bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of Melanocortin Receptor 3 as a new strategy to control experimental and rheumatoid arthritis
Authors: Patel Hetal Brijesh , Bombardieri Michele , Pitzalis Costantino , Perretti Mauro 
Published: June 2021

Study ObjectiveThe anti‐inflammatory properties of melanocortin peptides have long been established, though their main molecular target(s) is still elusive. Two receptors (MC1R and MC3R) have been suggested as their main target, but the patho‐physiological impact of this important homeostatic anti‐inflammatory system is unclear: we focused here on experimental and rheumatoid (RA) arthritis.MethodsMouse Studies (1) Arthritis was induced by K/BxN serum transfer (200 μl) into wild type (WT), recessive yellow e/e (Mc1r inactive mutant) and Mc3r−/− mice and disease profiles monitored. (2) Gene expression analysis was performed in arthritic paw joints using qPCR. (3) Daily treatment with vehicle or D[Trp8]‐γ‐MSH (MC3R agonist) was given to WT and Mc3r−/− mice (20 μg) induced with K/BxN arthritis and disease profiles assessed. Human Studies qPCR was used to analyse MCR and/or pro‐inflammatory cytokine mRNA levels in RA synovium transplanted into SCID mice treated with D[Trp8]‐γ‐MSH.ResultsUpon K/BxN serum transfer, Mc3r−/− mice displayed a marked disease exacerbation whereas no different profile of disease development was displayed by the Mc1r mutant and WT mice. This heightened presence of disease in Mc3r−/− null mice was confirmed by histological analysis of paw joints. At peak of arthritic profile (D6), mRNA analysis revealed up‐regulation of Rankl, Mcp‐1, Nos2 and Il‐1β, Il‐6 in Mc3r−/− mice compared to WT. Treatment of arthritic mice with D[Trp8]‐γ‐MSH significantly attenuated disease. In another preclinical model, stimulation of human MC3R with D[Trp8]‐γ‐MSH inhibited human IL‐1β, IL‐6, TNF‐α and RANKL gene expression in RA synovium transplanted into SCID mice.ConclusionsThese findings identify MC3R‐mediated signaling as a novel anti‐inflammatory pathway for innovative therapeutic targeting in RA.
The role of MCT1 and MCT4 in drug‐induced muscle disorders
Authors: Leung Yat Hei , Lu Jennifer , Papillon Marie‐Ève , Bélanger François , Turgeon Jacques , Michaud Véronique 
Published: June 2021

BackgroundMuscle injury, including myopathy, is a common side effect of some drugs, and particularly of statins. We hypothesized that these side effects are related to intracellular accumulation of lactic acid through monocarboxylate transporters, MCT1 and MCT4. Our objective was to investigate whether the transport of lactic acid is modulated by statins and other acidic drugs.MethodsCell lines used as models for MCT1 and MCT4 were Hs578T and MDA‐MB‐231, respectively. The cells were incubated with [14C]lactic acid at 37°C and the intracellular concentration of radioactive lactic acid was measured. Inhibition studies were conducted by co‐incubating the cells with different concentrations of acidic drugs (e.g. statins, gemfibrozil, irbesartan, losartan, valsartan, loratadine, ibuprofen, naproxen, and salicylic acid) and lactic acid.ResultsAtorvastatin and loratadine showed the highest inhibition with IC50 of 20 μM and 2μM, respectively. Fluvastatin and irbesartan showed an intermediate inhibition with IC50 of 100–1000 μM, while drugs such as lovastatin and NSAID showed low or no inhibition (IC50 >;1000 μM).ConclusionsThese results imply that atorvastatin and other acidic drugs can lead to the accumulation of lactic acid due to the blockage of MCT1 and MCT4. Further studies are required to link the intracellular accumulation of lactic acid and drug‐induced muscle pain.Research supports; CIHR and HSF
Role of localized calcium events in regulation of vascular tone: A theoretical investigation
Authors: Parikh Jaimit , Kapela Adam , Tsoukias Nikolaos M 
Published: June 2021

