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1.
Cell Rep ; 42(8): 112846, 2023 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-37516961

RESUMO

Several phospholipid (PL) molecules are intertwined with some mitochondrial complex I (CI) subunits in the membrane domain of CI, but their function is unclear. We report that when the Drosophila melanogaster ortholog of the intramitochondrial PL transporter, STARD7, is severely disrupted, assembly of the oxidative phosphorylation (OXPHOS) system is impaired, and the biogenesis of several CI subcomplexes is hampered. However, intriguingly, a restrained knockdown of STARD7 impairs the incorporation of NDUFS5 and NDUFA1 into the proximal part of the CI membrane domain without directly affecting the incorporation of subunits in the distal part of the membrane domain, OXPHOS complexes already assembled, or mitochondrial cristae integrity. Importantly, the restrained knockdown of STARD7 appears to induce a modest amount of cardiolipin remodeling, indicating that there could be some alteration in the composition of the mitochondrial phospholipidome. We conclude that PLs can regulate CI biogenesis independent of their role in maintaining mitochondrial membrane integrity.


Assuntos
Membranas Mitocondriais , Fosfolipídeos , Animais , Membranas Mitocondriais/metabolismo , Fosfolipídeos/metabolismo , Drosophila melanogaster/metabolismo , Mitocôndrias/metabolismo , Cardiolipinas/metabolismo , Fosforilação Oxidativa
2.
Curr Med Chem ; 30(2): 178-202, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35619266

RESUMO

There is a long history of informal use of Cannabis sativa (commonly called cannabis) for many purposes, including treating various ailments worldwide. However, the legalization of cannabis in multiple countries, specifically for medical purposes, has grabbed the researchers' attention to discover the scientific evidence regarding cannabis's beneficial effects. Among over 500 identified compounds (cannabinoids), Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are two major active cannabinoids derived from cannabis. Cannabinoids exert their effects through cannabinoid receptors (CB1R and CB2R). In the recent past, clinical trials have shown the efficacy of cannabis and cannabinoids for various human ailments, such as cancer, neurological disorders, inflammatory bowel disease, chronic pain, and metabolic disorders. The commonly used constituents and derivatives of cannabis include CBD, THC, THCV, dronabinol, nabilone, and nabiximol. The cannabis constituents have also been used in combination with other agents, such as megestrol acetate, in some clinical trials. The common routes for the administration of cannabis are oral, sublingual, or topical. Cannabis has also been consumed through smoking, inhalation, or with food and tea. A maximum of 572 patients and a minimum of nine patients have participated in a single clinical trial. Cannabis is legalized in some countries with restrictions, such as Belize, Canada, Colombia, Costa Rica, The Czech Republic, Jamaica, Netherlands, South Africa, Spain, and Uruguay. This article provides a compilation of published studies focusing on clinal trials on the therapeutic effects of cannabis. The adverse effects of cannabis and its constituents are also discussed.


Assuntos
Canabidiol , Canabinoides , Cannabis , Humanos , Dronabinol/farmacologia , Canabinoides/uso terapêutico , Canabinoides/farmacologia , Canabidiol/uso terapêutico , Agonistas de Receptores de Canabinoides
3.
Chemosphere ; 225: 247-258, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30877919

RESUMO

The study reports the effects of an herbicide (atrazine) and a plasticizer (Bisphenol A, BPA) on the transcriptional modulation of a mismatch repair gene (mlh1) and its adverse consequences on female fertility using Drosophila as a model. Through a chemical screen, we show that exposure to atrazine or BPA significantly downregulates mlh1 and the exposed flies had reduced fertility with smaller ovaries having reduced number of mature oocytes and abnormal distribution of ovarian follicles with increased apoptosis in them. These females had increased double-strand breaks as well as reduced synaptonemal complex formation in their ovaries suggesting altered meiotic crossing over. The eggs of these females were defective in their maternal transcripts as well as proteins and consequently, after fertilization, these eggs exhibited abnormal embryonic development. Interestingly, these phenotypes parallel that of mlh1 mutants. Further, exposure of females having reduced Mlh1 levels (mlh1e00130/CyO) to atrazine or BPA caused severe defective phenotypes at a higher proportion than normal flies. Our findings reveal the critical role of mlh1 in atrazine and BPA mediated female reproductive toxicity, and opens up a possibility of toxicants affecting female fertility by modulating the MMR genes.


