Examining the relationship between genetic risk for depression and youth episodic stress exposure.

BACKGROUND: Offspring of depressed mothers have elevated risk of developing depression because they are exposed to greater stress. While generally assumed that youth's increased exposure to stress is due to the environmental effects of living with a depressed parent, youth's genes may influence stress exposure through gene-environment correlations (rGEs). To understand the relationship between risk for depression and stress, we examined the effects of polygenic risk for depression on youth stress exposure. METHODS: We examined the relations of a polygenic risk score (PRS) for depression (DEP-PRS), as well as PRSs for 5 other disorders, with youth stress exposure. Data were from a longitudinal study of a community sample of youth and their parents (n = 377) focusing on data collected at youth's aged 12 and 15 assessments. RESULTS: Elevated youth DEP-PRS was robustly associated with increased dependent stress, particularly interpersonal events. Exploratory analyses indicated that findings were driven by major stress and were not moderated by maternal nor paternal history of depression, and of the 5 additional PRSs tested, only elevated genetic liability for bipolar I was associated with increased dependent stress-particularly non-interpersonal events. LIMITATIONS: Like other PRS studies, we focused on those of European ancestry thus, generalizability of findings is limited. CONCLUSION: Polygenic risk contributes to youth experiencing stressful life events which are dependent on their behavior. This rGE appears to be specific to genetic risk for mood disorders.

Family interactions in toddlerhood influence social competence in preschool age: Accounting for genetic and prenatal influences.

Identification of early promotive and risk factors for social competence is important for fostering children's successful social development; particularly given social competence is essential for children's later academic and psychological well-being. While research suggests that the early parent-child relationship, genetics, and prenatal influences are associated with social competence, there is less research considering how these factors may operate together to shape children's social competence in early childhood. Using a genetically informed sample from the Early Growth and Development Study (N = 561), we examined multiple levels of influence (i.e., genetic, prenatal, parenting, and child characteristics) on children's social competence at 4.5 years old. Results from structural equation models showed adoptive mother overreactivity at 18 months was positively associated with child dysregulation at 27 months, which, in turn, was associated with lower levels of social competence at 4.5 years. Also, child reactivity at 18 months was independently associated with higher levels of adoptive mother overreactivity at 27 months, which, in turn, was associated with lower levels of social competence at 4.5 years. Finally, we found an evocative effect on adoptive fathers' overreactivity at 18 months such that prenatal birth mother distress was negatively associated with adoptive fathers' overreactivity at 18 months. Overall, this study found evidence for genetic influences, and bidirectional associations between parent and child in toddlerhood that are related to lower levels of social competence when children were 4.5 years old. We also found that the prenatal environment was associated with parenting, but not with child behavior directly. This study's ability to simultaneously examine multiple domains of influence helps provide a more comprehensive picture of important mechanisms and developmental periods for children's early social competence.

Concomitant Administration of Red Ginseng Extract with Lactic Acid Bacteria Increases the Plasma Concentration of Deglycosylated Ginsenosides in Healthy Human Subjects.

With the increased frequency of red ginseng extract (RGE) and lactic acid bacteria (LAB) co-administration, we aimed to investigate the interactions between RGE and LAB with regard to in vitro and in vivo deglycosylation metabolism and the pharmacokinetics of ginsenosides. As a proof-of-concept study, five healthy humans were administered RGE (104.1 mg of total ginsenosides/day) with or without co-administration of LAB (2 g, 1 billion CFU/day) for 2 weeks, and the plasma concentrations of ginsenosides in human plasma were monitored. The plasma exposure to compound K (CK), ginsenoside Rh2 (GRh2), protopanaxadiol (PPD), and protopanaxatriol (PPT) in the concomitant administration RGE and LAB groups increased by 2.7-, 2.1-, 1.6-, and 3.5-fold, respectively, compared to those in the RGE administration group, without a significant change in Tmax. The plasma concentrations of GRb1, GRb2, and GRc remained unchanged, whereas the AUC values of GRd and GRg3 significantly decreased in the concomitant administration RGE and LAB groups. To understand the underlying mechanism, the in vitro metabolic activity of ginsenosides was measured during the fermentation of RGE or individual ginsenosides in the presence of LAB for 1 week. Consistent with the in vivo results, co-incubation with RGE and LAB significantly increased the formation rate of GRh2, CK, PPD, and PPT. These results may be attributed to the facilitated deglycosylation of GRd and GRg3 and the increased production of GRh2, CK, PPD, and PPT by the co-administration of LAB and RGE. In conclusion, LAB supplementation increased the plasma concentrations of deglycosylated ginsenosides, such as GRh2, CK, PPD, and PPT, through facilitated deglycosylation metabolism of ginsenosides in the intestine.

