Intratumoral and peritumoral radiomics model for the preoperative prediction of cribriform component in invasive lung adenocarcinoma: a multicenter study.

PURPOSE: This study aimed to investigate the predictive value of intratumoral and peritumoral radiomics model for the cribriform component (CC) of invasive lung adenocarcinoma (LUAD). MATERIALS AND METHODS: The 144 patients with invasive LUAD from our center were randomly divided into training set (n = 100) and internal validation set (n = 44) in a ratio of 7:3, and 75 patients from center 2 were regarded as the external validation set. Clinical risk factors were examined using univariate and multivariate logistic regression to construct the clinical model. We extracted radiomics features from gross tumor volume (GTV), gross and peritumoral volume (GPTV), and peritumoral volume (PTV), respectively. Radiomics models were constructed with selected features. A combined model based on the optimal Radscore and clinically independent predictors was constructed, and its predictive performance was assessed by receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis (DCA). RESULTS: The area under curves (AUCs) of the GTV model were 0.882 (95% CI 0.817-0.948), 0.794 (95% CI 0.656-0.932), and 0.766 (95% CI 0.657-0.875) in the training, internal validation, and external validation sets, and the PTV model had AUCs of 0.812 (95% CI 0.725-0.899), 0.749 (95% CI 0.597-0.902), and 0.670 (95% CI 0.543-0.798) in the training, internal validation, and external validation sets, respectively. However, the GPTV radiomics model showed better predictive performance compared with the GTV and PTV radiomics models, with the AUCs of 0.950 (95% CI 0.911-0.989), 0.844 (95% CI 0.728-0.959), and 0.815 (95% CI 0.713-0.917) in the training, internal validation and external validation sets, respectively. In the clinical model, tumor shape, lobulation sign and maximal diameter were the independent predictors of CC in invasive LUAD. The combined model including independent clinical predictors and GPTV-Radscore show the considerable instructive to clinical practice, with the AUCs of 0.954(95% CI 0.918-0.990), 0.861(95% CI 0.752-0.970), and 0.794(95% CI 0.690-0.898) in training, internal validation, and external validation sets, respectively. DCA showed that the combined model had good clinical value and correction effect. CONCLUSION: Radiomics model is a very powerful tool for predicting CC growth pattern in invasive LUAD and can help clinicians make the strategies of treatment and surveillance in patients with invasive LUAD.

Effect and mechanism of Qingre Huashi decoction on drug-resistant Helicobacter pylori.

BACKGROUND: Helicobacter pylori (HP), the most common pathogenic microorganism in the stomach, can induce inflammatory reactions in the gastric mucosa, causing chronic gastritis and even gastric cancer. HP infection affects over 4.4 billion people globally, with a worldwide infection rate of up to 50%. The multidrug resistance of HP poses a serious challenge to eradication. It has been de-monstrated that compared to bismuth quadruple therapy, Qingre Huashi decoction (QHD) combined with triple therapy exhibits comparable eradication rates but with a lower incidence of adverse reactions; in addition, QHD can directly inhibit and kill HP in vitro. AIM: To explore the effect and mechanism of QHD on clinically multidrug-resistant and strong biofilm-forming HP. METHODS: In this study, 12 HP strains were isolated in vitro after biopsy during gastroscopy of HP-infected patients. In vitro, the minimum inhibitory concentration (MIC) values for clinical HP strains and biofilm quantification were determined through the E-test method and crystal violet staining, respectively. The most robust biofilm-forming strain of HP was selected, and QHD was evaluated for its inhibitory and bactericidal effects on the strain with strong biofilm formation. This assessment was performed using agar dilution, E-test, killing dynamics, and transmission electron microscopy (TEM). The study also explored the impact of QHD on antibiotic resistance in these HP strains with strong biofilm formation. Crystalline violet method, scanning electron microscopy, laser confocal scanning microscopy, and (p)ppGpp chromatographic identification were employed to evaluate the effect of QHD on biofilm in strong biofilm-forming HP strains. The effect of QHD on biofilm and efflux pump-related gene expression was evaluated by quantitative polymerase chain reaction. Non-targeted metabolomics with UHPLC-MS/MS was used to identify potential metabolic pathways and biomarkers which were different between the NC and QHD groups. RESULTS: HP could form biofilms of different degrees in vitro, and the intensity of formation was associated with the drug resistance of the strain. QHD had strong bacteriostatic and bactericidal effects on HP, with MICs of 32-64 mg/mL. QHD could inhibit the biofilm formation of the strong biofilm-forming HP strains, disrupt the biofilm structure, lower the accumulation of (p)ppGpp, decrease the expression of biofilm-related genes including LuxS, Spot, glup (HP1174), NapA, and CagE, and reduce the expression of efflux pump-related genes such as HP0605, HP0971, HP1327, and HP1489. Based on metabolomic analysis, QHD induced oxidative stress in HP, enhanced metabolism, and potentially inhibited relevant signaling pathways by upregulating adenosine monophosphate (AMP), thereby affecting HP growth, metabolism, and protein synthesis. CONCLUSION: QHD exerts bacteriostatic and bactericidal effects on HP, and reduces HP drug resistance by inhibiting HP biofilm formation, destroying its biofilm structure, inhibiting the expression of biofilm-related genes and efflux pump-related genes, enhancing HP metabolism, and activating AMP in HP.

