Pathogenic CD8 T cell responses are driven by neutrophil-mediated hypoxia in cutaneous leishmaniasis.

Cutaneous leishmaniasis caused by Leishmania parasites exhibits a wide range of clinical manifestations. Although parasites influence disease severity, cytolytic CD8 T cell responses mediate disease. While these responses originate in the lymph node, we find that expression of the cytolytic effector molecule granzyme B is restricted to lesional CD8 T cells in Leishmania - infected mice, suggesting that local cues within inflamed skin induce cytolytic function. Expression of Blimp-1 ( Prdm1 ), a transcription factor necessary for cytolytic CD8 T cell differentiation, is driven by hypoxia within the inflamed skin. Hypoxia is further enhanced by the recruitment of neutrophils that consume oxygen to produce reactive oxygen species, ultimately increasing granzyme B expression in CD8 T cells. Importantly, lesions from cutaneous leishmaniasis patients exhibit hypoxia transcription signatures that correlate with the presence of neutrophils. Thus, targeting hypoxia-driven signals that support local differentiation of cytolytic CD8 T cells may improve the prognosis for patients with cutaneous leishmaniasis, as well as other inflammatory skin diseases where cytolytic CD8 T cells contribute to pathogenesis.

Whole Foods Introduction Associated With Symptomatic Anastomotic Ulceration in Children With Short Bowel Syndrome.

OBJECTIVES: Anastomotic ulceration (AU) is a rare but life-threatening complication of pediatric short bowel syndrome (SBS). AUs may be challenging to detect and refractory to treatment. This study aimed to identify features associated with symptomatic bleeding AUs in children with SBS and factors that may impact resolution of bleeding. The relationship between dietary changes and symptomatic anastomotic hemorrhage was also explored. METHODS: We conducted a retrospective chart review of 381 patients cared for in the Intestinal Rehabilitation Program at our center from 2013 to 2022. Patients with symptomatic AUs were identified based on at least 1 endoscopic procedure showing AUs and evidence of clinically significant gastrointestinal bleeding. We collected patient demographics, clinical characteristics, dietary history, radiologic imaging, and histopathology. We used descriptive statistics to identify patterns of presentation. RESULTS: AUs were identified in 22 patients who were followed for a median duration of 2.9 years after anastomotic ulcer identification. AUs uniformly evolved years after the initial anastomosis (median 3.2 years). Characteristics included bowel stricture (4/22), small bowel-colon anastomosis (19/22), partial colectomy (17/22), and an increase in whole foods fraction (12/18). Bleeding resolved with operative intervention in the majority with anastomotic stricture (3/4). Recurrent bleeding was common in those without stricture (13/18). In a subset of patients without stricture, whole food reduction was associated with improvement or resolution of bleeding (5/6). CONCLUSIONS: We observed a higher proportion of patients with AUs who responded to surgical intervention in the subset of children with definitive anastomotic strictures versus those without, suggesting that careful characterization of intestinal anatomy may be critical to predicting response to therapy. We also observed that bleeding from AU typically first manifested within 1 year of a shift from elemental or hydrolyzed enteral formula to a whole food-based diet (including commercial blenderized feeds), which may indicate that components of the enteral diet play a role in the pathogenesis of AU. Further studies are needed to validate these hypotheses.

Unraveling the aging dynamics in the simultaneous immobilization of soil metal(loid)s using oxides.

