Platycodi radix aqueous extract salvages doxorubicin-induced senescence by mitochondrial reactive oxygen species reduction in umbilical cord matrix stem cells.

Platycodi radix is a widely used herbal medicine that contains numerous phytochemicals beneficial to health. The health and biological benefits of P. radix have been found across various diseases. The utilization of umbilical cord stromal stem cells, derived from Wharton's jelly of the human umbilical cord, has emerged as a promising approach for treating degenerative diseases. Nevertheless, growing evidence indicates that the function of stem cells declines with age, thereby limiting their regenerative capacity. The primary objective in this study is to investigate the beneficial effects of P. radix in senescent stem cells. We conducted experiments to showcase that diminished levels of Lamin B1 and Sox-2, along with an elevation in p21, which serve as indicative markers for the senescent stem cells. Our findings revealed the loss of Lamin B1 and Sox-2, coupled with an increase in p21, in umbilical cord stromal stem cells subjected to a low-dose (0.1 µM) doxorubicin (Dox) stimulation. However, P. radix restored the Dox-damage in the umbilical cord stromal stem cells. P. radix reversed the senescent conditions when the umbilical cord stromal stem cells exposed to Dox-induced reactive oxygen species (ROS) and mitochondrial membrane potential are significantly changed. In Dox-challenged aged umbilical cord stromal stem cells, P. radix reduced senescence, increased longevity, prevented mitochondrial dysfunction and ROS and protected against senescence-associated apoptosis. This study suggests that P. radix might be as a therapeutic and rescue agent for the aging effect in stem cells. Inhibition of cell death, mitochondrial dysfunction and aging-associated ROS with P. radix provides additional insights into the underlying molecular mechanisms.

Diosgenin Attenuates Myocardial Cell Apoptosis Triggered by Oxidative Stress through Estrogen Receptor to Activate the PI3K/Akt and ERK Axes.

Cardiovascular diseases in post-menopausal women are on a rise. Oxidative stress is the main contributing factor to the etiology and pathogenesis of cardiovascular diseases. Diosgenin, a member of steroidal sapogenin, is structurally similar to estrogen and has been shown to have antioxidant effects. Therefore, we aimed to investigate the effects of diosgenin in preventing oxidation-induced cardiomyocyte apoptosis and assessed its potential as a substitute substance for estrogen in post-menopausal women. Apoptotic pathways and mitochondrial membrane potential were measured in H9c2 cardiomyoblast cells and neonatal cardiomyocytes treated with diosgenin for 1[Formula: see text]h prior to hydrogen peroxide (H2O2) stimulation. H2O2-stimulated H9c2 cardiomyoblast cells displayed cytotoxicity and apoptosis via the activation of both Fas-dependent and mitochondria-dependent pathways. Additionally, it led to the instability of the mitochondrial membrane potential. However, the H2O2-induced H9c2 cell apoptosis was rescued by diosgenin through IGF1 survival pathway activation. This led to the recovery of the mitochondrial membrane potential by suppressing the Fas-dependent and mitochondria-dependent apoptosis. Diosgenin also inhibited H2O2-induced cytotoxicity and apoptosis through the estrogen receptor interaction with PI3K/Akt and extracellular regulated protein kinases 1/2 activation in myocardial cells. In this study, we confirmed that diosgenin attenuated H2O2-induced cytotoxicity and apoptosis through estrogen receptors-activated phosphorylation of PI3K/Akt and ERK signaling pathways in myocardial cells via estrogen receptor interaction. All results suggest that H2O2-induced myocardial damage is reduced by diosgenin due to its interaction with estrogen receptors to decrease the damage. Herein, we conclude that diosgenin might be a potential substitute substance for estrogen in post-menopausal women to prevent heart diseases.

Fisetin attenuates doxorubicin-induced cardiotoxicity by inhibiting the insulin-like growth factor II receptor apoptotic pathway through estrogen receptor-α/-ß activation.

