3-4-dihydroxyphenyllactic-acid and Inflammation

The primary cause of acute cardiovascular events with high mortality is the rupture of atherosclerotic plaque followed by thrombosis. Sodium Danshensu (SDSS) has shown potential in inhibiting the inflammatory response in macrophages and preventing early plaque formation in atherosclerotic mice. However, the specific targets and detailed mechanism of action of SDSS are still unclear.. This study aims to investigate the efficacy and mechanism of SDSS in inhibiting inflammation in macrophages and stabilizing vulnerable plaques in atherosclerosis (AS).. The efficacy of SDSS in stabilizing vulnerable plaques was demonstrated using various techniques such as ultrasound, Oil Red O staining, HE staining, Masson staining, immunohistochemistry, and lipid analysis in ApoE. Initially, the administration of SDSS led to a decrease in the formation and area of aortic plaque, while also stabilizing vulnerable plaques in ApoE. SDSS stabilized vulnerable plaques and suppressed inflammatory responses by inhibiting the NF-κB pathway through its targeting of IKKβ.

Topics: Animals; Apolipoproteins E; Atherosclerosis; I-kappa B Kinase; Inflammation; Macrophages; Mice; Molecular Docking Simulation; NF-kappa B; Plaque, Atherosclerotic; Protein Serine-Threonine Kinases; Signal Transduction

Cerebral ischemia-reperfusion injury (CI/RI) is the main cause of disability and death in stroke without satisfactory therapeutic effect. Inflammation mediated by activation of astrocytes and microglia is the main pathological mechanism of CI/RI. Danshensu (DSS) has been shown to exert anti-inflammatory effects against brain injury. However, limited by its poor cellular permeability and low bioavailability, it is still needed the new DSS preparations with the ability to cross the blood-brain barrier (BBB) and target inflammatory glial cells. In this study, we developed phosphatidylserine (PS) and transferrin (TF) modified liposomes carrying DSS (TF/PS/DSS-LPs) to improve the therapeutic efficacy against ischemic stroke. First, TF molecules targeted transferrin receptor (TfR) that is overexpressed in the BBB. Following the liposomes enter the brain, PS modification allowed the liposomes to target and bind to the overexpressed phosphatidylserine-specific receptors (PSRs) on the surface of astrocytes and microglia. Furthermore, it enhanced the uptake of TF/PS/DSS-LPs by astrocytes and microglia, while polarizing astrocytes from A1 to A2 and microglia from M1 to M2, reducing neuronal inflammation, and ultimately ameliorating cerebral ischemic injury. Thus, TF/PS/DSS-LPs could potentially serve as a promising strategy for the CI/RI treatment.

Topics: Astrocytes; Brain Ischemia; Humans; Inflammation; Lipopolysaccharides; Liposomes; Microglia; Phosphatidylserines; Reperfusion Injury

Guanxinning Injection (GXNI) is used clinically to treat cardiac injury, but its active components and mode of action remains unclear. Therefore, a myocardial ischemia/reperfusion injury (MIRI) model-based integrated strategy including function evaluation, RNA-seq analysis, molecular docking, and cellular thermal shift assay (CETSA) was employed to elucidate the effect and mechanism of GXNI and its main ingredient on cardiac injury. These results revealed that GXNI significantly improved cardiac dysfunction and myocardial injury in I/R mice. RNA-seq analysis clarified that CXCR1-mediated interleukin-8 pathway played a critical role in MIRI. Molecular docking screening identified danshensu (DSS) as the major active components of GXNI targeting CXCR1 protein, which was confirmed in an oxygen-glucose deprivation/reoxygenation-induced cardiomyocytes damage model showing that GXNI and DSS reduced the protein expression of CXCR1 and its downstream NF-κB, COX-2, ICAM-1 and VCAM-1. CETSA and isothermal dose-response fingerprint curves confirmed that DSS combined with CXCR1 in a dose-dependent manner. Furthermore, GXNI and DSS significantly decreased the expression levels of IL-6, IL-1β and TNF-α and the number of neutrophils in post I/R myocardial tissue. In conclusion, this study revealed that GXNI and its active components DSS exert inhibitory effects on inflammatory factor release and leukocyte infiltration to improve I/R-induced myocardial injury by down-regulating CXCR1-NF-κB-COX-2/ICAM-1/VCAM-1 pathway.

