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BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to the obesity epidemic. However, non-obese MASLD (body mass index [BMI] < 25 kg/m2 for Asians) is not uncommon, especially among Asian American populations. Preliminary research has demonstrated sarcopenia, a muscle-wasting syndrome, to be a major risk factor for non-obese Chinese MASLD. This study examined serum creatinine (SCr), a sarcopenia biomarker, and other prominent MASLD biomarkers for their ability to predict moderate to severe fibrosis (≥7.5 kPa or ≥F2 fibrosis) in the Chinese American MASLD population. METHODS: A total of 296 Chinese American MASLD patients were categorized by BMI and fibrosis severity. As per World Health Organization guidelines for Asians, we identified obese MASLD (BMI ≥ 25 kg/m2) in 191 subjects (64.5%) and non-obese MASLD (BMI < 25 kg/m2) in 105 subjects (35.5%). Multivariate logistic regressions were performed to ascertain which biomarkers served as independent predictors of ≥F2 fibrosis. Wilcoxon signed-rank tests were conducted to compare MASLD cohorts (stratified by gender) and the healthy adult population on SCr distribution. RESULTS: The obese MASLD cohorts had higher rates of ≥F2 fibrosis and type 2 diabetes mellitus compared to their older, non-obese counterparts. For obese MASLD patients, higher age (P < 0.05), increased BMI (P < 0.01), increased AST (P < 0.05), and decreased platelets (P < 0.05) independently predicted ≥F2 fibrosis. For non-obese MASLD patients, lowered SCr (P < 0.05) levels served as the main predictor of ≥F2 fibrosis. Female MASLD patients had markedly lower SCr distributions (P < 0.001) compared to the healthy female population, with 26.8% having SCr levels below the normal range. CONCLUSIONS: In summary, SCr was the predominant predictor of moderate to severe fibrosis in non-obese Chinese American MASLD patients. The high rate of decreased SCr levels in Chinese American MASLD women suggests that this population may be at higher risk for muscle mass loss, which can lead to liver fat accumulation.
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BACKGROUND: Diabetic foot ulcers (DFUs) are common sequelae of diabetes mellitus. Currently, the effect of DFUs on total joint arthroplasty (TJA) outcomes is sparsely evaluated. This study investigated whether DFU patients undergoing TJA increases risk of (1) prosthetic joint infections (PJI), (2) surgical site infections (SSI), (3) sepsis, (4) readmissions, and (5) revisions. METHODS: Using PearlDiver, a retrospective query from January 1, 2010 to October 31, 2020 was performed. DFU patients undergoing total knee arthroplasty (TKA) and total hip arthroplasty (THA) were included and 1:5 propensity score matched with controls using age, sex, body mass index, and various comorbidities (33,155 TKA patients [DFU = 5,529; control = 27,626]; 17,146 THA patients [DFU = 2,862; control = 14,284]). Outcomes included rates of PJI, SSI, sepsis, readmissions, and revisions. Multivariate logistical regressions calculated odds ratios (ORs), 95% confidence intervals, and P values (P < .001 as significance threshold). RESULTS: DFU increased risk of sepsis within 90 days of TKA (OR 4.59; P < .001) and THA (OR 4.87; P < .001). DFU did not increase risk of PJI at 90 days for TKA (OR 0.8; P = .1) or THA (OR 0.85; P = .34) but did by 2 years post-TKA (OR 1.51; P < .001) and THA (OR 1.55; P < .001). Risk of SSI increased in DFU cohort following TKA and THA at 90 days and 2 years and at 90-day readmissions and 2-year revisions. CONCLUSION: DFU patients undergoing TJA demonstrated increased risk of postoperative sepsis and PJI. Furthermore, DFU patients demonstrated an increased risk of SSI, readmissions, and revisions. Providers should counsel DFU patients about postoperative risks.
