Nonlinear dose-response association of moderate-to-vigorous physical activity with hyperuricemia in US adults: NHANES 2007-2018.

BACKGROUND: The relationship between physical activity and hyperuricemia (HUA) remains inconsistent, and the dose-response association between moderate-to- vigorous physical activity (MVPA) level and HUA still unclear. In this study, we aimed to investigate the dose-response association of MVPA with HUA, and to explore an appropriate range of MVPA level for preventing HUA. METHODS: Data from the US National Health and Nutrition Examination Survey (NHANES) 2007-2018 were used, including 28740 non-gout adult Americans. MVPA level was self-reported using the Global Physical Activity Questionnaire and serum uric acid was measured using timed endpoint method. The dose-response relationship between MVPA level and HUA was modeled with restricted cubic spline analysis. Logistic regression analysis were applied to estimate odd ratios (ORs) and 95% confidence intervals (CIs) of the relationships between MVPA level and HUA. RESULTS: A total of 28740 adults were included in the study (weighted mean age, 47.3 years; 46.5% men), with a prevalence rate of HUA was 17.6%. The restricted cubic spline functions depicted a general U-shaped relationship between MVPA level and HUA. The MVPA level of 933 and 3423 metabolic equivalent (MET) -min/wk were the cut-off discriminating for the risk of HUA. Participants with MVPA levels in the range of 933-3423 MET-min/wk had lower risk of HUA and they had the lowest risk when MVPA levels at around 1556 MET-min/wk. Compared with the moderate-activity group (600-2999 Met-min/wk), the low-activity group (< 600 Met-min/wk) had a greater risk of HUA (OR, 1.13 [95%CI, 1.02-1.26]) after fully adjusting for potential confounders. CONCLUSIONS: Compared with the moderate MVPA level, the low MVPA level was associated with the higher risk of HUA. And there may be a U-shaped dose-response relationship between MVPA level and HUA. When MVPA level was approximately 933-3423 MET-min/wk, the risk of HUA may at a lower level and the risk reached the lowest when MVPA level at around 1556 MET-min/wk.

The genetic susceptibility analysis of TAAR1 rs8192620 to methamphetamine and heroin abuse and its role in impulsivity.

Abnormal genetic polymorphism of trace amine-associated receptor 1 (TAAR1) rs8192620 site has been confirmed to induce methamphetamine (MA) use and drug craving. However, the genetic susceptibility difference between MA addicts and heroin addicts is unknown. This study evaluated genetic heterogeneity of TAAR1 rs8192620 between MA and heroin addicts and elucidated whether rs8192620 genotypes associated with discrepancy in emotional impulsivity, which would help to instruct individualized treatment in addiction via acting on TAAR1 and evaluate risk of varied drug addiction. Participants consisting of gender-matched 63 MA and 71 heroin abusers were enrolled in the study. Due to mixed drug usage in some MA addicts, MA users were further subdivided into 41 only-MA (only MA taking) and 22 mixed-drug (Magu composed of about 20% MA and 70% caffeine) abusers. Via inter-individual single nucleotide polymorphism (SNP) analysis and two-sample t tests, respectively, the genotypic and Barratt Impulsiveness Scale-11 (BIS-11) scores differences between groups were completed. With following genotypic stratification, the differences in BIS-11 scores between groups were analyzed through two-sample t test. Individual SNP analysis showed significant differences in alleles distribution of rs8192620 between MA and heroin subjects (p = 0.019), even after Bonferroni correction. The TT homozygotes of rs8192620 dominated in MA participants, while C-containing genotypes in heroin (p = 0.026). There was no association of genotypes of TAAR1 rs8192620 with addicts' impulsivity. Our research indicates that the TAAR1 gene polymorphism might mediate the susceptibility discrepancy between MA and heroin abuse.

Extracellular vesicles from adipose stem cells ameliorate allergic rhinitis in mice by immunomodulatory.

