The crucial relationship between miRNA-27 and CSE/H2S, and the mechanism of action of GLP-1 in myocardial hypertrophy.

Cardiac hypertrophy is the most prevalent compensatory heart disease that ultimately leads to spontaneous heart failure. Mounting evidence suggests that microRNAs (miRs) and endogenous hydrogen sulfide (H2S) play a crucial role in the regulation of cardiac hypertrophy. In this study, we aimed to investigate whether inhibition of miR-27a could protect against cardiac hypertrophy by modulating H2S signaling. We established a model of cardiac hypertrophy by obtaining hypertrophic tissue from mice subjected to transverse aortic constriction (TAC) and from cells treated with angiotensin-II. Molecular alterations in the myocardium were quantified using quantitative real time PCR (qRT-PCR), Western blotting, and ELISA. Morphological changes were characterized by hematoxylin and eosin (HE) staining and Masson's trichrome staining. Functional myocardial changes were assessed using echocardiography. Our results demonstrated that miR-27a levels were elevated, while H2S levels were reduced in TAC mice and myocardial hypertrophy. Further luciferase and target scan assays confirmed that cystathionine-γ-lyase (CSE) was a direct target of miR-27a and was negatively regulated by it. Notably, enhancement of H2S expression in the heart was observed in mice injected with recombinant adeno-associated virus vector 9 (rAAV9)-anti-miR-27a and in cells transfected with a miR-27a inhibitor during cardiac hypertrophy. However, this effect was abolished by co-transfection with CSE siRNA and the miR-27a inhibitor. Conversely, injecting rAAV9-miR-27a yielded opposite results. Interestingly, our findings demonstrated that glucagon-like peptide-1 (GLP-1) agonists could mitigate myocardial damage by down-regulating miR-27a and up-regulating CSE. In summary, our study suggests that inhibition of miR-27a holds therapeutic promise for the treatment of cardiac hypertrophy by increasing H2S levels. Furthermore, our findings unveil a novel mechanism of GLP-1 agonists involving the miR-27a/H2S pathway in the management of cardiac hypertrophy.

Tumor necrosis factor α1 decreases mucosal immune and antioxidant response in the midgut of hybrid fish (white crucian carp ♀ × red crucian carp ♂).

Tumor necrosis factor α1 (TNFα) is a pleiotropic cytokine involved in immune regulation and cellular homeostasis, but the crucial role of TNFα in fish gut remained unclear. The current study aimed to evaluate the immunoregulatory function of TNFα1 on gut barrier in a novel hybrid fish (WR), which was produced by crossing white crucian carp (Carassius cuvieri, ♀) with red crucian carp (Carassius auratus red var, ♂). In this study, WR-tnfα1 sequence was identified, and a high-level expression was detected in the intestine. Elevated levels of WR-tnfα1 expressions were detected in immune-related tissues and cultured fish cells on stimulation. The appearance of vacuolization and submucosal rupture was observed in TNFα1-treated midgut of WR, along with elevated levels of goblet cell atrophy, whereas no significant changes were detected in most expressions of tight-junction genes and mucin genes. In contrast, WR receiving gut perfusion with WR-TNFα1 showed a remarkable decrease in antioxidant status in midgut, whereas the expression levels of apoptotic genes and redox responsive genes increased sharply. These results suggested that TNFα1 could exhibit a detrimental effect on antioxidant defense and immune regulation in the midgut of WR.

Non-volatile and volatile compound changes in blueberry juice inoculated with different lactic acid bacteria strains.

BACKGROUND: Lactic acid bacteria (LABs) are widely present in foods and affect the flavour of fermented cultures. This study investigates the effects of fermentation with Lactobacillus acidophilus JYLA-16 (La), Lactobacillus plantarum JYLP-375 (Lp), and Lactobacillus rhamnosus JYLR-005 (Lr) on the flavour profile of blueberry juice. RESULTS: This study showed that all LABs strains preferentially used glucose rather than fructose as the carbon source during fermentation. Lactic acid was the main fermentation product, reaching 7.76 g L-1 in La-fermented blueberry juice, 5.86 g L-1 in Lp-fermented blueberry juice, and 6.41 g L-1 in Lr-fermented blueberry juice. These strains extensively metabolized quinic acid, whereas oxalic acid metabolism was almost unaffected. Sixty-four volatile compounds were identified using gas chromatography-ion mobility spectrometry (GC-IMS). All fermented blueberry juices exhibited decreased aldehyde levels. Furthermore, fermentation with La was dominated by alcohols, Lp was dominated by esters, and Lr was dominated by ketones. Linear discriminant analysis of the electronic nose and principal component analysis of the GC-IMS data effectively differentiated between unfermented and fermented blueberry juices. CONCLUSION: This study informs LABs selection for producing desirable flavours in fermented blueberry juice and provides a theoretical framework for flavour detection. © 2023 Society of Chemical Industry.

