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1.
J Bone Miner Res ; 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34747055

RESUMO

Hallmarks of aging-associated osteoporosis include bone loss, bone marrow adipose tissue (BMAT) expansion, and impaired osteoblast function. Endogenous glucocorticoid levels increase with age, and elevated glucocorticoid signaling, associated with chronic stress and dysregulated metabolism, can have a deleterious effect on bone mass. Canonical glucocorticoid signaling through the glucocorticoid receptor (GR) was recently investigated as a mediator of osteoporosis during the stress of chronic caloric restriction. To address the role of the GR in an aging-associated osteoporotic phenotype, the current study utilized female GR conditional knockout (GR-CKO; GRfl/fl :Osx-Cre+) mice and control littermates on the C57BL/6 background aged to 21 months and studied in comparison to young (3- and 6-month-old) mice. GR deficiency in Osx-expressing cells led to low bone mass and BMAT accumulation that persisted with aging. Surprisingly, however, GR-CKO mice also exhibited alterations in muscle mass (reduced % lean mass and soleus fiber size), accompanied by reduced voluntary physical activity, and also exhibited higher whole-body metabolic rate and elevated blood pressure. Moreover, increased lipid storage was observed in GR-CKO osteoblastic cultures in a glucocorticoid-dependent fashion despite genetic deletion of the GR, and could be reversed via pharmacological inhibition of the mineralocorticoid receptor (MR). These findings provide evidence of a role for the GR (and possibly the MR) in facilitating healthy bone maintenance with aging in females. The effects of GR-deficient bone on whole-body physiology also demonstrate the importance of bone as an endocrine organ and suggest evidence for compensatory mechanisms that facilitate glucocorticoid signaling in the absence of osteoblastic GR function; these represent new avenues of research that may improve understanding of glucocorticoid signaling in bone toward the development of novel osteogenic agents. © 2021 American Society for Bone and Mineral Research (ASBMR).

2.
J Investig Med ; 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34799422

RESUMO

BACKGROUND: Renal transplant patients are at increased risk for mucormycosis. Diabetes, neutropenia, deferoxamine therapy, and immunosuppressive medications have been associated with increased risk of mucormycosis in studies of solid organ transplant recipients. To focus on renal transplant patients, the US Renal Data System (USRDS) was queried to determine the incidence and risk factors for mucormycosis. METHODS: All renal transplant patients in the USRDS from 1988 to 2015 were queried for a diagnosis of mucormycosis after the first transplant date using ICD-9 and ICD-10 codes. The International Classification of Diseases (ICD) codes, which currently exist in the ninth and tenth revisions, are a global system of classification used to code diagnoses, procedures, and symptoms. We defined proven mucormycosis by a histopathologic or fungal stain procedure code within 7 days of the diagnosis code. Logistic regression controlling for person-years at risk was used to examine demographic and clinical diagnosis risk factors for mucormycosis. RESULTS: Of the 306,482 renal transplant patients, 222 (0.07%) had codes consistent with proven mucormycosis. The incidence of mucormycosis increased from 1990 to 2000 (peak 17.6 per 100,000 person-years) and subsequently demonstrated more variability. Hispanic ethnicity (OR=1.45), age 65 years or greater (OR=1.64), other or black race compared with white race (OR=1.96 and 1.74), cadaver or other donor type (OR=2.41), and receiving tacrolimus (OR=2.09) were associated with increased risk. Comorbidities associated with decreased risk of mucormycosis included female sex (OR=0.68), iron overload (OR=0.56), and receiving mycophenolate mofetil (OR=0.67) or azathioprine (OR=0.53). CONCLUSIONS: In renal transplant patients, age, deceased donor graft transplant, tacrolimus administration, race other than white, and Hispanic ethnicity were associated with increased risk of mucormycosis. Unexpectedly, iron overload was protective. Mucormycosis is a rare infection in renal transplant patients which should be considered in patients with the above risk factors after more common infections have been ruled out.

3.
Mediators Inflamm ; 2021: 2911578, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34621138

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), affecting multiple organ systems, including the respiratory tract and lungs. Several studies have reported that the tryptophan-kynurenine pathway is altered in COVID-19 patients. The tryptophan-kynurenine pathway plays a vital role in regulating inflammation, metabolism, immune responses, and musculoskeletal system biology. In this minireview, we surmise the effects of the kynurenine pathway in COVID-19 patients and how this pathway might impact muscle and bone biology.


