Global genomic instability caused by reduced expression of DNA polymerase ε in yeast.

SignificanceAlthough most studies of the genetic regulation of genome stability involve an analysis of mutations within the coding sequences of genes required for DNA replication or DNA repair, recent studies in yeast show that reduced levels of wild-type enzymes can also produce a mutator phenotype. By whole-genome sequencing and other methods, we find that reduced levels of the wild-type DNA polymerase ε in yeast greatly increase the rates of mitotic recombination, aneuploidy, and single-base mutations. The observed pattern of genome instability is different from those observed in yeast strains with reduced levels of the other replicative DNA polymerases, Pol α and Pol δ. These observations are relevant to our understanding of cancer and other diseases associated with genetic instability.

Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade.

There is limited knowledge about the metabolic reprogramming induced by cancer therapies and how this contributes to therapeutic resistance. Here we show that although inhibition of PI3K-AKT-mTOR signaling markedly decreased glycolysis and restrained tumor growth, these signaling and metabolic restrictions triggered autophagy, which supplied the metabolites required for the maintenance of mitochondrial respiration and redox homeostasis. Specifically, we found that survival of cancer cells was critically dependent on phospholipase A2 (PLA2) to mobilize lysophospholipids and free fatty acids to sustain fatty acid oxidation and oxidative phosphorylation. Consistent with this, we observed significantly increased lipid droplets, with subsequent mobilization to mitochondria. These changes were abrogated in cells deficient for the essential autophagy gene ATG5 Accordingly, inhibition of PLA2 significantly decreased lipid droplets, decreased oxidative phosphorylation, and increased apoptosis. Together, these results describe how treatment-induced autophagy provides nutrients for cancer cell survival and identifies novel cotreatment strategies to override this survival advantage.

Single-Nucleotide-Specific Lipidic Nanoflares for Precise and Visible Detection of KRAS Mutations via Toehold-Initiated Self-Priming DNA Polymerization.

Accurate identification of single-nucleotide mutations in circulating tumor DNA (ctDNA) is critical for cancer surveillance and cell biology research. However, achieving precise and sensitive detection of ctDNAs in complex physiological environments remains challenging due to their low expression and interference from numerous homologous species. This study introduces single-nucleotide-specific lipidic nanoflares designed for the precise and visible detection of ctDNA via toehold-initiated self-priming DNA polymerization (TPP). This system can be assembled from only a single cholesterol-conjugated multifunctional molecular beacon (MMB) via hydrophobicity-mediated aggregation. This results in a compact, high-density, and nick-hidden arrangement of MMBs on the surface of lipidic micelles, thereby enhancing their biostability and localized concentrations. The assay commences with the binding of frequently mutated regions of ctDNA to the MMB toehold domain. This domain is the proximal holding point for initiating the TPP-based strand-displacement reaction, which is the key step in enabling the discrimination of single-base mutations. We successfully detected a single-base mutation in ctDNA (KRAS G12D) in its wild-type gene (KRAS WT), which is one of the most frequently mutated ctDNAs. Notably, coexisting homologous species did not interfere with signal transduction, and small differences in these variations can be visualized by fluorescence imaging. The limit of detection was as low as 10 amol, with the system functioning well in physiological media. In particular, this system allowed us to resolve genetic mutations in the KRAS gene in colorectal cancer, suggesting its high potential in clinical diagnosis and personalized medicine.

Viscoelastic Supramolecular Hyaluronan-Peptide Cross-Linked Hydrogels.

Viscoelasticity plays a key role in hydrogel design. We designed a physically cross-linked hydrogel with tunable viscoelasticity, comprising supramolecular-assembled peptides coupled to hyaluronan (HA), a native extracellular matrix component. We then explored the structural and molecular mechanisms underlying the mechanical properties of a series of these HA-peptide hydrogels. By modifying the peptide sequence, we modulated both long- and short-time stress relaxation rates as a way to target viscoelasticity with limited impact on stiffness, leading to gels that relax up to 60% of stress in 10 min. Gels with the highest viscoelasticity exhibited large mesh sizes and ß-sheet secondary structures. The stiffness of the gel correlated with hydrogen bonding between the peptide chains. These gels are cytocompatible: highly viscoelastic gels that mimic the native skin microenvironment promote dermal fibroblast cell spreading. Moreover, HA-peptide gels enabled cell encapsulation, as shown with primary human T cells. Overall, these physically-cross-linked hydrogels enable tunable viscoelasticity that can be used to modulate cell morphology.

