Monocyte-Derived Macrophages Aggravate Cardiac Dysfunction After Ischemic Stroke in Mice.

BACKGROUND: Cardiac damage induced by ischemic stroke, such as arrhythmia, cardiac dysfunction, and even cardiac arrest, is referred to as cerebral-cardiac syndrome (CCS). Cardiac macrophages are reported to be closely associated with stroke-induced cardiac damage. However, the role of macrophage subsets in CCS is still unclear due to their heterogeneity. Sympathetic nerves play a significant role in regulating macrophages in cardiovascular disease. However, the role of macrophage subsets and sympathetic nerves in CCS is still unclear. METHODS AND RESULTS: In this study, a middle cerebral artery occlusion mouse model was used to simulate ischemic stroke. ECG and echocardiography were used to assess cardiac function. We used Cx3cr1GFPCcr2RFP mice and NLRP3-deficient mice in combination with Smart-seq2 RNA sequencing to confirm the role of macrophage subsets in CCS. We demonstrated that ischemic stroke-induced cardiac damage is characterized by severe cardiac dysfunction and robust infiltration of monocyte-derived macrophages into the heart. Subsequently, we identified that cardiac monocyte-derived macrophages displayed a proinflammatory profile. We also observed that cardiac dysfunction was rescued in ischemic stroke mice by blocking macrophage infiltration using a CCR2 antagonist and NLRP3-deficient mice. In addition, a cardiac sympathetic nerve retrograde tracer and a sympathectomy method were used to explore the relationship between sympathetic nerves and cardiac macrophages. We found that cardiac sympathetic nerves are significantly activated after ischemic stroke, which contributes to the infiltration of monocyte-derived macrophages and subsequent cardiac dysfunction. CONCLUSIONS: Our findings suggest a potential pathogenesis of CCS involving the cardiac sympathetic nerve-monocyte-derived macrophage axis.

Inhibition of PARP1 improves cardiac function after myocardial infarction via up-regulated NLRC5.

The incidence and mortality rate of myocardial infarction are increasing per year in China. The polarization of macrophages towards the classically activated macrophages (M1) phenotype is of utmost importance in the progression of inflammatory stress subsequent to myocardial infarction. Poly (ADP-ribose) polymerase 1(PARP1) is the ubiquitous and best characterized member of the PARP family, which has been reported to support macrophage polarization towards the pro-inflammatory phenotype. Yet, the role of PARP1 in myocardial ischemic injury remains to be elucidated. Here, we demonstrated that a myocardial infarction mouse model induced cardiac damage characterized by cardiac dysfunction and increased PARP1 expression in cardiac macrophages. Inhibition of PARP1 by the PJ34 inhibitors could effectively alleviate M1 macrophage polarization, reduce infarction size, decrease inflammation and rescue the cardiac function post-MI in mice. Mechanistically, the suppression of PARP1 increase NLRC5 gene expression, and thus inhibits the NF-κB pathway, thereby decreasing the production of inflammatory cytokines such as IL-1ß and TNF-α. Inhibition of NLRC5 promote infection by effectively abolishing the influence of this mechanism discussed above. Interestingly, inhibition of NLRC5 promotes cardiac macrophage polarization toward an M1 phenotype but without having major effects on M2 macrophages. Our results demonstrate that inhibition of PARP1 increased NLRC5 gene expression, thereby suppressing M1 polarization, improving cardiac function, decreasing infarct area and attenuating inflammatory injury. The aforementioned findings provide new insights into the proinflammatory mechanisms that drive macrophage polarization following myocardial infarction, thereby introducing novel potential targets for future therapeutic interventions in individuals affected by myocardial infarction.

Identification and molecular mechanisms of novel antioxidant peptides from fermented broad bean paste: A combined in silico and in vitro study.

