The role of immune system in atherosclerosis: Molecular mechanisms, controversies, and future possibilities.

Numerous cardiovascular disorders have atherosclerosis as their pathological underpinning. Numerous studies have demonstrated that, with the aid of pattern recognition receptors, cytokines, and immunoglobulins, innate immunity, represented by monocytes/macrophages, and adaptive immunity, primarily T/B cells, play a critical role in controlling inflammation and abnormal lipid metabolism in atherosclerosis. Additionally, the finding of numerous complement components in atherosclerotic plaques suggests yet again how heavily the immune system controls atherosclerosis. Therefore, it is essential to have a thorough grasp of how the immune system contributes to atherosclerosis. The specific molecular mechanisms involved in the activation of immune cells and immune molecules in atherosclerosis, the controversy surrounding some immune cells in atherosclerosis, and the limitations of extrapolating from relevant animal models to humans were all carefully reviewed in this review from the three perspectives of innate immunity, adaptive immunity, and complement system. This could provide fresh possibilities for atherosclerosis research and treatment in the future.

Saponins as therapeutic candidates for atherosclerosis.

Drug development for atherosclerosis, the underlying pathological state of ischemic cardiovascular diseases, has posed a longstanding challenge. Saponins, classified as steroid or triterpenoid glycosides, have shown promising therapeutic potential in the treatment of atherosclerosis. Through an exhaustive examination of scientific literature spanning from May 2013 to May 2023, we identified 82 references evaluating 37 types of saponins in terms of their prospective impacts on atherosclerosis. These studies suggest that saponins have the potential to ameliorate atherosclerosis by regulating lipid metabolism, inhibiting inflammation, suppressing apoptosis, reducing oxidative stress, and modulating smooth muscle cell proliferation and migration, as well as regulating gut microbiota, autophagy, endothelial senescence, and angiogenesis. Notably, ginsenosides exhibit significant potential and manifest essential pharmacological attributes, including lipid-lowering, anti-inflammatory, anti-apoptotic, and anti-oxidative stress effects. This review provides a comprehensive examination of the pharmacological attributes of saponins in atherosclerosis, with particular emphasis on their role in the regulation of lipid metabolism regulation and anti-inflammatory effects. Thus, saponins may warrant further investigation as a potential therapy for atherosclerosis. However, due to various reasons such as low oral bioavailability, the clinical application of saponins in the treatment of atherosclerosis still needs further exploration.

Tiaogan daozhuo formula attenuates atherosclerosis via activating AMPK -PPARγ-LXRα pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Tiaogan Daozhuo Formula (TGDZF) is a common formulation against atherosclerosis, however, there is limited understanding of its therapeutic mechanism. AIM OF THIS STUDY: To examine the effectiveness of TGDZF in the treatment of atherosclerosis and to explore its mechanisms. MATERIALS AND METHODS: In ApoE-/- mice, atherosclerosis was induced by a high-fat diet for 12 weeks and treated with TGDZF at different doses. The efficacy of TGDZF in alleviating atherosclerosis was evaluated by small animal ultrasound and histological methods. Lipid levels were measured by biochemical methods. The capacity of cholesterol efflux was tested with a cholesterol efflux assay in peritoneal macrophage, and the expression of AMPKα1, PPARγ, LXRα, and ABCA1 was examined at mRNA and protein levels. Meanwhile, RAW264.7-derived macrophages were induced into foam cells by ox-LDL, and different doses of TGDZF-conducting serum were administered. Similarly, we examined differences in intracellular lipid accumulation, cholesterol efflux rate, and AMPKα1, PPARγ, LXRα, and ABCA1 levels following drug intervention. Finally, changes in the downstream molecules were evaluated following the inhibition of AMPK by compound C or PPARγ silencing by small interfering RNA. RESULTS: TGDZF administration reduced aortic plaque area and lipid accumulation in aortic plaque and hepatocytes, and improved the serum lipid profiles of ApoE-/- mice. Further study revealed that its efficacy was accompanied by an increase in cholesterol efflux rate and the expression of PPARγ, LXRα, and ABCA1 mRNA and protein, as well as the promotion of AMPKα1 phosphorylation. Moreover, similar results were caused by the intervention of TGDZF-containing serum in vitro experiments. Inhibition of AMPK and PPARγ partially blocked the regulatory effect of TGDZF, respectively. CONCLUSIONS: TGDZF alleviated atherosclerosis and promoted cholesterol efflux from macrophages by activating the AMPK-PPARγ-LXRα-ABCA1 pathway.

