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BACKGROUND: Melatonin, one of the most versatile hormones in the body, is well appreciated in managing circadian rhythm and for antioxidant properties. Produced in the pineal gland and within mitochondria, melatonin influences many physiologic processes through receptor mediated and direct effects. OBJECTIVE: The present investigation explores the evolving pharmacologic properties of melatonin, as well as current therapeutic uses in areas where mitigating oxidative stress, inflammation, and cellular senescence. This review also delves into novel therapeutic potential of melatonin and how current research is revealing a wide array of therapeutic promise in pain medicine. STUDY DESIGN: A systematic review of randomized controlled trials (RCTs) and observational studies was performed using various search engines focused on melatonin and its role in pain medicine. METHODS: The available literature on melatonin and pain medicine was reviewed. A comprehensive literature search of multiple databases from 1966 to July 2024, including manual searches of the bibliography of known review articles was performed. Quality assessment of the included studies and best evidence synthesis were incorporated into qualitative and quantitative evidence synthesis. OUTCOME MEASURES: The primary outcome measure was the proportion of patients receiving melatonin with significant relief and functional improvement of greater than 50% of at least 3 months. Duration of relief was categorized as short-term (less than 6 months) and long-term (greater than 6 months). RESULTS: Melatonin can affect intervertebral disc (IVD) health through the enhancement of survival and function of nucleus pulposus cells, primarily through activation of the ERK1/2 signaling pathway. Melatonin also influences the biochemical environment of the IVD by modulating inflammation and oxidative stress, crucial factors in the pathogenesis of disc degeneration. Melatonin has been shown to reduce senescence and promote autophagy within disc cells, vital for clearing out damaged cellular components, preserving cellular function and preventing deterioration associated with aging and degenerative diseases. LIMITATIONS: Despite the availability of multiple studies, the paucity of clinical pain related literature is considered as the major drawback. CONCLUSION: Based on the present systematic review, melatonin plays a critical role in sleep, but evolving studies have demonstrated substantive roles in mitigating degenerative conditions in various tissues, including IVD degeneration. Ongoing studies will better clarify the role of melatonin as a potential therapeutic agent, including the targeted delivery to various body regions.
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Degeneración del Disco Intervertebral , Melatonina , Melatonina/uso terapéutico , Humanos , Degeneración del Disco Intervertebral/tratamiento farmacológico , Antioxidantes/uso terapéutico , Antioxidantes/farmacología , Estrés Oxidativo/efectos de los fármacos , Manejo del Dolor/métodosRESUMEN
BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, affecting individuals over 65. AD is also a multifactorial disease, with disease mechanisms incompletely characterized, and disease-modifying therapies are marginally effective. Biomarker signatures may shed light on the diagnosis, disease mechanisms, and the development of therapeutic targets. tRNA-derived RNA fragments (tRFs), a family of recently discovered small non-coding RNAs, have been found to be significantly enhanced in human AD hippocampus tissues. However, whether tRFs change in body fluids is unknown. OBJECTIVE: To investigate whether tRFs in body fluids are impacted by AD. METHODS: We first used T4 polynucleotide kinase-RNA-seq, a modified next-generation sequencing technique, to identify detectable tRFs in human cerebrospinal fluid and serum samples. The detectable tRFs were then compared in these fluids from control, AD, and mild cognitive impairment patients using tRF qRT-PCR. The stability of tRFs in serum was also investigated by checking the change in tRFs in response to protein digestion or exosome lysis. RESULTS: Among various tRFs, tRF5-ProAGG seemed to be impacted by AD in both cerebrospinal fluid and serum. AD-impacted serum tRF5-ProAGG showed a correlation with the AD stage. Putative targets of tRF5-ProAGG in the hippocampus were also predicted by a computational algorithm, with some targets being validated experimentally and one of them being in a negative correlation with tRF5-ProAGG even using a small size of samples. CONCLUSIONS: tRF5-ProAGG showed the potential as an AD biomarker and may play a role in disease progression.
