Co-treatment with the seed of Carthamus tinctorius L. and the aerial part of Taraxacum coreanum synergistically suppresses Aß25-35-induced neurotoxicity by altering APP processing.

Accumulation of ß-amyloid peptide (Aß) induces neurotoxicity, which is the primary risk factor in the pathogenesis of Alzheimer's disease (AD). The cleavage of amyloid precursor protein (APP) by the ß- (BACE) and γ- (PS1, PS2) secretases is a critical step in the amyloidogenic pathway. The induction of neuronal apoptosis by Aß involves increased expression of B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) and decreased Bcl-2 expression. The seed of Carthamus tinctorius L. (CTS) and the aerial part of Taraxacum coreanum (TC) are traditional herbs used to treat several neurodegenerative diseases. In this study, the neuroprotective effects of co-treatment with CTS and TC on Aß-induced neurotoxicity in SH-SY5Y neuroblastoma cells and the underlying mechanisms were investigated. CTS, TC, and the co-treatment (CTS + TC) were added to Aß25-35-treated SH-SY5Y cells. CTS + TC synergistically increased cell viability and inhibited reactive oxygen species production. CTS + TC resulted in significant downregulation of BACE, PS1, PS2, and APP, as well as the 99-aa C-terminal domain of APP, compared with either CTS or TC alone. Compared with the single herbs, co-treatment with CTS and TC markedly decreased the expression of Bax and increased the expression of Bcl-2, consistent with its anti-apoptotic effects. These findings suggest that co-treatment with CTS and TC may be useful for AD prevention.

Comparison of the outcomes between sorafenib and lenvatinib as the first-line systemic treatment for HBV-associated hepatocellular carcinoma: a propensity score matching analysis.

BACKGROUND/AIM: In a randomized controlled trial, lenvatinib was non-inferior to sorafenib in overall survival (OS) of patients with unresectable hepatocellular carcinoma (uHCC). This study aimed to compare the effects of sorafenib and lenvatinib as first-line systemic therapy against uHCC with real-world data in chronic hepatitis B patients. METHODS: This retrospective single-center study involved 132 patients with HBV-related uHCC. Propensity score matching (PSM) was used to balance the baseline characteristics, including age, sex, serum alpha-fetoprotein levels, Child-Pugh class, tumor size, and tumor stage. The primary endpoint was overall survival (OS), and the secondary endpoints included progression-free survival (PFS), time to progression (TTP), and tumor response. RESULTS: After PSM, the final analysis included 44 patients treated with lenvatinib and 88 with sorafenib. The OS (7.0 vs 9.2 months, p = 0.070) and PFS (4.6 vs 2.4 months, p = 0.134) were comparable between the two drugs. Multivariable analysis showed that lenvatinib and sorafenib were not independent prognostic factors of OS (adjusted hazard ratio = 1.41, 95% confidence interval = 0.96-2.08, p = 0.077) after adjustment for baseline alpha-fetoprotein levels, total bilirubin levels, alanine aminotransferase level, performance status, tumor stage, and tumor size. However, the lenvatinib group had a significantly prolonged TTP (5.2 vs 2.5 months, p = 0.018) and a higher objective response rate (18.2% vs 4.5%, p = 0.020) and disease control rate (77.3% vs 47.7%, p = 0.001) than the sorafenib group. CONCLUSIONS: Our study demonstrated that lenvatinib had a comparable OS and PFS but longer TTP and better tumor response compared to sorafenib in patients with HBV-related uHCC.

Cirsium japonicum var. Maackii Improves Cognitive Impairment under Amyloid Beta25-35-Induced Alzheimer's Disease Model.

Abnormal production and degradation of amyloid beta (Aß) in the brain lead to oxidative stress and cognitive impairment in Alzheimer's disease (AD). Cirsium japonicum var. maackii (CJM) is widely used as an herbal medicine and has antibacterial and anti-inflammatory properties. This study focused on the protective effect of the ethyl acetate fraction from CJM (ECJM) on Aß 25-35-induced control mice. In the T-maze and novel object recognition test, ECJM provided higher spatial memory and object recognition compared to Aß 25-35 treatment alone. In the Morris water maze test, ECJM-administered mice showed greater learning and memory abilities than Aß 25-35-induced control mice. Additionally, ECJM-administered mice experienced inhibited lipid peroxidation and nitric oxide production in a dose-dependent manner. The present study indicates that ECJM improves cognitive impairment by inhibiting oxidative stress in Aß 25-35-induced mice. Therefore, CJM may be useful for the treatment of AD and may be a potential material for functional foods.

