Search Results (347)

Parkinson’s disease (PD) is a prevalent neurodegenerative disease for which no effective treatment currently exists. In this study, we identified formononetin (FMN), a neuroprotective component found in herbal medicines such as Astragalus membranaceus and Glycyrrhiza uralensis, as a potential agent targeting multiple pathways involved in PD. To investigate the anti-PD effects of FMN, we employed Caenorhabditis elegans (C. elegans) PD models, specifically the transgenic strain NL5901 and the MPP(+)-induced strain BZ555, to investigate the effects of FMN on the key pathological features of PD, including dyskinesia, dopamine neuron damage, and reactive oxygen species (ROS) accumulation. The MPP(+)-induced SH-SY5Y cell PD model was utilized to evaluate the effects of FMN on cell viability, ROS accumulation, and mitochondrial dysfunction. The signaling pathway induced by FMN was analyzed using transcriptomic techniques and subsequently validated in vitro. Our results indicate that FMN significantly reduced ROS accumulation and improved both dopaminergic neuron vitality and dyskinesia in the C. elegans PD models. In the cell PD model, FMN significantly reduced ROS accumulation and enhanced mitochondrial membrane potential (MMP) and cell viability. A transcriptomic analysis suggested that the effects of FMN are associated with Nrf2 activation. Furthermore, ML385, a specific Nrf2 inhibitor, blocked the beneficial effects of FMN in vitro, indicating that FMN ameliorates dyskinesia and protects dopaminergic neurons through Nrf2 signaling pathway activation. In addition, the effects of FMN on ameliorating dyskinesia and protecting dopamine neurons were comparable to those of the Nrf2 agonist of sulforaphane (SFN) in vivo. The results of this study confirm that FMN exerts significant anti-PD effects primarily through the Nrf2 signaling pathway. These findings provide crucial insights for the development of anti-PD therapies. Full article

The primary cause of postharvest loss in table grape fruit is attributed to gray mold, which is caused by Botrytis cinerea. The present study confirmed the inhibitory effects of nystatin on the growth and development of B. cinerea, which led to a remarkable reduction in the severity of gray mold on table grape fruits. Furthermore, the application of nystatin disrupted the membrane permeability of B. cinerea, causing increased cellular leakage and cell death. In addition, the transcriptome analysis showed that the application of nystatin effectively modulated the transcriptional profile of genes involved in ribosome and mitochondrion biogenesis, as well as oxidoreductase activity, thereby disrupting the homeostasis of cellular organelles. Moreover, the nystatin treatment down-regulated genes associated with membrane trafficking, protein degradation by the ubiquitin–proteasome system, and the autophagy process, ultimately attenuating the pathogenicity of B. cinerea. Collectively, nystatin can be considered a viable agent for managing gray mold on table grape fruit. Full article

Retinal pigment epithelial (RPE) is an oxidation-resistant cell. But if it is subjected to various harmful stimuli for a prolonged period, an excessive amount of oxyradical will be generated to cause retinal dysfunction. We investigated and elucidated the protective mechanism of Sea buckthorn proanthocyanidins (SBP) against oxidative damage in RPE. In this study, we established an oxidative damage model of adult retinal pigment epithelial cell line-19 (ARPE-19) using hydrogen peroxide (H₂O₂), followed by different concentrations of SBP for 24 h. The finding demonstrated that SBP effectively inhibited the generation of malondialdehyde (MDA), restored the activity of superoxide dismutase (SOD) and content of glutathione (GSH), and significantly eliminated the level of reactive oxygen species (ROS) and oxidative stress. It was revealed that 100 µg/mL of SBP was more suitable for restoring oxidative damage in ARPE-19, which enhanced cell activity and migration ability and maintained normal cell morphology. In addition, SBP increased the expression of Bcl-2, decreased the expression of Bax and caspase-3, and activated the Nrf2/HO-1 signaling pathway to protect ARPE-19 from oxidative stress. Moreover, SBP could restore the morphology and quantity of mitochondria and inhibit mitochondrial permeability and swelling. The present results provide a theoretical basis for the protective and restorative effect of SBP in retinopathy caused by oxidative stress. Full article

