Targeted drug delivery of engineered mesenchymal stem/stromal-cell-derived exosomes in cardiovascular disease: recent trends and future perspectives.

In recent years, stem cells and their secretomes, notably exosomes, have received considerable attention in biomedical applications. Exosomes are cellular secretomes used for intercellular communication. They perform the function of intercellular messengers by facilitating the transport of proteins, lipids, nucleic acids, and therapeutic substances. Their biocompatibility, minimal immunogenicity, targetability, stability, and engineerable characteristics have additionally led to their application as drug delivery vehicles. The therapeutic efficacy of exosomes can be improved through surface modification employing functional molecules, including aptamers, antibodies, and peptides. Given their potential as targeted delivery vehicles to enhance the efficiency of treatment while minimizing adverse effects, exosomes exhibit considerable promise. Stem cells are considered advantageous sources of exosomes due to their distinctive characteristics, including regenerative and self-renewal capabilities, which make them well-suited for transplantation into injured tissues, hence promoting tissue regeneration. However, there are notable obstacles that need to be addressed, including immune rejection and ethical problems. Exosomes produced from stem cells have been thoroughly studied as a cell-free strategy that avoids many of the difficulties involved with cell-based therapy for tissue regeneration and cancer treatment. This review provides an in-depth summary and analysis of the existing knowledge regarding exosomes, including their engineering and cardiovascular disease (CVD) treatment applications.

Multifunctional nanocarriers for targeted drug delivery and diagnostic applications of lymph nodes metastasis: a review of recent trends and future perspectives.

Lymph node metastasis is a frequent occurrence in a variety of tumour forms and poses an enormous challenge to cancer treatment. This process is critical to the development of the disease and is frequently linked to a poor prognosis. Over 90% of cancerous cells move through lymph nodes, making them important entry routes for the spread of cancer cells. The prognosis of cancer patients is significantly impacted by lymph node metastases, which also affects treatment choices. Targeting lymph node metastases presents numerous difficulties for conventional medication delivery techniques. It is still very difficult to selectively target cancer cells in lymph nodes without risking injury to healthy organs and unforeseen consequences. Additionally, systemic delivery of drugs is hampered by the slow flow rate of lymphatic vessels. Chemotherapeutic medicines' poor solubility and stability further reduce their effectiveness when taken orally. Additionally, the extracellular matrix that surrounds lymph node tumours is extensive, which makes it difficult for conventional pharmaceutical delivery systems to reach cancer cells. The development of nanocarriers for precise drug delivery to LNs has attracted a lot of interest to overcome these obstacles. Most solid tumours first spread through the lymphatic system, hence effective drug administration to these tissues is essential for better therapeutic results. Nanocarriers have several benefits, including the capacity to pass through barriers like blood-brain barriers and membranes to reach the lymphatic system. High medication dosages can be enclosed thanks to the physicochemical characteristics of nanocarriers, such as their higher surface-to-volume ratio. Additionally, ligands, antibodies, polymers, or biological molecules can be attached to nanocarrier surfaces to change their properties, allowing for the targeted delivery of lymph node epithelial cells. This use of nanocarriers for drug delivery maximizes on-target effects and related adverse effects while improving the effectiveness of medication delivery to target locations. More research and development in this field is needed to optimize nanocarrier design, increase targeting capabilities, and expand clinical applications for better cancer care.

Protective effect of mussel polysaccharide on cyclophosphamide-induced intestinal oxidative stress injury via Nrf2-Keap1 signaling pathway.