Topics: Animals; Cyclooxygenase 2; Inflammation; Intercellular Adhesion Molecule-1; Mice; Molecular Docking Simulation; Myocardial Reperfusion Injury; NF-kappa B; Receptors, Interleukin-8A; Signal Transduction; Vascular Cell Adhesion Molecule-1

Danshensu (DSS) is a water-soluble phenolic compound in Danshen (Salvia Miltiorrhiza Radix et Rhizoma). Although various pharmacological activities have been recognized, little is known regarding its anti-inflammatory effect and related molecular mode of action. In the current study, bone marrow-derived macrophages (BMMs) were activated by a Toll-like receptor 2 (TLR2) agonist Pam3CSK4 with or without DSS intervention. Production of pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-12 (IL-12) was detected by both enzyme-linked immunosorbent assay (ELISA) and real-time quantitative PCR (RT-qPCR). Activation of signaling pathways involving nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) was assessed by Western blot. Additionally, RNA sequencing (RNA-seq) combined with bioinformatics analyses was applied to investigate the molecular mechanisms of DSS. Emphasis was placed on the construction of the protein-protein interaction (PPI) network and transcription factor (TF) enrichment analysis of data including co-regulated differentially expressed genes (DEGs) in the Pam3CSK4 vs. control and DSS vs. Pam3CSK4 groups. The RT-qPCR and ELISA results showed that DSS effectively inhibited the expressions of IL-6 and IL-12, indicating a significant anti-inflammatory effect. Western blot verified that DSS suppressed the phosphorylation of p65, which was in accordance with the results of the TF enrichment analysis. Additionally, the PPI network analysis showed several key molecules, including lactoferrin (Ltf), CC-chemokine receptor 7 (Ccr7), interferon-gamma (IFN-γ) and C-X-C motif chemokine ligand 9 (Cxcl9), to be regulatory genes that responded to DSS treatment. Overall, our study revealed that DSS has a pronounced anti-inflammatory effect involving TLR2 and macrophages through the NF-κB signaling pathway, which supports the novel application of DSS in the treatment of relevant diseases including atherosclerosis and ischemic or ischemic/perfusion injury of the heart and brain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Female; Gene Expression Profiling; Gene Expression Regulation; Inflammation; Interleukin-12; Interleukin-6; Lactates; Lipopeptides; Macrophages; Mice; Mice, Inbred C57BL; NF-kappa B; Phosphorylation; Protein Interaction Maps; RNA, Messenger; Salvia miltiorrhiza; Signal Transduction; Toll-Like Receptor 2

Alcoholic liver disease (ALD) is the major cause of chronic liver disease and a global health concern. ALD pathogenesis is initiated with liver steatosis, and ALD can progress to steatohepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma. Salvianic acid A (SAA) is a phenolic acid component of Danshen, a Chinese herbal medicine with possible hepatoprotective properties. The purpose of this study was to investigate the effect of SAA on chronic alcoholic liver injury and its molecular mechanism. We found that SAA significantly inhibited alcohol-induced liver injury and ameliorated ethanol-induced hepatic inflammation. These protective effects of SAA were likely carried out through its suppression of the BRD4/HMGB1 signalling pathway, because SAA treatment largely diminished alcohol-induced BRD4 expression and HMGB1 nuclear translocation and release. Importantly, BRD4 knockdown prevented ethanol-induced HMGB1 release and inflammatory cytokine production in AML-12 cells. Similarly, alcohol-induced pro-inflammatory cytokines were blocked by HMGB1 siRNA. Collectively, our results reveal that activation of the BRD4/HMGB1 pathway is involved in ALD pathogenesis. Therefore, manipulation of the BRD4/HMGB1 pathway through strategies such as SAA treatment holds great therapeutic potential for chronic alcoholic liver disease therapy.

Topics: Animals; Cell Nucleus; Cells, Cultured; Cytokines; Down-Regulation; HMGB1 Protein; Inflammation; Lactates; Liver; Liver Diseases, Alcoholic; Male; Mice; Nuclear Proteins; Protective Agents; Rats; Rats, Wistar; Signal Transduction; Transcription Factors

To clarify the effects on and the mechanism of salvianic acid A sodium (SAAS) in the recovery of motor function after spinal cord injury.. In vivo and in vitro experiments were carried out in this research to determine the effects of SAAS on tissue damage, neuron survival, microglia polarization, and inflammation after spinal cord injury (SCI). Differentially expressed genes treated with SAAS were screened by transcriptome sequencing, and the molecular mechanism was investigated simultaneously.. The results revealed that SAAS could promote type M2 polarization of microglia and reduce the proportion of type M1. In this way, it reduced the secretion and expression of inflammatory factors. Compared with Lipopolysaccharides(LPS), 345 genes were upregulated and 407 genes were downregulated in the LPS + SAAS treatment group. In the SAAS group, expression levels of Ndufa12, IL-6, TNF-α, and Vdac1 were significantly reduced, while a marked elevation was found in MIP2. In addition, results found in an animal model showed that SAAS could obviously facilitate motor function recovery of mice after spinal cord injury, and it had a good protective effect on spinal cord tissue and neuron cells.. As a result, the present study clarified both the protective effect of SAAS on neurons after spinal cord injury and the anti-inflammatory effect of microglia, which is expected to serve as a theoretical basis for clinical treatment.

