Ligustrazine improves the compensative effect of Akt survival signaling to protect liver Kupffer cells in trauma-hemorrhagic shock rats.

Trauma-hemorrhagic shock (THS) is a medical emergency that is encountered by physicians in the emergency department. Chuan Xiong is a traditional Chinese medicine and ligustrazine is a natural compound from it. Ligustrazine improves coronary blood flow and reduces cardiac ischemia in animals through Ca2+ and ATP-dependent vascular relaxation. It also decreases the platelets' bioactivity and reduces reactive oxygen species formation. We hypothesized that ligustrazine could protect liver by decreasing the inflammation response, protein production, and apoptosis in THS rats. Ligustrazine at doses of 100 and 1000 µg/mL was administrated in Kupffer cells isolated from THS rats. The protein expressions were detected via western blot. The THS showed increased inflammation response proteins, mitochondria-dependent apoptosis proteins, and had a compensation effect on the Akt pathway. After ligustrazine treatment, the hemorrhagic shock Kupffer cells decreased inflammatory response and mitochondria-dependent apoptosis and promoted a more compensative effect of the Akt pathway. It suggests ligustrazine reduces inflammation response and mitochondria-dependent apoptosis induced by THS in liver Kupffer cells and promotes more survival effects by elevating the Akt pathway. These findings demonstrate the beneficial effects of ligustrazine against THS-induced hepatic injury, and ligustrazine could be a potential medication to treat the liver injury caused by THS.

Daidzein Synergizes with Gefitinib to Induce ROS/JNK/c-Jun Activation and Inhibit EGFR-STAT/AKT/ERK Pathways to enhance Lung Adenocarcinoma cells chemosensitivity.

Lung cancer is the major cause of cancer associated mortality. Mutations in EGFR have been implicated in lung cancer pathogenesis. Gefitinib (GF) is a RTKI (receptor tyrosine kinase inhibitor) first-choice drug for EGFR mutated advanced lung cancer. However, drug toxicity and cancer cell resistance lead to treatment failure. Consequently, new therapeutic strategies are urgently required. Therefore, this study was aimed at identifying tumor suppressive compounds that can synergistically improve Gefitinib chemosensitivity in the lung cancer treatment. Medicinal plants offer a vast platform for the development of novel anticancer agents. Daidzein (DZ) is an isoflavone compound extracted from soy plants and has been shown to possess many medicinal benefits. The anticancer potential of GF and DZ combination treatment was investigated using MTT, western blot, fluorescent microscopy imaging, flow cytometry and nude mice tumor xenograft techniques. Our results demonstrate that DZ synergistically induces c-Jun nuclear translocation through ROS/ASK1/JNK and downregulates EGFR-STAT/AKT/ERK pathways to activate apoptosis and a G0/G1 phase cell cycle blockade. In in-vivo, the combination treatment significantly suppressed A549 lung cancer cells tumor xenograft growth without noticeable toxicity. Daidzein supplements with current chemotherapeutic agents may well be an alternative strategy to improve the treatment efficacy of lung adenocarcinoma.

Calycosin alleviates H2 O2 -induced astrocyte injury by restricting oxidative stress through the Akt/Nrf2/HO-1 signaling pathway.

Oxidative stress-induced brain cell damage is a crucial factor in the pathogenesis of reactive oxygen species (ROS)-associated neurological diseases. Further, studies show that astrocytes are an important immunocompetent cell in the brain and play a potentially significant role in various neurological diseases. Therefore, elimination of ROS overproduction might be a potential strategy for preventing and treating neurological diseases. Accumulating evidence indicates that calycosin, a main active ingredient in the Chinese herbal medicine Huangqi (Radix Astragali Mongolici), is a potential therapeutic candidate with anti-inflammation and/or anticancer effects. Here, we investigated the protective effect of calycosin in brain astrocytes by mimicking in vitro oxidative stress using H2 O2 . The results revealed that H2 O2 significantly induced ROS and inflammatory factor (tumor necrosis factor [TNF]-α and interleukin [IL]-1ß) production, whereas post-treatment with calycosin dramatically and concentration-dependently suppressed H2 O2 -induced damage by enhancing cell viability, repressing ROS and inflammatory factor production, and increasing superoxide dismutase (SOD) expression. Additionally, we found that calycosin facilitated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and promoted its nuclear translocation, thereby inducing the expression of antioxidant molecules (heme oxygenase [HO]-1 and SOD) following H2 O2 treatment. Moreover, calycosin did not attenuated H2 O2 -induced astrocyte damage and ROS production in the presence of the ML385 (a Nrf2-specific inhibitor) and following Nrf2 silencing. Furthermore, calycosin failed to increase Akt phosphorylation and mitigate H2 O2 -induced astrocyte damage in the presence of the LY294002 (a selective phosphatidylinositol 3-kinase inhibitor), indicating that calycosin-mediated regulation of oxidative-stress homeostasis involved Akt/Nrf2/HO-1 signaling. These findings demonstrated that calycosin protects against oxidative injury in brain astrocytes by regulating oxidative stress through the AKT/Nrf2/HO-1 signaling pathway.