A structural variation in the promoter of the leucoanthocyanidin reductase gene AaLAR1 enhances freezing tolerance by modulating proanthocyanidin accumulation in kiwifruit (Actinidia arguta).

Proanthocyanidins (PAs) are important metabolites that enhance freezing tolerance of plants. Actinidia arguta, especially freezing-tolerant germplasms, accumulate abundant PAs in dormant shoots and thereby enhance freezing tolerance, but the underlying mechanism is unknown. In this study, we used two A. arguta with contrasting cold-resistant phenotypes, KL and RB, to explore the mechanisms in response to cold tolerance. We determined that a leucoanthocyanidin reductase gene (AaLAR1) was more highly expressed in freezing-tolerant KL than in freezing-sensitive RB. Moreover, overexpressing AaLAR1 in kiwifruit promoted PAs biosynthesis and enhanced cold tolerance. The AaLAR1 promoters of various A. arguta germplasms differ due to the presence of a 60-bp deletion in cold-tolerant genotypes that forms a functional binding site for MYC-type transcription factor. Yeast one-hybrid and two-hybrid, dual-luciferase reporter, bimolecular fluorescence complementation and coimmunoprecipitation assays indicated that the AaMYC2a binds to the MYC-core cis-element in the AaLAR1 promoter with the assistance of AaMYB5a, thereby promoting PAs accumulation in the shoots of cold-tolerant kiwifruit. We conclude that the variation in the AaLAR1 promoter and the AaMYC2a-AaMYB5a-AaLAR1 module shape freezing tolerance in A. arguta. The identification of a key structural variation in the AaLAR1 promoter offers a new target for resistance breeding of kiwifruit.

GFRAL Is Widely Distributed in the Brain and Peripheral Tissues of Mice.

In 2017, four independent publications described the glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as receptor for the growth differentiation factor 15 (GDF15, also MIC-1, NAG-1) with an expression exclusively in the mice brainstem area postrema (AP) and nucleus tractus solitarii (NTS) where it mediates effects of GDF15 on reduction of food intake and body weight. GDF15 is a cell stress cytokine with a widespread expression and pleiotropic effects, which both seem to be in contrast to the reported highly specialized localization of its receptor. This discrepancy prompts us to re-evaluate the expression pattern of GFRAL in the brain and peripheral tissues of mice. In this detailed immunohistochemical study, we provide evidence for a more widespread distribution of this receptor. Apart from the AP/NTS region, GFRAL-immunoreactivity was found in the prefrontal cortex, hippocampus, nucleus arcuatus and peripheral tissues including liver, small intestine, fat, kidney and muscle tissues. This widespread receptor expression, not taken into consideration so far, may explain the multiple effects of GDF-15 that are not yet assigned to GFRAL. Furthermore, our results could be relevant for the development of novel pharmacological therapies for physical and mental disorders related to body image and food intake, such as eating disorders, cachexia and obesity.

Screening and identification of photoresponse factors in kiwifruit (Actinidia arguta) development.

