Bronchial arterial chemoembolization with Drug-Eluting beads plus sequential chemotherapy for the treatment of stage III and IV lung squamous cell carcinoma.

PURPOSE: This retrospective study aimed to investigate the effectiveness and safety of bronchial arterial chemoembolization with drug-eluting beads (DEB-BACE) plus chemotherapy versus chemotherapy alone in patients with stage III and IV lung squamous cell carcinoma (LSCC) who are not appropriate candidates for radiochemotherapy. MATERIALS AND METHODS: In this retrospective analysis, we screened all adult patients undergoing either DEB-BACE plus chemotherapy or chemotherapy alone for stage III or IV LCSS at authors' center from January 2018 to August 2021. Each 21-day chemotherapy cycle consisted of intravenous injection of gemcitabine (1.0 g/m2) on days 1 and 8 and cisplatin 75 (mg/m2) on day 1. The planned cycles were 4. DEB-BACE consisted of microcatheter infusion of CalliSpheres beads carrying cisplatin (75 mg/m2) and gemcitabine (1.0 g/m2), at 3 weeks prior to chemotherapy. The primary outcome was overall survival (OS). The secondary outcomes included progression-free survival (PFS), pulmonary response, and adverse events (AEs). RESULTS: The final analysis included 95 patients in the chemotherapy group and 41 patients in the combination treatment group. The median OS was 14 months (95 % CI 11.0-17.0) in the chemotherapy group and 19 months (95 % CI 18.0-24.0) in the combination group (P = 0.015). In multivariate Cox regression analysis, DEB-BACE plus chemotherapy was associated with lower risk of death versus chemotherapy only (HR 0.16, 95 % CI 0.05-0.52; log rank test P = 0.003). The median PFS was 6 months (95 % CI 4.0-7.0) in the chemotherapy group and 8 months (95 % CI 6.0-8.0) in the combination group (P = 0.015). The pulmonary objective response rate (ORR) and disease control rate (DCR) were 48.4 % and 62.1 % in chemotherapy group versus 82.9 % and 90.2 % in combination group (P < 0.001 and = 0.001, respectively). AEs occurred in 133 patients (97.8 %). The rate of bone marrow suppression was 48.4 % (46/95) in the chemotherapy group versus 7.3 % (3/41) in the combination group (P < 0.001). CONCLUSION: Compared with chemotherapy alone, DEB-BACE plus chemotherapy was associated with longer survival outcomes and lower rate of bone marrow suppression.

Advances in the study of IL-17 in neurological diseases and mental disorders.

Interleukin-17 (IL-17), a cytokine characteristically secreted by T helper 17 (Th17) cells, has attracted increasing attention in recent years because of its importance in the pathogenesis of many autoimmune or chronic inflammatory diseases. Recent studies have shown that neurological diseases and mental disorders are closely related to immune function, and varying degrees of immune dysregulation may disrupt normal expression of immune molecules at critical stages of neural development. Starting from relevant mechanisms affecting immune regulation, this article reviews the research progress of IL-17 in a selected group of neurological diseases and mental disorders (autism spectrum disorder, Alzheimer's disease, epilepsy, and depression) from the perspective of neuroinflammation and the microbiota-gut-brain axis, summarizes the commonalities, and provides a prospective outlook of target application in disease treatment.

Expression of Concern: Low-intensity focused ultrasound (LIFU)-activated nanodroplets as a theranostic agent for noninvasive cancer molecular imaging and drug delivery.

Expression of Concern for 'Low-intensity focused ultrasound (LIFU)-activated nanodroplets as a theranostic agent for noninvasive cancer molecular imaging and drug delivery' by Jianxin Liu et al., Biomater. Sci., 2018, 6, 2838-2849, https://doi.org/10.1039/C8BM00726H.

TREM-1 as a potential prognostic biomarker associated with immune infiltration in clear cell renal cell carcinoma.

