Antioxidant Sirt1/Akt axis expression in resveratrol pretreated adipose-derived stem cells increases regenerative capability in a rat model with cardiomyopathy induced by diabetes mellitus.

High-glucose (HG) suppresses mesenchymal stem cell (MSC) functions, resulting in a decrease in cardiac regenerative capability for MSC in diabetes mellitus (DM). Resveratrol enhances MSC functions under stress. This study explores if cardiac regenerative capability can be enhanced in MSCs pretreated with resveratrol in DM rats receiving MSCs. In vitro evidence confirms that HG decreases MSCs capability through suppression of survival markers, AMP-activated protein kinase (AMPK)/Sirtuin 1 (Sirt1) axis, and expression of apoptotic markers. All of these markers are improved when MSCs are cocultured with resveratrol. Wistar male rats were randomly divided into Sham, DM (DM rats), DM rats with autologous transplantation of adipose-derived stem cells (DM + ADSC), and DM rats with resveratrol pretreated ADSC (DM + RSVL-ADSC). Compared to the Sham, DM induces pathological pathways (including fibrosis, hypertrophy, and apoptosis) and suppresses survival as well as the AMPK/Sirt1 axis in the DM group. DM + ADSC slightly improves the above pathways whereas DM + RSVL-ADSC significantly improves the above pathways when compared to the DM group. These results illustrate that resveratrol pretreated with MSCs may show clinical potential in the treatment of heart failure in patients with DM.

Chemoresistance-Associated Silencing of miR-4454 Promotes Colorectal Cancer Aggression through the GNL3L and NF-κB Pathway.

Guanine nucleotide-binding protein-like-3-like (GNL3L) is a crucial regulator of NF-κB signaling that is aberrantly activated during diverse chemoresistance-associated cellular processes. However, the molecular mechanisms of GNL3L tumor initiation and resistant state are largely unknown. Moreover, the identification of predictive biomarkers is necessary to effectively generate therapeutic strategies for metastatic human colorectal cancer (CRC). This study aims to identify how cells acquire resistance to anticancer drugs and whether the downregulation of miR-4454 is associated with the progression of CRC. Here, we have shown that the overexpression of miR-4454 in resistant tumors is a crucial precursor for the posttranscriptional repression of GNL3L in human chemoresistant CRC progression, and we used doxycycline induced miR-4454 overexpression that significantly reduced tumor volume in a subcutaneous injection nude mice model. Together, these observations highlight that the downregulation of miR-4454 in resistant clones is prominently responsible for maintaining their resistance against anticancer drug therapy. Our study indicates that the development of miR-4454 as a microRNA-based therapeutic approach to silence GNL3L may remarkably reduce oncogenic cell survival that depends on GNL3L/NF-κB signaling, making miR-4454 a candidate for treating metastatic human CRC.

The combined inhibition of the CaMKIIδ and calcineurin signaling cascade attenuates IGF-IIR-induced cardiac hypertrophy.

Cardiac hypertrophy is a common phenomenon observed in progressive heart disease associated with heart failure. Insulin-like growth factor receptor II (IGF-IIR) has been much implicated in myocardial hypertrophy. Our previous studies have found that increased activities of signaling mediators, such as calcium/calmodulin-dependent protein kinase II (CaMKII) and calcineurin induces pathological hypertrophy. Given the critical roles played by CaMKII and calcineurin signaling in the progression of maladaptive hypertrophy, we anticipated that inhibition of CaMKII and calcineurin signaling may attenuate IGF-IIR-induced cardiac hypertrophy. The current study, therefore, investigated the effects of IGF-IIR activation on the CaMKII and calcineurin signaling and whether the combinatorial inhibition of the CaMKIIδ and calcineurin signaling could ameliorate IGF-IIR-induced pathological hypertrophy. In the present study, we induced IGF-IIR through the cardiomyocyte-specific transduction of IGFIIY27L via adeno-associated virus 2 (AAV2) to evaluate its effects on cardiac hypertrophy. Interestingly, it was observed that the activation of IGF-IIR signaling through IGFIIY27L induces significant hypertrophy of the myocardium and increased cardiac apoptosis and fibrosis. Moreover, we found that Leu27 IGF-II significantly induced calcineurin and CaMKII expression. Furthermore and importantly, the combinatorial treatment with CaMKII and calcineurin inhibitors significantly alleviates IGF-IIR-induced hypertrophic responses. Thus, it could be envisaged that the inhibition of IGF-IIR may serve as a promising candidate for attenuating maladaptive hypertrophy. Both calcineurin and CaMKII could be valuable targets for developing treatment strategies against hypertension-induced cardiomyopathies.

