Visualizing a Cold Stress-Specific Pulse Wave in Traditional Pulse Diagnosis ('Tight Pulse') Correlated with Vascular Changes in the Radial Artery Induced by a Cold Pressor Trial.

Radial pulse diagnosis is the most common method to examine the human health state in Traditional East Asian Medicine (TEAM). A cold stress-related suboptimal health state (subhealth) is often undetectable during routine medical examinations, however, it can be detected through the palpation of specific pulse waves, particularly a 'tight pulse', in TEAM. Therefore, this study examined a correlation between 'tight pulse' and vascular changes in the radial artery (RA) induced by a cold pressor trial (CPT). Twenty healthy subjects underwent sequentially control trial and CPT with room-temperature and ice-cold water, respectively, on the right forearm. The radial pulse and vascular changes were then examined on the left arm. The radial pulse scores for frequencies of 'tight pulse' with strong arterial tension increased after the CPT compared with the control trial. The pulse scores were reversely correlated with the RA thickness and volumes in ultrasonography, but not with changes in the systolic/diastolic blood pressure. The RA thickness-based vascular surface and three-dimensional images visualized a 'tight pulse' showing the vasoconstriction and bumpy-/rope-shaped vascular changes in the radial pulse diagnostic region after the CPT. These findings provide valuable insights into the potential integration of clinical radial pulse diagnosis with ultrasonography for cold-related subhealth.

Protective Effects of Red Ginseng Against Tacrine-Induced Hepatotoxicity: An Integrated Approach with Network Pharmacology and Experimental Validation.

Introduction: Tacrine, an FDA-approved acetylcholinesterase inhibitor, has shown efficacy in treating Alzheimer's disease, but its clinical use is limited by hepatotoxicity. This study investigates the protective effects of red ginseng against tacrine-induced hepatotoxicity, focusing on oxidative stress. Methods: A network depicting the interaction between compounds and targets was constructed for RG. Effect of RG was determined by MTT and FACS analysis with cells stained by rhodamine 123. Proteins were extracted and subjected to immunoblotting for apoptosis-related proteins. Results: The outcomes of the network analysis revealed a significant association, with 20 out of 82 identified primary RG targets aligning with those involved in oxidative liver damage including notable interactions within the AMPK pathway. in vitro experiments showed that RG, particularly at 1000µg/mL, mitigated tacrine-induced apoptosis and mitochondrial damage, while activating the LKB1-mediated AMPK pathway and Hippo-Yap signaling. In mice, RG also protected the liver injury induced by tacrine, as similar protective effects to silymarin, a well-known drug for liver toxicity protection. Discussion: Our study reveals the potential of RG in mitigating tacrine-induced hepatotoxicity, suggesting the administration of natural products like RG to reduce toxicity in Alzheimer's disease treatment.

Anti-Osteoarthritic Effects of Antarctic Krill Oil in Primary Chondrocytes and a Surgical Rat Model of Knee Osteoarthritis.

Osteoarthritis (OA) is characterized by progressive cartilage destruction and synovitis; however, there are no approved disease-modifying OA drugs. Krill oil (KO) has been reported to possess anti-inflammatory properties and alleviate joint pain in knee OA, indicating its potential to target the inflammatory mechanism of OA. Therefore, the anti-OA effects of KO were investigated in primary chondrocytes and a surgical rat model of knee OA. The oral administration of KO at 200 and 100 mg/kg for 8 weeks improved joint swelling and mobility in the animal model and led to increased bone mineral density and compressive strength in the cartilage. The oral KO doses upregulated chondrogenic genes (type 2 collagen, aggrecan, and Sox9), with inhibition of inflammation markers (5-lipoxygenase and prostaglandin E2) and extracellular matrix (ECM)-degrading enzymes (MMP-2 and MMP-9) in the cartilage and synovium. Consistently, KO treatments increased the viability of chondrocytes exposed to interleukin 1α, accompanied by the upregulation of the chondrogenic genes and the inhibition of the ECM-degrading enzymes. Furthermore, KO demonstrated inhibitory effects on lipopolysaccharide-induced chondrocyte inflammation. Histopathological and immunohistochemical analyses revealed that KO improved joint destruction and synovial inflammation, probably due to the anti-inflammatory, anti-apoptotic, and chondrogenic effects. These findings suggest the therapeutic potential of KO for knee OA.

