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International Journal of Environmental... May 2024The effects of exposure to airborne particulate matter with a size of 10 μm or less (PM) on C57BL/6 mouse corneas, their response to (PA) infection, and the protective...
The effects of exposure to airborne particulate matter with a size of 10 μm or less (PM) on C57BL/6 mouse corneas, their response to (PA) infection, and the protective effects of SKQ1 were determined. C57BL/6 mouse corneas receiving PBS or SKQ1 were exposed to control (air) or PM for 2 weeks, infected, and the disease was documented by clinical score, PMN quantitation, bacterial plate count, RT-PCR and Western blot. PBS-treated, PM-exposed corneas did not differ at 1 day postinfection (dpi), but exhibited earlier (3 dpi) corneal thinning compared to controls. By 3 dpi, PM significantly increased corneal mRNA levels of several pro-inflammatory cytokines, but decreased IL-10, NQO1, GR1, GPX4, and Nrf2 over control. SKQ1 reversed these effects and Western blot selectively confirmed the RT-PCR results. PM resulted in higher viable bacterial plate counts at 1 and 3 dpi, but SKQ1 reduced them at 3 dpi. PM significantly increased MPO in the cornea at 3 dpi and was reduced by SKQ1. SKQ1, used as an adjunctive treatment to moxifloxacin, was not significantly different from moxifloxacin alone. Exposure to PM increased the susceptibility of C57BL/6 to PA infection; SKQ1 significantly reversed these effects, but was not effective as an adjunctive treatment.
Topics: Animals; Mice, Inbred C57BL; Pseudomonas Infections; Particulate Matter; Pseudomonas aeruginosa; Mice; Cornea; Disease Susceptibility; Cytokines; Female; Air Pollutants
PubMed: 38928968
DOI: 10.3390/ijerph21060722 -
Diagnostics (Basel, Switzerland) Jun 2024It was demonstrated that differentiated thyroid cancer (DTC) patients may develop multiple primary tumors (MPT) during follow-up. Many studies showed an association...
PURPOSE
It was demonstrated that differentiated thyroid cancer (DTC) patients may develop multiple primary tumors (MPT) during follow-up. Many studies showed an association between reduced telomere length and cancer phenotype; in particular, the short telomeres were associated with the development of a primary tumor. However, the role of altered telomere length in MPT development has not yet been demonstrated. The aim of this study was to evaluate the possible correlation between a short telomere length in blood leukocytes and the risk of developing MPT in DTC patients.
PATIENTS AND METHODS
We retrospectively evaluated 167 DTC patients followed up for a median of 13.6 years. Our control group was represented by 105 healthy subjects without any thyroid disease or present or past history of tumors. Our study groups, age-matched, were evaluated for the relative telomere length measured in leukocytes of peripheral venous blood.
RESULTS
The relative telomere length (RTL) was significantly different in healthy subjects compared to the total group of differentiated thyroid cancer patients [ < 0.0001]. Shorter telomeres length was observed in DTC patients with ( = 32) and without ( = 135) MPT compared to healthy subjects ( < 0.0001 and = 0.0002, respectively). At multivariate analysis, the parameters independently associated with the presence of MPT were RTL [OR: 0.466 (0.226-0.817), = 0.018] and the familial DTC [OR: 2.949 (1.142-8.466), = 0.032].
CONCLUSIONS
The results of this study suggest a role of the relative telomere length in predicting MPT development in DTC patients. Our results contribute to increasing the knowledge of the genetic mechanisms underlying MPT development in DTC patients, considering relative telomere length as a possible prognostic marker.
PubMed: 38928626
DOI: 10.3390/diagnostics14121210 -
International Journal of Molecular... Jun 2024Genetic insights help us to investigate disease pathogenesis and risk. The ABCA1 protein encoded by is involved in transporting cholesterol across the cell membrane....
