Can J Psychiatry. 2021 Nov 16:7067437211058847. doi: 10.1177/07067437211058847. Online ahead of print.

NO ABSTRACT

PMID:34783587 | DOI:10.1177/07067437211058847

Pharmacogenomics. 2021 Nov 16. doi: 10.2217/pgs-2021-0116. Online ahead of print.

ABSTRACT

The expression of ATP-binding cassette transporter (ABC transporters) has been reported in various tissues such as the lung, liver, kidney, brain and intestine. These proteins account for the efflux of different compounds and metabolites across the membrane, thus decreasing the concentration of the toxic compounds. ABC transporter genes play a vital role in the development of multidrug resistance, which is the main obstacle that hinders the success of chemotherapy. Preclinical and clinical trials have investigated the probability of overcoming drug-associated resistance and substantial toxicities. The focus has been put on several strategies to overcome multidrug resistance. These strategies include the development of modulators that can modulate ABC transporters. This knowledge can be translated for clinical oncology treatment in the future.

PMID:34783261 | DOI:10.2217/pgs-2021-0116

Pharmacogenomics. 2021 Nov 16. doi: 10.2217/pgs-2021-0105. Online ahead of print.

ABSTRACT

Aim: To identify novel genes associated with adverse effects of levonorgestrel (LNG) implants based on comparative whole-exome sequencing. Materials & methods: A cohort comprising 104 participants, including 52 controls and 52 women with LNG-related adverse effects, was recruited. Seven cases and eight controls were selected for whole-exome sequencing. We verified 13 single nucleotide variations (SNVs) related with integrin-mediated signaling pathway and cell proliferation using the MassARRAY platform. Results: Finally, we screened 49 cases and 52 controls for analyses. Two SNVs (rs7255721 and rs1042522) were located in ADAMTS10 and TP53, respectively, and significantly different between two groups. These two SNVs lead to changes in protein structure and physicochemical parameters. Conclusion: Here, we defined two pathogenic mutations related to adverse LNG effects.

PMID:34783250 | DOI:10.2217/pgs-2021-0105

Eur J Hum Genet. 2021 Nov 16. doi: 10.1038/s41431-021-01004-7. Online ahead of print.

ABSTRACT

The Dutch Pharmacogenetics Working Group (DPWG) guideline presented here, presents the gene-drug interaction between the genes CYP2C19 and CYP2D6 and antidepressants of the selective serotonin reuptake inhibitor type (SSRIs). Both genes' genotypes are translated into predicted normal metabolizer (NM), intermediate metabolizer (IM), poor metabolizer (PM), or ultra-rapid metabolizer (UM). Evidence-based dose recommendations were obtained, based on a structured analysis of published literature. In CYP2C19 PM patients, escitalopram dose should not exceed 50% of the normal maximum dose. In CYP2C19 IM patients, this is 75% of the normal maximum dose. Escitalopram should be avoided in UM patients. In CYP2C19 PM patients, citalopram dose should not exceed 50% of the normal maximum dose. In CYP2C19 IM patients, this is 70% (65-75%) of the normal maximum dose. In contrast to escitalopram, no action is needed for CYP2C19 UM patients. In CYP2C19 PM patients, sertraline dose should not exceed 37.5% of the normal maximum dose. No action is needed for CYP2C19 IM and UM patients. In CYP2D6 UM patients, paroxetine should be avoided. No action is needed for CYP2D6 PM and IM patients. In addition, no action is needed for the other gene-drug combinations. Clinical effects (increase in adverse events or decrease in efficacy) were lacking for these other gene-drug combinations. DPWG classifies CYP2C19 genotyping before the start of escitalopram, citalopram, and sertraline, and CYP2D6 genotyping before the start of paroxetine as "potentially beneficial" for toxicity/effectivity predictions. This indicates that genotyping prior to treatment can be considered on an individual patient basis.

PMID:34782755 | DOI:10.1038/s41431-021-01004-7

Curr Probl Cardiol. 2021 Nov 12:101043. doi: 10.1016/j.cpcardiol.2021.101043. Online ahead of print.

