J Crohns Colitis. 2022 Jan 12:jjac004. doi: 10.1093/ecco-jcc/jjac004. Online ahead of print.

ABSTRACT

Exactly 70 years ago mercaptopurine (1951) was discovered by Gertrude Elion as a novel treatment option for acute leukemia. A total of three thiopurines (also thioguanine (1950) and azathioprine (1957)) were developed over time. These immunosuppressive drugs were also successfully introduced a few decades later to prevent rejection of transplanted organs and to treat several autoimmune diseases. For the discovery of thiopurines and other antimetabolite drugs she was rewarded in 1988, together with George Hitchings and James Black, with the Nobel Prize in Physiology or Medicine. Important steps have been made in recent years to unravel its metabolism, mode of action and pharmacogenetics. Till today thiopurine (based) therapy remains an essential immunosuppressive approach in treating patients with inflammatory bowel disease.

PMID:35024806 | DOI:10.1093/ecco-jcc/jjac004

Acta Pharm Sin B. 2021 Dec;11(12):3779-3790. doi: 10.1016/j.apsb.2021.11.022. Epub 2021 Dec 4.

ABSTRACT

PEGylated-l-asparaginase (PEG-ASNase) is a chemotherapeutic agent used to treat pediatric acute lymphoblastic leukemia (ALL). Its use is avoided in adults due to its high risk of liver injury including hepatic steatosis, with obesity and older age considered risk factors of the injury. Our study aims to elucidate the mechanism of PEG-ASNase-induced liver injury. Mice received 1500 U/kg of PEG-ASNase and were sacrificed 1, 3, 5, and 7 days after drug administration. Liver triglycerides were quantified, and plasma bilirubin, ALT, AST, and non-esterified fatty acids (NEFA) were measured. The mRNA and protein levels of genes involved in hepatic fatty acid synthesis, β-oxidation, very low-density lipoprotein (VLDL) secretion, and white adipose tissue (WAT) lipolysis were determined. Mice developed hepatic steatosis after PEG-ASNase, which associated with increases in bilirubin, ALT, and AST. The hepatic genes Ppara, Lcad/Mcad, Hadhb, Apob100, and Mttp were upregulated, and Srebp-1c and Fas were downregulated after PEG-ASNase. Increased plasma NEFA, WAT loss, and adipose tissue lipolysis were also observed after PEG-ASNase. Furthermore, we found that PEG-ASNase-induced liver injury was exacerbated in obese and aged mice, consistent with clinical studies of ASNase-induced liver injury. Our data suggest that PEG-ASNase-induced liver injury is due to drug-induced lipolysis and lipid redistribution to the liver.

PMID:35024306 | PMC:PMC8727916 | DOI:10.1016/j.apsb.2021.11.022

Expert Opin Drug Metab Toxicol. 2022 Jan 13. doi: 10.1080/17425255.2021.2029406. Online ahead of print.

ABSTRACT

INTRODUCTION: Despite new treatment options for inflammatory bowel disease (IBD), conventional thiopurines remain a common treatment option for maintaining remission, particularly in non-Westernized countries. Therapeutic drug monitoring (TDM) is advised in standard care for optimizing therapy strategies to improve effectiveness, reveal nonadherence and reduce toxicity. Still, the rationale of TDM is debated.

AREAS COVERED: Key insights on TDM of thiopurine metabolites are discussed. The pharmacology of thiopurines is described, emphasizing the interindividual differences in pharmacogenetics, pharmacokinetics and pharmacodynamics. Pharmacological differences between conventional thiopurines and tioguanine are outlined. Finally, several optimization strategies for thiopurine therapy in IBD are discussed.

EXPERT OPINION: TDM has been a useful, but limited, tool to individualize thiopurine therapy. Pharmacokinetic data on the active thiopurine metabolites, derived from measurements in erythrocytes, associated with clinical response only partially predict effectiveness and toxicity. An additional pharmacodynamic marker, such as Rac1/pSTAT3 expression in leukocytes, may improve applicability of TDM in the future.