The Genetic, Environmental, and Cultural Forces Influencing Youth Antisocial Behavior Are Tightly Intertwined.

The aggressive and rule-breaking behaviors that constitute youth antisocial behavior (ASB) are shaped by intertwined genetic, developmental, familial, spatial, temporal, cultural, interpersonal, and contextual influences operating across multiple levels of analysis. Genetic influences on ASB, for example, manifest in different ways during different developmental periods, and do so in part as a function of exposure to harsh parenting, delinquent peers, and disadvantaged neighborhoods. There is also clear evidence documenting societal effects, time-period effects, sex-assigned-at-birth effects, and cohort effects, all of which point to prominent (and possibly interconnected) cultural influences on ASB. In short, ASB is shaped by individuals' current and prior environmental experiences, genetic risks, and the time and place in which they live. This review seeks to illuminate already documented instances of interplay among the multilevel etiologic forces impinging on youth ASB, with the goal of facilitating additional research.

Rg3-enriched red ginseng extract promotes lung cancer cell apoptosis and mitophagy by ROS production.

BACKGROUND: Red Ginseng has been used for many years to treat diseases. Ginsenoside Rg3 has documented therapeutic effects, including anticancer and anti-inflammatory activities. However, the anticancer effect of Rg3-enriched red ginseng extract (Rg3-RGE) and its underlying mechanisms have not been fully explored. We investigated whether Rg3-RGE plays an anti-tumor role in lung cancer cells. METHODS: To examine the effect of Rg3-RGE on lung cancer cells, we performed cell viability assays, flow cytometry, western blotting analysis, and immunofluorescence to monitor specific markers. RESULTS: Rg3-RGE significantly inhibited cell proliferation and induced mitochondria-dependent apoptosis. Furthermore, Rg3-RGE also increased expression of mitophagy-related proteins such as PINK1 and Parkin. In addition, treatment with Rg3-RGE and mitophagy inhibitors stimulated cell death by inducing mitochondria dysfunction. CONCLUSIONS: Rg3-RGE could be used as a therapeutic agent against lung cancer.

Panax ginseng and its ginsenosides: potential candidates for the prevention and treatment of chemotherapy-induced side effects.

Chemotherapy-induced side effects affect the quality of life and efficacy of treatment of cancer patients. Current approaches for treating the side effects of chemotherapy are poorly effective and may cause numerous harmful side effects. Therefore, developing new and effective drugs derived from natural non-toxic compounds for the treatment of chemotherapy-induced side effects is necessary. Experiments in vivo and in vitro indicate that Panax ginseng (PG) and its ginsenosides are undoubtedly non-toxic and effective options for the treatment of chemotherapy-induced side effects, such as nephrotoxicity, hepatotoxicity, cardiotoxicity, immunotoxicity, and hematopoietic inhibition. The mechanism focus on anti-oxidation, anti-inflammation, and anti-apoptosis, as well as the modulation of signaling pathways, such as nuclear factor erythroid-2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1), P62/keap1/Nrf2, c-jun N-terminal kinase (JNK)/P53/caspase 3, mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinases (ERK), AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase kinase 4 (MKK4)/JNK, and phosphatidylinositol 3-kinase (PI3K)/AKT. Since a systemic review of the effect and mechanism of PG and its ginsenosides on chemotherapy-induced side effects has not yet been published, we provide a comprehensive summarization with this aim and shed light on the future research of PG.

Effect of Lactic Acid Bacteria on the Pharmacokinetics and Metabolism of Ginsenosides in Mice.

