Clin Pharmacol Drug Dev. 2021 Aug 2. doi: 10.1002/cpdd.966. Online ahead of print.

ABSTRACT

Omeprazole blocks the gastric H+ /K+ adenosine triphosphatase, thus inhibiting gastric acid secretion, and is metabolized by cytochrome P450 (CYP) 2C19. Due to the physiological changes in the elderly, there are different pharmacokinetic consequences compared to young people. The aim of this study was to evaluate the pharmacokinetic profiles of omeprazole in 15 elderly participants according to the CYP2C19 genotype. The concentration-time profiles of omeprazole and its metabolites, 5-hydroxy (5-OH) omeprazole and omeprazole sulfone, were similar between the CYP2C19 extensive metabolizer (EM) and intermediate metabolizer groups. In contrast, when comparing the EM group and CYP2C19 poor metabolizer (PM) group, the EM/PM geometric mean ratio (95% confidence interval) of area under the plasma concentration-time curve from time of dosing to the last measurable concentration was 0.52 (0.27-1.01) and that of the IM group was 0.71 (0.32-1.59), indicating that the exposure of omeprazole in the PM group was increased. The exposure of 5-OH omeprazole was significantly decreased in the PM group when compared to the EM group, with an EM/PM geometric mean ratio (95% confidence interval) of 2.20 (1.50-3.22). In conclusion, the tendency of drug exposure according to the CYP2C19 genotype in the elderly and young adults was similar in that the exposure level was highest in the PM group. However, when compared to young adults, the difference between the genotype groups was smaller in the elderly.

PMID:34337876 | DOI:10.1002/cpdd.966

Obes Rev. 2021 Aug 1. doi: 10.1111/obr.13309. Online ahead of print.

ABSTRACT

The global prevalence of obesity increases yearly along with a rising demand for efficacious, safe, and accessible treatments. Neuromodulation interventions (i.e., deep brain stimulation [DBS], transcranial magnetic stimulation [TMS], transcranial direct current stimulation [tDCS], percutaneous neurostimulation [PENS], vagus nerve stimulation [VNS], and gastric electrical stimulation [GES]) have been proposed as novel therapies. This systematic review sought to examine the safety and efficacy of neuromodulation therapies in reducing body weight in patients with obesity. Using PRISMA guidelines, we performed a systematic review for studies on neuromodulation for the treatment of obesity, resulting in 60 trials included (7 DBS, 5 TMS, 7 tDCS, 17 PENS and VNS, and 24 GES; a total of 3,042 participants). While promising results have been reported in open label studies, double-blinded randomized clinical trials often did not reach their primary endpoints, with no technique inducing a striking reduction in body weight. Bearing in mind the complexity and multifactorial nature of obesity, it is possible that a single treatment may not be enough for patients to lose or maintain the weight lost at long term.

PMID:34337843 | DOI:10.1111/obr.13309

Neurogastroenterol Motil. 2021 Aug 1:e14217. doi: 10.1111/nmo.14217. Online ahead of print.

ABSTRACT

BACKGROUND: Esophagitis is prevalent in patients with esophageal dysmotility despite acid suppression, likely related to poor esophageal clearance. Esophageal atresia (EA) is a classic model of dysmotility where this observation holds true. In adult non-dysmotility populations, failure of esophagitis to respond to proton pump inhibitors (PPI) has been linked to variants in CYP2C19 that influence the activity of the encoded enzyme. It is unknown if CYP2C19 metabolizer phenotype contributes to PPI-refractory, non-allergic esophagitis in EA.

METHODS: We performed a cross-sectional study of 314 children with (N = 188) and without (N = 126) EA who were on PPI therapy at the time of endoscopy to evaluate for possible gastroesophageal reflux disease. Patients with eosinophilic esophagitis and/or fundoplication were excluded. Clinical and histology data were collected. Genomic DNA from biopsy samples was genotyped for polymorphisms in CYP2C19.