Deep ocean minerals inhibit IL-6 and IGFIIR hypertrophic signaling pathways to attenuate diabetes-induced hypertrophy in rat hearts.

We previously reported that deep sea water (DSW) prolongs the life span of streptozotocin (STZ)-induced diabetic rats by the compensatory augmentation of the insulin like growth factor (IGF)-I survival signaling and inhibition of apoptosis. Here, we investigated the effects of DSW on cardiac hypertrophy in diabetic rats. Cardiac hypertrophy was induced in rats by using STZ (65 mg/kg) administered via IP injection. DSW was prepared by mixing DSW mineral extracts and desalinated water. Different dosages of DSW-1X (equivalent to 37 mg Mg2+·kg-1·day-1), 2X (equivalent to 74 mg Mg2+·kg-1·day-1) and 3X (equivalent to 111 mg Mg2+·kg-1·day-1) were administered to the rats through gavage for 4 wk. Cardiac hypertrophy was evaluated by the heart weight-to-body weight ratio and the cardiac tissue cross-sectional area after hematoxylin and eosin staining. The protein levels of the cardiac hypertrophy signaling molecules were determined by Western blot. Our results showed that the suppressive effects of the DSW treatment on STZ-induced cardiac hypertrophy were comparable to those of MgSO4 administration and that the hypertrophic marker brain natriuretic peptide (BNP) was decreased by DSW. In addition, DSW attenuated both the eccentric hypertrophy signaling pathway, IL-6-MEK-STAT3, and the concentric signaling pathway, IGF-II-PKCα-CaMKII, in DM rat hearts. The cardiac hypertrophy-associated activation of extracellular signal-regulated kinase (ERK) and the upregulation of the transcription factor GATA binding protein 4 (GATA4) were also negated by treatment with DSW. The results from this study suggest that DSW could be a potential therapeutic agent for the prevention and treatment of diabetic cardiac hypertrophy.NEW & NOTEWORTHY Deep sea water, containing high levels of minerals, improve cardiac hypertrophy in diabetic rats through attenuating the eccentric signaling pathway, IL-6-MEK5-STAT3, and concentric signaling pathway, IGF2-PKCα-CaMKII. The results from this study suggest that deep sea water could be a potential therapeutic agent for the prevention and treatment of diabetic cardiac hypertrophy.

Insulin-like growth factor II receptor-α is a novel stress-inducible contributor to cardiac damage underpinning doxorubicin-induced oxidative stress and perturbed mitochondrial autophagy.

Doxorubicin (DOX) is an anthracycline antibiotic commonly employed for the treatment of various cancers. However, its therapeutic uses are hampered by side effects associated with cumulative doses during the course of treatment. Whereas deregulation of autophagy in the myocardium has been involved in a variety of cardiovascular diseases, the role of autophagy in DOX-induced cardiomyopathy remains debated. Our earlier studies have shown that DOX treatment in a rat animal model leads to increased expression of the novel stress-inducible protein insulin-like growth factor II receptor-α (IGF-IIRα) in cardiac tissues, which exacerbated the cardiac injury by enhancing oxidative stress and p53-mediated mitochondria-dependent cardiac apoptosis. Through this study, we investigated the contribution of IGF-IIRα to dysregulation of autophagy in heart using both in vitro H9c2 cells (DOX treated, 1 µM) and in vivo transgenic rat models (DOX treated, 5 mg/kg ip for 6 wk) overexpressing IGF-IIRα specifically in the heart. We found that IGF-IIRα primarily localized to mitochondria, causing increased mitochondrial oxidative stress that was severely aggravated by DOX treatment. This was accompanied by a significant perturbation in mitochondrial membrane potential and increased leakage of cytochrome c, causing increased cleaved caspase-3 activity. There were significant alterations in phosphorylated AMP-activated protein kinase (p-AMPK), phosphorylated Unc-51 like kinase-1 (p-ULK1), PARKIN, PTEN-induced kinase 1 (PINK1), microtubule-associated protein 1 light chain 3 (LC3), and p62 proteins, which were more severely disrupted under the combined effect of IGF-IIRα overexpression plus DOX. Finally, LysoTracker Red staining showed that IGF-IIRα overexpression causes lysosomal impairment, which was rescued by rapamycin treatment. Taken together, we found that IGF-IIRα leads to mitochondrial oxidative stress, decreased antioxidant levels, disrupted mitochondrial membrane potential, and perturbed mitochondrial autophagy contributing to DOX-induced cardiomyopathy.

