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Science Translational Medicine Dec 2023Chagas disease, caused by the protozoan parasite , affects millions of people in the Americas and across the world, leading to considerable morbidity and mortality....
Chagas disease, caused by the protozoan parasite , affects millions of people in the Americas and across the world, leading to considerable morbidity and mortality. Current treatment options, benznidazole (BNZ) and nifurtimox, offer limited efficacy and often lead to adverse side effects because of long treatment durations. Better treatment options are therefore urgently required. Here, we describe a pyrrolopyrimidine series, identified through phenotypic screening, that offers an opportunity to improve on current treatments. In vitro cell-based washout assays demonstrate that compounds in the series are incapable of killing all parasites; however, combining these pyrrolopyrimidines with a subefficacious dose of BNZ can clear all parasites in vitro after 5 days. These findings were replicated in a clinically predictive in vivo model of chronic Chagas disease, where 5 days of treatment with the combination was sufficient to prevent parasite relapse. Comprehensive mechanism of action studies, supported by ligand-structure modeling, show that compounds from this pyrrolopyrimidine series inhibit the Q active site of cytochrome b, part of the cytochrome bc complex of the electron transport chain. Knowledge of the molecular target enabled a cascade of assays to be assembled to evaluate selectivity over the human cytochrome b homolog. As a result, a highly selective and efficacious lead compound was identified. The combination of our lead compound with BNZ rapidly clears parasites, both in vitro and in vivo, and shows great potential to overcome key issues associated with currently available treatments.
Topics: Animals; Humans; Cytochromes b; Trypanocidal Agents; Chagas Disease; Trypanosoma cruzi; Parasites
PubMed: 38091410
DOI: 10.1126/scitranslmed.adg8105 -
Biochemistry. Biokhimiia Oct 2023This work represents an overview of electron transport regulation in chloroplasts as considered in the context of structure-function organization of photosynthetic... (Review)
Review
This work represents an overview of electron transport regulation in chloroplasts as considered in the context of structure-function organization of photosynthetic apparatus in plants. Main focus of the article is on bifurcated oxidation of plastoquinol by the cytochrome bf complex, which represents the rate-limiting step of electron transfer between photosystems II and I. Electron transport along the chains of non-cyclic, cyclic, and pseudocyclic electron flow, their relationships to generation of the trans-thylakoid difference in electrochemical potentials of protons in chloroplasts, and pH-dependent mechanisms of regulation of the cytochrome bf complex are considered. Redox reactions with participation of molecular oxygen and ascorbate, alternative mediators of electron transport in chloroplasts, have also been discussed.
Topics: Electron Transport; Cytochrome b6f Complex; Cytochromes b; Electrons; Chloroplasts; Photosynthesis; Oxidation-Reduction
PubMed: 38105016
DOI: 10.1134/S0006297923100036 -
Scientific Reports Jun 2023Mitochondrial function in adipocyte is an important aspect in maintaining metabolic homeostasis. Our previous observation showed that circulating levels of...
Mitochondrial function in adipocyte is an important aspect in maintaining metabolic homeostasis. Our previous observation showed that circulating levels of adrenomedullin (ADM) and mRNA and protein for ADM in omental adipose tissue were higher in patients with gestational diabetes mellitus (GDM), and these alterations are accompanied by glucose and lipid metabolic dysregulation, but the impact of ADM on mitochondrial biogenesis and respiration in human adipocyte remain elusive. The present study demonstrated that: (1) Increasing doses of glucose and ADM inhibit human adipocyte mRNA expressions of mitochondrial DNA (mtDNA)-encoded subunits of electron transport chain, including nicotinamide adenine dinucleotide dehydrogenase (ND) 1 and 2, cytochrome (CYT) b, as well as ATPase 6; (2) ADM significantly increases human adipocyte mitochondrial reactive oxygen species generation and this increase is reversed by ADM antagonist, ADM22-52, but treatment with ADM does not significantly affect mitochondrial contents in the adipocytes; (3) Adipocyte basal and maximal oxygen consumption rate are dose-dependently suppressed by ADM, thus results in impaired mitochondrial respiratory capacity. We conclude that elevated ADM observed in diabetic pregnancy may be involved in glucose and lipid dysregulation through compromising adipocyte mitochondrial function, and blockade of ADM action may improve GDM-related glucose and adipose tissue dysfunction.
