Association of cardiovascular health metrics with all-cause and cardiovascular disease mortality in chronic kidney disease: A cohort study.

BACKGROUND AND AIMS: Since the global burden of chronic kidney disease (CKD) is rising rapidly, the study aimed to assess the association of cardiovascular health (CVH) metrics with all-cause and cardiovascular disease (CVD) mortality among individuals with CKD. METHODS AND RESULTS: The cohort study included 5834 participants with CKD from the National Health and Nutrition Examination Survey 1999-2018. A composite CVH score was calculated based on smoking status, physical activity, body mass index, blood pressure, total cholesterol, diet quality, and glucose control. Primary outcomes were all-cause and CVD mortality as of December 31, 2019. Multivariable-adjusted Cox proportional hazards models were used to estimate the association between CVH metrics and deaths in CKD patients. During a median follow-up of 7.2 years, 2178 all-cause deaths and 779 CVD deaths were documented. Compared to participants with ideal CVH, individuals with intermediate CVH exhibited a 46.0% increase in all-cause mortality (hazard ratio, 1.46; 95% confidence interval: 1.17, 1.83), while those with poor CVH demonstrated a 101.0% increase (2.01; 1.54, 2.62). For CVD mortality, individuals with intermediate CVH experienced a 56.0% increase (1.56; 1.02, 2.39), and those with poor CVH demonstrated a 143.0% increase (2.43; 1.51, 3.91). Linear trends were noted for the associations of CVH with both all-cause mortality (P for trend <0.001) and CVD mortality (P for trend = 0.02). CONCLUSIONS: Lower CVH levels were associated with higher all-cause and CVD mortality in individuals with CKD, which highlights the importance of maintaining good CVH in CKD patients.

Irisin attenuates type 1 diabetic cardiomyopathy by anti-ferroptosis via SIRT1-mediated deacetylation of p53.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia-reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known. METHODS AND RESULTS: T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose. CONCLUSION: This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.

Design, Synthesis, and In vitro Anti-cervical Cancer Activity of a Novel MDM2-p53 Inhibitor Based on a Chalcone Scaffold.

OBJECTIVE: Several novel fluorinated chalcone derivatives were synthesized, and their in vitro anticervical cancer activity and mechanism of action were investigated using the parent nucleus of licorice chalcone as the lead compound backbone and MDM2-p53 as the target. METHODS: In this study, 16 novel chalcone derivatives (3a-3r) were designed and synthesized by molecular docking technology based on the licorice chalcone parent nucleus as the lead compound scaffold and the cancer apoptosis regulatory target MDM2-p53. The structures of these compounds were confirmed by 1H-NMR, 13C-NMR, and HR-ESI-MS. The inhibitory effects of the compounds on the proliferation of three human cervical cancer cell lines (SiHa, HeLa, and C-33A) and two normal cell lines (H8 and HaCaT) were determined by MTT assay, and the initialstructure-activity relationship was analyzed. Transwell and flow cytometry were used to evaluate the effects of target compounds on the inhibition of cancer cell migration and invasion, apoptosis induction, and cell cycle arrest. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot (WB) were used to detect the effects of candidate compounds on mRNA, p53, and Murine double minute 2 (MDM2) protein expression. The binding characteristics of the target compounds to the MDM2 protein target in the p53-MDM2 pathway were evaluated by molecular docking technology. RESULTS: The target compounds had considerable inhibitory activity on the proliferation of three cervical cancer cell lines. Among them, compound 3k (E)-3-(4-(dimethylamino)phenyl)-2-methyl-1-(3-(trifluoromethyl)phenyl) prop-2-en-1-one) showed the highest activity against HeLa cells (IC50=1.08 µmol/L), which was better than that of the lead compound Licochalcone B, and 3k showed lower toxicity to both normal cells. Compound 3k strongly inhibited the migration and invasion of HeLa cells and induced apoptosis and cell cycle arrest at the G0/G1 phase. Furthermore, compound 3k upregulated the expression of p53 and BAX and downregulated the expression of MDM2, MDMX, and BCL2. Moreover, molecular docking results showed that compound 3k could effectively bind to the MDM2 protein (binding energy: -9.0 kcal/mol). These results suggest that the compounds may activate the p53 signaling pathway by inhibiting MDM2 protein, which prevents cancer cell proliferation, migration, and invasion and induces apoptosis and cell cycle arrest in cancer cells. CONCLUSION: This study provides a new effective and low-toxicity drug candidate from licochalcone derivatives for treating cervical cancer.

