TransAC4C-a novel interpretable architecture for multi-species identification of N4-acetylcytidine sites in RNA with single-base resolution.

N4-acetylcytidine (ac4C) is a modification found in ribonucleic acid (RNA) related to diseases. Expensive and labor-intensive methods hindered the exploration of ac4C mechanisms and the development of specific anti-ac4C drugs. Therefore, an advanced prediction model for ac4C in RNA is urgently needed. Despite the construction of various prediction models, several limitations exist: (1) insufficient resolution at base level for ac4C sites; (2) lack of information on species other than Homo sapiens; (3) lack of information on RNA other than mRNA; and (4) lack of interpretation for each prediction. In light of these limitations, we have reconstructed the previous benchmark dataset and introduced a new dataset including balanced RNA sequences from multiple species and RNA types, while also providing base-level resolution for ac4C sites. Additionally, we have proposed a novel transformer-based architecture and pipeline for predicting ac4C sites, allowing for highly accurate predictions, visually interpretable results and no restrictions on the length of input RNA sequences. Statistically, our work has improved the accuracy of predicting specific ac4C sites in multiple species from less than 40% to around 85%, achieving a high AUC > 0.9. These results significantly surpass the performance of all existing models.

Molecular mechanism of renal lipid accumulation in diabetic kidney disease.

Diabetic kidney disease (DKD) is a leading cause of end stage renal disease with unmet clinical demands for treatment. Lipids are essential for cell survival; however, renal cells have limited capability to metabolize overloaded lipids. Dyslipidaemia is common in DKD patients and renal ectopic lipid accumulation is associated with disease progression. Unveiling the molecular mechanism involved in renal lipid regulation is crucial for exploring potential therapeutic targets. In this review, we focused on the mechanism underlying cholesterol, oxysterol and fatty acid metabolism disorder in the context of DKD. Specific regulators of lipid accumulation in different kidney compartment and TREM2 macrophages, a lipid-related macrophages in DKD, were discussed. The role of sodium-glucose transporter 2 inhibitors in improving renal lipid accumulation was summarized.

Native top-down mass spectrometry for higher-order structural characterization of proteins and complexes.

Progress in structural biology research has led to a high demand for powerful and yet complementary analytical tools for structural characterization of proteins and protein complexes. This demand has significantly increased interest in native mass spectrometry (nMS), particularly native top-down mass spectrometry (nTDMS) in the past decade. This review highlights recent advances in nTDMS for structural research of biological assemblies, with a particular focus on the extra multi-layers of information enabled by TDMS. We include a short introduction of sample preparation and ionization to nMS, tandem fragmentation techniques as well as mass analyzers and software/analysis pipelines used for nTDMS. We highlight unique structural information offered by nTDMS and examples of its broad range of applications in proteins, protein-ligand interactions (metal, cofactor/drug, DNA/RNA, and protein), therapeutic antibodies and antigen-antibody complexes, membrane proteins, macromolecular machineries (ribosome, nucleosome, proteosome, and viruses), to endogenous protein complexes. The challenges, potential, along with perspectives of nTDMS methods for the analysis of proteins and protein assemblies in recombinant and biological samples are discussed.

External validation of the SYNTAX score II 2020 in patients with chronic renal insufficiency.

BACKGROUND: The SYNTAX score Ⅱ 2020 (SSⅡ-2020) was created as a customized decision-making tool for individuals diagnosed with complex coronary artery disease (CAD). Nevertheless, there has been a scarcity of research investigating the long-term predictive significance of SSⅡ-2020 for patients with both CAD and chronic renal insufficiency (CRI) who undergo percutaneous coronary intervention (PCI). AIMS: We sought to showcase the prognostic capacity of SSII-2020 in evaluating long-term all-cause mortality (ACM) within this high-risk patient cohort. METHODS: A retrospective cohort comprising 1156 individuals diagnosed with CRI and exhibiting left main CAD, three-vessel CAD or both was included in this investigation. We categorized participants into three groups based on the optimal SSII-2020 threshold for predicting long-term ACM, determined using the X-tile software. RESULTS: At the median follow-up duration of 6.3 years, the ACM rates were determined to be 10% in the low, 17% in the moderate, and 28% in the high SSII-2020 groups (p < 0.001). Employing multivariate Cox regression analysis, it was observed that the high SSII-2020 group exhibited a 3.289-fold increased risk of ACM (95% confidence interval [CI]: 2.229-4.856, p < 0.001) compared with the low SSII-2020 group, whereas the high SSII-2020 group displayed a 1.757-fold (95% CI: 1.190-2.597, p = 0.005) in comparison to the median SSII-2020 groups. Compared with SSII, the SSII-2020 had an incremental value for predicting 7-year ACM (C-index: 0.662 vs. 0.534, p = 0.007; IDI: 0.016, p < 0.001). CONCLUSIONS: SSII-2020 enhances long-term ACM prediction, facilitates improved risk stratification, and improves clinical utility for PCI patients with complex CAD and CRI.