Background: Human adipose tissue-derived stem cells (hADSCs) exert potent immunosuppressive effects in the allogeneic transplantation treatment. In mouse model of allergic rhinitis (AR), ADSCs partially ameliorated AR. However, no study has evaluated the potential therapeutic effects of hADSC-derived extracellular vesicles (hADSC-EVs) on AR. Methods: Female BALB/c mice were sensitized and challenged with ovalbumin (OVA) to induce AR. One day after the last nasal drop, each group received phosphate buffered saline (PBS) or hADSC-EVs treatment. Associated symptoms and biological changes were then assessed. Results: hADSC-EV treatment significantly alleviated nasal symptoms, and reduced inflammatory infiltration. Serum levels of OVA-specific IgE, interleukin (IL)-4 and interferon (IFN)-γ were all significantly reduced. The mRNA levels of IL-4 and IFN-γ in the spleen also changed accordingly. The T helper (Th)1/Th2 cell ratio increased. The treatment efficacy index of hADSC-EV was higher than that of all human-derived MSCs in published reports on MSC treatment of AR. ADSC-EVs exhibited a greater therapeutic index in most measures when compared to our previous treatment involving ADSCs. Conclusion: These results demonstrated that hADSC-EVs could ameliorate the symptoms of AR by modulating cytokine secretion and Th1/Th2 cell balance. hADSC-EVs could potentially be a viable therapeutic strategy for AR. Further animal studies are needed to elucidate the underlying mechanisms and to optimize potential clinical protocols.

MIR938 rs2505901 T>C polymorphism is associated with increased neuroblastoma risk in Chinese children.

Neuroblastoma (NB) is a kind of childhood cancer that is a prevailing and deadly solid neoplasm among pediatric malignancies. The transcriptional output of MIR938 is capable of participating in the posttranscriptional modulation of gene expression, whereby it exerts its regulatory effect by modulating both the stability and translation of target mRNAs. Previous studies showed that MIR938 was associated with many cancers. Hence, functional genetic variants in the MIR938 can be attributed to NB risk. We recruited 402 neuroblastoma patients and 473 controls from the Children's Hospital of Nanjing Medical University and genotyped one MIR938 single-nucleotide polymorphism (SNP) (rs2505901 T>C). There were significant associations between the rs2505901 T>C and NB risk [CC vs. TT: adjusted odds ratio (OR) = 1.90, 95% confidence interval (CI) = 1.02-3.55, P=0.045; CC vs. TT/TC: adjusted OR = 2.02, 95% CI = 1.09-3.75, P=0.026]. This analysis of genotypes revealed that T>C increased the risk of NB. Some borderline significant different relationships were observed in the stratified analyses: age ≤ 18 months (adjusted OR = 2.95, 95% CI = 0.92-9.51, P=0.070), male sex (adjusted OR = 2.19, 95% CI = 0.95-5.08, P=0.067), and clinical stage III+IV (adjusted OR = 2.12, 95% CI = 0.98-4.56, P=0.055). The present study revealed that the MIR938 rs2505901 T>C polymorphism may be a potential risk factor for neuroblastoma in Chinese children. In the long term, conducting large and diverse sample studies from different ethnicities will indeed be crucial in determining the role of MIR938 polymorphisms in NB risk. By including individuals from various ethnic backgrounds, researchers can account for potential genetic variations that may exist between populations.

Association Between the XRCC1, GSTM1, and GSTT1 Polymorphisms in Model of Thyroid Cancer: A Meta-Analysis.

Thyroid cancer is the most common malignant tumor of the endocrine system, and its incidence is increasing worldwide each year. This study aimed to explore the association between XRCC1, GSTM1, and GSTT1 polymorphisms in the model of thyroid cancer. The experiment was conducted by searching PubMed, Embase, and Web of Science, with the last search performed in March 2022. A total of 12 studies were included in this meta-analysis, with sample sizes ranging from 211 to 1124. The proportion of XRCC1 polymorphisms (rs25489, GG) in thyroid cancer was slightly lower than that of the normal control group, but the difference was not statistically significant (Mean difference=1.13, 95% CI: 0.99-1.28, p=0.08). The proportion of XRCC1 polymorphisms (rs25489, GA) in thyroid cancer was significantly lower than that of the normal control group (Mean difference=1.32, 95% CI: 1.16-1.52, p<0.00001). The proportion of XRCC1 polymorphisms (rs25489, AA) in thyroid cancer was slightly lower than that of the normal control group, but again, the difference was not statistically significant (Mean difference=0.78, 95% CI: 0.61-1.01, p=0.06). Similarly, the proportion of XRCC1 polymorphisms (rs25487, GG) and (rs25487, GA) in thyroid cancer was lower than that of the normal control group, but the differences were not statistically significant (p=0.22 and p=0.49, respectively). In conclusion, this study found that the proportion of XRCC1 polymorphisms (rs25489, AA) in thyroid cancer was lower than that of the normal control group.

Targeting LncRNA LLNLR-299G3.1 with antisense oligonucleotide inhibits malignancy of esophageal squamous cell carcinoma cells in vitro and in vivo.