Localized calcium (Ca2+) events like sparks, puffs, pulsars and sparklets have been identified in the vascular cells. They have been suggested to play an important role in modulation of vessel tone. Theoretical modeling can provide quantitative insights and improve the fundamental understanding of the generation of these localized Ca2+ events. Hence we develop detailed finite element cellular models of Ca2+ dynamics and membrane electrophysiology in smooth muscle and endothelial cells. These models are integrated and modified to include myoendothelial projections with localized IP3 receptors, intermediate conductance Ca2+ activated potassium channels (IKCa) and TRPV4 channels. Activation of TRPV4 channels resulted in localized Ca2+ signals (sparklets). A single TRPV4 channel activation in absence of other channels and pumps resulted in localized calcium increase >;100nM and a spatial spread of ~ 6μm. The parameters of sparklets are affected by variety of factors of which open time of the channel, cooperative gating of the channels, diffusion coefficient of calcium and channel current can be the most important. The localized Ca2+ increase can activate IKCa channels and cause endothelium‐derived hyperpolarizing response modulating the vascular tone. The study provides a novel theoretical tool to examine the mechanisms behind localized calcium events and the regulation of vascular tone.(Supported by NIH SC1HL95101).
MR or AT1R gene silencing in the PVN markedly attenuates Ang II‐induced hypertension in rats
Authors: Chen Aidong , Huang Bing S , Wang Hong‐Wei , Leenen Frans H.H. 
Published: June 2021

Functional studies suggest that circulating Ang II activates an aldosterone‐MR‐endogenous ouabain (EO)‐ AT1R pathway in the hypothalamus and thereby causes hypertension. The present study examined whether intra‐PVN infusion of AAV‐MR‐siRNA or AAV‐AT1aR‐siRNA attenuates Ang II‐induced hypertension in rats. Two wks after bilateral intra‐PVN infusion of AAV‐MR‐siRNA (1 μl of 2.5 × 1010 genomic particles / ml), MR mRNA and protein expression in the PVN were reduced by 56% and 31% (P<0.01), compared with rats infused with AAV‐SCM‐siRNA. In 2nd set of rats, 1 week following bilateral intra‐PVN infusion of AAV‐MR‐siRNA, AAV‐AT1aR‐siRNA (1 μl of 2.5 × 1010 genomic particles / ml) or AAV‐SCM‐siRNA, Ang II was infused subcutaneously at 500ng/kg/min. After 2 weeks, AAV‐AT1aR‐siRNA significantly attenuated, whereas AAV‐MR‐siRNA largely prevented the Ang II‐induced hypertension. These results suggest that MR activation in the PVN plays a major role in Ang II‐induced hypertension, and genetic intervention of MR or AT1R production by AAV‐siRNA into specific nuclei provides new insights into the actual pathways of MR‐EO neuromodulation.

MAP (mmHg)
HR (bpm)

AAV‐SCM‐siRNA ( n=5)
113 ± 2
377 ± 8

AAV‐SCM‐siRNA +Ang II ( n=5)
192 ± 7 a
416 ± 15

AAV‐AT1aR‐siRNA+ Ang II ( n=7)
153 ± 8*, Δ
411 ± 12

AAV‐MR‐siRNA + Ang II ( n=7)
121 ± 6
377 ± 12

Data=means± SE.
p<0.05, vs. others,
p<0.05, vs. AAV‐SCM,
p<0.05, vs. AAV‐MR.

(Supported by grant # FRN:MOP‐74432 from the Canadian Institutes of Health Research)
The ventilatory response to muscle metaboreflex stimulation in patients with COPD
Authors: Bruce Richard Michael , Turner Alice , White Michael John 
Published: June 2021

