Adult-type anomalous origin of the left coronary artery from the pulmonary artery and right coronary-right atrial fistula: a case report.

BACKGROUND: Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital cardiac anomaly, mortality rates in infancy reach approximately 90%, with only a small number of patients surviving into adulthood, therefore, most of the literature reports mainly focus on infantile type. CASE PRESENTATION: A 55-year-old female was admitted due to persistent repeated chest pain experienced and had worsened for unknown reasons. Color doppler echocardiography, coronary computed tomographic angiography, and coronary angiography confirmed the diagnosis of ALCAPA and concurrent right coronary artery-right atrial fistula. The symptoms of chest pain exhibited notable improvement subsequent to corrective surgery for the anomalous origin of the coronary artery. CONCLUSIONS: This report shows an unique case of ALCAPA in an adult patient, characterizing the condition's combination with a right coronary-right atrial fistula, and it is prone to misdiagnosis and misdiagnosis. We aim to provide valuable insights for clinical diagnosis and treatment of ALCAPA.

Gastrin exerts a protective effect against myocardial infarction via promoting angiogenesis.

BACKGROUND: It is known that increased gastrin concentration is negatively correlated with cardiovascular mortality, and plasma gastrin levels are increased in patients after myocardial infarction (MI). However, whether gastrin can play a protective role in MI remains unknown. METHODS: Adult C57BL/6 mice were subjected to ligation of the left anterior descending coronary artery (LAD) and subcutaneous infusion of gastrin (120 µg/Kg body weight/day, 100 µL in the pump) for 28 days after MI. Plasma gastrin concentrations were measured through an ELISA detection kit. Mice were analyzed by echocardiography after surgery. CD31 and VEGF expression were quantified using immunofluorescence staining or/and western blot to assess the angiogenesis in peri-infarct myocardium. Capillary-like tube formation and cell migration assays were performed to detect gastrin-induced angiogenesis. RESULTS: We found that gastrin administration significantly ameliorated MI-induced cardiac dysfunction and reduced fibrosis at 28 days in post-MI hearts. Additionally, gastrin treatment significantly decreased cardiomyocyte apoptosis and increased angiogenesis in the infarct border zone without influencing cardiomyocyte proliferation. In vitro results revealed that gastrin up-regulated the PI3K/Akt/vascular endothelial growth factor (VEGF) signaling pathway and promoted migration and tube formation of human coronary artery endothelial cells (HCAECs). Cholecystokinin 2 receptor (CCK2R) mediated the protective effect of gastrin since the CCK2R blocker CI988 attenuated the gastrin-mediated angiogenesis and cardiac function protection. CONCLUSION: Our data revealed that gastrin promoted angiogenesis and improved cardiac function in post-MI mice, highlighting its potential as a therapeutic target candidate.

Cadmium exposure induces endothelial dysfunction via disturbing lipid metabolism in human microvascular endothelial cells.

Cadmium (Cd) is an occupational and environmental heavy metal pollutant derived from many sources that is linked to endothelial homeostasis. The endothelium is an important site of Cd deposition, while increasing evidence has revealed there is a close relationship between endothelial dysfunction and abnormal lipid metabolism. However, the effects of the alterations in lipid metabolism on endothelial cells (ECs) after Cd exposure still remain unclear. In our study, human microvascular endothelial cells (HMEC-1) were exposed to 40-µM Cd for 6, 12, or 24 h or 10-, 20-, or 40-µM Cd for 24 h, respectively. The Cd exposure accelerated the decomposition of triglyceride (TG) and resulted in the accumulation of free fatty acids (FFAs). These changes stimulated cytotoxicity, impaired fatty acid oxidation (FAO), induced reactive oxygen species (ROS) generation, altered the mitochondrial membrane potential (MMP), and decreased the ATP content, which eventually led to endothelial dysfunction and cell death. In summary, exposure to cadmium caused endothelial dysfunction by disrupting lipid metabolism in HMEC-1. These changes were mainly due to FFA accumulation and FAO inhibition, which further induced ROS generation and mitochondrial dysfunction. Moreover, our results provide novel insight into understanding the alterations of lipid metabolism induced by Cd exposure in ECs.