Regulated cell death pathways and their roles in homeostasis, infection, inflammation, and tumorigenesis.

Pyroptosis, apoptosis, necroptosis, and ferroptosis, which are the most well-studied regulated cell death (RCD) pathways, contribute to the clearance of infected or potentially neoplastic cells, highlighting their importance in homeostasis, host defense against pathogens, cancer, and a wide range of other pathologies. Although these four RCD pathways employ distinct molecular and cellular processes, emerging genetic and biochemical studies have suggested remarkable flexibility and crosstalk among them. The crosstalk among pyroptosis, apoptosis and necroptosis pathways is more evident in cellular responses to infection, which has led to the conceptualization of PANoptosis. In this review, we provide a brief overview of the molecular mechanisms of pyroptosis, apoptosis, necroptosis, and ferroptosis and their importance in maintaining homeostasis. We discuss the intricate crosstalk among these RCD pathways and the current evidence supporting PANoptosis, focusing on infectious diseases and cancer. Understanding the fundamental processes of various cell death pathways is crucial to inform the development of new therapeutics against many diseases, including infection, sterile inflammation, and cancer.

Optimal acupuncture protocol improving symptoms of typical dry eye syndrome: meta-analysis and systematic review.

Previous meta-analyses have shown a superiority of acupuncture over artificial tear for treating typical dry eye syndrome (DES). However, given that the acupuncture protocols were quite diverse in the randomized controlled trials (RCTs) included in the meta-analyses, it is necessary to establish the acupuncture guidelines. Thus, the optimal acupuncture protocol involved in improvements of tear-film breakup time (BUT) or Schirmer tear test (STT) was examined by meta-analyses for RCTs in patients with typical DES. Eight databases until Jun 2018 were searched for 21 RCTs (n = 1542 eyes) comparing effectiveness of acupuncture versus artificial tear control. Indirect comparison of Bucher analysis was used to find specific acupoints (SAPs) improving BUT or STT by comparing the outcomes between subgroups of the RCTs including and excluding certain SAPs. Meta-analysis was examined for the outcomes in subgroups of the RCTs based on the number of SAPs, and network meta-analysis was for multiple pairwise comparisons across the protocols using the SAPs to yield relative effects. The Bucher analyses identified nine SAPs with positive effects on BUT or STT, and the positive relations of two SAPs involved in improvements of both BUT and STT suggested potential combinations of three ('KI3-LI4-SP6' or 'KI3-GB14-ST2') or four SAPs ('KI3-BL1-EX-HN7-SP6'). Subgroup meta-analyses showed the SAP-depending improvements of BUT or STT in the subgroups including more than three SAPs, compared with the artificial tear control. Meta-regression and network meta-analyses revealed significant correlations between the number of SAPs and the improvements of BUT and STT, and demonstrated that acupuncture using four SAPs for 21-30 days, particularly at two-three times per week, can be optimal for improving the symptoms of typical DES. These results provide useful information for guiding acupuncture in clinical trials for DES.

Systemic and molecular analysis dissect the red ginseng induction of apoptosis and autophagy in HCC as mediated with AMPK.