This study aims to investigate the effect of lactic acid bacteria (LAB) on in vitro and in vivo metabolism and the pharmacokinetics of ginsenosides in mice. When the in vitro fermentation test of RGE with LAB was carried out, protopanaxadiol (PPD) and protopanaxadiol (PPD), which are final metabolites of ginsenosides but not contained in RGE, were greatly increased. Compound K (CK), ginsenoside Rh1 (GRh1), and GRg3 also increased by about 30%. Other ginsenosides with a sugar number of more than 2 showed a gradual decrease by fermentation with LAB for 7 days, suggesting the involvement of LAB in the deglycosylation of ginsenosides. Incubation of single ginsenoside with LAB produced GRg3, CK, and PPD with the highest formation rate and GRd, GRh2, and GF with the lower rate among PPD-type ginsenosides. Among PPT-type ginsenosides, GRh1 and PPT had the highest formation rate. The amoxicillin pretreatment (20 mg/kg/day, twice a day for 3 days) resulted in a significant decrease in the fecal recovery of CK, PPD, and PPT through the blockade of deglycosylation of ginsenosides after single oral administrations of RGE (2 g/kg) in mice. The plasma concentrations of CK, PPD, and PPT were not detectable without change in GRb1, GRb2, and GRc in this group. LAB supplementation (1 billion CFU/2 g/kg/day for 1 week) after the amoxicillin treatment in mice restored the ginsenoside metabolism and the plasma concentrations of ginsenosides to the control level. In conclusion, the alterations in the gut microbiota environment could change the ginsenoside metabolism and plasma concentrations of ginsenosides. Therefore, the supplementation of LAB with oral administrations of RGE would help increase plasma concentrations of deglycosylated ginsenosides such as CK, PPD, and PPT.

Near infrared light fluorescence imaging-guided biomimetic nanoparticles of extracellular vesicles deliver indocyanine green and paclitaxel for hyperthermia combined with chemotherapy against glioma.

BACKGROUND: We investigated the therapeutic effect of targeting extracellular vesicles (EVs) loaded with indocyanine green (ICG) and paclitaxel (PTX) on glioma. METHODS: Raw264.7 cells were harvested to extract EVs for the preparation of ICG/PTX@RGE-EV by electroporation and click chemistry. We evaluated the success of modifying Neuropilin-1 targeting peptide (RGE) on the EV membrane of ICG/PTX@RGE-EV using super-resolution fluorescence microscopy and flow cytometry. Spectrophotometry and high performance liquid chromatography (HPLC) were implemented for qualitative and quantitative analysis of the ICG and PTX loaded in EVs. Photothermal properties of the vesicles were evaluated by exposing to 808-nm laser light. Western blot analysis, cell counting kit 8 (CCK-8), Calcein Acetoxymethyl Ester/propidium iodide (Calcein-AM/PI) staining, and flow cytometry were utilized for assessing effects of vesicle treatment on cellular behaviors. A nude mouse model bearing glioma was established to test the targeting ability and anti-tumor action of ICG/PTX@RGE-EV in vivo. RESULTS: Under exposure to 808-nm laser light, ICG/PTX@RGE-EV showed good photothermal properties and promotion of PTX release from EVs. ICG/PTX@RGE-EV effectively targeted U251 cells, with activation of the Caspase-3 pathway and elevated apoptosis in U251 cells through chemotherapy combined with hyperthermia. The anti-tumor function of ICG/PTX@RGE-EV was confirmed in the glioma mice via increased accumulation of PTX in the ICG/PTX@RGE-EV group and an increased median survival of 48 days in the ICG/PTX@RGE-EV group as compared to 25 days in the PBS group. CONCLUSION: ICG/PTX@RGE-EV might actively target glioma to repress tumor growth by accelerating glioma cell apoptosis through combined chemotherapy-hyperthermia.

Oral administration of hydrolyzed red ginseng extract improves learning and memory capability of scopolamine-treated C57BL/6J mice via upregulation of Nrf2-mediated antioxidant mechanism.