Aqueous extract of Solanum nigrum attenuates Angiotensin-II induced cardiac hypertrophy and improves cardiac function by repressing protein kinase C-ζ to restore HSF2 deSUMOlyation and Mel-18-IGF-IIR signaling suppression.

ETHNOPHARMACOLOGICAL RELEVANCE: Solanum nigrum, commonly known as Makoi or black shade has been traditionally used in Asian countries and other regions of world to treat liver disorders, diarrhoea, inflammatory conditions, chronic skin ailments (psoriasis and ringworm), fever, hydrophobia, painful periods, eye diseases, etc. It has been observed that S. nigrum contains substances, like steroidal saponins, total alkaloid, steroid alkaloid, and glycoprotein, which show anti-tumor activity. However; there is no scientific evidence of the efficacy of S. nigrum in the treatment of cardiac hypertrophy. AIM: To investigate the ability of S. nigrum to attenuate Angiotensin II - induced cardiac hypertrophy and improve cardiac function through the suppression of protein kinase PKC-ζ and Mel-18-IGF-IIR signaling leading to the restoration of HSF2 desumolyation. MATERIALS AND METHODS: Cardiomyoblast cells (H9c2) were challenged with 100 nM Angiotensin-II (AngII) for 24 h and were then treated with different concentration of S.nigrum or Calphostin C for 24 h. The hypertrophic effect in cardiomyoblast cells were determined by immunofluorescence staining and the modulations in hypertrophic protein marker along with Protein Kinase C-ζ, MEL18, HSF2, and Insulin like growth factor II (IGFIIR), markers were analyzed by western blotting. In vivo experiments were performed using 12 week old male Wistar Kyoto rats (WKY) and Spontaneously hypertensive rats (SHR) separated into five groups. [1]Control WKY, [2] WKY -100 mg/kg of S.nigrum treatment, [3] SHR, [4] SHR-100 mg/kg of S.nigrum treatment, [5] SHR-300 mg/kg of S.nigrum treatment. S. nigrum was administered intraperitoneally for 8 week time interval. RESULTS: Western blotting results indicate that S. nigrum significantly attenuates AngII induced cardiac hypertrophy. Furthermore, actin staining confirmed the ability of S. nigrum to ameliorate AngII induced cardiac hypertrophy. Moreover, S. nigrum administration suppressed the hypertrophic signaling mediators like Protein Kinase C-ζ, Mel-18, and IGFIIR in a dose-dependent manner and HSF2 activation (restore deSUMOlyation) that leads to downregulation of IGF-IIR expression. Additionally in vivo experiments demonstrate the reduced heart sizes of S. nigrum treated SHRs rats when compared to control WKY rats. CONCLUSION: Collectively, the data reveals the cardioprotective effect of S. nigrum inhibiting PKC-ζ with alleviated IGF IIR level in the heart that profoundly remits cardiac hypertrophy for hypertension-induced heart failure.

Leu27 IGF-II-induced hypertrophy in H9c2 cardiomyoblasts is ameliorated by saffron by regulation of calcineurin/NFAT and CaMKIIδ signaling.

The insulin-like growth factor II receptor (IGF-IIR) induces myocardial hypertrophy under various pathological conditions like diabetes and hypertension via G protein receptors like Gαq or Gαs. Increased expression of the ligand IGF II and IGF-IIR induces pathological hypertrophy through downstream signaling mediators such as calcineurin, nuclear factor of activated T cells 3 and calcium-calmodulin (CaM)-dependent kinase II (CaMKII)-histone deacetylase 4 (HDAC4). The dried stigma of Crocus sativus L. (saffron) has a long repute as a traditional medicine against various disorders. In the present study, we have investigated whether C. sativus extract (CSE) canameliorate Leu27 IGF-II triggered hypertrophy and have elucidated the underlying mechanism of protection. Additionally, the effects of oleic acid (OA), an activator of calcineurin and CaMKII was investigated thereof. The results demonstrate that CSE can ameliorate Leu27 IGF-II-induced hypertrophy seemingly through regulation of calcineurin-NFAT3 and CaMKII-HDAC4 signaling cascade.

