mFOLFIRINOX versus mFOLFOX 6 as adjuvant treatment for high-risk stage III colon cancer - the FROST trial: study protocol for a multicenter, randomized controlled, phase II trial.

BACKGROUND: High-risk stage III colon cancer has a considerably poorer prognosis than stage II and low-risk stage III colon cancers. Nevertheless, most guidelines recommend similar adjuvant treatment approaches for all these stages despite the dearth of research focusing on high-risk stage III colon cancer and the potential for improved prognosis with intensive adjuvant treatment. Given the the proven efficacy of triplet chemotherapy in metastatic colorectal cancer treatment, the goal of this study is to evaluate the oncologic efficacy and safety of mFOLFIRINOX in comparison to those of the current standard of care, mFOLFOX 6, as an adjuvant treatment for patients diagnosed with high-risk stage III colon cancer after radical resection. METHODS: This multicenter, randomized (1:1), open-label, phase II trial will assess and compare the effectiveness and toxicity of mFOLFIRINOX and mFOLFOX 6 in patients with high-risk stage III colon cancer after radical resection. The goal of the trial is to enroll 312 eligible patients, from 11 institutes, aged between 20 and 70 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, or between 70 and 75 with an ECOG performance status of 0. Patients will be randomized into two arms - Arm A, the experimental arm, and Arm B, the reference arm - and will receive 12 cycles of mFOLFIRINOX and mFOLFOX 6 every 2 weeks, respectively. The primary endpoint of this study is the 3-year disease-free survival, and secondary endpoints include the 3-year overall survival and treatment toxicity. DISCUSSION: The Frost trial would help determine the oncologic efficacy and safety of adjuvant triplet chemotherapy for high-risk stage III colon cancers and ultimately improve prognoses. TRIAL REGISTRATION: ClinicalTrials.gov NCT05179889, registered on 17 December 2021.

Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus R0 resection for resectable colorectal cancer with peritoneal metastases and low peritoneal cancer index scores: a collaborative observational study from Korea and Japan.

BACKGROUND: The benefits of hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS) for colorectal cancer with peritoneal metastasis (CPM) remain controversial. R0 resection without peritoneal stripping might be as effective as CRS plus HIPEC. The authors aimed to compare the long-term oncological outcomes of patients with CPM and peritoneal cancer index (PCI) scores less than or equal to 6 who underwent R0 resection in Japan with those who underwent CRS plus HIPEC in Korea. MATERIALS AND METHODS: This international, retrospective cohort study was conducted in Korea and Japan using a prospectively collected clinical database. Patients who underwent surgery from July 2014 to December 2021 for CPM with a PCI score of less than or equal to 6 and completeness of the cytoreduction score-0 were included. The primary outcome was relapse-free survival (RFS), and the secondary outcomes were overall survival, peritoneal RFS (PRFS), and postoperative outcomes. RESULTS: The 3-year RFS was significantly longer in the CRS+HIPEC group than in the R0 resection group: 35.9% versus 6.9% ( P <0.001); 31.0% versus 6.7% ( P =0.040) after propensity score matching. The median PRFS was significantly longer in the CRS+HIPEC group than in the R0 resection group: 24.5 months versus 17.2 months ( P =0.017). The 3-year overall survival and postoperative complications did not significantly differ between the two groups. CONCLUSIONS: RFS and PRFS rates were significantly prolonged after CRS plus HIPEC, whereas postoperative complications and length of hospital stay were not increased. Therefore, curative CRS plus HIPEC may be considered a treatment strategy for selected patients with resectable CPM and low PCI scores.

Preoperative sequential short-course radiation therapy and FOLFOX chemotherapy versus long-course chemoradiotherapy for locally advanced rectal cancer: a multicenter, randomized controlled trial (SOLAR trial).