Leishmaniasis encompasses a group of neglected diseases caused by flagellated protozoa belonging to the Leishmania genus, associated with high morbidity and mortality. The search for compounds with anti-Leishmania activity that exhibit lower toxicity and can overcome the emergence of resistant strains remains a significant goal. In this context, the calpain inhibitor MDL28170 has previously demonstrated deleterious effects against promastigote forms of Leishmania amazonensis, which led us to investigate its role on axenic amastigote forms. The calpain inhibitor MDL28170 was able to decrease the viability of amastigotes in a typically dose-dependent manner. The treatment with the IC₅₀ dose (13.5 μM) for 72 h led to significant amastigote lysis and increased cell-to-cell aggregation. Ultrastructural analysis revealed several cellular alterations, including disruption of the trans-Golgi network and the formation of autophagosomes when treated with MDL28170 at ½ × IC₅₀ dose. Additionally, mitochondrial swelling and the formation of concentric membranous structures inside the mitochondrion were observed after incubation with the IC₅₀ dose. These results reinforce the potential application of the calpain inhibitor MDL28170 against L. amazonensis, highlighting its effectiveness and possible mechanism of action against the parasite. Full article

The plasticity elongation of mesocotyl (MES) and coleoptile (COL) largely determines the morphology of maize seedlings under abiotic stresses. The profilin (PRF) proteins play a pivotal role in cytoskeleton dynamics and plant development via regulating actin polymerization. However, little is known about whether and how the expression of the ZmPRF gene family regulates MES and COL elongation in maize under adverse abiotic stresses. Here, a total of eight ZmPRF gene members were identified in the maize genome. They were mainly located in the cytoplasm, chloroplast, and mitochondrion, and clearly divided into four classes, based on phylogenetic analysis. Segmental duplication was the main driver for the expansion of ZmPRF genes. Ka/Ks analysis indicated that most ZmPRF genes were intensely purified and selected. Promoter cis-element analysis suggested their potential roles in response to growth and development, stress adaption, hormone response, and light response. The protein–protein interaction network and two independent RNA-sequencing analyses revealed that eight ZmPRF genes and their thirty-seven interacting genes showed varied expression patterns in MES and COL of three maize genotypes under different sowing depths, 24-epibrassinolide application, and light spectral-quality treatments, of which ZmPRF3.3 was a potential core conserved gene for breeding application. Moreover, the quantitative real-time PCR (qRT-PCR) verified that the relative expression levels of most ZmPRF genes in MES and COL under above treatments were significantly correlated with the plasticity elongation of MES and COL in maize. Therefore, these results perform a comprehensive overview of the ZmPRF family and will provide valuable information for the validation of the function of ZmPRF genes in maize development under diverse abiotic stress. Full article

Photosynthetic eukaryotes have metabolic pathways that occur in distinct subcellular compartments. However, because metabolites synthesized in one compartment, including fixed carbon compounds and reductant generated by photosynthetic electron flows, may be integral to processes in other compartments, the cells must efficiently move metabolites among the different compartments. This review examines the various photosynthetic electron flows used to generate ATP and fixed carbon and the trafficking of metabolites in the green alga Chlamydomomas reinhardtii; information on other algae and plants is provided to add depth and nuance to the discussion. We emphasized the trafficking of metabolites across the envelope membranes of the two energy powerhouse organelles of the cell, the chloroplast and mitochondrion, the nature and roles of the major mobile metabolites that move among these compartments, and the specific or presumed transporters involved in that trafficking. These transporters include sugar-phosphate (sugar-P)/inorganic phosphate (Pi) transporters and dicarboxylate transporters, although, in many cases, we know little about the substrate specificities of these transporters, how their activities are regulated/coordinated, compensatory responses among transporters when specific transporters are compromised, associations between transporters and other cellular proteins, and the possibilities for forming specific ‘megacomplexes’ involving interactions between enzymes of central metabolism with specific transport proteins. Finally, we discuss metabolite trafficking associated with specific biological processes that occur under various environmental conditions to help to maintain the cell’s fitness. These processes include C4 metabolism in plants and the carbon concentrating mechanism, photorespiration, and fermentation metabolism in algae. Full article