Assuntos
Atrazina/farmacologia , Compostos Benzidrílicos/farmacologia , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Fertilidade/efeitos dos fármacos , Proteína 1 Homóloga a MutL/genética , Oogênese/genética , Fenóis/farmacologia , Animais , Drosophila melanogaster/efeitos dos fármacos , Feminino , Fertilidade/genética , Herbicidas/farmacologia , Oogênese/efeitos dos fármacos
4.
Chemosphere ; 201: 144-158, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29524815

RESUMO

Adaptive behaviour of an organism has relevance towards developing better resistance in subsequent generations following xenobiotic exposures. Using a genetically tractable and functional insect model, Drosophila melanogaster, we aimed to examine the resistance of the organism against repeated exposures of benzene, an industrial and environmental-chemical and a class I human carcinogen. While 100 mM benzene exposure to one-day old flies for seven days caused ∼95% mortality (F0), its exposure to subsequent generations of flies led a significant decrease in mortality with maximum survival (∼85%) as evident at F28 generation. While burden of benzene and its toxic metabolites was higher in initial generations, in latter generations (F24-F28), concentrations of less toxic metabolites were higher. In parallel, improved metabolism, less oxidative stress, less induction of hsp60 and hsp70 and higher induction of hsp26 and hsp27 along with increased gene dose ratio of three genes (cyp6g1, mrp1, and cyp12d1) were observed in latter generations of benzene exposed flies with maximum benefit accrued in F28 generation. The resistance developed in flies of F28 generation had a negative impact on reproduction which might be due to a cost against selection. The study demonstrates development of benzene resistance in Drosophila with permanent genetic changes.


Assuntos
Benzeno/toxicidade , Proteínas de Drosophila/genética , Drosophila melanogaster/efeitos dos fármacos , Resistência a Medicamentos/genética , Estresse Oxidativo/efeitos dos fármacos , Animais , Benzeno/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas de Choque Térmico/genética , Inativação Metabólica , Estresse Oxidativo/genética , Reprodução/efeitos dos fármacos
5.
Eur J Cell Biol ; 97(2): 75-89, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29290392

RESUMO

Mismatch repair (MMR) system, a conserved DNA repair pathway, plays crucial role in DNA recombination and is involved in gametogenesis. The impact of alterations in MMR family of proteins (bacterial MutS and MutL homologues) on mammalian fertility is well documented. However, an insight to the role of MMR in reproduction of non-mammalian organisms is limited. Hence, in the present study, we analysed the impact of mlh1 (a MutL homologue) on meiotic crossing over/recombination and fertility in a genetically tractable model, Drosophila melanogaster. Using mlh1e00130 hypomorphic allele, we report female specific adverse reproductive outcome for reduced mlh1 in Drosophila: mlh1e00130 homozygous females had severely reduced fertility while males were fertile. Further, mlh1e00130 females contained small ovaries with large number of early stages as well as significantly reduced mature oocytes, and laid fewer eggs, indicating discrepancies in egg production and ovulation. These observations contrast the sex independent and/or male specific sterility and normal follicular development as well as ovulation reported so far for MMR family proteins in mammals. However, analogous to the role(s) of mlh1 in meiotic crossing over and DNA repair processes underlying mammalian fertility, ovarian follicles from mlh1e00130 females contained significantly increased DNA double strand breaks (DSBs) and reduced synaptonemal complex foci. In addition, large proportion of fertilized eggs display discrepancies in egg activation and fail to proceed beyond stage 5 of embryogenesis. Hence, reduction of the Mlh1 protein level leads to defective oocytes that fail to complete embryogenesis after fertilization thereby reducing female fertility.