Genetic insights help us to investigate disease pathogenesis and risk. The ABCA1 protein encoded by is involved in transporting cholesterol across the cell membrane. Genetic variations in the gene are well documented; however, their role in the development of diabetic dyslipidemia still needs to be explored. This study aimed to identify the associations of rs757194699 (K1587Q) and rs2066714 (I883M) with dyslipidemia in type 2 diabetes and performed molecular simulations. In our case-control study, 330 individuals were divided equally into a diabetic dyslipidemia cases and a healthy controls. Allele-specific polymerase chain reaction and restriction fragment length polymorphism were performed to screen selected variants of the gene. Sanger sequencing was also performed to find genetic mutations in exon 5 of the gene. The C allele of rs757194699 was observed at a high frequency in cases compared to controls and followed the overdominant genetic model ( < 0.0001, OR:3.84; CI:1.67-8.82). The frequency of G allele of rs2066714 was significantly higher in cases compared to controls and followed the genetic model of codominant (< 0.0001, OR: 39.61; CI:9.97-157.32), dominant ( < 0.0001,OR:59.59; CI:15.19-233.81), overdominant (< 0.0001, OR:9.75; CI:3.16-30.11), and log-additive (< 0.0001, OR:42.15; CI:11.08-160.40). In silico modeling and docking revealed that rs2066714 and rs757194699 produced deleterious conformational changes in the ABCA1 protein, resulting in alterations in the binding of the apoA1 protein. There were no genetic variations found in exon-5 in Sanger sequencing. The G allele of rs2066714 and C allele of rs757194699 in the gene were found to be risk alleles in the development of dyslipidemia in type 2 diabetes. These polymorphisms could alter the binding site of ABCA1 with apoA1 thus disturbs the reverse cholesterol transport.
Topics: Humans; Diabetes Mellitus, Type 2; ATP Binding Cassette Transporter 1; Dyslipidemias; Genetic Predisposition to Disease; Male; Female; Middle Aged; Polymorphism, Single Nucleotide; Case-Control Studies; Alleles; Gene Frequency; Aged; Molecular Docking Simulation
PubMed: 38928502
DOI: 10.3390/ijms25126796 -
International Journal of Molecular... Jun 2024Hereditary breast and ovarian cancer (HBOC) syndrome is a genetic condition that increases the risk of breast cancer by 80% and that of ovarian cancer by 40%. The most...
Hereditary breast and ovarian cancer (HBOC) syndrome is a genetic condition that increases the risk of breast cancer by 80% and that of ovarian cancer by 40%. The most common pathogenic variants (PVs) causing HBOC occur in the gene, with more than 3850 reported mutations in the gene sequence. The prevalence of specific PVs in has increased across populations due to the effect of founder mutations. Therefore, when a founder mutation is identified, it becomes key to improving cancer risk characterization and effective screening protocols. The only founder mutation described in the Mexican population is the deletion of exons 9 to 12 of (), and its description focuses on the gene sequence, but no transcription profiles have been generated for individuals who carry this gene. In this study, we describe the transcription profiles of cancer patients and healthy individuals who were heterozygous for PV by analyzing the differential expression of both alleles compared with the homozygous control group using RT-qPCR, and we describe the isoforms produced by the wild-type and alleles using nanopore long-sequencing. Using the Kruskal-Wallis test, our results showed a similar transcript expression of the wild-type allele between the healthy heterozygous group and the homozygous control group. An association between the recurrence and increased expression of both alleles in HBOC patients was also observed. An analysis of the sequences indicated four wild-type isoforms with diagnostic potential for discerning individuals who carry the PV and identifying which of them has developed cancer.
