To What Extent Do Iodomethane and Bromomethane Undergo Analogous Reactions?

Iodomethane and bromomethane (CH3I/CH3Br) are common chemicals, but their chemistry on nanometals is not fully understood. Here, we analyze the reactivity of Rhn+ (n = 3-30) clusters with halomethanes and unveil the spin effect and concentration dependence in the C-H and C-X bond activation. It is found that the reactions under halomethane-rich conditions differ from those under metal-rich conditions. Both CH3I and CH3Br undergo similar dehydrogenation on the Rhn+ clusters in the presence of small quantity reactants; however, different reactions are observed in the presence of sufficient CH3I/CH3Br, showing dominant Rh(CH3Br)x+ (x = 1-4) products but a series of RhnCxHyIz+ species (x = 1-4, y = 1-12, and z = 1-5) pertaining to H2, HI, or CH4 removal. Density functional theory calculations reveal that the dehydrogenation and demethanation of CH3Br are relatively less exothermic and will be deactivated by sufficient gas collisions if helium cooling takes away energy immediately; instead, the successive adsorption of CH3Br gives rise to a series of Rh(CH3Br)x+ species with accidental C-Br bond dissociation.

A review of per- and polyfluoroalkyl substances (PFASs) removal in constructed wetlands: Mechanisms, enhancing strategies and environmental risks.

PER: Polyfluoroalkyl substances (PFASs), typical persistent organic pollutants detected in various water environments, have attracted widespread attention due to their undesirable effects on ecology and human health. Constructed wetlands (CWs) have emerged as a promising, cost-effective, and nature-based solution for removing persistent organic pollutants. This review summarizes the removal performance of PFASs in CWs, underlying PFASs removal mechanisms, and influencing factors are also discussed comprehensively. Furthermore, the environmental risks of PFASs-enriched plants and substrates in CWs are analyzed. The results show that removal efficiencies of total PFASs in various CWs ranged from 21.3% to 98%. Plant uptake, substrate absorption and biotransformation are critical pathways in CWs for removing PFASs, which can be influenced by the physiochemical properties of PFASs, operation parameters, environmental factors, and other pollutants. Increasing dissolved oxygen supply and replacing traditional substrates in CWs, and combining CWs with other technologies could significantly improve PFASs removal. Further, CWs pose relatively lower ecological and environmental risks in removing PFASs, which indicates CWs could be an alternative solution for controlling PFASs in aquatic environments.

Distinct roles of biochar and pyrite substrates in enhancing nutrient and heavy metals removal in intermittent-aerated constructed wetlands: Performances and mechanism.

Constructed wetlands have been widely employed as a cost-effective and environmentally friendly alternative for treating primary and secondary sewage effluents. In this study, biochar and pyrite were utilized as electron donor substrates in intermittent-aerated vertical flow constructed wetlands to strengthen the nutrient and heavy metals removal simultaneously, and the response of nutrient reduction and microbial community to heavy metals stress was also explored. The results indicated that biochar addition exhibited a better nitrogen removal, while pyrite addition greatly promoted the phosphorus removal. Moreover, the high removal efficiencies of Cu2+, Pb2+ and Cd2+ (above 90%) except for Zn2+ were obtained in each system. However, the exposure of heavy metals decreased phosphorus removal while had little effect on nitrogen removal. The influent load and intermittent aeration implementation led to a significant shift in microbial community structures, but microbial biodiversity and abundance decreased under the exposure of heavy metals. Particularly, Thiobacillus and Ferritrophicum, associated with sulfur autotrophic denitrification and iron autotrophic denitrification, were more abundant in pyrite-based wetland systems.

Occurrence of polycyclic aromatic hydrocarbons in the Yellow River delta: Sources, ecological risks, and microbial response.