Immobilization represents the most extensively utilized technique for the remediation of soils contaminated by heavy metals and metalloids. However, it is crucial to acknowledge that contaminants are not removed during this process, thereby leaving room for potential mobilization over time. Currently, our comprehension of the temporal variations in immobilization efficacy, specifically in relation to amendments suitable for industrial sites, remains very limited. To address this knowledge gap, our research delved into the aging characteristics of diverse oxides, hydroxides, and hydroxy-oxides (collectively referred to as oxides) for the simultaneous immobilization of arsenic (As), cadmium (Cd), and antimony (Sb) in soils procured from 16 contaminated industrial sites. Our findings unveiled that Ca-oxides initially showed excellent immobilization performance for As and Sb within 7 days but experienced substantial mobilization by up to 71 and 13 times within 1 year, respectively. In contrast, the efficacy of Cd immobilization by Ca-oxides was enhanced with the passage of time. Fe- and Mg-oxides, which primarily operate through encapsulation or surface complexation, exhibited steady immobilization performances over time. This reliable and commendable immobilization effect was observed across distinct soils characterized by varying physicochemical properties, including pH, texture, CEC, TOC, and EC, underscoring the suitability of such amendments for immobilizing metal(loid)s in diverse soil types. MgO, in particular, displayed even superior immobilization performance over time, owing primarily to gradual hydration and physical entrapment effects. Remarkably, Mg-Al LDHs emerged as the most effective candidate for the simultaneous immobilization of As, Cd, and Sb. The results obtained from this study furnish valuable data for future investigations on the immobilization of metals and metalloids in industrial soils. They enable the projection of immobilization performance and offer practical guidance in selecting suitable amendments for the immobilization of metal(loid)s.

Comprehensive assessment of soil and dust heavy metal(loid)s exposure scenarios at residential playgrounds in Beijing, China.

Small playgrounds situated within residential communities are popular recreational areas. However, heavy metal(loid)s (HMs) in soil or equipment dust may pose a public health risk. This study provides a comprehensive assessment of the health risk associated with HMs exposure at residential playgrounds in cities, a field that has not been thoroughly investigated previously. 70 soil and 70 equipment dust samples were collected from 30 urban and 40 suburban playgrounds in Beijing. Results indicated significant enrichment of Cu, As, and Ni in the soil with Enrichment Factors (EFs) >5 from both anthropogenic and lithogenic sources. Correlation analyses showed that the levels of Be, Cr, Mn, Co, Ni in soil and Be, Mn, As, Cd in dust were positively correlated with the distance to the nearest highway, with p-values < 0.01. Enrichment and correlation analyses contributed to a better understanding of the sources and transport pathways of HMs in urban environment. Based on a site-specific Conceptual Site Model (CSM), the carcinogenic risks (CRs) and Hazard Quotients (HQs) were quantified for residents as the ratio of HMs exposure to reference doses. Risk assessment indicated the mean predicted CR for children and adults exposed to soil was 3.75 × 10-6 and 5.29 × 10-6, respectively, while that at dust exposure scenarios was lower, at 2.47 × 10-6 and 3.49 × 10-6, respectively, all of which were at the upper end of U.S. EPA's acceptable criteria of 1 × 10-6 to 1 × 10-4. Among the HMs, As and Ni were identified as the priority control contaminants due to significant contribution to CRs. Furthermore, the spatial distribution revealed an increasing trend in health risk from the urban center to the suburbs. This study emphasizes the need for effective measures to mitigate potential health risk and enhance the safety of recreational areas, particularly for susceptible individuals.

TCMFP: a novel herbal formula prediction method based on network target's score integrated with semi-supervised learning genetic algorithms.

Traditional Chinese medicine (TCM) has accumulated thousands years of knowledge in herbal therapy, but the use of herbal formulas is still characterized by reliance on personal experience. Due to the complex mechanism of herbal actions, it is challenging to discover effective herbal formulas for diseases by integrating the traditional experiences and modern pharmacological mechanisms of multi-target interactions. In this study, we propose a herbal formula prediction approach (TCMFP) combined therapy experience of TCM, artificial intelligence and network science algorithms to screen optimal herbal formula for diseases efficiently, which integrates a herb score (Hscore) based on the importance of network targets, a pair score (Pscore) based on empirical learning and herbal formula predictive score (FmapScore) based on intelligent optimization and genetic algorithm. The validity of Hscore, Pscore and FmapScore was verified by functional similarity and network topological evaluation. Moreover, TCMFP was used successfully to generate herbal formulae for three diseases, i.e. the Alzheimer's disease, asthma and atherosclerosis. Functional enrichment and network analysis indicates the efficacy of targets for the predicted optimal herbal formula. The proposed TCMFP may provides a new strategy for the optimization of herbal formula, TCM herbs therapy and drug development.