BACKGROUND: Light is essential for kiwifruit development, in which photoresponse factors contributes greatly to the quality formation. 'Light sensitive hypocotyls, also known as light-dependent short hypocotyls' (LSH) gene family can participate in fruit development as photoresponse factor. However, the key LSH gene that determine kiwifruit development remains unclear. This study aim to screen and identify the key gene AaLSH9 in A. arguta. MATERIALS AND METHODS: Genome-wide identification of the LSH gene family was used to analyse LSH genes in kiwifruit. Homologous cloning was used to confirm the sequence of candidate LSH genes. qRT-PCR and cluster analysis of expression pattern were used to screen the key AaLSH9 gene. Subcellular localization of AaLSH9 in tobacco leaves and overexpression of AaLSH9 in Arabidopsis thaliana hy5 mutant plants were used to define the acting place in cell and identify molecular function, respectively. RESULTS: We identified 15 LSH genes, which were divided into two sub-families namely A and B. Domain analysis of A and B showed that they contained different domain organizations, which possibly played key roles in the evolution process. Three LSH genes, AaLSH2, AaLSH9, and AaLSH11, were successfully isolated from Actinidia arguta. The expression pattern and cluster analysis of these three AaLSH genes suggested AaLSH9 might be a key photoresponse gene participating in fruit development in A. arguta. Subcellular localization showed AaLSH9 protein was located in the nucleus. The overexpression of AaLSH9 gene in Arabidopsis thaliana hy5 mutant plants partially complemented the long hypocotyls of hy5 mutant, implying AaLSH9 played a key role as photoresponse factor in cells. In addition, the seed coat color of A. thaliana over-expressing AaLSH9 became lighter than the wide type A.thaliana. Finally, AaCOP1 was confirmed as photoresponse factor to participate in developmental process by stable transgenic A. thaliana. CONCLUSIONS: AaLSH9 can be involved in kiwifruit (A. arguta) development as key photoresponse factor. Our results not only identified the photoresponse factors AaLSH9 and AaCOP1 but also provided insights into their key role in fruit quality improvement in the process of light response.

Chloroxine inhibits pancreatic cancer progression through targeted antagonization of the PI3K/AKT/mTOR signaling pathway.

BACKGROUND: Patients with pancreatic cancer have a dismal prognosis due to tumor cell infiltration and metastasis. Many reports have documented that EMT and PI3K-AKT-mTOR axis control pancreatic cancer cell infiltration and metastasis. Chloroxine is an artificially synthesized antibacterial compound that demonstrated anti-pancreatic cancer effects in our previous drug-screening trial. We have explored the impact of chloroxine on pancreatic cancer growth, infiltration, migration, and apoptosis. METHODS: The proliferation of pancreatic cancer cell lines (PCCs) treated with chloroxine was assessed through real-time cell analysis (RTCA), colony formation assay, CCK-8 assay, as well as immunofluorescence. Chloroxine effects on the infiltrative and migratory capacities of PCCs were assessed via Transwell invasion and scratch experiments. To assess the contents of EMT- and apoptosis-associated proteins in tumor cells, we adopted Western immunoblotting as well as immunofluorescence assays, and flow cytometry to determine chloroxine effects on PCCs apoptosis. The in vivo chloroxine antineoplastic effects were explored in nude mice xenografts. RESULTS: Chloroxine repressed pancreatic cancer cell growth, migration, and infiltration in vitro, as well as in vivo, and stimulated apoptosis of the PCCs. Chloroxine appeared to inhibit PCC growth by Ki67 downregulation; this targeted and inhibited aberrant stimulation of the PI3K-AKT-mTOR signaling cascade, triggered apoptosis in PCC via mitochondria-dependent apoptosis, and modulated the EMT to inhibit PCC infiltration and migration. CONCLUSIONS: Chloroxine targeted and inhibited the PI3K-AKT-mTOR cascade to repress PCCs growth, migration, as well as invasion, and triggered cellular apoptosis. Therefore, chloroxine may constitute a potential antineoplastic drug for the treatment of pancreatic cancer.

Gut microbiome and frailty: insight from genetic correlation and mendelian randomization.

