mir-605-3p prevents liver premetastatic niche formation by inhibiting angiogenesis via decreasing exosomal nos3 release in gastric cancer.

BACKGROUND: Cancer-induced pre-metastatic niches (PMNs) play a decisive role in promoting metastasis by facilitating angiogenesis in distant sites. Evidence accumulates suggesting that microRNAs (miRNAs) exert significant influence on angiogenesis during PMN formation, yet their specific roles and regulatory mechanisms in gastric cancer (GC) remain underexplored. METHODS: miR-605-3p was identified through miRNA-seq and validated by qRT-PCR. Its correlation with the clinicopathological characteristics and prognosis was analyzed in GC. Functional assays were performed to examine angiogenesis both in vitro and in vivo. The related molecular mechanisms were elucidated using RNA-seq, immunofluorescence, transmission electron microscopy, nanoparticle tracking analysis, enzyme-linked immunosorbent assay, luciferase reporter assays and bioinformatics analysis. RESULTS: miR-605-3p was screened as a candidate miRNA that may regulate angiogenesis in GC. Low expression of miR-605-3p is associated with shorter overall survival and disease-free survival in GC. miR-605-3p-mediated GC-secreted exosomes regulate angiogenesis by regulating exosomal nitric oxide synthase 3 (NOS3) derived from GC cells. Mechanistically, miR-605-3p reduced the secretion of exosomes by inhibiting vesicle-associated membrane protein 3 (VAMP3) expression and affects the transport of multivesicular bodies to the GC cell membrane. At the same time, miR-605-3p reduces NOS3 levels in exosomes by inhibiting the expression of intracellular NOS3. Upon uptake of GC cell-derived exosomal NOS3, human umbilical vein endothelial cells exhibited increased nitric oxide levels, which induced angiogenesis, established liver PMN and ultimately promoted the occurrence of liver metastasis. Furthermore, a high level of plasma exosomal NOS3 was clinically associated with metastasis in GC patients. CONCLUSIONS: miR-605-3p may play a pivotal role in regulating VAMP3-mediated secretion of exosomal NOS3, thereby affecting the formation of GC PMN and thus inhibiting GC metastasis.

Novel nano-drug delivery system for natural products and their application.

The development of natural products for potential new drugs faces obstacles such as unknown mechanisms, poor solubility, and limited bioavailability, which limit the broadened applicability of natural products. Therefore, there is a need for advanced pharmaceutical formulations of active compounds or natural products. In recent years, novel nano-drug delivery systems (NDDS) for natural products, including nanosuspensions, nanoliposomes, micelle, microemulsions/self-microemulsions, nanocapsules, and solid lipid nanoparticles, have been developed to improve solubility, bioavailability, and tissue distribution as well as for prolonged retention and enhanced permeation. Here, we updated the NDDS delivery systems used for natural products with the potential enhancement in therapeutic efficiency observed with nano-delivery systems.

Poly (ADP-ribose) polymerases 16 triggers pathological cardiac hypertrophy via activating IRE1α-sXBP1-GATA4 pathway.