ABSTRACT

Genetic polymorphisms or variations, randomly distributed in a population, may cause drug-gene response variations. Investigation into these polymorphisms may identify novel mechanisms contributing to a specific disease process. Such investigation necessitates the use of Mendelian randomization, an analytical method that uses genetic variants as instrumental variables for modifiable risk factors that affect population health1. In the past decade, advances in our understanding of genetic polymorphisms have enabled the identification of genetic variants in candidate genes that impact low-density lipoprotein cholesterol (LDL-C) regulating pathways and cardiovascular disease (CVD) outcomes. A specific candidate gene of interest is that of the LDL receptor degrading protein, PCSK9. In fact, loss-of-function genetic variants for the PCSK9 gene are what first highlighted this pathway as a candidate for pharmacological inhibition. PCSK9 inhibitors (PCSK9i) are a class of cholesterol-lowering medications that provide significant reductions in LDL by inhibiting the degradation of LDL receptors (LDLR). These inhibitors have also been found to reduce production and enhance clearance of lipoprotein A [Lp(a)], an LDL-like particle currently under study as a separate risk factor for atherosclerotic CVD. Here, we discuss the promise of personalized medicine in developing a more efficacious and individualized pharmacogenomics-based approach for the use of PCSK9i that considers genetic variation and targets different patient populations. This review explores the pharmacogenomics of PCSK9i in the context of PCSK9 allele variants related to drug-metabolizing enzymes and responses since more studies are demonstrating that some patients are hyporesponsive or non-responsive to PCSK9i 2. In summary, the pharmacogenomics of PCSK9 are a promising therapeutic target and genetic information from prospective randomized clinical trials is warranted to gain a full understanding of the efficacy and cost-effectiveness of such allele/gene-guided PCSK9i therapy.

PMID:34780866 | DOI:10.1016/j.cpcardiol.2021.101043

Br J Clin Pharmacol. 2021 Nov 15. doi: 10.1111/bcp.15144. Online ahead of print.

ABSTRACT

AIM: Cancer patients with reduced dihydropyrimidine dehydrogenase (DPD) activity are at increased risk of severe fluoropyrimidine (FP)-related adverse events (AE). Guidelines recommend FP dosing adjusted to genotype-predicted DPD activity based on four DPYD variants (rs3918290, rs55886062, rs67376798, rs56038477). We evaluated relationship between three further DPYD polymorphisms [c.496A>G (rs2297595), *6 (c.2194G>A, rs1801160) and *9A (c.85T>C, rs1801265)] and the risk of severe AEs.

METHODS: Consecutive FP-treated adult patients were genotyped for "standard" and tested DPYD variants, and for UGT1A1*28 if irinotecan was included, and were monitored for the occurrence of grade ≥3 (National Cancer Institute Common Terminology Criteria) vs. grade 0-2 AEs. For each of the tested polymorphisms, variant allele carriers were matched to respective wild type controls (optimal full matching combined with exact matching, in respect to: age, sex, type of cancer, type of FP, DPYD activity score, use of irinotecan/UGT1A1, adjuvant therapy, radiotherapy, biological therapy and genotype on the remaining two tested polymorphisms).

RESULTS: Of the 503 included patients (82.3% colorectal cancer), 283 (56.3%) developed grade ≥3 AEs, mostly diarrhea and neutropenia. Odds of grade ≥3 AEs were higher in c.496A>G variant carriers (n=127) than in controls (n=376) [OR=5.20 (95%CI 1.88-14.3), Bayesian OR=5.24 (95% CrI 3.06-9.12)]. Odds tended to be higher in c.2194G>A variant carries (n=58) than in controls (n=432) [OR=1.88 (0.95-3.73), Bayesian OR=1.90 (1.03-3.56)]. c.85T>G did not appear associated with grade ≥3 AEs (206 variant carriers vs. 284 controls).

CONCLUSION: DPYD c.496A>G and possibly c.2194G>A variants might need to be considered for inclusion in the DPYD genotyping panel.

PMID:34780066 | DOI:10.1111/bcp.15144

Oncol Rep. 2022 Jan;47(1):16. doi: 10.3892/or.2021.8227. Epub 2021 Nov 15.