Accumulating evidence has indicated that long non-coding RNAs (lncRNAs) play critical roles in the development and progression of cancers, including esophageal squamous cell carcinoma (ESCC). However, the mechanisms of lncRNAs in ESCC are still incompletely understood and therapeutic attempts for in vivo targeting cancer-associated lncRNA remain a challenge. By RNA-sequencing analysis, we identified that LLNLR-299G3.1 was a novel ESCC-associated lncRNA. LLNLR-299G3.1 was up-regulated in ESCC tissues and cells and promoted ESCC cell proliferation and invasion. Silencing of LLNLR-299G3.1 with ASO (antisense oligonucleotide) resulted in opposite effects. Mechanistically, LLNLR-299G3.1 bound to cancer-associated RNA binding proteins and regulated the expression of cancer-related genes, including OSM, TNFRSF4, HRH3, and SSTR3. ChIRP-seq (chromatin isolation by RNA purification and sequencing) revealed that these genes contained enriched chromatin binding sites for LLNLR-299G3.1. Rescue experiments confirmed that the effects of LLNLR-299G3.1 on ESCC cell proliferation were dependent on interaction with HRH3 and TNFRSF4. Therapeutically, intravenous delivery of placental chondroitin sulfate A binding peptide-coated nanoparticles containing antisense oligonucleotide (pICSA-BP-ANPs) strongly inhibited ESCC tumor growth and significantly improved animal survival in vivo. Overall, our results suggest that LLNLR-299G3.1 promotes ESCC malignancy through regulating gene-chromatin interactions and targeting ESCC by pICSA-BP-ANPs may be an effective strategy for the treatment of lncRNA-associated ESCC.

The association of periodontal disease and oral health with hypertension, NHANES 2009-2018.

BACKGROUND: Hypertension is a worldwide public health problem. We sought to explore the interaction of oral health and smoking on hypertension, and periodontal disease and smoking on hypertension. METHODS: We included 21,800 participants aged ≧ 30 years from the National Health and Nutrition Examination Survey (NHANES) 2009-2018. Information of oral health and periodontal disease were self-reported. Blood pressure was taken by trained personnel and/or physicians at mobile testing center. Multiple logistic regression was used to estimate the association between oral health, periodontal disease and the prevalence of hypertension. The effects of oral health and periodontal disease on hypertension under smoking status and age were analyzed by stratified and interaction analysis. RESULTS: A total of 21,800 participants were investigated, including 11,017 (50.54%) in hypertensive group and 10,783 (49.46%) in non-hypertensive group. Compared with the excellent/very good of oral health, the multivariable-adjusted OR of good, fair, and poor were 1.13 (95% CI, 1.02-1.27), 1.30 (95% CI, 1.15-1.47), and 1.48 (95% CI, 1.22-1.79) (p for trend < 0.001) for hypertension, respectively. Compared without periodontal disease group, the multivariable-adjusted OR of periodontal disease for hypertension was 1.21 (95% CI ,1.09-1.35) (p for trend < 0.001). Furthermore, we found the interactions between periodontal disease and smoking, oral health and smoking, periodontal disease and age, oral health and age were p < 0.001. CONCLUSIONS: An association between oral health and periodontal disease with the prevalence of hypertension was identified. There exists interactive effect of periodontal disease and smoking, oral health and smoking, periodontal disease and age, oral health and age on hypertension in American population over 30 years of age and older.

T cell-mediated tumor killing patterns in head and neck squamous cell carcinoma identify novel molecular subtypes, with prognosis and therapeutic implications.

As an important process in cancer immunotherapy, T cell-mediated tumor killing (TTK) enhances the immune response of patients. However, the role of TTK in Head and Neck Squamous Cell Carcinoma (HNSCC) patients still needs further exploration. Therefore, we comprehensively analyzed the gene expression information and clinical characteristics of 1063 HNSCC in five cohorts. Univariate regression, differential expression analysis, and gene mutation profiling were combined to identify the important genes regulating the sensitivity of tumor cells to T cell-mediated killing (GSTTK) in HNSCC. A total of 20 GSTTK were identified as important genes of HNSCC. Patients were divided into C1 and C2 subgroups (TTK patterns) and displayed significant prognostic differences. Patients with C2 subtype had dismal prognosis characteristic compared to C1 subtype in all validation cohorts. Patients with C1 subgroup exhibited robust immune profile and C1 subgroup patients were significantly enriched in metabolically relevant functions. Notably, the multi-omics analysis found that C1 subgroup have higher mutation burden and C2 subgroup patients had significantly higher copy number variation. Drug sensitivity analysis found that multiple first-line chemotherapeutic drugs were more sensitive in patients with subgroup C1. In conclusion, the establishment of GSTTK provides guidance and assistance to clinicians in the personalized management and treatment of HNSCC patients.