BACKGROUND: The tumor immune microenvironment plays a crucial role in the efficacy of various therapeutics. However, their correlation is not yet completely understood in Clear cell renal cell carcinoma (ccRCC). This study aimed to investigate the potential of TREM-1 as a potential novel biomarker for ccRCC. METHODS: We constructed a ccRCC immune prognostic signature. The clinical characteristics, the status of the tumor microenvironment, and immune infiltration were analyzed through the ESTIMATE and CIBERSORT algorithms for the hub gene, while the Gene Set Enrichment Analysis and PPI analysis were performed to predict the function of the hub gene. Immunohistochemical staining was used to detect the expression of TREM-1 in renal clear cell carcinoma tissues. RESULTS: The CIBERSORT and ESTIMATE algorithms revealed that TREM-1 was correlated with the infiltration of 12 types of immune cells. Therefore, it was determined that TREM-1 was involved in numerous classical pathways in the immune response via GSEA analysis. In Immunohistochemical staining, we found that the expression of TREM-1 was significantly upregulated with increasing tumor grade in renal clear cell carcinoma, and elevated TREM-1 expression was associated with poor prognosis. CONCLUSIONS: The results suggest that TREM-1 may act as an implicit novel prognostic biomarker in ccRCC that could be utilized to facilitate immunotherapeutic strategy.

Postoperative subacute static progressive stretch does not increase the risk of distal lower limb venous thromboembolism.

PURPOSE: Static progressive stretch (SPS) can be applied to treat chronic joint stiffness. However, the impacts of subacute application of SPS to the distal lower limbs, where deep vein thrombosis (DVT) is common, on venous thromboembolism remain unclear. This study aims to explore the risk of venous thromboembolism events following subacute application of SPS. METHODS: A retrospective cohort study was conducted on patients diagnosed with DVT following a lower extremity orthopedic surgery before being transferred to the rehabilitation ward from May 2017 to May 2022. Patients with unilateral lower limb comminuted para-articular fractures, transferred to rehabilitation ward for further treatment within 3 weeks after operation, followed up more than 12 weeks since initial manual physiotherapy, and diagnosed DVT by ultrasound before rehabilitation course were included in the study. Patients with polytrauma, without evidence of previous peripheral vascular disease or incompetence, had medication for thrombosis treatment or prophylaxis before the operation, detected with paralysis due to nervous system impairment, infected after operation during the regime, or with acute progression of DVT were excluded. The included patients were randomized to the standard physiotherapy and the SPS integrated groups for observation. Associated DVT and pulmonary embolism data were collected during the physiotherapy course to compare the groups. SSPS 28.0 and GraphPad Prism 9 were used for data processing. A p < 0.05 was set significant difference. RESULTS: In total of 154 patients with DVT participating in this study, 75 of them were treated with additional SPS for postoperative rehabilitation. The participants in the SPS group showed improved range of motion (12.3° ± 6.7°). However, in the SPS group, there was no difference in thrombosis volume between the start and termination (p = 0.106, p = 0.787, respectively), although difference was seen intra-therapy (p < 0.001). Contingency analysis revealed the pulmonary embolism incidence (OR = 0.703) in the SPS group compared to the mean physiotherapy. CONCLUSION: The SPS technique is a safe and reliable option to prevent potential joint stiffness without aggravating the risk of distal DVT for postoperative patients suffering from relevant trauma.

Multistep sequence-controlled supramolecular polymerization by the combination of multiple self-assembly motifs.

The precise sequence control of polymer chain is an important research topic of polymer chemistry. Although some methods such as iterative synthesis and supramolecular polymerization have been developed to fabricate sequence-controllable polymer, it is still a great challenge to consecutively prepare multiple supramolecular polymers with different sequence structures. In this work, through the reasonable utilization of assembly motifs, we integrated multiple host-guest recognitions and metal coordination interactions to prepare different sequence-controlled supramolecular polymers by a multistep assembly strategy. This research provides inspiration for the design and preparation of supramolecular polymers with different sequence structures.

HMGB1 in nervous system diseases: A common biomarker and potential therapeutic target.

High-mobility group box-1 (HMGB1) is a nuclear protein associated with early inflammatory changes upon extracellular secretion expressed in various cells, including neurons and microglia. With the progress of research, neuroinflammation is believed to be involved in the pathogenesis of neurological diseases such as Parkinson's, epilepsy, and autism. As a key promoter of neuroinflammation, HMGB1 is thought to be involved in the pathogenesis of Parkinson's disease, stroke, traumatic brain injury, epilepsy, autism, depression, multiple sclerosis, and amyotrophic lateral sclerosis. However, in the clinic, HMGB1 has not been described as a biomarker for the above-mentioned diseases. However, the current preclinical research results show that HMGB1 antagonists have positive significance in the treatment of Parkinson's disease, stroke, traumatic brain injury, epilepsy, and other diseases. This review discusses the possible mechanisms by which HMGB1 mediates Parkinson's disease, stroke, traumatic brain injury, epilepsy, autism, depression, multiple sclerosis, amyotrophic lateral sclerosis, and the potential of HMGB1 as a biomarker for these diseases. Future research needs to further explore the underlying molecular mechanisms and clinical translation.