ABSTRACT

The devastating complications of coronavirus disease 2019 (COVID‑19) result from the dysfunctional immune response of an individual following the initial severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection. Multiple toxic stressors and behaviors contribute to underlying immune system dysfunction. SARS‑CoV‑2 exploits the dysfunctional immune system to trigger a chain of events, ultimately leading to COVID‑19. The authors have previously identified a number of contributing factors (CFs) common to myriad chronic diseases. Based on these observations, it was hypothesized that there may be a significant overlap between CFs associated with COVID‑19 and gastrointestinal cancer (GIC). Thus, in the present study, a streamlined dot‑product approach was used initially to identify potential CFs that affect COVID‑19 and GIC directly (i.e., the simultaneous occurrence of CFs and disease in the same article). The nascent character of the COVID‑19 core literature (~1‑year‑old) did not allow sufficient time for the direct effects of numerous CFs on COVID‑19 to emerge from laboratory experiments and epidemiological studies. Therefore, a literature‑related discovery approach was used to augment the COVID‑19 core literature‑based 'direct impact' CFs with discovery‑based 'indirect impact' CFs [CFs were identified in the non‑COVID‑19 biomedical literature that had the same biomarker impact pattern (e.g., hyperinflammation, hypercoagulation, hypoxia, etc.) as was shown in the COVID‑19 literature]. Approximately 2,250 candidate direct impact CFs in common between GIC and COVID‑19 were identified, albeit some being variants of the same concept. As commonality proof of concept, 75 potential CFs that appeared promising were selected, and 63 overlapping COVID‑19/GIC potential/candidate CFs were validated with biological plausibility. In total, 42 of the 63 were overlapping direct impact COVID‑19/GIC CFs, and the remaining 21 were candidate GIC CFs that overlapped with indirect impact COVID‑19 CFs. On the whole, the present study demonstrates that COVID‑19 and GIC share a number of common risk/CFs, including behaviors and toxic exposures, that impair immune function. A key component of immune system health is the removal of those factors that contribute to immune system dysfunction in the first place. This requires a paradigm shift from traditional Western medicine, which often focuses on treatment, rather than prevention.

PMID:34779496 | DOI:10.3892/or.2021.8227

Front Pharmacol. 2021 Oct 29;12:749786. doi: 10.3389/fphar.2021.749786. eCollection 2021.

ABSTRACT

Populations used to create warfarin dose prediction algorithms largely lacked participants reporting Hispanic or Latino ethnicity. While previous research suggests nonlinear modeling improves warfarin dose prediction, this research has mainly focused on populations with primarily European ancestry. We compare the accuracy of stable warfarin dose prediction using linear and nonlinear machine learning models in a large cohort enriched for US Latinos and Latin Americans (ULLA). Each model was tested using the same variables as published by the International Warfarin Pharmacogenetics Consortium (IWPC) and using an expanded set of variables including ethnicity and warfarin indication. We utilized a multiple linear regression model and three nonlinear regression models: Bayesian Additive Regression Trees, Multivariate Adaptive Regression Splines, and Support Vector Regression. We compared each model's ability to predict stable warfarin dose within 20% of actual stable dose, confirming trained models in a 30% testing dataset with 100 rounds of resampling. In all patients (n = 7,030), inclusion of additional predictor variables led to a small but significant improvement in prediction of dose relative to the IWPC algorithm (47.8 versus 46.7% in IWPC, p = 1.43 × 10-15). Nonlinear models using IWPC variables did not significantly improve prediction of dose over the linear IWPC algorithm. In ULLA patients alone (n = 1,734), IWPC performed similarly to all other linear and nonlinear pharmacogenetic algorithms. Our results reinforce the validity of IWPC in a large, ethnically diverse population and suggest that additional variables that capture warfarin dose variability may improve warfarin dose prediction algorithms.

PMID:34776967 | PMC:PMC8585774 | DOI:10.3389/fphar.2021.749786

Pharmacogenomics J. 2021 Nov 13. doi: 10.1038/s41397-021-00261-5. Online ahead of print.