sgcocaller and comapr: personalised haplotype assembly and comparative crossover map analysis using single-gamete sequencing data.

Profiling gametes of an individual enables the construction of personalised haplotypes and meiotic crossover landscapes, now achievable at larger scale than ever through the availability of high-throughput single-cell sequencing technologies. However, high-throughput single-gamete data commonly have low depth of coverage per gamete, which challenges existing gamete-based haplotype phasing methods. In addition, haplotyping a large number of single gametes from high-throughput single-cell DNA sequencing data and constructing meiotic crossover profiles using existing methods requires intensive processing. Here, we introduce efficient software tools for the essential tasks of generating personalised haplotypes and calling crossovers in gametes from single-gamete DNA sequencing data (sgcocaller), and constructing, visualising, and comparing individualised crossover landscapes from single gametes (comapr). With additional data pre-possessing, the tools can also be applied to bulk-sequenced samples. We demonstrate that sgcocaller is able to generate impeccable phasing results for high-coverage datasets, on which it is more accurate and stable than existing methods, and also performs well on low-coverage single-gamete sequencing datasets for which current methods fail. Our tools achieve highly accurate results with user-friendly installation, comprehensive documentation, efficient computation times and minimal memory usage.

Antibacterial activity and antibacterial mechanism of flavaspidic acid BB against Staphylococcus haemelyticus.

BACKGROUND: Staphylococcus haemolyticus (S. haemolyticus) is the main etiological factor in skin and soft tissue infections (SSTI). S. haemolyticus infections are an important concern worldwide, especially with the associated biofilms and drug resistance. Herein, we investigated the inhibitory effect of Flavaspidic acid BB obtained from plant extractions on clinical S. haemolyticus strains and their biofilms. Moreover, we predicted its ability to bind to the protein-binding site by molecular simulation. Since the combination of Hsp70 and RNase P synthase after molecular simulation with flavaspidic acid BB is relatively stable, enzyme-linked immunosorbent assay (ELISA) was used to investigate Hsp70 and RNase P synthase to verify the potential antimicrobial targets of flavaspidic acid BB. RESULTS: The minimum inhibitory concentrations (MIC) of flavaspidic acid BB on 16 clinical strains of S. haemolyticus was 5 ~ 480 µg/mL, and BB had a slightly higher inhibitory effect on the biofilm than MUP. The inhibitory effect of flavaspidic acid BB on biofilm formation was better with an increase in the concentration of BB. Molecular simulation verified its ability to bind to the protein-binding site. The combination of ELISA kits showed that flavaspidic acid BB promoted the activity of Hsp70 and inhibited the activity of RNase P, revealing that flavaspidic acid BB could effectively inhibit the utilization and re-synthesis of protein and tRNA synthesis, thus inhibiting bacterial growth and biofilm formation to a certain extent. CONCLUSIONS: This study could potentially provide a new prospect for the development of flavaspidic acid BB as an antibacterial agent for resistant strains.

Does omega-3 PUFA-enriched oral nutritional intervention benefit cancer patients receiving chemo (radio) therapy? A systematic review and meta-analysis of randomized controlled trials.

