Iridoids rich fraction from Valeriana jatamansi Jones promotes axonal regeneration and motor functional recovery after spinal cord injury through activation of the PI3K/Akt signaling pathway.

Valeriana jatamansi Jones (VJJ), renowned for its extensive history in traditional Chinese medicine and ethnomedicine within China, is prevalently utilized to alleviate ailments such as epigastric distension and pain, gastrointestinal disturbances including food accumulation, diarrhea, and dysentery, as well as insomnia and other diseases. Moreover, the Iridoid-rich fraction derived from Valeriana jatamansi Jones (IRFV) has demonstrated efficacy in facilitating the recuperation of motor functions after spinal cord injury (SCI). This study is aimed to investigate the therapeutic effect of IRFV on SCI and its underlying mechanism. Initially, a rat model of SCI was developed to assess the impact of IRFV on axonal regeneration. Subsequently, employing the PC12 cell model of oxidative damage, the role and mechanism of IRFV in enhancing axonal regeneration were explored using the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway inhibitor LY294002. Ultimately, the same inhibitor was administered to SCI rats to confirm the molecular mechanism through which IRFV promotes axonal regeneration by activating the PI3K/Akt signaling pathway. The results showed that IRFV significantly enhanced motor function recovery, reduced pathological injury, and facilitated axonal regeneration in SCI rats. In vitro experiments revealed that IRFV improved PC12 cell viability, augmented axonal regeneration, and activated the PI3K/Akt signaling pathway. Notably, the inhibition of this pathway negated the therapeutic benefits of IRFV in SCI rats. In conclusion, IRFV promote promotes axonal regeneration and recovery of motor function after SCI through activation of the PI3K/Akt signaling pathway.

Robust positive association between serum urate and the risk of chronic obstructive pulmonary disease: hospital-based cohort and Mendelian randomisation study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and hyperuricaemia are both characterised by systemic inflammation. Preventing chronic diseases among the population with common metabolic abnormality is an effective strategy. However, the association of hyperuricaemia with the higher incidence and risk of COPD remains controversial. Therefore, replicated researches in populations with distinct characteristics or demographics are compellingly warranted. METHODS: This cohort study adopted a design of ambispective hospital-based cohort. We used propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) to minimise the effects of potential confounding factors. A Cox regression model and restricted cubic spline (RCS) model were applied further to assess the effect of serum urate on the risk of developing COPD. Finally, we conducted a two-sample Mendelian randomisation (MR) analysis to explore evidence of causal association. RESULTS: There is a higher incidence in the population with hyperuricaemia compared with the population with normal serum urate (22.29/1000 person-years vs 8.89/1000 person-years, p=0.009). This result is robust after performing PSM (p=0.013) and IPTW (p<0.001). The Cox model confirms that hyperuricaemia is associated with higher risk of developing COPD (adjusted HR=3.35 and 95% CI=1.61 to 6.96). Moreover, RCS shows that the risk of developing COPD rapidly increases with the concentration of serum urate when it is higher than the reference (420 µmol/L). Finally, in MR analysis, the inverse variance weighted method evidences that a significant causal effect of serum urate on COPD (OR=1.153, 95% CI=1.034 to 1.289) is likely to be true. The finding of MR is robust in the repeated analysis using different methods and sensitivity analysis. CONCLUSIONS: Our study provides convincing evidence suggesting a robust positive association between serum urate and the risk of developing COPD, and indicates that the population with hyperuricaemia is at high risk of COPD in the Chinese population who seek medical advice or treatment in the hospital.

Circular RNA hsa_circ_0050386 suppresses non-small cell lung cancer progression via regulating the SRSF3/FN1 axis.

