-
Biomedicine & Pharmacotherapy =... Oct 2021β-blockers are commonly prescribed to treat multiple cardiovascular (CV) diseases, but, frequently, adverse drug reactions and intolerance limit their use in clinical... (Meta-Analysis)
Meta-Analysis
β-blockers are commonly prescribed to treat multiple cardiovascular (CV) diseases, but, frequently, adverse drug reactions and intolerance limit their use in clinical practice. Interindividual variability in response to β-blockers may be explained by genetic differences. In fact, pharmacogenetic interactions for some of these drugs have been widely studied, such as metoprolol. But studies that explore genetic variants affecting bisoprolol response are inconclusive, limited or confusing because of mixed results with other β-Blockers, different genetic polymorphisms observed, endpoint studied etc. Because of this, we performed a systematic review in order to find relevant genetic variants affecting bisoprolol response. We have found genetic polymorphism in several genes, but most of the studies focused in ADRB variants. The ADRB1 Arg389Gly (rs1801253) was the most studied genetic polymorphism and it seems to influence the response to bisoprolol, although studies are inconclusive. Even, we performed a meta-analysis about its influence on systolic/diastolic blood pressure in patients treated with bisoprolol, but this did not show statistically significant results. In conclusion, many genetic polymorphisms have been assessed about their influence on patients´ response to bisoprolol and the ADRB1 Arg389Gly (rs1801253) seems the most relevant genetic polymorphism in this regard but results have not been confirmed with a meta-analysis. Our results support the need of further studies about the impact of genetic variants on bisoprolol response, considering different genetic polymorphisms and conducting single and multiple SNPs analysis, including other clinical parameters related to bisoprolol response in a multivariate study.
Topics: Adrenergic beta-1 Receptor Antagonists; Bisoprolol; Blood Pressure; Cardiovascular Diseases; Humans; Pharmacogenetics; Polymorphism, Single Nucleotide; Receptors, Adrenergic, beta-1; Treatment Outcome
PubMed: 34470728
DOI: 10.1016/j.biopha.2021.112069 -
Stress and Health : Journal of the... Oct 2022The COVID-19 pandemic imposed profound effects on health and daily life, with widespread stress exposure and increases in psychiatric symptoms. Despite these challenges,...
The COVID-19 pandemic imposed profound effects on health and daily life, with widespread stress exposure and increases in psychiatric symptoms. Despite these challenges, pandemic research provides unique insights into individual differences in emotion and cognition that predict responses to stress, with general implications for understanding stress vulnerability. We examined predictors of responses to COVID-19-related stress in an online sample of 450 emerging adults recruited in May 2020 to complete questionnaires assessing baseline stress and psychiatric symptoms, rumination, cognitive reappraisal use and intolerance of uncertainty. Stress and symptoms were re-assessed 3 months later (N = 200). Greater pandemic-related stressful events were associated with increases in symptoms of depression, anxiety and alcohol use severity. Additionally, individual differences in emotional and cognitive styles emerged as longitudinal predictors of stress responses. Specifically, greater rumination predicted increased depression. Reduced cognitive reappraisal use interacted with stress to predict increases in alcohol use. An unexpected pattern emerged for intolerance of uncertainty, such that stress was associated with increases in depression for those high in intolerance of uncertainty but increases in alcohol use at relatively low levels of intolerance of uncertainty. These results highlight unique vulnerabilities that predict specific outcomes following stress exposure and offer potential prevention targets.
Topics: Adult; Anxiety; Anxiety Disorders; COVID-19; Depression; Humans; Pandemics
PubMed: 34979053
DOI: 10.1002/smi.3125 -
Journal of Behavioral Medicine Aug 2020Exposure to stress is associated with poor outcomes in people with chronic pain. Dispositional variables, such as pain catastrophizing and distress intolerance, may...
Exposure to stress is associated with poor outcomes in people with chronic pain. Dispositional variables, such as pain catastrophizing and distress intolerance, may impact reactivity to stressors. Importantly, these variables can be modified with treatment. The aim of this study was to investigate whether pain catastrophizing and distress intolerance were associated with tolerance of a pain stressor or a psychosocial stressor, and heightened negative affect following these stressors. A sample of 50 adults with chronic pain completed self-report measures and pain and psychosocial stress inductions. Results indicated that pain catastrophizing was associated with heightened anxiety during pain induction. Distress intolerance was associated with negative affect following a psychosocial stressor, and with poorer tolerance of the psychosocial stressor. Pain catastrophizing and distress intolerance are related factors, however, they exhibit distinct associations with amplification of pain and psychosocial stress reactivity. These variables may be important treatment targets in people with chronic pain.