WHSC1 is involved in DNA damage, cellular senescence and immune response in hepatocellular carcinoma progression.

Wolf-Hirschhorn syndrome candidate 1 (WHSC1) is a transcriptional regulatory protein that encodes a histone methyltransferase to control H3K36me2 modification. WHSC1 was upregulated and associated with poor prognosis in HCC. The elevated WHSC1 likely due to the alterations of DNA methylation or RNA modification. WHSC1 perhaps form a chromatin cross talk with H3K27me3 and DNA methylation to regulate transcription factors expression in HCC. Functional analysis indicated that WHSC1 was involved in DNA damage repair, cell cycle, cellular senescence and immune regulations. Furthermore, WHSC1 was associated with the infiltrating levels of B cell, CD4+, Tregs and macrophage cells. Therefore, our findings suggested that WHSC1 might function as a promotor regulator to affect the development and progression of HCC. Thus, WHSC1 could be a potential biomarker in predicting the prognosis and therapeutic target for patients with HCC.

Bioinspired simultaneous regulation in fluorescence of AIEgen-embedded hydrogels.

The development of stimuli-responsive functional fluorescent hydrogels is of great significance for the realization of artificial intelligence. In the present work, we design and synthesize a stimulus-responsive hydrogel embedded with an aggregation-induced emission (AIE) monomer, in which the fluorescence brightness and intensity can be tuned. The hydrogel embedded with tetraphenylethene-grafted-poly[3-sulfopropyl methacrylate potassium salt] (TPE-PSPMA) as the functional element is prepared by the radical polymerization method. Among them, the TPE core exhibits adaptive fluorescence ability through the AIE effect, while the PSPMA chain provides tunable hydrophilic properties under an external stimulus. The effect of different cationic surfactants with different lengths of hydrophobic tails on the fluorescence properties of TPE-PSPMA in solution is systematically investigated. With cationic surfactants, such as cetyltrimethylammonium bromide (CTAB), the fluorescence intensity is gradually tuned from 1059 to 4623. And the fluorescence intensities increase with the growth of hydrophobic tails of surfactants, which results from hydrophobicity-induced electrostatic interactions among surfactants and polymer chains. Furthermore, an obvious tunable fluorescence feature of hydrogel copolymerized TPE-PSPMA is realized, resulting from the change of brightness and the dynamic increase of fluorescence intensity (from 1031 to 3138) for the hydrogel immersed in CTAB solution with different soaking times. Such a typical fluorescence-regulated behavior can be attributed to the AIE of the TPE-PSPMA chain and the electrostatic interaction between the surfactant and the anionic polymer chain. The designed TPE-PSPMA-based hydrogel is responsive to stimuli, inspiring the development of intelligent systems such as soft robots and smart wearables.

Integrated analysis of the faecal metagenome and serum metabolome reveals the role of gut microbiome-associated metabolites in the detection of colorectal cancer and adenoma.

OBJECTIVE: To profile gut microbiome-associated metabolites in serum and investigate whether these metabolites could distinguish individuals with colorectal cancer (CRC) or adenoma from normal healthy individuals. DESIGN: Integrated analysis of untargeted serum metabolomics by liquid chromatography-mass spectrometry and metagenome sequencing of paired faecal samples was applied to identify gut microbiome-associated metabolites with significantly altered abundance in patients with CRC and adenoma. The ability of these metabolites to discriminate between CRC and colorectal adenoma was tested by targeted metabolomic analysis. A model based on gut microbiome-associated metabolites was established and evaluated in an independent validation cohort. RESULTS: In total, 885 serum metabolites were significantly altered in both CRC and adenoma, including eight gut microbiome-associated serum metabolites (GMSM panel) that were reproducibly detected by both targeted and untargeted metabolomics analysis and accurately discriminated CRC and adenoma from normal samples. A GMSM panel-based model to predict CRC and colorectal adenoma yielded an area under the curve (AUC) of 0.98 (95% CI 0.94 to 1.00) in the modelling cohort and an AUC of 0.92 (83.5% sensitivity, 84.9% specificity) in the validation cohort. The GMSM model was significantly superior to the clinical marker carcinoembryonic antigen among samples within the validation cohort (AUC 0.92 vs 0.72) and also showed promising diagnostic accuracy for adenomas (AUC=0.84) and early-stage CRC (AUC=0.93). CONCLUSION: Gut microbiome reprogramming in patients with CRC is associated with alterations of the serum metabolome, and GMSMs have potential applications for CRC and adenoma detection.