ABSTRACT

No biomarkers are available to predict patients at risk of developing hypertension induced by VEGF-pathway inhibitors. This study aimed to identify predictive biomarkers of hypertension induced by these drugs using a discovery-replication approach. The discovery set included 140 sorafenib-treated patients (TARGET study) genotyped for 973 SNPs in 56 genes. The most statistically significant SNPs associated with grade ≥2 hypertension were tested for association with grade ≥2 hypertension in the replication set of a GWAS of 1039 bevacizumab-treated patients from four clinical trials (CALGB/Alliance). In the discovery set, rs444904 (G > A) in PIK3R5 was associated with an increased risk of sorafenib-induced hypertension (p = 0.006, OR = 3.88 95% CI 1.54-9.81). In the replication set, rs427554 (G > A) in PIK3R5 (in complete linkage disequilibrium with rs444904) was associated with an increased risk of bevacizumab-induced hypertension (p = 0.008, OR = 1.39, 95% CI 1.09-1.78). This study identified a predictive marker of drug-induced hypertension that should be evaluated for other VEGF-pathway inhibitors.ClinicalTrials.gov Identifier:NCT00073307 (TARGET).

PMID:34775477 | DOI:10.1038/s41397-021-00261-5

Clin Transl Oncol. 2021 Nov 13. doi: 10.1007/s12094-021-02708-4. Online ahead of print.

ABSTRACT

5-Fluorouracil (5-FU) and oral fluoropyrimidines, such as capecitabine, are widely used in the treatment of cancer, especially gastrointestinal tumors and breast cancer, but their administration can produce serious and even lethal toxicity. This toxicity is often related to the partial or complete deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, which causes a reduction in clearance and a longer half-life of 5-FU. It is advisable to determine if a DPD deficiency exists before administering these drugs by genotyping DPYD gene polymorphisms. The objective of this consensus of experts, in which representatives from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology participated, is to establish clear recommendations for the implementation of genotype and/or phenotype testing for DPD deficiency in patients who are candidates to receive fluoropyrimidines. The genotyping of DPYD previous to treatment classifies individuals as normal, intermediate, or poor metabolizers. Normal metabolizers do not require changes in the initial dose, intermediate metabolizers should start treatment with fluoropyrimidines at doses reduced to 50%, and poor metabolizers are contraindicated for fluoropyrimidines.

PMID:34773566 | DOI:10.1007/s12094-021-02708-4

Genes Chromosomes Cancer. 2021 Nov 13. doi: 10.1002/gcc.23012. Online ahead of print.

ABSTRACT

Two new treatments have recently become standard of care for patients with metastatic colorectal cancer (mCRC): encorafenib (BRAF inhibitor) associated with cetuximab (anti-EGFR) in the second or third line of chemotherapy for BRAF V600E tumors, and pembrolizumab (an anti PD-1 immune checkpoint inhibitor) for tumors harboring microsatellite instability (MSI)-high and/or deficient mismatch repair (dMMR). Furthermore, 30% of BRAF V600E mutated mCRC are MSI/dMMR through a sporadic hypermethylation of the promoter of hMLH1. We report here, for the first time, the case of a patient with BRAF V600E, PIK3CA and SMAD4 mutated and dMMR/MSI mCRC, in whom we observed an atypical response pattern under the sequence of pembrolizumab followed by the doublet encorafenib and cetuximab treatment. The patient was progressive after a single cycle of pembrolizumab followed by a rapid complete response after only two months of treatment with encorafenib and cetuximab, discovered during R0 cyto-reduction surgery for peritoneal carcinomatosis. This article is protected by copyright. All rights reserved.

PMID:34773327 | DOI:10.1002/gcc.23012

Int J Mol Sci. 2021 Oct 29;22(21):11761. doi: 10.3390/ijms222111761.

ABSTRACT

BACKGROUND: Acid phosphatase and its regulation are important objects of biological and clinical research and play an important role in the development and treatment of prostate and bone diseases. The newly patented aminoalkanol (4-[2-hydroxy-3-(propan-2-ylamino)propyl]-1,7-dimethyl-8,9-diphenyl-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5,10-trione hydrochloride) (I) and (4-[3-(dimethylamino)-2-hydroxypropyl]-1,7-dimethyl-8,9-diphenyl-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5,10-trione hydrochloride) (II) derivatives have potential anticancer activity, and their influence on enzymatic activity can significantly impact the therapeutic effects of acid phosphatase against many diseases. Therefore, in this study, we investigated the action of compounds (I) and (II) on acid phosphatase.

