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Preclinical research remains hampered by an inadequate representation of human tissue environments which results in inaccurate predictions of a drug candidate’s effects and target’s suitability. While human 2D and 3D cell cultures and organoids have been extensively improved to mimic the precise structure and function of human tissues, major challenges persist since only few of these models adequately represent the complexity of human tissues. The development of skin-on-chip technology has allowed the transition from static 3D cultures to dynamic 3D cultures resembling human physiology. The integration of vasculature, immune system, or the resident microbiome in the next generation of SoC, with continuous detection of changes in metabolism, would potentially overcome the current limitations, providing reliable and robust results and mimicking the complex human skin. This review aims to provide an overview of the biological skin constituents and mechanical requirements that should be incorporated in a human skin-on-chip, permitting pharmacological, toxicological, and cosmetic tests closer to reality.

Epidermal growth factor (EGF) is a member of the EGF-like ligands family, which plays a vital role in cell proliferation, differentiation, and folliculogenesis through binding with EGF receptors, including ErbB1 (EGFR/HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). In mammals, many functional roles of EGF have been reported in the ovaries and breasts. However, little is known about the functions of EGF in the pituitary, especially in teleost. In this study, using grass carp pituitary cells as the model, we try to examine the direct pituitary actions of EGF in teleost. Firstly, transcriptomic analysis showed that 599 different expressed genes (DEGs) between the control and EGF-treatment group were mainly involved in cell proliferation, cell migration, signal transduction, and transcriptional regulation. Then, we further confirmed that EGF could significantly induce UTS1, EGR1, and MMP13 mRNA expression in a time-and dose-dependent manner. The stimulatory actions of EGF on UTS1 and EGR1 mRNA expression were mediated by the MEK1/2/ERK1/2 and PI3K/AKT/mTOR pathways coupled with both ErbB1 and ErbB2 in grass carp pituitary cells. The receptor specificity and signal transductions for the corresponding responses on MMP13 mRNA expression were also similar, except that the ErbB2 and PI3K/AKT/mTOR pathway were not involved. As we know, MMP13 could release EGF from HB-EGF. Interestingly, our data also showed that the MMPs inhibitor BB94 could suppress EGF-induced UTS1 and EGR1 mRNA expression. These results, taken together, suggest that the stimulatory actions of EGF on UTS1 and EGR1 mRNA expression could be enhanced by EGF-induced MMP13 expression in the pituitary.

Abstract Background Echocardiographic measurements are important prognostic indicators but might be influenced by heart rate and blood pressure. This is particularly important when comparing repeated examinations. Hypothesis To determine the effect of physiological stress at mildly increased heart rates and pharmacological challenge using IV administration of N-butylscopolammonium bromide and metamizol sodium on heart rate, blood pressure, and echocardiographic measurements. Animals Twenty healthy Warmblood horses. Methods Randomized crossover study. Horses were examined echocardiographically by 2-dimensional, M-mode, pulsed wave (PW) Doppler, and PW tissue Doppler imaging with simultaneous ECG recording and noninvasive blood pressure measurements during rest, physiological stress, and pharmacological challenge. Cardiac dimensions and functions were measured by a blinded observer. Data were analyzed using repeated-measures analysis of variance. Results Mean heart rate and arterial blood pressure were significantly higher during physiological stress (46 ± 2 bpm, 93 ± 16 mm Hg) and pharmacological challenge (62 ± 13 bpm, 107 ± 17 mm Hg) compared with rest (34 ± 3 bpm, 86 ± 12 mm Hg; P < .05). Compared with rest, physiological stress resulted in increased left atrial fractional area change (34.3 ± 7.5 vs 27.3 ± 5.1%; P = .01) and left ventricular late diastolic radial wall motion velocity (13 ± 3 vs 10 ± 2 cm/s; P = .01) but had no significant effect on most other echocardiographic variables. Compared with rest, pharmacological challenge led to significantly decreased left atrial and diastolic ventricular dimensions (left ventricular internal diameter: 10.3 ± 0.9 vs 10.7 ± 0.8 cm; P = .01), increased aortic and pulmonary diameters, and ventricular wall thickness. Conclusions and Clinical Importance Physiological stress at mildly increased heart rates significantly enhanced atrial pump function. Larger heart rate and blood pressure increases during pharmacological challenge resulted in altered cardiac dimensions. This should be taken into account when evaluating echocardiographic measurements at increased heart rates.