The hard-shelled mussel (Mytilus coruscus) has been used as a traditional Chinese medicine and health food in China for centuries. Polysaccharides from mussel has been reported to have multiple biological functions, however, it remains unclear whether mussel polysaccharide (MP) exerts protective effects in intestinal functions, and the underlying mechanisms of action remain unclear. The aim of this study was to investigate the protective effects and mechanism of MP on intestinal oxidative injury in mice. In this study, 40 male BALB/C mice were used, with 30 utilized to produce an animal model of intestinal oxidative injury with intraperitoneal injection of cyclophosphamide (Cy) for four consecutive days. The protective effects of two different doses of MP (300 and 600 mg/kg) were assessed by investigating the change in body weight, visceral index, and observing colon histomorphology. Moreover, the underlying molecular mechanisms were investigated by measuring the antioxidant enzymes and related signaling molecules through ELISA, real-time PCR, and western blot methods. The results showed that MP pretreatment effectively protected the intestinal from Cy-induced injury: improved the colon tissue morphology and villus structure, increased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities, and reduced malondialdehyde (MDA) content in serum and colon tissues. Meanwhile, MP also significantly increased the expression levels of SOD, GSH-Px, heme oxygenase-1 (HO-1), and nuclear factor E2-related factor 2 (Nrf2) mRNA in colon tissues. Further, western blot results showed that the expression of Nrf2 protein was significantly upregulated while kelch-like ECH-associated protein 1 (Keap1) was significantly downregulated by MP in the colonic tissues. This study indicates that MP can ameliorate Cy-induced oxidative stress injury in mice, and Nrf2-Keap1 signaling pathway may mediate these protective effects.

Catalpol improves impaired neurovascular unit in ischemic stroke rats via enhancing VEGF-PI3K/AKT and VEGF-MEK1/2/ERK1/2 signaling.

Neurovascular unit (NVU) is organized multi-cellular and multi-component networks that are essential for brain health and brain homeostasis maintaining. Neurovascular unit dysfunction is the central pathogenesis process of ischemic stroke. Thus integrated protection of NVU holds great therapeutic potential for ischemic stroke. Catalpol, classified into the iridoid monosaccharide glycoside, is the main active ingredient of the radix from traditional Chinese medicine, Rehmannia glutinosa Libosch, that exhibits protective effects in several brain-related diseases. In the present study, we investigated whether catalpol exerted protective effects for NVU in ischemic stroke and the underlying mechanisms. MCAO rats were administered catalpol (2.5, 5.0, 10.0 mg·kg-1·d-1, i.v.) for 14 days. We showed that catalpol treatment dose-dependently reduced the infarction volume and significantly attenuated neurological deficits score in MCAO rats. Furthermore, catalpol treatment significantly ameliorated impaired NVU in ischemic region by protecting vessel-neuron-astrocyte structures and morphology, and promoting angiogenesis and neurogenesis to replenish lost vessels and neurons. Moreover, catalpol treatment significantly increased the expression of vascular endothelial growth factor (VEGF) through up-regulating PI3K/AKT signaling, followed by increasing FAK and Paxillin and activating PI3K/AKT and MEK1/2/ERK1/2 pathways. The protective mechanisms of catalpol were confirmed in an in vitro three-dimensional NVU model subjected to oxygen-glucose deprivation. In conclusion, catalpol protects NVU in ischemic region via activation of PI3K/AKT signaling and increased VEGF production; VEGF further enhances PI3K/AKT and MEK1/2/ERK1/2 signaling, which may trigger a partly feed-forward loop to protect NVU from ischemic stroke.

Inhibitory effects of piceatannol on human cytomegalovirus (hCMV) in vitro.

Human cytomegalovirus (hCMV) is a ubiquitous herpesvirus, which results in the establishment of a latent infection that persists throughout the life of the host and can be reactivated when the immunity is low. Currently, there is no vaccine for hCMV infection, and the licensed antiviral drugs mainly target the viral enzymes and have obvious adverse reactions. Thus, it is important to search for compounds with anti-hCMV properties. The present study aimed to investigate the suppressive effects of piceatannol on hCMV Towne strain infection and the putative underlying mechanisms using human diploid fibroblast WI-38 cells. Piceatannol supplementation prevented the lytic changes induced by hCMV infection in WI-38 cells. Furthermore, piceatannol suppressed the expression of hCMV immediate-early (IE) and early (E) proteins as well as the replication of hCMV DNA in a dose-dependent manner. Moreover, hCMV-induced cellular senescence was suppressed by piceatannol, as shown by a decline in the senescence-associated ß-galactosidase (SA-ß-Gal) activity and decreased production of intracellular reactive oxygen species (ROS). p16INK4a, a major senescence-associated molecule, was dramatically elevated by current hCMV infection that was attenuated by pre-incubation with piceatannol in a dose-dependent manner. These results demonstrated that piceatannol suppressed the hCMV infection via inhibition of the activation of p16INK4a and cellular senescence induced by hCMV. Together, these findings indicate piceatannol as a novel and potent anti-hCMV agent with the potential to be developed as an effective treatment for chronic hCMV infection.

