Protein arginine methyltransferase-1 stimulates dopaminergic neuronal cell death in a Parkinson's disease model.

Recent studies have revealed that protein arginine methyltransferases (PRMTs) are responsible for diverse neurodegenerative diseases. However, their pathophysiological role in dopaminergic neuronal death in Parkinson's disease (PD) has not been evaluated. In this study, we demonstrated that 1-Methyl-4-phenylpyridinium iodide (MPP+), rotenone and paraquat, which cause dopaminergic neuronal cell death, increased PRMT1 expression in dopaminergic cell line. Dopaminergic neuronal cell death was increased by PRMT1 overexpression. MPP+-induced cell death was attenuated by PRMT1 knockdown. Poly (ADP-ribose) polymerase-1 (PARP1) expression and activity, poly-ADP-ribosylation (PARylation), were elevated by MPP+. Moreover, we found that PRMT1 positively regulates nuclear translocation of apoptosis-inducing factor (AIF). Elevated PRMT1 expression was observed in the substantia nigra pars compacta of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-injected mice. Furthermore, MPTP-induced dopaminergic neuronal death was reduced in PRMT1 haploinsufficient (prmt1+/-) mice. These data suggest that PRMT1 is implicated in PARP1/AIF-mediated dopaminergic neuronal cell death, which might be involved in the pathology of PD. Therefore, our results propose PRMT1 as a new target to develop a potential treatment of PD.

Subchronic toxicity evaluation of ethanol extract of Cassia tora L. seeds in rats.

Cassia tora Linn. is an annual or perennial plant of the Fabaceae/Leguminosae family. It is used in traditional medicine for various biological activities including anti-constipation, anti-inflammatory, visual acuity, and hepato-protective activities. The present study was carried out to investigate the potential toxicity of C. tora L. seed ethanol extract (CTSEE) following a 13-week repeated oral administration to Sprague-Dawley rats. CTSEE was administered orally to male and female rats for 13 weeks at 0 (control), 500, 1000, and 2000 mg/kg/day (n = 10, for male and female rats for each dose). Additional recovery groups from the control group and high dose group were observed for a 4-week recovery period. At the end of the treatment and recovery periods, animals were sacrificed, and their organs were weighed and blood samples collected. There were no treatment-related adverse effects in clinical signs, body weight, food consumption, estrous cycle, sperm parameters, urinalysis, hematology, serum biochemistry, necropsy findings, organ weight, and histopathology at any doses tested. Under the present experimental conditions, the no-observed-adverse-effect level of the CTSEE was >2000 mg/kg/day in both genders, and no target organs were identified.

Effect of Saururus chinensis leaves extract on type II collagen-induced arthritis mouse model.

BACKGROUND: Saururus chinensis leaves have been used as traditional medicine in Korea for pain, intoxication, edema, and furuncle. According to previous reports, these leaves exert renoprotective, neuroprotective, and antioxidant effects by attenuating inflammatory responses. However, the beneficial effect of Saururus chinensis leaves on arthritis has not been elucidated. Thus, we evaluated the water extract of Saururus chinensis leaves (SHW) using type II collagen-induced arthritis (CIA) mice models. METHODS: Quantitative analysis of major components from SHW was performed by HPLC. Arthritis was induced by injection of type II collagen. Each group was orally administered SHW (100 mg/kg and 500 mg/kg). Methotrexate (MTX) was used as a positive control. Serum levels of interleukin-6, TNF-alpha, and type II collagen IgG in the animal models were measured using ELISA. Histological features were observed by H&E staining. RESULTS: Quantitative analysis of SHW showed the contents as 56.4 ± 0.52 mg/g of miquelianin, 7.75 ± 0.08 mg/g of quercetin 3-O-(2"-O-ß -glucopyranosyl)-α-rhamnopyranoside, and 3.17 ± 0.02 mg/g of quercitrin. Treatment with 500 mg/kg SHW decreased the serum level of Interleukin-6 (IL-6), TNF-alpha, and collagen IgG in the CIA model. Moreover, SHW treatment diminished the swelling of hind limbs and monocyte infiltration in blood vessels in CIA animal models. The results indicate that SHW could decrease CIA-induced arthritis in vivo. CONCLUSIONS: The results indicate that SHW could be used to improving arthritis by reducing inflammatory factors (IL-6 and TNF-alpha). However, further experiments are required to determine how SHW influences signal transduction in animal models.

