Isoliquiritigenin ameliorates advanced glycation end-products toxicity on renal proximal tubular epithelial cells.

Diabetic nephropathy is a serious chronic complication affecting at least 25% of diabetic patients. Hyperglycemia associated advanced glycation end-products (AGEs) increase tubular epithelial-myofibroblast transdifferentiation (TEMT) and extracellular matrix synthesis and thereby causes renal fibrosis. The chalcone isoliquiritigenin, found in many herbs of Glycyrrhiza family, is known for potential health-promoting effects. However, their effects on AGE-associated renal proximal tubular fibrosis are not known yet. In this study, the effect of isoliquiritigenin on AGE-induced renal proximal tubular fibrosis was determined in cultured HK-2 cell line. The results show that 200 µg/mL of AGE-induced TEMT and the formed myofibroblasts synthesized collagen to increase extracellular matrix formation thereby lead to renal tubular fibrosis. However, treatment with 200 nM of isoliquiritigenin considerably inhibited the TEMT and suppressed the TGFß/STAT3 mechanism to inhibit collagen secretion. Therefore, isoliquiritigenin effectively suppressed AGE-induced renal tubular fibrosis.

Poria cocos (Fuling) targets TGFß/Smad7 associated collagen accumulation and enhances Nrf2-antioxidant mechanism to exert anti-skin aging effects in human dermal fibroblasts.

Oxidative stress is a major cause of aging related skin injuries. Hydrogen peroxide related ROS accumulation triggers increase in matrix metalloproteinases and elevated collagen degradation, which is a characteristic of skin aging. In this study, we investigated the protective effect of Poria cocos, used widely in the treatment of inflammatory diseases, against H2 O2 induced oxidative stress. The aqueous extract of dried P. cocos was obtained by heating 10 g in 500 ml of distilled water. The mixture was evaporated up to 400 ml and the remaining 100 ml was filtered through muslin cloth repeatedly to obtain a clear aqueous extract of the P. cocos. Hs68 human dermal fibroblast cells were challenged with 100 µM of H2 O2 for 24 h. Following H2 O2 challenge, the cells were treated with increasing concentration of P. cocos extract (100-400 µg/ml) for 24 h. P. cocos extract hindered the H2 O2 induced cell death significantly that was correlated with reduction in ROS accumulation. Western blot analysis show that P. cocos extract suppressed the expression of metallomatrix proteinases, inflammatory markers and skin aging markers, but increased TGF-ß1 levels and antioxidant related proteins. These data suggest that P. cocos is effective in attenuating oxidative stress associated skin aging effects and may be a potential agent in cosmetics products.

Glycyrrhiza uralensis root extract ameliorates high glucose-induced renal proximal tubular fibrosis by attenuating tubular epithelial-myofibroblast transdifferentiation by targeting TGF-ß1/Smad/Stat3 pathway.

Growing evidences indicate that high glucose toxicity-associated fibrotic effects play a pivotal role in diabetic nephropathy (DN). Tubular epithelial-myofibroblast transdifferentiation is a major hallmark of renal fibrosis event under diabetic stress. Roots of Glycyrrhiza uralensis (Radix glycyrrhizae) used as a sweetener and traditional Chinese medicine possess high potential for renal protection. In this study, a cell model for high glucose (HG) injury with HK-2 renal proximal tubular epithelial cell line and a type-II-diabetes model with Apoeem1/Narl /Narl mice was established and the beneficial effects of aqueous R. glycyrrhizae extract (RGE) was investigated. RGE-induced regulation on the high glucose-induced excessive production of TGF-ß1 and the Smad/Stat3 mechanisms of renal fibrosis were determined. HK-2 cells were challenged with 45 mM of high glucose for 48 hr. Following high glucose challenge, the cells were treated with 0.5, 1, and 1.5 mg/ml concentrations of RGE. The effect of RGE on DN was determined using high fructose diet-induced type-II-diabetes in Apoeem1/Narl /Narl mice models. Our results showed that RGE suppressed the expression of HG-induced TGFß signaling and associated fibrosis mechanism better than the pharmacological drug acarbose. These data suggest that RGE as a potential herbal supplement in attenuating fibrosis-associated diabetic nephropathy and a potential agent in diabetes treatments.

IGF IIRα-triggered pathological manifestations in the heart aggravate renal inflammation in STZ-induced type-I diabetes rats.

Pathological manifestations in either heart or kidney impact the function of the other and form the basis for the development of cardiorenal syndrome. However, the mechanism or factors involved in such scenario are not completely elucidated. In our study, to find the correlation between late fetal gene expression in diabetic hearts and their influence on diabetic nephropathy, we created a rat model with cardiac specific overexpression of IGF-IIRα, which is an alternative splicing variant of IGFIIR, expressed in pathological hearts. In this study, transgenic rats over expressing cardiac specific IGF-IIRα and non-transgenic animal models established in SD rats were administered with single dose of streptozotocin (STZ, 55 mg/Kg) to induce Type I diabetes. The correlation between IGF-IIRα and kidney damages were further determined based on their intensity of damage in the kidneys. The results show that cardiac specific overexpression of IGF-IIRα elevates the diabetes associated inflammation and morphological changes in the kidneys. The diabetic transgenic rats showed advancement in the pathological features such a renal tubular damage, collagen accumulation and enhancement in STAT3 associated mechanism of renal fibrosis. The results therefore show that that IGF-IIRα expression in the heart during pathological condition may worsen symptoms of diabetic nephropathy in rats.