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Artritis Infecciosa , Artroplastia de Reemplazo de Cadera , Artroplastia de Reemplazo de Rodilla , Diabetes Mellitus , Pie Diabético , Infecciones Relacionadas con Prótesis , Sepsis , Humanos , Estudios Retrospectivos , Pie Diabético/epidemiología , Pie Diabético/cirugía , Pie Diabético/complicaciones , Artroplastia de Reemplazo de Rodilla/efectos adversos , Artroplastia de Reemplazo de Cadera/efectos adversos , Infección de la Herida Quirúrgica/etiología , Infección de la Herida Quirúrgica/complicaciones , Artritis Infecciosa/etiología , Sepsis/complicaciones , Sepsis/epidemiología , Factores de Riesgo , Infecciones Relacionadas con Prótesis/etiología , Infecciones Relacionadas con Prótesis/complicaciones , Diabetes Mellitus/cirugíaRESUMEN
BACKGROUND: Despite advances in treatment, myocardial infarction (MI) is a leading cause of heart failure and death worldwide, with both ischemia and reperfusion (I/R) causing cardiac injury. A previous study using a mouse model of nonreperfused MI showed activation of brown adipose tissue (BAT). Recent studies showed that molecules secreted by BAT target the heart. We investigated whether BAT attenuates cardiac injury in I/R and sought to identify potential cardioprotective proteins secreted by BAT. METHODS: Myocardial I/R surgery with or without BAT transplantation was performed in wild-type (WT) mice and in mice with impaired BAT function (uncoupling protein 1 [Ucp1]-deficient mice). To identify potential cardioprotective factors produced by BAT, RNA-seq (RNA sequencing) was performed in BAT from WT and Ucp1-/- mice. Subsequently, myocardial I/R surgery with or without BAT transplantation was performed in Bmp3b (bone morphogenetic protein 3b)-deficient mice, and WT mice subjected to myocardial I/R were treated using BMP3b. RESULTS: Dysfunction of BAT in mice was associated with larger MI size after I/R; conversely, augmenting BAT by transplantation decreased MI size. We identified Bmp3b as a protein secreted by BAT after I/R. Compared with WT mice, Bmp3b-deficient mice developed larger MIs. Increasing functional BAT by transplanting BAT from WT mice to Bmp3b-deficient mice reduced I/R injury whereas transplanting BAT from Bmp3b-deficient mice did not. Treatment of WT mice with BMP3b before reperfusion decreased MI size. The cardioprotective effect of BMP3b was mediated through SMAD1/5/8. In humans, the plasma level of BMP3b increased after MI and was positively correlated with the extent of cardiac injury. CONCLUSIONS: The results of this study suggest a cardioprotective role of BAT and BMP3b, a protein secreted by BAT, in a model of I/R injury. Interventions increasing BMP3b levels or targeting Smad 1/5 may represent novel therapeutic approaches to decrease myocardial damage in I/R injury.
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Enfermedad de la Arteria Coronaria , Factor 10 de Diferenciación de Crecimiento , Infarto del Miocardio , Isquemia Miocárdica , Daño por Reperfusión Miocárdica , Animales , Humanos , Ratones , Tejido Adiposo Pardo/metabolismo , Factor 10 de Diferenciación de Crecimiento/metabolismo , Ratones Endogámicos C57BL , Infarto del Miocardio/metabolismo , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/tratamiento farmacológico , ReperfusiónRESUMEN
BACKGROUND: Diabetes mellitus (DM) and obesity are associated with total knee arthroplasty (TKA) complications. Semaglutide, a medication for DM and weight loss, can potentially affect TKA outcomes. This study investigated whether semaglutide use during TKA demonstrates fewer: (1) medical complications; (2) implant-related complications; (3) readmissions; and (4) costs. METHODS: A retrospective query was performed using a National database to 2021. Patients undergoing TKA for osteoarthritis with DM and semaglutide use were successfully propensity score-matched to controls semaglutide = 7,051; control = 34,524. Outcomes included 90-day postoperative medical complications, 2-year implant-related complications, 90-day readmissions, in-hospital lengths of stay, and costs. Multivariate logistical regressions calculated odds ratios (ORs), 95% confidence intervals, and P values (P < .003 as significance threshold after Bonferroni correction). RESULTS: Semaglutide cohorts had higher incidence and odds of myocardial infarction (1.0 versus 0.7%; OR 1.49; P = .003), acute kidney injury (4.9 versus 3.9%; OR 1.28; P < .001), pneumonia (2.8 versus 1.7%; OR 1.67; P < .001), and hypoglycemic events (1.9 versus 1.2%; OR 1.55; P < .001), but lower odds of sepsis (0 versus 0.4%; OR 0.23; P < .001). Semaglutide cohorts also had lower odds of prosthetic joint infections (2.1 versus 3.0%; OR 0.70; P < .001) and readmission (7.0 versus 9.4%; OR 0.71; P < .001), and trended toward lower odds of revisions (4.0 versus 4.5%; OR 0.86; P = .02) and 90-day costs ($15,291.66 versus $16,798.46; P = .012). CONCLUSION: Semaglutide use during TKA decreased risk for sepsis, prosthetic joint infections, and readmissions, but also increased risk for myocardial infarction, acute kidney injury, pneumonia, and hypoglycemic events.