A rapid and simple HPLC-MS/MS method for the therapeutic drug monitoring of six special-grade antimicrobials in pediatric patients.

Meropenem, linezolid, fluconazole, voriconazole, posaconazole, and vancomycin are six important antimicrobials used for severe infections in critically ill patients listed in special-grade antimicrobials in China. The six antimicrobials' highly variable pharmacodynamics and pharmacokinetics in critically ill pediatric patients present significant challenges to clinicians in ensuring optimal therapeutic targets. Therefore, therapeutic drug monitoring of these antimicrobials in human plasma is necessary to obtain their plasma concentration. A rapid, simple, and sample-saving high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed, which could simultaneously determine all six antimicrobials. It required only 10 µL of plasma and a one-step protein precipitation process. Chromatographic separation was achieved on a reversed-phase column (C18, 30 × 2.1 mm, 2.6 µm) via gradient elution using water and acetonitrile containing 0.1 % formic acid as mobile phase. The injection volume was 2 µL, and the total run time was only 2.5 min. Detection was done using a Triple Quad™ 4500MD tandem mass spectrometer coupled with an electrospray ionization (ESI) source in positive mode. The calibration curves ranged from 0.5 to 64 µg/mL for meropenem and fluconazole, 0.2-25.6 µg/mL for linezolid and voriconazole, 0.1-12.8 µg/mL for posaconazole and 1-128 µg/mL for vancomycin, with the coefficients of correlation all greater than 0.996. Furthermore, the method was validated rigorously according to the European Medicines Agency (EMA) guidelines, demonstrating excellent accuracy (from 93.0 % to 110.6 %) and precision (from 2.0 % to 12.8 %). Moreover, its applicability to various matrices (including serum, hemolytic plasma, and hyperlipidemic plasma) was evaluated. Thus, this method was successfully applied to routine therapeutic drug monitoring for critically ill pediatric patients and other patients in need.

Research Advance of Chinese Medicine in Treating Atherosclerosis: Focus on Lipoprotein-Associated Phospholipase A2.

As a serious cardiovascular disease, atherosclerosis (AS) causes chronic inflammation and oxidative stress in the body and poses a threat to human health. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a member of the phospholipase A2 (PLA2) family, and its elevated levels have been shown to contribute to AS. Lp-PLA2 is closely related to a variety of lipoproteins, and its role in promoting inflammatory responses and oxidative stress in AS is mainly achieved by hydrolyzing oxidized phosphatidylcholine (oxPC) to produce lysophosphatidylcholine (lysoPC). Moreover, macrophage apoptosis within plaque is promoted by localized Lp-PLA2 which also promotes plaque instability. This paper reviews those researches of Chinese medicine in treating AS via reducing Lp-PLA2 levels to guide future experimental studies and clinical applications related to AS.

Sodium Danshensu ameliorates cerebral ischemia/reperfusion injury by inhibiting CLIC4/NLRP3 inflammasome-mediated endothelial cell pyroptosis.

Endothelial pyroptosis promotes cerebral ischemia/reperfusion injury (CIRI). Sodium Danshensu (SDSS) has been shown to attenuate CIRI and have anti-inflammatory properties in endothelial cells. However, the mechanism and effect of SDSS on alleviating endothelial pyroptosis after CIRI remains poorly understood. Thus, we aimed to investigate the efficacy and mechanism of SDSS in reducing endothelial pyroptosis. It has been shown that SDSS administration inhibited NLRP3 inflammasome-mediated pyroptosis. As demonstrated by protein microarrays, molecular docking, CETSA and ITDRFCETSA , SDSS bound strongly to CLIC4. Furthermore, SDSS can decrease its expression and inhibit its translocation. Its effectiveness was lowered by CLIC4 overexpression but not by knockdown. Overall The beneficial effect of SDSS against CIRI in this study can be ascribed to blocking endothelial pyroptosis by binding to CLIC4 and then inhibiting chloride efflux-dependent NLRP3 inflammasome activation.

Jia-Wei-Kai-Xin-San Treatment Alleviated Mild Cognitive Impairment through Anti-Inflammatory and Antiapoptotic Mechanisms in SAMP8 Mice.

