bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Peptides that Block the Interaction between Wnt and Frizzled
Authors: Hermans Kevin , Fernández‐Llamazares Ana , Dailly Nicolas , Blankesteijn W Matthijs , Timmerman Peter 
Published: June 2021

IntroductionWnt/Frizzled signaling is involved in many developmental processes but is mostly silent in healthy adult organs. However, a reactivation of this signaling pathway is generally observed during pathological conditions, which makes it a promising therapeutic target. The recently presented crystal structure of Xenopus Wnt8 in complex with the cysteine rich domain (CRD) of Frizzled8 demonstrates that Wnt has a shape resembling the outline of a hand with a thumb and index finger grasping the CRD at two opposing sites. The thumb contains a palmitic acid lipid at the tip that engages a groove on the CRD whereas the index finger forms a strong hydrophobic contact with a groove on the opposite side of the CRD. Here we investigated the antagonistic properties of peptides that resemble fragments of Wnts that interact with the CRD of Frizzled receptors on canonical Wnt/Frizzled signaling in cell‐based assays.MethodsPeptides resembling the thumb and index finger of Wnt3a and Wnt5a were synthesized and tested in HEK293 and 3T3 cells expressing the TOPFlash reporter. Canonical Wnt signaling was induced by addition of Wnt3a conditioned medium.ResultsPeptide fragments of both thumb and index finger demonstrated inhibition of Wnt3a induced signaling in micromolar concentrations. Combined administration of both fragments demonstrated an additive inhibition. Furthermore, we demonstrated that palmitoylation, tertiary structure and length of the peptide are critical for antagonistic activity.ConclusionFragments of Wnt that interact with Frizzled CRDs can serve as new antagonists for Wnt/Frizzled signaling.Supported by the Dutch Heart Foundation (2010B196) and Cyttron (FES0908)
Teratogenic Effects Of Some Commonly Used Medicinal Plants On The Cardiovascular System
Authors: Afolayan Gbenga , Afolayan Olasunmbo , Awodele Olufunsho , Agbaje Esther , Kumar Suresh , Klingler Rebekah , Svoboda Kurt , Carvan Michael 
Published: June 2021

The use of medicinal plants by pregnant women has not been extensively validated and screened for their influence on offspring. The aim of this study was to determine the medicinal plants used, prevalence of their use among pregnant women in Lagos state, Nigeria, and to investigate the effect of these plants on cardiovascular system development. An Ethnobothanical survey was carried out among traditional herbal practitioners and pregnant women attending antenatal clinics in Lagos State public hospitals using structured questionnaires. Transgenic zebrafish embryos were treated with various concentrations (0.08mg/ml – 1.28mg/ml) of plant extracts between 4 – 72 hours post‐fertilization to determine the effects on the cardiovascular system.The survey showed that 44.2% of the pregnant women used herbal medicine and 50% of these women had used Enantia chlorantha which was among the recommended plants for use by herb sellers. Pericardial edema and the presence of a tubular heart were observed in the 1.28mg/ml group. There was also, a significant dose dependent decrease in the blood flow rate and a disruption in the morphology of the intersegmental vessels some of which failed to develop.These research findings suggest that Enantia chlorantha possibly has an effect on angiogenesis. And it, offers a basis for further investigation of the molecular mechanism by which this plant might be responsible for these effects.
Inhibitory effects of Leishmanial sphingolipid on Endotoxin induced macrophage activation and sepsis associated inflammatory injury
Authors: Das Subhadip , Das Saha Krishna 
Published: June 2021

Sepsis is the reflection of systemic immune response that manifests in the sequential inflammatory process in presence of infection with excessive production of inflammatory mediators and causes severe tissue injuries. Total lipid of attenuated Leishmania donovani establish as a bioactive. Moreover, sphingolipids moderate various cellular processes. So, this finding encourages us to evaluate inflammatory response in system using the microbial sphingolipid.In this study, we have used bacterial endotoxin stimulated macrophages to evaluate the efficacy of leishmanial sphingolipid (LSPL) towards the amelioration of inflammatory mediators (TNF‐α, IL‐1β, IL‐6, IL‐17, IL‐10) and transcriptional factors with associated TLR4‐CD14 expression. In vivo system, endotoxin induced murine sepsis model was used in focusing on multiple organ injury (Lungs, Liver, and Kidney) and status of different cytokine‐chemokine(s) storm. Due to the effect of LSPL, endotoxin induced inflammatory cytokine‐chemokine(s) levels were significantly reduced in serum and other major organs with the reduction of vascular permeability factors and suppressed the expression of cell adhesion molecule in septic mice evident by immunochemical approaches.These findings indicate that LSPL may prove to be a potential anti‐inflammatory agent as protection against bacterial sepsis with associated organ injury.
Role of Calcium Sensitivity of Troponin C in the Development of Dilated Cardiomyopathy
Authors: Tikunova Svetlana , Singh Sonal , Fan Qiying , Hernandez Adriana , Portillo Jesus , McConnell Bradley 
Published: June 2021