Although data indicate omega-3 polyunsaturated fatty acids are beneficial nutrients in cancer therapy, the evidences for efficacy of nutritional interventions during chemo (radio) therapy are still limited. The leading goal of the present meta-analysis was to summarize randomized controlled trials involving the administration of ω-3 PUFA-enriched oral nutritional supplements during chemo (radio) therapy, and evaluate the effects on nutritional status and clinical outcomes in patients. We systematically searched PubMed, Embase, Web of Science, Cochrane databases to identify interventions assessing body weight, BMI, immune and inflammatory indicators, plasma omega-3 fatty acids and adverse events, with subgroup analyses for region, types of ω-3 fatty acids, dose, duration and dosage form. In total, 22 studies including 1155 participants met the inclusion criteria. Meta-analysis showed a significant increase in body weight (BW) (WMD = 0.59 kg, 95% CI: 0.06, 1.13, P = 0.03), body mass index (BMI) (WMD = 0.43 kg/m2, 95% CI: 0.07, 0.79, P = 0.02), and plasma total ω-3 fatty acids (SMD = 2.52, 95% CI: 1.27, 3.78, P<0.0001), and a significant reduction in plasma levels of C-reactive protein (CRP) (SMD= -0.53, 95% CI: -0.80, -0.25, P = 0.0001), tumor necrosis factor-α (TNF-α) (WMD = -0.40 pg/mL, 95% CI: -0.80, -0.01, P = 0.05), interleukin 6 (IL-6) (WMD = -1.25 pg/mL, 95% CI: -2.41, -0.10, P = 0.03) and the incidence of adverse events (RR= 0.72, 95% CI: 0.54, 0.95, P = 0.02). However, plasma albumin levels (WMD = 0.02 mg/dL, 95% CI: -0.13, 0.18, P = 0.75) was remained unaffected. Overall, our meta-analysis provides evidences that the consumption of ω-3 PUFA-enriched oral nutritional supplements exert beneficial effects on nutritional status and clinical outcomes in patients undergoing chemo (radio) therapy.

Human umbilical cord mesenchymal stem cell-derived extracellular vesicles loaded with miR-223 ameliorate myocardial infarction through P53/S100A9 axis.

Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have been proposed as a promising strategy for myocardial infarction (MI). This study aims to explore the mechanism of human umbilical cord MSCs (hucMSCs)-derived EVs loaded with miR-223 on MI. Inflammation, cell biological functions, and fibrosis in vitro were measured. Furthermore, MI rat models were established to verify the role of EVs-miR-223 in vivo. The binding relationship between miR-223 and P53 was confirmed. ChIP assay was utilized to observe the combination of P53 and S100A9. The suppressed fibrosis of cardiomyocytes occurred with cells overexpressing miR-223. MiR-223 contributed to the angiogenesis of HUVECs. P53 was a target gene of miR-223. In vivo, miR-223 relieved myocardial fibrosis and inflammation infiltration, and promoted the angiogenesis in MI rats. HucMSC-derived EVs loaded with miR-223 mitigates MI and promotes myocardial repair through the P53/S100A9 axis, manifesting the underlying therapy values of hucMSC-derived EVs loaded with miR-223 in MI.

A Natural Compound Containing a Disaccharide Structure of Glucose and Rhamnose Identified as Potential N-Glycanase 1 (NGLY1) Inhibitors.

N-glycanase 1 (NGLY1) is an essential enzyme involved in the deglycosylation of misfolded glycoproteins through the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway, which could hydrolyze N-glycan from N-glycoprotein or N-glycopeptide in the cytosol. Recent studies indicated that NGLY1 inhibition is a potential novel drug target for antiviral therapy. In this study, structure-based virtual analysis was applied to screen candidate NGLY1 inhibitors from 2960 natural compounds. Three natural compounds, Poliumoside, Soyasaponin Bb, and Saikosaponin B2 showed significantly inhibitory activity of NGLY1, isolated from traditional heat-clearing and detoxifying Chinese herbs. Furthermore, the core structural motif of the three NGLY1 inhibitors was a disaccharide structure with glucose and rhamnose, which might exert its action by binding to important active sites of NGLY1, such as Lys238 and Trp244. In traditional Chinese medicine, many compounds containing this disaccharide structure probably targeted NGLY1. This study unveiled the leading compound of NGLY1 inhibitors with its core structure, which could guide future drug development.

Application of small angle X-ray scattering in exploring the effect of edible oils with different unsaturation FAs on bioaccessibility of stigmasterol oleate.

