RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Gelsemium dynamized dilutions (GDD) are known as a remedy for a wide range of behavioral and psychological symptoms of depression and anxiety at ultra-low doses, yet the underlying mechanisms of the mode of action of G. sempervirens itself are not well understood. AIM OF THE STUDY: The present study was designed to examine the neuroprotective effects of Gelsemium preparations in counteracting stress-related mitochondrial dysfunctions in neuronal cells. MATERIALS AND METHODS: We started by studying how serum deprivation affects the mitochondrial functions of human neuroblastoma (SH-SY5Y) cells. Next, we looked into the potential of various Gelsemium dilutions to improve cell survival and ATP levels. After identifying the most effective dilutions, 3C and 5C, we tested their ability to protect SH-SY5Y cells from stress-induced mitochondrial deficits. We measured total and mitochondrial superoxide anion radicals using fluorescent dyes dihydroethidium (DHE) and the red mitochondrial superoxide indicator (MitoSOX). Additionally, we assessed total nitric oxide levels with 4,5-diaminofluorescein diacetate (DAF-2DA), examined the redox state using pRA305 cells stably transfected with a plasmid encoding a redox-sensitive green fluorescent protein, and analyzed mitochondrial network morphology using an automated high-content analysis device, Cytation3. Furthermore, we investigated bioenergetics by measuring ATP production with a bioluminescence assay (ViaLighTM HT) and evaluated mitochondrial respiration (OCR) and glycolysis (ECAR) using the Seahorse Bioscience XF24 Analyzer. Finally, we determined cell survival using an MTT reduction assay. RESULTS: Our research indicates that Gelsemium dilutions (3C and 5C) exhibited neuroprotective effects by: - Normalizing total and mitochondrial superoxide anion radicals and total nitric oxide levels. - Regulating the mitochondrial redox environment and mitochondrial networks morphology. - Increasing ATP generation as well as OCR and ECAR levels, thereby reducing the viability loss induced by serum withdrawal stress. CONCLUSIONS: These findings highlight that dynamized Gelsemium preparations may have neuroprotective effects against stress-induced cellular changes in the brain by regulating mitochondrial functions, essential for the survival, plasticity, and function of neurons in depression.

Asunto(s)

RESUMEN

Calcium ions (Ca2+) play pivotal roles in regulating numerous cellular functions, including metabolism and growth, in normal and cancerous cells. Consequently, Ca2+ signaling is a vital determinant of cell fate and influences both cell survival and death. These intracellular signals are susceptible to modulation by various factors, including changes in the extracellular environment, which leads to mechanical alterations. However, the effect of extracellular matrix (ECM) stiffness variations on intracellular Ca2+ signaling remains underexplored. In this study, we aimed to elucidate the mechanisms of Ca2+ regulation through the mitochondria, which are crucial to Ca2+ homeostasis. We investigated how Ca2+ regulatory mechanisms adapt to different levels of ECM stiffness by simultaneously imaging the mitochondria and endoplasmic reticulum (ER) in live cells using genetically encoded biosensors. Our findings revealed that the uptake of mitochondrial Ca2+ through Voltage-Dependent Anion Channel 1 (VDAC1), facilitated by intracellular tubulin, is influenced by ECM stiffness. Unraveling these Ca2+ regulatory mechanisms under various conditions offers a novel perspective for advancing biomedical studies involving Ca2+ signaling.

