bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulatory Effect of Fruit‐derived Nanoparticle on Intestinal Transporters
Authors: Fujita Daichi , Arai Toshiki , Shirasaki Yuma , Iwamoto Yui , Komori Hisakazu , Nakanishi Takeo , Tamai Ikumi 
Published: June 2021

Drug food interaction is an important issue, since intake of food often alters pharmacokinetics and subsequently reduces efficacy and/or adverse effect of concurrently administered drugs. Although it has been reported that diet or beverage affects drug transporters and drug metabolizing enzymes, they were explained only by small molecules in foods. Recently, several studies have shown that plant‐derived nanoparticles (NPs) taken up by the intestinal cells affect intestinal function. NP should contain large molecules such as protein, lipid and nucleic acid derived plant cell stably. Although large molecules are not stable by digestion and impermeable into the cells, those in NP could be overcome those matters. Thus, we investigated that edible plant‐derived NP on intestinal transporter as factor involved in drug‐food interaction. Apple and grapefruit were squeezed and NP fraction was collected by ultra‐centrifugal separation. The fraction contained 100 to 400 nm particles and small molecules such as flavonoid and furanocoumarins that affect intestinal transporter were mostly excluded. When lipid membrane of NP fraction is labeled by PKH26 and incubated with Caco‐2 cells, the signals of fluorescence of labeled NP were observed in the cells, showing internalization of the NP. When mRNA expression and transport activity in Caco‐2 cells were evaluated after exposure with those NP fraction, several transporters such as ASBT, OCTN2 and OATP2B1 out of examined nine transporters showed decreased expressions and activity. Moreover, when NPs were disrupted by sonication or boiling, NPs were significantly decreased and those changes in expression of transporter genes were mostly disappeared. When mRNA expression in HEK293 cells transfected with cDNA of OATP2B1 was evaluated by those NP fraction, mRNA of OATP2B1 was only decreased in HEK293 cells transfected with plasmid containing 3′ untranslated region (UTR) of OATP2B1. These results suggested that edible plant‐derived NPs, which reduce mRNA expression of intestinal transporters, could be one of possible mechanisms of drug‐food interaction. Furthermore, 3′UTR was involved in decreased mRNA of OATP2B1, suggesting that plant microRNA contained affected mRNA expression. In conclusion, fruit‐derived NP reduced mRNA expression and activity of intestinal transporter, suggesting that high molecules in NP are involved in drug food interaction. Moreover, it is possible that plant‐derived NPs contribute to regulation of transporters for drugs and nutrients absorption by expression modulation of transporters.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Wnt and TLR4 Pathway modulators as a Promising Therapeutic Strategy in the Treatment of Glioblastoma
Authors: Esposito Emanuela , Casili Giovanna , Campolo Michela , Lanza Marika , Filippone Alessia , Cuzzocrea Salvatore 
Published: June 2021

Glioblastomas (GMB) are highly aggressive brain tumors. Despite recent improvements of care in the fields of surgical resection, radiotherapy and alkylating chemotherapy, the 5‐year survival rate for patients with GBM remains low and additional therapies are needed. Various pathways are involved in glioma tumorigenesis, among which the Wingless (Wnt) signaling. Dickkopf protein‐related protein 3 (Dkk‐3) interacts with proteins of Wnt pathway as inhibitor. The Wnt signaling contributes to activity of the claudins, important components of Tight junctions (TJ), implicated in blood‐brain barrier (BBB) formation, whose expression was altered selectively in cerebral microvessels of human GBM. The aim of this study was to determine the role of Wnt pathways to directly regulate tumor grown, apoptosis process by targeting Dkk‐3, TJ alteration involving claudin‐5 and to suggest possible therapeutic interactions involving Wnt/Toll‐like receptors (TLRs) pathways. In the present study we investigated the expression of Dkk‐3, Claudin‐5, apoptosis markers and TLR‐4 receptor protein levels in in vitro studies on U‐138MG and A‐172 human glioma cell lines and in GBM human patient's tissues. We showed a significant Dkk‐3 and claudin‐5 down regulation, with the apoptosis process involvement and with an interesting TLR‐4/Wnt modulation. We concluded that Wnt and TLR4 pathway modulators might shift the balance from tumor growth stasis to cytotoxic responses, representing a promising approach in the treatment of glioblastoma.Support or Funding InformationNo foundingThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The broad‐spectrum antiemetic efficacy of the ryanodine receptor antagonist, dantrolene, in the least shrew (Cryptotis parva)
Authors: Zhong Weixia , Darmani Nissar A. 
Published: June 2021