Gaillardia pulchella is an important plant species with pharmacological and ornamental applications. It contains a wide array of phytocompounds which play roles against diseases. In vitro propagation requires callogenesis and differentiation of plant organs, which offers a sustainable, alternative synthesis of compounds. The morphogenetic processes and the underlying mechanisms are, however, known to be under genetic regulation and are little understood. The present study investigated these events by generating transcriptome data, with de novo assembly of sequences to describe shoot morphogenesis molecularly in G. pulchella. The RNA was extracted from the callus of pre- and post-shoot organogenesis time. The callus induction was optimal using leaf segments cultured onto MS medium containing α-naphthalene acetic acid (NAA; 2.0 mg/L) and 6-benzylaminopurine (BAP; 0.5 mg/L) and further exhibited a high shoot regeneration/caulogenesis ability. A total of 68,366 coding sequences were obtained using Illumina150bpPE sequencing and transcriptome assembly. Differences in gene expression patterns were noted in the studied samples, showing opposite morphogenetic responses. Out of 10,108 genes, 5374 (53%) were downregulated, and there were 4734 upregulated genes, representing 47% of the total genes. Through the heatmap, the top 100 up- and downregulating genes’ names were identified and presented. The up- and downregulated genes were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Important pathways, operative during G. pulchella shoot organogenesis, were signal transduction (13.55%), carbohydrate metabolism (8.68%), amino acid metabolism (5.11%), lipid metabolism (3.75%), and energy metabolism (3.39%). The synthesized proteins displayed phosphorylation, defense response, translation, regulation of DNA-templated transcription, carbohydrate metabolic processes, and methylation activities. The genes’ product also exhibited ATP binding, DNA binding, metal ion binding, protein serine/threonine kinase -, ATP hydrolysis activity, RNA binding, protein kinase, heme and GTP binding, and DNA binding transcription factor activity. The most abundant proteins were located in the membrane, nucleus, cytoplasm, ribosome, ribonucleoprotein complex, chloroplast, endoplasmic reticulum membrane, mitochondrion, nucleosome, Golgi membrane, and other organellar membranes. These findings provide information for the concept of molecular triggers, regulating programming, differentiation and reprogramming of cells, and their uses. Full article

Age-related macular degeneration (AMD) is marked by a progressive loss of central vision and is the third leading cause of irreversible blindness worldwide. The exact mechanisms driving the progression of this macular degenerative condition remain elusive, and as of now, there are no available preventative measures for dry AMD. According to ancient records, ginseng affects the eyes by brightening them and enhancing wisdom. Modern pharmacological research shows that the active ingredients in ginseng, ginsenosides, may be used to prevent or improve eye diseases that threaten vision. Some articles have reported that ginsenoside Rg3 can treat diabetic retinopathy in mice, but no reports exist on its effects and mechanisms in AMD. Therefore, the role and mechanism of ginsenoside Rg3 in AMD warrant further study. This study aims to investigate the effects of Rg3 on AMD and its underlying molecular mechanisms. We established a mouse model of AMD to examine the impact of ginsenoside Rg3 on NaIO₃-induced apoptosis in the retina and to explore the related intrinsic mechanisms. The in vivo results indicated that ginsenoside Rg3 prevents NaIO₃-induced apoptosis in retinal pigment epithelial cells by inhibiting reactive oxygen species production and preventing the reduction in mitochondrial membrane potential. Additionally, we assessed the levels of protein expression within the apoptosis pathway. Ginsenoside Rg3 decreased the expression of Bax, cleaved caspase-3, and cleaved caspase-9 proteins. Additionally, it increased the expression of Bcl-2 by decreasing P-JNK levels. Moreover, our in vivo results showed that ginsenoside Rg3 enhanced retinal structure, increased the relative thickness of the retina, and decreased the extent of disorganization in both the inner and outer nuclear layers. Ginsenoside Rg3 may safeguard the retina against NaIO₃-induced cell apoptosis by attenuating reactive-oxygen-species-mediated mitochondrial dysfunction, in which the JNK signaling pathway is also involved. These findings suggest that ginsenoside Rg3 has the potential to prevent or attenuate the progression of AMD and other retinal pathologies associated with NaIO₃-mediated apoptosis. Full article

