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Congestive heart failure is one of the most prevalent and deadly complications of type 2 diabetes that is frequently associated with pulmonary dysfunction. Among many factors that contribute to development and progression of diabetic complications is angiotensin II (Ang2). Activation of pathological arm of renin-angiotensin system results in increased levels of Ang2 and signaling through angiotensin type 1 receptor. This pathway is well recognized for its role in induction of oxidative stress (OS), inflammation, hypertrophy and fibrosis. Angiotensin (1-7) [A(1-7)], through activation of Mas receptor, opposes the actions of Ang2 which can result in the amelioration of diabetic complications; enhancing the overall welfare of diabetic patients. In this study, 8 week-old db/db mice were administered A(1-7) daily via subcutaneous injections. After 16 weeks of treatment, echocardiographic assessment of heart function demonstrated significant improvement in cardiac output, stroke volume and shortening fraction in diabetic animals. A(1-7) also prevented cardiomyocyte hypertrophy, apoptosis, lipid accumulation, and decreased diabetes-induced fibrosis and OS in the heart tissue. Treatment with A(1-7) reduced levels of circulating proinflammatory cytokines that contribute to the low grade inflammation observed in diabetes. In addition, lung pathologies associated with type 2 diabetes, including fibrosis and congestion, were decreased with treatment. OS and macrophage infiltration were also reduced in the lungs after treatment with A(1-7). Long-term administration of A(1-7) to db/db mice is effective in improving heart and lung function in db/db mice. Treatment prevented pathological remodeling of the tissues and reduced OS, fibrosis and inflammation.
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Angiotensina I/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Cardiotônicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Angiotensina I/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Citocinas/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Fibrose , Coração/efeitos dos fármacos , Coração/fisiologia , Hipoglicemiantes/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologiaRESUMO
In the event of a nuclear disaster, the individuals proximal to the source of radiation will be exposed to combined radiation injury. As irradiation delays cutaneous repair, the purpose of this study was to elucidate the effect of combined radiation and burn injury (CRBI) on apoptosis and inflammation at the site of skin injury. Male C57Bl/6 mice were exposed to no injury, thermal injury only, radiation only (1 and 6 Gy) and CRBI (1 and 6 Gy) and euthanized at various times after for skin collection. TUNEL staining revealed that the CRBI 6 Gy group had a delayed and increased apoptotic response. This correlated with decreased recovery of live cells as compared to the other injuries. Similar response was observed when cleaved-caspase-3 immunohistochemical staining was compared between CRBI 6 Gy and thermal injury. TNFR1, caspase 8, Bax and IL-6 mRNA expression revealed that the higher CRBI group had delayed increase in mRNA expression as compared to thermal injury alone. RIPK1 mRNA expression and necrotic cell counts were delayed in the CRBI 6 Gy group to day 5. TNF-α and NFκB expression peaked in the CRBI 6 Gy group at day 1 and was much higher than the other injuries. Also, inflammatory cell counts in the CRBI 6 Gy group were lower at early time points as compared to thermal injury by itself. These data suggest that CRBI delays and exacerbates apoptosis and inflammation in skin as well as increases necrosis thus resulting in delayed wound healing.
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Apoptose/efeitos da radiação , Queimaduras/patologia , Lesões Experimentais por Radiação/patologia , Lesões por Radiação/metabolismo , Pele/efeitos da radiação , Animais , Biomarcadores/metabolismo , Queimaduras/metabolismo , Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Necrose/metabolismo , Lesões Experimentais por Radiação/metabolismo , Pele/metabolismo , TranscriptomaRESUMO
Amyotrophic lateral sclerosis (ALS) continues to pose a significant challenge due to the disease complexity and heterogeneous manifestations. Despite recent drug approvals, there remains a critical need for the development of more effective therapies. This review explores the underlying mechanisms involved; including neuroinflammation, glutamate mediated excitotoxicity, mitochondrial dysfunction, and hypermetabolism, and how researchers are trying to develop novel drugs to target these pathways. While progress has been made, the unmet need of ALS patients highlights the urgency for continued research and resource allocation in the pursuit of effective treatments.