BACKGROUND: Lung cancer is the most prevalent cancer worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of all cases. Circular RNAs(circRNA) play crucial roles in regulating the progression of lung cancer. Despite the identification of a large number of circRNAs, their expression patterns, functions, and mechanisms of action in NSCLC development remain unclear.This study aims to investigate the transcriptional expressions, functions, and potential mechanisms of circRNA hsa_circ_0050386 in NSCLC. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized for the analysis of hsa_circ_0050386 expression. Cell proliferation was detected using the IncuCyte Live Cell Analysis System and clone formation assays. Migration and invasion of NSCLC cells were evaluated through Transwell assays. Flow cytometry was performed to assay cell cycle and apoptosis. Western blot was used to investigate protein expression. Protein binding analysis was conducted by employing pull-down assays, RNA immunoprecipitation (RIP), and mass spectrometry. The role of hsa_circ_0050386 in vivo was evaluated through the use of a xenograft model. RESULTS: The study discovered that hsa_circ_0050386 displayed lower expression levels in NSCLC tissues when compared to adjacent normal tissues. Patients exhibiting lower levels of hsa_circ_0050386 expression exhibited an inverse correlation with the Clinical Stage, T-stage, and M-stage of NSCLC. Functionally, hsa_circ_0050386 suppressed the proliferation and invasion of NSCLC cells both in vitro and in vivo. A comprehensive examination exposed the interaction between hsa_circ_0050386 and RNA binding protein Serine and arginine-rich splicing factor 3 (SRSF3), resulting in the down-regulation of Fibronectin 1 (FN1) expression, which inhibits the progression of NSCLC. CONCLUSIONS: Our study shows that hsa_circ_0050386 suppresses the malignant biological behavior of NSCLC cells by down-regulating the expression of FN1, and may serve as a potential biomarker and therapeutic target for NSCLC treatment.

An integrative pan-cancer analysis of WWC family genes and functional validation in lung cancer.

The WW and C2 domain containing (WWC) protein family functions as scaffolds regulating cell proliferation and organ growth control through the Hippo signaling pathway. However, their pan-cancer dysregulation and mechanistic roles in signaling transduction have remained unclear. We performed integrated pan-cancer analyses of WWC family gene expression using data from The Cancer Genome Atlas (TCGA) across 33 different cancer types. Prognostic relevance was evaluated by survival analyses. WWC genetic alterations, DNA methylation, pathway activities, drug response, and tumor immunology were analyzed using online databases. Furthermore, we examined the functional roles of WWCs in lung cancer cells. We observed aberrant WWC expression in various cancers, which associated with patient prognosis. WWC hypermethylation occurred in many cancers and exhibited negative correlation with expression, alongside mutations linked to poor outcomes. Pathway analysis implicated WWCs as Hippo pathway scaffolds, while drug sensitivity analysis suggested associations with diverse chemotherapies. Additionally, pan-cancer analyses elucidated vital immunomodulatory roles for WWC through heterogeneous correlations with immune cell infiltrates, checkpoint molecules, tumor mutation burden, microsatellite instability, and chemokine pathways across cancers. Experimentally, WWCs suppressed lung cancer cell proliferation, migration, and invasion while enhancing apoptosis and paclitaxel chemosensitivity. Mechanistically, WWCs bound large tumor suppressor 1 and 2 (LATS1/2) kinases to stimulate phosphorylation cascades, thereby inhibiting nuclear translocation of the Yes-associated protein (YAP) oncoprotein. Taken together, our multi-omics characterization provides comprehensive evidence for WWCs as putative tumor suppressors across cancers via Hippo pathway modulation. WWCs may serve as prognostic markers and therapeutic targets in lung cancer.

Effects of a lower limb walking exoskeleton on quality of life and activities of daily living in patients with complete spinal cord injury: A randomized controlled trial.

BACKGROUND: In recent years, lower limb walking exoskeletons have been widely used in the study of spinal cord injury (SCI). OBJECTIVE: To explore the effect of a lower limb walking exoskeleton on quality of life and functional independence in patients with motor complete SCI. METHODS: This was a multi-center, single blind, randomized controlled trial. A total of 16 SCI patients were randomly assigned to either the exoskeleton-assisted walking (EAW) group (n= 8) or the conventional group (n= 8). Both groups received conventional rehabilitation training, including aerobic exercise and strength training. The EAW group additionally conducted the exoskeleton-assisted walking training using an AIDER powered robotic exoskeleton for 40-50 minutes, 5 times/week for 8 weeks. World Health Organization quality of life-BREF (WHOQOL-BREF) and the Spinal Cord Independence Measure III (SCIM-III) were used for assessment before and after training. RESULTS: There was an increasing tendency of scores in the psychological health, physical health, and social relationships domain of WHOQOL-BREF in the EAW group after the intervention compared with the pre-intervention period, but there was no significant difference (P> 0.05). SCIM-III scores increased in both groups compared to pre-training, with only the conventional group showing a significant difference after 8 weeks of training (P< 0.05). CONCLUSION: A lower limb walking exoskeleton may have potential benefits for quality of life and activities of daily living in patients with motor complete SCI.

