scholarly journals The First Evaluation of a Geroscience Biomarker Index (TAME-BI) in a Trial of Caloric Restriction and Exercise

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 79-79
Author(s):  
Jamie Justice ◽  
Mark Espeland ◽  
Denise Houston ◽  
Stephen Kritchevsky ◽  
Barbara Nicklas ◽  
...  
Keyword(s):  
Caloric Restriction ◽  
Left Ventricular ◽  
Walk Speed ◽  
Time Treatment ◽  
Biomarkers Of Aging ◽  
Tnf Α ◽  
Treatment Interaction ◽  
C And N ◽  
First Time ◽  
Minute Walk Distance

Abstract We leveraged the WF OAIC biorepository to measure a consensus-derived panel of blood-based biomarkers of aging and constructed a geroscience-guided biomarker index (TAME-BI), testing it for the first time in a clinical trial. We measured IL-6, TNF-α-receptor-I, growth differentiating factor-15, cystatin C, and N-terminal pro-B-type natriuretic peptide in a 20-week randomized trial of caloric restriction (CR), aerobic exercise (EX), CR+EX, or attention-control in 88 patients (67±5years) with heart failure with preserved ejection fraction (HFpEF). We calculated TAME-BI (analyte levels ranked, binned by quintile, and summed) and found a time×treatment interaction for improved TAME-BI with intervention (p≤0.05) and detected associations between change in TAME-BI and change in six-minute walk distance (r= -0.24), usual walk speed (r= -0.23), and left ventricular relative wall thickness (r= 0.31). In sum, CR+EX intervention improved TAME-BI and changes in TAME-BI were associated with changes in key functional measures in older HFpEF patients.

scholarly journals Anti-Rheumatic Effect of Antisense Oligonucleotide Cytos-11 Targeting TNF-α Expression

2021 ◽  
Vol 22 (3) ◽  
pp. 1022
Author(s):  
Tatyana P. Makalish ◽  
Ilya O. Golovkin ◽  
Volodymyr V. Oberemok ◽  
Kateryna V. Laikova ◽  
Zenure Z. Temirova ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Rat Model ◽  
Peripheral Blood ◽  
Antisense Oligonucleotide ◽  
Joint Inflammation ◽  
Blood Concentrations ◽  
Tnf Α ◽  
Effective Drugs ◽  
First Time

The urgency of the search for inexpensive and effective drugs with localized action for the treatment of rheumatoid arthritis continues unabated. In this study, for the first time we investigated the Cytos-11 antisense oligonucleotide suppression of TNF-α gene expression in a rat model of rheumatoid arthritis induced by complete Freund’s adjuvant. Cytos-11 has been shown to effectively reduce peripheral blood concentrations of TNF-α, reduce joint inflammation, and reduce pannus development. The results achieved following treatment with the antisense oligonucleotide Cytos-11 were similar to those of adalimumab (Humira®); they also compared favorably with those results, which provides evidence of the promise of drugs based on antisense technologies in the treatment of this disease.

scholarly journals Effects of irbesartan on phenotypic alterations in monocytes and the inflammatory status of hypertensive patients with left ventricular hypertrophy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jingsi Zhang ◽  
Lina Yang ◽  
Yanchun Ding
Keyword(s):  
Ventricular Hypertrophy ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Left Ventricular ◽  
Target Organ ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Hypertensive Patients ◽  
Inflammatory Status ◽  
Tnf Α

Abstract Background Circulating monocytes and tissue macrophages play complex roles in the pathogenesis of hypertension and the resulting target organ damage. In this study, we observed alterations in the monocyte phenotype and inflammatory state of hypertensive patients with left ventricular hypertrophy (LVH) and studied the effects of irbesartan in these patients. This study might reveal a novel mechanism by which irbesartan alleviates LVH, and it could provide new targets for the prevention and treatment of hypertensive target organ damage. Methods CD163 and CD206 expression on monocytes and IL-10 and TNF-α levels in the serum of hypertensive patients with or without LVH and of healthy volunteers were detected. Furthermore, we treated monocytes from the LVH group with different concentrations of irbesartan, and then, CD163, CD206, IL-10 and TNF-α expression was detected. Results We found, for the first time, that the expression of CD163, CD206 and IL-10 in the LVH group was lower than that in the non-LVH group and healthy control group, but the TNF-α level in the LVH group was significantly higher. Irbesartan upregulated the expression of CD163 and CD206 in hypertensive patients with LVH in a concentration-dependent manner. Irbesartan also increased the expression of IL-10 and inhibited the expression of TNF-α in monocyte culture supernatants in a concentration-dependent manner. Conclusions Our data suggest that inflammation was activated in hypertensive patients with LVH and that the monocyte phenotype was mainly proinflammatory. The expression of proinflammatory factors increased while the expression of anti-inflammatory factors decreased. Irbesartan could alter the monocyte phenotype and inflammatory status in hypertensive patients with LVH. This previously unknown mechanism may explain how irbesartan alleviates LVH. Trail registration The study protocols were approved by the Ethical Committee of the Second Affiliated Hospital of Dalian Medical University. Each patient signed the informed consent form.