Myeloidcells in the immunosuppressive microenvironment in glioblastoma: The characteristics and therapeutic strategies.

Glioblastoma (GBM) is the most common and lethal malignant tumor of the central nervous system in adults. Conventional therapies, including surgery, radiotherapy, and chemotherapy, have limited success in ameliorating patient survival. The immunosuppressive tumor microenvironment, which is infiltrated by a variety of myeloid cells, has been considered a crucial obstacle to current treatment. Recently, immunotherapy, which has achieved great success in hematological malignancies and some solid cancers, has garnered extensive attention for the treatment of GBM. In this review, we will present evidence on the features and functions of different populations of myeloid cells, and on current clinical advances in immunotherapies for glioblastoma.

Clinical and lifestyle patterns in Asian children with inflammatory bowel disease in the U.S.

BACKGROUND: While there are many epidemiologic studies of Asian immigrants to the West and risk of inflammatory bowel disease (IBD), the phenotype and lifestyle of Asian patients, particularly children, with IBD are not well described. In this study, we describe lifestyle practices, such as dietary pattern, as well as disease phenotype in Asian American children with IBD. METHODS: We reviewed the records of children with IBD, ages 0 to 21 years old, and race identified as Asian, Indian, or Pacific Islander. Patients who received outpatient IBD care at our center between January 2013 and January 2020 were included. We excluded patients who were international second opinions, who did not have a definitive diagnosis of IBD, and in whom a diagnosis of IBD was made after 18 years of age. A survey, including a food frequency questionnaire adapted from NHANES DSQ with modifications to include culturally appropriate food elements, was designed and conducted within this cohort to assess for dietary patterns. RESULTS: Asian patients in our cohort have similar phenotypes as non-Asians with few distinctive differences. There was a Crohn's disease and male predominance similar with non-Asians. However, there was a high rate of proctitis in ulcerative colitis in Asian patients. Asian patients reported a typical dietary pattern that reflects a Westernized pattern rather than a traditional pattern. Despite a similar dietary pattern, there was a high rate of 25-OH Vitamin D deficiency (44%) and insufficiency (40%). CONCLUSIONS: This single center study showed that the phenotype of Asian children with IBD in the U.S. is similar with that of non-Asian with a few distinct differences. The Asian children in our cohort reported following a Westernized dietary pattern and lifestyle. However, there was a high rate of Vitamin D deficiency surrounding diagnosis, suggesting a need for vigilant monitoring.

Tongxinluo attenuates atherosclerosis by inhibiting ROS/NLRP3/caspase-1-mediated endothelial cell pyroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongxinluo (TXL) is one of the most common traditional Chinese medicines and plays a vital role in treating atherosclerosis (AS). Endothelial cell (EC) pyroptosis plays a crucial role in the development of AS. Previous research revealed the inhibitory function of TXL in EC apoptosis and autophagy. However, whether TXL can inhibit the pyroptosis of ECs has not been determined. AIM OF THE STUDY: To explore the influence of TXL on EC pyroptosis and determine its underlying mechanism of action in AS. MATERIALS AND METHODS: The TXL components were determined by ultra-performance liquid chromatography coupled with a photodiode array detector. We used ApoE-/- mice to establish a disease model of AS. After treatment with TXL, we recorded pathological changes in the mice and performed immunofluorescence staining of mice aortas. We also measured protein and gene levels to explore the influence of TXL on pyroptosis in vivo. The model was established by stimulating mouse aortic endothelial cells (MAECs) with oxidized low-density lipoprotein (ox-LDL) and analyzing the effect of TXL on pyroptosis by Western blotting (WB), real-time PCR (RT-PCR), and flow cytometry (FCM). We also investigated the impact of TXL on reactive oxygen species (ROS) by FCM and WB. RESULTS: Ten major components of TXL were detected. The vivo results showed that TXL inhibited the development of AS and decreased EC pyroptosis, the activation of caspase-1, and the release of inflammatory cytokines. The vitro experiments showed that TXL significantly reduced the extent of injury to MAECs by oxidized LDL (ox-LDL). TXL reversed the high expression of gasdermin D and other proteins induced by ox-LDL and had a significant synergistic effect with the caspase-1 inhibitor VX-765. We also confirmed that TXL decreased the accumulation of ROS and the expression levels of its essential regulatory proteins Cox2 and iNOS. When ROS accumulation was reduced, EC pyroptotic damage was reduced accordingly. CONCLUSION: Our results indicated that TXL inhibited EC pyroptosis in AS. Reducing the accumulation of ROS may be the essential mechanism of AS inhibition by TXL.

