Incidence and risk factors of ventilator-associated pneumonia in the intensive care unit: a systematic review and meta-analysis.

Background: Ventilator-associated pneumonia (VAP) is a serious complication occurring in critically ill patients receiving mechanical ventilation in the intensive care unit (ICU). This study attempted to analyze VAP incidence in the ICU using a meta-analysis, investigate risk factors for VAP occurrence, and examine influence of VAP on outcomes. Methods: A search was carried out in the Web of Science, PubMed, Embase, and The Cochrane Library databases to identify studies on incidence and risk factors of VAP in ICU patients. Study quality was tested by the Newcastle-Ottawa Scale. Data related to risk factors, incidence, and outcomes were utilized for meta-analysis. Meta-analysis was conducted using Stata 18 and Review Manager 5.4. Results: Seventeen articles were included, comprising 6,222 patients, and incidence of VAP was 30% [95% confidence interval (CI): 24-37%]. Risk factor analysis showed that males [odds ratio (OR): 1.50; 95% CI: 1.29-1.75; P<0.001], smoking (OR: 1.30; 95% CI: 1.08-1.57; P=0.007) and Acute Physiology and Chronic Health Evaluation II (APACHE II) score [weighted mean difference (WMD): 1.30; 95% CI: 0.31-2.30; P=0.01] were risk factors for VAP. Antibiotic prophylaxis (OR: 0.79; 95% CI: 0.63-0.99; P=0.04) was a protect factor for VAP. Compared with non-VAP patients, VAP patients had a prolonged duration of mechanical ventilation (WMD: 6.96; 95% CI: 5.42-8.50; P<0.001), ICU length of stay (WMD: 7.91; 95% CI: 5.43-10.39; P<0.001) and total length of hospital stay (WMD: 8.09; 95% CI: 3.70-12.48; P=0.0003). There was no significant difference in mortality rate between VAP and non-VAP patients (OR: 1.13; 95% CI: 0.79-1.63; P=0.50). Conclusions: VAP incidence in the ICU was around 30%. Male, smoking, and high APACHE II score were risk factors for VAP, while antibiotic prophylaxis was a protective factor for VAP. VAP could lead to prolonged mechanical ventilation, ICU stay, and hospital stay, but it did not influence mortality.

Curcumol derivatives exhibit ameliorating effects on lipopolysaccharide-induced acute lung injury: Synthesis, biological evaluation, structure-activity relationship and action mechanism.

Acute lung injury (ALI) is an intricate clinical disease marked by high mortality and a sudden start. Currently, although there are no specific therapeutics for ALI, the administration of anti-inflammatory drugs is a promising treatment strategy. Curcumol, a terpenoid natural product, has demonstrated significant anti-inflammatory activity. Herein, we designed and synthesised 42 curcumol derivatives using curcumol as the core scaffold. These derivatives underwent in vitro screening for anti-inflammatory activity, and their structure-activity relationship was assessed. Among them, derivative 2 exhibited potent anti-inflammatory potential, inhibiting the expression of inflammatory markers at the nanomolar level. In addition, its water solubility was considerably improved, thereby laying the foundation for enhanced druggability. Derivative 2 also ameliorated lipopolysaccharide (LPS)-induced ALI and reduced pulmonary inflammation at a dose of 5 mg/kg. Proteomics analysis revealed that the anti-inflammatory effect of this compound primarily involved the mTOR signalling pathway. Furthermore, molecular docking and cellular thermal shift assays indicated that GSK3ß is a critical target of action of derivative 2, as verified via western blotting. These findings suggest that derivative 2 can be a lead therapeutic compound for ALI, with GSK3ß emerging as a promising novel target for the development of specific anti-ALI drugs.

Schisandra chinensis lignans improve insulin resistance by targeting TLR4 and activating IRS-1/PI3K/AKT and NF-κB signaling pathways.