PMID:35023443 | DOI:10.1080/17425255.2021.2029406

Pharmacogenomics. 2022 Jan 13. doi: 10.2217/pgs-2021-0155. Online ahead of print.

ABSTRACT

Tweetable abstract Pharmacogenetic tests are a promising strategy to improve safety and effectiveness of HIV therapy. However, implementation can be challenging in populations with complex genetic structure.

PMID:35023374 | DOI:10.2217/pgs-2021-0155

Cancer Res. 2022 Jan 12:canres.2058.2021. doi: 10.1158/0008-5472.CAN-21-2058. Online ahead of print.

ABSTRACT

Enhancer RNAs (eRNA) regulate gene expression and play critical roles in cancer. Using large-scale omics data from The Cancer Genome Atlas (TCGA), we systematically investigated the impact of genetic variants on eRNA expression and identified ~1 million eRNA quantitative trait loci (eRNA-QTL) as cis- and trans-acting. Over 16,000 eRNA-QTLs were associated with patient overall survival. Assessing the impact of eRNAs on >1,000 imputed anti-cancer drug responses across ~10,000 cancer patients revealed > 7 million significant associations. Furthermore, ~240,000 significant associations were identified between eRNA expression and immune cell abundance deconvoluted by TIMER, CIBERSORT, ImmuCellAI, and ImmuneCellGSVA. Finally, a user-friendly data portal was generated: Genetic, Pharmacogenomic, and Immune landscapes of eRNAs (GPIeR, https://hanlab.tamhsc.edu/GPIeR/). GPIeR is a large-scale multi-dimensional data portal that can be used to explore eRNA-associated genetic variants, drug responses, and immune infiltration with the purpose of facilitating functional and clinical investigations of eRNAs in cancer.

PMID:35022213 | DOI:10.1158/0008-5472.CAN-21-2058

Haematologica. 2022 Jan 13. doi: 10.3324/haematol.2021.280305. Online ahead of print.

ABSTRACT

Not available.

PMID:35021610 | DOI:10.3324/haematol.2021.280305

JAMA Psychiatry. 2022 Jan 12. doi: 10.1001/jamapsychiatry.2021.3799. Online ahead of print.

ABSTRACT

IMPORTANCE: About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts.

OBJECTIVE: To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples.

DESIGN, SETTING, AND PARTICIPANTS: Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10 501) and individuals with non-TRS (n = 20 325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]).

MAIN OUTCOMES AND MEASURES: GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition.

RESULTS: The study included a total of 85 490 participants (48 635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P = .04).

CONCLUSIONS AND RELEVANCE: In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance.

PMID:35019943 | DOI:10.1001/jamapsychiatry.2021.3799

Support Care Cancer. 2022 Jan 11. doi: 10.1007/s00520-022-06818-9. Online ahead of print.

ABSTRACT

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is a frequently seen burdensome adverse event of cancer therapy. The 5-HT3 receptor antagonist ondansetron has improved the rates of CINV but, unfortunately, up to 30% of patients do not obtain satisfactory control. This study examined whether genetic variations in a relevant drug-metabolizing enzyme (CYP2D6), transporter (ABCB1), or receptor (5-HT3) were associated with ondansetron failure.

METHODS: DNA was extracted from blood and used to genotype: ABCB1 (3435C > T (rs1045642) and G2677A/T (rs2032582)), 5-HT3RB (rs3758987 T > C and rs45460698 (delAAG/dupAAG)), and CYP2D6 variants. Ondansetron failure was determined by review of the medical records and by patient-reported outcomes (PROs).