Manganese stabilization in mine tailings by MgO-loaded rice husk biochar: Performance and mechanisms.

Leachable metal in abandoned mine tailings may be toxic to vegetation, affecting effective ecological restoration. In this study, MRB was synthesized through MgCl2·6H2O wet impregnation followed by duplicate slow pyrolysis. Manganese tailings were mixed with MRB, rice husk biochar (RB), and MgO at a dosage of 0-5%, followed by 90-day incubation. Toxicity characteristic leaching procedure and sequential leaching were used to analyze the leachability and species of Mn in tailings, while a stabilization mechanism was proposed with the support of the characterization of the tailings before and after amendment. Results suggested MRB addition significantly decreased leachable Mn by 63.8%, reducing from 59.88 mg/L to 21.68 mg/L, while only a 14.39% reduction was achieved by rice husk biochar (RB). The sharp decline of leachable Mn after 90-day mixing was contributed by the transformation from labile to stable fractions. A microporous biochar matrix along with the uniform dispersion of MgO active component were both responsible for the better Mn stabilization. Only less than 10% of the variation in substrate pH was observed with the increase of MgO loading or incubation time. Linear correlation analyses indicated substrate pH's strongl negative relationship with leachable Mn and moderately positive relationship with residual fraction. Characterization results revealed that MRB exhibited different stabilization mechanisms in mine tailings, where Mn was likely to be stabilized by direct interaction with active MgO or indirect alkaline precipitation to form stable MgMn2O4, Mn(CH3COO)2, and MnO(OH)2. This work validated the promoting potential of recycling agricultural biomass waste for the amendment of manganese mine tailings.

Dietary fiber-based regulation of bile salt hydrolase activity in the gut microbiota and its relevance to human disease.

Complications of short bowel syndrome (SBS) include malabsorption and bacterial overgrowth, requiring prolonged dependence on parenteral nutrition (PN). We hypothesized that the intolerance of whole food in some SBS patients might be due to the effect of dietary fiber on the gut microbiome. Shotgun metagenomic sequencing and targeted metabolomics were performed using biospecimens collected from 55 children with SBS and a murine dietary fiber model. Bioinformatic analyses were performed on these datasets as well as from a healthy human dietary intervention study. Compared to healthy controls, the gut microbiota in SBS had lower diversity and increased Proteobacteria, a pattern most pronounced in children on PN and inversely correlated with whole food consumption. Whole food intake correlated with increased glycoside hydrolases (GH) and bile salt hydrolases (BSH) with reduced fecal conjugated bile acids suggesting that dietary fiber regulates BSH activity via GHs. Mechanistic evidence supporting this notion was generated via fecal and plasma bile acid profiling in a healthy human fiber-free dietary intervention study as well as in a dietary fiber mouse experiment. Gaussian mixture modeling of fecal bile acids was used to identify three clinically relevant SBS phenotypes. Dietary fiber is associated with bile acid deconjugation likely via an interaction between gut microbiota BSHs and GHs in the small intestine, which may lead to whole food intolerance in patients with SBS. This mechanism not only has potential utility in clinical phenotyping and targeted therapeutics in SBS based on bile acid metabolism but may have relevance to other intestinal disease states.