Caterpillar Medicinal Mushroom, Cordyceps militaris (Ascomycota), Attenuates Aß1-42-Induced Amyloidogenesis and Inflammatory Response by Suppressing Amyloid Precursor Protein Progression and p38 MAPK/JNK Activation.

The deposition of amyloid beta (Aß) is a neuropathological feature of Alzheimer's disease (AD). Cordyceps militaris is an edible medicinal fungus in Asian countries with antioxidative, antiaging, antitumor, and immunomodulatory effects. In this study, we investigated the neuroprotective mechanisms of C. militaris in the brain of Aß1-42-injected AD mice. An intracerebroventricular injection of Aß1-42 (total 3 µg/mouse) resulted in neurological damage, including amyloidogenesis and neuroinflammation; however, C. militaris attenuated Aß1-42-induced amyloidogenesis and inflammatory responses. Oral administration of C. militaris at concentrations of 100 and 200 mg/kg suppressed acetylcholinesterase activity. In addition, C. militaris treatment downregulated amyloid precursor protein levels, with a decrease in ß-secretase activity. Moreover, C. militaris significantly enhanced the expression of brain-derived neurotrophic factor. Furthermore, C. militaris-administered groups had inactivated inflammatory responses by downregulation of inducible nitric oxide synthase and cyclooxygenase-2 protein expression. The injection of Aß1-42 resulted in the activation of p38 MAPK and c-Jun N-terminal kinase, which was rescued by C. militaris. These results suggest that C. militaris has a protective effect against Aß1-42-induced neurological damage.

Amelioration effects of Cirsium japonicum var. maackii extract/fractions on amyloid beta25-35-induced neurotoxicity in SH-SY5Y cells and identification of the main bioactive compound.

Amyloid beta (Aß) is a neurotoxic peptide, and the accumulation of Aß in the brain is the major characteristic of Alzheimer's disease (AD). Recently, the beneficial effects of Cirsium japonicum var. maackii (CJM) on brain health has attracted much attention. In the present study, we investigated the ability and protective mechanisms of CJM to attenuate neuronal toxicity caused by Aß using SH-SY5Y cells. Aß25-35 treatment decreased cell viability, whereas CJM extract/fractions increased cell viability in Aß25-35-treated cells. We found that CJM treatment prevented the accumulation of reactive oxygen species observed in Aß25-35-treated control cells. Furthermore, Aß25-35-mediated production of inflammatory cytokines such as interleukin-1ß was significantly suppressed by CJM. In addition, apoptotic factors were modulated in CJM-treated cells by downregulating B-cell lymphoma-2-associated X protein and upregulating B-cell lymphoma-2 protein expression. The assays showed that the ethyl acetate (EtOAc) fraction of CJM has greater neuroprotective bioactivities compared with the other extract/fractions. The main neuroprotective active compound from the EtOAc fraction of CJM was identified as pectolinarin using ultraperformance liquid chromatography-quadrupole time-of-flight-mass spectrometry. Collectively, this study not only describes the neuroprotective effect of CJM against Aß25-35via the regulation of oxidative, inflammatory, and apoptotic signaling pathways, but also provides useful information for future studies on the mechanism of novel medicinal sources based on pectolinarin isolated from CJM.

Effect of Vigna angularis on High-Fat Diet-Induced Memory and Cognitive Impairments.

High-fat diet (HFD)-induced obesity is related to cognitive and memory dysfunction. Much attention was focused on functional foods as a therapeutic strategy to treat cognitive decline by obesity. In the present study, we confirmed the protective effect of Vigna angularis (VA) on cognitive and memory impairment in an obese mouse model. For 16 weeks, mice were fed HFD and VA extract was administered during 4 weeks at 100 and 200 mg/kg. The cognitive abilities of HFD-induced mice were evaluated using behavioral tests. Compared with the control group, VA groups were improved spatial and recognition ability. In T-maze and novel object recognition tests, VA 100 and VA 200 groups showed increased ratios of exploration of a novel object/route compared to a familiar object/route. Moreover, VA 100 and VA 200 groups reached the platform faster than the control group in a Morris water maze test. Therefore, VA extract may protect against HFD-induced cognitive impairment and memory dysfunction. (PNU-IACUC; approval no. PNU-2019-2166).

