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1.
ORAI1 Ca2+ Channel as a Therapeutic Target in Pathological Vascular Remodelling.
Shawer, H, Norman, K, Cheng, CW, Foster, R, Beech, DJ, Bailey, MA
Frontiers in cell and developmental biology. 2021;:653812
Abstract
In the adult, vascular smooth muscle cells (VSMC) are normally physiologically quiescent, arranged circumferentially in one or more layers within blood vessel walls. Remodelling of native VSMC to a proliferative state for vascular development, adaptation or repair is driven by platelet-derived growth factor (PDGF). A key effector downstream of PDGF receptors is store-operated calcium entry (SOCE) mediated through the plasma membrane calcium ion channel, ORAI1, which is activated by the endoplasmic reticulum (ER) calcium store sensor, stromal interaction molecule-1 (STIM1). This SOCE was shown to play fundamental roles in the pathological remodelling of VSMC. Exciting transgenic lineage-tracing studies have revealed that the contribution of the phenotypically-modulated VSMC in atherosclerotic plaque formation is more significant than previously appreciated, and growing evidence supports the relevance of ORAI1 signalling in this pathologic remodelling. ORAI1 has also emerged as an attractive potential therapeutic target as it is accessible to extracellular compound inhibition. This is further supported by the progression of several ORAI1 inhibitors into clinical trials. Here we discuss the current knowledge of ORAI1-mediated signalling in pathologic vascular remodelling, particularly in the settings of atherosclerotic cardiovascular diseases (CVDs) and neointimal hyperplasia, and the recent developments in our understanding of the mechanisms by which ORAI1 coordinates VSMC phenotypic remodelling, through the activation of key transcription factor, nuclear factor of activated T-cell (NFAT). In addition, we discuss advances in therapeutic strategies aimed at the ORAI1 target.
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2.
L-Glutamine Supplementation Improves the Benefits of Combined-Exercise Training on Oral Redox Balance and Inflammatory Status in Elderly Individuals.
Almeida, EB, Santos, JMB, Paixão, V, Amaral, JB, Foster, R, Sperandio, A, Roseira, T, Rossi, M, Cordeiro, TG, Monteiro, FR, et al
Oxidative medicine and cellular longevity. 2020;:2852181
Abstract
Although regular combined aerobic-resistance exercises can ameliorate the inflammatory status and redox balance in elderly population, it is unclear whether protein or specific amino acid supplementation could improve such benefits. Therefore, we aimed to evaluate the inflammatory status and redox indexes through of the saliva of 34 elderly subject nonpractitioners (NP group, 73.3 ± 6.6 years) and 49 elderly subject practitioners of a combined-exercise training in moderate intensity (CET group, 71.9 ± 5.8 years) before (pre) and after (post) 30 days of supplementation with L-glutamine (Gln) or placebo (PL). Our results showed that, both in pre- and postsupplementation, the salivary levels of nitric oxide (NO·) and TNF-α were lower, whereas the levels of uric acid and IL-10 (as well as IL-10/TNF-α ratio) were higher in the CET groups than in the NP groups. In postsupplementation, both groups supplemented with Gln (NP-Gln and CET-Gln) showed higher salivary uric acid levels compared to baseline. In addition, lower NO· levels were found in the CET-Gln group postsupplementation than presupplementation values. Whereas the CET-Gln group showed lower GSH levels postsupplementation, NP-Gln subjects showed lower GSSG levels at the same time point, both compared to baseline. Interestingly, salivary peroxidase activity was lower only in NP groups (NP-PL and NP-Gln) postsupplementation than baseline values. A positive significant correlation between salivary peroxidase activity and GSH levels, and also between salivary peroxidase activity and uric acid levels were observed in the CET-Gln group both pre- and postsupplementation. No differences were found in albumin, total antioxidant activity (TEAC), and reducing power analysis between groups, pre- or postsupplementation. In conclusion, the elderly subjects from the CET group showed a better inflammatory response and redox balance and, for the first time, it was shown that daily supplementation with Gln for 30 days can improve these benefits with putative association with a healthy aging.