Dantrolene, a muscle relaxant, is clinically used for treatment of muscle spasticity as well as malignant hyperthermia since it inhibits Ca2+ ion release from intracellular sarcoplasmic reticulum stores by antagonizing ryanodine receptors (RyRs). We have recently demonstrated that intracellular Ca2+ mobilization is involved in emesis, and the dihydropyridines, L‐type Ca2+ channels blockers such as nifedipine and amlodipine, have broad spectrum antiemetic activity. Substantial evidence indicates that a physical and functional connection between LTCC and RyR mediates Ca2+‐induced Ca2+ release. The aim of this study was to evaluate the antiemetic efficacy of dantrolene. Fully effective emetic doses of diverse emetogens such as selective and/or nonselective agonists of serotonergic 5‐HT3 (e.g. 5‐HT or 2‐Me‐5‐HT)‐, tachykinin NK1 (e.g. GR73632)‐, dopamine D2 (e.g. quinpirole)‐, cholinergic M1 (e.g. McN‐A343 or pilocarpine)‐receptors, the Ca2+ LTCC agonist (FPL 64176), the inhibitor of the endoplasmic reticulum Ca2+ pump (thapsigargin), or the chemotherapeutic agent cisplatin, were administered intraperitoneally in the least shrew to induce vomiting. The antiemetic potential of dantrolene was evaluated against the discussed emetogens. Dantrolene pre‐treatment (0.1–10 mg/kg, i.p.) in a dose‐dependent and potent manner attenuated both the vomit frequency and percentage of shrews vomiting in response to administration of 5‐HT (5 mg/kg), 2‐Me‐5‐HT (5 mg/kg), GR73632 (5 mg/kg), quinpirole (2 mg/kg), McN‐A343 (2 mg/kg), pilocarpine (2 mg/kg), FPL 64176 (10 mg/kg) or thapsigargin (0.5 mg/kg). Though dantrolene alone failed to affect cisplatin‐induced vomiting, a combination of non‐effective doses of dantrolene (2 mg/kg) and the 5‐HT3 receptor antagonist palonosetron (0.05 mg/kg) were more effective against chemotherapeutic agent cisplatin‐induced vomiting during both acute and delayed phase than their corresponding doses tested alone. In conclusion our data supports the notion that: i) Ca2+‐mobilization signals play an important role in emesis; and ii) the RyRs can be a potential therapeutic target for the treatment of emesis.Support or Funding InformationNIH‐NCI RO1CA207287This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The effects of cardiac contraction on cerebral oxygenation during supraventricular and ventricular tachycardia
Authors: Komine Hidehiko , Machino Takeshi , Yamagami Fumi , Nogami Akihiko , Aonuma Kazutaka , Tsurushima Hideo , Ishii Kei , Hatori Yasuhiro , Gwak Jongseong , Takahashi Naoki , Kitazaki Satoshi , Akamatsu Motoyuki 
Published: June 2021

Cerebral vasoconstriction during hypotension with ventricular tachycardia has been reported, but the underling mechanism was unclear. We tested a hypothesis that the cardiac contraction, i.e. heart rate and/or contractility, causes cerebral vasoconstriction and thereby a decrease in cerebral oxygenation during supraventricular tachycardia (SVT) and ventricular tachycardia (VT). Heart rate (HR), arterial blood pressure (AP), and the prefrontal tissue oxygen index (TOI) with near‐infrared spectroscopy were measured during electrophysiological study in 8 patients. We selected similar hypotension trials ranging from −30 to −50 mmHg in SVT (10 trials, 4 patients) and VT (9 trials, 4 patients), and then compared HR and TOI responses. Although the decreases in AP were similar in SVT and VT (−37 ± 2 vs. −38 ± 2 mmHg), the prefrontal TOI decreased greater in SVT than VT (−5.2 ± 0.4 vs. −3.3 ± 0.6%, P < 0.05). HR increased greater in SVT than VT (85 ± 3 vs. 74 ± 8 beats/min, P < 0.05), and the increase in HR correlated with the TOI fall (r = −0.80, P < 0.05). The ejection fraction in SVT and VT were 70 ± 2 and 44 ± 14%. These results suggest that a higher cardiac contraction with tachycardia may lead to decrease in cerebral oxygenation, which is irrespective of hypotension.Support or Funding InformationThis study is supported by Automotive and Medical Concert Consortium (AMECC)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Duty Cycle Impairs Functional Sympatholysis During Moderate Intensity Hand‐grip Exercise
Authors: Caldwell Jacob T. , Hammer Shane M. , Post Hunter K. , Alexander Andrew M. , Didier Kaylin K. , Lovoy Garrett M. , Ade Carl J. 
Published: June 2021