Improving flame retardant and electromagnetic interference shielding properties of poly(lactic acid)/poly(ε-caprolactone) composites using catalytic imidazolium modified CNTs and ammonium polyphosphate.

The flame retardants and electromagnetic interference (EMI) shielding performance were enhanced by using imidazolium-functionalized polyurethane (IPU) modified multi-walled carbon nanotubes (CNTs) and ammonium polyphosphate (APP) for polylactic acid (PLA)/polycaprolactone (PCL) composites. The PLA/PCL/10APP/8CNT/1.6IPU composite containing 10 wt% APP and 8 wt% imidazolium modified CNTs reached the limiting oxygen index (LOI) value of 30.3 % and passed the V-0 rating in UL-94 tests. Moreover, the peak of the heat release rate (pHRR) and total heat release (THR) for this composite reached around 302 kW/m2 and 64 KJ/m2, which were decreased by 39.1 % and 15.8 % compared with that of PLA/PCL/10APP composite. The improved flame retardancy was attributed to the interplay of catalytic, barrier, and condensed char forming of imidazolium-modified CNTs and APP. IPU catalyzed the charring effect of the polymer matrix during combustion and regulated the migration of more CNTs to disperse at the two-phase interface. The dispersion of imidazolium-modified CNTs and co-continuous phase structure of the composites can establish continuous conductive pathways. The PLA/PCL/APP/CNT/IPU composite obtained a higher conductivity compared to the PLA/PCL/APP/CNT composite and whose EMI SE reached 33.9 dB, which is a promising candidate for next-generation sustainable and protective plastics.

Dysregulated Arginine Metabolism Is Linked to Retinal Degeneration in Cep250 Knockout Mice.

Purpose: Degeneration of retinal photoreceptors is frequently observed in diverse ciliopathy disorders, and photoreceptor cilium gates the molecular trafficking between the inner and the outer segment (OS). This study aims to generate a homozygous global Cep250 knockout (KO) mouse and study the resulting phenotype. Methods: We used Cep250 KO mice and untargeted metabolomics to uncover potential mechanisms underlying retinal degeneration. Long-term follow-up studies using optical coherence tomography (OCT) and electroretinography (ERG) were performed. Results: OCT and ERG results demonstrated gradual thinning of the outer nuclear layer (ONL) and progressive attenuation of the scotopic ERG responses in Cep250-/- mice. More TUNEL signal was observed in the ONL of these mice. Immunostaining of selected OS proteins revealed mislocalization of these proteins in the ONL of Cep250-/- mice. Interestingly, untargeted metabolomics analysis revealed arginine-related metabolic pathways were altered and enriched in Cep250-/- mice. Mis-localization of a key protein in the arginine metabolism pathway, arginase 1 (ARG1), in the ONL of KO mice further supports this model. Moreover, adeno-associated virus (AAV)-based retinal knockdown of Arg1 led to similar architectural and functional alterations in wild-type retinas. Conclusions: Altogether, these results suggest that dysregulated arginine metabolism contributes to retinal degeneration in Cep250-/- mice. Our findings provide novel insights that increase understanding of retinal degeneration in ciliopathy disorders.

A novel type of Brassica napus with higher stearic acid in seeds developed through genome editing of BnaSAD2 family.

