To explore the pathogenesis of anterior resection syndrome by magnetic resonance imaging rectal defecography.

BACKGROUND: Over 90% of rectal cancer patients develop low anterior resection syndrome (LARS) after sphincter-preserving resection. The current globally recognized evaluation method has many drawbacks and its subjectivity is too strong, which hinders the research and treatment of LARS. AIM: To evaluate the anorectal function after colorectal cancer surgery by quantifying the index of magnetic resonance imaging (MRI) defecography, and pathogenesis of LARS. METHODS: We evaluated 34 patients using the standard LARS score, and a new LARS evaluation index was established using the dynamic images of MRI defecography to verify the LARS score. RESULTS: In the LARS score model, there were 10 (29.41%) mild and 24 (70.58%) severe cases of LARS. The comparison of defecation rate between the two groups was 29.36 ± 14.17% versus 46.83 ± 18.62% (P = 0.004); and MRI-rectal compliance (MRI-RC) score was 3.63 ± 1.96 versus 7.0 ± 3.21 (P = 0.001). Severe and mild LARS had significant differences using the two evaluation methods. There was a significant negative correlation between LARS and MRI-RC score (P < 0.001), and they had a negative correlation with defecation rate (P = 0.028). CONCLUSION: MRI defecography and standard LARS score can both be used as an evaluation index to study the pathogenesis of LARS.

Adaptive enhancement of cataractous retinal images for contrast standardization.

Cataract affects the quality of fundus images, especially the contrast, due to lens opacity. In this paper, we propose a scheme to enhance different cataractous retinal images to the same contrast as normal images, which can automatically choose the suitable enhancement model based on cataract grading. A multi-level cataract dataset is constructed via the degradation model with quantified contrast. Then, an adaptive enhancement strategy is introduced to choose among three enhancement networks based on a blurriness classifier. The blurriness grading loss is proposed in the enhancement models to further constrain the contrast of the enhanced images. During test, the well-trained blurriness classifier can assist in the selection of enhancement networks with specific enhancement ability. Our method performs the best on the synthetic paired data on PSNR, SSIM, and FSIM and has the best PIQE and FID on 406 clinical fundus images. There is a 7.78% improvement for our method compared with the second on the introduced [Formula: see text] score without over-enhancement according to [Formula: see text], which demonstrates that the proper enhancement by our method is close to the high-quality images. The visual evaluation on multiple clinical datasets also shows the applicability of our method for different blurriness. The proposed method can benefit clinical diagnosis and improve the performance of computer-aided algorithms such as vessel tracking and vessel segmentation.

Multi-omics analysis reveals interferon-stimulated gene OAS1 as a prognostic and immunological biomarker in pan-cancer.

Introduction: OAS1(2'-5'-oligoadenylate synthetase 1) is a member of the Interferon-Stimulated Genes which plays an important role in the antiviral process. In recent years, the role of OAS1 in tumors has attracted attention, and it was found to be associated with prognosis in several tumors. However, the mechanism by which OAS1 affects tumors is unclear and pan-cancer study of OAS1 is necessary to better understand its implication in cancers. Methods: The expression, prognostic value, genetic alteration, alternative splicing events of OAS1 in pan-cancers were analyzed using TCGA, GTEx, HPA, GEPIA and OncoSplicing databases. OAS1 associated immune cell infiltration was evaluated using the ESTIMATE, xCell, CIBERSORT and QUANTISEQ algorithm. Single cell transcriptome data download using TISH database. Finally, the roles of the OAS1 on apoptosis, migration and invasion were investigated in two pancreatic cancer cells. Results: Our results revealed significant differences in OAS1 expression among various tumors, which had prognostic implications. In addition, we investigated the impact of OAS1 on genomic stability, methylation status, and other factors across different types of cancer, and the effects of these factors on prognosis. Notably, our study also demonstrated that OAS1 overexpression can contribute to CTL dysfunction and macrophage M2 polarization. In addition, cell experiments showed that the knockdown of OAS1 could reduce the invasive ability and increased the apoptosis rate of PAAD cells. Discussion: These results confirmed that OAS1 could be a prognostic biomarker and therapeutic target for its potential role in CTL dysfunction and macrophage M2 polarization.