Mechanism of Valeriana Jatamansi Jones for the treatment of spinal cord injury based on network pharmacology and molecular docking.

Spinal cord injury (SCI) is characterized by high rates of disability and death. Valeriana jatamansi Jones (VJJ), a Chinese herbal medicine, has been identified to improve motor function recovery in rats with SCI. The study aimed to analyze the potential molecular mechanisms of action of VJJ in the treatment of SCI. The main ingredients of VJJ were obtained from the literature and the SwissADME platform was used to screen the active ingredients. The Swiss TargetPrediction platform was used to predict the targets of VJJ, and the targets of SCI were obtained from the GeneCards and OMIM databases. The intersecting genes were considered potential targets of VJJ in SCI. The protein-protein interaction network was constructed using the STRING database and the hub genes of VJJ for SCI treatment were screened according to their degree values. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed using the Metascape database. Cytoscape software was used to construct the "herb-ingredient-target-pathway" network. Preliminary validation was performed using molecular docking via Auto Dock Vina software. A total of 56 active ingredients of VJJ, mainly iridoids, were identified. There were 1493 GO items (P < .01) and 173 signaling pathways (P < .01) obtained from GO and Kyoto Encyclopedia of Genes and Genomes enrichment, including the phosphoinositide-3-kinase (PI3K)-protein kinase B (Akt) signaling pathway, hypoxia-inducible factor 1 signaling pathway, and tumor necrosis factor signaling pathway. Molecular docking revealed that 12 hub genes enriched in the PI3K/Akt signaling pathway had a high binding affinity for the active ingredient of VJJ. VJJ may exert its therapeutic effects on SCI through the iridoid fraction, acting on signal transducer and activator of transcription 3, CASP3, AKT1, tumor necrosis factor, mammalian target of rapamycin, interleukin 6, and other hub genes, which may be related to the PI3K/Akt signaling pathway.

Genetic susceptibility loci of lung cancer are associated with malignant risk of pulmonary nodules and improve malignancy diagnosis based on CEA levels.

Objective: The heightened prevalence of pulmonary nodules (PN) has escalated its significance as a public health concern. While the precise identification of high-risk PN carriers for malignancy remains an ongoing challenge, genetic variants hold potentials as determinants of disease susceptibility that can aid in diagnosis. Yet, current understanding of the genetic loci associated with malignant PN (MPN) risk is limited. Methods: A frequency-matched case-control study was performed, comprising 247 MPN cases and 412 benign NP (BNP) controls. We genotyped 11 established susceptibility loci for lung cancer in a Chinese cohort. Loci associated with MPN risk were utilized to compute a polygenic risk score (PRS). This PRS was subsequently incorporated into the diagnostic evaluation of MPNs, with emphasis on serum tumor biomarkers. Results: Loci rs10429489G>A, rs17038564A>G, and rs12265047A>G were identified as being associated with an increased risk of MPNs. The PRS, formulated from the cumulative risk effects of these loci, correlated with the malignant risk of PNs in a dose-dependent fashion. A high PRS was found to amplify the MPN risk by 156% in comparison to a low PRS [odds ratio (OR)=2.56, 95% confidence interval (95% CI), 1.40-4.67]. Notably, the PRS was observed to enhance the diagnostic accuracy of serum carcinoembryonic antigen (CEA) in distinguishing MPNs from BPNs, with diagnostic values rising from 0.716 to 0.861 across low- to high-PRS categories. Further bioinformatics investigations pinpointed rs10429489G>A as an expression quantitative trait locus. Conclusions: Loci rs10429489G>A, rs17038564A>G, and rs12265047A>G contribute to MPN risk and augment the diagnostic precision for MPNs based on serum CEA concentrations.

The role of EPAS1 polymorphisms on COPD susceptibility in southern Chinese.