This study aimed to investigate the antioxidative and cytoprotective activity of antioxidant peptides from fermented broad bean paste (FBBP) and explore their potential molecular mechanisms using a combined in silico and in vitro approach. Seven novel antioxidant peptides (VSRRFIYYL, SPAIPLP, PVPPPGG, KKDGYWWAKFK, LAWY, LGFMQF, and LPGCP) identified by integrated approaches of peptidomics and in silico bioinformatic analysis were synthesized, exhibiting strong antioxidant potential against in vitro radicals. Molecular docking results suggested that these peptides could form stable hydrogen bonds and solvent-accessible surface with key amino acid residues of Keap1, thus potentially regulating the Keap1-Nrf2 pathway by occupying the Nrf2-binding site on Keap1. Additionally, they exhibited strong cellular antioxidant activity and could protect HepG2 cells from AAPH-induced oxidative injury by reducing reactive oxygen species and MDA accumulation. This study firstly unraveled the molecular mechanisms of antioxidant peptides from FBBP, and provided a new theoretical basis for the high-value utilization of FBBP.

Role of galectin-3 in cardiac dysfunction induced by subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a severe acute cerebrovascular event that not only impairs the central nervous system but also negatively affects various other organs, including the heart. The underlying mechanisms, however, remain unclear. In this study, we discovered that mice with SAH exhibited significant cardiac injuries, such as extended QT and QTc intervals, cardiac fibrosis, and reduced cardiac ejection fractions. This phenomenon was accompanied by increased galectin-3 expression in the cardiac ventricle and can be reversed by galectin-3 inhibitor TD139. Interestingly, we also observed increased co-expression of galectin-3 in macrophage within the heart tissue of SAH mice. Additionally, when macrophage activation was suppressed using the beta-blocker propranolol, cardiac function improved, and galectin-3 expression in the cardiac tissue decreased. Collectively, our findings offer new insights into the role of galectin-3 in SAH-related cardiac dysfunction and suggest a macrophage-galectin-3 axis as a potential therapeutic strategy.

Revealing the Secret of Umami Taste of Peptides Derived from Fermented Broad Bean Paste.

To understand the umami taste of fermented broad bean paste (FBBP) and explore the umami mechanism, eight peptides (PKALSAFK, NKHGSGK, SADETPR, EIKKAALDANEK, DALAHK, LDDGR, and GHENQR) were separated and identified via ultrafiltration, RP-HPLC, and UPLC-QTOF-MS/MS methods. Sensory experiments suggested that eight novel peptides showed umami/umami-enhancing and salt-enhancing functions. Significantly, the threshold of EIKKAALDANEK in aqueous solution exceeded that of most umami peptides reported in the past 5 years. The omission test further confirmed that umami peptides contributed to the umami taste of FBBP. Molecular docking results inferred that all peptides easily bind with Ser, Glu, His, and Asp residues in T1R3 through hydrogen bonds and electrostatic interactions. The aromatic interaction, hydrogen bond, hydrophilicity, and solvent-accessible surface (SAS) were the main interaction forces. This work may contribute to revealing the secret of the umami taste of FBBP and lay the groundwork for the efficient screening of umami peptides.

Isolation, identification and characterization of taste peptides from fermented broad bean paste.

Pixian broad-bean paste (PBBP) is a famous fermented condiment in China, which may produce abundant flavor peptides during the fermentation process. Herein, the flavor peptides from fermented broad-bean (FB) were separated and identified via ethanol precipitation, macroporous resin, and ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) methods. The results showed that there were fifteen novel flavor peptides in FB. Among them, six peptides (i.e. ALDELGT, AELTPEP, SAALQAG, SFEAVEAAPT, EQDNDGNNIFSGFKR, QTFNTEEDTAK, and DAPASGN) were perceived umami with threshold values ranging from 0.76 to 1.84 mmol L-1. And they had both salty-enhancing and umami-enhancing abilities. Meanwhile, novel peptides (i.e. GGLRIINPEGQQ, SIITPPERQ, GGLSIITPPERQA, GGLRIINPEG, SIITPPER, RIINPEGQQ, DALNVNRHIV, and LPKILLLQLV) were perceived bitter with threshold values ranging from 0.56 to 2.89 mmol L-1. And the monosodium glutamate (MSG) solution had a certain masking effect on bitter peptides. GFSSEFLA showed a strong sweet taste. From peptide sequence analysis, it was found that Aspergillus oryzae and broad-bean were important taste-active sources of the flavor peptides in FB. Besides, the synthetic peptides showed a much better sensory taste than the mixtures of the corresponding amino acids. It indicated that peptides might play an important role in deciding the taste of FB. Significantly, it is the first time that the isolated flavor peptides were identified from FB.