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BACKGROUND: Higher order regulation of autonomic function is maintained by the coordinated activity of specific cortical and subcortical brain regions, collectively referred to as the central autonomic network (CAN). Autonomic changes are frequently observed in Alzheimer's disease (AD) and dementia, but no studies to date have investigated whether plasma AD biomarkers are associated with CAN functional connectivity changes in at risk older adults. METHODS: Independently living older adults (N = 122) without major neurological or psychiatric disorder were recruited from the community. Participants underwent resting-state brain fMRI and a CAN network derived from a voxel-based meta-analysis was applied for overall, sympathetic, and parasympathetic CAN connectivity using the CONN Functional Toolbox. Sensorimotor network connectivity was studied as a negative control. Plasma levels of amyloid (Aß42, Aß40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were assessed using digital immunoassay. The relationship between plasma AD biomarkers and within-network functional connectivity was studied using multiple linear regression adjusted for demographic covariates and Apolipoprotein E (APOE) genotype. Interactive effects with APOE4 carrier status were also assessed. RESULTS: All autonomic networks were positively associated with Aß42/40 ratio and remained so after adjustment for age, sex, and APOE4 carrier status. Overall and parasympathetic networks were negatively associated with GFAP. The relationship between the parasympathetic CAN and GFAP was moderated by APOE4 carrier status, wherein APOE4 carriers with low parasympathetic CAN connectivity displayed the highest plasma GFAP concentrations (B = 910.00, P = .004). Sensorimotor connectivity was not associated with any plasma AD biomarkers, as expected. CONCLUSION: The present study findings suggest that CAN function is associated with plasma AD biomarker levels. Specifically, lower CAN functional connectivity is associated with decreased plasma Aß42/40, indicative of cerebral amyloidosis, and increased plasma GFAP in APOE4 carriers at risk for AD. These findings could suggest higher order autonomic and parasympathetic dysfunction in very early-stage AD, which may have clinical implications.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Imageamento por Ressonância Magnética , Humanos , Feminino , Doença de Alzheimer/sangue , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/diagnóstico por imagem , Idoso , Masculino , Biomarcadores/sangue , Peptídeos beta-Amiloides/sangue , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Fragmentos de Peptídeos/sangue , Sistema Nervoso Autônomo/fisiopatologia , Proteína Glial Fibrilar Ácida/sangue , Idoso de 80 Anos ou mais , Proteínas de Neurofilamentos/sangue , Doenças do Sistema Nervoso Autônomo/sangue , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Doenças do Sistema Nervoso Autônomo/etiologiaRESUMO
Visit-to-visit blood pressure variability (BPV) predicts age-related hippocampal atrophy, neurodegeneration, and memory decline in older adults. Beat-to-beat BPV may represent a more reliable and efficient tool for prospective risk assessment, but it is unknown whether beat-to-beat BPV is similarly associated with hippocampal neurodegeneration, or with plasma markers of neuroaxonal/neuroglial injury. Independently living older adults without a history of dementia, stroke, or other major neurological disorders were recruited from the community (N = 104; age = 69.5 ± 6.7 (range 55-89); 63% female). Participants underwent continuous blood pressure monitoring, brain MRI, venipuncture, and cognitive testing over two visits. Hippocampal volumes, plasma neurofilament light, and glial fibrillary acidic protein levels were assessed. Beat-to-beat BPV was quantified as systolic blood pressure average real variability during 7-min of supine continuous blood pressure monitoring. The cross-sectional relationship between beat-to-beat BPV and hippocampal volumes, cognitive domain measures, and plasma biomarkers was assessed using multiple linear regression with adjustment for demographic covariates, vascular risk factors, and average systolic blood pressure. Elevated beat-to-beat BPV was associated with decreased left hippocampal volume (P = .008), increased plasma concentration of glial fibrillary acidic protein (P = .006), and decreased memory composite score (P = .02), independent of age, sex, average systolic blood pressure, total intracranial volume, and vascular risk factor burden. In summary, beat-to-beat BPV is independently associated with decreased left hippocampal volume, increased neuroglial injury, and worse memory ability. Findings are consistent with prior studies examining visit-to-visit BPV and suggest beat-to-beat BPV may be a useful marker of hemodynamic brain injury in older adults.