scholarly journals Cardioprotective effects of Ginsenoside compound-Mc1 and Dendrobium Nobile Lindl against myocardial infarction in an aged rat model: Involvement of TLR4/NF-κB signaling pathway

2021 ◽  
Vol 19 ◽  
pp. 205873922110005
Author(s):  
Yongle Sun ◽  
Jing Geng ◽  
Deyu Wang
Keyword(s):  
Myocardial Infarction ◽  
Combination Therapy ◽  
Infarct Size ◽  
Signaling Pathway ◽  
Left Ventricular ◽  
Male Rats ◽  
Dendrobium Nobile ◽  
Tnf Α ◽  
Cardioprotective Effects ◽  
Dendrobium Nobile Lindl

Aging is the crucial co-morbidity that prevents the full cardioprotection against myocardial ischemia/reperfusion (I/R) injury. Combination therapy as a promising strategy may overcome this clinical problem. This study aimed to investigate the cardioprotective effects of Ginsenoside compound-Mc1 (GMc1) and Dendrobium Nobile Lindl (DNL) in myocardial I/R injury and explore the involvement of the TLR4/NF-κB signaling pathway in aged rats. In vivo I/R injury and myocardial infarction was established by temporary coronary ligation in 22–24 months’ old Sprague Dawley male rats. GMc1 (10 mg/kg) and DNL (80 mg/kg) were administered intraperitoneally for 4 weeks and orally for 14 days, respectively, before I/R injury. Infarct size was measured through triphenyl-tetrazolium-chloride staining. ELISA assay was conducted to quantify the levels of cardiotroponin, and myocardial content of TNF-α and glutathione. Western blotting was employed to detect the expression of TLR4/MyD88/NF-κB proteins. GMc1 and DNL significantly reduced the infarct size to a similar extent ( p < 0.05) but their combined effect was greater than individual ones ( p < 0.01). Combination therapy significantly restored the left ventricular end-diastolic and developed pressures at the end of reperfusion as compared with the untreated group ( p < 0.01). Although the GMc1 and DNL reduced the levels of inflammatory cytokine TNF-α and increased the contents of antioxidant glutathione significantly, their individual effects on the reduction of protein expression of TLR4/MyD88/NF-κB pathway were not consistent. However, their combination could significantly reduce all parameters of this inflammatory pathway as compared to untreated I/R rats ( p < 0.001). Therefore, the combined treatment with GMc1 and DNL increased the potency of each intervention in protecting the aged hearts against I/R injury. Reduction in the activity of the TLR4/MyD88/NF-κB signaling pathway and subsequent modulation of the activity of inflammatory cytokines and endogenous antioxidants play an important role in this cardioprotection.

scholarly journals EPA is More Effective than DHA to Improve Depression-Like Behavior, Glia Cell Dysfunction and Hippcampal Apoptosis Signaling in a Chronic Stress-Induced Rat Model of Depression

2020 ◽  
Vol 21 (5) ◽  
pp. 1769 ◽  
Author(s):  
Zhilan Peng ◽  
Cai Zhang ◽  
Ling Yan ◽  
Yongping Zhang ◽  
Zhiyou Yang ◽  
...  
Keyword(s):  
Body Weight Loss ◽  
Cholesterol Concentration ◽  
Depression Treatment ◽  
Mild Stress ◽  
Related Function ◽  
Cell Dysfunction ◽  
Epa And Dha ◽  
Tnf Α ◽  
Immobility Time ◽  
First Time

