AP39 through AMPK-ULK1-FUNDC1 pathway regulates mitophagy, inhibits pyroptosis, and improves doxorubicin-induced myocardial fibrosis.

Doxorubicin induces myocardial injury and fibrosis. Still, no effective interventions are available. AP39 is an H2S donor that explicitly targets mitochondria. This study investigated whether AP39 could improve doxorubicin-induced myocardial fibrosis. Doxorubicin induced significant myocardial fibrosis while suppressing mitophagy-related proteins and elevating pyroptosis-related proteins. Conversely, AP39 reverses these effects, enhancing mitophagy and inhibiting pyroptosis. In vitro experiments revealed that AP39 inhibited H9c2 cardiomyocyte pyroptosis, improved doxorubicin-induced impairment of mitophagy, reduced ROS levels, ameliorated the mitochondrial membrane potential, and upregulated AMPK-ULK1-FUNDC1 expression. In contrast, AMPK inhibitor (dorsomorphin) and ULK1 inhibitor (SBI-0206965) reversed AP39 antagonism of doxorubicin-induced FUNDC1-mediated impairment of mitophagy and secondary cardiomyocyte pyroptosis. These results suggest that mitochondria-targeted H2S can antagonize doxorubicin-induced pyroptosis and impaired mitophagy in cardiomyocytes via AMPK-ULK1-FUNDC1 and ameliorated myocardial fibrosis and remodeling.

AP39 inhibits ferroptosis by inhibiting mitochondrial autophagy through the PINK1/parkin pathway to improve myocardial fibrosis with myocardial infarction.

BACKGROUND AND PURPOSE: Research has revealed the involvement of mitochondrial autophagy and iron death in the pathogenesis of myocardial fibrosis. The objective of this study is to investigate whether the mitochondrial-targeted H2S donor AP39 inhibits mitochondrial autophagy and antagonizes myocardial cell iron death through the PINK1/Parkin pathway, thereby improving myocardial fibrosis in rats with myocardial infarction. EXPERIMENTAL APPROACH: A rat model of myocardial infarction was created by intraperitoneal injection of a high dose of isoproterenol, and H9c2 myocardial cells were subjected to hypoxic injury induced by CoCl2. Western blot, RT-PCR, transmission electron microscopy, immunohistochemistry, as well as echocardiography, and studies on isolated hearts were employed. KEY RESULTS: In the hearts of rats with myocardial infarction, there was a significant accumulation of interstitial collagen fibers, accompanied by downregulation of CSE protein expression, activation of the PINK1/Parkin signaling pathway, and activation of mitochondrial autophagy. Intervention with AP39 resulted in a significant improvement of the aforementioned changes, which could be reversed by the addition of PAG. Similar results were observed in vitro experiments. Furthermore, the addition of CCCP reversed the antagonistic effect of AP39 on myocardial cell iron death, while the addition of RSL3 reversed the inhibitory effect of AP39 on collagen production in myocardial cells. CONCLUSION AND IMPLICATIONS: The mitochondrial-targeted H2S donor AP39 can inhibit mitochondrial autophagy through the PINK1/Parkin pathway, antagonize myocardial cell iron death, and improve myocardial fibrosis in rats with myocardial infarction.

The application of two-phase composite absorbent systems consisting of BAD and seawater resources in the wet treatment of ship exhaust gas.

The impact of ship emissions on the environment cannot be ignored and should be controlled. The possibility of applying seawater electrolysis technology and a novel amide absorbent (BAD, C12H25NO) to the simultaneous desulfurization and denitrification of ship exhaust gas is entirely confirmed by using various seawater resources. Concentrated seawater (CSW) with high salinity can effectively reduce the heat generated during electrolysis and the escape of chlorine. The initial pH of the absorbent can greatly affect the NO removal capacity of the system, and the BAD could keep the pH range suitable for NO oxidation in the system for a long time. The use of fresh seawater (FSW) to dilute the electrolysis of concentrated seawater (ECSW) to make an aqueous oxidant is a more reasonable scheme; the average removal efficiencies of SO2, NO, and NOx were 97.10%, 75.41%, and 74.28%, respectively. The synergistic effect of HCO3 -/CO3 2- and BAD was shown to further restrict NO2 escape.

Hydrogen sulfide alleviates hypothyroidism-induced myocardial fibrosis in rats through stimulating autophagy and inhibiting TGF-ß1/Smad2 pathway.