Assuntos
Doenças Ósseas/etiologia , COVID-19/complicações , Cinurenina/metabolismo , Doenças Musculares/etiologia , SARS-CoV-2 , Triptofano/metabolismo , Animais , Humanos , Receptores de Hidrocarboneto Arílico/fisiologia , Transdução de Sinais/fisiologia
4.
J Invest Dermatol ; 141(11): 2558-2561, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34688406

RESUMO

The calcium-sensing receptor (CaSR) is important in the skin, contributing to several epidermal functions, including differentiation, water permeability barrier repair, and wound healing. Celli et al. (2021) show that CaSR levels are reduced in keratinocytes/skin from aged individuals, with resulting impairment of key functions. CaSR agonists can correct these defects, suggesting a possible therapy to combat aging-related delayed skin wound healing.

5.
JBMR Plus ; 5(10): e10517, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34693188

RESUMO

Aging results in a general decline in function in most systems. This is particularly true with respect to the skeleton and renal systems, impacting mineral homeostasis. Calcium and phosphate regulation requires tight coordination among the intestine, bone, parathyroid gland, and kidney. The role of the intestine is to absorb calcium and phosphate from the diet. The bone stores or releases calcium and phosphate depending on the body's needs. In response to low plasma ionized calcium concentration, the parathyroid gland produces parathyroid hormone, which modulates bone turnover. The kidney reabsorbs or excretes the minerals and serves as the final regulator of plasma concentration. Many hormones are involved in this process in addition to parathyroid hormone, including fibroblast growth factor 23 produced by the bone and calcitriol synthesized by the kidney. Sclerostin, calcitonin, osteoprotegerin, and receptor activator of nuclear factor-κB ligand also contribute to tissue-specific regulation. Changes in the function of organs due to aging or disease can perturb this balance. During aging, the intestine cannot absorb calcium efficiently due to decreased expression of key proteins. In the bone, the balance between bone formation and bone resorption tends toward the latter in older individuals. The kidney may not filter blood as efficiently in the later decades of life, and the expression of certain proteins necessary for mineral homeostasis declines with age. These changes often lead to dysregulation of organismal mineral homeostasis. This review will focus on how mineral homeostasis is impacted by aging with a particular emphasis on the kidney's role in this process. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

6.
J Investig Med ; 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34518317

RESUMO

Septic arthritis is important to consider in any patient who presents with joint pain because it is a medical emergency with an 11% fatality rate. Diagnosis and treatment may improve prognosis; however, many patients do not regain full joint function. In patients with end-stage renal disease (ESRD), immune dysfunction due to uremia and chronic vascular access leads to increased risk of infection. We examined the incidence, risk factors and sequelae of septic arthritis in a cohort of hemodialysis patients. The US Renal Data System was queried for diagnoses of septic arthritis and selected sequelae using International Statistical Classification of Diseases and Related Health Problems-9 and Current Procedural Terminology-4 codes in patients who initiated hemodialysis between 2005 and 2010. Multivariable logistic regression was used to determine potential risk factors for septic arthritis and its sequelae. 7009 cases of septic arthritis were identified, an incidence of 514.8 per 100,000 persons per year. Of these patients, 2179 were diagnosed with a documented organism within 30 days prior to or 14 days after the septic arthritis diagnosis, with methicillin-resistant Staphylococcus aureus infections (57.4%) being the most common. Significant risk factors for septic arthritis included history of joint disease, immune compromise (diabetes, HIV, cirrhosis), bacteremia and urinary tract infection. One of the four sequelae examined (joint replacement, amputation, osteomyelitis, Clostridioides difficile infection) occurred in 25% of septic arthritis cases. The high incidence of septic arthritis and the potential for serious sequelae in patients with ESRD suggest that physicians treating individuals with ESRD and joint pain/inflammation should maintain a high clinical suspicion for septic arthritis.