Apolipoprotein-L1 (APOL1) is a membrane-interacting protein induced by inflammation, which confers human resistance to infection by African trypanosomes. APOL1 kills Trypanosoma brucei through induction of apoptotic-like parasite death, but two T. brucei clones acquired resistance to APOL1, allowing them to cause sleeping sickness. An APOL1 C-terminal sequence alteration, such as occurs in natural West African variants G1 and G2, restored human resistance to these clones. However, APOL1 unfolding induced by G1 or G2 mutations enhances protein hydrophobicity, resulting in kidney podocyte dysfunctions affecting renal filtration. The mechanism involved in these dysfunctions is debated. The ability of APOL1 to generate ion pores in trypanosome intracellular membranes or in synthetic membranes was provided as an explanation. However, transmembrane insertion of APOL1 strictly depends on acidic conditions, and podocyte cytopathology mainly results from secreted APOL1 activity on the plasma membrane, which occurs under non-acidic conditions. In this review, I argue that besides inactivation of APOL3 functions in membrane dynamics (fission and fusion), APOL1 variants induce inflammation-linked podocyte toxicity not through pore formation, but through plasma membrane disturbance resulting from increased interaction with cholesterol, which enhances cation channels activity. A natural mutation in the membrane-interacting domain (N264K) abrogates variant APOL1 toxicity at the expense of slightly increased sensitivity to trypanosomes, further illustrating the continuous mutual adaptation between host and parasite. Full article

Background: T-cell-based adoptive cell therapies have emerged at the forefront of cancer immunotherapies; however, failed long-term survival and inevitable exhaustion of transplanted T lymphocytes in vivo limits clinical efficacy. Leukemia blasts possess enhanced glycolysis (Warburg effect), exploiting their microenvironment to deprive nutrients (e.g., glucose) from T cells, leading to T-cell dysfunction and leukemia progression. Methods: Thus, we explored whether genetic reprogramming of T-cell metabolism could improve their survival and empower T cells with a competitive glucose-uptake advantage against blasts and inhibit their uncontrolled proliferation. Results: Here, we discovered that high-glucose concentration reduced the T-cell expression of glucose transporter GLUT1 (SLC2A1) and TFAM (mitochondrion transcription factor A), an essential transcriptional regulator of mitochondrial biogenesis, leading to their impaired expansion ex vivo. To overcome the glucose-induced genetic deficiency in metabolism, we engineered T cells with lentiviral overexpression of SLC2A1 and/or TFAM transgene. Multi-omics analyses revealed that metabolic reprogramming promoted T-cell proliferation by increasing IL-2 release and reducing exhaustion. Moreover, the engineered T cells competitively deprived glucose from allogenic blasts and lessened leukemia burden in vitro. Conclusions: Our findings propose a novel T-cell immunotherapy that utilizes a dual strategy of starving blasts and cytotoxicity for preventing uncontrolled leukemia proliferation. Full article

The bread wheat cultivar (Triticum aestivum L. cv. Sagittario) as a parental line and its mutant, drought-tolerant lines (Mutant lines 4 and 5) were subjected to polyethylene glycol (PEG)-induced drought. Drought stress resulted in decreased chlorophyll levels and the accumulation of proline and TBARS, despite increases in activities of catalase, peroxidase, and superoxide dismutase enzymes. Transcription of the genes encoding these enzymes and delta-1-pyrroline 5-carboxylase synthetase was induced by drought. 2-DE gel electrophoresis analysis identified differentially expressed proteins (DEPs) in the mutant lines, which are distinguished by “chloroplast”, “mitochondrion”, “pyruvate dehydrogenase complex”, and “homeostatic process” terms. The drought tolerance of the mutant lines might be attributed to improved photosynthesis, efficient ATP synthesis, and modified antioxidant capacity. In addition to proteomics data, the drought tolerance of wheat genotypes might also be assessed by chlorophyll content and TaPOX gene expression. To our knowledge, this is the first proteomic analysis of gamma-induced mutants of bread wheat. These findings are expected to be utilized in plant breeding studies. Full article

Chlorellacean members are common in aquatic or subaerial habitats, and many of them have significant economic value. Taxonomic reports and organelle genome data for the Nannochloris clade, an important subgroup within this family, are limited, hindering the understanding and exploitation of this clade. In this study, a fusiform-celled strain, FACHB-3607, was isolated from a pond in China. Through examination of morphological characteristics and phylogenetic analyses of rbcL, 18S rDNA, and ITS, it was identified as a new species within the Nannochloris clade, named Koliella bifissiva sp. nov. In addition, this study provided a first insight into the organellar genomes of the genus Koliella. The K. bifissiva chloroplast had a 99.8 kb genome, and the mitochondrion had a 40.8 kb genome, which are moderate sizes within the Nannochloris clade. Phylogenomic analysis showed that K. bifissiva is most closely related to Nannochloris sp. “desiccata”, followed by Marvania. In contrast, Picochlorum was the most distantly related species. The organelle genomes of the Nannochloris clade display dynamic evolution, reflected in variations in genome size, gene content and order, and selection pressure. This research enhances our knowledge of species diversity and evolutionary history in the Nannochloris clade. Full article