Upregulation of IGF-IIRα intensifies doxorubicin-induced cardiac damage.

Cardiotoxicity by doxorubicin hampers its therapeutic potential as an anticancer drug, but mechanisms leading to cardiotoxicity remain contentious. Through this study, the functional contribution of insulin-like growth factor receptor type II α (IGF-IIRα) which is a novel stress-inducible protein was explored in doxorubicin-induced cardiac stress. Employing both in vitro H9c2 cells and in vivo transgenic rat models (SD-TG [IGF-IIRα]) overexpressing IGF-IIRα specifically in heart, we found that IGF-IIRα leads to cardiac structural abnormalities and functional perturbations that were severely aggravated by doxorubicin-induced cardiac stress. Overexpression of IGF-IIRα leads to cumulative elevation of stress associated cardiac hypertrophy and apoptosis factors. There was a significant reduction of survival associated proteins p-Akt and estrogen receptor ß/α, and abnormal elevation of cardiac hypertrophy markers such as atrial natriuretic peptide, cardiac troponin-I, and apoptosis-inducing agents such as p53, Bax, and cytochrome C, respectively. IGF-IIRα also altered the expressions of AT1R, ERK1/2, and p38 proteins. Besides, IGF-IIRα also increased the reactive oxygen species production in H9c2 cells which were markedly aggravated by doxorubicin treatment. Together, we showed that IGF-IIRα is a novel stress-induced protein that perturbed cardiac homeostasis and cumulatively exacerbated the doxorubicin-induced cardiac injury that perturbed heart functions and ensuing cardiomyopathy.

CHIP attenuates lipopolysaccharide-induced cardiac hypertrophy and apoptosis by promoting NFATc3 proteasomal degradation.

Carboxyl-terminus of Hsc70 interacting protein (CHIP) is a chaperone-dependent E3-ubiquitin ligase with important function in protein quality control system. In the current research endeavor, we have investigated the putative role of CHIP in lipopolysaccharides (LPS)-induced cardiomyopathies. Basically, H9c2 cardiomyoblasts were transfected with CHIP for 24 hr, and thereafter, treated with LPS for 12 hr. Concomitantly, western blot analysis, actin staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and coimmunoprecipitation studies were performed to investigate the underlying intricacies. Interestingly, western blot analysis revealed that the expression of hypertrophy and apoptosis-related proteins were considerably reduced following overexpression of CHIP. Moreover, Actin staining and TUNEL assay further ascertained the attenuation of cardiac hypertrophy and apoptosis following overexpression of CHIP respectively. These aspects instigate the role of CHIP in attenuation of LPS-induced cardiomyopathies. Additionally and importantly, co-immunoprecipitation and western blot studies revealed that CHIP plausibly promotes degradation of nuclear factor of activated T cells 3 (NFATc3) through ubiquitin-proteasomal pathway. Taken together, our study reveals that CHIP attenuates LPS-induced cardiac hypertrophy and apoptosis perhaps by promoting NFATc3 proteasomal degradation.

Taiwanin C elicits apoptosis in arecoline and 4-nitroquinoline-1-oxide-induced oral squamous cell carcinoma cells and hinders proliferation via epidermal growth factor receptor/PI3K suppression.

Oral Squamous Cell Carcinoma (OSSC) is a major life-threatening disease with high incidence in the Southeast Asian countries. Chronic exposure to arecoline causes genetic changes in the epithelial cells of the oral mucosa, induces proliferation through activation of the EGF receptor and promotes downstream COX-2 expression. Taiwanin C, a podophyllotoxin derived from Taiwania cryptomerioides Hayata is known to inhibit COX activity and to hinder PGE2 production in macrophages. In this study a tumor cell line T28 and a non-tumor cell line N28 derived from mice OSCC models were used to study the effect of Taiwanin C on PGE2 associated COX-2 expression and cell cycle regulators. Taiwanin C activated p21 protein expression, down-regulated cell cycle regulatory proteins, elevated apoptosis and down-regulated p-PI3K/p-Akt survival mechanism in T28 oral cancer cells. Our results therefore emphasize the therapeutic potential of Taiwanin C against arecoline-induced oral cancer.