Adipose-derived stem cells promote the repair of chemotherapy-induced premature ovarian failure by inhibiting granulosa cells apoptosis and senescence.

BACKGROUND: Chemotherapeutic drugs, particularly alkylating cytotoxics such as cyclophosphamide (CTX), play an important role to induce premature ovarian failure (POF). Hormone replacement therapy (HRT) is a widely used treatment to improve hormone secretion. However, the long-term HRT increases the risk of breast cancer and cardiovascular disease are attracting concerns. Therefore, there is an urgent need to develop a safe and effective treatment for POF. METHOD: Adipose-derived stem cells (ADSCs) were isolated and identified from human adipose tissue. For POF modeling, CTX were intraperitoneal injected into CTX-acute group, CTX-chronic group, CTX-acute + ADSCs group and CTX-chronic + ADSCs group rats; For transplantation, ADSCs were transplanted into POF rats through tail-vein. The control group rats were injected with PBS. The effects of POF modeling and transplantation were determined by estrous cycle analysis, histopathological analysis, immunohistochemical staining and apoptosis-related marker. To evaluate the effects of ADSC on granulosa cells in vitro, CTX-induced senescent KGN cells were co-cultured with ADSCs, and senescent-related marker expression was investigated by immunofluorescent staining. RESULTS: In vivo studies revealed that ADSCs transplantation reduced the apoptosis of ovarian granulosa cells and secretion of follicle-stimulating hormone. The number of total follicles, primordial follicles, primary follicles, and mature follicles and secretion of anti-Müllerian hormone and estradiol (E2) were also increased by ADSCs. The estrous cycle was also improved by ADSC transplantation. Histopathological analysis showed that CTX-damaged ovarian microenvironment was improved by ADSCs. Furthermore, TUNEL staining indicated that apoptosis of granulosa cells was decreased by ADSCs. In vitro assay also demonstrated that ADSC markedly attenuated CTX-induced senescence and apoptosis of granulosa cell. Mechanistically, both in vivo and in vitro experiments proved that ADSC transplantation suppressed activation of the PI3K/Akt/mTOR axis. CONCLUSION: Our experiment demonstrated that a single injection of high-dose CTX was a less damaging chemotherapeutic strategy than continuous injection of low-dose CTX, and tail-vein injection of ADSCs was a potential approach to promote the restoration of CTX-induced POF.

Brain recovery of the NAc fibers and prediction of craving changes in person with heroin addiction: A longitudinal study.

BACKGROUND: Progress have been made in brain function recovery after long-term abstinence in person with heroin addiction (PHA). However, less is known about whether the nucleus accumbens (NAc) white matter pathways can recover in PHA by prolonged abstinence. METHODS: Forty-two PHA and Thirty-nine age- and gender- matched healthy controls (HCs) were recruited. Two MRI scans were obtained at baseline (PHA1) and 8-month follow-up (PHA2). We employed tractography atlas-based analysis (TABS) method to investigate fractional anisotropy (FA) changes in NAc fiber tracts (i.e., Insula-NAc, ventral tegmental area (VTA)-NAc, medial prefrontal cortex (MPFC)-NAc) in PHA. A partial least square regression (PLSR) analysis was carried to explore whether FA of NAc fiber tracts can predict longitudinal craving changes. RESULTS: Relative to HCs, lower FA was found in the right Insula-NAc and VTA-NAc fiber tracts in PHA1, and PHA2 showed increased FA values in these tracts compared with PHA1. Furthermore, changes of FA of NAc fiber tracts can predict longitudinal craving changes (r = 0.51). Additionally, craving changes can also be predicted from FA changes in the left Insula-NAc (r = 0.601) and VTA-NAc (r = 0.384) fiber alone. CONCLUSIONS: Results indicated that the right Insula-NAc and VTA-NAc fiber tracts are potential biomarkers for brain recovery. Prediction of craving changes highlighted the utility of structural markers to inform clinical decision-making of treatment for PHA.

Glioma stem cells and neural stem cells respond differently to BMP4 signaling.