Topics: Female; Humans; Pregnancy; Adipocytes; Adrenomedullin; Cytochromes b; Diabetes, Gestational; DNA, Mitochondrial; Glucose; Lipids; Mitochondria; RNA, Messenger
PubMed: 37311963
DOI: 10.1038/s41598-023-36622-2 -
Parasites & Vectors Sep 2023Coccidiosis caused by Eimeria zuernii (Eimeriidae: Coccidia) represents a significant economic threat to the bovine industry. Understanding the evolutionary and genetic...
BACKGROUND
Coccidiosis caused by Eimeria zuernii (Eimeriidae: Coccidia) represents a significant economic threat to the bovine industry. Understanding the evolutionary and genetic biology of E. zuernii can assist in new interaction developments for the prevention and control of this protozoosis.
METHODS
We defined the evolutionary and genetic characteristics of E. zuernii by sequencing the complete mitogenome and analyzing the genetic diversity and population structure of 51 isolates collected from eight yak breeding parks in China.
RESULTS
The 6176-bp mitogenome of E. zuernii was linear and encoded typical mitochondrial contents of apicomplexan parasites, including three protein-coding genes [PCGs; cytochrome c oxidase subunits I and III (cox1 and cox3), and cytochrome b (cytb)], seven fragmented small subunit (SSU) and 12 fragmented large subunit (LSU) rRNAs. Genome-wide comparative and evolutionary analyses showed cytb and cox3 to be the most and least conserved Eimeria PCGs, respectively, and placed E. zuernii more closely related to Eimeria mephitidis than other Eimeria species. Furthermore, cox1-based genetic structure defined 24 haplotypes of E. zuernii with high haplotype diversities and low nucleotide diversities across eight geographic populations, supporting a low genetic structure and rapid evolutionary rate as well as a previous expansion event among E. zuernii populations.
CONCLUSIONS
To our knowledge, this is the first study presenting the phylogeny, genetic diversity, and population structure of the yak E. zuernii, and such information, together with its mitogenomic data, should contribute to a better understanding of the genetic and evolutionary biological studies of apicomplexan parasites in bovines.
Topics: Cattle; Animals; Eimeria; Genome, Mitochondrial; Coccidiosis; Biological Evolution; Cytochromes b; Genetic Variation
PubMed: 37661262
DOI: 10.1186/s13071-023-05925-8 -
Scientific Reports Jun 2023Molecular characterization of fish muscle proteins are nowadays considered as a key component to understand the role of specific proteins involved in various...