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Lesión Renal Aguda , Artritis Infecciosa , Artroplastia de Reemplazo de Rodilla , Infarto del Miocardio , Neumonía , Sepsis , Humanos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Tiempo de Internación , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & control , Artritis Infecciosa/etiología , Neumonía/complicaciones , Sepsis/complicaciones , Hipoglucemiantes , Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/etiología , Lesión Renal Aguda/prevención & control , Infarto del Miocardio/etiología , Readmisión del PacienteRESUMEN
Fibrosis is a common and debilitating pathological process that affects many organ systems and contributes to connective tissue disorders in orthopaedics. Tendons heal after acute and chronic injury through a process of fibrovascular scar tissue formation, and soft tissue joint capsules can be affected after traumatic joint injury, leading to arthrofibrosis. Although the precise underlying mechanisms are still being elucidated, fibrosis is thought to be a consequence of dysregulated immune and cytokine signaling that leads to myofibroblast activation and proliferation and subsequent excessive collagen deposition. Current treatments for connective tissue fibrosis include physical therapy and surgery, but there are no therapies that directly target the underlying cellular and molecular mechanisms of fibrosis. Many pharmacological agents have been used to successfully target fibrosis in other tissues and organ systems and thus are a promising treatment option to fill this gap. However, limited evidence is available to guide the use of these agents in musculoskeletal connective tissues. This article provides an overview of pharmacological therapies that have potential to treat connective tissue fibrosis in patients with musculoskeletal conditions, along with the current supporting evidence and future uses of each therapy.
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Artropatías , Ortopedia , Humanos , Fibrosis , Tejido Conectivo/patología , Cicatriz/patologíaRESUMEN
BACKGROUND: Previous studies have examined the transcriptomes and mechanical properties of whole tendons in different regions of the body. However, less is known about these characteristics within a single tendon. PURPOSE: To develop a regional transcriptomic atlas and evaluate the region-specific mechanical properties of Achilles tendons. STUDY DESIGN: Descriptive laboratory study. METHODS: Achilles tendons from 2-month-old male Sprague Dawley rats were used. Tendons were isolated and divided into proximal, middle, and distal thirds for RNA sequencing (n = 5). For mechanical testing, the Achilles muscle-tendon-calcaneus unit was mounted in a custom-designed materials testing system with the unit clamped over the musculotendinous junction (MTJ) and the calcaneus secured at 90° of dorsiflexion (n = 9). Tendons were stretched to 20 N at a constant speed of 0.0167 mm/s. Cross-sectional area, strain, stress, and Young modulus were determined in each tendon region. RESULTS: An open-access, interactive transcriptional atlas was generated that revealed distinct gene expression signatures in each tendon region. The proximal and distal regions had the largest differences in gene expression, with 2596 genes significantly differentially regulated at least 1.5-fold (q < .01). The proximal tendon displayed increased expression of genes resembling a tendon phenotype and increased expression of nerve cell markers. The distal region displayed increases in genes involved in extracellular matrix synthesis and remodeling, immune cell regulation, and a phenotype similar to cartilage and bone. There was a 3.72-fold increase in Young modulus from the proximal to middle region (P < .01) and an additional 1.34-fold increase from the middle to distal region (P = .027). CONCLUSION: Within a single tendon, there are region-specific transcriptomic signatures and mechanical properties, and there is likely a gradient in the biological and functional phenotype from the proximal origin at the MTJ to the distal insertion at the enthesis. CLINICAL RELEVANCE: These findings improve our understanding of the underlying biological heterogeneity of tendon tissue and will help inform the future targeted use of regenerative medicine and tissue engineering strategies for patients with tendon disorders.