Asymmetric dimethylarginine (ADMA) treatment induces apoptosis in cultured rat mesangial cells via endoplasmic reticulum stress activation.

Asymmetric dimethylarginine (ADMA), a high risk factor for endothelial dysfunction and cardiovascular disease (CVD), has been reported to promote cellular dysfunction via endoplasmic reticulum (ER) stress activation in various cells. Additionally, increased serum ADMA levels have been observed in incipient kidney diseases. Previously, we reported that activated ER stress is associated with mesangial cell apoptosis, observed mainly in overt nephropathy or chronic kidney disease (CKD). However, the effect of ADMA on mesangial cell apoptosis is unknown. Thus, we investigated the effects of ADMA on mesangial cell apoptosis and ER stress signaling. ADMA treatment increased caspase-3 activity and activated three branches of ER stress signaling (PERK, IRE1, and ATF6) that induce mesangial cell apoptosis. Pharmacological inhibitors of ER stress (inhibitors of PERK, IRE1, and S1P) attenuated ADMA-induced cleavage of caspase-3 and induced a decrease in the mitochondrial membrane potential. Furthermore, these inhibitors diminished the number of apoptotic cells induced by ADMA treatment. Taken together, our results indicated that ADMA treatment induces mesangial cell apoptosis via ER stress signaling. These results suggest that ADMA-induced mesangial cell apoptosis could contribute to the progression of overt nephropathy and CKD.

Effects of Eurya japonica extracts on human corneal epithelial cells and experimental dry eye.

Eurya japonica (EJ) leaves have been indicated to exert anti-oxidative and anti-inflammatory effects. Dry eye disease (DED) is a chronic inflammatory disease and oxidative stress is closely associated with DED. The aim of the present study was to analyze the therapeutic efficacy of EJ in DED using human corneal epithelial (HCE) cells and a mouse model of experimental dry eye (EDE). EJ extracts (0.001, 0.01 and 0.1%) were used to treat HCE cells. Cell viability and mitochondrial function were detected using a EZ-Cytox cell viability assay kit and mitochondrial membrane potential assays. Dichlorofluorescein diacetate (DCF-DA) assay was used to measure cellular reactive oxygen species (ROS) levels. Subsequently, eye drops consisting of BSS or 0.001%, 0.01 and 0.1% EJ extracts were applied for treatment of EDE. At 7 days, conjunctival ROS production was measured using a DCF-DA assay. Tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, 10 kDa interferon gamma-induced protein 10 (IP-10) and monokine induced by interferon-γ (MIG) levels in the conjunctiva were analyzed using a multiplex immunobead assay. Tear film and ocular surface parameters were measured. Treatment with EJ extracts in HCE cells effectively improved cell viability, ROS levels and mitochondrial function. Mice treated with 0.01 and 0.1% EJ extracts indicated a significant decrease in ROS, TNF-α, IL-1ß, IP-10 and MIG levels compared with the EDE or BSS groups. Furthermore, a significant improvement in all clinical parameters was observed in the 0.01 and 0.1% EJ extract groups. EJ extracts could decrease cytotoxicity and ROS production in HCE cells. Additionally, topical EJ extracts reduced oxidative damage and inflammation and improved clinical signs of EDE, suggesting that EJ extracts may be used as an adjunctive therapy for DED.

A 13-week repeated oral dose toxicity evaluation and a 4-week recovery evaluation of the Sam So Eum (SSE) in male and female rats.