RESULTS: CYP2C19 metabolizer phenotypes were not associated with presence or severity of esophagitis (P = 0.994). In a multivariate logistic regression adjusted for potential confounders, EA was the strongest and only significant predictor of esophagitis (odds ratio 2.72, P = 0.023). Using negative binomial regression, we found that CYP2C19 phenotype was not a significant predictor of eosinophil count in children with PPI-refractory esophagitis.

CONCLUSIONS: Patients with EA are significantly more likely to experience PPI-refractory, non-allergic esophagitis than controls regardless of CYP2C19 metabolizer phenotype, suggesting that factors other than CYP2C19 genetics, including dysmotility, are the primary drivers of esophagitis in EA. CYP2C19 genotype failed to predict PPI-refractory, non-allergic esophagitis in both EA and non-EA children.

PMID:34337835 | DOI:10.1111/nmo.14217

ACS Omega. 2021 Jul 12;6(29):18610-18622. doi: 10.1021/acsomega.1c01135. eCollection 2021 Jul 27.

ABSTRACT

Hypertension adversely affects the quality of life in humans across modern society. Studies have attributed increased reactive oxygen species production to the pathophysiology of hypertension. So far, a specific drug to control the disease perfectly has not been developed. However, artichoke, an edible vegetable, plays an essential role in treating many diseases due to its potent antioxidant activities. The objective of this study is to evaluate the effect of artichoke bud extract (ABE) on heart tissue metabolomics of hypertensive rats. Spontaneously hypertensive rats and Wistar-Kyoto (WKY) rats were divided into six groups, then exposed to different doses comprising ABE, Enalapril Maleate, or 1% carboxylmethyl cellulose for 4 weeks. Their blood pressures were recorded at 0, 2, 3, and 4 weeks after the start of the test period. Thereafter, all rats were anesthetized, and blood was collected from their cardiac apexes. Then, we measured the levels for 15 kinds of serum biochemical parameters. An established orthogonal partial least square-discriminant analysis model completed the metabolomic analysis. Hypertensive rats in the ABE group exhibited well-controlled blood pressure, relative to those in the model group. Specifically, artichoke significantly lowered serum levels for total protein (TP), albumin (ALB), and uric acid (UA) in the hypertensive rats. This effect involved the action of eight metabolites, including guanine, 1-methylnicotinamide, p-aminobenzoic acid, NAD, NADH, uridine 5'-monophosphate, adenosine monophosphate, and methylmalonic acid. Collectively, these findings suggest that ABE may play a role in affecting oxidative stress and purine, nicotinate, and nicotinamide metabolism.

PMID:34337201 | PMC:PMC8319930 | DOI:10.1021/acsomega.1c01135

Front Med (Lausanne). 2021 Jul 16;8:681907. doi: 10.3389/fmed.2021.681907. eCollection 2021.

ABSTRACT

Thiopurines have been a cornerstone in the treatment of inflammatory bowel disease (IBD). Although they have been used for more than 50 years, there are still some unsolved issues about their efficacy and, also, some safety concerns, mainly the risk of myelosuppression and life-threatening lymphoproliferative disorders. Furthermore, the development of biological therapy raises the question whether there is still a role for thiopurines in the IBD treatment algorithm. On the other hand, limited cost and wide availability make thiopurines a reasonable option in settings of limited resources and increasing prevalence of IBD. In fact, there is a growing interest in optimizing thiopurine therapy, since pharmacogenomic findings suggest that a personalized approach based on the genotyping of some molecules involved in its metabolism could be useful to prevent side effects. Polymorphisms of thiopurine methyltransferase enzyme (TPMT) that result in low enzymatic activity have been associated with an increased risk of myelotoxicity, especially in Caucasians; however, in Asians it is assumed that the variants of nudix hydrolase 15 (NUDT15) are more relevant in the development of toxicity. Age is also important, since in elderly patients the risk of complications seems to be increased. Moreover, the primo-infection of Epstein Barr virus and cytomegalovirus under thiopurine treatment has been associated with severe lymphoproliferative disorders. In addition to assessing individual characteristics that may influence thiopurines treatment outcomes, this review also discusses other strategies to optimize the therapy. Low-dose thiopurines combined with allopurinol can be used in hypermethylators and in thiopurine-related hepatotoxicity. The measurement of metabolites could be useful to assess compliance, identify patients at risk of adverse events and also facilitating the management of refractory patients. Thioguanine is also a rescue therapy in patients with toxicity related to conventional thiopurine therapy. Finally, the current indications for thiopurines in monotherapy or in combination with biologics, as well as the optimal duration of treatment, are also reviewed.