RESUMEN

Currently, no specific treatment exists to alleviate metabolic dysfunction-associated fatty liver (MAFLD). Previously, Poria cocos (PC) effectively relieved MAFLD, but its bioactive components are still unknown. The bioactive substances in PC that regulate mitochondria function to alleviate MAFLD were thus determined. The L02 hepatocyte model induced by fat emulsion and the MAFLD rat model induced by a high-fat diet (HFD) were developed to explore the efficacy of PC against MAFLD. The activity of PC-derived components in the liver mitochondria of HFD-fed rats was evaluated using the L02 hepatocyte model. Additionally, the PC-derived components from the liver mitochondria were identified by ultra-high performance liquid chromatography/mass spectrometry. Finally, the anti-steatosis ability of PC-derived monomers and monomers groups was evaluated using the adipocyte model. PC maintained the mitochondrial ultrastructure, alleviated mitochondrial oxidative stress, and regulated the energy metabolism and the fatty acid ß oxidation to relieve lipid emulsion-induced cellular steatosis and HFD-induced MAFLD. PC-derived components entering the liver mitochondria inhibited oxidative stress injury and improved the energy metabolism to fight cellular steatosis. Additionally, 15 chemicals were identified in the PC-treated rat liver mitochondria. These identified chemical molecules and molecule groups in the mitochondria prevented cellular steatosis by regulating mitochondrial oxidative stress and energy metabolism. PC restores mitochondrial structure and function, alleviating MAFLD, which is related to oxidative stress, energy metabolism, and fatty acid ß oxidation. The identified 15 components may be the main effective PC components regulating mitochondria function to alleviate MAFLD. Thus, PC may be a promising mitochondrial regulator to prevent MAFLD.

RESUMEN

Background: Non-steroidal anti-inflammatory drugs (NSAIDs), such as diclofenac (DCF), form a significant group of environmental contaminants. When the toxic effects of DCF on plants are analyzed, authors often focus on photosynthesis, while mitochondrial respiration is usually overlooked. Therefore, an in vivo investigation of plant mitochondria functioning under DCF treatment is needed. In the present work, we decided to use the green alga Chlamydomonas reinhardtii as a model organism. Methods: Synchronous cultures of Chlamydomonas reinhardtii strain CC-1690 were treated with DCF at a concentration of 135.5 mg × L-1, corresponding to the toxicological value EC50/24. To assess the effects of short-term exposure to DCF on mitochondrial activity, oxygen consumption rate, mitochondrial membrane potential (MMP) and mitochondrial reactive oxygen species (mtROS) production were analyzed. To inhibit cytochrome c oxidase or alternative oxidase activity, potassium cyanide (KCN) or salicylhydroxamic acid (SHAM) were used, respectively. Moreover, the cell's structure organization was analyzed using confocal microscopy and transmission electron microscopy. Results: The results indicate that short-term exposure to DCF leads to an increase in oxygen consumption rate, accompanied by low MMP and reduced mtROS production by the cells in the treated populations as compared to control ones. These observations suggest an uncoupling of oxidative phosphorylation due to the disruption of mitochondrial membranes, which is consistent with the malformations in mitochondrial structures observed in electron micrographs, such as elongation, irregular forms, and degraded cristae, potentially indicating mitochondrial swelling or hyper-fission. The assumption about non-specific DCF action is further supported by comparing mitochondrial parameters in DCF-treated cells to the same parameters in cells treated with selective respiratory inhibitors: no similarities were found between the experimental variants. Conclusions: The results obtained in this work suggest that DCF strongly affects cells that experience mild metabolic or developmental disorders, not revealed under control conditions, while more vital cells are affected only slightly, as it was already indicated in literature. In the cells suffering from DCF treatment, the drug influence on mitochondria functioning in a non-specific way, destroying the structure of mitochondrial membranes. This primary effect probably led to the mitochondrial inner membrane permeability transition and the uncoupling of oxidative phosphorylation. It can be assumed that mitochondrial dysfunction is an important factor in DCF phytotoxicity. Because studies of the effects of NSAIDs on the functioning of plant mitochondria are relatively scarce, the present work is an important contribution to the elucidation of the mechanism of NSAID toxicity toward non-target plant organisms.

Asunto(s)

RESUMEN

Parkinson's disease (PD) is a prevalent and intricate neurological condition resulting from a combination of several factors, such as genetics, environment, and the natural process of aging. Degeneration of neurons in the substantia nigra pars compacta (SN) can cause motor and non-motor impairments in patients with PD. In PD's etiology, inflammation and mitochondrial dysfunction play significant roles in the disease's development. Studies of individuals with PD have revealed increased inflammation in various brain areas. Furthermore, mitochondrial dysfunction is an essential part of PD pathophysiology. Defects in the components of the mitochondrial nucleus, its membrane or internal signaling pathways, mitochondrial homeostasis, and morphological alterations in peripheral cells have been extensively documented in PD patients. According to these studies, neuroinflammation and mitochondrial dysfunction are closely connected as pathogenic conditions in neurodegenerative diseases like PD. Given the mitochondria's role in cellular homeostasis maintenance in response to membrane structural flaws or mutations in mitochondrial DNA, their dynamic nature may present therapeutic prospects in this area. Recent research investigates mitochondrial transplantation as a potential treatment for Parkinson's disease in damaged neurons. This review delves into the impact of inflammation and mitochondrial dysfunction on PD occurrence, treatment approaches, and the latest developments in mitochondrial transplantation, highlighting the potential consequences of these discoveries.