BACKGROUND: Phytosterol can improve its lipid solubility, lipophilic/hydrophilic balance and bioaccessibility by esterification with fatty acids, which increases its practical application range in the food industry. In the present study, small angle X-ray scattering combined with the pH-stat in vitro digestion model was applied to continuously monitor the molecular structure evolution of mixed micelles during digestion and investigate the effect of three edible oils (olive oil with 72.41 ± 0.57% oleic, sunflower seed oil with 63.45 ± 0.78% linoleic, refined linseed oil with 51.74 ± 0.34% linolenic) on bioaccessibility of stigmasterol oleate in vitro. RESULTS: The release degree and rate of fatty acids in the three edible oil systems (kOO+ST-OA = 0.0501, kSO+ ST-OA = 0.0357, kLO+ST-OA = 0.0323) was compared. The three different edible oils had similar impact on the formation of dietary mixed micelles during the simulatedin vitro digestion of stigmasterol oleate, although there were significant differences in molecular morphology and composition of mixed micelles. The results showed that the vesicles formed by linoleic oil (SO system) or linolenic oil (LO system) were easy to dissociate. The largest average number and diameter of vesicles (5.55 × 1016 cm-3 and 2230.75 Å), the most stable vesicle structure and the fastest fatty acid release rate were observed in the OO system. CONCLUSION: Compared to linoleic (SO system) or linolenic (LO system), the oleic (OO system) could facilitate the transformation of micelles to vesicles and maintain the stability of its membrane, significantly promotin the dissolution of stigmasterol and improving bioaccessibility. © 2023 Society of Chemical Industry.

Synthesis of eicosapentaenoic acid-enriched medium- and long-chain triglyceride by lipase-catalyzed transesterification: a novel strategy for clinical nutrition intervention.

BACKGROUND: Eicosapentaenoic acid (EPA) has been recognized as a promising nutrient to improve therapeutic efficacy for cancer patients. Nevertheless, there are certain limitations to the application of EPA due to its structural characteristics. To maximize the nutritive value of EPA, a type of medium- and long-chain triacylglycerol (MLCT) enriched with EPA was designed and synthesized using the lipase-catalyzed transesterification of medium-chain triglyceride (MCT) and EPA-enriched fish oil (FO). RESULTS: The optimum synthesis conditions for EPA-enriched MLCT used Lipozyme RM as catalyst, and had a substrate mass ratio (MCT/EPA-enriched FO) of 3:1, lipase loading of 80 g kg-1 , a reaction temperature of 60 °C, and a reaction time of 6 h. The MLCT content was as high as 80.79% after the transesterification reaction and the purification, and the content of MLCT containing EPA accounted for 70.21%. The distribution of EPA at the sn-2 position showed a significant increase in MLCT compared with the original substrate, from 18.89% to 26.93%. The in vitro digestion results demonstrated that MLCT had a significantly higher EPA bioaccessibility than the original substrate. CONCLUSION: Eicosapentaenoic acid-enriched MLCT was developed. This may provide a novel strategy for clinical nutritional intervention. © 2023 Society of Chemical Industry.

Puerarin attenuates diabetic kidney injury through interaction with Guanidine nucleotide-binding protein Gi subunit alpha-1 (Gnai1) subunit.

Radix puerariae, a traditional Chinese herbal medication, has been used to treat patients with diabetic kidney disease (DKD). Our previous studies demonstrated that puerarin, the active compound of radix puerariae, improves podocyte injury in type 1 DKD mice. However, the direct molecular target of puerarin and its underlying mechanisms in DKD remain unknown. In this study, we confirmed that puerarin also improved DKD in type 2 diabetic db/db mice. Through RNA-sequencing odf isolated glomeruli, we found that differentially expressed genes (DEGs) that were altered in the glomeruli of these diabetic mice but reversed by puerarin treatment were involved mostly in oxidative stress, inflammatory and fibrosis. Further analysis of these reversed DEGs revealed protein kinase A (PKA) was among the top pathways. By utilizing the drug affinity responsive target stability method combined with mass spectrometry analysis, we identified guanine nucleotide-binding protein Gi alpha-1 (Gnai1) as the direct binding partner of puerarin. Gnai1 is an inhibitor of cAMP production which is known to have protection against podocyte injury. In vitro, we showed that puerarin not only interacted with Gnai1 but also increased cAMP production in human podocytes and mouse diabetic kidney in vivo. Puerarin also enhanced CREB phosphorylation, a downstream transcription factor of cAMP/PKA. Overexpression of CREB reduced high glucose-induced podocyte apoptosis. Inhibition of PKA by Rp-cAMP also diminished the effects of puerarin on high glucose-induced podocyte apoptosis. We conclude that the renal protective effects of puerarin are likely through inhibiting Gnai1 to activate cAMP/PKA/CREB pathway in podocytes.

