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Objectives: The symptoms of COVID-19 resemble those of a variety of mild to severe clinical conditions. Having epidemiological knowledge of the clinical symptoms of COVID‑19 and associated factors may help health workers to diagnose and manage the disease. Assessment of COVID-19’s clinical symptoms is therefore necessary to support health workers in Banten, Indonesia. Materials and Methods: In this descriptive cross-sectional study, we purposively analysed 1492 medical records from our online COVID-19 database. All data were analysed in a consecutive manner and were shown as percentages or significances. Results: Medical records revealed that 577 patients (39%) were male and 915 (61%) were female. Our sample contained 106 patients (7%) who tested positive for COVID-19. Among these 106 patients, 70 were asymptomatic (66%) while the rest (34%) had single or multiple clinical symptoms. The most common symptom was fever (16%), followed by cough (15%), fatigue (11%), headache (11%), dysphagia (10%), rhinorrhoea (8%), nausea (7%), dyspnoea (4%) and diarrhoea (2%). Subsequently, gender differences were found to be significantly associated with positive cases (p

Recently, much attention has been focused on the exploration of the ethnomedicine containing the antioxidant property for limiting the harmful effects of excessive reactive oxygen species (ROS) generation in the body. Bauhinia scandens has been reported to exert antioxidant property however which part of the plant has not been fully elucidated yet. The study aimed to investigate the antioxidant activity of Bauhinia scandens especially in the bark and leaf parts. The antioxidant activity of this plant was measured using 1,1-diphenyl- 2-picrylhydrazyl (DPPH) assay method. The inhibitory concentration 50 (IC50) of each sample was calculated to show the antioxidant activity. The IC50 value of Bauhinia scandens barks and leaves ethanolic extract were 34.77 µg/ml and 113.50 µg/ml respectively and standard ascorbic acid (as positive control) IC50 was 79.57 µg/ml. To our knowledge, this is the first study to show Bauhinia scandens barks ethanolic extract exerts higher antioxidant activity compared to ascorbic acid. This activity may relate to the specific Phytochemicals in Bauhinia scandens.

Introduction: 14-3-3 protein plays an important role in protecting cardiac cells from hypertrophy and endoplasmic reticulum stress during pressure overload elicited by aortic banding (AB) surgery; however, the relation among these protective roles is largely unknown. Methods: We investigated the in vivo role of 14-3-3 protein in two protocols involving C57/BL-6 mice and dominant negative (DN) 14-3-3η mice subjected to three- or seven-days pressure overload stimulation by applying AB surgery. The protein expressions of cardiac hypertrophy and ER stress markers, including atrial natriuretic peptide (ANP), galectin-3, glucose-regulated protein (GRP)78, calreticulin as well as 14-3-3 protein was analyzed by western blot. Results: Three- or seven-day pressure overload stimulation significantly increased the heart weight/body weight (HW/BW) ratio; cardiomyocyte diameter; and the protein expression levels of ANP, GRP78 as well as 14-3-3 in the C57/BL-6 mice. Partial inactivation of 14-3-3 protein in the DN 14-3-3η mice significantly increased the protein expression of ANP, Galectin-3, GRP78, and calreticulin after three- or seven-days AB surgery. Conclusion: These results suggest that 14-3-3 protein, as a molecular chaperone, protects against pathological cardiac hypertrophy, at least in part, by maintaining the normal ER function through the regulation of GRP78 and calreticulin.

Obesity is characterized with excessive accumulation of the body fat which occurs when the energy intake exceeds the expenditure. It is routinely associated with insulin resistance and hyperinsulinemia. Additionally, suppressing insulin level protects female mice from weight gaining. Cinnamon [Cinnamomum burmannii (Ness) Bl. Cortex] suppresses hyperinsulinemia condition in the type 2 diabetic rat suggesting the possible beneficial its role in the obesity. We aimed to investigate the effect of Cinnamon extract in the normal obese subjects. In this preliminary cross-over clinical trial, 24 normal obese subjects were recruited and divided randomly into two groups i.e. treatment and placebo. Two grams of the cinnamon extract were given twice daily for 56 days in the treatment group. Normal obese subjects given placebo were allocated as the placebo group. After the treatment, each of the group ran a one month run-in period, then the groups were crossovered for the next 56 days. Body mass index (BMI), insulin serum level, cholesterol and triglyceride plasma levels were measured at the beginning and at the end of the study. No diet restriction nor exercise intervention was given during the study. At the end of the study, BMI in the treatment group (58%) were slightly reduced when compared to the placebo group (33%), however, it was not significantly different (p>0.05). Moreover, significantly reduction in the insulin serum level was observed in 63% subject in the treatment group compared to 33% subject in the placebo group (p < 0.05). Additionally, there were no significant differences of cholesterol and triglyceride plasma level observed in the both group. In conclusion, cinnamon extract may give beneficial role in the normal obese subjects by suppressing the serum insulin level. Further studies are required to elucidate the specific role of cinnamon in preventing weight gain.

Background: Placenta accreta spectrum disorder (PAS), such as placenta accreta, placenta increta, and placenta percreta are causes of post-partum hemorrhage causing maternal morbidity and mortality. The major risk issues are prior caesarean section, placenta previa, advanced maternal age, multiparity, and preeclampsia. A reliable antenatal diagnosis is required for this serious condition. To reduce the incidence of maternal morbidity and mortality due to massive bleeding, it is necessary to make an early diagnosis in order for the surgical approach can be planned in the future. High birth rates and cesarean delivery are the cause of an increase in the incidence of PAS in middle / low-income countries. Additional diagnostic methods, advanced surgical methods, and other interventional radiological methods can greatly contribute to reducing maternal morbidity and mortality in high-income countries but are frequently not available in low-resource settings. Therefore, an inexpensive management strategy is an important issue.Methods: This is a retrospective case series. The patients suspected of PAS are reassessed histologically for the diagnosis confirmation. The information about risk factors, time to decide a definite diagnosis, monitoring vital signs, resuscitation, blood transfusions, surgical management, and maternal outcomes are detailed in a table.Result: We reported five women with PAS, diagnosed and managed in our hospital, with different conditions at admission and a different risk factor for PAS. All of the patients undergoing subtotal hysterectomy and uterine tissue samples were sent to the anatomical pathology department for histopathological examination. Red blood cell transfusions were used in all patients and transfer of patients to the intensive care unit was carried out postoperatively. Complications related to monitoring occurred in one patient such as acute kidney injury. There was one maternal death that occurred.Conclusion: Antenatal diagnosis is essential in outlining the best management strategy in patients with PAS. The clinical approach was able to prove valuable when PAS is suspected before delivery. In low-resource settings, lack of interventional radiology services and prenatal diagnostic may probably impact patients management with PAS.International Journal of Human and Health Sciences Vol. 05 No. 04 October’21 Page: 503-509