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Enfermedad de Alzheimer , Suero , Humanos , Suero/metabolismo , Enfermedad de Alzheimer/genética , ARN de Transferencia/genética , ARN de Transferencia/metabolismo , ARN , BiomarcadoresRESUMEN
The master molecular regulators and mechanisms determining longevity and health span include nitric oxide (NO) and superoxide anion radicals (SOR). L-arginine, the NO synthase (NOS) substrate, can restore a healthy ratio between the dangerous SOR and the protective NO radical to promote healthy aging. Antioxidant supplementation orchestrates protection against oxidative stress and damage-L-arginine and antioxidants such as vitamin C increase NO production and bioavailability. Uncoupling of NO generation with the appearance of SOR can be induced by asymmetric dimethylarginine (ADMA). L-arginine can displace ADMA from the site of NO formation if sufficient amounts of the amino acid are available. Antioxidants such as ascorbic acids can scavenge SOR and increase the bioavailability of NO. The topics of this review are the complex interactions of antioxidant agents with L-arginine, which determine NO bioactivity and protection against age-related degeneration.
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Antioxidantes , Óxido Nítrico , Humanos , Óxido Nítrico/metabolismo , Antioxidantes/farmacología , Longevidad , Óxido Nítrico Sintasa/metabolismo , Arginina/metabolismoRESUMEN
Tryptophan is a rate-limiting essential amino acid and a unique building block of peptides and proteins [...].
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Estado Nutricional , Triptófano , Aminoácidos Esenciales , Péptidos , Triptófano/metabolismoRESUMEN
Sporadic late-onset Alzheimer's disease (AD) is the most frequent cause of dementia associated with aging. Due to the progressive aging of the population, AD is becoming a healthcare burden of unprecedented proportions. Twenty years ago, it was reported that some indole molecules produced by the gut microbiota possess essential biological activities, including neuroprotection and antioxidant properties. Since then, research has cemented additional characteristics of these substances, including anti-inflammatory, immunoregulatory, and amyloid anti-aggregation features. Herein, we summarize the evidence supporting an integrated hypothesis that some of these substances can influence the age of onset and progression of AD and are central to the symbiotic relationship between intestinal microbes and the brain. Studies have shown that some of these substances' activities result from interactions with biologically conserved pathways and with genetic risk factors for AD. By targeting multiple pathologic mechanisms simultaneously, certain indoles may be excellent candidates to ameliorate neurodegeneration. We propose that management of the microbiota to induce a higher production of neuroprotective indoles (e.g., indole propionic acid) will promote brain health during aging. This area of research represents a new therapeutic paradigm that could add functional years of life to individuals who would otherwise develop dementia.