Background: Hepatocellular carcinoma (HCC) has a high incidence and is one of the highest mortality cancers when advanced stage is proceeded. However, Anti-cancer drugs available for treatment are limited and new anti-cancer drugs and new ways to treat them are minimal. We examined that the effects and possibility of Red Ginseng (RG, Panax ginseng Meyer) as new anti-cancer drug on HCC by combining network pharmacology and molecular biology. Materials and Methods: Network pharmacological analysis was employed to investigate the systems-level mechanism of RG focusing on HCC. Cytotoxicity of RG was determined by MTT analysis, which were also stained by annexin V/PI staining for apoptosis and acridine orange for autophagy. For the analyze mechanism of RG, we extracted protein and subjected to immunoblotting for apoptosis or autophagy related proteins. Results: We constructed compound-target network of RG and identified potential pathways related to HCC. RG inhibited growth of HCC through acceleration of cytotoxicity and reduction of wound healing ability of HCC. RG also increased apoptosis and autophagy through AMPK induction. In addition, its ingredients, 20S-PPD (protopanaxadiol) and 20S-PPT (protopanaxatriol), also induced AMPK mediated apoptosis and autophagy. Conclusion: RG effectively inhibited growth of HCC cells inducing apoptosis and autophagy via ATG/AMPK in HCC cells. Overall, our study suggests possibility as new anti-cancer drug on HCC by proof for the mechanism of the anti-cancer action of RG.

Acupuncture Inhibits Morphine Induced-Immune Suppress via Antioxidant System.

Objectives: A powerful analgesic called Morphine causes addiction behaviors and immune suppression as a potential oxidative stressor. Acupuncture showed to inhibit oxidative stress-induced hepatic damage, regulate reactive oxygen species, and attenuate morphine addiction behaviors. Therefore, we investigated the potential effects of acupuncture on morphine-induced immune suppression. Materials and Methods: Rats received morphine intravenously through implanted catheters for 3, 7, or 21 days to determine the optimal condition for morphine-induced immune suppression. Second, we examined whether intravenous (iv.) or intraperitoneal (ip.) administration produced different results. Third, the effects of acupuncture in rats who received morphine for 21 days were investigated. Spleen and submandibular lymph node (S-LN) weights and natural killer (NK) cell activity were measured, and the white pulp diameter, total and cortical spleen thicknesses, and the number of lymphoid follicles in S-LNs were examined. The number of immunoreactive cells was also measured. Results: Decreased organ weights and increased atrophic changes were observed as morphine-induced immune suppression. However, dose-dependent increased immune suppression was not observed between 5.0 mg/kg and 10.0 mg/kg of morphine. And, 3-day withdrawal did not affect. Similar histopathological findings were observed in 5.0 and 10.0 ip. rats when compared to equal dosages of iv., respectively. The morphine induced-immune suppression evidenced by spleen and left S-LN weights, splenic NK cell activities, histopathological findings, and the immunoreactive cell number were normalized by acupuncture. Conclusion: These results indicate that acupuncture inhibits morphine-induced immune suppression, maybe via antioxidative action.

Lactobacillus crispatus Limits Bladder Uropathogenic E. coli Infection by Triggering a Host Type I Interferon Response.

Many urinary tract infections (UTIs) are recurrent because uropathogens persist within the bladder epithelial cells (BECs) for extended periods between bouts of infection. Because persistent uropathogens are intracellular, they are often refractive to antibiotic treatment. The recent discovery of endogenous Lactobacillus spp. in the bladders of healthy humans raised the question of whether these endogenous bacteria directly or indirectly impact intracellular bacterial burden in the bladder. Here, we report that in contrast to healthy women, female patients experiencing recurrent UTIs have a bladder population of Lactobacilli that is markedly reduced. Exposing infected human BECs to L. crispatus in vitro markedly reduced the intracellular uropathogenic Escherichia coli (UPEC) load. The adherence of Lactobacilli to BECs was found to result in increased type I interferon (IFN) production, which in turn enhanced the expression of cathepsin D within lysosomes harboring UPECs. This lysosomal cathepsin D-mediated UPEC killing was diminished in germ-free mice and type I IFN receptor-deficient mice. Secreted metabolites of L. crispatus seemed to be responsible for the increased expression of type I IFN in human BECs. Intravesicular administration of Lactobacilli into UPEC-infected murine bladders markedly reduced their intracellular bacterial load suggesting that components of the endogenous microflora can have therapeutic effects against UTIs.

