Miracle-dz/UniFAR-FTUs huggingface dataset:
Histamine H4 receptors in the gastrointestinal tract

Histamine is a well‐established mediator involved in a variety of physiological and pathophysiological mechanisms and exerts its effect through activation of four histamine receptors (H1–H4). The histamine H4 receptor is the newest member of this histamine receptor family, and is expressed throughout the gastrointestinal tract as well as in the liver, pancreas and bile ducts. Functional studies using a combination of selective and non‐selective H4 receptor ligands have rapidly increased our knowledge of H4 receptor involvement in gastrointestinal processes both under physiological conditions and in models of disease. Strong evidence points towards a role for H4 receptors in the modulation of immune‐mediated responses in gut inflammation such as in colitis, ischaemia/reperfusion injury, radiation‐induced enteropathy and allergic gut reactions. In addition, data have emerged implicating H4 receptors in gastrointestinal cancerogenesis, sensory signalling, and visceral pain as well as in gastric ulceration. These studies highlight the potential of H4 receptor targeted therapy in the treatment of various gastrointestinal disorders such as inflammatory bowel disease, irritable bowel syndrome and cancer.
Multiparameter Screening Reveals a Role for Na (cid:2) Channels in Cytokine-Induced (cid:3) -Cell Death

Pancreatic (cid:2) -cell death plays a role in both type 1 and type 2 diabetes, but clinical treatments that specifically target (cid:2) -cell survival have not yet been developed. We have recently developed live-cell imaging-based, high-throughput screening methods capable of identifying factors that modulate pancreatic (cid:2) -cell death, with the hope of finding drugs that can intervene in this process. In the present study, we used a high-content screen and the Prestwick Chemical Library of small molecules to identify drugs that block cell death resulting from exposure to a cocktail of cytotoxic cytokines (25 ng/mL TNF- (cid:3) , 10 ng/mL IL-1 (cid:2) , and 10 ng/mL IFN- (cid:4) ). Data analysis with self-organizing maps revealed that 19 drugs had profiles similar to that of the no cytokine condition, indicating protection. Carbamazepine, an antiepileptic Na (cid:2) channel inhibitor, was particularly interesting because Na (cid:2) channels are not generally considered targets for antiapoptotic therapy in diabetes and because the function of these channels in (cid:2) -cells has not been well studied. We analyzed the expression and characteristics of Na (cid:2) currents in mature (cid:2) -cells from MIP-GFP mice. We confirmed the dose-dependent protective effects of carbamazepine and another use-dependent Na (cid:2) channel blocker in cytokine-treated mouse islet cells. Carbamazepine fluorescence resonance energy transfer (FRET) sensor for detection of caspase-3/7 activation were seeded into 96-well plates and cultured as described previously (13, 15). Cells were stained with 50 ng/mL Hoechst33342(Invitrogen),0.5 (cid:5) g/mLpropidiumiodide(PI)(Sig-ma-Aldrich), and a 3:500 dilution of annexin V–conjugated to Alexa Fluor 647 (Invitrogen). Cells were treated with test drugs in the presence of 22.2 mM glucose containing DMEM supple-mented with 10% vol/vol FBS and a cytokine cocktail (25 ng/mL TNF- (cid:3) , 10 ng/mL IL-1 (cid:2) , and 10 ng/mL IFN- (cid:4) ; R&D Systems). After 30 hours of treatments, cells were imaged with ImageXpress Micro (Molecular Devices) at 37°C and 5% CO 2 . The fluorescent emission of Hoechst 33342 and enhanced blue fluorescent protein 2 (eBFP2), excited at 386/23 nm, was captured with a 445/20 nm filter. PI excitation and emission wavelengths passed through 562/40 and 624/40 nm filters, respectively. Alexa Fluor 647 excitation and emission wavelengths passed through 628/40 and 692/40 nm filters, respectively. Enhanced green fluorescent protein (eGFP) excitation and emission wavelengths passed through 472/30 and 520/35 nm filters, respectively. FRET between eBFP2 and eGFP decreases upon activation of caspase-3/7 and was measured using a 520/35 nm filter and normalized to eBFP2 emission intensity. Time-lapse images for the secondary screens were cap-turedevery2hoursandanalyzedusingMetaXpressSoftware(Mo- lecular Devices).
Validity of Using Background Leukemia Incidence Rates with Cohort Mortality-Based Potency Estimates to Calculate Excess Lifetime Risk