Background: Alleviating mild cognitive impairment (MCI) is crucial to delay the progression of Alzheimer's disease (AD). Jia-Wei-Kai-Xin-San (JWKXS) is applied for treating AD with MCI. However, the mechanism of JWKXS in the treatment of MCI is unclear. Thus, this study aimed to investigate the effect and mechanism of JWKXS in SAMP8 mice models of MCI. Methods: MCI models were established to examine learning and memory ability and explore the pathomechanisms in brain of SAMP8 mice at 4, 6, and 8 months. The mice were treated for 8 weeks and the effects of JWKXS on MCI were characterized through Morris water maze and HE/Nissl's/immunohistochemical staining. Its mechanism was predicted by the combination of UPLC-Q-TOF/MS and system pharmacology analysis, further verified with SAMP8 mice, BV2 microglial cells, and PC12 cells. Results: It was found that 4-month-old SAMP8 mice exhibited MCI. Two months of JWKXS treatment improved the learning and memory ability, alleviated the hippocampal tissue and neuron damage. Through network pharmacology, four key signaling pathways were found to be involved in treatment of MCI by JWKXS, including TLR4/NF-κB pathway, NLRP3 inflammasome activation, and intrinsic and extrinsic apoptosis. In vitro and in vivo experiments demonstrated that JWKXS attenuated neuroinflammation by inhibiting microglia activation, suppressing TLR4/NF-κB and NLRP3 inflammasome pathways, and blocking the extrinsic and intrinsic apoptotic pathways leading to neuronal apoptosis suppression in the hippocampus. Conclusion: JWKXS treatment improved the learning and memory ability and conferred neuroprotective effects against MCI by inducing anti-inflammation and antiapoptosis. Limitations. The small sample size and short duration of the intervention limit in-depth investigation of the mechanisms. Future Prospects. This provides a direction for further clarification of the anti-AD mechanism, and provides certain data support for the formulation to move toward clinical practice.

Inflammatory signaling pathways in the treatment of Alzheimer's disease with inhibitors, natural products and metabolites (Review).

The intricate nature of Alzheimer's disease (AD) pathogenesis poses a persistent obstacle to drug development. In recent times, neuroinflammation has emerged as a crucial pathogenic mechanism of AD, and the targeting of inflammation has become a viable approach for the prevention and management of AD. The present study conducted a comprehensive review of the literature between October 2012 and October 2022, identifying a total of 96 references, encompassing 91 distinct pharmaceuticals that have been investigated for their potential impact on AD by inhibiting neuroinflammation. Research has shown that pharmaceuticals have the potential to ameliorate AD by reducing neuroinflammation mainly through regulating inflammatory signaling pathways such as NF­κB, MAPK, NLRP3, PPARs, STAT3, CREB, PI3K/Akt, Nrf2 and their respective signaling pathways. Among them, tanshinone IIA has been extensively studied for its anti­inflammatory effects, which have shown significant pharmacological properties and can be applied clinically. Thus, it may hold promise as an effective drug for the treatment of AD. The present review elucidated the inflammatory signaling pathways of pharmaceuticals that have been investigated for their therapeutic efficacy in AD and elucidates their underlying mechanisms. This underscores the auspicious potential of pharmaceuticals in ameliorating AD by impeding neuroinflammation.

LncRNA/CircRNA-miRNA-mRNA Axis in Atherosclerotic Inflammation: Research Progress.

Atherosclerosis is characterized by chronic inflammation of the arterial wall. However, the exact mechanism underlying atherosclerosis-related inflammation has not been fully elucidated. To gain insight into the mechanisms underlying the inflammatory process that leads to atherosclerosis, there is need to identify novel molecular markers. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-protein-coding RNAs (lncRNAs) and circular RNAs (circRNAs) have gained prominence in recent years. LncRNAs/circRNAs act as competing endogenous RNAs (ceRNAs) that bind to miRNAs via microRNA response elements (MREs), thereby inhibiting the silencing of miRNA target mRNAs. Inflammatory mediators and inflammatory signaling pathways are closely regulated by ceRNA regulatory networks in atherosclerosis. In this review, we discuss the role of LncRNA/CircRNA-miRNA-mRNA axis in atherosclerotic inflammation and how it can be targeted for early clinical detection and treatment.

Does an apple a day keep away diseases? Evidence and mechanism of action.