Interleukin 17A deficiency alleviates neuroinflammation and cognitive impairment in an experimental model of diabetic encephalopathy.

Interleukin 17A (IL-17A) was previously shown to be a key pro-inflammatory factor in diabetes mellitus and associated complications. However, the role of IL-17A in diabetic encephalopathy remains poorly understood. In this study, we established a mouse model of diabetic encephalopathy that was deficient in IL-17A by crossing Il17a-/- mice with spontaneously diabetic Ins2Akita (Akita) mice. Blood glucose levels and body weights were monitored from 2-32 weeks of age. When mice were 32 weeks of age, behavioral tests were performed, including a novel object recognition test for assessing short-term memory and learning and a Morris water maze test for evaluating hippocampus-dependent spatial learning and memory. IL-17A levels in the serum, cerebrospinal fluid, and hippocampus were detected with enzyme-linked immunosorbent assays and real-time quantitative polymerase chain reaction. Moreover, proteins related to cognitive dysfunction (amyloid precursor protein, ß-amyloid cleavage enzyme 1, p-tau, and tau), apoptosis (caspase-3 and -9), inflammation (inducible nitric oxide synthase and cyclooxygenase 2), and occludin were detected by western blot assays. Pro-inflammatory cytokines including tumor necrosis factor-α, interleukin-1ß, and interferon-γ in serum and hippocampal tissues were measured by enzyme-linked immunosorbent assays. Microglial activation and hippocampal neuronal apoptosis were detected by immunofluorescent staining. Compared with that in wild-type mice, mice with diabetic encephalopathy had higher IL-17A levels in the serum, cerebrospinal fluid, and hippocampus; downregulation of occludin expression; lower cognitive ability; greater loss of hippocampal neurons; increased microglial activation; and higher expression of inflammatory factors in the serum and hippocampus. IL-17A knockout attenuated the abovementioned changes in mice with diabetic encephalopathy. These findings suggest that IL-17A participates in the pathological process of diabetic encephalopathy. Furthermore, IL-17A deficiency reduces diabetic encephalopathy-mediated neuroinflammation and cognitive defects. These results highlight a role for IL-17A as a mediator of diabetic encephalopathy and potential target for the treatment of cognitive impairment induced by diabetic encephalopathy.

Supramolecular polymer gels: from construction methods to functionality.

Supramolecular polymer gels (SPGs) are precisely designed gels brought together by noncovalent interactions to form three-dimensional network structures of polymers. SPGs combine the merits of supramolecular polymers and gels, such as stimuli-responsiveness, self-healing, and self-adaptation, which endows SPGs with potential application value in the fields of biomaterials, etc. Recently, much effort has been made to design new SPGs and related materials with high performance. Herein, we review the research endeavor and future directions of SPGs depending on the construction methods, topological structures, stimuli-responsiveness, and functionality. We hope that the review will provide reference values for the researchers working in supramolecular chemistry and gels.

Crown Ether-Based Supramolecular Polymers: From Synthesis to Self-Assembly.

Supramolecular polymers not only possess many advantages of traditional polymers, but also have many unique characteristics. Supramolecular polymers can be constructed by self-assembly of various noncovalent interactions. Host-guest interaction, as one important type of noncovalent interactions, has been widely applied to construct supramolecular polymers. From the perspective of classification of the recognition system motifs, host-guest recognition motifs mainly include crown ether, cyclodextrin, calixarene, cucurbituril, and pillararene-based host-guest recognition pairs. Crown ethers, as the first-generation macrocyclic hosts, have played a very important part in the development of supramolecular chemistry. Due to the easy modification of crown ethers, various crown ether derivatives have been prepared by attaching some functional groups to the edges of crown ethers, which endowed them with some interesting properties and made them ideal candidates for the fabrication of supramolecular polymers. This review gives a review of the preparation of crown ether-based supramolecular polymers (CSPs) and summarizes crown ether-based recognition pairs, organization methods, topological structures, stimuli-responsiveness, and functional characteristics.