Dedifferentiation, Proliferation, and Redifferentiation of Adult Mammalian Cardiomyocytes After Ischemic Injury.

BACKGROUND: Adult mammalian hearts have a limited ability to generate new cardiomyocytes. Proliferation of existing adult cardiomyocytes (ACMs) is a potential source of new cardiomyocytes. Understanding the fundamental biology of ACM proliferation could be of great clinical significance for treating myocardial infarction (MI). We aim to understand the process and regulation of ACM proliferation and its role in new cardiomyocyte formation of post-MI mouse hearts. METHODS: ß-Actin-green fluorescent protein transgenic mice and fate-mapping Myh6-MerCreMer-tdTomato/lacZ mice were used to trace the fate of ACMs. In a coculture system with neonatal rat ventricular myocytes, ACM proliferation was documented with clear evidence of cytokinesis observed with time-lapse imaging. Cardiomyocyte proliferation in the adult mouse post-MI heart was detected by cell cycle markers and 5-ethynyl-2-deoxyuridine incorporation analysis. Echocardiography was used to measure cardiac function, and histology was performed to determine infarction size. RESULTS: In vitro, mononucleated and bi/multinucleated ACMs were able to proliferate at a similar rate (7.0%) in the coculture. Dedifferentiation proceeded ACM proliferation, which was followed by redifferentiation. Redifferentiation was essential to endow the daughter cells with cardiomyocyte contractile function. Intercellular propagation of Ca2+ from contracting neonatal rat ventricular myocytes into ACM daughter cells was required to activate the Ca2+-dependent calcineurin-nuclear factor of activated T-cell signaling pathway to induce ACM redifferentiation. The properties of neonatal rat ventricular myocyte Ca2+ transients influenced the rate of ACM redifferentiation. Hypoxia impaired the function of gap junctions by dephosphorylating its component protein connexin 43, the major mediator of intercellular Ca2+ propagation between cardiomyocytes, thereby impairing ACM redifferentiation. In vivo, ACM proliferation was found primarily in the MI border zone. An ischemia-resistant connexin 43 mutant enhanced the redifferentiation of ACM-derived new cardiomyocytes after MI and improved cardiac function. CONCLUSIONS: Mature ACMs can reenter the cell cycle and form new cardiomyocytes through a 3-step process: dedifferentiation, proliferation, and redifferentiation. Intercellular Ca2+ signal from neighboring functioning cardiomyocytes through gap junctions induces the redifferentiation process. This novel mechanism contributes to new cardiomyocyte formation in post-MI hearts in mammals.

Therapeutic effect of a novel Wnt pathway inhibitor on cardiac regeneration after myocardial infarction.

After myocardial infarction (MI), the heart is difficult to repair because of great loss of cardiomyoctyes and lack of cardiac regeneration. Novel drug candidates that aim at reducing pathological remodeling and stimulating cardiac regeneration are highly desirable. In the present study, we identified if and how a novel porcupine inhibitor CGX1321 influenced MI and cardiac regeneration. Permanent ligation of left anterior descending (LAD) coronary artery was performed in mice to induce MI injury. Cardiac function was measured by echocardiography, infarct size was examined by TTC staining. Fibrosis was evaluated with Masson's trichrome staining and vimentin staining. As a result, CGX1321 administration blocked the secretion of Wnt proteins, and inhibited both canonical and non-canonical Wnt signaling pathways. CGX1321 improved cardiac function, reduced myocardial infarct size, and fibrosis of post-MI hearts. CGX1321 significantly increased newly formed cardiomyocytes in infarct border zone of post-MI hearts, evidenced by the increased EdU+ cardiomyocytes. Meanwhile, CGX1321 increased Ki67+ and phosphohistone H3 (PH3+) cardiomyocytes in culture, indicating enhanced cardiomyocyte proliferation. The mRNA microarray showed that CGX1321 up-regulated cell cycle regulating genes such as Ccnb1 and Ccne1 CGX1321 did not alter YAP protein phosphorylation and nuclear translocation in cardiomyocytes. In conclusion, porcupine inhibitor CGX1321 reduces MI injury by limiting fibrosis and promoting regeneration. It promotes cardiomyocyte proliferation by stimulating cell cycle regulating genes with a Hippo/YAP-independent pathway.