A fundus image classification framework for learning with noisy labels.

Fundus images are widely used in the screening and diagnosis of eye diseases. Current classification algorithms for computer-aided diagnosis in fundus images rely on large amounts of data with reliable labels. However, the appearance of noisy labels degrades the performance of data-dependent algorithms, such as supervised deep learning. A noisy label learning framework suitable for the multiclass classification of fundus diseases is presented in this paper, which combines data cleansing (DC), adaptive negative learning (ANL), and sharpness-aware minimization (SAM) modules. Firstly, the DC module filters the noisy labels in the training dataset based on the prediction confidence. Then, the ANL module modifies the loss function by choosing complementary labels, which are neither the given labels nor the labels with the highest confidence. Moreover, for better generalization, the SAM module is applied by simultaneously optimizing the loss and its sharpness. Extensive experiments on both private and public datasets show that our method greatly promotes the performance for classification of multiple fundus diseases with noisy labels.

TRAF1 improves cisplatin-induced acute kidney injury via inhibition of inflammation and metabolic disorders.

BACKGROUND: Cisplatin-induced acute kidney injury (AKI) is a severe clinical complication with no satisfactory therapies in the clinic. Tumor necrosis factor receptor (TNFR)-associated factor 1 (TRAF1) plays a vital role in both inflammation and metabolism. However, the TRAF1 effect in cisplatin induced AKI needs to be evaluated. METHODS: We observed the role of TRAF1 in eight-week-old male mice and mouse proximal tubular cells both treated with cisplatin by examining the indicators associated with kidney injury, apoptosis, inflammation, and metabolism. RESULTS: TRAF1 expression was decreased in cisplatin-treated mice and mouse proximal tubular cells (mPTCs), suggesting a potential role of TRAF1 in cisplatin-associated kidney injury. TRAF1 overexpression significantly alleviated cisplatin-triggered AKI and renal tubular injury, as demonstrated by reduced serum creatinine (Scr) and urea nitrogen (BUN) levels, as well as the ameliorated histological damage and inhibited upregulation of NGAL and KIM-1. Moreover, the NF-κB activation and inflammatory cytokine production enhanced by cisplatin were significantly blunted by TRAF1. Meanwhile, the increased number of apoptotic cells and enhanced expression of BAX and cleaved Caspase-3 were markedly decreased by TRAF1 overexpression both in vivo and vitro. Additionally, a significant correction of the metabolic disturbance, including perturbations in energy generation and lipid and amino acid metabolism, was observed in the cisplatin-treated mice kidneys. CONCLUSION: TRAF1 overexpression obviously attenuated cisplatin-induced nephrotoxicity, possibly by correcting the impaired metabolism, inhibiting inflammation, and blocking apoptosis in renal tubular cells. GENERAL SIGNIFICANCE: These observations emphasize the novel mechanisms associated to metabolism and inflammation of TRAF1 in cisplatin-induced kidney injury.

Detection of enrofloxacin residues in dairy products based on their fluorescence quenching effect on AgInS2 QDs.

Water-soluble AgInS2 (AIS) quantum dots (QDs) were successfully prepared through the one-pot water phase method with thioglycolic acid (TGA) as the stabilizing agent. Because enrofloxacin (ENR) effectively quenches the fluorescence of AIS QDs, a highly-sensitive fluorescence detection method is proposed to detect ENR residues in milk. Under optimal detection conditions, there was a good linear relationship between the relative fluorescence quenching amount (ΔF/F0) of AgInS2 with ENR and ENR concentration (C). The detection range was 0.3125-20.00 µg/mL, r = 0.9964, and the detection limit (LOD) was 0.024 µg/mL (n = 11). The average recovery of ENR in milk ranged from 95.43 to 114.28%. The method established in this study has advantages including a high sensitivity, a low detection limit, simple operation and a low cost. The fluorescence quenching mechanism of AIS QDs with ENR was discussed and the dynamic quenching mechanism of light-induced electron transfer was proposed.