Bioactive dipeptide from potato protein hydrolysate combined with swimming exercise prevents high fat diet induced hepatocyte apoptosis by activating PI3K/Akt in SAMP8 mouse.

Obesity in aged population have surges the occurrence of various metabolic disorders including Nonalcoholic fatty liver disease (NAFLD). Apoptosis in the liver is one of the causative factors for NAFLD-induced liver damage. Plants derived bioactive peptides have been shown as an alternative treatment approach for the treating NAFLD due to its less toxicity. Moderate exercise has been reported to improve cellular physiological function prevent age associated metabolic disorders. In the present study, we evaluate the effects of bioactive dipeptide (IF) derived from alcalase potato-protein hydrolysates and swimming exercise in preventing High Fat Diet (HFD)-induced liver damage in senescence accelerated mouse-prone 8 (SAMP8) mice model. Mouse were fed with HFD for 6 weeks followed by oral IF administration or swimming exercise and both for 8 weeks. HFD induces significant structural changes in liver of HFD fed SAMP8 mouse. Both IF administration and exercise prevent the structural abnormalities induced by HFD, however, combined IF treatment and exercise offer better protection. Combined IF treatment and exercise activate PI3K/Akt cell survival protein and effectively inhibit Fas-FADD-induced apoptosis in HFD fed aged mouse. Oral supplementation of bioactive peptide IF combined with moderate swimming exercise effectively alleviate HFD-induced hepatic injury in aged mice.

Arecoline induces heart injure via Fas/Fas ligand apoptotic pathway in heart of Sprague-Dawley rat.

Habitual chewing of areca nut increases the risk of cardiovascular disease mortality, but less report demonstrate the toxic mechanism of areca nut on heart. To investigate toxicity of areca nut on cardiomyocytes, we induced the heart injury with arecoline to evaluate the acute damage of areca nut on heart. Different concentrations of are coline (lowdosage: 5 mg/kg/day and high dosage 50 mg/kg/day) were injected into Sprague-Dawley rat via intra-peritoneal method for 21 days to create negative effects of arecoline on cardiomyocyte. Themyocardial architecture of the rat heart was observed. The arecoline-induced apoptotic proteins were analysed via western blotting. The myocardialarchitecture of heart was injured with arecoline and TUNEL stain was also shown are coline-induced cardiac apoptosis. Arecoline promoted the protein expression of both Fas dependent snd mitochondrial dependent apoptosis. In summary, arecoline induces cardiac toxicity and apoptosis by inducing both death receptor and mitochondria-dependent apoptotic pathways on heart.

Cardioprotective effects of transplanted adipose-derived stem cells under Ang II stress with Danggui administration augments cardiac function through upregulation of insulin-like growth factor 1 receptor in late-stage hypertension rats.

In aging hypertensive conditions, deterioration of insulin-like growth factor 1 receptor (IGF1R) cause a pathological impact on hypertensive hearts with an increased Ang II level. Recovering these adverse conditions through transplanted adipose-derived stem cells is a challenging approach. Moreover, Danggui, a Traditional Chinese medicine (TCM), is used for the treatment of cardioprotective effects. In this study, to evaluate whether the combined effect of MSCs and TCM can recover the cardiac function in late-stage hypertension rats. We observed that lower dose of Danggui crude extract treatment showed an increased level of cell viability with maintained stemness properties and growth rate in rat adipose-derived stem cells (rADSCs). Further, we cocultured the H9c2 cells with rADSCs and the results revealed that Danggui-treated MSCs enhanced the IGF1R expression and attenuated the hypertrophy in H9c2 cells against Ang II challenge by immunoblot and rhodamine-phalloidin staining. In addition, Danggui crude extract was also quantified and characterized by HPLC and LC-MS analysis. Furthermore, the in vivo study was performed by considering 11 months old rats (n = 7). Importantly, the oral administration of Danggui crude extract with stem cells intravenous injection in SHR-D-ADSCs group showed a combination effect to augment the cardiac function through enhancement of ejection fraction, fractional shortening, contractility function in the late-stage hypertension conditions. We have also observed a decreased apoptosis rate in the heart tissue of SHR-D-ADSCs group. Taken together, these results indicate that the combinatorial effects of Danggui crude extract and stem cell therapy enhanced cardiac function in late-stage SHR rats.