Dietary oleic acid supplementation and blood inflammatory markers: a systematic review and meta-analysis of randomized controlled trials.

The aim of this systematic review and meta-analysis was to analyze data from randomized controlled trials (RCTs) assessing the effects of oleic acid (OA) supplementation on blood inflammatory markers in adults. PubMed, EMBASE and Cochrane Library databases were systematically searched from 1950 to 2019, with adults and a minimum intervention duration of 4 weeks. The effect size was estimated, adopting standardized mean difference (SMD) and 95% confidence interval (CI). Of the 719 identified studies, thirty-one RCTs involving 1634 subjects were eligible. The results of this study revealed that increasing OA supplementation significantly reduced C-reactive protein (CRP) (SMD: -0.11, 95% CI: -0.21, -0.01, P = 0.038). However, dietary OA consumption did not significantly affect tumor necrosis factor (TNF) (SMD: -0.05, 95% CI: -0.19, 0.10, P = 0.534), interleukin 6 (IL-6) (SMD: 0.01, 95% CI: -0.10, 0.13, P = 0.849), fibrinogen (SMD: 0.08, 95% CI: -0.16, 0.31, P = 0.520), plasminogen activator inhibitor type 1 (PAI-1) activity (SMD: -0.11, 95% CI: -0.34, 0.12, P = 0.355), soluble intercellular adhesion molecule-1 (sICAM-1) (SMD: -0.06, 95% CI: -0.26, 0.13, P = 0.595) or soluble vascular cell adhesion molecule-1 (sVCAM-1) (SMD: -0.04, 95% CI: -0.27, 0.18, P = 0.701). Overall, the meta-analysis demonstrated that dietary OA supplementation significantly reduced CRP, yet did not affect other inflammatory markers including TNF, IL-6, fibrinogen, PAI-1 activity, sICAM-1or sVCAM-1.

Non-invasive myocardial work index contributes to early identification of impaired left ventricular myocardial function in uremic patients with preserved left ventricular ejection fraction.

BACKGROUND: Cardiac damage is the leading cause of death in uremic patients. This study aimed to evaluate the application of non-invasive myocardial work index (NIMWI) by echocardiography in assessing the left ventricular (LV) systolic function in uremic patients. METHODS: Twenty-six uremic patients and 27 age- and sex-matched healthy volunteers were enrolled in the study. Except for the conventional echocardiographic parameters, the LV myocardial work (MW) parameters including GWI (myocardial global work index), GCW (global constructive work), GWW (global wasted work), and GWE (global work efficiency) were calculated in study participants. Differences in MW parameters between the uremic and normal groups were compared by independent-sample t-test. Receiver operating characteristic (ROC) curves were constructed for MW parameters to detect abnormal LV systolic function in uremic patients. RESULTS: Compared with the normal group, GWW was significantly increased and GWE decreased in the uremic group (P < 0.05). Area under the curve (AUC) for GWE by the ROC analysis was 0.966. The best threshold, sensitivity and specificity values of GWE to detect abnormality of LV systolic function in uremic patients were 92.5%, 0.89 and 0.96, respectively. CONCLUSIONS: NIMWI may be applied to assess the global MW of uremic patients. The presence of reduced GWE can help identify impaired left ventricular myocardial function in uremic patients with preserved LV ejection fraction with a high sensitivity and specificity.

Distinctive gene expression patterns and imprinting signatures revealed in reciprocal crosses between cattle sub-species.

BACKGROUND: There are two genetically distinct subspecies of cattle, Bos taurus taurus and Bos taurus indicus, which arose from independent domestication events. The two types of cattle show substantial phenotypic differences, some of which emerge during fetal development and are reflected in birth outcomes, including birth weight. We explored gene expression profiles in the placenta and four fetal tissues at mid-gestation from one taurine (Bos taurus taurus; Angus) and one indicine (Bos taurus indicus; Brahman) breed and their reciprocal crosses. RESULTS: In total 120 samples were analysed from a pure taurine breed, an indicine breed and their reciprocal cross fetuses, which identified 6456 differentially expressed genes (DEGs) between the two pure breeds in at least one fetal tissue of which 110 genes were differentially expressed in all five tissues examined. DEGs shared across tissues were enriched for pathways related to immune and stress response functions. Only the liver had a substantial number of DEGs when reciprocal crossed were compared among which 310 DEGs were found to be in common with DEGs identified between purebred livers; these DEGs were significantly enriched for metabolic process GO terms. Analysis of DEGs across purebred and crossbred tissues suggested an additive expression pattern for most genes, where both paternal and maternal alleles contributed to variation in gene expression levels. However, expression of 5% of DEGs in each tissue was consistent with parent of origin effects, with both paternal and maternal dominance effects identified. CONCLUSIONS: These data identify candidate genes potentially driving the tissue-specific differences between these taurine and indicine breeds and provide a biological insight into parental genome effects underlying phenotypic differences in bovine fetal development.

