RESUMO
Mitochondria play a key role in cancer and their involvement is not limited to the production of ATP only. Mitochondria also produce reactive oxygen species and building blocks to sustain rapid cell proliferation; thus, the deregulation of mitochondrial function is associated with cancer disease development and progression. In cancer cells, a metabolic reprogramming takes place through a different modulation of the mitochondrial metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, the Krebs cycle, glutamine and heme metabolism. Alterations of mitochondrial homeostasis, in particular, of mitochondrial biogenesis, mitophagy, dynamics, redox balance, and protein homeostasis, were also observed in cancer cells. The use of drugs acting on mitochondrial destabilization may represent a promising therapeutic approach in tumors in which mitochondrial respiration is the predominant energy source. In this review, we summarize the main mitochondrial features and metabolic pathways altered in cancer cells, moreover, we present the best known drugs that, by acting on mitochondrial homeostasis and metabolic pathways, may induce mitochondrial alterations and cancer cell death. In addition, new strategies that induce mitochondrial damage, such as photodynamic, photothermal and chemodynamic therapies, and the development of nanoformulations that specifically target drugs in mitochondria are also described. Thus, mitochondria-targeted drugs may open new frontiers to a tailored and personalized cancer therapy.
Assuntos
Mitocôndrias , Neoplasias , Humanos , Mitocôndrias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fosforilação Oxidativa , Ciclo do Ácido Cítrico , Oxirredução , Espécies Reativas de Oxigênio/metabolismoRESUMO
Caseinolytic protease P (ClpP) is a mitochondrial serine protease. In mammalian cells, the heterodimerization of ClpP and its AAA+ ClpX chaperone results in a complex called ClpXP, which has a relevant role in protein homeostasis and in maintaining mitochondrial functionality through the degradation of mitochondrial misfolded or damaged proteins. Recent studies demonstrate that ClpP is upregulated in primary and metastatic human tumors, supports tumor cell proliferation, and its overexpression desensitizes cells to cisplatin. Interestingly, small modulators of ClpP activity, both activators and inhibitors, are able to impair oxidative phosphorylation in cancer cells and to induce apoptosis. This review provides an overview of the role of ClpP in regulating mitochondrial functionality, in supporting tumor cell proliferation and cisplatin resistance; finally, we discuss whether this protease could represent a new prognostic marker and therapeutic target for the treatment of cancer.
Assuntos
Biomarcadores Tumorais/metabolismo , Endopeptidase Clp/metabolismo , Mitocôndrias/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/terapia , Animais , Apoptose/genética , Biomarcadores Tumorais/genética , Proliferação de Células/genética , Endopeptidase Clp/genética , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Metástase Neoplásica , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/patologiaRESUMO
Functional alterations in irritable bowel syndrome have been associated with defects in bioenergetics and the mitochondrial network. Effects of high fat, adequate-protein, low carbohydrate ketogenic diet (KD) involve oxidative stress, inflammation, mitochondrial function, and biogenesis. The aim was to evaluate the KD efficacy in reducing the effects of stress on gut mitochondria. Newborn Wistar rats were exposed to maternal deprivation to induce IBS in adulthood. Intestinal inflammation (COX-2 and TRL-4); cellular redox status (SOD 1, SOD 2, PrxIII, mtDNA oxidatively modified purines); mitochondrial biogenesis (PPAR-γ, PGC-1α, COX-4, mtDNA content); and autophagy (Beclin-1, LC3 II) were evaluated in the colon of exposed rats fed with KD (IBD-KD) or standard diet (IBS-Std), and in unexposed controls (Ctrl). IBS-Std rats showed dysfunctional mitochondrial biogenesis (PPAR-γ, PGC-1α, COX-4, and mtDNA contents lower than in Ctrl) associated with inflammation and increased oxidative stress (higher levels of COX-2 and TLR-4, SOD 1, SOD 2, PrxIII, and oxidatively modified purines than in Ctrl). Loss of autophagy efficacy appeared from reduced levels of Beclin-1 and LC3 II. Feeding of animals with KD elicited compensatory mechanisms able to reduce inflammation, oxidative stress, restore mitochondrial function, and baseline autophagy, possibly via the upregulation of the PPAR-γ/PGC-1α axis.