Resveratrol regulates paracrine function of cardiac microvascular endothelial cells under hypoxia/reoxygenation condition.

The secreted factors from cardiac microvascular endothelial cells (CMECs) regulate the physiological activity of adjacent tissues and could be modulated by myocardial ischemia/reperfusion injury (MIRI). How this paracrine function of CMECs is regulated by MIRI and resveratrol remains to be elucidated. CMECs pretreated with/ without resveratrol were subjected to hypoxia/reoxygenation (H/R). Apoptosis was measured by flowcytometry. Protein antibody arrays were performed to find the alteration of cytokine secreted by CMECs. The Gene Ontology analysis was applied to interpret the function of modulated factors. We revealed resveratrol inhibited apoptosis of CMECs dose-dependently after H/R and reached its peak effect at the concentration of 100 µM. 29 factors were significantly changed by H/R, and resveratrol at 100 µM changed 98 types of factors compared with the H/R group. Among these factors, eight were increased by H/R and then were decreased by resveratrol. Eleven were attenuated by H/R and further decreased by resveratrol. Insulin-like growth factor binding protein-1 was upregulated by H/R and it was further increased by resveratrol. The altered factors were involved in cell proliferation, cell growth, cell motility, chemotaxis, angiogenesis and vasculogenesis. The study suggests that resveratrol inhibits the apoptosis and modulates the paracrine function of CMECs under ischemia/reperfusion condition.

Blenderized enteral nutrition in pediatric short gut syndrome: Tolerance and clinical outcomes.

BACKGROUND: Blenderized feeds consisting of whole food components are emerging as a preferred approach to enteral nutrition. However, there is limited evidence-based guidance for this strategy in short bowel syndrome (SBS). We aimed to explore the tolerance and clinical outcome of blenderized feeds in patients with SBS. METHOD: We conducted a single-center, retrospective study of blenderized feeds in pediatric SBS. Of the 376 patients screened, 58 met inclusion criteria. Three patients were excluded because of a history of bowel transplant. Demographics, clinical history, and nutrition history were collected and analyzed. RESULT: Patients had improved diarrhea though worsening gas while receiving blenderized feeds. There was no significant difference in small bowel length in patients who discontinued blends compared with those who continued. However, patients with colonic resection were more likely to discontinue the blends. In a subgroup of patients who lost weight despite improved diarrhea (n = 19), most had a history of ileocecal valve (ICV) and colonic resection, but no difference in small bowel length compared with those who did not lose weight. CONCLUSION: Our cohort of patients with SBS experienced improved gastrointestinal symptoms and stool quality on blenderized feeds. Patients without an ICV and with colonic resection were more prone to weight loss. Stepwise titration of blenderized formula with previous formula regimen may be needed in a subset of patients to optimize tolerance and weight gain. Further study is warranted to understand factors contributing to variable tolerance and weight gain on blenderized formulas to guide their use in patients with SBS.

Synergistic multiple active species driven fast estrone oxidation by δ-MnO2 in the existence of methanol.

Endocrine-disrupting chemicals (EDCs) cause serious threats to human health. Five types of MnO2 were synthesized and characterized. They exhibited different removal performances for three EDCs, i.e., estrone (E1), ethynylestradiol (EE2) and bisphenol A (BPA). Only δ-MnO2 can completely remove E1 within 120 min at pH 3.0. Free Mn (III) was determined at the beginning of the reaction and participated in the EDCs removal process. Electron spin resonance (ESR) indicated that δ-MnO2 could produce superoxide anions (·O2-) and singlet oxygen (1O2) in the existence of methanol. The reactive oxygen species (ROS) quenching experiments showed 1O2 have certain contribution to the E1 removal by δ-MnO2. The source of ROS is mainly the lattice oxygen from δ-MnO2, and can be replenished through the layer structure destruction caused by the reaction between Mn(III) and E1. The ROS dependent EDCs removal by δ-MnO2 leads to a deep understanding on this well-known oxidant.