Introduction: Prolonged hyperglycemia may lead to several detrimental microvascular or macrovascular complications in the chronic diabetes mellitus. Thus, achieving normal glycemic condition remains the most important strategy in the diabetes mellitus. Stevia rebaudiana plays an important role on the blood glucose reduction, however, its role in the chronic diabetes mellitus has not been fully elucidated yet.Method: Stevia rebaudiana dry extract (400 mg/kg BW) were given daily by oral gavage for 84 days in rat with diabetes. The measurement of blood glucose concentration were done monthly during the study. Urine output was analyzed on the day 1 and 84. Additionally, lipid profile were measured on the day 84.Results: Compared to the normal rat, significant hyperglycemia were observed in the diabetic rat. Blood glucose concentration tends to decrease in the rat received Stevia rebaudiana extract (St), however, significant difference was achieved on the day 84 of the study confronted to the diabetic rats. Moreover, lower concentration of plasma cholesterol concentration and urine output reduction was significantly observed in the St rat compared to the D rat on the day 84.Discussion: Daily intake of Stevia rebaudiana extract on its therapeutic doses may play beneficial role in the chronic diabetes mellitus by gradually reduced blood glucose concentration, urine output and plasma cholesterol concentration. However, further cellular analysis were required to explicate the exact mechanism.International Journal of Human and Health Sciences Vol. 05 No. 01 January’21 Page: 22-26

Background: Indonesia is a country that has diversity of spices and types of cuisine. In the early 70s, the use of MSG (monosodium glutamate) as a flavor enhancer began to be popular in Indonesia. It replaces natural flavor such as sugar, salt or spices because its affordable price compared to natural flavor. MSG as food additive is added to foods that exceed limits and may cause a negative effect to the body. One of the effects is the increasing of free radicals that can lead to various degenerative diseases such as blood vessel disorders and others. White turmeric is a common spice that widely used by Indonesian. Several studies have reported the benefits of white turmeric as an antifungal, antimicrobial and so on. The objective of this research is to find the effects of white turmeric extract in improving endogenous antioxidants to suppress the free radical effects because of the excessive use of MSG. Materials and Method: We measured the activity of SOD, catalase and GSHreductase as endogenous antioxidants in mice treated with MSG and white turmeric. The subjects of this study used 24 Sprague Dawley male rats aged 2-6 months; weight 100-150 grams, which were randomly divided into 6 groups. The control group did not receive any treatment. The MSG group was given MSG (4800mg / kg/ day). Groups 3 and 4 were given MSG and white turmeric extract, respectively (100 mg / kg / day and 200 mg / kg / day). Groups 5 and 6 were given MSG and vitamin C respectively (250 mg / kg / day and 500 mg / kg/ day) after 14 days of treatment; the activity of enzyme measured by Abcam Enzyme Kit and detected by Spectrophotometer Thermo Scientific Multi-scan Go. Result: The administration of white turmeric extracts will increase SOD and Catalase activity, and reduce GSH-reductase activity . Conclusion: White turmeric extract will help the work of endogenous antioxidant enzymes in counteracting free radicals produced from MSG metabolism. International Journal of Human and Health Sciences Vol. 05 No. 01 January’21 Page: 31-34

Introduction: Hyperglycemia has become the main characteristic of diabetes mellitus. Persistent hyperglycemia directly activates cell death pathway that plays pivotal role in the diabetic complication including diabetic cardiomyopathy. Syzygium polyanthum plays a beneficial role in the diabetic condition by reducing the blood glucose concentration, however the role of this natural resources in preventing further complication of diabetes mellitus has not been revealed fully yet. Method: Syzygium polyanthum dry extract (300 mg/kg body weight) were given daily for 28 days in the streptozotocin-induced diabetic rat. Measurement of blood glucose concentration were done three times during the study, meanwhile cholesterol concentration, myocardial diameter and cardiac apoptosis were measured on the day 28 of the study. Cardiac apoptosis was analyzed by the TdT-mediated dUTP nick end-labelling (TUNEL Assay). Results: Persistent hyperglycemia as well as cardiac apoptosis was significantly observed in the diabetic rat (D) on the day 28 of the study confronted to the normal rat (N). Interestingly, significant blood glucose reduction in concomitant with a lesser concentration of cardiac apoptosis were observed in the diabetic rat received 28 days Syzygium polyanthum extract (DS) confronted to the D rat. Additionally, lower plasma cholesterol concentration was significantly observed in the DS rat confronted to the D rat. Discussion: Significant cardiac apoptosis was observed in consistent with persistent hyperglycemia in the D rat as well as lesser cardiac apoptosis was observed in accordance with blood glucose concentration reduction in the DS rat. Therefore, Syzygium polyanthum may play beneficial role in the diabetic-associated cardiac apoptosis through its direct effect on the blood glucose concentration reduction. However further analysis should be done to fully elucidate the apoptotic pathway that involved. International Journal of Human and Health Sciences Vol. 05 No. 01 January’21 Page: 16-2 1