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3.
Daily Intake of Fermented Milk Containing Lactobacillus casei Shirota (Lcs) Modulates Systemic and Upper Airways Immune/Inflammatory Responses in Marathon Runners.
Vaisberg, M, Paixão, V, Almeida, EB, Santos, JMB, Foster, R, Rossi, M, Pithon-Curi, TC, Gorjão, R, Momesso, CM, Andrade, MS, et al
Nutrients. 2019;11(7)
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Plain language summary
Athletes undergoing high-intensity efforts show increased incidence of upper respiratory tract infections (URTI), both in the context of competitions and during strenuous training. The aim of this study was to evaluate the influence of the daily intake of fermented milk (containing Lactobacillus casei Shirota) on the systemic and upper airway immune/inflammatory responses before and after a race in marathon runners who previously reported upper respiratory symptoms (URS) after an exhaustive physical exercise session. The study is a double-blind randomised clinical study which recruited 42 male amateur marathon runners with an average age of 39 years. The participants were randomly separated into two groups: Lactobacillus casei Shirota group (n=20) or the placebo group (n=22). Results indicate that daily ingestion of fermented milk (containing Lactobacillus casei Shirota) was able to control both immunological and inflammatory responses in the blood and also in the upper airways mucosal of amateurs´ runners after a marathon. Authors conclude that Lactobacillus casei Shirota is able to modulate the systemic and airways immune responses post-marathon, presenting protective effects.
Abstract
BACKGROUND Although Lactobacillus casei Shirota (LcS) can benefit the immune status, the effects of LcS in the immune/inflammatory responses of marathon runners has never been evaluated. Therefore, here we evaluated the effect of daily ingestion of fermented milk containing or not LcS in the systemic and upper airway immune/inflammatory responses before and after a marathon. METHODS Forty-two male marathon runners ingested a fermented milk containing 40 billion of LcS/day (LcS group, n = 20) or placebo (unfermented milk, n = 22) during 30 days pre-marathon. Immune/inflammatory parameters in nasal mucosa and serum, as well as concentrations of secretory IgA (SIgA) and antimicrobial peptides in saliva, were evaluated before and after fermented milk ingestion, immediately, 72 h, and 14 d post-marathon. RESULTS Higher proinflammatory cytokine levels in serum and nasal mucosa, and also lower salivary levels of SIgA and antimicrobial peptides, were found immediately post-marathon in the placebo group compared to other time points and to LcS group. In opposite, higher anti-inflammatory levels and reduced neutrophil infiltration on nasal mucosa were found in the LcS group compared to other time points and to the placebo group. CONCLUSION For the first time, it is shown that LcS is able to modulate the systemic and airways immune responses post-marathon.
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4.
Picomolar, selective, and subtype-specific small-molecule inhibition of TRPC1/4/5 channels.
Rubaiy, HN, Ludlow, MJ, Henrot, M, Gaunt, HJ, Miteva, K, Cheung, SY, Tanahashi, Y, Hamzah, N, Musialowski, KE, Blythe, NM, et al
The Journal of biological chemistry. 2017;(20):8158-8173
Abstract
The concentration of free cytosolic Ca2+ and the voltage across the plasma membrane are major determinants of cell function. Ca2+-permeable non-selective cationic channels are known to regulate these parameters, but understanding of these channels remains inadequate. Here we focus on transient receptor potential canonical 4 and 5 proteins (TRPC4 and TRPC5), which assemble as homomers or heteromerize with TRPC1 to form Ca2+-permeable non-selective cationic channels in many mammalian cell types. Multiple roles have been suggested, including in epilepsy, innate fear, pain, and cardiac remodeling, but limitations in tools to probe these channels have restricted progress. A key question is whether we can overcome these limitations and develop tools that are high-quality, reliable, easy to use, and readily accessible for all investigators. Here, through chemical synthesis and studies of native and overexpressed channels by Ca2+ and patch-clamp assays, we describe compound 31, a remarkable small-molecule inhibitor of TRPC1/4/5 channels. Its potency ranged from 9 to 1300 pm, depending on the TRPC1/4/5 subtype and activation mechanism. Other channel types investigated were unaffected, including TRPC3, TRPC6, TRPV1, TRPV4, TRPA1, TRPM2, TRPM8, and store-operated Ca2+ entry mediated by Orai1. These findings suggest identification of an important experimental tool compound, which has much higher potency for inhibiting TRPC1/4/5 channels than previously reported agents, impressive specificity, and graded subtype selectivity within the TRPC1/4/5 channel family. The compound should greatly facilitate future studies of these ion channels. We suggest naming this TRPC1/4/5-inhibitory compound Pico145.