7.
Int J Mol Sci ; 22(16)2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34445455

RESUMO

Glycerol is used in many skin care products because it improves skin function. Anecdotal reports by patients on the National Psoriasis Foundation website also suggest that glycerol may be helpful for the treatment of psoriasis, although to date no experimental data confirm this idea. Glycerol entry into epidermal keratinocytes is facilitated by aquaglyceroporins like aquaporin-3 (AQP3), and its conversion to phosphatidylglycerol, a lipid messenger that promotes keratinocyte differentiation, requires the lipid-metabolizing enzyme phospholipase-D2 (PLD2). To evaluate whether glycerol inhibits inflammation and psoriasiform lesion development in the imiquimod (IMQ)-induced mouse model of psoriasis, glycerol's effect on psoriasiform skin lesions was determined in IMQ-treated wild-type and PLD2 knockout mice, with glycerol provided either in drinking water or applied topically. Psoriasis area and severity index, ear thickness and ear biopsy weight, epidermal thickness, and inflammatory markers were quantified. Topical and oral glycerol ameliorated psoriasiform lesion development in wild-type mice. Topical glycerol appeared to act as an emollient to induce beneficial effects, since even in PLD2 knockout mice topical glycerol application improved skin lesions. In contrast, the beneficial effects of oral glycerol required PLD2, with no improvement in psoriasiform lesions observed in PLD2 knockout mice. Our findings suggest that the ability of oral glycerol to improve psoriasiform lesions requires its PLD2-mediated conversion to phosphatidylglycerol, consistent with our previous report that phosphatidylglycerol itself improves psoriasiform lesions in this model. Our data also support anecdotal evidence that glycerol can ameliorate psoriasis symptoms and therefore might be a useful therapy alone or in conjunction with other treatments.


Assuntos
Glicerol/farmacologia , Imiquimode/efeitos adversos , Psoríase/tratamento farmacológico , Pele/metabolismo , Animais , Aquaporina 3/genética , Aquaporina 3/metabolismo , Modelos Animais de Doenças , Humanos , Imiquimode/farmacologia , Camundongos , Camundongos Knockout , Fosfolipase D/deficiência , Fosfolipase D/metabolismo , Psoríase/induzido quimicamente , Psoríase/genética , Psoríase/metabolismo
8.
J Investig Med ; 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34426458

RESUMO

Renal transplant patients are immunosuppressed and are at increased risk of opportunistic infections, including Nocardia infection. In renal transplant patients, information on the incidence and risk factors associated with nocardiosis is limited. To address the incidence and risk factors associated with nocardiosis in a large renal transplant population, we used the US Renal Data System (USRDS). Sequelae of allograft failure or rejection after infection were also examined. Demographics, clinical risk factors, Nocardia diagnosis, and allograft failure following Nocardia infection were queried in USRDS renal transplant patients using International Classification of Diseases, Ninth Revision (ICD-9) codes in billing claims and Centers for Medicare and Medicaid Services Form 2728. Generalized linear models were used to determine the risk factors associated with nocardiosis, and Cox proportional hazards models were used to examine the association of risk factors with graft failure among patients with Nocardia infection. Of 203,233 renal transplant recipients identified from 2001 to 2011, 657 (0.32%) were diagnosed with Nocardia infection. Pneumonia was the most frequent presentation (15.2%), followed by brain abscess (8.4%). Numerous factors associated with increased Nocardia infection included age >65 years (OR=2.10, 95% CI 1.71 to 2.59), history of transplant failure (OR=1.28, CI 1.02 to 1.60) or history of rejection (OR=4.83, CI 4.08 to 5.72), receipt of a deceased donor transplant (OR=1.23, CI 1.03 to 1.46), and treatment with basiliximab (OR=1.25, CI 1.00 to 1.55), cyclosporine (OR=1.30, CI 1.03 to 1.65), tacrolimus (OR=2.45, CI 2.00 to 3.00), or thymoglobulin (OR=1.89, CI 1.59 to 2.25). In patients with nocardiosis administration of antithymocyte globulin (HR=2.76), chronic obstructive pulmonary disease (HR=2.47), and presentation of Nocardia infection with brain abscess (HR=1.85) were associated with an increased risk of graft failure. This study provides new information to enhance early recognition and targeted treatment of nocardiosis in renal transplant patients.