A bio-inspired co-simulation crawling robot enabled by a carbon dot-doped dielectric elastomer.

Flexible actuation materials play a crucial role in biomimetic robots. Seeking methods to enhance actuation and functionality is one of the directions in which actuators strive to meet the high-performance and diverse requirements of environmental conditions. Herein, by utilizing the method of adsorbing N-doped carbon dots (NCDs) onto SiO2 to form clusters of functional particles, a NCDs@SiO2/PDMS elastomer was prepared and its combined optical and electrical co-stimulation properties were effectively harnessed to develop a biomimetic crawling robot resembling Rhagophthalmus (firefly). The introduction of NCDs@SiO2 cluster particles not only effectively improves the mechanical and dielectric properties of the elastomer but also exhibits fluorescence response and actuation response under the co-stimulation of UV and electricity, respectively. Additionally, a hybrid dielectric elastomer actuator (DEA) with a transparent SWCNT mesh electrode exhibits two notable advancements: an 826% increase in out-of-plane displacement under low electric field stimulation compared to the pure matrix and the ability of NCDs to maintain a stable excited state within the polymer for an extended duration under UV-excitation. Simultaneously, the transparent biomimetic crawling robot can stealthily move in specific environments and fluoresce under UV light.

EPA and DHA Alleviated Chronic Dextran Sulfate Sodium Exposure-Induced Depressive-like Behaviors in Mice and Potential Mechanisms Involved.

Patients with ulcerative colitis (UC) have higher rates of depression. However, the mechanism of depression development remains unclear. The improvements of EPA and DHA on dextran sulfate sodium (DSS)-induced UC have been verified. Therefore, the present study mainly focused on the effects of EPA and DHA on UC-induced depression in C57BL/6 mice and the possible mechanisms involved. A forced swimming test and tail suspension experiment showed that EPA and DHA significantly improved DSS-induced depressive-like behavior. Further analysis demonstrated that EPA and DHA could significantly suppress the inflammation response of the gut and brain by regulating the NLRP3/ASC signal pathway. Moreover, intestine and brain barriers were maintained by enhancing ZO-1 and occludin expression. In addition, EPA and DHA also increased the serotonin (5-HT) concentration and synaptic proteins. Interestingly, EPA and DHA treatments increased the proportion of dominant bacteria, alpha diversity, and beta diversity. In conclusion, oral administration of EPA and DHA alleviated UC-induced depressive-like behavior in mice by modulating the inflammation, maintaining the mucosal and brain barriers, suppressing neuronal damage and reverting microbiota changes.

Effects of short-term supplementation with DHA-enriched phosphatidylcholine and phosphatidylserine on lipid profiles in the brain and liver of n-3 PUFA-deficient mice in early life after weaning.

BACKGROUND: Lack of n-3 polyunsaturated fatty acids during the period of maternity drastically lowers the docosahexaenoic acid (DHA) level in the brain of offspring and studies have demonstrated that different molecular forms of DHA are beneficial to brain development. The aim of this study was to investigate the effect of short-term supplementation with DHA-enriched phosphatidylserine (PS) and phosphatidylcholine (PC) on DHA levels in the liver and brain of congenital n-3-deficient mice. RESULTS: Dietary supplementation with DHA significantly changed the fatty acid composition of various phospholipid molecules in the cerebral cortex and liver while DHA-enriched phospholipid was more effective than DHA triglyceride (TG) in increasing brain and liver DHA. Both DHA-PS and DHA-PC could effectively increase the DHA levels, but DHA in the PS form was superior to PC in the contribution of DHA content in the brain ether-linked PC (ePC) and liver lyso-phosphatidylcholine molecular species. DHA-PC showed more significant effects on the increase of DHA in liver TG, PC, ePC, phosphatidylethanolamine (PE) and PE plasmalogen (pPE) molecular species and decreasing the arachidonic acid level in liver PC plasmalogen, ePC, PE and pPE molecular species compared with DHA-PS. CONCLUSION: The effect of dietary interventions with different molecular forms of DHA for brain and liver lipid profiles is different, which may provide theoretical guidance for dietary supplementation of DHA for people. © 2024 Society of Chemical Industry.

Target-Induced Stepwise Disintegration of Starlike Branched and Multiplex Embedded Systems for Amplified Detection of Serum MicroRNA.