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5.
Immunological Responses to Total Hip Arthroplasty.
Man, K, Jiang, LH, Foster, R, Yang, XB
Journal of functional biomaterials. 2017;(3)
Abstract
The use of total hip arthroplasties (THA) has been continuously rising to meet the demands of the increasingly ageing population. To date, this procedure has been highly successful in relieving pain and restoring the functionality of patients' joints, and has significantly improved their quality of life. However, these implants are expected to eventually fail after 15-25 years in situ due to slow progressive inflammatory responses at the bone-implant interface. Such inflammatory responses are primarily mediated by immune cells such as macrophages, triggered by implant wear particles. As a result, aseptic loosening is the main cause for revision surgery over the mid and long-term and is responsible for more than 70% of hip revisions. In some patients with a metal-on-metal (MoM) implant, metallic implant wear particles can give rise to metal sensitivity. Therefore, engineering biomaterials, which are immunologically inert or support the healing process, require an in-depth understanding of the host inflammatory and wound-healing response to implanted materials. This review discusses the immunological response initiated by biomaterials extensively used in THA, ultra-high-molecular-weight polyethylene (UHMWPE), cobalt chromium (CoCr), and alumina ceramics. The biological responses of these biomaterials in bulk and particulate forms are also discussed. In conclusion, the immunological responses to bulk and particulate biomaterials vary greatly depending on the implant material types, the size of particulate and its volume, and where the response to bulk forms of differing biomaterials are relatively acute and similar, while wear particles can initiate a variety of responses such as osteolysis, metal sensitivity, and so on.
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6.
A calcipotriene/betamethasone dipropionate two-compound scalp formulation in the treatment of scalp psoriasis in Hispanic/Latino and Black/African American patients: results of the randomized, 8-week, double-blind phase of a clinical trial.
Tyring, S, Mendoza, N, Appell, M, Bibby, A, Foster, R, Hamilton, T, Lee, M
International journal of dermatology. 2010;(11):1328-33
Abstract
The calcipotriene/betamethasone dipropionate two-compound scalp formulation has been shown to be safe and effective in the treatment of scalp psoriasis over 8 weeks, but the patients studied were mainly White and non-Hispanic. The aim of this study was to evaluate the efficacy and safety of the two-compound scalp formulation in the treatment of scalp psoriasis in Hispanic/Latino and Black/African American patients. A total of 99 Hispanic/Latino and 78 Black/African American patients were randomized double-blind in a 3:1 ratio to 8 weeks of once daily treatment of scalp psoriasis with either the two-compound scalp formulation (n=135) or its vehicle (n=42). In the two-compound group, 71.9% of patients had cleared or minimal disease at week 8 by the investigator's global assessment compared to 40.5% in the vehicle group (odds ratio 3.30; 95% CI 1.62-6.72; P<0.001). For the five secondary efficacy response criteria, three (total sign score, thickness of scalp psoriasis, patient's global assessment) showed that two-compound scalp formulation was statistically significantly more effective than its vehicle, and the other two (redness and scaliness of scalp psoriasis) approached statistical significance in favor of the two-compound scalp formulation. There was no statistically significant difference (P=1.00) between the percentage of patients with adverse reactions in the two-compound group (7.0%) and the vehicle group (7.9%). The two-compound scalp formulation is safe and effective in the treatment of scalp psoriasis over 8 weeks in Hispanic/Latino and Black/African American patients.