心臓・腎臓など糖尿病性臓器障害の進展は, AMP活性化プロテインキナーゼ(AMPK)と小胞体ストレスが関与する. AMPKと小胞体ストレスは, 糖尿病性臓器障害における新治療薬の標的となりうることが示唆される. 糖尿病性腎症モデルの腎臓では酸化ストレス・炎症・線維化・脂肪沈着が亢進している. クルクミンはこれらを改善し, 安価な糖尿病腎症の予防薬・治療薬となりうることが示唆される., Diabetic nephropathy (DN) is the leading cause of chronic kidney disease (CKD) in patients starting renal replacement therapy and affects ～ 40 % of type 1 and type 2 diabetic patients. Hyperglycemia plays a key role in the pathogenesis of long-term complications in diabetes mellitus. This process is influenced by individual susceptibility (i.e. genetic determinants) and by accelerating factors such as hypertension, inflammation and dyslipidemia, all of which are able to stimulate generation of reactive oxygen species (ROS). The increased of ROS production causes tissue damage through 4 major mechanisms: (1) increased flux of glucose and other sugars through the polyol pathway; (2) increased intracellular formation of advanced glycation end products (AGEs) and its receptor; receptor for AGEs (RAGE) and its activating ligands; (3) activation of protein kinase C (PKC) isoforms; and (4) overactivity of the hexosamine pathway. The PKC signaling pathway is the postulate that has received the most attention lately. PKC activation is involved in the regulation of vascular permeability and contractility, endothelial cell activation and vasoconstriction, extracellular matrix (ECM) synthesis and turnover, abnormal angiogenesis, excessive apoptosis, leucocyte adhesion, abnormal growth factor signaling and cytokine action, as well as abnormal cell growth and angiogenesis, all of which are involved in the pathophysiology of diabetic vascular complications. There is growing evidence that abnormal lipid metabolism and renal accumulation of lipids play a role in the pathogenesis of DN. Sterol regulatory elemen-binding proteins (SREBPs) are transcription factors that regulate fatty acid and cholesterol synthesis. SREBPs belong to basic helix-loop-helix-leucine zipper family and activate the entire program of fatty acid and cholesterol synthesis in liver. Currently, there are three SREBPs isoforms that have been identified and characterized, namely, SREBP-1a, SREBP-1c, and SREBP-2. Multiple lines of evidence suggest that SREBP-1 and SREBP-2 have different relative effects on target genes. SREBP-1 preferentially activates genes involved in fatty acid and triglyceride synthesis, including Acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), whereas SREBP-2 preferentially activates genes involved in cholesterol biosynthesis such as hydroxymethylglutaryl CoA synthase, hydroxymethylglutaryl CoA reductase, farnesyl diphosphate synthase, and squalene synthase. It has been demonstrated that there is an inverse correlation between 5' Adenosine monophosphate-activated protein kinase (AMPK) and SREBP-1c activity in hepatocytes and in livers of re-fed mice and ethanol-fed mice. In fact, AMPK is sufficient and necessary for the suppression of SREBP-1c proteolytic processing, nuclear translocation, and gene expression of target lipogenic enzymes in response to AMPK activators, such as polyphenols and metformin, in primary hepatocytes under conditions mimicking in vivo hyperglycemia and hyperinsulinemia. Curcumin is the major active constituent of turmeric, a yellow compound originally isolated from the plant Curcuma longa L. and has been used as a dietary spice and coloring agent in foods. It has a wide spectrum of biological and pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, anti-obesity, and anticancer properties, prevents liver injury and kidney toxicity. We investigated the role of curcumin in experimental type 1 diabetic rats. Our results suggest that curcumin could ameliorate hyperglycemia, hyperlipidemia, inflammation and fibrosis in kidney tissues associated with DN which involved the dual blockade of both PKCα and PKCβ1 activities, reduced macrophage infiltration through the inhibition of NF-κB, and reduced renal triglyceride accumulation through the modulation of AMPK-SREBP pathway. Collectively, my present study provides data to support the role of curcumin in ameliorating DN in rats.

Scope We hypothesized that curcumin, by increasing the expression of nuclear factor-erythroid-2-related factor 2 (Nrf2), could reduce oxidative stress, inflammation, and renal fibrosis in remnant kidney. Methods and results Sprague-Dawley rats were subjected to 5/6 nephrectomy and randomly assigned to untreated (Nx), curcumin-treated (75 mg/kg/day, orally), and telmisartan-treated groups (10 mg/kg/day, orally; as positive control). Sham-operated rats also served as controls. Five/sixth nephrectomy caused renal dysfunction, as evidenced by elevated proteinuria, blood urea nitrogen, and plasma creatinine, and decreased creatinine clearance that were ameliorated by curcumin or telmisartan treatment. The Nx rats demonstrated reduced Nrf2 protein expression, whereas the Kelch-like ECH-associated protein 1 was upregulated and heme oxygenase-1 level was significantly diminished. Consequently, Nx animals had significantly higher kidney malondialdehyde concentration and lower glutathione peroxidase activity, which was associated with the upregulation of nicotinamide adenine dinucleotide phosphatase oxidase subunit (p67phox and p22phox), NF-kappaB p65, TNF-α, TGF-β1, cyclooxygenase-2, and fibronectin accumulation in remnant kidney. Interestingly, all of these changes were ameliorated by curcumin or telmisartan. Conclusion These findings demonstrate that, by modulating Nrf2-Keap1 pathway, the curcumin effectively attenuates oxidative stress, inflammation, and renal fibrosis, which suggest that curcumin hold promising potential for safe treatment of chronic kidney disease.

The development of diabetic cardiomyopathy is accompanied with a high membrane-bound protein kinase C (PKC) levels. Curcumin is a naturally occurring compound which is known to inhibit PKC activity. However, the effects of curcumin on ameliorating diabetic cardiomyopathy are still undefined. We evaluated whether curcumin treatment is associated with the modulation of PKC-α and -β₂-mitogen-activated protein kinase (MAPK) pathway in experimental diabetic cardiomyopathy. Diabetes was induced in male Sprague-Dawley rats by streptozotocin (STZ). Curcumin (100mg/kg/day) was started three weeks after STZ injection and was given for 8 weeks. We demonstrate that curcumin significantly prevented diabetes-induced translocation of PKC-α and -β2 to membranous fraction and diabetes-induced increased phosphorylation of p38MAPK and extracellular regulated-signal kinase (ERK)1/2 in left ventricular tissues of diabetic rats. Curcumin treatment also markedly decreased NAD(P)H oxidase subunits (p67phox, p22phox, gp91phox), growth factors (transforming growth factor-β, osteopontin) and myocyte enhancer factor-2 protein expression as well as inhibited NF-κB activity at nuclear level. Furthermore, curcumin decreased the mRNA expression of transcriptional coactivator p300 and atrial natriuretic peptide, decreased accumulation of ECM protein and reversed the increment of superoxide production in left ventricular tissues, as evidenced by dihydroethidium staining. It is also significantly lowered plasma glucose and attenuated oxidative stress, as determined by lipid peroxidation and activity of anti-oxidant enzyme, and as a result attenuated cardiomyocyte hypertrophy, myocardial fibrosis and left ventricular dysfunction. Taken together, it is suggested that curcumin by inhibiting PKC-α and -β₂-MAPK pathway may be useful as an adjuvant therapy for the prevention of diabetic cardiomyopathy.