Platycodin D reverses histone deacetylase inhibitor resistance in hepatocellular carcinoma cells by repressing ERK1/2-mediated cofilin-1 phosphorylation.

BACKGROUND: Chemoresistance remains the main obstacle in hepatocellular carcinoma (HCC) therapy. Despite significant advances in HCC therapy, HCC still has a poor prognosis. Thus, there is an urgent need to identify a treatment target to reverse HCC chemotherapy resistance. Platycodon grandiflorus (PG) is a perennial herb that has been used as food and traditional Chinese medicine for thousands of years in Northeast Asia. Platycodin D (PD), a main active triterpenoid saponin found in the root of PG, has been reported to possess anticancer properties in several cancer cell lines, including HCC; however, the reversal effect of this molecule on HCC chemoresistance remains largely unknown. PURPOSE: This study aimed to investigate the role and the mechanism of PD-mediated reversal of the histone deacetylase inhibitor (HDACi) resistance in HCC cells. METHODS: Human HCC cells (HA22T) and HDACi-resistant (HDACi-R) cells were used. Cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Combination index was used to calculate the synergism potential. Expression of ERK1/2 (total/phospho), cofilin-1 (total/phospho) and apoptosis-related protein was determined using western blotting. Mitochondrial membrane potential was assessed using the JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine iodide) probe. Apoptosis was detected using the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Mitochondrial reactive oxygen species generation was measured using the MitoSOX Red fluorescent probe. RESULTS: We found that PD treatment inhibited cell viability both in HA22T HCC and HDACi-R cells. Inhibition of ERK1/2 by PD98059 could reverse drug resistance in HDACi-R cells treated with PD98059 and PD. Nevertheless, pre-treatment with U46619, an ERK1/2 activator, rescued PD-induced apoptosis by decreasing levels of apoptosis-related proteins in HCC cells. The combined treatment of PD with apicidin a powerful HDACi, dramatically enhanced the apoptotic effect in HDACi-R cells. CONCLUSION: For the first time, we showed that PD reversed HDACi resistance in HCC by repressing ERK1/2-mediated cofilin-1 phosphorylation. Thus, PD can potentially be a treatment target to reverse HCC chemotherapy resistance in future therapeutic trials.

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.

Induction of Autophagy by Vasicinone Protects Neural Cells from Mitochondrial Dysfunction and Attenuates Paraquat-Mediated Parkinson's Disease Associated α-Synuclein Levels.

Mitochondrial dysfunction and disturbed mitochondrial dynamics were found to be common phenomena in the pathogenesis of Parkinson's disease (PD). Vasicinone is a quinazoline alkaloid from Adhatoda vasica. Here, we investigated the autophagy/mitophagy-enhancing effect of vasicinone and explored its neuroprotective mechanism in paraquat-mimic PD modal in SH-SY5Y cells. Vasicinone rescued the paraquat-induced loss of cell viability and mitochondrial membrane potential. Subsequently, the accumulation of mitochondrial reactive oxygen species (ROS) was balanced by an increase in the expression of antioxidant enzymes. Furthermore, vasicinone restored paraquat-impaired autophagy and mitophagy regulators DJ-1, PINK-1 and Parkin in SH-SY5Y cells. The vasicinone mediated autophagy pathways were abrogated by treatment with the autophagy inhibitor 3-MA, which lead to increases α-synuclein accumulation and decreased the expression of p-ULK and ATG proteins and the autophagy marker LC3-II compared to that observed without 3-MA treatment. These results demonstrated that vasicinone exerted neuroprotective effects by upregulating autophagy and PINK-1/Parkin mediated mitophagy in SH-SY5Y cells.

Bioactive peptides attenuate cardiac apoptosis in spontaneously hypertensive rat hearts through activation of autophagy and mitochondrial biogenesis pathway.