Hypothyroidism alone can lead to myocardial fibrosis and result in heart failure, but traditional hormone replacement therapy does not improve the fibrotic situation. Hydrogen sulfide (H2S), a new gas signaling molecule, possesses anti-inflammatory, antioxidant, and anti-fibrotic capabilities. Whether H2S could improve hypothyroidism-induced myocardial fibrosis are not yet studied. In our study, H2S could decrease collagen deposition in the myocardial tissue of rats caused by hypothyroidism. Furthermore, in hypothyroidism-induced rats, we found that H2S could enhance cystathionine-gamma-lyase (CSE), not cystathionine ß-synthase (CBS), protein expressions. Finally, we noticed that H2S could elevate autophagy levels and inhibit the transforming growth factor-ß1 (TGF-ß1) signal transduction pathway. In conclusion, our experiments not only suggest that H2S could alleviate hypothyroidism-induced myocardial fibrosis by activating autophagy and suppressing TGF-ß1/SMAD family member 2 (Smad 2) signal transduction pathway, but also show that it can be used as a complementary treatment to conventional hormone therapy.

Gaseous signal molecule SO2 regulates autophagy through PI3K/AKT pathway inhibits cardiomyocyte apoptosis and improves myocardial fibrosis in rats with type II diabetes.

Myocardial fibrosis is a key link in the occurrence and development of diabetic cardiomyopathy. Its etiology is complex, and the effect of drugs is not good. Cardiomyocyte apoptosis is an important cause of myocardial fibrosis. The purpose of this study was to investigate the effect of gaseous signal molecule sulfur dioxide (SO2) on diabetic myocardial fibrosis and its internal regulatory mechanism. Masson and TUNEL staining, Western-blot, transmission electron microscopy, RT-qPCR, immunofluorescence staining, and flow cytometry were used in the study, and the interstitial collagen deposition, autophagy, apoptosis, and changes in phosphatidylinositol 3-kinase (PI3K)/AKT pathways were evaluated from in vivo and in vitro experiments. The results showed that diabetic myocardial fibrosis was accompanied by cardiomyocyte apoptosis and down-regulation of endogenous SO2-producing enzyme aspartate aminotransferase (AAT)1/2. However, exogenous SO2 donors could up-regulate AAT1/2, reduce apoptosis of cardiomyocytes induced by diabetic rats or high glucose, inhibit phosphorylation of PI3K/AKT protein, up-regulate autophagy, and reduce interstitial collagen deposition. In conclusion, the results of this study suggest that the gaseous signal molecule SO2 can inhibit the PI3K/AKT pathway to promote cytoprotective autophagy and inhibit cardiomyocyte apoptosis to improve myocardial fibrosis in diabetic rats. The results of this study are expected to provide new targets and intervention strategies for the prevention and treatment of diabetic cardiomyopathy.

A brand new two-phase wet oxidation absorption system for the simultaneous removal of SO2 and NOX from simulated marine exhaust gas.

Marine engine exhaust emissions are increasingly harmful to the natural environment and human health and must be controlled. A self-synthesized amide (BAD, C12H25NO) in the laboratory shows a strong absorption capacity of nitric acid and nitrous acid, which may solve the problem that only using chlorine-based oxidant as an absorbent cannot completely absorb or retain NO2 produced by NO oxidation in previous studies. Based on Multiwfn and VMD (Visual Molecular Dynamics) program calculation, the formation mechanism of hydrogen bonds between BAD with nitric acid and nitrous acid was revealed by electrostatic potential (ESP) analysis and further confirmed by FT-IR (Fourier transform infrared spectroscopy) spectra research. Subsequently, simultaneous removal of SO2 and NOX from simulated flue gas was carried out by using NaClO/BAD as a two-phase composite absorbent, and the maximum removal efficiencies of SO2 and NOX were 98.9% and 86.6%, respectively. The recycling experiments and the engineering experiments showing that NaClO/BAD can solve the problem of absorption of NO2, and it can be a promising composite absorbent in wet desulfurization and denitrification of marine engine exhaust gas in practical applications.

Progress of ship exhaust gas control technology.

Ship emissions problems caused by the rapid development of maritime trade can't be ignored. The NOX, SOX, CO2, PM and other toxic substances contained in the exhaust gas are extremely harmful to the environment and human health. In order to cope with the adverse effects of ship emissions and the increasingly stringent emission regulations formulated by the IMO and governments, the shipping industry needs to adopt new clean energy and high-efficiency exhaust control technologies to reduce ship emissions. This paper provides a comprehensive review, including: (1) The impact of pollutants such as NOX, SOX, CO2 and PM emitted by ships on the environment and human health; (2) New regulations about ship exhaust emissions; (3) Application of clean energy such as LNG, biodiesel, methanol, hydrogen and ammonia on ships; (4) After-treatment technology of ship exhaust gas such as SCR and EGR. And focusing on the principles, uses, characteristics, implementation obstacles and prospects of different energy and technologies, with a view to provide some help for the research on ship exhaust emissions control.

Genetic impact of ZNF804A on cognitive function in patients with bipolar I disorder.