BACKGROUND: Pressure overload-induced pathological cardiac hypertrophy is an independent predecessor of heart failure (HF), which remains the leading cause of worldwide mortality. However, current evidence on the molecular determinants of pathological cardiac hypertrophy is still inadequacy. This study aims to elucidate the role and mechanisms of Poly (ADP-ribose) polymerases 16 (PARP16) in the pathogenesis of pathological cardiac hypertrophy. METHODS: Gain and loss of function approaches were used to demonstrate the effects of genetic overexpression or deletion of PARP16 on cardiomyocyte hypertrophic growth in vitro. Ablation of PARP16 by transducing the myocardium with serotype 9 adeno-associated virus (AAV9)-encoding PARP16 shRNA were then subjected to transverse aortic construction (TAC) to investigate the effect of PARP16 on pathological cardiac hypertrophy in vivo. Co-immunoprecipitation (IP) and western blot assay were used to detect the mechanisms of PARP16 in regulating cardiac hypertrophic development. RESULTS: PARP16 deficiency rescued cardiac dysfunction and ameliorated TAC-induced cardiac hypertrophy and fibrosis in vivo, as well as phenylephrine (PE)-induced cardiomyocyte hypertrophic responses in vitro. Whereas overexpression of PARP16 exacerbated hypertrophic responses including the augmented cardiomyocyte surface area and upregulation of the fetal gene expressions. Mechanistically, PARP16 interacted with IRE1α and ADP-ribosylated IRE1α and then mediated the hypertrophic responses through activating the IRE1α-sXBP1-GATA4 pathway. CONCLUSIONS: Collectively, our results implicated that PARP16 is a contributor to pathological cardiac hypertrophy at least in part via activating the IRE1α-sXBP1-GATA4 pathway, and may be regarded as a new potential target for exploring effective therapeutic interventions of pathological cardiac hypertrophy and heart failure.

A retro-inverso modified peptide alleviated ovalbumin-induced asthma model by affecting glycerophospholipid and purine metabolism of immune cells.

Allergic asthma is a heterogeneous disease involving a variety of inflammatory cells. Immune imbalance or changes in the immune microenvironment are the essential causes that promote inflammation in allergic asthma. Tetraspanin CD81 can be used as a platform for receptor clustering and signal transmission owing to its special transmembrane structure and is known to participate in the physiological processes of cell proliferation, differentiation, adhesion, and migration. Previous studies have shown that CD81-targeting peptidomimetics exhibit anti-allergic lung inflammation. However, due to the low metabolic stability of peptide drugs, their druggability is limited. Here, we aimed to generate a metabolically stable anti-CD81 peptide, evaluate its anti-inflammatory action and establish its mechanism of action. Based on previous reports, we applied retro-inverse peptide modification to obtain a new compound, PD00 (NH2-D-Gly-D-Ser-D-Thr-D-Tyr-D-Thr-D-Gln-D-Gly-COOH), with high metabolic stability. Enhanced ultraperformance liquid chromatography-tandem mass spectrometry was used to investigate the in vitro and in vivo metabolic stabilities of PD00. The affinities of PD00 and CD81 were studied using molecular docking and surface plasmon resonance techniques. An ovalbumin (OVA)-induced asthma model was used to evaluate the effects of PD00 in vivo. Mice were treated with different concentrations of PD00 (175 and 350 µg/kg) for 10 days. Airway hyperresponsiveness (AHR) to acetyl-ß-methacholine (Mch), inflammatory cell counts in the bronchoalveolar lavage fluid, and serum OVA-specific IgE levels were detected in the mice at the end of the experiment. Lung tissues were collected for haematoxylin and eosin staining, untargeted metabolomic analysis, and single-cell transcriptome sequencing. PD00 has a high affinity for CD81; therefore, administration of PD00 markedly ameliorated AHR and airway inflammation in mice after OVA sensitisation and exposure. Serum OVA-specific IgE levels decreased considerably. In addition, PD00 treatment increased glycerophospholipid and purine metabolism in immune cells. Collectively, PD00 may regulate the glycerophospholipid and purine metabolism pathways to ameliorate the pathophysiological features of asthma. These findings suggest that PD00 is a potential compound for the treatment of asthma.

HDAC4 promotes the growth and metastasis of gastric cancer via autophagic degradation of MEKK3.