Topics: Humans; BRCA1 Protein; Female; Alleles; Hereditary Breast and Ovarian Cancer Syndrome; Middle Aged; Genetic Predisposition to Disease; Adult; Founder Effect; Exons; Breast Neoplasms; Heterozygote; Mutation; Mexico; Ovarian Neoplasms; Clinical Relevance
PubMed: 38928478
DOI: 10.3390/ijms25126773 -
International Journal of Molecular... Jun 2024Lung cancer has an unfavorable prognosis with a rate of low overall survival, caused by the difficulty of diagnosis in the early stages and resistance to therapy. In... (Review)
Review
Lung cancer has an unfavorable prognosis with a rate of low overall survival, caused by the difficulty of diagnosis in the early stages and resistance to therapy. In recent years, there have been new therapies that use specific molecular targets and are effective in increasing the survival chances of advanced cancer. Therefore, it is necessary to find more specific biomarkers that can identify early changes in carcinogenesis and allow the earliest possible treatment. Vitamin D (VD) plays an important role in immunity and carcinogenesis. Furthermore, the vitamin D receptor (VDR) regulates the expression of various genes involved in the physiological functions of the human organism. The genes encoding the VDR are extremely polymorphic and vary greatly between human populations. To date, there are significant associations between VDR polymorphism and several types of cancer, but the data on the involvement of VDR polymorphism in lung cancer are still conflicting. Therefore, in this review, our aim was to investigate the relationship between VDR single-nucleotide polymorphisms in humans and the degree of risk for developing lung cancer. The studies showcased different gene polymorphisms to be associated with an increased risk of lung cancer: , , , , and . In addition, there is a strong positive correlation between VD deficiency and lung cancer development. Still, due to a lack of awareness, the assessment of VD status and VDR polymorphism is rarely considered for the prediction of lung cancer evolution and their clinical applicability, despite the fact that studies have shown the highest risk for lung cancer given by TaqI gene polymorphisms and that VDR polymorphisms are associated with more aggressive cancer evolution.
Topics: Humans; Receptors, Calcitriol; Lung Neoplasms; Vitamin D; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease; Risk Factors
PubMed: 38928369
DOI: 10.3390/ijms25126664 -
International Journal of Molecular... Jun 2024Mutations and inactivation of the TP53 gene are frequently observed in various types of malignancies. Precise knowledge of the genetic structure and detection of...
Mutations and inactivation of the TP53 gene are frequently observed in various types of malignancies. Precise knowledge of the genetic structure and detection of mutation hotspots are crucial, as these indicate a high probability of developing cancer. The aim of our study was to perform the bioinformatic detection of mutation hotspots in the TP53 gene in patients diagnosed with malignant colon neoplasms using self-developed software (version 1). We compared TP53 gene sequences from 50 healthy individuals with those from 50 patients diagnosed with colorectal carcinoma. Of the 50 samples from cancer patients, the most frequent mutations were observed in exons 5 and 8 (12 mutations per exon) and gene sequences of 12 samples, which differed from those of the 50 samples from healthy individuals. Based on our results, the distribution of mutations in the TP53 gene structure was not even across different exons. By comparing the gene sequences of healthy individuals with those of colon cancer samples, we conclude that structural changes occurring in similar gene regions are not associated with increases in susceptibility to malignancies in every case, namely, that the pathological mechanism is multifactorial.
Topics: Humans; Colorectal Neoplasms; Computational Biology; Mutation; Tumor Suppressor Protein p53; Exons; Male; Female; Middle Aged; Aged; Genetic Predisposition to Disease
PubMed: 38928318
DOI: 10.3390/ijms25126612 -
International Journal of Molecular... Jun 2024Age-related macular degeneration (AMD) is a chronic disease, which often develops in older people, but this is not the rule. AMD pathogenesis changes include the... (Review)
Review
Age-related macular degeneration (AMD) is a chronic disease, which often develops in older people, but this is not the rule. AMD pathogenesis changes include the anatomical and functional complex. As a result of damage, it occurs, in the retina and macula, among other areas. These changes may lead to partial or total loss of vision. This disease can occur in two clinical forms, i.e., dry (progression is slowly and gradually) and exudative (wet, progression is acute and severe), which usually started as dry form. A coexistence of both forms is possible. AMD etiology is not fully understood. Extensive genetic studies have shown that this disease is multifactorial and that genetic determinants, along with environmental and metabolic-functional factors, are important risk factors. This article reviews the impact of heavy metals, macro- and microelements, and genetic factors on the development of AMD. We present the current state of knowledge about the influence of environmental factors and genetic determinants on the progression of AMD in the confrontation with our own research conducted on the Polish population from Kuyavian-Pomeranian and Lubusz Regions. Our research is concentrated on showing how polluted environments of large agglomerations affects the development of AMD. In addition to confirming heavy metal accumulation, the growth of risk of acute phase factors and polymorphism in the genetic material in AMD development, it will also help in the detection of new markers of this disease. This will lead to a better understanding of the etiology of AMD and will help to establish prevention and early treatment.