Dopamine receptor D2 on CD4+ T cells is protective against neuroinflammation and neurodegeneration in a mouse model of Parkinson's disease.

Parkinson's disease (PD) is a chronic neurodegenerative disease. Recently, neuroinflammation driven by CD4+ T cells has been involved in PD pathophysiology. Human and murine lymphocytes express all the five subtypes of dopamine receptors (DRs), DRD1 to DRD5. However, roles of DRs particularly DRD2 expressed on CD4+ T cells in PD remain elucidated. Global Drd1- or Drd2-knockout (Drd1-/- or Drd2-/-) mice or CD4+ T cell-specific Drd2-knockout (Drd2fl/fl/CD4Cre) mice were intraperitoneally injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD with the different mutants. On the 7th day following MPTP injection, mice were assessed for dopaminergic neurodegeneration, locomotor impairments, microglial activation, as well as CD4+ T-cell differentiation and function. Furthermore, in vitro CD4+ T cells were exposed to DRD2 agonist and antagonist and then differentiation and function of the cells were determined. MPTP induced dopaminergic neuronal loss in the nigrostriatal system, motor coordinative and behavioral impairments, microglial activation, and CD4+ T-cell polarization to pro-inflammatory T-helper (Th)1 and Th17 phenotypes. Importantly, either Drd2-/- or Drd2fl/fl/CD4Cre mice manifested more severe dopaminergic neurodegeneration, motor deficits, microglial activation, and CD4+ T-cell bias towards Th1 and Th17 phenotypes in response to MPTP, but Drd1-/- did not further alter MPTP intoxication. DRD2 agonist sumanirole inhibited shift of CD4+ T cells obtained from MPTP-intoxicated mice to Th1 and Th17 phenotypes and DRD2 antagonist L-741,626 reversed sumanirole effects. These findings suggest that DRD2 expressed on CD4+ T cells is protective against neuroinflammation and neurodegeneration in PD. Thus, developing a therapeutic strategy of stimulating DRD2 may be promising for mitigation of PD.

Combination LSD1 and HOTAIR-EZH2 inhibition disrupts cell cycle processes and induces apoptosis in glioblastoma cells.

Glioblastoma (GBM) is the most common primary central nervous system tumor and has a poor prognosis, with a median survival time of only 14 months from diagnosis. Abnormally expressed long noncoding RNAs (lncRNAs) are important epigenetic regulators of chromatin modification and gene expression regulation in tumors, including GBM. We previously showed that the lncRNA HOTAIR is related to the cell cycle progression and can be used as an independent predictor in GBM. Lysine-specific demethylase 1 (LSD1), binding to 3' domain of HOTAIR, specifically removes mono- and di-methyl marks from H3 lysine 4 (H3K4) and plays key roles during carcinogenesis. In this study, we combined a HOTAIR-EZH2 disrupting agent and an LSD1 inhibitor, AC1Q3QWB (AQB) and GSK-LSD1, respectively, to block the two functional domains of HOTAIR and potentially provide therapeutic benefit in the treatment of GBM. Using an Agilent Human ceRNA Microarray, we identified tumor suppressor genes upregulated by AQB and GSK-LSD1, followed by Chromatin immunoprecipitation (ChIP) assays to explore the epigenetic mechanisms of genes activation. Microarray analysis showed that AQB and GSK-LSD1 regulate cell cycle processes and induces apoptosis in GBM cell lines. Furthermore, we found that the combination of AQB and GSK-LSD1 showed a powerful effect of inhibiting cell cycle processes by targeting CDKN1A, whereas apoptosis promoting effects of combination therapy were mediated by BBC3 in vitro. ChIP assays revealed that GSK-LSD1 and AQB regulate P21 and PUMA, respectively via upregulating H3K4me2 and downregulating H3K27me3. Combination therapy with AQB and GSK-LSD1 on tumor malignancy in vitro and GBM patient-derived xenograft (PDX) models shows enhanced anti-tumor efficacy and appears to be a promising new strategy for GBM treatment through its effects on epigenetic regulation.

The lipid-lowering drug fenofibrate combined with si-HOTAIR can effectively inhibit the proliferation of gliomas.