BACKGROUND: Korean ginseng (Panax ginseng Meyer) contains a variety of ginsenosides that can be metabolized to a biologically active substance, compound K. Previous research showed that compound K could be enriched in the red ginseng extract (RGE) after hydrolysis by pectinase. The current study investigated whether the enzymatically hydrolyzed red ginseng extract (HRGE) containing a notable level of compound K has cognitive improving and neuroprotective effects. METHODS: A scopolamine-induced hypomnesic mouse model was subjected to behavioral tasks, such as the Y-maze, passive avoidance, and the Morris water maze tests. After sacrificing the mice, the brains were collected, histologically examined (hematoxylin and eosin staining), and the expressions of antioxidant proteins analyzed by western blot. RESULTS: Behavioral assessment indicated that the oral administration of HRGE at a dosage of 300 mg/kg body weight reversed scopolamine-induced learning and memory deficits. Histological examination demonstrated that the hippocampal damage observed in scopolamine-treated mouse brains was reduced by HRGE administration. In addition, HRGE administration increased the expression of nuclear-factor-E2-related factor 2 and its downstream antioxidant enzymes NAD(P)H:quinone oxidoreductase and heme oxygenase-1 in hippocampal tissue homogenates. An in vitro assay using HT22 mouse hippocampal neuronal cells demonstrated that HRGE treatment attenuated glutamate-induced cytotoxicity by decreasing the intracellular levels of reactive oxygen species. CONCLUSION: These findings suggest that HRGE administration can effectively alleviate hippocampus-mediated cognitive impairment, possibly through cytoprotective mechanisms, preventing oxidative-stress-induced neuronal cell death via the upregulation of phase 2 antioxidant molecules.

Alleviation of Ulcerative Colitis Potentially through th1/th2 Cytokine Balance by a Mixture of Rg3-enriched Korean Red Ginseng Extract and Persicaria tinctoria.

Ginseng is a vastly used herbal supplement in Southeast Asian countries. Red ginseng extract enriched with Rg3 (Rg3-RGE) is a formula that has been extensively studied owing to its various biological properties. Persicaria tinctoria (PT), belonging to the Polygonaceae family, has also been reported for its anti-inflammatory properties. Ulcerative colitis (UC) is inflammation of the large intestine, particularly in the colon. This disease is increasingly common and has high probability of relapse. We investigated, separately and in combination, the effects of Rg3-RGE and PT using murine exemplary of UC induced by DSS (Dextran Sulfate Sodium). For in vitro and in vivo experiments, nitric oxide assay, qRT-Polymerase Chain Reaction (PCR), Western blot, ulcerative colitis introduced by DSS, Enzyme Linked Immunosorbent Assay (ELISA), and flow cytometry analysis were performed. The results obtained demonstrate that treatment with Rg3-RGE + PT showed synergism to suppress inflammation (in vitro) in RAW 264.7 cells via mitogen-activated protein kinase and nuclear factor κB pathways. Moreover, in C57BL/6 mice, this mixture exhibits strong anti-inflammatory effects in restoring colon length, histopathological damage, pro-inflammatory mediators, and cytokines amount, and decreasing levels of NLRP3 inflammasome (in vivo). Our results recommend that this mixture can be used for the prevention of UC as a prophylactic/therapeutic supplement.

Regulatory roles of ginseng on inflammatory caspases, executioners of inflammasome activation.

Inflammation is an immune response that protects against pathogens and cellular stress. The hallmark of inflammatory responses is inflammasome activation in response to various stimuli. This subsequently activates downstream effectors, that is, inflammatory caspases such as caspase-1, 4, 5, 11, and 12. Extensive efforts have been made on developing effective and safe anti-inflammatory therapeutics, and ginseng has long been traditionally used as efficacious and safe herbal medicine in treating various inflammatory and inflammation-mediated diseases. Many studies have successfully shown that ginseng plays an anti-inflammatory role by inhibiting inflammasomes and inflammasome-activated inflammatory caspases. This review discusses the regulatory roles of ginseng on inflammatory caspases in inflammatory responses and also suggests new research areas on the anti-inflammatory function of ginseng, which provides a novel insight into the development of ginseng as an effective and safe anti-inflammatory herbal medicine.

Herb-Drug Interaction of Red Ginseng Extract and Ginsenoside Rc with Valsartan in Rats.