9.
Am J Med Sci ; 362(1): 24-33, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33798461

RESUMO

BACKGROUND: Psoriasis impairs the quality of life of approximately 7.5 million Americans and is associated with serious comorbidities. Because of chronic vascular access and epidermal dysfunction, end-stage renal disease (ESRD) patients with psoriasis may be at greater risk for infection, and psoriasis treatment could affect this risk. METHODS: A retrospective cohort analysis was performed using the United States Renal Data System from 2004-2011 to investigate the association of psoriasis with infections common to ESRD patients, as well as the effect of psoriasis treatment on infection risk as well as mortality. RESULTS: A total of 8,911 psoriasis patients were identified. Psoriasis was associated with a significantly increased risk for all queried infections, especially cellulitis (adjusted relative risk = 1.55), conjunctivitis (1.47), and onychomycosis (1.36). Psoriasis treatment (systemic, local, and light) was associated with a significantly decreased risk of some infections. Psoriasis treatment was also correlated with a significantly decreased risk of mortality, with systemic therapies (biologics and other immunosuppressants) showing the greatest reduction (adjusted hazard ratio = 0.55). CONCLUSIONS: These results suggest that psoriasis-ESRD patients may have an increased risk of infection and treatment of psoriasis is associated with a reduced risk of some infections and improved survival.


Assuntos
Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/mortalidade , Psoríase/tratamento farmacológico , Psoríase/mortalidade , Dermatopatias Infecciosas/tratamento farmacológico , Dermatopatias Infecciosas/mortalidade , Corticosteroides/administração & dosagem , Idoso , Estudos de Coortes , Bases de Dados Factuais/tendências , Fármacos Dermatológicos/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Estudos Retrospectivos
10.
Am J Med Sci ; 361(4): 485-490, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33637307

RESUMO

BACKGROUND: Spinal epidural abscess (SEA) is an uncommon and highly morbid infection of the epidural space. End-stage renal disease (ESRD) patients are known to be at increased risk of developing SEA; however, there are no studies that have described the risk factors and outcomes of SEA in ESRD patients utilizing the United States Renal Data System (USRDS). METHODS: To determine risk factors, morbidity, and mortality associated with SEA in ESRD patients, a retrospective case-control study was conducted using the USRDS. ESRD patients diagnosed with SEA between 2005 and 2010 were identified, and logistic regression was performed to examine correlates of SEA, as well as risk factors associated with mortality in SEA-ESRD patients. RESULTS: The prevalence of SEA amongst ESRD patients was 0.39% (n = 1,697). Patients with SEA were more likely to be male [adjusted Odds Ratio (OR) = 1.22], black (OR = 1.19), diabetic (OR = 1.26), with catheter access (OR = 1.29), and less likely to be ≥65 years old (OR = 0.64). Osteomyelitis, bacteremia/septicemia, MRSA, and endocarditis were all significantly associated with increased risk of SEA (OR = 1.54-5.14). Age ≥65 years (HR = 1.45), urinary tract infections (HR = 1.26), decubitus ulcers (HR=1.37), and post-SEA paraplegia (HR = 1.25) were significantly associated with mortality among those with SEA. CONCLUSIONS: As described in previous literature, risk factors for SEA included infections, diabetes, and indwelling catheters. Additionally, clinicians should be aware of the risk factors for mortality in SEA-ESRD patients. As the largest study of SEA to date, our report identifies important risk factors for SEA in ESRD patients, and novel data regarding their mortality-associated risk factors.


Assuntos
Abscesso Epidural/epidemiologia , Falência Renal Crônica/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Abscesso Epidural/etiologia , Abscesso Epidural/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morbidade , Estudos Retrospectivos , Fatores de Risco , Estados Unidos/epidemiologia , Adulto Jovem
11.
J Invest Dermatol ; 141(1): 11-14, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33342506

RESUMO

The results in the article by Zhou et al. (2020) demonstrate that the antidiabetic drug phenformin inhibits skin tumor growth and promotes keratinocyte differentiation, and an underlying mechanism is also defined. In this commentary, additional potential mechanisms through which phenformin may exert its antitumorigenic effect are described. Thus, the proposed repurposing of phenformin to treat skin cancer has merit.


Assuntos
Neoplasias , Fenformin , Monofosfato de Adenosina , Reposicionamento de Medicamentos , Humanos , Hipoglicemiantes/farmacologia , Fenformin/farmacologia
12.
Med Hypotheses ; 144: 110277, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33254581