Mitochondrial DNA oxidative damage contributes to cardiomyocyte ischemia/reperfusion-injury in rats: cardioprotective role of lycopene.

Mitochondrial (mt) dysfunction and oxidative stress are involved in the pathogenesis of ischemia/reperfusion (I/R)-injury. Lycopene, a lipophilic antioxidant found mainly in tomatoes and in other vegetables and fruits, can protect mtDNA against oxidative damage. However, the role of mtDNA in myocardial I/R-injury is unclear. In the present study, we aimed to determine if and how lycopene protects cardiomyocytes from I/R-injury. In both in vitro and in vivo studies, I/R-injury increased mt 8-hydroxyguanine (8-OHdG) content, decreased mtDNA content and mtDNA transcription levels, and caused mitochondrial dysfunction in cardiomyocytes. These effects of I/R injury on cardiomycoytes were blocked by pre-treatment with lycopene. MtDNA depletion alone was sufficient to induce cardiomyocyte death. I/R-injury decreased the protein level of a key activator of mt transcription, mitochondrial transcription factor A (Tfam), which was blocked by lycopene. The protective effect of lycopene on mtDNA was associated with a reduction in mitochondrial ROS production and stabilization of Tfam. In conclusion, lycopene protects cardiomyocytes from the oxidative damage of mtDNA induced by I/R-injury.

PD150606 protects against ischemia/reperfusion injury by preventing µ-calpain-induced mitochondrial apoptosis.

Calpain plays an important role in myocardial ischemia/reperfusion (I/R) injury. PD150606, a nonpeptide, cell-permeable and noncompetitive calpain inhibitor, has been shown to have protective properties in ischemic disease. The aims of the present study were to investigate whether PD150606 could alleviate myocardial I/R injury and to examine the possible mechanisms involved. The I/R model was established in vivo in C57BL/6 mice and in vitro using neonatal mouse cardiomyocytes, respectively. To evaluate the protective effects of PD150606 on I/R injury, we measured the myocardial infarct area, apoptosis, and expression of cleaved caspase-3. We also investigated the underlying mechanisms by examining mitochondrial function as reflected by the ATP concentration, translocation of cytochrome c, dynamics of mPTP opening, and membrane potential (ΔΨm), coupled with calpain activity. Pretreatment with PD150606 significantly reduced the infarct area and apoptosis caused by I/R. PD150606 pretreatment also reduced mitochondrial dysfunction by inhibiting calpain activation. Moreover, we found that µ-calpain is the main contributor to I/R-induced calpain activation. Knockdown of µ-calpain with siRNA significantly reversed calpain activation, mitochondrial dysfunction, and cardiomyocyte apoptosis caused by I/R in vitro. Our results suggest that PD150606 may protect against I/R injury via preventing µ-calpain-induced mitochondrial apoptosis.

Differential expression and DNA methylation of angiotensin type 1A receptors in vascular tissues during genetic hypertension development.

Angiotensin type 1a receptor (AT1aR) is thought to play an important role in the development of hypertension. However, it is unknown how the AT1aR expression in vascular tissue is changed during the development of hypertension or if the degree of methylation in the AT1aR promoter correlates with the expression of AT1aR. To address these questions, we measured AT1aR mRNA, protein expression, and methylation status of the AT1aR promoter in the aorta and mesenteric artery of male spontaneously hypertensive rats (SHRs) and age-matched Wistar-Kyoto (WKY) rats acting as controls at pre-hypertensive (4 weeks), evolving (10 weeks), and established (20 weeks) stages of hypertension. The expression of the AT1aR mRNA and protein was not different between the SHRs and WKY rats at 4 weeks. However, they were significantly greater in SHRs than in WKY rats at 20 weeks. Bisulfite sequencing revealed that the AT1aR promoter from the aorta and mesenteric artery of the SHRs was progressively hypo-methylated with age as compared with their WKY rat counterparts. These results suggest that the heightened AT1aR expression in SHRs is related to the AT1aR promoter hypo-methylation, which might be a consequence of the increased blood pressure and may be important in the maintenance of high blood pressure.