Observational studies have shown that the gut microbiome is associated with frailty. However, whether these associations underlie causal effects remains unknown. Thus, this study aimed to assess the genetic correlation and causal relationships between the genetically predicted gut microbiome and frailty using linkage disequilibrium score regression (LDSC) and Mendelian Randomization (MR). Summary statistics for the gut microbiome were obtained from a genome-wide association study (GWAS) meta-analysis of the MiBioGen consortium (N = 18,340). Summary statistics for frailty were obtained from a GWAS meta-analysis, including the UK Biobank and TwinGene (N = 175,226). We used LDSC and MR analyses to estimate the genetic correlation and causality between the genetically predicted gut microbiome and frailty. Our findings indicate a suggestive genetic correlation between Christensenellaceae R-7 and frailty. Moreover, we found evidence for suggestive causal effects of twelve genus-level gut microbes on frailty using at least two MR methods. There was no evidence of horizontal pleiotropy or heterogeneity in the MR analysis. This study provides suggestive evidence for a potential genetic correlation and causal association between several genetically predicted gut microbes and frailty. More population-based observational studies and animal experiments are required to clarify this association and the underlying mechanisms.

A High-K+ Affinity Transporter (HKT) from Actinidia valvata Is Involved in Salt Tolerance in Kiwifruit.

Ion transport is crucial for salt tolerance in plants. Under salt stress, the high-affinity K+ transporter (HKT) family is mainly responsible for the long-distance transport of salt ions which help to reduce the deleterious effects of high concentrations of ions accumulated within plants. Kiwifruit is well known for its susceptibility to salt stress. Therefore, a current study was designed to decipher the molecular regulatory role of kiwifruit HKT members in the face of salt stress. The transcriptome data from Actinidia valvata revealed that salt stress significantly induced the expression of AvHKT1. A multiple sequence alignment analysis indicated that the AvHKT1 protein contains three conserved amino acid sites for the HKT family. According to subcellular localization analysis, the protein was primarily present in the cell membrane and nucleus. Additionally, we tested the AvHKT1 overexpression in 'Hongyang' kiwifruit, and the results showed that the transgenic lines exhibited less leaf damage and improved plant growth compared to the control plants. The transgenic lines displayed significantly higher SPAD and Fv/Fm values than the control plants. The MDA contents of transgenic lines were also lower than that of the control plants. Furthermore, the transgenic lines accumulated lower Na+ and K+ contents, proving this protein involvement in the transport of Na+ and K+ and classification as a type II HKT transporter. Further research showed that the peroxidase (POD) activity in the transgenic lines was significantly higher, indicating that the salt-induced overexpression of AvHKT1 also scavenged POD. The promoter of AvHKT1 contained phytohormone and abiotic stress-responsive cis-elements. In a nutshell, AvHKT1 improved kiwifruit tolerance to salinity by facilitating ion transport under salt stress conditions.

Association between digestive diseases and sarcopenia among Chinese middle-aged and older adults: a prospective cohort study based on nationally representative survey.

Objectives: Patients with digestive diseases frequently suffer from dyspepsia and malabsorption, which may lead to muscle loss due to malnutrition. However, it is not clear whether digestive diseases are associated with sarcopenia. This study aims to explore the longitudinal association between digestive diseases and sarcopenia in middle-aged and older adults based on a nationally representative survey from China. Methods: We used a prospective cohort study including 7,025 middle-aged and older adults aged ≥45 years from the 2011 to 2015 waves China Health and Retirement Longitudinal Study (CHARLS). Digestive diseases were identified using self-report. The assessment of sarcopenia was based on the Asian Working Group for Sarcopenia 2019 Consensus and included three components of muscle strength, physical performance, and muscle mass. Cox hazards regression was used to examine the association between digestive diseases and sarcopenia. Results: The prevalence of digestive diseases and the incidence of sarcopenia in middle-aged and older adults were 22.6% (95% CI = 21.6-23.6%) and 8.5% (95% CI = 7.8-9.1%). After adjusting for 15 covariates composed of three sets (demographic characteristics, lifestyles, and health status), digestive diseases were associated with a higher risk of sarcopenia (HR = 1.241, 95% CI = 1.034-1.490, P < 0.05). The associations were more pronounced among men, older adults aged 60-79, rural residents, and married people. In addition, the association between digestive diseases and sarcopenia was robust in the sensitivity analysis. Conclusion: Digestive diseases were associated with an increased risk of sarcopenia in middle-aged and older adults aged ≥45 years. Early intervention of digestive diseases may help to reduce the incidence of sarcopenia in middle-aged and older adults.

The Emerging Roles of E3 Ligases and DUBs in Neurodegenerative Diseases.