Malignant glioma is a highly heterogeneous and invasive primary brain tumor characterized by high recurrence rates, resistance to combined therapy, and dismal prognosis. Glioma stem cells (GSCs) are likely responsible for tumor progression, resistance to therapy, recurrence, and poor prognosis owing to their high self-renewal and tumorigenic potential. As a family member of BMP signaling, bone morphogenetic protein4 (BMP4) has been reported to induce the differentiation of GSCs and neural stem cells (NSCs). However, the molecular mechanisms underlying the BMP4-mediated effects in these two cell types are unclear. In this study, we treated hGSCs and hNSCs with BMP4 and compared the phenotypic and transcriptional changes between these two cell types. Phenotypically, we found that the growth of hGSCs was greatly inhibited by BMP4, but the same treatment only increased the cell size of hNSCs. While the RNA sequencing results showed that BMP4 treatment evoked significantly transcriptional changes in both hGSCs and hNSCs, the profiles of differentially expressed genes were distinct between the two groups. A gene set that specifically targeted the proliferation and differentiation of hGSCs but not hNSCs was enriched and then validated in hGSC culture. Our results suggested that hGSCs and hNSCs responded differently to BMP4 stimulation. Understanding and investigating different responses between hGSCs and hNSCs will benefit finding partner factors working together with BMP4 to further suppress GSCs proliferation and stemness without disturbing NSCs.

Partial recovery of the left DLPFC-right insula circuit with reduced craving in abstinent heroin users: a longitudinal study.

The phenomenon of brain recovery after long-term abstinence has been reported in substance use disorders. However, few longitudinal studies have been conducted to observe the potential recovery in heroin users, and little is known about the neural mechanism underlying the decreased craving after prolonged abstinence. The 8-month longitudinal study was carried out in 29 heroin users and 30 healthy controls. By choosing the L_DLPFC, which was activated by the heroin cue as the seeding region, different brain connection patterns were compared between healthy controls and heroin users by using Granger causality analysis (GCA) at baseline. Then, a paired t test was employed to detect the potential recovery of L_DLPFC circuits after prolonged abstinence. The visual analog scale (VAS) and trail-making test-A (TMT-A) were adopted to investigate craving and cognitive control impairment, respectively. The neuroimaging changes were then correlated with behavioral improvements. Similar analyses were applied for the mirrored right DLPFC to verify the lateralization hypothesis of the DLPFC in addiction. In the longitudinal study, enhanced GCA coefficients were observed in the L_DLPFC-R_insula circuit of heroin users after long-term abstinence and were associated with craving score changes. At baseline, decreased GCA coefficients from the left DLPFC to the bilateral SMA and right putamen, together with the reduced GCA strength from the bilateral OFC to the left DLPFC, were found between HUs and HCs. Our findings extended the brain recovery phenomenon into the field of heroin and suggested that the increased regulation of the L_DLPFC over the insula after prolonged abstinence was important for craving inhibition.

A novel necroptosis-related LncRNA signature for prediction of prognosis and therapeutic responses of head and neck squamous cell carcinoma.

Background: Long non-coding RNAs (lncRNAs) play an essential role in the occurrence and prognosis of tumors, and it has great potential as biomarkers of tumors. However, the roles of Necroptosis-related lncRNA (NRLs) in Head and neck squamous cell carcinoma (HNSCC) remain elusive. Methods: We comprehensively analyzed the gene expression and clinical information of 964 HNSCC in four cohorts. LASSO regression was utilized to construct a necroptosis-related lncRNA prognosis signature (NLPS). We used univariate and multivariate regression to assess the independent prognostic value of NLPS. Based on the optimal cut-off, patients were divided into high- and low-risk groups. In addition, the immune profile, multi-omics alteration, and pharmacological landscape of NLPS were further revealed. Results: A total of 21 NRLs associated with survival were identified by univariate regression in four cohorts. We constructed and validated a best prognostic model (NLPS). Compared to the low-risk group, patients in the high group demonstrated a more dismal prognosis. After adjusting for clinical features by multivariate analysis, NLPS still displayed independent prognostic value. Additionally, further analysis found that patients in the low-risk group showed more abundant immune cell infiltration and immunotherapy response. In contrast, patients in the high-risk group were more sensitive to multiple chemotherapeutic agents. Conclusion: As a promising tool, the establishment of NLPS provides guidance and assistance in the clinical management and personalized treatment of HNSCC.

Potential brain recovery of frontostriatal circuits in heroin users after prolonged abstinence: A preliminary study.