Ponytail Left Anterior Descending Artery: A Case Report.

Division of the anterior descending branch into many small arteries is a rare coronary anomaly. We report the case of a 64-year-old female with severe stenosis (>75%) in the proximal region of the anterior descending branch as indicated by coronary computed tomography angiography (CCTA). In addition, coronary angiography showed that the anterior descending branch of the coronary artery split into numerous small arteries, an anomaly that can confound clinical examination.

Development and validation of a machine learning-based readmission risk prediction model for non-ST elevation myocardial infarction patients after percutaneous coronary intervention.

To investigate the factors that influence readmissions in patients with acute non-ST elevation myocardial infarction (NSTEMI) after percutaneous coronary intervention (PCI) by using multiple machine learning (ML) methods to establish a predictive model. In this study, 1576 NSTEMI patients who were hospitalized at the Affiliated Hospital of North Sichuan Medical College were selected as the research subjects. They were divided into two groups: the readmitted group and the non-readmitted group. The division was based on whether the patients experienced complications or another incident of myocardial infarction within one year after undergoing PCI. Common variables selected by univariate and multivariate logistic regression, LASSO regression, and random forest were used as independent influencing factors for NSTEMI patients' readmissions after PCI. Six different ML models were constructed using these common variables. The area under the ROC curve, accuracy, sensitivity, and specificity were used to evaluate the performance of the six ML models. Finally, the optimal model was selected, and a nomogram was created to visually represent its clinical effectiveness. Three different methods were used to select seven representative common variables. These variables were then utilized to construct six different ML models, which were subsequently compared. The findings indicated that the LR model exhibited the most optimal performance in terms of AUC, accuracy, sensitivity, and specificity. The outcome, admission mode (walking and non-walking), communication ability, CRP, TC, HDL, and LDL were identified as independent predicators of readmissions in NSTEMI patients after PCI. The prediction model constructed by the LR algorithm was the best. The established column graph model established proved to be effective in identifying high-risk groups with high accuracy and differentiation. It holds a specific predictive value for the occurrence of readmissions after direct PCI in NSTEMI patients.

[Lycopene protects against hypoxia/reoxygenation-injury by preventing calpain activation].

OBJECTIVE: To investigate the possible mechanism of lycopene on protecting against hypoxia/reoxygenation (H/R)-injury. METHODS: Primary cultured cardiomyocytes, isolated from neonatal mouse, were divided into three groups randomly: control group (C) ; H/R group(4 h H followed by 8 h R); lycopene+H/R group(L+H/R), in which the cardiomyocytes were pretreated with lycopene for 4 h before H/R. The survival of cardiomyocytes was counted. Apoptotic cells were detected by TUNEL assays. The release of cytochrome c from mitochondrial matrix into the cytosol, the activity of caspase-3, intracellular ROS levels and the activity of calpain were also determined in these groups respectively at the same time. RESULTS: The pretreatment of cardiomyocytes with lycopene significantly improved the survival of cardiomyocytes [C: (89.84 ± 5.15)%, H/R: (63.59 ± 5.11)%, L+H/R: (79.25 ± 1.48)%, P < 0.05] and reduced the extent of apoptosis [C: ( 10.37 ± 1.25)%, H/R: (32.03 ± 4.79)%, L+H/R: (22.57 ± 3.22)%, P < 0.05], significantly reduced caspase-3 activation [C: (2.61 ± 0.19), H/R: (5.82 ± 0.92), L+H/R: (3.74 ± 0.64) pNA pmol/µg protein, P < 0.05]. To further study the mechanism underlying the benefits of lycopene, interactions between lycopene and calpain activation were examined. Lycopene pretreatment of cardiomyocytes suppressed the activation of calpain(C:272.33 ± 300.46, H/R: 1156.00 ± 212.02, L+H/R: 607.33 ± 166.23, P < 0.05) by reducing the H/R induced increased intracellular ROS levels [C: 100%, H/R: (239.79 ± 27.27)%, L+H/R: (188.19 ± 17.63)%, P < 0.05]. CONCLUSION: Lycopene may protect against hypoxia/reoxygenation-induced injury by preventing calpain activation.