Assuntos
Dieta Cetogênica , Intestinos/patologia , Síndrome do Intestino Irritável/dietoterapia , Biogênese de Organelas , Estresse Psicológico , Animais , Animais Recém-Nascidos , Autofagia , Proteína Beclina-1/metabolismo , Modelos Animais de Doenças , Microbioma Gastrointestinal , Inflamação , Privação Materna , Proteínas Associadas aos Microtúbulos/química , Mitocôndrias/metabolismo , Oxirredução , Estresse Oxidativo , Ratos , Ratos WistarRESUMO
Calorie restriction (CR) is the most efficacious treatment to delay the onset of age-related changes such as mitochondrial dysfunction. However, the sensitivity of mitochondrial markers to CR and the age-related boundaries of CR efficacy are not fully elucidated. We used liver samples from ad libitum-fed (AL) rats divided in: 18-month-old (AL-18), 28-month-old (AL-28), and 32-month-old (AL-32) groups, and from CR-treated (CR) 28-month-old (CR-28) and 32-month-old (CR-32) counterparts to assay the effect of CR on several mitochondrial markers. The age-related decreases in citrate synthase activity, in TFAM, MFN2, and DRP1 protein amounts and in the mtDNA content in the AL-28 group were prevented in CR-28 counterparts. Accordingly, CR reduced oxidative mtDNA damage assessed through the incidence of oxidized purines at specific mtDNA regions in CR-28 animals. These findings support the anti-aging effect of CR up to 28 months. Conversely, the protein amounts of LonP1, Cyt c, OGG1, and APE1 and the 4.8 Kb mtDNA deletion content were not affected in CR-28 rats. The absence of significant differences between the AL-32 values and the CR-32 counterparts suggests an age-related boundary of CR efficacy at this age. However, this only partially curtails the CR benefits in counteracting the generalized aging decline and the related mitochondrial involvement.
Assuntos
Envelhecimento , Restrição Calórica/efeitos adversos , DNA Mitocondrial/metabolismo , Fígado/patologia , Mitocôndrias/patologia , Biogênese de Organelas , Estresse Oxidativo , Animais , DNA Mitocondrial/genética , Fígado/metabolismo , Masculino , Mitocôndrias/genética , Mitocôndrias/metabolismo , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos F344RESUMO
The completion of the Special Issue dedicated to "mtDNA and mitochondrial stress signaling in human diseases" requests a final overall look to highlight the most valuable findings among the many presented data [...].
Assuntos
DNA Mitocondrial , Suscetibilidade a Doenças , Mitocôndrias/genética , Mitocôndrias/metabolismo , Transdução de Sinais , Estresse Fisiológico , Humanos , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismoRESUMO
Dietary gliadin may show a broad spectrum of toxicity. The interplay between mitochondria and gliadin-induced oxidative stress has not been thoroughly examined in the intestinal epithelium. In this kinetic study, Caco-2 cells were exposed for 24 h to pepsin-trypsin-digested gliadin, alone or in combination with the antioxidant 2,6-di-tbutyl-p-cresol (BHT), and the effects on mitochondrial biogenesis and mtDNA were studied. Cells ability to recover from stress was determined after 24 h and 48 h of incubation in the culture medium. Gliadin-induced oxidative stress evoked a compensatory response. The stressor triggered a rapid and significant increase of Peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α) and Peroxiredoxin III (PrxIII) proteins, and mtDNA amount. As for the effects of gliadin on mtDNA integrity, strand breaks, abasic sites, and modified bases were analyzed in three mtDNA regions. D-loop appeared a more fragile target than Ori-L and ND1/ND2. The temporal trend of the damage at D-loop paralleled that of the amount of mtDNA. Overall, a trend toward control values was shown 48 h after gliadin exposure. Finally, BHT was able to counteract the effects of gliadin. Results from this study highlighted the effects of gliadin-induced oxidative stress on mitochondria, providing valuable evidence that might improve the knowledge of the pathophysiology of gluten-related disorders.