Apples and their products exemplify the recently reemphasized link between dietary fruit intake and the alleviation of human disease. Their consumption does indeed improve human health due to their high phytochemical content. To identify potentially relevant articles from clinical trials, some epidemiological studies and meta-analyses, and in vitro and in vivo studies (cell cultures and animal models), PubMed was searched from January 1, 2012, to May 15, 2022. This review summarized the potential effects of apple and apple products (juices, puree, pomace, dried apples, extracts rich in apple bioactives and single apple bioactives) on health. Apples and apple products have protective effects against cardiovascular diseases, cancer, as well as mild cognitive impairment and promote hair growth, healing of burn wounds, improve the oral environment, prevent niacin-induced skin flushing, promote the relief of UV-induced skin pigmentation, and improve the symptoms of atopic dermatitis as well as cedar hay fever among others. These effects are associated with various mechanisms, such as vascular endothelial protection, blood lipids lowering, anti-inflammatory, antioxidant, antiapoptotic, anti-invasion, and antimetastatic effects. Meanwhile, it has provided an important reference for the application and development of medicine, nutrition, and other fields.

Melatonin as a therapeutic agent for alleviating endothelial dysfunction in cardiovascular diseases: Emphasis on oxidative stress.

The vascular endothelium is vital in maintaining cardiovascular health by regulating vascular permeability and tone, preventing thrombosis, and controlling vascular inflammation. However, when oxidative stress triggers endothelial dysfunction, it can lead to chronic cardiovascular diseases (CVDs). This happens due to oxidative stress-induced mitochondrial dysfunction, inflammatory responses, and reduced levels of nitric oxide. These factors cause damage to endothelial cells, leading to the acceleration of CVD progression. Melatonin, a natural antioxidant, has been shown to inhibit oxidative stress and stabilize endothelial function, providing cardiovascular protection. The clinical application of melatonin in the prevention and treatment of CVDs has received widespread attention. In this review, based on bibliometric studies, we first discussed the relationship between oxidative stress-induced endothelial dysfunction and CVDs, then summarized the role of melatonin in the treatment of atherosclerosis, hypertension, myocardial ischemia-reperfusion injury, and other CVDs. Finally, the potential clinical use of melatonin in the treatment of these diseases is discussed.

A cross-sectional study exploring the relationship between the dietary inflammatory index and hyperlipidemia based on the National Health and Nutrition Examination Survey (2005-2018).

BACKGROUND: Hyperlipidemia is closely associated with dietary patterns and inflammation. However, the relationship between hyperlipidemia and the inflammatory potential of diets remains unexplored. The research was conducted to examine the relationship between hyperlipidemia and dietary inflammatory index (DII). METHODS: The data utilized in the research were acquired from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. The information on dietary intake was gathered by conducting 24-h dietary recall interviews. Restricted cubic spline (RCS) and Survey-weighted logistic regression were utilized to determine the association between DII and hyperlipidemia. Furthermore, stratification analysis was carried out. RESULTS: This study included 8982 individuals with and 3458 without hyperlipidemia. Participants with hyperlipidemia exhibited higher DII scores than those without hyperlipidemia. Following adjustment for gender, age, race, education level, marital status, poverty, drinking status, diabetes, hypertension, smoking status, body mass index (BMI), chronic kidney disease (CKD), cardiovascular disease (CVD), and hemoglobin (Hb), the association between the prevalence of hyperlipidemia and DII remained significant. The RCS data demonstrated that the hyperlipidemia prevalence did not exhibit an increase until the DII score was approximately 2.78. Stratification analysis revealed that the association between DII and hyperlipidemia persisted in all subgroups. CONCLUSIONS: DII was associated with hyperlipidemia, and the threshold DII score for the risk of hyperlipidemia was 2.78.

Therapeutic Candidates for Alzheimer's Disease: Saponins.

Drug development for Alzheimer's disease, the leading cause of dementia, has been a long-standing challenge. Saponins, which are steroid or triterpenoid glycosides with various pharmacological activities, have displayed therapeutic potential in treating Alzheimer's disease. In a comprehensive review of the literature from May 2007 to May 2023, we identified 63 references involving 40 different types of saponins that have been studied for their effects on Alzheimer's disease. These studies suggest that saponins have the potential to ameliorate Alzheimer's disease by reducing amyloid beta peptide deposition, inhibiting tau phosphorylation, modulating oxidative stress, reducing inflammation, and antiapoptosis. Most intriguingly, ginsenoside Rg1 and pseudoginsenoside-F11 possess these important pharmacological properties and show the best promise for the treatment of Alzheimer's disease. This review provides a summary and classification of common saponins that have been studied for their therapeutic potential in Alzheimer's disease, showcasing their underlying mechanisms. This highlights the promising potential of saponins for the treatment of Alzheimer's disease.