Clinical evidence indicated that eicosapentaenoic acid (EPA) was more effective than docosahexaenoic acid (DHA) in depression treatment. However, possible mechanisms remain unclear. Here, a chronic unpredictable mild stress (CUMS)-induced model of depression was used to compare EPA and DHA anti-depressant effects. After EPA or DHA feeding, depression-like behavior, brain n-3/n-6 PUFAs profile, serum corticosterone and cholesterol concentration, hippocampal neurotransmitters, microglial and astrocyte related function, as well as neuronal apoptosis and survival signaling pathways were studied. EPA was more effective than DHA to ameliorate CUMS-induced body weight loss, and depression-like behaviors, such as increasing sucrose preference, shortening immobility time and increasing locomotor activity. CUMS-induced corticosterone elevation was reversed by bother fatty acids, while increased cholesterol was only reduced by EPA supplement. Lower hippocampal noradrenaline and 5-hydroxytryptamine concentrations in CUMS rats were also reversed by both EPA and DHA supplement. However, even though CUMS-induced microglial activation and associated increased IL-1β were inhibited by both EPA and DHA supplement, increased IL-6 and TNF-α levels were only reduced by EPA. Compared to DHA, EPA could improve CUMS-induced suppressive astrocyte biomarkers and associated BDNF-TrkB signaling. Moreover, EPA was more effective than DHA to attenuate CUMS-induced higher hippocampal NGF, GDNF, NF-κB, p38, p75, and bax expressions, but reversed bcl-2 reduction. This study for the first time revealed the mechanisms by which EPA was more powerful than DHA in anti-inflammation, normalizing astrocyte and neurotrophin function and regulating NF-κB, p38 and apoptosis signaling. These findings reveal the different mechanisms of EPA and DHA in clinical depression treatment.

scholarly journals Selective TNF-α targeting with infliximab attenuates impaired oxygen metabolism and contractile function induced by an acute exposure to air particulate matter

2015 ◽  
Vol 309 (10) ◽  
pp. H1621-H1628 ◽  
Author(s):  
Timoteo Marchini ◽  
Verónica D'Annunzio ◽  
Mariela L. Paz ◽  
Lourdes Cáceres ◽  
Mariana Garcés ◽  
...  
Keyword(s):  
Particulate Matter ◽  
Saline Solution ◽  
Contractile Function ◽  
Left Ventricular ◽  
Acute Exposure ◽  
Control Group ◽  
Contractile Reserve ◽  
Mice Model ◽  
Cardiovascular Morbidity And Mortality ◽  
Tnf Α

Inflammation plays a central role in the onset and progression of cardiovascular diseases associated with the exposure to air pollution particulate matter (PM). The aim of this work was to analyze the cardioprotective effect of selective TNF-α targeting with a blocking anti-TNF-α antibody (infliximab) in an in vivo mice model of acute exposure to residual oil fly ash (ROFA). Female Swiss mice received an intraperitoneal injection of infliximab (10 mg/kg body wt) or saline solution, and were intranasally instilled with a ROFA suspension (1 mg/kg body wt). Control animals were instilled with saline solution and handled in parallel. After 3 h, heart O2 consumption was assessed by high-resolution respirometry in left ventricle tissue cubes and isolated mitochondria, and ventricular contractile reserve and lusitropic reserve were evaluated according to the Langendorff technique. ROFA instillation induced a significant decrease in tissue O2 consumption and active mitochondrial respiration by 32 and 31%, respectively, compared with the control group. While ventricular contractile state and isovolumic relaxation were not altered in ROFA-exposed mice, impaired contractile reserve and lusitropic reserve were observed in this group. Infliximab pretreatment significantly attenuated the decrease in heart O2 consumption and prevented the decrease in ventricular contractile and lusitropic reserve in ROFA-exposed mice. Moreover, infliximab-pretreated ROFA-exposed mice showed conserved left ventricular developed pressure and cardiac O2 consumption in response to a β-adrenergic stimulus with isoproterenol. These results provides direct evidence linking systemic inflammation and altered cardiac function following an acute exposure to PM and contribute to the understanding of PM-associated cardiovascular morbidity and mortality.

scholarly journals The stress hyperglycaemia ratio is associated with left ventricular remodelling after first acute ST-segment elevation myocardial infarction

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shuai Meng ◽  
Yong Zhu ◽  
Kesen Liu ◽  
Ruofei Jia ◽  
Jing Nan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
St Segment Elevation ◽  
Segment Elevation Myocardial Infarction ◽  
Stress Hyperglycaemia ◽  
St Segment ◽  
Significant Difference ◽  
First Time