Objective: COPD is the most common chronic respiratory disease with complex environmental and genetic etiologies. It was reported that EPAS1 might participate in the occurrence and development of respiratory diseases. However, the association between EPAS1 and COPD was unclear. Methods: First, a case-control study enrolling 1130 COPD patients and 1115 healthy controls in Guangzhou was conducted to clarify the association between EPAS1 polymorphisms and COPD susceptibility. Secondly, a prevalence study recruited 882 participants in Gansu to verify the effect of positive polymorphisms on lung function. Finally, the 10-year absolute risk considering environmental factors and genetic variations was calculated by the method of Gail and Bruzzi. Results: EPAS1 rs13419896 AA genotype reduced COPD risk in southern Chinese (AA vs. GG: adjusted OR = 0.689, 95% CI = 0.498-0.955; AA vs. GG/GA: adjusted OR = 0.701, 95% CI = 0.511-0.962). Further, the rs13419896 A allele was significantly associated with higher pre-FEV1/pre-FVC in both the Guangzhou and Gansu populations (P < 0.05). Smoking status, coal as fuels, education level, and rs13419896 G > A were finally retained to develop a relative risk model for males. Smoking status, biomass as fuels, and rs13419896 G > A were retained in the female model. The population-attributable risk of the male or female model was 0.457 (0.283-0.632) and 0.421 (0.227-0.616), respectively. Conclusions: This study first revealed that EPAS1 rs13419896 G > A decreased COPD susceptibility and could be a genetic marker to predict the 10-year absolute risk for COPD.

EPO rs1617640 A>C is a Protective Factor for Chronic Obstructive Pulmonary Disease: A Case Control Study.

BACKGROUND: The occurrence and development of chronic obstructive pulmonary disease (COPD) are regulated by environmental and genetic factors. In hypoxia, Erythropoietin (EPO) satisfies the body's need for oxygen by promoting the production of red blood cells. Hypoxia was proven to be a common physiological condition in COPD progression and associated with many complications. Some studies have found that EPO is involved in the development of COPD. But the mechanism has not been fully proven. METHODS: We conducted a case-control study enrolled 1095 COPD patients and 1144 healthy controls in Guangdong Province to evaluate the association between EPO polymorphisms (rs1617640 A>C, rs507392 A>G, rs564449 G>T) and COPD susceptibility. 872 participants from southern Gansu Province were recruited to verify the effect of EPO polymorphisms on lung function. RESULTS: EPO rs1617640 C allele reduced COPD susceptibility in southern Chinese significantly (AC vs. AA: adjusted Odds ratio (OR) = 0.805, 95% CI = 0.669-0.969; AC+CC vs. AA: adjusted OR = 0.822, 95% CI = 0.689-0.980). However, there was no association between rs507392 A>G and rs564449 G>T polymorphisms and COPD susceptibility (p > 0.05). We further observed that the rs1617640 C allele was associated with higher FEV1 and FVC in Guangdong and Gansu populations significantly (both p < 0.05). In brief, the level of FEV1 and FVC increased with the C allele number. We modeled the relative risk for men and women, in which the population-attributable risks chances were 0.449 (0.258-0.641) and 0.262 (0.128-0.396) respectively. In this model, smoking status, coal as fuels, education level, and rs1617640 A>C were finally retained for males, while smoking status, biomass as fuels, and1617640 A>C were retained for females. In the end, using the method developed by Gail and Bruzzi, we fitted a 10-year absolute risk model for southern Chinese with different individual relative risks, which was presented as a table. CONCLUSIONS: In conclusion, this study found that EPO rs1617640 A>C polymorphism is associated with COPD susceptibility in southern Chinese, and the C allele was associated with better lung function. In addition, it could also be considered a genetic marker associated with environmental factors to predict the absolute 10-year risk of COPD in southern Chinese.

An EMT-related genes signature as a prognostic biomarker for patients with endometrial cancer.