This research investigated the distribution, sources, and ecological risks of polycyclic aromatic hydrocarbons (PAHs) in the Yellow River Delta (YRD), China, emphasizing the response of soil microorganisms. The study involved quantitative analyses of 16 PAHs specified by the U.S. Environmental Protection Agency (USEPA) in both water and soil, utilizing metagenomic technique to determine the response of microbial communities and metabolism within the soil. Results noted that PAHs in the water mainly originate from pyrogenic source and in the soil originate from mixture source, with higher concentrations found in wetland areas compared to river regions. The ecological risk assessment revealed low-to-moderate risk. Microbial analysis demonstrated increased diversity and abundance of bacteria associated with PAHs in areas with higher PAHs pollution. Metagenomic insights revealed significant effects of organic carbon on PAHs degradation genes (ko00624 and ko00626), as well as significant differences in specific metabolic pathways including phenanthrene degradation, with key enzymes showing significant differences between the two environments. The study underscores the importance of understanding PAHs distribution and microbial responses to effectively manage and mitigate pollution in estuarine environments.

Investigating the vertical distribution of dissolved organic matter in 5-m soil profiles in farmland and typical woodland on the southern loess plateau.

With the implementation of the 'Grain-for-Green' program on the Chinese Loess Plateau (CLP), drought-tolerant deep-rooted plants have been increasingly introduced to the northwest in China. However, the vertical features of dissolved organic matter (DOM) in deep soil profiles on CLP during the 'Grain-for-Green' program is still not well understood. In the study, ultraviolet-visible (UV-Vis) spectroscopy and three-dimensional fluorescence excitation-emission matrices (3D-EEMs) with parallel factor analysis (PARAFAC) were used to characterize DOM in 5-m profile of farmland and forestland (Pinus tabulaeformis and Robinia pseudoacacia) in the southern CLP. The results demonstrated that the average dissolved organic carbon (DOC) content of the surface layer of farmland (119.3 mg kg-1 soil) was lower than that of forestland (Pinus tabulaeformis 175.5 mg kg-1 soil; Robinia pseudoacacacia 166.4 mg kg-1 soil). The DOC content gradually decreased with increasing soil depth and reached stability after 2 m depth. Three substances, including tryptophan-like substances (C1) and two humic acid-like substances (C2, C3), were detected from all samples. Tryptophan-like substances (C1) significantly increased with soil depth while humic acid-like substances (C2, C3) significantly decreased particularly in farmland. The humic acid-like content of surface soils (Robinia pseudoacacia) was relatively higher, but the difference between the two vegetation soils was not significant. The freshness index (ß/α) values of DOM as well as biological index (BIX) values were significantly higher in farmland than that in forestland, and the humification index (HIX) values were lower than in forestland soils, indicating that the change of soil DOM in farmland was more active than that in forestland and more dependent on local terrestrial sources. These results could contribute to a better understanding of the vertical distribution and features of soil DOM during the 'Grain-for-Green' program of CLP.

Highly efficient phosphorous removal in constructed wetland with iron scrap: Insights into the microbial removal mechanism.

Excessive phosphorus (P) in surface water can lead to serious eutrophication and economic losses. Iron-based constructed wetland (CW) is considered as a promising solution to eliminate P effectively due to the advantage of low-cost. However, there is limited available information on the microbial removal mechanism of P in iron-based CW up to now. Therefore, CW with iron scrap was constructed to investigate the treatment performance and microbial removal mechanism in this study. Results showed that efficient and stable P removal (97.09 ± 1.90%) was achieved in iron scrap-based CW during the experiment period, which was attributed to the precipitation of iron and P and improved microbially mediated P removal. Metagenomic analysis showed that microbial diversity was enhanced and phosphate accumulating organisms (e.g., Dechloromonas and Tetrasphaera) were enriched in CW with iron scrap, which explained higher P removal reasonably. In addition, the abundance of genes involved in the P starvation (e.g., phoB), uptake and transport (e.g., pstB) were enhanced in iron scrap-based CW. Enrichment analysis demonstrated that phosphotransferase pathway was also significantly up-regulated in CW with iron scraps, indicating that the energy supply of microbial P removal was enhanced. These findings provide a better understanding of the microbial removal mechanism of P in iron-based CW.

Enhancement of organics and nutrient removal and microbial mechanism in vertical flow constructed wetland under a static magnetic field.