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.

Exercise training augments Sirt1-signaling and attenuates cardiac inflammation in D-galactose induced-aging rats.

Exercise is known to be beneficial in controlling aging associated disorders however, the consequence of long-term exercise on cardiac health among aging population is not much clear. In this study the protective effect of exercise on aging associated cardiac disorders was determined using a D-galactose-induced aging model. Eight weeks old Sprague Dawley rats were given intraperitoneal injection of 150 mL/kg D-galactose. Swimming exercise was provided in warm water for 60 min/day for five days per week. Hematoxylin and eosin staining of cardiac tissue sections revealed cardiomyocyte disarrangements in the aging rat hearts but long-term exercise training showed improvements in the cardiac histology. Exercise training also enhanced the expression levels of proteins such as SIRT1, PGC-1α and AMPKα1 that are associated with energy homeostasis and further suppressed aging associated inflammatory cytokines. Our results show that long-term exercise training potentially enhances SIRT1 associated anti-aging signaling and provide cardio-protection against aging.

Cryptotanshinone (Dsh-003) from Salvia miltiorrhiza Bunge inhibits prostaglandin E2-induced survival and invasion effects in HA22T hepatocellular carcinoma cells.

Human hepatocellular carcinoma (HCC) is currently the second most common cancer and one of the leading causes of cancer-related mortality in Taiwan. Previous reports show that the expression of (E-type prostaglandin 2) EP2 and (E-type prostaglandin 4) EP4 are elevated in HCC and further demonstrate that Prostaglandin E2 (PGE2) induces HA22T cell proliferation and metastasis through EP2 and EP4 receptor. Danshen (root of Salvia miltiorrhiza Bunge) is a very important and popular traditional Chinese herbal medicine which is widely and successfully used against breast cancer, leukemia, pancreatic cancer, and head and neck squamous carcinoma cells. In this study, we used Cryptotansinone (Dsh-003) (MW 269.14) from Danshen to investigate their effect and corresponding mechanism of action in PGE2-treated HA22T cells. Dsh-003 inhibited HA22T cell viability and further induced cell apoptosis in PGE2-treated HA22T cells. Furthermore, Dsh-003 inhibited EP2, EP4, and their downstream effector such as p-PI3K and p-Akt expression in HA22T hepatocellular carcinoma cells. We also observed that Dsh-003 blocked PGE2-induced cell migration by down-regulating PGE2-induced ß-catenin expression and by up-regulating E-cadherin and GSK3-ß expression. All these findings suggest that Dsh-003 inhibit human HCC cell lines and could potentially be used as a novel drug for HCC treatment.

Bioactive Peptide Improves Diet-Induced Hepatic Fat Deposition and Hepatocyte Proinflammatory Response in SAMP8 Ageing Mice.

BACKGROUND/AIMS: High-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) poses therapeutic challenges in elderly subjects. Due to lack of efficient drug therapy, plant-based bioactive peptides have been studied as alternative strategy in NAFLD and for less toxicity in elderly. To mimic fatty liver in aging conditions, researchers highly commended the genetically engineered strains SAMP8 (senescence-accelerated mice prone 8). However, there is a paucity of reports about the anti-steatosis effects of bioactive peptides against fatty liver development under a combined action of high-fat diet exposure and aging process. This study was conducted to evaluate the activity of DIKTNKPVIF peptide synthesized from alcalase-generated potato protein hydrolysate (PH), on reducing HFD-driven and steatosis-associated proinflammatory reaction in ageing model. METHODS: Five groups of six-month-old SAMP8 mice (n=4, each) were fed either a normal chow (NC group) for 14 weeks upon sacrifice, or induced with a 6-week HFD feeding, then treated without (HCO group) or with an 8-week simultaneous administration of peptide (HPEP group), protein (HPH group) or probucol (HRX group). Liver organs were harvested from each group for histological analysis and immunoblot assay. RESULTS: In contrast to NC, extensive fat accumulation was visualized in the liver slides of HCO. Following the trends of orally administered PH, intraperitoneally injected peptide reduces hepatic fat deposition and causes at protein level, a significant decrease in HFD-induced proinflammatory mediators p-p38 MAPK, FGF-2, TNF-α, IL-6 with concomitant reactivation of AMPK. However, p-Foxo1 and PPAR-α levels were slightly changed. CONCLUSION: Oral supplementation of PH and intraperitoneal injection of derived bioactive peptide alleviate proinflammatory reaction associated with hepatosteatosis development in elderly subjects, through activation of AMPK.

