase 65 (anti-GAD65) antibody was positive in both serum and cerebrospinal fluid (CSF). After intravenous immunoglobulin (IVIG) and methylprednisolone (IVMP) administration, the symptoms of vertigo and vomiting resolved, with cognitive impairment and cerebellar ataxia remaining. This is the first report of autoimmune encephalitis (AIE) as an n-irAE of toripalimab.

Pretreatment topological disruptions of whole-brain networks exist in childhood absence epilepsy: A resting-state EEG-fMRI study.

PURPOSE: Childhood absence epilepsy (CAE) is associated with functional changes in specific brain regions and connections. However, little is known about the topological properties of the functional brain connectome in drug naive CAE. METHODS: We adopted the resting-state EEG-fMRI and graph theoretic approach to investigate both local and global brain functional network properties of drug naive CAE during interictal resting state compared with healthy control. In addition, we computed the partial correlation coefficient to estimate the correlation between the functional network metrics and the measured disease duration or the age at seizure onset. RESULTS: The functional connectome in drug naive CAE showed decreased small-worldness and normalized clustering coefficient at the global level. At the nodal level, decreased nodal centralities were mainly in bilateral prefrontal-thalamocortical circuit and increased nodal centralities mainly in left hippocampus and right middle temporal gyrus (p < 0.05). In addition, the duration of the epilepsy was significantly correlated with the nodal efficiency in left middle frontal gyrus (r = -0.627, p = 0.012). CONCLUSION: The pretreatment topological disruptions of whole-brain networks exist in drug naive patients with CAE and the functional impairment mainly involve the prefrontal-thalamocortical circuit. These findings in the homogeneous group of CAE indicate that the aberrant topological organization of functional brain network is an intrinsic feature of CAE and provide topologic insights into understanding the pathophysiological mechanisms of CAE.

Resveratrol Attenuates Hyperoxia Lung Injury in Neonatal Rats by Activating SIRT1/PGC-1α Signaling Pathway.

OBJECTIVES: Our previous study showed that resveratrol (Res) attenuates apoptosis and mitochondrial dysfunction in alveolar epithelial cell injury induced by hyperoxia by activating the SIRT1/PGC-1α signaling pathway. In the present study, we investigated whether Res protects against hyperoxia-induced lung injury in neonatal rats by activating SIRT1/PGC-1α signaling pathway. METHODS: Naturally delivered neonatal rats were randomly divided into six groups: normoxia + normal saline, normoxia + dimethyl sulfoxide (DMSO), normoxia + Res, hyperoxia + normal saline, hyperoxia + DMSO, and hyperoxia + Res. Lung tissue samples were collected on postnatal days 1, 7, and 14. Hematoxylin and eosin staining was used to evaluate lung development. Dual-immunofluorescence staining, real-time polymerase chain reaction, and western blotting were used to evaluate the levels of silencing information regulator 2-related enzyme 1 (SIRT1), peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), nuclear respiratory factor 1 (Nrf1), Nrf2, transcription factor A (TFAM) and citrate synthase, the number of mitochondrial DNA (mtDNA) and mitochondria, the integrity of mtDNA, and the expression of TFAM in mitochondria. RESULTS: We found that hyperoxia insulted lung development, whereas Res attenuated the hyperoxia lung injury. Res significantly upregulated the levels of SIRT1, PGC-1α, Nrf1, Nrf2, TFAM, and citrate synthase; promoted TFAM expression in the mitochondria; and increased the copy number of ND1 and the ratio of ND4/ND1. CONCLUSIONS: Our data suggest that Res attenuates hyperoxia-induced lung injury in neonatal rats, and this was achieved, in part, by activating the SIRT1/PGC-1α signaling pathway to promote mitochondrial biogenesis. KEY POINTS: · Hyperoxia insulted lung development in neonatal rats.. · Resveratrol promoted mitochondrial biogenesis to attenuate hyperoxia lung injury in neonatal rats.. · Resveratrol, at least in part, promoted mitochondrial biogenesis by activating the SIRT1/PGC-1α signaling pathway..