Could the EQ-5D-3L predict all-cause mortality in older Chinese? Evidence from a 5-year longitudinal study in eastern China.

PURPOSE: To assess the ability of the 3-level EQ-5D (i.e., EQ-5D-3L) in predicting all-cause mortality in older Chinese adults. METHODS: The data were from a 5-year longitudinal study, Weitang Geriatric Diseases Study, including 4579 community-dwelling older people in eastern China, with the mean age of 72.5 years at baseline and female being 52.0%. Three multivariable logistic regression models were adopted to assess the associations of the baseline EQ-5D data [i.e., the EQ-5D problems, EQ-5D-3L index score, and EQ-5D visual analog scale (VAS) score] with the 5-year all-cause mortality, adjusting for socio-demographic characteristics, and subsequently, health conditions and lifestyle habits. RESULTS: A total of 183 participants died over the 5-year study period. A larger proportion of the dead reported problems in physical dimensions (i.e., including three dimensions: mobility, self-care, and usual activities, p < 0.05 for all). The mean EQ-5D index score (0.928) and EQ-VAS score (79.7) of the living were higher than those of the dead (0.915 and 73.2, p < 0.05 for both). In multivariable logistic analyses, the EQ-5D health problems in the physical-related dimensions [odds ratio (OR) 2.16, p < 0.05] and the EQ-VAS score (OR: 0.97, p < 0.001) were associated with the 5-year all-cause mortality when adjusting for socio-demographic characteristics, health conditions, and lifestyle habits. CONCLUSIONS: It appears that the EQ-5D-3L could predict mortality in general older Chinese, which could be used to detect high-risk older individuals in China.

Circ_0082182 promotes oncogenesis and metastasis of colorectal cancer in vitro and in vivo by sponging miR-411 and miR-1205 to activate the Wnt/ß-catenin pathway.

BACKGROUND: Circular RNAs (circRNAs) are a class of endogenous single-strand RNA transcripts with crucial regulation in human cancers. The objective of this study is to investigate the role of circ_0082182 in CRC and its specific functional mechanism. METHODS: The quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure the levels of circ_0082182, microRNA-411 (miR-411) and microRNA-1205 (miR-1205). Cell proliferation was detected by Cell counting Kit-8 (CCK-8) and colony formation assays. Flow cytometry was used for determining cell cycle and cell apoptosis. Cell apoptosis was also assessed by caspase3 and caspase9 activities. Cell migration and invasion were examined using scratch assay and transwell assay. The interaction between circ_0082182 and miRNA was validated by the dual-luciferase reporter and biotinylated RNA pull-down assays. Wnt/ß-catenin pathway and epithelial-mesenchymal transition (EMT)-associated proteins were quantified by Western blot. Xenograft model was established for the research of circ_0082182 in vivo. RESULTS: Circ_0082182 was upregulated in CRC and could predict the poor prognosis of CRC patients. Functionally, circ_0082182 promoted CRC cell proliferation, cell cycle progression, and metastasis while inhibited apoptosis. Subsequently, circ_0082182 was shown to act as the sponges of miR-411 and miR-1205. MiR-411 and miR-1205 were identified as tumor inhibitors in CRC. Furthermore, circ_0082182 promoted the CRC progression via sponging miR-411 and miR-1205. Moreover, circ_0082182 facilitated the Wnt/ß-catenin pathway and EMT process by targeting miR-411 and miR-1205. In vivo, circ_0082182 accelerated the CRC tumorigenesis and EMT process by activating the Wnt/ß-catenin pathway by downregulating the expression of miR-411 or miR-1205. CONCLUSION: This study showed that circ_0082182 functioned as an oncogene in the developing process of CRC by sponging miR-411 or miR-1205 to activate the Wnt/ß-catenin pathway. Circ_0082182 might be a molecular target in the diagnosis and treatment of CRC.