Anti-Apoptosis and Anti-Fibrosis Effects of Eriobotrya Japonica in Spontaneously Hypertensive Rat Hearts.

Myocardial apoptosis and fibrosis represent important contributing factors for development of hypertension-induced heart failure. The present study aims to investigate the potential effects of Eriobotrya japonica leaf extract (EJLE) against hypertension-induced cardiac apoptosis and fibrosis in spontaneously hypertensive rats (SHRs). Twelve-week-old male rats were randomly divided into four different groups; control Wistar Kyoto (WKY) rats, hypertensive SHR rats, SHR rats treated with a low dose (100 mg/kg body weight) of EJLE and SHR rats treated with a high dose (300 mg/kg body weight) of EJLE. Animals were acclimatized for 4 weeks and thereafter were gastric fed for 8 weeks with two doses of EJLE per week. The rats were then euthanized following cardiac functional analysis by echocardiography. The cardiac tissue sections were examined by Terminal Deoxynucleotidyl Transferase-Mediated Deoxyuridine Triphosphate (dUTP) Nick End-Labeling (TUNEL) assay, histological staining and Western blotting to assess the cardio-protective effects of EJ in SHR animals. Echocardiographic measurements provided convincing evidence to support the ability of EJ to ameliorate crucial cardiac functional characteristics. Furthermore, our results reveal that supplementation of EJLE effectively attenuated cardiac apoptosis and fibrosis and also enhanced cell survival in hypertensive SHR hearts. Thus, the present study concludes that EJLE potentially provides cardio-protective effects against hypertension-induced cardiac apoptosis and fibrosis in SHR animals.

17ß-Estradiol and/or estrogen receptor alpha signaling blocks protein phosphatase 1 mediated ISO induced cardiac hypertrophy.

Earlier studies have shown that estrogen possess protective function against the development of pathological cardiac hypertrophy. However, the molecular mechanisms of estrogens (E2) protective effect are poorly understood. Additionally, abnormal activation of ß-adrenergic signaling have been implicated in the development of pathological cardiac remodeling. However, the role of serine/threonine protein phosphatase 1 (PP1) in pathological cardiac remodeling under the influence of ß-adrenergic signaling have been sparsely investigated. In this study, we assessed the downstream effects of abnormal activation of PP1 upon isoproterenol (ISO) induced pathological cardiac changes. We found that pre-treatment of 17ß-estradiol (E2), tet-on estrogen receptor-α, or both significantly inhibited ISO-induced increase in cell size, hypertrophy marker gene expression and cytosolic calcium accumulation in H9c2 cells. Additionally, treatment with estrogen receptor inhibitor (ICI) reversed those effects, implicating role of E2 in inhibiting pathological cardiac remodeling. However, specific inhibition of ERα using melatonin, reduced ISO-induced PP1c expression and enhanced the level of ser-16 phosphorylated phospholamban (PLB), responsible for regulation of sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity. Furthermore, hypertrophic effect caused by overexpression of PP1cα was reduced by treatment with specific inhibitor of ERα. Collectively, we found that estrogen and estrogen receptor-α have protective effect against pathological cardiac changes by suppressing PP1 expression and its downstream signaling pathway, which further needs to be elucidated.

Estrogen and/or Estrogen Receptor α Inhibits BNIP3-Induced Apoptosis and Autophagy in H9c2 Cardiomyoblast Cells.