RESULTS: One hundred twenty-nine patients were approached; 103 consented. Participants were less than 1 to 33 years (mean 6.85). A total of 39.8% was female, 58.3% was White (22.3% Black, 19.4% other), and 24.3% was Hispanic. A majority had leukemia or lymphoma, and 41 (39.8%) met the definition of ondansetron failure. Of variants tested, rs45460698 independently showed a significant difference in risk of ondansetron failure between a mutant (any deletion) and normal allele (p = 0.0281, OR 2.67). Age and BMI were both predictive of ondansetron failure (age > 12 (OR 1.12, p = 0.0012) and higher BMI (OR 1.13, p = 0.0119)). In multivariate analysis, age > 12 was highly predictive of ondansetron failure (OR 7.108, p = 0.0008). rs45460698 was predictive when combined with an increased nausea phenotype variant of rs1045642 (OR 3.45, p = 0.0426).

CONCLUSION: Select phenotypes of 5-HT3RB and ABCB1, age, and potentially BMI can help predict increased risk for CINV in a diverse pediatric oncology population.

PMID:35018520 | DOI:10.1007/s00520-022-06818-9

Int J Infect Dis. 2022 Jan 8:S1201-9712(22)00004-2. doi: 10.1016/j.ijid.2022.01.003. Online ahead of print.

ABSTRACT

OBJECTIVE: No population PK model of isoniazid (INH) has been reported for the Indonesian population with tuberculosis (TB). Therefore, we aimed to develop a population PK model to optimize pharmacotherapy of INH based on therapeutic drug monitoring (TDM) implementation in Indonesian TB patients.

MATERIALS AND METHODS: INH concentrations, N-Acetyltransferase 2 (NAT2) genotypes, and clinical data were collected from Dr. Soetomo General Academic Hospital, Indonesia. A nonlinear mixed-effect model was used to develop and validate the population PK model.

RESULTS: A total of 107 TB patients (with 153 samples) were involved in this study. A one-compartment model with allometric scaling for bodyweight effect described well the PK of INH. The NAT2 acetylator phenotype significantly affected INH clearance. The mean clearance rates for the rapid, intermediate, and slow NAT2 acetylator phenotypes were 55.9, 37.8, and 17.7 L/h, respectively. Our model was well-validated through visual predictive checks and bootstrapping.

CONCLUSIONS: We established the population PK model for INH in Indonesian TB patients using the NAT2 acetylator phenotype as a significant covariate. Our Bayesian forecasting model should enable optimization of TB treatment for INH in Indonesian TB patients.

PMID:35017103 | DOI:10.1016/j.ijid.2022.01.003

J Eat Disord. 2022 Jan 11;10(1):6. doi: 10.1186/s40337-022-00529-6.

ABSTRACT

BACKGROUND: Orthorexia nervosa (ON) is characterized by an excessive, obsessive concern with healthy eating generating psychological complications and even malnutrition at a caloric and protein level. Current evidence suggests that people with greater food knowledge are the most likely to be affected, placing nutrition students as a populational risk group. Since there are no nationwide studies dealing with orthorexia nervosa in this risk group, the present pilot study intends to identify risk factors for orthorexia nervosa in a sample of Nutrition and Dietetics students in Chile.

METHOD: A descriptive cross-sectional pilot study was done on 90 Nutrition and Dietetics students from a Chilean university, representing 70% of its population. The ORTHO-11-ES instrument was applied to determine ON risk, along with consulting about attitudinal, physical-clinical and social variables. Statistical tests were performed in GraphPad PRISM 8.0®, applying probability ratios and personal correlation, between the sociodemographic variables and the risk of orthorexia nervosa. This study was approved by the university Ethics Committee based on the Helsinki Declaration.

RESULTS: 23.3% of the studied population was at risk of suffering ON. Associated variables were being in the second year of their major (OR 2.22), coming from a charter school (OR 3.00) and cohabitation being limited to ≤ 1 person (OR 2.47). Particularly, declared physical activity limits are associated to the risk of suffering ON (Sedentary OR 2.42, Heavy OR 3.53), as well as time spent on the social network Instagram (< 1 h OR 2.77, > 3 h OR 1.80).