RESUMEN

Sarcopenia, the progressive loss of muscle mass and function, universally affects older adults and is closely associated with frailty and reduced quality of life. Despite the inevitable consequences of sarcopenia and its relevance to healthspan, no pharmacological therapies are currently available. Ghrelin is a gut-released hormone that increases appetite and body weight through acylation. Acylated ghrelin activates its receptor, growth hormone secretagogue receptor 1a (GHSR1a), in the brain by binding to it. Studies have demonstrated that acyl and unacylated ghrelin (UnAG) both have protective effects against acute pathological conditions independent of receptor activation. Here, we investigated the long-term effects of UnAG in age-associated muscle atrophy and contractile dysfunction in mice. Four-month-old and 18-month-old mice were subjected to either UnAG or control treatment for 10 months. UnAG did not affect food consumption or body weight. Gastrocnemius and quadriceps muscle weights were reduced by 20%-30% with age, which was partially protected against by UnAG. Specific force, force per cross-sectional area, measured in isolated extensor digitorum longus muscle was diminished by 30% in old mice; however, UnAG prevented the loss of specific force. UnAG also protected from decreases in mitochondrial respiration and increases in hydrogen peroxide generation of skeletal muscle of old mice. Results of bulk mRNA-seq analysis and our contractile function data show that UnAG reversed neuromuscular junction impairment that occurs with age. Collectively, our data revealed the direct role of UnAG in mitigating sarcopenia in mice, independent of food consumption or body weight, implicating UnAG treatment as a potential therapy against sarcopenia.

RESUMEN

Parkinson's disease (PD) stands as the second most common neurological disorder after Alzheimer's disease, primarily affecting the elderly population and significantly compromising their quality of life. The precise etiology of PD remains elusive, but recent research has shed light on potential factors, including the formation of α-synuclein aggregates, oxidative stress, neurotransmitter imbalances, and dopaminergic neurodegeneration in the substantia nigra pars compacta (SNpc) region of the brain, culminating in motor symptoms such as bradykinesia, akinesia, tremors, and rigidity. Monoamine oxidase (MAO) is an essential enzyme, comprising two isoforms, MAO-A and MAO-B, responsible for the oxidation of monoamines such as dopamine. Increased MAO-B activity is responsible for decreased dopamine levels in the SNpc region of mid brain which is remarkably associated with the pathogenesis of PD-like manifestations. Inhibitors of MAO-B enhance striatal neuronal responses to dopamine, making them valuable in treating PD, which involves dopamine deficiency. Clinically approved MAO-B inhibitors such as selegiline, L-deprenyl, pargyline, and rasagiline are employed in the management of neurodegenerative conditions associated with PD. Current therapeutic interventions including MAO-B inhibitors for PD predominantly aim to alleviate these motor symptoms but often come with a host of side effects that can be particularly challenging for the patients. While effective, they have limitations, prompting a search for alternative treatments, there is a growing interest in exploring natural products notably flavonoids as potential sources of novel MAO-B inhibitors. In line with that, the present review focuses on natural flavonoids of plant origin that hold promise as potential candidates for the development of novel MAO-B inhibitors. The discussion encompasses both in vitro and in vivo studies, shedding light on their potential therapeutic applications. Furthermore, this review underscores the significance of exploring natural products as valuable reservoirs of MAO-B inhibitors, offering new avenues for drug development and addressing the pressing need for improved treatments in PD-like pathological conditions. The authors of this review majorly explore the neuroprotective potential of natural flavonoids exhibiting notable MAO-B inhibitory activity and additionally multi-targeted approaches in the treatment of PD with clinical evidence and challenges faced in current therapeutic approaches.