Salidroside Delays Cellular Senescence by Stimulating Mitochondrial Biogenesis Partly through a miR-22/SIRT-1 Pathway.

Calorie restriction (CR) is a nongenetic intervention with a robust effect on delaying aging in mammals and other organisms. A mild stimulation on mitochondrial biogenesis induced by CR seems to be an important action mode for its benefits. Here, we reported that a component isolated from Rhodiola rosea L., salidroside, delays replicative senescence in human fibroblasts, which is related to its stimulation on mitochondrial biogenesis by activating SIRT1 partly resulted from inhibition on miR-22. Salidroside increased the mitochondrial mass that accompanied an increment of the key regulators of mitochondrial biogenesis including PGC-1α, NRF-1, and TFAM and reversed the mitochondrial dysfunction in presenescent 50PD cells, showing a comparable effect to that of resveratrol. SIRT1 is involved in the inducement of mitochondrial biogenesis by salidroside. The declined expression of SIRT1 in 50PD cells compared with the young 30PD cells was prevented upon salidroside treatment. In addition, pretreatment of EX-527, a selective SIRT1 inhibitor, could block the increased mitochondrial mass and decreased ROS production induced by salidroside in 50PD cells, resulting in an accelerated cellular senescence. We further found that salidroside reversed the elevated miR-22 expression in presenescent cells according to a miRNA array analysis and a subsequent qPCR validation. Enforced miR-22 expression by using a Pre-miR-22 lentiviral construct induced the young fibroblasts (30PD) into a senescence state, accompanied with increased senescence-related molecules including p53, p21, p16, and decreased SIRT1 expression, a known target of miR-22. However, salidroside could partly impede the senescence progression induced by lenti-Pre-miR-22. Taken together, our data suggest that salidroside delays replicative senescence by stimulating mitochondrial biogenesis partly through a miR22/SIRT1 pathway, which enriches our current knowledge of a salidroside-mediated postpone senility effect and provides a new perspective on the antidecrepitude function of this naturally occurring compound in animals and humans.

Regorafenib suppresses colon tumorigenesis and the generation of drug resistant cancer stem-like cells via modulation of miR-34a associated signaling.

BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent malignancies in the world and developed drug resistance has represented one of the most challenging tasks for management. The current therapeutic regimens may select and enrich cancer stem-like cells (CSCs) resulting in the increased resistance against treatment, metastatic potential and mortality. Regorafenib is a multi-kinase inhibitor, an FDA-approved last-of-line treatment for patients with chemo-refractory metastatic CRC. However, regorafenib's potential effects on CSCs have not been fully elucidated. METHODS: Here, we developed two 5-FU resistant CRC cell lines, HCT-116R and DLD-1R and showed the increased CSCs characteristics such as increased side-population cells, tumor sphere formation and expression of stemness markers. These cell lines and CSCs properties were used for evaluating the potential of regorafenib in suppressing CSCs. RESULTS: We showed that regorafenib treatment decreased the stemness phenotypes including tumor sphere formation, and side-population, of both HCT-116R and DLD-1R cells. Additionally, regorafenib suppressed the cell viability in both cell lines synergistically with 5-FU. In vivo, the combination of regorafenib and 5-FU significantly suppressed the tumorigenesis and stemness markers of 5-FU resistant DLD-1R. Mechanistically, regorafenib-mediated effects were associated with the induction of tumor suppressor miR-34a and suppression of WNT/ß-catenin signaling. Our findings demonstrated that regorafenib treatment was associated with the increased level of miR-34a, resulting in reversing drug resistance and cancer-initiating cell phenotypes by degrading WNT/ß-catenin in CRC. CONCLUSION: Regorafenib might be a potential drug for colon cancer stem-like cells and it should be investigated in future clinical trials.

Depletion of HDAC1, 7 and 8 by Histone Deacetylase Inhibition Confers Elimination of Pancreatic Cancer Stem Cells in Combination with Gemcitabine.