Neuroscientists have devoted efforts to explore potential brain recovery after prolonged abstinence in heroin users (HU). However, not much is known about whether frontostriatal circuits can recover after prolonged abstinence in HU. An eight-month longitudinal study was carried out for HU. Two MRI scans were obtained at baseline (HU1) and 8-month follow-up (HU2). The functional and structural connectivities of dorsal and ventral frontostriatal pathways were measured by resting-state functional connectivity (RSFC) and diffusion tensor imaging (DTI). Correlation analyses were employed to reveal the associations between neuroimaging and behavioral changes. Results suggested that relative to healthy controls (HCs), HU1 showed lower fractional anisotropy (FA) in the right dorsolateral prefrontal cortex (DLPFC)-to-caudate tracts and medial orbitofrontal cortex (mOFC)-to-nucleus accumbens (NAc) tracts as well as decreased RSFC in the left mOFC-NAc circuits. Longitudinal results revealed reduced craving and enhanced cognitive control in HU2 compared with HU1. After prolonged abstinence, HU2 showed increased FA values in the right DLPFC-caudate and mOFC-NAc tracts as well as increased RSFC strength in the bilateral mOFC-NAc circuits compared with HU1. In addition, changes in RSFC and FA values in the right mOFC-NAc circuit were negatively correlated with craving score changes. Similarly, negative correlations were also found between changes of RSFC in the bilateral DLPFC-caudate circuits and TMT-A scores. We provided scientific evidence for brain recovery of the dorsal and ventral frontostriatal circuits in HU after prolonged abstinence, and these circuits may be potential neuroimaging biomarkers for cognition and craving changes.

PM2.5 promotes NSCLC carcinogenesis through translationally and transcriptionally activating DLAT-mediated glycolysis reprograming.

BACKGROUND: Airborne fine particulate matter (PM2.5) has been associated with lung cancer development and progression in never smokers. However, the molecular mechanisms underlying PM2.5-induced lung cancer remain largely unknown. The aim of this study was to explore the mechanisms by which PM2.5 regulated the carcinogenesis of non-small cell lung cancer (NSCLC). METHODS: Paralleled ribosome sequencing (Ribo-seq) and RNA sequencing (RNA-seq) were performed to identify PM2.5-associated genes for further study. Quantitative real time-PCR (qRT-PCR), Western blot, and immunohistochemistry (IHC) were used to determine mRNA and protein expression levels in tissues and cells. The biological roles of PM2.5 and PM2.5-dysregulated gene were assessed by gain- and loss-of-function experiments, biochemical analyses, and Seahorse XF glycolysis stress assays. Human tissue microarray analysis and 18F-FDG PET/CT scans in patients with NSCLC were used to verify the experimental findings. Polysome fractionation experiments, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assay were implemented to explore the molecular mechanisms. RESULTS: We found that PM2.5 induced a translation shift towards glycolysis pathway genes and increased glycolysis metabolism, as evidenced by increased L-lactate and pyruvate concentrations or higher extracellular acidification rate (ECAR) in vitro and in vivo. Particularly, PM2.5 enhanced the expression of glycolytic gene DLAT, which promoted glycolysis but suppressed acetyl-CoA production and enhanced the malignancy of NSCLC cells. Clinically, high expression of DLAT was positively associated with tumor size, poorer prognosis, and SUVmax values of 18F-FDG-PET/CT scans in patients with NSCLC. Mechanistically, PM2.5 activated eIF4E, consequently up-regulating the expression level of DLAT in polysomes. PM2.5 also stimulated transcription factor Sp1, which further augmented transcription activity of DLAT promoter. CONCLUSIONS: This study demonstrated that PM2.5-activated overexpression of DLAT and enhancement in glycolysis metabolism contributed to the tumorigenesis of NSCLC, suggesting that DLAT-associated pathway may be a therapeutic target for NSCLC.

DAF-16 is involved in colonic metabolites of ferulic acid-promoted longevity and stress resistance of Caenorhabditis elegans.

BACKGROUND: Ferulic acid (FA) is a dietary polyphenol widely found in plant tissues. It has long been considered to have health-promoting qualities. However, the biological properties of dietary polyphenols depend largely on their absorption during digestion, and the effects of their intestinal metabolites on human health have attracted the interest of researchers. This study evaluated the effects of three main colonic metabolites of FA - 3-(3,4-dihydroxyphenyl)propionic acid (3,4diOHPPA), 3-(3-hydroxyphenyl)propionic acid (3OHPPA) and 3-phenylpropionic acid (3PPA) - on longevity and stress resistance in Caenorhabditis elegans. RESULTS: Our results showed that 3,4diOHPPA, 3OHPPA and 3PPA extended the lifespan under normal conditions in C. elegans whereas FA did not. High doses of 3,4diOHPPA (0.5 mmol L-1 ), 3OHPPA (2.5 mmol L-1 ) and 3PPA (2.5 mmol L-1 ) prolonged the mean lifespan by 11.2%, 13.0% and 10.6%, respectively. Moreover, 3,4diOHPPA, 3OHPPA and 3PPA treatments promoted stress tolerance against heat, UV irradiation and paraquat. Furthermore, three metabolites ameliorated physical functions, including reactive oxygen species and malondialdehyde levels, motility and pharyngeal pumping rate. The anti-aging activities mediated by 3,4diOHPPA, 3OHPPA and 3PPA depend on the HSF-1 and JNK-1 linked insulin/IGF-1 signaling pathway, which converge onto DAF-16. CONCLUSION: The current findings suggest that colonic metabolites of FA have the potential for use as anti-aging bioactivate compounds. © 2022 Society of Chemical Industry.