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Transcriptoma , Masculino , Ratas , Animales , Transcriptoma/genética , Ratas Sprague-DawleyRESUMEN
AIM OF THE STUDY: Non-alcoholic fatty liver disease (NAFLD), a globally prevailing chronic liver condition, refers to a spectrum of disease ranging from bland steatosis to steatohepatitis causing fibrosis without significant alcohol intake. Prominent risk factors (RFs) include obesity, type 2 diabetes mellitus, and dyslipidemia. Currently, no established hierarchy exists for the influence of metabolic RFs on NAFLD progression. This retrospective cohort study investigated and ranked the independent and combined effects of three major RFs on NAFLD progression. MATERIAL AND METHODS: 652 NAFLD patients with ≥ 1 RF were categorized by RF combination to examine yearly changes in RF severity with liver stiffness measurement (LSM) over five years. Body mass index (BMI), hemoglo- bin A1c (HbA1c), total cholesterol (TC), and LSM were reviewed. RESULTS: In patients with any single improving RF, decreases in BMI were associated with a yearly LSM change of -1.26 kPa, while decreases in HbA1c and TC were associated with a change of -0.51 kPa and -0.56 kPa, respectively. In patients with any single worsening RF, increases in BMI were correlated with an LSM change of +0.74 kPa and increases in HbA1c and TC were correlated with a change of +0.43 kPa and +0.16 kPa, respectively. Patients with three RFs had the greatest LSM changes for both improving (-3.68 kPa) and worsening (+3.19 kPa) groups. The strongest predictors for LSM change were BMI and HbA1c, with standardized ß coefficients of 0.236 and 0.226 (p < 0.001), while TC had the least influence [0.112 (p < 0.01), F(3,647) = 11.458, p < 0.001, R 2 = 0.155]. CONCLUSIONS: Obesity was the most prominent RF. Treatment of all three RFs over a five-year period presented a high likelihood of fibrosis stage regression for NAFLD patients.
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BACKGROUND: Early challenges to axonal physiology, active transport, and ultrastructure are endemic to age-related neurodegenerative disorders, including those affecting the optic nerve. Chief among these, glaucoma causes irreversible vision loss through sensitivity to intraocular pressure (IOP) that challenges retinal ganglion cell (RGC) axons, which comprise the optic nerve. Early RGC axonopathy includes distal to proximal progression that implicates a slow form of Wallerian degeneration. In multiple disease models, including inducible glaucoma, expression of the slow Wallerian degeneration (WldS) allele slows axon degeneration and confers protection to cell bodies. METHODS: Using an inducible model of glaucoma along with whole-cell patch clamp electrophysiology and morphological analysis, we tested if WldS also protects RGC light responses and dendrites and, if so, whether this protection depends upon RGC type. We induced glaucoma in young and aged mice to determine if neuroprotection by WldS on anterograde axonal transport and spatial contrast acuity depends on age. RESULTS: We found WldS protects dendritic morphology and light-evoked responses of RGCs that signal light onset (αON-Sustained) during IOP elevation. However, IOP elevation significantly reduces dendritic complexity and light responses of RGCs that respond to light offset (αOFF-Sustained) regardless of WldS. As expected, WldS preserves anterograde axon transport and spatial acuity in young adult mice, but its protection is significantly limited in aged mice. CONCLUSION: The efficacy of WldS in conferring protection to neurons and their axons varies by cell type and diminishes with age.