BACKGROUND: The epithelial-mesenchymal transition (EMT) plays an indispensable role in the development and progression of Endometrial cancer (EC). Nevertheless, little evidence is reported to uncover the functionality and application of EMT-related molecules in the prognosis of EC. This study aims to develop novel molecular markers for prognosis prediction in patients with EC. METHODS: RNA sequencing profiles of EC patients obtained from The Cancer Genome Atlas (TCGA) database were used to screen differential expression genes (DEGs) between tumors and normal tissues. The Cox regression model with the LASSO method was utilized to identify survival-related DEGs and to establish a prognostic signature whose performance was evaluated by Kaplan-Meier curve, receiver operating characteristic (ROC) and calibration curve. Eventually, functional enrichment analysis and cellular experiments were performed to reveal the roles of prognosis-related genes in EC progression. RESULTS: A total of 540 EMT-related DEGs in EC were screened, and subsequently a four-gene risk signature comprising SIRT2, SIX1, CDKN2A and PGR was established to predict overall survival of EC. This risk signature could serve as a meaningfully independent indicator for EC prognosis via multivariate Cox regression (HR = 2.002, 95%CI = 1.433-2.798; P < 0.001). The nomogram integrating the risk signature and clinical characteristics exhibited robust validity and performance at predicting EC overall survival indicated by ROC and calibration curve. Functional enrichment analysis revealed that the EMT-related genes risk signature was associated with extracellular matrix organization, mesenchymal development and cellular component morphogenesis, suggesting its possible relevance to epithelial-mesenchymal transition and cancer progression. Functionally, we demonstrated that the silencing of SIX1, SIRT2 and CDKN2A expression could accelerate the migratory and invasive capacities of tumor cells, whereas the downregulation of PGR dramatically inhibited cancer cells migration and invasion. CONCLUSIONS: Altogether, a novel four-EMT-related genes signature was a potential biomarker for EC prognosis. These findings might help to ameliorate the individualized prognostication and therapeutic treatment of EC patients.

A novel LINC00478 serves as a tumor suppressor in endometrial carcinoma progression.

BACKGROUND: Long noncoding RNAs (lncRNAs) are involved in the pathogenesis and progression of various cancers, but their roles in endometrial cancer (EC) are largely unknown. METHODS: The expressions of LINC00478 and PTBP1 in EC tissues were determined by RT-qPCR. Cell counting kit-8, flow cytometry and Transwell assays were executed for detecting the roles of LINC00478 in EC cells proliferation, migration and invasion. The mouse-xenograft models were established by subcutaneous injection in vivo. The interaction between LINC00478 and PTBP1 was confirmed by RNA pull-down assay and RNA-binding protein immunoprecipitation assay. RESULTS: LINC00478 was significantly down-regulated in EC tissues while compared to that in their paracancerous samples, and a higher expression level of LINC00478 was negatively correlated with clinical progress of EC patients. Functional experiments in vivo and in vitro revealed that LINC00478 overexpression could dramatically retard the proliferation of EC cells, decrease the rate of colony formation, suppress the migration and invasion abilities of EC cells in vitro and inhibit tumor growth in vivo. Mechanistically, LINC00478 regulated the expression of PTBP1, a key factor in the Warburg effect, and affected the metabolic process of EC cells. CONCLUSIONS: LINC00478 acts as a tumor suppressor in EC by negatively controlling PTBP1 expression and influencing the Warburg effect, providing a potential biomarker and therapeutic target for patients with EC.

LncRNA-Encoded Micropeptide ACLY-BP Drives Lipid Deposition and Cell Proliferation in Clear Cell Renal Cell Carcinoma via Maintenance of ACLY Acetylation.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of lethal kidney cancer. Reprogramming of fatty acid and glucose metabolism resulting in the accumulation of lipids and glycogen in the cytoplasm is a hallmark of ccRCC. Here, we identified a micropeptide ACLY-BP encoded by the GATA3-suppressed LINC00887, which regulated lipid metabolism and promoted cell proliferation and tumor growth in ccRCC. Mechanistically, the ACLY-BP stabilizes the ATP citrate lyase (ACLY) by maintaining ACLY acetylation and preventing ACLY from ubiquitylation and degradation, thereby leading to lipid deposition in ccRCC and promoting cell proliferation. Our results may offer a new clue for the therapeutic approaches and the diagnostic assessment for ccRCC. IMPLICATIONS: This study identifies ACLY-BP encoded by LINC00887 as a lipid-related micropeptide that stabilizes ACLY to generate acetyl-CoA, driving lipid deposition and promoting cell proliferation in ccRCC.

Changes in COVID-19 vaccine hesitancy at different times among residents in Guangzhou, China.