The Plasmodium falciparum mitochondrial electron transport chain (mETC) is responsible for essential metabolic pathways such as de novo pyrimidine synthesis and ATP synthesis. The mETC complex III (cytochrome bc₁ complex) is responsible for transferring electrons from ubiquinol to cytochrome c and generating a proton gradient across the inner mitochondrial membrane, which is necessary for the function of ATP synthase. Recent studies have revealed that the composition of Plasmodium falciparum complex III (PfCIII) is divergent from humans, highlighting its suitability as a target for specific inhibition. Indeed, PfCIII is the target of the clinically used anti-malarial atovaquone and of several inhibitors undergoing pre-clinical trials, yet its role in parasite biology has not been thoroughly studied. We provide evidence that the universally conserved subunit, PfRieske, and the new parasite subunit, PfC3AP2, are part of PfCIII, with the latter providing support for the prediction of its divergent composition. Using inducible depletion, we show that PfRieske, and therefore, PfCIII as a whole, is essential for asexual blood stage parasite survival, in line with previous observations. We further found that depletion of PfRieske results in gametocyte maturation defects. These phenotypes are linked to defects in mitochondrial functions upon PfRieske depletion, including increased sensitivity to mETC inhibitors in asexual stages and decreased cristae abundance alongside abnormal mitochondrial morphology in gametocytes. This is the first study that explores the direct role of the PfCIII in gametogenesis via genetic disruption, paving the way for a better understanding of the role of mETC in the complex life cycle of these important parasites and providing further support for the focus of antimalarial drug development on this pathway. Full article

Background and Objectives: Atherosclerosis is one of the main reasons for cardiovascular disease development. This study aimed to analyze the association of mtDNA mutations and atherosclerotic plaques in carotid arteries of patients with atherosclerosis and conditionally healthy study participants from the Novosibirsk region. Methods: PCR fragments of DNA containing the regions of 10 investigated mtDNA mutations were pyrosequenced. The heteroplasmy levels of mtDNA mutations were analyzed using a quantitative method based on pyrosequencing technology developed by M. A. Sazonova and colleagues. Results: In the analysis of samples of patients with atherosclerotic plaques of the carotid arteries and conditionally healthy study participants from the Novosibirsk region, four proatherogenic mutations in the mitochondrial genome (m.5178C>A, m.652delG, m.12315G>A and m.3256C>T) and three antiatherogenic mutations in mtDNA (m.13513G>A, m.652insG, and m.14846G>A) were detected. A west–east gradient was found in the distribution of the mtDNA mutations m.5178C>A, m.3256C>T, m.652insG, and m.13513G>A. Conclusions: Therefore, four proatherogenic mutations in the mitochondrial genome (m.5178C>A, m.652delG, m.12315G>A, and m.3256C>T) and three antiatherogenic mutations in mtDNA (m.13513G>A, m.652insG, and m.14846G>A) were detected in patients with atherosclerotic plaques in their carotid arteries from the Novosibirsk region. Full article

Acute myeloid leukemia (AML) has a poor survival rate for both pediatric and adult patients due to its frequent relapse. To elucidate the bioenergetic principle underlying AML relapse, we investigated the transcriptional regulation of mitochondrial–nuclear dual genomes responsible for metabolic plasticity in treatment-resistant blasts. Both the gain and loss of function results demonstrated that NFκB2, a noncanonical transcription factor (TF) of the NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) family, can control the expression of TFAM (mitochondrial transcription factor A), which is known to be essential for metabolic biogenesis. Furthermore, genetic tracking and promoter assays revealed that NFκB2 is in the mitochondria and can bind the specific “TTGGGGGGTG” region of the regulatory D-loop domain to activate the light-strand promoter (LSP) and heavy-strand promoter 1 (HSP1), promoters of the mitochondrial genome. Based on our discovery of NFκB2′s novel function of regulating mitochondrial–nuclear dual genomes, we explored a novel triplet therapy including inhibitors of NFκB2, tyrosine kinase, and mitochondrial ATP synthase that effectively eliminated primary AML blasts with mutations of the FMS-related receptor tyrosine kinase 3 (FLT3) and displayed minimum toxicity to control cells ex vivo. As such, effective treatments for AML must include strong inhibitory actions on the dual genomes mediating metabolic plasticity to improve leukemia prognosis. Full article