CONCLUSIONS: There is an ON risk prevalence of 23.3% in the present pilot sample under study, indicating that years of study, cohabitation, secondary educational establishment, physical activity and Instagram use constitute associated factors for the studied condition. Some results vary from international evidence, describing a dual nature in the variables for Instagram time and declared physical activity for ON risk. This study needs replication in more representative samples and longitudinal character with control groups which can confirm the studied elements as ON risk factors. Orthorexia nervosa (ON) is an expression created to indicate a possible new eating disorder characterized by excessive and obsessive preoccupation with healthy eating. Some of its most distinctive traits include marked anxiety over food, exaggerated fear over the appearance of some diseases and shame about physical appearance. This ultimately impacts food choice, planning, acquisition, preparation and consumption, creating psychological complications along with some associated with malnutrition. Considering that Nutrition students are an at-risk group, the present pilot study evaluated its prevalence and associated factors in a specific sample in Chile. Conditions associated with the risk of orthorexia nervosa identified in the present study include: number of hours spent using Instagram, limited cohabitation, extreme physical activity, and number of years in the major. These results should be taken cautiously, with their association confirmed in follow-up studies.

PMID:35016711 | DOI:10.1186/s40337-022-00529-6

Drug Metab Pharmacokinet. 2021 Dec 4;43:100436. doi: 10.1016/j.dmpk.2021.100436. Online ahead of print.

ABSTRACT

6-Mercaptopurine (6-MP) is commonly used for treatment of acute lymphoblastic leukemia (ALL). The incidence of hematotoxicity caused by this drug is quite high in Asians even using a standard low dosage regimen. The present study was aimed to elucidate the impact of thiopurine S-methyltransferase (TPMT), a nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), inosine triphosphatase (ITPA) and ATP Binding Cassette Subfamily C Member 4 (ABCC4) polymorphisms on hematotoxicity in pediatric patients who received a standard low starting dose of 6-MP. One hundred and sixty-nine pediatric patients were enrolled and their genotypes were determined. Patients who carried NUDT15∗3 and NUDT15∗2 genotypes were at a 10-15 fold higher risk of severe neutropenia than those of the wild-type during the early months of the maintenance phase. Risk of neutropenia was not significantly increased in patients with other NUDT15 variants as well as in patients with TPMT, ITPA or ABCC4 variants. These results suggest that NUDT15 polymorphisms particularly, NUDT15∗3 and NUDT15∗2, play major roles in 6-MP-induced severe hematotoxicity even when using a standard low dosage of 6-MP and genotyping of these variants is necessary in order to obtain precise tolerance doses and avoid severe hematotoxicity in pediatric patients.

PMID:35016134 | DOI:10.1016/j.dmpk.2021.100436

Eur Neuropsychopharmacol. 2022 Jan 8;55:112-157. doi: 10.1016/j.euroneuro.2021.12.005. Online ahead of print.

ABSTRACT

Variation in the expression level and activity of genes involved in drug disposition and action in tissues of pharmacological importance have been increasingly investigated in patients treated with psychotropic drugs. Findings are promising, but reliable predictive biomarkers of response have yet to be identified. Here we conducted a PRISMA-compliant systematic search of PubMed, Scopus and PsycInfo up to 12 September 2020 for studies investigating RNA expression levels in cells or biofluids from patients with major depressive disorder, schizophrenia or bipolar disorder characterized for response to psychotropic drugs (antidepressants, antipsychotics or mood stabilizers) or adverse effects. Among 5497 retrieved studies, 123 (63 on antidepressants, 33 on antipsychotics and 27 on mood stabilizers) met inclusion criteria. Studies were either focused on mRNAs (n = 96), microRNAs (n = 19) or long non-coding RNAs (n = 1), with only a minority investigating both mRNAs and microRNAs levels (n = 7). The most replicated results include genes playing a role in inflammation (antidepressants), neurotransmission (antidepressants and antipsychotics) or mitochondrial function (mood stabilizers). Compared to those investigating response to antidepressants, studies focused on antipsychotics or mood stabilizers more often showed lower sample size and lacked replication. Strengths and limitations of available studies are presented and discussed in light of the specific designs, methodology and clinical characterization of included patients for transcriptomic compared to DNA-based studies. Finally, future directions of transcriptomics of psychopharmacological interventions in psychiatric disorders are discussed.