Assuntos
Antioxidantes/farmacologia , Hidroxitolueno Butilado/farmacologia , Gliadina/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Células CACO-2 , DNA Mitocondrial/genética , Gliadina/efeitos adversos , Humanos , Mitocôndrias/genética , Biogênese de OrganelasRESUMO
Mitochondrial oxidative stress accumulates with aging and age-related diseases and induces alterations in mitochondrial DNA (mtDNA) content. Since mtDNA qualitative alterations are also associated with aging, repair of mtDNA damage is of great importance. The most relevant form of DNA repair in this context is base excision repair (BER), which removes oxidized bases such as 8-oxoguanine (8-oxoG) and thymine glycol through the action of the mitochondrial isoform of the specific 8-oxoG DNA glycosylase/apurinic or apyrimidinic (AP) lyase (OGG1) or the endonuclease III homolog (NTH1). Mouse strains lacking OGG1 (OGG1-/-) or NTH1 (NTH1-/-) were analyzed for mtDNA alterations. Interestingly, both knockout strains presented a significant increase in mtDNA content, suggestive of a compensatory mtDNA replication. The mtDNA "common deletion" was not detected in either knockout mouse strain, likely because of the young age of the mice. Formamidopyrimidine DNA glycosylase (Fpg)-sensitive sites accumulated in mtDNA from OGG1-/- but not from NTH1-/- mice. Interestingly, the D-loop region was most severely affected by the absence of OGG1, suggesting that this region may be a hotspot for oxidative damage. Thus, we speculate that mtDNA alterations may send a stress message to evoke cell changes through a retrograde mitochondrial-nucleus communication.
Assuntos
Dano ao DNA/genética , DNA Glicosilases/genética , DNA Mitocondrial/genética , Deleção de Genes , Purinas/metabolismo , Animais , Pareamento de Bases/genética , Camundongos Knockout , Oxirredução , Deleção de SequênciaRESUMO
While mitochondrial dysfunction is acknowledged as a major feature of aging, much less is known about the role of mitochondria in extended longevity. Livers from aged (28-month-old) and extremely aged (32-month-old) rats were analyzed for citrate synthase activity, mitochondrial transcription factor A (TFAM) amount, mitochondrial DNA (mtDNA), and 4.8 Kb "common deletion" contents. None of the assayed parameters differed significantly between age groups. TFAM-binding to mtDNA and the incidence of 8-oxo-deoxyguanosine in specific mtDNA regions, encompassing the origins of mtDNA replication (D-loop and Ori-L) and the 16-bp long direct repeat 1 (DR1) of the 4.8 Kb deletion, were determined. A decrease in TFAM binding was unveiled at all regions in extremely aged in comparison with aged rats. Reduced incidence of oxidized purines at all assayed regions was detected in 32-month-old rats compared with the 28-month-old group. A significant positive correlation between the incidence of 8-oxo-deoxoguanosine and TFAM-bound mtDNA was found at D-Loop and Ori-L regions only in 28-month-old rats. The absence of such correlation in 32-month-old rats indicates a different, fine-tuned regulation of TFAM binding in the two age groups and supports the existence of two different paces in aging and extended aging.
