Cancers (Basel). 2022 Jan 14;14(2):409. doi: 10.3390/cancers14020409.

ABSTRACT

PURPOSE: To assess cytotoxic effect of ciprofloxacin conjugates with fatty acids on prostate cancer cells (LNCaP and DU-145) with different hormone sensitivity, based on previous promising results from the PC3 cells.

METHODS: Cytotoxicity were estimated using MTT and LDH tests, whereas its mechanisms were estimated by apoptosis and IL-6 assays. The intensity of proteins involved in lipid metabolism was determined using ML-CS assay.

RESULTS: The hormone insensitive DU-145 cells were more vulnerable than the hormone sensitive LNCaP cells. The IC50 values for oleic (4), elaidic (5) and docosahexaenoic acid (8) conjugates were 20.2 µM, 17.8 µM and 16.5 µM, respectively, in DU-145 cells, whereas in LNCaP cells IC50 exceeded 20 µM. The strong conjugate cytotoxicity was confirmed in the LDH test, the highest (70.8%) for compound (5) and 64.2% for compound (8) in DU-145 cells. This effect was weaker for LNCaP cells (around 60%). The cytotoxic effect of unconjugated ciprofloxacin and fatty acids was weaker. The early apoptosis was predominant in LNCaP while in DU-145 cells both early and late apoptosis was induced. The tested conjugates decreased IL-6 release in both cancer cell lines by almost 50%. Proteomic analysis indicated influence of the ciprofloxacin conjugates on lipid metabolic proteins in prostatic cancer.

CONCLUSION: Our findings suggested the cytotoxic potential of ciprofloxacin conjugates with reduction in proteins involved in prostate cancer progress.

PMID:35053570 | DOI:10.3390/cancers14020409

Cancers (Basel). 2022 Jan 14;14(2):407. doi: 10.3390/cancers14020407.

ABSTRACT

Progression to metastatic disease occurs in about half of all men who develop prostate cancer (PC), one of the most common cancers in men worldwide. Androgen deprivation therapy has been the mainstay therapy for patients with metastatic PC (mPC) since the 1940s. In the last decade, there has been unprecedented advancement in systemic therapies, e.g., taxane, androgen-signalling pathway inhibitors, and biomarker-driven targeted therapies for various stages of disease, resulting in overall survival improvement. Adding to ongoing controversies over how best to treat these patients is the recognition that ethnicity may influence prognosis and outcomes. This review discusses recent evidence for the impacts of Asian ethnicity specifically, which includes environmental, sociocultural, and genetic factors, on the approach to pharmacological management of mPC. Clear inter-ethnic differences in drug tolerability, serious adverse events (AEs), and genetic heterogeneity must all be considered when dosing and scheduling for treatment, as well as designing future precision studies in PC.

PMID:35053569 | DOI:10.3390/cancers14020407

Cancers (Basel). 2022 Jan 13;14(2):387. doi: 10.3390/cancers14020387.

ABSTRACT

The active forms of vitamin D3 (calcitriol and tacalcitol) coupled to the vitamin D receptor (VDR) are known to exhibit anti-cancer properties. However, not all cancer cells are sensitive to the active forms of vitamin D3 and its analogs. The study aimed to determine whether polymorphism of VDR is responsible for the sensitivity of human leukemia and lymphoma cells to calcitriol and tacalcitol. The impact of calcitriol and tacalcitol on the proliferation and morphology of nine different leukemia and lymphoma cell lines was determined. Only MV-4-11, Thp-1, and HL-60 cell lines sensitive to proliferation inhibition by calcitriol and tacalcitol showed morphology changes. Subsequently, the levels of the VDR and 1,25D3-MARRS proteins of calcitriol and tacalcitol binding receptors and the VDR receptor polymorphism in human leukemia and lymphoma cells were ascertained. Contrary to the current understanding, higher levels of VDR are not responsible for the greater sensitivity of cells to calcitriol and tacalcitol. Importantly, we first showed that sensitivity to calcitriol and tacalcitol in leukemias and lymphomas could be determined by the VDR polymorphism. The FokI polymorphism and the presence of the "bat" haplotype were observed only in the sensitive cells.