[A case of Rubinstein-Taybi syndrome caused by a variant of EP300 gene].

OBJECTIVE: To explore the clinical characteristics and genetic etiology of a child with Rubinstein-Taybi syndrome (RSTS). METHODS: A child who was admitted to the Children's Hospital of Soochow University on October 3, 2021 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and his parents were collected. The child was subjected to whole exome sequencing (WES), and candidate variant was verified by Sanger sequencing of his family members and bioinformatic analysis. RESULTS: The patient, a 9-year-and-４-month-old boy, had manifested unique facies, microcephaly, broad toes, growth retardation, and intellectual impairment. WES revealed that he has harbored a heterozygous c.3604G>T (p.E1202*) variant in exon 20 of the EP300 gene. Sanger sequencing confirmed that neither of his parents has carried the same variant. The variant was not found in the Shenzhou Genome data Cloud, ExAC, 1000 Genomes and gnomAD databases．Analysis with SIFT, PolyPhen-2 and CADD online software has predicted the variant to be harmful. Based on the guidelines formulated by the American College of Medical Genetics and Genomics, the variant was rated as pathogenic (PVS1＋PS2＋PM2_Supporting) . CONCLUSION: The heterozygous c.3604G>T variant of the EP300 gene probably underlay the RSTS type 2 in this child. Above finding has also expanded the variation spectrum of the EP300 gene.

Rapid Microstructure Homogenization of a Laser Melting Deposition Additive Manufactured Ti-6.5Al-3.5Mo-1.5Zr-0.3Si Alloy by Electropulsing.

The typical microstructure of the laser melting deposition (LMD) additive-manufactured Ti-6.5Al-3.5Mo-1.5Zr-0.3Si alloy (TC11) contains the heat-affected bands (HABs), the narrow bands (NBs) and the melting pools (MPs) that formed due to the reheating and superheating effects during the layer-by-layer manufacturing process. Characterization results indicated that the coarse primary α lath (αp) and transformed ß (ßt) structures were located in the HABs, while the fine basketweave structure was formed inside the MPs. The rapid modifications of microstructure and tensile properties of the LMD-TC11 via electropulsing treatment (EPT) were investigated. The initial heterogeneous microstructure transformed into a complete basketweave structure and the HABs vanished after EPT. Thus, a more homogeneous microstructure was achieved in the EPT sample. The ultrafast microstructural changes were mainly attributed to the solid state phase transformation during electropulsing. The tensile properties of the sample were basically stable, except that the yield strength decreased as EPT voltage increased. This study suggests that EPT could be a promising method to modify the microstructure and mechanical properties of the additive-manufactured alloys in a very short time.

Dendritic cell-derived IL-27 p28 regulates T cell program in pathogenicity and alleviates acute graft-versus-host disease.

Interleukin 27 (IL-27), a heterodimeric cytokine composed of Epstein-Barr virus-induced 3 and p28, is a pleiotropic cytokine with both pro-and anti-inflammatory properties. However, the precise role of IL-27 in acute graft-versus-host disease is not yet fully understood. In this study, utilizing mice with IL-27 p28 deficiency in dendritic cells (DCs), we demonstrated that IL-27 p28 deficiency resulted in impaired Treg cell function and enhanced effector T cell responses, corresponding to aggravated aGVHD in mice. In addition, using single-cell RNA sequencing, we found that loss of IL-27 p28 impaired Treg cell generation and promoted IL-1R2+TIGIT+ pathogenic CD4+ T cells in the thymus at a steady state. Mechanistically, IL-27 p28 deficiency promoted STAT1 phosphorylation and Th1 cell responses, leading to the inhibition of Treg cell differentiation and function. Finally, patients with high levels of IL-27 p28 in serum showed a substantially decreased occurrence of grade II-IV aGVHD and more favorable overall survival than those with low levels of IL-27 p28. Thus, our results suggest a protective role of DC-derived IL-27 p28 in the pathogenesis of aGVHD through modulation of the Treg/Teff cell balance during thymic development. IL-27 p28 may be a valuable marker for predicting aGVHD development after transplantation in humans.