RESUMO

A hypothesis concerning the potential utility of surfactant supplementation for the treatment of critically ill patients with COVID-19 is proposed, along with a brief summary of the data in the literature supporting this idea. It is thought that surfactant, which is already approved by the Food and Drug Administration for intratracheal administration to treat neonatal respiratory distress syndrome in pre-term infants, could benefit COVID-19-infected individuals by: (1) restoring surfactant damaged by lung infection and/or decreased due to the virus-induced death of the type II pneumocytes that produce it and (2) reducing surface tension to decrease the work of breathing and limit pulmonary edema. In addition, a constituent of surfactant, phosphatidylglycerol, could mitigate COVID-19-induced lung pathology by: (3) decreasing excessive innate immune system stimulation via its inhibition of toll-like receptor-2 and -4 activation by microbial components and cellular proteins released by damaged cells, thereby limiting inflammation and the resultant pulmonary edema, and (4) possibly blocking spread of the viral infection to non-infected cells in the lung. Therefore, it is suggested that surfactant preparations containing phosphatidylglycerol be tested for their ability to improve lung function in critically ill patients with COVID-19.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/terapia , Fosfatidilgliceróis/uso terapêutico , Surfactantes Pulmonares/uso terapêutico , Adulto , Células Epiteliais Alveolares/efeitos dos fármacos , Animais , COVID-19/fisiopatologia , Bovinos , Estado Terminal , Humanos , Imunidade Inata , Inflamação , Pulmão/patologia , Modelos Teóricos , Edema Pulmonar/imunologia , Suínos
13.
Int J Mol Sci ; 21(18)2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32933099

RESUMO

Although aging is considered a normal process, there are cellular and molecular changes that occur with aging that may be detrimental to health. Osteoporosis is one of the most common age-related degenerative diseases, and its progression correlates with aging and decreased capacity for stem cell differentiation and proliferation in both men and women. Tryptophan metabolism through the kynurenine pathway appears to be a key factor in promoting bone-aging phenotypes, promoting bone breakdown and interfering with stem cell function and osteogenesis; however, little data is available on the impact of tryptophan metabolites downstream of kynurenine. Here we review available data on the impact of these tryptophan breakdown products on the body in general and, when available, the existing evidence of their impact on bone. A number of tryptophan metabolites (e.g., 3-hydroxykynurenine (3HKYN), kynurenic acid (KYNA) and anthranilic acid (AA)) have a detrimental effect on bone, decreasing bone mineral density (BMD) and increasing fracture risk. Other metabolites (e.g., 3-hydroxyAA, xanthurenic acid (XA), picolinic acid (PIA), quinolinic acid (QA), and NAD+) promote an increase in bone mineral density and are associated with lower fracture risk. Furthermore, the effects of other tryptophan breakdown products (e.g., serotonin) are complex, with either anabolic or catabolic actions on bone depending on their source. The mechanisms involved in the cellular actions of these tryptophan metabolites on bone are not yet fully known and will require further research as they are potential therapeutic targets. The current review is meant as a brief overview of existing English language literature on tryptophan and its metabolites and their effects on stem cells and musculoskeletal systems. The search terms used for a Medline database search were: kynurenine, mesenchymal stem cells, bone loss, tryptophan metabolism, aging, and oxidative stress.


Assuntos
Envelhecimento/metabolismo , Sistema Musculoesquelético/metabolismo , Células-Tronco/metabolismo , Triptofano/metabolismo , Animais , Humanos
14.
J Investig Med ; 68(5): 1002-1010, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32503931

RESUMO

Human papillomavirus (HPV) causes the majority of cervical, anal/rectal, and oropharyngeal cancers in women. End-stage renal disease (ESRD) is also associated with an increased risk of malignancy, but the incidence of and risk factors for HPV-associated cancers in US dialysis patients are not defined. We queried the US Renal Data System for women with HPV-associated cancers and assessed for incidence of cancer diagnosis and association of risk factors. From 2005 to 2011, a total of 1032 female patients with ESRD had 1040 HPV-associated cancer diagnoses. Patients had a mean age of 65 years, were mostly white (63%), and on hemodialysis (92%). Cervical cancer (54%) was the most common, followed by anal/rectal (34%), and oropharyngeal (12%). The incidence of HPV-associated cancers in patients with ESRD increased yearly, with up to a 16-fold increased incidence compared with the general population. Major risk factors associated with the development of any HPV-associated cancer included smoking (adjusted relative risk=1.89), alcohol use (1.87), HIV (2.21), and herpes infection (2.02). Smoking, HIV, and herpes infection were prominent risk factors for cervical cancer. The incidence of HPV-associated cancers in women with ESRD is rising annually and is overall higher than in women of the general population. Tobacco use is a universal risk factor. For cervical cancer, the presence of HIV and herpes are important comorbidities. Recognizing risk factors associated with these cancers may improve diagnosis and facilitate survival. The role of HPV vaccination in at-risk dialysis patients remains to be defined but warrants further study.