Despite annual increases in the incidence and prevalence of neurodegenerative diseases, there is a lack of effective treatment strategies. An increasing number of E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs) have been observed to participate in the pathogenesis mechanisms of neurodegenerative diseases, on the basis of which we conducted a systematic literature review of the studies. This review will help to explore promising therapeutic targets from highly dynamic ubiquitination modification processes.

P2X7Rs: new therapeutic targets for osteoporosis.

Increasing evidence suggests that both the occurrence and progression of osteoporosis are associated with inflammation, especially in primary osteoporosis. The maintenance of skeletal homeostasis is dependent on the complex regulation of bone metabolism. Numerous evidence suggested that purinoceptor networks are essential for bone homeostasis. In this review, the relationship between inflammation and the development of osteoporosis and the role of P2X7 receptor (P2X7R) in regulating the dynamic regulation of bone reconstruction were covered. We also discussed how P2X7R regulates the balance between resorption and bone formation by osteoblasts and reviewed the relevance of P2X7R polymorphisms in skeletal physiology. Finally, we analyzed potential targets of P2X7R for osteoporosis.

Development of a 135K SNP genotyping array for Actinidia arguta and its applications for genetic mapping and QTL analysis in kiwifruit.

Kiwifruit (Actinidia spp) is a woody, perennial and deciduous vine. In this genus, there are multiple ploidy levels but the main cultivated cultivars are polyploid. Despite the availability of many genomic resources in kiwifruit, SNP genotyping is still a challenge given these different levels of polyploidy. Recent advances in SNP array technologies have offered a high-throughput genotyping platform for genome-wide DNA polymorphisms. In this study, we developed a high-density SNP genotyping array to facilitate genetic studies and breeding applications in kiwifruit. SNP discovery was performed by genome-wide DNA sequencing of 40 kiwifruit genotypes. The identified SNPs were stringently filtered for sequence quality, predicted conversion performance and distribution over the available Actinidia chinensis genome. A total of 134 729 unique SNPs were put on the array. The array was evaluated by genotyping 400 kiwifruit individuals. We performed a multidimensional scaling analysis to assess the diversity of kiwifruit germplasm, showing that the array was effective to distinguish kiwifruit accessions. Using a tetraploid F1 population, we constructed an integrated linkage map covering 3060.9 cM across 29 linkage groups and performed QTL analysis for the sex locus that has been identified on Linkage Group 3 (LG3) in Actinidia arguta. Finally, our dataset presented evidence of tetrasomic inheritance with partial preferential pairing in A. arguta. In conclusion, we developed and evaluated a 135K SNP genotyping array for kiwifruit. It has the advantage of a comprehensive design that can be an effective tool in genetic studies and breeding applications in this high-value crop.

Revealing the novel effect of Jinghua Weikang capsule against the antibiotic resistance of Helicobacter pylori.

Background: Helicobacter pylori (H. pylori) infects half of the human population globally. Eradication rates with triple or quadruple therapy have decreased owing to the increasing rate of antibiotic resistance. Jinghua Weikang capsule (JWC) is the first and most popular Chinese patent medicine approved by the state for the treatment of gastritis and peptic ulcers caused by H. pylori infection in China. Previous studies have found that JWC has a certain bactericidal effect on drug-resistant H. pylori and its major component, Chenopodium ambrosioides L. inhibits biofilm formation, but the mechanism remains unclear. This study focused on drug-resistant H. pylori and explored whether JWC could reverse drug resistance and its related mechanisms. Method: The agar plate dilution method, E-test method, and killing kinetics assay were used to evaluate the bactericidal effect of JWC on antibiotic-resistant H. pylori and its effect on antibiotic resistance. Sanger sequencing was used to detect mutations in drug resistance genes. The crystal violet method, scanning electron microscopy, and confocal laser scanning microscopy were used to evaluate the effects of JWC on biofilms. qPCR was performed to evaluate the effect of JWC on the expression of efflux pump-related genes. qPCR and immunofluorescence were used to evaluate the effects of JWC on H. pylori adhesion. Results: JWC showed considerable antibacterial activity against drug-resistant H. pylori strains, with minimum inhibitory concentration (MIC) values ranging from 64 to 1,024 µg/ml. The MIC of metronidazole (MTZ) against H. pylori 26,695-16R decreased from 64 to 6 µg/ml after treatment with 1/2 MIC of JWC. The resistance of H. pylori 26,695-16R to MTZ was reversed by JWC, and its effect was better than that of PaßN and CCCP. H. pylori 26,695-16R is a moderate biofilm-forming strain, and JWC (16-64 µg/ml) can inhibit the formation of biofilms in H. pylori 26,695-16R. JWC reduced the expression of HP0605-HP0607 (hefABC), HP0971-HP0969 (hefDEF), HP1327-HP1329 (hefGHI), and HP1489-HP1487. JWC reduced the adhesion of H. pylori to GES-1 cells and the expression of adhesives NapA, SabA, and BabA. Conclusion: The reversal of MTZ resistance by JWC may be achieved through the adhesin/efflux pump-biofilm pathway.