Functional sympatholysis is a well‐known mechanism that blunts the sympathetic vasoconstrictor signal in working muscle, enabling blood flow to be maintained during exercise in the moderate intensity domain. Recent work has demonstrated that exercise intensity and contraction frequency effects functional sympatholysis via changes in metabolic rate. However, less is known about the effects duty cycle (DC) on functional sympatholysis, which alters the time that intramuscular pressure is developed throughout a contraction cycle independent of changes in frequency and intensity. Given that a higher duty cycle (i.e., 50% DC) attenuates muscle blood flow to the working limb, potentially leading to a greater metabolite buildup, we hypothesized that a 20% DC would show greater percent change in forearm vascular conductance (%Δ FVC) and forearm blood flow (%Δ FBF) when compared to 50% duty cycle.METHODSEight healthy male subjects (age: 25 ± 1 yrs; height: 176.8 ± 1.5 cm; weight: 84 ± 5 kg) agreed to participate in the current investigation. Subjects began with a four‐minute resting protocol, two‐minutes of supine blood pressure and blood flow and two‐minutes utilizing lower‐body negative pressure (LBNP; ‐30 mmHg) to increase sympathetic outflow. Subjects then underwent two exercise conditions in a randomized order consisting of 20% and 50% DC (20%:50% or 50%:20%) with ~10 min between trials to allow blood pressure and blood flow to return to baseline. All hand‐grip exercise was performed at 20 contractions per minute at a workload of 20% of subject's maximal voluntary contraction.RESULTSAbsolute FVC during the 20% duty cycle condition was significantly higher than the 50% duty cycle (20%: 398 ± 34; 50%: 327 ± 37 ml min−1 mmHg−1; P < 0.01). FBF was also significantly higher in the 20% duty cycle condition (20%: 392 ± 21; 50%: 330 ± 29 ml min−1; P < 0.01). During steady state hand‐grip exercise coupled with LBNP, %Δ FVC, an indicator of sympathetically‐mediated vasoconstriction, showed a larger percent reduction during 20% duty cycle (20%: −12.6 ± 1.5%; 50%: 1.4 ± 3.9%; P < 0.01).CONCLUSIONThe results of the current investigation suggest that the 20% DC had a greater sympathetically‐mediated vasoconstrictor response compared to the 50% duty cycle.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Dynamic Renal Blood Flow Autoregulation During Recovery From Acute Kidney Injury (AKI)
Authors: Thomson Scott Culver , Pham Hai , Singh Prabhleen 
Published: June 2021

BackgroundIf efficiency of RBF autoregulation is impaired during recovery from AKI, then the recovering kidney would be susceptible to recurrent injury from fluctuating blood pressure or nerve traffic. Hence, it is worthwhile to know about RBF autoregulation in the injured kidney for someone prescribing treatments to patients with AKI that impinge on systemic hemodynamics, such as hemodialysis.MethodsWistar rats were subjected to 60 minutes of bilateral renal ischemia and studied again after 1, 7, or 28 days (4–7 animals per group). GFR was measured by inulin clearance and while RBF (Transonics flow probe) and BP (arterial catheter) were recorded for 2 hours at 1Hz. Time series were used to calculate admittance gain from short‐term Fourier transforms, and autoregulatory step responses in the time domain by a method of moving averages.ResultsRBF returned to baseline within 1 day of ischemia‐reperfusion, while GFR normalized some time between the 1 and 4 week time points. Step responses reveal the RBF autoregulation was less efficient at the 1 and 7 day time points when GFR was low but was nearly normal at 4 weeks into renal recovery. Tubuloglomerular feedback (TGF) signatures (resonance in the admittance gain around 0.03 Hz and transient overshoot in the step response at ~ 30 seconds) were missing while the GFR was low, but were restored at 4 weeks when GFR had returned to normal. Admittance gain shown in figure where TGF and myogenic resonance peaks denoted. Step responses shown without error bars for clarity, but the major apparent intergroup differences were significant.ConclusionThe findings are consistent with prior prediction that RBF autoregulation should be less efficient in the absence of a varying TGF signal, which is necessarily the case when GFR is low. A caveat is that, while the spontaneous BP power was good enough to yield robust admittance functions and step responses, these studies don't address the response to large BP disturbance, where the deficit in autoregulation could be more profound. Additional experiments with BP forcings would be required for that.Support or Funding InformationDepartment of Veterans Affairs
Denervation of Peripheral Chemoreceptors Decreases Heart Rate During Bilateral Carotid Occlusion in Unanesthetized Rats
Authors: Brognara Fernanda , Castania Jaci Airton , Dias Daniel Penteado Martins , Kanashiro Alexandre , Ulloa Luis , Fazan Rubens , Salgado Helio Cesar 
Published: June 2021