Assuntos
Alphapapillomavirus/fisiologia , Falência Renal Crônica/complicações , Neoplasias/epidemiologia , Neoplasias/virologia , Infecções por Papillomavirus/complicações , Idoso , Feminino , Humanos , Incidência , Neoplasias/complicações , Fatores de Risco
15.
Bone Rep ; 12: 100270, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32395570

RESUMO

Mechanisms leading to age-related reductions in bone formation and subsequent osteoporosis are still incompletely understood. We recently demonstrated that kynurenine (KYN), a tryptophan metabolite, accumulates in serum of aged mice and induces bone loss. Here, we report on novel mechanisms underlying KYN's detrimental effect on bone aging. We show that KYN is increased with aging in murine bone marrow mesenchymal stem cells (BMSCs). KYN reduces bone formation via modulating levels of CXCL12 and its receptors as well as histone deacetylase 3 (Hdac3). BMSCs responded to KYN by significantly decreasing mRNA expression levels of CXCL12 and its cognate receptors, CXCR4 and ACKR3, as well as downregulating osteogenic gene RUNX2 expression, resulting in a significant inhibition in BMSCs osteogenic differentiation. KYN's effects on these targets occur by increasing regulatory miRNAs that target osteogenesis, specifically miR29b-1-5p. Thus, KYN significantly upregulated the anti-osteogenic miRNA miR29b-1-5p in BMSCs, mimicking the up-regulation of miR-29b-1-5p in human and murine BMSCs with age. Direct inhibition of miR29b-1-5p by antagomirs rescued CXCL12 protein levels downregulated by KYN, while a miR29b-1-5p mimic further decreased CXCL12 levels. KYN also significantly downregulated mRNA levels of Hdac3, a target of miR-29b-1-5p, as well as its cofactor NCoR1. KYN is a ligand for the aryl hydrocarbon receptor (AhR). We hypothesized that AhR mediates KYN's effects in BMSCs. Indeed, AhR inhibitors (CH-223191 and 3',4'-dimethoxyflavone [DMF]) partially rescued secreted CXCL12 protein levels in BMSCs treated with KYN. Importantly, we found that treatment with CXCL12, or transfection with an miR29b-1-5p antagomir, downregulated the AhR mRNA level, while transfection with miR29b-1-5p mimic significantly upregulated its level. Further, CXCL12 treatment downregulated IDO, an enzyme responsible for generating KYN. Our findings reveal novel molecular pathways involved in KYN's age-associated effects in the bone microenvironment that may be useful translational targets for treating osteoporosis.

16.
Am J Physiol Cell Physiol ; 318(6): C1144-C1153, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32267715

RESUMO

The skin is essential for terrestrial life. It is responsible for regulating water permeability and functions as a mechanical barrier that protects against environmental insults such as microbial infection, ultraviolet light, injury, and heat and cold, which could damage the cells of the body and compromise survival of the organism. This barrier is provided by the outer layer, the epidermis, which is composed predominantly of keratinocytes; keratinocytes undergo a program of differentiation to form the stratum corneum comprising the cornified squame "bricks" and lipid "mortar." Dysregulation of this differentiation program can result in skin diseases, including psoriasis and nonmelanoma skin cancers, among others. Accumulating evidence in the literature indicates that the water-, glycerol-, and hydrogen peroxide-transporting channel aquaporin-3 (AQP3) plays a key role in various processes involved in keratinocyte function, and abnormalities in this channel have been observed in several human skin diseases. Here, we discuss the data linking AQP3 to keratinocyte proliferation, migration, differentiation, and survival as well as its role in skin properties and functions like hydration, water retention, wound healing, and barrier repair. We also discuss the mechanisms regulating AQP3 levels, localization, and function and the anomalies in AQP3 that are associated with various skin diseases.