PMID:34336887 | PMC:PMC8322650 | DOI:10.3389/fmed.2021.681907

Front Med (Lausanne). 2021 Jul 15;8:652091. doi: 10.3389/fmed.2021.652091. eCollection 2021.

ABSTRACT

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) are T cells-mediated life-threatening immune reactions, most commonly induced by drug. The last decade has seen significant progress in SCARs research. Recent studies have unveiled the pathogenesis of SCARs involved in susceptible genes, including human leukocyte antigens (HLA) and drugs-T cell receptor (TCR) interaction that may trigger T cell activation with downstream immune signaling of cytokines/chemokines and specific cytotoxic proteins releases. Advances in identification of multiple genetic alleles associated with specific drugs related SCARS in different populations is an important breakthrough in recent years for prevention of SCARs. This article summarized the findings on genetic factors related to SJS/TEN, especially for HLA.

PMID:34336873 | PMC:PMC8319741 | DOI:10.3389/fmed.2021.652091

Front Pharmacol. 2021 Jul 14;12:711940. doi: 10.3389/fphar.2021.711940. eCollection 2021.

ABSTRACT

Olanzapine, aripiprazole and risperidone are atypical antipsychotics or neuroleptics widely used for schizophrenia treatment. They induce various adverse drug reactions depending on their mechanisms of action: metabolic effects, such as weight gain and alterations of glucose and lipid metabolism; hyperprolactinemia and extrapyramidal effects, such as tremor, akathisia, dystonia, anxiety and distress. In this review, we listed polymorphisms associated with individual response variability to olanzapine, aripiprazole and risperidone. Olanzapine is mainly metabolized by cytochrome P450 enzymes, CYP1A2 and CYP2D6, whereas aripiprazole and risperidone metabolism is mainly mediated by CYP2D6 and CYP3A4. Polymorphisms in these genes and other enzymes and transporters, such as enzymes from the uridine 5'-diphospho-glucuronosyltransferase (UGT) family and ATP-binding cassette sub-family B member 1 (ABCB1), are associated to differences in pharmacokinetics. The three antipsychotics act on dopamine and serotonin receptors, among others, and several studies found associations between polymorphisms in these genes and variations in the incidence of adverse effects and in the response to the drug. Since olanzapine is metabolized by CYP1A2, a lower starting dose should be considered in patients treated with fluvoxamine or other CYP1A2 inhibitors. Regarding aripiprazole, a reduced dose should be administered in CYP2D6 poor metabolizers (PMs). Additionally, a reduction to a quarter of the normal dose is recommended if the patient is treated with concomitant CYP3A4 inhibitors. Risperidone dosage should be reduced for CYP2D6 PMs and titrated for CYPD6 ultrarapid metabolizers (UMs). Moreover, risperidone dose should be evaluated when a CYP2D6, CYP3A4 or ABCB1 inhibitor is administered concomitantly.

PMID:34335273 | PMC:PMC8316766 | DOI:10.3389/fphar.2021.711940

Pharmgenomics Pers Med. 2021 Jul 24;14:915-926. doi: 10.2147/PGPM.S306358. eCollection 2021.