The role of skeletal muscle metaboreceptive afferents in human cardiorespiratory control can be examined using post exercise circulatory occlusion (PECO). We have shown that the ventilatory responses to PECO are augmented in humans during concurrent hypercapnia. We now aim to determine whether PECO produces ventilatory responses in COPD patients who do and do not retain CO2.With Ethical approval, 18 COPD patients and 9 aged matched controls performed 2 trials. In both trials participants rested for 2 minutes followed by 2 minutes of rhythmic handgrip exercise. Upon cessation of exercise in the PECO trial a cuff around the upper arm was inflated to 200mmHg for 2 minutes before cuff deflation.PECO maintained blood pressure significantly above baseline levels in COPD patients and control participants (+ 7 mmHg and + 8 mmHg respectively). However ventilation during PECO was only maintained above baseline levels in COPD patients (+2–3 l.min‐1). There was no difference in this response between retainers and non‐retainers of CO2.These results suggest that metaboreflex activation causes ventilatory responses in patients with COPD but not in healthy aged matched controls. However as there was no difference in the ventilatory response to PECO in CO2 retainers and non‐retainers it appears that chronic hypercapnia is not the underlying mechanism behind the response.
Sex‐based comparisons in oxidative DNA damage following 2h moderate cycling exercise
Authors: Yasuda Nobuo , Tanioka Toshihiro 
Published: June 2021

The purpose of the study was to determine the effects of 2h moderate cycling exercise on whole body oxidative DNA damage and repair in men and women. Recreationally active men (M, n=13; age: 19.9±1.4 year; height: 171.2±3.6 cm; body weight: 67.5±11.9 kg; body mass index: 23.0±3.5 kg/m2; body fat: 15.1±6.6 %) and women (W, n=12; 20.±90.3 year; height: 160.1±5.6 cm; body weight: 54.7±5.8 kg; body mass index: 21.3±1.8 kg/m2; body fat: 21.7±3.0 % [mean±SD]) served as the subjects. Before (Pre) and after (immediately Post and Post 24 hours) 2h cycling exercise at 60% VO2 peak, spot urine samples were collected for later analysis of 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG) determined with high performance liquid chromatography. With regard to 8‐OHdG level (ng/mg Creatinine), two‐way (time × sex) analysis of variances (ANOVA) showed no significant main effects for time, sex or interaction (Pre: 3.0±1.2, Post: 3.6±1.2, Post‐24h: 3.2±1.1 for M; Pre: 3.2±1.2, Post: 3.5±1.1, Post‐24h: 3.2±0.9 for W). However, there was a tendency for 8‐OHdG to be higher following exercise and return to the baseline level at Post‐24h in both men and women. These findings indicate that men and women show similar whole body DNA damage and repair after 2h moderate cycling exercise, which appears not to induce cumulative harmful oxidative stress.Supported partly by funds from the Grant‐in‐Aid for Scientific Research (C) in Japan (Grant No.23500867).
Casein peptide supplementation enhances training effects on mitochondrial biogenesis of skeletal muscle in mice
Authors: Matsunaga Yutaka , Tamura Yuki , Masuda Hiroyuki , Takahashi Yumiko , Hoshino Daisuke , Hatta Hideo 
Published: June 2021

AimsCasein peptide consists of few amino acids. Previous studies reported that oral amino acid supplementation enhanced training effects and endurance performance. However, effects of peptide supplementation are unclear. Therefore, the aim of this study was to determine whether peptide supplementation enhances training effects on mitochondrial biogenesis of skeletal muscle.Methods6weeks old male ICR mice were randomly assigned to casein peptide (0.2 mg/g BW) ingestion group (CP) or equal amount of water ingestion group (CON). They were provided with high fat diet (56.7% fat) ad libitum and ingested either casein peptide or water (7 times/week) 30 min before endurance training (20–25 m/min×60 min, 5 times/week, for 6 weeks). All mice were sacrificed 48 h after the last training session. Muscle glycogen concentrations, muscular citrate synthase (CS) and β‐hydroxyacyl‐CoA dehydrogenase (β‐HAD) activities, which are mitochondrial enzyme activity, were measured.ResultsMuscle glycogen concentrations were higher in CP group than in CON group (p<0.05). Muscular citrate synthase activity was significantly higher in CP group than in CON group (p<0.05) and β‐HAD activity tended to be higher in CP group than in CON group (p=0.08).ConclusionCasein peptide supplementation enhances training effects on mitochondrial biogenesis of skeletal muscle in mice. Supported by Morinaga Milk Industry CO., LTD.
New, puzzling insights on the old and unsolved forelimb/hindlimb enigma: comparative evolutionary myological studies
Authors: Diogo Rui , Linde‐Medina Marta 
Published: June 2021