Trichostatin A (TSA) possess histone deacetylase (HDAC) inhibitory potential, can reverse the deactivation of tumor suppressor genes and inhibit tumor cell proliferation. We evaluated the effect of TSA on HDAC expression, tumor cell proliferation, and cancer stem cells (CSCs) activities in pancreatic ductal adenocarnoma (PDAC) cells. The PDAC cell lines MiaPaCa-2 and PANC-1 were distinctly sensitive to TSA, with enhanced apoptosis, compared to SAHA. TSA or SAHA inhibited vimentin, HDACs 1, 7 and 8, upregulated E-cadherin mRNA and protein levels in the PDAC cells, and time-dependently downregulated Oct-4, Sox-2, and Nanog, as well as inhibited PDAC tumorsphere formation. TSA also induces accumulation of acetylated histones, while increasing histone 3 lysine 4 or 9 dimethylation levels in PDAC cells and enhancing the epigenetic activity of SAHA. The anti-CSCs effect of TSA was like that obtained by silencing HDAC-1 or 7 using siRNA, and enhances Gemcitabine activity. Our study highlights the molecular targetability of HDACs 1, 7, and 8, confirm their PDAC-CSCs maintaining role, and demonstrate that compared to SAHA, TSA modulates the epigenetically- mediated oncogenic activity of PDAC-CSCs, and potentiate Gemcitabine therapeutic activity, making a case for further exploration of TSA activity alone or in combination with Gemcitabine in PDAC therapy.

Decreased expression of Zwint-1 is associated with poor prognosis in hepatocellular carcinoma.

BACKGROUND AND AIM: ZW10 interacting kinetochore protein 1 (Zwint-1), one of the major kinetochore proteins, is essential for kinetochore function, such as spindle assembly checkpoint function and kinetochore-microtubule attachment. Recently, it has been found over-expressed in some human cancers, including ovarian cancer, bladder cancer, and pulmonary adenocarcinoma. However, few studies of the expression of Zwint-1 in hepatocellular carcinoma (HCC) have been reported. This study is aimed to investigate the expression of Zwint-1 and its relationship with clinical pathological characters in HCC. METHODS: The expression of Zwint-1 protein was analyzed by immunohistochemistry staining on tissue microarrays containing 171 HCC tissues and 187 control non-tumorous liver tissues. The relationships between the Zwint-1 expression and the clinicopathological parameters, and survival analysis were investigated using SPSS software 13.0. RESULTS: Zwint-1 was found uniformly expressed in adjacent non-tumorous liver tissues (184/187, 98.40%), while was significantly decreased in HCC tissues, or even absent (150 of 171, 61.82%, P<0.001). The expression of Zwint-1 was negatively associated with age, tumor size, and Edmondson Grade. Besides, HCC patients with low Zwint-1 expression were also correlated with poor overall survival of the patients. CONCLUSIONS: Decreased expression of Zwint-1 was associated with poor prognosis in HCC.

Incidence rates and clinical Symptoms of Salmonella, Vibrio parahaemolyticus, and Shigella infections in China, 1998-2013.

INTRODUCTION: The etiological and clinical characteristics of patients with infectious diarrhea have changed during the last decade in Shanghai. METHODOLOGY: The records of 29,210 patients with infectious diarrhea in the outpatient department of the Jinshan Hospital (Shanghai, China) between January 1998 and December 2013 were analyzed. RESULTS: A total of 2,849 samples were positive for intestinal pathogenic bacteria including Vibrio parahaemolyticus (2,489; 84.0%), Salmonella spp. (235; 8.3%), and Shigella spp. (125; 4.4%). V. parahaemolyticus infections are mainly characterized by abdominal pain, nausea, and vomiting, whereas Shigella spp. infections can, in addition, induce fever. In contrast, Salmonella infections can produce all of these symptoms but in a smaller percentage of patients. During the 16-year study, both the number of patients and the positive infection rate declined. Notably, the rate of infections by V. parahaemolyticus decreased while the detection rates of Salmonella spp. increased year by year from 2006 on with the introduction of a new detection method. CONCLUSIONS: Salmonella has been identified as the third-most frequent cause of diarrhea from 1998-2006, as the second-most frequent cause from 2006-2010, and as the most frequent cause from 2011-2013, which was mainly due to a sharp decrease of V. parahaemolyticus infections in 2011-2013. Salmonella strains collected in 2011-2013 showed high susceptibility to imipenem (100%) and meropenem (100%), whereas susceptibilities for ampicillin (39%) and piperacillin (40%) were low.

Essential Roles of TIM-1 and TIM-4 Homologs in Adaptive Humoral Immunity in a Zebrafish Model.