Topics: Animals; Chemokine CXCL2; Disease Models, Animal; Down-Regulation; Gene Expression; Inflammation; Lactates; Male; Microglia; NADPH Dehydrogenase; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Up-Regulation; Voltage-Dependent Anion Channel 1

Danshensu is a bioactive constituent of Salvia miltiorrhiza, a plant commonly used in traditional Chinese medicine. In this study, we investigated the pharmacological efficacy of sodium danshensu, or named salvianic acid A sodium (SAS) on ultraviolet B (UVB)-mediated corneal inflammatory injury in mice.. Albino mice were divided into one blank control group, and three UVB radiation groups, i.e. SAS-untreated group, and prophylactic treatment groups with SAS at 1 and 10 mg/kg via oral administration. The structure integrity and inflammatory changes of cornea were assessed by surface evaluation of smoothness, topographic distortion, opacity, lissamine green staining, and histologic tissue staining. The inflammatory cytokines was measured by bead-based ELISA assays.. Prophylactic treatment of SAS significantly inhibited pathologic changes, improved tissue structural integrity, and reduced inflammatory injury in the cornea after UVB exposure. Dosing with SAS treatment attenuated the incidence rate of leukocyte influx by inhibit increase of interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1, and tumor necrosis factor-α. Treatment with 10 mg/kg SAS was more effective in preventing the onset of corneal damage than that with 1 mg/kg SAS.. These results indicate that SAS exhibit the pharmacological efficacy on corneal protection through its inhibition of UVB induced photodamage and subsequently inflammatory injury in vivo.

Topics: Administration, Oral; Animals; Cornea; Cytokines; Disease Models, Animal; Drugs, Chinese Herbal; Enzyme-Linked Immunosorbent Assay; Eye Burns; Inflammation; Keratitis; Lactates; Mice; Ultraviolet Rays

Acute pancreatitis (AP), a common abdominal inflammatory disorder, is characterized by premature intracellular activation of digestive proteases within pancreatic acini and a consecutive systemic inflammatory response. Although the mechanism remains to be fully understood, inflammation is the main cause of pancreatic damage in AP. A novel compound [4-(2-acetoxy-3-((R)-3-(benzylthio)-1-methoxy-1-oxopropan-2-ylamino)-3-oxopropyl)-1,2-phenylene diacetate (DSC)], derived from danshensu, exhibits anti-inflammatory and anti-apoptotic properties

Topics: Acute Disease; Animals; Antioxidants; Biological Products; Cells, Cultured; Ceruletide; Disease Models, Animal; Female; Heme Oxygenase-1; Inflammasomes; Inflammation; Lactates; Macrophages; Mice; Mice, Inbred BALB C; Neutrophils; NF-E2-Related Factor 2; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Pancreas; Pancreatitis; Phenylacetates; Signal Transduction; STAT3 Transcription Factor

To explore potency material bases of Xuebijing (XBJ) formula, and to analyze its effects at the molecular network level.. Totally 16 sepsis-related targets were selected and classified into three categories such as inflammation, immune, and coagulation referring to biological roles. Then molecular database of chemical compositions in XBJ formula were constructed to explore mutual actions with inflammation, immune, and coagulation targets.. Danshen root and safflower, with more effector molecules with immune and coagulation targets, have extensive anticoagulation and anti-inflammation effects. The former 10 molecules with better mutual actions with sepsis targets were sequenced as tryptophane, danshensu, gallic acid, salvianolic acid D, protocatechuic acid, salvianolic acid A, danshensu C, vanillic acid, rosmarinic acid, phenylalanine. There existed two phenomena in XBJ formula as follows. One component had stronger actions with multi-targets, for example, danshensu had actions with 13 targets. Meanwhile, different components acted on the same target protein, for example, 8 molecules acted with MD-2.. XBJ formula had certain potential synergistic effects with sepsis targets, which could provide certain referential roles for findina new type anti-septic drugs.

Topics: Caffeic Acids; Drugs, Chinese Herbal; Gallic Acid; Hydroxybenzoates; Inflammation; Lactates; Sepsis