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Background: Blood pressure variability is increasingly linked with cerebrovascular disease and Alzheimer's disease, independent of mean blood pressure levels. Elevated blood pressure variability is also associated with attenuated cerebrovascular reactivity, which may have implications for functional hyperemia underpinning brain network connectivity. It remains unclear whether blood pressure variability is related to functional network connectivity. We examined relationships between beat-to-beat blood pressure variability and functional connectivity in brain networks vulnerable to aging and Alzheimer's disease. Methods: 53 community-dwelling older adults (mean [SD] age = 69.9 [7.5] years, 62.3% female) without history of dementia or clinical stroke underwent continuous blood pressure monitoring and resting state fMRI scan. Blood pressure variability was calculated as variability independent of mean. Functional connectivity was determined by resting state fMRI for several brain networks: default, salience, dorsal attention, fronto-parietal, and language. Multiple linear regression examined relationships between short-term blood pressure variability and functional network connectivity. Results: Elevated short-term blood pressure variability was associated with lower functional connectivity in the default network (systolic: standardized ß = -0.30 [95% CI -0.59, -0.01], p = .04). There were no significant associations between blood pressure variability and connectivity in other functional networks or between mean blood pressure and functional connectivity in any network. Discussion: Older adults with elevated short-term blood pressure variability exhibit lower resting state functional connectivity in the default network. Findings support the role of blood pressure variability in neurovascular dysfunction and Alzheimer's disease. Blood pressure variability may represent an understudied early vascular risk factor for neurovascular dysfunction relevant to Alzheimer's disease, with potential therapeutic implications.
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The renin-angiotensin system (RAS) plays an important role in wound repair; however, little is known pertaining to RAS expression in response to thermal injury and the combination of radiation plus burn injury (CRBI). The purpose of this study was to test the hypothesis that thermal injury modifies expression of RAS components and CRBI delayed this up-regulation of RAS. Skin from uninjured mice was compared with mice receiving local thermal injury or CRBI (injury site). Skin was analyzed for gene and protein expression of RAS components. There was an initial increase in the expression of various components of RAS following thermal injury. However, in the higher CRBI group there is an initial decrease in AT(1b) (vasoconstriction, pro-proliferative), AT(2) (vasodilation, differentiation), and Mas (vasodilation, anti-inflammatory) gene expression. This corresponded with a delay and decrease in AT(1) , AT(2) , and MAS protein expression in fibroblasts and keratinocytes. The reduction in RAS receptor positive fibroblasts and keratinocytes correlated with a reduction in collagen deposition and keratinocyte infiltration into the wounded area resulting in a delay of reepithelialization following CRBI. These data support the hypothesis that delayed wound healing observed in subjects following radiation exposure may be in part due to decreased expression of RAS.
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Queimaduras/metabolismo , Colágeno/metabolismo , Lesões Experimentais por Radiação/metabolismo , Sistema Renina-Angiotensina , Pele/metabolismo , Cicatrização , Bloqueadores do Receptor Tipo 1 de Angiotensina II/metabolismo , Bloqueadores do Receptor Tipo 2 de Angiotensina II/metabolismo , Animais , Queimaduras/patologia , Modelos Animais de Doenças , Feminino , Fibroblastos/metabolismo , Expressão Gênica , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Lesões Experimentais por Radiação/patologia , Pele/lesões , Pele/patologia , Regulação para CimaRESUMO
BACKGROUND: Patients with systemic lupus erythematosus have a higher incidence of cardiovascular disease than the general population. Antihypertensive drugs that modify the renin-angiotensin system (RAS) are used to protect renal function in lupus nephritis and may also have extrarenal effects that lower cardiovascular disease risk due to their anti-inflammatory properties. In this study, we compared the effects of RAS vs non-RAS antihypertensive drugs on cardiovascular disease incidence in patients with lupus. METHODS: Using a medical insurance claims dataset, 220,168 patients with lupus were identified, of which 31,647 patients (4018 patients prescribed RAS drugs, 27,629 patients prescribed non-RAS drugs) were eligible for the study. Patients had a mean age of 46.1 years, were 93.0% female, and healthy (96.9% Charlson Comorbidity Index score 0-4). Patients in the 2 drug groups were propensity score matched using demographic data, risk factors, and comorbidities. RESULTS: Use of RAS vs non-RAS drugs lowered the relative risk (RR) of diagnosis of cardiovascular disease (RR 0.80; 95% confidence interval [CI], 0.74-0.87), which was more pronounced after propensity score matching (RR 0.62; 95% CI, 0.57-0.68). The decreased risk in cardiovascular disease occurred regardless of lupus nephritis status (with lupus nephritis: RR 0.51; 95% CI, 0.39-0.65; without lupus nephritis: RR 0.65; 95% CI, 0.59-0.72). RAS-modifying therapies significantly increased cardiovascular disease-free survival probability over a 5-year period (86.0% vs 78.3% probability). CONCLUSIONS: RAS-modifying drugs reduced the risk of cardiovascular disease in patients with systemic lupus erythematosus in this dataset. These findings have the potential to impact clinical decision-making with regards to hypertension management in patients with lupus.