DNA nanotechnology has shown great promise for biosensing and molecular recognition. However, the practical application of conventional DNA biosensors is constrained by inadequate target stimuli, intricate design schemes, multicomponent systems, and susceptibility to nuclease degradation. To overcome these limitations, we present a class of starlike branched and multiplex embedded system (SBES) with an integrated functional design and cascade exponential amplification for serum microRNA (miRNA) detection. The DNA arms can be integrated into an all-in-one system by surrounding a branch point, with each arm endowed with specific functionalities by embedding different DNA fragments. These fragments include a segment complementary to the target miRNA for the recognition element, palindromic tails for self-primed polymerization, and a region with the same sequences as the target serving as the target analogue. Upon exposure to a target miRNA, the DNA arms unwind in a stepwise manner through palindrome-mediated dimerization and polymerization. This enables target recycling for subsequent reactions while releasing the target analogue to generate a secondary response in a feedback manner. A comparative analysis illustrates that the signal-to-noise ratio (SNR) of a full SBES with a feedback strategy is approximately 250% higher than the system without a feedback design. We demonstrate that the four-arm 4pSBES has the benefits of multifunctional integration, enhanced sensitivity, and low false-positive signals, which makes this approach ideally suited for clinical diagnosis. Moreover, an upgraded SBES with additional DNA arms (e.g., 6pSBES) can be constructed to allow multifunctional extension, offering unprecedented opportunities to build versatile DNA nanostructures for biosensing.

Branch-Shaped Trapping Device Regulates Accelerated Catalyzed Hairpin Assembly and Its Application for MicroRNA In Situ Imaging.

Enzyme-free DNA strand displacement process is often practical when detecting miRNAs expressed at low levels in living cells. However, the poor kinetics, tedious reaction period, and multicomponent system hamper its in vivo applications to a great extent. Herein, we design a branch-shaped trapping device (BTD)-based spatial confinement reactor and applied it for accelerated miRNA in situ imaging. The reactor consists of a pair of trapped probe-based catalyzed hairpin assembly (T-CHA) reactions attached around the BTD. The trapping device naturally offered CHA reactions a good spatial-confinement effect by integrating the metastable probes (MHPa and MHPb) of the traditional CHA with the four-branched arm of BTD, which greatly improved the localized concentration of probes and shortened their physical distance. The autonomous and progressive walk of miRNA on the four-arm nanoprobes via T-CHA can rapidly tie numerous four-arm nanoprobes into figure-of-eight nanoknots (FENs), yielding strong fluorescence that is proportional to the miRNA expression level. The unique nanoarchitecture of the FEN also benefits the restricted freedom of movement (FOM) in a confined cellular environment, which makes the system ideally suitable for in situ imaging of intracellular miRNAs. In vitro and in situ analyses also demonstrated that the T-CHA overall outperformed the dissociative probe-based CHA (D-CHA) in stability, reaction speed, and amplification sensitivity. The final application of the T-CHA-based four-arm nanoprobe for imagings of both cancer cells and normal cells shows the potential of the platform for accurately and timely revealing miRNA in biological systems.

Supplementation of n-3 PUFAs in Adulthood Attenuated Susceptibility to Pentylenetetrazol Induced Epilepsy in Mice Fed with n-3 PUFAs Deficient Diet in Early Life.

The growth and development of the fetus and newborn throughout pregnancy and lactation are directly related to the nutritional status of the mother, which has a significant impact on the health of the offspring. The purpose of this experiment was to investigate the susceptibility of n-3 polyunsaturated fatty acid deficiency in early life to seizures in adulthood. The n-3 PUFAs-deficient mice's offspring were established and then fed with α-LNA diet, DHA-enriched ethyl ester, and DHA-enriched phospholipid-containing diets for 17 days at the age of eight weeks. During this period, animals received intraperitoneal injections of 35 mg/kg of pentylenetetrazol (PTZ) every other day for eight days. The results showed that dietary n-3 PUFA-deficiency in early life could aggravate PTZ-induced epileptic seizures and brain disorders. Notably, nutritional supplementation with n-3 PUFAs in adulthood for 17 days could significantly recover the brain n-3 fatty acid and alleviate the epilepsy susceptibility as well as raise seizure threshold to different levels by mediating the neurotransmitter disturbance and mitochondria-dependent apoptosis, demyelination, and neuroinflammation status of the hippocampus. DHA-enriched phospholipid possessed a superior effect on alleviating the seizure compared to α-LNA and DHA-enriched ethyl ester. Dietary n-3 PUFA deficiency in early life increases the susceptibility to PTZ-induced epilepsy in adult offspring, and nutritional supplementation with n-3 PUFAs enhances the tolerance to the epileptic seizure.