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Envejecimiento/patología , Glaucoma/patología , Proteínas del Tejido Nervioso , Neuroprotección/fisiología , Células Ganglionares de la Retina/patología , Animales , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
In the central nervous system, glycogen-derived bioenergetic resources in astrocytes help promote tissue survival in response to focal neuronal stress. However, our understanding of the extent to which these resources are mobilized and utilized during neurodegeneration, especially in nearby regions that are not actively degenerating, remains incomplete. Here we modeled neurodegeneration in glaucoma, the world's leading cause of irreversible blindness, and measured how metabolites mobilize through astrocyte gap junctions composed of connexin 43 (Cx43). We elevated intraocular pressure in one eye and determined how astrocyte-derived metabolites in the contralateral optic projection responded. Remarkably, astrocyte networks expand and redistribute metabolites along distances even 10 mm in length, donating resources from the unstressed to the stressed projection in response to intraocular pressure elevation. While resource donation improves axon function and visual acuity in the directly stressed region, it renders the donating tissue susceptible to bioenergetic, structural, and physiological degradation. Intriguingly, when both projections are stressed in a WT animal, axon function and visual acuity equilibrate between the two projections even when each projection is stressed for a different length of time. This equilibration does not occur when Cx43 is not present. Thus, Cx43-mediated astrocyte metabolic networks serve as an endogenous mechanism used to mitigate bioenergetic stress and distribute the impact of neurodegenerative disease processes. Redistribution ultimately renders the donating optic nerve vulnerable to further metabolic stress, which could explain why local neurodegeneration does not remain confined, but eventually impacts healthy regions of the brain more broadly.
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Astrocitos , Glaucoma/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Animales , Astrocitos/metabolismo , Astrocitos/fisiología , Conexina 43/genética , Conexina 43/metabolismo , Femenino , Uniones Comunicantes/metabolismo , Presión Intraocular/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Glaucoma is a group of optic neuropathies associated with aging and sensitivity to intraocular pressure (IOP). The disease causes vision loss through the degeneration of retinal ganglion cell neurons and their axons in the optic nerve. Using an inducible model of glaucoma, we elevated IOP in the squirrel monkey (Saimiri boliviensis) using intracameral injection of 35 µm polystyrene microbeads and measured common pathogenic outcomes in the optic projection. A 42% elevation in IOP over 28 weeks reduced anterograde transport of fluorescently-labeled cholera toxin beta from retina to the lateral geniculate nucleus (60% decrease), and to the superior colliculus (49% decrease). Pressure also reduced survival of ganglion cellaxons in the optic nerve by 22%. The same elevation caused upregulation of proteins associated with glaucomatous neurodegeneration in the retina and optic nerve, including complement 1q, interleukin 6, and brain-derived neurotrophic factor. That axon degeneration in the nerve lagged deficits in anterograde transport is consistent with progression in rodent models, while the observed protein changes also occur in tissue from human glaucoma patients. Thus, microbead occlusion in a non-human primate with a visual system similar to our own represents an attractive model to investigate neurodegenerative mechanisms and therapeutic interventions for glaucoma.