Doxorubicin (DOX), an effective chemotherapeutic drug, has been used to treat various cancers; however, its cardiotoxic side effects restrict its therapeutic efficacy. Fisetin, a flavonoid phytoestrogen derived from a range of fruits and vegetables, has been reported to exert cardioprotective effects against DOX-induced cardiotoxicity; however, the underlying mechanisms remain unclear. This study investigated fisetin's cardioprotective role and mechanism against DOX-induced cardiotoxicity in H9c2 cardiomyoblasts and ovariectomized (OVX) rat models. MTT assay revealed that fisetin treatment noticeably rescued DOX-induced cell death in a dose-dependent manner. Moreover, western blotting and TUNEL-DAPI staining showed that fisetin significantly attenuated DOX-induced cardiotoxicity in vitro and in vivo by inhibiting the insulin-like growth factor II receptor (IGF-IIR) apoptotic pathway through estrogen receptor (ER)-α/-ß activation. The echocardiography, biochemical assay, and H&E staining results demonstrated that fisetin reduced DOX-induced cardiotoxicity by alleviating cardiac dysfunction, myocardial injury, oxidative stress, and histopathological damage. These findings imply that fisetin has a significant therapeutic potential against DOX-induced cardiotoxicity.

Small Molecule Compound Nerolidol attenuates Hypertension induced hypertrophy in spontaneously hypertensive rats through modulation of Mel-18-IGF-IIR signalling.

BACKGROUND: Cardiovascular diseases are caused by multitudes of stress factors like hypertension and their outcomes are associated with high mortality and morbidity worldwide. Nerolidol, a naturally occurring sesquiterpene found in several plant species, embodies various pharmacological benefits against numerous health disorders. However, their effects on hypertension induced cardiac complications are not completely understood. PURPOSE: The present study is to elucidate the efficacy of nerolidol against hypertension related cardiac hypertrophy in spontaneously hypertensive rats (SHRs). STUDY DESIGN: For preliminary in vitro studies, H9c2 cardiomyoblasts cells were challenged with 200 nM Angiotensin-II (AngII) for 12 h and were then treated with nerolidol for 24 h. The hypertrophic effect in H9c2 cells were analyzed by actin staining and the modulations in hypertrophic protein markers and mediators were determined by Western blotting analysis. For in vivo experiments, sixteen week-old male Wistar Kyoto (WKY) and SHRs were segregated into five groups (n = 9): Control WKY, hypertensive SHRs, SHRs with low dose (75 mg/kg b.w/day) nerolidol, SHRs with high dose (150 mg/kg b.w/day) nerolidol and SHR rats treated with an anti-hypertensive drug captopril (50 mg/kg b.w/day). Nerolidol treatment was given orally for 8 weeks and were analysed through Echocardiography. After euthanasia, hematoxylin and eosin staining, Immunohistochemical analysis and Western blotting was performed on left ventricle tissue. RESULTS: Western blotting analysis revealed that nerolidol significantly attenuates AngII induced expression of hypertrophic markers ANP and BNP in H9c2 cardiomyoblasts. In addition, actin staining further ascertained the potential of nerolidol to ameliorate AngII induced cardiac hypertrophy. Moreover, nerolidol administration suppressed the hypertrophic signalling mediators like calcineurin, GATA4, Mel-18, HSF-2 and IGFIIR in a dose-dependent fashion. In silico studies also ascertained the role of Mel-18 in the ameliorative effects of nerolidol. Further, these intriguing in vitro results were further confirmed in in vivo SHR model. Oral neraolidol in SHRs efficiently reduced blood pressure and ameliorated hypertension induced cardiac hypertrophic effects by effectively reducing the levels of proteins involved in cardiac MeL-18-HSF2-IGF-IIR signalling. CONCLUSION: Collectively, the data reveals that the cardioprotective effect of nerolidol against hypertension induced hypertrophy involves reduction in blood pressure and regulation of the cardiac Mel-18-IGFIIR signalling cascade.