PMID:35016057 | DOI:10.1016/j.euroneuro.2021.12.005

J Hum Genet. 2022 Jan 11. doi: 10.1038/s10038-021-01009-6. Online ahead of print.

ABSTRACT

Host genetic factors have been shown to play a role in SARs-CoV-2 infection in diverse populations. However, the genetic landscape differs among various ethnicities; therefore, we explored the host genetic factors associated with COVID-19 disease susceptivity and disease severity in a Thai population. We recruited and genotyped 212 unrelated COVID-19 Thai patients and 36 controls using AxiomTM Human Genotyping SARs-COV-2 array, including 847,384 single nucleotide polymorphisms related to SARs-COV-2 pathogenesis, immune response, and related comorbidity No SNPs passed the genome-wide significance threshold of p value <1 × 10-8. However, with a threshold of p value <1 × 10-5, a locus on chromosome 5q32 was found to have a suggestive association with COVID-19 disease susceptibility (p value 6.9 × 10-6; Q-Q plot λ = 0.805, odds ratio 0.02). Notably, IL17B is a gene located in this linkage disequilibrium block and is previously shown to play a part in inflammation and pneumonia. Additionally, a suggestive locus on chromosome 12q22, harboring EEA1 and LOC643339, was associated with COVID-19 disease severity (p value 1.3 × 10-6 - 4.4 × 10-6, Q-Q plot λ = 0.997, odds ratio 0.28-0.31). EEA1 is involved in viral entry into cells, while LOC643339 is a long non-coding RNA. In summary, our study suggested loci on chromosomes 5q32 and 12q22 to be linked to COVID-19 disease susceptibility and disease severity, respectively. The small sample size of this study may lessen the likelihood that the association found is real, but it could still be true. Further study with a larger cohort is required to confirm these findings.

PMID:35013560 | DOI:10.1038/s10038-021-01009-6

Cells. 2021 Dec 28;11(1):86. doi: 10.3390/cells11010086.

ABSTRACT

Exposure to the antibacterial agent triclosan (TCS) is associated with abnormal placenta growth and fetal development during pregnancy. Peroxisome proliferator-activated receptor γ (PPARγ) is crucial in placenta development. However, the mechanism of PPARγ in placenta injury induced by TCS remains unknown. Herein, we demonstrated that PPARγ worked as a protector against TCS-induced toxicity. TCS inhibited cell viability, migration, and angiogenesis dose-dependently in HTR-8/SVneo and JEG-3 cells. Furthermore, TCS downregulated expression of PPARγ and its downstream viability, migration, angiogenesis-related genes HMOX1, ANGPTL4, VEGFA, MMP-2, MMP-9, and upregulated inflammatory genes p65, IL-6, IL-1β, and TNF-α in vitro and in vivo. Further investigation showed that overexpression or activation (rosiglitazone) alleviated cell viability, migration, angiogenesis inhibition, and inflammatory response caused by TCS, while knockdown or inhibition (GW9662) of PPARγ had the opposite effect. Moreover, TCS caused placenta dysfunction characterized by the significant decrease in weight and size of the placenta and fetus, while PPARγ agonist rosiglitazone alleviated this damage in mice. Taken together, our results illustrated that TCS-induced placenta dysfunction, which was mediated by the PPARγ pathway. Our findings reveal that activation of PPARγ might be a promising strategy against the adverse effects of TCS exposure on the placenta and fetus.

PMID:35011648 | DOI:10.3390/cells11010086

Materials (Basel). 2021 Dec 21;15(1):16. doi: 10.3390/ma15010016.