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Doenças Cardiovasculares , Hipertensão , Nefrite Lúpica , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Anti-Hipertensivos/efeitos adversos , Sistema Renina-Angiotensina , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Nefrite Lúpica/complicações , Nefrite Lúpica/tratamento farmacológico , Estudos Retrospectivos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Fatores de Risco , Antagonistas de Receptores de Angiotensina/uso terapêuticoRESUMO
Background: Increased blood pressure variability (BPV) is a risk factor for cerebral small vessel disease (CSVD) and neurodegeneration, independent of age and average blood pressure, particularly in apolipoprotein E4 (APOE4) carriers. However, it remains uncertain whether BPV elevation is a cause or a consequence of vascular brain injury, or to what degree injury to the central autonomic network (CAN) may contribute to BPV-associated risk in APOE4 carriers. Methods: Independently living older adults (n=70) with no history of stroke or dementia were recruited from the community and underwent 5 minutes of resting beat-to-beat blood pressure monitoring, genetic testing, and brain MRI. Resting BPV, APOE genotype, CSVD burden on brain MRI, and resting state CAN connectivity by fMRI were analyzed. Causal mediation and moderation analysis evaluated BPV and CAN effects on CSVD in APOE4 carriers (n=37) and non-carriers (n=33). Results: Higher BPV was associated with the presence and extent of CSVD in APOE4 carriers, but not non-carriers, independent of CAN connectivity (B= 18.92, P= .02), and CAN connectivity did not mediate the relationship between BPV and CSVD. In APOE4 carriers, CAN connectivity moderated the relationship between BPV and CSVD, whereby BPV effects on CSVD were greater in those with lower CAN connectivity (B= 36.43, P= .02). Conclusions: Older APOE4 carriers with higher beat-to-beat BPV exhibit more extensive CSVD, independent of average blood pressure, and the strength of CAN connectivity does not mediate these effects. Findings suggest increased BPV is more likely a cause, not a consequence, of CSVD. BPV is more strongly associated with CSVD in APOE4 carriers with lower rsCAN connectivity, suggesting CAN dysfunction and BPV elevation may have synergistic effects on CSVD. Further studies are warranted to understand the interplay between BPV and CAN function in APOE4 carriers.
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BACKGROUND: Elevated blood pressure (BP) variability is predictive of increased risk for stroke, cerebrovascular disease, and other vascular brain injuries, independent of traditionally studied average BP levels. However, no studies to date have evaluated whether BP variability is related to diminished cerebrovascular reactivity, which may represent an early marker of cerebrovascular dysfunction presaging vascular brain injury. METHODS: The present study investigated BP variability and cerebrovascular reactivity in a sample of 41 community-dwelling older adults (mean age 69.6 [SD 8.7] years) without a history of dementia or stroke. Short-term BP variability was determined from BP measurements collected continuously during a 5-minute resting period followed by cerebrovascular reactivity during 5-minute hypocapnia and hypercapnia challenge induced by visually guided breathing conditions. Cerebrovascular reactivity was quantified as percent change in cerebral perfusion by pseudo-continuous arterial spin labeling (pCASL)-MRI per unit change in end-tidal CO2. RESULTS: Elevated systolic BP variability was related to lower whole brain cerebrovascular reactivity during hypocapnia (ß = -0.43 [95% CI -0.73, -0.12]; P = 0.008; adjusted R2 =.11) and hypercapnia (ß = -0.42 [95% CI -0.77, -0.06]; P = 0.02; adjusted R2 = 0.19). CONCLUSIONS: Findings add to prior work linking BP variability and cerebrovascular disease burden and suggest BP variability may also be related to prodromal markers of cerebrovascular dysfunction and disease, with potential therapeutic implications.