A novel approach for relapsed/refractory FLT3mut+ acute myeloid leukaemia: synergistic effect of the combination of bispecific FLT3scFv/NKG2D-CAR T cells and gilteritinib.

BACKGROUND: Patients with relapsed/refractory acute myeloid leukaemia (AML) with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) have limited treatment options and poor prognosis. Therefore, novel treatment modalities are needed. Since high expression of natural killer group 2 member D ligands (NKG2DLs) can be induced by FLT3 inhibitors, we constructed dual-target FLT3 single-chain fragment variable (scFv)/NKG2D-chimeric antigen receptor (CAR) T cells, and explored whether FLT3 inhibitors combined with FLT3scFv/NKG2D-CAR T cells could have synergistic anti-leukaemia effects. METHODS: FLT3scFv and NKG2D expression in CAR T cells, FLT3 and NKG2DL expression in AML cells, and the in vitro cytotoxicity of combining CAR T cells with gilteritinib were assessed by flow cytometry. The therapeutic effect was evaluated in a xenograft mouse model established by injection of MOLM-13 cells. Mechanisms underlying the gilteritinib-induced NKG2DL upregulation were investigated using siRNA, ChIP-QPCR and luciferase assays. RESULTS: The FLT3scFv/NKG2D-CAR T cells specifically lysed AML cells both in vitro and in the xenograft mouse model. The efficacy of FLT3scFv/NKG2D-CAR T cells was improved by gilteritinib-pretreatment. The noncanonical NF-κB2/Rel B signalling pathway was found to mediate gilteritinib-induced NKG2DL upregulation in AML cells. CONCLUSIONS: Bispecific FLT3scFv/NKG2D-CAR T cells can effectively eradicate AML cells. The FLT3 inhibitor gilteritinib can synergistically improve this effect by upregulating NF-κB2-dependent NKG2DL expression in AML cells.

Comparative analysis on the immunoregulatory roles of ferritin M in hybrid fish (Carassius cuvieri ♀ × Carassius auratus red var ♂) and its parental species after bacterial infection.

Ferritin M is involved in the regulation of fish immunity. In this study, open reading frame (ORF) sequences of ferritin M from hybrid fish and its parental species were 534 bp. Tissue-specific analysis indicated that the highest level of ferritin M from red crucian carp was observed in kidney, while peaked expressions of ferritin M from white crucian carp and hybrid carp were observed in gill. Elevated levels of ferritin M from hybrid carp and its parental species were detected in immune-related tissues following Aeromonas hydrophila infection or in cultured fish cell lines after lipopolysaccharide (LPS) challenge. Ferritin M overexpression could attenuate NF-κB and TNFα promoter activity in their respective fish cells. Purified ferritin M fusion proteins elicited in vitro binding activity to A. hydrophila and Edwardsiella tarda, lowered bacterial dissemination to tissues and alleviated inflammatory response. Furthermore, treatment with ferritin M fusion proteins could mitigate bacteria-induced liver damage and rescue antioxidant activity. These results suggested that ferritin M in hybrid fish showed a similar immune defense against bacteria infection in comparison with those of its parental species.

A novel ferritin L (FerL) in hybrid crucian carp could participate in host defense against Aeromonas hydrophila infection and diminish inflammatory signals.

FerL, a multifunctional iron-storage polypeptide, not only exhibited a regulatory role in iron metabolism, but also participated in the regulation of fish immunity. In this study, ORF sequence of WR-FerL was 522 bp, encoding 173 amino acid residues. Tissue-specific analysis revealed that the highest expression of WR-FerL was detected in spleen. A. hydrophila challenge and LPS stimulation could sharply enhance WR-FerL mRNA expression in tissues and fish cells, respectively. Purified WR-FerL fusion peptide exhibited in vitro binding activity to A. hydrophila and endotoxin, limited bacterial dissemination to tissues as well as attenuated A. hydrophila-induced production of pro-inflammatory cytokines. Moreover, WR-FerL overexpression could abrogate NF-κB and TNFα promoter activity in fish cells. These results indicated that WR-FerL could play an important role in host defense against A. hydrophila infection.