ABSTRACT Data from occupational cohort mortality studies have been used to derive exposure-response curves and general population excess lifetime cancer risks, given low-level, chronic exposure. Using an actuarial method, mortality-based rate ratios associated with cumulative exposures are applied to age-specific background cancer mortality rates for a theoretical population aged birth to 70 years. In one recent U.S. Environmental Protection Agency health assessment, a mortality-based leukemia relative rate model was used with background leukemia incidence rates, rather than mortality rates, to calculate excess lifetime risk of leukemia incidence. We examined the validity and implications of this novel approach, while considering possible bias if a potential leukemogen did not pose equal risk by cell type. Limited sensitivity analyses were also conducted. Our analyses show that using total leukemia mortality-based potency estimates with background incidence rates will introduce a biased estimate of excess lifetime risk, the direction of which varies by potency and the histological type of leukemia. These biases were somewhat increased on adjustment for possible greater susceptibility of children. For potent carcinogens, the traditional approach provides a reasonable approximation of excess lifetime mortality risk for both the more and less fatal forms of leukemia, even after adjustments for children and is, therefore, to be preferred. Less consistency by leukemia cell type and background rate was observed for flatter exposure-response curves. This evaluation illustrates the importance of carefully examining the impact of methodological changes to calculations of excess lifetime risk before implementation.
MERCURY POISONING IN TUNGSTENMOLYBDENUM ROD AND WIRE MANUFACTURING INDUSTRY

In the United States at present there are five or six establishments which manufacture the bulk of tungsten, molybdenum and tungsten-molybdenum combinations used for electrical contacts and filaments in the great and diversified electrical and radio industries of the nation. In addition to these special plants the large electrical manufacturing concerns have departments which process these metallic products and serve as auxiliary sources of supply. This industry is relatively young and, since the pure metals used in the fabrication of rod and wire are not apparently toxic, it has aroused but little interest from the standpoint of industrial health. However, the processing of tungsten and molybdenum involves the use of metallic mercury and introduces the hazard of exposure to the toxic vapors of that metal. In order to appreciate the mechanism for development of mercurialism among workmen employed in this industry it is necessary to have some knowledge of metal
Possible pharmacotherapy for nifedipine‐induced gingival overgrowth: 18α‐glycyrrhetinic acid inhibits human gingival fibroblast growth

This investigation aimed to establish the basis of a pharmacotherapy for nifedipine‐induced gingival overgrowth. Gingival overgrowth has been attributed to the enhanced growth of gingival fibroblasts. In this study, we investigated the effects of 18‐α‐glycyrrhetinic acid (18α‐GA) on growth, the cell cycle, and apoptosis and on the regulators of these processes in gingival fibroblasts isolated from patients who presented with nifedipine‐induced gingival overgrowth.
Compound 9a, a novel synthetic histone deacetylase inhibitor, protects against septic injury in mice by suppressing MAPK signalling

Sepsis is a life‐threatening clinical condition characterized by uncontrolled inflammatory responses and is a major cause of death in intensive care units. Histone deacetylase (HDAC) inhibitors have recently exhibited anti‐inflammatory properties. MAPK phosphatase (MKP) suppresses MAPK signalling, which plays an important role in inflammatory responses. The purpose of this study was to investigate the protective mechanisms of Compound 9a, a newly synthetized HDAC inhibitor, against septic injury.
α1B‐Adrenoceptor signalling regulates bone formation through the up‐regulation of CCAAT/enhancer‐binding protein δ expression in osteoblasts

The sympathetic nervous system regulates bone remodelling, in part, through ß2‐adrenoceptor signalling. However, the physiological role of α1‐adrenoceptor signalling in bone in vivo remains unclear. Therefore, to obtain a deeper understanding of bone remodelling by the sympathetic nervous system, we investigated the role of α1B‐adrenoceptor signalling in bone metabolism.
Relative systemic availability of budesonide in patients with asthma after inhalation from two dry powder inhalers