Bilateral carotid occlusion (BCO) has been used as a maneuver to cause global reflex activation of the sympathetic nervous system in both unanesthetized and anesthetized animals. It is known that the cardiovascular effects of BCO involve not only the baroreceptors but also the chemoreceptors. However, to our knowledge, the cardiovascular responses produced during BCO in the absence of the peripheral chemoreceptors has not been studied in unanesthetized rats. Therefore, the present study aimed to examine the responses of arterial pressure and heart rate to BCO in unanesthetized rats with selective denervation of peripheral chemoreceptors. Under ketamine/xylazine anesthesia Wistar Hannover rats were implanted with pneumatic cuffs around the common carotid arteries for BCO. Catheters were also inserted into the femoral artery and vein for blood pressure recording and drug administration (to test the effectiveness of denervation), respectively. Rats were divided into two groups: INTACT (n = 7) and chemoreceptors removed (CHEMO‐X; n = 8). In the next day, BCO was performed for 20s in unanesthetized rats. As compared to baseline condition BCO promoted, in both groups, an increase in systolic (INTACT: 133 ± 5 vs. 211 ± 8 mmHg; CHEMO‐X: 142 ± 3 vs. 210 ± 4 mmHg), diastolic (INTACT: 92 ± 5 vs. 145 ± 7 mmHg; CHEMO‐X: 100 ± 2 vs. 140 ± 3 mmHg) and mean arterial pressure (INTACT: 111 ± 5 vs. 173 ± 7 mmHg; CHEMO‐X: 119 ± 2 vs. 168 ± 3 mmHg). Of note, the increase in arterial pressure was similar in both groups; however, while BCO did not promote a change of the heart rate in the INTACT group (321 ± 9 vs. 318 ± 7 bpm), the rats from the QUIMIO‐X group displayed significant bradycardia (352 ± 7 vs. 315 ± 14 bpm). These findings indicate that the presence of the peripheral chemoreceptors did not affect the hypertensive response elicited by BCO, but their absence determined a reflex bradycardia during this occlusive maneuver. This mechanism deserves further investigation.Support or Funding InformationFAPESP (Proc. 2017/05163‐6 and 2013/20549‐7).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Association of Bilateral Pulse Wave Velocity and Inter‐Arm Systolic Blood Pressure Difference in Apparently Healthy Individuals
Authors: Jensen Brock T. , Walsh Maureen A. , Clarke Melanie M. , Allen Sarah R. , Wikert Tianna N. , Brush Amanda C. , Holmstrup Michael E. 
Published: June 2021