CKD-5, a novel pan-histone deacetylase inhibitor, synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma.

BACKGROUND: Histone deacetylase inhibitors (HDACIs) have distinctive epigenetic targets involved in hepatocarcinogenesis and chemoresistance. A recent phase I/II study reported the possibility of HDACI as a chemosensitizer in sorafenib-resistant patients. In this study, we evaluated whether CKD-5, a novel pan-HDACI, can potentiate the efficacy of sorafenib. METHODS: The anticancer effect of CKD-5 with and without sorafenib was evaluated in vitro using an MTS assay with human HCC cells (SNU-3058 and SNU-761) under both normoxic and hypoxic conditions. Microarray analysis was performed to investigate the mechanism of cell death, which was also evaluated by small interfering RNA (siRNA) transfection and subsequent immunoblot assays. In vivo experiments were conducted using two different murine HCC models. C3H mice implanted with MH134 cells and C57BL/6 mice implanted with RIL-175 cells were treated with weekly CKD-5 with and without sorafenib for 2 weeks. RESULTS: CKD-5 treatment significantly suppressed human HCC cell growth in both normoxic and hypoxic conditions. Microarray analysis and real-time PCR showed that CKD-5 treatment significantly increased peripherin expression in HCC cells and that downregulation of peripherin by siRNA decreased CKD-5-induced apoptosis. The combination of CKD-5 and sorafenib decreased cell viability more effectively than sorafenib or CKD-5 monotherapy in human and murine HCC cells. The effectiveness of the combination therapy was consistently demonstrated in the animal models. Histological and biochemical analyses demonstrated good tolerance of CKD-5 plus sorafenib in vivo. CONCLUSION: CKD-5 may enhance sorafenib efficacy through epigenetic regulation. The combination of CKD-5 and sorafenib might be a novel therapeutic option for the treatment of HCC.

The Protective Effects of Acer okamotoanum and Isoquercitrin on Obesity and Amyloidosis in a Mouse Model.

Obesity increases risk of Alzheimer's Disease (AD). A high fat diet (HFD) can lead to amyloidosis and amyloid beta (Aß) accumulation, which are hallmarks of AD. In this study, protective effects of the ethyl acetate fraction of Acer okamotoanum (EAO) and isoquercitrin were evaluated on obesity and amyloidosis in the HFD- and Aß-induced mouse model. To induce obesity and AD by HFD and Aß, mice were provided with HFD for 10 weeks and were intracerebroventricularly injected with Aß25-35. For four weeks, 100 and 10 mg/kg/day of EAO and isoquercitrin, respectively, were administered orally. Administration of EAO and isoquercitrin significantly decreased body weight in HFD and Aß-injected mice. Additionally, EAO- and isoquercitrin-administered groups attenuated abnormal adipokines release via a decrease in leptin and an increase in adiponectin levels compared with the control group. Furthermore, HFD and Aß-injected mice had damaged liver tissues, but EAO- and isoquercitrin-administered groups attenuated liver damage. Moreover, administration of EAO and isoquercitrin groups down-regulated amyloidosis-related proteins in the brain such as ß-secretase, presenilin (PS)-1 and PS-2 compared with HFD and Aß-injected mice. This study indicated that EAO and isoquercitrin attenuated HFD and Aß-induced obesity and amyloidosis, suggesting that they could be effective in preventing and treating both obesity and AD.

Effectiveness of nivolumab versus regorafenib in hepatocellular carcinoma patients who failed sorafenib treatment.

BACKGROUND/AIMS: Several treatment options are currently available for patients with hepatocellular carcinoma (HCC) failing previous sorafenib treatment. We aimed to compare the effectiveness of regorafenib and nivolumab in these patients. METHODS: Consecutive HCC patients who received regorafenib or nivolumab after failure of sorafenib treatment were included. Primary endpoint was overall survival (OS) and secondary endpoints were time to progression, tumor response rate, and adverse events. Inverse probability of treatment weighting (IPTW) using the propensity score was conducted to reduce treatment selection bias. RESULTS: Among 150 study patients, 102 patients received regorafenib and 48 patients received nivolumab. Median OS was 6.9 (95% confidence interval [CI], 3.0-10.8) months for regorafenib and 5.9 (95% CI, 3.7-8.1) months for nivolumab (P=0.77 by log-rank test). In multivariable analysis, nivolumab was associated with prolonged OS (vs. regorafenib: adjusted hazard ratio [aHR], 0.54; 95% CI, 0.30-0.96; P=0.04). Time to progression was not significantly different between groups (nivolumab vs. regorafenib: aHR, 0.82; 95% CI, 0.51-1.30; P=0.48). HRs were maintained after IPTW. Objective response rates were 5.9% and 16.7% in patients treated with regorafenib and nivolumab, respectively (P=0.04). CONCLUSION: After sorafenib failure, the use of nivolumab may be associated with improved OS and better objective response rate as compared to using regorafenib.