Isoflurane Attenuates Cerebral Ischaemia-Reperfusion Injury via the TLR4-NLRP3 Signalling Pathway in Diabetic Mice.

Ischaemic stroke is a severe disease worldwide. Restoration of blood flow after ischaemic stroke leads to cerebral ischaemia-reperfusion injury (CIRI). Various operations, such as cardiac surgery with deep hypothermic circulatory arrest, predictably cause cerebral ischaemia. Diabetes is related to the occurrence of perioperative stroke and exacerbates neurological impairment after stroke. Therefore, the choice of anaesthetic drugs has certain clinical significance for patients with diabetes. Isoflurane (ISO) exerts neuroprotective and anti-neuroinflammatory effects in patients without diabetes. However, the role of ISO in cerebral ischaemia in the context of diabetes is still unknown. Toll-like receptor 4 (TLR4) and NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation play important roles in microglia-mediated neuroinflammatory injury. In this study, we treated a diabetic middle cerebral artery occlusion mouse model with ISO. We found that diabetes exacerbated cerebral ischaemia damage and that ISO exerted neuroprotective effects in diabetic mice. Then, we found that ISO decreased TLR4-NLRP3 inflammasome activation in microglia and the excessive autophagy induced by CIRI in diabetic mice. The TLR4-specific agonist CRX-527 reversed the neuroprotective effects of ISO. In summary, our study indicated that ISO exerts neuroprotective effects against the neuroinflammation and autophagy observed during diabetic stroke via the TLR4-NLRP3 signalling pathway.

Macrophage-NLRP3 Inflammasome Activation Exacerbates Cardiac Dysfunction after Ischemic Stroke in a Mouse Model of Diabetes.

Ischemic stroke is one of the leading causes of death worldwide. In the post-stroke stage, cardiac dysfunction is common and is known as the brain-heart interaction. Diabetes mellitus worsens the post-stroke outcome. Stroke-induced systemic inflammation is the major causative factor for the sequential complications, but the mechanism underlying the brain-heart interaction in diabetes has not been clarified. The NLRP3 (NLR pyrin domain-containing 3) inflammasome, an important component of the inflammation after stroke, is mainly activated in M1-polarized macrophages. In this study, we found that the cardiac dysfunction induced by ischemic stroke is more severe in a mouse model of type 2 diabetes. Meanwhile, M1-polarized macrophage infiltration and NLRP3 inflammasome activation increased in the cardiac ventricle after diabetic stroke. Importantly, the NLRP3 inflammasome inhibitor CY-09 restored cardiac function, indicating that the M1-polarized macrophage-NLRP3 inflammasome activation is a pathway underlying the brain-heart interaction after diabetic stroke.

The Clinical Outcomes After Intratympanic Gentamicin Injection to Treat Menière's Disease: A Meta-analysis.

OBJECTIVES: In recent decades, intratympanic gentamicin (ITG) has increasingly been used to treat intractable Menière's disease (MD). We performed a meta-analysis of pooled clinical outcomes, exploring whether ITG was effective and safe. DATA SOURCES: Cochrane Library database, Embase, and Medline. STUDY SELECTION: We searched scientific and medical databases to March 2018 for articles evaluating clinical outcomes after ITG treatment of intractable MD according to the American Academy of Otolaryngology Head and Neck Surgery (AAO-HNS) guidelines. DATA EXTRACTION: We performed a meta-analysis to evaluate treatment efficacy and safety. Quantitative and descriptive information of included RCTs was obtained. DATA SYNTHESIS: We ultimately evaluated 49 of the initially retrieved 1,062 citations (the 49 articles included data from a total of 2,344 MD patients). In almost all studies, patients served as their own controls; "before-and-after" clinical outcomes were reported. The I metric was used to explore heterogeneity. CONCLUSION: Overall, our results seem to provide the limited evidence about efficacy and toxicity effects of ITG. However, clinical outcomes require further confirmation; many included studies were poorly designed, less than 2 years for reporting results in MD are in the majority of patients. More long-term prospective follow-up, high-quality, large-scale, randomized controlled trials are needed to confirm that ITG is safe and effective when used to treat intractable MD.