ABSTRACT Background: To improve dosing consistency and product features, budesonide inhalation powder delivered via a dry powder inhaler (DPI) (DPI‑A* 200 μg) was redesigned to include lactose, a newly shaped mouthpiece, and a new dose indicator (DPI‑B*). Budesonide DPI‑B is available in two strengths (90 μg, 180 μg). Objective: To compare the relative rate and extent of the systemic availability of budesonide inhaled via DPI‑A and DPI‑B and test for systemic absorption bioequivalence. Methods: Adults (n =37) with asthma as defined by the American Thoracic Society were randomized in an open-label, crossover, single-center, single-dose study to budesonide DPI‑A 200 μg × 4 inhalations, budesonide DPI‑B 180 μg × 4 inhalations, or budesonide DPI‑B 90 μg × 8 inhalations, on 3 days, each separated by a washout period of ≥ 5 days. Plasma samples were collected immediately before and up to 12 h after dosing. Primary pharmacokinetic variables were area under the drug plasma concentration–time curve from 0 to infinity (AUC0–∞) and maximum plasma concentration (Cmax); plasma concentration at 12 h (C12h) and time to maximum plasma concentration (Tmax) were secondary variables. Treatments were considered bioequivalent if the 90% confidence intervals (CIs) for their AUC0–∞ and Cmax ratios fell between 80 and 125%. Adverse events were collected. Results: The 90% CIs for the ratios of AUC0–∞ and Cmax for budesonide DPI‑A 200 μg and DPI‑B 180 μg and for both budesonide DPI‑B strengths fell between 80% and 125% (AUC0–∞: budesonide DPI‑B 180 μg × 4/DPI‑A 200 μg × 4: 96.3% [90 % CI: 90.9, 102.1]; budesonide DPI‑B 180 μg × 4/DPI‑B 90 μg × 8: 92.2% [90 % CI: 87.0, 97.7]; Cmax: (budesonide DPI‑B 180 μg × 4/DPI‑A 200 μg × 4: 100.4% [95 % CI: 92.1, 109.4]; budesonide DPI‑B 180 μg × 4/DPI‑B 90 μg × 8: 94.4% [90 % CI: 86.6, 102.9]). No differences in C12h and Tmax were found between treatments. All treatments were well tolerated. Conclusions: Budesonide DPI‑A 200 μg and DPI‑B 180 μg have systemic absorption bioequivalence, and DPI‑B 90 μg and 180 μg are dose-strength equivalent when administered at the same dose. These results may not be generalized to all patients with asthma, as this analysis included only patients with mild-to-moderate asthma aged ≥ 19 years.
Cell culture models of the human cornea — a comparative evaluation of their usefulness to determine ocular drug absorption in‐vitro

Cell culture models of the cornea are continually developed to replace the isolated animal cornea for transcorneal drug absorption studies. The aim of this study was to determine and compare epithelial tightness and permeability of currently available corneal cell culture models to avoid interlaboratory variability and to assess their usefulness for in‐vitro permeation studies. Pure epithelial cell culture models (CEPI, SIRC and HCE‐T cell lines), primary cultures of human corneal epithelium (HCEpiC) and the two commercially available models (RHC and Epiocular), as well as organotypic human cornea constructs (HCC, HCC‐HCE‐T), were investigated and data were compared with those obtained from the excised bovine cornea. Barrier properties were assessed by measurements of transepithelial electrical resistance (TEER) and permeability of three passively absorbed substances (mannitol, testosterone and timolol maleate) with different physico‐chemical properties. TEER experiments revealed weak barrier functions for all of the investigated epithelial models (≤100–200 Ω cm2), except the HCE‐T cell line. Transport studies confirmed TEER results insofar that models showing low TEER values also had higher permeation rates in comparison with the excised bovine cornea. However, models based on HCE‐T cells demonstrated similar barrier properties to isolated corneal tissue. The corneal models investigated in our laboratory show clear differences in epithelial barrier function. In‐vitro systems comprising the HCE‐T cell line seem to be most appropriate to replace excised animal cornea for assessing corneal permeability.
Vascular actions of relaxin: nitric oxide and beyond

The peptide hormone relaxin regulates the essential maternal haemodynamic adaptations in early pregnancy through direct actions on the renal and systemic vasculature. These vascular actions of relaxin occur mainly through endothelium‐derived NO‐mediated vasodilator pathways and improvements in arterial compliance in small resistance‐size arteries. This work catalysed a plethora of studies which revealed quite heterogeneous responses across the different regions of the vasculature, and also uncovered NO‐independent mechanisms of relaxin action. In this review, we first describe the role of endogenous relaxin in maintaining normal vascular function, largely referring to work in pregnant and male relaxin‐deficient animals. We then discuss the diversity of mechanisms mediating relaxin action in different vascular beds, including the involvement of prostanoids, VEGF, endothelium‐derived hyperpolarisation and antioxidant activity in addition to the classic NO‐mediated vasodilatory pathway. We conclude the review with current perspectives on the vascular remodelling capabilities of relaxin.
Smooth muscle‐generated methylglyoxal impairs endothelial cell‐mediated vasodilatation of cerebral microvessels in type 1 diabetic rats