Low and unstable pollutant removal is regarded as the bottleneck problem in constructed wetlands (CWs) for wastewater treatment. This study investigated the effect of static magnetic field (MF) on enhancing the purification efficiency and microbial mechanism in vertical flow CW systems for treating domestic wastewater. The results showed that MF-CWs outperformed control systems in terms of treatment performance, with average removal efficiencies of COD, NH4+-N, TN, and TP reaching 92.58%, 73.58%, 72.53%, and 95.83%, respectively. The change of malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) activity indicated that MF application was beneficial for plant health. Additionally, higher ammonia monooxygenase (AMO) activity in MF-CWs suggested the removal of NH4+-N was facilitated. The high-throughput sequencing results demonstrated that MF application could enrich the functional bacteria such as Patescibacteria phylum, mainly, including Gammaproteobacteria, Betaproteobacteria, and Alphaproteobacteria, which further accelerated pollutants transformation. These findings would be beneficial in understanding pollutant removal processes and their mechanism in CWs with MF application.

TNFα antagonist in combination with PD-1 blocker to prevent or retard malignant transformation of B[a]P-induced chronic lung inflammation.

Benzo[a]pyrene (B[a]P) is a typical complete carcinogen in tobacco, but its mechanism of inducing the development of chronic pneumonia and consequent lung cancer is unclear. Here we elucidated the role of myeloid-derived suppressor cells (MDSCs) in developing B[a]P-induced chronic lung inflammation and efficacy of immunotherapy in preventing subsequent malignant transformation. Our study showed that as B[a]P could induce the accumulation of MDSCs in lung tissues and enhance the immunosuppressive effect regulated by cytokines and metabolites, thereby promoting the formation of immunosuppressive microenvironment, where effector T cells were exhausted, NK cells were dysfunctional, regulatory T (Treg) cells were expanded, polarized alveolar macrophages were transformed from M1 to M2. Subsequently, we performed the immunotherapy to block TNFɑ only or both TNFɑ and PD-1 at the early- or middle-stage of B[a]P-induced chronic lung inflammation to ameliorate the immunosuppressive microenvironment. We found that TNFɑ antagonist alone or with PD-1 blocker was shown to exert therapeutic effects on malignant transformation at the early stage of B[a]P-induced chronic lung inflammation. Taken together, our findings demonstrated that B[a]P-induced chronic lung inflammation resulted in the accumulation of MDSCs in lung tissues and exercise their immunosuppressive functions, thereby developing an immunosuppressive microenvironment, thus TNFɑ antagonist alone or with PD-1 blocker could prevent or retard the malignant transformation of B[a]P-induced chronic lung inflammation.

Trypanosomes have divergent kinesin-2 proteins that function differentially in flagellum biosynthesis and cell viability.

Trypanosoma brucei, the causative agent of African sleeping sickness, has a flagellum that is crucial for motility, pathogenicity, and viability. In most eukaryotes, the intraflagellar transport (IFT) machinery drives flagellum biogenesis, and anterograde IFT requires kinesin-2 motor proteins. In this study, we investigated the function of the two T. brucei kinesin-2 proteins, TbKin2a and TbKin2b, in bloodstream form trypanosomes. We found that, compared to kinesin-2 proteins across other phyla, TbKin2a and TbKin2b show greater variation in neck, stalk and tail domain sequences. Both kinesins contributed additively to flagellar lengthening. Silencing TbKin2a inhibited cell proliferation, cytokinesis and motility, whereas silencing TbKin2b did not. TbKin2a was localized on the flagellum and colocalized with IFT components near the basal body, consistent with it performing a role in IFT. TbKin2a was also detected on the flagellar attachment zone, a specialized structure that connects the flagellum to the cell body. Our results indicate that kinesin-2 proteins in trypanosomes play conserved roles in flagellar biosynthesis and exhibit a specialized localization, emphasizing the evolutionary flexibility of motor protein function in an organism with a large complement of kinesins.

By restoring autophagic flux and improving mitochondrial function, corosolic acid protects against Dox-induced cardiotoxicity.