ABSTRACT

PURPOSE: Plasma efavirenz (EFV) concentrations within therapeutic levels are essential to successfully treat patients suffering from human immunodeficiency virus (HIV) type 1. In addition to the drug-metabolizing enzyme CYP2B6, other phase II drug-metabolizing enzymes and transporters may have an important role in the pharmacokinetics of EFV. Thus, the influence of phase II drug-metabolizing enzymes and drug transporters on plasma EFV levels was investigated in Thai HIV patients receiving EFV.

PATIENTS AND METHODS: Genotyping was performed by TaqMan® real-time PCR in 149 HIV-infected Thai adults, and plasma efavirenz concentration was measured by a validated high-performance liquid chromatography in 12 hours after dosing steady-state plasma samples at week 12 and 24.

RESULTS: Patients with three or more copies of SULT1A1 had significantly lower median plasma EFV concentrations than those carrying two copies at week 12 (p=0.046) and SULT1A1*2 (c.638G>A) carriers had significantly lower median plasma EFV concentrations compared to those not carrying the variant at week 24 (p=0.048). However, no significant association was found after adjusting for CYP2B6 genotype.

CONCLUSION: Genetic variation in a combination of SULT1A1*2 and SULT1A1 copy number may contribute to variability in EFV metabolism and thereby may impact drug response. The influence of a combination between the SULT1A1 and CYP2B6 genotype on EFV pharmacokinetics should be further investigated in a larger study population.

PMID:34335044 | PMC:PMC8318725 | DOI:10.2147/PGPM.S306358

J Sci Med Sport. 2021 Jul 14:S1440-2440(21)00179-1. doi: 10.1016/j.jsams.2021.07.003. Online ahead of print.

ABSTRACT

OBJECTIVES: The aim of the study was to identify predictors determining the course of COVID-19 and antibody response in elite athletes.

DESIGN: Observational study.

METHODS: Routine medical screening with physical examination, resting ECG, and laboratory tests including antibody response was performed 12-68 days after the diagnosis of COVID-19 in 111 athletes of different sports.

RESULTS: Clinical symptoms were observed in 84% of subjects. The severity of COVID-19 was mild in 82% of athletes and moderate in 2% of cases. Athletes aged above 26 and male were more likely to develop symptomatic COVID-19. Asymptomatic subjects were younger and predominantly female. In 18% of subjects, symptoms were still present 20 (12-68) days (median and range) since positive diagnosis. Antibody response was observed in 88% of athletes, and its magnitude correlated with time since diagnosis of COVID-19 (RT-PCR), fatigue, fever, and conjunctivitis. There were no differences in antibody response between groups distinguished by sports discipline (p = 0.50), and sex (p = 0.59), and antibody response did not correlate with BMI (p = 0.12), age (p = 0.13), the number of symptoms (p = 0.43) or their duration (p = 0.19).

CONCLUSIONS: The severity of COVID-19 in elite athletes is predominantly mild and without complications. Athletes can return to sport after two symptom-free weeks and additional heart screening is usually not required. Determination of antibodies has been shown to be a useful indicator of a previous COVID-19 disease, and some symptoms can be used as predictors of antibody response.

PMID:34334321 | DOI:10.1016/j.jsams.2021.07.003

Support Care Cancer. 2021 Aug 1. doi: 10.1007/s00520-021-06451-y. Online ahead of print.

NO ABSTRACT

PMID:34333715 | DOI:10.1007/s00520-021-06451-y

Cancer Chemother Pharmacol. 2021 Jul 31. doi: 10.1007/s00280-021-04327-w. Online ahead of print.

ABSTRACT

PURPOSE: Fluoropyrimidines are one of the most used drug class to treat cancer patients, although they show high levels of associated toxicity. This study analyzed 33 polymorphisms in 17 pharmacogenes involved with the pharmacogenomics of fluoropyrimidines, in gastrointestinal cancer patients undergoing fluoropyrimidine-based treatment in the Brazilian Amazon.