Most textbooks and papers state that the structures of the tetrapod fore and hindlimb are serial homologues but these statements seem to be due to a confusion between the serial homology of the vertebrate pelvic and pectoral appendages as a whole and of their structures, leading to a crucial question being overlooked: why are the skeletal and particularly the muscle structures of the fore and hindlimb actually so strikingly similar to each other? We provide an updated discussion of these questions and present a surprising and puzzling result of our comparative myological studies: in humans the number of forelimb muscles/muscle groups with clear ‘equivalents’ in the hindlimb (19) is actually substantially higher than in taxa such as rats (14), lizards (14) and even salamanders (18). Furthermore, at least five of the 19 modern human adult forelimb elements that have a clear hindlimb ‘equivalent’ derive from embryonic anlages that are very different from the ones giving rise to their adult hindlimb ‘equivalents’. These data contradict the hypothesis that the similarity in muscle structures between the forelimb and hindlimb of tetrapods such as modern humans are due to their origin as serial homologues; this similarity is instead the result of phylogenetically independent evolutionary changes leading to a parallelism/convergence due to developmental, functional constraints, topological and phylogenetic constraints.Grant Funding Source: Start‐up package of Howard University College of Medicine
Biomarkers of acute rejection in renal transplant: a proteomic approach
Authors: Perez Juliana Dineia , Sakata Maisa Mayumi , Cunha Tatiana Sousa , Arita Danielle Yuri , Colucci Juliana Almada , Junior Helio Todesco Silva , Pestana Jose Osmar Medina , Casarini Dulce Elena 
Published: June 2021

Kidney transplant is the best treatment for patients with end stage renal failure. Acute rejection (AR) is the major impediment to success in renal transplantation. We aimed to identify biomarkers candidates for acute renal rejection using plasma using LC‐MSE.Analysis was performed with plasma from 25 renal transplant patients with stable renal graft function ‐ control group (Ct) ‐ and 9 patients with acute graft rejection ‐ rejection group (Rej).We have detected 19 proteins overexpressed in the Rej group compared to Ct group, 02 proteins were underexpressed and 04 that were present only in the Rej group. Among the 19 overexpressed proteins we have selected 03 candidates for AR biomarkers in this model of renal graft. This overexpression was confirmed by Western Blotting. They are: alpha‐1 antitrypsin (A1AT) also known as SERPIN1, alpha‐2 antiplasmin (A2AP) called SERPINF2 and serum amyloid A (SAA). These proteins are involved in the acute phase response and are strongly associated among itself. With this study we identified a number of new targets in plasma that can be used in the future to monitor the patient. These proteins may be validated in the future as markers of acute rejection in renal transplantation. This is the first study using the technique of LC‐MSE to investigate proteomic changes in plasma of kidney transplant patients. (Supported Fapesp).
The role of PML in oxidative stress responses
Authors: Guo Shuang , Cheng Xiwen , Kao Hung‐Ying 
Published: June 2021

Oxidative stress is a consequence of an imbalance between reactive oxygen species (ROS) production and the ability of cytoprotective system to detoxify the reactive intermediates. Nuclear factor erythroid 2‐related factor 2 (Nrf2) is a transcription factor that plays essential roles in trans‐activating cytoprotective genes via binding to the antioxidant response elements (AREs) in their upstream promoter regions. Promyelocytic leukemia protein (PML), a tumor suppressor protein, is down‐regulated in many cancer types. Using biochemical, molecular and cellular biology techniques and animal tissues, we investigated the role of PML in oxidative responses. We show that PML negatively controls protein abundance and trans‐activating capacity of Nrf2. Mitochondrial defects observed in tissues isolated from PML−/− mice contribute to ROS elevations and Nrf2 activations. We also demonstrate that sulforaphane (SFN), an antioxidant, regulates Nrf2 activity through controlling subcellular distribution of PML. Taken together, we have uncovered a novel regulatory mechanism in which PML functions as an oxidative sensor to regulate the expression of antioxidant genes through regulation of Nrf2 activity.This study is supported by NIH R01 DK078965 and HL093269.
Eating an avocado a day does not change body composition or blood cholesterol in healthy students
Authors: Johnson Maxwell Bates , Burns‐Whitmore Bonny , Spalding Thomas , Sancho‐Madriz Martin F. 
Published: June 2021