Despite effective anticancer effects, the use of doxorubicin (Dox) is limited due to its side effects as cardiotoxicity. Corosolic acid (CRA) is a pentacyclic triterpene acid isolated from Lagerstroemia speciosa L. (Banaba) leaves, and it has also been shown to improve myocardial hypertrophy and myocardial infarction which expected to be used in clinical pharmaceuticals. The purpose of this study was to explore whether CRA can improve myocardial injury caused by Dox and to clarify potential mechanisms. C57 BL/6J mice and AMPKα2 knockout mice were given a single intraperitoneal (i.p.) injection of Dox (5 mg/kg) every week for 4 weeks, while normal saline (NS) was used as control. Mice were given CRA (10 mg/kg or 20 mg/kg) or equal volumes of normal saline daily after the first time i.p. injection of Dox. After 4 weeks, echocardiography, gravimetric, hemodynamic, histological, and biochemical analyses were conducted. After Dox injury, compared with the control group, CRA increased the survival rate of mice, improved the cardiac function, decreased the oxidative stress, and reduced the apoptosis. CRA may function by promoting transcription factor EB (TFEB) nuclear translocation and thus restoring autophagic flux. We also observed that CRA protected mitochondrial structure and function, which may benefit from oxidative stress reduction or TFEB activation. In vitro, the protective effect of CRA is reversed by TFEB deletion. Then, we evaluated the expression of AMPKα2/mTOR C1 signaling pathway, the main pathway of TFEB activation. In vivo and in vitro, CRA promoted TFEB nuclear translocation by activating AMPKα2/mTOR C1 signaling, while ablating AMPKα2 reversed these results and accompanied with a decrease in the ability of CRA to resist Dox-induced cardiotoxicity. Thus, we suggested that CRA activated TFEB in an AMPKα2-dependent manner to protect against Dox cardiotoxicity. This study confirms the role and mechanism of CRA in the treatment of Dox-induced cardiac injury. Dox-induced damage to autophagy includes autophagosomes maturation disorders and autophagolysosomes acidification defects, CRA restored autophagic flux, and promoted lysosomal degradation by activating TFEB in an AMPKα2-depended manner, stabilized mitochondrial function, ultimately protected against Dox-induced cardiotoxicity.

Distributions and interactions of dissolved organic matter and heavy metals in shallow groundwater in Guanzhong basin of China.

Groundwater as the primary source of fresh water particularly in semi-arid regions is heavily threatened by various pollutants such as dissolved organic matter (DOM) and heavy metals due to anthropogenic activities. In this study, 113 shallow groundwater samples were collected from Guanzhong basin of China to explore spatial distributions and interactions of DOM and heavy metals (Fe, Mn and Cu). Fluorescence excitation-emission spectrophotometry with parallel factor analysis showed that DOM in groundwater mainly contained three humic-like and two protein-like substances with an average dissolved organic carbon (DOC) concentration of 12.85 mg L-1. Average Mn and Cu concentrations in groundwater were 19.92 µg L-1 and 7.05 µg L-1 with an increasing trend from west to east, whereas Fe concentration in central regions was much higher (34.23 µg L-1). Structural equation modeling analysis indicated that DOM in groundwater could be significantly affected by surface water, and heavy metals were influenced by urbanization. Moreover, DOM could strongly influence the bioavailability, migration, and transformation of Mn in groundwater. These findings would be beneficial for the effective utilization and protection of groundwater resources.

Optimizing agricultural biomass application to enhance nitrogen removal in vertical flow constructed wetlands for treating low-carbon wastewater.