Edaravone, a novel antioxidant, acts by trapping hydroxyl radicals, quenching active oxygen and so on. Its cardioprotective activity against experimental autoimmune myocarditis (EAM) was reported. Nevertheless, it remains to be determined whether edaravone protects against cardiac remodelling in dilated cardiomyopathy (DCM). The present study was undertaken to assess whether edaravone attenuates myocardial fibrosis, and examine the effect of edaravone on cardiac function in rats with DCM after EAM. Rat model of EAM was prepared by injection with porcine cardiac myosin 28 days after immunization, we administered edaravone intraperitoneally at 3 and 10 mg/kg/day to rats for 28 days. The results were compared with vehicle-treated rats with DCM. Cardiac function, by haemodynamic and echocardiographic study and histopathology were performed. Left ventricular (LV) expression of NADPH oxidase subunits (p47(phox), p67(phox), gp91(phox) and Nox4), fibrosis markers (TGF-β(1) and OPN), endoplasmic reticulum (ER) stress markers (GRP78 and GADD 153) and apoptosis markers (cytochrome C and caspase-3) were measured by Western blotting. Edaravone-treated DCM rats showed better cardiac function compared with those of the vehicle-treated rats. In addition, LV expressions of NADPH oxidase subunits levels were significantly down-regulated in edaravone-treated rats. Furthermore, the number of collagen-III positive cells in the myocardium of edaravone-treated rats was lower compared with those of the vehicle-treated rats. Our results suggest that edaravone ameliorated the progression of DCM by modulating oxidative and ER stress-mediated myocardial apoptosis and fibrosis.

Mulberry is commonly used as silkworm diet and an alternative medicine in Japan and China, has recently reported to contain many antioxidative flavanoid compounds and having the free radical scavenging effects. Antioxidants reduce cardiac oxidative stress and attenuate cardiac dysfunction in animals with pacing-induced congestive heart failure. Hence we investigated the cardioprotective effect of mulberry leaf powder in rats with experimental autoimmune myocarditis. Eight-week-old Lewis rats immunized with cardiac myosin were fed with either normal chow or a diet containing 5% mulberry leaf powder and were examined on day 21. ML significantly decreased oxidative stress, myocyte apoptosis, cellular infiltration, cardiac fibrosis, mast cell density, myocardial levels of sarco/endo-plasmic reticulum Ca(2+) ATPase2, p22(phox), receptor for advanced glycation end products, phospho-p38 mitogen activated protein kinase, phospho-c-Jun NH(2)-terminal protein kinase, glucose regulated protein78, caspase12 and osteopontin levels in EAM rats. These results may suggest that mulberry diet can preserve the cardiac function in experimental autoimmune myocarditis by modulating oxidative stress induced MAPK activation and further afford protection against endoplasmic reticulum stress mediated apoptosis.

There is evidence that the activation of renal angiotensin (Ang)-II plays a critical role in the pathogenesis of diabetic kidney diseases (DN) via the ER stress-induced renal apoptosis. Since, the potential negative role of Ang-II in the pathogenesis of ER stress-mediated apoptosis is poorly understood; we evaluated whether treatment of mice with AT-1R specific blocker, olmesartan is associated with the reduction of ER stress-induced renal apoptosis in streptozotocin (STZ)-induced diabetic animal model. We employed western blot analysis to measure the renal protein expressions level of NADPH oxidase subunits, ER chaperone GRP78 and the ER-associated apoptosis proteins. Furthermore, TUNEL staining was used to measure the renal apoptosis. Additionally, dihydroethidium staining and TBARS assay, and immunohistochemistry were performed to measure the renal superoxide radical production and lipid peroxidation, and activation of an Ang-II, respectively. The diabetic kidney mice were found to have increased protein expressions of NADPH oxidase subunits, GRP78 and ER-associated apoptosis proteins, such as TRAF2, IRE-1α, CHOP, p-JNK and procaspase-12, in comparison to normal mice, and which were significantly blunted by the olmesartan treatment in diabetic kidney mice. Furthermore, the diabetic kidney mice were found to have significant increment in renal apoptosis, superoxide radical production, MDA level and activation of an Ang-II and which were also attenuated by the olmesartan treatment. Considering all the findings, it is suggested that the AT-1R specific blocker-olmesartan treatment could be a potential therapy in treating ER stress-induced renal apoptosis via the modulation of AT-1R/CHOP-JNK-Caspase12 pathway in STZ-induced diabetic mice.

Oxidative stress has been strongly implicated in the pathogenesis of diabetic encephalopathy (DE). Numerous studies have demonstrated a close relationship between oxidative stress and AMPK activation in various disorders, including diabetes-related brain disorders. Since curcumin has powerful antioxidant properties, this study investigated its effects on hyperglycaemia-mediated oxidative stress and AMPK activation in rats with DE. Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ-55 mg/kg BW). The diabetic rats were then orally administered curcumin (100 mg/kg BW) or vehicle for 8 weeks. The cerebra of the diabetic rats displayed upregulated protein expression of AdipoR1, p-AMPKα1, Tak1, GLUT4, NADPH oxidase sub-units, caspase-12 and 3-NT and increased lipid peroxidation in comparison with the controls and all of these effects were significantly attenuated with curcumin treatment, except for the increase in AdipoR1 expressions. These results provide a new insight into the beneficial effects of curcumin on hyperglycaemia-mediated DE, which are produced through the down-regulation of AMPK-mediated gluconeogenesis associated with its anti-oxidant property.