Assuntos
Envelhecimento/metabolismo , Dano ao DNA , Mitocôndrias Hepáticas/metabolismo , Fatores de Transcrição/metabolismo , Envelhecimento/genética , Animais , DNA Mitocondrial/metabolismo , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Masculino , Ligação Proteica , RatosRESUMO
Sarcopenia is a well-known geriatric syndrome that has been endorsed over the years as a biomarker allowing for the discrimination, at a clinical level, of biological from chronological age. Multiple candidate mechanisms have been linked to muscle degeneration during sarcopenia. Among them, there is wide consensus on the central role played by the loss of mitochondrial integrity in myocytes, secondary to dysfunctional quality control mechanisms. Indeed, mitochondria establish direct or indirect contacts with other cellular components (e.g. endoplasmic reticulum, peroxisomes, lysosomes/vacuoles) as well as the extracellular environment through the release of several biomolecules. The functional implications of these interactions in the context of muscle physiology and sarcopenia are not yet fully appreciated and represent a promising area of investigation. Here, we present an overview of recent findings concerning the interrelation between mitochondrial quality control processes, inflammation and the metabolic regulation of muscle mass in the pathogenesis of sarcopenia highlighting those pathways that may be exploited for developing preventive and therapeutic interventions against muscle aging.
Assuntos
Envelhecimento/metabolismo , Mitocôndrias/metabolismo , Músculos/metabolismo , Sarcopenia/metabolismo , Animais , HumanosRESUMO
BACKGROUND: Coeliac disease (CD) is a gluten-sensitive autoimmune disorder. Gluten toxicity encompasses a wide spectrum of target organ functions and pathologies, including the activation of the immune response and triggering of oxidative stress. The aim of this study was to investigate inflammation and the redox balance in patients with active CD, and to evaluate whether alteration of mitochondrial function is involved in the disease status. DESIGN: In this prospective case-control study, blood samples from sixteen adult CD patients and sixteen healthy controls (HC) were investigated for IL-1ß, IL-6 and IL-8 plasma concentrations, for serum PON1 arylesterase, total and MnSOD antioxidant enzyme activities, induced TBARs levels, and for lymphocyte mtDNA content. RESULTS: Patients showed IL-8 and IL-1ß concentrations significantly higher than HC counterparts. Patients had a significantly higher content of induced TBARS compared to HC value, indicating a shift in their serum redox balance towards pro-oxidant species. The assay of antioxidant enzyme activities showed a significant 25% increase in PON1, a higher total SOD, and a significant 21% higher MnSOD in patients compared to HC. Lymphocyte mtDNA content in patients was significantly twofold higher than in HC, supporting the induction of mitochondrial biogenesis. The patients' mitochondrial compensatory response may explain the correlation between MnSOD activity and mtDNA content. The patients' mitochondrial oxidative stress, cooperating to cytokines secretion, may justify the correlation between IL-1ß concentration and mtDNA content. CONCLUSIONS: These results highlight the mitochondrial involvement in CD and suggest the evaluation of the mtDNA content as a potential diagnostic and follow-up parameter.
Assuntos
Doença Celíaca/metabolismo , Mitocôndrias/fisiologia , Doenças Mitocondriais/metabolismo , Adulto , Antioxidantes/metabolismo , Arildialquilfosfatase/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Metilação de DNA/fisiologia , Feminino , Humanos , Interleucinas/metabolismo , Linfócitos/fisiologia , Masculino , Oxirredução , Estresse Oxidativo/fisiologia , Estudos Prospectivos , Superóxido Dismutase/metabolismoRESUMO
Advanced age is characterized by several changes, one of which is the impairment of the homeostasis of intestinal microbiota. These alterations critically influence host health and have been associated with morbidity and mortality in older adults. "Inflammaging," an age-related chronic inflammatory process, is a common trait of several conditions, including sarcopenia. Interestingly, imbalanced intestinal microbial community has been suggested to contribute to inflammaging. Changes in gut microbiota accompanying sarcopenia may be attenuated by supplementation with pre- and probiotics. Although muscle aging has been increasingly recognized as a biomarker of aging, the pathophysiology of sarcopenia is to date only partially appreciated. Due to its development in the context of the age-related inflammatory milieu, several studies favor the hypothesis of a tight connection between sarcopenia and inflammaging. However, conclusive evidence describing the signaling pathways involved has not yet been produced. Here, we review the current knowledge of the changes in intestinal microbiota that occur in advanced age with a special emphasis on findings supporting the idea of a modulation of muscle physiology through alterations in gut microbial composition and activity.