Sodium Danshensu stabilizes atherosclerotic vulnerable plaques by targeting IKKß mediated inflammation in macrophages.

BACKGROUND: 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. OBJECTIVE: This study aims to investigate the efficacy and mechanism of SDSS in inhibiting inflammation in macrophages and stabilizing vulnerable plaques in atherosclerosis (AS). MATERIALS AND METHODS: 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-/- mice. Subsequently, IKKß was identified as a potential target of SDSS through protein microarray, network pharmacology analysis, and molecular docking. Additionally, ELISA, RT-qPCR, Western blotting, and immunofluorescence were employed to measure the levels of inflammatory cytokines, IKKß, and NF-κB pathway-related targets, thereby confirming the mechanism of SDSS in treating AS both in vivo and in vitro. Finally, the impact of SDSS was observed in the presence of an IKKß-specific inhibitor. RESULTS: Initially, the administration of SDSS led to a decrease in the formation and area of aortic plaque, while also stabilizing vulnerable plaques in ApoE-/- mice. Furthermore, it was identified that IKKß serves as the primary binding target of SDSS. Additionally, both in vivo and in vitro experiments demonstrated that SDSS effectively inhibits the NF-κB pathway by targeting IKKß. Lastly, the combined use of the IKKß-specific inhibitor IMD-0354 further enhanced the beneficial effects of SDSS. CONCLUSIONS: SDSS stabilized vulnerable plaques and suppressed inflammatory responses by inhibiting the NF-κB pathway through its targeting of IKKß.

Therapeutic Role and Potential Mechanism of Resveratrol in Atherosclerosis: TLR4/NF-κB/HIF-1α.

Atherosclerosis, the main pathological basis of cardiovascular disease, is a chronic inflammatory disease that severely affects the quality of human life. Resveratrol (Res) is a natural polyphenol that is a major component of many herbs and foods. The present study analyzed resveratrol from the perspective of visualization and bibliometric analysis and found that resveratrol is closely related to the inflammatory response in cardiovascular diseases (associated with atherosclerosis). To explore the specific molecular mechanism of resveratrol, network pharmacology and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used, in which HIF-1α signaling may be a key pathway in the treatment of AS. Furthermore, we induced the polarization of macrophage RAW264.7 to M1 type to generate inflammatory response by the combination of lipopolysaccharide (LPS) (200 ng/mL) + interferon-γ (IFN-γ) (2.5 ng/mL). LPS and IFN-γ increased the inflammatory factor levels of IL-1ß, TNF-α, and IL-6 in RAW264.7, and the proportion of M1-type macrophages also increased, but the expression of inflammatory factors decreased after resveratrol administration, which confirmed the anti-inflammatory effect of resveratrol in AS. In addition, we found that resveratrol downregulated the protein expression of toll-like receptor 4 (TLR4)/NF-κB/hypoxia inducible factor-1 alpha (HIF-1α). In conclusion, resveratrol has a significant anti-inflammatory effect, alleviates HIF-1α-mediated angiogenesis, and prevents the progression of AS through the TLR4/NF-κB signaling pathway.

Sacubitril/valsartan: research progress of multi-channel therapy for cardiorenal syndrome.

Cardiorenal syndrome (CRS) results from complex interaction between heart and kidneys, inducing simultaneous acute or chronic dysfunction of these organs. Although its incidence rate is increasing with higher mortality in patients, effective clinical treatment drugs are currently not available. The literature suggests that renin-angiotensin-aldosterone system (RAAS) and diuretic natriuretic peptide (NP) system run through CRS. Drugs only targeting the RAAS and NPs systems are not effective. Sacubitril/valsartan contains two agents (sacubitril and valsartan) that can regulate RAAS and NPs simultaneously. In the 2017 American College of Cardiology/American Heart Association/American Heart Failure (HF) ssociation (ACC/AHA/HFSA) guideline, sacubitril/valsartan was recommended as standard therapy for HF patients. The latest research shows that Combined levosimendan and Sacubitril/Valsartan markets are protected the heart and kidney against cardiovascular syndrome in rat. However, fewer studies have reported its therapeutic efficacy in CRS treatment, and their results are inconclusive. Therefore, based on RAAS and NPs as CRS biomarkers, this paper summarizes possible pathophysiological mechanisms and preliminary clinical application effects of sacubitril/valsartan in the prevention and treatment of CRS. This will provide a pharmacological justification for expanding sacubitril/valsartan use to the treatment of CRS.