Agricultural biomass waste in rural areas has been identified as an economical solid carbon sources in constructed wetlands (CWs) for treating low C/N ratio domestic sewage. However, little information is available regarding its optimal utilization as a media amendment for enhancing nitrogen removal in CWs. In this study, vertical flow CWs with different walnut peel amendment proportions (0%, 25%, 50%, 75%) were developed to explore the effects of biomass dosage on the treatment performance, nitrous oxide (N2O) emission and microbial metabolites. Results showed that the addition of biomass significantly enhanced the denitrification performance in all CWs, and the higher total nitrogen (TN) removal efficiency (91.14-97.16%) was achieved in CWs with the optimal dosage of 25%. While the addition of biomass resulted in a slight increase in N2O emission (20.56-270.13 µg m-2 h-1) compared with control systems. Additionally, the biomass addition increased the accumulation of extracellular polymeric substances (EPS) by facilitating microbial processes. Higher total EPS production was observed in CW with 25% biomass, and the proportion of tightly bound EPS (48%) dominated in the total EPS in different CWs.

Endothelial ERG alleviates cardiac fibrosis via blocking endothelin-1-dependent paracrine mechanism.

Cardiac endothelium communicates closely with adjacent cardiac cells by multiple cytokines and plays critical roles in regulating fibroblasts proliferation, activation, and collagen synthesis during cardiac fibrosis. E26 transformation-specific (ETS)-related gene (ERG) belongs to the ETS transcriptional factor family and is required for endothelial cells (ECs) homeostasis and cardiac development. This study aims at investigating the potential role and molecular basis of ERG in fibrotic remodeling within the adult heart. We observed that ERG was abundant in murine hearts, especially in cardiac ECs, but decreased during cardiac fibrosis. ERG knockdown within murine hearts caused spontaneously cardiac fibrosis and dysfunction, accompanied by the activation of multiple Smad-dependent and independent pathways. However, the direct silence of ERG in cardiac fibroblasts did not affect the expression of fibrotic markers. Intriguingly, ERG knockdown in human umbilical vein endothelial cells (HUVECs) promoted the secretion of endothelin-1 (ET-1), which subsequently accelerated the proliferation, phenotypic transition, and collagen synthesis of cardiac fibroblasts in a paracrine manner. Suppressing ET-1 with either a neutralizing antibody or a receptor blocker abolished ERG knockdown-mediated deleterious effect in vivo and in vitro. This pro-fibrotic effect was also negated by RGD (Arg-Gly-Asp)-peptide magnetic nanoparticles target delivery of ET-1 small interfering RNA to ECs in mice. More importantly, we proved that endothelial ERG overexpression notably prevented pressure overload-induced cardiac fibrosis. Collectively, endothelial ERG alleviates cardiac fibrosis via blocking ET-1-dependent paracrine mechanism and it functions as a candidate for treating cardiac fibrosis. • ERG is abundant in murine hearts, especially in cardiac ECs, but decreased during fibrotic remodeling. • ERG knockdown causes spontaneously cardiac fibrosis and dysfunction. • ERG silence in HUVECs promotes the secretion of endothelin-1, which in turn activates cardiac fibroblasts in a paracrine manner. • Endothelial ERG overexpression prevents pressure overload-induced cardiac fibrosis.

An oxygen-passivated vanadium cluster [V@V10O15]- with metal-metal coordination produced by reacting Vn- with O2.

Vanadium cluster anions are highly reactive making the preparation of pure Vn- and the observation of their reactivity extremely challenging. Herein, well-resolved anionic Vn- clusters are prepared enabling an in-depth study on their reactions with O2 in the gas phase. While pure metal clusters of a magic number are not identified due to the strong V-O bonding, interestingly an unexpected oxide V11O15- was experimentally observed in surviving O2 etching reactions. First-principles theory calculations indicate that V11O15- possesses a body-centered pentagonal prism structure (D5h, ), with the V@V10 core fully protected by 15 oxygen bridges. Such an oxygen-protected metal cluster [V@V10O15]- exhibits typical superatom orbital features pertaining to the V@V10 core which shows effective metal-metal coordination bonding. Meanwhile, the high stability of [V@V10O15]- is reinforced by the V-O-V conjugation interactions which help to maintain the structural integrity, resulting in 3D inorganic aromaticity. This finding of such an oxygen-passivated superatom cluster sheds light on the bonding nature in ligand-protected metal clusters via wet synthesis.