Background: Vaccination as a fundamental pillar of promoting public health and interest is critical to limiting the COVID-19 pandemic. However, many citizens are still hesitant about this epidemic prevention measure. This article aimed to understand the COVID-19 vaccination and hesitancy rates among Guangzhou residents at different points in time as well as to explore the relevant factors that cause vaccination hesitancy. Methods: We conducted a total of nine cross-sectional surveys by enrolling 12,977 questionnaires among Guangzhou residents through the online survey software called "WenJuanXing" between April 2021 and December 2022, and residents made their choices by judging their willingness to vaccinate. These surveys collected data on the participants' sociodemographic characteristics, vaccination status, vaccine hesitancy, and factors influencing this hesitancy. The Chi-squared test was used for univariate analysis and the multivariate logistic regression model was used to further adjust the influence of the confounding factors to evaluate the main factors affecting the hesitancy of the COVID-19 vaccine at different periods. Results: Over the course of 2021-2022, a total of 12,977 residents in the study area were surveyed. The vaccine hesitancy rates fluctuated over time. From April to June 2021, the vaccine hesitancy rate decreased from 30% to 9.1% and then increased to 13.7% in November. However, from April to December 2022, the hesitancy rate continued to rise from 13.4% to 30.4%. Vaccination rates, the epidemic waves of COVID-19, and changes in policies may all be possible factors that contributed to these fluctuations in vaccine hesitancy rates. We found statistically significant correlations between factors, such as residence, education, and occupation, and vaccine hesitancy at certain points of time. The results of the surveys in April and June 2021 showed that rural residents showed higher vaccine hesitancy rate than urban residents. Their lower education level was associated with higher vaccine hesitancy. Workers and farmers are more likely to have vaccine hesitancy than people with other occupations. The univariate analysis showed that people with underlying medical conditions and lower perceived health status were more likely to experience vaccine hesitation. Logistic regression analysis revealed that the health status of individuals is the most important factor leading to vaccine hesitancy, and residents' underestimation of domestic risks and overconfidence in personal protection measures were also contributing factors. At different stages, vaccine hesitancy among residents was related to vaccine side effects, safety and efficacy, convenience fluctuation, and various factors. Conclusion: In the present study, we found that vaccine hesitancy did not display a consistent downward trend but it fluctuated over time. Higher education, residing in urban areas, lower perceived disease risk, and concerns about the vaccine's safety and side effects were risk factors for vaccine hesitancy. Implementing appropriate interventions and educational programs tailored to address these risk factors may prove to be effective in enhancing public confidence on vaccination.

EIF4a3-regulated circRABL2B regulates cell stemness and drug sensitivity of lung cancer via YBX1-dependent downregulation of MUC5AC expression.

Identification of mucin modulators is of remarkable significance to facilitate mucin-based antineoplastic therapy. However, little is known about circular RNAs (circRNAs) on regulating mucins. Dysregulated mucins and circRNAs were identified via high-throughput sequencing and their relationships with lung cancer survival were analyzed in tumor samples of 141 patients. The biological functions of circRABL2B were determined via gain- and loss-of-function experiments and exosome-packaged circRABL2B treatment in cells, patient-derived lung cancer organoids and nude mice. We identified that circRABL2B was negatively correlated with MUC5AC. Patients with low circRABL2B and high MUC5AC displayed the poorest survival (HR=2.00; 95% CI=1.12-3.57). Overexpressed circRABL2B significantly inhibited cell malignant phenotypes, while it knock-down exerted opposite effects. CircRABL2B interacted with YBX1 to inhibit MUC5AC, and subsequently suppressed integrin ß4/pSrc/p53 signaling and impoverished cell stemness, and promoted erlotinib sensitivity. Exosome-packaged circRABL2B exerted significant anti-cancer actions in cells, patient-derived lung cancer organoids and nude mice. Meanwhile, circRABL2B in plasma exosomes could distinguish early-stage lung cancer patients from healthy controls. Finally, we found circRABL2B was downregulated at the transcriptional level, and EIF4a3 involved the formation of circRABL2B. In conclusion, our data suggest that circRABL2B counteracts lung cancer progression via MUC5AC/integrin ß4/pSrc/p53 axis, which provides a rationale to enhance the efficacy of anti-MUCs treatment in lung cancer.

Probiotic intervention benefits multiple neural behaviors in older adults with mild cognitive impairment.