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Transtornos Cerebrovasculares , Hipertensão , Acidente Vascular Cerebral , Humanos , Idoso , Hipercapnia , Hipocapnia , Pressão Sanguínea/fisiologia , Circulação Cerebrovascular/fisiologiaRESUMO
Dilation of perivascular spaces (PVS) in the brain may indicate poor fluid drainage due to the accumulation of perivascular cell debris, waste, and proteins, including amyloid-beta (Aß). No prior study has assessed whether plasma Aß levels are related to PVS in older adults without dementia. Independently living older adults (N = 56, mean age = 68.2 years; Standard deviation (SD) = 6.5; 30.4% male) free of dementia or clinical stroke were recruited from the community and underwent brain MRI and venipuncture. PVS were qualitatively scored and dichotomized to low PVS burden (scores 0-1,) or high PVS burden (score>1). Plasma was assayed using a Quanterix Simoa Kit to quantify Aß42 and Aß40 levels. A significant difference was observed in plasma Aß42/Aß40 ratio between low and high PVS burden, controlling for age (F[1, 53] = 5.59, p = 0.022, η2 = 0.10), with lower Aß42/Aß40 ratio in the high PVS burden group. Dilation of PVS is associated with a lower plasma Aß42/Aß40 ratio, which may indicate higher cortical amyloid deposition. Future longitudinal studies examining PVS changes, and the pathogenesis of AD are warranted.
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Doença de Alzheimer , Masculino , Humanos , Idoso , Feminino , Peptídeos beta-Amiloides , Fragmentos de Peptídeos , Encéfalo , BiomarcadoresRESUMO
This randomized, double-blind, placebo-controlled Phase 2 clinical trial explored NorLeu(3)-A(1-7) (DSC127) safety and healing efficacy in diabetic foot ulcers. Patients with chronic, noninfected, neuropathic, or neuroischemic plantar Wagner Grade 1 or 2 foot ulcers (n = 172) were screened for nonhealing. Subjects were randomized to receive 4 weeks' once-daily topical treatment with 0.03% DSC127 (n = 26), 0.01% DSC127 (n = 27), or Placebo (n = 24), followed by 20 weeks' standard of care. DSC127 was assessed for safety (including laboratory values and adverse events), primary efficacy (% ulcers completely epithelialized at Week 12), and durability of effect. Baseline, demography, and safety parameters were compared between intent-to-treat groups and were comparable. Dose-response curves for DSC127 effect on % area reduction from baseline at Week 12 (40% placebo; 67% 0.01% DSC127; 80% 0.03% DSC127) and 24 (23% placebo; 53% 0.01% DSC127; 95% 0.03% DSC127) followed a log-linear pattern for both intent-to-treat and per-protocol populations. Covariate analysis compared reduction in ulcer area, depth, and volume from baseline; reductions in the 0.03% DSC127 group were greater at Weeks 12 and 24. Placebo-treated ulcers healed in a median 22 weeks vs. 8.5 weeks for 0.03%DSC127 (p = 0.04). This study provides preliminary evidence that DSC127 is safe and effective in accelerating the healing of diabetic foot ulcers.
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Indutores da Angiogênese/farmacologia , Angiotensina II/farmacologia , Pé Diabético/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Cicatrização/efeitos dos fármacos , Administração Tópica , Indutores da Angiogênese/administração & dosagem , Angiotensina II/administração & dosagem , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Pé Diabético/patologia , Pé Diabético/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/administração & dosagem , Resultado do TratamentoRESUMO
In this review, the relationship between bioenergetics, mitochondrial dysfunction, and inflammation will be and how they contribute to neurodegeneration, specifically in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) will be reviewed. Long-term changes in mitochondrial function, autophagy dysfunction, and immune activation are commonalities shared across these age-related disorders. Genetic risk factors for these diseases support an autophagy-immune connection in the underlying pathophysiology. Critical areas of deeper evaluation in these bioenergetic processes may lead to potential therapeutics with efficacy across multiple neurodegenerative diseases.