Topics: Adult; Anxiety; Catastrophization; Chronic Pain; Female; Humans; Male; Middle Aged; Psychological Distress; Self Report
PubMed: 31376099
DOI: 10.1007/s10865-019-00086-5 -
Current Opinion in Supportive and... Jun 2017Pain is one of the most common and feared symptoms associated with a new diagnosis of cancer and its subsequent treatment. Unfortunately, it remains undertreated in... (Review)
Review
PURPOSE OF REVIEW
Pain is one of the most common and feared symptoms associated with a new diagnosis of cancer and its subsequent treatment. Unfortunately, it remains undertreated in around one third of patients. It has been recently postulated that one mechanism for this could be failure to recognize neuropathic pain. One attractive option in both the case of neuropathic pain and pain associated with intolerable side effects of prescribed opioids is the use of 'topiceuticals', as a means of targeted pain relief with potentially fewer side effects. The present review summarizes the evidence base for the various topiceuticals available for the treatment of localized neuropathic pain.
RECENT FINDINGS
The recent evidence base for established treatments such as capsaicin and lignocaine is examined. A variety of novel and previously used therapies are considered.
SUMMARY
The use of topiceuticals in localized neuropathic pain associated with malignancy remain a valuable option with many advantages over systemic treatments. In addition to anecdotal reports of efficacy, there is a growing body of evidence to consider the early use of topical lignocaine and capsaicin in this context. The authors' have proposed a guideline including the use of topiceuticals to aid in the management of neuropathic pain.
Topics: Administration, Cutaneous; Analgesics, Opioid; Anesthetics, Local; Cancer Pain; Capsaicin; Clinical Trials as Topic; Clonidine; Drug Therapy, Combination; Humans; Lidocaine; Menthol; Neuralgia; Pain Management; Pain Measurement
PubMed: 28460372
DOI: 10.1097/SPC.0000000000000271 -
British Journal of Industrial Medicine Feb 1979Facial flushing and other symptoms were reported by 19 of a group of 102 men who worked with dimethylformamide (DMF). Twenty-six of the 34 episodes occurred after the...
Facial flushing and other symptoms were reported by 19 of a group of 102 men who worked with dimethylformamide (DMF). Twenty-six of the 34 episodes occurred after the workers had consumed alcoholic drinks. The metabolite N-methylformamide (MF) was detected in the urine on 45 occasions, the highest recorded concentration being 77 microliter/litre. The highest recorded concentration of DMF in air was 200 ppm. The DMF-ethanol reaction is possibly attributable to the inhibition of acetaldehyde metabolism, probably by MF.
Topics: Air Pollutants, Occupational; Dimethylformamide; Drug Interactions; Ethanol; Face; Formamides; Humans; Male; Time Factors; Vasodilation
PubMed: 444443
DOI: 10.1136/oem.36.1.63 -
Biomolecules Mar 2023Accumulating evidence has demonstrated the association between alcohol overconsumption and the development of insulin resistance. However, the underlying mechanisms are...
Accumulating evidence has demonstrated the association between alcohol overconsumption and the development of insulin resistance. However, the underlying mechanisms are not completely understood. To investigate the requirement and sufficiency of hepatocyte toll-like receptor 4 (TLR4) in alcohol-induced insulin resistance, we used two mouse models (Tlr4 and Tlr4) that allow ablation of TLR4 only in hepatocytes (Tlr4) and restoration of endogenous TLR4 expression in hepatocytes on a TLR4-null background (Tlr4 × Alb-Cre), respectively. A Lieber-DeCarli feeding model was used to induce glucose intolerance and insulin resistance in mice. Glucose tolerance test, insulin tolerance test, and insulin signaling experiments were performed to examine systemic and tissue-specific insulin sensitivity. We found that alcohol-fed hepatocyte TLR4 deficient mice (Tlr4) had lower blood glucose levels in response to intraperitoneal injection of insulin. Moreover, increased phosphorylation of glycogen synthase kinase-3β (GSK3β) was observed in the liver of Tlr4 mice after chronic alcohol intake. In contrast, when hepatic TLR4 was reactivated in mice (Tlr4 × Alb-Cre), alcohol feeding caused glucose intolerance in these mice compared with littermate controls (Tlr4). In addition, AKT phosphorylation was dramatically reduced in the liver and epididymal white adipose tissue (eWAT) of alcohol-fed Tlr4 × Alb-Cre mice, which was similar to that of mice with whole-body TLR4 reactivation (Tlr4 × Zp3-Cre). Collectively, these findings suggest that hepatocyte TLR4 is both required and sufficient in the development of insulin resistance induced by alcohol overconsumption.