Dilated cardiomyopathy (DCM) is a disease of cardiac muscle characterized by left ventricular dilation and systolic dysfunction. In 30‐40% of all cases, DCM is believed to be caused by mutations of cytoskeletal and sarcomeric proteins. The objective of this project was to determine whether decreasing the calcium sensitivity of the regulatory N‐domain of cardiac troponin C (cTnC) is sufficient to trigger the development of DCM. In order to achieve the desired objective, we knocked‐in a calcium desensitizing D73NcTnC substitution into the cardiac and slow skeletal muscle of mice.The heterozygous knock‐in mice on C57BL/6J background appeared phenotypically normal and were fertile. Western blotting demonstrated that levels of cTnC, cTnI, or phosphorylation of cTnI by protein kinase A were not affected by the D73NcTnC mutation. At four, eight and twelve weeks, knock‐in mice exhibited increased heart weight‐to‐body weight ratios. Echocardiography showed that at eight weeks, knock‐in mice exhibited increased left ventricular dimensions with thinner walls. Echocardiography also showed that contractility parameters such as ejection fraction and fractional shortening were dramatically reduced in knock‐in mice, while heart rate was not affected. Electrocardiography demonstrated that knock‐in mice exhibited prolonged QRS and QTc intervals. Small but significant increase in fibrotic lesions was observed at twelve weeks in the ventricles of knock‐in mice. Death of the heterozygous knock‐in mice occurred between six and nineteen weeks. Thus, knock‐in mice were able to closely recapitulate the phenotypes of human patients with DCM.
Effect of Small Chemicals like N‐Methyl Pyrrolidone (NMP) on the Orchestration of Bone Remodeling by Osteocytes
Authors: Siegenthaler Barbara , Ghayor Chafik , Weber Franz 
Published: June 2021

Osteoporosis is a bone disease that is characterized by gradually decreasing bone mass and hence increasing fracture risk with age. This bone mass is regulated by a tightly controlled balance between osteoblasts and osteoclasts orchestrated by osteocytes. Mediators of this orchestration are nitric oxide, RANKL, prostaglandin, and Sclerostin. The latter is expressed by mature osteocytes and has been shown to compete with Wnt signaling, thereby negatively regulating bone formation.Recently our lab identified N‐Methyl Pyrrolidone (NMP) as a potent agent for bone regeneration on the level of osteoblasts and osteoclasts. The aim of this study was to characterize the effect of NMP and NMP‐like small molecules on osteocytes.We used the mouse osteocytic cell line IDG‐SW3 and the rat mature osteoblast cell line UMR‐106 to investigate the effect of small the chemicals on the expression levels of Sclerostin. Chemical treatment was performed in different concentrations over multiple weeks. Cell viability was measured to investigate for toxic chemical concentrations and Alkaline Phosphatase activity assays were performed to check the cellular potential of calcium deposition. Furthermore, total RNA was isolated and real time PCR performed to assess for gene expression alterations with the different treatments.Our preliminary results indicate the NMP and NMLs are capable to reduce sclerostin expression and thereby could possibly diminish the competitive binding to the LRP5/6 receptors and facilitate bone formation. Further experiments are needed to investigate the effect of NMP and NMLs on bone cells to understand the molecular and cellular basis of their possible anti‐osteoporotic potential.
Role of PGE2/EP2 Receptor Signaling on The Effects of Neonatal Hyperoxia on Airway Smooth Muscle
Authors: Sopi Ramadan , Mladenov Mitko , Dreshaj Ismail , Neziri Burim , Mehmeti Mirsad , Bislimi Kemajl , Jakupaj Muharrem 
Published: June 2021