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Objective: We sought to determine the impact of Type 2 Diabetes Mellitus (T2D) anti-hyperglycemic medications (A-HgM) on risk of Alzheimer's disease (AD) and related dementias (ADRD) outcomes including vascular dementia, and non-AD dementia such as frontotemporal, Lewy body, and mixed etiology dementias. Research Design and Methods: This retrospective cohort study used the US-based Mariner claims dataset. 1,815,032 T2D participants 45 years and older with records 6 months prior and at least 3 years after the diagnosis of T2D were included. Claims were surveyed for a diagnosis of AD and ADRD 12 months post T2D diagnosis. A propensity score approach was used to minimize selection bias. Analyses were conducted between January 1st and February 28th, 2021. Results: In this cohort study A-HgM exposure was associated with decreased diagnosis of AD (RR, 0.61; 95% CI, 0.59-0.62; p < 0.001), vascular dementia (RR, 0.72; 95% CI, 0.69-0.74; p < 0.001) and non-AD dementia (RR, 0.67; 95% CI, 0.66-0.68; p < 0.001). Metformin was associated with the greatest risk reduction and insulin with the least reduction in risk compared to patients not receiving A-HgM for ADRD risk. Of interest, patients with a diagnosis of AD, while either on metformin or insulin, were older in age and predominately female, than individuals on these drugs that did not develop AD. Mean (SD) follow-up was 6.2 (1.8) years. Conclusion: After controlling for age, sex, and comorbidities, A-HgM in patients with T2D was associated with a reduced risk of AD and ADRD. These findings provide evidence in support of T2D as a risk factor for AD and ADRD and the beneficial impact of early and effective control of hyperglycemia to mitigate risk.
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BACKGROUND: Prostate cancer and multiple neurodegenerative diseases (NDD) share an age-associated pattern of onset. Therapy of prostate cancer is known to impact cognitive function. The objective of this study was to determine the impact of multiple classes of androgen-targeting therapeutics (ATT) on the risk of NDD. METHODS: A retrospective cohort study of men aged 45 and older with prostate within the US-based Mariner claims data set between January 1 and 27, 2021. A propensity score approach was used to minimize measured and unmeasured selection bias. Disease risk was determined using Kaplan-Meier survival analyses. RESULTS: Of the 1,798,648 men with prostate cancer, 209,722 met inclusion criteria. Mean (SD) follow-up was 6.4 (1.8) years. In the propensity score-matched population, exposure to ATT was associated with a minimal increase in NDD incidence (relative risk [RR], 1.07; 95% CI, 1.05-1.10; p < 0.001). However, GnRH agonists alone were associated with significantly increased NDD risk (RR, 1.47; 95% CI, 1.30-1.66; p <0.001). Abiraterone, commonly administered with GnRH agonists and low-dose prednisone, was associated with a significantly decreased risk (RR, 0.77; 95% CI, 0.68-0.87; p < 0.001) of any NDD. CONCLUSIONS: Among patients with prostate cancer, GnRH agonist exposure was associated with an increased NDD risk. Abiraterone acetate reduced the risks of Alzheimer's disease and Parkinson's disease conferred by GnRH agonists, whereas the risk for ALS was reduced by androgen receptor inhibitors. Outcomes of these analyses contribute to addressing controversies in the field and indicate that GnRH agonism may be a predictable instigator of risk for NDD with opportunities for risk mitigation in combination with another ATT.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Hormônio Liberador de Gonadotropina , Doenças Neurodegenerativas , Neoplasias da Próstata , Antagonistas de Androgênios/efeitos adversos , Androgênios , Hormônio Liberador de Gonadotropina/agonistas , Humanos , Masculino , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/epidemiologia , Estudos RetrospectivosRESUMO
Neurological aging is frequently viewed as a linear process of decline, whereas in reality, it is a dynamic non-linear process. The dynamic nature of neurological aging is exemplified during midlife in the female brain. To investigate fundamental mechanisms of midlife aging that underlie risk for development of Alzheimer's disease (AD) in late life, we investigated the brain at greatest risk for the disease, the aging female brain. Outcomes of our research indicate that mid-life aging in the female is characterized by the emergence of three phases: early chronological (pre-menopause), endocrinological (peri-menopause) and late chronological (post-menopause) aging. The endocrinological aging program is sandwiched between early and late chronological aging. Throughout the three stages of midlife aging, two systems of biology, metabolic and immune, are tightly