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Envejecimiento/metabolismo , Enfermedad de Alzheimer/metabolismo , Eje Cerebro-Intestino/fisiología , Encéfalo/metabolismo , Microbioma Gastrointestinal/fisiología , Indoles/metabolismo , Envejecimiento/genética , Enfermedad de Alzheimer/genética , Animales , Humanos , Mediadores de Inflamación/metabolismo , Neuroprotección/fisiologíaRESUMEN
BACKGROUND: Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to insulin. IR has been associated with multiple conditions, including chronic pain. Fibromyalgia (FM) is one of the common generalized chronic painful conditions with an incidence rate affecting 3% to 6% of the population. Substantial interest and investigation into FM continue to generate many hypotheses.The relationship between IR and FM has not been explored. IR is known to cause abnormalities in the cerebral microvasculature, leading to focal hypoperfusion. IR also has been shown to cause cognitive impairment in FM patients, as in parkinsonism. As demonstrated by advanced imaging methods, similar brain perfusion abnormalities occur in the brain of patients with FM as with IR. OBJECTIVES: To determine the potential association between FM and IR. SETTING: Subspecialty pain medicine clinics. STUDY DESIGN: Observational cross-sectional study. METHODS: Laboratory data was extracted through a retrospective review of medical records from patients who had met the American College of Rheumatology (ACR) criteria for FM. The Hemoglobin A1c (HbA1c) values from 33 patients with FM were compared with the means of the glycated HbA1c levels of 2 control populations. In addition, established indices of IR [Quantitative Insulin Sensitivity Check Index (QUICKI) and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)] were calculated in a subgroup of patients in whom the analytes necessary for these calculations were available. To assess for confounding factors, the associations between HbA1c, QUICKI, HOMA-IR, fasting insulin levels, and glucose, after controlling for age, were explored by multiple analyses of variance with relation to gender and ethnicity. RESULTS: We found an association between IR and FM that was independent of age, gender, and ethnicity. We found that patients with FM belong to a distinct population that can be segregated from the control groups by their HbA1c levels, a surrogate marker of IR. This was demonstrated by analyzing the data after introducing an age correction into a linear regression model. This strategy showed significant differences between patients with FM and control subjects (P < 0.0001 and P = 0.0002, for 2 separate control populations, respectively). A subgroup analysis using the QUICKI and HOMA-IR showed that all patients with FM in this subgroup (100%) exhibited laboratory abnormalities pointing to IR. LIMITATIONS: Small observational cross-sectional study. There are also intrinsic limitations that are attributed to cross-sectional studies. CONCLUSION: The association demonstrated in this study warrant further investigation, including the pursuit of randomized, double-blind clinical trials to determine the effect of improving insulin sensitivity in FM related pain scores. Such studies could unveil a potential pathogenetic relationship between FM, central pain, and IR. Based on these initial findings, we present the hypothesis that IR may underlie pathological mechanisms leading to central pain. If confirmed, this may lead to a paradigm shift in the management of central pain.
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Fibromialgia/sangre , Fibromialgia/epidemiología , Resistencia a la Insulina/fisiología , Dolor/sangre , Dolor/epidemiología , Adulto , Anciano , Biomarcadores/sangre , Estudios Transversales , Método Doble Ciego , Ayuno/sangre , Femenino , Fibromialgia/diagnóstico , Hemoglobina Glucada/metabolismo , Humanos , Insulina/administración & dosificación , Masculino , Persona de Mediana Edad , Dolor/diagnóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: The re-engineered definition of clinical guidelines in 2011 from the IOM (Institute of Medicine) states, "clinical practice guidelines are statements that include recommendations intended to optimize patient care that is informed by a systematic review of evidence and an assessment of the benefit and harms of alternative care options." The revised definition distinguishes between the term "clinical practice guideline" and other forms of clinical guidance derived from widely disparate development processes, such as consensus statements, expert advice, and appropriate use criteria. OBJECTIVE: To assess the literature and develop methodology for evidence synthesis and development of comprehensive evidence-based guidelines for interventional techniques in chronic spinal pain. METHODS: A systematic review of the literature including methodology of guideline development encompassing GRADE approach for guidance on evidence synthesis with recommendations. RESULTS: Some of the many factors described in 2011 continue as of 2020 and impede the development of clinical practice guidelines. These impediments include biases due to a variety of conflicts and confluence of interest, inappropriate and poor methodological quality, poor writing and ambiguous presentation, projecting a view that these are not applicable to individual patients or too restrictive with the elimination of clinician autonomy, and overzealous and inappropriate recommendations, either positive, negative, or non-committal. Thus, ideally, a knowledgeable, multidisciplinary panel of experts with true lack of bias and confluence of interest must develop guidelines based on a systematic review of the existing evidence. This manuscript describes evidence synthesis from observational studies, various types of randomized controlled trials (RCTs), and, finally, methodological and reporting quality of systematic reviews. The manuscript also describes various methods utilized in the assessment of the quality of observational studies, diagnostic accuracy studies, RCTs, and systematic reviews. LIMITATIONS: Paucity of publications with appropriate evidence synthesis methodology in reference to interventional techniques. CONCLUSION: This review described comprehensive evidence synthesis derived from systematic reviews, including methodologic quality and bias measurement. The manuscript described various methods utilized in the assessment of the quality of the systematic reviews, RCTs, diagnostic accuracy studies, and observational studies.