N-3 PUFA Deficiency Aggravates Streptozotocin-Induced Pancreatic Injury in Mice but Dietary Supplementation with DHA/EPA Protects the Pancreas via Suppressing Inflammation, Oxidative Stress and Apoptosis.

It has been reported that dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) exert therapeutic potential for the preservation of functional ß-cell mass. However, the effect of dietary n-3 PUFA deficiency on pancreatic injury and whether the supplementation of n-3 PUFA could prevent the development of pancreatic injury are still not clear. In the present study, an n-3 PUFA deficiency mouse model was established by feeding them with n-3 PUFA deficiency diets for 30 days. Results showed that n-3 PUFA deficiency aggravated streptozotocin (STZ)-induced pancreas injury by reducing the insulin level by 18.21% and the HOMA ß-cell indices by 31.13% and the area of islet by 52.58% compared with the STZ group. Moreover, pre-intervention with DHA and EPA for 15 days could alleviate STZ-induced pancreas damage by increasing the insulin level by 55.26% and 44.33%, the HOMA ß-cell indices by 118.81% and 157.26% and reversed the area of islet by 196.75% and 205.57% compared to the n-3 Def group, and the effects were significant compared to γ-linolenic acid (GLA) and alpha-linolenic acid (ALA) treatment. The possible underlying mechanisms indicated that EPA and DHA significantly reduced the ration of n-6 PUFA to n-3 PUFA and then inhibited oxidative stress, inflammation and islet ß-cell apoptosis levels in pancreas tissue. The results might provide insights into the prevention and alleviation of pancreas injury by dietary intervention with PUFAs and provide a theoretical basis for their application in functional foods.

A Comparative Study about the Neuroprotective Effects of DHA-Enriched Phosphatidylserine and EPA-Enriched Phosphatidylserine against Oxidative Damage in Primary Hippocampal Neurons.

Nerve damage caused by accumulated oxidative stress is one of the characteristics and main mechanisms of Alzheimer's disease (AD). Previous studies have shown that phosphatidylserine (PS) rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) plays a significant role in preventing and mitigating the progression of AD. However, whether DHA-PS and EPA-PS can directly protect primary hippocampal neurons against oxidative damage has not been studied. Here, the neuroprotective functions of DHA-PS and EPA-PS against H2O2/t-BHP-induced oxidative damage and the possible mechanisms were evaluated in primary hippocampal neurons. It was found that DHA-PS and EPA-PS could significantly improve cell morphology and promote the restoration of neural network structure. Further studies showed that both of them significantly alleviated oxidative stress-mediated mitochondrial dysfunction. EPA-PS significantly inhibited the phosphorylation of ERK, thus playing an anti-apoptotic role, and EPA-PS significantly increased the protein expressions of p-TrkB and p-CREB, thus playing a neuroprotective role. In addition, EPA-PS, rather than DHA-PS could enhance synaptic plasticity by increasing the expression of SYN, and both could significantly reduce the expression levels of p-GSK3ß and p-Tau. These results provide a scientific basis for the use of DHA/EPA-enriched phospholipids in the treatment of neurodegenerative diseases, and also provide a reference for the development of related functional foods.

Genome-wide mapping of spontaneous genetic alterations in diploid yeast cells.

Genomic alterations including single-base mutations, deletions and duplications, translocations, mitotic recombination events, and chromosome aneuploidy generate genetic diversity. We examined the rates of all of these genetic changes in a diploid strain of Saccharomyces cerevisiae by whole-genome sequencing of many independent isolates (n = 93) subcloned about 100 times in unstressed growth conditions. The most common alterations were point mutations and small (<100 bp) insertion/deletions (n = 1,337) and mitotic recombination events (n = 1,215). The diploid cells of most eukaryotes are heterozygous for many single-nucleotide polymorphisms (SNPs). During mitotic cell divisions, recombination can produce derivatives of these cells that have become homozygous for the polymorphisms, termed loss-of-heterozygosity (LOH) events. LOH events can change the phenotype of the cells and contribute to tumor formation in humans. We observed two types of LOH events: interstitial events (conversions) resulting in a short LOH tract (usually less than 15 kb) and terminal events (mostly cross-overs) in which the LOH tract extends to the end of the chromosome. These two types of LOH events had different distributions, suggesting that they may have initiated by different mechanisms. Based on our results, we present a method of calculating the probability of an LOH event for individual SNPs located throughout the genome. We also identified several hotspots for chromosomal rearrangements (large deletions and duplications). Our results provide insights into the relative importance of different types of genetic alterations produced during vegetative growth.