Assuntos
Aquaporina 3/metabolismo , Epiderme/metabolismo , Queratinócitos/metabolismo , Psoríase/metabolismo , Água/metabolismo , Animais , Diferenciação Celular , Movimento Celular , Proliferação de Células , Epiderme/patologia , Humanos , Queratinócitos/patologia , Estado de Hidratação do Organismo , Permeabilidade , Psoríase/patologia , Transdução de Sinais , Cicatrização
17.
Mol Pharmacol ; 97(5): 324-335, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32173651

RESUMO

Skin serves not only as a protective barrier to microbial entry into the body but also as an immune organ. The outer layer, the epidermis, is composed predominantly of keratinocytes, which can be stimulated to produce proinflammatory mediators. Although some inflammation is useful to defend against infection, excessive or persistent inflammation can lead to the development of inflammatory skin diseases, such as psoriasis, a common skin disorder affecting approximately 2% of the US population. We have previously found that phosphatidylglycerol (PG) derived from soy can inhibit inflammation in a contact irritant ear edema mouse model. Here, we investigated the ability of soy PG to inhibit inflammatory mediator expression in response to activators of the pattern recognition receptors, toll-like receptor-2 (TLR2) and -4 (TLR4). We found that in epidermal keratinocytes, soy PG inhibited TLR2 and TLR4 activation and inflammatory mediator expression in response to a synthetic triacylated lipopeptide and lipopolysaccharide, respectively, as well as an endogenous danger-associated molecular pattern. However, at higher concentrations, soy PG alone enhanced the expression of some proinflammatory cytokines, suggesting a narrow therapeutic window for this lipid. Dioleoylphosphatidylglycerol (DOPG), but not dioleoylphosphatidylcholine, exerted a similar inhibitory effect, completely blocking keratinocyte inflammatory mediator expression induced by TLR2 and TLR4 activators as well as NFκB activation in a macrophage cell line (RAW264.7); however, DOPG was not itself proinflammatory even at high concentrations. Furthermore, DOPG had no effect on NFκB activation in response to a TLR7/8 agonist. Our results suggest that DOPG could be used to inhibit excessive skin inflammation. SIGNIFICANCE STATEMENT: Although inflammation is beneficial for clearing an infection, in some cases, the infection can be excessive and/or become chronic, thereby resulting in considerable tissue damage and pathological conditions. We show here that the phospholipid phosphatidylglycerol can inhibit the activation of toll-like receptors 2 and 4 of the innate immune system as well as the downstream inflammatory mediator expression in response to microbial component-mimicking agents in epidermal keratinocytes that form the physical barrier of the skin.


Assuntos
Mediadores da Inflamação/metabolismo , Queratinócitos/metabolismo , Padrões Moleculares Associados a Patógenos/farmacologia , Fosfatidilgliceróis/farmacologia , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Calgranulina B/farmacologia , Humanos , Imidazóis/farmacologia , Lipopeptídeos/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Células RAW 264.7 , Receptores de Reconhecimento de Padrão/metabolismo , Proteínas Recombinantes/farmacologia , Soja/química
18.
Invest Ophthalmol Vis Sci ; 61(3): 29, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32186673

RESUMO

Purpose: In contact with the external environment, the cornea can easily be injured. Although corneal wounds generally heal rapidly, the pain and increased risk of infection associated with a damaged cornea, as well as the impaired healing observed in some individuals, emphasize the need for novel treatments to accelerate corneal healing. We previously demonstrated in epidermal keratinocytes that the glycerol channel aquaporin-3 (AQP3) interacts with phospholipase D2 (PLD2) to produce the signaling phospholipid phosphatidylglycerol (PG), which has been shown to accelerate skin wound healing in vivo. We hypothesized that the same signaling pathway might be operational in corneal epithelial cells. Methods: We used co-immunoprecipitation, immunohistochemistry, scratch wound healing assays in vitro, and corneal epithelial wound healing assays in vivo to determine the role of the AQP3/PLD2/PG signaling pathway in corneal epithelium. Results: AQP3 was present in human corneas in situ, and AQP3 and PLD2 were co-immunoprecipitated from corneal epithelial cell lysates. The two proteins could also be co-immunoprecipitated from insect cells simultaneously infected with AQP3- and PLD2-expressing baculoviruses, suggesting a likely direct interaction. A particular PG, dioleoylphosphatidylglycerol (DOPG), enhanced scratch wound healing of a corneal epithelial monolayer in vitro. DOPG also accelerated corneal epithelial wound healing in vivo, both in wild-type mice and in a mouse model exhibiting impaired corneal wound healing (AQP3 knockout mice). Conclusions: These results indicate the importance of the AQP3/PLD2/PG signaling pathway in corneal epithelial cells and suggest the possibility of developing DOPG as a pharmacologic therapy to enhance corneal wound healing in patients.