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7.
Use of calcipotriene cream (Dovonex cream) following acute treatment of psoriasis vulgaris with the calcipotriene/betamethasone dipropionate two-compound product (Taclonex): a randomized, parallel-group clinical trial.
White, S, Vender, R, Thaçi, D, Haverkamp, C, Naeyaert, JM, Foster, R, Martinez Escribano, JA, Cambazard, F, Bibby, A
American journal of clinical dermatology. 2006;(3):177-84
Abstract
INTRODUCTION A calcipotriene/betamethasone dipropionate two-compound product (Taclonex ointment) has been shown to be safe and effective in the treatment of psoriasis over 4 weeks. Since treatment of psoriasis is generally long-term, the objective of this study was to investigate the efficacy and safety of transferring patients to maintenance treatment with calcipotriene cream (Dovonex cream) following a 4-week treatment period with the two-compound product. METHODS Patients with psoriasis were randomized to one of the following three treatment groups: 4 weeks of the two-compound product followed by 8 weeks of calcipotriene cream (calcipotriene cream group); 4 weeks of the two-compound product followed by 8 weeks of calcipotriene cream on weekdays and the two-compound product on weekends (alternating group); 4 weeks of the two-compound product followed by 8 weeks of vehicle of calcipotriene cream (vehicle group). All medications were applied once daily. RESULTS A total of 1136 patients were randomized: 383 to the calcipotriene cream group, 377 to the alternating group, and 376 to the vehicle group. The mean percentage change in the Psoriasis Area and Severity Index from baseline to the end of the trial was -44.5% in the calcipotriene cream group, -58.4% in the alternating group, and -33.1% in the vehicle group. The mean difference between the calcipotriene cream and vehicle groups (primary treatment comparison) was -11.7% (95% CI -17.9, -5.5), which was statistically significant (p<0.001), and the mean difference between the alternating and vehicle groups was -24.7% (95% CI -30.9, -18.5), which was also statistically significant (p<0.001). For the investigators' global assessment of disease severity at the end of the trial, the differences between the calcipotriene cream and vehicle groups, and between the alternating and vehicle groups, were statistically significant (p<0.001), showing superior efficacy in the nonvehicle groups. The results were similar for the patients' global assessment of response to treatment. There were 43 patients (11.3%) with adverse drug reactions in the calcipotriene cream group, 28 (7.6%) in the alternating group, and 32 (8.6%) in the vehicle group. There were no statistically significant differences in the incidence of adverse drug reactions in the calcipotriene cream group relative to the vehicle group (odds ratio 1.36; 95% CI 0.84, 2.21; p=0.21), or in the alternating group relative to the vehicle group (odds ratio 0.87; 95% CI 0.51, 1.48; p=0.61). CONCLUSION Four weeks of treatment with the calcipotriene/betamethasone dipropionate two-compound product followed by 8 weeks of maintenance treatment with calcipotriene cream is effective and safe. As an alternative maintenance regimen, treatment with calcipotriene cream on weekdays and the two-compound product on weekends is also effective and safe.
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8.
Understanding variety: tasting different foods delays satiation.