The synergistic effect of sea cucumber saponins and caffeine on preventing obesity in high-fat diet-fed mice by extending the action duration of caffeine.

BACKGROUND: Sea cucumber saponins (SCSs) exhibit a unique structure and high bioactivities and might have specialized implications on caffeine metabolic process by altering the activity of N-demethylation enzyme CYP1A2. The present study aimed to clarify the effects of SCS on caffeine metabolism in vivo and in vitro, as well as the synergistic anti-obesity effect of SCS and caffeine on high-fat diet-induced obese mice. RESULTS: Results found that SCS administration significantly postponed the elimination rate of caffeine and its metabolites in vivo, and further study found CYP1A2-mediated caffeine metabolism was remarkably inhibited in a dose-dependent manner in vitro. The synergistic effect of the SCS and caffeine combination could decrease the total weight of white adipose tissue by 52% compared with high-fat diet-treated group. CONCLUSION: SCS could prolong caffeine action time, and the combination of the two substances exhibited joint action on high-fat diet-induced obese mice. These findings might provide a basis for the development of functional foods and potential application using the combination of SCS and caffeine. © 2022 Society of Chemical Industry.

Phosphatidylglucose alleviates atherosclerosis by increasing cholesterol alienation to bile acids and cholesterol efflux in ApoE-/- mice.

BACKGROUND: Phosphatidylcholine (PC) is considered to be the major dietary source for choline, which is associated with atherosclerosis progress. Thus, phosphatidylglucose (PG) was prepared by enzymatic modification of PC to investigate the effects on atherosclerosis in apolipoprotein E deficient (ApoE-/- ) mice, as well as to investigate its dose-response relationship. RESULTS: The results showed that dietary PG significantly decreased the atherosclerotic lesion area in a dose-dependent manner. Further studies found that intervention with a 0.8 g kg-1 and 2 g kg-1 PG diet for 4 months significantly decreased free cholesterol level and thus reduced total cholesterol levels in serum. The results of cholesterol distribution among lipoproteins showed that dietary PG significantly decreased low-density lipoprotein levels in ApoE-/- mice. In addition, only administration of high-dose PG significantly reduced total cholesterol levels in liver tissues by 31.2%. Furthermore, mice treated with high-dose PG had an expanded bile acid pool and increased the ratio of conjugated bile acids to unconjugated bile acids in the liver, serum and gallbladder by increasing hepatic gene expression of primary and conjugated bile acid synthesis. Additionally, low-dose and high-dose PG significantly increased total fecal sterols by 20.8% and 11.9%, respectively, by increasing sitosterol and ethylcoprostanol levels. CONCLUSION: These results indicate that PG alleviated atherosclerosis in a dose-dependent manner by increasing cholesterol alienation to bile acids and cholesterol efflux. © 2023 Society of Chemical Industry.

Swelling of Serum-Stable DNA Nanoparticles upon Target-Induced Conformational Rearrangement of Sensing Probes for the Signal-On Detection of Cancer-Related Genes.

Nuclease-resistant assay probes are of significant importance for biochemical analysis and disease diagnosis. In this contribution, a reconfigurable lipidic moiety-attached DNA nanoparticle (LDN) is constructed from a cholesterol-conjugated multifunctional hairpin-type DNA probe (Chol-DP) by hydrophobicity-mediated self-assembly. The LDN holds high serum stability and displays a low false-positive signal even in a complex biological milieu. The hydrophobic cholesterol moiety enables the hydrophobicity-mediated assembly, while hydrophilic DNA sequence serves as a recognition element and a polymerization template. The initiator-activated strand displacement amplification (SDA) reaction can convert the hairpin-shaped probe into rigid double-stranded DNA (dsDNA), causing the conformational rearrangement-based LDN swelling that can be used to reliably and fluorescently signal the cancer-related p53 gene. The size increase and structural reconfiguration are confirmed by dynamic light scattering (DLS) analysis and confocal microscopy imaging, respectively. Target p53 is specifically detected down to 10 pM. The whole assay process involved only several simple mixing steps. Recovery test and blind test further confirm the feasibility of the use of the LDN for the detection of target DNA in a complex biological milieu, indicating a promising nanotool for biomedical applications.

Long-term survival in a patient with advanced lung adenocarcinoma harboring synchronous EGFR exon 18 G719A and BRAF V600E mutations and treated with afatinib: a case report.