TIM-1 and TIM-4 proteins have become increasingly attractive for their critical functions in immune modulation, particularly in CD4(+) Th2 cell activation. Thus, these proteins were hypothesized to regulate adaptive humoral immunity. However, further evidence is needed to validate this hypothesis. This study describes the molecular and functional characteristics of TIM-1 and TIM-4 homologs from a zebrafish (Danio rerio) model (D. rerio TIM [DrTIM]-1 and DrTIM-4). DrTIM-1 and DrTIM-4 were predominantly expressed in CD4(+) T cells and MHC class II(+) APCs under the induction of Ag stimulation. Blockade or knockdown of both DrTIM-1 and DrTIM-4 significantly decreased Ag-specific CD4(+) T cell activation, B cell proliferation, Ab production, and vaccinated immunoprotection against bacterial infection. This result suggests that DrTIM-1 and DrTIM-4 serve as costimulatory molecules required for the full activation of adaptive humoral immunity. DrTIM-1 was detected to be a trafficking protein located in the cytoplasm of CD4(+) T cells. It can translocate onto the cell surface under stimulation by TIM-4-expressing APCs, which might be a precise regulatory strategy for CD4(+) T cells to avoid self-activation before APCs stimulation. Furthermore, a unique alternatively spliced soluble DrTIM-4 variant was identified to exert a negative regulatory effect on the proliferation of CD4(+) T cells. The above findings highlight a novel costimulatory mechanism underlying adaptive immunity. This study enriches the current knowledge on TIM-mediated immunity and provides a cross-species understanding of the evolutionary history of costimulatory systems throughout vertebrate evolution.

Genetic characteristics of vancomycin resistance gene cluster in Enterococcus spp.

Vancomycin resistant enterococci has become an important nosocomial pathogen since it is discovered in late 1980s. The products, encoded by vancomycin resistant gene cluster in enterococci, catalyze the synthesis of peptidoglycan precursors with low affinity with glycopeptide antibiotics including vancomycin and teicoplanin and lead to resistance. These vancomycin resistant gene clusters are classified into nine types according to their gene sequences and organization, or D-Ala:D-Lac (VanA, VanB, VanD and VanM) and D-Ala:D-Ser (VanC, VanE, VanG, VanL and VanN) ligase gene clusters based on the differences of their encoded ligases. Moreover, these gene clusters are characterized by their different resistance levels and infection models. In this review, we summarize the classification, gene organization and infection model of vancomycin resistant gene cluster in Enterococcus spp.

Prevalence of clinical meticillin-resistant Staphylococcus aureus (MRSA) with high-level mupirocin resistance in Shanghai and Wenzhou, China.

A total of 803 clinical meticillin-resistant Staphylococcus aureus (MRSA) isolates obtained from Shanghai and Wenzhou in China were subjected to a screening test by disk diffusion for detection of mupirocin resistance. Among the 803 strains, 53 (6.6%) were mupirocin-resistant. Of these 53 strains, all were discovered by the agar dilution method and polymerase chain reaction (PCR) to be high-level mupirocin-resistant and to harbour the mupA gene. Plasmid DNA hybridisation and curing experiments disclosed that mupA was located on a large plasmid varying in size between 23.0kb and 52.4kb in all strains. Susceptibility testing of 10 antibiotics revealed that resistance rates between the Shanghai isolates and the Wenzhou isolates to trimethoprim/sulfamethoxazole and rifampicin differed significantly. Molecular typing by pulsed-field gel electrophoresis (PFGE), staphylococcal chromosomal cassette mec (SCCmec) and staphylococcal protein A (spa) revealed that PFGE A-SCCmec IIIA-spa t030 and PFGE B-SCCmec IIIA-spa t030 represented all of the Wenzhou strains, whereas PFGE N-SCCmec I-spa t318, PFGE P-SCCmec III-spa t037, PFGE I-SCCmec III-spa t037 and PFGE M-SCCmec IIIA-spa t002 were the predominant profiles among Shanghai isolates. These findings indicated that high-level mupirocin resistance mediated by plasmids prevailed in the clinical mupirocin-resistant MRSA from Shanghai and Wenzhou and was mainly related to the transmission of clones.

Antimicrobial susceptibility and molecular epidemiology of Streptococcus pneumoniae isolated from Shanghai, China.