Although chronic sympathetic activation provides inotropic and chronotropic support to the failing heart, such activation may also have deleterious effects, including the direct cardiotoxic effects of catecholamines, activation of the renin-angiotensin-aldosterone system and an increase in myocardial oxygen demand. These observations indicate that β-blockade might be beneficial in the treatment of heart failure resulting from dilated cardiomyopathy or ischaemic heart disease. Carvedilol is a non-selective β-blocker acting on β1-, β2-, and α1-adrenoceptors. It possesses potent anti-oxidant and anti-apoptotic properties, along with neuroprotective, vasculoprotective, cardioprotective effects, and it has reduced overall mortality in patients with heart failure in controlled clinical trials. Its role in treating cardiomyopathy requires focus. The fact that anthracyclines are cardiotoxic seriously narrows their therapeutic index in cancer therapy. The cardiotoxic risk increases with the cumulative dose and may lead to congestive heart failure and dilated cardiomyopathy in adults and in children. This review focuses on recent research regarding the beneficial effects of carvedilol in the treatment of dilated cardiomyopathy and to revisit the available evidence on the cardioprotection of carvedilol when associated with anthracycline and to explain the mechanisms underlying the benefits of their co-administration.

Cardiotoxicity, which results from intense cardiac oxidative stress and inflammation, is the main limiting factor of the anthracyclines. Carvedilol, a beta blocker that is used as a multifunctional neurohormonal antagonist, has been shown to act not only as an anti-oxidant, but also as an anti-inflammatory drug. This study was designed to evaluate whether carvedilol exerts a protective role against inflammation-mediated cardiotoxicity in the daunorubicin (DNR)-induced rats. Carvedilol was administered orally to the rats every day for 6 weeks at a cumulative dose of 9 mg/kg body weight DNR. DNR significantly induced cardiac damage and worsened cardiac function as well as increased cardiac mast cell density, elevating the myocardial protein and mRNA expression levels of tumor necrosis factor-α, vascular cell adhesion molecule-1, inter-cellular adhesion molecule-1, nuclear factor kappa-B, cyclooxygenase-2, monocyte chemotactic protein -1 and interleukin -6 compared to that in the control group. Cotreatment with carvedilol significantly attenuated the myocardial protein and mRNA expression levels of these inflammatory markers, decreased cardiac mast cell density, improved histological cardiac damage and cardiac functions. In conclusion, inflammation plays a significant role in DNR-induced cardiotoxicity, and carvedilol contributes to cardioprotection against inflammation-mediated cardiotoxicity in DNR-induced rats through its anti-inflammatory mechanism.

The beneficial effects of telmisartan on Angiotensin (Ang)-II mediated oxidative stress and renal fibrosis in streptozotocin (STZ)-induced diabetic nephropathy (DN) were studied. Thirty mice were divided into normal (NG), STZ-induced diabetic (DG) and telmisartan-treated diabetic (TG) groups. Compared with NG mice, DG mice showed significant up-regulations of AT-1R, TGF-β1, p-p38MAPK, p-MAPKAPK-2, p-Akt, p47phox, p67phox, gp91phox protein and collagen-III and all of these were significantly reversed in TG mice. The down-regulated protein expression of Ang-(1-7) mas receptor, ACE-2, PPAR-γ and PGC-1α were observed in DG mice and a significant up-regulation effect of telmisartan has been seen in the TG mice. Furthermore, TG mice showed reduced expression of fibronectin, production of superoxide radical as well as renal hypertrophy and fibrosis when compared with DG mice. These findings suggest that Ang-II plays a significant role in DN and telmisartan would be beneficial in reducing oxidative stress and fibrosis in STZ-induced DN.

Doxorubicin (Dox) is a widely used antitumor drug, but its application is limited because of its cardiotoxic side effects. Increased expression of p38α mitogen-activated protein kinase (MAPK) promotes cardiomyocyte apoptosis and is associated with cardiac dysfunction induced by prolonged agonist stimulation. However, the role of p38α MAPK is not clear in Dox-induced cardiac injury. Cardiac dysfunction was induced by a single injection of Dox into wild-type (WT) mice and transgenic mice with cardiac-specific expression of a dominant-negative mutant form of p38α MAPK (TG). Left ventricular (LV) fractional shortening and ejection fraction were higher and the expression levels of phospho-p38 MAPK and phospho-MAPK-activated mitogen kinase 2 were significantly suppressed in TG mouse heart compared to WT mice after Dox injection. Production of LV proinflammatory cytokines, cardiomyocyte DNA damage, myocardial apoptosis, caspase-3-positive cells, and phospho-p53 expression were decreased in TG mice after Dox injection. Moreover, LV expression of NADPH oxidase subunits and reactive oxygen species was significantly less in TG mice compared to WT mice after Dox injection. These findings suggest that p38α MAPK may play a role in the regulation of cardiac function, oxidative stress, and inflammatory and apoptotic mediators in the heart after Dox administration.

Diabetes mellitus increases the risk of heart failure independently of underlying coronary artery disease, and many believe that diabetes leads to cardiomyopathy. The underlying pathogenesis is partially understood. Several factors may contribute to the development of cardiac dysfunction in the absence of coronary artery disease in diabetes mellitus. There is growing evidence that excess generation of highly reactive free radicals, largely due to hyperglycemia, causes oxidative stress, which further exacerbates the development and progression of diabetes and its complications. Hyperglycemia-induced oxidative stress is a major risk factor for the development of micro-vascular pathogenesis in the diabetic myocardium, which results in myocardial cell death, hypertrophy, fibrosis, abnormalities of calcium homeostasis and endothelial dysfunction. Diabetes-mediated biochemical changes show cross-interaction and complex interplay culminating in the activation of several intracellular signaling molecules. Diabetic cardiomyopathy is characterized by morphologic and structural changes in the myocardium and coronary vasculature mediated by the activation of various signaling pathways. This review focuses on the oxidative stress and signaling pathways in the pathogenesis of the cardiovascular complications of diabetes, which underlie the development and progression of diabetic cardiomyopathy.