Probiotic supplements were shown to improve cognitive function in Alzheimer's disease (AD) patients. However, it is still unclear whether this applies to older individuals with mild cognitive impairment (MCI). We aimed to explore the effects of probiotic supplementation on multiple neural behaviors in older adults with MCI. Forty-two MCI patients (age > 60 years) were randomly divided into two groups and consumed either probiotics (n=21) or placebo (n=21) for 12 weeks. Various scale scores, gut microbiota measures and serological indicators were recorded pre- and posttreatment. After 12 weeks of intervention, cognitive function and sleep quality were improved in the probiotic group compared with those in the control group, and the underlying mechanisms were associated with changes in the intestinal microbiota. In conclusion, our study demonstrated that probiotic treatment enhanced cognitive function and sleep quality in older MCI patients, thus providing important insights into the clinical prevention and treatment of MCI.

Development and validation of nomogram including high altitude as a risk factor for COPD: A cross-sectional study based on Gansu population.

Background: Chronic Obstructive Pulmonary Disease (COPD) is a common and harmful disease that requires an effective tool to early screen high-risk individuals. Gansu has unique environments and customs, leading to the different prevalence and etiology of COPD from other regions. The association between altitude and COPD once attracted epidemiologists' attention. However, the prevalence in Gansu and the role of altitude are still unclarified. Methods: In Gansu, a multistage stratified cluster sampling procedure was utilized to select a representative sample aged 40 years or older. The questionnaire and spirometry examination were implemented to collect participants' information. The diagnosis and assessment of COPD were identified by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criterion, while post-bronchodilator FEV1/FVC < LLN was for sensitivity analysis. Furthermore, the effect of high altitude on COPD was evaluated by the logistic regression model after propensity score matching (PSM). Finally, the participants were randomly divided into training and validation sets. The training set was used to screen the relative factors and construct a nomogram which was further assessed by the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) in the two sets. Results: There were 2,486 eligible participants in the final analysis, of which 1,584 lived in low altitudes and 902 lived in high altitudes. Based on the GOLD criterion, the crude and standardized prevalences in Gansu were 20.4% (18.7-22.0) and 19.7% (17.9-21.6). After PSM, the logistic regression model indicated that high altitude increased COPD risk [PSM OR: 1.516 (1.162-1.978)]. Altitude, age, sex, history of tuberculosis, coal as fuel, and smoking status were reserved for developing a nomogram that demonstrated excellent discrimination, calibration, and clinical benefit in the two sets. Conclusions: COPD has become a serious public health problem in Gansu. High altitude is a risk factor for COPD. The nomogram has satisfactory efficiency in screening high-risk individuals.

Sensory-Guided Identification and Characterization of Kokumi-Tasting Compounds in Green Tea (Camellia sinensis L.).

The chemical substances responsible for the kokumi taste of green tea infusion are still unclear. Here, we isolated the kokumi compound-containing fractions from green tea infusion through ultrafiltration, and the major kokumi compounds were characterized as γ-Glu-Gln and γ-Glu-Cys-Gly (GSH) through ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS). The results indicated that peptides and amino acids were essential compounds in the kokumi-enriched fractions for conducting the sense of kokumi. L-theanine had an enhancing effect on the kokumi taste of green tea infusion, which was confirmed in the sensory reconstitution study. Thus, peptides, especially γ-Glu-Gln and GSH, are the major kokumi compounds in green tea infusion, which has the potential of improving the flavor of tea beverages.

Joint effects of polycyclic aromatic hydrocarbons, smoking, and XPC polymorphisms on damage in exon 2 of KRAS gene among young coke oven workers.

Genetic polymorphisms may contribute to individual susceptibility to DNA damage induced by environmental exposure. In this study, we evaluate the effects of co-exposure to PAHs, smoking and XPC polymorphisms, alone or combined, on damage in exons. A total of 288 healthy male coke oven workers were enrolled into this study, and urinary 1-hydroxypyrene (1-OH-Pyr) was detected. Base modification in exons of KRAS and BRAF gene, and polymorphisms of XPC were determined in plasma by real-time PCR. We observed 1-OH-Pyr was positively related to damage in exon 2 of KRAS (KRAS-2) and in exon 15 of BRAF (BRAF-15), respectively, and KRAS-2 and BRAF-15 were significantly associated with increased 1-OH-Pyr. A stratified analysis found 1-OH-Pyr was significantly associated with KRAS-2 in both smokers and non-smokers, while 1-OH-Pyr was significantly associated with BRAF-15 only in smokers. Additionally, individuals carrying both rs2228001 G-allele (GG+GT) and rs3731055 GG homozygote (GG) genotype appeared to have more significant effect on KRAS-2. The high levels of 1-OH-Pyr were associated with KRAS-2 only in rs2228001 GG+GT genotype carriers and the high levels of 1-OH-Pyr were associated with KRAS-2 only in rs3731055 GG genotype carriers and the most severe KRAS-2 was observed among subjects carrying all four of the above risk factors. Our findings indicated the co-exposure effect of PAHs and smoking could increase the risk of KRAS-2 by a mechanism partly involving XPC polymorphisms.