Abstract Background Left ventricular negative remodelling after ST-segment elevation myocardial infarction (STEMI) is considered as the major cause for the poor prognosis. But the predisposing factors and potential mechanisms of left ventricular negative remodelling after STEMI remain not fully understood. The present research mainly assessed the association between the stress hyperglycaemia ratio (SHR) and left ventricular negative remodelling. Methods We recruited 127 first-time, anterior, and acute STEMI patients in the present study. All enrolled patients were divided into 2 subgroups equally according to the median value of SHR level (1.191). Echocardiography was conducted within 24 h after admission and 6 months post-STEMI to measure left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), and left ventricular end-systolic diameter (LVESD). Changes in echocardiography parameters (δLVEF, δLVEDD, δLVESD) were calculated as LVEF, LVEDD, and LVESD at 6 months after infarction minus baseline LVEF, LVEDD and LVESD, respectively. Results In the present study, the mean SHR was 1.22 ± 0.25 and there was significant difference in SHR between the 2 subgroups (1.05 (0.95, 1.11) vs 1.39 (1.28, 1.50), p < 0.0001). The global LVEF at 6 months post-STEMI was significantly higher in the low SHR group than the high SHR group (59.37 ± 7.33 vs 54.03 ± 9.64, p  = 0.001). Additionally, the global LVEDD (49.84 ± 5.10 vs 51.81 ± 5.60, p  = 0.040) and LVESD (33.27 ± 5.03 vs 35.38 ± 6.05, p  = 0.035) at 6 months after STEMI were lower in the low SHR group. Most importantly, after adjusting through multivariable linear regression analysis, SHR remained associated with δLVEF (beta = −9.825, 95% CI −15.168 to −4.481, p  < 0.0001), δLVEDD (beta = 4.879, 95% CI 1.725 to 8.069, p  = 0.003), and δLVESD (beta = 5.079, 95% CI 1.421 to 8.738, p  = 0.007). Conclusions In the present research, we demonstrated for the first time that SHR is significantly correlated with left ventricular negative remodelling after STEMI.

Abstract P138: Long-term Effects Of Severe Caloric Restriction To The Heart Function

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Aline M De Souza ◽  
Jonathas Almeida ◽  
Nataliia Shults ◽  
Hong Ji ◽  
Kathryn Sandberg
Keyword(s):  
Cardiovascular Disease ◽  
Caloric Restriction ◽  
Heart Function ◽  
Left Ventricular ◽  
Structure And Function ◽  
Long Term Effects ◽  
Isolated Hearts ◽  
Ad Libitum ◽  
And Function

Severe caloric restriction (sCR) increases the risk for acute cardiovascular disease. Less understood are the long-term effects on cardiovascular disease risk after the sCR period has ended. We investigated the effects of sCR on heart structure and function months after refeeding (sCR-Refed). Female Fischer rats (3-months-old) were maintained on (CT) ad libitum or a 60% caloric restricted diet for 2 weeks. Thereafter, all rats received ad libitum chow for 3 months and they were analyzed by precision ultrasound to assess their heart function. After imaging, the animals were sacrificed and the hearts were subjected to ischemia-reperfusion (I/R) using a Langendorff preparation. After 2 weeks of sCR, rats lost 15% of their initial body weight (BW) [% (100*(Final-Initial/Initial)): CT, 1.5±0.8 vs sCR, -15.4±1.1; p<0.001;n=8]. After 3 months of refeeding, there was no detectable difference in BW between CT and sFR-Refed groups. Isolated hearts from the sCR-Refed rats exhibited worse myocardial pathology after I/R compared to CT rats. The parallel orientation of myofibers and striations normally present in cardiomyocytes was lost in sCR-Refed rats. Further analysis revealed uneven blood-filling of the microcirculatory vessels and prominent interstitial edema of the myocardium. Hearts from sCR-Refed rats had more atrophied cardiomyocytes than CT [Atrophied/Total (%): CT, 0.2±0.1 vs sCR-Refed, 50.6±1.1; p<0.001; n=5]. The number of arrhythmic events during a 30 min ischemic interval in isolated hearts doubled after 2 weeks on the sCR diet ( data not shown ) and remained doubled 3 months later [Arrhythmias (% of time): CT, 34±8 vs sCR-Refed, 68±9; p=0.02; n=8]. Ultrasound imaging showed no difference in stroke volume, coronary perfusion pressure and left ventricular mass. However, the thickness of the left ventricular posterior wall was significantly reduced in sCR-Refed rats [(mm): CT, 2.55 ±0.03 vs sCR-Refed, 2.10±0.04; p=0.002; n=4]. These findings indicate heart structure and function remained damaged months after the sCR period ended and BW was restored. These studies have adverse cardiovascular risk implications for who are subjected either voluntarily (crash diets) or involuntarily (very low food security) to periods of inadequate caloric intake.