The purpose of this study was to investigate the herb-drug interactions involving red ginseng extract (RGE) or ginsenoside Rc with valsartan, a substrate for organic anion transporting polypeptide (OATP/Oatp) transporters. In HEK293 cells overexpressing drug transporters, the protopanaxadiol (PPD)-type ginsenosides- Rb1, Rb2, Rc, Rd, Rg3, compound K, and Rh2-inhibited human OATP1B1 and OATP1B3 transporters (IC50 values of 7.99-68.2 µM for OATP1B1; 1.36-30.8 µM for OATP1B3), suggesting the herb-drug interaction of PPD-type ginsenosides involving OATPs. Protopanaxatriol (PPT)-type ginsenosides-Re, Rg1, and Rh1-did not inhibit OATP1B1 and OATP1B3 and all ginsenosides tested didn't inhibit OCT and OAT transporters. However, in rats, neither RGE nor Rc, a potent OATP inhibitor among PPD-type ginsenoside, changed in vivo pharmacokinetics of valsartan following repeated oral administration of RGE (1.5 g/kg/day for 7 days) or repeated intravenous injection of Rc (3 mg/kg for 5 days). The lack of in vivo herb-drug interaction between orally administered RGE and valsartan could be attributed to the low plasma concentration of PPD-type ginsenosides (5.3-48.4 nM). Even high plasma concentration of Rc did not effectively alter the pharmacokinetics of valsartan because of high protein binding and the limited liver distribution of Rc. The results, in conclusion, would provide useful information for herb-drug interaction between RGE or PPD-type ginsenosides and Oatp substrate drugs.

Medicinal potential of Panax ginseng and its ginsenosides in atopic dermatitis treatment.

Atopic dermatitis (AD) is a chronic and relapsing inflammatory disease that affects 1%-20% of people worldwide. Despite affecting many people, AD current treatments, such as corticosteroids and calcineurin inhibitors, have not only harmful secondary effects but are also often ineffective. Therefore, natural nontoxic compounds are on high demand for developing new effective AD treatments. Panax ginseng Meyer has been used traditionally for its promising healing and restorative properties to treat many diseases including skin disorders, reason why in this review we want to explore the research performed with AD and P. ginseng as well as determining its potential for new drug development. Previous researches have shown that P. ginseng has positive effects in AD patients such as lower eczema area and severity index, transepidermal water loss, and immunoglobulin E levels and better quality of sleep. In vivo animal models, as well, have shown positive results to P. ginseng and derived ginsenosides, such as the decrease of transepidermal water loss, immunoglobulin E levels in serum, allergy-related cytokines, and downregulation of NF-κB, MAPK, and Ikaros pathways. All of these previous data suggest that P. ginseng and its derived ginsenosides are undoubtedly a nontoxic effective option to treat AD.

The E Is in the G: Gene-Environment-Trait Correlations and Findings From Genome-Wide Association Studies.

Genome-wide association studies (GWASs) have shown that pleiotropy is widespread (i.e., the same genetic variants affect multiple traits) and that complex traits are polygenic (i.e., affected by many genetic variants with very small effect sizes). However, despite the growing number of GWASs, the possible contribution of gene-environment correlations (rGEs) to pleiotropy and polygenicity has been mostly ignored. rGEs can lead to environmentally mediated pleiotropy or gene-environment-trait correlations (rGETs), given that an environment that is affected by one genetically influenced phenotype, can in turn affect a different phenotype. By adding correlations with environmentally mediated genetic variants, rGETs can contribute to polygenicity. Socioeconomic status (SES) and the experience of stressful life events may, for example, be involved in rGETs. Both are genetically influenced and have been associated with a myriad of physical and mental disorders. As a result, GWASs of these disorders may find the genetic correlates of SES and stressful life events. Consequently, some of the genetic correlates of physical and mental disorders may be modified by public policy that affects environments such as SES and stressful life events. Thus, identifying rGETs can shed light on findings from GWASs and have important implications for public health.

Red ginseng extract regulates differentiation of monocytes to macrophage and inflammatory signalings in human monocytes.

This study was aimed to investigate the effect of red ginseng extract (RGE) on monocyte to macrophage differentiation and inflammatory signalings in THP-1 human monocytes. In HPLC analysis, RGE contained saponin level of 516 µg/mg (extract) with 14 ginsenosides. RGE effectively suppressed the monocyte-to-macrophage differentiation induced by phorbol 12-myristate 13-acetated (PMA) by inhibiting the THP-1 cell adhesion. This result is evidenced by the down-regulation of cluster of differentiation molecule ß (CD11ß) and CD36. RGE significantly reduced translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) (78%), while cytosolic NF-κB was increased (53%), compared with LPS group. In addition, RGE significantly increased the protein abundance of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its target protein, hemoxygenase-1 (HO-1), but, Kelch-like ECH-associated protein 1 (KEAP1), a negative regulator of Nrf2, was greatly decreased by RGE. Furthermore, RGE effectively mediated the regulation of Nrf2 level in nucleus and cytoplasm of THP-1.