METHODS: The study population was composed of 216 patients, 92 of whom have an anatomopathological diagnosis of gastric cancer and 124 of colorectal cancer. The single nucleotide polymorphisms (SNP) were genotyped by allelic discrimination using the TaqMan OpenArray Genotyping technology, with a panel of 32 customized assays, run in a QuantStudio ™ 12K Flex Real-Time PCR System (Applied Biosystems, Life Technologies, Carlsbad USA). Ancestry analysis was performed using 61 autosomal ancestry informative markers (AIMs).

RESULTS: The study population show mean values of 48.1% European, 31.1% Amerindian, and 20.8% African ancestries. A significant risk association for general and severe toxicity was found in the rs4451422 of FPGS (p = 0.001; OR 3.40; CI 95% 1.65-7.00 and p = 0.006; OR 4.63; CI 95% 1.56-13.72, respectively) and the rs9524885 of ABCC4 (p = 0.023; OR 2.74; CI 95% 1.14-6.65 and p = 0.024; OR 5.36; IC 95% 1.24-23.11, respectively) genes. The rs760370 in the SLC29A1 gene (p = 0.009; OR 6.71; CI 95% 1.16-8.21) and the rs1801133 in the MTHFR toxicity (p = 0.023; OR 3.09; CI 95% 1.16-8.21) gene also demonstrated to be significant, although only for severe toxicity. The results found in this study did not have statistics analysis correction.

CONCLUSION: Four polymorphisms of the ABCC4, FPGS, SLC29A1, and MTHFR genes are likely to be potential predictive biomarkers for precision medicine in fluoropyrimidine-based treatments in the population of the Brazilian Amazon, which is constituted by a unique genetic background.

PMID:34331561 | DOI:10.1007/s00280-021-04327-w

Transl Psychiatry. 2021 Jul 30;11(1):413. doi: 10.1038/s41398-021-01480-x.

ABSTRACT

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

PMID:34330890 | DOI:10.1038/s41398-021-01480-x

Curr Pharm Teach Learn. 2021 Sep;13(9):1236-1243. doi: 10.1016/j.cptl.2021.06.043. Epub 2021 Jun 22.

ABSTRACT

BACKGROUND AND PURPOSE: The role of pharmacists in pharmacogenomics (PGx) use clinically is expanding, leading to increased pharmacy education requirements. Current reports indicate that PGx is primarily taught through didactic courses, indicating a need for applied coursework in pharmacy curricula, including laboratory exercises and clinical experiences. Such courses are instrumental in helping students connect the science of PGx to patient care.

EDUCATIONAL ACTIVITY AND SETTING: An advanced PGx independent study and a similar advanced pharmacy practice experience (APPE) were developed. These courses included personal genetic testing, raw genetic sequence data analysis, and wet-laboratory genetic testing. The APPE included sessions with clinical pharmacists who use PGx and a genetic counselor, as well as a visit to a genetic reference laboratory. A pre-/post-examination and survey were used to measure the courses' effectiveness and student perceptions of their abilities, PGx, and course components. For this pilot study one student per course was evaluated.

FINDINGS: Each student completed all components of the courses successfully, supporting the feasibility of their implementation. Examination scores increased for both students with improvement in knowledge from basic genetics to clinical application. Both students also had a more positive perception of PGx after the courses and valued the various course components.

SUMMARY: Through this unique course format, pharmacy students developed expertise in understanding and implementing PGx which allowed them to gain skills that go beyond an introductory course. Our experience may provide guidance to other pharmacy programs in adding more applied PGx education to their curricula.

PMID:34330404 | DOI:10.1016/j.cptl.2021.06.043

BMC Cancer. 2021 Jul 30;21(1):872. doi: 10.1186/s12885-021-08615-9.