Background Despite millions of COVID‐19 cases in the United States, it remains unknown whether a history of COVID‐19 infection impacts the safety of pharmacologic myocardial perfusion imaging stress testing (pharmacologic MPI). Hypothesis The aim of this study was to assess if a prior COVID‐19 infection was associated with a higher risk of complications during and following pharmacologic MPI testing. Methods This retrospective cohort analysis included 179 803 adults (≥18 years) from the PharMetrics® Plus claims database who underwent pharmacologic MPI between March 1, 2020 and February 28, 2021. Patients with a history of COVID‐19 infection (COVID‐19 group) were compared with propensity‐score matched no‐COVID‐19 history group for reversal agent use, 30‐day resource use, and post‐MPI cardiac events/procedures. Results The most commonly used stress agent was regadenoson (91.7%). The COVID‐19 group (n = 6372; 3.5%) had slightly higher: reversal agent use (difference 1.13% [95% confidence interval [CI]: 0.33, 1.92]), all‐cause costs (difference USD$128 [95% CI: $ 73–$181]), and office visits (81.5% vs. 77.0%) than the no‐COVID‐19 group. Prior COVID‐19 infection did not appear to impact subsequent cardiac events/procedures. Conclusions COVID‐19 history was associated with slightly higher reversal agent use, all‐cause costs, and office visits after pharmacologic MPI; however, the differences were not clinically meaningful. Concerns for use of stress agents in patients with prior COVID‐19 do not appear to be warranted. In a retrospective cohort analysis of 179 803 adults from a large claims database, prior COVID‐19 infection did not impact reversal agent use or resource costs associated with pharmacologic myocardial perfusion imaging (MPI) stress testing in a clinically meaningful way. Overall, reductions in the use of pharmacologic MPI during early 2020 and some regional differences in reversal agent use were noted.

Breast cancer is the most prevalent cancer in woman worldwide. It has the highest number of new cases which amounted to 40 per 100,000 cases per year, 12.9% of which leads to death. Epigenetic alteration plays a vital role in the process of cancer cell formation and propagation. DNA methylation is one of the most common types of epigenetic alteration which generally leads to breast cancer. The DNA Methylation, a transfer of methyl group from S-adenosyl-methionine (SAM) to cytosine in the CpG dinucleotide, is catalysed by a DNA Methyltransferase-1 (DNMT1) enzyme. In the present study, we performed a virtual screening of natural product compounds as an inhibitor of the DNMT1 enzyme. Virtual screening was conducted on 26,731 natural products obtained from the NCBI PubChem database. Three steps of rigid and one step of flexible molecular docking simulations were performed using MOE 2014.09. Through the simulations, 10 best ligands based on the Gibbs free binding energies ΔGbinding) and the ligand-enzyme complex interactions were identified. The pharmacological test was conducted to observe the physicochemical, toxicity, carcinogenicity-mutagenicity, and bioactivity properties by employing DataWarrior 4.7.2., Toxtree, Molinspiration, admetSAR, and SWISSADME software. The results revealed that three best ligands from the phenolic group were selected due to their exceptional pharmacological characteristics as the drug candidate for breast cancer therapy.