Asunto(s)

RESUMEN

The detection of a secondary inorganic phosphate (Pi) resonance, a possible marker of mitochondrial content in vivo, using phosphorus magnetic resonance spectroscopy (31P-MRS), poses technical challenges at 3 Tesla (T). Overcoming these challenges is imperative for the integration of this biomarker into clinical research. To evaluate the repeatability and reliability of measuring resting skeletal muscle alkaline Pi (Pialk) using with 31P-MRS at 3 T. After an initial set of experiments on five subjects to optimize the sequence, resting 31P-MRS of the quadriceps muscles were acquired on two visits (~4 days apart) using an intra-subjects design, from 13 sedentary to moderately active young male and female adults (22 ± 3 years old) within a whole-body 3 T MR system. Measurement variability attributed to changes in coil position, shimming procedure, and spectral analysis were quantified. 31P-MRS data were acquired with a 31P/-proton (1H) dual-tuned surface coil positioned on the quadriceps using a pulse-acquire sequence. Test-retest absolute and relative repeatability was analyzed using the coefficient of variation (CV) and intra-class correlation coefficients (ICC), respectively. After sequence parameter optimization, Pialk demonstrated high intra-subject repeatability (CV: 10.6 ± 5.4%, ICC: 0.80). Proximo-distal change in coil position along the length of the quadriceps introduced Pialk quantitation variability (CV: 28 ± 5%), due to magnetic field inhomogeneity with more distal coil locations. In contrast, Pialk measurement variability due to repeated shims from the same muscle volume (0.40 ± 0.09mM; CV: 6.6%), and automated spectral processing (0.37 ± 0.01mM; CV: 2.3%), was minor. The quantification of Pialk in skeletal muscle via surface coil 31P-MRS at 3 T demonstrated excellent reproducibility. However, caution is advised against placing the coil at the distal part of the quadriceps to mitigate shimming inhomogeneity.

RESUMEN

BACKGROUND: Medium-chain fatty acids (MCFAs) and docosahexaenoic acid (DHA) could affect the occurrence of mild cognitive impairment (MCI). ß-hydroxybutyrate (BHB), mitochondrial DNA copy number (mtDNAcn) and mitochondrial DNA (mtDNA) deletions might be their potential mechanisms. This study aimed to explore the relationship between MCFAs, DHA and MCI, and potential mechanisms. METHODS: This study used data from Tianjin Elderly Nutrition and Cognition (TENC) cohort study, 120 individuals were identified with new onset MCI during follow-up, 120 individuals without MCI were selected by 1:1 matching sex, age, and education levels as the control group from TENC. Conditional logistic regression analysis and mediation effect analysis were used to explore their relationship. RESULTS: Higher serum octanoic acid levels (OR: 0.633, 95% CI: 0.520, 0.769), higher serum DHA levels (OR: 0.962, 95% CI: 0.942, 0.981), and more mtDNAcn (OR: 0.436, 95% CI: 0.240, 0.794) were associated with lower MCI risk, while more mtDNA deletions was associated with higher MCI risk (OR: 8.833, 95% CI: 3.909, 19.960). Mediation analysis suggested that BHB and mtDNAcn, in series, have mediation roles in the association between octanoic acid and MCI risk, and mtDNA deletions have mediation roles in the association between DHA and MCI risk. CONCLUSION: Higher serum octanoic acid and DHA levels were associated with lower MCI risk. Octanoic acid could affect the incidence of MCI through BHB, then mitochondria function, or through mitochondria function, or directly. Serum DHA level could affect the incidence of MCI through mitochondria function, or directly.