It was shown that neonatal hyperoxic‐exposure associates with airway hyperresponsiveness and impaired nonadrenergic noncholinergic relaxation. It was demonstrated that reduced relaxant responses were associated with an impairment of prostaglandin E2 (PGE2) release from airway smooth muscle (ASM). In this study we tested the hypothesis that supplementation of PGE2 or EP2 agonists to ASM restore relaxant responses. Tracheal cylinders were obtained from 12 days rat pups exposed to hyperoxia or room air for seven days. These cylinders were used to study contractile and relaxant responses. In hyperoxic tracheal preparations the contractile responses to bethanechol were enhanced as compared to room air controls. These enhanced contractile responses were attenuated by pre‐incubation of tissues with PGE2 (1µM). Similar effect was showed by using an EP2 agonist. This effect of PGE2 and EP2 agonist was reversed by an EP2 antagonist. PGE2 and EP2 induced dose response relaxations of ASM, which were reduced by an EP2 antagonist.We conclude that PGE2 induces relaxation of airways via EP2 receptors, and the use of EP2 agonists may serve as a therapeutic approach to overcome the adverse effects of neonatal hyperoxia on relaxant responses of ASM.Support by MEST
The Mitochondrial Permeability Transition Pore Regulator Cyclophilin D Exhibits Tissue‐Specific Control of Metabolic Homeostasis
Authors: Laker Rhianna , Taddeo Evan , Zhang Mei , Hoehn Kyle , Yan Zhen 
Published: June 2021

The mitochondrial permeability transition pore (mPTP) is a key regulator of mitochondrial health, and the mPTP has been implicated in the pathogenesis of metabolic disease. Cyclophilin D (CypD) is a critical regulator that directly binds to mPTP constituents to facilitate pore opening. Mice lacking CypD in all tissues are protected from diet‐induced glucose intolerance; however, the tissue‐specific function of CypD and mPTP have not been ascertained. To determine the functional role of CypD in metabolic tissues that control glucose homeostasis, we generated liver‐specific and muscle‐specific CypD knockout mice (LKO and MKO, respectively; n=9‐11/gp). These mice were fed either normal chow (NC) or 45% high fat diet (HFD) and evaluated for metabolic phenotypes. We observed that MKO mice were statistically identical to floxed controls with respect to body weight gain or glucose tolerance when fed either diet. However, LKO mice fed HFD developed greater hepatic steatosis, adipose mass, glucose intolerance and pyruvate intolerance compared with flox control mice. These findings demonstrate that CypD has tissue‐specific roles in the context of metabolic physiology, and the loss of CypD in liver is sufficient to exacerbate whole‐body metabolic dysfunction with high fat feeding.Supported by NIH grant R01AR050429
Aging alters Mitochondrial Respiratory Capacity and Function in Human Skeletal Muscle
Authors: Porter Craig , Hurren Nicholas , Cotter Matthew , Reidy Paul , Dillon Edgar , Durham William , Sheffield‐Moore Melinda , Sidossis Labros , Rasmussen Blake , Børsheim Elisabet 
Published: June 2021

Mitochondrial health is critical to physiological function, particularly in tissues with high ATP turnover, such a striated muscle. It has been postulated that derangements in mitochondrial function in skeletal muscle contribute to impaired physical function in older adults. Here, we determined mitochondrial respiratory capacity and function in m. vastus lateralis biopsies obtained from young and older adults.21 young (28±5 yrs) and 27 older (63±9 yrs) adults were studied. Mitochondrial respiration was determined in permeabilized myofibers after the addition of substrates, inhibitors and uncouplers. Thereafter, flux control ratios and coupling control factors were calculated.Maximal coupled respiration (P) was higher in muscle from young vs. older subjects (58±3 vs. 44±3 pmol·mg‐1·s‐1, P<0.01), as was maximal uncoupled respiration (E) (63±4 vs. 51±3 pmol·mg‐1·s‐1, P<0.05). Oligomycin sensitivity was lower in older adults (P<0.05), as was the flux control ratio (P/E) (P<0.05). Calculation of respiratory function revealed lower respiration linked to ATP production (P<0.001) and greater residual respiration (P<0.01) in older adults.Mitochondrial respiratory capacity and function are altered in skeletal muscle of older individuals. In particular, ATP production is less efficient in muscle from older adults. These data suggest a role for skeletal muscle mitochondria dysfunction in senescence.NIH R01AG033761, R01AR049877, P30AG024832, P30AG028718, UL1TR000071, NIDRR H133P110012, Shriners 84090.
MicroRNA‐21 Ablation Exacerbates Aldosterone‐Mediated Cardiac Injury, Remodeling and Dysfunction
Authors: Syed Maryam , Ball Jana , Mathis Keisa , Hall Michael , Ryan Michael , Rothenberg Marc , Romero Damian 
Published: June 2021