Investigation of indole biodegradation by Cupriavidus sp. strain IDO with emphases on downstream biotransformation and indigo production.

Indole, as a typical N-heterocyclic aromatic pollutant, poses risks to living things; however, indole-biotransformation mechanisms remain under-discussed, especially those related to its downstream biotransformation. Here, we systematically investigated the characteristics of indole degradation by strain Cupriavidus sp. IDO. We found that Cupriavidus sp. IDO could utilize 25 to 150 mg/L indole within 40 h and identified three intermediates (2-oxindole, indigo, and isatin). Additionally, integrated genomics and proteomics analysis of the indole biotransformation mechanism in strain IDO revealed 317 proteins showing significant changes (262 upregulated and 55 downregulated) in the presence of indole. Among these, three clusters containing indole oxidoreductase, CoA-thioester ligase, and gentisate 1,2-oxidoreductase were identified as potentially responsible for upstream and downstream indole metabolism. Moreover, HPLC-MS and -omics analysis offered insight into the indole-degradation pathway in strain IDO. Furthermore, the indole oxidoreductase IndAB, which initiates indole degradation, was heterologously expressed in Escherichia coli BL21(DE3). Optimization by the response surface methodology resulted in a maximal production of 135.0 mg/L indigo by the recombination strains in tryptophan medium. This work enriches our understanding of the indole-biodegradation process and provides new insights into multiple indole-degradation pathways in natural environments.

Identification of metabolic biomarkers to predict treatment outcome and disease progression in multiple myeloma.

The relationship between metabolites and multiple myeloma (MM) is becoming a research focus in the field. In this study, we performed metabolic profiling of multiple myeloma and identified potential metabolites associated with clinical characteristics, therapeutic efficacy, and prognosis of the disease. Fifty-five patients with newly-diagnosed multiple myeloma and thirty-seven healthy controls from August 2016 to October 2017 were randomly collected. The serum metabolic profiling was investigated by gas chromatography-mass spectrometry (GC-MS) technique and underwent statistical analysis. Twenty-seven metabolites were found to be significantly different between healthy controls and multiple myeloma patients. Eleven metabolites were significantly elevated, while sixteen metabolites were decreased in the multiple myeloma population. Metabolic changes were also observed in patients with renal impairment and bone destruction. Levels of urea were significantly decreased after treatment while levels of hypotaurine showed significant increase in the good-effect group (P<0.05), but not in the no-good-effect group (P>0.05). In multivariate statistical analyses, high cysteine and high hypotaurine are independent risk factors for poor treatment outcome. After adjustment for critical clinical characteristics, patients with high levels of glycolic acid and xylitol were found to be less likely to experience disease progression. Multiple myeloma demonstrates different metabolic characteristics compared with the healthy population. Among multiple myeloma patients, renal impairment and bone destruction showed additional metabolic characteristics. Cysteine and hypotaurine have value in predicting the treatment outcome, while glycolic acid and xylitol may be important prognostic factors for multiple myeloma.

miR-214 Protects Against Uric Acid-Induced Endothelial Cell Apoptosis.