RESUMEN

Mitochondria, the powerhouses of the cell, play pivotal roles in cellular processes ranging from energy production to innate immunity. Their unique double-membrane structure typically sequesters mitochondrial DNA (mtDNA) from the rest of the cell. However, under oxidative or immune stress, mtDNA can escape into the cytoplasm, posing a threat as a potential danger signal. The accumulation of cytoplasmic mtDNA can disrupt cellular immune balance and trigger cell death. Our research unveils a novel quality control mechanism, which we term "nucleoid-phagy", that safeguards cellular homeostasis by clearing mislocalized mtDNA. We demonstrate that TFAM, a key protein involved in mtDNA folding and wrapping, accompanies mtDNA into the cytoplasm under stress conditions. Remarkably, TFAM acts as an autophagy receptor, interacting with LC3B to facilitate the autophagic clearance of cytoplasmic mtDNA, thereby preventing the activation of the pro-inflammatory CGAS-STING1 pathway. This study provides unprecedented insights into cytoplasmic mtDNA quality control and offers new perspectives on mitigating inflammatory responses in mitochondrial-related diseases.

RESUMEN

The levels of nicotinamide adenine dinucleotide (NADH) dehydrogenase [ubiquinone] iron-sulfur protein 2 (NDUFS2, a subunit of NADH dehydrogenase) decrease in aged tissues, and these reductions may be partly associated with age-related conditions such as Parkinson's disease. Aging leads to many mitochondrial defects, such as biogenesis disruption, dysfunction, defects in the mitochondrial membrane potential, and production of reactive oxygen species, that may be highly related to NDUFS2 expression. The relationship between NDUFS2 and postovulatory oocyte aging in pigs remains unknown. In this study, we investigated changes in NDUFS2 expression during postovulatory aging (POA). Furthermore, NDUFS2 was knocked down via dsRNA microinjection at the MII stage to evaluate the effects on mitochondrial-related processes during POA. The mRNA expression of NDUFS2 decreased significantly after 48-h aging compared with that in fresh oocytes. NDUFS2 knockdown (KD) significantly impaired the maintenance of oocyte morphology and blastocyst development of embryos after POA. The levels of PGC1α (mitochondrial biogenesis-related proteins) decreased significantly after NDUFS2 KD, while the level of GSNOR, a protein denitrosylase, was reduced by NDUFS2 KD after 48 h of aging. These data suggest that NDUFS2 is vital for maintaining the oocyte quality during POA in pigs.

RESUMEN

Acute pancreatitis (AP) is a common gastrointestinal disease with high morbidity and mortality rate. Unfortunately, neither the etiology nor the pathophysiology of AP are fully understood and causal treatment options are not available. Recently we demonstrated that heparanase (Hpa) is adversely involved in the pathogenesis of AP and inhibition of this enzyme ameliorates the manifestation of the disease. Moreover, a pioneer study demonstrated that Aspirin has partial inhibitory effect on Hpa. Another compound, which possesses a mild pancreato-protective effect against AP, is Trehalose, a common disaccharide. We hypothesized that combination of Aspirin, Trehalose, PG545 (Pixatimod) and SST0001 (Roneparstat), specific inhibitors of Hpa, may exert pancreato-protective effect better than each drug alone. Thus, the current study examines the pancreato-protective effects of Aspirin, Trehalose, PG545 and SST0001 in experimental model of AP induced by cerulein in wild-type (WT) and Hpa over-expressing (Hpa-Tg) mice. Cerulein-induced AP in WT mice was associated with significant rises in the serum levels of lipase (X4) and amylase (X3) with enhancement of pancreatic edema index, inflammatory response, and autophagy. Responses to cerulein were all more profound in Hpa-Tg mice versus WT mice, evident by X7 and X5 folds increase in lipase and amylase levels, respectively. Treatment with Aspirin or Trehalose alone and even more so in combination with PG545 or SST0001 were highly effective, restoring the serum level of lipase back to the basal level. Importantly, a novel newly synthesized compound termed Aspirlose effectively ameliorated the pathogenesis of AP as a single agent. Collectively, the results strongly indicate that targeting Hpa by using anti-Hpa drug combinations constitute a novel therapy for this common orphan disease.