Flavonoids from Acer okamotoanum Inhibit Adipocyte Differentiation and Promote Lipolysis in the 3T3-L1 Cells.

Flavonoids, quercitrin, isoquercitrin (IQ), and afzelin, were isolated from ethyl acetate fraction of Acer okamotoanum. We investigated anti-obesity effects and mechanisms of three flavonoids from A. okamotoanum in the differentiated 3T3-L1 cells. The differentiated 3T3-L1 cells increased triglyceride (TG) contents, compared with non-differentiated normal group. However, treatments of three flavonoids from A. okamotoanum decreased TG contents without cytotoxicity. In addition, they showed significant down-regulation of several adipogenic transcription factors, such as γ-cytidine-cytidine-adenosine-adenosine-thymidine/enhancer binding protein -α, -ß, and peroxisome proliferator-activated receptor-γ, compared with non-treated control group. Furthermore, treatment of the flavonoids inhibited expressions of lipogenesis-related proteins including fatty acid synthase, adipocyte protein 2, and glucose transporter 4. Moreover, IQ-treated group showed significant up-regulation of lipolysis-related proteins such as adipose triglyceride lipase and hormone-sensitive lipase. In addition, flavonoids significantly activated 5'-adenosine monophosphate-activated protein kinase (AMPK) compared to control group. In particular, IQ showed higher inhibition of TG accumulation by regulation of pathways related with both adipogenesis and lipolysis, than other flavonoids. The present results indicated that three flavonoids of A. okamotoanum showed anti-obesity activity by regulation of adipocyte differentiation, lipolysis, and AMPK signaling, suggesting as an anti-obesity functional agents.

Effects of collagen peptides from skate (Raja kenojei) skin on improvements of the insulin signaling pathway via attenuation of oxidative stress and inflammation.

It has been well established that hepatic insulin signaling is significantly affected by the antioxidative status of the liver. In this study, we first confirmed that skate skin collagen peptide (SSCP) administration has dose-dependent positive effects on the change in the glucose level as evidenced by oral glucose tolerance tests. Therefore, the beneficial effects of SSCP-showing antioxidative and anti-inflammatory activities-on insulin resistance were examined in high-fat diet (HFD)-fed mice. C57BL/6J mice orally received SSCP at doses of 100, 200, and 300 mg per kg bw per day along with a HFD for 8 weeks (n = 9 per group). Water was given to the HFD- or chow diet-only group as a vehicle. Compared with the HFD group, the final body weight was reduced in all the SSCP-treated groups in a dose-dependent manner. The hepatic protein expression levels of the phosphorylated insulin receptor substrate, phosphorylated phosphatidylinositol 3-kinase, and phosphorylated protein kinase B were increased in the SSCP-treated groups, which led to reduced plasma insulin and HOMA-IR levels (P < 0.05). The hepatic protein expression levels of nuclear factor erythroid 2-related factor 2-mediated antioxidant enzymes were increased in the SSCP-treated groups, whereas those of nuclear factor kappa B-regulated inflammatory enzymes and mediators were decreased (P < 0.05). These effects were dose-dependent. It is apparent that SSCP might enhance insulin sensitivity by increasing the antioxidative status and suppressing the inflammatory response in the liver.

Acer okamotoanum inhibits adipocyte differentiation by the regulation of adipogenesis and lipolysis in 3T3­L1 cells.