PMID:35053549 | DOI:10.3390/cancers14020387

Pharmacopsychiatry. 2022 Jan 20. doi: 10.1055/a-1737-1527. Online ahead of print.

NO ABSTRACT

PMID:35052001 | DOI:10.1055/a-1737-1527

Cardiovasc Drugs Ther. 2022 Jan 20. doi: 10.1007/s10557-021-07302-y. Online ahead of print.

ABSTRACT

BACKGROUND: Elderly status is steadily increasing among patients with acute coronary syndrome (ACS). Dual antiplatelet therapy (DAPT) with aspirin and a potent P2Y12 receptor inhibitor is the cornerstone of treatment to prevent recurrent thrombotic complications in patients with ACS. However, DAPT in older patients is challenged by a concurrent heightened risk of ischemia and bleeding. The aim of this study is to evaluate the pharmacodynamic and pharmacokinetic profile of a lower dose of ticagrelor (60 mg twice daily) among elderly patients during the early phase of ACS.

STUDY DESIGN: PLINY THE ELDER (PLatelet INhibition with two different doses of potent P2y12 inhibitors in THE ELDERly population) (NCT04739384) is a prospective, randomized, open-label, crossover trial to evaluate the non-inferiority of a lower dose of ticagrelor (60 mg twice daily) compared with a standard dose (90 mg twice daily) among elderly patients with ACS undergoing percutaneous coronary intervention (PCI). A total of 50 patients, aged 75 years or more, with indication to potent P2Y12 receptor inhibitors will be randomized within 3 days from PCI for the index ACS. Patients with indication to oral anticoagulant therapy, treatment with glycoprotein IIb/IIIa inhibitors, or active bleeding will be excluded. The primary endpoint is platelet reactivity determined by P2Y12 reaction units (PRU) (VerifyNow, Accumetrics, San Diego, CA, USA) after treatment with ticagrelor 60 or 90 mg twice daily for 14 days. Secondary endpoints will include other pharmacodynamic tests of ADP-induced aggregation (light transmittance aggregometry and multiple electrode aggregometry) and determination of pharmacokinetic profile (plasma levels of ticagrelor and its metabolite AR-C124910XX) by high performance liquid chromatography-tandem mass spectrometry.

CONCLUSIONS: The PLINY THE ELDER trial will determine whether a lower dose of ticagrelor confers non-inferior platelet inhibition compared with the standard dose in the early phase of ACS among elderly patients undergoing PCI, informing future clinical investigation.

PMID:35048203 | DOI:10.1007/s10557-021-07302-y

Front Oncol. 2022 Jan 3;11:576911. doi: 10.3389/fonc.2021.576911. eCollection 2021.

ABSTRACT

Recent studies reveal that tumor microenvironment contributes to breast cancer (BRCA) development, progression, and therapeutic response. However, the contribution of the tumor microenvironment-related genes in routine diagnostic testing or therapeutic decision making for BRCA remains elusive. Immune/stromal/ESTIMATE scores calculated by the ESTIMATE algorithm quantify immune and stromal components in a tumor, and thus can reflect tumor microenvironment. To investigate the association of the tumor microenvironment-related genes with invasive BRCA prognosis, here we analyzed the immune/stromal/ESTIMATE scores in combination with The Cancer Genome Atlas (TCGA) database in invasive BRCA. We found that immune/stromal/ESTIMATE scores were significantly correlated with the invasive BRCA clinicopathological factors. Based on the immune/stromal/ESTIMATE scores, we extracted a series of differential expression genes (DEGs) related to the tumor microenvironment. Survival analysis was further performed to identify a list of high-frequency DEGs (HF-DEGs), which exhibited prognostic value in invasive BRCA. Importantly, consistent with the results of bioinformatics analysis, immunohistochemistry results showed that high SASH3 expression was associated with a good prognosis in invasive BRCA patients. Our findings suggest that the tumor microenvironment-related HF-DEGs identified in this study have prognostic values and may serve as potential biomarkers and therapeutic targets for invasive BRCA.