Bilateral, either simultaneous or sequentially measured, blood pressure (BP) is used for the screening and diagnosis of inter‐arm systolic blood pressure difference (ISBPD). ISBPD, wherein a difference of ≥10 mmHg in systolic BP between arms is noted, is associated with peripheral vascular disease, type 2 diabetes, and arterial stiffness. Similarly, arterial stiffness is a strong determinant of cardiovascular risk. Pulse wave velocity (PWV) is widely used as the gold‐standard measurement of arterial stiffness. However, bilateral PWV is not commonly performed, and procedural measurement of PWV has yet to achieve clear standardization. Further, existing evidence is very limited regarding the relationship of bilateral carotid‐radial PWV measurement and ISBPD.PURPOSETo determine the association between bilateral BP and carotid‐radial PWV.METHODSTo identify the relationship between bilateral carotid‐radial PWV measurement and BP, we studied 53 subjects (26±7.4 years, 57% female) with no known cardiovascular disease. Bilateral BP was acquired both sequentially (BPSEQ) and simultaneously (BPSIM) following a 10‐minute rest period in the supine position. Right and left carotid‐radial distances were measured using an Infantometer. Bilateral carotid‐radial PWV was obtained using a Complior Analyse™ simultaneously. T‐tests were performed to determine differences in BPSEQ and BPSIM and right and left carotid‐radial pulse wave velocity (PWVR; PWVL), and correlation coefficients determined the relationship between bilateral BP and PWV differences (PWVD).RESULTSBilateral BPSEQ and BPSIM measurement was similar (1.5±7.2 mmHg and 1.2±4.6 mmHg, respectively; P > 0.05) and BP was not different between arms regardless of method (P > 0.05). Interestingly, bilateral carotid‐radial PWV was different (PWVR = 7.8±1.3 m/s and PWVL = 7.3±1.1 m/s; P < 0.05). BPSEQ and BPSIM is poorly correlated to PWVD (R = −.09 and R = .009, respectively; P > 0.05). However, PWVR was strongly correlated to PWVD (R = .63; P < 0.05).CONCLUSIONSGreater PWV is associated with a greater bilateral PWV difference. The consideration for bilateral measurement of PWV deserves further investigation. Bilateral BP and PWV differences may be valuable additions to a cardiovascular risk profile.Support or Funding InformationPennsylvania State System of Higher Education, Faculty Professional Development CouncilThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Beneficial Effects of Nrf2 Activation on Vascular Function and Detrimental Effects of Nrf2 Activation on Renal Function in Dahl Salt‐Sensitive Rats
Authors: Lombard Julian H. , Fink Katie , Cloutier Dustin , Bukowy John , Kozak Kaleigh , McCord Joe 
Published: June 2021

The master antioxidant and cell protective transcription factor nuclear factor (erythroid‐derived 2)‐like‐2 (Nrf2) plays a key role in maintaining redox homeostasis by binding to antioxidant response elements (ARE) in the promoter regions of multiple antioxidant genes. The goal of these experiments was to determine whether direct activation of Nrf2‐mediated antioxidant defenses with Protandim (~40 mg/m2 per day for 2 weeks): 1) ameliorates endothelial dysfunction and oxidative stress in cerebral arteries of Dahl salt‐sensitive (SS) rats fed high salt (HS; 4% NaCl) diet; 2) improves renal function; and 3), increases skeletal muscle microvessel density in HS‐fed SS rats. Protandim treatment restored endothelium‐dependent vasodilation in response to acetylcholine (ACh) in the middle cerebral artery (MCA) of SS rats fed HS diet, but failed to increase skeletal muscle microvessel density or improve glomerular injury scores. Nrf2 activation also led to elevated urinary albumin levels and increased protein casting in renal tubules of HS‐fed SS rats. Protandim downregulated the expression of the pro‐oxidative transcription factor Kruppel‐like factor 9 (Klf9) in cerebral arteries but upregulated Klf9 expression in kidneys of HS‐fed SS rats fed HS diet. These findings support the hypothesis that pharmacological activation of Nrf2 during high and sustained levels of oxidative stress can have either beneficial effects (cerebral arteries) or detrimental effects that may be mediated by upregulation of Klf9 (kidney). These differential effects could have contributed to the failure of the BEACON clinical trial involving Nrf2 activation in patients with type 2 diabetes and advanced (stage 4) kidney disease; and may provide safety guidelines for therapeutic administration of Nrf2 activators in conditions characterized by elevated oxidative stress.Support or Funding InformationNIH #R01‐HL128242 and #R21‐OD018309‐JHLThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of Shikonin on Cardiac Wound Healing in Mice
Authors: Cai Ashley , Cai Zheqing 
Published: June 2021

Shikonin has been shown to have properties of improving open wound healing, but it is not known whether shikonin is effective in promoting cardiac repair after myocardial infarction (MI). We hypothesize that shikonin can improve wound healing in infarcted hearts. We created MI models by ligating the coronary artery in mice. We treated the infarcted mice with 5 mg/kg of shikonin a day through oral gavage, or the same volume of distilled water was given to the control group. After seven days of treatment, we documented the heart weight and body weight, and the hearts were photographed and the infarct size was measured. The ratio of heart weight to body weight was calculated.We found that the infarct area in treated mice was significantly smaller than in the control group. While there was no significant difference in body weight between the two groups, but the ratio of heart weight to body weight in the treated group was much smaller than in the control group. In conclusion, shikonin was effective in helping wound healing in the heart after MI. Future studies will be directed to further study how shikonin functions at the cellular level and whether it improves cardiac function.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.