METHODS: Capillary electrophoresis was used to evaluate the inhibition of acid phosphatase. Lineweaver-Burk plots were constructed to compare the Km of this enzyme in the presence of inhibitors (I) or (II) with the Km in solutions without these inhibitors.

RESULTS: Compound (I) showed a stronger competitive inhibition against acid phosphatase, whereas derivative (II) showed a weaker competitive type of inhibition. The detailed kinetic studies of these compounds showed that their type and strength of inhibition as well as affinity depend on the kind of substituent occurring in the main chemical molecule.

CONCLUSIONS: This study is of great importance because the disclosed inhibition of acid phosphatase by compounds (I) and (II) raises the question of whether these compounds could have any effect on the treatment possibilities of prostate diseases.

PMID:34769193 | DOI:10.3390/ijms222111761

Int J Mol Sci. 2021 Oct 29;22(21):11737. doi: 10.3390/ijms222111737.

ABSTRACT

Thoracic aortic aneurysm (TAA) formation is a multifactorial process that results in diverse clinical manifestations and drug responses. Identifying the critical factors and their functions in Marfan syndrome (MFS) pathogenesis is important for exploring personalized medicine for MFS. Methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) polymorphisms have been correlated with TAA severity in MFS patients. However, the detailed relationship between the folate-methionine cycle and MFS pathogenesis remains unclear. Fbn1C1039G/+ mice were reported to be a disease model of MFS. To study the role of the folate-methionine cycle in MFS, Fbn1C1039G/+ mice were treated orally with methionine or vitamin B mixture (VITB), including vitamins B6, B9, and B12, for 20 weeks. VITB reduced the heart rate and circumference of the ascending aorta in Fbn1C1039G/+ mice. Our data showed that the Mtr and Smad4 genes were suppressed in Fbn1C1039G/+ mice, while VITB treatment restored the expression of these genes to normal levels. Additionally, VITB restored canonical transforming-growth factor β (TGF-β) signaling and promoted Loxl1-mediated collagen maturation in aortic media. This study provides a potential method to attenuate the pathogenesis of MFS that may have a synergistic effect with drug treatments for MFS patients.

PMID:34769168 | DOI:10.3390/ijms222111737

Int J Mol Sci. 2021 Oct 28;22(21):11696. doi: 10.3390/ijms222111696.

ABSTRACT

Pharmacogenomic studies in epilepsy are justified by the high prevalence rate of this disease and the high cost of its treatment, frequent drug resistance, different response to the drug, the possibility of using reliable methods to assess the control of seizures and side effects of antiepileptic drugs. Candidate genes encode proteins involved in pharmacokinetic processes (drug transporters, metabolizing enzymes), pharmacodynamic processes (receptors, ion channels, enzymes, regulatory proteins, secondary messengers) and drug hypersensitivity (immune factors). This article provides an overview of the literature on the influence of genetic factors on treatment in epilepsy.

PMID:34769124 | DOI:10.3390/ijms222111696

J Clin Med. 2021 Oct 29;10(21):5086. doi: 10.3390/jcm10215086.