PMID:35047378 | PMC:PMC8761742 | DOI:10.3389/fonc.2021.576911

Front Pharmacol. 2022 Jan 3;12:810295. doi: 10.3389/fphar.2021.810295. eCollection 2021.

ABSTRACT

[This corrects the article DOI: 10.3389/fphar.2020.601572.].

PMID:35046829 | PMC:PMC8762335 | DOI:10.3389/fphar.2021.810295

Postgrad Med J. 2022 Jan 19:postgradmedj-2021-140341. doi: 10.1136/postgradmedj-2021-140341. Online ahead of print.

ABSTRACT

PURPOSE OF THE STUDY: The risk of bone fracture is high in patients with chronic kidney disease (CKD), and aggressive treatment to reduce fragility fracture risk is the major strategy. However, the outcomes of osteoporosis medications in patients with CKD remain unclear.

STUDY DESIGN: Patients with stage 3-5 CKD during 2011-2019 were enrolled. Patients were divided into two groups based on receiving osteoporosis medications (bisphosphonates, raloxifene, teriparatide or denosumab) or not. Two groups were matched at a 1:1 ratio by using propensity scores. The outcomes of interest were bone fractures, cardiovascular (CV) events and all-cause mortality. Cox proportional hazard regression models were applied to identify the risk factors. Additional stratified analyses by cumulative dose, treatment length and menopause condition were performed.

RESULTS AND CONCLUSIONS: 67 650 patients were included. After propensity score matching, 1654 patients were included in the study and control group, respectively. The mean age was 70.2±12.4 years, and 32.0% of patients were men. After a mean follow-up of 3.9 years, the incidence rates of bone fracture, CV events and all-cause mortality were 2.0, 1.7 and 6.5 per 1000 person-months, respectively. Multivariate analysis results showed that osteoporosis medications reduced the risk of CV events (HR, 0.35; 95% CI, 0.18 to 0.71; p=0.004), but did not alleviate the risks of bone fracture (HR, 1.48; 95% CI, 0.73 to 2.98; p=0.28) and all-cause mortality (HR, 0.93; 95% CI, 0.67 to 1.28; p=0.65). Stratified analysis showed that bisphosphonates users have most benefits in the reduction of CV events (HR, 0.26; 95% CI, 0.11 to 0.64; p=0.003). In conclusion, osteoporosis medications did not reduce the risk of bone fractures, or mortality, but improved CV outcomes in patients with CKD.

PMID:35046111 | DOI:10.1136/postgradmedj-2021-140341

Inflammopharmacology. 2022 Jan 18. doi: 10.1007/s10787-021-00921-9. Online ahead of print.

ABSTRACT

OBJECTIVE: Methotrexate (MTX) is the anchor drug in the treatment of rheumatoid arthritis (RA) and the therapeutic response to MTX has been observed to vary widely among these patients. The aim of this study was to investigate ABCB1 gene (the multidrug resistant 1 gene; MDR1 gene) polymorphism in patients with RA and to evaluate the relation between MTX unresponsiveness and this polymorphism.

METHODS: Forty-five patients with RA administered MTX were included in this pharmacogenetic cross-sectional study. The gender, age, body mass index (BMI), rheumatoid factor (RF) positivity, anti-cyclic citrullinated peptide (anti-CCP) positivity, doses of MTX and glucocorticoids were recorded. In addition, initial and third month disease activity (DAS28, Simplified and Clinical Disease Activity Index; SDAI and CDAI) scores were evaluated. We also examined frequencies of two single-nucleotide polymorphisms (SNPs), G2677T and C3435T, within the gene encoding ABCB1.

RESULTS: 22 patient's responsive and 20 patients unresponsive to MTX were enrolled. Initial demographic and disease related factors were similar between patients responsive or nonresponsive to MTX. In the third month evaluation, disease activity scores were significantly higher in patients unresponsive to MTX (p < 0.05). In addition, almost all patients unresponsive to MTX (19 of the 20 patients) presented heterozygosity in C3435T (p < 0.000).

