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Alzheimer's disease (AD) is the leading cause of dementia, mainly affecting elderly individuals. AD is characterized by ß-amyloid plaques, abnormal tau tangles, neuronal loss, and metabolic disruptions. Recent studies have revealed the involvement of the kynurenine (KP) pathway and the aryl hydrocarbon receptor (AhR) in AD development. The KP pathway metabolizes tryptophan to produce neuroactive substances like kynurenine, kynurenic acid, and quinolinic acid. In AD, high levels of kynurenine and the neurotoxic quinolinic acid are associated with increased neuroinflammation and excitotoxicity; conversely, reduced levels of kynurenic acid, which acts as a glutamate receptor antagonist, compromise neuroprotection. Research has indicated elevated KP metabolites and enzymes in the hippocampus of AD patients and other tissues such as blood, cerebrospinal fluid, and urine. However, the finding that KP metabolites are AD biomarkers in blood, cerebrospinal fluid, and urine has been controversial. This controversy, stemming from the lack of consideration of the specific stage of AD, details of the patient's treatment, cognitive deficits, and psychiatric comorbidities, underscores the need for more comprehensive research. AhR, a ligand-activated transcription factor, regulates immune response, oxidative stress, and xenobiotic metabolism. Various ligands, including tryptophan metabolites, can activate it. Some studies suggest that AhR activation contributes to AD, while others propose that it provides neuroprotection. This discrepancy may be explained by the specific ligands that activate AhR, highlighting the complex relationship between the KP pathway, AhR activation, and AD, where the same pathway can produce both neuroprotective and harmful effects.
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Persistent infection with high-risk human papillomavirus remains the primary factor associated with the progression of cervical squamous intraepithelial lesions and the development of cervical cancer. Nevertheless, a combination of factors, including genetic predisposition, immune response, hormonal influences, and nutritional status, contribute synergistically to the development of cervical cancer. Among the various factors involved in the pathogenesis and therapy of cervical cancer, retinoids have gained considerable attention due to their multifaceted roles in different cellular processes. This review investigates defects within the vitamin A metabolism pathway and their correlation with cervical cancer. Additionally, it integrates epidemiological and experimental findings to discuss the potential utility of retinoid-based therapies, either alone or combined with other therapies, as agents against premalignant lesions and cervical cancer.
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Lesões Pré-Cancerosas , Retinoides , Neoplasias do Colo do Útero , Humanos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/patologia , Feminino , Retinoides/uso terapêutico , Lesões Pré-Cancerosas/tratamento farmacológico , Lesões Pré-Cancerosas/patologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/tratamento farmacológico , Vitamina A/uso terapêuticoRESUMO
Cervical cancer is a public health problem diagnosed in advanced stages, and its main risk factor is persistent high-risk human papillomavirus infection. Today, it is necessary to study new treatment strategies, such as immunotherapy, that use different targets of the tumor microenvironment. In this study, the K14E7E2 mouse was used as a cervical cancer model to evaluate the inhibition of indolamine-2,3-dioxygenase 1 (IDO-1) and C-X-C chemokine receptor type 2 (CXCR-2) as potential anti-tumor targets. DL-1MT and SB225002 were administered for 30 days in two regimens (R1 and R2) based on combination and single therapy approaches to inhibit IDO-1 and CXCR-2, respectively. Subsequently, the reproductive tracts were resected and analyzed to determine the tumor areas, and IHCs were performed to assess proliferation, apoptosis, and CD8 cellular infiltration. Our results revealed that combined inhibition of IDO-1 and CXCR-2 significantly reduces the areas of cervical tumors (from 196.0 mm2 to 58.24 mm2 in R1 and 149.6 mm2 to 52.65 mm2 in R2), accompanied by regions of moderate dysplasia, decreased papillae, and reduced inflammation. Furthermore, the proliferation diminished, and apoptosis and intra-tumoral CD8 T cells increased. In conclusion, the combined inhibition of IDO-1 and CXCR-2 is helpful in the antitumor response against preclinical cervical cancer.