Diabetic cardiomyopathy and nephropathy induce endoplasmic reticulum stress (ERS) and ERS-initiated apoptosis. The primary function of 14-3-3 protein is to inhibit apoptosis, but the roles of this protein in protecting against cardiac ERS and apoptosis in the diabetic heart are largely unknown. In this study, we investigated the in vivo role of 14-3-3 protein in diabetic ERS and apoptosis using streptozotocin (STZ)-induced transgenic mice that showed cardiac-specific expression of a dominant negative (DN) 14-3-3η protein mutant. The expression levels of cardiac glucose-regulated protein (GRP) 78, inositol-requiring enzyme (Ire) 1α, and tumor necrosis factor receptor (TNFR)-associated factor (TRAF) 2 protein were significantly increased in the diabetic DN 14-3-3η mice compared with the diabetic wild-type. Moreover, cardiac apoptosis and the expression of CCAAT / enhancer binding protein homology protein (CHOP), caspase-12, and cleaved caspase-12 protein were significantly increased in the diabetic DN 14-3-3η mice. In conclusion, partial depletion of 14-3-3 protein in the diabetic heart exacerbates cardiac ERS and activates ERS-induced apoptosis pathways, at least in part, through the regulation of CHOP and caspase-12 via the Ire1α/TRAF2 pathway. The enhancement of 14-3-3 protein expression can be used as a novel protective therapy against ERS and ERS-initiated apoptosis in the diabetic heart. Keywords:: 14-3-3 protein, diabetes mellitus, endoplasmic reticulum stress, apoptosis, glucose-regulated protein (GRP) 78

Diabetic nephropathy is the most common cause of end-stage renal disease. It is assumed that hyperglycemia is one of the major systemic risk factors for diabetic complications. Numerous hypotheses exist to enlighten the adverse effect of hyperglycemia. One of these hypotheses is the activation of the calcium- and phospholipid-dependent protein kinase C signaling pathway by hyperglycemia which subsequently mediates cellular response and affects gene expression and protein function to cause cellular dysfunction and damage. It is well known that the intracellular protein kinase C activation is achieved by the elevated diacylglycerol levels in vascular tissues as well as in nonvascular tissues. Besides diacylglycerol, oxidative stress has also been reported to induce prolonged activation of protein kinase C within cells through the reactive oxygen species. Activation of protein kinase C and oxidative stress have been associated with vascular alterations such as increases in permeability of endothelial cells, extracellular matrix synthesis, cell growth and apoptosis, angiogenesis, and cytokines activation and inhibition. These derangements in vascular cell homeostasis caused by the activation protein kinase C as well as oxidative stress are connected to the occurrence of pathologies affecting large vessel and small vessel complications. Accumulating evidences have also shown that the inflammation process is an essential pathogenetic mechanism in diabetic nephropathy. Therefore, modulation of this process is an important target for both metabolic and hemodynamic derangements in diabetic nephropathy. In this review, we will discusses the role of protein kinase C, oxidative stress and inflammation process and the signaling pathway in the pathogenesis of diabetic nephropathy.

Candesartan cilexetil, an angiotensin (Ang) II receptor 1 blocker was reported to suppress the myocardial damage in various cardiovascular complications but the mode by which it is effective in preventing the progression of dilated cardiomyopathy (DCM) is unknown. Emerging evidences suggest that, at least, part of the benefits observed with the use of AT1 receptor blockers could be attributed to the increased Ang (1-7) levels observed during administration of these agents. Identification of the novel components of the RAS, ACE2 and Ang (1-7) receptor mas, provided essential elements for considering the existence of a vasodilator arm of the RAS, represented by the ACE2-Ang (1-7)-mas axis. In this study, rat model of DCM was prepared by injection with porcine cardiac myosin. Twenty-eight days after immunization, candesartan cilexetil was administered intraperitoneally at 1 or 10mg/kg/day to rats for four weeks. Myocardial expression of Ang receptors and markers of calcium homeostasis, endoplasmic reticulum (ER) stress and apoptosis were measured by Western blotting and histopathological staining techniques. Candesartan improved the functional markers in a dose-dependent manner and also upregulated Ang (1-7), ACE2 and mas1 in the myocardium of DCM rats. Various ER stress and apoptosis markers were attenuated and the number apoptotic cells were significantly lower in the candesartan treated rats compared with those of the vehicle group. These findings suggest that candesartan treatment prevented the progression of DCM by activation of the counter regulatory arm of the RAS and possibly through modulation of ER stress and subsequently, cardiac apoptosis.

Diabetic cardiomyopathy is associated with increased oxidative stress and inflammation. Mammalian 14-3-3 proteins are dimeric phosphoserine-binding proteins that participate in signal transduction and regulate several aspects of cellular biochemistry. The aim of the study presented here was to clarify the role of 14-3-3 protein in the mitogen activated protein kinase (MAPK) and nuclear factor-kB (NF-κB) signaling pathway after experimental diabetes by using transgenic mice with cardiac-specific expression of a dominant-negative 14-3-3 protein mutant (DN 14-3-3). Significant p-p38 MAPK activation in DN 14-3-3 mice compared to wild type mice (WT) after diabetes induction and with a corresponding up regulation of its downstream effectors, p-MAPK activated protein kinase 2 (MAPKAPK-2). Marked increases in cardiac hypertrophy, fibrosis and inflammation were observed with a corresponding up-regulation of atrial natriuretic peptide, osteopontin, connective tissue growth factor, tumor necrosis factor α, interleukin (IL)-1β, IL-6 and cellular adhesion molecules. Moreover, reactive oxygen species, left ventricular expression of NADPH oxidase subunits, p22 phox, p67 phox, and Nox4, and lipid peroxidation levels were significantly increased in diabetic DN 14-3-3mice compared to diabetic WT mice. Furthermore, myocardial NF-κB activation, inhibitor of kappa B-α degradation and mRNA expression of proinflammatory cytokines were significantly increased in DN 14-3-3 mice compared to WT mice after diabetes induction. In conclusion, our data suggests that depletion of 14-3-3 protein induces cardiac oxidative stress, inflammation and remodeling after experimental diabetes induction mediated through p38 MAPK, MAPKAPK-2 and NF-κB signaling.

