RESUMEN
Abdominal obesity coupled with polygenic hereditary defects is considered the initial event in the development of metabolic syndrome (MS). The purpose of this study was to analyse the frequency with which polymorphic loci of adiponectin (ADIPOQ) and leptin (LEP) genes occur in patients with MS and the association between the symptoms of MS and these polymorphisms. DNA was isolated from the whole blood of 207 patients with MS and 100 healthy individuals (control group) using the phenol-chloroform method. Gene polymorphisms were determined using real-time polymerase chain reaction (PCR). The most common variant of the ADIPOQ (rs2241766) gene among MS patients was the GT genotype. The A allele of the LEP (rs7799039) gene was found to be the most frequent in MS patients. The highest systolic blood pressure was found in carriers of the GG genotype of the LEP (rs7799039) gene. The carriers of the ADIPOQ (rs2241766) GT genotype were associated with the highest systolic blood pressure and body mass index (BMI); carriers of the ADIPOQ (rs2241766) GG genotype were associated with the highest diastolic blood pressure, hyperglycaemia, and elevated glycated haemoglobin (HbA1c). The results of this study allowed us to establish the unique gene variants associated with the risk of developing MS in the Crimean population.
Asunto(s)
Adiponectina , Síndrome Metabólico , Receptores de Leptina , Adiponectina/genética , Cloroformo , Hemoglobina Glucada/genética , Humanos , Leptina/genética , Síndrome Metabólico/genética , Fenoles , Polimorfismo de Nucleótido Simple , Receptores de Bombesina/genética , Receptores del Factor Estimulante de Colonias/genética , Receptores de Formil Péptido/genética , Receptores de Leptina/genética , Canal Liberador de Calcio Receptor de RianodinaRESUMEN
BACKGROUND: The development of persistent endoplasmic reticulum (ER) stress is one of the cornerstones of prostate carcinogenesis; however, the mechanism is missing. Also, alcohol is a physiological ER stress inducer, and the link between alcoholism and progression of prostate cancer (PCa) is well documented but not well characterized. According to the canonical model, the mediator of ER stress, ATF6, is cleaved sequentially in the Golgi by S1P and S2P proteases; thereafter, the genes responsible for unfolded protein response (UPR) undergo transactivation. METHODS: Cell lines used were non-malignant prostate epithelial RWPE-1 cells, androgen-responsive LNCaP, and 22RV1 cells, as well as androgen-refractory PC-3 cells. We also utilized PCa tissue sections from patients with different Gleason scores and alcohol consumption backgrounds. Several sophisticated approaches were employed, including Structured illumination superresolution microscopy, Proximity ligation assay, Atomic force microscopy, and Nuclear magnetic resonance spectroscopy. RESULTS: Herein, we identified the trans-Golgi matrix dimeric protein GCC185 as a Golgi retention partner for both S1P and S2P, and in cells lacking GCC185, these enzymes lose intra-Golgi situation. Progression of prostate cancer (PCa) is associated with overproduction of S1P and S2P but monomerization of GCC185 and its downregulation. Utilizing different ER stress models, including ethanol administration, we found that PCa cells employ an elegant mechanism that auto-activates ER stress by fragmentation of Golgi, translocation of S1P and S2P from Golgi to ER, followed by intra-ER cleavage of ATF6, accelerated UPR, and cell proliferation. The segregation of S1P and S2P from Golgi and activation of ATF6 are positively correlated with androgen receptor signaling, different disease stages, and alcohol consumption. Finally, depletion of ATF6 significantly retarded the growth of xenograft prostate tumors and blocks production of pro-metastatic metabolites. CONCLUSIONS: We found that progression of PCa associates with translocation of S1P and S2P proteases to the ER and subsequent ATF6 cleavage. This obviates the need for ATF6 transport to the Golgi and enhances UPR and cell proliferation. Thus, we provide the novel mechanistic model of ATF6 activation and ER stress implication in the progression of PCa, suggesting ATF6 is a novel promising target for prostate cancer therapy.
Asunto(s)
Estrés del Retículo Endoplásmico , Retículo Endoplásmico/metabolismo , Neoplasias de la Próstata/metabolismo , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Aparato de Golgi/metabolismo , Xenoinjertos , Humanos , Masculino , Metaloendopeptidasas/metabolismo , Ratones , ATPasas de Translocación de Protón Mitocondriales/genética , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Proproteína Convertasas/metabolismo , Neoplasias de la Próstata/etiología , Neoplasias de la Próstata/patología , Unión Proteica , Transporte de Proteínas , Serina Endopeptidasas/metabolismoRESUMEN
The urgency of the search for inexpensive and effective drugs with localized action for the treatment of rheumatoid arthritis continues unabated. In this study, for the first time we investigated the Cytos-11 antisense oligonucleotide suppression of TNF-α gene expression in a rat model of rheumatoid arthritis induced by complete Freund's adjuvant. Cytos-11 has been shown to effectively reduce peripheral blood concentrations of TNF-α, reduce joint inflammation, and reduce pannus development. The results achieved following treatment with the antisense oligonucleotide Cytos-11 were similar to those of adalimumab (Humira®); they also compared favorably with those results, which provides evidence of the promise of drugs based on antisense technologies in the treatment of this disease.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Oligonucleótidos Antisentido/uso terapéutico , Factor de Necrosis Tumoral alfa/genética , Animales , Silenciador del Gen , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Having observed how botanicals and other natural compounds are used by nature to control pests in the environment, we began investigating natural polymers, DNA and RNA, as promising tools for insect pest management. Over the last decade, unmodified short antisense DNA oligonucleotides have shown a clear potential for use as insecticides. Our research has concentrated mainly on Lymantria dispar larvae using an antisense oligoRING sequence from its inhibitor-of-apoptosis gene. In this article, we propose a novel biotechnology to protect plants from insect pests using DNA insecticide with improved insecticidal activity based on a new antisense oligoRIBO-11 sequence from the 5.8S ribosomal RNA gene. This investigational oligoRIBO-11 insecticide causes higher mortality among both L. dispar larvae grown in the lab and those collected from the forest; in addition, it is more affordable and faster acting, which makes it a prospective candidate for use in the development of a ready-to-use preparation.