Preventive and Therapeutic Effects of Krill Oil on Obesity and Obesity-Induced Metabolic Syndromes in High-Fat Diet-Fed Mice.

Obesity increases the risks of metabolic syndromes including nonalcoholic fatty liver disease (NAFLD), diabetic dyslipidemia, and chronic kidney disease. Dietary krill oil (KO) has shown antioxidant and anti-inflammatory properties, thereby being a therapeutic potential for obesity-induced metabolic syndromes. Thus, the effects of KO on lipid metabolic alteration were examined in a high-fat diet (HFD)-fed mice model. The HFD model (n = 10 per group) received an oral gavage with distilled water as a control, metformin at 250 mg/kg, and KO at 400, 200, and 100 mg/kg for 12 weeks. The HFD-induced weight gain and fat deposition were significantly reduced in the KO treatments compared with the control. Blood levels were lower in parameters for NAFLD (e.g., alanine aminotransferase, and triglyceride), type 2 diabetes (e.g., glucose and insulin), and renal dysfunction (e.g., blood urea nitrogen and creatinine) by the KO treatments. The KO inhibited lipid synthesis through the modification of gene expressions in the liver and adipose tissues and adipokine-mediated pathways. Furthermore, KO showed hepatic antioxidant activities and glucose lowering effects. Histopathological analyses revealed that the KO ameliorated the hepatic steatosis, pancreatic endocrine/exocrine alteration, adipose tissue hypertrophy, and renal steatosis. These analyses suggest that KO may be promising for inhibiting obesity and metabolic syndromes.

Combination Effects of Metformin and a Mixture of Lemon Balm and Dandelion on High-Fat Diet-Induced Metabolic Alterations in Mice.

Metformin, the first-line drug for type 2 diabetes mellitus (T2DM), has additional effects on improvements of nonalcoholic fatty liver disease (NAFLD); however, there are no treatments for both T2DM and NAFLD. Previous studies have shown hepatoprotective effects of a mixture of lemon balm and dandelion (LD) through its antioxidant and anti-steatosis properties. Thus, combination effects of metformin and LD were examined in a high-fat diet (HFD)-induced metabolic disease mouse model. The model received an oral administration of distilled water, monotherapies of metformin and LD, or a metformin combination with LD for 12 weeks. The HFD-induced weight gain and body fat deposition were reduced more by the combination than either monotherapy. Blood parameters for NAFLD (i.e., alanine aminotransferase and triglyceride), T2DM (i.e., glucose and insulin), and renal functions (i.e., blood urea nitrogen and creatinine) were reduced in the combination. The combination further enhanced hepatic antioxidant activities, and improved insulin resistance via the AMP-activated protein kinase and lipid metabolism pathways. Histopathological analyses revealed that the metformin combination ameliorated the hepatic hypertrophy/steatosis, pancreatic endocrine/exocrine alteration, fat tissue hypertrophy, and renal steatosis, more than either monotherapy. These results suggest that metformin combined with LD can be promising for preventing and treating metabolic diseases involving insulin resistance.

Therapeutic effects of acupuncture in typical dry eye: a systematic review and meta-analysis.

Acupuncture is a treatment option for dry eye syndrome (DES), but its efficacy remains still controversial. We assessed the effectiveness of this treatment for typical DES without specific aetiologies. Eight databases up through June 2018 were searched for randomized clinical trials (RCTs) comparing treatments of acupuncture with artificial tears. The risk of bias was assessed using Cochrane criteria, and a random effects model was used for meta-analyses on tear-film breakup time (BUT), Schirmer test, corneal fluorescein staining (CFS), ocular surface disease index, visual analogue scale and score of symptoms (SOS). Subgroup and sensitivity analyses were conducted to explore the heterogeneity, and publication bias was assessed by funnel plot using Egger's test. Twenty-one RCTs in 19 studies (n = 1542 eyes) met our eligible criteria. The results demonstrated the superiority of acupuncture in improving the symptoms of BUT, Schirmer test, CFS and SOS, compared to artificial tears acting alone. The BUT and Schirmer test were also more improved in acupuncture combination with artificial tears than artificial tears alone. Further subgroup analyses suggest that acupuncture applied at 2.0-3.0 times per week for 21-30 days may be optimal for treating typical DES. This provides useful information for guiding acupuncture in the clinical trials.