Estrogen-dependent depressor response of melatonin via baroreflex afferent function and intensification of PKC-mediated Nav1.9 activation.

Recent studies suggest that melatonin (Mel) plays an important role in the regulation of blood pressure (BP) via the aortic baroreflex pathway. In this study, we investigated the interaction between the baroreflex afferent pathway and Mel-mediated BP regulation in rats under physiological and hypertensive conditions. Mel (0.1, 0.3, and 1.0 mg/mL) was microinjected into the nodose ganglia (NG) of rats. We showed that Mel-induced reduction of mean arterial pressure in female rats was significantly greater than that in male and in ovariectomized rats under physiological condition. Consistently, the expression of Mel receptors (MTNRs) in the NG of female rats was significantly higher than that of males. In L-NAME-induced hypertensive and spontaneously hypertensive rat models, MTNRs were upregulated in males but downregulated in female models. Interestingly, Mel-induced BP reduction was found in male hypertensive models. In whole-cell recording from identified baroreceptor neurons (BRNs) in female rats, we found that Mel (0.1 µM) significantly increased the excitability of a female-specific subpopulation of Ah-type BRNs by increasing the Nav1.9 current density via a PKC-mediated pathway. Similar results were observed in baroreceptive neurons of the nucleus tractus solitarius, showing the facilitation of spontaneous and evoked excitatory post-synaptic currents in Ah-type neurons. Collectively, this study reveals the estrogen-dependent effect of Mel/MTNRs under physiological and hypertensive conditions is mainly mediated by Ah-type BRNs, which may provide new theoretical basis and strategies for the gender-specific anti-hypertensive treatment in clinical practice.

Transcriptome analysis and co-expression network reveal the mechanism linking mitochondrial function to immune regulation in red crucian carp (Carassius auratus red var) after Aeromonas hydrophila challenge.

Aeromonas hydrophila is a common pathogen of freshwater fish. In this study, A. hydrophila infection was shown to cause tissue damage, trigger physiological changes as well as alter the expression profiles of immune- and metabolic-related genes in immune tissues of red crucian carp (RCC). Transcriptome analysis revealed that acute A. hydrophila infection exerted a profound effect on mitochondrial oxidative phosphorylation linking metabolic regulation to immune response. In addition, we further identified cellular senescence, apoptosis, necrosis and mitogen-activated protein kinase signal pathways as crucial signal pathways in the kidney of RCC subjected to A. hydrophila infection. These findings may have important implications for understanding modulation of immunometabolic response to bacterial infection.

Spatial and interdecadal differences in climatic suitability for winter wheat in China from 1985 to 2014.

The evident climate jump after 2000 in China may have greatly influenced the production of winter wheat, which is one of the nation's major grain crops. To evaluate the impacts of climate change on winter wheat production and identify the climatic factors primarily responsible, we used daily meteorological data from 2244 stations and integrated indicators to examine the decadal changes in the potential plantable zone (PPZ), growth periods, and climatic suitability for winter wheat in China from 1985 to 1999 and from 2000 to 2014. The results showed the following: (1) The PPZ has decreased by approximately 9%, and the main reason may be the increased frequency of extreme cold events in northern China from 2000 to 2014. (2) In most of the PPZ, the suitable sowing date has been delayed, the potential maturity date has advanced, and total days during the potential growing season have significantly decreased because of the increasing temperature. (3) The suitable area and optimal area of winter wheat have significantly decreased by 9% and 13%, respectively. The changes in climatic suitability are affected by both temperature and radiation in the north, whereas the impact is more from precipitation in the south. The climate may be changing in a direction unsuitable for winter wheat. As global warming and climate extremes intensify in the future, winter wheat production may become more challenging, and adequate measures should be adopted to guarantee reliable and high yields.

The baroreflex afferent pathway plays a critical role in H2S-mediated autonomic control of blood pressure regulation under physiological and hypertensive conditions.