ABSTRACT

In our previous study, we showed that sildenafil citrate (SC), a selective PDE5A blocker, modulated NK cell activity in patients with recurrent pregnancy loss, which correlated with positive pregnancy outcomes. It was found that NK cells had a pivotal role in decidualization, angiogenesis, spiral artery remodeling, and the regulation of trophoblast invasion. Thus, in the current study, we determined the effects of SC on angiogenic factor expression and production, as well as idNK cell activity in the presence of nitric synthase blocker L-NMMA. Methods: NK cells (CD56+) were isolated from the peripheral blood of 15 patients and 15 fertile women on MACS columns and cultured in transformation media containing IL-15, TGF-β, and AZA-a methylation agent-for 7 days in hypoxia (94% N2, 1% O2, 5% CO2). Cultures were set up in four variants: (1) with SC, (2) without SC, (3) with NO, a synthase blocker, and (4) with SC and NO synthase blocker. NK cell activity was determined after 7 days of culturing as CD107a expression after an additional 4h of stimulation with K562 erythroleukemia cells. The expression of the PDE5A, VEGF-A, PIGF, IL-8, and RENBP genes was determined with quantitative real-time PCR (qRT-PCR) using TaqMan probes and ELISA was used to measure the concentrations of VEGF-A, PLGF, IL-8, Ang-I, Ang-II, IFN-γ proteins in culture supernatants after SC supplementation. Results: SC downregulated PDE5A expression and had no effect on other studied angiogenic factors. VEGF-A expression was increased in RPL patients compared with fertile women. Similarly, VEGF production was enhanced in RPL patients' supernatants and SC increased the concentration of PIGF in culture supernatants. SC did not affect the expression or concentration of other studied factors, nor idNK cell activity, regardless of NO synthase blockade.

PMID:34768607 | DOI:10.3390/jcm10215086

J Clin Med. 2021 Oct 22;10(21):4875. doi: 10.3390/jcm10214875.

ABSTRACT

The early diagnosis of malignant mesothelioma (MM) could improve the prognosis of MM patients. To confirm an MM diagnosis, an immunohistochemical analysis of several tumor tissue markers, including calretinin, is currently required. Our aim is to evaluate serum calretinin as a potential biomarker in asbestos-related diseases, especially in MM. Our study includes 549 subjects: 164 MM patients, 117 subjects with asbestosis, 195 subjects with pleural plaques and 73 occupationally asbestos-exposed subjects without asbestos-related diseases. The serum calretinin concentration was determined with a commercially available enzyme immunoassay. Data on the soluble mesothelin-related peptides (SMRP) concentration are available from previous studies. MM patients had a significantly higher calretinin concentration than subjects without disease, subjects with pleural plaques or subjects with asbestosis (all p < 0.001). The histological type was significantly associated with serum calretinin: patients with sarcomatoid MM had lower calretinin than patients with the epithelioid type (p = 0.001). In a ROC curve analysis, the area under the curve for calretinin concentration predicting MM was 0.826 (95% CI = 0.782-0.869; p < 0.001). At the cutoff value of 0.32 ng/mL, sensitivity was 0.683, while specificity was 0.886. The combination of calretinin and SMRP had the highest predictive value. Calretinin is a useful biomarker that can distinguish MM from other asbestos-related diseases and could, therefore, contribute to an earlier non-invasive diagnosis of MM.

PMID:34768395 | DOI:10.3390/jcm10214875

J Am Acad Child Adolesc Psychiatry. 2021 Nov 9:S0890-8567(21)01938-9. doi: 10.1016/j.jaac.2021.11.001. Online ahead of print.

NO ABSTRACT

PMID:34767918 | DOI:10.1016/j.jaac.2021.11.001

J Cachexia Sarcopenia Muscle. 2021 Nov 11. doi: 10.1002/jcsm.12849. Online ahead of print.

ABSTRACT

BACKGROUND: Age-related muscle dysfunctions are common disorders resulting in poor quality of life in the elderly. Probiotic supplementation is a potential strategy for preventing age-related sarcopenia as evidence suggests that probiotics can enhance muscle function via the gut-muscle axis. However, the effects and mechanisms of probiotics in age-related sarcopenia are currently unknown. In this study, we examined the effects of Lactobacillus casei Shirota (LcS), a probiotic previously reported to improve muscle function in young adult mice.

METHODS: We administered LcS (1 × 108 or 1 × 109 CFU/mouse/day) by oral gavage to senescence-accelerated mouse prone-8 mice for 12 weeks (16- to 28-week-old). Sixteen-week-old and 28-week-old SMAP8 mice were included as non-aged and aged controls, respectively. Muscle condition was evaluated using dual-energy X-ray absorptiometry for muscle mass, holding impulse and grip strength tests for muscle strength, and oxygen consumption rate, gene expressions of mitochondrial biogenesis, and mitochondrial number assays for mitochondria function. Inflammatory cytokines were determined using enzyme-linked immunosorbent assay. Gas chromatography-mass spectrometry was utilized to measure the short-chain fatty acid levels. The gut microbiota was analysed based on the data of 16S rRNA gene sequencing of mouse stool.