Schisandra chinensis, a traditional Chinese medicine, has been widely applied in China to treat diabetes and its complications. The aim of this study was to discover the active compounds and explain related molecular mechanism contributing to the anti-diabetic effect of Schisandra chinensis. Herein, the therapeutic effects of Schisandra chinensis extracts on type 2 diabetes mellitus (T2DM) were firstly confirmed in vivo. Subsequently, various lignans were isolated from Schisandra chinensis and tested for hypoglycemic activity in palmitic acid-induced insulin-resistant HepG2 (IR-HepG2) cells. Among these lignans, R-biar-(7S,8R)-6,7,8,9-tetrahydro-1,2,3,12,13,14-hexamethoxy-7,8-dimethyl-7-dibenzo [a, c] cyclooctenol (compound 2) and Gomisin A (compound 4) were identified significantly increased the glucose consumption in IR-HepG2 cells. Meanwhile, compounds 2 and 4 activated the insulin receptor substrate-1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/Ak strain transforming (AKT) pathway, which regulates glucose transporter 2 (GLUT2) and glucose-6-phosphatase (G6Pase), essential for gluconeogenesis and glucose uptake. These compounds also inhibited the nuclear factor-κB (NF-κB) signaling pathway, reducing interleukin-6 (IL-6) levels. Importantly, the hypoglycemic effects of compounds 2 and 4 were diminished after Toll-like receptor 4 (TLR4) knockdown. Cellular thermal shift assays confirmed increased TLR4 protein stability upon treatment with these compounds, indicating direct binding to TLR4. Furthermore, TLR4 knockdown reversed the effects of compounds 2 and 4 on the NF-κB and IRS-1/PI3K/AKT pathways. Taken together, compounds 2 and 4 alleviate IR by targeting TLR4, thereby modulating the NF-κB and IRS-1/PI3K/AKT pathways. These findings suggest that compounds 2 and 4 could be developed as therapeutic agents for T2DM.

Centipeda minima and 6-O-angeloylplenolin enhance the efficacy of immune checkpoint inhibitors in non-small cell lung cancer.

BACKGROUND: Chemotherapeutic agents including cisplatin, gemcitabine, and pemetrexed, significantly enhance the efficacy of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) by increasing PD-L1 expression and potentiating T cell cytotoxicity. However, the low response rate and adverse effects limit the application of chemotherapy/ICI combinations in patients. METHODS: We screened for medicinal herbs that could perturb PD-L1 expression and enhance T cell cytotoxicity in the presence of anti-PD-L1 antibody, and investigated the underlying mechanisms. RESULTS: We found that the aqueous extracts of Centipeda minima (CM) significantly enhanced the cancer cell-killing activity and granzyme B expression level of CD8+ T cells, in the presence of anti-PD-L1 antibody. Both CM and its active component 6-O-angeloylplenolin (6-OAP) upregulated PD-L1 expression by suppressing GSK-3ß-ß-TRCP-mediated ubiquitination and degradation. CM and 6-OAP significantly enhanced ICI-induced reduction of tumor burden and prolongation of overall survival of mice bearing NSCLC cells, accompanied by upregulation of PD-L1 and increase of CD8+ T cell infiltration. CM also exhibited anti-NSCLC activity in cells and in a patient-derived xenograft mouse model. CONCLUSIONS: These data demonstrated that the induced expression of PD-L1 and enhancement of CD8+ T cell cytotoxicity underlay the beneficial effects of 6-OAP-rich CM in NSCLCs, providing a clinically available and safe medicinal herb for combined use with ICIs to treat this deadly disease.

Potential of natural products in inflammation: biological activities, structure-activity relationships, and mechanistic targets.