Topics: Animals; Mice; Ethanol; Glucose Intolerance; Hepatocytes; Insulin; Insulin Resistance; Liver; Mice, Inbred C57BL; Toll-Like Receptor 4
PubMed: 36979389
DOI: 10.3390/biom13030454 -
Journal of Bone and Mineral Research :... Oct 1991Primary hyperparathyroidism (PHPT) is characterized by hypersecretion of parathyroid hormone (PTH) leading to hypercalcemia and relative hypophosphatemia. PTH acts by... (Review)
Review
Primary hyperparathyroidism (PHPT) is characterized by hypersecretion of parathyroid hormone (PTH) leading to hypercalcemia and relative hypophosphatemia. PTH acts by binding to cell surface receptors coupled to G proteins. Cyclic AMP is the classic second messenger of PTH action, but substantial evidence indicates that PTH also acts to stimulate formation of the dual second messengers, inositol trisphosphate and diacylglycerol, thereby mobilizing intracellular calcium. The physiologic actions of PTH include (1) an increase in extracellular fluid ionized calcium through direct actions on kidney and bone, the classic target organs for PTH, and (2) a decrease in extracellular fluid phosphate primarily through renal action. The pathophysiologic effects of PTH arise from (1) direct actions of PTH on bone and kidney, and possibly on nonclassic target organs, and (2) indirect effects of altered mineral homeostasis. PTH hypersecretion in PHPT can lead to bony demineralization, nephrolithiasis, and hypercalcemic crisis. PHPT may also be associated with mental disturbances, neuromuscular disease, hypertension, and glucose intolerance.
Topics: Binding Sites; Calcium; GTP-Binding Proteins; Humans; Hypercalcemia; Hyperparathyroidism; Inositol Phosphates; Kidney; Parathyroid Hormone; Phosphates; Second Messenger Systems
PubMed: 1763667
DOI: 10.1002/jbmr.5650061407 -
Nutrients Oct 2023Excessive intake of sugar, and particularly fructose, is closely associated with the development and progression of metabolic syndrome in humans and animal models....
Excessive intake of sugar, and particularly fructose, is closely associated with the development and progression of metabolic syndrome in humans and animal models. However, genetic disorders in fructose metabolism have very different consequences. While the deficiency of fructokinase, the first enzyme involved in fructose metabolism, is benign and somewhat desirable, missense mutations in the second enzyme, aldolase B, causes a very dramatic and sometimes lethal condition known as hereditary fructose intolerance (HFI). To date, there is no cure for HFI, and treatment is limited to avoiding fructose and sugar. Because of this, for subjects with HFI, glucose is their sole source of carbohydrates in the diet. However, clinical symptoms still occur, suggesting that either low amounts of fructose are still being consumed or, alternatively, fructose is being produced endogenously in the body. Here, we demonstrate that as a consequence of consuming high glycemic foods, the polyol pathway, a metabolic route in which fructose is produced from glucose, is activated, triggering a deleterious mechanism whereby glucose, sorbitol and alcohol induce severe liver disease and growth retardation in aldolase B knockout mice. We show that generically and pharmacologically blocking this pathway significantly improves metabolic dysfunction and thriving and increases the tolerance of aldolase B knockout mice to dietary triggers of endogenous fructose production.
Topics: Humans; Animals; Mice; Fructose Intolerance; Fructose; Fructose-Bisphosphate Aldolase; Liver Diseases; Digestive System Diseases; Glucose; Mice, Knockout
PubMed: 37892451
DOI: 10.3390/nu15204376 -
Frontiers in Physiology 2017Acute ingestion of alcohol is often accompanied by cardiovascular dysregulation, malaise and even syncope. The full hemodynamic and cutaneous responses to the...