CONCLUSION: We determined heterozygosity in C3435T SNP of ABCB1 gene (multidrug resistant 1 gene) in almost all patients with RA who were non-responders to MTX. This result may contribute to predict unresponsiveness to MTX in RA. Individualized treatment strategies based on the pharmacogenetic characteristics of MTX may lead to optimization of the treatment.

PMID:35043269 | DOI:10.1007/s10787-021-00921-9

Mol Cancer. 2022 Jan 18;21(1):20. doi: 10.1186/s12943-021-01490-9.

ABSTRACT

BACKGROUND: The immunotherapy with immune checkpoints inhibitors (ICI) has changed the life expectancy in metastatic melanoma (MM) patients. Nevertheless, several patients do not respond hence, the identification and validation of novel biomarkers of response to ICI is of crucial importance. Circulating extracellular vesicles (EVs) such as PD-L1+ EV mediate resistance to anti-PD1, instead the role of PD1+ EV is not fully understood.

METHODS: We isolated the circulating EVs from the plasma of an observational cohort study of 71 metastatic melanoma patients and correlated the amount of PD-L1+ EVs and PD1+ EVs with the response to ICI. The analysis was performed according to the origin of EVs from the tumor and the immune cells. Subsequently, we analysed the data in a validation cohort of 22 MM patients to assess the reliability of identified EV-based biomarkers. Additionally we assessed the involvement of PD1+ EVs in the seizure of nivolumab and in the perturbation of immune cells-mediated killing of melanoma spheroids.

RESULTS: The level of PD-L1+ EVs released from melanoma and CD8+ T cells and that of PD1+ EVs irrespective of the cellular origin were higher in non-responders. The Kaplan-Meier curves indicated that higher levels of PD1+ EVs were significantly correlated with poorer progression-free survival (PFS) and overall survival (OS). Significant correlations were found for PD-L1+ EVs only when released from melanoma and T cells. The multivariate analysis showed that high level of PD1+ EVs, from T cells and B cells, and high level of PD-L1+ EVs from melanoma cells, are independent biomarkers of response. The reliability of PD-L1+ EVs from melanoma and PD1+ EVs from T cells in predicting PFS was confirmed in the validation cohort through the univariate Cox-hazard regression analysis. Moreover we discovered that the circulating EVs captured nivolumab and reduced the T cells trafficking and tumor spheroids killing.

CONCLUSION: Our study identified circulating PD1+ EVs as driver of resistance to anti-PD1, and highlighted that the analysis of single EV population by liquid biopsy is a promising tool to stratify MM patients for immunotherapy.

PMID:35042524 | DOI:10.1186/s12943-021-01490-9

Pharmacogenomics. 2022 Jan 19. doi: 10.2217/pgs-2021-0152. Online ahead of print.

ABSTRACT

Aim: To explore the pharmacogenetic differentiation across Latin American populations, using the fixation index statistics (FST). Materials & methods: FST analyses were applied to 1519 pharmacogenetic markers in the 1000 Genomes Admixed American superpopulation (1KG_AMR) and an admixed Brazilian sample. Results: Allele-specific FST values for the overall cohort point to little overall pharmacogenetic differentiation (average FST = 0.017); however, moderate differentiation (FST = 0.05-0.15) was observed for 83 markers, while large differentiation (FST = 0.15-0.25) was restricted to three markers. Pairwise FST analysis identified three markers with very large differentiation (FST >0.25). Conclusion: The present study verifies and extends previous reports of little overall pharmacogenetic divergence across Latin America, although a number of markers display substantial differentiation.

PMID:35042408 | DOI:10.2217/pgs-2021-0152

Pharmacogenomics. 2022 Jan 19. doi: 10.2217/pgs-2021-0098. Online ahead of print.