Long non-coding RNA LSAMP-1 is down-regulated in non-small cell lung cancer and predicts a poor prognosis.

BACKGROUND: Long noncoding RNAs (lncRNAs) are emerging as master regulators for gene expression and thus play a vital role in human tumorigenesis and progression. But the involvement of novel lncRNAs in non-small cell lung cancer (NSCLC) remains largely unelucidated. METHODS: A total of 170 NSCLC and their adjacent non-tumor tissues were enrolled to detect the expression of Lnc-LSAMP-1 by RT-qPCR. The effects of Lnc-LSAMP-1 on cell proliferation, migration, invasion and drug-sensitivity were determined by in vitro and in vivo experiments. The proteins that interact with Lnc-LSAMP-1were confirmed by RNA pull-down assay. RNA-sequencing were used to identify the potential targets of Lnc-LSAMP-1 in NSCLC. RESULTS: We found that Lnc-LSAMP-1 was significantly down-regulated in 170 cases of NSCLC tissues when compared to their adjacent non-cancerous tissues. Loss expression of Lnc-LSAMP-1 was notably correlated with unfavorable prognosis of NSCLC patients. The ectopic expression of Lnc-LSAMP-1 drastically inhibited lung cancer cell proliferation, viability, invasion and migration ability, arrested cell cycle and facilitated apoptosis. Chemotherapy sensitization experiments showed that over-expressed Lnc-LSAMP-1 enhanced the inhibition of cell proliferation induced by TKI. Mechanistically, Lnc-LSAMP-1-LSAMP formed a complex which could protect the degradation of LSAMP gene, and thus exerted crucial roles in NSCLC progression and TKI targeted treatment. CONCLUSIONS: Consequently, our findings highlight the function and prognostic value of Lnc-LSAMP-1 in NSCLC and provide potential novel therapeutic targets and prognostic biomarkers for patients with NSCLC.

Salt-inducible kinases inhibitor HG-9-91-01 targets RIPK3 kinase activity to alleviate necroptosis-mediated inflammatory injury.

Receptor-interacting protein kinase 3 (RIPK3) functions as a central regulator of necroptosis, mediating signaling transduction to activate pseudokinase mixed lineage kinase domain-like protein (MLKL) phosphorylation. Increasing evidences show that RIPK3 contributes to the pathologies of inflammatory diseases including multiple sclerosis, infection and colitis. Here, we identified a novel small molecular compound Salt-inducible Kinases (SIKs) inhibitor HG-9-91-01 inhibiting necroptosis by targeting RIPK3 kinase activity. We found that SIKs inhibitor HG-9-91-01 could block TNF- or Toll-like receptors (TLRs)-mediated necroptosis independent of SIKs. We revealed that HG-9-91-01 dramatically decreased cellular activation of RIPK3 and MLKL. Meanwhile, HG-9-91-01 inhibited the association of RIPK3 with MLKL and oligomerization of downstream MLKL. Interestingly, we found that HG-9-91-01 also trigger RIPK3-RIPK1-caspase 1-caspase 8-dependent apoptosis, which activated cleavage of GSDME leading to its dependent pyroptosis. Mechanistic studies revealed that SIKs inhibitor HG-9-91-01 directly inhibited RIPK3 kinase activity to block necroptosis and interacted with RIPK3 and recruited RIPK1 to activate caspases leading to cleave GSDME. Importantly, mice pretreated with HG-9-91-01 showed resistance to TNF-induced systemic inflammatory response syndrome. Consistently, HG-9-91-01 treatment protected mice against Staphylococcus aureus-mediated lung damage through targeting RIPK3 kinase activity. Overall, our results revealed that SIKs inhibitor HG-9-91-01 is a novel inhibitor of RIPK3 kinase and a potential therapeutic target for the treatment of necroptosis-mediated inflammatory diseases.