Assuntos
Envelhecimento/fisiologia , Disbiose/microbiologia , Microbioma Gastrointestinal/fisiologia , Intestinos/microbiologia , Músculos/fisiologia , Sarcopenia/microbiologia , Animais , HumanosRESUMO
Type I endometrial cancer (EC) is the most common form of EC, displaying less aggressive behavior than type II. The development of type I endometrial cancer is considered a multistep process, with slow progression from normal endometrium to hyperplasia, the premalignant form, and endometrial cancer as a result of an unopposed estrogenic stimulation. The role of mitochondria in type I EC tumor progression and prognosis is currently emerging. This review aims to explore mitochondrial alterations in this cancer and in endometrial hyperplasia focusing on mitochondrial DNA mutations, respiratory complex I deficiency, and the activation of mitochondrial quality control systems. A deeper understanding of altered mitochondrial pathways in type I EC could provide novel opportunities to discover new diagnostic and prognostic markers as well as potential therapeutic targets.
Assuntos
DNA Mitocondrial/genética , Neoplasias do Endométrio/genética , Mitocôndrias/genética , Mutação , Lesões Pré-Cancerosas/genética , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Neoplasias do Endométrio/metabolismo , Feminino , Humanos , Mitocôndrias/metabolismo , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Lesões Pré-Cancerosas/metabolismo , PrognósticoRESUMO
Pathogenic mtDNA mutations associated with alterations of respiratory complex I, mitochondrial proliferation (oncocytic-like phenotype) and increase in antioxidant response were previously reported in type I endometrial carcinoma (EC). To evaluate whether in the presence of pathogenic mtDNA mutations other mitochondrial adaptive processes are triggered by cancer cells, the expression level of proteins involved in mitochondrial dynamics, mitophagy, proteolysis and apoptosis were evaluated in type I ECs harboring pathogenic mtDNA mutations and complex I deficiency. An increase in the fission protein Drp1, in the mitophagy protein BNIP3, in the mitochondrial protease CLPP, in the antioxidant and anti-apoptotic protein ALR and in Bcl-2 as well as a decrease in the fusion protein Mfn2 were found in cancer compared to matched non malignant tissue. Moreover, the level of these proteins was measured in type I EC, in hyperplastic (the premalignant form) and in non malignant tissues to verify whether the altered expression of these proteins is a common feature of endometrial cancer and of hyperplastic tissue. This analysis confirmed in type I EC samples, but not in hyperplasia, an alteration of the expression level of these proteins. These results suggest that in this cancer mitochondrial fission, antioxidant and anti-apoptotic response may be activated, as well as the discharge of damaged mitochondrial proteins as adaptation processes to mitochondrial dysfunction.
Assuntos
Complexo I de Transporte de Elétrons/deficiência , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Mitocôndrias/metabolismo , Mitofagia , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/metabolismo , Complexo I de Transporte de Elétrons/genética , Feminino , Humanos , Proteínas Mitocondriais , Proteínas de Neoplasias , Proteólise , Células Tumorais CultivadasRESUMO
Among the complex determinants of aging, mitochondrial dysfunction has been in the spotlight for a long time. As the hub for many cellular functions, the maintenance of an adequate pool of functional mitochondria is crucial for tissue homeostasis. Their unique role in energy supply makes these organelles essential, especially in those tissues strictly dependent on oxidative metabolism. Mitochondrial quality control (MQC) is ensured by pathways related to protein folding and degradation as well as by processes involving the entire organelle, such as biogenesis, dynamics, and mitophagy. Dysfunctional MQC, oxidative stress and inflammation are hallmarks of senescence and chronic degenerative diseases. One of the consequences of age-related failing MQC and oxidative stress is the release of mitochondria-derived damage-associated molecular patterns (DAMPs). Through their bacterial ancestry, these molecules contribute to mounting an inflammatory response by interacting with receptors similar to those involved in pathogen-associated responses. Mitochondrial DAMPs, especially cell-free mitochondrial DNA, have recently become the subject of intensive research because of their possible involvement in conditions associated with inflammation, such as aging and degenerative diseases. Here, we review the contribution of mitochondrial DAMPs to inflammation and discuss some of the mechanisms at the basis of their generation.