Excess aldosterone (ALDO) causes hypertension and cardiac hypertrophy, inflammation and fibrosis that lead to cardiac dysfunction. We previously reported that ALDO/SALT increases left ventricle (LV) miR‐21 expression, but whether this upregulation is protective, deleterious or a bystander is unknown. We used mice with genetic ablation of miR‐21 to study its role in ALDO/SALT‐mediated cardiac hypertrophy, fibrosis and dysfunction.Uninephrectomized male miR‐21 knockout (miR21KO) or wild‐type (WT) mice were treated with ALDO (0.15 µg/h) and SALT (1.0 % NaCl + 0.3 % KCl) or vehicle for 2 or 8 weeks (N=24/group). Analysis of cardiac tissue by weight and WGA staining revealed ALDO/SALT exacerbated LV hypertrophy (4.6 vs. 4.1 mg/g BW, p<0.05) and LV cardiomyocyte cross‐sectional area (208 vs. 195 µm2, p<0.01) in miR21KO vs. WT mice, respectively. Upregulation of fibrosis markers (Ctgf, collagen I, collagen III, fibronectin, lysyl oxidase), quantified by qRT‐PCR, was exacerbated by ALDO/SALT in miR21KO LV (2‐ to 7‐fold, p<0.05) vs. WT mice. Interstitial (0.46 vs. 0.35 %, p<0.05) and perivascular (0.32 vs. 0.27 %, p<0.05) fibrosis, determined by picrosirius red staining, was exacerbated by ALDO/SALT in miR21KO vs. WT mice. Blood pressure (BP), measured by indwelling carotid artery catheters in conscious mice, was raised to similar levels by ALDO/SALT in miR21KO vs. WT mice.Our results show that miR‐21 ablation exacerbates ALDO/SALT‐mediated cardiac hypertrophy, fibrosis and dysfunction independently of BP, suggesting that therapies that increase cardiac levels of miR‐21 may benefit patients with excess ALDO.
Effect of Noni Pulp (Morinda citrifolia l.) and Vitamin C in Rats Subjected to Stress by Restriction of Movement
Authors: Lopes Luana , Azevedo Waldir , Teixeira Halbannara , Santos Priscila , Santos Hidelberto , Ogawa Wataro 
Published: June 2021

The model of restraint is used to induce stress. Ascorbic acid is a biomarker stored in the adrenal (AAA) whose depletion measures the stress level. Noni has been subject of research because of the potential benefits, but studies associated with stress are scarce, and the pulp seems to contain high levels of vitamin C (VITC). Rats treated with distilled water (gavage) for 14 days were used as controls (C, n = 8); Stress (S, n = 8), treated with distilled water (gavage, 14 days); Noni + stress group (SN, n = 6), treated pulp of noni (gavage, 14 days);Stress + VITC group (SvitC, n = 7) treated with VITC (gavage, 14 days). SN and SvitC received the same dosage of VITC, which in the SN group was determined by titration of the pulp of noni. The procedure was stressful for pet bottles (500 mL) for 1 h / day / 7 days. The adrenal glands were weighed and extracted with AAA metaphosphoric acid. The filtrate was reacted with 2,6‐dichlorophenol indophenol and absorbance reading taken in spectrophotometer (λ = 520 ηm), inserted in the standard curve of ascorbic acid, standardized weights of the adrenals and body. Approval of CEUA under number 017. Data were analyzed using ANOVA and Tukey results show significant depletion of AAA in group S compared to C (p = 0.053) and in groups SN and SvitC no AAA depletion compared to C. It is concluded that possibly the combating stress action noni is due to the vitamin C content in the pulp of this fruit.

Rats
Control Group ugAAA/100mgAdrenal/100gBodyWeight
Stress Group / ugAAA/100mgAdrenal/100gBodyWeight
Stress + Noni Group/ ugAAA/100mgAdrenal/100gBodyWeight
Stress + VITC Group/ ugAAA/100mgAdrenal/100gBodyWeight

1
53,39105339
34,27910812
53,05312158
46,95012019

2
44,24261893
32,64925373
63,42821782
74,2464539

3
52,94006428
38,88750622
60,11479988
55,37917922

4
40,29100547
31,49325827
62,61824905
66,76718701

5
54,11566135
34,78447632
33,83190883
48,97720334

6
48,42196282
37,46436955
44,16282642
40,63548658

7
65,90104111
37,20238095

32,77972028

8
52,1609538
39,11960892

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Upregulation of miR‐21 Restores Cardioprotection under Diabetic Conditions
Authors: Olson Jessica , Yan Yasheng , Bai Xiaowen , Liang Mingyu , Bosnjak Zeljko 
Published: June 2021