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Dolor Crónico , Dolor Crónico/diagnóstico , Dolor Crónico/terapia , Humanos , Revisiones Sistemáticas como AsuntoRESUMEN
Fibromyalgia (FM) is one of the most frequent generalized pain disorders with poorly understood neurobiological mechanisms. This condition accounts for an enormous proportion of healthcare costs. Despite extensive research, the etiology of FM is unknown and thus, there is no disease modifying therapy available for this condition. We show that most (if not all) patients with FM belong to a distinct population that can be segregated from a control group by their glycated hemoglobin A1c (HbA1c) levels, a surrogate marker of insulin resistance (IR). This was demonstrated by analyzing the data after introducing an age stratification correction into a linear regression model. This strategy showed highly significant differences between FM patients and control subjects (p < 0.0001 and p = 0.0002, for two separate control populations, respectively). A subgroup of patients meeting criteria for pre-diabetes or diabetes (patients with HbA1c values of 5.7% or greater) who had undergone treatment with metformin showed dramatic improvements of their widespread myofascial pain, as shown by their scores using a pre and post-treatment numerical pain rating scale (NPRS) for evaluation. Although preliminary, these findings suggest a pathogenetic relationship between FM and IR, which may lead to a radical paradigm shift in the management of this disorder.
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BACKGROUND: Several cell-based therapies have been proposed in recent years the management of low back pain, including the injection of medicinal signaling cells or mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP). However, there is only emerging clinical evidence to support their use at this time. OBJECTIVE: To assess the effectiveness of MSCs or PRP injections in the treatment of low back and lower extremity pain. STUDY DESIGN: A systematic review and metaanalysis of the effectiveness of PRP and MSCs injections in managing low back and lower extremity pain. DATA SOURCES: PubMed, Cochrane Library, US National Guideline Clearinghouse, prior systematic reviews, and reference lists. The literature search was performed from 1966 through June 2018. STUDY SELECTION: Randomized trials, observational studies, and case reports of injections of biologics into the disc, epidural space, facet joints, or sacroiliac joints. DATA EXTRACTION: Data extraction and methodological quality assessment were performed utilizing Cochrane review methodologic quality assessment and Interventional Pain Management Techniques - Quality Appraisal of Reliability and Risk of Bias Assessment (IPM-QRB) and Interventional Pain Management Techniques - Quality Appraisal of Reliability and Risk of Bias Assessment for Nonrandomized Studies (IPM-QRBNR). The evidence was summarized utilizing principles of best evidence synthesis on a scale of 1 to 5. DATA SYNTHESIS: Twenty-one injection studies met inclusion criteria. There were 12 lumbar disc injections, 5 epidural, 3 lumbar facet joint, and 3 sacroiliac joint studies RESULTS: Evidence synthesis based on a single-arm metaanalysis, randomized controlled trials (RCTs), and observational studies, disc injections of PRP and MSCs showed Level 3 evidence (on a scale of Level I through V). Evidence for epidural injections based on single-arm metaanalysis, a single randomized controlled trial and other available studies demonstrated Level 4 (on a scale of Level I through V) evidence. Similarly, evidence for lumbar facet joint injections and sacroiliac joint injections without metaanalysis demonstrated Level 4 evidence (on a scale of Level I through V). LIMITATIONS: Lack of high quality RCTs. CONCLUSION: The findings of this systematic review and single-arm metaanalysis shows that MSCs and PRP may be effective in managing discogenic low back pain, radicular pain, facet joint pain, and sacroiliac joint pain, with variable levels of evidence in favor of these techniques. KEY WORDS: Chronic low back pain, regenerative therapy, medicinal signaling or mesenchymal stem cells, platelet-rich plasma, disc injection, lumbar facet joint injections, sacroiliac joint injections.