Protective Effects of Traditional Polyherbs on Cisplatin-Induced Acute Kidney Injury Cell Model by Inhibiting Oxidative Stress and MAPK Signaling Pathway.

Acute kidney injury (AKI) is a disease caused by sudden renal dysfunction, which is an important risk factor for chronic renal failure. However, there is no effective treatment for renal impairment. Although some traditional polyherbs are commercially available for renal diseases, their effectiveness has not been reported. Therefore, we examined the nephroprotective effects of polyherbs and their relevant mechanisms in a cisplatin-induced cell injury model. Rat NRK-52E and human HK-2 subjected to cisplatin-induced AKI were treated with four polyherbs, Injinhotang (IJ), Ucha-Shinki-Hwan (US), Yukmijihwang-tang (YJ), and UrofenTM (Uro) similar with Yondansagan-tang, for three days. All polyherbs showed strong free radical scavenging activities, and the treatments prevented cisplatin-induced cell death in both models, especially at 1.2 mg/mL. The protective effects involved antioxidant effects by reducing reactive oxygen species and increasing the activities of superoxide dismutase and catalase. The polyherbs also reduced the number of annexin V-positive apoptotic cells and the expression of cleaved caspase-3, along with inhibited expression of mitogen-activated protein kinase-related proteins. These findings provide evidence for promoting the development of herbal formulas as an alternative therapy for treating AKI.

Protective Effects of Traditional Herbal Formulas on Cisplatin-Induced Nephrotoxicity in Renal Epithelial Cells via Antioxidant and Antiapoptotic Properties.

Acute kidney injury (AKI) is characterized by a rapid loss of renal function. Drug-induced AKI accounts for up to 60% of all cases, resulting in a severe threat particularly to hospitalized patients, but there are no effective treatments. Four polyherbal formulas, Bojungikki-tang (BJ), Palmijihwang-tang (PJ), Oryeong-san (OR), and Wiryeong-tang (WR), have long been used for treatments of symptoms of kidney disease in traditional Korean medicine. Even though they are commercially available, evidences supporting the efficacy on AKI are still lacking. Therefore, the effectiveness of polyherbs on AKI and the underlying mechanisms were examined. Renal cell damage was induced by cisplatin at 20 µM and 16 µM in proximal tubular epithelial cell lines of rat NRK-52E and human HK-2, respectively. The cells were treated with the polyherbal formals for 3 days, and the cell viability, antioxidant activities, and apoptosis were examined. In addition, the proliferative effects were assessed under serum-free conditions. The results were compared with those of the vehicle-treated cells as a control. Three polyherbs BJ, PJ, and WR but not OR showed strong free radical scavenging activities in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. The treatments of BJ, PJ, OR, and WR significantly increased the cell viabilities under cisplatin-induced nephrotoxicity. Consistent with the results of the DPPH assay, superoxide dismutase and catalase activities were increased in the cisplatin-induced cell model treated with BJ, PJ, and WR but not with OR. However, annexin-V-positive cells and cleaved caspase 3 expression were significantly reduced in the cell model treated with all of the polyherbs. Cell proliferation was observed in treatment with all of the polyherbs, which was particularly evident in the OR-treated cells. This provides effective complementary evidences to promote the development of traditional herbal formulas to treat AKI.

Effects of free feeding time system and energy level to improve the reproductive performance of lactating sows during summer.