Hetherington, MM, Foster, R, Newman, T, Anderson, AS, Norton, G
Physiology & behavior. 2006;(2):263-71
Abstract
Variety stimulates intake by as much as 40% following both simultaneous and sequential presentations. Varying sensory and other characteristics of foods could sustain interest in eating and delay the development of satiation. Two experiments set out to explore this by investigating the effect of introducing different foods to taste and rate during intake of a snack. In Experiment 1, 33 participants (23 female) attended the lab on four occasions, to eat sweet or salted popcorn (depending on preference). In a counterbalanced order participants ate ad libitum (control), or were interrupted during eating to taste and rate either the food they were eating (same condition: SC), another food with shared taste characteristics (congruent condition: CC) or a food with a different taste (incongruent condition: IC). Overall participants consumed significantly more in CC and IC than in SC [F(3,90) = 2.74, p<0.05], and pleasantness ratings of the eaten food during CC and IC remained high relative to SC, demonstrating a delay in the normal decline in pleasantness associated with satiation. In Experiment 2, 47 participants (31 female) were allocated to either a food focus (FF) or food distraction (FD) condition, in which intake of chocolate was interrupted during eating to taste and rate chocolate only (FF) or this food and a cheese cracker (FD). FD (94 +/- 9.3 g) participants ate significantly more than FF (68 +/- 9.5 g) and in support of findings from Experiment 1 pleasantness ratings during eating declined more rapidly during FF than FD. Variety may stimulate food intake, in part, by delaying the development of satiation which extends eating and therefore amount consumed. Encouraging consumers to focus on eating should facilitate the normal decline in pleasantness of the food and serve to limit intake.
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9.
Tinzaparin sodium: a review of its pharmacology and clinical use in the prophylaxis and treatment of thromboembolic disease.
Cheer, SM, Dunn, CJ, Foster, R
Drugs. 2004;(13):1479-502
Abstract
Tinzaparin sodium (tinzaparin; innohep) is a low molecular weight heparin (LMWH) formed by the enzymatic degradation of porcine unfractionated heparin (UFH). In clinical trials, once-daily subcutaneous (SC) tinzaparin was effective and generally well tolerated in the prophylaxis and treatment of thromboembolic disease. SC tinzaparin 75 anti-Xa IU/kg/day showed similar thromboprophylactic efficacy to adjusted-dosage oral warfarin in patients undergoing total hip arthroplasty; in patients undergoing knee replacement, the incidence of deep vein thrombosis (DVT) was significantly lower with tinzaparin. The drug had similar efficacy to equivalent-dosage SC enoxaparin sodium in orthopaedic surgery. In patients undergoing general surgery, SC tinzaparin 3500 anti-Xa IU/day was of equivalent thromboprophylactic efficacy to SC UFH 5000IU twice daily. Encouraging preliminary results have been obtained with tinzaparin in the prevention of DVT in patients with complete motor paralysis. In the initial treatment of acute proximal DVT and pulmonary embolism, SC tinzaparin 175 anti-Xa IU/kg/day was at least as effective as adjusted-dosage intravenous (IV) UFH. In the outpatient treatment of venous thromboembolism, tinzaparin has demonstrated similar efficacy to dalteparin sodium (dalteparin) and warfarin. Tinzaparin was effective in preventing clotting in haemodialysis circuits; the anticoagulant efficacy of tinzaparin in patients undergoing haemodialysis was similar to that of SC dalteparin and similar to or less than (although in this case the tinzaparin dose was too low for sufficient anticoagulant efficacy) that of IV UFH. Advantages of tinzaparin over UFH and warfarin include ease of administration and lack of need for laboratory monitoring. Tinzaparin is more cost effective than UFH in the treatment of established thromboembolic disease, and home-based treatment with tinzaparin may offer greater cost benefits than hospital-based therapy. Tinzaparin is well tolerated, including in elderly patients and those with renal impairment receiving long-term treatment. Incidences of major bleeding complications were low and reports of heparin-induced thrombocytopenia were infrequent in clinical studies. In conclusion, tinzaparin is a valuable LMWH in the prophylaxis and management of thromboembolic disease.
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10.
Emerging role of calprotectin in gastroenterology.
Poullis, A, Foster, R, Mendall, MA, Fagerhol, MK
Journal of gastroenterology and hepatology. 2003;(7):756-62
Abstract
Calprotectin is a calcium and zinc binding protein of the S100 family derived predominantly from neutrophils and monocytes. It is detectable in body fluids and tissue samples and is emerging as a valuable marker in the diagnosis, and the monitoring and determining of the prognosis of commonly encountered gastroenterological conditions. Fecal calprotectin, in particular, has for a long time been regarded as a promising marker of gastrointestinal pathology and has now been established as a routine test in Norway and at several centers in the UK.