A polygenic score for body mass index is associated with depressive symptoms via early life stress: Evidence for gene-environment correlation.

Increasing childhood obesity rates are associated with not only adverse physical, but also mental health outcomes, including depression. These negative outcomes may be caused and/or exacerbated by the bullying and shaming overweight individuals experience. As body mass index (BMI) can be highly heritable, we hypothesized that a genetic risk for higher BMI, will predict higher early life stress (ELS), which in turn will predict higher depressive symptoms in adulthood. Such a process will reflect an evocative gene-environment correlation (rGE) wherein an individual's genetically influenced phenotype evokes a reaction from the environment that subsequently shapes the individual's health. We modeled genetic risk using a polygenic score of BMI derived from a recent large GWAS meta-analysis. Self-reports were used for the assessment of ELS and depressive symptoms in adulthood. The discovery sample consisted of 524 non-Hispanic Caucasian university students from the Duke Neurogenetics Study (DNS; 278 women, mean age 19.78 ±â€¯1.23 years) and the independent replication sample consisted of 5930 white British individuals from the UK biobank (UKB; 3128 women, mean age 62.66 ±â€¯7.38 years). A significant mediation effect was found in the DNS (indirect effect = 0.207, bootstrapped SE = .10, bootstrapped 95% CI: 0.014 to 0.421), and then replicated in the UKB (indirect effect = 0.04, bootstrapped SE = .01, bootstrapped 95% CI: 0.018 to 0.066). Higher BMI polygenic scores predicted higher ELS, which in turn predicted higher depressive symptoms. Our findings suggest that evocative rGE may contribute to weight-related mental health problems and stress the need for interventions that aim to reduce weight bias, specifically during childhood.

The Southern Illinois Twins/Triplets and Siblings Study (SITSS): A Longitudinal Study of Early Child Development.

This article reviews the Southern Illinois Twins/Triplets and Siblings Study (SITSS) and describes some of the findings related to recent projects that were completed using this sample. At this time, the SITSS has enrolled 375 twin pairs, 12 triplet families, 1 family of quadruplets, 98 nontwin sibling pairs and 287 singletons. Testing begins for twins and triplets as young as age 1 and then occurs yearly on their birthdays until 5 years of age. Through age 20, various follow-up studies have been conducted on the SITSS sample to examine their social, emotional, and cognitive development across childhood and adolescence from a behavioral genetic perspective. A variety of methodologies have been used to investigate gene-environment correlations (rGE) and gene-environment interactions (GxE). Advanced statistical procedures (e.g., genetic likelihood indices and multilevel modeling) have been utilized to further investigate genetic underpinnings of behavior. Recent results have indicated genetic influences on the aggressiveness of preschoolers' media preferences, increased problem behaviors related to young children's overestimation of self-competence, and the influence of early life temperament and internalizing problems on adolescent health behaviors. Additionally, the SITSS has provided evidence for evocative rGE for various behaviors (aggression, prosocial and play), as well as findings supporting interactions between the dopamine receptor D4 gene (DRD4) and the environment (peer victimization, prenatal birth complications and parental sensitivity). Together, by use of multitrait and multimethodological investigations, this behavior genetic data set assists in furthering our understanding of biological and environmental influences on children's development.

Nonsaponin fraction of Korean Red Ginseng attenuates cytokine production via inhibition of TLR4 expression.

BACKGROUND: Ginsenosides of Korean Red Ginseng extracts (RGE) and its saponin components suppress secretion of inflammasome-mediating cytokines, whereas the nonsaponin fraction (NS) of RGE oppositely stimulates cytokine secretion. Although direct exposure of NS to macrophages in mice induces cytokine production, oral administration of NS has not been studied in inflammasome-related disease in animal models. METHODS: Mice were fed RGE or NS for 7 days and then developed peritonitis. Peritoneal cytokines were measured, and peritoneal exudate cells (PECs) were collected to assay expression levels of a set of toll-like receptors (TLRs) and cytokines in response to NS ingestion. In addition, the role of intestinal bacteria in NS-fed mice was assessed. The effect of preexposure to NS in bone marrow-derived macrophages (BMDMs) on cytokine production was further confirmed. RESULTS: NS ingestion attenuated secretion of peritoneal cytokines resulting from peritonitis. In addition, the isolated PECs from NS-fed mice presented lower TLR transcription levels than PECs from control diet-fed mice. BMDMs treated with NS showed downregulation of TLR4 mRNA and protein expression, which was mediated by the TLR4-MyD88-NFκB signal pathway. BMDMs pretreated with NS produced less cytokines in response to TLR4 ligands. CONCLUSION: NS administration directly inhibits TLR4 expression in inflammatory cells such as macrophages, thereby reducing secretion of cytokines during peritonitis.