Lipolysis stimulating peptides of potato protein hydrolysate effectively suppresses high-fat-diet-induced hepatocyte apoptosis and fibrosis in aging rats.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common outcomes of obesity and is characterized by the accumulation of triglycerides, increased tissue apoptosis, and fibrosis. NAFLD is more common among elderly than in younger age groups, and it causes serious hepatic complications. OBJECTIVE: In this study, alcalase treatment derived potato protein hydrolysate (APPH) with lipolysis-stimulating property has been evaluated for its efficiency to provide hepato-protection in a high-fat-diet (HFD)-fed aging rats. DESIGN: Twenty-four-month-old SD rats were randomly divided into six groups (n=8): aged rats fed with standard chow, HFD-induced aged obese rats, HFD with low-dose (15 mg/kg/day) APPH treatment, HFD with moderate (45 mg/kg/day) APPH treatment, HFD with high (75 mg/kg/day) APPH treatment, and HFD with probucol. RESULTS: APPH was found to reduce the NAFLD-related effects in rat livers induced by HFD and all of the HFD-fed rats exhibited heavier body weight than those with control chow diet. However, the HFD-induced hepatic fat accumulation was effectively attenuated in rats administered with low (15 mg/kg/day), moderate (45 mg/kg/day), and high (75 mg/kg/day) doses of APPH. APPH oral administration also suppressed the hepatic apoptosis- and fibrosis-related proteins induced by HFD. CONCLUSIONS: Our results thus indicate that APPH potentially attenuates hepatic lipid accumulation and anti-apoptosis and fibrosis effects in HFD-induced rats. APPH may have therapeutic potential in the amelioration of NAFLD liver damage.

Early Fluid Resuscitation by Lactated Ringer's Solution Alleviate the Cardiac Apoptosis in Rats with Trauma-Hemorrhagic Shock.

Cardiac trauma has been recognized as a complication associated with blunt chest trauma involving coronary artery injury, myocardium contusion and myocardial rupture. Secondary cardiac injuries after trauma supposed to be a critical factor in trauma patients, but the mechanism is not fully explored. Overproduction of TNF-alpha had been reported in multiple trauma animals, this induces oxidative stress resulting in cardiac apoptosis. Apoptosis gradually increases after trauma and reaches to a maximum level in 12 h time. TNF-alpha increases the expression of NFkB, and induces the expression of caspase-3 and resulted in cell apoptosis. The effect can be attenuated by non-selective caspase inhibitor and IL10. Fas induced cardiac apoptosis and hypertrophy in ischemic heart disease. In this study, we demonstrated a trauma-hemorrhagic shock (THS) model in rats and resuscitated rats by lactated Ringer's (L/R) solution after shock in different hours (0 hour, 4 hours, 8 hours). NFkB gradually increased after the first 8 hours of shock, and can be reduced by fluid resuscitation. NFkB is known as a downstream pathway of Fas related apoptosis, we found Fas ligand, caspase-8 levels elevate after shock, and can be reduced by resuscitation. In addition, resuscitation can activate insulin-like growth factor (IGF-1)/Akt pathway, at the same time. It can block mitochondrial damage by decrease the effect of tBid. In conclusion, THS can induce secondary cardiac injury. Fas showed to be an important element in caspase cascade induced myocardium apoptosis. By L/R fluid resuscitation, the suppression of caspase cascade and activation of IGF-I/Akt pathway showed antiapoptotic effects in traumatic heart of rats.

Correction: Early Fluid Resuscitation by Lactated Ringer's Solution Alleviate the Cardiac Apoptosis in Rats with Trauma-Hemorrhagic Shock.

[This corrects the article DOI: 10.1371/journal.pone.0165406.].

Protocatechuic Acid from Alpinia oxyphylla Induces Schwann Cell Migration via ERK1/2, JNK and p38 Activation.

Alpinia oxyphylla MIQ (Alpinate Oxyphyllae Fructus, AOF) is an important traditional Chinese medicinal herb whose fruits is widely used to prepare tonics and is used as an aphrodisiac, anti salivary, anti diuretic and nerve-protective agent. Protocatechuic acid (PCA), a simple phenolic compound was isolated from the kernels of AOF. This study investigated the role of PCA in promoting neural regeneration and the underlying molecular mechanisms. Nerve regeneration is a complex physiological response that takes place after injury. Schwann cells play a crucial role in the endogenous repair of peripheral nerves due to their ability to proliferate and migrate. The role of PCA in Schwann cell migration was determined by assessing the induced migration potential of RSC96 Schwann cells. PCA induced changes in the expression of proteins of three MAPK pathways, as determined using Western blot analysis. In order to determine the roles of MAPK (ERK1/2, JNK, and p38) pathways in PCA-induced matrix-degrading proteolytic enzyme (PAs and MMP2/9) production, the expression of several MAPK-associated proteins was analyzed after siRNA-mediated inhibition assays. Treatment with PCA-induced ERK1/2, JNK, and p38 phosphorylation that activated the downstream expression of PAs and MMPs. PCA-stimulated ERK1/2, JNK and p38 phosphorylation was attenuated by individual pretreatment with siRNAs or MAPK inhibitors (U0126, SP600125, and SB203580), resulting in the inhibition of migration and the uPA-related signal pathway. Taken together, our data suggest that PCA extract regulate the MAPK (ERK1/2, JNK, and p38)/PA (uPA, tPA)/MMP (MMP2, MMP9) mediated regeneration and migration signaling pathways in Schwann cells. Therefore, PCA plays a major role in Schwann cell migration and the regeneration of damaged peripheral nerve.