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Modelos Animales de Enfermedad , Glaucoma/fisiopatología , Presión Intraocular , Saimiri , Animales , Supervivencia Celular , Complemento C1q/análisis , Glaucoma/diagnóstico , Glaucoma/patología , Humanos , Interleucina-6/análisis , Masculino , Nervio Óptico/patología , Nervio Óptico/fisiopatología , Saimiri/fisiologíaRESUMEN
The nitric oxide - guanylyl cyclase-1 - cyclic guanylate monophosphate (NO-GC-1-cGMP) pathway has emerged as a potential pathogenic mechanism for glaucoma, a common intraocular pressure (IOP)-related optic neuropathy characterized by the degeneration of retinal ganglion cells (RGCs) and their axons in the optic nerve. NO activates GC-1 to increase cGMP levels, which are lowered by cGMP-specific phosphodiesterase (PDE) activity. This pathway appears to play a role in both the regulation of IOP, where reduced cGMP levels in mice leads to elevated IOP and subsequent RGC degeneration. Here, we investigated whether potentiation of cGMP signaling could protect RGCs from glaucomatous degeneration. We administered the PDE5 inhibitor tadalafil orally (10â¯mg/kg/day) in murine models of two forms of glaucoma - primary open angle glaucoma (POAG; GC-1-/- mice) and primary angle-closure glaucoma (PACG; Microbead Occlusion Model) - and measured RGC viability at both the soma and axon level. To determine the direct effect of increased cGMP on RGCs in vitro, we treated axotomized whole retina and primary RGC cultures with the cGMP analogue 8-Br-cGMP. Tadalafil treatment increased plasma cGMP levels in both models, but did not alter IOP or mean arterial pressure. Nonetheless, tadalafil treatment prevented degeneration of RGC soma and axons in both disease models. Treatment of whole, axotomized retina and primary RGC cultures with 8-Br-cGMP markedly attenuated both necrotic and apoptotic cell death pathways in RGCs. Our findings suggest that enhancement of the NO-GC-1-cGMP pathway protects the RGC body and axon in murine models of POAG and PACG, and that enhanced signaling through this pathway may serve as a novel glaucoma treatment, acting independently of IOP.
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GMP Cíclico/metabolismo , Glaucoma/metabolismo , Degeneración Retiniana/metabolismo , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Animales , Apoptosis/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Glaucoma/prevención & control , Guanilato Ciclasa/genética , Guanilato Ciclasa/metabolismo , Ratones Noqueados , Inhibidores de Fosfodiesterasa 5/administración & dosificación , Ratas Sprague-Dawley , Degeneración Retiniana/prevención & control , Células Ganglionares de la Retina/efectos de los fármacos , Transducción de Señal , Tadalafilo/administración & dosificaciónRESUMEN
BACKGROUND: Volatile anesthetics increase levels of the neurotransmitter nitric oxide (NO) and the secondary messenger molecule cyclic guanosine monophosphate (cGMP) in the brain. NO activates the enzyme guanylyl cyclase (GC) to produce cGMP. We hypothesized that the NO-GC-cGMP pathway contributes to anesthesia-induced unconsciousness. METHODS: Sevoflurane-induced loss and return of righting reflex (LORR and RORR, respectively) were studied in wild-type mice (WT) and in mice congenitally deficient in the GC-1α subunit (GC-1-/- mice). Spatial distributions of GC-1α and the GC-2α subunit in the brain were visualized by in situ hybridization. Brain cGMP levels were measured in WT and GC-1-/- mice after inhaling oxygen with or without 1.2% sevoflurane for 20 min. RESULTS: Higher concentrations of sevoflurane were required to induce LORR in GC-1-/- mice than in WT mice (1.5 ± 0.1 vs. 1.1 ± 0.2%, respectively, n = 14 and 14, P < 0.0001). Similarly, RORR occurred at higher concentrations of sevoflurane in GC-1-/- mice than in WT mice (1.0 ± 0.1 vs. 0.8 ± 0.1%, respectively, n = 14 and 14, P < 0.0001). Abundant GC-1α and GC-2α mRNA expression was detected in the cerebral cortex, medial habenula, hippocampus, and cerebellum. Inhaling 1.2% sevoflurane for 20 min increased cGMP levels in the brains of WT mice from 2.6 ± 2.0 to 5.5 ± 3.7 pmol/mg protein (n = 13 and 10, respectively, P = 0.0355) but not in GC-1-/- mice. CONCLUSION: Congenital deficiency of GC-1α abolished the ability of sevoflurane anesthesia to increase cGMP levels in the whole brain, and increased the concentration of sevoflurane required to induce LORR. Impaired NO-cGMP signaling raises the threshold for producing sevoflurane-induced unconsciousness in mice.