Abstract P210: Central Blockade Of Tumor Necrosis Factor-Á-Converting Enzyme (tace) Ameliorates Neuroinflammation, Sympathetic Excitation And Cardiac Dysfunction In Heart Failure Rat

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Yang Yu ◽  
Baojian Xue ◽  
Hanzeng Li ◽  
Qing Chen ◽  
Mingxuan Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Body Weight ◽  
Growth Factor ◽  
Tumor Necrosis Factor ◽  
Cardiac Dysfunction ◽  
Tumor Necrosis ◽  
Left Ventricular ◽  
Male Rats ◽  
Tnf Α ◽  
Necrosis Factor

TACE is a key metalloprotease involved in ectodomain shedding of tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-α. We previously reported that TACE-mediated production of TNF-α in the hypothalamic paraventricular nucleus (PVN) contributes to the sympathetic excitation in heart failure (HF). Additionally, the upregulated TGF-α in the PVN transactivates the epidermal growth factor receptor (EGFR) to activate extracellular signal-regulated kinase (ERK) 1/2 in HF. Here we sought to determine whether central inhibition of TACE attenuates neuroinflammation and prevents the progress of HF. Male rats underwent coronary artery ligation to induce HF or sham surgery (Sham). These rats were treated with bilateral PVN microinjection of a TACE siRNA or control siRNA while some rats received a 4-week intracerebroventricular (ICV) infusion of TACE inhibitor TAPI-0 or vehicle. Compared with Sham rats, HF rats treated with control siRNA, had higher (*P<0.05) levels of TNF-α (7.88±1.32* vs 2.77±0.98 pg/mL) and TGF-α (28.27±2.76* vs 11.62±2.48 pg/mL) in cerebrospinal fluid, and increased mRNA expression of TACE (2.53±0.30* vs 1.04±0.12), TNF-α (3.43±0.55* vs 1.03±0.11), TNF-α receptor 1 (2.32±0.27* vs 1.07±0.19), cyclooxygenase-2 (2.96±0.31* vs 1.10±0.19) and TGF-α (2.68±0.41* vs 1.06±0.14) in the PVN, but these levels were markedly reduced (39-54%*) in TACE siRNA-treated HF rats. Compared with control HF rats, HF rats treated with TACE siRNA had reduced expression of phosphorylated (p-) NF-κB p65 (1.27±0.14 vs 0.84±0.07*), p-EGFR (0.52±0.05 vs 0.37±0.04*) and p-ERK1/2 (1.06±0.10 vs 0.62±0.09*) in the PVN. Moreover, the elevated plasma norepinephrine levels, lung/body weight, heart/body weight and left ventricular (LV) end-diastolic pressure along with decreased LV dP/dt max in HF rats-treated with control siRNA were significantly attenuated in HF rats treated with TACE siRNA. Treatments with TACE siRNA in the PVN also improved the indicators of cardiac hypertrophy and fibrosis of HF. ICV infusion of TAPI-0 had the similar effects with PVN TACE siRNA on these variables in HF. These data indicate that central interventions suppressing TACE activity ameliorate neuroinflammation, sympathetic activation and cardiac dysfunction in HF.

DNA enzyme targeting TNF-α mRNA improves hemodynamic performance in rats with postinfarction heart failure

2001 ◽  
Vol 281 (5) ◽  
pp. H2211-H2217 ◽  
Author(s):  
Per Ole Iversen ◽  
Gunnar Nicolaysen ◽  
Mouldy Sioud
Keyword(s):  
Heart Failure ◽  
Therapeutic Potential ◽  
Diastolic Pressure ◽  
Substantial Reduction ◽  
Left Ventricular ◽  
Lung Weight ◽  
Cleavage Activity ◽  
Arterial Blood ◽  
Modified Dna ◽  
Tnf Α

Tumor necrosis factor-α (TNF-α) probably affects the pathogenesis of heart failure. Here we have investigated the therapeutic potential of a nuclease-resistant DNA enzyme that specifically cleaves TNF-α mRNA. A phosphorothioate-modified DNA enzyme was designed to retain similar cleavage activity as its unmodified version, and that inhibited the expression of TNF-α in vitro. To test its efficacy in vivo, postinfarction congestive heart failure was induced in anesthetized rats by ligation of the left coronary artery. A 4-wk treatment with the DNA enzyme induced a substantial reduction in left ventricular end-diastolic pressure and lung weight concomitant with an increase in arterial blood pressure and myocardial blood flow compared with controls. The concentration of TNF-α in coronary sinus blood was markedly lowered on treatment, and myocardial TNF-α mRNA was substantially reduced. Recovery studies showed that the DNA enzyme cleavage activity was present within the myocardium throughout the observation period and had no apparent toxic effects. Our findings indicate that DNA enzyme-based therapy may hold promise in the treatment of this debilitating disease.

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