KEY MESSAGE: Modifications of multiple copies of the BnaSAD2 gene family with genomic editing technology result in higher stearic acid content in the seed of polyploidy rapeseed. Solid fats from vegetable oils are widely used in food processing industry. Accumulating data showed that stearic acid is more favorite as the major composite among the saturate fatty acids in solid fats in considerations of its effects on human health. Rapeseed is the third largest oil crop worldwide, and has potential to be manipulated to produce higher saturated fatty acids as raw materials of solid fats. Toward that end, we identified four SAD2 gene family members in B. napus genome and established spatiotemporal expression pattern of the BnaSAD2 members. Genomic editing technology was applied to mutate all the copies of BnaSAD2 in this allopolyploid species and mutants at multiple alleles were generated and characterized to understand the effect of each BnaSAD2 member on blocking desaturation of stearic acid. Mutations occurred at BnaSAD2.A3 resulted in more dramatic changes of fatty acid profile than ones on BnaSAD2.C3, BnaSAD2.A5 and BnaSAD2.C4. The content of stearic acid in mutant seeds with single locus increased dramatically with a range of 3.1-8.2%. Furthermore, combination of different mutated alleles of BnaSAD2 resulted in more dramatic changes in fatty acid profiles and the double mutant at BnaSAD2.A3 and BnaSAD2.C3 showed the most dramatic phenotypic changes compared with its single mutants and other double mutants, leading to 11.1% of stearic acid in the seeds. Our results demonstrated that the members of BnaSAD2 have differentiated in their efficacy as a Δ9-Stearoyl-ACP-Desaturase and provided valuable rapeseed germplasm for breeding high stearic rapeseed oil.

Immunostimulant Hydrogel-Guided Tumor Microenvironment Reprogramming to Efficiently Potentiate Macrophage-Mediated Cellular Phagocytosis for Systemic Cancer Immunotherapy.

Macrophage-mediated cellular phagocytosis (MMCP) plays a critical role in conducting antitumor immunotherapy but is usually impaired by the intrinsic phagocytosis evading ability of tumor cells and the immunosuppressive tumor microenvironment (TME). Herein, a MMCP-boosting hydrogel (TCCaGM) was elaborately engineered by encapsulating granulocyte-macrophage colony-stimulating factor (GM-CSF) and a therapeutic nanoplatform (TCCaN) that preloaded with the tunicamycin (Tuni) and catalase (CAT) with the assistance of CaCO3 nanoparticles (NPs). Strikingly, the hypoxic/acidic TME was efficiently alleviated by the engineered hydrogel, "eat me" signal calreticulin (CRT) was upregulated, while the "don't eat me" signal CD47 was downregulated on tumor cells, and the infiltrated DCs were recruited and activated, all of which contributed to boosting the macrophage-mediated phagocytosis and initiating tumor-specific CD8+ T cells responses. Meanwhile, the remodeled TME was beneficial to accelerate the polarization of tumor-associated macrophages (TAMs) to the antitumoral M1-like phenotype, further heightening tumoricidal immunity. With the combination of PD-1 antibody (αPD-1), the designed hydrogel significantly heightened systemic antitumor immune responses and long-term immunological effects to control the development of primary and distant tumors as well as suppress tumor metastasis and recurrence, which established an optimal strategy for high-performance antitumor immunotherapy.

RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is characterized by a high incidence of brain metastasis (BrM) and a poor prognosis. As the most lethal form of breast cancer, BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies. Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis (BCBrM), but the underlying mechanisms are far from being fully elucidated. METHODS: Through analysis of BCBrM transcriptome data from mice and patients, and immunohistochemical validation on patient tissues, we identified and verified the specific down-regulation of retinoic acid receptor responder 2 (RARRES2), a multifunctional adipokine and chemokine, in BrM of TNBC. We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies. Key signaling pathway components were evaluated using multi-omics approaches. Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2. RESULTS: We found that down-regulation of RARRES2 is specifically associated with BCBrM, and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming. Mechanistically, reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue (PTEN)-mammalian target of rapamycin (mTOR)-sterol regulatory element-binding protein 1 (SREBP1) signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment. CONCLUSIONS: Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of BrM. RARRES2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.

