Estimating the impact of drug addiction causes heart damage.

To date, few studies have investigated the toxicological effects of the combined use of amphetamine and heroin in the heart. Hence, the aim of this study was to identify indicators for clinical evaluation and prevention of cardiac injury induced by the combined use of amphetamine and heroin. Four different groups were analyzed: (1) normal group (n＝25；average age＝35 ± 6.8); (2) heart disease group (n＝25；average age＝58 ± 17.2); (3) drug abusers (n = 27; average age = 37 ± 7.7); (4) drug abstainers (previous amphetamine-heroin users who had been drug-free for more than two weeks; n = 22; average age = 35 ± 5.6). The activity of MMPs, and levels of TNF-α, IL-6, GH, IGF-I, and several serum biomarkers were examined to evaluate the impact of drug abuse on the heart. The selected plasma biomarkers and classic cardiac biomarkers were significantly increased compared to the normal group. The zymography data showed the changes in cardiac-remodeling enzymes MMP-9 and MMP-2 among combined users of amphetamine and heroin. The levels of TNF-α and IL-6 only increased in the heart disease group. Growth hormone was increased; however, IGF-I level decreased with drug abuse and the level was not restored by abstinence. We speculated that the amphetamine-heroin users might pose risk to initiate heart disease even though the users abstained for more than two weeks. The activity change of MMP-9 and MMP-2 can be a direct reason affecting heart function. The indirect reason may be related to liver damage by drug abuse reduce IGF-1 production to protect heart function.

Andrographolide mitigates cardiac apoptosis to provide cardio-protection in high-fat-diet-induced obese mice.

Excessive intake of high fat diet (HFD) and associated obese conditions are critical contributors of cardiac diseases. In this study, an active metabolite andrographolide from Andrographis paniculata was found to ameliorate HFD-induced cardiac apoptosis. C57/BL6 mouse were grouped as control (n = 9), obese (n = 8), low dose (25 mg/kg/d) andrographolide treatment (n = 9), and high dose (50 mg/kg/d) andrographolide treatment (n = 9). The control group was provided with standard laboratory chow and the other groups were fed with HFD. Andrographolide was administered through oral gavage for 1 week. Histopathological analysis showed increase in apoptotic nuclei and considerable cardiac-damages in the obese group signifying cardiac remodeling effects. Further, Western blot results showed increase in pro-apoptotic proteins and decrease in the proteins of IGF-1R-survival signaling. However, feeding of andrographolide significantly reduced the cardiac effects of HFD. The results strongly suggest that andrographolide supplementation can be used for prevention and treatment of cardiovascular disease in obese patients.

A minireview of E4BP4/NFIL3 in heart failure.

Heart failure (HF) remains a major cause of morbidity and mortality worldwide. The primary cause identified for HF is impaired left ventricular myocardial function, and clinical manifestations may lead to severe conditions like pulmonary congestion, splanchnic congestion, and peripheral edema. Development of new therapeutic strategies remains the need of the hour for controlling the problem of HF worldwide. Deeper insights into the molecular mechanisms involved in etiopathology of HF indicate the significant role of calcium signaling, autocrine signaling pathways, and insulin-like growth factor-1 signaling that regulates the physiologic functions of heart growth and development such as contraction, metabolism, hypertrophy, cytokine signaling, and apoptosis. In view of these facts, a transcription factor (TF) regulating the myriad of these signaling pathways may prove as a lead candidate for development of therapeutics. Adenovirus E4 promoter-binding protein (E4BP4), also known as nuclear-factor, interleukin 3 regulated (NFIL3), a type of basic leucine zipper TF, is known to regulate the signaling processes involved in the functioning of heart. The current review discusses about the expression, structure, and functional role of E4BP4 in signaling processes with emphasis on calcium signaling mechanisms, autocrine signaling, and insulin-like growth factor II receptor-mediated processes regulated by E4BP4 that may regulate the pathogenesis of HF. We propose that E4BP4, being the critical component for the regulation of the above signaling processes, may serve as a novel therapeutic target for HF, and scientific investigations are merited in this direction.

Hypoxia suppresses myocardial survival pathway through HIF-1α-IGFBP-3-dependent signaling and enhances cardiomyocyte autophagic and apoptotic effects mainly via FoxO3a-induced BNIP3 expression.

The HIF-1α transcriptional factor and the BH-3 only protein BNIP3 are known to play fundamental roles in response to hypoxia. The objective of this research is to investigate the molecular mechanisms and the correlation of HIF-1α, BNIP3 and IGFBP-3 in hypoxia-induced cardiomyocytes injuries. Heart-derived H9c2 cells and neonatal rat ventricular myocytes (NRVMs) were incubated in normoxic or hypoxic conditions. Hypoxia increased HIF-1α expression and activated the downstream BNIP3 and IGFBP-3 thereby triggered mitochondria-dependent apoptosis. Moreover, IGF1R/PI3K/Akt signaling was attenuated by HIF-1α-dependent IGFBP-3 expression to enhance hypoxia-induced apoptosis. Autophagy suppression with 3-methyladenine or siATG5 or siBeclin-1 significantly decreased myocardial apoptosis under hypoxia. Knockdown of FoxO3a or BNIP3 significantly abrogated hypoxia-induced autophagy and mitochondria-dependent apoptosis. Moreover, prolonged-hypoxia induced HIF-1α stimulated BNIP3 and enhanced IGFBP-3 activation to inhibit IGF1R/PI3K/Akt survival pathway and mediate mitochondria-dependent cardiomyocyte apoptosis. HIF-1α and FoxO3a blockage are sufficient to annul the change of excessive hypoxia of hearts.