Inhibitors of the NLRP3 inflammasome pathway as promising therapeutic candidates for inflammatory diseases (Review).

The inflammasome regulates innate immunity by serving as a signaling platform. The Nod­like receptor protein 3 (NLRP3) inflammasome, equipped with NLRP3, the adaptor protein apoptosis­associated speck­like protein (ASC) and pro­caspase­1, is by far the most extensively studied and well­characterized inflammasome. A variety of stimuli can activate the NLRP3 inflammasome. When activated, the NLRP3 protein recruits the adaptor ASC protein and activates pro­caspase­1, resulting in inflammatory cytokine maturation and secretion, which is associated with inflammation and pyroptosis. However, the aberrant activation of the NLRP3 inflammasome has been linked to various inflammatory diseases, including atherosclerosis, ischemic stroke, Alzheimer's disease, diabetes mellitus and inflammatory bowel disease. Therefore, the NLRP3 inflammasome has emerged as a promising therapeutic target for inflammatory diseases. In the present review, systematic searches were performed using 'NLRP3 inhibitor(s)' and 'inflammatory disease(s)' as key words. By browsing the literature from 2012 to 2022, 100 articles were retrieved, of which 35 were excluded as they were reviews, editorials, retracted or unavailable online, and 65 articles were included. According to the retrieved literature, the current understanding of NLRP3 inflammasome pathway activation in inflammatory diseases was summarize, and inhibitors of the NLRP3 inflammasome pathway targeting the NLRP3 protein and other inflammasome components or products were highlighted. Additionally, the present review briefly discusses the current novel efforts in clinical research.

Molecular mechanisms of hepatotoxicity induced by compounds occurring in Evodiae Fructus.

Evodiae Fructus (EF) is a common herbal medicine with thousands of years of medicinal history in China, which has been demonstrated with many promising pharmacological effects on cancer, cardiovascular diseases and Alzheimer's disease. However, there have been increasing reports of hepatotoxicity associated with EF consumption. Unfortunately, in a long term, many implicit constituents of EF as well as their toxic mechanisms remain poorly understood. Recently, metabolic activation of hepatotoxic compounds of EF to generate reactive metabolites (RMs) has been implicated. Herein, we capture metabolic reactions relevant to hepatotoxicity of these compounds. Initially, catalyzed by the hepatic cytochrome P450 enzymes (CYP450s), the hepatotoxic compounds of EF are oxidized to generate RMs. Subsequently, the highly electrophilic RMs could react with nucleophilic groups contained in biomolecules, such as hepatic proteins, enzymes, and nucleic acids to form conjugates and/or adducts, leading to a sequence of toxicological consequences. In addition, currently proposed biological pathogenesis, including oxidative stress, mitochondrial damage and dysfunction, endoplasmic reticulum (ER) stress, hepatic metabolism disorder, and cell apoptosis are represented. In short, this review updates the knowledge on the pathways of metabolic activation of seven hepatotoxic compounds of EF and provides considerable insights into the relevance of proposed molecular hepatotoxicity mechanisms from a biochemical standpoint, for the purpose of providing a theoretical guideline for the rational application of EF in clinics.

Anti-inflammatory therapy of atherosclerosis: focusing on IKKß.

Chronic low-grade inflammation has been identified as a major contributor in the development of atherosclerosis. Nuclear Factor-κappa B (NF-κB) is a critical transcription factors family of the inflammatory pathway. As a major catalytic subunit of the IKK complex, IκB kinase ß (IKKß) drives canonical activation of NF-κB and is implicated in the link between inflammation and atherosclerosis, making it a promising therapeutic target. Various natural product derivatives, extracts, and synthetic, show anti-atherogenic potential by inhibiting IKKß-mediated inflammation. This review focuses on the latest knowledge and current research landscape surrounding anti-atherosclerotic drugs that inhibit IKKß. There will be more opportunities to fully understand the complex functions of IKKß in atherogenesis and develop new effective therapies in the future.