Assuntos
Envelhecimento , Inflamação , Mitocôndrias/metabolismo , Alarminas/metabolismo , DNA Mitocondrial/metabolismo , Humanos , Mitocôndrias/genética , Dinâmica Mitocondrial , Mitofagia , Estresse OxidativoRESUMO
Until now glucosamine sulfate (GS) has been the most widely used supplement and has been shown to be efficacious in the treatment of osteoarthritis (OA). Methylsulfonylmethane (MSM) and boswellic acids (BA) are new effective supplements for the management of inflammation and joint degeneration, according to previous experimental studies. The aim of our study is to test the effectiveness of association of MSM and BA in comparison with GS in knee arthritis.In this prospective randomized clinical trial, MEBAGA (Methylsulfonylmethane and Boswellic Acids versus Glucosamine sulfate in the treatment of knee Arthritis), 120 participants affected by arthritis of the knee were randomly assigned to an experimental group (MB group) or a control group (GS group) treated for 60 days with 5 g of MSM and 7.2 mg of BA or with 1500 mg of GS daily, respectively. At the 2-month (T1) and 6-months (T2) follow-up , the efficacy of these two nutraceuticals was assessed using the visual analog pain scale (VAS) and the Lequesne Index (LI) for joint function, along with the use of anti-inflammatory drugs (non-steroidal anti-inflammatory drugs and anti-cyclooxygenase-2).The repeated measures ANOVA analysis shows that for VAS, LI, and the use of anti-inflammatory drugs scores there are improvements due to the time in the two groups (respectively, F=26.0; P<0.0001; F=4.15; P=0.02; F=3.38; P=0.04), with a tendency to better values for the MB group at T2.On the basis of these preliminary data, we could support the efficacy of the MSM in association with BA in the treatment of OA. These results are consistent with the anti-inflammatory and chondroprotective effects previously occurred in experimental studies. This new combination of integration (MSM and BS) has presented good results and satisfactory in comparison with GS, until now the cornerstone of the treatment of arthritis in according to guidelines.
Assuntos
Dimetil Sulfóxido/uso terapêutico , Glucosamina/uso terapêutico , Osteoartrite do Joelho/tratamento farmacológico , Sulfonas/uso terapêutico , Triterpenos/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Escala Visual AnalógicaRESUMO
Three different flavoring methods of olive oil were tested employing two different herbs, thyme and oregano. The traditional method consist in the infusion of herbs into the oil. A second scarcely diffused method is based on the addition of herbs to the crushed olives before the malaxation step during the extraction process. The third innovative method is the implementation of the ultrasound before the olive paste malaxation. The objective of the study is to verify the effect of the treatments on the quality of the product, assessed by means of the chemical characteristics, the phenol composition and the radical scavenging activity of the resulting oils. The less favorable method was the addition of herbs directly to the oil. A positive effect was achieved by the addition of herbs to the olive paste and other advantages were attained by the employment of ultrasound. These last two methods allow to produce oils "ready to sell", instead the infused oils need to be filtered. Moreover, the flavoring methods applied during the extraction process determine a significant increment of phenolic content and radical scavenging activity of olive oils. The increments were higher when oregano is used instead of thyme. Ultrasound inhibited the olive polyphenoloxidase, the endogenous enzyme responsible for olive oil phenol oxidation. This treatment of olive paste mixed with herbs before malaxation was revealed as the most favorable method due to the best efficiency, reduced time consumption and minor labor, enhancing the product quality of flavored olive oil.