Acer okamotoanum is reported to have various antioxidant, anti­inflammatory and beneficial immune system effects. The anti­adipocyte differentiation effects and mechanisms of the ethyl acetate (EtOAc) fraction of an A. okamotoanum extraction was investigated in 3T3­L1 adipocyte cells. Treatment with differentiation inducers increased the level of triglycerides (TGs) in 3T3­L1 adipocyte cells compared with an untreated control. However, the EtOAc fraction of A. okamotoanum significantly decreased TGs. Treatment with 1, 2.5 and 5 µg/ml showed weak activity, but TG production was inhibited at 10 µg/ml compared with the control. In addition, A. okamotoanum caused a significant downregulation of proteins related to adipogenesis, such as γ­cytidine­cytidine­adenosine­adenosine­thymidine/enhancer binding protein­α, ­ß and peroxisome proliferator­activated receptor­Î³, compared with the untreated control. Furthermore, A. okamotoanum significantly upregulated lipolysis related protein, hormone­sensitive lipase and the phosphorylation of adenosine monophosphate­activated protein kinase (AMPK). Therefore, these results indicate that A. okamotoanum suppressed adipogenesis and increased lipolysis and the activation of AMPK, suggesting a protective role in adipocyte differentiation.

Caterpillar Medicinal Mushroom, Cordyceps militaris (Ascomycetes), Protects Aß1-42-Induced Neurologic Damage in C6 Glial Cells.

Alzheimer's disease (AD) shows neurological symptoms common to cognitive disorders and memory loss. Several hypotheses have suggested that the accumulation of amyloid-beta peptide (Aß) and reduction of acetylcholine synthesis cause AD. Natural ingredients, such as Cordyceps militaris, have been widely used for AD treatment. Herein, we investigated the protective role of C. militaris against neural dysfunction. First, Aß1-42 peptide solution was incubated at 37°C for 3 days for aggregation. Next, C6 glial cells were treated with 25 µM of Aß1-42 solution, followed by the addition of C. militaris ethanol extract (0.5, 1, 1.25, and 2.5 µg/mL); the cell viability, reactive oxygen species (ROS) production, and protein expressions were then evaluated. Reduction of viability of, and ROS generation in, Aß1-42-treated cells were observed and compared with those in the control group. The expression levels of inducible nitric oxide synthase and cyclooxygenase-2, as well as those of phospho-p38 mitogen-activated protein kinase and phospho-c-Jun N-terminal kinase, were reduced in C. militaris-treated glial cells. Moreover, the expression of brain-derived neurotrophic factor in the C. militaris-treated cells was significantly higher than that in the control group. Thus, our findings indicate that C. militaris has the potential to protect Aß-induced neurological damage.

Acer okamotoanum and isoquercitrin improve cognitive function via attenuation of oxidative stress in high fat diet- and amyloid beta-induced mice.

Obesity induced by high-fat diet (HFD) and accumulation of amyloid beta (Aß) are known as a risk factor of Alzheimer's disease. We previously identified isoquercitrin (IQ) as an active compound of Acer okamotoanum. In the present study, we investigated the protective effects of the active ethyl acetate (EtOAc) fraction from A. okamotoanum and IQ on HFD and Aß25-35-induced cognitive impairment mice. C57BL/6J mice were fed with HFD for 10 weeks and then Aß25-35 was injected intracerebroventricularly (i.c.v.). The EtOAc fraction of A. okamotoanum and IQ were administered orally for 4 weeks at 100 and 10 mg kg-1 day-1, respectively. Learning and memory functions were evaluated using behavioral tests including T-maze, object recognition and Morris water maze tests. The HFD and Aß25-35 injection significantly impaired cognitive and memory function. However, administration of A. okamotoanum and IQ improved spatial cognitive ability and object recognition ability in T-maze and novel object recognition tests. In addition, A. okamotoanum and IQ-administered groups showed enhanced learning and memory function compared with HFD and Aß25-35-induced cognitive impairment mice in the Morris water maze test. Furthermore, administration of A. okamotoanum and IQ attenuated oxidative stress in the brain via inhibition of reactive oxygen species production, lipid peroxidation, and nitric oxide formation. Therefore, we suggest that A. okamotoanum and IQ improve HFD- and Aß25-35-induced cognitive impairment by inhibition of oxidative stress, and A. okamotoanum and IQ might be potential candidates for prevention and treatment of obesity- and Aß-induced cognitive impairment.

Safflower (Carthamus tinctorius L.) seed attenuates memory impairment induced by scopolamine in mice via regulation of cholinergic dysfunction and oxidative stress.