BACKGROUND: Histone deacetylases (HDACs) have been shown to be involved in tumorigenesis, but their precise role and molecular mechanisms in gastric cancer (GC) have not yet been fully elucidated. METHODS: Bioinformatics screening analysis, qRT-PCR, and immunohistochemistry (IHC) were used to identify the expression of HDAC4 in GC. In vitro and in vivo functional assays illustrated the biological function of HDAC4. RNA-seq, GSEA pathway analysis, and western blot revealed that HDAC4 activated p38 MAPK signalling. Immunofluorescence, western blot, and IHC verified the effect of HDAC4 on autophagy. ChIP and dual-luciferase reporter assays demonstrated that the transcriptional regulation mechanism of HDAC4 and ATG4B. RESULTS: HDAC4 is upregulated in GC and correlates with poor prognosis. In vitro and in vivo assays showed that HDAC4 contributes to the malignant phenotype of GC cells. HDAC4 inhibited the MEF2A-driven transcription of ATG4B and prevented MEKK3 from p62-dependent autophagic degradation, thus activating p38 MAPK signalling. Reciprocally, the downstream transcription factor USF1 enhanced HDAC4 expression by regulating HDAC4 promoter activity, forming a positive feedback loop and continuously stimulating HDAC4 expression and p38 MAPK signalling activation. CONCLUSION: HDAC4 plays an oncogenic role in GC, and HDAC4-based targeted therapy would represent a novel strategy for GC treatment.

Association of DNA methylation and transcriptome reveals epigenetic etiology of heart failure.

Epigenetic modifications viz. DNA methylation, histone modifications, and RNA-based alterations play a crucial role in the development of cardiovascular diseases. In this study, we investigated DNA methylation with an aim to reveal the epigenetic etiology of heart failure. Sprague-Dawley rats surviving myocardial infarction developed acute heart failure in 1 week. Genomic DNA methylation changes were profiled by bisulfite sequencing, and gene expression levels were analyzed by RNA-seq in failing and sham-operation hearts. A total of 3480 differentially methylated genes in the promoter regions including transcriptional start site and 1934 transcriptome-altered genes were identified in the defected hearts. Common differential genes were enriched by the gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway, and protein-protein interaction for HF phenotypes. Among these, Mettl11b, HDAC3, HDAC11, ubiquitination-related genes, and snoRNAs are new epigenetic classifiers that had not been reported yet, which may be important regulators in HF.

The regulatory role of MiR-203 in oxidative stress induced cell injury through the CBS/H2S pathway.

Hydrogen Sulfide (H2S) mediates biological effects in a variety of ways. Due to its strong reducing potential, H2S has been recognized to have an important role in oxidative stress induced hypoxia. It has been reported that H2S production and miRNA can mutually regulate each other. H2S is produced by the catalytic activity of cystathionine-ß-synthase (CBS), which is under the regulation of miRNAs. In this study, we used target gene prediction software, and identified miR-203 as a potential regulator of CBS. We verified this finding using an oxygen and glucose deprivation (OGD) hypoxia cell model in SH-SY5Y cells and pMIR-REPORT™ luciferase miRNA expression reporter vector. Furthermore, transfecting SH-SY5Y cells with miRNA agomir (agonist) and antagomir (antagonist) by lipofectamin RNAiMAX, we further validated miR-203 as a direct regulator of CBS. We also found that miR-203 protects from cell injury by regulating lipid peroxidation, cell apoptosis, and mitochondrial membrane potential. These findings suggest that while over-expression of miR-203 can aggravate OGD induced cell injury, inhibition of miR-203 can protect against OGD induced cell injury. Based on our data and that of others, we propose that miR-203 may regulate oxidative stress induced cell injury by regulating CBS expression and adjusting the levels of H2S production.

S-Propargyl-cysteine prevents concanavalin A-induced immunological liver injury in mice.