PDCD6 Promotes Hepatocellular Carcinoma Cell Proliferation and Metastasis through the AKT/GSK3ß/ß-catenin Pathway.

Objective: Programmed cell death 6 (PDCD6), a Ca 2+-binding protein, has been reported to be aberrantly expressed in all kinds of tumors. The aim of this study was to explore the role and mechanism of PDCD6 in hepatocellular carcinomas (HCCs). Methods: The expression levels of PDCD6 in liver cancer patients and HCC cell lines were analyzed using bioinformatics and Western blotting. Cell viability and metastasis were determined by methylthiazol tetrazolium (MTT) and transwell assays, respectively. And Western blotting was used to test related biomarkers and molecular pathway factors in HCC cell lines. LY294002, a PI3K inhibitor inhibiting AKT, was used to suppress the AKT/GSK3ß/ß-catenin pathway to help evaluate the role of this pathway in the HCC carcinogenesis associated with PDCD6. Results: The analysis of The Cancer Genome Atlas Database suggested that high PDCD6 expression levels were relevant to liver cancer progression. This was consistent with our finding of higher levels of PDCD6 expression in HCC cell lines than in normal hepatocyte cell lines. The results of MTT, transwell migration, and Western blotting assays revealed that overexpression of PDCD6 positively regulated HCC cell proliferation, migration, and invasion. Conversely, the upregulation of PDCD6 expression in the presence of an AKT inhibitor inhibited HCC cell proliferation, migration, and invasion. In addition, PDCD6 promoted HCC cell migration and invasion by epithelial-mesenchymal transition. The mechanistic investigation proved that PDCD6 acted as a tumor promoter in HCC through the AKT/GSK3ß/ß-catenin pathway, increasing the expression of transcription factors and cellular proliferation and metastasis. Conclusion: PDCD6 has a tumor stimulative role in HCC mediated by AKT/GSK3ß/ß-catenin signaling and might be a potential target for HCC progression.

Structural, antioxidant, and immunomodulatory activities of an acidic exopolysaccharide from Lactiplantibacillus plantarum DMDL 9010.

This study investigated the structural, antioxidant, and immunomodulatory activities of acidic exopolysaccharide (EPS-LP2) isolated from Lactiplantibacillus plantarum DMDL 9010. EPS-LP2 is composed of fucose (Fuc), arabinose (Ara), galactose (Gal), glucose (Glc), mannose (Man), and D-fructose (Fru) with a molar ratio of 0.13: 0.69: 8.32: 27.57: 62.07: 0.58: 0.46, respectively. Structural analysis of EPS-LP2 exhibited a smooth irregular lamellar surface, rod-like structure with swollen ends and slippery surfaces, and good thermal stability. Based on the methylation and NMR analysis, sugar residues including t-Manp, t-Glcp, 2-Manp, 6-Galp, 6-Glcp, and 4-Glcp were found to exist in EPS-LP2. In the 50∼400 µg/ml range, EPS-LP2 showed negligible neurotoxicity to RAW264.7 cells. Moreover, EPS-LP2 could protect RAW264.7 cells from oxidative injury by lowering the generation of reactive oxygen species (ROS), malondialdehyde (MDA), and the secretion of lactate dehydrogenase (LDH). In contrast, an increase in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and the concentrations of glutathione (GSH) were observed. Immunoreactivity assays showed that EPS-LP2 could suppress the expression of NO, tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6) and inhibit the activation of the mitogen-activated protein kinase (MAPK)/nuclear factor-κB-gene binding (NF-κB) cell pathway. Conclusively, EPS-LP2 could be a potential natural antioxidant and immunomodulatory agent in functional foods and medicines.

Expression dynamics of periodic transcripts during cancer cell cycle progression and their correlation with anticancer drug sensitivity.