Endothelial cell‐mediated vasodilatation of cerebral arterioles is impaired in individuals with Type 1 diabetes (T1D). This defect compromises haemodynamics and can lead to hypoxia, microbleeds, inflammation and exaggerated ischaemia‐reperfusion injuries. The molecular causes for dysregulation of cerebral microvascular endothelial cells (cECs) in T1D remains poorly defined. This study tests the hypothesis that cECs dysregulation in T1D is triggered by increased generation of the mitochondrial toxin, methylglyoxal, by smooth muscle cells in cerebral arterioles (cSMCs).
Gene therapy via inducible nitric oxide synthase: a tool for the treatment of a diverse range of pathological conditions

Nitric oxide (NO·) is a reactive nitrogen radical produced by the NO synthase (NOS) enzymes; it affects a plethora of downstream physiological and pathological processes. The past two decades have seen an explosion in the understanding of the role of NO· biology, highlighting various protective and damaging modes of action. Much of the controversy surrounding the role of NO· relates to the differing concentrations generated by the three isoforms of NOS. Both calcium‐dependent isoforms of the enzyme (endothelial and neuronal NOS) generate low‐nanomolar/picomolar concentrations of NO·. By contrast, the calcium‐independent isoform (inducible NOS (iNOS)) generates high concentrations of NO·, 2–3 orders of magnitude greater. This review summarizes the current literature in relation to iNOS gene therapy for the therapeutic benefit of various pathological conditions, including various states of vascular disease, wound healing, erectile dysfunction, renal dysfunction and oncology. The available data provide convincing evidence that manipulation of endogenous NO· using iNOS gene therapy can provide the basis for future clinical trials.
Effect of hypercholesterolaemia on myocardial function, ischaemia–reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning

Hypercholesterolaemia is considered to be a principle risk factor for cardiovascular disease, having direct negative effects on the myocardium itself, in addition to the development of atherosclerosis. Since hypercholesterolaemia affects the global cardiac gene expression profile, among many other factors, it results in increased myocardial oxidative stress, mitochondrial dysfunction and inflammation triggered apoptosis, all of which may account for myocardial dysfunction and increased susceptibility of the myocardium to infarction. In addition, numerous experimental and clinical studies have revealed that hyperlcholesterolaemia may interfere with the cardioprotective potential of conditioning mechanisms. Although not fully elucidated, the underlying mechanisms for the lost cardioprotection in hypercholesterolaemic animals have been reported to involve dysregulation of the endothelial NOS‐cGMP, reperfusion injury salvage kinase, peroxynitrite‐MMP2 signalling pathways, modulation of ATP‐sensitive potassium channels and apoptotic pathways. In this review article, we summarize the current knowledge on the effect of hypercholesterolaemia on the non‐ischaemic and ischaemic heart as well as on the cardioprotection induced by drugs or ischaemic preconditioning, postconditioning and remote conditioning. Future perspectives concerning the mechanisms and the design of preclinical and clinical trials are highlighted.
Aspirin‐triggered lipoxin A4 inhibits atherosclerosis progression in apolipoprotein E−/− mice

Atherosclerosis is characterized by a chronic non‐resolving inflammation in the arterial wall. Aspirin‐triggered lipoxin A4 (ATL) is a potent anti‐inflammatory mediator, involved in the resolution of inflammation. However, the therapeutic potential of immune targeting by means of ATL in atherosclerosis has not previously been explored. The aim of the present study was to determine the effects of ATL and its receptor Fpr2 on atherosclerosis development and progression in apolipoprotein E deficient (ApoE−/−) mice.
Pharmacokinetics of drugs in rats with diabetes mellitus induced by alloxan or streptozocin: comparison with those in patients with type I diabetes mellitus