Renal artery thrombosis in SARS-CoV-2 infection: a case report.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is identified as the pneumonia and acute respiratory distress syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). The intravascular thrombotic phenomena related to the COVID-19 are emerging as an important complication that contribute to significant mortality. CASE PRESENTATION: We present a 62-year-old man with severe COVID-19 and type 2 diabetes. After symptomatic and supportive treatment, the respiratory function was gradually improved. However, the patient suddenly developed abdominal pain, and the enhanced CT scan revealed renal artery thrombosis. Given the risk of surgery and the duration of the disease, clopidogrel and heparin sodium were included in the subsequent treatment. The patient recovered and remained stable upon follow-up. CONCLUSIONS: Thrombosis is at a high risk in patients with severe COVID-19 pneumonia because of hypercoagulable state, blood stasis and endothelial injury. Thrombotic events caused by hypercoagulation status secondary to vascular endothelial injury deserves our attention. Because timely anticoagulation can reduce the risk of early complications, as illustrated in this case report.

Full-Length Transcriptome and RNA-Seq Analyses Reveal the Mechanisms Underlying Waterlogging Tolerance in Kiwifruit (Actinidia valvata).

Actinidia valvata possesses waterlogging tolerance; however, the mechanisms underlying this trait are poorly characterized. Here, we performed a transcriptome analysis by combining single-molecule real-time (SMRT) sequencing and Illumina RNA sequencing and investigated the physiological responses of the roots of KR5 (A. valvata, a tolerant genotype) after 0, 12, 24 and 72 h of waterlogging stress. KR5 roots responded to waterlogging stress mainly via carbohydrate and free amino acids metabolism and reactive oxygen species (ROS) scavenging pathways. Trehalose-6-phosphate synthase (TPS) activity, alcohol dehydrogenase (ADH) activity and the total free amino acid content increased significantly under waterlogging stress. The nicotinamide adenine dinucleotide-dependent glutamate synthase/alanine aminotransferase (NADH-GOGAT/AlaAT) cycle was correlated with alanine accumulation. Levels of genes encoding peroxidase (POD) and catalase (CAT) decreased and enzyme activity increased under waterlogging stress. Members of the LATERAL ORGAN BOUNDARIES (LOB), AP2/ERF-ERF, Trihelix and C3H transcription factor families were identified as potential regulators of the transcriptional response. Several hub genes were identified as key factors in the response to waterlogging stress by a weighted gene co-expression network analysis (WGCNA). Our results provide insights into the factors contributing to waterlogging tolerance in kiwifruit, providing a basis for further studies of interspecific differences in an important plant trait and for molecular breeding.

Mitochondrial-derived damage-associated molecular patterns amplify neuroinflammation in neurodegenerative diseases.

Both mitochondrial dysfunction and neuroinflammation are implicated in neurodegeneration and neurodegenerative diseases. Accumulating evidence shows multiple links between mitochondrial dysfunction and neuroinflammation. Mitochondrial-derived damage-associated molecular patterns (DAMPs) are recognized by immune receptors of microglia and aggravate neuroinflammation. On the other hand, inflammatory factors released by activated glial cells trigger an intracellular cascade, which regulates mitochondrial metabolism and function. The crosstalk between mitochondrial dysfunction and neuroinflammatory activation is a complex and dynamic process. There is strong evidence that mitochondrial dysfunction precedes neuroinflammation during the progression of diseases. Thus, an in-depth understanding of the specific molecular mechanisms associated with mitochondrial dysfunction and the progression of neuroinflammation in neurodegenerative diseases may contribute to the identification of new targets for the treatment of diseases. In this review, we describe in detail the DAMPs that induce or aggravate neuroinflammation in neurodegenerative diseases including mtDNA, mitochondrial unfolded protein response (mtUPR), mitochondrial reactive oxygen species (mtROS), adenosine triphosphate (ATP), transcription factor A mitochondria (TFAM), cardiolipin, cytochrome c, mitochondrial Ca2+ and iron.