A balance between the development and suppression of inflammation can always be found in the body. When this balance is disturbed, a strong inflammatory response can damage the body. It sometimes is necessary to use drugs with a significant anti-inflammatory effect, such as nonsteroidal anti-inflammatory drugs and steroid hormones, to control inflammation in the body. However, the existing anti-inflammatory drugs have many adverse effects, which can be deadly in severe cases, making research into new safer and more effective anti-inflammatory drugs necessary. Currently, numerous types of natural products with anti-inflammatory activity and distinct structural features are available, and these natural products have great potential for the development of novel anti-inflammatory drugs. This review summarizes 260 natural products and their derivatives with anti-inflammatory activities in the last two decades, classified by their active ingredients, and focuses on their structure-activity relationships in anti-inflammation to lay the foundation for subsequent new drug development. We also elucidate the mechanisms and pathways of natural products that exert anti-inflammatory effects via network pharmacology predictions, providing direction for identifying subsequent targets of anti-inflammatory natural products.

Guided isolation of enantiomeric lignans from Cimicifuga heracleifolia Kom. by antioxidant activity and molecular networking.

Under the guidance of antioxidant evaluation combined with molecular networking, six pairs of enantiomeric lignans including seven undescribed ones (1a, 2a/2b-4a/4b), along with five known analogs (1b, 5a/5b-6a/6b) were isolated from Cimicifuga heracleifolia Kom. Their structures were determined by extensive spectroscopic data analysis, including HRESIMS, 1D and 2D NMR, experimental and calculated ECD. All the enantiomeric isolates were evaluated for antioxidation by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and 2, 2'-azino-bis (3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS) free radical scavenging tests. Compounds 1a and 3a/3b exhibited great DPPH and ABTS scavenging activities. The results are of great value for understanding structurally interesting enantiomeric lignans with antioxidant activity from C. heracleifolia in depth and providing its further development in functional evaluation and drug development.

Characterization of the metabolites of Eucommiae Cortex in rats provides a further insight into its estrogen-like effective substances.

Eucommiae Cortex is one of important traditional Chinese medicines (TCMs) used in Asia for preventing and treating osteoporosis induced by estrogen deficiency. However, the low exposure of prototype components in Eucommiae Cortex in vivo is difficult to interpret its efficacy. Under the guidance of UPLC-Q/TOF-MS, 42 metabolites including 32 lignans and 10 phenolics, 21 of which were new compounds, were isolated from rat urine and feces after oral administration of aqueous extract of E. ulmoides Oliv. by various chromatographic techniques. Their structures were determined based on extensive physicochemical analyses and spectral data. Their absolute configurations were determined by experimental and calculated ECD spectra, along with the calculated NMR with DP4 evaluation. Additionally, all isolated metabolites were evaluated for their estrogen-like activities, and there are 15 metabolites having estrogen-like effects after assessing influences in MCF-7 cells. Further, Dual Luciferase Reporter Gene Assay was used to determine their activation with estrogen receptor, M10 and M11 mixtures, M14, M19, M33, M27, M31, M38-M41 could activate ERα, and M19 and M41 could activate ERß. These results not only clarify the pharmacological substances of Eucommiae Cortex, but also provide a basis for guiding its clinical application.

A Natural Self-Assembled Gel-Sponge with Hierarchical Porous Structure for Rapid Hemostasis and Antibacterial.

Developing hemostatic agents with reliable biosafety and high efficiency has paramount clinical significance for saving lives. Herein, inspired from traditional Chinese medicine, a sponge (BC-S) with hierarchical porous structure is proposed for the treatment of bleeding. The BC-S is prepared by a simple self-assembly method employing Bletilla Striata polysaccharide and quaternary amine alkaloids (QA) from Bletilla Striata and Coptidis Rhizoma. The ideal cation donor encapsulated in the helical structure of BSP enlarges the inter-layer space of sponge by the action of electrostatic repulsion, forming wider channels which can accelerate the diversion speed of absorbed blood. Then, platelets and erythrocytes are trapped tightly in the reticular structure and extruded to deformation, activation. Subsequently, fibrin network forms and reinforces the internal multilayer mesh, blocks the outflow of blood. QA is released from the sponge skeleton mainly driven by a combination of surface erosion and potentially solution diffusion among pore to provide long-term antibacterial activity. Benefiting from the well-designed structure and the effective hemostatic mechanism, the BC-S displays more excellent hemostatic performance in different models in vivo and in vitro compared with typical gelatin hemostatic sponge. This work is expected to boost the development of emerging hemostatic agents.