ABSTRACT

BACKGROUND: Despite the progress in assessment and treatment of breast cancer, being diagnosed with it or receiving chemotherapy treatment is still conceived as a traumatic experience. Women develop negative thoughts about life and death with detrimental effects on their daily physical functioning/activities, emotional state and overall quality of life. The aim of our study was to evaluate the level of anxiety and depression among breast cancer patients receiving chemotherapy and explore the correlation between these psychological disorders, clinical, sociodemographic and genetic factors.

METHODS: A cross-sectional study was conducted among breast cancer patients undergoing intravenous chemotherapy at the oncology outpatient unit of Hôtel-Dieu de France hospital (November 2017-June 2019; Ethical approval number: CEHDF1016). All patients gave their written informed consent and completed several validated scales, including the Hospital Anxiety and Depression scale (HADS) for the assessment of anxiety and depression. Sleep quality, insomnia, cognitive function, fatigue and pain were also evaluated. Genotyping for certain gene polymorphisms (CLOCK, PER2, CRY2, OPRM1, ABCB1, COMT, DRD2) was performed using the Lightcycler® (Roche).

RESULTS: A total of 112 women was included. The prevalence of depression was 43.4%, and 56.2% of the patients reported anxiety (based on the HADS classification). Multivariable analysis showed that higher cognitive scores and taking fosaprepitant were significantly associated with lower depression and anxiety scores. Moreover, being married compared to single was also associated with lower depression scores, whereas higher PSQI scores (worse sleep quality) and having the PER2 AA variant genotype compared to GG were significantly associated with higher depression scores. Finally, reporting a more severe insomnia and having the COMT Met/Met genotype were significantly associated with a higher anxiety score.

CONCLUSIONS: Our study demonstrated a strong relationship between depression scores and cognitive impairment, sleep quality, marital status, fosaprepitant intake, and PER2 polymorphism, while anxiety scores were correlated to cognitive impairment, insomnia severity, fosaprepitant intake, and COMT polymorphism. The association with PER polymorphism was not previously reported. Identification of genetic and clinical risk factors for anxiety and depression would help clinicians implement an individualized management therapy aiming at preventing and alleviating the burden of these symptoms in breast cancer patients, hence improving their overall quality of life.

PMID:34330229 | DOI:10.1186/s12885-021-08615-9

J Clin Pharmacol. 2021 Jul 30. doi: 10.1002/jcph.1946. Online ahead of print.

ABSTRACT

Brexpiprazole is an oral antipsychotic agent indicated for use in patients with schizophrenia, or as adjunctive treatment for major depressive disorder (MDD). As CYP2D6 contributes significantly to brexpiprazole metabolism, there is a label-recommended 50% reduction in dose among patients with the CYP2D6 poor metabolizer phenotype. This study uses a whole-body physiologically-based pharmacokinetic (PBPK) model to compare the pharmacokinetics of brexpiprazole in patients known to be extensive (EM) and poor metabolizers (PMs). A PBPK model was constructed, verified, and validated against brexpiprazole clinical data, and simulations of 500 subjects were performed to establish the median time-to-effective concentrations in EMs and PMs. The PBPK simulations captured brexpiprazole PK well and demonstrated significant differences in the time to effective concentrations between EMs and PMs according to the label-recommended titration. Additionally, these simulations suggest that CYP2D6 PMs consistently achieve lower Ctrough concentrations than CYP2D6 EMs. Simulations using an alternative dosing strategy of BID dosing (as opposed to QD) in PMs during the first week of brexpiprazole dosing yielded more consistent plasma concentrations between EMs and PMs, without exceeding the AUC observed in the EMs. Taken together, the results of these PBPK simulations suggest that product labeling for brexpiprazole titration in CYP2D6 PMs likely overcompensates for the decreased clearance seen in this population. We propose an alternative dosing strategy that decreases the time to effective concentrations and recommend a re-evaluation of steady-state PK in this population to potentially allow for higher daily doses in CYP2D6 PMs. This article is protected by copyright. All rights reserved.