integrated through a network of signaling cascades. The network of signaling between these two systems of biology underlie an orchestrated sequence of adaptative starvation responses that shift the brain from near exclusive dependence on a single fuel, glucose, to utilization of an auxiliary fuel derived from lipids, ketone bodies. The dismantling of the estrogen control of glucose metabolism during mid-life aging is a critical contributor to the shift in fuel systems and emergence of dynamic neuroimmune phenotype. The shift in fuel reliance, puts the largest reservoir of local fatty acids, white matter, at risk for catabolism as a source of lipids to generate ketone bodies through astrocytic beta oxidation. APOE4 genotype accelerates the tipping point for emergence of the bioenergetic crisis. While outcomes derived from research conducted in the female brain are not directly translatable to the male brain, the questions addressed in a female centric program of research are directly applicable to investigation of the male brain. Like females, males with AD exhibit deficits in the bioenergetic system of the brain, activation of the immune system and hallmark Alzheimer's pathologies. The drivers and trajectory of mechanisms underlying neurodegeneration in the male brain will undoubtedly share common aspects with the female in addition to factors unique to the male. Preclinical and clinical evidence indicate that midlife endocrine aging can also be a transitional bridge to autoimmune disorders. Collectively, the data indicate that endocrinological aging is a critical period "tipping point" in midlife which can initiate emergence of the prodromal stage of late-onset-Alzheimer's disease. Interventions that target both immune and metabolic shifts that occur during midlife aging have the potential to alter the trajectory of Alzheimer's risk in late life. Further, to achieve precision medicine for AD, chromosomal sex is a critical variable to consider along with APOE genotype, other genetic risk factors and stage of disease.
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Doença de Alzheimer , Envelhecimento , Doença de Alzheimer/prevenção & controle , Apolipoproteína E4/metabolismo , Encéfalo/metabolismo , Feminino , Humanos , Corpos Cetônicos , MasculinoRESUMO
Blood pressure variability is an emerging risk factor for Alzheimer's disease in older adults, independent of average blood pressure levels. Growing evidence suggests increased blood pressure variability is linked to Alzheimer's disease pathophysiology indexed by cerebrospinal fluid and positron emission tomography markers, but relationships with plasma Alzheimer's disease markers have not been investigated. In this cross-sectional study of 54 community-dwelling older adults (aged 55-88, mean age 69.9 [8.2 SD]), elevated blood pressure variability over 5 min was associated with lower levels of plasma Aß1-42 (standardized ß = - 0.36 [95% CI - 0.61, - 0.12]; p = 0.005; adjusted R2 = 0.28) and Aß1-42: Aß1-40 ratio (ß = - 0.49 [95% CI - 0.71, - 0.22]; p < 0.001; adjusted R2 = 0.28), and higher levels of total tau (ß = 0.27 [95% CI 0.01, 0.54]; p = 0.04; adjusted R2 = 0.19) and Ptau181:Aß1-42 ratio (ß = 0.26 [95% CI 0.02, 0.51]; p = 0.04; adjusted R2 = 0.22). Findings suggest higher blood pressure variability is linked to plasma biomarkers of increased Alzheimer's disease pathophysiology.
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Doença de Alzheimer , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores , Pressão Sanguínea , Estudos Transversais , Humanos , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia Computadorizada por Raios X , Proteínas tau/líquido cefalorraquidianoRESUMO
OBJECTIVE: This study determined the influence of a 2-component polyethylene glycol surgical sealant (Coseal) as an adhesion prevention device on sepsis-related mortality and/or systemic bacterial translocation to the spleen. STUDY DESIGN: A bacterial inoculum and telemetry probe were implanted in 50 treated and 49 untreated rats. Telemetry probes monitored core-body temperature to determine time of death. Spleens were collected on day 3 for quantitative bacteriology of Escherichia coli and Bacteroides fragilis. RESULTS: Median survival time and mortality of treated rats (37.0 hours, 54.0%) were noninferior to untreated rats (47.5 hours, 55.1%). Median E coli titers in treated rats (2.24 log colony forming units/spleen) were significantly less than untreated rats (4.32 log colony forming units/spleen). B fragilis titers were not different. CONCLUSION: This study demonstrates intraperitoneal administration of a 2-component polyethylene glycol surgical sealant as an adhesion prevention device does not alter time to death or sepsis-related mortality and/or systemic bacterial translocation to the spleen.