Puerol and pueroside derivatives from Pueraria lobata and their anti-inflammatory activity.

Five undescribed puerols and puerosides and three known analogues were obtained from the roots of Pueraria lobata. Their structures were determined by comprehensive analysis of spectroscopic data and chemical methods. Since puerol D and puerol C were racemic compounds, resolved into their enantiomers, and their absolute configurations were determined by experimental and calculated ECD spectra. Six of the isolates were evaluated for their inhibitory activities on NO generation and the expression of inflammatory factors in the LPS-stimulated RAW 264.7 macrophage cells. The results showed that (S)-puerol C, (R)-puerol C, isokuzubutenolide A and kuzubutenolide A significantly decreased the NO production (IC50 values in the range of 16.87-39.95 µM). Meanwhile, (S)-puerol C, isokuzubutenolide A and kuzubutenolide A also reduced the mRNA expression of inflammatory factors (TNF-α, IL-1ß and IL-6).

Current perspectives and trend of nanomedicine in cancer: A review and bibliometric analysis.

The limitations of traditional cancer treatments are driving the creation and development of new nanomedicines. At present, with the rapid increase of research on nanomedicine in the field of cancer, there is a lack of intuitive analysis of the development trend, main authors and research hotspots of nanomedicine in the field of cancer, as well as detailed elaboration of possible research hotspots. In this review, data collected from the Web of Science Core Collection database between January 1st, 2000, and December 31st, 2021, were subjected to a bibliometric analysis. The co-authorship, co-citation, and co-occurrence of countries, institutions, authors, literature, and keywords in this subject were examined using VOSviewer, Citespace, and a well-known online bibliometrics platform. We collected 19,654 published papers, China produced the most publications (36.654%, 7204), followed by the United States (29.594%, 5777), and India (7.780%, 1529). An interesting fact is that, despite China having more publications than the United States, the United States still dominates this field, having the highest H-index and the most citations. Acs Nano, Nano Letters, and Biomaterials are the top three academic publications that publish articles on nanomedicine for cancer out of a total of 7580 academic journals. The most significant increases were shown for the keywords "cancer nanomedicine", "tumor microenvironment", "nanoparticles", "prodrug", "targeted nanomedicine", "combination", and "cancer immunotherapy" indicating the promising area of research. Meanwhile, the development prospects and challenges of nanomedicine in cancer are also discussed and provided some solutions to the major obstacles.

Pharmacokinetics of Five Alkaloids and their Metabolites in Normal and Diabetic Rats after Oral Administration of Rhizoma coptidis.

Rhizoma coptidis has been clinically used for a long time for the treatment of various diseases in China, such as hypertension, diabetes, and inflammation. Previous studies have shown that alkaloid components of Rhizoma coptidis extract could be extensively metabolized and the metabolites were also considered to be the therapeutic material basis. However, until now, pharmacokinetic studies of the in vivo metabolites have not been revealed yet. The aim of the present study was to characterize the pharmacokinetics and excretions of five main alkaloids (berberine, jatrorrhizine, palmatine, epiberberine, and coptisine) and their seven metabolites (berberrubine, demethyleneberberine, jatrorrhizine-3-O-ß-D-glucuronide, thalifendine-10-O-ß-D-glucuronide, berberrubine-9-O-ß-D-glucuronide, demethyleneberberine-2-O-sulfate, and demethyleneberberine-2-O-ß-D-glucuronide) in rats after oral administration of Rhizoma coptidis extract. Meanwhile, comparative pharmacokinetics and excretions of these analytes in diabetic model rats were also investigated, since Rhizoma coptidis is widely used for the treatment of diabetes. Our results showed that the in vivo existing forms of alkaloid components were phase II metabolites, highlighting the glucuronidation metabolic pathway. In diabetic model rats, the utilization of Rhizoma coptidis alkaloids was significantly increased and the biotransformation of berberine into berberrubine was significantly inhibited.