Assuntos
Drosophila melanogaster/fisiologia , Proteína 1 Homóloga a MutL/metabolismo , Oócitos/metabolismo , Folículo Ovariano/metabolismo , Animais , Drosophila melanogaster/metabolismo , Feminino , Fertilidade , Meiose
6.
Life Sci ; 185: 8-14, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28728902

RESUMO

MicroRNAs (miRNAs) constitute a class of small (18-22 nucleotides) non-coding RNAs that regulate gene expression at the post-transcriptional level. Caenorhabditis elegans, Drosophila melanogaster, and many other small organisms have been instrumental in deciphering the biological functions of miRNAs. While some miRNAs from small organisms are highly conserved across the taxa, others are organism specific. The miRNAs are known to play a crucial role during development and in various cellular functions such as cell survival, cell proliferation, and differentiation. The miRNAs associated with fragile X syndrome, Parkinson's disease, Alzheimer's disease, diabetes, cancer, malaria, infectious diseases and several other human diseases have been identified from small organisms. These organisms have been used as platforms in deciphering the functions of miRNAs in the pathogenesis of human diseases and to study miRNA biogenesis. Small organisms have also been used in the development of miRNA-based diagnostic, prognostic and therapeutic strategies. The molecular techniques such as genome sequencing, northern blot analysis, and quantitative RT-PCR, have been used in deciphering the functions of miRNAs in small organisms. How miRNAs from small organisms especially those from Drosophila and C. elegans regulate development and disease pathogenesis is the focus of this review. The outstanding questions raised by our current understanding are discussed.


Assuntos
Regulação da Expressão Gênica/genética , MicroRNAs/genética , Animais , Northern Blotting , Caenorhabditis elegans/genética , Diferenciação Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Drosophila melanogaster/genética , Humanos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos
7.
J Hazard Mater ; 304: 360-9, 2016 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-26590872

RESUMO

microRNAs (miRNAs) as one of the major epigenetic modulators negatively regulate mRNAs at post transcriptional level. It was therefore hypothesized that modulation of miRNAs by hexavalent Chromium [Cr(VI)], a priority environmental chemical, can affect DNA damage. In a genetically tractable model, Drosophila melanogaster, role of maximally up-regulated miRNA, dme-miR-314-3p, on DNA damage was examined by exposing the third instar larvae to 5.0-20.0 µg/ml Cr(VI) for 24 and 48 h. mus309, a Drosophila homologue of human Bloom's syndrome and predicted as one of the potential targets of this miRNA, was confirmed as its target by 5'RLM-RACE assay. A significant down-regulation of mus309 was observed in dme-miR-314-3p overexpression strain (myo-gal4>UAS-miR-314-3p) as compared with that in parental strains (myo-gal4 and UAS-miR-314-3p) and in w(1118). A significant increase in DNA damage including double strand breaks generation was observed in exposed myo-gal4>UAS-miR-314 and mus309 mutants as compared with that in parental strain and in unexposed control. A significant down-regulation of cell cycle regulation genes (CycA, CycB and cdc2) was observed in these exposed genotypes. Collectively, the study demonstrates that dme-miR-314-3p can mediate the downregulation of repair deficient gene mus309 leading to increased DNA damage and cell cycle arrest in exposed organism which may affect Cr(VI) mediated carcinogenesis.