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Persistent infection with Helicobacter pylori (H. pylori) is an important factor in gastric diseases. The vacA and cagA virulence factors of H. pylori contribute to the development of these diseases. Triple therapy containing clarithromycin has been used to eradicate this infection. Unfortunately, resistance to this antibiotic is the primary cause of treatment failure. This study aimed to determine the prevalence of clarithromycin resistance-associated mutations and to assess the relationship between virulence factors and Mexican patients infected with H. pylori. The cagA and vacA genotypes were determined by multiplex PCR. Furthermore, a qPCR was used to identify mutations of the 23S rRNA gene. This study reported a prevalence of 84.3% of H. pylori among patients with gastric diseases, and the vacA s1m1/cagA+ genotype was the most frequent (44.8%) in antrum and corpus. Analysis of the 23S rRNA gene revealed a 19.8% prevalence of clarithromycin resistance-associated mutations. The most prevalent mutations were A2143G (56%) and A2142C (25%). A significant association (p < 0.05) between the A2142G and the vacA s1m1/cagA+ genotype was detected. In conclusion, we report a high prevalence (>15%) of clarithromycin resistance-associated mutations, and we found an association between the genotypes of virulence factors and a mutation in the 23S rRNA gene.
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According to their oncogenic properties, Human Papillomaviruses (HPVs) are classified into two types: Low-Risk (LR-HPVs) and High-Risk Human Papillomaviruses (HR-HPVs). The immune system naturally controls the majority of HPV infections; however, when the HR-HPV infection is persistent, the risk of developing cervical cancer increases. Previous studies indicate that multiple-infection or coinfection with HR-HPV occurs frequently and can potentiate the development of cervical lesions. This study aimed to establish the HPV coinfection rate in squamous intraepithelial lesions from Mexican patients. For HPV detection, we performed PCR on 55 cervical lesions diagnosed by colposcopy. We detected the presence of HPV infection in 87.27% (48/55) of the lesions; interestingly, HPV coinfection was observed in 70.83% (34/48) of these samples. We also evaluated HPV infection in adjacent areas without morphological changes from 25 samples. The results showed that 80% (20/25) of these were HPV-positive and, curiously, all presented HPV-16 infection. In conclusion, our results revealed a high prevalence of HPV coinfection in cervical lesions in Mexican patients, and these results contribute to future research focused on the role that HPV coinfection plays in the development of cervical cancer.
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Alphapapillomavirus/fisiologia , Coinfecção/virologia , Infecções por Papillomavirus/complicações , Displasia do Colo do Útero/virologia , Neoplasias do Colo do Útero/virologia , Adulto , Coinfecção/epidemiologia , Feminino , Humanos , México , Infecções por Papillomavirus/epidemiologia , Prevalência , Neoplasias do Colo do Útero/epidemiologia , Displasia do Colo do Útero/epidemiologiaRESUMO
Tight junctions (TJs) are cellcell adhesion structures frequently altered by oncogenic transformation. In the present study the role of human papillomavirus (HPV) 16 E7 oncoprotein on the sealing of TJs was investigated and also the expression level of claudins in mouse cervix and in epithelial MadinDarby Canine Kidney (MDCK) cells. It was found that there was reduced expression of claudins 1 and 10 in the cervix of 7monthold transgenic K14E7 mice treated with 17ßestradiol (E2), with invasive cancer. In addition, there was also a transient increase in claudin1 expression in the cervix of 2monthold K14E7 mice, and claudin10 accumulated at the border of cells in the upper layer of the cervix in FvB mice treated with E2, and in K14E7 mice treated with or without E2. These changes were accompanied by an augmented paracellular permeability of the cervix in 2 and 7monthold FvB mice treated with E2, which became more pronounced in K14E7 mice treated with or without E2. In MDCK cells the stable expression of E7 increased the space between adjacent cells and altered the architecture of the monolayers, induced the development of an acute peak of transepithelial electrical resistance accompanied by a reduced expression of claudins 1, 2 and 10, and an increase in claudin4. Moreover, E7 enhances the ability of MDCK cells to migrate through a 3D matrix and induces cell stiffening and stress fiber formation. These observations revealed that cell transformation induced by HPV16 E7 oncoprotein was accompanied by changes in the pattern of expression of claudins and the degree of sealing of epithelial TJs.