Cholinergic dysfunction and oxidative stress are the most common causes of Alzheimer's disease (AD). Safflower seed contains various anti-oxidant and cholinergic improvement compounds, such as serotonin and its derivatives. In the present study, we investigated the protective effects and mechanisms of a safflower seed extract on scopolamine-induced memory impairment in a mouse model. The safflower seed extract was orally administered at a dose of 100 mg kg-1 day-1, and then behavior tests (such as T-maze and novel object recognition tests) were conducted. Acetyl cholinesterase (AChE) activity, reactive oxygen species (ROS) production, and antioxidant enzymes in the brain were measured. In behavior tests, the novel route exploration and object recognition were improved by the administration of the safflower seed extract, which suggests that the safflower seed extract improves memory function in the scopolamine-treated mouse model. In addition, the safflower seed extract-administered group showed inhibition of the AChE activity and improved cholinergic dysfunction. Furthermore, the administration of the safflower seed extract resulted in lower ROS production and higher antioxidant enzyme levels as compared to the scopolamine-treated group, suggesting the protective role of the safflower seed extract against oxidative stress. The results of the present study suggest that the safflower seed extract improves scopolamine-induced memory deficits via the inhibition of cholinergic dysfunction and oxidative stress. Therefore, safflower seeds might become a promising agent for memory improvement in AD patients.

Protective Effects of Serotonin and its Derivatives, N-Feruloylserotonin and N-(p-Coumaroyl) Serotonin, Against Cisplatin-Induced Renal Damage in Mice.

This study examined whether serotonin and two of its derivatives, N -feruloylserotonin and N -( p -coumaroyl) serotonin, have a renoprotective effect in a mouse model of cisplatin-induced acute renal failure. Cisplatin (20 mg/kg body weight) was administered by intraperitoneal injection to male BALB/c mice that had received oral serotonin, N -feruloylserotonin or N -( p -coumaroyl) serotonin (7.5 mg/kg body weight per day) during the preceding 2 days. At 3 days after the cisplatin injection, serum and renal biochemical factors, oxidative stress, inflammation and apoptosis-related protein expression were evaluated, and histological examinations were performed. Cisplatin caused reduction in body weight and an increase in kidney weight; however, N -( p -coumaroyl) serotonin and N -feruloylserotonin attenuated these effects. Moreover, the serotonin derivatives significantly decreased serum urea nitrogen and creatinine levels. They also significantly reduced the level of reactive oxygen species and upregulated the expression of glutathione peroxidase in the kidney. Furthermore, the serotonin derivatives improved the abnormal expression of mitogen-activated protein kinases activation-dependent inflammation- and apoptosis-related protein and caused less renal damage. These results provide important evidence that N -( p -coumaroyl) serotonin and N -feruloylserotonin exert a pleiotropic effect on several parameters related to oxidative stress, inflammation and apoptosis. The derivatives also have a renoprotective effect in cisplatin-treated mice; however, this effect is higher with N -( p -coumaroyl) serotonin.

Efficacy of Sorafenib for the Treatment of Post-Transplant Hepatocellular Carcinoma Recurrence.

BACKGROUND: The role of sorafenib in patients with hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) has been rarely studied. The aim of this study was to evaluate the efficacy of sorafenib in post-LT era. METHODS: Consecutive patients with post-transplant HCC recurrence not eligible to resection or locoregional therapy were included. Patients receiving best supportive care (BSC) until 2007 were compared with those treated by sorafenib thereafter. RESULTS: Of a total of 65 patients, 20 patients received BSC and 45 received sorafenib. Clinical characteristics were similar between two groups except that sorafenib group received tacrolimus and mammalian target-of-rapamycin inhibitors more frequently than BSC group. Treatment with sorafenib conferred a survival advantage as compared with BSC for survival after recurrence (median, 14.2 vs. 6.8 months; P = 0.01). In multivariate analyses, high serum α-fetoprotein level, synchronous intrahepatic recurrence and distant metastasis at the time of recurrence, and BSC were independently associated with poorer survival after recurrence. Sorafenib treatment was associated with better survival after recurrence as compared with BSC (hazard ratio, 0.25; 95% confidence interval, 0.10-0.62; P = 0.002). In addition, sorafenib group showed tolerable toxicity in the post-transplant setting. CONCLUSION: Sorafenib may be beneficial in patients with post-transplant HCC recurrence.

Synergistic effect of ursodeoxycholic acid on the antitumor activity of sorafenib in hepatocellular carcinoma cells via modulation of STAT3 and ERK.