Our previous genetic study identified a variant rs1344706 in the zinc finger protein 804A (ZNF804A) gene conferring susceptibility to bipolar disorder subtype I (BD-I) in Han Chinese. Literature documented that this variant may affect brain structure and function. As such, we attempted to identify whether the rs1344706 polymorphism influences cognitive function in patients with bipolar disorder I. We recruited 177 patients with bipolar disorder in remission period. Cognitive function was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The single nucleotide polymorphisms (SNP) rs1344706 was genotyped using TaqMan assays. Analysis of covariance (ANCOVA) analysis showed a significant genotypic effect on RBANS immediate memory (P = 0.002) and total score (P = 0.001). Post hoc analysis showed that the patients with T/T genotype have lower RBANS immediate memory and total scores than those with T/G or G/G genotypes. When the patients were stratified by sex, such significances are only seen in male patients, but not female patients. Our findings suggested a sex-specific effect of ZNF804A rs1344706 polymorphism on cognitive function in patients with bipolar disorder-I.

A Comprehensive Analysis of the Effect of SIRT1 Variation on the Risk of Schizophrenia and Depressive Symptoms.

Depressive symptoms could be considered a mutual manifestation of major depressive disorder and schizophrenia. Rs3758391 is a functional locus of Sirtuin (SIRT1) involving depression etiology. In this study, we hypothesized that the SIRT1 SNP rs3758391 might be a hazard for schizophrenia pathogenesis, especially related to the appearance of depressive symptoms. We recruited 723 healthy controls and 715 schizophrenia patients, the occurrence of psychotic and depressive symptoms was evaluated by Calgary Depression Scale (CDSS) and PANSS. Meanwhile, qt-PCR was used to detect the mRNA levels of SIRT1 in peripheral blood of 197 olanzapine monotherapy schizophrenia patients. 45.6% of schizophrenia patients had depressive symptoms. In the patient group, mRNA levels of patients with depressive symptoms were significantly lower than those without depressive symptoms (P < 0.01). CDSS scores of schizophrenia patients with different rs3758391 genotypes were significantly different (P < 0.01). Post hoc comparisons indicated that the CDSS scores of rs3758391 C/C and C/T carriers were higher than those of T/T carriers (Ps < 0.01). In the occipital cortex, our eQTL analysis showed that there was a clear correlation between rs3758391 and the SIRT1 mRNA levels. Our preliminary findings provide suggestive evidence that SIRT1 makes schizophrenia patients more prone to depressive symptoms. This SNP might be a biomarker of depression in schizophrenia.

Homocysteine, but not MTHFR gene polymorphism, influences depressive symptoms in patients with schizophrenia.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is the key enzyme of folate metabolism in the process of one-carbon cycle and its deficiency results in elevated homocysteine concentration. In this study, we hypothesized that MTHFR C677T polymorphism and homocysteine concentration may play important roles in the development of depressive symptoms in schizophrenia. METHODS: We recruited 715 patients with stable schizophrenia, and among them, 197 schizophrenia patients under olanzapine monotherapy were enrolled for homocysteine concentration analysis. The Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS) were employed to evaluate psychiatric and depressive symptoms. RESULTS: When the 715 schizophrenia patients were evaluated by CDSS, 326 individuals (45.6%) had depressive symptoms. No significant differences were observed in C677T genotype and allele distributions between the schizophrenia with or without depression groups. Schizophrenia patients with depression have higher levels of homocysteine than those without depression (P = 0.019). There was a positive correlation between the homocysteine levels and CDSS score (r = 0.22, P = 0.002). CONCLUSION: Our findings suggested that higher levels of homocysteine may be a risk factor for the development of depressive symptoms in schizophrenia patients.

Identification of TNFA influencing MDD risk and clinical features in Han Chinese.

OBJECTIVE: Our recent genetic-neuroimaging study observed that the rs1799724 polymorphism within the TNFA gene encoding TNF-α selectively affects the anatomy of visual cortex in patients with MDD. In this study, we hypothesized that TNFA is risk factor to MDD, and TNFA rs1799724 polymorphism may be a susceptibility locus for this disorder and its clinical features. METHODS: We enrolled 807 MDD samples and 822 healthy volunteers in Eastern China. There were 104 drug-naïve first episode MDD patients recruited. The Hamilton Rating Scale for Depression -17 (HRSD-17) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were performed to evaluate the severity of depressive symptoms and cognitive function, respectively. RESULTS: Patients with MDD have higher levels of TNFA than healthy controls (F = 20.78, P < 0.01). There were no significant differences in genotype or allele distributions of the rs1799724 polymorphism between the MDD and control groups. MDD patients with T/T or T/C genotypes of rs1799724 polymorphism have higher somatic factor and total scores of HAMD than those with C/C genotype. The patients with T/T or T/C genotypes have significantly higher TNFA mRNA levels than those with C/C genotype (F = 4.91, P = 0.029). CONCLUSION: Our findings supported that TNFA may have an important role in the pathophysiology of MDD. Although SNP rs1799724 is not an etiological factor for MDD in Han Chinese, this SNP may be associated with somatic symptom in patients with MDD.