CONTEXT: S-Propargyl-cysteine (SPRC), an endogenous H2S modulator, exerts anti-inflammatory effects on cardiovascular and neurodegenerative disease, but it remains unknown whether SPRC can prevent autoimmune hepatitis. OBJECTIVE: To evaluate the preventive effect of SPRC on concanavalin A (Con A)-induced liver injury and uncover the underlying mechanisms. MATERIALS AND METHODS: Mice were randomly divided into five groups: control, Con A, SPRC (5 and 10 mg/kg injected intravenously once a day for 7 days), and propargylglycine (PAG; 50 mg/kg injected intraperitoneally 0.5 h before SPRC for 7 days). All mice except the controls were intravenously injected with Con A (20 mg/kg) on day 7. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were evaluated using kits. Inflammatory cytokines (TNF-α and IFN-γ) in the blood and in the liver were detected by ELISA Kit and real-time PCR, respectively. The expression of mitogen-activated protein kinase (MAPK) pathway proteins (p-JNK and p-Akt) and apoptosis proteins (Bax and Bcl-2) was detected using western blotting. RESULTS: SPRC reduced the levels of AST (p < 0.05) and ALT (p < 0.01) and decreased the release of the inflammatory cytokines. Mechanistically, SPRC increased H2S level (p < 0.05) and promoted cystathionine γ-lyase (CSE) expression (p < 0.05). SPRC inhibited the MAPK pathway activation and the apoptosis pathway. All the effects of SPRC were blocked by the CSE inhibitor PAG. CONCLUSIONS: SPRC prevents Con A-induced liver injury in mice by promoting CSE expression and producing endogenous H2S. The mechanisms include reducing the release of inflammatory cytokines, attenuating MAPK pathway activation, and alleviating apoptosis.

[Effect and mechanism of leonurine on pressure overload-induced cardiac hypertrophy in rats].

To investigate the effects of leonurine(Leo) on abdominal aortic constriction(AAC)-induced cardiac hypertrophy in rats and its mechanism. A rat model of pressure overload-induced cardiac hypertrophy was established by AAC method. After 27-d intervention with high-dose(30 mg·kg~(-1)) and low-dose(15 mg·kg~(-1)) Leo or positive control drug losartan(5 mg·kg~(-1)), the cardiac function was evaluated by hemodynamic method, followed by the recording of left ventricular systolic pressure(LVSP), left ventricular end-diastolic pressure(LVESP), as well as the maximum rate of increase and decrease in left ventricular pressure(±dp/dt_(max)). The degree of left ventricular hypertrophy was assessed based on heart weight index(HWI) and left ventricular mass index(LVWI). Myocardial tissue changes and the myocardial cell diameter(MD) were measured after hematoxylin-eosin(HE) staining. The contents of angiotensin Ⅱ(AngⅡ) and angiotensin Ⅱ type 1 receptor(AT1 R) in myocardial tissue were detected by ELISA. The level of Ca~(2+) in myocardial tissue was determined by colorimetry. The protein expression levels of phospholipase C(PLC), inositol triphosphate(IP3), AngⅡ, and AT1 R were assayed by Western blot. Real-time quantitative PCR(qRT-PCR) was employed to determine the mRNA expression levels of ß-myosin heavy chain(ß-MHC), atrial natriuretic factor(ANF), AngⅡ, and AT1 R. Compared with the model group, Leo decreased the LVSP, LVEDP, HWI, LVWI and MD values, but increased ±dp/dt_(max) of the left ventricle. Meanwhile, it improved the pathological morphology of myocardial tissue, reduced cardiac hypertrophy, edema, and inflammatory cell infiltration, decreased the protein expression levels of PLC, IP3, AngⅡ, AT1 R, as well as the mRNA expression levels of ß-MHC, ANF, AngⅡ, AT1 R, c-fos, and c-Myc in myocardial tissue. Leo inhibited AAC-induced cardiac hypertrophy possibly by influencing the RAS system.

The Cardiovascular Effects of Hydrogen Sulfide: The Epigenetic Mechanisms.

Hydrogen sulfide (H2S), known as a gas signal molecule, plays an important role in the development of cardiovascular diseases (CVD) through mechanisms such as angiogenesis, vasodilation, and anti-vascular endothelial cell senescence. Current studies have shown that H2S can regulate cardiac function through epigenetic regulation. The regulation has opened up a new avenue for the study of CVD development mechanism and H2S related drug discoveries.