Assuntos
Aromatizantes/química , Manipulação de Alimentos/métodos , Olea/química , Azeite de Oliva/química , Origanum/química , Thymus (Planta)/química , Catecol Oxidase/metabolismo , Sequestradores de Radicais Livres/análise , Sequestradores de Radicais Livres/química , Humanos , Extração Líquido-Líquido , Pomadas/química , Olea/enzimologia , Azeite de Oliva/isolamento & purificação , Azeite de Oliva/normas , Oxirredução , Fenóis/análise , Fenóis/química , Folhas de Planta/química , Proteínas de Plantas/metabolismo , PaladarRESUMO
BACKGROUND: Mitochondrial Transcription Factor A (TFAM) is regarded as a histone-like protein of mitochondrial DNA (mtDNA), performing multiple functions for this genome. Aging affects mitochondria in a tissue-specific manner and only calorie restriction (CR) is able to delay or prevent the onset of several age-related changes also in mitochondria. METHODS: Samples of the frontal cortex and soleus skeletal muscle from 6- and 26-month-old ad libitum-fed and 26-month-old calorie-restricted rats and of the livers from 18- and 28-month-old ad libitum-fed and 28-month-old calorie-restricted rats were used to detect TFAM amount, TFAM-binding to mtDNA and mtDNA content. RESULTS: We found an age-related increase in TFAM amount in the frontal cortex, not affected by CR, versus an age-related decrease in the soleus and liver, fully prevented by CR. The semi-quantitative analysis of in vivo binding of TFAM to specific mtDNA regions, by mtDNA immunoprecipitation assay and following PCR, showed a marked age-dependent decrease in TFAM-binding activity in the frontal cortex, partially prevented by CR. An age-related increase in TFAM-binding to mtDNA, fully prevented by CR, was found in the soleus and liver. MtDNA content presented a common age-related decrease, completely prevented by CR in the soleus and liver, but not in the frontal cortex. CONCLUSIONS: The modulation of TFAM expression, TFAM-binding to mtDNA and mtDNA content with aging and CR showed a trend shared by the skeletal muscle and liver, but not by the frontal cortex counterpart. GENERAL SIGNIFICANCE: Aging and CR appear to induce similar mitochondrial molecular mechanisms in the skeletal muscle and liver, different from those elicited in the frontal cortex.
Assuntos
Envelhecimento/genética , Restrição Calórica , DNA Mitocondrial/metabolismo , Fatores de Transcrição/metabolismo , Envelhecimento/metabolismo , Animais , DNA Mitocondrial/genética , Lobo Frontal/metabolismo , Regulação da Expressão Gênica , Fígado/metabolismo , Músculo Esquelético/metabolismo , Especificidade de Órgãos , Ligação Proteica , Ratos , Fatores de Transcrição/genéticaRESUMO
Even though the initial treatment of carpal tunnel syndrome (CTS) is conservative, knowledge of the clinical effects of supplements and of some methods of physiotherapy is still preliminary. Many biological mechanisms can support the administration of shock wave therapy (ESWT) or of alpha lipoic acid (ALA) based nutraceutical, conjugated linoleic acid (GLA), anti-oxidants and Echinacea angustifolia for CTS. The shock waves reduce the nerve compression, produce an anti-inflammatory action, and accelerate the regeneration of neuropathy. ALA and GLA induce antioxidant protective actions, reduce inflammation, promote neuroregeneration, and decrease pain. The Echinacea modulates the endogenous cannabinoid system.The aim of study is to verify the efficiency of shock wave therapy versus nutraceutical composed of ALA, GLA, and Echinacea in CTS. Sixty patients were enrolled in this study and they were randomly assigned to one of two treatments. Both groups showed significant improvements in pain, symptoms' severity and functional scores, and electrodiagnostic results until the sixth month. We verified a trend to a better pain regression in the nutraceutical group. The presence of the medicinal Echinacea represents an added value to the antioxidant effect in ALA and GLA, which can justify this result. ESWT or the association of ALA, GLA, and Echinacea proved to be two effective treatments for controlling symptoms and improving the evolution of CTS.