New perspective toward nutritional support for malnourished cancer patients: Role of lipids.

To improve the difficulties related to malnutrition, nutritional support has become an essential part of multidisciplinary comprehensive treatment for cancer. Lipids are essential nutrient source for the human body, and nowadays in clinical practices, it has a positive interventional effect on patients suffering from cancer. However, contribution of lipids in nutritional support of cancer patients is still poorly understood. Moreover, the sensory and physicochemical properties of lipids can severely restrict their applications in lipid-rich formula foods. In this review article, for the first time, we have presented a summary of the existing studies which were related to the associations between different lipids and improved malnutrition in cancer patients and discussed possible mechanisms. Subsequently, we discussed the challenges and effective solutions during processing of lipids into formula foods. Further, by considering existing problems in current lipid nutritional support, we proposed a novel method for the treatment of malnutrition, including developing individualized lipid nutrition for different patients depending on the individual's genotype and enterotype. Nonetheless, this review study provides a new direction for future research on nutritional support and the development of lipid-rich formula foods for cancer patients, and probably will help to improve the efficacy of lipids in the treatment of cancer malnutrition.

Role of SIRT1 in HIV-associated kidney disease.

Human immunodeficiency virus (HIV) infection of kidney cells can lead to HIV-associated nephropathy (HIVAN) and aggravate the progression of other chronic kidney diseases. Thus, a better understanding of the mechanisms of HIV-induced kidney cell injury is needed for effective therapy against HIV-induced kidney disease progression. We have previously shown that the acetylation and activation of key inflammatory regulators, NF-κB p65 and STAT3, were increased in HIVAN kidneys. Here, we demonstrate the key role of sirtuin 1 (SIRT1) deacetylase in the regulation of NF-κB and STAT3 activity in HIVAN. We found that SIRT1 expression was reduced in the glomeruli of human and mouse HIVAN kidneys and that HIV-1 gene expression was associated with reduced SIRT1 expression and increased acetylation of NF-κB p65 and STAT3 in cultured podocytes. Interestingly, SIRT1 overexpression, in turn, reduced the expression of negative regulatory factor in podocytes stably expressing HIV-1 proviral genes, which was associated with inactivation of NF-κB p65 and a reduction in HIV-1 long terminal repeat promoter activity. In vivo, the administration of the small-molecule SIRT1 agonist BF175 or inducible overexpression of SIRT1 specifically in podocytes markedly attenuated albuminuria, kidney lesions, and expression of inflammatory markers in Tg26 mice. Finally, we showed that the reduction in SIRT1 expression by HIV-1 is in part mediated through miR-34a expression. Together, our data provide a new mechanism of SIRT1 regulation and its downstream effects in HIV-1-infected kidney cells and indicate that SIRT1/miR-34a are potential drug targets to treat HIV-related kidney disease.

Mice lacking DUSP6/8 have enhanced ERK1/2 activity and resistance to diet-induced obesity.

Extracellular signal-regulated kinase 1 and 2 (ERK1/2) have been implicated as important regulators of metabolic homeostasis. Here we generated a new mouse model with genetic deletion of two ERK1/2 phosphatases, dual specificity phosphatase (DUSP) 6 and 8, to further define the role of ERK1/2 in obesity development. Dusp6/8 double-null mice demonstrated elevated ERK1/2 phosphorylation in multiple tissues, without any change of phosphorylation of p38 and c-Jun N-terminal kinases (JNKs). Elevated ERK1/2 activity in Dusp6/8 double-null mice was associated with larger hearts and other organs, consistent with greater rate of cell proliferation in these mice. However, ERK1/2 activation was not sufficient to protect the mouse hearts from pathological hypertrophy and interstitial fibrosis following angiotensin II and phenylephrine stimulation. Interestingly, mice lacking DUSP6/8 were resistant to high-fat diet-induced obesity. Serum triglyceride, lipid content in the liver and visceral adipose tissues was also dramatically reduced in Dusp6/8 double-null mice. Furthermore, Dusp6/8 double-null mice had improved glucose tolerance. Mechanistically, we found out that elevated ERK1/2 activity increased the expression levels of genes involved in lipid metabolism and glucose homeostasis. Together, our data suggest that ERK1/2 play an essential role for the management of metabolic homeostasis.