Bacteriophage SRD2021 Recognizing Capsular Polysaccharide Shows Therapeutic Potential in Serotype K47 Klebsiella pneumoniae Infections.

Klebsiella pneumoniae is an opportunistic pathogen posing an urgent threat to global public health, and the capsule is necessary for K. pneumoniae infection and virulence. Phage-derived capsule depolymerases have shown great potential as antivirulence agents in treating carbapenem-resistant K. pneumoniae (CRKP) infections. However, the therapeutic potential of phages encoding depolymerases against CRKP remains poorly understood. In this study, we identified a long-tailed phage SRD2021 specific for mucoid CRKP with capsular K47 serotype, which is the predominant infectious K-type in Asia. Genome sequencing revealed that ΦSRD2021 belonged to the Drulisvirus genus and exhibited a capsular depolymerase domain in its tail fiber protein. A transposon-insertion library of host bacteria was constructed to identify the receptor for ΦSRD2021. We found that most phage-resistant mutants converted to a nonmucoid phenotype, including the mutant in wza gene essential for capsular polysaccharides export. Further knockout and complementation experiments confirmed that the Δwza mutant avoided adsorption by ΦSRD2021, indicating that the K47 capsular polysaccharide is the necessary receptor for phage infection. ΦSRD2021 lysed the bacteria mature biofilms and showed a therapeutic effect on the prevention and treatment of CRKP infection in the Galleria mellonella model. Furthermore, ΦSRD2021 also reduced the colonized CRKP in mouse intestines significantly. By recognizing the host capsule as a receptor, our results showed that ΦSRD2021 may be used as a potential antibacterial agent for K47 serotype K. pneumoniae infections.

Corrigendum to "Metabolic profiling of icaritin in rats using UHPLC-Q/TOF-MS" [Chinese Herbal Medicines 11 (2019) 185-191].

[This corrects the article DOI: 10.1016/j.chmed.2019.03.008.].

Flavonoids from Eucommia ulmoides and their in vitro hepatoprotective activities.

A phytochemical investigation of the barks of Eucommia ulmoides Oliv. resulted in the isolation of 18 flavonoids (1-18). The new compound, eucommiaflavone (1) was structurally elucidated by various spectroscopic analyses. In particular, Mo2(OAc)4-induced circular dichroism (ICD) analysis was applied to determine the absolute configuration of 1. Furthermore, five flavonoids (4, 9, 11, 13, and 15) revealed significant in vitro hepatoprotective activity against D-galactosamine-induced cytotoxicity in human hepatoma HepG2 cells.

A Combined Phytochemistry and Network Pharmacology Approach to Reveal the Effective Substances and Mechanisms of Wei-Fu-Chun Tablet in the Treatment of Precancerous Lesions of Gastric Cancer.

Wei-Fu-Chun (WFC) tablet is a commercial medicinal product approved by China Food and Drug Administration, which is made of Panax ginseng C.A.Mey., Citrus aurantium L., and Isodon amethystoides (Benth.). WFC has been popularly used for the treatment of precancerous lesions of gastric cancer (PLGC) in clinical practice. In this study, a UHPLC-ESI-Q-TOF/MS method in both positive and negative ion mode was employed to rapidly survey the major constituents of WFC. 178 compounds including diterpenoids, triterpenes, sesquiterpenes, flavonoids, saponins, phenylpropanoids, lignans, coumarins, organic acids, fatty acids, quinones, and sterols, were identified by comparing their retention times, accurate mass within 5 ppm error, and MS fragmentation ions. In addition, 77 absorbed parent molecules and nine metabolites in rat serum were rapidly characterized by UHPLC-ESI-Q-TOF/MS. The network pharmacology method was used to predict the active components, corresponding therapeutic targets, and related pathways of WFC in the treatment of PLGC. Based on the main compounds in WFC and their metabolites in rat plasma and existing databases, 13 active components, 48 therapeutic targets, and 61 pathways were found to treat PLGC. The results of PLGC experiment in rats showed that WFC could improve the weight of PLGC rats and the histopathological changes of gastric mucosa partly by inhibiting Mitogen-activated protein kinase (MAPK) signaling pathway to increase pepsin secretion. This study offers an applicable approach to identify chemical components, absorbed compounds, and metabolic compounds in WFC, and provides a method to explore bioactive ingredients and action mechanisms of WFC.