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Claudinas/biossíntese , Papillomavirus Humano 16/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Infecções por Papillomavirus/metabolismo , Junções Íntimas/metabolismo , Neoplasias do Colo do Útero/virologia , Animais , Células Cultivadas , Claudinas/genética , Claudinas/metabolismo , Modelos Animais de Doenças , Cães , Feminino , Papillomavirus Humano 16/isolamento & purificação , Humanos , Camundongos , Camundongos Transgênicos , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologiaRESUMO
In women, serum levels of CTSB, GKN2, LIPF, LIPFG, AZGP1, TOP2A and PGA4 are proposed as predictive markers of gastric cancer. It is unknown whether GKN1 expression varies with the sex of patients with chronic gastritis or gastric cancer. We studied 36 patients with histopathological diagnosis of chronic gastritis from the state of Guerrero, Mexico. PCR was performed for H. pylori detection and GKN1 expression was determined by RT-qPCR and western blot. GKN1 mRNA expression was significantly lower in patients with chronic follicular gastritis than in those with chronic chemical gastritis (p = 0.00071). The mRNA and protein level of expression of GKN1 were significantly lower in women with chronic follicular gastritis than in men with the same condition (p = 0.0279 and p = 0.0014, respectively); the lowest levels of GKN1 were detected in women with H. pylori-positive follicular gastritis (p = 0.0175 and p = 0.0111, respectively). Through a bioinformatic analysis, estrogen response elements were identified in the GKN1 promoter.
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Biomarcadores/análise , Gastrite/patologia , Infecções por Helicobacter/complicações , Helicobacter pylori/isolamento & purificação , Hormônios Peptídicos/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Feminino , Seguimentos , Gastrite/epidemiologia , Gastrite/metabolismo , Gastrite/microbiologia , Infecções por Helicobacter/microbiologia , Humanos , México/epidemiologia , Pessoa de Meia-Idade , Hormônios Peptídicos/genética , Prognóstico , Adulto JovemRESUMO
OBJECTIVE: This work aimed to determine if cataractous changes associated with EMT occurring in the K14E6 mice lenses are associated with TGF-ß and Wnt/ß-catenin signaling activation. MATERIALS AND METHODS: Cataracts of K14E6 mice were analysed histologically; and components of TGF-ß and Wnt/ß-catenin signaling were evaluated by Western blot, RT-qPCR, in situ RT-PCR, IHC, or IF technics. Metalloproteinases involved in EMT were also assayed using zymography. The endogenous stabilisation of Smad7 protein was also assessed using an HDAC inhibitor. RESULTS: The K14E6 mice, which displayed binocular cataracts in 100% of the animals, exhibited loss of tissue organisation, cortical liquefaction, and an increase in the number of hyperproliferative-nucleated cells with mesenchymal-like characteristics in the lenses. Changes in lenses' cell morphology were due to actin filaments reorganisation, activation of TGF-ß and Wnt/ß-catenin pathways, and the accumulation of MTA1 protein. Finally, the stabilisation of Smad7 protein diminishes cell proliferation, as well as MTA1 protein levels. CONCLUSION: The HPV16-E6 oncoprotein induces EMT in transgenic mice cataracts. The molecular mechanism may involve TGF-ß and Wnt/ß-catenin pathways, suggesting that the K14E6 transgenic mouse could be a useful model for the study or treatment of EMT-induced cataracts.
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Catarata/metabolismo , Transição Epitelial-Mesenquimal , Papillomavirus Humano 16/metabolismo , Proteínas Oncogênicas Virais/biossíntese , Proteínas Repressoras/biossíntese , Fator de Crescimento Transformador beta/metabolismo , Via de Sinalização Wnt , Animais , Catarata/genética , Catarata/patologia , Modelos Animais de Doenças , Papillomavirus Humano 16/genética , Camundongos , Camundongos Transgênicos , Proteínas Oncogênicas Virais/genética , Proteínas Repressoras/genética , Fator de Crescimento Transformador beta/genéticaRESUMO
OBJECTIVE: The aim of this work was to compare the early gene expression profiles in the skin of HPV16-E6 transgenic mice regulated by the E6 PDZ-binding motif. MATERIALS AND METHODS: The global transcriptional profiles in dorsal skin biopsies from K14E6 and K14E6Δ146-151 transgenic mice were compared using microarrays. Relevant genes obtained from the most differentially expressed processes were further examined by RT-qPCR, in situ RT-PCR, Western blot, or immunofluorescence. RESULTS: The transcriptomic landscape of K14E6 versus K14E6Δ146-151 shows that the most affected expression profiles were those related to keratinocyte differentiation, stem cell maintenance, and keratinization. Additionally, downregulation of epidermal stemness markers such as K15 and CD34, as well as the upregulation of cytokeratin 6b, appeared to be dependent on the E6 PDZ-binding motif. Finally, wound healing, a physiological process linked to stemness, is impaired in the K14E6 mice compared to K14E6Δ146-151. CONCLUSION: The E6 PDZ-binding motif appears to affect stemness and keratinization during early stages of skin carcinogenesis. As E6 plays a significant role in HPV-induced skin carcinogenesis, the K14E6 versus K14E6Δ146-151 transcriptional profile provides a source of valuable data to uncover novel E6 functions in the skin.