BACKGROUND: Preoperative (chemo)radiotherapy has been widely used as an effective treatment for locally advanced rectal cancer (LARC), leading to a significant reduction in pelvic recurrence rates. Because early administration of intensive chemotherapy for LARC has more advantages than adjuvant chemotherapy, total neoadjuvant therapy (TNT) has been introduced and evaluated to determine whether it can improve tumor response or treatment outcomes. This study aims to investigate whether short-course radiotherapy (SCRT) followed by intensive chemotherapy improves oncologic outcomes compared with traditional preoperative long-course chemoradiotherapy (CRT). METHODS: A multicenter randomized phase II trial involving 364 patients with LARC (cT3-4, cN+, or presence of extramural vascular invasion) will be conducted. Patients will be randomly assigned to the experimental or control arm at a ratio of 1:1. Participants in the experimental arm will receive SCRT (25 Gy in 5 fractions, daily) followed by four cycles of FOLFOX (oxaliplatin, 5-fluorouracil, and folinic acid) as a neoadjuvant treatment, and those in the control arm will receive conventional radiotherapy (45-50.4 Gy in 25-28 fractions, 5 times a week) concurrently with capecitabine or 5-fluorouracil. As a mandatory surgical procedure, total mesorectal excision will be performed 2-5 weeks from the last cycle of chemotherapy in the experimental arm and 6-8 weeks after the last day of radiotherapy in the control arm. The primary endpoint is 3-year disease-free survival, and the secondary endpoints are tumor response, overall survival, toxicities, quality of life, and cost-effectiveness. DISCUSSION: This is the first Korean randomized controlled study comparing SCRT-based TNT with traditional preoperative LC-CRT for LARC. The involvement of experienced colorectal surgeons ensures high-quality surgical resection. SCRT followed by FOLFOX chemotherapy is expected to improve disease-free survival compared with CRT, with potential advantages in tumor response, quality of life, and cost-effectiveness. TRIAL REGISTRATION: This trial is registered at Clinical Research Information under the identifier Service KCT0004874 on April 02, 2020, and at Clinicaltrial.gov under the identifier NCT05673772 on January 06, 2023.

Prognostic role of body composition in peritoneal carcinomatosis patients undergoing cytoreduction and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Bioelectric impedance analysis (BIA)-measured body composition and nutritional status have been used as prognostic indicators in various cancer cohorts. This study investigated whether BIA could provide information on prognosis in peritoneal carcinomatosis patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: We retrospectively analyzed the data of 99 patients with preoperative BIA data among those who underwent CRS and HIPEC. The association between BIA-derived parameters and intraoperative peritoneal cancer index (PCI) score was assessed. Predictive analysis for the occurrence of postoperative morbidities including major complications (Clavien-Dindo classification 3-4) and re-admission within 30 days after surgery as well as 1 year mortality was also performed. RESULTS: BIA-derived mineral (r = 0.224, p = 0.027), fat (r = - 0.202, p = 0.048), and total body water (TBW)/fat-free mass (FFM) (r = - 0.280, p = 0.005) showed significant associations with intraoperative PCI score. Lower TBW/FFM was an independent predictor of major postoperative complications (OR 0.047, 95% CI 0.003-0.749, p = 0.031) and re-admission (OR 0.094, 95% CI 0.014-0.657, p = 0.017) within 30 days after surgery. Higher fat mass was also independently associated with a higher risk of major postoperative complications (OR 1.120, 95% CI 1.006-1.248, p = 0.039) and re-admission (OR 1.123, 95% CI 1.024-1.230, p = 0.013). Intraoperative PCI score > 20 (OR 4.489, 95% CI 1.191-16.917, p = 0.027) and re-admission within 30 days after surgery (OR 5.269, 95% CI 1.288-21.547, p = 0.021) independently predicted postoperative 1-year mortality. CONCLUSIONS: We demonstrate that preoperative BIA-derived TBW/FFM and fat mass were significantly correlated with metastatic extent, assessed by PCI score, in patients with peritoneal carcinomatosis. In addition, BIA-derived TBW/FFM and fat mass showed independent predictability for postoperative 30-day major complications and re-admission in patients undergoing CRS and HIPEC. Our findings suggest that assessment of BIA may improve discrete risk stratification in patients who are planned to receive CRS and HIPEC.

8-Methoxypsoralen Induces Apoptosis by Upregulating p53 and Inhibits Metastasis by Downregulating MMP-2 and MMP-9 in Human Gastric Cancer Cells.