ABSTRACT

The aggregated risk of major adverse cardiovascular events (MACE) in acute coronary syndrome (ACS) patients inheriting CYP2C19 loss-of function (LoF) alleles who underwent percutaneous coronary intervention (PCI) and were treated with clopidogrel is controversial. In the current study, we searched the literature in different databases for eligible studies. The risk ratio (RR) was measured where p<0.05 was statistically significant. The ACS patients with either one or two CYP2C19 LoF alleles who underwent PCI, treated with clopidogrel were correlated with a significantly escalated risk of MACE compared with noncarriers (RR: 1.53, 95% CI: 1.39-1.69, p<0.00001), driven by CV death (RR: 1.88, 95% CI: 1.18-3.01, p=0.008), MI (RR: 1.67, 95% CI: 1.21-2.31, p=0.002) and ST (RR: 1.90, 95% CI: 1.27-2.84, p=0.002). Patients with two CYP2C19 LoF alleles were correlated with significantly greater risk of MACE compared with noncarriers (RR: 3.91, 95% CI: 2.78-5.50, p<0.00001). Further analysis revealed that the risk of MACE was markedly significant in Asian patients (RR: 2.02, 95% CI: 1.67-2.44, p<0.00001) and was comparatively low significance in western patients (RR: 1.35, 95% CI: 1.20-1.52, p<0.00001). There was no significantly different bleeding events in patients with CYP2C19 LoF alleles compared with noncarriers (RR: 0.99, 95% CI: 0.85-1.15, p=0.87). The ACS patients inheriting CYP2C19 LoF alleles, who underwent PCI and were treated with clopidogrel were correlated with significantly increased risk of MACE compared with noncarriers.

PMID:35042400 | DOI:10.2217/pgs-2021-0098

Pharmacogenomics. 2022 Jan 19. doi: 10.2217/pgs-2021-0129. Online ahead of print.

ABSTRACT

Aim: To evaluate the effect of pharmacogenomics (PGx) education for pharmacists. Materials & Methods: Three-part weekly webinar series occurred in 2021. Pharmacists were assessed on their PGx knowledge at baseline and after each webinar. The primary end point was a change in the percent of correct responses between the baseline and week 1 assessment. Secondary end points included change in knowledge at weeks 4-8 and change in self-efficacy. Results: In total, 19 of 58 participants were eligible for the primary analysis, which showed an average improvement of 37% (p < 0.0001). Knowledge remained consistent between week 1 and weeks 4-8. Average self-efficacy increased (p < 0.0001) and was maintained at weeks 4-8. Conclusion: The PGx webinar series resulted in a lasting improvement in PGx knowledge and self-efficacy.

PMID:35042388 | DOI:10.2217/pgs-2021-0129

J Mol Diagn. 2022 Jan 15:S1525-1578(22)00003-4. doi: 10.1016/j.jmoldx.2021.12.001. Online ahead of print.

ABSTRACT

Clinical laboratories offering genome sequencing have the opportunity to return pharmacogenomic findings to patients, providing the added benefit of preemptive testing that could help inform medication selection or dosing throughout the lifespan. Implementation of pharmacogenomic reporting must address several challenges, including inherent limitations in short-read genome sequencing methods, gene and variant selection, standardization of genotype and phenotype nomenclature, and choice of guidelines and drugs to report. An automated pipeline, lmPGX, was developed as an end-to-end solution which produces two versions of a pharmacogenomic report, presenting either Clinical Pharmacogenetics Implementation Consortium or U.S. Food and Drug Administration guidelines for 12 genes. The pipeline was validated for performance using reference samples and pharmacogenetic data from the Genetic Testing Reference Materials Coordination Program. To determine performance and limitations, lmPGX was compared to three additional publicly available pharmacogenomic pipelines. The lmPGX pipeline offers clinical labs an opportunity for seamless integration of pharmacogenomic results with genome reporting.

PMID:35041930 | DOI:10.1016/j.jmoldx.2021.12.001

J Mol Diagn. 2022 Jan 15:S1525-1578(22)00006-X. doi: 10.1016/j.jmoldx.2021.11.008. Online ahead of print.