ABSTRACT

In this work we developed a bi-functional Bacterial-Nano-Cellulose (BNC) carrier system for cell cultures of Chelidonium majus-a medicinal plant producing antimicrobial compounds. The porous BNC was biosynthesized for 3, 5 or 7 days by the non-pathogenic Komagataeibacter xylinus bacteria and used in three forms: (1) Without removal of K. xylinus cells, (2) partially cleaned up from the remaining K. xylinus cells using water washing and (3) fully purified with NaOH leaving no bacterial cells remains. The suspended C. majus cells were inoculated on the BNC pieces in liquid medium and the functionalized BNC was harvested and subjected to scanning electron microscopy observation and analyzed for the content of C. majus metabolites as well as to antimicrobial assays and tested for potential proinflammatory irritating activity in human neutrophils. The highest content and the most complex composition of pharmacologically active substances was found in 3-day-old, unpurified BNC, which was tested for its bioactivity. The assays based on the IL-1β, IL-8 and TNF-α secretion in an in vitro model showed an anti-inflammatory effect of this particular biomatrix. Moreover, 3-day-old-BNC displayed antimicrobial and antibiofilm activity against Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans. The results of the research indicated a possible application of such modified composites, against microbial pathogens, especially in local surface infections, where plant metabolite-enriched BNC may be used as the occlusive dressing.

PMID:35009165 | DOI:10.3390/ma15010016

Int J Mol Sci. 2021 Dec 31;23(1):467. doi: 10.3390/ijms23010467.

ABSTRACT

Gastric cancer (GC) is the fifth leading cause of cancer deaths in the world, with variations across geographical regions and ethnicities. Emerging evidence indicates that miRNA expression is dysregulated in GC and its polymorphisms may contribute to these variations, which has yet to be explored in Latin American populations. In a case-control study of 310 GC patients and 311 healthy donors from Chile, we assessed the association of 279 polymorphisms in 242 miRNA genes. Two novel polymorphisms were found to be associated with GC: rs4822739:C>G (miR-548j) and rs701213:T>C (miR-4427). Additionally, rs1553867776:T>TCCCCA (miR-4274) and rs12416605:C>T (miR-938) were associated with intestinal-type GC, and rs4822739:C>G (miR-548j) and rs1439619:T>G (miR-3175) with TNM I-II stage. The polymorphisms rs6149511:T> TGAAGGGCTCCA (miR-6891), rs404337:G>A (miR-8084), and rs1439619:T>G (miR-3175) were identified among H.pylori-infected GC patients and rs7500280:T>C (miR-4719) and rs1439619:T>G (miR-3175) were found among H. pylori cagPAI+ infected GC cases. Prediction analysis suggests that seven polymorphisms could alter the secondary structure of the miRNA, and the other one is located in the seed region of miR-938. Targets of miRNAs are enriched in GC pathways, suggesting a possible biological effect. In this study, we identified seven novel associations and replicated one previously described in Caucasian population. These findings contribute to the understanding of miRNA genetic polymorphisms in the GC pathogenesis.

PMID:35008894 | DOI:10.3390/ijms23010467

Int J Mol Sci. 2021 Dec 31;23(1):421. doi: 10.3390/ijms23010421.

ABSTRACT

Autophagy is an intracellular mechanism that maintains cellular homeostasis in different tissues. This process declines in cartilage due to aging, which is correlated with osteoarthritis (OA), a multifactorial and degenerative joint disease. Several studies show that microRNAs regulate different steps of autophagy but only a few of them participate in OA. Therefore, epigenetic modifications could represent a therapeutic opportunity during the development of OA. Besides, polyphenols are bioactive components with great potential to counteract diseases, which could reverse altered epigenetic regulation and modify autophagy in cartilage. This review aims to analyze epigenetic mechanisms that are currently associated with autophagy in OA, and to evaluate whether polyphenols are used to reverse the epigenetic alterations generated by aging in the autophagy pathway.

PMID:35008847 | DOI:10.3390/ijms23010421

Int J Mol Sci. 2021 Dec 29;23(1):378. doi: 10.3390/ijms23010378.