Assuntos
Infecções por Bacteroides/prevenção & controle , Infecções por Escherichia coli/prevenção & controle , Doenças Peritoneais/prevenção & controle , Polietilenoglicóis/uso terapêutico , Baço/microbiologia , Animais , Infecções por Bacteroides/microbiologia , Bacteroides fragilis , Escherichia coli , Infecções por Escherichia coli/microbiologia , Feminino , Estimativa de Kaplan-Meier , Doenças Peritoneais/microbiologia , Ratos , Ratos Sprague-Dawley , Telemetria , Aderências Teciduais/microbiologia , Aderências Teciduais/prevenção & controleRESUMO
In the wake of the COVID-19 pandemic it has become clear that there is a need for therapies that are capable of reducing damage caused to patients from infections. Infections that induce Acute Respiratory Distress Syndrome (ARDS) are especially devastating because lung damage is so critical and difficult to manage. Angiotensin (1-7) [A(1-7)] has already been shown to protect pulmonary health and architecture in various models of disease. There is also evidence that A(1-7) can modulate immune function and protect various organs (lung, kidney, and heart) from oxidative damage and inflammation. Here we focus on making a case for the development of novel therapies that target the protective arm of the Renin Angiotensin System (RAS).
Assuntos
Angiotensina I/uso terapêutico , Betacoronavirus/fisiologia , Infecções por Coronavirus/complicações , Fragmentos de Peptídeos/uso terapêutico , Pneumonia Viral/complicações , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/virologia , Angiotensina I/fisiologia , Enzima de Conversão de Angiotensina 2 , Animais , COVID-19 , Infecções por Coronavirus/mortalidade , Humanos , Pandemias , Fragmentos de Peptídeos/fisiologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/mortalidade , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , SARS-CoV-2RESUMO
Patients with Systemic Lupus Erythematosus (SLE) suffer from a chronic inflammatory autoimmune disease that results from the body's immune system targeting healthy tissues which causes damage to various organ systems. Patients with lupus are still in need of effective therapies to treat this complex, multi-system disease. Because polymorphisms in ACE are associated with the activity of SLE and lupus nephritis and based on well-documented renal-protective effects of Renin Angiotensin System (RAS)-modifying therapies, ACE-I are now widely used in patients with SLE with significant efficacy. Our research explores alternate ways of modifying the RAS as a potential for systemic therapeutic benefit in the MRL-lpr mouse model of SLE. These therapeutics include; angiotensin (1-7) [A(1-7)], Nor-Leu-3 Angiotensin (1-7) (NorLeu), Losartan (ARB), and Lisinopril (ACE-I). Daily systemic treatment with all of these RAS-modifying therapies significantly reduced the onset and intensity in rash formation and swelling of the paw. Further, histology showed a corresponding decrease in hyperkeratosis and acanthosis in skin sections. Important immunological parameters such as decreased circulating anti-dsDNA antibodies, lymph node size, and T cell activation were observed. As expected, the development of glomerular pathologies was also attenuated by RAS-modifying therapy. Improved number and health of mesenchymal stem cells (MSCs), as well as reduction in oxidative stress and inflammation may be contributing to the reduction in SLE pathologies. Several studies have already characterized the protective role of ACE-I and ARBs in mouse models of SLE, here we focus on the protective arm of RAS. A(1-7) in particular demonstrates several protective effects that go beyond those seen with ACE-Is and ARBs; an important finding considering that ACE-Is and ARBs are teratogenic and can cause hypotension in this population. These results offer a foundation for further pharmaceutical development of RAS-modifying therapies, that target the protective arm, as novel SLE therapeutics that do not rely on suppressing the immune system.