ETHNOPHAMACOLOGICAL RELEVANCE: Sam So Eum (SSE), used in traditional Korean medicine, has been prescribed for the treatment of various ailments including emesis, and fever for centuries. SSE is known by several different names (Shen Su Yin in traditional Chinese medicine; Jin So In traditional Japanese Kampo medicine). It is a mixture of medicinal plants including Panax ginseng C. A. Mey., Perilla frutescens (L.) Britton, and Peucedanum praeruptorum Dunn. Studies have revealed that SSE has many pharmacological effects including anti-inflammatory, anti-cancer, and anti-allergic properties, but its toxic effects have not been evaluated in vivo. Recently, the use of traditional medicinal herbs to treat various diseases has increased, owing to increased number of studies supporting their efficacy. However, safety evaluations for toxicity and other adverse effects have not been extensive. It is commonly considered that natural products extracted from traditional medicinal herbs are safer than synthetic drugs, but this lacks a scientific basis. Thus, in this study, we evaluated the toxicity of SSE in male and female rats. AIM OF THE STUDY: To evaluated the safety of SSE in male and female rats. MATERIALS AND METHODS: SSE was administered orally for 13 weeks at 1000, 2000, and 4000 mg kg-1·day-1, and then the rats were maintained for 4 weeks without SSE administration (recovery evaluation). RESULTS: We observed the animals for changes in clinical signs, including hematological parameters, and food consumption; serum chemistry profiling and urinalysis were also carried out. Creatinine levels in the serum were significantly increased following oral administration of SSE at 2000 and 4000 mg kg-1·day-1 in male and female rats, but returned to the normal levels during the recovery period. In addition, SSE administration does not cause kidney and liver toxicity. Thus, we determined that the no-observed-adverse-effect level of SSE is 4000 mg kg-1·day-1. The no-observed-effect level of SSE was determined to be 1000 mg kg-1·day-1, because serum creatinine was increased by oral administration of SSE at 2000 and 4000 mg kg-1·day-1 in male and female rats. CONCLUSIONS: SSE administration does not cause toxicity at 4000 mg kg-1·day-1 in male and female rats.

Water Extract of Acori Graminei Rhizoma Attenuates Features of Rheumatoid Arthritis in DBA/1 Mice.

The dry rhizome of Acorus gramineus Solander, known as Acori Graminei Rhizoma, is used to treat dementia, stroke, eczema, and indigestion in traditional Chinese medicine, traditional Korean medicine, and traditional Japanese Kampo medicine. Previous studies have reported that Acori Graminei Rhizoma extract ameliorated cognitive impairment in Aß1-42 injected mice. However, the effect of Acori Graminei Rhizoma on type II collagen induced arthritis (CIA) has not been elucidated. Thus, we evaluated the water extract of Acori Graminei Rhizoma (WAG) in CIA mice models. Male DBA/1 mice were separated into five groups (NOR; n=10, CON; n=10, CIA + methotrexate (MTX); n=10, CIA + 100 mg/kg WAG; n=10, CIA + 500 mg/kg WAG; n=10). CIA was induced by injecting the mice with bovine type II collagen, after which the mice were treated with WAG and/or MTX. Hematological parameters and liver and kidney serum toxicity markers were analyzed. Further, serum levels of interleukin (IL)-6, TNF-α, and type II collagen IgG were analyzed via enzyme-linked immunosorbent assay (ELISA). Treatment with 500 mg/kg WAG decreased serum levels of IL-6, TNF-α, and collagen IgG in a CIA model. Moreover, WAG treatment decreased CIA-induced swelling of mouse hind legs, infiltration of inflammatory cells into the synovial membrane, and blood neutrophil levels. WAG administration did not influence hematological parameters or kidneys and liver toxicity markers. WAG may be used to treat arthritis by reducing the inflammation indicators. However, further experiments are required to determine how WAG affects inflammation mechanisms in vitro and in vivo.

Beneficial Effects of Cynaroside on Cisplatin-Induced Kidney Injury In Vitro and In Vivo.

Anti-cancer drugs such as cisplatin and doxorubicin are effectively used more than radiotherapy. Cisplatin is a chemotherapeutic drug, used for treatment of various forms of cancer. However, it has side effects such as ototoxicity and nephrotoxicity. Cisplatin-induced nephrotoxicity increases tubular damage and renal dysfunction. Consequently, we investigated the beneficial effect of cynaroside on cisplatin-induced kidney injury using HK-2 cell (human proximal tubule cell line) and an animal model. Results indicated that 10 µM cynaroside diminished cisplatin-induced apoptosis, mitochondrial dysfunction and caspase-3 activation, cisplatin-induced upregulation of caspase-3/MST-1 pathway decreased by treatment of cynaroside in HK-2 cells. To confirm the effect of cynaroside on cisplatin-induced kidney injury in vivo, we used cisplatin exposure animal model (20 mg/kg, balb/c mice, i.p., once a day for 3 days). Renal dysfunction, tubular damage and neutrophilia induced by cisplatin injection were decreased by cynaroside (10 mg/kg, i.p., once a day for 3 days). Results indicated that cynaroside decreased cisplatin-induced kidney injury in vitro and in vivo, and it could be used for improving cisplatin-induced side effects. However, further experiments are required regarding toxicity by high dose cynaroside and caspase-3/MST-1-linked signal transduction in the animal model.