A novel tRNA-derived fragment AS-tDR-007333 promotes the malignancy of NSCLC via the HSPB1/MED29 and ELK4/MED29 axes.

BACKGROUND: Transfer RNA-derived fragments (tRFs) are a new class of small non-coding RNAs. Recent studies suggest that tRFs participate in some pathological processes. However, the biological functions and mechanisms of tRFs in non-small cell lung cancer (NSCLC) are largely unknown. METHODS: Differentially expressed tRFs were identified by tRF and tiRNA sequencing using 9 pairs of pre- and post-operation plasma from patients with NSCLC. Quantitative real-time PCR (qRT-PCR) and fluorescence in situ hybridization (FISH) were used to determine the levels of tRF in tissues, plasma, and cells. Gain- and loss-of-function experiments were implemented to investigate the oncogenic effects of tRF on NSCLC cells in vitro and in vivo. Chromatin immunoprecipitation (ChIP), luciferase reporter, RNA pulldown, mass spectrum, RNA immunoprecipitation (RIP), Western blot, co-immunoprecipitation (Co-IP) assays, and rescue experiments were performed to explore the regulatory mechanisms of tRF in NSCLC. RESULTS: AS-tDR-007333 was an uncharacterized tRF and significantly up-regulated in NSCLC tissues, plasma, and cells. Clinically, AS-tDR-007333 overexpression could distinguish NSCLC patients from healthy controls and associated with poorer prognosis of NSCLC patients. Functionally, overexpression of AS-tDR-007333 enhanced proliferation and migration of NSCLC cells, whereas knockdown of AS-tDR-007333 resulted in opposite effects. Mechanistically, AS-tDR-007333 promoted the malignancy of NSCLC cells by activating MED29 through two distinct mechanisms. First, AS-tDR-007333 bound to and interacted with HSPB1, which activated MED29 expression by enhancing H3K4me1 and H3K27ac in MED29 promoter. Second, AS-tDR-007333 stimulated the expression of transcription factor ELK4, which bound to MED29 promoter and increased its transcription. Therapeutically, inhibition of AS-tDR-007333 suppressed NSCLC cell growth in vivo. CONCLUSIONS: Our study identifies a new oncogenic tRF and uncovers a novel mechanism that AS-tDR-007333 promotes NSCLC malignancy through the HSPB1-MED29 and ELK4-MED29 axes. AS-tDR-007333 is a potential diagnostic or prognostic marker and therapeutic target for NSCLC.

Recovery of superior frontal gyrus cortical thickness and resting-state functional connectivity in abstinent heroin users after 8 months of follow-up.

Compared with healthy controls, heroin users (HUs) show evidence of structural and functional brain alterations. However, little is known about the possibility of brain recovery after protracted heroin abstinence. The purpose of this study was to investigate whether brain recovery is possible after protracted abstinence in HUs. A total of 108 subjects with heroin addiction completed structural and functional scans, and 61 of those subjects completed 8-month follow-up scans. Resting-state data and 3D-T1 MR images were collected for all participants, first at baseline and again after 8 months. Cognitive function and craving were measured by the Trail Making Test-A (TMT-A) and Visual Analog Scale for Craving, respectively. The cortical thickness and resting-state functional connectivity (RSFC) differences were then analyzed and compared between baseline and follow-up, and correlations were obtained between neuroimaging and behavioral changes. HUs demonstrated improved cognition (shorter TMT-A time) and reduced craving at the follow-up (HU2) relative to baseline (HU1), and the cortical thickness in the bilateral superior frontal gyrus (SFG) was significantly greater at HU2 than at HU1. Additionally, the RSFC of the left SFG with the inferior frontal gyrus (IFG), insula, and nucleus accumbens and that of the right SFG with the IFG, insula and orbitofrontal cortex (OFC) were increased at HU2. The changes in TMT-A time were negatively correlated with the RSFC changes between the left SFG and the bilateral IFG, the bilateral caudate, and the right insula. The changes in craving were negatively correlated with the RSFC changes between the left OFC and the bilateral SFG. Our results demonstrated that impaired frontal-limbic neurocircuitry can be partially restored, which might enable improved cognition as well as reduced craving in substance-abusing individuals. We provided novel scientific evidence for the partial recovery of brain circuits implicated in cognition and craving after protracted abstinence.