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Dolor de la Región Lumbar/terapia , Trasplante de Células Madre Mesenquimatosas/métodos , Manejo del Dolor/métodos , Plasma Rico en Plaquetas , Medicina Regenerativa/métodos , Dolor Crónico/tratamiento farmacológico , HumanosRESUMEN
Amyloid-ß proteins (Aß) of 42 (Aß42) and 40 aa (Aß40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer's disease (AD). A number of rare mutations linked to familial AD (FAD) on the Aß precursor protein (APP), Presenilin-1 (PS1), Presenilin- 2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the ε4 allele of Apolipoprotein E (ApoE-ε4) foster the accumulation of Aß and also induce the entire spectrum of pathology associated with the disease. Aß accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by ß-site APP cleaving enzyme (BACE1) and γ-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate Aß. Although Aß accumulates in all forms of AD, the only pathways known to be affected in FAD increase Aß production by APP gene duplication or via base substitutions on APP and γ-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer Aß42 or both Aß40 and Aß42. However, the vast majority of AD patients accumulate Aß without these known mutations. This led to proposals that impairment of Aß degradation or clearance may play a key role in AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of γ-secretase inhibitors to paradoxically increase the yield of Aß and we have recently established that the mechanism is by skirting Aß degradation. This review outlines major cellular pathways of Aß degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for Aß turnover.
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Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/genética , Animales , Apolipoproteínas E/genética , Humanos , Modelos Biológicos , Mutación , Placa Amiloide/patología , Presenilina-1/metabolismo , Presenilina-2/metabolismo , Transducción de Señal/genéticaRESUMEN
BACE1 (ß-secretase) and α-secretase cleave the Alzheimer's amyloid ß protein (Aß) precursor (APP) to C-terminal fragments of 99 aa (CTFß) and 83 aa (CTFα), respectively, which are further cleaved by γ-secretase to eventually secrete Aß and Aα (a.k.a. P3) that terminate predominantly at residues 40 and 42. A number of γ-secretase inhibitors (GSIs), such as N-[N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT), have been developed with the goal of reducing Aß to treat Alzheimer's disease (AD). Although most studies show that DAPT inhibits Aß in a dose-dependent manner several studies have also detected a biphasic effect with an unexpected increase at low doses of DAPT in cell cultures, animal models and clinical trials. In this article, we confirm the increase in Aß40 and Aß42 in SH-SY5Y human neuroblastoma cells treated with low doses of DAPT and identify one of the mechanisms for this paradox. We studied the pathway by first demonstrating that stimulation of Aß, a product of γ-secretase, was accompanied by a parallel increase of its substrate CTFß, thereby demonstrating that the inhibitor was not anomalously stimulating enzyme activity at low levels. Secondly, we have demonstrated that inhibition of an Aß degrading activity, endothelin converting enzyme (ECE), yielded more Aß, but abolished the DAPT-induced stimulation. Finally, we have demonstrated that Aα, which is generated in the secretory pathway before endocytosis, is not subject to the DAPT-mediated stimulation. We therefore conclude that impairment of γ-secretase can paradoxically increase Aß by transiently skirting Aß degradation in the endosome. This study adds to the growing body of literature suggesting that preserving γ-secretase activity, rather than inhibiting it, is important for prevention of neurodegeneration.