Cardiovascular disease is the leading cause of death in the U.S. Primary risk factors includes high serum cholesterol and high percent body fat composition. Diets high in monounsaturated fats (MUFA) have been shown to improve serum lipid profile without negatively altering body composition. Our study sought to determine if daily ingestion of avocados, a food high in MUFA, elicits the same response in healthy people. Free‐living, healthy male and female students (age 18–40) completed a parallel design; a four‐week avocado‐free (AF) run‐in followed by a random assignment to one of two eight‐week treatment periods: AF or avocado‐enriched (AE) treatment. Body composition and serum lipid analyses were measured at the beginning and end of each period. Neither treatment produced a change in total, LDL, HDL cholesterols, triacylglycerides, or body composition. The AE group resisted an increase in the non‐HDL:HDL ratio exhibited by the AF treatment. Though improvement in total serum lipid profile wasn't observed, results suggest that an avocado‐enriched diet might reduce cardiovascular disease risk in a healthy population. Additionally, a diet rich in avocado does not contribute to changes in body composition, suggesting that foods high in MUFA do not alter body composition in free‐living, healthy people.Grant Funding Source: Agricultural Research Institute and College of Agriculture, Cal Poly Pomona
Glucagon‐like Peptide‐2 Therapy Improves Outcomes of Intestinal Adaptation and Decreases Relative Apoptosis in a Distal Intestinal Resection Neonatal Piglet Model of Short Bowel Syndrome
Authors: Suri Megha , Turner Justine M. , Nation Patrick N. , Wizzard Pamela , Brubaker Patricia L. , Sigalet David L. , Wales Paul W. 
Published: June 2021

Glucagon‐like peptide‐2 (GLP‐2) is an intestinotrophic hormone produced in the ileum and colon that has been shown to augment intestinal adaptation in adult short bowel syndrome (SBS). Endogenous GLP‐2 levels and intestinal adaptation are reduced in distal intestinal resection (DIR) animal models of SBS that lack remnant ileum.We hypothesize that exogenous GLP‐2 will improve clinical, morphological, and histological outcomes of intestinal adaptation in a DIR neonatal piglet model of SBS.Twelve piglets underwent a 75% DIR with a jejunocolic anastomosis. Parenteral nutrition (PN) started on day 1 and was weaned as enteral nutrition (EN) was advanced. On day 2, piglets were randomized to IV GLP‐2 (11nmol/kg/day) or saline. Comparisons were made using the Student's t‐test, and p<0.05 was considered statistically significant.GLP‐2‐ vs saline‐treated DIR piglets had fewer days of diarrhea (8.0±0.7 vs 12.3±0.4d), fewer days on PN (10.0±0.6 vs 13.8±0.2d), increased bowel length (19±4 vs −5±3%), and deeper jejunal crypts (248±21 vs 172±12μm). The fold increase in jejunal villus apoptosis was lower for DIR piglets vs surgical controls (1.1±0.1 vs 2.3±0.6 fold) in response to GLP‐2.GLP‐2 therapy improves clinical, morphological, and histological outcomes of intestinal adaptation in a DIR neonatal piglet model of SBS, and reduces relative apoptosis. These results support a potential role for GLP‐2 therapy in pediatric SBS.
Increasing amylose content of starch stimulates fermentation and is bifidogenic in weaned pigs
Authors: Fouhse Janelle Margaret , Gänzle Michael , Regmi Prajwal , van Kempen Theo , Zijlstra Ruurd 
Published: June 2021