Enhanced Intestinal Permeability and Plasma Concentration of Metformin in Rats by the Repeated Administration of Red Ginseng Extract.

We aimed to assess the potential herb-drug interactions between Korean red ginseng extract (RGE) and metformin in rats in terms of the modulation of metformin transporters, such as organic cation transporter (Oct), multiple toxin and extrusion protein (Mate), and plasma membrane monoamine transporter (Pmat). Single treatment of RGE did not inhibit the in vitro transport activity of OCT1/2 up to 500 µg/mL and inhibited MATE1/2-K with high IC50 value (more than 147.8 µg/mL), suggesting that concomitant used of RGE did not directly inhibit OCT- and MATE-mediated metformin uptake. However, 1-week repeated administration of RGE (1.5 g/kg/day) (1WRA) to rats showed different alterations in mRNA levels of Oct1 depending on the tissue type. RGE increased intestinal Oct1 but decreased hepatic Oct1. However, neither renal Oct1/Oct2 nor Mate1/Pmat expression in duodenum, jejunum, ileum, liver, and kidney were changed in 1WRA rats. RGE repeated dose also increased the intestinal permeability of metformin; however, the permeability of 3-O-methyl-d-glucose and Lucifer yellow was not changed in 1WRA rats, suggesting that the increased permeability of metformin by multiple doses of RGE is substrate-specific. On pharmacokinetic analysis, plasma metformin concentrations following intravenous injection were not changed in 1WRA, consistent with no significant change in renal Oct1, Oct2, and mate1. Repeated doses of RGE for 1 week significantly increased the plasma concentration of metformin, with increased half-life and urinary excretion of metformin following oral administration of metformin (50 mg/kg), which could be attributed to the increased absorption of metformin. In conclusion, repeated administration of RGE showed in vivo pharmacokinetic herb-drug interaction with metformin, with regard to its plasma exposure and increased absorption in rats. These results were consistent with increased intestinal Oct1 and its functional consequence, therefore, the combined therapeutic efficacy needs further evaluation before the combination and repeated administration of RGE and metformin, an Oct1 substrate drug.

Effects of Red Ginseng Extract on the Pharmacokinetics and Elimination of Methotrexate via Mrp2 Regulation.

We aimed to investigate the effects of red ginseng extract (RGE) on the expression of efflux transporters and to study the pharmacokinetics of representative substrate. For this, rats received single or repeated administration of RGE (1.5 g/kg/day) for 1 and 2 weeks via oral gavage. mRNA and protein levels of multidrug resistance-associated protein2 (Mrp2), bile salt export pump (Bsep), and P-glycoprotein (P-gp) in the rat liver were measured via real-time polymerase chain reaction and Western blot analysis. Ginsenosides concentrations from the rat plasma were also monitored using a liquid chromatography⁻tandem mass spectrometry (LC⁻MS/MS) system. Plasma concentrations of ginsenoside Rb1, Rb2, Rc, and Rd following repeated administration of RGE for 1 and 2 weeks were comparable but significantly higher than those after single administration of RGE. These dosing regimens did not induce significant biochemical abnormalities in the liver, kidneys, and lipid homeostasis. In the RGE repeated oral administration groups, the mRNA and protein levels of Mrp2 significantly decreased. Accordingly, we investigated the changes in the pharmacokinetics of methotrexate, a probe substrate for Mrp2, following intravenous administration of 3 mg/kg methotrexate to rats in the RGE 1-week repeated oral administration group, compared to that in the control group. Biliary excretion, but not urinary excretion, of methotrexate decreased in the RGE repeated administration group, compared to that in the control group. Consequently, the plasma concentrations of methotrexate slightly increased in the RGE repeated administration group. In conclusion, repeated administration of RGE for 1 week resulted in a decrease in Mrp2 expression without inducing significant liver or kidney damage. Pharmacokinetic herb⁻drug interaction between RGE and methotrexate might occur owing to the decrease in the mRNA and protein levels of Mrp2.