Furanocoumarin 8-methoxypsoralen (8-MOP) is the parent compound that naturally occurs in traditional medicinal plants used historically. 8-MOP has been employed as a photochemotherapeutic component of Psoralen + Ultraviolet A (PUVA) therapy for the treatment of vitiligo and psoriasis. Although the role of 8-MOP in PUVA therapy has been studied, little is known about the effects of 8-MOP alone on human gastric cancer cells. In this study, we observed anti-proliferative effect of 8-MOP in several human cancer cell lines. Among these, the human gastric cancer cell line SNU1 is the most sensitive to 8-MOP. 8-MOP treated SNU1 cells showed G1-arrest by upregulating p53 and apoptosis by activating caspase-3 in a dose-dependent manner, which was confirmed by loss-of-function analysis through the knockdown of p53-siRNA and inhibition of apoptosis by Z-VAD-FMK. Moreover, 8-MOPinduced apoptosis is not associated with autophagy or necrosis. The signaling pathway responsible for the effect of 8-MOP on SNU1 cells was confirmed to be related to phosphorylated PI3K, ERK2, and STAT3. In contrast, 8-MOP treatment decreased the expression of the typical metastasis-related proteins MMP-2, MMP-9, and Snail in a p53-independent manner. In accordance with the serendipitous findings, treatment with 8-MOP decreased the wound healing, migration, and invasion ability of cells in a dose-dependent manner. In addition, combination treatment with 8-MOP and gemcitabine was effective at the lowest concentrations. Overall, our findings indicate that oral 8-MOP has the potential to treat early human gastric cancer, with fewer side effects.

A study of the therapeutic mechanism of Jakyakgamcho-Tang about functional dyspepsia through network pharmacology research.

Herbal medicines have traditionally been used as an effective digestive medicine. However, compared to the effectiveness of Herbal medicines, the treatment mechanism has not been fully identified. To solve this problem, a system-level treatment mechanism of Jakyakgamcho-Tang (JGT), which is used for the treatment of functional dyspepsia (FD), was identified through a network pharmacology study. The two components, paeoniae radix alba and licorice constituting JGT were analyzed based on broad information on chemical and pharmacological properties, confirming 84 active chemical compounds and 84 FD-related targets. The JGT target confirmed the relationship with the regulation of various biological movements as follows: cellular behaviors of muscle and cytokine, calcium ion concentration and homeostasis, calcium- and cytokine-mediated signalings, drug, inflammatory response, neuronal cells, oxidative stress and response to chemical. And the target is enriched in variety FD-related signaling as follows: MAPK, Toll-like receptor, NOD-like receptor, PI3K-Akt, Apoptosis and TNF signaling pathway. These data give a new approach to identifying the molecular mechanisms underlying the digestive effect of JGT.

Anti-arthritic effects of Schisandra chinensis extract in monosodium iodoacetate-induced osteoarthritis rats.

The present study aimed to investigate the therapeutic effects of Schisandra chinensis (SC) extract on clinical symptoms of osteoarthritis and the modulating effect on the mechanisms associated with the progression of osteoarthritis in a rat model of monosodium iodoacetate (MIA)-induced osteoarthritis. Osteoarthritis-induced rats were randomized into four groups: MIA injection control (MC), MIA injection with celecoxib (PC), MIA injection with SC extract 100 mg/kg (SC100), and MIA injection with SC extract 200 mg/kg (SC200). Another healthy group received a saline injection as a negative control (NC). During the treatment, weight-bearing measurements were performed once a week for 4 weeks. Histopathological and biochemical analyses of the joints, blood, and chondrocyte tissue were performed following the completion of treatment. Compared with MC rats, SC rats demonstrated significantly alleviated pain behavior, bone erosion, and cartilage degradation. SC reduced serum levels of matrix metalloproteinases and pro-inflammatory cytokines. SC treatment also reversed the levels of biomarkers such as Collagen II and ADAMTS4 in the cartilage tissue. Moreover, SC administration inhibited the phosphorylation levels of nuclear factor kappa B (NF-κB) and NF-κB Inhibitor alpha. This study demonstrates that SC ameliorated osteoarthritis at in vivo level. Our results suggest that SC might be a potential therapeutic agent for osteoarthritis.