BACKGROUND: The cell cycle is at the center of cellular activities and is orchestrated by complex regulatory mechanisms, among which transcriptional regulation is one of the most important components. Alternative splicing dramatically expands the regulatory network by producing transcript isoforms of genes to exquisitely control the cell cycle. However, the patterns of transcript isoform expression in the cell cycle are unclear. Therapies targeting cell cycle checkpoints are commonly used as anticancer therapies, but none of them have been designed or evaluated at the alternative splicing transcript level. The utility of these transcripts as markers of cell cycle-related drug sensitivity is still unknown, and studies on the expression patterns of cell cycle-targeting drug-related transcripts are also rare. METHODS: To explore alternative splicing patterns during cell cycle progression, we performed sequential transcriptomic assays following cell cycle synchronization in colon cancer HCT116 and breast cancer MDA-MB-231 cell lines, using flow cytometry and reference cell cycle transcripts to confirm the cell cycle phases of samples, and we developed a new algorithm to describe the periodic patterns of transcripts fluctuating during the cell cycle. Genomics of Drug Sensitivity in Cancer (GDSC) drug sensitivity datasets and Cancer Cell Line Encyclopedia (CCLE) transcript datasets were used to assess the correlation of genes and their transcript isoforms with drug sensitivity. We identified transcripts associated with typical drugs targeting cell cycle by determining correlation coefficients. Cytotoxicity assays were used to confirm the effect of ENST00000257904 against cyclin dependent kinase 4/6 (CDK4/6) inhibitors. Finally, alternative splicing transcripts associated with mitotic (M) phase arrest were analyzed using an RNA synthesis inhibition assay and transcriptome analysis. RESULTS: We established high-resolution transcriptome datasets of synchronized cell cycle samples from colon cancer HCT116 and breast cancer MDA-MB-231 cells. The results of the cell cycle assessment showed that 43,326, 41,578 and 29,244 transcripts were found to be periodically expressed in HeLa, HCT116 and MDA-MB-231 cells, respectively, among which 1280 transcripts showed this expression pattern in all three cancer cell lines. Drug sensitivity assessments showed that a large number of these transcripts displayed a higher correlation with drug sensitivity than their corresponding genes. Cell cycle-related drug screening showed that the level of the CDK4 transcript ENST00000547281 was more significantly associated with the resistance of cells to CDK4/6 inhibitors than the level of the CDK4 reference transcript ENST00000257904. The transcriptional inhibition assay following M phase arrest further confirmed the M-phase-specific expression of the splicing transcripts. Combined with the cell cycle-related drug screening, the results also showed that a set of periodic transcripts, for example, ENST00000314392 (a dolichyl-phosphate mannosyltransferase polypeptide 2 isoform transcript), was more associated with drug sensitivity than the levels of their corresponding gene transcripts. CONCLUSIONS: In summary, we identified a panel of cell cycle-related periodic transcripts and found that the levels of transcripts of drug target genes showed different values for predicting drug sensitivity, providing novel insights into alternative splicing-related drug development and evaluation.

Mechanically robust and flame-retardant poly(lactide)/poly(butylene adipate-co-terephthalate) composites based on carbon nanotubes and ammonium polyphosphate.

In order to synchronously improve mechanical and flame retardant properties of polylactide/poly(butylene adipate-co-terephthalate) (PLA/PBAT) composites, a series of multifunctional composites containing multi-walled carbon nanotubes (CNTs), ammonium polyphosphate (APP) and a commercial multifunctional epoxy oligomer (MEO) as chain extender were prepared via melt blending. The results show that the optimal flame retardant properties of PLA5-PBAT5/10A/6C composite containing 6 % CNTs and 10 wt% APP, presented the limited oxygen index reached 28.3 % and exhibited a decrease in peak heat release rate (pHRR) and total heat release (THR) to 368 kJ/m2 and 72 MJ/m2, respectively because of the co-continuous phase, CNTs network and condensed effect of APP. Meanwhile, the construction of co-continuous phases endows PLA5-PBAT5 with better mechanical compared to PLA8-PBAT2 composites. The elongation at break reaches (245.9 %) and notched impact strength (16.5 kJ/m2) of PLA5-PBAT5/10A/6C were higher than the PLA8-PBAT2/10A/6C by 16.0 and 283.7 %.