ABSTRACT

Clinical pharmacogenomic (PGx) testing typically uses targeted genotyping, which only detects variants included in the test design and may vary among laboratories. To evaluate the potential patient impact of genotyping as compared to sequencing, which can detect common and rare variants, an in silico targeted genotyping panel was developed based on the variants most commonly included in clinical tests and applied to a cohort of 10,030 participants who underwent sequencing for CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, DPYD, SLCO1B1, TPMT, UGT1A1, and VKORC1. The results of in silico targeted genotyping were compared to the clinically reported sequencing results. Of the 10,030 participants, 2,780 (28%) had at least one potentially clinically relevant variant/allele identified by sequencing that would not have been detected in a standard targeted genotyping panel. The genes with largest number of participants with variants only detected by sequencing were SLCO1B1, DPYD, and CYP2D6, which impacted 13%, 6.3%, and 3.5% of participants, respectively. DPYD (112 variants) and CYP2D6 (103 variants) had the largest number of unique variants detected only by sequencing. Although targeted genotyping detects the majority of clinically significant PGx variants, sequencing-based approaches are necessary to detect rare variants that collectively impact many patients. However, efforts to establish PGx variant classification systems and nomenclature to accommodate rare variants will be required to adopt sequencing-based PGx.

PMID:35041929 | DOI:10.1016/j.jmoldx.2021.11.008

Mol Biol Rep. 2022 Jan 18. doi: 10.1007/s11033-021-07079-1. Online ahead of print.

ABSTRACT

BACKGROUND: Artemisinin (ART) is an anti-malaria natural compound with a moderate anticancer action. As a metabolite of ART, dihydroartemisinin (DHA) may have stronger anti-colorectal cancer (CRC) bioactivities. However, the effects of DHA and ART on CRC chemoprevention, including adaptive immune regulation, have not been systematically evaluated and compared.

METHODS: Coupled with a newly-established HPLC analytical method, enteric microbiome biotransformation was conducted to identify if the DHA is a gut microbial metabolite of ART. The anti-CRC potential of these compounds was compared using two different human CRC cell lines for cell cycle arrest, apoptotic induction, and anti-inflammation activities. Naive CD4+ T cells were also obtained for testing the compounds on the differentiation of Treg, Th1 and Th17.

RESULTS: Using compound extraction and analytical methods, we observed for the first time that ART completely converted into its metabolites by gut microbiome within 24 h, but no DHA was detected. Although ART did not obviously influence cancer cell growth in the concentration tested, DHA very significantly inhibited the cancer cell growth at relatively low concentrations. DHA included G2/M cell cycle arrest via upregulation of cyclin A and apoptosis. Both ART and DHA downregulated the pro-inflammatory cytokine expression. The DHA significantly promoted Treg cell proliferation, while both ART and DHA inhibited Th1 and Th17 cell differentiation.

CONCLUSIONS: As a metabolite of ART, DHA possessed stronger anti-CRC activities. The DHA significantly inhibited cell growth via cell cycle arrest, apoptosis induction and anti-inflammation actions. The adaptive immune regulation is a related mechanism of actions for the observed effects.

PMID:35040004 | DOI:10.1007/s11033-021-07079-1

Acta Diabetol. 2022 Jan 17. doi: 10.1007/s00592-021-01832-5. Online ahead of print.

ABSTRACT

AIMS: Cataract formation is accelerated by hyperglycemia due to the excessive production of oxidative stress. This study aimed to examine the underlaying role of glutathione peroxidase 1 (GPX1) rs1800668, catalase (CAT) rs1001179 and superoxide dismutase 1 (SOD1) 50 bp Indel promotor region variants in the pathogenesis of cataract in patients with diabetes.

METHODS: A population-based case-control study of n=680 individuals was conducted which comprised of four respective groups: type 2 diabetes mellitus, diabetic cataract, senile cataract patients and controls. Screening of genotypes was performed by allele-specific (AS) and conventional polymerase chain reaction (PCR). Statistical testing was carried out using SPSS© 20.0, MedCal© and SNPStats© software's. Bioinformatics analysis of linkage disequilibrium was done by HaploView© software 7.0.