The reproductive performance of lactating sows was investigated by using different feeding methods including conventional feeding (CF, 3 times/d) or free feeding (FF), and different dietary energy level including low energy (LE: 3,300) or high energy (HE: 3,400 kcal/kg) during the hot season. A total of twenty-eight crossbred (Yorkshire × Landrace) sows were distributed into four treatments as a 2 × 2 factorial arrangement. Sows in the FF group showed lower body weight and backfat loss (p < 0.05) compared with the CF group. Backfat loss during lactation was lower (p < 0.05) in sows fed HE diet than in that fed LE diet. There were no significant differences in litter survival rate and weaning to estrus interval, but the litter weight at weaning was improved (p < 0.05) in FF and HE sows. Hence, it is concluded that using the free-feeding system or increased dietary energy density leads to improved sow performance during hot ambient temperature.

Effects of Balneotherapy in Jeju Magma-Seawater on Knee Osteoarthritis Model.

Balneotherapy is a common non-pharmacological treatment for osteoarthritis (OA), however, the efficacy is controversial in knee OA. Jeju magma-seawater (JMS) has high contents of various minerals, which has anti-inflammatory and antioxidant properties via an oral route. Thus, we examined the effects of JMS bathing on knee OA and the combination effects with diclofenac sodium as an anti-inflammatory drug. Knee OA was induced by transection of the anterior cruciate ligament and the partial meniscectomy in rat. The rats were administered subcutaneously saline or diclofenac sodium in saline, followed by bathing in thermal distilled water or JMS for 8 weeks. The model represented the characteristic changes of the cartilage degradation, osteophyte formation and synovial inflammation, and the relevant symptoms of the joint swelling and stiffness. However, the JMS bathing reduced the joint thickness and improved the mobility. It also contributed to a well-preserved tissue supported by increases in bone mineral density of the joint and decreases in Mankin scores in the cartilages. The effects involved anti-inflammation, chondroprotection, anti-apoptosis, and chondrogenesis. Overall, the JMS bathing in combination with diclofenac sodium showed a similar trend associated with synergic effects. It suggests that JMS bathing can be promising for a clinical use in knee OA.

The Ratio of Dietary n-3 Polyunsaturated Fatty Acids Influences the Fat Composition and Lipogenic Enzyme Activity in Adipose Tissue of Growing Pigs.

Currently, there is a growing interest among consumers in selecting healthier meat with a greater proportion of essential fatty acids (FA). This experiment was conducted to evaluate the role of different ratios of dietary n-6:n-3 on growth performance, FA profile of longissimus dorsi (LD), relative gene expression of cytokines, meat quality, and blood parameters in finishing pigs. A total of 108 finishing pigs was randomly allotted to three treatments including a control (basal diet) and low ratios (4:1 and 2:1) of n-6:n-3. The 4:1 and 2:1 diets decreased the overall stearic acid in LD. There were reductions in the content of stearic acid, palmitoleic acid, total saturated acid, and n-6:n-3 ratio of LD in pigs fed 4:1 and 2:1 diet compared with the control diet. The 4:1 and 2:1 diets increased the concentration of α-Linolenic acid and polyunsaturated FA in the LD of pigs. Acetyl-CoA carboxylase enzyme gene was down-regulated in pigs fed 2:1 diet compared with finishing pigs fed the control or 4:1 diets. The relative expression of hormone-sensitive lipase was increased in pigs fed 2:1 and 4:1 ratio diets. Lower total cholesterol of plasma was observed in finishing pigs fed 2:1 and 4:1 diets. The cooking loss ratio of meat was lower in pigs fed the 2:1 and 4:1 diets compared with the control diet. Pigs fed the 4:1 and 2:1 diets had greater final body weight. In conclusion, the 2:1 and 4:1 diets have the potential to increase the meat quality and growth performance of pigs.