Molecular characterization of fish muscle proteins are nowadays considered as a key component to understand the role of specific proteins involved in various physiological and metabolic processes including their up and down regulation in the organisms. Coldwater fish specimens including snow trouts hold different types of proteins which help them to survive in highly diversified temperatures fluctuating from 0 to 20 °C. So, in current study, the liquid chromatography mass spectrometry using label free quantification technique has been used to investigate the muscle proteome profile of Schizothorax labiatus. For proteomic study, two weight groups of S. labiatus were taken from river Sindh. The proteomic analysis of group 1 revealed that a total of 235 proteins in male and 238 in female fish were recorded. However, when male and female S. labiatus were compared with each other on the basis of spectral count and abundance of peptides by ProteinLynx Global Server software, a total of 14 down-regulated and 22 up-regulated proteins were noted in this group. The highly down-regulated ones included homeodomain protein HoxA2b, retinol-binding protein 4, MHC class II beta chain and proopiomelanocortin while as the highly expressed up-regulated proteins comprised of gonadotropin I beta subunit, NADH dehydrogenase subunit 4, manganese superoxide dismutase, recombinase-activating protein 2, glycosyltransferase, chymotrypsin and cytochrome b. On the other hand, the proteomic characterisation of group 2 of S. labiatus revealed that a total of 227 proteins in male and 194 in female fish were recorded. When male and female S. labiatus were compared with each other by label free quantification, a total of 20 down-regulated and 18 up-regulated proteins were recorded. The down-regulated protein expression of group 2 comprised hepatic lipase, allograft inflammatory factor-1, NADH dehydrogenase subunit 4 and myostatin 1 while the highly expressed up-regulated proteins included glycogen synthase kinase-3 beta variant 2, glycogen synthase kinase-3 beta variant 5, cholecystokinin, glycogen synthase kinase-3 beta variant 3 and cytochrome b. Significant (P < 0.05) difference in the expression of down-regulated and up-regulated proteins was also noted between the two sexes of S. labiatus in each group. According to MS analysis, the proteins primarily concerned with the growth, skeletal muscle development and metabolism were down-regulated in river Sindh, which indicates that growth of fish during the season of collection i.e., winter was slow owing to less food availability, gonad development and low metabolic activity. While, the proteins related to immune response of fish were also noted to be down-regulated thereby signifying that the ecosystem has less pollution loads, microbial, pathogenic and anthropogenic activities. It was also found that the proteins involved in glycogen metabolism, reproductive and metabolic processes, particularly lipid metabolism were up-regulated in S. labiatus. The significant expression of these proteins may be connected to pre-spawning, gonad development and use of stored food as source of energy. The information generated in this study can be applied to future research aimed at enhancing food traceability, food safety, risk management and authenticity analysis.
Topics: Animals; Male; Female; Ecosystem; Trout; Chromatography, Liquid; Proteomics; Cytochromes b; Tandem Mass Spectrometry; Cyprinidae; Fish Proteins; Glycogen Synthase Kinases
PubMed: 37349327
DOI: 10.1038/s41598-023-35646-y -
Archives of Razi Institute Jun 2023Goats are the earliest domesticated ruminants. The local goat, , is considered one of the most important animals globally to provide good livestock production under...
Goats are the earliest domesticated ruminants. The local goat, , is considered one of the most important animals globally to provide good livestock production under harsh environmental conditions. This study aimed to detect the genetic structures of the local Iraqi goats bred in the central and southern regions of the country and investigate the possibility of benefiting from their genetic structures to construct improvement programs for increasing the productivity of these animals. To this end, blood samples were taken from 15 domestic black goats. A total of 10 ml of each animal's blood was placed in plastic containers of 10 ml. The DNA was extracted and sent to the laboratories of Juan Ju University, People's Republic of China, to analyze the sequences of the nitrogenous bases of the () gene. The results showed the presence of a genetic morphology for a segment of 670 base pairs for all the studied samples, and 15 sequences of this strain were recorded in the gene bank under the following accession numbers (LC496353.1:1-LC496367.1:1). The sequences of the nitrogenous bases of this segment of the gene, which were registered in the gene bank of some international goat breeds, were used for comparison with the sequences of black Iraqi goats to analyze the phylogenetic tree, calculate the genetic distance, study haplotypes, and calculate neutrality. The results showed the presence of one mutation in the studied segment of the gene, with a size of 670 bp. The mutation in base 46 of the studied gene converted from the purine group to the pyrimidine group (the shift from the nitrogen leaders A
Topics: Humans; Animals; Goats; Phylogeny; Cytochromes b; Iraq; Genotype; Amino Acids
PubMed: 38028851
DOI: 10.22092/ARI.2022.359888.2499 -
Parasites & Vectors Aug 2023Angiostrongylus cantonensis (rat lungworm) is the main pathogen responsible for eosinophilic meningitis in humans. One of its intermediate snail hosts, Achatina fulica,...