MIL-101-Cr/Fe/Fe-NH2 for Efficient Separation of CH4 and C3H8 from Simulated Natural Gas.

Adsorptive separation based on porous solid adsorbents has emerged as an excellent effective alternative to energy-intensive conventional separation methods in a low energy cost and high working capacity manner. However, there are few stable mesoporous metal-organic frameworks (MOFs) for efficient purification of methane from other light hydrocarbons in natural gas. Herein, we report a series of stable mesoporous MOFs, MIL-101-Cr/Fe/Fe-NH2, for efficient separation of CH4 and C3H8 from a ternary mixture CH4/C2H6/C3H8. Experimental results show that all three MOFs possess excellent thermal, acid/basic, and hydrothermal stability. Single-component adsorption suggested that they have high C3H8 adsorption capacity and commendable selectivity for C3H8 and C2H6 over CH4. Transient breakthrough experiments further certified the ability of direct separation of CH4 from simulated natural gas and indirect recovery of C3H8 from the packing column. Theoretical calculations illustrated that the van der Waals force proportional to the molecular weight is the key factor and that the structural integrity and defect can impact separation performances.

Introducing surface-to-surface matching technique to evaluate mandibular symmetry: A retrospective study.

Objectives: This study introduced a three-dimensional (3D) surface-to-surface matching technique to evaluate the mandibular symmetry of teenagers and adults with unilateral second molar scissor bite. Methods: The targets came from 73 cone-beam computed tomography (CBCT) images with unilateral second molar scissor bite, including teenagers (n = 30) and adults (n = 43). 73 images without scissor bite and matched in sex and age were selected as controls. The scans were developed into 3D mandible models and seven mandibular functional unit models, including condylar process (Co), coronoid process (Cr), mandibular ramus (Ra), mandibular angle (Ma), alveolar process (Ap), mandibular body (Mb) and chin process (Ch). The surface-to-surface matching technique was introduced. 3D deviation analysis and matching percentages calculation were performed and compared to evaluate the symmetry of the mandible. Results: Comparisons were made between the study samples and control samples. For teenagers, the matching percentages of the entire mandible (55.31 ± 7.24%), Mb (69.04 ± 9.22%) and Co (65.19 ± 10.67%) in the study group were lower than that of the entire mandible (60.87 ± 6.38%) (P <0.01), Mb (75.0 ± 8.71%) (P <0.05) and Co (70.25 ± 8.20%) (P <0.05) in the control group. While Ap, Ra, Ch, Cr and Ma showed no statistically significant differences (P >0.05). For adults, the matching percentages of the entire mandible (48.88 ± 9.77%), Ap (65.83 ± 11.21%), Mb (64.43 ± 12.03%), Ch (79.17 ± 10.29%), Ra (64.11 ± 9.84%) and Co (61.08 ± 11.64%) in the study group were lower than the entire mandible (59.28 ± 5.49%) (P <0.01), Ap (73.65 ± 9.10%) (P <0.01), Mb (71.66 ± 8.40%) (P <0.01), Ch (83.86 ± 5.59%) (P <0.05), Ra (68.54 ± 7.87%) (P <0.05) and Co (66.20 ± 10.62%) (P <0.05) of the control group. Only Cr and Ma showed no statistically significant differences (P >0.05). Conclusion: Mandibular asymmetry was observed in both teenagers and adults with unilateral second molar scissor bite. Moreover, compared with teenagers, more mandibular units of adult patients were affected. Clinical significance: Based on the surface-to-surface matching technique, the symmetric and morphological information of the mandible can be converted into visual color maps and quantitative descriptions. This method can bring convenience to the study of the growth of mandible, orthodontic treatment and orthognathic surgery design.