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Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/metabolismo , Células Cultivadas , Endosomas/fisiología , Enzimas Convertidoras de Endotelina , Humanos , Metaloendopeptidasas/antagonistas & inhibidores , Metaloendopeptidasas/metabolismo , Modelos Biológicos , ProteolisisRESUMEN
OBJECTIVES: To understand the cleavage of the amyloid ß protein (Aß) precursor (APP) by γ-secretase and to determine its changes in a representative familial Alzheimer disease (FAD) mutation. METHODS: Transfected cells expressing wild-type and FAD mutant APP were analyzed for changes in the levels of the major secreted Aß species and of the corresponding intracellular C-terminal APP fragments (APP intracellular domain, AICD) generated by γ-secretase, whereas radio-sequencing was used to precisely identify the resulting cleavage site(s). RESULTS: The AICD fragment(s) generated by γ-secretase cleavage comigrated in gels with a 50-residue synthetic peptide used as control, which is smaller than the 59 and 57 residues predicted from Aß ending at positions 40 (Aß40) and 42 (Aß42), respectively. In agreement with previous findings, an FAD mutant form of presenilin 1 (PS1-M139V) significantly increased the longer Aß42 while showing trends toward reducing Aß40. AICD levels were reduced by the mutation, suggesting that γ-secretase activity may be actually impaired by the mutation. Radiosequence analysis in cells expressing wild-type PS1 detected γ-secretase cleavage sites at the Aß peptide bond L(49)-V(50) to generate a 50-amino acid (aa) AICD fragment (AICD50) and the Aß peptide bond T(48)-L(49), generating an AICD of 51 aa (AICD51). No other cleavage sites were reliably detected. CONCLUSIONS: Based on findings that the FAD mutation that increases Aß42 also reduces AICD, we propose that γ-secretase activity is impaired by FAD mutations and predict that physiologic and environmental agents that inhibit γ-secretase will actually induce AD pathogenesis rather that prevent it. Furthermore, we propose that the cleavage site to generate AICD is naturally ragged and occurs predominantly at two sites 48 and 49 aa from the start of the Aß sequence. Thus, end specific antibodies to these two sites will need to be generated to study the quantitative relationships between these two cleavages in sporadic AD and FAD.
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Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/metabolismo , Fragmentos de Péptidos/química , Secuencia de Aminoácidos , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Células CHO , Cricetulus , Datos de Secuencia Molecular , Mutación , Fragmentos de Péptidos/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismoRESUMEN
Current evidence suggests that Alzheimer's disease (AD) is a multi-factorial disease that starts with accumulation of multiple proteins. We have previously proposed that inhibition of γ-secretase may impair membrane recycling causing neurodegeneration starting at synapses (Sambamurti K., Suram A., Venugopal C., Prakasam A., Zhou Y., Lahiri D. K. and Greig N. H. A partial failure of membrane protein turnover may cause Alzheimer's disease: a new hypothesis. Curr. Alzheimer Res., 3, 2006, 81). We also proposed familal AD mutations increase Aß42 by inhibiting γ-secretase. Herein, we discuss the failure of Eli Lilly's γ-secretase inhibitor, semagacestat, in clinical trials in the light of our hypothesis, which extends the problem beyond toxicity of Aß aggregates. We elaborate that γ-secretase inhibitors lead to accumulation of amyloid precursor protein C-terminal fragments that can later be processed by γ-secretase to yields bursts of Aß to facilitate aggregation. Although we do not exclude a role for toxic Aß aggregates, inhibition of γ-secretase can affect numerous substrates other than amyloid precursor protein to affect multiple pathways and the combined accumulation of multiple peptides in the membrane may impair its function and turnover. Taken together, protein processing and turnover pathways play an important role in maintaining cellular homeostasis and unless we clearly see consistent disease-related increase in their levels or activity, we need to focus on preserving their function rather than inhibiting them for treatment of AD and similar diseases.