Weaning causes digestive disorder in pigs primarily due to unstable gut microbiota. Increasing dietary amylose increases substrate available for microbial fermentation. Weaned pigs (n = 32) were allocated to 1 of 4 diets containing 67% starch with 0, 20, 28 or 63% amylose, respectively, for 21 days. In colonic digesta, Bacteroides increased (P < 0.05) with 63% amylose compared to 20 and 28%. Bifidobacteria spp. increased (P < 0.05) and Clostridium clusters IV and XIVa decreased (P < 0.01) with 63% amylose in cecal and colonic digesta. Lactobacillus decreased (P < 0.05) in cecal and colonic digesta with 28% amylose compared to 0, 20, and 63%. Total VFA concentration in cecal and colonic digesta increased (P < 0.01) with 63% amylose. Propionate concentration in cecal digesta increased (P < 0.01) with 63% amylose. Acetate and propionate concentration in colonic digesta increased (P < 0.01) with 63% amylose. pH decreased (P < 0.01) in ileal, cecal and colonic digesta with 63% amylose. Villus height and crypt depth were not affected by amylose content. Increasing amylose content can modulate gut microbial profiles, VFA concentrations, and pH that may play a protective role against pathogenic bacteria.Grant Funding Source: Canadian Swine Research and Development Cluster, Danisco, Provimi
Selectins and integrins in ischemia‐reperfusion and sepsis induced murine acute kidney injury
Authors: Herter Jan Michael , Block Helena , Rossiant Jan , Stadtmann Anika , Zarbock Alexander 
Published: June 2021

Ischemia‐reperfusion induced kidney injury has been the most frequently used model for acute kidney injury (AKI) in mice. However, sepsis is the leading cause of AKI in critical care patients in a clinical setting. We established a new sepsis induced kidney injury model using cecal ligation and compared it to the established model of ischemia‐reperfusion induced AKI. Furthermore we characterized both models using monoclonal antibodies against the most important selectins and integrins involved in neutrophil recruitment and evaluated leukocyte recruitment using intravital microscopy of the kidney cortex, FACS and histologic analysis of kidney tissue and assessed organ function by measuring serum creatinine. We here report that both models reveal similar characteristics concerning P‐ and E‐selectin as well as the β2‐integrins Mac‐1 and LFA‐1.This study was supported by grants from the German Research Foundation (AZ 428/3–1, AZ 428/6–1, SFB 1009/A5 to A.Z and HE‐6810/1–1 to J.H.).
Withapysalin induced cardiac positive inotropism: in vitro and in vivo studies
Authors: Nascimento NIlberto R , Amorim Luciana Siqueira , Gomes Victor M , Santos Claudia F , Fonteles Manasses C 
Published: June 2021

The cardiac effects of Withapysalin F, isolated from Acnistus arborescens were evaluated in vivo and in vitro. Guinea pigs were infused with Withapysalin F (25 and 50 μg/Kg/min) and them evaluated parameters such as maximum intraventricular pressure, heart rate, dP/dt maximum, dP/dT minimum and tau, comparing to control and isoproterenol (1 μg bolus). Withaphysalin F increased maximal intraventricular pressure and dP/dt, while there was no significant change in frequency, minimum dP/dT and tau. In vitro assays, concentration‐response curves (0.2 to 145 μM) were made in spontaneous beating right atrium as left stimulated electrically atrium. Withapysalin F increased force in the right atrium by 250 ± 50%, without chronotropic effect. Withapysalin F increased tension by 338.75 ± 21.55% in the left atria. Propranolol (1μM), did not inhibit the positive inotropism. No changes in cAMP levels were detected. Furthermore, pretreatment with H89 (10 μM), a PKA inhibitor, did not decrease Withaphysalin F positive inotropic effect in guinea pig left atrium. However, incubation of ruthenium red (70 μM) abolished the positive inotropism promoted by Withaphysalin F. Withaphysalin F inotropic activity appears to be dependent on the activity of RYR2 receptors regardless of increase of cAMP and activation of PKA. This project was approved by the ethics committee with the protocol number: 12235749–3.Financial Support: FUNCAP