Asunto(s)
Insecticidas/aislamiento & purificación , Mariposas Nocturnas/genética , Oligodesoxirribonucleótidos Antisentido/farmacología , ARN Ribosómico 5.8S/genética , Animales , Biotecnología/métodos , Genes de ARNr , Insecticidas/farmacología , Larva/efectos de los fármacosRESUMEN
Skin cancer has always been and remains the leader among all tumors in terms of occurrence. One of the main factors responsible for skin cancer, natural and artificial UV radiation, causes the mutations that transform healthy cells into cancer cells. These mutations inactivate apoptosis, an event required to avoid the malignant transformation of healthy cells. Among these deadliest of cancers, melanoma and its 'younger sister', Merkel cell carcinoma, are the most lethal. The heavy toll of skin cancers stems from their rapid progression and the fact that they metastasize easily. Added to this is the difficulty in determining reliable margins when excising tumors and the lack of effective chemotherapy. Possibly the biggest problem posed by skin cancer is reliably detecting the extent to which cancer cells have spread throughout the body. The initial tumor is visible and can be removed, whereas metastases are invisible to the naked eye and much harder to eliminate. In our opinion, antisense oligonucleotides, which can be used in the form of targeted ointments, provide real hope as a treatment that will eliminate cancer cells near the tumor focus both before and after surgery.
Asunto(s)
Antineoplásicos/uso terapéutico , Melanoma , Mutación , Oligonucleótidos Antisentido/uso terapéutico , Neoplasias Cutáneas , Rayos Ultravioleta/efectos adversos , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/efectos de la radiación , Humanos , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Melanoma/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patologíaRESUMEN
Antisense oligonucleotides (ASO), short single-stranded polymers based on DNA or RNA chemistries and synthesized in vitro, regulate gene expression by binding in a sequence-specific manner to an RNA target. The functional activity and selectivity in the action of ASOs largely depends on the combination of nitrogenous bases in a target sequence. This simple and natural property of nucleic acids provides an attractive route by which scientists can create different ASO-based techniques. Over the last 50 years, planned and realized applications in the field of antisense and nucleic acid nanotechnologies have produced astonishing results and posed new challenges for further developments, exemplifying the essence of the post-genomic era. Today the majority of ASOs are chemically modified and/or incorporated within nanoparticles to enhance their stability and cellular uptake. This review critically analyzes some successful cases using the antisense approach in medicine to address severe diseases, such as Duchenne muscular dystrophy and spinal muscular atrophy, and suggests some prospective directions for future research. We also examine in detail the elaboration of unmodified insect-specific DNA insecticides and RNA preparations in the areas of agriculture and forestry, a relatively new branch of ASO that allows circumvention of the use of non-selective chemical insecticides. When considering the variety of successful ASO modifications with an efficient signal-to-noise ratio of action, coupled with the affordability of in vitro oligonucleotide synthesis and post-synthesis procedures, we predict that the next half-century will produce a fruitful yield of tools created from effective ASO-based end products.
Asunto(s)
Agentes de Control Biológico/farmacología , Mariposas Nocturnas/efectos de los fármacos , Atrofia Muscular Espinal/terapia , Distrofia Muscular de Duchenne/terapia , Fármacos Neuromusculares/uso terapéutico , Oligonucleótidos Antisentido/genética , Agricultura/métodos , Animales , Agentes de Control Biológico/síntesis química , Agentes de Control Biológico/historia , ADN/antagonistas & inhibidores , ADN/genética , ADN/metabolismo , Agricultura Forestal/métodos , Regulación de la Expresión Génica/efectos de los fármacos , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Larva/efectos de los fármacos , Larva/genética , Larva/metabolismo , Mariposas Nocturnas/genética , Mariposas Nocturnas/crecimiento & desarrollo , Mariposas Nocturnas/metabolismo , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/patología , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patología , Nanopartículas/administración & dosificación , Nanopartículas/química , Fármacos Neuromusculares/síntesis química , Fármacos Neuromusculares/historia , Oligonucleótidos Antisentido/síntesis química , Oligonucleótidos Antisentido/metabolismo , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Baculovirus IAP (inhibitor-of-apoptosis) genes originated by capture of host genes. Unmodified short antisense DNA oligonucleotides (oligoDNAs) from baculovirus IAP genes can down-regulate specific gene expression profiles in both baculovirus-free and baculovirus-infected insects. In this study, gypsy moth (Lymantria dispar) larvae infected with multiple nucleopolyhedrovirus (LdMNPV), and LdMNPV-free larvae, were treated with oligoDNA antisense to the RING (really interesting new gene) domain of the LdMNPV IAP-3 gene. The results with respect to insect mortality, biomass accumulation, histological studies, RT-PCR, and analysis of DNA apoptotic fragmentation suggest that oligoRING induced increased apoptotic processes in both LdMNPV-free and LdMNPV-infected insect cells, but were more pronounced in the latter. These data open up possibilities for promising new routes of insect pest control using antisense phosphodiester DNA oligonucleotides.