Oral administration of green tea Epigallocatechin-3-gallate reduces oxidative stress and enhances restoration of cardiac function in diabetic rats receiving autologous transplantation of adipose-derived stem cells.

BACKGROUND: Cardio-dysfunction is one of the complications in patients with diabetes mellitus (DM). This paper aimed to investigate if oral administration of green tea Epigallocatechin-3-gallate (EGCG, E) and transplantation of adipose-derived stem cells (ADSC) show cross effects on the treatment of cardiomyopathy in rats with type 1 DM. MATERIALS AND METHODS: Wistar male rats were divided into four groups (each group contained 8 animals) including sham, DM (diabetic group), DM + ADSC (DM group with ADSC treatment) and DM + ADSC + E (DM + ADSC group with oral administration of EGCG). RESULTS: Pathological parameters including hypertrophy, inflammation, and fibrosis were activated in DM group. By contrast, all parameters were significantly improved in treatment group (DM + ADSC group). In addition, improvement of pathological parameters in DM + ADSC + E was significantly better than DM + ADSC. CONCLUSION: We found that EGCG can increase expression of survival marker in ADSC under high glucose environment and reduce serum oxidative stress in DM rats.

Role of potato protein hydrolysate and exercise in preventing high-fat diet-induced hepatocyte apoptosis in senescence-accelerated mouse.

Nonalcoholic fatty liver disease (NAFLD) is considered to be a serious clinical complication, which could cause significant liver dysfunction including fibrosis, cirrhosis, and cancer. Obesity could lead to NAFLD and contributes to liver disorder and related complicated liver diseases. Effect of exercise combined with alcalase treatment derived potato protein hydrolysate (APPH) on high-fat diet (HFD)-induced hepatic injury was investigated in senescence accelerated mouse-prone 8 (SAMP8) mice in the present study. Mice were divided into six groups (n = 6): Group I-Control, Group II-HFD, Group III-Exercise, Group IV-HFD + APPH, Group V-HFD + Exercise, and Group VI-HFD + Exercise + APPH. Combined APPH treatment and exercise offer better cytoprotection in HFD-induced histological changes than APPH treatment and exercise alone. Further, APPH and exercise activate the cell survival proteins PI3K/Akt and prevent FasL/FADD-mediated apoptosis in HFD fed SAMP8 mouse. APPH with swimming exercise effectively modulate HFD-induced liver damage and apoptosis in aged mice through activation of PI3K/Akt protein. PRACTICAL APPLICATIONS: Exercise training is proven to reduce the health problems associated with aging and obesity, however, intensity and duration of the exercise differs between individuals. We used integrated pharmacological and nonpharmacological approach as a therapeutic strategy for preventing HFD-induced hepatic injury in aged subjects.

Carthamus tinctorius L. extract activates insulin-like growth factor-I receptor signaling to inhibit FAS-death receptor pathway and suppress lipopolysaccharides-induced H9c2 cardiomyoblast cell apoptosis.