The process of autophagy in heart cells maintains homeostasis during cellular stress such as hypoxia by removing aggregated proteins and damaged organelles and thereby protects the heart during the times of starvation and ischemia. However, autophagy can lead to substantial cell death under certain circumstances. BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), a hypoxia-induced marker, has been shown to induce both autophagy and apoptosis. A BNIP3-docked organelle, e.g., mitochondria, also determines whether autophagy or apoptosis will take place. Estrogen (E2) and estrogen receptor (ER) alpha (ERα) have been shown to protect the heart against mitochondria-dependent apoptosis. The aim of the present study is to investigate the mechanisms by which ERα regulates BNIP3-induced apoptosis and autophagy, which is associated with hypoxic injury, in cardiomyoblast cells. An in vitro model to mimic hypoxic injury in the heart by engineering H9c2 cardiomyoblast cells to overexpress BNIP3 was established. Further, the effects of E2 and ERα in BNIP3-induced apoptosis and autophagy were determined in BNIP3 expressing H9c2 cells. Results from TUNEL assay and Immunoflourecense assay for LC3 puncta formation, respectively, revealed that ERα/E2 suppresses BNIP3-induced apoptosis and autophagy. The Western blot analysis showed ERα/E2 decreases the protein levels of caspase 3 (apoptotic marker), Atg5, and LC3-II (autophagic markers). Co-immunoprecipitation of BNIP3 and immunoblotting of Bcl-2 and Rheb showed that ERα reduced the interaction between BNIP3 and Bcl-2 or Rheb. The results confirm that ERα binds to BNIP3 causing a reduction in the levels of functional BNIP3 and thereby inhibits cellular apoptosis and autophagy. In addition, ERα attenuated the activity of the BNIP3 promoter by binding to SP-1 or NFκB sites.

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.

Adipose-derived stem cells decrease cardiomyocyte damage induced by porphyromonas gingivalis endotoxin through suppressing hypertrophy, apoptosis, fibrosis, and MAPK markers.

Heart failure is one of the complications related to periodontal disease. In addition to drugs or herbal medicines, stem cell therapy shows potential in the treatment of cardiomyopathy. This study investigates if stem cells exhibit beneficial effects on cardiomyocyte damage induced by porphyromonas gingivalis endotoxin (Pg-LPS). From the experimental results we find that Pg-LPS reduce cardiomyocyte viability via the activation of apoptosis, hypertrophy, fibrosis and MAPK signaling. Pg-LPS damaged cardiomyocytes co-cultured with adipose-derived stem cells (ADSC) increases cardiomyocyte viability through suppressing the pathological markers described above. Further evidence implies that survival marker, IGF1, secreted from ADSC, may play an important role in the Pg-LPS induced protective effect on cardiomyocyte damage.

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.

E4BP4 inhibits AngII-induced apoptosis in H9c2 cardiomyoblasts by activating the PI3K-Akt pathway and promoting calcium uptake.

The bZIP transcription factor E4BP4 is a survival factor that is known to be elevated in diseased heart and promote cell survival. In this study the role of E4BP4 on angiotensin-II (AngII)-induced apoptosis has been examined in in vitro cell model. H9c2 cardiomyoblast cells that overexpressed E4BP4 were exposed to AngII to observe the cardio-protective effects of E4BP4 on hypertension related apoptosis. The results from TUNEL assays revealed that E4BP4 significantly attenuated AngII-induced apoptosis. Further analysis by Western blot and RT-PCR showed that E4BP4 inhibited AngII-induced IGF-II mRNA expression and cleavage of caspase-3 through the PI3K-Akt pathway. In addition, E4BP4 enhanced calcium reuptake into the sacroplasmic reticulum by down-regulating PP2A and by up-regulating the phosphorylation of PKA and PLB proteins. Our findings indicate that E4BP4 functions as a survival factor in cardiomyoblasts by inhibiting IGF-II transcription and by regulating calcium cycling.

The multifaceted link between inflammation and human diseases.

Increasing reports on epidemiological, diagnostic, and clinical studies suggest that dysfunction of the inflammatory reaction results in chronic illnesses such as cancer, arthritis, arteriosclerosis, neurological disorders, liver diseases, and renal disorders. Chronic inflammation might progress if injurious agent persists; however, more typically than not, the response is chronic from the start. Distinct to most changes in acute inflammation, chronic inflammation is characterized by the infiltration of damaged tissue by mononuclear cells like macrophages, lymphocytes, and plasma cells, in addition to tissue destruction and attempts to repair. Phagocytes are the key players in the chronic inflammatory response. However, the important drawback is the activation of pathological phagocytes, which might result from continued tissue damage and lead to harmful diseases. The longer the inflammation persists, the greater the chance for the establishment of human diseases. The aim of this review was to focus on advances in the understanding of chronic inflammation and to summarize the impact and involvement of inflammatory agents in certain human diseases.