Environmental polycyclic aromatic hydrocarbon exposure in relation to metabolic syndrome in US adults.

The present study examined the associations of polycyclic aromatic hydrocarbon (PAH) exposure with metabolic syndrome (MetS) and its components. Data were from 5181 US adults recruited in the National Health and Nutrition Examine Survey 2001-2012. Environmental PAH exposure was estimated as concentrations of urinary PAH metabolites. Weighted quantile sum (WQS) regression and modified Poisson regression were separately conducted to estimate the associations of mixed and single PAH metabolites with MetS and its components. WQS regression analyses showed that participants with higher mixed PAH exposure had increased prevalence of MetS (prevalence ratio, 1.12; 95 % confidence interval, 1.06, 1.19), elevated waist circumference (1.07; 1.02, 1.12), elevated fasting blood glucose (1.07; 1.00, 1.14), elevated triglycerides (1.19; 1.09, 1.30), and reduced high-density lipoprotein cholesterol (1.11; 1.03, 1.20). In the models for single PAH metabolites, higher levels of 1-hydroxynaphthalene (1.15; 1.00, 1.32), 2-hydroxynaphthalene (1.20; 1.05, 1.38), 1-hydroxyphenanthrene (1.18; 1.04, 1.34), 2-hydroxyphenanthrene (1.38; 1.22, 1.57), and 1-pyrene (1.19; 1.05, 1.34) were respectively associated with increased prevalence of MetS (highest tertile vs lowest tertile). In addition, linear trends were noted for the associations of these PAH metabolites with MetS (all P for linear association ≤0.047). Smokers, drinkers, and participants with poor diet quality showed stronger associations between certain PAH metabolite with MetS. The findings suggest that the prevalence of MetS and its components increases when PAH exposure is at a high level, and that lifestyle factors, such as cigarette smoking, alcohol consumption, and diet quality, could modify the positive associations of certain PAH exposure with MetS.

DNA Methylation Modulates Aging Process in Adipocytes.

Aging has been recognized to be a highly complex biological health problem with a high risk of chronic diseases, including type 2 diabetes, atherosclerosis, chronic bronchitis or emphysema, cancer and Alzheimer's disease. Particularly, age-related turnover in adipose tissue is a major contributor to metabolic syndromes and shortened lifespan. Adipocytes undergo senescence in early stage, which results in adipose tissue metabolic dysfunction, redistribution, and inflammation. The well-established association between DNA methylation (DNAm) and aging has been observed in the past few decades. Indeed, age-related alteration in DNAm is highly tissue-specific. This review intends to summarize the advancements how DNAm changes coupled with aging process in adipose tissue, by which DNAm regulates cellular senescence, metabolic function, adipokine secretion and beiging process in adipocytes. Elucidation of the effect of DNAm on adipose aging would have great potential to the development of epigenetic therapeutic strategies against aging-related diseases in clinical settings.

Antitumor Activities of tRNA-Derived Fragments and tRNA Halves from Non-pathogenic Escherichia coli Strains on Colorectal Cancer and Their Structure-Activity Relationship.