RESULTS: The LcS supplementation reduced age-related declines in muscle mass (>94.6%, P < 0.04), strength (>66% in holding impulse and >96.3% in grip strength, P < 0.05), and mitochondrial function (P < 0.05). The concentration of short-chain fatty acids (acetic, isobutyric, butyric, penic, and hexanoic acid) was recovered by LcS (>65.9% in the mice given high dose of LcS, P < 0.05) in the aged mice, and LcS attenuated age-related increases in inflammation (P < 0.05) and reactive oxygen species (>89.4%, P < 0.001). The high dose of LcS supplementation was also associated with distinct microbiota composition as indicated by the separation of groups in the beta-diversity analysis (P = 0.027). LcS supplementation altered predicted bacterial functions based on the gut microbiota. Apoptosis (P = 0.026), p53 signalling (P = 0.017), and non-homologous end-joining (P = 0.031) were significantly reduced, whereas DNA repair and recombination proteins (P = 0.043), RNA polymerase (P = 0.008), and aminoacyl-tRNA biosynthesis (P = 0.003) were increased. Finally, the genera enriched by high-dose LcS [linear discriminant analysis (LDA) score > 2.0] were positively correlated with healthy muscle and physiological condition (P < 0.05), while the genera enriched in aged control mice (LDA score > 2.0) were negatively associated with healthy muscle and physiological condition (P < 0.05).

CONCLUSIONS: Lactobacillus casei Shirota represents an active modulator that regulates the onset and progression of age-related muscle impairment potentially via the gut-muscle axis.

PMID:34766473 | DOI:10.1002/jcsm.12849

Front Pharmacol. 2021 Oct 26;12:733285. doi: 10.3389/fphar.2021.733285. eCollection 2021.

ABSTRACT

Tacrolimus is an essential immunosuppressant for the prevention of rejection in solid organ transplantation. Its low therapeutic index and high pharmacokinetic variability necessitates therapeutic drug monitoring (TDM) to individualise dose. However, rejection and toxicity still occur in transplant recipients with blood tacrolimus trough concentrations (C0) within the target ranges. Peripheral blood mononuclear cells (PBMC) have been investigated as surrogates for tacrolimus's site of action (lymphocytes) and measuring allograft tacrolimus concentrations has also been explored for predicting rejection or nephrotoxicity. There are relatively weak correlations between blood and PBMC or graft tacrolimus concentrations. Haematocrit is the only consistent significant (albeit weak) determinant of tacrolimus distribution between blood and PBMC in both liver and renal transplant recipients. In contrast, the role of ABCB1 pharmacogenetics is contradictory. With respect to distribution into allograft tissue, studies report no, or poor, correlations between blood and graft tacrolimus concentrations. Two studies observed no effect of donor ABCB1 or CYP3A5 pharmacogenetics on the relationship between blood and renal graft tacrolimus concentrations and only one group has reported an association between donor ABCB1 polymorphisms and hepatic graft tacrolimus concentrations. Several studies describe significant correlations between in vivo PBMC tacrolimus concentrations and ex vivo T-cell activation or calcineurin activity. Older studies provide evidence of a strong predictive value of PBMC C0 and allograft tacrolimus C0 (but not blood C0) with respect to rejection in liver transplant recipients administered tacrolimus with/without a steroid. However, these results have not been independently replicated in liver or other transplants using current triple maintenance immunosuppression. Only one study has reported a possible association between renal graft tacrolimus concentrations and acute tacrolimus nephrotoxicity. Thus, well-designed and powered prospective clinical studies are still required to determine whether measuring tacrolimus PBMC or graft concentrations offers a significant benefit compared to current TDM.

PMID:34764868 | PMC:PMC8576179 | DOI:10.3389/fphar.2021.733285

Sci Rep. 2021 Nov 11;11(1):22452. doi: 10.1038/s41598-021-01417-w.

NO ABSTRACT

PMID:34764341 | DOI:10.1038/s41598-021-01417-w