Hydrogen Sulfide and the Immune System.

Hydrogen sulfide (H2S) is the "third gasotransmitter" recognized alongside nitric oxide (NO) and carbon monoxide (CO). H2S exhibits an array of biological effects in mammalian cells as revealed by studies showing important roles in the cardiovascular system, in cell signalling processes, post-translational modifications and in the immune system. Regarding the latter, using pharmacological and genetic approaches scientists have shown this molecule to have both pro- and anti-inflammatory effects in mammalian systems. The anti-inflammatory effects of H2S appeared to be due to its inhibitory action on the nuclear factor kappa beta signalling pathway; NF-kB representing a transcription factor involved in the regulation pro-inflammatory mediators like nitric oxide, prostaglandins, and cytokines. In contrast, results from several animal model describe a more complicated picture and report on pro-inflammatory effects linked to exposure to this molecule; linked to dosage used and point of administration of this molecule. Overall, roles for H2S in several inflammatory diseases spanning arthritis, atherosclerosis, sepsis, and asthma have been described by researchers. In light this work fascinating research, this chapter will cover H2S biology and its many roles in the immune system.

Hydrogen Sulfide: a Novel Immunoinflammatory Regulator in Rheumatoid Arthritis.

Hydrogen sulfide (H2S), an endogenous, gaseous, signaling transmitter, has been shown to have vasodilative, anti-oxidative, anti-inflammatory, and cytoprotective activities. Increasing evidence also indicates that H2S can suppress the production of inflammatory mediators by immune cells, for example, T cells and macrophages. Inflammation is closely related to an immune response in several diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), and cancer. Considering these biological effects of H2S, a potential role in the treatment of immune-related RA is being exploited. In the present review, we will provide an overview of the therapeutic potential of H2S in RA treatment.

SCM-198 ameliorates endometrial inflammation via suppressing the LPS-JNK-cJUN/cFOS-TLR4-NF-κB pathway.

Endometritis is an inflammatory disease of the endometrium, which is responsible for endometrial dysfunction, decidualization failure, and increased incidence of early pregnancy loss. SCM-198, a synthetic form of leonurine, is well known to possess anti-inflammatory effects. SCM-198 has been reported to display beneficial effects on endometritis. However, the specific mechanisms of SCM-198 in preventing endometritis remain unknown. In this study, we focused on the molecular mechanism of SCM-198 in inhibiting endometritis. The anti-inflammatory effects and the related signaling pathways of SCM-198 were studied in vitro using human endometrial stromal cells (hESCs). Reverse transcriptase-polymerase chain reaction and western blot analysis results demonstrated that SCM-198 markedly inhibited lipopolysaccharide (LPS)-induced endometrial inflammatory response by suppressing the LPS-JNK-cJUN/cFOS-TLR4-NF-κB pathway. The preventive and therapeutic effects of SCM-198 on endometrial inflammation were explored by using a mouse model of LPS-induced endometritis. SCM-198 produced essentially the same effects when administered either post-treatment (after LPS) or pre-treatment (before LPS) via vaginal or intraperitoneal administration. In vivo results indicated that SCM-198 is a potential effective drug for the treatment of endometritis.

Targeting JMJD3 histone demethylase mediates cardiac fibrosis and cardiac function following myocardial infarction.