Carthamus tinctorius L. (Compositae) is used in Chinese medicine to treat heart disease and inflammation. In our previous study, we found that C. tinctorius L. inhibited lipopolysaccharides (LPS)-induced tumor necrosis factor-alpha (TNF-α) activation, JNK expression, and apoptosis in H9c2 cardiomyoblast cells. The present study was performed to investigate the protective effect of C. tinctorius extract (CTF) on LPS-challenged H9c2 myocardioblast cell and to explore the possible underlying mechanism. Cell viability assay showed that LPS treatment decreased the cell viability of H9c2 cell, whereas CTF treatment reversed LPS cytotoxicity in a dose-dependent manner, especially in the LPS + CTF 25 (µg/mL) group. LPS treatment-induced apoptosis was determined by transferase-mediated dUTP nick end labeling assay, and by Western blot. LPS-induced apoptotic bodies were decreased following CTF treatment. Expression of TNF-α, FAS-L, FAS, FADD, caspase-8, BID, and t-BID was significantly increased in LPS-treated H9c2 cells. In contrast, it was significantly suppressed by the administration of CTF extract. In addition, CTF treatment activates antiapoptotic proteins, Bcl-2 and p-Bad, and downregulates Bax, cytochrome-c, caspase-9, caspase-3, and apoptosis-inducing factor expression. Furthermore, CTF exerted cytoprotective effects by activating insulin-like growth factor-I (IGF-I) signaling pathway leading to downregulation of the apoptotic proteins involved in FAS death receptor pathway. In addition, AG1024 and IGF-I receptor (IGF-IR) inhibitor and siRNA silencing reverses the effect of CTF implying that CTF functions through the IGF-IR pathway to inhibit LPS-induced H9c2 apoptosis. These results suggest that treatment with CTF extract prevented the LPS-induced apoptotic response through IGF-I pathway.

Alpinia oxyphylla Miq extract ameliorates cardiac fibrosis associated with D-galactose induced aging in rats.

Cardiac fibrosis is a common pathophysiological process observed during chronic and stress-induced acceleration of cardiac aging. Fibrosis is a necessary process during wound healing and tissue repair. However, its deposition in organs would proceed to scarring and organ damage. Here Alpinate Oxyphyllae Fructus (AOF), a Chinese medicine extract was used to protect aging heart from collagen accumulation. About 8 weeks old, male SD rats were randomly divided into (i) Control, (ii) D-galactose induced aging (IA), (iii) IA + AOF 50 (AOF low, AL), (iv) IA + AOF 100 (AOF medium, AM), (v) IA + AOF 150 (AOF high, AH) mg/kg/day, AOF was administered orally. After 8 weeks rats were sacrificed and hearts were collected. Results showed collagen deposition and up-regulation of matrix metalloproteinases-MMP-2 and -9 in D-galactose-induced aging rats. Furthermore, western blotting and immunostaining were also confirmed the upregulation of TGF-ß1 mediated fibrosis in aging induced rats. However, collagen deposition and fibrosis were significantly decreased by AOF treatments (AM and AH). AOF treatments salvaged the cardiac fibrosis. Hence, AOF might be a potential therapeutic agent in the prevention of cardiac fibrosis associated with aging. The protective effects of AOF might have promising results in anti-aging treatments.

Eriobotrya japonica ameliorates cardiac hypertrophy in H9c2 cardiomyoblast and in spontaneously hypertensive rats.

Eriobotrya japonica (EJ) is a traditional Chinese plant with high medicinal value. EJ extracts are reported to exhibit antioxidant and anti-inflammatory biological attributes. The current study aims to evaluate the prospective efficacy of E. japonica leave extract (EJLE) against Angiotensin-II induced cardiac hypertrophy in H9c2 cardiomyoblast and in spontaneously hypertensive rats (SHRs). For the in vitro studies, Angiotensin-II pretreated H9c2 cells were treated with EJLE and analyzed through Western blotting and rhodamine phalloidin staining for their cardio-protective attributes. In the in vivo studies, 12-week-old SHRs were randomly divided into groups: SHRs supplemented with EJLE, control SHR group supplemented with PBS; in addition, a control group of Wistar-Kyoto rats (WKY) was also employed. All rats were supplemented twice a week for 8 week time interval. Finally, echocardiography, morphological, histology, and Western blot analysis were performed to assess their role against cardiac hypertrophy. Interestingly, we could observe that supplementation of EJLE could rescue Ang-II induced cardiac hypertrophy as evident through Western blot, rhodamine phalloidin staining, and Hematoxylin-Eosin staining. Notably, morphological and echocardiography data provided further supports for their ability to ameliorate cardiac characteristics. Cumulatively, the results clearly suggests that supplementation of EJLE promotes cardio-protective effects through amelioration of cardiac hypertrophy in vitro and in vivo.