Fibronectin type III domain-containing 5 in cardiovascular and metabolic diseases: a promising biomarker and therapeutic target.

Cardiovascular and metabolic diseases are the leading causes of death and disability worldwide and impose a tremendous socioeconomic burden on individuals as well as the healthcare system. Fibronectin type III domain-containing 5 (FNDC5) is a widely distributed transmembrane glycoprotein that can be proteolytically cleaved and secreted as irisin to regulate glycolipid metabolism and cardiovascular homeostasis. In this review, we present the current knowledge on the predictive and therapeutic role of FNDC5 in a variety of cardiovascular and metabolic diseases, such as hypertension, atherosclerosis, ischemic heart disease, arrhythmia, metabolic cardiomyopathy, cardiac remodeling, heart failure, diabetes mellitus, and obesity.

Matrine attenuates pathological cardiac fibrosis via RPS5/p38 in mice.

Pathological cardiac fibrosis is a common feature in multiple cardiovascular diseases that contributes to the occurrence of heart failure and life-threatening arrhythmias. Our previous study demonstrated that matrine could attenuate doxorubicin-induced oxidative stress and cardiomyocyte apoptosis. In this study, we investigated the effect of matrine on cardiac fibrosis. Mice received aortic banding (AB) operation or continuous injection of isoprenaline (ISO) to generate pathological cardiac fibrosis and then were exposed to matrine lavage (200 mg·kg-1·d-1) or an equal volume of vehicle as the control. We found that matrine lavage significantly attenuated AB or ISO-induced fibrotic remodeling and cardiac dysfunction. We also showed that matrine (200 µmol/L) significantly inhibited the proliferation, migration, collagen production, and phenotypic transdifferentiation of cardiac fibroblasts. Mechanistically, matrine suppressed p38 activation in vivo and in vitro, and overexpression of constitutively active p38 completely abolished the protective effects of matrine. We also demonstrated that ribosomal protein S5 (RPS5) upregulation was responsible for matrine-mediated inhibition on p38 and fibrogenesis. More importantly, matrine was capable of ameliorating preexisting cardiac fibrosis in mice. In conclusion, matrine treatment attenuates cardiac fibrosis by regulating RPS5/p38 signaling in mice, and it might be a promising therapeutic agent for treating pathological cardiac fibrosis.

6-Gingerol protects against cardiac remodeling by inhibiting the p38 mitogen-activated protein kinase pathway.

6-Gingerol, a pungent ingredient of ginger, has been reported to possess anti-inflammatory and antioxidant activities, but the effect of 6-gingerol on pressure overload-induced cardiac remodeling remains inconclusive. In this study, we investigated the effect of 6-gingerol on cardiac remodeling in in vivo and in vitro models, and to clarify the underlying mechanisms. C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with 6-gingerol (20 mg/kg, ig) three times a week (1 week in advance and continued until the end of the experiment). Four weeks after TAC surgery, the mice were subjected to echocardiography, and then sacrificed to harvest the hearts for analysis. For in vitro study, neonatal rat cardiomyocytes and cardiac fibroblasts were used to validate the protective effects of 6-gingerol in response to phenylephrine (PE) and transforming growth factor-ß (TGF-ß) challenge. We showed that 6-gingerol administration protected against pressure overload-induced cardiac hypertrophy, fibrosis, inflammation, and dysfunction in TAC mice. In the in vitro study, we showed that treatment with 6-gingerol (20 µM) blocked PE-induced-cardiomyocyte hypertrophy and TGF-ß-induced cardiac fibroblast activation. Furthermore, 6-gingerol treatment significantly decreased mitogen-activated protein kinase p38 (p38) phosphorylation in response to pressure overload in vivo and extracellular stimuli in vitro, which was upregulated in the absence of 6-gingerol treatment. Moreover, transfection with mitogen-activated protein kinase kinase 6 expressing adenoviruses (Ad-MKK6), which specifically activated p38, abolished the protective effects of 6-gingerol in both in vitro and in vivo models. In conclusion, 6-gingerol improves cardiac function and alleviates cardiac remodeling induced by pressure overload in a p38-dependent manner. The present study demonstrates that 6-gingerol is a promising agent for the intervention of pathological cardiac remodeling.