Assuntos
Epitélio Corneano/efeitos dos fármacos , Limbo da Córnea/efeitos dos fármacos , Fosfatidilgliceróis/farmacologia , Cicatrização/fisiologia , Animais , Aquaporina 3/metabolismo , Western Blotting , Movimento Celular , Proliferação de Células , Células Cultivadas , Epitélio Corneano/metabolismo , Humanos , Imunoprecipitação , Limbo da Córnea/metabolismo , Masculino , Camundongos , Camundongos Knockout , Microscopia de Fluorescência , Fosfolipase D/metabolismo , Células Sf9/metabolismo , Transdução de Sinais/fisiologia , Transfecção
19.
Exp Dermatol ; 29(4): 380-386, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32003033

RESUMO

The water and glycerol channel, aquaporin-3 (AQP3), plays an important role in the skin epidermis, with effects on hydration, permeability barrier repair and wound healing; therefore, information about the mechanisms regulating its expression is important for a complete understanding of skin function physiologically and in disease conditions. We previously demonstrated that histone deacetylase inhibitors (HDACi) induce the mRNA and protein expression of AQP3, in part through the p53 family, transcription factors for which acetylation is known to affect their regulatory activity. Another set of transcription factors previously shown to induce AQP3 expression and/or regulate skin function are the peroxisome proliferator-activated receptors (PPARs). Since there are reports that PPARs are also acetylated, we examined the involvement of these nuclear hormone receptors in HDACi-induced AQP3 expression. We first verified that a PPARγ agonist upregulated AQP3 mRNA and protein levels and that this increase was blocked by a PPARγ antagonist. We then showed that the PPARγ antagonist also inhibited AQP3 expression induced both by a broad-spectrum HDACi and an HDAC3-selective inhibitor. Interestingly, a PPARα antagonist also inhibited HDACi-induced AQP3 expression. These antagonist effects were observed in both primary mouse and normal human keratinocytes. Furthermore, PPARγ overexpression enhanced HDACi-stimulated AQP3 mRNA levels. Thus, our results suggest that PPARγ and/or PPARα may play a role in regulating AQP3 levels in the skin; based on the ability of PPAR agonists to promote epidermal differentiation and/or inhibit proliferation, topical PPAR agonists might be considered as a therapy for hyperproliferative skin disorders, such as psoriasis.


Assuntos
Aquaporina 3/biossíntese , Inibidores de Histona Desacetilases/farmacologia , Queratinócitos/citologia , PPAR alfa/metabolismo , Adenoviridae/metabolismo , Animais , Animais Recém-Nascidos , Diferenciação Celular , Proliferação de Células , Sistemas de Liberação de Medicamentos , Células Epidérmicas/metabolismo , Epiderme/metabolismo , Humanos , Queratinócitos/metabolismo , Camundongos , PPAR alfa/antagonistas & inibidores , Permeabilidade , Fenótipo , Pele/metabolismo , Dermatopatias/metabolismo
20.
Exp Gerontol ; 133: 110885, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32088397

RESUMO

Tryptophan is an essential amino acid catabolized initially to kynurenine (kyn), an immunomodulatory metabolite that we have previously shown to promote bone loss. Kyn levels increase with aging and have also been associated with neurodegenerative disorders. Picolinic acid (PA) is another tryptophan metabolite downstream of kyn. However, in contrast to kyn, PA is reported to be neuroprotective and further, to promote osteogenesis in vitro. Thus, we hypothesized that PA might be osteoprotective in vivo. In an IACUC-approved protocol, we fed PA to aged (23-month-old) C57BL/6 mice for eight weeks. In an effort to determine potential interactions of PA with dietary protein we also fed PA in a low-protein diet (8%). The mice were divided into four groups: Control (18% dietary protein), +PA (700 ppm); Low-protein (8%), +PA (700 ppm). The PA feedings had no impact on mouse weight, body composition or bone density. At sacrifice bone and stem cells were collected for analysis, including µCT and RT-qPCR. Addition of PA to the diet had no impact on trabecular bone parameters. However, marrow adiposity was significantly increased in PA-fed mice, and in bone marrow stromal cells isolated from these mice increases in the expression of the lipid storage genes, Plin1 and Cidec, were observed. Thus, as a downstream metabolite of kyn, PA no longer showed kyn's detrimental effects on bone but instead appears to impact energy balance.


Assuntos
Adiposidade , Triptofano , Animais , Densidade Óssea , Medula Óssea , Camundongos , Camundongos Endogâmicos C57BL , Ácidos Picolínicos
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