Protective effects of fermented rice extract on ulcerative colitis induced by dextran sodium sulfate in mice.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD), characterized by the gut mucosal ulceration. Growing evidence indicates that dysregulation of immune response to the commensal microbiota involves the pathogenesis of IBD. Previous studies have demonstrated the favorable probiotic effects of fermented rice extracts through triple fermentation with Saccharomyces cerevisiae and Weissella cibaria (FRe). Thus, the therapeutic potential of FRe for UC was examined. Dextran sodium sulfate UC mice model was orally administered distilled water as a control, sulfasalazine, or FRe at 300, 200, and 100 mg/kg, once a day for a week. The UC control exhibited body weight loss, bloody stools, and colonic shortening. However, the FRe, especially at 300 mg/kg, led to a reduction in weight loss, disease activity index scores, and colon weight, and an increase in colorectal length. The histopathological analyses revealed mild changes involved in the colonic crypt and mucosal damages in the FRe groups, along with inhibited inflammation. Indeed, the FRe reduced neutrophil infiltration and production of proinflammatory cytokines (i.e., tumor necrosis factor-α, interleukin-6/-8). This was accompanied by the down-regulation of nuclear factor-kappa B. The gene expression responsible for the intestinal barrier integrity (i.e., Zonna occludens-1/-2, Claudin-1, Occludin, Mucin-1/-2) was up-regulated in the FRe groups. In addition, the FRe reduced lipid peroxidation and enhanced antioxidant activity. Interestingly, the microbiota dysbiosis was attenuated in the FRe groups, and the number of beneficial bacteria, Lactobacilli and Bifidobacteria, was increased. It suggests that the FRe potently ameliorate UC as a functional food.

Effects of Yukmijihwang-tang, a Polyherb, on the Pharmacokinetics of Metformin.

Metformin is one of the most common medicines for the treatment of type 2 diabetes, however, recent studies suggest that concomitant antihyperglycemic agents should be administered for better efficacy. Yukmijihwang-tang (YMJHT) is a nephroprotective polyherb prescribed for renal disorders or diabetic mellitus in traditional Korean medicine. Therefore, the pharmacokinetics between metformin and YMJHT were examined for their coadministration. Rats were orally coadministered with metformin and YMJHT as a combination group or metformin and distilled water as the corresponding control. Then, the metformin concentration in plasma and its pharmacokinetic parameters including maximum concentration (Cmax) and area under the plasma concentration time curve (AUC) were analyzed. There were no interactions between metformin and YMJHT in the single coadministration at intervals within 5 min. However, pretreatments with YMJHT for 6 days increased the metformin concentration and its Cmax and AUC (p<0.05). The repeated coadministration for 8 days increased the Cmax of metformin (p<0.05). Conversely, when the combination was coadministered at 2h -intervals, there were no interactions between metformin and YMJHT after a single dosing or repeated dosing of coadministration for 7 days. These results of the present study will help structure proper dosing regimens for the concomitant therapy of metformin and YMJHT.

Acute and Subchronic Oral Toxicity of Fermented Green Tea with Aquilariae Lignum in Rodents.

Green tea is generally considered safe, but there have been concerns regarding side effects relating to the main component, catechins, especially hepatotoxicities. We have previously shown beneficial effects of fermented green tea with Aquilariae Lignum (fGT) via an oral route in diabetic and obese models. Thus, the toxicological safety of fGT was assessed at limited oral doses for a rodent. Mice or rats of both genders were orally administered distilled water as a control and fGT at 2.0, 1.0, and 0.5 g/kg. There were no mortalities or gross abnormalities in the fGT groups for 2 weeks following the single oral dose in mice. No fGT-relevant abnormalities were found in postmortem and histopathological examinations, suggesting LD50 of fGT at more than 2.0 g/kg with no specific target organs. There were also no fGT-relevant mortalities or abnormal signs in the repeated oral dose for 13 weeks in rats. In the fGT groups, no body weight changes or daily metabolic changes were found, and hematological and serum biochemical ranges were normal. The postmortem and histopathological examinations revealed few fGT-related abnormalities in most of the organs including the liver, although slight lymphoid cell hyperplasia in the lymph node was observed in a few rats with fGT at 2.0 g/kg. This may be secondary to increased immune response to the highest dose because there were no histopathological lesions or organ weight changes. It suggests nontoxic safety of fGT at up to 2.0 g/kg, which provides useful information for clinical use.