The anthelmintic drug niclosamide induces GSK-ß-mediated ß-catenin degradation to potentiate gemcitabine activity, reduce immune evasion ability and suppress pancreatic cancer progression.

Niclosamide, a cell-permeable salicylanilide, was approved by the Food and Drug Administration for its anthelmintic efficiency. A growing body of evidence in recent years suggests that niclosamide exhibits potential tumor-suppressive activity. However, the role and molecular mechanism of niclosamide in pancreatic cancer remain unclear. In this study, niclosamide inhibited proliferation of pancreatic cancer cells (PCCs), induced apoptosis via the mitochondrial-mediated pathway, and suppressed cell migration and invasion by antagonizing epithelial-to-mesenchymal transition. Also, niclosamide inhibited tumor growth and metastasis in pancreatic cancer xenograft mouse models. Mechanistically, niclosamide exerted these therapeutic effects via targeting ß-catenin. Niclosamide did not reduce ß-catenin mRNA expression in PCCs, but significantly downregulated its protein level. Moreover, niclosamide induced ß-catenin phosphorylation and protein degradation. Interestingly, niclosamide also induced GSK-3ß phosphorylation, which is involved in the ubiquitination degradation of ß-catenin. Pharmacological activation of ß-catenin by methyl vanillate and ß-catenin overexpression abolished the inhibitory effects of niclosamide. Furthermore, niclosamide potentiated the antitumor effect of the chemotherapy drug gemcitabine and reduced the ability of cancer immune evasion by downregulating the expression levels of PD-L1, which is involved in T cell immunity. Thus, our study indicated that niclosamide induces GSK-ß-mediated ß-catenin degradation to potentiate gemcitabine activity, reduce immune evasion ability, and suppress pancreatic cancer progression. Niclosamide may be a potential therapeutic candidate for pancreatic cancer.

OsWRKY62 and OsWRKY76 Interact with Importin α1s for Negative Regulation of Defensive Responses in Rice Nucleus.

Background OsWRKY62 and OsWRKY76, two close members of WRKY transcription factors, function together as transcriptional repressors. OsWRKY62 is predominantly localized in the cytosol. What are the regulatory factors for OsWRKY62 nuclear translocation? Results In this study, we characterized the interaction of OsWRKY62 and OsWRKY76 with rice importin, OsIMα1a and OsIMα1b, for nuclear translocation. Chimeric OsWRKY62.1-GFP, which is predominantly localized in the cytoplasm, was translocated to the nucleus of Nicotiana benthamiana leaf cells in the presence of OsIMα1a or OsIMαΔIBB1a lacking the auto-inhibitory importin ß-binding domain. OsIMαΔIBB1a interacted with the WRKY domain of OsWRKY62.1, which has specific bipartite positively charged concatenated amino acids functioning as a nuclear localization signal (NLS). Similarly, we found that OsIMαΔIBB1a interacted with the AvrPib effector of rice blast fungus Magnaporthe oryzae, which contains a scattered distribution of positively charged amino acids. Furthermore, we identified a nuclear export signal (NES) in OsWRKY62.1 that inhibited nuclear transportation. Overexpression of OsIMα1a or OsIMα1b enhanced resistance to M. oryzae, whereas knockout mutants decreased resistance to the pathogen. However, overexpressing both OsIMα1a and OsWRKY62.1 were slightly more susceptible to M. oryzae than OsWRKY62.1 alone. Ectopic overexpression of OsWRKY62.1-NES fused gene compromised the enhanced susceptibility of OsWRKY62.1 to M. oryzae. Conclusion These results revealed the existence of NLS and NES in OsWRKY62. OsWRKY62, OsWRKY76, and AvrPib effector translocate to nucleus in association with importin α1s through new types of nuclear localization signals for negatively regulating defense responses.