Background: Uric acid (UA) has been reported to be an important risk factor for cardiovascular diseases and can cause endothelial cell apoptosis through unclear mechanisms. Accumulating evidence has demonstrated that miR-214 plays a pivotal role in the pathogenesis of cardiovascular diseases. This study was to investigate the role of miR-214 in UA-induced endothelial cell apoptosis and the underlying mechanism. Material and methods: We enrolled 30 patients with hyperuricemia and 32 healthy controls and analyzed the levels of miR-214 in the serum of the participants. Then mouse aorta endothelial cells (MAECs) were treated with UA to induce cell apoptosis. An miR-214 mimic and a specific COX-2 inhibitor (NS398) were used to confirm the roles of these molecules in mediating UA-induced MAEC apoptosis or COX-2/PGE2 cascade activation. Results: A significant reduction in circulating miR-214 in the hyperuricemia patients compared with the healthy controls, along with a negative correlation with UA levels was observed. In the MAECs, UA treatment strikingly increased apoptosis as shown by the upregulation of BAX and cleaved Caspase-3 and the increased number of apoptotic cells. Interestingly, the expression of COX-2 was also upregulated at both the protein and mRNA levels during UA-induced cell apoptosis. In addition, an miR-214 mimic blocked UA-induced MAEC apoptosis, COX-2 induction and PGE2 secretion. The inhibition of COX-2 markedly ameliorated UA-induced apoptotic response and PGE2 production in MAECs. Luciferase activity assays further confirmed that COX-2 is a target gene of miR-214 in endothelial cells. Conclusion: We concluded that miR-214 could alleviate UA-induced MAEC apoptosis possibly by inhibiting the COX-2/PGE2 cascade.

Chloroquine attenuates lithium-induced NDI and proliferation of renal collecting duct cells.

Lithium is widely used in psychiatry as the golden standard for more than 60 yr due to its effectiveness. However, its adverse effect has been limiting its long-term use in clinic. About 40% of patients taking lithium develop nephrogenic diabetes insipidus (NDI). Lithium can also induce proliferation of collecting duct cells, leading to microcyst formation in the kidney. Lithium was considered an autophagy inducer that might contribute to the therapeutic benefit of neuropsychiatric disorders. Thus, we hypothesized that autophagy may play a role in lithium-induced kidney nephrotoxicity. To address our hypothesis, we fed mice with a lithium-containing diet with chloroquine (CQ), an autophagy inhibitor, concurrently. Lithium-treated mice presented enhanced autophagy activity in the kidney cortex and medulla. CQ treatment significantly ameliorated lithium-induced polyuria, polydipsia, natriuresis, and kaliuresis accompanied with attenuated downregulation of aquaporin-2 and Na+-K+-2Cl- cotransporter protein. The protective effect of CQ on aquaporin-2 protein abundance was confirmed in cultured cortical collecting duct cells. In addition, we found that lithium-induced proliferation of collecting duct cells was also suppressed by CQ as detected by proliferating cell nuclear antigen staining. Moreover, both phosphorylated mammalian target of rapamycin and ß-catenin expression, which have been reported to be increased by lithium and associated with cell proliferation, were reduced by CQ. Taken together, our study demonstrated that CQ protected against lithium-induced NDI and collecting duct cell proliferation possibly through inhibiting autophagy.

MicroRNA-214 targets COX-2 to antagonize indoxyl sulfate (IS)-induced endothelial cell apoptosis.