Diabetic kidney disease has been associated with the presence of lipid deposits. We assumed that curcumin, a polyphenol, would attenuate the tissue dyslipidemic condition through activation of 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation and suppression of sterol regulatory element-binding protein (SREBP)-1c in the kidney and would prevent renal progression in experimental type 1 diabetic rats. Diabetes was induced with streptozotocin (STZ) (55 mg/kg) by intraperitoneal injection in male Sprague–Dawley rats. Three weeks after STZ injection, rats were divided into three groups, namely, control, diabetic and diabetic treated with curcumin (100 mg/kg/day) by gavage for 8 weeks. We found that curcumin decreased plasma triglyceride and the amount of renal triglyceride significantly. Furthermore, treatment of diabetic rats with curcumin increased the phosphorylation of AMPK and prevented the increased renal expression of SREBP-1c and, as a result, decreased the expression of acetyl CoA carboxylase and fatty acid synthase as well as adipose differentiation-related protein, a marker of cytoplasmic droplets. We also demonstrate that curcumin significantly suppressed the increased expression of transforming growth factor β, vascular endothelial growth factor and extracellular matrix proteins such as type IV collagen and fibronectin. In addition, curcumin treatment increased nephrin expression to near-normal levels in diabetic rats. These results demonstrated that curcumin protects against the development of diabetic nephropathy through the AMPK–SREBP pathway and the reduction of renal triglyceride accumulation which could be a possible mechanism by which curcumin preserves renal function in diabetes.

Background/Aims: Pressure overload stimulation is known to elicit disturbances in the endoplasmic reticulum (ER), which leads to ER stress (ERS). p38 mitogen-activated protein kinase (MAPK) plays an important role in mediating apoptotic processes, however, the roles of this kinase in activating ERS-initiated apoptosis in pressure-overloaded hearts are largely unknown. Methods: We clarified the role of p38α MAPK in ERS-associated apoptosis by subjecting transgenic mice displaying cardiac specific dominant negative (DN) mutant p38α MAPK over-expression to seven day pressure overload. Results: Seven days pressure overload resulted in the same extent of cardiac hypertrophy and ERS in the wild-type (WT) and DN p38α mice compared with the sham mice. It also activated inositol-requiring enzyme (Ire)-1α and its downstream molecule, tumor necrosis factor receptor (TNFR)-associated factor (TRAF)2 in the WT and DN p38α mice compared with the sham mice. Interestingly, increased myocardial apoptosis and the up-regulation of CCAAT/enhancer binding protein homology protein (CHOP) expression compared with those in the sham mice were found in the aortic-banded WT mice, but not in the DN p38α mice. Conclusion: Partial inhibition of p38α protein blocked the activation of CHOP-mediated apoptotic processes during pressure overload by partially inhibiting signaling from the Ire-1α/TRAF2 to its down-stream molecule, CHOP.

There is increasing evidence that angiotensin (Ang)-II plays an unprecedented role in diabetic complications. It could also be an important therapeutic target for ameliorating various diseases, especially diabetic nephropathy (DN). We therefore studied the beneficial effects of olmesartan, an Ang-II type 1 receptor (AT-1R) blocker in streptozotocin (150 mg/kg, BW)-induced diabetic kidney disease in mice. The diabetic kidney mice displayed upregulated protein expression levels of AT-1R, AT-2R, ERK-1/2, p-p38 MAPK, p-MAPKAPK-2, ET-1, p-JNK, p-c-Jun, TGF-β1, and gp91-phox, and all of these effects were expectedly downregulated by an olmesartan treatment. Also, immunohistochemical analysis, and Azan-Mallory and HE staining were performed to examine the expression of collagen-III and fibronectin, renal fibrosis, and hypertrophy, respectively. Furthermore, olmesartan treatment significantly abrogated the downregulation of ACE-2 and Ang-(1–7) mas R protein expression in diabetic kidney mice. Considering all these findings together, the AT-1R/MAPK pathway might be a potential therapeutic target in diabetes kidney disease, and olmesartan treatment could have beneficial effects on DN by modulating the AT-1R/MAPK pathway.

Autoimmune responses and inflammation are involved in the pathogenesis of many cardiovascular diseases. There is compelling evidence that inflammatory mechanisms may contribute to progressive heart failure. Thus, myocardial infiltration of lymphocytes and mononuclear cells, increased expression of pro-inflammatory chemokines and cytokines and circulating autoantibodies are frequently observed in myocarditis and dilated cardiomyopathy (DCM). Experimental autoimmune myocarditis (EAM) in rodents may be elicited by immunization of cardiac myosin and EAM in rats mimics human fulminant myocarditis in the acute phase and human DCM in the chronic phase. Our animal model, EAM was demonstrated to progress into the clinicopathological state similar to DCM in the chronic phase, and was found to be characterized by the enlargement of the heart, dilatation of ventricles, diffuse and extensive myocardial fibrosis, besides being a cellular immunity and inflammation mediated disease. Severity of myocarditis was characterized by increased inflammation, cardiac fibrosis and decreased myocardial performance in rats with DCM. Pharmacological interventions such as angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) significantly attenuated the myosin-induced inflammation and cardiac fibrosis and thereby improving myocardial function in rats with DCM. A growing body of evidence shows that ACEI and ARBs contribute to the pharmaceutical management of patients with heart failure mediated by immune and inflammatory response. The purpose of this review is to emphasize the role of inflammation and myocardial fibrosis in rats with DCM after EAM and study the effects of pharmacological interventions such as ACEI, ARBs in the treatment of heart failure through the suppression of inflammatory cytokines and fibrosis.