In mammals, the tachykinin 3 (TAC3)/tachykinin receptor 3 (TACR3) systems have been confirmed to play an important role in the regulation of puberty onset. Using grass carp pituitary cells as the model, our recent study found that the TAC3 gene products could significantly induce somatolactin α (SLα) synthesis and secretion via TACR3 activation. In the present study, we seek to examine if pituitary TACR3 can serve as a regulatory target and contribute to TAC3 interactions with other SLα regulators. Firstly, grass carp TACR3 was cloned and tissue distribution showed that it could be highly detected in grass carp pituitary. Using HEK293 cells as the model, functional expression also revealed that grass carp TACR3 exhibited ligand binding selectivity and post-receptor signaling highly comparable to its mammalian counterpart. Using grass carp pituitary cells as the model, TACR3 mRNA expression could be stimulated by insulin-like growth factor (IGF)-I and -II via the IGF-I receptor coupled to phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) pathways. Interestingly, IGF-I/-II cotreatment could also significantly enhance TAC3-induced SLα mRNA expression and the potentiating effect was dependent on TACR3 expression and activation of adenylate cyclase (AC)/cAMP/protein kinase A (PKA), phospholipase C (PLC)/inositol 1,4,5-triphosphate (IP3)/protein kinase C (PKC), and Ca2+/calmodulin (CaM)/calmodulin-dependent protein kinase II (CaMK-II) cascades. Besides, IGF-I-induced Akt phosphorylation but not MEK, extracellular signal-regulated kinase (ERK1/2), and P38MAPK phosphorylation was notably enhanced by TACR3 activation. These results, as a whole, suggest that the potentiating effect of IGFs on TAC3 gene products-induced SLα mRNA expression was mediated by TACR3 upregulation and functional crosstalk of post-receptor signaling in the pituitary.

Some specifics of cardiac stress protocols, i.e., stressor used or exercise level achieved, may impact myocardial perfusion imaging (MPI) accuracy. Four-hundred and seventy-five patients were submitted to MPI and coronary angiography. MPI was performed after exercise (303 patients) or dipyridamole stress (172 patients). A coronary stenosis ≥70% was considered significant. In case of exercise test, a peak heart rate (HR) <85% of the maximal age predicted was considered submaximal and categorized as follows: >75% and <85% (“Group 1”); <75% (“Group 2”). At coronary angiography, 312/475 (66%) patients showed significant stenosis. In the overall population, MPI showed a high accuracy in unmasking significant coronary stenosis, independently of the stress protocol adopted (AUC .76 for exercise vs .78 for vasodilator; P = NS). However, in case of an exercise stress test, a significant interaction between peak %HR and MPI diagnostic power was evident. While an elevated accuracy was still maintained in “Group 1” patients (AUC .79; P vs maximal exercise = NS), a significant drop was demonstrated in “Group 2” patients (AUC .66; P vs maximal exercise = .012, and P vs “Group 1” = .042). The accuracy of MPI is not influenced by the stress protocol adopted. Exercise MPI maintains an elevated accuracy as long as the %HR remains >75%.

BackgroundThe Basel Asymptomatic High-Risk Diabetics’ Outcome Trial (BARDOT) demonstrated that asymptomatic diabetic patients with an abnormal myocardial perfusion scintigraphy (MPS) were at increased risk of major adverse cardiovascular events (MACEs) at 2-year follow-up. It remains unclear whether this finding holds true even for a longer follow-up.MethodsFour hundred patients with type 2 diabetes, neither history nor symptoms of coronary artery disease (CAD), were evaluated clinically and with MPS. Patients were followed up for 5 years. Major adverse cardiovascular events (MACEs) were defined as all-cause death, myocardial infarction, or late coronary revascularization.ResultsAt baseline, an abnormal MPS (SSS ≥ 4 or SDS ≥ 2) was found in 87 of 400 patients (22%). MACE within 5 years occurred in 14 patients with abnormal MPS (16.1%) and in 22 with normal scan (1.7%), p = 0.009; 15 deaths were recorded. Patients with completely normal MPS (SSS and SDS = 0) had lower rates of MACEs than patients with abnormal scans (2.5% vs. 7.0%, p = 0.032). Patients with abnormal MPS who had undergone revascularization had a lower mortality rate and a better event-free survival from MI and revascularization than patients with abnormal MPS who had either undergone medical therapy only or could not be revascularized (p = 0.002).ConclusionsMPS may have prognostic value in asymptomatic diabetic patients at high cardiovascular risk over a follow-up period of 5 years. Patients with completely normal MPS have a low event rate and may not need retesting within 5 years. Patients with an abnormal MPS have higher event rates and may benefit from a combined medical and revascularization approach.