Integration of transcriptomics, metabolomics, and lipidomics reveals the mechanisms of doxorubicin-induced inflammatory responses and myocardial dysfunction in mice.

Doxorubicin (DOX) is an anthracycline antineoplastic agent that has limited clinical utility due to its dose-dependent cardiotoxicity. Although the exact mechanism remains unknown, inflammatory responses have been implicated in DOX-induced cardiotoxicity (DIC). In this study, we analyzed the transcriptomic, metabolomic as well as lipidomic changes in the DOX-treated mice to explore the underlying mechanisms of DIC. We found that continuous intraperitoneal DOX injections (3 mg/kg/d) for a period of five days significantly induced cardiac dysfunction and cardiac injury in male C57BL/6 J mice (8 weeks old). This corresponded to a significant increase in the myocardial levels of IL-4, IL-6, IL-10, IL-17 and IL-12p70. Furthermore, inflammation-related genes such as Ptgs2, Il1b, Cxcl5, Cxcl1, Cxcl2, Mmp3, Ccl2, Ccl12, Nfkbia, Fos, Mapk11 and Tnf were differentially expressed in the DOX-treated group, and enriched in the IL-17 and TNF signaling pathways. Besides, amino acids, peptides, imidazoles, toluenes, hybrid peptides, fatty acids and lipids such as Hex1Cer, Cer, SM, PG and ACCa were significantly associated with the expression pattern of inflammation-related genes. In conclusion, the integration of transcriptomic, metabolomic and lipidomic data identified potential new targets and biomarkers of DIC.

Irisin protects cardiomyocytes against hypoxia/reoxygenation injury via attenuating AMPK mediated endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress plays a central role in myocardial ischemia/reperfusion (I/R) injury. Irisin has been reported to have protective properties in ischemia disease. In this study, we aimed at investigating whether irisin could alleviate myocardial I/R injury by ER stress attenuation. The in vitro model of hypoxia/reoxygenation (H/R) was established, which resembles I/R in vivo. Cell viability and apoptosis were estimated. Expressions of cleaved caspase-3, cytochrome c, GRP78, pAMPK, CHOP, and eIF2α were assessed by western blot. Our results revealed that pre-treatment with irisin significantly decreased cytochrome c release from mitochondria and caspase-3 activation caused by H/R. Irsin also reduced apoptosis and increased cell viability. These effects were abolished by AMPK inhibitor compound C pre-treatment. Also, GRP78 and CHOP expressions were up-regulated in the H/R group compared to the control group; however, irisin attenuated their expression. The pAMPK level was significantly decreased compared to the control, and this effect could be partly reversed by metformin pre-treatment. These results suggest that ER stress is associated with cell viability decreasing and cardiomyocytes apoptosis induced by H/R. Irisin could efficiently protect cardiomyocytes from H/R-injury via attenuating ER stress and ER stress-induced apoptosis.

Mesenchymal stem cell-derived exosomal microRNA-182-5p alleviates myocardial ischemia/reperfusion injury by targeting GSDMD in mice.