Pharmacologic Effects of Oxaliplatin Instability in Chloride-Containing Carrier Fluids on the Hyperthermic Intraperitoneal Chemotherapy to Treat Colorectal Cancer In Vitro and In Vivo.

BACKGROUND: Oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) involves mixing oxaliplatin with 5% dextrose solution (5DW) to prevent the structural degradation of oxaliplatin in chloride-containing fluids. This study evaluated oxaliplatin degradation in carrier fluids containing different chloride ion concentrations to determine a carrier fluid that is optimal for use in oxaliplatin-based HIPEC. METHODS: Five types of carrier fluids (normal saline, half saline, 5DW, Dianeal PD-2 peritoneal dialysis solution, and non-chloride Dianeal solution) were compared. An in vitro study was performed that monitored an oxaliplatin concentration of 1 ml (2 mg/ml) oxaliplatin mixed in 24 ml of each carrier fluid during 3 days to evaluate the rate of oxaliplatin degradation in each carrier fluid. An in vivo study, which subjected Sprague-Dawley rats to HIPEC for 60 min, also was performed. The efficacy of each carrier fluid for preserving oxaliplatin was evaluated using area under the curve (AUC) ratios between peritoneal fluid and plasma. RESULTS: The degradation rate of oxaliplatin in non-chloride fluids was significantly lower than in chloride-containing fluids. However, the rate was less than 10 to 15% at 30 min. The in vivo study indicated that oxaliplatin concentrations in peritoneal fluids did not differ significantly, whereas those in plasma did differ. The AUC ratios of both normal saline and Dianeal were higher than those of 5DW and non-Cl- Dianeal solutions. CONCLUSIONS: Chloride-containing fluids, such as normal saline or Dianeal, which display high absorption rates of oxaliplatin and acceptable degradation rates, may be more beneficial for use in oxaliplatin-based HIPEC than 5DW.

Honeysuckle Berry (Lonicera caerulea L.) Inhibits Lipase Activity and Modulates the Gut Microbiota in High-Fat Diet-Fed Mice.

Honeysuckle berry (HB, Lonicera caerulea L.) is an oriental herbal medicine reported to have beneficial effects on metabolic disorders, such as obesity and non-alcoholic fatty liver disease. The fruit part of HB is rich in anthocyanin, a type of polyphenol. Most studies credit the antioxidant and anti-inflammatory properties of HB as the mechanisms of its effectiveness. This study investigated the inhibitory effects of HB on lipase using an in vitro assay and the modulatory effect of HB on gut microbiota in high-fat diet (HFD)-fed mice. HB inhibited pancreatic lipase activity with IC50 values of approximately 0.47 mg/mL. The fecal triglyceride (TG) levels were higher from the HFD of the HB-fed mice than they were for the control mice. Moreover, the fecal microbiota from the HFD of the HB-fed mice had relatively lower Firmicutes and higher Bacteroidetes than that from the HFD-only mice. These results suggest that HB modulates gut microbiota composition, which may contribute to body fat reduction. Hence, HB could present a useful agent for treating metabolic diseases through lower TG uptake and the regulation of gut microflora.

Impact of Mitomycin-C-Induced Neutropenia after Hyperthermic Intraperitoneal Chemotherapy with Cytoreductive Surgery in Colorectal Cancer Patients with Peritoneal Carcinomatosis.