Myocardial fibrosis is the pathological consequence of injury-induced fibroblastto-myofibroblast transition, resulting in increased stiffness and diminished cardiac function. Histone modification has been shown to play an important role in the pathogenesis of cardiac fibrosis. Here, we identified H3K27me3 demethylase JMJD3/KDM6B promotes cardiac fibrosis via regulation of fibrogenic pathways. Using neonatal rat cardiac fibroblasts (NRCF), we show that the expression of endogenous JMJD3 is induced by angiotensin II (Ang II), while the principle extracellular matrix (ECM) such as fibronectin, CTGF, collagen I and III are increased. We find that JMJD3 inhibition markedly enhances the suppressive mark (H3K27me3) at the beta (ß)-catenin promoter in activated cardiac fibroblasts, and then substantially decreases expression of fibrogenic gene. Both inhibition of ß-catenin-mediated transcription with ICG-001 and genetic loss of ß-catenin can prevent Ang II-induced ECM deposition. Most importantly, in vivo inhibition of JMJD3 rescues myocardial ischemia-induced cardiac fibrosis and cardiac dysfunction. Collectively, our findings are the first to report a novel role of histone demethylase JMJD3 in the pro-fibrotic cardiac fibroblast phenotype, pharmacological targeting of JMJD3 might represent a promising therapeutic approach for the treatment of human cardiac fibrosis and other fibrotic diseases.

eNOS-Nitric Oxide System Contributes to a Novel Antiatherogenic Effect of Leonurine via Inflammation Inhibition and Plaque Stabilization.

Leonurine (LEO) is a bioactive small molecular compound that has protective effects on the cardiovascular system and prevents the early progression of atherosclerosis; however, it is not clear whether LEO is effective for plaque stability. A novel mouse atherosclerosis model involving tandem stenosis (TS) of the right carotid artery combined with western diet (WD) feeding was used. Apolipoprotein E gene-deficient mice were fed with a WD and received LEO administration daily for 13 weeks. TS was introduced 6 weeks after the onset of experiments. We found that LEO enhanced plaque stability by increasing fibrous cap thickness and collagen content while decreasing the population of CD68-positive cells. Enhanced plaque stability by LEO was associated with the nitric oxide synthase (NOS)-nitric oxide (NO) system. LEO restored the balance between endothelial NOS(E)- and inducible NOS(iNOS)-derived NO production; suppressed the NF-κB signaling pathway; reduced the level of the inflammatory infiltration in plaque, including cytokine interleukin 6; and downregulated the expression of adhesion molecules. These findings support the distinct role of LEO in plaque stabilization. In vitro studies with oxidized low-density lipoprotein-challenged human umbilical vein endothelial cells revealed that LEO balanced NO production and inhibited NF-κB/P65 nuclear translocation, thus mitigating inflammation. In conclusion, the restored balance of the NOS-NO system and mitigated inflammation contribute to the plaque-stabilizing effect of LEO. SIGNIFICANCE STATEMENT: LEO restored the balance between endothelial NOS and inducible NOS in NO production and inhibited excessive inflammation in atherosclerotic "unstable" and rupture-prone plaques in apolipoprotein E gene-deficient mice. The protective effect of LEO for stabilizing atherosclerotic plaques was due to improved collagen content, increased fibrous cap thickness, and decreased accumulation of macrophages/foam cells. So far, LEO has passed the safety and feasibility test of phase I clinical trial.

Fra-1 plays a critical role in angiotensin II-induced vascular senescence.

Vascular aging has a strong relationship with cardiovascular disease. Fos-related antigen 1 (Fra-1), also referred to as Fos-like antigen 1, is a transcription factor and has been reported to be involved in many pathologic processes. Here, we demonstrate that Fra-1 plays a critical role in angiotensin II (Ang II)-induced vascular senescence. Fra-1 expression is increased significantly in Ang II-induced rat aortic endothelial cell (RAEC) senescence and the arteries from Ang II-infused mice. Interestingly, silencing Fra-1 blocks Ang II-induced senescence phenotypes in RAECs, including decreased senescence-associated ß-galactosidase staining, and mitigated proliferation suppression and senescence-associated secretory phenotype. Further, knocking down Fra-1 inhibits vascular aging phenotypes in an Ang II-infused mice model. The up-regulated Fra-1 also exists in human atherosclerotic plaques and Ang II-induced vascular smooth muscle cells as well as in replicated senescence RAECs. Mechanistic studies reveal that Fra-1 preferentially associates with c-Jun and binds to the cyclin-dependent kinase inhibitor 1a (p21) and cyclin-dependent kinase inhibitor 2a (p16) promoter region, leading to elevated gene expression, which causes senescence-related phenotypes. In conclusion, our results identify that Fra-1 plays a novel and key role in promoting vascular aging by directly binding and transcriptionally activating p21 and p16 signaling, suggesting intervention of Fra-1 is a potential strategy for preventing aging-associated cardiovascular disorders.-Yang, D., Xiao, C., Long, F., Wu, W., Huang, M., Qu, L., Liu, X., Zhu, Y. Fra-1 plays a critical role in angiotensin II-induced vascular senescence.