Metabolic Activation and Covalent Protein Binding of Berberrubine: Insight into the Underlying Mechanism Related to Its Hepatotoxicity.

INTRODUCTION: Berberrubine (BRB), an isoquinoline alkaloid, is a major constituent of medicinal plants Coptis chinensis Franch or Phellodendron chinense Schneid. BRB exhibits various pharmacological activities, whereas exposure to BRB may cause toxicity in experimental animals. METHODS: In this study, we thoroughly investigated the liver injury induced by BRB in mice and rats. To explore the underlying mechanism, a study of the metabolic activation of BRB was conducted. Furthermore, covalent modifications of cysteine residues of proteins were observed in liver homogenate samples of animals after exposure to BRB, by application of an exhaustive proteolytic digestion method. RESULTS: It was demonstrated that BRB-induced hepatotoxicities in a time- and dose-dependent manner, based on the biochemical parameters ALT and AST. H&E stained histopathological examination showed the occurrence of obvious edema in liver of mice after intraperitoneal (i.p.) administration of BRB at a single dose of 100 mg/kg. Slight hepatotoxicity was also observed in rats given the same doses of BRB after six weeks of gavage. As a result, four GSH adducts derived from reactive metabolites of BRB were detected in microsomal incubations with BRB fortified with GSH as a trapping agent. Moreover, four cys-based adducts derived from reaction of electrophilic metabolites of BBR with proteins were found in livers. CONCLUSION: These results suggested that the formation of protein adducts originating from metabolic activation of BRB could be a crucial factor of the mechanism of BRB-induced toxicities.

New cytotoxic withanolides from Physalis minima.

Phytochemical investigation of Physalis minima led to the isolation of six new withanolides, including physaminilides HK (1-4), two artificial withanolides (5-6), and 19 known ones (7-25). Their structures were elucidated on the basis of spectroscopic analysis, including NMR and electronic circular dichroism (ECD) data. The isolates were evaluated for their cytotoxic activities against A375 human melanoma cells. Compounds 1, 8-9, 12-13, 15-17 and 19 exhibited significant cytotoxic activities with IC50 values in the range of 1.2-7.5 µM.

Systematic screening and characterization of absorbed constituents and in vivo metabolites in rats after oral administration of Rhizoma coptidis using UPLC-Q-TOF/MS.

Rhizoma coptidis has been used for a long time in China owing to its anti-bacterial, anti-diabetes, anti-hyperlipidemia and anti-obesity activities. However, the in vivo biotransformation of Rhizoma coptidis is still unclear to date. In this study, a three-step strategy using UPLC-Q-TOF/MS was applied to clarify the in vivo absorbed constituents and metabolites in rats after oral administration of Rhizoma coptidis. First, alkaloids in Rhizoma coptidis extract were identified. Second, six abundant alkaloids (berberine, palmatine, coptisine, epiberberine, jatrorrhizine, and columbamine) were selected as representative prototypes and the metabolic fates of them in rats were investigated to obtain a database of Rhizoma coptidis-derived metabolites. Finally, the metabolic profiles of Rhizoma coptidis were fully elucidated based on the above-mentioned results. In summary, 29 alkaloids were identified in Rhizoma coptidis, and a database of Rhizoma coptidis-derived metabolites was obtained with 144 characterized metabolites. A total of 89 xenobiotics including 12 absorbed constituents and 77 metabolites were identified in dosed rat biosamples. Major metabolic pathways of Rhizoma coptidis were hydroxylation, reduction, methylation, demethylation, demethylenation, desaturation, glucuronidation and sulfation. This is the first systematic study on the in vivo absorbed constituents and metabolic profiling of Rhizoma coptidis and will be beneficial for its further studies.