Platycodin D Reverses Pathological Cardiac Hypertrophy and Fibrosis in Spontaneously Hypertensive Rats.

Platycodin D (PD) is the main active saponin isolated from Platycodon grandiflorum (PG) and is reported to exhibit anticancer, anti-angiogenic, anti-inflammation and anti-obesity biological effects. The current study aims to evaluate the therapeutic efficacy of PD in cardiac fibrosis and for hypertrophy in spontaneous hypertension rats (SHRs) and to verify inhibition of the signaling pathway. Significant increases in the cardiac functional indices of left ventricular internal diameter end diastole (LVIDd) and left ventricular internal diameter end systole (LVIDs); the eccentric hypertrophy marker p-MEK5; concentric hypertrophy markers, such as CaMKII[Formula: see text] and calcineurin; and expression levels of NFATc3, p-GATA4 and BNP were observed in spontaneously hypertensive groups. PD treatment reversed these increases in SHRs. In addition, an increase in the fibrosis markers FGF2, uPA, MMP2, MMP9, TGF[Formula: see text]-1 and CTGF during cardiac hypertrophy was detected by western blotting analyses. These results demonstrated that PD treatment considerably attenuates cardiac fibrosis. Histopathological examination revealed that PD treatment remarkably reduced collagen accumulation in contrast to spontaneously hypertensive groups. This study clearly suggests that PD provides myocardial protection by alleviating two damaging responses to hypertension, fibrosis and hypertrophy, in the heart.

Lupeol alters ER stress-signaling pathway by downregulating ABCG2 expression to induce Oxaliplatin-resistant LoVo colorectal cancer cell apoptosis.

Colorectal cancer (CRC) is one of the most common cancers and causes of cancer-related death. There are several first-line chemotherapeutic drugs used to treat CRC. Oxaliplatin (OXA) is an alkylating cytotoxic agent that is usually combined with other chemotherapeutic drugs to treat stage II and stage III CRC. However, cancer cells commonly acquire multidrug resistance (MDR), which is a major obstruction to cancer treatment. Recent studies have shown that natural components from traditional Chinese medicine or foods that have many biological functions may be new adjuvant therapies in clinical trials. We challenged LoVo CRC cell lines with OXA in a dose-dependent manner to create an OXA-resistant model. The expression of ABCG2 was significantly higher, and levels of endoplasmic reticulum (ER) stress markers were lower than those Parental cells. However, Lupeol, which is found in fruits and vegetables, has been shown to have bioactive properties, including anti-tumor properties that are relevant to many diseases. In our study, Lupeol downregulated cell viability and activated cell apoptosis. Moreover, Lupeol decreased the expression of ABCG2 and activated ER stress to induce OXA-resistant cell death. Importantly, the anti-tumor effect of Lupeol in OXA-resistant cells was higher than that of LoVo Parental cells. In addition, we also confirmed our results with a xenograft animal model, and the tumor size significantly decreased after Lupeol injections. Our findings show that Lupeol served as a strong chemoresistant sensitizer and could be a new adjuvant therapy method for chemoresistant patients.

Thymoquinone suppresses migration of LoVo human colon cancer cells by reducing prostaglandin E2 induced COX-2 activation.