Effects of the Traditional Chinese Medicine Tang Luo Ning on Intestinal Flora and Oxidative Stress in Diabetic Rats.

OBJECTIVE: To determine the effects of TLN on glycolipid metabolism, oxidative stress, and intestinal flora in diabetic rat. MATERIALS AND METHODS: Thirty-five male Sprague-Dawley (SD) rats (180-200 g) were divided into two groups. The normal group was fed a standard-chow diet, whereas, in the model group, diabetes was induced by intraperitoneal administration of streptozotocin (STZ) combined with a high-fat sucrose diet. Then, the model group was randomly allocated to four groups: DM (diabetes model) and TLNH (TLN high dose), TLNL (TLN low dose), and NAC (N-acetylcysteine). Rats in the TLNH, TLNL, and NAC groups were intragastrically administered TLN and NAC for 12 weeks. Subsequently, their weights, fasting glucose levels, serum lipids, serum insulin, serum ROS, and intestinal flora were determined. RESULTS: The weight and intestinal flora abundance of the DM group were significantly lower than those of the normal group, whereas their total serum cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), serum reactive oxygen species (ROS), and serum insulin (INS) levels were significantly higher than those of the normal group. TC and LDL-C levels in the TLNL group and DM group were similar, whereas FBG, INS, and ROS levels in the TLNL group were obviously lower than those in the DM group. Compared with the DM group, there was a significant increase in intestinal flora abundance in the TLNL group. At the phylum level, the ratio of Firmicutes to Bacteroidetes (core microbiota) varied in all groups. However, in the DM group, Firmicutes abundance decreased, whereas that of Bacteroidetes increased. An opposite trend was observed in the TLN-treated groups. CONCLUSIONS: TLN, which showed a dose-dependent therapeutic effect, can effectively decrease serum lipid, serum insulin, blood glucose, and serum ROS levels. It can also rebalance the ratio of Firmicutes to Bacteroidetes. Furthermore, the low-dose TLN treatment was most efficacious.

Highly selective colorimetric determination of catechol based on the aggregation-induced oxidase-mimic activity decrease of δ-MnO2.

Multiple enzyme-like activities of manganese oxides (MnO2) have been reported and applied in catalysis, biosensors, and cancer therapy. Here, we report that catechol can be determined colorimetrically based on the 3,3',5,5'-tetramethylbenzidine (TMB) oxidase-like activity of δ-MnO2. The detection was based on pre-incubation of catechol containing water samples with δ-MnO2, and then the residual TMB oxidase-like activity of reacted δ-MnO2 was linearly dependent on the catechol concentration in the range of 0.5 to 10 µM. This determination method was stable at pH 3.73-6.00 and was not affected by ion strength up to 200 µM. Common co-solutes in water bodies (50 µM) have negligible effects and excellent selectivity of catechol among various phenolic compounds (15 µM) was facilitated. Both reduction and aggregation of δ-MnO2 were observed during the incubation process with catechol, and aggregation-induced TMB oxidase-mimic activity decrease was the main factor for this colorimetric determination.

Coupling the phenolic oxidation capacities of a bacterial consortium and in situ-generated manganese oxides in a moving bed biofilm reactor (MBBR).