Objectives In rats with diabetes mellitus induced by alloxan (DMIA) or streptozocin (DMIS), changes in the cytochrome P450 (CYP) isozymes in the liver, lung, kidney, intestine, brain, and testis have been reported based on Western blot analysis, Northern blot analysis, and various enzyme activities. Changes in phase II enzyme activities have been reported also. Hence, in this review, changes in the pharmacokinetics of drugs that were mainly conjugated and metabolized via CYPs or phase II isozymes in rats with DMIA or DMIS, as reported in various literature, have been explained. The changes in the pharmacokinetics of drugs that were mainly conjugated and mainly metabolized in the kidney, and that were excreted mainly via the kidney or bile in DMIA or DMIS rats were reviewed also. For drugs mainly metabolized via hepatic CYP isozymes, the changes in the total area under the plasma concentration–time curve from time zero to time infinity (AUC) of metabolites, AUCmetabolite/AUCparent drug ratios, or the time‐averaged nonrenal and total body clearances (CLNR and CL, respectively) of parent drugs as reported in the literature have been compared.
β‐Caryophyllene protects against alcoholic steatohepatitis by attenuating inflammation and metabolic dysregulation in mice

β‐Caryophyllene (BCP) is a plant‐derived FDA approved food additive with anti‐inflammatory properties. Some of its beneficial effects in vivo are reported to involve activation of cannabinoid CB2 receptors that are predominantly expressed in immune cells. Here, we evaluated the translational potential of BCP using a well‐established model of chronic and binge alcohol‐induced liver injury.
Utilizing melatonin to combat bacterial infections and septic injury

Melatonin, also known as N‐acetyl‐5‐methoxytryptamine, is a ubiquitously acting molecule that is produced by the pineal gland and other organs of animals, including humans. As melatonin and its metabolites are potent antioxidants and free radical scavengers, they are protective against a variety of disorders. Moreover, multiple molecular targets of melatonin have been identified, and its actions are both receptor‐mediated and receptor‐independent. Recent studies have shown that melatonin may be useful in fighting against sepsis and septic injury due to its antioxidative and anti‐inflammatory actions; the results generally indicate a promising therapeutic application for melatonin in the treatment of sepsis. To provide a comprehensive understanding regarding the protective effects of melatonin against septic injury, in the present review we have evaluated the published literature in which melatonin has been used to treat experimental and clinical sepsis. Firstly, we present the evidence from studies that have used melatonin to resist bacterial pathogens. Secondly, we illustrate the protective effect of melatonin against septic injury and discuss the possible mechanisms. Finally, the potential directions for future melatonin research against sepsis are summarized.
Versão em português, adaptação transcultural e validação do Questionário de Claudicação de Edimburgo

OBJECTIVE: Translation, cultural adaptation and validation of the Brazilian Portuguese version of the Edinburgh Claudication Questionnaire (ECQ) a specific tool to assess intermittent claudication. METHODS: The Brazilian Portuguese version of the ECQ was developed after authorization by the University of Edinburgh. It was applied to 217 individuals: Sao Paulo Capital District residents with complaints of leg pain. Individuals under research were invited through mass communication media to participate in the I Campaign to Fight Peripheral Arterial Disease (PAD). In stage 1, participants filled out the ECQ and another questionnaire on risk factors and cardiovascular history. In stage 2, participants had anthropometric measures and ankle-brachial index (ABI) at rest measured by vascular Doppler. In case of doubt, vascular treadmill test was applied (VTT). PAD condition was defined by ABI 65 years) and non-elderly subjects. CONCLUSION: The Brazilian Portuguese version of the Edinburgh claudication questionnaire maintained good sensitivity and specificity and can be recommended for screening of PAD in clinical practice and epidemiological research in Brazil.
The role of link workers: a secondary care perspective

Purpose – There is an increasing emphasis on strengthening links between the primary and specialist services in order to provide more effective care for patients. The aim of this paper is to focus on a study to engage frontline, secondary care clinicians in a process of reflection on the role of link workers and to identify their view of priorities.Design/methodology/approach – The paper adopts a mixed method study involving focus groups (qualitative method with deductive approach) followed by a survey (quantitative method with an interpretative approach). Findings – The essential role of link workers in managing clinical throughput/flow and improving communication with general practitioners is highlighted. In contrast, crisis intervention and relapse prevention were identified to be of least importance, probably indicating the role of crisis teams and community teams in fulfilling these functions, respectively.Practical implications – It has become apparent through this evaluation that there may be a need.