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Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores Enzimáticos/uso terapéutico , Animales , HumanosRESUMEN
Our group has demonstrated that the amphiphilic character of alpha-phenyl-N-tert-butyl nitrone based agents is a key feature in determining their bioactivity and protection against oxidative toxicity. In this work, we report the synthesis of a new class of amphiphilic amide nitrones. Their hydroxyl radical scavenging activity and radical reducing potency were shown using ABTS competition and ABTS(+) reduction assays, respectively. Cyclic voltammetry was used to investigate their redox behavior, and the effects of the substitution of the PBN on the charge density of the nitronyl atoms, the electron affinity, and the ionization potential were computationally rationalized. The protective effects of amphiphilic amide nitrones in cell cultures exposed to oxidotoxins greatly exceeded those exerted by the parent compound PBN. They decreased electron and proton leakage as well as hydrogen peroxide formation in isolated rat brain mitochondria at nanomolar concentration. They also significantly enhanced mitochondrial membrane potential. Finally, dopamine-induced inhibition of complex I activity was antagonized by pretreatment with these agents. These findings indicate that amphiphilic amide nitrones are much more than just radical scavenging antioxidants but may act as a new class of bioenergetic agents directly on mitochondrial electron and proton transport.
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Encéfalo/metabolismo , Mitocondrias/metabolismo , Óxidos de Nitrógeno/química , Óxidos de Nitrógeno/farmacología , Estrés Oxidativo/efectos de los fármacos , Tensoactivos/farmacología , Animales , Benzotiazoles/química , Encéfalo/efectos de los fármacos , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Peróxido de Hidrógeno/química , Espectroscopía de Resonancia Magnética , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Óxidos de Nitrógeno/síntesis química , Rotación Óptica , Oxidación-Reducción , Ratas , Ratas Sprague-Dawley , Espectrometría de Masa por Ionización de Electrospray , Ácidos Sulfónicos/química , Tensoactivos/síntesis química , Tensoactivos/químicaRESUMEN
Aging is a multi-factorial process, however, it is generally accepted that reactive oxygen species (ROS) are significant contributors. Mitochondria are important players in the aging process because they produce most of the cellular ROS. Despite the strength of the free-radical hypothesis, the use of free radical scavengers to delay aging has generated mixed results in vertebrate models, and clinical evidence of efficacy is lacking. This is in part due to the production of pro-oxidant metabolites by many antioxidants while scavenging ROS, which counteract their potentially beneficial effects. As such, a more effective approach is to enhance mitochondrial metabolism by reducing electron leakage with attendant reduction of ROS generation. Here, we report on the actions of a novel endogenous indole derivative, indolepropionamide (IPAM), which is similar in structure to melatonin. Our results suggest that IPAM binds to the rate-limiting component of oxidative phosphorylation in complex I of the respiratory chain and acts as a stabilizer of energy metabolism, thereby reducing ROS production. IPAM reversed the age-dependent decline of mitochondrial energetic capacity and increased rotifer lifespan, and it may, in fact, constitute a novel endogenous anti-aging substance of physiological importance.
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Indoles/farmacología , Longevidad/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Envejecimiento , Animales , Transporte de Electrón , Metabolismo Energético , Fosforilación Oxidativa , Sustancias Protectoras , Especies Reactivas de Oxígeno , RoedoresRESUMEN
Amyloid-beta (Abeta) accumulates in several types of retinal degeneration and in Alzheimer's disease (AD), but its source has been unclear. We detected the neuronal 695 amino acid form of amyloid-beta protein precursor (AbetaPP) in the normal retina and AbetaPP751 in the retinal pigment epithelium (RPE) and anterior eye tissues. Similar to the brain, alpha- and beta-secretases cleaved AbetaPP to soluble derivatives (sAbetaPP) alpha or beta and membrane-bound C-terminal fragments alpha or beta in the retina and RPE. Levels of sAbetaPP were particularly high in the vitreous and low in aqueous humor revealing a molecular barrier for AbetaPP. In contrast, Abeta40 and Abeta42 levels were only 50% lower in the aqueous than the vitreous humor, indicating relatively barrier-free movement of Abeta. These studies demonstrated a relatively high yield of AbetaPP and Abeta in the ocular fluids, which may serve as a trackable marker for AD. In addition, failure of free clearance from the eye may trigger retina degeneration in a manner similar to Abeta-related neurodegeneration in AD.