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Anestésicos por Inhalación/farmacología , Guanilato Ciclasa/genética , Éteres Metílicos/farmacología , Animales , Encéfalo/metabolismo , Guanosina Monofosfato/metabolismo , Ratones Noqueados , Reflejo de Enderezamiento/efectos de los fármacos , SevofluranoRESUMEN
The processes that define mammalian physiology evolved millions of years ago in response to ancient signaling molecules, most of which were acquired by ingestion and digestion. In this way, evolution inextricably linked diet to all major physiological systems including the nervous system. The importance of diet in neurological development is well documented, although the mechanisms by which diet-derived signaling molecules (DSMs) affect cognition are poorly understood. Studies on the positive impact of nutritive and non-nutritive bioactive molecules on brain function are encouraging but lack the statistical power needed to demonstrate strong positive associations. Establishing associations between DSMs and cognitive functions like mood, memory and learning are made even more difficult by the lack of robust phenotypic markers that can be used to accurately and reproducibly measure the effects of DSMs. Lastly, it is now apparent that processes like neurogenesis and neuroplasticity are embedded within layers of interlocked signaling pathways and gene regulatory networks. Within these interdependent pathways and networks, the various transducers of DSMs are used combinatorially to produce those emergent adaptive gene expression responses needed for stimulus-induced neurogenesis and neuroplasticity. Taken together, it appears that cognition is encoded genomically and modified by epigenetics and epitranscriptomics to produce complex transcriptional programs that are exquisitely sensitive to signaling molecules from the environment. Models for how DSMs mediate the interplay between the environment and various neuronal processes are discussed in the context of the food-brain axis.
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Human studies suggest that insulin resistance and obesity are associated with a decrease in B-type natriuretic peptide (BNP) plasma concentrations. The objective of the study was to gain insights into the mechanisms involved in the association between insulin resistance and decreased BNP plasma concentrations. Mice fed a high-fat, high-fructose (HFHF) diet for 4 weeks developed mild obesity and systemic insulin resistance. Elevated plasma concentrations of insulin, glucose and triglycerides were noted. The HFHF diet was also associated with myocardial insulin resistance, characterized by an impaired response of the phosphoinositide 3-kinase-AKT (PI3K-AKT) pathway to insulin in the left ventricle. Myocardial BNP expression and protein were decreased in HFHF-fed mice compared with control animals. Exposure of cardiomyocytes to 100 nm insulin activated PI3K-AKT signalling (15 min) and induced a 1.9 ± 0.3-fold increase in BNP gene expression (6 h). Prolonged exposure of cardiomyocytes to a high insulin concentration (100 nm) for 48 h induced insulin resistance, characterized by an impaired response of the PI3K-AKT signalling pathway and a decreased response of the BNP gene expression to insulin. The decreased response in BNP gene expression was reproduced by treating cardiomyocytes for 7 h with a PI3-kinase inhibitor (wortmannin). In conclusion, HFHF diet in vivo, prolonged exposure to an elevated concentration of insulin or inhibition of the PI3K-AKT pathway in vitro all decrease BNP mRNA levels; this decrease may in turn contribute to the decreased BNP peptide concentrations in plasma observed in insulin-resistant individuals.