EGFR and BRAF V600E mutations are both early driven and usually mutually exclusive. We report the case of a 59-year-old woman diagnosed with advanced lung adenocarcinoma harboring coexisting EGFR exon 18 G719A and BRAF V600E mutations. She experienced a long-term response to oral afatinib, with a progression-free survival rate of 33 months and an overall survival rate of 11 years. Lung adenocarcinoma with synchronous EGFR G719A and BRAF V600E mutations is rare and has not been previously reported. This case highlights the importance of an adequate response to afatinib and provides an optimal therapeutic option for such patients.

Structure-switchable aptamer-arranged reconfigurable DNA nanonetworks for targeted cancer therapy.

The structural DNA nanotechnology holds great potential application in bioimaging, drug delivery and cancer therapy. Herein, an intelligent aptamer-incorporated DNA nanonetwork (Apt-Nnes) is demonstrated for cancer cell imaging and targeted drug delivery, which essentially is a micron-scale pattern with the thickness of double-stranded monolayer. Cancer cell-surface receptors can make it perform magical transformation into small size of nanosheet intermediates and specifically enter target cells. The binding affinity of Apt-Nnes is increased by 3-fold due to multivalent binding effect of aptamers and it can maintain the structural integrity in fetal bovine serum (FBS) for 8 h. More interestingly, target cancer cells can cause the structural disassembly, and each resulting unit transports 4963 doxorubicin (Dox) into target cells, causing the specific cellular cytotoxicity. The cell surface receptor-mediated disassembly of large size of DNA nanostructures into small size of fractions provides a valuable insight into developing intelligent DNA nanostructure suitable for biomedical applications.

A Comparative Study of the Anti-Obesity Effects of Dietary Sea Cucumber Saponins and Energy Restriction in Response to Weight Loss and Weight Regain in Mice.

Dietary supplementation of sea cucumber saponins and calorie restriction have been proved to be effective in alleviating obesity, but the differences of anti-obesity effects between sea cucumber saponins and energy restriction during weight loss and weight regain are still unknown. In the present study, high-fat-induced obesity mice were randomly divided into three groups, including a high-fat diet group (HF), an energy restriction by 40% group (HF-L), and a sea cucumber saponins group (HF-S), to compare the effects of dietary sea cucumber saponins and energy restriction on the weight, glucose, and lipid metabolism of obese mice during weight loss and weight regain. The results showed that dietary 0.06% sea cucumber saponins and limiting energy intake by 40% had the same weight loss effect. Interestingly, sea cucumber saponins could alleviate impaired glucose tolerance and insulin resistance caused by obesity. In addition, the inhibited SREBP-1c mediated lipogenesis might lead to the alleviation of weight regain after resuming the high-fat diet even when sea cucumber saponins were no longer supplemented. In contrast, limiting energy intake tended to promote lipid synthesis in the liver and white adipose tissue after restoring a high-fat diet, and inflammation was also induced. The findings indicated that sea cucumber saponins could replace calorie restriction to prevent obesity and might be used as a functional food or drug to resist obesity and related diseases caused by obesity.

EPA-Enriched Phospholipids Alleviate Renal Interstitial Fibrosis in Spontaneously Hypertensive Rats by Regulating TGF-ß Signaling Pathways.

Hypertensive nephropathy is a chronic kidney disease caused by hypertension. Eicosapentaenoic acid (EPA) has been reported to possess an antihypertensive effect, and our previous study suggested that EPA-enriched phospholipid (EPA-PL) had more significant bioactivities compared with traditional EPA. However, the effect of dietary EPA-PL on hypertensive nephropathy has not been studied. The current study was designed to examine the protection of EPA-PL against kidney damage in spontaneously hypertensive rats (SHRs). Treatment with EPA-PL for three weeks significantly reduced blood pressure through regulating the renin-angiotensin system in SHRs. Moreover, dietary EPA-PL distinctly alleviated kidney dysfunction in SHRs, evidenced by reduced plasma creatinine, blood urea nitrogen, and 24 h proteinuria. Histology results revealed that treatment of SHRs with EPA-PL alleviated renal injury and reduced tubulointerstitial fibrosis. Further mechanistic studies indicated that dietary EPA-PL remarkably inhibited the activation of TGF-ß and Smad 3, elevated the phosphorylation level of PI3K/AKT, suppressed the activation of NF-κB, reduced the expression of pro-inflammatory cytokines, including IL-1ß and IL-6, and repressed the oxidative stress and the mitochondria-mediated apoptotic signaling pathway in the kidney. These results indicate that EPA-PL has potential value in the prevention and alleviation of hypertensive nephropathy.