Impacts of aeration and biochar on physiological characteristics of plants and microbial communities and metabolites in constructed wetland microcosms for treating swine wastewater.

Constructed wetlands (CWs) by modifying operation strategies or substrates have grown in popularity in recent years for improving the treatment capacity. However, few studies focused on the responses of wetland vegetation and associated microorganisms in CWs for treating high-strength wastewaters. This study evaluated the long-term responses of plants and microbes in CWs with biochar and intermittent aeration for treating real swine wastewater. The results showed that intermittent aeration or combined with biochar could decrease the stress response of wetland plants against the swine wastewater. Biochar addition promoted the production of extracellular polymeric substances (EPS, total 516.27 mg L-1) mainly including protein-like, humic-like and tryptophan-like components. However, intermittent aeration resulted in the EPS reduction (99.24 mg L-1). As for microbial communities, biochar addition supported rich and diverse microbial communities (652 OTUs), while the combination with biochar and aeration could not improve diversity of microbes (597 OTUs). Additionally, the combination altered the microbial community structures and changed microbial composition correlated with environmental factors.

TLR9 deficiency alleviates doxorubicin-induced cardiotoxicity via the regulation of autophagy.

Doxorubicin is a commonly used anthracycline chemotherapeutic drug. Its application for treatment has been impeded by its cardiotoxicity as it is detrimental and fatal. DNA damage, cardiac inflammation, oxidative stress and cell death are the critical links in DOX-induced myocardial injury. Previous studies found that TLR9-related signalling pathways are associated with the inflammatory response of cardiac myocytes, mitochondrial dysfunction and cardiomyocyte death, but it remains unclear whether TLR9 could influence DOX-induced heart injury. Our current data imply that DOX-induced cardiotoxicity is ameliorated by TLR9 deficiency both in vivo and in vitro, manifested as improved cardiac function and reduced cardiomyocyte apoptosis and oxidative stress. Furthermore, the deletion of TLR9 rescued DOX-induced abnormal autophagy flux in vivo and in vitro. However, the inhibition of autophagy by 3-MA abolished the protective effects of TLR9 deletion on DOX-induced cardiotoxicity. Moreover, TLR9 ablation suppressed the activation of p38 MAPK during DOX administration and may promote autophagy via the TLR9-p38 MAPK signalling pathway. Our study suggests that the deletion of TLR9 exhibits a protective effect on doxorubicin-induced cardiotoxicity by enhancing p38-dependent autophagy. This finding could be used as a basis for the development of a prospective therapy against DOX-induced cardiotoxicity.

Combination treatment of perifosine and valsartan showed more efficiency in protecting against pressure overload induced mouse heart failure.

The optimum strategy for heart failure (HF) treatment has yet to be elucidated. This study intended to test the benefit of a combination of valsartan (VAL) and perifosine (PER), a specific AKT inhibitor, in protecting against pressure overload induced mouse HF. Mouse were subjected to aortic banding (AB) surgery to establish HF models and then were given vehicle (HF), VAL (50 mg/kg/d), PER (30 mg/kg/d) or combination of VAL and PER for 4 weeks. Mouse with sham surgery treated with VEH were used for control (VEH). VAL or PER treatment could significantly alleviate mouse heart weight, attenuate cardiac fibrosis and improve cardiac function. The combination treatment of VAL and PER presented much better benefit compared with VAL or PER group respectively. PER treatment significantly inhibited AKT/GSK3ß/mTORC1 signaling. Besides the classic AT1 inhibition, VAL treatment significantly inhibited MAPK (ERK1/2) signaling. Furthermore, VAL and PER treatment could markedly prevent neonatal rat cardiomyocyte hypertrophy and the activation of neonatal rat cardiac fibroblast. Combination of VAL and PER also presented superior beneficial effects than single treatment of VAL or PER in vitro experiments respectively. This study presented that the combination of valsartan and PER may be a potential treatment for HF prevention.