Cystathionine γ-lyase deficiency aggravates obesity-related insulin resistance via FoxO1-dependent hepatic gluconeogenesis.

Hepatic gluconeogenesis makes a significant contribution to the pathogenesis of obesity and its related insulin resistance. Cystathionine γ-lyase (CSE; also cystathionase), a principal hydrogen sulfide (H2S)-synthesizing enzyme in the liver, is involved in glucose and lipid metabolism disorders. However, the roles and precise mechanisms of CSE/H2S in obesity and its related insulin resistance remain obscure. Here we show that CSE knockout exacerbated high-fat diet-induced mouse obesity as well as its related insulin resistance. Further study elucidated that the inhibition of insulin and AMPK signaling pathways by CSE deficiency resulted in nuclear accumulation of Forkhead box protein O1 and subsequently promoted hepatic gluconeogenesis. These phenomena can be reversed by NaHS supplementation. However, in wild-type mice, NaHS treatment ameliorates high fat diet-induced obesity and metabolism disorders, indicating that maintaining an appropriate level of H2S is critical for its mutual change of positive and negative effects of obesity-associated insulin resistance. Our study reveals a double-edged sword effect and a novel mechanism for CSE/H2S in obesity associated with insulin resistance and provides evidence for CSE/H2S as a promising therapeutic potential target for obesity-related insulin resistance.-Guo, W., Li, D., You, Y., Li, W., Hu, B., Zhang, S., Miao, L., Xian, M., Zhu, Y., Shen, X. Cystathionine γ-lyase deficiency aggravates obesity-related insulin resistance via FoxO1-dependent hepatic gluconeogenesis.

Combinational applicaton of silybin and tangeretin attenuates the progression of non-alcoholic steatohepatitis (NASH) in mice via modulating lipid metabolism.

Silybin (SB) is widely used to treat chronic liver diseases, especially this compound is much efficient for the treatments of alcoholic and non-alcoholic steatohepatitis (NASH). However, low bioavailability seriously limits wide-application of SB in biomedical niche. Prior to this study, we found that tangeretin (TG) could remarkably increase the bioavailability of SB by the inhibition of efflux transporters, which encourges us to therapeutical discovery of SB and TG combitional use against NASH. Here, we revealed that TG is capable of improving hepatic-protective activity of SB in mice with NASH by interfering liver oxidative stress, inflammation, and lipid accumulation. In addition, TG was observed to enhance the exposural level of SB in the plasma and liver of mice. Our metabolome assay confirmed that amino acid metabolism and lipid biosynthesis mostly accounted for combitional use of SB and TG to teat NASH in mice, basically biosynthesis of unsaturated fatty acids was mostly affected. Notably, significant inhibitions in fatty acid generating and transporting proteins such as G6PD, FABP4, LPL and CD36/FAT, and cholesterol metabolism enzyme CYP27A1 as well as nuclear transcription factors FXR, PPAR-γ, and LXR were illustrated to decipher therapeutic mechanisms of SB and TG against experimental NASH. Taken together, the strategy based combitional use of SB and TG has a potential-capacity to treat NASH.