BACKGROUND: Fenofibrate is a fibric acid derivative known to have a lipid-lowering effect. Although fenofibrate-induced peroxisome proliferator-activated receptor alpha (PPARα) transcription activation has been shown to play an important role in the malignant progression of gliomas, the underlying mechanisms are poorly understood. METHODS: In this study, we analyzed TCGA database and found that there was a significant negative correlation between the long noncoding RNA (lncRNA) HOTAIR and PPARα. Then, we explored the molecular mechanism by which lncRNA HOTAIR regulates PPARα in cell lines in vitro and in a nude mouse glioma model in vivo and explored the effect of the combined application of HOTAIR knockdown and fenofibrate treatment on glioma invasion. RESULTS: For the first time, it was shown that after knockdown of the expression of HOTAIR in gliomas, the expression of PPARα was significantly upregulated, and the invasion and proliferation ability of gliomas were obviously inhibited. Then, glioma cells were treated with both the PPARα agonist fenofibrate and si-HOTAIR, and the results showed that the proliferation and invasion of glioma cells were significantly inhibited. CONCLUSIONS: Our results suggest that HOTAIR can negatively regulate the expression of PPARα and that the combination of fenofibrate and si-HOTAIR treatment can significantly inhibit the progression of gliomas. This introduces new ideas for the treatment of gliomas.

11p11.12p12 duplication in a family with intellectual disability and craniofacial anomalies.

BACKGROUND: Potocki-Shaffer syndrome (PSS) is a rare contiguous gene deletion syndrome marked by haploinsufficiency of genes in chromosomal region 11p11.2p12. Approximately 50 cases of PSS have been reported; however, a syndrome with a PSS-like clinical phenotype caused by 11p11.12p12 duplication has not yet been reported. METHODS: 11p11.12p12 duplication syndrome was identified and evaluated using a multidisciplinary protocol. Diagnostic studies included intelligence testing, thorough physical examination, electroencephalography (EEG), magnetic resonance imaging (MRI) of the brain, ultrasonography, biochemical tests and karyotype analysis. Next-generation sequencing analysis clarified the location of the chromosomal variations, which was confirmed by chromosome microarray analysis (CMA). Whole-exome sequencing (WES) was performed to exclude single nucleotide variations (SNVs). A wider literature search was performed to evaluate the correlation between the genes contained in the chromosomal region and clinical phenotypes. RESULTS: The proband was a 36-year-old mother with intellectual disability (ID) and craniofacial anomalies (CFA). She and her older son, who had a similar clinical phenotype, both carried the same 11p11.12p12 duplication with a copy number increase of approximately 10.5 Mb (chr11:40231033_50762504, GRCh37/hg19) in chromosome bands 11p11.12p12. In addition, she gave birth to a child with a normal phenotype who did not carry the 11p11.12p12 duplication. By literature research and DECIPHER, we identified some shared and some distinct features between this duplication syndrome and PSS. One or more of ALX4, SLC35C1, PHF21A and MAPK8IP1 may be responsible for 11p11.12p12 duplication syndrome. CONCLUSIONS: We present the first report of 11p11.12p12 duplication syndrome. It is an interesting case worth reporting. The identification of clinical phenotypes will facilitate genetic counselling. A molecular cytogenetic approach was helpful in identifying the genetic aetiology of the patients and potential candidate genes with triplosensitive effects involved in 11p11.12p12 duplication.

Changes in the Gut Microbiota of Children with Autism Spectrum Disorder.

Alterations in the gut microbiota may influence gastrointestinal (GI) dysbiosis frequently reported in individuals with autism spectrum disorder (ASD). In this study, we sequenced the bacterial 16S rRNA gene to evaluate changes in fecal microbiota between 48 children with ASD and 48 healthy children in China. At the phylum level, the number of Firmicutes, Proteobacteria, and Verrucomicrobia decreased in children with ASD, while the Bacteroidetes/Firmicutes was significantly higher in autistic children due to enrichment of Bacteroidetes. At the genus level, the amount of Bacteroides, Prevotella, Lachnospiracea_incertae_sedis, and Megamonas increased, while Clostridium XlVa, Eisenbergiella, Clostridium IV, Flavonifractor, Escherichia/Shigella, Haemophilus, Akkermansia, and Dialister decreased in children with ASD relative to the controls. Significant increase was observed in the number of species synthesizing branched-chain amino acids (BCAAs), like Bacteroides vulgatus and Prevotella copri, while the numbers of Bacteroides fragilis and Akkermansia muciniphila decreased in children with ASD compared to the controls. Most importantly, the highest levels of pathogenic bacteria were different for each child with ASD in this cohort. We found that only one functional module, cellular antigens, was enriched in children with ASD, and other pathways like lysine degradation and tryptophan metabolism were significantly decreased in children with ASD. These findings provide further evidence of altered gut microbiota in Chinese ASD children and may contribute to the treatment of patients with ASD. LAY SUMMARY: This study characterized the gut bacteria composition of 48 children with ASD and 48 neurotypical children in China. The metabolic disruptions caused by altered gut microbiota may contribute significantly to the neurological pathophysiology of ASD, including significant increases in the number of species synthesizing BCAAs, and decreases in the number of probiotic species. These findings suggest that a gut microbiome-associated therapeutic intervention may provide a novel strategy for treating GI symptoms frequently seen in individuals with ASD. Autism Res 2020, 13: 1614-1625. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