Topics: Humans; Macular Degeneration; Risk Factors; Genetic Predisposition to Disease; Metals, Heavy; Environmental Exposure; Immunogenetics
PubMed: 38928273
DOI: 10.3390/ijms25126567 -
International Journal of Molecular... Jun 2024Alcohol use disorder is considered a chronic and relapsing disorder affecting the central nervous system. The serotonergic system, mainly through its influence on the...
Alcohol use disorder is considered a chronic and relapsing disorder affecting the central nervous system. The serotonergic system, mainly through its influence on the mesolimbic dopaminergic reward system, has been postulated to play a pivotal role in the underlying mechanism of alcohol dependence. The study aims to analyse the association of the rs6295 polymorphism of the gene in women with alcohol use disorder and the association of personality traits with the development of alcohol dependence, as well as the interaction of the rs6295, personality traits, and anxiety with alcohol dependence in women. The study group consisted of 213 female volunteers: 101 with alcohol use disorder and 112 controls. NEO Five-Factor and State-Trait Anxiety Inventories were applied for psychometric testing. Genotyping of rs6295 was performed by real-time PCR. We did not observe significant differences in rs6295 genotypes ( = 0.2709) or allele distribution ( = 0.4513). The AUD subjects scored higher on the anxiety trait ( < 0.0001) and anxiety state ( < 0.0001) scales, as well as on the neuroticism ( < 0.0001) and openness ( = 0134) scales. Significantly lower scores were obtained by the AUD subjects on the extraversion ( < 0.0001), agreeability ( < 0.0001), and conscientiousness ( < 0.0001) scales. Additionally, we observed a significant effect of rs6295 genotype interaction and alcohol dependency, or lack thereof, on the openness scale ( = 0.0016). In summary, this study offers a comprehensive overview of alcohol dependence among women. It offers valuable insights into this complex topic, contributing to a more nuanced understanding of substance use among this specific demographic. Additionally, these findings may have implications for developing prevention and intervention strategies tailored to individual genetic and, most importantly, personality and anxiety differences.
Topics: Humans; Female; Receptor, Serotonin, 5-HT1A; Alcoholism; Personality; Adult; Anxiety; Middle Aged; Polymorphism, Single Nucleotide; Genotype; Genetic Predisposition to Disease; Alleles; Genetic Association Studies; Case-Control Studies
PubMed: 38928270
DOI: 10.3390/ijms25126563 -
International Journal of Molecular... Jun 2024The FUT2 gene encodes an enzyme called α-1,2-fucosyltransferase, which is involved in the formation of blood group antigens AB0(H) and is also involved in the processes...