Acute ingestion of alcohol is often accompanied by cardiovascular dysregulation, malaise and even syncope. The full hemodynamic and cutaneous responses to the combination of alcohol and sugar (i.e., alcopops), a common combination in young people, and the mechanisms for the propensity to orthostatic intolerance are not well established. Thus, the purpose of this study was to evaluate the cardiovascular and cutaneous responses to alcopops in young subjects. Cardiovascular and cutaneous responses were assessed in 24 healthy young subjects (12 men, 12 women) sitting comfortably and during prolonged active standing with a 30-min baseline and 130 min following ingestion of 400 mL of either: water, water + 48 g sugar, water + vodka (1.28 mL.kg of body weight, providing 0.4 g alcohol.kg), water + sugar + vodka, according to a randomized cross-over design. Compared to alcohol alone, vodka + sugar induced a lower breath alcohol concentration (BrAC), blood pressure and total peripheral resistance ( < 0.05), a higher cardiac output and heart rate ( < 0.05) both in sitting position and during active standing. In sitting position vodka + sugar consumption also led to a greater increase in skin blood flow and hand temperature ( < 0.05) and a decrease in baroreflex sensitivity ( < 0.05). We observed similar results between men and women both in sitting position and during active standing. Despite lower BrAC, ingestion of alcopops induced acute vasodilation and hypotension in sitting position and an encroach of the hemodynamic reserve during active standing. Even if subjects did not feel any signs of syncope these results could be of clinical importance with higher doses of alcohol or if combined to other hypotensive challenges.
PubMed: 29176950
DOI: 10.3389/fphys.2017.00860 -
Molecular Metabolism Dec 2023Alcohol-associated liver disease (ALD) is the leading cause of liver-related mortality worldwide. Current strategies to manage ALD focus largely on advanced stage...
Ceramide synthase 6 (CerS6) is upregulated in alcohol-associated liver disease and exhibits sex-based differences in the regulation of energy homeostasis and lipid droplet accumulation.
OBJECTIVE
Alcohol-associated liver disease (ALD) is the leading cause of liver-related mortality worldwide. Current strategies to manage ALD focus largely on advanced stage disease, however, metabolic changes such as glucose intolerance are apparent at the earliest stage of alcoholic steatosis and increase the risk of disease progression. Ceramides impair insulin signaling and accumulate in ALD, and metabolic pathways involving ceramide synthase 6 (CerS6) are perturbed in ALD during hepatic steatosis. In this study, we aimed to investigate the role of CerS6 in ALD development and the relevance of CerS6 to human ALD.
METHODS
C57BL/6 WT and CerS6 KO mice of both sexes were fed either a Lieber-DeCarli control (CON) or 15% ethanol (EtOH) diet for six weeks. In vivo metabolic tests including glucose and insulin tolerance tests (GTT and ITT) and energy expenditure were performed. The mice were euthanized, and serum and liver lipids and liver histology were examined. For in vitro studies, CerS6 was deleted in human hepatocytes, VL17A and cells were incubated with EtOH and/or C-ceramides. RNAseq analysis was performed in livers from mice and human patients with different stages of ALD and diseased controls.
RESULTS
After six weeks on an EtOH diet, CerS6 KO mice had reduced body weight, food intake, and %fat mass compared to WT mice. Energy expenditure increased in both male and female KO mice, however, was only statistically significant in male mice. In response to EtOH, WT mice developed mild hepatic steatosis, while steatosis was ameliorated in KO mice as determined by H&E and ORO staining. KO mice showed significantly decreased long-chain ceramide species, especially C-ceramides, in the serum and liver tissues compared to WT mice. CerS6 deletion decreased serum TG and NEFA only in male not female mice. CerS6 deletion improved glucose tolerance and insulin resistance in EtOH-fed mice of both sexes. RNAseq analysis revealed that 74 genes are significantly upregulated and 66 genes are downregulated by CerS6 deletion in EtOH-fed male mice, with key network pathways including TG biosynthetic process, positive regulation of lipid localization, and fat cell differentiation. Similar to RNAseq results, absence of CerS6 significantly decreased mRNA expression of lipid droplet associated proteins in EtOH-fed mice. In vitro, EtOH stimulation significantly increased PLIN2 protein expression in VL17A cells while CerS6 deletion inhibited EtOH-mediated PLIN2 upregulation. C-ceramide treatment significantly increased PLIN2 protein expression compared to CON. Notably, progression of ALD in humans was associated with increased hepatic CerS6 expression.
CONCLUSIONS
Our findings demonstrate that CerS6 deletion improves glucose homeostasis in alcohol-fed mice and exhibits sex-based differences in the attenuation of EtOH-induced weight gain and hepatic steatosis. Additionally, we unveil that CerS6 plays a major role as a regulator of lipid droplet biogenesis in alcohol-induced intra-hepatic lipid droplet formation, identifying it as a putative target for early ALD management.
Topics: Animals; Female; Humans; Male; Mice; Ceramides; Ethanol; Fatty Liver; Glucose; Homeostasis; Insulins; Lipid Droplets; Liver Diseases, Alcoholic; Mice, Inbred C57BL; Perilipin-2
PubMed: 37714377
DOI: 10.1016/j.molmet.2023.101804