BACKGROUND
Angiostrongylus cantonensis (rat lungworm) is the main pathogen responsible for eosinophilic meningitis in humans. One of its intermediate snail hosts, Achatina fulica, was already present in many countries around the world before it appeared in the West Indies in the late 1980s. In the French territories in the Caribbean and northern South America, the first cases of human neuroangiostrongyliasis were reported in Martinique, Guadeloupe and French Guiana in 2002, 2013 and 2017, respectively. In order to better characterize angiostrongyliasis in Guadeloupe, particularly its geographical origin and route of introduction, we undertook molecular characterization of adult worms of Angiostrongylus cantonensis and its intermediate host Achatina fulica.
METHODS
Genomic DNA of adult Angiostrongylus cantonensis and Achatina fulica was extracted and amplified by polymerase chain reaction (PCR) targeting the mitochondrial genes cytochrome B and C for A. cantonensis and 16S ribosomal RNA for A. fulica. The PCR products were sequenced and studied by phylogenetic analysis.
RESULTS
Cytochrome B and cytochrome C molecular markers indicate a monophyletic lineage of A. cantonensis adult worms in Guadeloupe. Two sequences of A. fulica were identified.
CONCLUSIONS
These results confirm the recent introduction of both Angiostrongylus cantonensis and Achatina fulica into Guadeloupe. Achatina fulica in Guadeloupe shares a common origin with those in Barbados and New Caledonia, while Angiostrongylus cantonensis in Guadeloupe shares a common origin with those in Brazil, Hawaii and Japan.
Topics: Adult; Rats; Humans; Animals; Angiostrongylus cantonensis; Phylogeny; Guadeloupe; Cytochromes b; Snails; Brazil; Strongylida Infections; Angiostrongylus
PubMed: 37563598
DOI: 10.1186/s13071-023-05872-4 -
Genes Nov 2023A mutant, Δ, was generated to functionally characterize Sll1252. Δ exhibited a slow-growth phenotype at 70 µmol photons m s and glucose sensitivity. In Δ, the rate...
A mutant, Δ, was generated to functionally characterize Sll1252. Δ exhibited a slow-growth phenotype at 70 µmol photons m s and glucose sensitivity. In Δ, the rate of PSII activity was not affected, whereas the whole chain electron transport activity was reduced by 45%. The inactivation of led to the upregulation of genes, which were earlier reported to be induced in DBMIB-treated wild-type, suggesting that Sll1252 may be involved in electron transfer from the reduced-PQ pool to Cyt . The inhibitory effect of DCMU on PSII activity was similar in both wild-type and Δ. However, the concentration of DBMIB for 50% inhibition of whole chain electron transport activity was 140 nM for Δ and 300 nM for wild-type, confirming the site of action of Sll1252. Moreover, the elevated level of the reduced-PQ pool in Δ supports that Sll1252 functions between the PQ pool and Cyt . Interestingly, we noticed that Δ reverted to wild-type phenotype by insertion of natural transposon, ISY523, at the disruption site. Δ, expressing only the C-terminal region of Sll1252, exhibited a slow-growth phenotype and disorganized thylakoid structure compared to wild-type and Δ (expressing only the N-terminal region). Collectively, our data suggest that Sll1252 regulates electron transfer between the PQ pool and the Cyt complex in the linear photosynthetic electron transport chain via coordinated function of both the N- and C-terminal regions of Sll1252.
Topics: Electron Transport; Cytochromes b; Synechocystis; Oxidation-Reduction; Cytochrome b6f Complex; Plastoquinone
PubMed: 38136973
DOI: 10.3390/genes14122151 -
BMC Genomics Aug 2023The Mongolian gazelle (Procapra gutturosa) population has shown a considerable range of contractions and local extinctions over the last century, owing to habitat...