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Insulina/fisiología , Péptido Natriurético Encefálico/biosíntesis , Obesidad/metabolismo , Androstadienos/farmacología , Animales , Glucemia/metabolismo , Dieta , Dieta Alta en Grasa , Inhibidores Enzimáticos/farmacología , Expresión Génica/efectos de los fármacos , Jarabe de Maíz Alto en Fructosa , Insulina/sangre , Resistencia a la Insulina , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Triglicéridos/sangre , WortmaninaRESUMEN
Brown adipose tissue (BAT) has well recognized thermogenic properties mediated by uncoupling protein 1 (UCP1); more recently, BAT has been demonstrated to modulate cardiovascular risk factors. To investigate whether BAT also affects myocardial injury and remodeling, UCP1-deficient (UCP1(-/-)) mice, which have dysfunctional BAT, were subjected to catecholamine-induced cardiomyopathy. At baseline, there were no differences in echocardiographic parameters, plasma cardiac troponin I (cTnI) or myocardial fibrosis between wild-type (WT) and UCP1(-/-) mice. Isoproterenol infusion increased cTnI and myocardial fibrosis and induced left ventricular (LV) hypertrophy in both WT and UCP1(-/-) mice. UCP1(-/-) mice also demonstrated exaggerated myocardial injury, fibrosis, and adverse remodeling, as well as decreased survival. Transplantation of WT BAT to UCP1(-/-) mice prevented the isoproterenol-induced cTnI increase and improved survival, whereas UCP1(-/-) BAT transplanted to either UCP1(-/-) or WT mice had no effect on cTnI release. After 3 days of isoproterenol treatment, phosphorylated AKT and ERK were lower in the LV's of UCP1(-/-) mice than in those of WT mice. Activation of BAT was also noted in a model of chronic ischemic cardiomyopathy, and was correlated to LV dysfunction. Deficiency in UCP1, and accompanying BAT dysfunction, increases cardiomyocyte injury and adverse LV remodeling, and decreases survival in a mouse model of catecholamine-induced cardiomyopathy. Myocardial injury and decreased survival are rescued by transplantation of functional BAT to UCP1(-/-) mice, suggesting a systemic cardioprotective role of functional BAT. BAT is also activated in chronic ischemic cardiomyopathy.
Asunto(s)
Tejido Adiposo Pardo/fisiología , Cardiomiopatías/patología , Cardiomiopatías/fisiopatología , Catecolaminas/efectos adversos , Remodelación Ventricular , Tejido Adiposo Pardo/trasplante , Animales , Biomarcadores/metabolismo , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Cardiomiopatías/inducido químicamente , Cardiomiopatías/diagnóstico por imagen , Cardiotónicos/metabolismo , Catecolaminas/administración & dosificación , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fibrosis , Regulación de la Expresión Génica/efectos de los fármacos , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/enzimología , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Canales Iónicos/deficiencia , Canales Iónicos/genética , Canales Iónicos/metabolismo , Isoproterenol/farmacología , Masculino , Ratones Endogámicos C57BL , Proteínas Mitocondriales/deficiencia , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Miocardio/patología , Miocitos Cardíacos , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Análisis de Supervivencia , Ultrasonografía , Proteína Desacopladora 1 , Remodelación Ventricular/efectos de los fármacosRESUMEN
Filamentous cyanobacteria of the order Nostocales display typical properties of multicellular organisms. In response to nitrogen starvation, some vegetative cells differentiate into heterocysts, where fixation of N(2) takes place. Heterocysts provide a micro-oxic compartment to protect nitrogenase from the oxygen produced by the vegetative cells. Differentiation involves fundamental remodeling of the gram-negative cell wall by deposition of a thick envelope and by formation of a neck-like structure at the contact site to the vegetative cells. Cell wall-hydrolyzing enzymes, like cell wall amidases, are involved in peptidoglycan maturation and turnover in unicellular bacteria. Recently, we showed that mutation of the amidase homologue amiC2 gene in Nostoc punctiforme ATCC 29133 distorts filament morphology and function. Here, we present the functional characterization of two amiC paralogues from Anabaena sp. strain PCC 7120. The amiC1 (alr0092) mutant was not able to differentiate heterocysts or to grow diazotrophically, whereas the amiC2 (alr0093) mutant did not show an altered phenotype under standard growth conditions. In agreement, fluorescence recovery after photobleaching (FRAP) studies showed a lack of cell-cell communication only in the AmiC1 mutant. Green fluorescent protein (GFP)-tagged AmiC1 was able to complement the mutant phenotype to wild-type properties. The protein localized in the septal regions of newly dividing cells and at the neck region of differentiating heterocysts. Upon nitrogen step-down, no mature heterocysts were developed in spite of ongoing heterocyst-specific gene expression. These results show the dependence of heterocyst development on amidase function and highlight a pivotal but so far underestimated cellular process, the remodeling of peptidoglycan, for the biology of filamentous cyanobacteria.