Hydrogen sulfide (H2S), which is closely related to various cardiovascular disorders, lowers blood pressure (BP), but whether this action is mediated via the modification of baroreflex afferent function has not been elucidated. Therefore, the current study aimed to investigate the role of the baroreflex afferent pathway in H2S-mediated autonomic control of BP regulation. The results showed that baroreflex sensitivity (BRS) was increased by acute intravenous NaHS (a H2S donor) administration to renovascular hypertensive (RVH) and control rats. Molecular expression data also showed that the expression levels of critical enzymes related to H2S were aberrantly downregulated in the nodose ganglion (NG) and nucleus tractus solitarius (NTS) in RVH rats. A clear reduction in BP by the microinjection of NaHS or L-cysteine into the NG was confirmed in both RVH and control rats, and a less dramatic effect was observed in model rats. Furthermore, the beneficial effects of NaHS administered by chronic intraperitoneal infusion on dysregulated systolic blood pressure (SBP), cardiac parameters, and BRS were verified in RVH rats. Moreover, the increase in BRS was attributed to activation and upregulation of the ATP-sensitive potassium (KATP) channels Kir6.2 and SUR1, which are functionally expressed in the NG and NTS. In summary, H2S plays a crucial role in the autonomic control of BP regulation by improving baroreflex afferent function due at least in part to increased KATP channel expression in the baroreflex afferent pathway under physiological and hypertensive conditions.

Plasma and intracerebral pharmacokinetics and pharmacodynamics modeling for the acetylcholine releasing effect of ginsenoside Rg1 in mPFC of Aß model rats.

Ginsenoside Rg1 is a major bioactive component of ginseng. Limited information is available regarding Rg1 concentrations in the central neural system and the corresponding relationship of plasma/intracerebral concentrations, and intracerebral effects of Rg1. Awake Aß model rats received a single subcutaneous administration of Rg1. Concentrations of unbound Rg1 and acetylcholine in the brain extracellular fluid and Rg1 in plasma were then determined. An Emax-two compartment pharmacokinetic/pharmacodynamics (PK/PD) model without effect compartment was finally obtained by evaluating three mechanism-based models. The corresponding relationship between the plasma PK and PD of Rg1 can be described as E = 119.05•C/(73.42 + C).[Formula: see text].

LTB4-induced anti-apoptosis and infiltration of neutrophils in rheumatoid arthritis.

Rheumatoid arthritis (RA) is the most common autoimmune disease, resulting in synovitis, joint pain and stiffness, even deformity and disability. The interactions between leukotriene B4 (LTB4) and neutrophils in RA progression have not been elucidated in detail. Our review focuses on the correlation of LTB4 and neutrophils in the development of RA especially in terms of infiltration and delayed life span of neutrophils. In this article, the roles of LTB4 in the anti-apoptosis of neutrophils will be detailed, which is achieved by suppressed pro-apoptotic Bax and up-regulated anti-apoptotic Mcl-1, and several key molecules, as well as signalling pathways and factors relevant to the enhancement of LTB4 production and functions. The mechanisms of LTB4-induced anti-apoptosis and infiltration of neutrophils provide more potential targets in the treatment of RA and recent therapeutic strategies are also discussed.

Metoprolol prevents neuronal dendrite remodeling in a canine model of chronic obstructive sleep apnea.

Obstructive sleep apnea (OSA) is closely associated with central nervous system diseases and could lead to autonomic nerve dysfunction, which is often seen in neurodegenerative diseases. Previous studies have shown that metoprolol prevents several chronic OSA-induced cardiovascular diseases through inhibiting autonomic nerve hyperactivity. It remains unclear whether chronic OSA can lead to dendritic remodeling in the brain, and whether metoprolol affects the dendritic remodeling. In this study we investigated the effect of metoprolol on dendrite morphology in a canine model of chronic OSA, which was established in beagles through clamping and reopening the endotracheal tube for 4 h every other day for 12 weeks. OSA beagles were administered metoprolol (5 mg· kg-1· d-1). The dendritic number, length, crossings and spine density of neurons in hippocampi and prefrontal cortices were assessed by Golgi staining. And the protein levels of hypoxia-inducible factor-1α (HIF-1α) and brain-derived neurotrophic factor (BDNF) were measured by Western blotting. We showed that chronic OSA successfully induced significant brain hypoxia evidenced by increased HIF-1α levels in CA1 region and dentate gyrus of hippocampi, as well as in prefrontal cortex. Furthermore, OSA led to markedly decreased dendrite number, length and intersections, spine loss as well as reduced BDNF levels. Administration of metoprolol effectively prevented the dendritic remodeling and spine loss induced by chronic OSA. In addition, administration of metoprolol reversed the decreased BDNF, which might be associated with the metoprolol-induced neuronal protection. In conclusion, metoprolol protects against neuronal dendritic remodeling in hippocampi and prefrontal cortices induced by chronic OSA in canine.

Pain and bone damage in rheumatoid arthritis: role of leukotriene B4.