Asunto(s)

RESUMEN

Calorie restriction (CR) is known to confer health benefits, including longevity and disease prevention. Although CR is promising in preventing chronic kidney disease (CKD), its potential impact on the progression of kidney fibrosis from acute kidney injury (AKI) to CKD remains unclear. Here, we present evidence that CR exacerbates renal damage in a mouse model of folic acid (FA)-induced renal fibrosis by altering mitochondrial metabolism and inflammation. Mice subjected to CR (60% of ad libitum) for 3 days were subjected to high dose of FA (250 mg/kg) injection and maintained under CR for an additional week before being sacrificed. Biochemical analyses showed that CR mice exhibited increased kidney injury and fibrosis. RNA sequencing analysis demonstrated decreased electron transport and oxidative phosphorylation (OXPHOS) in CR kidneys with injury, heightened inflammatory, and fibrotic responses. Decreased CR significantly decreased OXPHOS gene and protein levels and reduced ß-oxidation-associated proteins in the kidney. To determine whether defects in mitochondrial metabolism is associated with inflammation in the kidney, further in vitro experiments were performed. NRK52E kidney epithelial cells were treated with antimycin A to induce mitochondrial damage. Antimycin A treatment significantly increased chemokine expression via a STING-dependent pathway. Serum restriction in NRK49F kidney fibroblasts was observed to enhance the fibrotic response induced by TGFß under in vitro conditions. In summary, our results indicate that CR exacerbates fibrosis and inflammatory responses in the kidney by altering mitochondrial metabolism, highlighting the importance of adequate energy supply for an effective response to AKI and fibrosis development.

RESUMEN

Radiation-induced lung injury (RILI) is a prevalent complication of thoracic tumor radiotherapy and accidental radiation exposure. Pyrroloquinoline quinone (PQQ), a novel vitamin B, plays a crucial role in delaying aging, antioxidation, anti-inflammation, and antiapoptosis. This study aims to investigate the protective effect and mechanisms of PQQ against RILI. C57BL/6 mice were exposed to a 20 Gy dose of X-ray radiation on the entire thorax with or without daily oral administration of PQQ for 2 weeks. PQQ effectively mitigated radiation-induced lung tissue damage, inflammation, oxidative stress, and epithelial cell apoptosis. Additionally, PQQ significantly inhibited oxidative stress and mitochondrial damage in MLE-12 cells. Mechanistically, PQQ upregulated the mRNA and protein levels of MOTS-c in irradiated lung tissue and MLE-12 cells. Knockdown of MOTS-c by siRNA substantially attenuated the protective effects of PQQ on oxidative stress, inflammation, and apoptosis. In conclusion, PQQ alleviates RILI by preserving mitochondrial function through a MOTS-c-dependent mechanism, suggesting that PQQ may serve as a promising nutraceutical intervention against RILI.

RESUMEN

An abnormal increase in the expression of nuclear receptor subfamily 6 group A member 1 (NR6A1) in the hippocampus has been reported to result in depressive-like behavior in mice. However, the role of NR6A1 in the progression of neuronal death induced by ischemic stroke remains unknown. In this study, we observed an increase in NR6A1 in neurons in both in vivo and in vitro cerebral ischemic models. We found that knocking down NR6A1 in HT-22 neuronal cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) attenuated mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Conversely, NR6A1 overexpression exacerbated neuronal damage following OGD/R. NR6A1 hindered the transcription of mitonfusin 2 (MFN2), leading to a decrease in its expression. In contrast, MFN2 conferred the protective effect of NR6A1 silencing against both mitochondrial dysfunction and ER stress. In addition, NR6A1 silencing also attenuated brain infarction, ER stress, neuronal apoptosis, and loss of MFN2 in mice subjected to middle cerebral artery occlusion/reperfusion. These findings indicate that NR6A1 is a promising target for the treatment of neuronal death following cerebral ischemia. Furthermore, these results confirm the involvement of MFN2 in the effects of NR6A1 silencing. Therefore, targeting NR6A1 has potential as a viable strategy for the treatment of ischemic stroke.