BACKGROUND: Mitomycin-C (MMC) is the most commonly used chemotherapeutic agent for hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS). However, MMC has a side effect of myelosuppression. This study aimed to evaluate the clinical manifestations and impact of MMC-induced neutropenia after CRS and HIPEC in colorectal cancer patients. METHODS: A total of 124 colorectal cancer patients who underwent CRS with HIPEC between March 2015 and January 2019 were evaluated. Patients with malignancies of non-colorectal origin, hospital stay longer than 60 days, peritoneal cancer index > 30, and complete cytoreduction score > 2 were excluded. MMC 35 mg/m2 was administered for 90 min at 41-43 °C. The patients were divided into three groups: no neutropenia, mild neutropenia (grade 1-2), and severe neutropenia (grade 3-4). RESULTS: In total, mild and severe neutropenia occurred in 30 (24.2%) and 48 (38.7%) patients, respectively. Age and body surface area were significantly different among the neutropenia groups. Severe neutropenia developed significantly earlier than mild neutropenia (6.9 days vs. 10.4 days, p < 0.001) and also lasted significantly longer (4.6 days vs. 2.5 days, p = 0.005). The rate of major postoperative complications was significantly higher in the severe neutropenia group than in the no and mild neutropenia groups (8.3% vs. 6.7% vs. 6.5%, p = 0.015) CONCLUSIONS: Severe neutropenia starts earlier and lasts longer than mild neutropenia after CRS and HIPEC using an MMC triple method. The higher rate of major postoperative complications in patients with severe neutropenia highlights the importance of postoperative management during the neutropenia period.

An 8-week randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of red Platycodon grandiflorus root extract on enhancement of immune function.

BACKGROUND: The immune-enhancing effects of red Platycodon grandiflorus root extract (RPGE) has been reported in vitro and in vivo, but there are few studies on humans. Therefore, this study aimed to investigate the efficacy and safety of RPGE in enhancing immune function in healthy subjects. SUBJECTS AND METHODS: An 8-week randomized, double-blind, parallel, placebo-controlled clinical trial was conducted at the Gachon University Gil Medical Center, Incheon, South Korea. A total of 100 adults aged 20-75 years with white blood cell counts of 3000-10,000 cell/µL were randomly divided into two groups (RPGE group, 50 and placebo group, 50) using a computer-generated random list with a 1:1 allocation ratio. The subjects consumed RPGE (2 times/day, 2 tablets/time, 375 mg RPGE powder/tablet) or placebo for 8 weeks. All test foods for the human study were coded and administered under double-blind conditions. The primary outcome was a change in the NK cell activity after 8 weeks of treatment compared to the baseline. RESULTS: Among 100 subjects enrolled for the study, 87 completed the study. NK cell activity (p = 0.005) and IFN-γ level (p = 0.003) of the RPGE group (n = 41) were higher than those of the placebo group (n = 46). The findings of the safety assessment revealed absence of clinically significant changes in any test and serious adverse events throughout the study. CONCLUSION: In conclusion, these results demonstrate the efficacy and safety of RPGE, suggesting it to be a beneficial agent for enhancing immune function in humans. TRIAL REGISTRATION: CRIS Registration Number KCT0005945, https://cris.nih.go.kr.

Quality Indicators for Evaluating the Health Care of Patients with Rheumatoid Arthritis: a Korean Expert Consensus.

BACKGROUND: There is increasing interest in the quality of health care and considerable efforts are being made to improve it. Rheumatoid arthritis (RA) is a disease that can result in favorable outcomes when appropriate diagnosis and treatment are provided. However, several studies have shown that RA is often managed inappropriately. Therefore, the Korean College of Rheumatology aimed to develop quality indicators (QIs) to evaluate and improve the health care of patients with RA. METHODS: Preliminary QIs were derived based on the existing guidelines and QIs for RA. The final QIs were determined through two separate consensus meetings of experts. The consensus was achieved through a panel of experts who voted using the modified Delphi method. RESULTS: Fourteen final QIs were selected among 70 preliminary QIs. These included early referral to and regular follow-up with a rheumatologist, radiographs of the hands and feet, early initiation and maintenance of disease-modifying anti-rheumatic drug (DMARD) therapy, periodic assessment of disease activity, screening for drug safety and comorbidities, including viral hepatitis and tuberculosis before biologic DMARD therapy, periodic laboratory testing, supplementation with folic acid, assessment of the risk for cervical spine instability before general anesthesia, patient education, and specialized nurse. CONCLUSION: These QIs can be used to assess and improve the quality of health care for patients with RA.

Transcriptome Analysis of the Anti-TGFß Effect of Schisandra chinensis Fruit Extract and Schisandrin B in A7r5 Vascular Smooth Muscle Cells.