Alcalase potato protein hydrolysate (APPH) might have a very important role in therapeutic effects. This study aims to examine the beneficial effects of bioactive peptides (DIKTNKPVIF [DI] and IF) from APPH supplement in the regulation of cardiac apoptosis, autophagy, and mitochondrial biogenesis pathway in spontaneously hypertensive rats (SHR). We have investigated ejection fraction, fractional shortening, Tunel assay, apoptosis, autophagy, and mitochondrial biogenesis pathway marker expression to show the efficacy of bioactive peptides in an SHR model. Bioactive peptides significantly upregulate ejection fraction and fractional shortening in SHR rats. SHR rats exhibited higher protein expression of apoptotic markers such as BAD, cytochrome c, and caspase 3. Finally, the bioactive peptides upregulate survival proteins (p-AKT/p-PI3K), autophagy (Beclin1/LC3B), and mitochondrial biogenesis (p-AMPKα/SIRT1/PGC1α/p-Foxo3a/Nrf2/CREB) marker expressions compared with the SHR groups. In summary, the bioactive peptides protect the heart tissues through the activation of autophagy and mitochondrial biogenesis pathway and thereby attenuate cardiac apoptosis in a spontaneously hypertensive rat model.

Taiwanofungus camphoratus Combined With Amphotericin B for Metastatic Cancer Patients Unresponsive to or Unwilling to Undergo Chemotherapy: A Pilot Study.

CONTEXT: Taiwanofungus camphoratus is a parasitic mushroom found in the heartwood of Cinnamomum kanehirai and is used as a nutritional supplement. It has an anticancer action, both alone and synergistically with amphotericin B (AmB). OBJECTIVE: The study intended to assess the efficacy of a T camphoratus ethanol extract (TCEE) combined with AmB for patients with metastatic cancer whose cancer did not respond to multiline chemotherapy or who were unwilling to receive chemotherapy. DESIGN: The research team performed a retrospective analysis as a pilot study. SETTING: The study took place at a single hospital (Taipei Medical University Hospital, Taipei, Taiwan). PARTICIPANTS: Participants were 9 patients at the hospital who were terminally ill with metastatic cancer. INTERVENTIONS: The participants had received daily doses of 2-3 g of the TCEE in combination with a weekly dose of 20-25 mg of AmB in 500 cc of 5% glucose water, given intravenously in 4-6 h. OUTCOME MEASURES: Outcome measures included (1) a primary evaluation index measuring the efficacy of the treatment; (2) a measure of tumor burden that was estimated using the response evaluation criteria in solid tumors (RECIST 1.1), (3) a secondary evaluation index measuring survival duration, and (4) safety. RESULTS: The mean treatment time was 54.4 ± 18.3 wk. At the end of the study, 2 patients showed a continued complete response, 1 patient had a continued partial response, and 1 patient showed a stable disease. The other 5 participants had times to progression ranging from 24 to 48 wk, with a mean of 35.6 wk. The mean survival time was 57.8 ± 18.5 wk, and 5 patients were still alive at the end of the study. CONCLUSIONS: For patients whose metastatic cancer did not respond to multiline chemotherapy or who were unwilling to receive chemotherapy, the use of TCEE as an adjuvant therapy to AmB resulted in tumor suppression and a delay in time to disease progression. The preliminary results reported here can be used to guide a future, more extensive clinical study of the combination.

Blockchain-Enabled iWellChain Framework Integration With the National Medical Referral System: Development and Usability Study.