RESULTS: GPX1 (rs1800668) showed significant association with higher susceptibility of opacification in type 2 diabetes mellitus (χ2=23.0, Adjusted OR=1.63, 95% CI: 1.05-2.49, p<0.001). A protective role was anticipated by CAT variant (rs1001179) for the development of resistance against the pathogenicity of cataract with diabetes (χ2 = 107, Adjusted OR=0.17, 95% CI: 0.10-0.29, p<0.001). Linkage disequilibrium (LD) plot of GPX1 and CAT variants revealed that CTC-CTT haplotypes demonstrated the presence of linkage (D'=1.0) and co-inheritance (LOD=13.84) in patients of diabetic cataract.

CONCLUSIONS: GPX1 (rs1800668) variant may serve as an antioxidant biomarker for the assessment of risk for cataract in type 2 diabetes mellitus. GPX1 enzyme owed an antioxidant activity which can reduce the oxidative stress and hence could develop resistance in cataractogenesis. The findings could be beneficial as a potential target to the future pharmacogenomic studies of cataract prevention and eradication in diabetes mellitus.

PMID:35037135 | DOI:10.1007/s00592-021-01832-5

ACS Omega. 2021 Dec 20;7(1):669-682. doi: 10.1021/acsomega.1c05306. eCollection 2022 Jan 11.

ABSTRACT

A cobalt(III) complex, [Co(L)]Cl (complex 1, where L = 1,8-[N,N-bis{(3-formyl-2-hydroxy-5-methyl)benzyl}]-1,4,8,11-tetraaza-5,5,7,12,12,14-hexamethylcyclotetradecane) with distorted octahedral geometry has been synthesized and characterized using various spectroscopic techniques. The structure of the ligand has remarkably rich hydrogen intermolecular interactions such as H···H, H···C/C···H, and H···O/O···H that vary with the presence of the metal ion, and the structure of complex 1 has Cl···H interactions; this result has been proved by Hirshfeld surface and two-dimensional (2D) fingerprint maps analyses. The complex exhibits a quasi-reversible Co(III)/Co(II) redox couple with E 1/2 = -0.76 V. Calf thymus DNA (CT DNA) binding abilities of the ligand and complex 1 were confirmed by spectroscopic and electrochemical analyses. According to absorption studies, the ligand and complex 1 bind to CT DNA via intercalative binding mode, with intrinsic binding strengths of 1.41 × 103 and 8.64 × 103 M-1, respectively. A gel electrophoresis assay shows that complex 1 promotes the pUC19 DNA cleavage under dark and light irradiation conditions. Complex 1 has superior antimicrobial activity than the ligand. The cytotoxicity of complex 1 was tested against MDA-MB-231 breast cancer cells with values of IC50 of 1.369 μg mL-1 in the dark and 0.9034 μg mL-1 after light irradiation. Besides, cell morphological studies confirmed the morphological changes with AO/EB dual staining, reactive oxygen species (ROS) staining, mitochondria staining, and Hoechst staining on MDA-MB-231 cancer cells by fluorescence microscopy. Complex 1 was found to be a potent antiproliferative agent against MDA-MB-231 cells, and it can induce mitochondrial-mediated and caspase-dependent apoptosis with activation of downregulated caspases. The biotoxicity assay of complex 1 on the development of Artemia nauplii was evaluated at an IC50 value of 200 μg mL-1 and with excellent biocompatibility.

PMID:35036733 | PMC:PMC8756598 | DOI:10.1021/acsomega.1c05306

Am J Transl Res. 2021 Dec 15;13(12):13328-13335. eCollection 2021.