The FUT2 gene encodes an enzyme called α-1,2-fucosyltransferase, which is involved in the formation of blood group antigens AB0(H) and is also involved in the processes of vitamin B12 absorption and its transport between cells. FUT2 gene polymorphisms are associated with vitamin B12 levels in the body. Vitamin B12 deficiency associated with hyperhomocysteinemia is a major risk factor for cardiovascular diseases (CVDs), which are one of the main causes of death in patients after kidney transplantation. The aim of our study was to determine the impact of the rs602662 (G>A) polymorphism of the FUT2 gene on the functionality of transplanted kidneys and the risk of CVD in patients after kidney transplantation. The study included 402 patients treated with immunosuppression (183 patients taking cyclosporine (CsA) and 219 patients taking tacrolimus (TAC)). The analysis of the FUT2 rs602662 (G>A) polymorphism was performed using real-time PCR. Patients with CsA were more likely to be underweight (1.64% vs. 0.91%) and obese (27.87% vs. 15.98%), while those taking TAC were more likely to be of normal weight (39.27%) or overweight (43.84%). No statistically significant differences were observed comparing the mean blood pressure, both systolic and diastolic. The renal profile showed a higher median urea nitrogen concentration in patients with CsA (26.45 mg/dL (20.60-35.40) vs. 22.95 mg/dL (17.60-33.30), = 0.004). The observed frequency of rs602662 alleles of the FUT2 gene was similar in the analyzed groups. The A allele was present in 43.7% of patients with CsA and 41.1% of those taking TAC (OR = 0.898; 95% CI: 0.678-1.189; = 0.453). In the group with CsA, the GG genotype was present in 32.2% of patients, the GA in 48.1% and the AA in 19.7%. A similar distribution was obtained in the TAC group: GG-33.8%, GA-50.2%, and AA-16.0%. An association of genotypes containing the G allele with a higher incidence of hypertension was observed. The G allele was present in 65% of people with hypertension and in 56% of patients with normal blood pressure ( = 0.036). Moreover, the evaluation of the renal parameters showed no effect of the FUT2 polymorphism on the risk of organ rejection because the levels of creatinine, eGFR, potassium, and urea nitrogen were prognostic of successful transplantation. Our results suggest that the rs6022662 FUT2 polymorphism may influence the risk of cardiovascular diseases.
Topics: Humans; Fucosyltransferases; Galactoside 2-alpha-L-fucosyltransferase; Kidney Transplantation; Male; Female; Cardiovascular Diseases; Middle Aged; Polymorphism, Single Nucleotide; Adult; Risk Factors; Genetic Predisposition to Disease; Genotype; Immunosuppressive Agents; Cyclosporine; Tacrolimus
PubMed: 38928269
DOI: 10.3390/ijms25126562 -
International Journal of Molecular... Jun 2024Reactive pustular eruptions (RPEs) can manifest in a variety of conditions, including pustular psoriasis (PP) and adult-onset immunodeficiency syndrome due to...
Reactive pustular eruptions (RPEs) can manifest in a variety of conditions, including pustular psoriasis (PP) and adult-onset immunodeficiency syndrome due to anti-interferon-γ autoantibody (AOID). These RPEs can be attributed to different causes, one of which is genetic factors. However, the genetic basis for pustular skin diseases remains poorly understood. In our study, we conducted whole-exome sequencing on a cohort of 17 AOID patients with pustular reactions (AOID-PR) and 24 PP patients. We found that 76% and 58% of the AOID-PR and PP patients, respectively, carried rare genetic variations within the filaggrin (FLG) gene family. A total of 12 out of 21 SNPs on FLG had previously received clinical classifications, with only p.Ser2706Ter classified as pathogenic. In contrast, none of the FLG3 SNPs identified in this study had prior clinical classifications. Overall, these variations had not been previously documented in cases of pustular disorders, and two of them were entirely novel discoveries. Immunohistochemical analysis of skin biopsies revealed that FLG variants like p.Ser860Trp, p.Gly3903Ter, p.Gly2440Glu, and p.Glu2133Asp caused reductions in FLG levels similar to the pathogenic FLG p.Ser2706Ter. These results highlight rare FLG variants as potential novel genetic risk factors contributing to pustule formation in both AOID and PP.
Topics: Humans; Filaggrin Proteins; Intermediate Filament Proteins; Polymorphism, Single Nucleotide; Female; Male; Asian People; Adult; Middle Aged; Exome Sequencing; Genetic Predisposition to Disease; Psoriasis; Aged; Interferon-gamma; Autoantibodies; Skin
PubMed: 38928170
DOI: 10.3390/ijms25126466