Rheumatoid arthritis is a chronic autoimmune disease characterised by unbearable joint pain as well as bone and cartilage destruction. Although RA development is greatly controlled, the pain and bone damage failed to be relieved and managed. Leukotriene B4 (LTB4) has been proved to play an essential role in the induction of pain and bone damage. The nerve injury of RA can promote the production of LTB4, which act on their receptors, leading to the increased release of pro-inflammatory cytokines and ROS to reduce neuron viability and pain threshold. Moreover, LTB4-BLT1 activation can also increase intracellular calcium concentration and neuron excitability as well as NF-κB pathway activation, which further promote the production of MMP-9 and CXC3R-1. The mutual promotion between LTB4 and neutrophil accumulation accelerates the release of TNF-α and IL-ß, which enhance both peripheral and central nerve system sensitisation. LTB4 also involve in TrpV1 channel activation and modulation of P2X3 receptor activation. All above mechanisms contribute to the development of RA pain. IL-23, cPLA2 and PI3K increase the production of CD11b+Gr1high myeloid subtype and calcium concentration, which promote the production of LTB4 and further accelerate IL-17 and TNF activation as well as calcium influx to conduce to osteoclastogenesis, resulting in aggregated bone damage. Our review is the first to conclude the signalling pathways and associated molecules in LTB4-induced pain and bone damage.

Pharmacokinetics and acetylcholine releasing effects of ginsenoside Rg1 in hippocampus of beta-amyloid model rats.

This study aimed at investigating the pharmacokinetics (PK) and acetylcholine (Ach) releasing effects of ginsenoside Rg1 in hippocampus (HIP) of soluble oligomeric assemblies of amyloid beta (ADDLs) induced Alzheimer's disease (AD) model rats. Extracellular fluid was collected by microdialysis technique. The concentrations of Rg1 and Ach in dialysates were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The results showed, after administration, Rg1 was soon detected in the HIP of model rats and extracellular Ach concentrations in the HIP were significantly increased.

Transcriptomic Analysis of Vibrio parahaemolyticus Reveals Different Virulence Gene Expression in Response to Benzyl Isothiocyanate.

Vibrio parahaemolyticus isolated from seafood is a pathogenic microorganism that leads to several acute diseases that are harmful to our health and is frequently transmitted by food. Therefore, there is an urgent need for the control and suppression of this pathogen. In this paper, transcriptional analysis was used to determine the effect of treatment with benzyl isothiocyanate (BITC) extracted from cruciferous vegetables on V. parahaemolyticus and to elucidate the molecular mechanisms underlying the response to BITC. Treatment with BITC resulted in 332 differentially expressed genes, among which 137 genes were downregulated, while 195 genes were upregulated. Moreover, six differentially expressed genes (DEGs) in RNA sequencing studies were further verified by quantitative real-time polymerase chain reaction (qRT-PCR). Genes found to regulate virulence encoded an l-threonine 3-dehydrogenase, a GGDEF family protein, the outer membrane protein OmpV, a flagellum-specific adenosine triphosphate synthase, TolQ protein and VirK protein. Hence, the results allow us to speculate that BITC may be an effective control strategy for inhibiting microorganisms growing in foods.

Myocardial infarction-induced hippocampal microtubule damage by cardiac originating microRNA-1 in mice.

Cardiovascular diseases are risk factors for dementia, but the mechanisms remain elusive. Here, we report that myocardial infarction (MI) generated by the ligation of the left coronary artery (LCA) could lead to increased miR-1 levels in the hippocampus and blood with neuronal microtubule damage and decreased TPPP/p25 protein expression in the hippocampus. These changes could be prevented by a knockdown of miR-1 using hippocampal stereotaxic injections of anti-miR-1 oligonucleotide fragments carried by a lentivirus vector (lenti-pre-AMO-miR-1). TPPP/p25 protein was downregulated by miR-1 overexpression, upregulated by miR-1 inhibition, and unchanged by binding-site mutations or miR-masks, indicating that the TPPP/p25 gene was a potential target for miR-1. Additionally, the pharmacological inhibition of sphingomyelinase by GW4869 to inhibit exosome generation in the heart significantly attenuated the increased miR-1 levels in the hippocampi of transgenic (Tg) and MI mice. Collectively, the present study demonstrates that MI could directly lead to neuronal microtubule damage independent of MI-induced chronic brain hypoperfusion but involving the overexpression of miR-1 in the hippocampus that was transported by exosomes from infarcted hearts. This study reveals a novel insight into the molecular mechanisms of heart-to-brain communication at the miRNA level.