Sorafenib has been approved for the treatment of advanced stage hepatocellular carcinoma but has limited efficacy. Ursodeoxycholic acid exerts cytoprotective activities in hepatocytes and is believed to suppress tumorigenesis through cell cycle arrest and induction of apoptosis. The present study examined whether co­treatment with ursodeoxycholic acid has a synergistic effect on the antitumor activity of sorafenib in hepatocellular carcinoma cells. Notably, co­treatment with both agents more effectively inhibited cell proliferation than sorafenib or ursodeoxycholic acid alone. Furthermore, co­treatment inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and activated extracellular signal­regulated kinase (ERK), a mitogen­activated protein kinase, accompanied by excessive intracellular reactive oxygen species generation in hepatocellular carcinoma cells. Thus, chemotherapy with sorafenib and ursodeoxycholic combination may be efficacious in hepatocellular carcinoma by inhibiting cell proliferation and inducing apoptosis through reactive oxygen species­dependent activation of ERK and dephosphorylation of STAT3. The present findings may represent a promising therapeutic strategy for patients with advanced hepatocellular carcinoma.

Bioactive Compounds of Kimchi Inhibit Apoptosis by Attenuating Endoplasmic Reticulum Stress in the Brain of Amyloid ß-Injected Mice.

This study investigated the inhibitory effects of kimchi bioactive compounds against endoplasmic reticulum (ER) stress-induced apoptosis in amyloid beta (Aß)-injected mice. Mice received a single intracerebroventricular injection of Aß25-35, except for the normal group. Mice were subjected to oral administration of 10 mg of capsaicin, 50 mg of 3-(4'-hydroxyl-3',5'-dimethoxyphenyl)propionic acid (HDMPPA), 50 mg of quercetin, 50 mg of ascorbic acid, or 200 mg of kimchi methanol extract (KME) per kilogram of body weight for 2 weeks ( n = 7 per group). In the in vitro blood-brain barrier (BBB) permeability test, all bioactive compounds penetrated the BBB except ascorbic acid. The protein expression level of APP, BACE, and p-Tau elevated by Aß injection was decreased by kimchi bioactive compounds ( P < 0.05). Quercetin, HDMPPA, and KME decreased oxidative stress, as indicated by ROS and TBARS levels ( P < 0.05). The protein expression level of ER stress markers GRP78, p-PERK, p-eIF2α, XBP1, and CHOP and the proapoptotic molecules Bax, p-JNK, and cleaved caspases-3 and -9 decreased ( P < 0.05). In contrast, the protein expression level of antiapoptotic molecules Bcl2 and cIAP increased ( P < 0.05). These results were supported by histological analysis.

Neuroprotective Effect of Alpha-Linolenic Acid against Aß-Mediated Inflammatory Responses in C6 Glial Cell.

Therapeutic approaches for neurodegeneration, such as Alzheimer's disease (AD), have been widely studied. One of the critical hallmarks of AD is accumulation of amyloid beta (Aß). Aß induces neurotoxicity and releases inflammatory mediators or cytokines through activation of glial cell, and these pathological features are observed in AD patient's brain. The purpose of this study is to investigate the protective effect of alpha-linolenic acid (ALA) on Aß25-35-induced neurotoxicity in C6 glial cells. Exposure of C6 glial cells to 50 µM Aß25-35 caused cell death, overproduction of nitric oxide (NO), and pro-inflammatory cytokines release [interleukin (IL)-6 and tumor necrosis factor-α], while treatment of ALA increased cell viability and markedly attenuated Aß25-35-induced excessive production of NO and those inflammatory cytokines. Inhibitory effect of ALA on generation of NO and cytokines was mediated by down-regulation of inducible nitric oxide synthase and cyclooxygenase-2 protein and mRNA expressions. In addition, ALA treatment inhibited reactive oxygen species generation induced by Aß25-35 through the enhancement of the nuclear factor-erythroid 2-related factor-2 (Nrf-2) protein levels and subsequent induction of heme-oxygenase-1 (HO-1) expression in C6 glial cells dose- and time-dependently. Furthermore, the levels of neprilysin and insulin-degrading enzyme protein expressions, which contribute to degradation of Aß, were also increased by treatment of ALA compared to Aß25-35-treated control group. In conclusion, effects of ALA on Aß degradation were shown to be mediated through inhibition of inflammatory responses and activation of antioxidative system, Nrf-2/HO-1 signaling pathway, in C6 glial cells. Our findings suggest that ALA might have the potential for therapeutics of AD.