BACKGROUND
The Mongolian gazelle (Procapra gutturosa) population has shown a considerable range of contractions and local extinctions over the last century, owing to habitat fragmentation and poaching. A thorough understanding of the genetic diversity and structure of Mongolian gazelle populations in fragmented habitats is critical for planning effective conservation strategies.
RESULT
In this study, we used eight microsatellite loci and mitochondrial cytochrome b (Cytb) to compare the levels of genetic diversity and genetic structure of Mongolian gazelle populations in the Hulun Lake National Nature Reserve (HLH) with those in the China-Mongolia border area (BJ). The results showed that the nucleotide diversity and observed heterozygosity of the HLH population were lower than those of the BJ population. Moreover, the HLH and BJ populations showed genetic differentiation. We concluded that the HLH population had lower genetic diversity and a distinct genetic structure compared with the BJ population.
CONCLUSION
The genetic diversity of fragmented Mongolian gazelle populations, can be improved by protecting these populations while reinforcing their gene exchange with other populations. For example, attempts can be made to introduce new individuals with higher genetic diversity from other populations to reduce inbreeding.
Topics: Humans; Animals; Antelopes; China; Cytochromes b; Genetic Drift; Genetic Variation
PubMed: 37648967
DOI: 10.1186/s12864-023-09574-0 -
Parasites & Vectors Oct 2023Protozoan parasites of the genus Eimeria are the causative agents of chicken coccidiosis. Parasite resistance to most anticoccidial drugs is one of the major challenges...
BACKGROUND
Protozoan parasites of the genus Eimeria are the causative agents of chicken coccidiosis. Parasite resistance to most anticoccidial drugs is one of the major challenges to controlling this disease. There is an urgent need for a molecular marker to monitor the emergence of resistance against anticoccidial drugs, such as decoquinate.
METHODS
We developed decoquinate-resistant strains by successively exposing the Houghton (H) and Xinjiang (XJ) strains of E. tenella to incremental concentrations of this drug in chickens. Additionally, we isolated a decoquinate-resistant strain from the field. The resistance of these three strains was tested using the criteria of weight gain, relative oocyst production and reduction of lesion scores. Whole-genome sequencing was used to identify the non-synonymous mutations in coding genes that were highly associated with the decoquinate-resistant phenotype in the two laboratory-induced strains. Subsequently, we scrutinized the missense mutation in a field-resistant strain for verification. We also employed the AlphaFold and PyMOL systems to model the alterations in the binding affinity of the mutants toward the drug molecule.
RESULTS
We obtained two decoquinate-resistant (DecR) strains, DecR_H and XJ, originating from the original H and XJ strains, respectively, as well as a decoquinate-resistant E. tenella strain from the field (DecR_SC). These three strains displayed resistance to 120 mg/kg decoquinate administered through feed. Through whole-genome sequencing analysis, we identified the cytochrome b gene (cyt b; ETH2_MIT00100) as the sole mutated gene shared between the DecR_H and XJ strains and also detected this gene in the DecR_SC strain. Distinct non-synonymous mutations, namely Gln131Lys in DecR_H, Phe263Leu in DecR_XJ, and Phe283Leu in DecR_SC were observed in the three resistant strains. Notably, these mutations were located in the extracellular segments of cyt b, in close proximity to the ubiquinol oxidation site Q. Drug molecular docking studies revealed that cyt b harboring these mutants exhibited varying degrees of reduced binding ability to decoquinate.
CONCLUSIONS
Our findings emphasize the critical role of cyt b mutations in the development of decoquinate resistance in E. tenella. The strong correlation observed between cyt b mutant alleles and resistance indicates their potential as valuable molecular markers for the rapid detection of decoquinate resistance.
Topics: Animals; Eimeria tenella; Decoquinate; Cytochromes b; Parasites; Chickens; Mutation, Missense; Molecular Docking Simulation; Drug Resistance; Coccidiosis; Mutation; Poultry Diseases
PubMed: 37848977
DOI: 10.1186/s13071-023-05988-7