AIM: To identify potential anti-cancer constituents in natural extracts that inhibit cancer cell growth and migration. METHODS: Our experiments used high dose thymoquinone (TQ) as an inhibitor to arrest LoVo (a human colon adenocarcinoma cell line) cancer cell growth, which was detected by cell proliferation assay and immunoblotting assay. Low dose TQ did not significantly reduce LoVo cancer cell growth. Cyclooxygenase 2 (COX-2) is an enzyme that is involved in the conversion of arachidonic acid into prostaglandin E2 (PGE2) in humans. PGE2 can promote COX-2 protein expression and tumor cell proliferation and was used as a control. RESULTS: Our results showed that 20 µmol/L TQ significantly reduced human LoVo colon cancer cell proliferation. TQ treatment reduced the levels of p-PI3K, p-Akt, p-GSK3ß, and ß-catenin and thereby inhibited the downstream COX-2 expression. Results also showed that the reduction in COX-2 expression resulted in a reduction in PGE2 levels and the suppression of EP2 and EP4 activation. Further analysis showed that TG treatment inhibited the nuclear translocation of ß-catenin in LoVo cancer cells. The levels of the cofactors LEF-1 and TCF-4 were also decreased in the nucleus following TQ treatment in a dose-dependent manner. Treatment with low dose TQ inhibited the COX-2 expression at the transcriptional level and the regulation of COX-2 expression efficiently reduced LoVo cell migration. The results were further verified in vivo by confirming the effects of TQ and/or PGE2 using tumor xenografts in nude mice. CONCLUSION: TQ inhibits LoVo cancer cell growth and migration, and this result highlights the therapeutic advantage of using TQ in combination therapy against colorectal cancer.

Suppression of isoproterenol-induced apoptosis in H9c2 cardiomyoblast cells by daidzein through activation of Akt.

Increased serum norepinephrine level is one of pathological processes relating to heart disease (HD). Estrogens are considered as potential therapeutics for the treatment of HD; however, estrogen supplementation shows some side-effects, such as increasing the risk of developing breast, endometrial and ovarian cancers. This study investigated the cardio-protective effects of daidzein (Dai), a selective estrogen receptor modulator (SERM) from soy bean extract, in H9c2 cardiomyoblast cells treated with isoproterenol (ISO), a norepinephrine analog. In this in vitro model, H9c2 cells treated with Dai at different concentrations showed no statistical difference in cell viability. TdT-mediated digoxigenin-dUTP nick-end labeling (TUNEL) data and western blotting results indicated that Dai treated-H9c2 cells recovered from the damage induced by ISO. The recovery effects of Dai on ISO-induced damage were blocked by inhibition of Akt activation through adding Akt inhibitor. On the other hand, the fold changes of phosphorylated Akt (p-Akt)/Akt normalized with the control for con, 0.25, 0.5, 1, 3 and 24 h of treatment were 1, 2, 5, 13, 11 and 10, respectively. In conclusion, Dai ameliorates apoptosis of cardiomyoblasts induced by ISO through Akt signaling pathway.

Corrigendum to "Caffeic Acid Phenethyl Ester Inhibits Oral Cancer Cell Metastasis by Regulating Matrix Metalloproteinase-2 and the Mitogen-Activated Protein Kinase Pathway".

[This corrects the article DOI: 10.1155/2012/732578.].

San Huang Shel Shin Tang beta-cyclodextrin complex augmented the hepatoprotective effects against carbon tetrachloride-induced acute hepatotoxicity in rats.

BACKGROUND: San Huang Shel Shin Tang (SHSST) is a traditional herbal decoction used as a hepato-protective agent and is composed of Rheum officinale Baill, Scutellaria baicalnsis Geprgi and Coptis chinensis Franch (2:1:1 w/w). Beta-cyclodextrin (ß-CD) modification may potentially increase the solubility and spectral properties of SHSST. METHODS: In this research, the hepato-protective effects of unmodified SHSST, ß-CD modified SHSST complex (SHSSTc) and silymarin were evaluated in carbon tetrachloride (CCl4) induced acute hepatotoxicity in rats. RESULTS: SHHSTc (40 mg/kg/day) and silymarin (100 mg/kg/day) both decreased the CCl4-induced cirrhosis pathway-related transforming growth factor beta (TGF-ß) and apoptosis pathway-related caspase-8 protein expressions, but SHSST (40 mg/kg/day) did not reduce TGF-ß and caspase-8 significantly . Moreover, SHHSTc (40 mg/kg/day) enhanced the activation of insulin-like growth factor 1 receptor (IGF1R) mediated survival pathway than the silymarin (100 mg/kg/day) to protect the liver from damage induced by CCl4. CONCLUSIONS: ß-CD modification promotes hepato-protective effects of SHSST and reduces the required-dosage of the SHSST.