BACKGROUND: Medical referral is the transfer of a patient's care from one physician to another upon request. This process involves multiple steps that require provider-to-provider and provider-to-patient communication. In Taiwan, the National Health Insurance Administration (NHIA) has implemented a national medical referral (NMR) system, which encourages physicians to refer their patients to different health care facilities to reduce unnecessary hospital visits and the financial stress on the national health insurance. However, the NHIA's NMR system is a government-based electronic medical referral service, and its referral data access and exchange are limited to authorized clinical professionals using their national health smart cards over the NHIA virtual private network. Therefore, this system lacks scalability and flexibility and cannot establish trusting relationships among patients, family doctors, and specialists. OBJECTIVE: To eliminate the existing restrictions of the NHIA's NMR system, this study developed a scalable, flexible, and blockchain-enabled framework that leverages the NHIA's NMR referral data to build an alliance-based medical referral service connecting health care facilities. METHODS: We developed a blockchain-enabled framework that can integrate patient referral data from the NHIA's NMR system with electronic medical record (EMR) and electronic health record (EHR) data of hospitals and community-based clinics to establish an alliance-based medical referral service serving patients, clinics, and hospitals and improve the trust in relationships and transaction security. We also developed a blockchain-enabled personal health record decentralized app (DApp) based on our blockchain-enabled framework for patients to acquire their EMR and EHR data; DApp access logs were collected to assess patients' behavior and investigate the acceptance of our personal authorization-controlled framework. RESULTS: The constructed iWellChain Framework was installed in an affiliated teaching hospital and four collaborative clinics. The framework renders all medical referral processes automatic and paperless and facilitates efficient NHIA reimbursements. In addition, the blockchain-enabled iWellChain DApp was distributed for patients to access and control their EMR and EHR data. Analysis of 3 months (September to December 2018) of access logs revealed that patients were highly interested in acquiring health data, especially those of laboratory test reports. CONCLUSIONS: This study is a pioneer of blockchain applications for medical referral services, and the constructed framework and DApp have been applied practically in clinical settings. The iWellChain Framework has the scalability to deploy a blockchain environment effectively for health care facilities; the iWellChain DApp has potential for use with more patient-centered applications to collaborate with the industry and facilitate its adoption.

Protective effect of Fisetin against angiotensin II-induced apoptosis by activation of IGF-IR-PI3K-Akt signaling in H9c2 cells and spontaneous hypertension rats.

BACKGROUND: Fisetin, a polyphenolic compound, has drawn notable attention owing to its antioxidant, anti-inflammatory, anti-cancer and neuroprotective effects. However, the cardiac effects of fisetin are not clear yet. HYPOTHESIS: The aim of the present study is to examine the cardioprotective effect of fisetin against Ang-II induced apoptosis in H9c2 cells and in spontaneous hypertensive rats (SHR). METHODS/STUDY DESIGN: The in vitro protective effect of fisetin was evaluated after the cells were treated with fisetin (50 µM/ml/ 24  h) for 2  h prior or after Ang-II administration to induce apoptosis. For in vivo experiments, SHRs were orally administered with fisetin (10  mg/kg) twice a week for 6 weeks. Cellular apoptosis was analyzed by TUNEL staining assay and the modulation in the expression levels of proteins involved in apoptosis and cell survival were determined by western blotting. RESULTS: Our results demonstrate the potent cardioprotective efficacy of fisetin against Ang-II induced apoptosis in H9c2 cells and in SHR models. Fisetin administration reduced the apoptotic nuclei considerably And reduced the expression of apoptotic proteins such as TNF- α, Fas L, FADD, Cleaved caspase-3 and Cleaved PARP and increased the cell survival and anti-apoptotic proteins like Bcl-2, Bcl-xL, p-IGF1R, p-PI3K and p-AKT in both in vitro and in vivo models. CONCLUSION: In conclusion, the results of the present study reveal that fisetin activates the IGF-IR-dependent p-PI3K/p-Akt survival signaling pathway and suppresses the caspase dependent apoptosis.

Alpinate Oxyphyllae extracts enhance the longevity and homing of mesenchymal stem cells and augment their protection against senescence in H9c2 cells.

Adipose-derived mesenchymal stem cells (ADMSCs) are easily accessible and are attractive mesenchymal stem cells for use in regenerative medicine; however their application is frequently restricted due to various challenges present in the environment they are administered. Therefore ADMSCs are preferably preconditioned with various stimulating factors to overcome the barriers developed in any pathological conditions. Here we used ADMSCs from rat adipose based on the abundance of positive markers and preconditioned the cells with extracts from Alpinate Oxyphyllae Fructus (AOF), a traditional Chinese herb used for antiaging, associated various health benefits. The preconditioned stem cells were tested for their potential to drive H9c2 from doxorubicin (Dox)-induced aging. The AOF-treated stem cells enriched stemness in ADMSCs with respect to their stem cells' positive marker, and enhanced their longevity mechanism and elevated the stem cell homing-associated C-X-C chemokine receptor type 7 (CXCR7). The AOF preconditioned stem cells, when cocultured with H9c2 cells, showed effective protection to Dox-induced senescence and stem cell homing to damaged H9c2 cells. The presence of AOF provided greater protective effects in the Dox environment. In addition, AOF-pretreated ADMSCs showed enhanced migration than those treated with AOF in Dox environment. Therefore, our results show that administration of AOF preconditioned stem cells is potentially an effective strategy in the management of aging-associated cardiac disorders.