Cardiovascular disease (CVD) serves as the major cause of mortality in chronic kidney disease (CKD) patients. The injury of endothelium associated with the long-term challenge of uremic toxins including the toxic indoxyl sulfate (IS) is one of key pathological factors leading to CVD. However, the mechanisms of uremic toxins, especially the IS, resulting in endothelial injury, remain unclear. miR-214 was reported to contribute to the pathogenesis of cardiovascular diseases, while its role in IS-induced endothelial cell apoptosis is unknown. In this study, we investigated the role of microRNA-214 (miR-214) in IS-induced endothelial cell apoptosis and the underlying mechanisms using mouse aortic endothelial cells (MAECs). Following IS treatment, miR-214 was significantly downregulated in MAECs in line with enhanced cell apoptosis. Meanwhile, COX-2 was upregulated at both mRNA and protein levels along with increased secretion of PGE2 in medium. To define the role of miR-214 in IS-induced endothelial cell apoptosis, we modulated miR-214 level in MAECs and found that overexpression of miR-214 markedly attenuated endothelial cell apoptosis, while antagonism of miR-214 deteriorated cell death after IS challenge. Further analyses confirmed that COX-2 is a target gene of miR-214, and the inhibition of COX-2 by a specific COX-2 inhibitor NS-398 strikingly attenuated IS-induced endothelial cell apoptosis along with a significant blockade of PGE2 secretion. In conclusion, this study demonstrated an important role of miR-214 in protecting against endothelial cell damage induced by IS possibly by direct downregulation of COX-2/PGE2 axis.

Rescue of cognitive deficits in APP/PS1 mice by accelerating the aggregation of ß-amyloid peptide.

BACKGROUND: Brain amyloid deposition is one of the main pathological characteristics of Alzheimer's disease (AD). Soluble oligomers formed during the process that causes ß-amyloid (Aß) to aggregate into plaques are considered to have major neurotoxicity. Currently, drug development for the treatment of Alzheimer's disease has encountered serious difficulties. Our newly proposed solution is to accelerate the aggregation of Aß to reduce the amount of cytotoxic Aß oligomers in brain tissue. This strategy differs from the existing strategy of reducing the total Aß content and the number of amyloid plaques. METHOD: In this study, we screened a small library and found that a flavonoid compound (ZGM1) promoted the aggregation of ß-amyloid (Aß). We further verified the binding of ZGM1 to Aß42 using a microscale thermophoresis (MST) assay. Subsequently, we used dot blotting (DB), transmission electron microscopy (TEM), and thioflavin T fluorescence (ThT) measurements to study the aggregation of Aß under the influence of ZGM1. By using cell experiments, we determined whether ZGM1 can inhibit the cytotoxicity of Aß. Finally, we studied the protective effects of ZGM1 on cognitive function in APPswe/PS1 mice via behavioral experiments and measured the number of plaques in the mouse brain by thioflavin staining. RESULTS: ZGM1 can bind with Aß directly and mediate a new Aß assembly process to form reticular aggregates and reduce the amount of Aß oligomers. Animal experiments showed that ZGM1 can significantly improve cognitive dysfunction and that Aß plaque deposition in the brain tissue of mice in the drug-administered group was significantly increased. CONCLUSION: Our research suggests that promoting Aß aggregation is a promising treatment method for AD and deserves further investigation.

Application of an efficient indole oxygenase system from Cupriavidus sp. SHE for indigo production.

Indigo, one of the most widely used dyes, is mainly produced by chemical processes, which generate amounts of pollutants and need high energy consumption. Microbial production of indigo from indole has attracted much attention; however, the indole oxygenase has never been explored and applied for indigo production. In the present study, the indole oxygenase indAB genes were successfully cloned from Cupriavidus sp. SHE and heterologously expressed in Escherichia coli BL21(DE3) (designated as IND_AB). Strain IND_AB produced primarily indigo in tryptophan medium by high-performance liquid chromatography-mass spectroscopy (HPLC-MS) analysis. The preferable conditions for indigo production were pH 6.5 (normal pH), 30 °C, 150 rpm, strain inoculation concentration OD600 0.08, and induction with 1 mM IPTG at the time of inoculation. The optimal culture medium compositions were further determined as tryptophan 1.0 g/L, NaCl 3.55 g/L, and yeast extract 5.12 g/L based on single-factor experiment and response surface methodology. The highest indigo yield was 307 mg/L, which was 4.39-fold higher than the original value. This is the first study investigating indigo production using the indole oxygenase system and the results highlighted its potential in bio-indigo industrial application.