Anti-apoptotic effect of San Huang Shel Shin Tang cyclodextrin complex (SHSSTc) on CCl4 -induced hepatotoxicity in rats.

The metabolic loading is heavier in liver especially when injured or inflammation. San Huang Shel Shin Tang (SHSST) was an old traditional herbal decoction, which composed with Rheum officinale Baill, Scutellaria baicalnsis Geprgi and Coptis chinensis Franch (1:1:2 in weight), can provide a liver protection effects. We used a beta-cyclodextrin (ß-CD) drug modification method in reduce of the necessary dose of the SHSST. As the results, the FAS-FADD expressions leaded apoptosis in CCl4 intraperitoneal (IP) injection induced acute liver injury in rats. Silymarin, baicalein, SHSST, and SHSST ß-CD complex (SHSSTc) pretreatments protected liver through the decreasing of the expressions of FAS-FADD and downstream caspase-3 and caspase-8. Particularly, SHSSTc (30 mg/kg day) treatment enhanced cell survival pathway activation through the PI3K, Akt and Bad phosphorylation. Compared with SHSST as well as silymarin and baicalein, SHSSTc provided a magnificent liver protection effect, especially in survival pathway activation/TUNEL-apoptotic cell reduction/serum cholesterol level suppression. All these data suggested that ß-CD complex modified the SHSST and promoted the bioavailability and liver protection effects. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 663-670, 2016.

Silymarin Accelerates Liver Regeneration after Partial Hepatectomy.

Partial hepatectomy (PHx) is a liver regeneration physiological response induced to maintain homeostasis. Liver regeneration evolved presumably to protect wild animals from catastrophic liver loss caused by toxins or tissue injury. Silymarin (Sm) ability to stimulate liver regeneration has been an object of curiosity for many years. Silymarin has been investigated for use as an antioxidant and anticarcinogen. However, its use as a supportive treatment for liver damage is elusive. In this study, we fed silymarin (Sm, 25 mg/kg) to male Sprague-Dawley rats for 7 weeks. Surgical 2/3 PHx was then conducted on the rats at 6 hrs, 24 hrs, and 72 hrs. Western blot and RT-PCR were conducted to detect the cell cycle activities and silymarin effects on hepatic regeneration. The results showed that silymarin enhanced liver regeneration by accelerating the cell cycle in PHx liver. Silymarin led to increased G1 phase (cyclin D1/pRb), S phase (cyclin E/E2F), G2 phase (cyclin B), and M phase (cyclin A) protein and mRNA at 6 hrs, 24 hrs, and 72 hrs PHx. HGF, TGFα, and TGFß1 growth factor expressions were also enhanced. We suggest that silymarin plays a crucial role in accelerated liver regeneration after PHx.

Effects of rhodiola crenulata on mice hearts under severe sleep apnea.