Antidiabetic Effects of a Short Peptide of Potato Protein Hydrolysate in STZ-Induced Diabetic Mice.

Alcalase- generated potato protein hydrolysate (APPH) is a potential bioactive peptide against diabetes mellitus (DM) and DM-associated secondary effects in animal models. The aim of the present study was to find the efficiency of a deca-peptide DIKTNKPVIF (DF) from APPH against DM. Six-week-old male ICR mice were divided into the following groups: Control, Control+DF (received 50 mg/kg DF), streptozotocin (STZ)-induced DM group, DM+Acarbose group (20 mg/kg of acarbose), DM+DF-L (25 mg/kg of DF), DM+DF-H (50 mg/kg of DF), and DM+APPH (50 mg/kg of APPH). Comparable to APPH, treatment with DF effectively regulated blood glucose level and also controlled plasma total glycerol (TG), total cholesterol (TC), insulin, and HbA1c levels in DM animals. DF treatment also showed evidence of ameliorating DM-associated damages in the pancreatic islets and in the liver, heart, and kidney tissues. Therefore, the results demonstrate that the short synthetic peptide-DF may effectively provide protection against DM-associated damages.

Anti-hypertrophic and anti-apoptotic effects of short peptides of potato protein hydrolysate against hyperglycemic condition in cardiomyoblast cells.

Cardiomyocyte hypertrophy is a critical pathological phenomenon observed in diabetic cardiomyopathy. Various molecular events including the Calcineurin/nuclear factor of activated T-cell (NFAT) mediated signaling contributes to the pathogenesis of cardiac hypertrophy. While different new therapeutic interventions are investigated in order to overcome pathological hypertrophic effects, recent studies on peptide hydrolysates from common foods have gained interest. In this study the cytoprotective efficiency of two short peptides DIKTNKPVIF (DF) and a dipeptide IF from a potato protein hydrolysate were evaluated for their anti-hypertrophic effects against high glucose (HG) challenge. Murine cardio myoblast (H9c2) cells were challenges with 33 mM of glucose and after 1 h were treated with DF or IF for 24 h. The results showed enlargement in cell size, elevated ANP and BNP expression induced by HG however the abnormalities were efficiently attenuated by IF and DF. Further, HG increased the levels of calcineurin and NFATC3 which was markedly suppressed by DF and IF in H9c2 cells. The results further showed that DF and IF suppresses the activation of p38 in a dose dependent manner with no notable effects on JNK activation. DF and IF also attenuated the HG induced apoptotic effects in H9c2 cells by suppressing the apoptotic proteins and by enhancing the survival and anti-apoptotic proteins. Further, it should be noted that administration of both the fragments showed similar effects in all the analysis. Our results therefore showed that DF and IF of potato protein hydrolysate possess efficient protective effects against HG-induced cardiomyocyte damages by ameliorating the apoptotic and hypertrophic effects.

Lipolysis-Stimulating Peptide from Soybean Protects Against High Fat Diet-Induced Apoptosis in Skeletal Muscles.

Obesity is generally associated with low-grade chronic inflammation that involves the recruitment of macrophages and other inflammation factors to the adipocytes of obese individuals. Tumor necrosis factor-alpha (TNF-α), a cytokine associated with systemic inflammation, is elevated in conditions of obesity. TNF-α is an important factor that plays an important role in skeletal muscle wasting. Apoptosis of myonuclei contributes to the loss of muscle mass and therefore plays an important role in skeletal muscle atrophy. In mouse models that were fed a high fat diet (HFD), a lipolysis-stimulating peptide-VHVV (purified from hydrolysate resulting from flavourzyme treatment of soy protein) was found to reduce HFD-related apoptotic effects in mice skeletal muscle and potentially control atrophy. HFD fed mice had heavier body weight than those fed with normal chow, and VHVV administration restricted lipid accumulation in muscle tissues of mice fed with HFD but increased nutrient uptake. Moreover, specific concentrations of VHVV regulated TNF-α expression that was elevated by HFD, suppressed apoptosis-related proteins and regulated the proteins of lipid metabolism.

Pharmacological benefits of neferine - A comprehensive review.

This article recapitulates the existing in vitro and in vivo studies focusing on the effects of neferine-an alkaloid derivative of lotus plant, in various disease models and its effects on key signaling molecules. The review also compiles a large number of research studies that demonstrate methods for isolation and extraction, biosynthetic pathway, pharmacological activity and mode of action of neferine and their underlying mechanisms at cellular level. Neferine is a unique bis-benzylisoquinoline alkaloid that possesses a number of therapeutic effects such as anti-cancer, anti-diabetic, anti-aging, anti-microbial, anti-thrombotic, anti-arrhythmic, anti-inflammatory and even anti-HIV. It also enhances the anti-cancer properties of other anti-cancer drugs like cisplatin, adriamycin, taxol, etc. It is also reported to reverse chemo-resistance and enhance sensitivity of the cancer cells towards anti-cancer drugs. The underlying mechanisms for its activities mainly include apoptosis, autophagy and G1 arrest. Neferine protects them against the effect of drugs like cisplatin. The therapeutic properties of neferine is widely diverse, while it shows toxicity to cancer it also shows cyto-protective effects against cardio-vascular diseases, pulmonary disease, and is also effective against Alzheimer's disease and elicits anti-oxidative effect in many cellular systems. This article thus is the first ever attempt to review the therapeutic activities of neferine established in in vitro and in vivo models and to compile all the fragmented data available on the omnipotent activities of neferine.