tRNAs purified from non-pathogenic Escherichia coli strains (NPECSs) possess cytotoxic properties on colorectal cancer cells. In the present study, the bioactivity of tRNA halves and tRNA fragments (tRFs) derived from NPECSs are investigated for their anticancer potential. Both the tRNA halves and tRF mimics studied exhibited significant cytotoxicity on colorectal cancer cells, with the latter being more effective, suggesting that tRFs may be important contributors to the bioactivities of tRNAs derived from the gut microbiota. Through high-throughput screening, the EC83 mimic, a double-strand RNA with a 22-nucleotide (nt) 5'-tRF derived from tRNA-Leu(CAA) as an antisense chain, was identified as the one with the highest potency (50% inhibitory concentration [IC50] = 52 nM). Structure-activity investigations revealed that 2'-O-methylation of the ribose of guanosine (Gm) may enhance the cytotoxic effects of the EC83 mimic via increasing the stability of its tertiary structure, which is consistent with the results of in vivo investigations showing that the EC83-M2 mimic (Gm modified) exhibited stronger antitumor activity against both HCT-8 and LoVo xenografts. Consistently, 4-thiouridine modification does not. This provides the first evidence that the bioactivity of tRF mimics would be impacted by chemical modifications. Furthermore, the present study provides the first evidence to suggest that novel tRNA fragments derived from the gut microbiota may possess anticancer properties and have the potential to be potent and selective therapeutic molecules. IMPORTANCE While the gut microbiota has been increasingly recognized to be of vital importance for human health and disease, the current literature shows that there is a lack of attention given to non-pathogenic Escherichia coli strains. Moreover, the biological activities of tRNA fragments (tRFs) derived from bacteria have rarely been investigated. The findings from this study revealed tRFs as a new class of bioactive constituents derived from gut microorganisms, suggesting that studies on biological functional molecules in the intestinal microbiota should not neglect tRFs. Research on tRFs would play an important role in the biological research of gut microorganisms, including bacterium-bacterium interactions, the gut-brain axis, and the gut-liver axis, etc. Furthermore, the guidance on the rational design of tRF therapeutics provided in this study indicates that further investigations should pay more attention to these therapeutics from probiotics. The innovative drug research of tRFs as potent druggable RNA molecules derived from intestinal microorganisms would open a new area in biomedical sciences.

A tRNA-derived fragment from Chinese yew suppresses ovarian cancer growth via targeting TRPA1.

Drug discovery from plants usually focuses on small molecules rather than such biological macromolecules as RNAs. Although plant transfer RNA (tRNA)-derived fragment (tRF) has been associated with the developmental and defense mechanisms in plants, its regulatory role in mammals remains unclear. By employing a novel reverse small interfering RNA (siRNA) screening strategy, we show that a tRF mimic (antisense derived from the 5' end of tRNAHis(GUG) of Chinese yew) exhibits comparable anti-cancer activity with that of taxol on ovarian cancer A2780 cells, with a 16-fold lower dosage than that of taxol. A dual-luciferase reporter assay revealed that tRF-T11 directly targets the 3' UTR of oncogene TRPA1 mRNA. Furthermore, an Argonaute-RNA immunoprecipitation (AGO-RIP) assay demonstrated that tRF-T11 can interact with AGO2 to suppress TRPA1 via an RNAi pathway. This study uncovers a new role of plant-derived tRFs in regulating endogenous genes. This holds great promise for exploiting novel RNA drugs derived from nature and sheds light on the discovery of unknown molecular targets of therapeutics.

SUMOylation of PDPK1 Is required to maintain glycolysis-dependent CD4 T-cell homeostasis.

The immune system is finely tuned to fight against infections, eradicate neoplasms, and prevent autoimmunity. Protein posttranslational modification (PTM) constitutes a molecular layer of regulation to guarantee the proper intensity of immune response. Herein, we report that UBC9-mediated protein SUMOylation plays an essential role in peripheral CD4 T-cell proliferation, but without a perceptible impact on T-cell polarization. Both conventional T-cell (Tcon) and regulatory T-cell (Treg) maintenance are differentially affected, which was likely caused by a shared deficit in cell glycolytic metabolism. Mechanistically, PDPK1 (3-phosphoinositide-dependent protein-kinase 1) was identified as a novel SUMOylation substrate, which occurred predominantly at lysine 299 (K299) located within the protein-kinase domain. Loss of PDPK1 SUMOylation impeded its autophosphorylation at serine 241 (S241), thereby leading to hypoactivation of downstream mTORC1 signaling coupled with incompetence of cell proliferation. Altogether, our results revealed a novel regulatory mechanism in peripheral CD4 T-cell homeostatic proliferation, which involves SUMOylation regulation of PDPK1-mTORC1 signaling-mediated glycolytic process.