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Queratinas/metabolismo , Proteínas Oncogênicas Virais/química , Proteínas Oncogênicas Virais/metabolismo , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Células-Tronco/metabolismo , Transcrição Gênica , Motivos de Aminoácidos , Animais , Antígenos CD34/metabolismo , Biomarcadores/metabolismo , Caderinas/metabolismo , Diferenciação Celular , Queratinócitos/citologia , Queratinas/genética , Camundongos Transgênicos , Domínios PDZ , Transporte Proteico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Pele/metabolismo , Relação Estrutura-Atividade , Transcriptoma , Cicatrização , beta Catenina/metabolismoRESUMO
BACKGROUND: The vacA, cagA and babA2 genotypes of Helicobacter pylori are associated with gastric pathology. The objectives were to determine the frequency of infection and distribution of the vacA, cagA and babA2 genotypes of H. pylori in patients with gastric ulcer, chronic gastritis and gastric cancer, and to evaluate the association of virulent genotypes with diagnosis. METHODS: We studied 921 patients with symptoms of dyspepsia or with presumptive diagnosis of gastric cancer. The DNA of H. pylori and the vacA, cagA and babA2 genes was detected by PCR in total DNA from gastric biopsies. The association of H. pylori and of its cagA, vacA and babA2 genotypes with diagnosis was determined by calculating the odds ratio (OR). RESULTS: Chronic gastritis was confirmed in 767 patients, gastric ulcer in 115 and cancer in 39. The prevalence of H. pylori was 47.8, 49.6 and 61.5% in those groups, respectively. H. pylori was more frequent in the surrounding tissue (69.2%) than in the tumor (53.8%). The vacA s1m1 genotype predominated in the three groups (45.2, 61.4 and 83.3%, respectively). H. pylori was associated with cancer (ORadjusted = 2.08; 95% CI 1.05-4.13; p = 0.035) but not with ulcer (ORadjusted = 1.07; 95% CI 0.71-1.61; p = 0.728). The s1m1 genotype was associated with ulcer and cancer (ORadjusted = 2.02; 95% CI 1.12-3.62; p = 0.019 and ORadjusted = 6.58; 95% CI 2.15-20.08; p = 0.001, respectively). babA2 was associated with gastric cancer, and cagA was not associated with the diagnosis. CONCLUSIONS: In population from Southern Mexico, H. pylori and the s1m1 genotype were associated with gastric cancer and the s1m1/cagA+/babA2+ strains predominated in tumor and adjacent tissue.
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In developing countries, clarithromycin resistance and frequency of re-infection are factors that contribute to high prevalence of Helicobacter pylori infection. The aim of this research was determine the prevalence of clarithromycin resistance and its relation with A2142G, A2142C and A2143G mutations in the domain V of the 23S rRNA gene of H. pylori isolates in patients from Southern Mexico with chronic gastritis. Another purpose of this work was to study the prevalence of virulent genotypes and distribution of resistant strains according to the vacA/cagA/babA2 H. pylori genotypes. One hundred forty-four patients with chronic gastritis were studied. Forty-five H. pylori strains were isolated and clarithromycin susceptibility was determined by the disk-diffusion method. The 82.2% of the strains had the combination of alleles vacA s1 m1 and the cagA gene was detected in 77.8% and 40% of the strains were babA2 positive. The vacA s1 m1 genotype was detected more frequently in cagA(+) strains, vacA s1m1/cagA(+)/babA2(-) genotype was more frequent than vacA s1m1/cagA(+)/babA2(+), 37.8% and 33.3%, respectively. Eight strains were clarithromycin resistant, in three of these, point mutations were identified, but only in one strain the A2143G mutation associated with clarithromycin resistance was found. Other point mutations (A1821G, G1826A, T1830C, A2089G, T1600C, C1601T, C1602T, T1610C, A1611C and T1633G) that have not been associated with clarithromycin resistance were identified. The highest proportion of resistant strains was vacA s1m1/cagA(+) (62.5%). In patients from southern Mexico with chronic gastritis, the prevalence of clarithromycin resistance is within internationally accepted range (17.8%) and allows continued use of triple therapy for H. pylori eradication. However, it is necessary to monitor the evolution of clarithromycin resistance in this area. The largest proportion of resistant H. pylori strains is not harboring the A2142G, A2142C and A2143G mutations in the 23S rRNA gene (87.5%). The vacA s1m1/cagA(+) genotype was the most prevalent and among clarithromycin-resistant strains, this was the predominant.