Ultrasound and Clinical Characteristics of False-negative Results in Mammography Screening of Dense Breasts.

OBJECTIVE: We analyzed the clinical and ultrasound characteristics associated with false-negative mammography results in women with dense breasts. MATERIALS AND METHODS: The present study included 191 women (mean age, 54.47 ± 11.61 years; range, 31-75 years) who had presented from July 2015 to June 2018 with pathologically confirmed breast cancer. The mammography, conventional ultrasound, and elastography imaging results of these patients were reviewed. Breast density and screening cancer probability from mammography and conventional ultrasound imaging were scored using the Breast Imaging Reporting and Data System. Multivariate logistic regression analysis was performed to identify the factors independently associated with the false-negative results on breast mammographic screening. RESULTS: Of 191 confirmed breast cancer cases, 55 (28.8%) were assigned to category ≤ 3, and 136 (71.2%) were assigned to category ≥ 4a according to the mammography findings. All the breasts were graded mammographically as dense. A rougher margin (odds ratio [OR], 8.123; 95% confidence interval [CI], 1.731-38.127) was the strongest independent factor associated with negative results, followed by a lower stiffness ratio (OR, 7.773; 95% CI, 2.574-23.473), negative axillary lymph node status (OR, 5.066; 95% CI, 1.028-24.955), and softer lesions (OR, 1.037; 95% CI, 1.001-1.075). CONCLUSION: Women with dense breasts, a lower lesion/glandular tissue stiffness ratio, and softer cancer can easily lead to a misdiagnosis using mammography. By giving sufficient attention to the margin, earlier stage cancer with negative lymph node status are more likely to benefit from supplemental ultrasound imaging.

Protein kinase C-ε contributes to a chronic inhibitory effect of IL-1ß on voltage-gated sodium channels in mice with febrile seizure.

This study aimed to understand the role of Interleukin-1ß in mouse febrile seizures. To investigate the chronic effects of raised Interleukin-1ß on seizures, the sodium currents of hippocampal neurons were recorded by whole-cell voltage clamp. Interleukin-1ß inhibited sodium currents in mouse hippocampal neurons and verified that protein kinase C epsilon contributed to the effect of Interleukin-1ß exposure. The inhibitory effect was also identified in neurons from a protein kinase C epsilon null mutant mouse. Action potentials were recorded using a ramp depolarizing current. Peak spike depolarization was significantly reduced by Interleukin-1ß treatment, and was abolished following the administration of a protein kinase C epsilon inhibitor, εV1-2. However, neither Interleukin-1ß nor εV1-2 had any significant effect on spike threshold. Interleukin-1ß reduced the amplitude of action potentials due to its inhibitory effect on sodium channels. This is hypothesised to decrease the release of presynaptic transmitters of neuroexcitability, thus exerting a neuroprotective role in excitotoxicity. To ascertain the role of protein kinase C epsilon on febrile seizures in vivo, a heated water-bath model was used to identify susceptible mice. It was found that protein kinase C epsilon reduced susceptibility to, and frequency of, febrile seizure onset. This may be related to the neuroprotective effect of Interleukin-1ß on hippocampal neurons.

Human epididymis protein 4 (HE4) protects against cystic pulmonary fibrosis associated-inflammation through inhibition of NF-κB and MAPK singnaling.