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Precursor de Proteína beta-Amiloide/metabolismo , Ojo/metabolismo , Secuencia de Aminoácidos , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Humor Acuoso/química , Humor Acuoso/metabolismo , Líquidos Corporales/metabolismo , Química Encefálica/fisiología , Bovinos , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Cicloheximida/farmacología , Ensayo de Inmunoadsorción Enzimática , Ojo/anatomía & histología , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Inhibidores de la Síntesis de la Proteína/farmacología , Retina/metabolismo , Retina/patología , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/metabolismo , Cuerpo Vítreo/metabolismoRESUMEN
OBJECTIVE: Hypercholesterolemia is an early risk factor for Alzheimer's disease. Low-density lipoprotein (LDL) receptors might be involved in this disorder. Our objective was to determine the risk of mild cognitive impairment in a population of patients with heterozygous familial hypercholesterolemia, a condition involving LDL receptor dysfunction and lifelong hypercholesterolemia. METHODS: By using a cohort study design, patients with familial hypercholesterolemia (N=47) meeting inclusion criteria and comparison patients without familial hypercholesterolemia (N=70) were consecutively selected from academic specialty and primary care clinics, respectively. All patients were older than 50 years. Those with disorders that could affect cognition, including history of stroke or transient ischemic attacks, were excluded from both groups. Thirteen standardized neuropsychologic tests were performed in all subjects. Mutational analysis was performed in patients with familial hypercholesterolemia, and brain imaging was obtained in those with familial hypercholesterolemia and mild cognitive impairment. RESULTS: Patients with familial hypercholesterolemia showed a high incidence of mild cognitive impairment compared with those without familial hypercholesterolemia (21.3% vs 2.9%; P=.00). This diagnosis was unrelated to structural pathology or white matter disease. There were significant differences, independent of apolipoprotein E4 or E2 status, between those with familial hypercholesterolemia and those with no familial hypercholesterolemia in several cognitive measures, all in the direction of worse performance for those with familial hypercholesterolemia. CONCLUSION: Because prior studies have shown that older patients with sporadic hypercholesterolemia do not show a higher incidence of mild cognitive impairment, the findings presented suggest that early exposure to elevated cholesterol or LDL receptor dysfunction may be risk factors for mild cognitive impairment.
Asunto(s)
Trastornos del Conocimiento/epidemiología , Hiperlipoproteinemia Tipo II/complicaciones , LDL-Colesterol/sangre , Cognición/fisiología , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/etiología , Femenino , Estudios de Seguimiento , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/epidemiología , Incidencia , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Receptores de Lipoproteína/sangre , Estudios Retrospectivos , Factores de Riesgo , España/epidemiologíaRESUMEN
Here, we examine the currently available information which supports that the adipokine, leptin, is a major player in the biology and pathology of mammalian skin and its appendages. Specifically, the potent metabolic effects of leptin and its mimetics may be utilized to improve, preserve and restore skin regeneration and hair cycle progression, and may halt or even partially reverse some aspects of skin ageing. Since leptin can enhance mitochondrial activity and biogenesis, this may contribute to the wound healing-promoting and hair growth-modulatory effects of leptin. Leptin dependent intracellular signalling by the Janus kinase 2 dependent signal transducer and activator of transcription 3, adenosine monophosphate kinase, and peroxisome proliferator-activated receptor (PPAR) gamma coactivator/PPAR converges to mediate mitochondrial metabolic activation and enhanced cell proliferation which may orchestrate the potent developmental, trophic and protective effects of leptin. Since leptin and leptin mimetics have already been clinically tested, investigative dermatology is well-advised to place greater emphasis on the systematic exploration of the cutaneous dimensions and dermatological potential of this pleiotropic hormone.