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Claritromicina/farmacologia , Gastrite/microbiologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/patogenicidade , Adulto , Idoso , Antibacterianos/farmacologia , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Doença Crônica , Estudos Transversais , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/genética , Feminino , Gastrite/epidemiologia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/epidemiologia , Helicobacter pylori/genética , Humanos , Masculino , México/epidemiologia , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mutação , RNA Ribossômico 23S , VirulênciaRESUMO
BACKGROUND: Mammals have limited epithelial regeneration capacity. The K6b-E6/E7 mice model has been described as useful for the study of epithelial regeneration. The objective of this study is to compare the expression of E6/E7 oncogenes with those of cell proliferation and apoptosis during epithelization. The hypothesis of this study is that alterations in cell proliferation and apoptosis in K6b-E6/E7 mice will only occur during epithelization. METHODS: Deep 2 mm punches were performed in the middle of transgenic and control mice's ears. A biopsy was collected from the epithelization zone 72 hours and 2 weeks post-injury. Assays for cell proliferation and apoptosis were carried out by immunohistochemistry and TUNEL techniques, respectively. RT-PCR in situ was performed to compare E6/E7 expressions in the areas studied. RESULTS: Transgenic strain K6b-E6/E7 presented more proliferative cells and less apoptotic cells in epithelizated zones. This effect was limited to suprabasal stratum only, and correlates with E6/E7 oncogenes expression. Two weeks post-injury, cell proliferation and apoptosis were similar in both samples as the E6/E7 expression went down. CONCLUSION: K6b-E6/E7 mouse model is useful for epithelial regeneration. Its mechanisms should be considered for the treatment of deep wounds.
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Orelha Externa/fisiologia , Células Epiteliais/citologia , Animais , Apoptose/genética , Biópsia , Divisão Celular/genética , Orelha Externa/lesões , Epitélio/fisiologia , Regulação da Expressão Gênica , Papillomavirus Humano 16/genética , Marcação In Situ das Extremidades Cortadas , Queratina-6/genética , Camundongos , Camundongos Transgênicos , Proteínas Oncogênicas Virais/biossíntese , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus/biossíntese , Proteínas E7 de Papillomavirus/genética , Regeneração , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética , TransgenesRESUMO
BACKGROUND: This study was conducted to determine human papillomavirus (HPV) types in women with cervical cancer (CC) and normal cervical cytology in the Southern region of Mexico, and to know the contribution of HPV types and cofactors in cervical cancer etiology. METHODS: A case-control study was performed in 133 women with CC and 256 controls. HPV detection was done by MY09/11 and GP5+/GP6+ PCR systems and typing by restriction fragment length polymorphism or DNA sequencing. RESULTS: HPV was found in 100% of CC and 35.5% of controls. The genotype distribution in CC was: HPV 16 (66.8%), 18 (9%), 31 (7.5%), 45 (4.5%), 58 (3.7%), 69 (3%), 52 (1.6%), 6, 11, 33, 56, and 67 (0.8% each). Among controls, HPV 33 followed by HPV 16 were the most frequent. Cervical cancer was associated with HPV 16 (OR=573.5), HPV 18 (OR=804.4), and undetermined risk HPV (types 67 and 69) (OR=434.3). Age at first intercourse <16 years (OR=9.6) and > or =3 births (OR=16) were significant risk factors for CC. CONCLUSIONS: HPV 16, by far, is the most frequent type in CC, HPV 16 and 18 are responsible for 75.8% of the CC cases and high-risk HPV for 94.7%, which is useful data to take into account in vaccination programs. HPV 33 is the most frequent type in controls and high-risk HPV are more common than low-risk HPV.