ABSTRACT

Intersubject variability in drug response, whether related to efficacy or toxicity, is well recognized clinically. Over the years, drug selection from our pharmacologic armamentarium has moved from providers' preferred choices to more personalized treatments as clinicians' decisions are guided by data from clinical trials. Since the advent of more accessible and affordable pharmacogenomic (PGx) testing, the promise of precise pharmacotherapy has been made. Results have accumulated in the literature with numerous examples demonstrating the value of PGx to improve drug response or prevent drug toxicity. Unfortunately, limited availability of reimbursement policies has dampened the enthusiasm of providers and organizations. The clinical application of PGx knowledge remains difficult for most clinicians under real-world conditions in patients with numerous chronic conditions and polypharmacy. This may be due to phenoconversion, a condition where there is a discrepancy between the genotype-predicted phenotype and the observed phenotype. This condition complicates the interpretation of PGx results and may lead to inappropriate recommendations and clinical decision making. For this reason, regulatory agencies have limited the transfer of information from PGx laboratories directly to consumers, especially recommendations about the use of certain drugs. This mini-review presents cases (mexiletine, propafenone, clopidogrel, warfarin, codeine, procainamide) from historical observations where drug response was modified by phenoconversion. The cases illustrate, from decades ago, that we are still in great need of advanced clinical decision systems that cope with conditions associated with phenoconversion, especially in patients with polypharmacy.

PMID:35035679 | PMC:PMC8748136

J Oncol. 2022 Jan 6;2022:9529681. doi: 10.1155/2022/9529681. eCollection 2022.

ABSTRACT

Dermatologic diseases are the fourth most frequent nonfatal common illness, yet they have a psychological, economical, and professional burden that is comparable to or larger than other chronic conditions. From a survey in China of 6 provinces, the overall prevalence of psoriasis with squamous cell carcinoma was 0.47%. According to the current investigation, the outburst of skin disease was not associated with gender, but mainly with the climate of the environment; that is, dry cold weather will more likely to induce psoriasis. Approximately 3% of people around the world have psoriasis, which is near the most common autoimmune skin disease in adults. By simple estimation, there are at least two hundred million psoriasis patients in the world. Therefore, it is not just a simple health problem in a country or a region but a serious global challenge. Of note, about half of the adult patients had been reported to be sick in their childhood and they mostly fell ill around 10 years old. Actinic keratosis is perhaps the most common, followed by squamous cell carcinoma and, to a lesser extent, acne vulgaris, psoriasis, and hidradenitis suppurativa, as well as dermatitis herpetiformis. 5-Fluorouracil (5-FU) 0.5 percent is used topically to treat actinic keratosis and squamous cell carcinoma with good outcomes, while it might cause significant toxicity in certain patients. Dapsone, a Valosin-containing protein, is a medication that is often used to treat inflammatory skin disorders like psoriatic arthritis, but it can occasionally cause hemolytic anemia. Furthermore, biologic medications for the treatment of moderate-to-severe psoriasis and multiple squamous cell carcinoma have proven to be successful and safe; nevertheless, a small percentage of patients do not react to biologic treatment in the long term or do not respond at all. Based on the data from the China Food and Drug Administration, the majority of chemical drugs are utilized as the topical formulations, while Chinese medicines are mainly delivered by an oral route, suggesting that the market for topical preparations of Chinese medicine to treat skin diseases like psoriasis is worth exploration. This large interindividual diversity in response could be caused by changes in genes that encode proteins implicated in the disease's pathologic environment or the medication's mechanism of action. Pharmacogenetics is the study of the association between genetic differences and medication response, which is valuable for identifying nonresponsive patients and those who are more likely to suffer toxicity as a result of treatment. This study highlights the pharmacogenetic recommendations for dermatology therapies that have the strongest evidence at this time, highlighting those that have been incorporated in clinical practice guides. Pharmacogenetic clinical guidelines for multiple squamous cell carcinoma and psoriasis vulgaris were found in this investigation. Here, for multiple squamous cell carcinoma trichohyalin-like 1 (TCHHL1), 5-fluorouracil (5-FU) 0.5% is recommended. Along with that dapsone, Valosin-containing protein can be recommended for treating the psoriasis vulgaris. We made some clinical trials over the two diseases, and from the result obtained, we hypothesize that the suggested drug may be a novel therapeutic target in treating the multiple squamous cell carcinoma with psoriasis vulgaris.

PMID:35035485 | PMC:PMC8758264 | DOI:10.1155/2022/9529681