Phenolic wastewater containing phenol and 4-chlorophenol pose a risk to the environment and to human health. Treating them using chemical-biological coupling method is challenging. In this study, manganese oxidizing bacteria (MnOB) were enriched in moving bed biofilm reactor (MBBR) using synthetic phenol wastewater (800 mg L-1) to facilitate in situ production of biogenic manganese oxides (BioMnOx) after 90 days of operation. Then, 4-chlorophenol (4-CP) was added to the MBBR to simulate mixed phenolic wastewater. Comparing the MBBR (R1) without feeding Mn(II) and the MBBR with BioMnOx (R2) production, R2 exhibited robust phenol and 4-CP removal performance. 16S rRNA gene sequencing was employed to determine the microbial community. Subsequently, a batch experiment demonstrated that partly purified BioMnOx does not exhibits a capacity for phenol removal, but can efficiently remove 4-CP. Interestingly, 5-chloro-2-hydroxymuconic semialdehyde was found in the products of 4-CP degradation, which was the unique product of 4-CP degradation by catechol 2,3-dioxygenase (C23O). In both reactors, only catechol 1,2-dioxygenase (C12O) activity from microbes can be detected, indicating that the existence of BioMnOx provide an alternative pathway in addition to microbe driven 4-CP degradation. Overall, MBBR based MnOB enrichment under high phenol concentration was achieved, and 4-CP/phenol removal can be accelerated by in situ-formed BioMnOx. Considering the C23O-like activity of BioMnOx, our results suggest a new coupling strategy that involves nanomaterials and a microbial consortium.

Ginsenoside compound K attenuates cognitive deficits in vascular dementia rats by reducing the Aß deposition.

Ginsenoside compound K (CK) is the main metabolite of protopanaxadiol-type ginsenosides and has been demonstrated to exert neuroprotective and cognition-enhancing effects. The effects of CK on cognitive function in vascular dementia (VD) has not been elucidated. Therefore, the present study aims to elucidate the effects of CK on memory function as well as its potential mechanism in VD rats. Sprague-Dawley rats were subjected to Chronic Cerebral Hypoperfusion (CCH) by permanent bilateral common carotid artery occlusion (2VO). CCH induced neuronal damage and aggravated the aggregation of Amyloid-ß1-42 peptides (Aß1-42), which plays a critical role in the neurotoxicity and cognitive impairment. CK treatment attenuated CCH-induced Aß1-42 deposition and ameliorated cognition impairment. Furthermore, CK enhanced the activity of the pSer9-Glycogen synthase kinase 3ß (pSer9-GSK3ß) and the insulin degrading enzyme (IDE), which mainly involved the production and clearance of Aß1-42. Moreover, CK treatment enhanced the activity of protein kinase B (PKB/Akt), a key kinase in phosphatidylinositol 3 kinase (PI3K)/Akt pathway that can regulate the activity of GSK-3ß and IDE. In short, our findings provide the first evidence that CK might attenuate cognitive deficits and Aß1-42 deposition in the hippocampus via enhancing the expression of pSer9-GSK-3ß and IDE.

Aucubin Alleviates Seizures Activity in Li-Pilocarpine-Induced Epileptic Mice: Involvement of Inhibition of Neuroinflammation and Regulation of Neurotransmission.

Neuroinflammation and imbalance of neurotransmitters play pivotal roles in seizures and epileptogenesis. Aucubin (AU) is an iridoid glycoside derived from Eucommia ulmoides that possesses anti-inflammatory and neuroprotective effects. However, the anti-seizure effects of AU have not been reported so far. The present study was designed to investigate the effects of AU on pilocarpine (PILO) induced seizures and its role in the regulation of neuroinflammation and neurotransmission. We found that AU reduced seizure intensity and prolonged the latency of seizures. AU significantly attenuated the activation of astrocytes and microglia and reduced the levels of interleukine-1 beta (IL-1ß), high mobility group box 1 (HMGB1), tumor necrosis factor-α (TNF-α). Furthermore, the contents of γ-aminobutyric acid (GABA) were increased while the levels of glutamate were decreased in the hippocampus with AU treatment. The expression of γ-aminobutyric acid type A receptor subunit α1 (GABAARα1) and glutamate transporter-1 (GLT-1) protein were up-regulated in AU treatment group. However, AU had no significant effect on N-methyl-d-aspartate receptor subunit 2B (NR2B) expression in status epilepticus (SE). In conclusion, our findings provide the first evidence that AU can exert anti-seizure effects by attenuating gliosis and regulating neurotransmission. The results suggest that AU may be developed as a drug candidate for the treatment of epilepsy.