Aim： To investigate the pharmacokinetics, pharmacodynamics, and safety of higenamine, an active ingredient of Aconite root, in healthy Chinese volunteers. Methods：Ten subjects received continuous, intravenous infusion of higenamine at gradually escalating doses from 0.5 to 4.0 pg.kg^1.min 1, each dose was given for 3 min. Blood and urine samples were collected at designated time points to measure the concentrations of higenamine. Pharmacodynamics was assessed by measuring the subject＇s heart rate. A nonlinear mixed-effect modeling approach, using the software Phoenix NLME, was used to model the plasma concentration-time profiles and heart rate. Results： Peak concentrations （Cmax） of higenamine ranged from 15.1 to 44.0 ng/mL. The half-life of higenamine was 0.133 h （range, 0.107-0.166 h）, while the area under concentration-time curve （AUC）, extrapolated to infinity, was 5.39 ng-h.mL1 （range, 3.2-6.8 ng.h.mLl）. The volume of distribution （V） was 48 L （range, 30.8-80.6 L）. The total clearance （CL） was 249 L/h （range, 199-336 L/h）. Within 8 h, 9.3% （range, 4.6%-12.4%） of higenamine was recovered in the urine. The pharmacokinetics of higenamine was successfully described using a two-compartment model with nonlinear clearance. In the pharmacodynamic model, heart rates were related to the plasma drug concentrations using a simple direct effect model with baseline. The Eo, Emax, and EC5o were 68 bpm, 73 bpm and 8.1 pg/L, respectively. Conclusion： Higenamine has desirable pharmacokinetic and pharmacodynamic characteristics. The results provide important informa tion for future clinical studies on higenamine.

The serum GH cut-off value for pharmacological tests of GH secretion (PhT GH) depends on the type of test and also on the method used for determining serum GH. Cut-off serum GH values as different as 5-10 ng/ml, have been reported, and have been validated biochemically. We have used the growth velocity (GV)-standard deviation score (SDS) during the first year of treatment with rhGH to validate these cut-offs on a biological basis. Fifty pre-pubertal patients with short stature (height < or =-2 SDS and GV < or =-1.2 SDS) were studied. GH deficiency (GHD) was diagnosed in 39 patients, on the basis of clinical and auxological parameters and on the serum concentration of IGF-1, and non-GHD in the other 11 patients. Two PhT GH (arginine and clonidine) were carried out in the 50 patients. Serum GH was determined by two different methods: one detecting most of serum GH isoforms, named Total GH (HGH Bio-Tech, MAIA Clone), and another one, only detecting the 22 kDa GH, named 22K GH (GH-22K IFMA, Wallac). Basal data: all patients with GHD and with non-GHD had maximal serum GH response (MaxR) values below and above the cut-off, respectively, for the serum Total GH and 22K GH. The mean 22K GH/Total GH ratio was similar to previous publications. Post-rhGH treatment data: the two groups improved their height SDS during the first year of treatment, particularly patients with GHD. A receiver-operator curve was used to define the best threshold for post-treatment GV-SDS that separates GHD from non-GHD patients. This value was 1.91 GV-SDS. A negative correlation between first year treatment GV-SDS and pre-treatment serum GH MaxR was found for the two assays (p < 0.001). Then, the best cut-off GV-SDS, previously calculated with the receiver-operator curve (1.91 SDS) was used to interpolate the corresponding serum GH values, as determined by the two methods. For Total GH, the value was 10.8 ng/ml, and for 22K GH, it was 5.4 ng/ml. The cut-off values calculated by biological means to separate GHD from non-GHD were remarkably similar to those calculated biochemically (10.0 and 4.8 ng/ml, respectively) for Total and 22K GH. This is a biological validation for using different cut-off values, appropriate for each assay, to diagnose GHD.