PMID:34328221 | DOI:10.1002/jcph.1946

Biomed Pharmacother. 2021 Jul 18;141:111947. doi: 10.1016/j.biopha.2021.111947. Online ahead of print.

ABSTRACT

Cardiac fibroblasts (CF) play an important role in the healing process and in pathological remodeling of cardiac tissue. As sentinel cells in the heart, they respond to inflammatory stimuli, expressing cytokines and cell adhesion proteins, which ultimately lead to increased recruitment of monocytes and enhancement of the inflammatory response. Angiotensin II (Ang II) triggers an inflammatory response, leading to cardiac tissue remodeling. On the other hand, RvD1 has been shown to contribute to the resolution of inflammation; however, its role in Ang II-treated CF has not been addressed until now. The present research aimed to study the effect of RvD1 on cytokine levels, cell adhesion proteins expression in a model of Ang II-triggered inflammatory response. CF from adult Sprague Dawley rats were used to study mRNA and protein levels of MCP-1, IL-6, TNF-a, IL-10, ICAM-1 and VCAM-1; and adhesion of spleen mononuclear cells to CF after Ang II stimulation. Our results show that Ang II increased IL-6, MCP-1 and TNF-a mRNA levels, but only increased IL-6 and MCP-1 protein levels. These effects were blocked by Losartan, but not by PD123369. Moreover, RvD1 was able to prevent all Ang II effects in CF. Additionally, RvD1 reduced the intracellular Ca2+ increase triggered by Ang II, indicating that RvD1 acts in an early manner to block Ang II signaling. Conclusion: our findings confirm the pro-resolutive effects of inflammation by RvD1, which at the cardiovascular level, could contribute to repair damaged cardiac tissue.

PMID:34328122 | DOI:10.1016/j.biopha.2021.111947

Oxid Med Cell Longev. 2021 Jul 16;2021:3095514. doi: 10.1155/2021/3095514. eCollection 2021.

ABSTRACT

The genus Viburnum (Adoxaceae, Dipsacales) is of scientific interest due to the chemical components and diverse biological activities found across species of the genus, which includes more than 230 species of evergreen, semievergreen, or deciduous shrubs and small trees. Although frequently used as an ornament, the Viburnum species show biological properties with health-promoting effects. Fruits, flowers, and barks of certain species are used for pharmaceutical purposes or as cooking ingredients, hence containing biochemical compounds with health-promoting activity such are carotenoids, polyphenols, and flavonoids. However, its taxonomical determination is difficult, due to its wide distribution and frequent hybridizations; therefore, an objective classification would allow us to understand its biological activity based on its phytochemical components. More than sixty phytochemical compounds have been reported, where vibsanin-type diterpenes and their derivatives are the most prevalent. Leaves and twigs of V. dilatatum contain the largest number of phytochemicals among the genus. Through preclinical evidence, this study provides insight regarding antioxidant, antibacterial, anti-inflammatory, cytotoxic, and anticancer activities of genus Viburnum.

PMID:34326915 | PMC:PMC8310452 | DOI:10.1155/2021/3095514

Science. 2021 Jul 30;373(6554):541-547. doi: 10.1126/science.abi4708. Epub 2021 Jun 22.

ABSTRACT

Repurposing drugs as treatments for COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has drawn much attention. Beginning with sigma receptor ligands and expanding to other drugs from screening in the field, we became concerned that phospholipidosis was a shared mechanism underlying the antiviral activity of many repurposed drugs. For all of the 23 cationic amphiphilic drugs we tested, including hydroxychloroquine, azithromycin, amiodarone, and four others already in clinical trials, phospholipidosis was monotonically correlated with antiviral efficacy. Conversely, drugs active against the same targets that did not induce phospholipidosis were not antiviral. Phospholipidosis depends on the physicochemical properties of drugs and does not reflect specific target-based activities-rather, it may be considered a toxic confound in early drug discovery. Early detection of phospholipidosis could eliminate these artifacts, enabling a focus on molecules with therapeutic potential.