Expression of excision repair cross-complementation group 1 in locoregionally advanced nasopharyngeal carcinoma treated with cisplatin-based induction chemotherapy.

OBJECTIVE: The purpose of this study was to evaluate the expression of excision repair cross-complementation group 1 (ERCC1) in locoregionally advanced nasopharyngeal carcinoma (NPC) treated with cisplatin-based induction chemotherapy. METHODS: Eighty-five patients with locoregionally advanced NPC treated with cisplatin-based induction chemotherapy were included in this study. The expression level of ERCC1 protein in cancer tissues was detected by immunohistochemistry, and the expression level was divided into the high- and low-expression groups according to their expression level. The objective response rate (ORR) and the long-term disease control rate of two groups were compared between the two groups. RESULTS: The expression level of ERCC1 in NPC tissues was detected by immunohistochemistry. Forty-one cases had the high ERCC1 expression, and 44 cases had the low ERCC1 expression. The cases for complete response, partial response, stable disease, and progression disease were 1, 19, 21 in the ERCC1 high expression group and 3, 29, 12 for the ERCC1 low-expression group which indicated that the ORR in ERCC1 low group were significant higher than that of ERCC1 high expression group (P < 0.05). The 5-year overall survival, 5-year disease-free survival (DFS), and 5-year local recurrence-DFS were not statistical different between two group (P < 0.05); but the 5-year distant-DFS for ERCC1 low group were significant higher than ERCC1 high group (P < 0.05). CONCLUSION: Cisplatin-induced short-term ORR was decreased in nasopharyngeal carcinoma patients with high ERCC1 expression, which increased the risk of metastasis.

Effect of chitosan coating with cinnamon oil on the quality and physiological attributes of China jujube fruits.

Effects of chitosan coating with cinnamon oil on the physiological attributes and preservation quality of China jujube fruits during storage at 4°C for 60 days were investigated. Results indicated that weight loss and decay of jujube fruits were significantly reduced by chitosan-oil coating during the period of 60-day storage, which also exhibited a quite beneficial effect on maintaining the sensory quality for jujube fruits. Meanwhile, the contents of vitamin C and titratable acid decreased to 3.08 mg·g(-1) and 0.342% for the fruits treated by chitosan-oil coating (1.0% + 0.10%), respectively. Polyphenol oxidase, superoxide dismutase, and peroxidase activities were 13.40 U·g(-1), 14.53 U·g(-1), and 63.6 U·g(-1) at the end of storage, respectively. The contents of total soluble phenolics and MDA were 34.51 mg·g(-1) and 19.43 µmol·g(-1) for the combined coating treated samples and control fruits, respectively. These results suggested that the chitosan-oil coating might be recognized as one efficiency technology on the preservation quality of jujube fruits during the storage time.

Nucleotide polymorphism of the TNF gene cluster in six Chinese populations.

DNA variants in a 31-kb region of the human major histocompatibility complex, encompassing the tumor necrosis factor (TNF) gene cluster, were surveyed by direct sequencing of 283 unrelated individuals from six Chinese populations. A total of 273 polymorphic sites were identified, with nearly half of them novel. We observed an excess of rare variants and negative values of selection tests of the region, implying either that these populations experienced a historical expansion or that the surveyed region was subjected to natural selection. Different characteristics of the sequence variation in the six populations outline the genetic differentiation between Northern and Southern Chinese populations. The distributions of recombination rates are similar among all the populations, with variation in the magnitude and/or in the fine location of hot spots. Tag single-nucleotide polymorphisms (SNPs) selected from HapMap (Phase II) CHB data accounted for an average of 64% of common SNPs from the six Chinese populations. We also observed a limited transferability of tag SNPs between Chinese populations on the 31-kb region with an excess of untaggable SNPs and ragged linkage disequilibrium blocks. It suggested that the design and interpretation of future association studies should be more cautious, and that a resequencing approach may refine tag SNP selection on Chinese-specific disease mapping.