RESUMEN

BACKGROUND: Trypanosoma cruzi is transmitted to humans by hematophagous bugs belonging to the Triatominae subfamily. Its intra-vectorial cycle is complex and occurs exclusively in the insect's midgut. Dissecting the elements involved in the cross-talk between the parasite and its vector within the digestive tract should provide novel targets for interrupting the parasitic life cycle and affecting vectorial competence. These interactions are shaped by the strategies that parasites use to infect and exploit their hosts, and the host's responses that are designed to detect and eliminate parasites. The objective of the current study is to characterize the impact of T. cruzi establishment within its vector on the dynamics of its midgut. METHODS: In this study, we evaluated the impact of T. cruzi infection on protein expression within the anterior midgut of the model insect Rhodnius prolixus at 6 and 24 h post-infection (hpi) using high-throughput quantitative proteomics. RESULTS: Shortly after its ingestion, the parasite modulates the proteome of the digestive epithelium by upregulating 218 proteins and negatively affecting the expression of 11 proteins involved in a wide array of cellular functions, many of which are pivotal due to their instrumental roles in cellular metabolism and homeostasis. This swift response underscores the intricate manipulation of the vector's cellular machinery by the parasite. Moreover, a more in-depth analysis of proteins immediately induced by the parasite reveals a pronounced predominance of mitochondrial proteins, thereby altering the sub-proteomic landscape of this organelle. This includes various complexes of the respiratory chain involved in ATP generation. In addition to mitochondrial metabolic dysregulation, a significant number of detoxifying proteins, such as antioxidant enzymes and P450 cytochromes, were immediately induced by the parasite, highlighting a stress response. CONCLUSIONS: This study is the first to illustrate the response of the digestive epithelium upon contact with T. cruzi, as well as the alteration of mitochondrial sub-proteome by the parasite. This manipulation of the vector's physiology is attributable to the cascade activation of a signaling pathway by the parasite. Understanding the elements of this response, as well as its triggers, could be the foundation for innovative strategies to control the transmission of American trypanosomiasis, such as the development of targeted interventions aimed at disrupting parasite proliferation and transmission within the triatomine vector.

Asunto(s)

RESUMEN

Neurodegenerative disorders are typically "split" based on their hallmark clinical, anatomical, and pathological features, but they can also be "lumped" by a shared feature of impaired mitochondrial biology. This leads us to present a scientific framework that conceptualizes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) as "metabolic icebergs" comprised of a tip, a bulk, and a base. The visible tip conveys the hallmark neurological symptoms, neurodegenerative regions, and neuronal protein aggregates for each disorder. The hidden bulk depicts impaired mitochondrial biology throughout the body, which is multifaceted and may be subdivided into impaired cellular metabolism, cell-specific mitotypes, and mitochondrial behaviours, functions, activities, and features. The underlying base encompasses environmental factors, especially modern industrial toxins, dietary lifestyles, and cognitive, physical, and psychosocial behaviours, but also accommodates genetic factors specific to familial forms of AD, PD, and ALS, as well as HD. Over years or decades, chronic exposure to a particular suite of environmental and genetic factors at the base elicits a trajectory of impaired mitochondrial biology that maximally impacts particular subsets of mitotypes in the bulk, which eventually surfaces as the hallmark features of a particular neurodegenerative disorder at the tip. We propose that impaired mitochondrial biology can be repaired and recalibrated by activating "mitohormesis", which is optimally achieved using strategies that facilitate a balanced oscillation between mitochondrial stressor and recovery phases. Sustainably harnessing mitohormesis may constitute a potent preventative and therapeutic measure for people at risk of, or suffering with, neurodegenerative disorders.

Asunto(s)

RESUMEN

Lupus is characterized by the autoantibodies against nuclear Ags, underscoring the importance of identifying the B cell subsets driving autoimmunity. Our research focused on the mitochondrial activity and CXCR4 expression in CD11c+ B cells from lupus patients after ex vivo stimulation with a TLR9 agonist, CpG-oligodeoxyribonucleotide (ODN). We also evaluated the response of CD11c+ B cells in ODN-injected mice. Post-ex vivo ODN stimulation, we observed an increase in the proportion of CD11chi cells, with elevated mitochondrial activity and CXCR4 expression in CD11c+ B cells from lupus patients. In vivo experiments showed similar patterns, with TLR9 stimulation enhancing mitochondrial and CXCR4 activities in CD11chi B cells, leading to the generation of anti-dsDNA plasmablasts. The CXCR4 inhibitor AMD3100 and the mitochondrial complex I inhibitor IM156 significantly reduced the proportion of CD11c+ B cells and autoreactive plasmablasts. These results underscore the pivotal roles of mitochondria and CXCR4 in the production of autoreactive plasmablasts.