In this study, the antimicrobial resistance profiles of pneumococci isolated from respiratory specimens of patients from Shanghai, China, in 2004 and 2005 are described. Non-susceptible rates to penicillin and erythromycin among paediatric isolates (n=122) were 63.1% and 94.3%, respectively, whilst those of adult isolates (n=39) were 20.5% and 69.2%, respectively (P<0.0001 and P<0.0002). Nineteen serotypes were identified among 103 tested strains, 73.8% of which belonged to 19F, 14, 23F, 6B and 19A. The erm(B) gene was detected in 51 erythromycin-resistant strains (52.6%), the mef(E) gene in 5 strains (5.2%) and both erm(B) and mef(E) in 41 strains (42.3%). Among 45 sequence types (STs) determined by multilocus sequence typing (MLST) in these 103 isolates, 25 STs were new assignments and 9 STs contained 10 new alleles. On the other hand, 46 (68.7%) of 67 penicillin-non-susceptible S. pneumoniae and 51 (52.6%) of 97 macrolide-resistant S. pneumoniae were characterised as belonging to four international resistant clonal complexes, Taiwan(19F)-14, Spain(23F)-1, Spain(6B)-2 and Taiwan(23F)-15. Our findings indicate that the spread of international resistant clones played a predominant role in the emergence and increase of resistance in Shanghai. Conjugate vaccination may be a promising method to prevent the increase in pneumococcal resistance.

Coexistence of qnrB4 and qnrS1 in a clinical strain of Klebsiella pneumoniae.

AIM: To identify the location and the relationship, and to analyze the genetic background of 2 plasmid-mediated quinolone resistance genes, qnrB4 and qnrS1, carried by a clinical strain of Klebsiella pneumoniae (K pneumoniae). METHODS: The plasmids carrying qnrB4 or qnrS1 were identified by Southern blotting. A HindIII fragment containing qnrB4 or qnrS1 was cloned into plasmid puc18 and sequenced. RESULTS: qnrB4 and qnrS1 were located on 2 different plasmids, pHS7 and pHS8, and were 180 and 45 kb in size, respectively. A transconjugant carrying plasmid pHS7 bearing qnrB4 and another transconjugant carrying pHS9 bearing qnrB4 and qnrS1 were obtained by conjugation. Plasmid pHS8 bearing qnrS1 was also transferred to J53 by transformation. The ciprofloxacin minimal inhibitory concentrations (MIC) for J53 transconjugants or the transformant carrying qnrB4 only, qnrS1 only, and both qnrB4 and qnrS1 were 0.19, 0.25, and 0.25 mg/L, respectively, while the parent clinical strain of K pneumoniae had a MIC of 0.75 mg/L. qnrB4 was located in a sul1-type integron with blaDHA-1, ampR and psp genes in upstream and insertion sequence IS26, and sap genes in downstream of qnrB4. qnrS1 was not located in an integron, but IS26 was found both upstream and downstream, and IS2 was found directly upstream of qnrS1. CONCLUSION: qnrB and qnrS can be harbored simultaneously by a single clinical strain of K pneumoniae. These 2 genes are carried by 2 different plasmids and have different genetic environments in plasmid DNA structure.

Effect of heartbeat perception on heartbeat evoked potential waves.

OBJECTIVE: Early researches found that different heartbeat perceivers have different heartbeat evoked potential (HEP) waves. Two tasks were considered in our experiments to get more details about the differences between good and poor heartbeat perceivers at attention and resting state. METHODS: Thirty channels of electroencephalogram (EEG) were recorded in 22 subjects, who had been subdivided into good and poor heartbeat perceivers by mental tracking task. Principal component analysis (PCA) was applied to remove cardiac field artifact (CFA) from the HEP. RESULTS: (1) The good heart-beat perceivers showed difference between attention and resting state in the windows from 250 ms to 450 ms after R wave at C3 location and from 100 ms to 300 ms after R wave at C4 location; (2) The difference waveforms between good and poor heartbeat perceivers was a positive waveform at FZ from 220 ms to 340 ms after R wave, which was more significant in attention state. CONCLUSION: Attention state had more effect on the HEPs of good heartbeat perceivers than that of poor heartbeat perceivers; and perception ability influenced HEPs more strongly in the attention state than in the resting state.