Assuntos
Síndrome do Túnel Carpal/tratamento farmacológico , Echinacea/química , Ácidos Linoleicos Conjugados/uso terapêutico , Quercetina/uso terapêutico , Ácido Tióctico/uso terapêutico , Antioxidantes/uso terapêutico , Suplementos Nutricionais , Ondas de Choque de Alta Energia , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do TratamentoRESUMO
The natural polyphenol resveratrol (RSV) might counteract the skeletal muscle age-related loss of muscle mass and strength/function partly acting on mitochondria. This work analysed the effects of a six-week administration of RSV (50 mg/kg/day) in the oxidative Soleus (Sol) skeletal muscle of old rats (27 months old). RSV effects on key mitochondrial biogenesis proteins led to un unchanged amount of SIRT1 protein and a marked decrease (60 %) in PGC-1α protein. In addition, Peroxyredoxin 3 (PRXIII) protein decreased by 50 %, which on overall suggested the absence of induction of mitochondrial biogenesis by RSV in old Sol. A novel direct correlation between PGC-1α and PRXIII proteins was demonstrated by correlation analysis in RSV and ad-libitum (AL) rats, supporting the reciprocally coordinated expression of the proteins. RSV supplementation led to an unexpected 50 % increase in the frequency of the oxidized base OH8dG in mtDNA. Furthermore, RSV supplementation induced a 50 % increase in the DRP1 protein of mitochondrial dynamics. In both rat groups an inverse correlation between PGC-1α and the frequency of OH8dG as well as an inverse correlation between PRXIII and the frequency of OH8dG were also found, suggestive of a relationship between oxidative damage to mtDNA and mitochondrial biogenesis activity. Such results may indicate that the antioxidant activity of RSV in aged Sol impinged on the oxidative fiber-specific, ROS-mediated, retrograde communication, thereby affecting the expression of SIRT1, PGC-1α and PRXIII, reducing the compensatory responses to the age-related mitochondrial oxidative stress and decline.
Assuntos
Envelhecimento , Mitocôndrias Musculares , Músculo Esquelético , Biogênese de Organelas , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Ratos Wistar , Resveratrol , Sirtuína 1 , Animais , Resveratrol/farmacologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Masculino , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 1/metabolismo , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Ratos , Estilbenos/farmacologia , Antioxidantes/farmacologia , Peroxirredoxinas/metabolismo , DNA Mitocondrial/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Dinaminas/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacosRESUMO
BACKGROUND AND AIM: Supracondylar humeral fractures are the most common skeletal injury of childhood elbow. Treatment option for Gartland type II-III-IV fractures is based on closed reduction and percutaneous pinning (CRPP) fixation using Kirshner wires. Seldom open reduction is needed. Literature described different method of CRPP. The aim of the study is to report our experience in the surgical management of supracondylar humeral fractures comparing it with the literature, in order to identify useful information for a correct and better approach to reduce complications and improve clinical outcomes. METHODS: 148 patients with a mean age of 5.72 ± 2.52 years and with Gartland type II-III-IV humeral supracondylar fractures were treated with CRPP at our Orthopedic Pediatric Unit. They were divided into three groups according to surgical technique. Group A was represented by patients treated with cross pinning (1 medial and 1 lateral pin), Group B represented by 2 lateral pins while Group C represented by 2 lateral and one medial pin. Evaluation criteria are based on Mayo Elbow Performance Index (MEPI); Bauman's and Carrying Angle and Flynn's criteria. Data were recorded at the following times: T0 (before surgical procedure); T1 (one-month post-surgery); T2 (six months post-surgery). RESULTS: The three surgical techniques showed comparable results according to MEPI, Bauman's angle, Carrying's angle and Flynn's criteria from T0 to T1. There is an improvement for all Groups. Group C reported the best MEPI outcome at T2. However, 2 patients in this group did not show excellent results according to Flynn's criteria. CONCLUSIONS: There is no single and superior treatment for displaced humeral supracondylar fractures and that each fracture has its own personality.