Recent evidence indicates that exosomes derived from mesenchymal stem cells (MSCs) confer protective effects against myocardial ischemia/reperfusion (I/R) injury. Exosomes are carriers of potentially protective endogenous molecules, including microRNAs (miRNAs/miRs). The current study set out to test the effects of transferring miR-182-5p from MSC-derived exosomes into myocardial cells on myocardial I/R injury. First, an I/R mouse model was developed by left anterior descending coronary artery occlusion, and myocardial cells were exposed to hypoxia/reoxygenation (H/R) for in vitro I/R model establishment. Loss- and gain-of-function experiments of miR-182-5p and GSDMD were conducted to explore the effects of miR-182-5p via MSC-derived exosomes on cell pyroptosis and viability. GSDMD was robustly expressed in I/R-injured myocardial tissues and H/R-exposed myocardial cells. GSDMD upregulation promoted H/R-induced myocardial cell pyroptosis and reduced viability, corresponding to increased lactate dehydrogenase release, reactive oxygen species production, and pyroptosis. A luciferase assay demonstrated GSDMD as a target of miR-182-5p. In addition, exosomal miR-182-5p was found to diminish GSDMD-dependent cell pyroptosis and inflammation induced by H/R. Furthermore, MSC-derived exosomes carrying miR-182-5p improved cardiac function and reduced myocardial infarction, accompanied with reduced inflammation and cell pyroptosis in vivo. Taken together, our findings suggest a cardioprotective effect of exosomal miR-182-5p against myocardial I/R injury, shedding light on an attractive therapeutic strategy.

GSK3ß Exacerbates Myocardial Ischemia/Reperfusion Injury by Inhibiting Myc.

Myocardial ischemia/reperfusion (MI/R) injury is a life-threatening disease with high morbidity and mortality. Herein, the present study is conducted to explore the regulatory mechanism of GSK3ß in MI/R injury regarding cardiomyocyte apoptosis and oxidative stress. The MI/R injury mouse model and hypoxic reoxygenation (H/R) cell model were established. The expression pattern of GSK3ß, FTO, KLF5, and Myc was determined followed by their relation validation. Next, loss-of-function experiments were implemented to verify the effect of GSK3ß/FTO/KLF5/Myc on cardiomyocyte apoptosis and oxidative stress in the MI/R injury mouse model and H/R cell model. High expression of GSK3ß and low expression of FTO, KLF5, and Myc were observed in the MI/R injury mouse model and H/R cell model. GSK3ß promoted phosphorylation of FTO and KLF5, thus increasing the ubiquitination degradation of FTO and KLF5. A decrease of FTO and KLF5 was able to downregulate Myc expression, resulting in enhanced cardiomyocyte apoptosis and oxidative stress. These data together supported the crucial role that GSK3ß played in facilitating cardiomyocyte apoptosis and oxidative stress so as to accelerate MI/R injury, which highlights a promising therapeutic strategy against MI/R injury.

Integrin-Linked Kinase Activation Prevents Ventricular Arrhythmias Induced by Ischemia/Reperfusion Via Inhibition of Connexin 43 Remodeling.

Ischemia reperfusion (I/R)-induced arrhythmia is a serious complication in patients with cardiac infarction. Remodeling of connexin (Cx) 43, manifested as phosphorylation, contributes significantly to arrhythmogenesis. Integrin-linked kinase (ILK) attenuated ventricular remodeling and improved cardiac function in rats after myocardial infarction. We hypothesized that ILK, through Cx43 phosphorylation, would be protective against I/R-induced ventricular arrhythmias. Our study showed that I/R-induced ventricular arrhythmias were attenuated by an ILK agonist LPTP and worsened by the ILK inhibitor Cpd22. I/R disrupted Cx43 distribution, but it was partially normalized in the presence of LPTP. Compared with I/R, the phosphorylation of Akt was increased significantly after pretreatment with LPTP. The increase in phosphorylated Akt was physiologically significant because, in the presence of the Akt inhibitor MK2206, the protective effects of LPTP were blocked. This indicated that ILK activation prevented I/R-induced-ventricular arrhythmia, an effect potentially related to inhibition of Cx43 remodeling via Akt activation.

NLRP3-mediated pyroptosis aggravates pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction in mice: cardioprotective role of irisin.