IntroductionAnesthetic preconditioning (APC) has been shown to decrease myocardial infarct size following ischemia reperfusion injury. This protective effect is attenuated under diabetic conditions, but the underlying mechanisms are largely unknown. MicroRNAs are short, non‐coding nucleotide sequences that suppress and degrade mRNA. Previously, we have shown the functional role of miR‐21 as a novel mediator of APC. Now, we show for the first time its role in attenuated protection seen in diabetic conditions. We hypothesized that upregulation of miR‐21 would restore cardiac protection in animal and human models of diabetes.MethodsAttenuated APC was investigated in the db/db mouse, the T2DN rat, and in diabetic patient‐derived cardiomyocytes. miR‐21 expression was analyzed using qRT‐PCR and manipulated using GFP‐tagged mimics and antagomirs. Protein expression was examined via Western blot, and cell viability was assessed by propidium iodide staining. ResultsIn non‐diabetic models, isoflurane exposure caused a cardioprotective response. This response was abolished in diabetic models, as well as after knockdown of miR‐21. Diabetic models exhibited lower baseline levels of miR‐21 and a significant decrease in expression levels after exposure to isoflurane. This cardioprotective effect was restored using adenoviral‐mediated upregulation of miR‐21. ConclusionsOur results indicate an important role of miR‐21 in the impairment of APC under diabetic conditions. Further investigation into this phenomenon may suggest new therapeutic targets for reducing perioperative cardiovascular morbidity and mortality in both healthy and diabetic patients.
High fidelity biopotential recordings in mice using a novel telemetry implant
Authors: Guild Sarah‐Jane , Lau Sien Yee , Russell David , McCormick Daniel , Cuddy Helen , Budgett David , Kondo Masahiro , Malpas Simon 
Published: June 2021

We have developed a fully implantable telemetry device for use in mice.The telemeter is able to measure biopotential signals (EEG, EMG, ECG) at a sampling rate of 2000 Hz. The device has a volume of 1.45 cc with a unique contour design for subcutaneous implantation in mice over 20 gm in weight. A novel aspect to the device is that it contains no battery. Power to run the telemeter is provided by a wireless power pad placed under the cage of the animal. This provides continual operation of the telemeter (>90% data collection in a 24 hour period) during a range of normal animal behaviours. We have assessed the ability of this device to record biopotential signals for up to 3 months. We believe this technology offers new experimental paradigms to be explored.
Roles of Intracellular Free Zn2+ on Electrical and Mechanical Activities of the Heart
Authors: Değirmenci Sinan , Tuncay Erkan , Turan Belma 
Published: June 2021

Zinc is a vital metal in maintaining cellular functions in many cells and Zn2+ concentration is at the nanomolar range in resting cardiomyocytes. Very little is known about precise mechanisms controlling intracellular free Zn2+ distribution during cardiac function. To understand role of intracellular Zn2+ in cardiac physiology, in the present study, we measured simultaneously twitch tension and action potential (AP) in rat ventricular papillary muscles. The amplitude of twitch tension is 25% depressed while rates of both contraction and relaxation are markedly slowed down during a zinc‐ionophore, Zn‐pyrithione (ZnPT, 1 µM). Repolarizing durations at 25, 50, 75, 90% of AP full repolarization are significantly prolonged during this exposure. The whole‐cell voltage‐clamp technique was applied to isolated ventricular myocytes to investigate the effects of ZnPT exposures on L‐type Ca2+ channel currents (ICaL). In presence of Ca2+, Zn2+ exposures demonstrated strong inhibitory effects on ICaL with significant alteration in voltage dependency of the channels and a hump at around ‐40 mV in the current‐voltage relationship. Additionally, our preliminary data indicated that intracellular free Zn2+could inhibite a steady‐state K(+) current which modulates excitability and AP duration in cardiomyocytes. Therefore, our results suggested that an intracellular Zn2+ increase can induce depressed electrical and mechanical activity of cardiac preparations, in most, its modulatory action on transmembrane Ca2+ movements. Of note, in many pathological situations, including diabetes, the intracellular Zn2+ is increased, our results help to explain one of underlying mechanisms associated with cardiac dysfunction in these diseases.(Supported by grant from TUBITAK SBAG‐113S466)