Comparison of the behavior of human lung epithelial cell lines cultured at the air-liquid interface and assessment of their responses after benzo(a)pyrene exposure.

Polycyclic nitroaromatic compounds in HULIS as dominant pro-apoptotic agents in PM2.5: Biomass/coal combustion sources, structural insights, and biomarker discovery.

Primary congenital glaucoma (PCG) is a rare genetic disorder affecting the ocular drainage system, accounting for only 0.01-0.04% blindness related cases. However, its prevalence varies significantly in ethnicities, being higher in populations that practice consanguinity, such as Pakistan where approximately 70% of marriages are consanguineous. This study aimed to investigate the genetic cause of PCG in a large Pakistani family with autosomal recessive inheritance. A large multigenerational family having multiple consanguineous marriages resulting in fifteen affected individuals was recruited for the current study. All relevant clinical information was collected and venous blood drawn for further genetic analysis. The family was subjected to direct sequencing of CYP1B1 which is the most plausible candidate of PCG. The resulting candidate variant was further confirmed using BanII restriction enzyme analysis. The sequence analysis revealed a novel indel (c.862delinsCC) in exon 2 of the CYP1B1 gene, resulting in a frameshift mutation (p.Ala288Profs*39) thereby creating a premature stop codon 39 amino acids downstream. BanII restriction enzyme analysis further confirmed this putative null mutation co-segregating with the disease trait in all the family members of the pedigree. The novel indel, putative null mutation causes PCG related disease phenotypes. This genetic variant has a high penetrance but shows variable expressivity among the affected members of the family. This putative null mutation enhances the mutation spectrum of CYP1B1 globally and from Pakistan in particular.

Clozapine-associated perturbation of arachidonic acid metabolism: A future direction for clozapine-induced cardiotoxicity.

Diagnostic accuracy of next generation sequencing--based genetic research for primary glaucoma: A systematic review and meta-analysis.

Quantitative characterization of drug metabolism and transport alterations in obesity with metabolic fatty liver disease: A physiologically based pharmacokinetic modelling approach.

Kynurenine enhances aryl hydrocarbon receptor signaling and expression levels of multidrug resistance genes in head and neck squamous cell carcinoma cell lines but does not change the potency of antineoplastic drugs.

Epigenetic predictor of smoking status in buccal cells.

Some fruits are used as promising anticancer agents due to their antioxidant and antimutagenic properties. This work explores the potential of the fruit of Pourouma cecropiifolia Mart. as a source of compounds with anticancer activity. The research covers: (i) phytochemical profiling of hydroethanolic extracts from the peel, pulp, and seeds of P. cecropiifolia Mart. using liquid ultra-performance chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS); (ii) evaluation of antioxidant and anticancer potential of the extracts against carcinoma cell lines (HeLa, RKO, MCF-7, and T47D); and (iii) in silico docking analyses with human cytochrome P450 1A1 (CYP 1A1) and CYP 1B1. A total of 18 compounds were tentatively identified by UPLC-QTOF-MS, including flavonoids, phenolic glycosides, lignans, phenolic acids, terpenes, iridoid glycosides, proanthocyanidins, curcuminoids, and naphthodianthrone. Molecular docking simulations identified nortracheloside and epicatechin as potential inhibitors of CYP 1A1 and CYP 1B1, suggesting cytotoxic activity. The antiproliferation assay showed that pulp extracts had moderate activity against human breast ductal cancer cells.

The role of SIX6 gene in juvenile open-angle glaucoma: a subtle contributor to the mutational landscape.

The oxazaphosphorine alkylating drugs, cyclophosphamide and its structural isomer, ifosamide, are frequently employed in the field of oncology for cancer treatment and immunosuppression purposes. An effective treatment method against cyclophosphamide toxicity has been suggested using plant extracts with high levels of antioxidant constituents. This study evaluates in vitro anticancer activity and anticipates the potential of quinic acid from A. muricata fruit to impact cyclophosphamide metabolism using CYP 450 isoenzyme inhibition. The phytochemicals in the ethanolic extract of A. muricata fruit were initially identified and validated using Q-TOF LC-MS. The MTT assay, a widely used method in cancer research, was employed to assess the potential anticancer activity against MCF-7 cancer cell lines in an in vitro setting. In molecular docking, one of the isolated compounds, quinic acid, was therefore indented to be docked with CYP-450 proteins. In Q-TOF LC/MS analysis, the different peaks were obtained at different retention times, and the quinic acid was at the retention time of 3.1 minutes. The extract showed remarkable in vitro anticancer activity (IC50 value of 240.709 μg/mL) against MCF-7 cancer cell lines. The molecular docking study showed the most effective inhibition on CYP 3A4, CYP 2D6, CYP 2B6 and CYP 2C9 proteins, which indicated the interaction of quinic acid with CYP proteins and herbal drug interaction.