The exact mechanism of myocardial hypertrophy has not been completely elucidated. NOD-like receptor protein 3 (NLRP3) and the pyroptotic cascade play a critical role in cardiac hypertrophy and inflammation. The myokine irisin can inhibit NLRP3 activation, although its exact mechanism of action is unknown. In this study, we induced cardiac hypertrophy in a mouse model via aortic constriction (TAC) to further explore the pathological role of NLRP3 inflammasome-mediated pyroptosis and the potential therapeutic effects of irisin. Cardiac hypertrophy significantly increased the percentage of apoptotic cells and upregulated IL-1ß, cleaved caspase-1, and GSDMD-N that lie downstream of the NLRP3 inflammasome. Subsequently, irisin was co-administered to the TAC mice or angiotensin II (Ang-II)-treated cardiomyocytes to observe whether it could attenuate pyroptosis and cardiac hypertrophy. We established a direct association between pyroptosis and cardiac hypertrophy and found that pharmacological or genetic inhibition of NLRP3 attenuated cardiac hypertrophy. Furthermore, ectopic overexpression of NLRP3 abrogated the cardioprotective effects of irisin. To summarize, pyroptosis is a pathological factor in cardiac hypertrophy, and irisin is a promising therapeutic agent that inhibits NLRP3-mediated pyroptosis of cardiomyocytes.

8-Formylophiopogonanone B antagonizes doxorubicin-induced cardiotoxicity by suppressing heme oxygenase-1-dependent myocardial inflammation and fibrosis.

Doxorubicin (DOX) is a widely used antitumor drug that causes severe cardiotoxicity in patients; no effective strategy yet exists to address this problem. We previously reported that 8-formylophiopogonanone B (8-FOB), a natural isoflavone in Ophiopogon japonicas, antagonizes paraquat-induced hepatotoxicity. Here, we explored the mechanisms underlying DOX-induced cardiotoxicity as well as whether 8-FOB can alleviate DOX-induced cardiotoxicity. Acute cardiotoxicity was established by injecting C57BL/6J mice with a single dose of DOX (20 mg/kg, intraperitoneal). To elucidate the mechanisms underlying DOX-induced cardiotoxicity, differentially expressed genes between hearts from DOX-treated and control mice were identified from the Gene Expression Omnibus (GEO) database via GEO2R. Using the Cytoscape software plugin cytoHubba, five hub genes associated with DOX-induced cardiotoxicity were identified: CD68, PTEN, SERPINE1, AIF1, and HMOX1. However, of these, only HMOX1 protein expression levels were significantly increased after DOX treatment. We also confirmed that HMOX1-dependent myocardial inflammation and fibrosis were closely associated with DOX-induced cardiotoxicity. More importantly, 8-FOB protected against DOX-cardiotoxicity by ameliorating cardiac injury and dysfunction, reducing cardiac fibrosis and inflammatory cytokine release, and inhibiting HMOX1 expression. In conclusion, our results suggest that inhibition of HMOX1-dependent myocardial inflammatory insults and fibrosis is essential for 8-FOB to ameliorate DOX-caused cardiotoxicity.

Ginsenoside Rg1 Alleviates Podocyte Injury Induced by Hyperlipidemia via Targeting the mTOR/NF-κB/NLRP3 Axis.

BACKGROUND: Podocyte injury plays an important role in diabetic nephropathy (DN). The aim of this study was to determine the potential therapeutic effects of the ginsenoside Rg1 on hyperlipidemia-stressed podocytes and elucidate the underlying mechanisms. METHODS: In vitro and in vivo models of DN were established as previously described, and the expression levels of relevant markers were analyzed by Western blotting, real-time Polymerase Chain Reaction (PCR), immunofluorescence, and immunohistochemistry. RESULTS: Ginsenoside Rg1 alleviated pyroptosis in podocytes cultured under hyperlipidemic conditions, as well as in the renal tissues of diabetic rats, and downregulated the mammalian target of rapamycin (mTOR)/NF-κB pathway. In addition, Rg1 also inhibited hyperlipidemia-induced NLRP3 inflammasome in the podocytes, which was abrogated by the mTOR activator L-leucine (LEU). The antipyroptotic effects of Rg1 manifested as improved renal function in the DN rats. CONCLUSION: Ginsenoside Rg1 protects podocytes from hyperlipidemia-induced damage by inhibiting pyroptosis through the mTOR/NF-κB/NLRP3 axis, indicating a potential therapeutic function in DN.