ABSTRACT

Eleven novel imide-tetrazoles were synthesized. In the initial stage of research, in silico structure-based pharmacological prediction was conducted. All compounds were screened for antimicrobial activity using standard and clinical strains. Within the studied group, compounds 1-3 were recognized as leading structures with the most promising results in antimicrobial studies. Minimal inhibitory concentration values for compounds 1, 2, 3 were within the range of 0.8-3.2 μg/mL for standard and clinical Gram-positive and Gram-negative bacterial strains, showing in some cases higher activity than the reference Ciprofloxacin. Additionally, all three inhibited the growth of all clinical Staphylococci panels: Staphylococcus aureus (T5592; T5591) and Staphylococcus epidermidis (5253; 4243) with MIC values of 0.8 μg/mL. Selected compounds were examined in topoisomerase IV decatenation assay and DNA gyrase supercoiling assay, followed by suitable molecular docking studies to explore the possible binding modes. In summary, the presented transition from substrate imide-thioureas to imide-tetrazole derivatives resulted in significant increase of antimicrobial properties. The compounds 1-3 proposed here provide a promising basis for further exploration towards novel antimicrobial drug candidates.

PMID:35008805 | DOI:10.3390/ijms23010378

Int J Mol Sci. 2021 Dec 27;23(1):270. doi: 10.3390/ijms23010270.

ABSTRACT

Two aminoalkanol derivatives of 1,7-diEthyl-8,9-diphenyl-4azatricyclo (5.2.1.02.6) dec-8-ene-3,5,10-trione and two derivatives of 1,7-diMethyl-8,9-diphenyl-4-azatricyclo (5.2.1.02.6) dec-8-ene-3,5,10-trione were evaluated in vitro for their inhibition efficacy of acetylcholinesterase. The Km, Vmax, slope angles of Lineweaver-Burk plots, Ki and IC50 values showed that all four aminoalkanol derivatives are competitive inhibitors of acetylcholinesterase whose inhibitory potency depends, to a varying extent, on the nature of the four different substituents present in the main compound structure. Studies have shown that the most potent acetylcholinesterase inhibitors are derivatives containing isopropylamine and/or methyl substituents in their structure. In contrast, dimethylamine and/or ethyl substituents seem to have a weaker, albeit visible, effect on the inhibitory potency of acetylcholinesterase. Additionally, docking studies suggest that studied compounds binds with the peripheral anionic site and not enter into the catalytic pocket due to the presence of the sterically extended substituent.

PMID:35008697 | DOI:10.3390/ijms23010270

Int J Mol Sci. 2021 Dec 22;23(1):73. doi: 10.3390/ijms23010073.

ABSTRACT

The main problem precluding successful therapy with conventional taxanes is de novo or acquired resistance to taxanes. Therefore, novel experimental taxane derivatives (Stony Brook taxanes; SB-Ts) are synthesized and tested as potential drugs against resistant solid tumors. Recently, we reported alterations in ABCC3, CPS1, and TRIP6 gene expression in a breast cancer cell line resistant to paclitaxel. The present study aimed to investigate gene expression changes of these three candidate molecules in the highly resistant ovarian carcinoma cells in vitro and corresponding in vivo models treated with paclitaxel and new experimental Stony Brook taxanes of the third generation (SB-T-121605 and SB-T-121606). We also addressed their prognostic meaning in ovarian carcinoma patients treated with taxanes. We estimated and observed changes in mRNA and protein profiles of ABCC3, CPS1, and TRIP6 in resistant and sensitive ovarian cancer cells and after the treatment of resistant ovarian cancer models with paclitaxel and Stony Brook taxanes in vitro and in vivo. Combining Stony Brook taxanes with paclitaxel caused downregulation of CPS1 in the paclitaxel-resistant mouse xenograft tumor model in vivo. Moreover, CPS1 overexpression seems to play a role of a prognostic biomarker of epithelial ovarian carcinoma patients' poor survival. ABCC3 was overexpressed in EOC tumors, but after the treatment with taxanes, its up-regulation disappeared. Based on our results, we can suggest ABCC3 and CPS1 for further investigations as potential therapeutic targets in human cancers.

PMID:35008510 | DOI:10.3390/ijms23010073