Background: Primary congenital glaucoma (PCG) is a rare disease with an incidence of 1 in 12,000 to 18,000 in Europeans. The scarcity of the disease and limited access to genetic testing have hindered research, particularly within the Latvian population. Objectives: This study aims to present the preliminary results of a molecular genetic investigation into PCG in a Latvian cohort and to compare the prevalence of gene CYP1B1 variants with other European studies as well as to the general population in Latvia. Methods: Twenty probands with clinically diagnosed PCG and 36 family members enrolled in the study. Genetic testing was conducted using genomic DNA from peripheral blood using next generation sequencing (NGS) of seven selected genes: CYP1B1, FOXC1, FOXE3, PXDN, PITX2, PITX3, PAX6, and CPAMD8. Four probands had whole-genome sequencing (WGS). Results: All participants were of European ancestry, with no family history of PCG. Most probands were diagnosed in their first year of life, with a female to male ratio of 1:1.2 and with 80.0% of cases being unilateral. No CYP1B1 pathogenic variants were identified in the screened subjects. However, a heterozygous missense variant c.4357C>A (p.Pro4357Thr) in the PXDN gene was found in one proband and one of her parents that was classified as a variant of uncertain significance. Conclusions: This study represents the first genetic characterization of PCG in the Latvian population. Using NGS, we identified no pathogenic variants in the CYP1B1 gene among affected individuals. Preliminary evidence from this cohort does not support CYP1B1 variants as a predominant cause of PCG, though larger studies are needed to confirm this observation. Comprehensive genetic screening using whole-exome or whole-genome sequencing will be essential to identify the underlying genetic etiology of PCG in Latvia.

Obesity is a multifactorial disease, commonly observed both worldwide and in our country, triggered by environmental and genetic factors, adversely affecting all physiological functions of the body, and leading to an increase in body fat mass. Although various variants associated with susceptibility to obesity have been identified in genomic studies, these variants explain only a small portion of the genetic basis of obesity. This case-control study investigates, for the first time in the Turkish population, the relationship between CYP1B1 gene rs1056827 and rs1056836 polymorphisms in obesity patients undergoing surgical intervention (bariatric surgery). Genotyping of the polymorphisms was performed using Real-Time PCR in 63 female and 29 male obesity patients who underwent bariatric surgery and 40 female and 51 male nonobese individuals. In our study, genotype distributions for the CYP1B1 gene rs1056836 polymorphism were found to be 51.1% CC, 40.2% CG, and 8.7% GG in the case group and 46.2% CC, 47.3% CG, and 6.6% GG in the control group. The frequency of the C allele was 71.2%, and the G allele was 28.8% in the case group, while the frequency of the C allele was 70.3%, and the G allele was 29.7% in the control group. For the rs1056827 polymorphism, the genotype distributions were 10.8% GG, 35.9% GT, and 53.3% TT in the case group and 7.7% GG, 49.4% GT, and 42.9% TT in the control group. The frequency of the G allele was 28.8%, and the T allele was 71.2% in the case group, whereas the frequency of the G allele was 32.4%, and the T allele was 67.6% in the control group. No significant difference was found between the case and control groups in terms of anthropometric measurements and biochemical parameter values for the rs1056836 and rs1056827 polymorphisms of the CYP1B1 gene. Our study is valuable as it is the first to investigate the association of CYP1B1*2 (rs1056827) and CYP1B1*3 (rs1056836) polymorphisms with obesity, and it was determined that there was no difference in the investigated polymorphisms between the control group and the obesity group.

Heme-thiolate monooxygenase cytochrome P450 1B1, an old dog with many new tricks.

BackgroundSystemic lupus erythematosus (SLE), influenced by gut microbiota dysbiosis, is characterized by autoimmune and inflammatory responses. Human umbilical cord-derived mesenchymal stem cell (hUC-MSC) transplantation is an effective and safe treatment for refractory or severe SLE; however, the long-term efficacy and mechanisms of early hUC-MSC therapeutic benefits in SLE need further investigation.MethodsHere, lupus-prone MRL/MpJ-Faslpr (MRL/lpr) mice were divided into three groups: the control (Ctrl) group received saline injections, while the MSC and MSC-fecal microbiota transplantation (FMT) groups received early hUC-MSC transplants at weeks 6, 8, and 10. The MSC-FMT group also underwent FMT from the Ctrl group between weeks 9 and 13.ResultsOur results showed that early MSC treatment extended therapeutic effects up to 12 weeks, reducing autoantibodies, proinflammatory cytokines, B cells, and improving lupus nephritis. It also modulated the gut microbiota, increasing the abundance of beneficial bacteria, such as Lactobacillus johnsonii and Romboutsia ilealis, which led to higher levels of plasma tryptophan and butyrate metabolites. These metabolites activate the aryl hydrocarbon receptor (AHR), upregulate the Cyp1a1 and Cyp1b1 gene, enhance the zonula occludens 1 (ZO-1) protein, promote intestinal repair, and mitigate SLE progression. Notably, FMT from lupus mice significantly reversed hUC-MSC benefits, suggesting that the modulation of the gut microbiota plays a crucial role in the therapeutic response observed in MRL/lpr mice.ConclusionsThis research innovatively explores the early therapeutic window for MSCs in SLE, highlighting the partial mechanisms through which hUC-MSCs modulate the gut microbiota–tryptophan–AHR axis, thereby ameliorating SLE symptoms.Graphical