Reduced midbrain functional connectivity and recovery in abstinent heroin users.

Dopaminergic pathways from the midbrain to striatum as well as cortex are involved in addiction. However, the alternations of these pathways and whether the recoveries of aberrant circuits would be detected after prolonged abstinence in heroin users are rarely known. The resting-state functional connectivity (RSFC) patterns of midbrain (i.e., the ventral tegmental area (VTA) and substantia nigra (SN)) were compared between 40 abstinent heroin users with opioid use disorder (HUs) and 35 healthy controls (HCs). Then, we tested the functional recovery hypothesis by both cross-sectional and longitudinal design. For cross-sectional design, HUs were separated into short-term abstainers (STs) (3-15 days) and long-term abstainers (LTs) (>15 days). With regard to longitudinal design, 22 subjects among HUs were followed up for 10 months. A sandwich estimator method was used to analyze the differences between baseline HUs and follow-up HUs. HUs showed lower RSFC between midbrain and several cortical areas (medial orbitofrontal cortex (mOFC) and anterior cingulate cortex) compared with HCs. Besides, lower RSFC of VTA-right nucleus accumbens circuit as well as right SN- caudate circuit was also found in HUs. The enhanced RSFC value of VTA-left mOFC circuit was observed in LTs, compared with STs. Additionally, longitudinal design also revealed the increased RSFC values of the midbrain with frontal cortex after 10 months prolonged abstinence. We revealed abnormal functional organizations of midbrain-striato and midbrain-cortical circuits in HUs. More importantly, partially recovery of these dysfunctions can be found after long-term abstinence.

Association of Iron-Deficiency Anemia and Non-Iron-Deficiency Anemia with Neurobehavioral Development in Children Aged 6-24 Months.

(1) Background: Anemia has comprehensive adverse effects on the growth and development of children. In this study, we analyzed the potential effects of different types of anemia on early-life neurobehavioral development. (2) Methods: A total of 2601 children aged 6-24 months, whose parents agreed to participate in this study, underwent routine blood tests and neurobehavioral development assessment. The children's parents or other primary caregivers were interviewed with a face-to-face questionnaire at the time of enrollment in the study. Anemia was determined by hemoglobin < 110 g/L and classified into iron-deficiency and non-iron-deficiency anemia according to the levels of serum ferritin, C-reactive protein, and alpha-1-acid glycoprotein. Neurobehavioral development was assessed by the China Developmental Scale for Children and divided into five domains: gross motor, fine movement, adaptability, language, and social behavior. The development quotient (DQ) was used to measure the level of total neurobehavioral development and each domain of neurobehavioral development. (3) Results: The prevalence of anemia in children aged 6-24 months was 26.45%, of which iron-deficiency anemia only accounted for 27.33%. Compared with children without anemia, those with iron-deficiency anemia had a significantly lower developmental quotient (DQ) for total neurobehavioral development and gross motor and adaptability development. The partial regression coefficients were -1.33 (95% CI -2.36, -0.29; p = 0.012), -1.88 (95% CI -3.74, -0.03; p = 0.047), and 1.48 (95% CI -2.92, -0.05; p = 0.042), respectively. Children with non-iron-deficiency anemia had significantly lower DQ for total neurobehavioral development and gross motor and fine movement development than those without anemia. The partial regression coefficients were -0.94 (95% CI -1.64, -0.25; p = 0.008), -1.25 (95% CI -2.48, -0.03; p = 0.044), and -1.18 (95% CI -2.15, -0.21; p = 0.017), respectively. There were no statistically significant differences in total neurobehavioral development and the five domains of neurobehavioral development between children with non-iron-deficiency and iron-deficiency anemia. The partial ß values were 0.40 (95% CI -1.53, 2.33; p = 0.684), 0.21 (95% CI -1.39, 1.81; p = 0.795), 0.63 (95% CI -1.03, 2.28; p = 0.457), 0.16 (95% CI -1.78, 2.10; p = 0.871), 0.35 (95% CI -1.32, 2.01; p = 0.684), and 0.34 (95% CI -0.77, 1.46; p = 0.545), respectively. (4) Conclusions: Both iron-deficiency anemia and non-iron-deficiency anemia were negatively correlated with the neurobehavioral development of children. Negative correlations were found between iron-deficiency anemia and gross motor and adaptability development and between non-iron-deficiency anemia and gross motor and fine movement development.