Scope: We hypothesized that curcumin, a potent anti-oxidant, might be beneficial in ameliorating the development of diabetic nephropathy through inhibition of PKC-α and PKC-β1 activity-ERK1/2 pathway. Methods and results: Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ) (55 mg/kg) in rats. Three weeks after STZ injection, rats were divided into three groups, namely, normal, diabetic and diabetic treated with curcumin at 100 mg/kg/day, p.o., for 8 wk. At 11 wk after STZ injection, diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, increased blood urea nitrogen (BUN) and proteinuria, marked increases in lipid peroxidation, NOX4 and p67phox and decrease in anti-oxidant enzyme. All of these abnormalities were significantly reversed by curcumin. Furthermore, the high-glucose-induced PKC-α and PKC-β1 activities and phosphorylated ERK1/2 was significantly diminished by curcumin. Curcumin also attenuated the expression of TGF-β1, CTGF, osteopontin, p300 and ECM proteins such as fibronectin and type IV collagen. The high-glucose-induced expression of VEGF and its receptor VEGF receptor II (flk-1) was also ameliorated by curcumin. Conclusion: These results prove that curcumin produces dual blockade of both PKC-α and PKC-β1 activities, which suggests that curcumin is a potential adjuvant therapy for the prevention and treatment of diabetic nephropathy.

Anthracyclines, most powerful anticancer agents, suffer from their cardiotoxic effects, which may be due to the induction of oxidative stress. Carvedilol, a third-generation, nonselective β-adrenoreceptor antagonist, possesses both reactive oxygen species (ROS) scavenging and ROS suppressive effects. It showed protective effects against daunorubicin- (DNR-) induced cardiac toxicity by reducing oxidative stress and apoptosis. This study therefore was designed to examine the effects of carvedilol on DNR-induced cardiomyopathic rats, focused on the changes of left ventricular function, cardiac fibrosis, and hypertrophy. Carvedilol increased survival rate, prevented systolic and diastolic dysfunction, and attenuated myocardial fibrosis and hypertrophy. DNR alone treated rats showed upregulated myocardial expression of ANP, PKC-α, OPN, and TGF-β1 and downregulation of GATA-4 in comparison with control, and treatment with carvedilol significantly reversed these changes. The results of the present study add the available evidences on the cardioprotection by carvedilol when associated with anthracyclines and explain the mechanisms underlying the benefits of their coadministration.

Background/Aims: Excessive endoplasmic reticulum stress (ERS) triggers apoptosis in various conditions including diabetic cardiomyopathy and pressure overload-induced cardiac hypertrophy and heart failure. The primary function of 14-3-3 protein is to inhibit apoptosis, but the roles of this protein in protecting against cardiac ERS and apoptosis are largely unknown. Methods: We investigated the roles of 14-3-3 protein in vivo during cardiac ERS and apoptosis induced by pressure overload or thapsigargin injection using transgenic (TG) mice that showed cardiac-specific expression of dominant negative (DN) 14-3-3η. Results: Cardiac positive apoptotic cells and the expression of glucose-regulated protein (GRP)78, inositol-requiring enzyme (Ire)1α, tumor necrosis factor receptor (TNFR)-associated factor (TRAF)2, CCAAT/enhancer binding protein homology protein (CHOP), caspase-12, and cleaved caspase-12 protein were significantly increased in the pressure-overload induced DN 14-3-3η mice compared with that in the WT mice. Furthermore, thapsigargin injection significantly increased the expression of GRP78 and TRAF2 expression in DN 14-3-3η mice compared with that in the WT mice. Conclusion: The enhancement of 14-3-3 protein may provide a novel protective therapy against cardiac ERS and ERS-initiated apoptosis, at least in part, through the regulation of CHOP and caspase-12 via the Ire1α/TRAF2 pathway.

Excessive endoplasmic reticulum stress (ERS) triggers myocardial apoptosis. Sex differences appear to be an important determinant in the occurrence of stress and apoptosis through many pathways, but the roles of sex differences in the cardiac ERS and ERS-initiated apoptosis are largely unknown. In the present study, we investigated the in vivo role of sex differences in the cardiac ERS and apoptosis elicited by ascending aortic banding surgery or thapsigargin (Thap) injection using male and female C57BL/6 JAX mice. The surgery significantly increased the expression levels of cardiac glucose-regulated protein (GRP)78 and CCAAT/enhancer binding protein homology protein (CHOP) protein, increased the myocardial apoptosis and decreased the sarcoplasmic reticulum Ca2+-ATPase isoform (SERCA)2 immunoreactivity in the male mice relative to female mice. Furthermore, during ERS induction using Thap, myocardial apoptosis and the expression levels of cardiac GRP78, inositol-requiring enzyme (Ire)1α and tumor necrosis factor receptor-associated factor (TRAF)2 were significantly increased in male mice relative to female mice. Sex differences significantly affected the above results. Our data suggest that sex differences affected the response of myocardial tissues in dealing with cardiac ERS and further result of ERS, apoptosis, at least in part through the regulation of SERCA2, CHOP, Ire1α and TRAF2.

Background Chronic inflammation plays an important role in the progression of diabetic nephropathy (DN) and that the infiltration of macrophages in glomerulus has been implicated in the development of glomerular injury. We hypothesized that the plant polyphenolic compound curcumin, which is known to exert potent anti-inflammatory effect, would ameliorate macrophage infiltration in streptozotocin (STZ)-induced diabetic rats. Methods Diabetes was induced with STZ (55 mg/kg) by intraperitoneal injection in rats. Three weeks after STZ injection, rats were divided into three groups, namely, control, diabetic, and diabetic treated with curcumin at 100 mg/kg/day, p.o., for 8 weeks. The rats were sacrificed 11 weeks after induction of diabetes. The excised kidney was used to assess macrophage infiltration and expression of various inflammatory markers. Results At 11 weeks after STZ injection, diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, increased blood glucose, blood urea nitrogen and proteinuria, along with marked reduction in the body weight. All of these abnormalities were significantly reversed by curcumin. Hyperglycemia induced the degradation of IκBα and NF-κB activation and as a result increased infiltration of macrophages (52%) as well as increased proinflammatory cytokines: TNF-α and IL-1β. Curcumin treatment significantly reduced macrophage infiltration in the kidneys of diabetic rats, suppressed the expression of above proinflammatory cytokines and degradation of IκBα. In addition, curcumin treatment also markedly decreased ICAM-1, MCP-1 and TGF-β1 protein expression. Moreover, at nuclear level curcumin inhibited the NF-κB activity. Conclusion Our results suggested that curcumin treatment protect against the development of DN in rats by reducing macrophage infiltration through the inhibition of NF-κB activation in STZ-induced diabetic rats.