GABA tea attenuates cardiac apoptosis in spontaneously hypertensive rats (SHR) by enhancing PI3K/Akt-mediated survival pathway and suppressing Bax/Bak dependent apoptotic pathway.

Cardiomyocyte apoptosis is the major risk factor for the development of heart failure (HF). The purpose of this study was to evaluate the effects of Gamma-aminobutyric acid (GABA) tea on hypertension-induced cardiac apoptotic pathways in spontaneously hypertensive rats (SHR). In order to reveal the mechanisms, 36 male SHR at eight weeks of age, 200 g were divided into six groups. One group was fed water as a control group. Other rats were administered one of the following treatments: GABA tea at dose 150 and 300 mg/kg/day as low GABA tea (LGT) and high GABA tea (HGT) groups, respectively, pure GABA at dose 150 and 300 mg/kg/day as LG and HG groups, respectively, green tea (GT) as control of LGT and HGT groups. After 12 weeks, cardiac tissues were analyzed by histological analysis, western blotting, and TUNEL assays. GABA tea, GT, and pure GABA decreased hypertension-induced cardiac abnormalities, including abnormal myocardial architecture. In addition, GABA tea, GT, and pure GABA dramatically increased anti-apoptotic protein, Bcl2. Furthermore, GABA tea, GT, and pure GABA also decreased activated-caspase 9 and activated-caspase 3. Additionally, the survival associated protein IGF-I and PI3K/Akt were enhanced in cardiac tissues upon treatment. Our results showed an optimistic anti-apoptotic and pro-survival effects of GABA tea treatment against hypertensive rat hearts.

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.

Oolong tea prevents cardiomyocyte loss against hypoxia by attenuating p-JNK mediated hypertrophy and enhancing P-IGF1R, p-akt, and p-Badser136 activity and by fortifying NRF2 antioxidation system.

Tea, the most widely consumed natural beverage has been associated with reduced mortality risk from cardiovascular disease. Oolong tea is a partially fermented tea containing high levels of catechins, their degree of oxidation varies between 20%-80% causing differences in their active metabolites. In this study we examined the effect of oolong tea extract (OTE) obtained by oxidation at low-temperature for short-time against hypoxic injury and found that oolong tea provides cyto-protective effects by suppressing the JNK mediated hypertrophic effects and by enhancing the innate antioxidant mechanisms in neonatal cardiomyocytes and in H9c2 cells. OTE effectively attenuates 24 h hypoxia-triggered cardiomyocyte loss by suppressing caspase-3-cleavage and apoptosis in a dose-dependent manner. OTE also enhances the IGFIR/p-Akt associated survival-mechanism involving the elevation of p-Badser136 in a dose-dependent manner to aid cellular adaptations against hypoxic challenge. The results show the effects and mechanism of Oolong tea to provide cardio-protective benefits during hypoxic conditions.

Tanshinone IIA Inhibits ß-Catenin Nuclear Translocation and IGF-2R Activation via Estrogen Receptors to Suppress Angiotensin II-Induced H9c2 Cardiomyoblast Cell Apoptosis.

Cardiomyopathy involves changes in the myocardial ultra-structure, hypertrophy, apoptosis, fibrosis and inflammation. Angiotensin II (AngII) stimulates the expression of insulin like-growth factors (IGF-2) and IGF-2 receptor (IGF-2R) in H9c2 cardiomyoblasts and subsequently leads to apoptosis. Estrogen receptors protect cardiomyocytes from apoptosis and fibrosis. Tanshinone IIA (TSN), a main active ingredient from Danshen, has been shown to protect cardiomyocytes from death caused by different stress signals. Estrogen receptor α (ER) is required for the rapid activation of the IGF-1R signaling cascade. This study aimed to investigate whether TSN protected H9c2 cardiomyocytes from AngII-induced activation of IGF-2R pathway and hypertrophy via ERs. We found that AngII caused the reduction in IGF-1R phosphorylation and the elevation of ß-catenin and IGF-2R levels. This was reversed by increasing doses of TSN and of caspase-3 and ERK1/2 phosphorylation mediated by ERs. The phytoestrogen significantly attenuated AngII-induced apoptosis and suppressed the subsequent cardiac remodeling effect. Therefore, TSN reduced the AngII-induced activation of ß-catenin and IGF-2R pathways, apoptosis and cardiac remodeling via ERs in H9c2 cardiomyoblasts.