Assuntos
Cromo/toxicidade , Dano ao DNA , MicroRNAs/genética , RecQ Helicases/genética , Animais , Reparo do DNA , Drosophila/genética , Trato Gastrointestinal/metabolismo
8.
Free Radic Biol Med ; 83: 54-65, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25746179

RESUMO

Adverse reports on the exposure of organisms to dichlorvos (DDVP; an organophosphate insecticide) necessitate studies of organismal resistance/tolerance by way of pharmacological or genetic means. In the context of genetic modulation, a mutation in methuselah (mth; encodes a class II G-protein-coupled receptor (GPCR)) is reported to extend (~35%) the life span of Drosophila melanogaster and enhance their resistance to oxidative stress induced by paraquat exposure (short term, high level). A lack of studies on organismal tolerance of DDVP by genetic modulation prompted us to examine the protective efficacy of mth mutation in exposed Drosophila. Flies were exposed to 1.5 and 15.0 ng/ml DDVP for 12-48 h to examine oxidative stress endpoints and chemical resistance. After prolonged exposure of flies to DDVP, antioxidant enzyme activities, oxidative stress, glutathione content, and locomotor performance were assayed at various days (0, 10, 20, 30, 40, 50) of age. Flies with the mth mutation (mth(1)) showed improved chemical resistance and rescued redox impairment after acute DDVP exposure. Exposed mth(1) flies exhibited improved life span along with enhanced antioxidant enzyme activities and rescued oxidative perturbations and locomotor insufficiency up to middle age (~20 days) over similarly exposed w(1118) flies. However, at late (≥30 days) age, these benefits were undermined. Further, similarly exposed mth-knockdown flies showed effects similar to those observed in mth(1) flies. This study provides evidence of tolerance in organisms carrying a mth mutation against prolonged DDVP exposure and further warrants examination of similar class II GPCR signaling facets toward better organismal health.


Assuntos
Animais Geneticamente Modificados/crescimento & desenvolvimento , Diclorvós/toxicidade , Proteínas de Drosophila/genética , Drosophila melanogaster/crescimento & desenvolvimento , Tolerância a Medicamentos/genética , Longevidade/genética , Mutação/genética , Receptores Acoplados a Proteínas G/genética , Animais , Animais Geneticamente Modificados/genética , Anti-Helmínticos/toxicidade , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Proliferação de Células/efeitos dos fármacos , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Estresse Oxidativo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
9.
Age (Dordr) ; 36(3): 9628, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24535708

RESUMO

Dichloroacetic acid (DCA), a water disinfection by-product, has attained emphasis due to its prospect for clinical use against different diseases including cancer along with negative impact on organisms. However, these reports are based on the toxicological as well clinical data using comparatively higher concentrations of DCA without much of environmental relevance. Here, we evaluate cellular as well as organismal effects of DCA at environmentally and mild clinically relevant concentrations (0.02-20.0 µg/ml) using an established model organism, Drosophila melanogaster. Flies were fed on food mixed with test concentrations of DCA for 12-48 h to examine the induction of reactive oxygen species (ROS) generation, oxidative stress (OS), heat shock genes (hsps) and cell death along with organismal responses. We also examined locomotor performance, ROS generation, glutathione (GSH) depletion, expression of GSH-synthesizing genes (gclc and gclm), and hsps at different days (0, 10, 20, 30, 40, 50) of the age in flies after prolonged DCA exposure. We observed mild OS and induction of antioxidant defense system in 20.0 µg/ml DCA-exposed organism after 24 h. After prolonged exposure to DCA, exposed organism exhibited improved survival, elevated expression of hsp27, gclc, and gclm concomitant with lower ROS generation and GSH depletion and improved locomotor performance. Conversely, hsp27 knockdown flies exhibited reversal of the above end points. The study provides evidence for the attenuation of cellular and functional decline in aged Drosophila after prolonged DCA exposure and the effect of hsp27 modulation which further incites studies towards the therapeutic application of DCA.


Assuntos
Ácido Dicloroacético/administração & dosagem , Suplementos Nutricionais , Proteínas de Drosophila/genética , Drosophila melanogaster/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Longevidade/genética , RNA/genética , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Relação Dose-Resposta a Droga , Proteínas de Drosophila/biossíntese , Proteínas de Drosophila/efeitos dos fármacos , Seguimentos , Proteínas de Choque Térmico/biossíntese , Proteínas de Choque Térmico/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Reação em Cadeia da Polimerase , Espécies Reativas de Oxigênio/metabolismo
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