Colloidal tectonics for tandem synergistic Pickering interfacial catalysis: oxidative cleavage of cyclohexene oxide into adipic acid.

Supramolecular preorganization and interfacial recognition can provide useful architectures for colloidal building. To this aim, a novel approach, based on colloidal tectonics involving two surface-active particles containing both recognition and catalytic sites, has been developed for controlling the formation and the properties of Pickering emulsions. This was illustrated by the combination of dodecyltrimethylammonium phosphotungstate nanoparticles, [C12]3[PW12O40], and silica particles functionalized with alkyl and sulfonic acid groups, [C n /SO3H]@SiO2. The interfacial self-assembly occurs by the penetration of the alkyl chains of [C n /SO3H]@SiO2 into the [C12]3[PW12O40] supramolecular porous structure constituted of polar and apolar regions. The emulsions were used as a non-nitric acid route for adipic acid synthesis from the one-pot oxidative cleavage of cyclohexene oxide with aqueous H2O2. The catalytic performance was significantly boosted due to the synergistic interactions between the particles.

Characterization and functional gene analysis of a newly isolated indole-degrading bacterium Burkholderia sp. IDO3.

Indole is a common N-heterocyclic pollutant as well as a signaling molecule widespread in various environmental matrices. Several bacterial strains have been reported to be able to degrade indole, while the degradation capacity and functional enzymes are poorly documented. Herein, the degradation characteristics of a newly-isolated indole-degrading strain Burkholderia sp. IDO3 were carefully investigated. Strain IDO3 exhibited superior degradation ability which could completely remove 100 mg/L indole within 14 h in mineral salt medium. It maintained comparable degradation performance under conditions of pH 4.0-9.0, temperature 25-35 °C and rotary speed 0-250 r/min, and most of the tested heavy metals and organic pollutants did not significantly affect the degradation process. Two important intermediates, i.e. isatin and anthranilate, were identified in indole degradation process. The genomic clone library technique with indigo-based screening method was successfully applied to screen the functional genes. Heterologous expression assay proved that recombinant E. coli strain carrying indole oxygenase and reductase genes iifCD could transform indole to indigo. Bioinformatic analyses indicated that the newly obtained enzyme IifC_IDO3 formed a phylogenetically separate branch from other related aromatic oxygenases. This study provides new insights into our understanding of indole degradation by Burkholderia strains and offers efficient bacterial resource for indole bioremediation.

Targeting PPARα for the Treatment and Understanding of Cardiovascular Diseases.

Three members of the peroxisome proliferator-activated receptor (PPAR) family, PPARα, PPARγ, and PPARß/δ, have been investigated widely over the past few decades. Although the roles of these PPARs and their agonists/antagonists were defined in clinical and basic studies, the conflicting results from these studies indicate that more analysis is needed to understand the roles of PPARs. PPARα is a ligand-activated transcription factor that contributes to the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. In this review, we focus on the function and mechanisms of PPARα in the cardiovascular system under various pathological conditions, including vascular and heart injury, blood pressure regulation, and lipid disorder-related cardiovascular injury, as well as its polymorphisms and pharmacogenetic associations with cardiovascular diseases. The anti-inflammatory effect of PPARα in cardiovascular injury is mainly through inhibition of pro-inflammatory signaling pathways and improvement of the lipid profile. Moreover, PPARα also modulates the activity of endothelial nitric oxide synthase and resets the renin-angiotensin system to regulate vascular tone. PPARα gene variants appear to be associated with some cardiovascular risk factors, such as higher plasma lipid levels, cardiac growth, and increased risk of coronary artery disease. Nowadays, novel PPARα drugs with broad safety margins and therapeutic potential for metabolic syndrome and cardiovascular diseases are being developed and applied in the clinical setting. The insights from the current review shed new light on areas of further study and provide a better understanding of the role of PPARα in cardiovascular diseases.