The Effects of Ginsenoside Compound K Against Epilepsy by Enhancing the γ-Aminobutyric Acid Signaling Pathway.

The imbalance between the GABA-mediated inhibition and the glutamate-mediated excitation is the primary pathological mechanism of epilepsy. GABAergic and glutamatergic neurotransmission have become the most important targets for controlling epilepsy. Ginsenoside compound K (GCK) is a main metabolic production of the ginsenoside Rb1, Rb2, and Rc in the intestinal microbiota. Previous studies show that GCK promoted the release of GABA from the hippocampal neurons and enhanced the activity of GABAA receptors. GCK is shown to reduce the expression of NMDAR and to attenuate the function of the NMDA receptors in the brain. The anti-seizure effects of GCK have not been reported so far. Therefore, this study aimed to investigate the effects of GCK on epilepsy and its potential mechanism. The rat model of seizure or status epilepticus (SE) was established with either Pentylenetetrazole or Lithium chloride-pilocarpine. The Racine's scale was used to evaluate seizure activity. The levels of the amino acid neurotransmitters were detected in the pilocarpine-induced epileptic rats. The expression levels of GABAARα1, NMDAR1, KCC2, and NKCC1 protein in the hippocampus were determined via western blot or immunohistochemistry after SE. We found that GCK had deceased seizure intensity and prolonged the latency of seizures. GCK increased the contents of GABA, while the contents of glutamate remained unchanged. GCK enhanced the expression of GABAARα1 in the brain and exhibited a tendency to decrease the expression of NMDAR1 protein in the hippocampus. The expression of KCC2 protein was elevated by the treatment of GCK after SE, while the expression of NKCC1 protein was reversely down-regulated. These findings suggested that GCK exerted anti-epileptic effects by promoting the hippocampal GABA release and enhancing the GABAAR-mediated inhibitory synaptic transmission.

The Expression Alteration of BC1 RNA and its Interaction with Eukaryotic Translation Initiation Factor eIF4A Post-Status Epilepticus.

Abnormal dendritic sprouting and synaptic remodelling are important pathological features of temporal lobe epilepsy. BC1 RNA is a translation repressor involved in the regulation of the dendritic protein synthesis and mRNA transport, which is essential for dendritic development and plasticity. The expression alteration of BC1 RNA in the pilocarpine induced epilepsy model remains unknown. It is unclear if the interactions between BC1 RNA and eukaryotic initiation factor 4A (eIF4A) exists in this model. The purpose of this study was to investigate the expression changes of BC1 RNA and its interactions with eIF4A post-status epilepticus (SE). Chloride lithium and pilocarpine were used to induce the SE rat model. Either a whole brain or hippocampus tissues were collected at different time points after SE. The expression patterns of BC1 was detected by qPCR and in situ hybridization. The levels of eIF4AI/II protein expression were analyzed via western blotting and immunohistochemistry. The BC1 RNA-eIF4AI/II interaction was determined by electrophoretic mobility shift assay (EMSA). We found that the BC1 RNA levels decreased in hippocampus 3d, 1w and 2w post-SE before the levels recovered. The eIF4AI/II began to rise 3d post-SE and reached the maximum level 1w post-SE. After 1w post-SE the levels decreased in the hippocampal CA1, CA3 and DG subregions. EMSA analysis showed that BC1 RNA specifically interacted with the eIF4AI/II. The BC1 RNA-eIF4AI/II complex reduced to the lowest level 1w post-SE. Our results suggested that BC1 has a negative regulatory correlation with eIF4AI/II, where BC1 RNA could be involved in epileptogenesis by regulating dendritic protein synthesis.