Schisandra chinensis fruit extract (SCE) has been used as a traditional medicine for treating vascular diseases. However, little is known about how SCE and schisandrin B (SchB) affect transcriptional output-a crucial factor for shaping the fibrotic responses of the transforming growth factor ß (TGFß) signaling pathways in in vascular smooth muscle cells (VSMC). In this study, to assess the pharmacological effect of SCE and SchB on TGFß-induced transcriptional output, we performed DNA microarray experiments in A7r5 VSMCs. We found that TGFß induced distinctive changes in the gene expression profile and that these changes were considerably reversed by SCE and SchB. Gene Set Enrichment Analysis (GSEA) with Hallmark signature suggested that SCE or SchB inhibits a range of fibrosis-associated biological processes, including inflammation, cell proliferation and migration. With our VSMC-specific transcriptional interactome network, master regulator analysis identified crucial transcription factors that regulate the expression of SCE- and SchB-effective genes (i.e., TGFß-reactive genes whose expression are reversed by SCE and SchB). Our results provide novel perspective and insight into understanding the pharmacological action of SCE and SchB at the transcriptome level and will support further investigations to develop multitargeted strategies for the treatment of vascular fibrosis.

Fermentation of Sprouted Ginseng (Panax ginseng) Increases Flavonoid and Phenolic Contents to Attenuate Alcoholic Hangover and Acute Liver Injury in Mice.

Alcoholic liver damage is caused by ethanol and its oxidized intermediates, and endotoxin-induced acute liver failure is mediated by apoptosis and inflammation. We investigated whether extracts of sprouts of Panax ginseng (SG) attenuate alcohol or endotoxin-induced acute liver injury in mice. Whole SG contains eight times more ginsenosides than the root and, because it grows quickly ([Formula: see text]30 days) without using pesticides, the whole-plant can be harvested. The extracts were enriched in phenolics and flavonoids and showed high radical scavenging activities. Mice received oral administration of SG or fermented SG (FSG) extracts 1 h before an injection of either ethanol or lipopolysaccharide and D-galactosamine (LPS/GalN). The latency of righting reflex was monitored to examine the effect of extracts on relieving hangover symptoms. The results indicate that FSG significantly reduced the latency of righting reflex, SG and FSG increased the activity and expression of ethanol-metabolizing enzymes, and FSG decreased hepatic necrosis and plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). During the ethanol metabolism, cytochrome P450 2E1 expression was increased, but 4-hydroxynonenal levels were decreased by the extracts due to their anti-oxidant activity. LPS/GalN-induced liver injury was reduced by SG and FSG; plasma ALT and AST levels, hepatic necrosis, and apoptotic and inflammatory markers were all decreased. In conclusion, SG extracts attenuated ethanol-induced hangover and endotoxin-induced acute liver injury, and fermentation enhanced the efficacy with regard to relieving hangover.

Anti-Inflammatory Effects of Fermented Lotus Root and Linoleic Acid in Lipopolysaccharide-Induced RAW 264.7 Cells.

Inflammation is a protective response of the innate immune system. However, aberrant inflammatory responses lead to various diseases. Lotus root, the edible rhizome of Nelumbo nucifera, is a popular traditional herbal medicine in East Asia. In a previous study, we reported that fermented lotus root (FLR) alleviated ethanol/HCl-induced gastric ulcers in rats by modulating inflammation-related genes. However, the mechanisms underlying the anti-inflammatory effects of FLR and its major constituent, linoleic acid (LA), are still largely unknown. In this study, we investigated the anti-inflammatory effects of FLR and LA on lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 murine macrophages. We found that FLR inhibited LPS-induced expression of inflammatory mediators through down-regulation of NF-κB activity. Similarly, LA also attenuated LPS-induced inflammatory responses and reduced LPS-induced phosphorylation of proteins associated with NF-κB signaling, such as ERK, JNK, and p38. Overall, our results suggested that FLR and LA may effectively ameliorate inflammatory diseases.

Immunomodulatory effects of fermented Platycodon grandiflorum extract through NF-κB signaling in RAW 264.7 cells.