PMID:34326236 | DOI:10.1126/science.abi4708

Cancer. 2021 Jul 29. doi: 10.1002/cncr.33799. Online ahead of print.

ABSTRACT

BACKGROUND: Genetic and environmental factors are important determinants of nasopharyngeal carcinoma (NPC). NPC is associated with Epstein-Barr virus (EBV) infection. Studies have reported familial aggregation of NPC, but evidence has been mixed for elevated rates of cancers other than NPC.

METHODS: The authors reassessed their previous evaluation of familial aggregation of cancer in 348 high-risk Taiwanese multiplex families with 2 or more NPC cases enrolled between 1980 and 2003. Participants were linked to the Taiwan National Cancer Registry and National Death Registry to identify cancers.

RESULTS: In all, 2590 individuals contributed 37,959 person-years over an average of 15 years of follow-up; 314 incident cancers were identified. The authors computed multiple primary standardized incidence ratios (MP-SIRs) to evaluate the overall risk and the risk of infection-associated, EBV-associated, and individual cancers. The overall MP-SIR was 1.24 (95% confidence interval [CI], 1.10-1.38). The exclusion of excess NPC risk led to an overall MP-SIR of 1.11 (95% CI, 0.98-1.25). Similarly, the risk of cancers associated with infectious agents was driven by the excess in NPC, and its exclusion led to an MP-SIR of 1.22 (95% CI, 0.99-1.48) for infection-associated cancers and to an MP-SIR of 1.18 (95% CI, 0.72-1.82) for EBV-associated cancers. The authors observed a significant excess of second cancers among NPC cases (oral cancer, mouth cancer, tongue cancer, gum cancer, nasal cavity cancer, bone cancer, and non-Hodgkin lymphoma).

CONCLUSIONS: This reassessment of the largest NPC multiplex family study confirms the presence of NPC coaggregation within families in Taiwan but does not provide evidence for a broader familial syndrome involving NPC and other tumors. Among NPC cases, elevated rates of secondary cancers, mostly at the, head and neck and hematopoietic cancers suggest radiation treatment effects on subsequent cancer risk.

PMID:34324707 | DOI:10.1002/cncr.33799

J Recept Signal Transduct Res. 2021 Jul 29:1-13. doi: 10.1080/10799893.2021.1951756. Online ahead of print.

ABSTRACT

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed to treat inflammatory-related diseases, pain and fever. However, the prolong use of traditional NSAIDs leads to undesirable side effects such as gastric, ulceration, and renal toxicity due to lack of selectivity toward respective targets for COX-2, 5-LOX, and PDE4B. Thus, targeting multiple sites can reduce these adverse effects of the drugs and increase its potency. A series of methoxyflavones (F1-F5) were synthesized and investigated for their anti-inflammatory properties through molecular docking and inhibition assays. Among these flavones, only F2 exhibited selectivity toward COX-2 (Selectivity Index, SI: 3.90, COX-2 inhibition: 98.96 ± 1.47%) in comparison with celecoxib (SI: 7.54, COX-2 inhibition: 98.20 ± 2.55%). For PDEs, F3 possessed better selectivity to PDE4B (SI: 4.67) than rolipram (SI: 0.78). F5 had the best 5-LOX inhibitory activity among the flavones (33.65 ± 4.74%) but less than zileuton (90.81 ± 0.19%). Docking analysis indicated that the position of methoxy group and the substitution of halogen play role in determining the bioactivities of flavones. Interestingly, F1-F5 displayed favorable pharmacokinetic profiles and acceptable range of toxicity (IC50>70 µM) in cell lines with the exception for F1 (IC50: 16.02 ± 1.165 µM). This study generated valuable insight in designing new anti-inflammatory drug based on flavone scaffold. The newly synthesized flavones can be further developed as future therapeutic agents against inflammation.

PMID:34323638 | DOI:10.1080/10799893.2021.1951756