BACKGROUND: The goal of this study is to determine if Rhodiola Crenulata (RC) has protective effects on mice hearts with severe sleep apnea model. METHODS: Sixty-four C57BL/6 J mice 5-6 months old were distributed into 4 groups i.e. Control group (21% O2, 24 h per day, 8 weeks, n=16); Hypoxia group (Hypoxia: 7% O2 60 s, 20% O2 alternating 60 s, 8 h per day, 8 weeks, n=16); Hypoxia+90RC and Hypoxia+270RC group (Hypoxia for 1st 4 weeks and hypoxia pretreated 90 mg/Kg and 270 mg/Kg Rhodiola Crenulata by oral gavage per day for 2nd 4 weeks, each n=16). Excised hearts from 4 groups of mice were analyzed for heart weight index changes using H&E staining, TUNEL-positive assays and Western Blotting protein. RESULTS: Cardiac widely dispersed TUNEL-positive apoptotic cells in mice hearts were less in Hypoxia+RC90 and Hypoxia+RC270 than those in Hypoxia. Compared with Hypoxia, the protein levels of Fas ligand, Fas death receptors, Fas-Associated Death Domain (FADD), activated caspase 8, and activated caspase 3 (Fas dependent apoptotic pathways) were decreased in Hypoxia+RC90, Hypoxia+RC270. The protein levels of Bad, Bax, t-Bid, activated caspase 9, activated caspase 3 (mitochondria dependent apoptotic pathway) were less in Hypoxia+RC90, Hypoxia+RC270 than those in hypoxia. The protein levels of Bcl2, Bcl-xL, p-Bad (Bcl2-realted anti-apoptotic pathway) and VEGF, p-PI3k, p-AKT (VEGF-related pro-survival pathway) were higher in Hypoxia+RC90, Hypoxia+RC270 than those in hypoxia. CONCLUSIONS: Our findings suggest that Rhodiola Crenulata have protective effects on chronic intermittent hypoxia-induced cardiac widely dispersed apoptosis via Fas-dependent and mitochondria-dependent apoptotic and VEGF-related pro-survival pathway.

Thymoquinone induces caspase-independent, autophagic cell death in CPT-11-resistant lovo colon cancer via mitochondrial dysfunction and activation of JNK and p38.

Chemotherapy causes unwanted side effects and chemoresistance, limiting its effectiveness. Therefore, phytochemicals are now used as alternative treatments. Thymoquinone (TQ) is used to treat different cancers, including colon cancer. The irinotecan-resistant (CPT-11-R) LoVo colon cancer cell line was previously constructed by stepwise CPT-11 challenges to untreated parental LoVo cells. TQ dose-dependently increased the total cell death index and activated apoptosis at 2 µM, which then diminished at increasing doses. The possibility of autophagic cell death was then investigated. TQ caused mitochondrial outer membrane permeability (MOMP) and activated autophagic cell death. JNK and p38 inhibitors (SP600125 and SB203580, respectively) reversed TQ autophagic cell death. TQ was also found to activate apoptosis before autophagy, and the direction of cell death was switched toward autophagic cell death at initiation of autophagosome formation. Therefore, TQ resulted in caspase-independent, autophagic cell death via MOMP and activation of JNK and p38 in CPT-11-R LoVo colon cancer cells.

Alpinia oxyphylla Miquel fruit extract activates MAPK-mediated signaling of PAs and MMP2/9 to induce Schwann cell migration and nerve regeneration.

OBJECTIVES: This study investigates the molecular mechanisms by which Alpiniae oxyphyllae fructus (AOF) promotes neuron regeneration. METHODS: A piece of silicone rubber was guided across a 15 mm gap in the sciatic nerve of a rat. This nerve gap was then filled with different concentrations of AOF extract (0-200 mg/ml). We investigated the role of MAPK (ERK1/2, JNK and p38) pathways for AOF-induced matrix-degrading proteolytic enzyme (PAs and MMP2/9) production in RSC96 Schwann cells. RESULTS: The results showed that AOF increased the expressions of uPA, tPA, MMP-9, and MAPKs in vivo. In vitro, our results show that treatment with AOF extract induces ERK1/2, JNK, and p38 phosphorylation to activate the downstream PAs and MMPs signaling expression. AOF-stimulated ERK1/2, JNK, and p38 phosphorylation attenuated by individual pretreatment with siRNAs or inhibitors (U0126, SP600125 and SB203580), resulting in migration and uPA-related signal pathway inhibition. CONCLUSIONS: Taken together our data suggests the MAPKs (ERK1/2, JNK and p38), PAs (uPA, tPA), MMP (MMP2, MMP9) regenerative and migration signaling pathway of Schwann cells regulated by AOF extract might play a major role in Schwann cell migration and damaged peripheral nerve regeneration.