BACKGROUND/OBJECTIVES: Platycodon grandiflorum (PG), an oriental herbal medicine, has been known to improve liver function, and has both anti-inflammatory and antimicrobial properties. However, little is known about the immune-enhancing effects of PG and its mechanism. In this study, we aimed to investigate whether fermented PG extract (FPGE), which has increased platycodin D content, activates the immune response in a murine macrophage cell line, RAW 264.7. MATERIALS/METHODS: Cell viability was determined by Cell Counting Kit-8 assay and the nitric oxide (NO) levels were measured using Griess reagent. Cytokine messenger RNA levels of were monitored by quantitative reverse transcription polymerase chain reaction. To investigate the molecular mechanisms underlying immunomodulatory actions of FPGE in RAW 264.7 cells, we have conducted luciferase reporter gene assay and western blotting. RESULTS: We found that FPGE treatment induced macrophage cell proliferation in a dose-dependent manner. FPGE also modulated the expression of NO and pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6. The activation and phosphorylation levels of nuclear factor kappa B (NF-κB) were increased by FPGE treatment. Moreover, 5-aminoimidazole-4-carboxamide ribonucleotide, an activator of AMP-activated kinase (AMPK), significantly reduced both lipopolysaccharides- and FPGE-induced NF-κB reporter gene activity. CONCLUSIONS: Taken together, our findings suggest that FPGE may be a novel immune-enhancing agent acting via AMPK-NF-κB signaling pathway.

Platycodon grandiflorus Fermented Extracts Attenuate Endotoxin-Induced Acute Liver Injury in Mice.

Endotoxin-induced acute liver injury is mediated by an excessive inflammatory response, hepatocellular oxidative stress, and apoptosis. Traditional medicinal plants have been used to treat various disorders. Platycodon grandifloras (PG) has been shown to be beneficial in relieving cough and asthma and to have anti-tumor, anti-inflammatory, anti-diabetic activities. The pharmacological action of PG is mainly due to saponins, flavonoids, phenolic, and other compounds. However, raw PG exhibits some side effects at high doses. Here, we extracted raw PG with varying fermentation methods and examined its anti-inflammatory effect and associated signaling kinases in Raw264.7 cells. Then, we investigated the effect of fermented black PG (FBPG) on endotoxin-induced liver injury. Mice were administered FBPG orally at 1 h before the lipopolysaccharide and D-galactosamine (LPS/GalN) injection and sacrificed after 5 h. Black PG (BPG) and FBPG showed a significant reduction in pro-inflammatory cytokines and extracellular nitric oxide (NO); p-38 and ERK signaling was involved in reducing inducible NO synthase in Raw264.7 cells. Consistently, FBPG attenuates LPS/GalN-induced liver injury; plasma ALT and AST, hepatic necrosis, pro-inflammatory cytokines, apoptosis, and lipid peroxidation were all reduced. In conclusion, PG extracts, particularly FBPG, play anti-inflammatory, antioxidant, and anti-apoptotic roles, alleviating endotoxin-induced acute liver injury. Processing raw PG into FBPG extract may be clinically useful by improving the pharmacologically active ingredients and reducing the required dosage.

Development of Hazardous Materials Management Standard for Decoction Type of Personalized Herbal Medicine.

OBJECTIVES: This study was conducted to development of hazardous materials management standards for the decoction type of personalized herbal medicines (PHMs). METHODS: This study was conducted in two stages. We searched documents about criteria to use words such as 'Herb', 'Herbal medicine', and 'Botanical Drug' and summarized the results. We organized the committee consisted of seven experts, and held two meetings to reach an agreement on hazardous management standards of the decoction type of PHMs. RESULTS: The seven documents were presented in the literature review and six items related to hazardous management standards of decoction were identified. The second expert meeting brought that a total of six items, including heavy metal, pesticide residues, sulfur dioxide, benzopyrene, mycotoxin, and micro-organism limits, were selected for safety management of decoction type of PHMs. Also, the criteria and test methods for each standard were suggested for monitoring the decoction type of PHMs. CONCLUSION: The study suggested hazardous material management standards and criteria for the decoction types of PHMs. In the future, it would be necessary to conduct a pilot test to ensure the validity and credibility of the safety management standard and criteria. Furthermore, the government level safety management system should be introduced to verify the safety of decoction medicines.