Primary Congenital Glaucoma (PCG) is a severe form of glaucoma that affects infants and young children that damage and causes vision impairment. Despite being a well-known condition, the genetic basis of PCG, particularly in highly consanguineous populations like the Pashtun community, still needs to be explored. Six consanguineous Pashtun families (PCG-01, PCG-02, PCG-03, PCG-04, PCG-05, & PCG-07) suffering from PCG were recruited for whole exome sequencing. A prioritization strategy was employed to identify variants in known PCG-related genes, primarily focusing on CYP1B1. Sanger sequencing was carried out to validate candidate variants and perform segregation studies in affected individuals, siblings, parents, and controls. Whole exome sequencing revealed four pathogenic homozygous variants in six PCG families. Notably, a novel homozygous mutation, c.9delC (S4Afs9), was identified in the CYP1B1 gene in one family (PCG-07). Additionally, the previously unreported variant c.1168 C > A (p.R390S) was found in two families (PCG-2 and PCG-5). Known mutations, including c.868dupC (p. R290Pfs36) and c.1169G > A (p.R390H), were also detected in PCG-01 and PCG-04 families, respectively. Furthermore, a polymorphism, c.1294 C > G (p.L432V), was observed in family PCG-03. This study identifies novel pathogenic variants associated with PCG in consanguineous Pashtun families, highlighting the role of CYP1B1 mutations in PCG development. The findings contribute to a deeper understanding of the genetic basis of PCG and may aid in genetic counselling and early intervention strategies in affected populations.

The CYP1B1 gene encodes a cytochrome p450 monooxygenase enzyme, and over 150 variants have been associated with a spectrum of eye diseases, including primary congenital glaucoma, anterior segment dysgenesis, juvenile open-angle glaucoma, and primary open-angle glaucoma. Clinical genetics has yielded insights into the functions of the various CYP1B1 gene domains; however, animal studies are required to investigate the molecular role of CYP1B1 in the eye. While both zebrafish and mice express CYP1B1 in the developing eye, embryonic studies have shown disparate species-specific functions. In zebrafish, CYP1B1 regulates ocular fissure closure such that overexpression causes a remarkable phenotype consisting of the absence of the posterior eye wall. Adult CYP1B1 null zebrafish lack an ocular phenotype but show mild craniofacial abnormalities. In contrast, CYP1B1-/- mice display post-natal mild to severe trabecular meshwork degeneration due to increased oxidative stress damage. Interestingly, the retinal ganglion cells in CYP1B1 null mice may be more susceptible to damage secondary to increased intraocular pressure. Future studies, including detailed genotype-phenotype information and animal work elucidating the regulation, substrates, and downstream effects of CYP1B1, will yield important insights for developing molecularly targeted therapies that will aim to prevent vision loss in CYP1B1-related eye diseases.

Identification and structural analysis of pathogenic variants in MYOC and CYP1B1 genes in Indian JOAG patients.

Functional genomics of primary congenital glaucoma by pathway analysis and functional characterization of CYP1B1 mutations.

Distinct differences between sexes exist in various cardiovascular diseases. Moreover, there is a significant correlation between the pathogenesis of cardiac hypertrophy (CH) and the metabolites of arachidonic acid (AA) mediated by cytochrome P450 (CYP) enzymes. The potential link between these sex differences, the levels and the activity of CYP enzymes, and their AA-mediated metabolites remains to be elucidated. Male and female Sprague Dawley rats were injected with 1 mg/kg isoproterenol for 7 days to induce CH. Echocardiography was performed before and after the induction of CH. The hypertrophic markers and CYP enzyme levels were analyzed at the gene and protein levels using real-time polymerase chain reaction and Western blot, respectively. Heart microsomal proteins were incubated with AA, and the resulting metabolites were quantified using liquid chromatography-tandem mass spectrometry. Both sexes showed a significant degree of CH, albeit to varying extents, as the echocardiograph, heart weight/tibial length, and left ventricular parameters proved. In addition, the β/α-myosin heavy chain was 2-fold higher in male compared with female rats. Albeit the 20-hydroxyeicosatetraenoic acid (20-HETE) metabolite formation showed no increase in both sexes, the mid-chain HETEs (5- and 15-HETE) were higher in male rats, which paralleled the increase in the gene and protein levels of CYP1B1. The formation rate of the epoxyeicosatrienoic acids was almost unchanged in female-treated rats, while it was significantly decreased in male-treated rats. Our results suggest sexual dimorphism in the isoproterenol-induced CH in rats, specifically on the level of CYP enzymes and their AA-mediated metabolites. SIGNIFICANCE STATEMENT: Sexual dimorphism was observed in rats following isoproterenol-induced cardiac hypertrophy, with males showing a stronger hypertrophic response. This was linked to higher CYP1B1 gene and protein expression in males, along with sex-related differences in many cytochrome P450 enzyme activities and their mediated arachidonic acid metabolites. These findings emphasized the need for targeted, sex-specific therapeutic strategies for the management and treatment of cardiac hypertrophy and other cardiovascular disorders.