BACKGROUND: Cystic pulmonary fibrosis (CF) affects mostly the lung of the newborns. Chronic infection and inflammation become the major causes of morbidity and mortality in CF. However, the underlying molecular mechanisms causing CF still remain unclear. METHODS: ELISA assay was used to examine the expression of HE4 and pro-inflammatory cytokines in W126VA4 cells supernatant fluid. qRT-PCR was applicable to determine the mRNA level of HE4, α-SMA, collagen 1, MMP2, MMP9 and various interleukins. Immunofluorescent assay was used to test the expression of HE4 in WI-26 VA4 cells. Major elements of MAPK and NF-κB signals pathways were examined by western blot. RESULTS: We found higher expression of HE4 in CF patients serum and lung biopsy. Interestingly, HE4 expression was positively correlated with fibrosis markers expression. In addition,HE4 overexpression increased inflammatory cytokines secretion and fibrosis markers expression in WI-26 VA4 cells. And NF-κB pathways were responsible for elevated inflammation. In addition, HE4/MAPK/MMPs signaling cascades destroyed the normal extracellular matrix (ECM) and promoted fibrosis. CONCLUSIONS: Overall, we first identified that HE4 promoted CF-associated inflammation. Additionally, NF-κB and MAPK signalings were further validated to be responsible for CF-associated inflammation and ECM destruction. Characterization of lumacaftor/ivacaftor in CF-associated inflammation may provide a novel insight into clinical CF treatment.

Inhibition of microRNA-34a Suppresses Epileptiform Discharges Through Regulating Notch Signaling and Apoptosis in Cultured Hippocampal Neurons.

Epilepsy is characterized by recurrent unprovoked seizures and some seizures can cause neuronal apoptosis, which is possible to make contributions to the epilepsy phenotype, impairments in cognitive function or even epileptogenesis. Moreover, many studies have indicated that microRNA-34a (miRNA-34a) is involved in apoptosis through regulating Notch signaling. However, whether miRNA-34a participates in neuronal apoptosis after seizures remain unclear. Therefore, we aimed to explore the expression of miRNA-34a and its effects on the epileptiform discharge in spontaneous recurrent epileptiform discharges (SREDs) rat hippocampal neuronal pattern. Mg2+-free medium was used to induce SREDs, quantitative reverse-transcription polymerase chain reaction was used to detect the expression of miRNA-34a, western blot was used to determine the expression of Notch pathway and apoptosis-related proteins, and whole cell current clamp recordings was used to observe the alteration of epileptiform discharge. We found obvious apoptosis, increased expression of miRNA-34a and decreased expression of Notch signaling in Mg2+-free-treated neurons. Treatment with miRNA-34a inhibitor decreased the frequency of action potentials, activated Notch signaling and prevented neuronal apoptosis in Mg2+-free-treated neurons. However, treatment with miRNA-34a mimics increased the frequency of action potentials, down-regulated Notch signaling and promoted neuronal apoptosis in Mg2+-free-treated neurons. Furthermore, γ-secretase inhibitor N-[N-(3,5-di-uorophenacetyl)-1-alanyl]-S-phenylglycine t-butylester (DAPT), an inhibitor of Notch signaling, could weaken anti-apoptosis effect of miRNA-34a inhibitor. These results suggest that inhibition of miRNA-34a could suppress epileptiform discharges through regulating Notch signaling and apoptosis in the rat hippocampal neuronal model of SREDs.

Pillararene-based supramolecular polymers.

Pillararenes, as a new type of macrocyclic hosts, possess columnar structures and electron-rich cavities. Pillararenes not only recognize suitable cations, but also bind many neutral molecules. Due to the easy modification of pillararenes, various functional groups can be conveniently attached to the rim of pillararenes to provide suitable interaction sites, and the modified pillararenes even bind anionic guests. Thus, pillararenes and their derivatives have presented intriguing and unique host-guest recognition nature in the past few years, which make them ideal building blocks for the preparation of supramolecular polymers. Pillararene-based supramolecular polymers (PSPs) not only possess many merits of traditional covalent polymers but also have many specific properties, such as self-reparability, degradability, and self-adaptation. This feature paper gives an overview of the preparation of PSPs and covers recent research advance and future trends of pillararene-based host-guest pairs, assembly methods, topological architectures, stimuli-responsiveness, and functional features. We expect that the review will be helpful to researchers working in the fields of supramolecular chemistry and polymer science.