ZYZ-803, a novel hydrogen sulfide-nitric oxide conjugated donor, promotes angiogenesis via cross-talk between STAT3 and CaMKII.

Endothelial angiogenesis plays a vital role in recovery from chronic ischemic injuries. ZYZ-803 is a hybrid donor of hydrogen sulfide (H2S) and nitric oxide (NO). Previous studies showed that ZYZ-803 stimulated endothelial cell angiogenesis both in vitro and in vivo. In this study, we investigated whether the signal transducer and activator of transcription 3 (STAT3) and Ca2+/CaM-dependent protein kinase II (CaMKII) signaling was involved in ZYZ-803-induced angiogenesis. Treatment with ZYZ-803 (1 µM) significantly increased the phosphorylation of STAT3 (Tyr705) and CaMKII (Thr286) in human umbilical vein endothelial cells (HUVECs), these two effects had a similar time course. Pretreatment with WP1066 (STAT3 inhibitor) or KN93 (CAMKII inhibitor) blocked ZYZ-803-induced STAT3/CAMKII activation and significantly suppressed the proliferation and migration of HUVECs. In addition, pretreatment with the inhibitors significantly decreased ZYZ-803-induced tube formations along with the outgrowths of branch-like microvessels in aortic rings. In the mice with femoral artery ligation, administration of ZYZ-803 significantly increased the blood perfusion and vascular density in the hind limb, whereas co-administration of WP1066 or KN93 abrogated ZYZ-803-induced angiogenesis. By using STAT3 siRNA, we further explored the cross-talk between STAT3 and CaMKII in ZYZ-803-induced angiogenesis. We found that STAT3 knockdown suppressed ZYZ-803-induced HUVEC angiogenesis and affected CaMKII expression. ZYZ-803 treatment markedly enhanced the interaction between CaMKII and STAT3. ZYZ-803 treatment induced the nuclear translocation of STAT3. We demonstrated that both STAT3 and CaMKII functioned as positive regulators in ZYZ-803-induced endothelial angiogenesis and STAT3 was important in ZYZ-803-induced CaMKII activation, which highlights the beneficial role of ZYZ-803 in STAT3/CaMKII-related cardiovascular diseases.

SCM-198 protects endometrial stromal cells from oxidative damage through Bax/Bcl-2 and ERK signaling pathways.

Increasing amounts of evidence demonstrated that accumulative reactive oxygen species (ROS) and apoptosis of human endometrial stromal cells (ESCs) are closely associated with endometrial dysfunction induced by oxidative stress, which plays an important role in the pathological process of multiple gynecological and reproduction-related diseases. SCM-198, an alkaloid active component of Leonurus japonicas Houtt, has been reported to have anti-oxidative activity. However, the specific mechanisms of SCM-198 in the prevention of endometrial damage remain unknown. In the present study, we assessed the effect of SCM-198 on hydrogen peroxide (H2O2)-induced oxidative injury in ESCs. ESCs were pretreated with SCM-198 for 4 h and then challenged with H2O2. Morphology changes, apoptosis rate, and intracellular ROS production were measured to assess the level of oxidative injury. Flow cytometry and western blot analysis were performed to detect the expression levels of Bax, Bcl-2, active-caspase-3, and mitogen-activated protein kinases pathways. Classic inflammation cytokines were measured by real-time polymerase chain reactions. Our results showed that SCM-198 attenuated apoptosis and ROS generation of ESCs induced by H2O2. H2O2 induced the apparent apoptotic characteristics, including fragmentation of DNA, upregulation of Bax/Bcl2, activation of caspase-3, and secretion of inflammation cytokines, which were all ameliorated by SCM-198. Furthermore, H2O2-induced apoptosis-related ERK1/2 pathway activation was restrained by SCM-198 pretreatment. These findings suggested that SCM-198 could protect ESCs from oxidative injury, mainly by inhibiting oxidative stress and reducing apoptosis.