Curcumin metabolites contribute to the effect of curcumin on ameliorating insulin sensitivity in high-glucose-induced insulin-resistant HepG2 cells.

ETHNOPHARMACOLOGICAL EVIDENCE: Curcumin (CUR) is the active ingredient of Traditional Chinese Medicine turmeric (Curcuma longa L.), which has been used for treatment of diabetes in Ayurveda and China. CUR exerts potent anti-insulin-resistant effects in various cell lines. However, previous studies indicated CUR was metabolized extensively in vivo and massively degraded in a medium alkaline buffer solution. The real active component of the anti-insulin-resistant activity of CUR in vitro is not clear. AIM OF THE STUDY: Our study identified the functional contribution of the metabolites of CUR and the related molecular mechanism in improving insulin sensitivity. MATERIALS AND METHODS: HPLC and UPLC-QQQ-MS analyses were used to investigate the stability and metabolism of CUR in HepG2 cells. The effect of the metabolic products of CUR on insulin sensitivity was evaluated in high glucose (HG)-induced insulin-resistant HepG2 cells. A network pharmacology approach was used to examine the potential targets of the metabolites, and Western blotting was performed to verify changes in the targets. RESULTS: CUR was unstable in the cell culture medium, but the prototypes, metabolites and degradation products of CUR coexisted in the HepG2 cell culture experiment. The insulin sensitivity assay demonstrated that CUR and its metabolites enhanced insulin sensitivity in HG-induced insulin-resistant HepG2 cells, but the total degradation products of CUR may not play the major role. Similar to CUR, hexahydrocurcumin (HHC) and octahydrocurcumin (OHC) improved insulin sensitivity by strengthening the PI3K-AKT-GSK3B signal and suppressing the phosphorylation of ERK/JNK in HG-induced insulin-resistant HepG2 cells. CONCLUSIONS: Metabolites of CUR played a critical role in counteracting insulin resistance in HG-induced HepG2 cells. CUR exerted anti-insulin resistance effect in HepG2 cells in a multi-component, multi-target, and multi-pathway manner.

Inhibition of CYP2C9 by natural products: insight into the potential risk of herb-drug interactions.

Due to the rapidly increasing global interest in the use of herbs, phytomedicines and other natural products as medical or complementary remedies, concerns about the clinical medication safety have drawn much attention worldwide. Particularly, many natural ingredients exhibit inhibitory effects on cytochrome P450 (CYP) enzymes, which are the most important Phase I metabolism enzymes in liver. CYP2C9 is one of the most abundant CYP enzymes and responsible for the metabolism of over 15% clinical drugs, including oral sulfonylurea hypoglycemics, nonsteroidal anti-inflammatory agents, selective cyclooxygenase-2 inhibitors, antiepileptics, angiotensin II receptor inhibitors and anticoagulants. Diclofenac (4'-hydroxylase) and tolbutamide (methylhydroxylation) are widely used as probe substrates for CYP2C9. To date, numerous natural products have been reported to have the capabilities of inhibiting the catalytic activity of CYP2C9 and further influencing the pharmacokinetic and pharmacodynamic behaviors of drugs that are mainly metabolized by CYP2C9, leading to potential herb-drug interactions. Moreover, some fatal adverse interactions may occur for drugs with a narrow therapeutic window when they are coadministered with a CYP2C9 inhibitor, especially irreversible inactivators. For the purpose of better understanding the interactions of natural products with CYP2C9, we comprehensively reviewed the characteristics of CYP2C9, the natural ingredients that inhibit CYP2C9, the related research approaches and strategies, the types of inhibition and the underlying mechanisms.